Diagnostic criteria, severity classification and guidelines of systemic sclerosis

Abstract

Several effective drugs have been identified for the treatment of systemic sclerosis (SSc). However, in advanced cases, not only their effectiveness is reduced but they may be also harmful due to their side‐effects. Therefore, early diagnosis and early treatment is most important for the treatment of SSc. We established diagnostic criteria for SSc in 2003 and early diagnostic criteria for SSc in 2011, for the purpose of developing evaluation of each organ in SSc. Moreover, in November 2013, the American College of Rheumatology and the European Rheumatology Association jointly developed new diagnostic criteria for increasing their sensitivity and specificity, so we revised our diagnostic criteria and severity classification of SSc. Furthermore, we have revised the clinical guideline based on the newest evidence. In particular, the clinical guideline was established by clinical questions based on evidence‐based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of SSc.

Diagnostic Criteria

Major criterion

Skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints

Minor criteria

1. Skin thickening of the fingers: distal to the metacarpophalangeal (MCP) joints but proximal to the proximal interphalangeal (PIP) joints.
2. Abnormal nailfold capillaries: two or more nailfold bleeding sites are macroscopically visible on the fingers (nailfold bleeding [Fig. 1] repeatedly appears and disappears; therefore, if it occurs twice or more during the clinical course, the case is determined as positive) or characteristic findings of systemic sclerosis (SSc) are found with capillaroscopy or dermoscopy (as shown in Fig. 2, giant capillaries [arrowhead], capillary loss [inside dotted line] and capillary microhemorrhages [arrow]).

   

   Figure 1

   Nailfold bleeding.

   

   Figure 2

   Capillaroscopy imaging.

3. Fingertip pitting scars or digital tip ulcers: caused by circulatory disorder of the fingers, not by trauma or other causes.
4. Bibasilar pulmonary fibrosis
5. Positive for any of the following: anti‐Scl‐70 (topoisomerase I) antibodies, anticentromere antibodies or anti‐RNA polymerase III antibodies.

Exclusion criteria

The following diseases are excluded:

Nephrogenic sclerosing fibrosis, generalized morphea, eosinophilic fasciitis, scleredema diabeticorum, scleromyxedema, porphyria, lichen sclerosus, graft‐versus‐host disease, diabetic cheiroarthropathy, Crow–Fukase syndrome and Werner syndrome.

Diagnosis determination

Patients who satisfy the major criterion or (1) and one or more items of (2) to (5) of the minor criteria are diagnosed with SSc.

General Severity Classification

General

Medsger et al.¹ defined severity as damage (irreversible change) and activity (reversible change). Internationally, the modified Rodnan total skin thickness score (mRSS) is used to classify the severity of SSc,² and this is the focus point of various clinical trials. The mRSS generally correlates with visceral lesions, and it is probably useful for clinical trials that are performed between 1 and 2 years, due to the changes that occur in a relatively short time frame with treatment.

Table 1. New Minds recommendation grades

Presentation of the strength of recommendation
Recommendation grade
1	Strongly recommended
2	Advocated
None	When undecided
Evidence level of the classification
A	Strong conviction about the estimated effect
B	Moderate conviction about the estimated effect
C	Limited conviction about the estimated effect
D	Almost no conviction about the estimated effect

Table 2. Evidence level correspondence

Old evidence level classification		Evidence level classification used in this guideline
I	Evidence from systematic review/meta‐analysis of randomized controlled trial	A	I, II
II	Evidence from at least one randomized controlled trial	B	III
III	Evidence from at least one controlled study without randomization	C	IV
IVa	Evidence from analytical epidemiological studies (cohort study)	D	V, VI
IVb	Evidence from analytical epidemiological studies (case–control study, cross‐sectional study)
V	Evidence from descriptive studies (case reports, case series)
VI	Evidence from expert committee reports or opinions or clinical experience of respected authorities, not based on patient data

• Furthermore, state the strength of evidence in the strength of endorsements or recommendations (A, B, C, D)
• (Example) (1) Recommend implementing therapy I for patient P (1A) = (strong recommendation, based on strong evidence)
• (2) Propose implementing therapy I compared to therapy C for patient P (2C) = (weak recommendation, based on weak evidence)
• (3) Propose not implementing therapy I or therapy C for patient P (2D) = (weak recommendation, based on very weak evidence)
• (4) Strongly recommend not implementing therapy I for patient P (1B) = (strong recommendation, based on moderate evidence)

However, some cases have mild skin thickening as well as severe pulmonary fibrosis; therefore, using the mRSS alone does not necessarily reflect the severity that is found in individual cases. Therefore, in this severity guideline, we prefer that the severity of a case is determined based on the aspect with the highest severity score out of the: (i) skin; (ii) lungs; (iii) heart; (iv) kidneys; and (v) gastrointestinal tract.

General systemic (Table 3)

Table 3. Severity classification: General systemic

0 (normal)	Normal
1 (mild)	Weight loss of less than 5% to 10% compared with before onset
2 (moderate)	Weight loss of between 10% and 20% compared with before onset
3 (severe)	Weight loss of between 20% and 30% compared with before onset
4 (very severe)	Weight loss of more than 30% compared with before onset
Exceptions	Excluding patients who have deliberately dieted
Investigations	(1) Anemia (hematocrit), (2) platelet count, (3) erythrocyte sedimentation rate, (4) lactate dehydrogenase, (5) Health Assessment Questionnaire and (6) serum immunoglobulin G

The severity guideline that was proposed by Medsger et al. used weight loss and hematocrit levels, but a significant decline in the hematocrit level is almost never encountered in Japanese cases. Therefore, in this guideline, weight loss alone is used as the evaluation item and hematocrit levels should be discussed in the future.

Severity Classification of the Skin

Skin thickening

Modified Rodnan total skin thickness score:

• 0 (normal): 0
• 1 (mild): 1–9
• 2 (moderate): 10–19
• 3 (severe): 20–29
• 4 (very severe): >30

Joints (Table 4):

Table 4. Joint range of motion

Points	Standard	Wrist joint	Elbow joint	Knee joint
0	≥95%	≥152°	≥142.5°	≥123.5°
1	≥75% to <95%	≥120° to <152°	≥112.5° to <142.5°	≥97.5° to <123.5°
2	≥50% to <75%	≥80° to <120°	≥75° to <112.5°	≥65° to <97.5°
3	≥25% to <50%	≥40° to <80°	≥37.5° to <75°	≥32.5° to <65°
4	<25%	<40°	<37.5°	<32.5°

Normal range of motion for various joints: wrist joint 160°, elbow joint 150° and knee joint 130°Severity:

• 0 (normal): 0
• 1 (mild): 1–3
• 2 (moderate): 4–7
• 3 (severe): >8

Points to note: Limited range of motion is caused by hardening of the skin and/or soft tissue of the joint due to SSc or damage and/or absorption of the bone.

Severity Classification of the Lungs

Interstitial lung diease (Figs 3 and 4)

Figure 3

Evaluation of lesion expansion with chest high‐resolution computed tomography.

Figure 4

Severity classification: lungs. HRCT, high‐resolution computed tomography.

Figure 5

Clinical algorithm of skin thickening. *Anti‐Scl‐70 (topoisomerase I) antibodies, anti‐RNA polymerase antibodies (anti‐U3RNP antibodies, not yet listed under insurance). dcSSc, diffuse cutaneous systemic sclerosis.

The approximate area ratio (5% units) that is taken up by all the interstitial lung disease‐related lesions in the five slices that are shown in Figure 3 (ground‐glass opacity, reticular shadows, honeycombing and cystic lesions) is evaluated, and the average is regarded as the extent of lesions³. The severity is classified based on a combination of the extent of lesions on chest high‐resolution computed tomography (HRCT) and the forced vital capacity (FVC) predicted, and whether oxygen supplementation is required (Fig. 4).

Severity Classification of the Gastrointestinal Tract and Gastrointestinal Lesions

(1) Upper gastrointestinal tract lesions

0 (normal)	Normal
1 (mild)	Reduced lower esophageal peristalsis (no subjective symptoms)
2 (moderate)	Gastroesophageal reflux disease (GERD)
3 (severe)	Reflux esophagitis and associated dysphagia
4 (very severe)	Esophageal stenosis‐related dysphagia

(2) Lower gastrointestinal tract lesions

0 (normal)	Normal
1 (mild)	Gastrointestinal lesions with subjective symptoms (no treatment required)
2 (moderate)	Gastrointestinal lesions that require oral medication with antibacterial drugs or other treatment
3 (severe)	History of intestinal pseudo‐obstruction with malabsorption syndrome
4 (very severe)	Requires central venous nutrition therapy

Severity Classification of the Kidneys

Kidney lesions

	eGFR (mL/min per 1.73 m^2)*
0 (normal)	≥90
1 (mild)	60–89
2 (moderate)	45–59
3 (severe)	30–44
4 (very severe)	≤29 or initiation of hemodialysis

When the cause of the renal dysfunction has been identified as a disease other than SSc, it is excluded from evaluation using these criteria.

*Loss of muscle mass can occur in SSc; the estimated glomerural filtration rate (eGFR) predictive equation using cystein C is used, because cystein C tends to be unaffected by muscle mass.

• Men: (104 × Cys‐C^−1.019 × 0.996^age) − 8
• Women: (104 × Cys‐C^−1.019 × 0.996^age × 0.929) − 8
• Cys‐C: serum cystein C concentration (mg/L)

Severity Classification of the Heart and Cardiac Lesions (Table 5)

Table 5. Severity classification of the heart

	Subjective symptoms	Electrocardiography	Echocardiography
			Diastolic dysfunction	Left ventricular ejection fraction (EF)
0 (normal)	None	Normal range	No	EF>50%
1 (mild)	NYHA class I	Arrhythmia, conduction abnormality that does not require drug treatment	Yes
2 (moderate)	NYHA class II	Arrhythmia, conduction abnormality that requires drug treatment		40% < EF < 50%
3 (severe)	NYHA class III	Indicated for catheter ablation or pacemaker		EF < 40%
4 (very severe)	NYHA class IV

• NYHA, New York Heart Association.

The most severe item of each item's severity is set as the overall severity.

The early diastolic left ventricular inflow wave (E wave) and mitral annulus velocity (e’ wave) ratio of E/e’ > 15 is defined as diastolic dysfunction.

Severity Classification of Pulmonary Hypertension

0 (normal)	No PH
1 (mild)	PH, WHO Class I
2 (moderate)	PH, WHO Class II
3 (severe)	PH, WHO Class III
4 (very severe)	PH, WHO Class IV

A patient with a mean pulmonary arterial pressure (mPAP) of 25 mmHg or more at rest via right cardiac catheterization is diagnosed as having pulmonary hypertension (PH); but when right cardiac catheterization cannot be performed, a patient with a tricuspid regurgitation rate exceeding 3.4 m/min (=tricuspid pressure gradient exceeding 46 mmHg) on echocardiography is diagnosed with PH.

Severity Classification of the Blood Vessels

Vascular Lesions

0 (normal)	Normal
1 (mild)	Raynaud's phenomenon
2 (moderate)	Digital pitting ulcers
3 (severe)	Other skin ulcerations
4 (very severe)	Digital gangrene

The most severe lesion that is present clinically is set as the classification.

“Digital pitting ulcers” refers to small ulcerative lesions that are distal to the proximal interphalangeal joint.

Guidelines for the Treatment of Skin Thickening

CQ1 Is the mRSS useful for determining skin thickening?

Recommendation: The mRSS is useful for quantitatively evaluating skin thickening, and using this scoring system is recommended.

Recommendation level: 1B

Explanation: No method has been established to quantify skin thickening qualitatively. The skin score, which semiquantitatively evaluates skin thickening through palpation only, is widely used, and it is considered the most useful indicator among those currently in use.

The skin score that is widely used internationally is the mRSS, which was published by Clements et al.⁴ This method divides the body into 17 sites (the fingers, dorsum of the hands, forearms, upper arms, face, chest, abdomen, thighs, lower legs and dorsum of the feet), and the skin thickening is evaluated based on four grades ranging 0–3 (0 = normal, 1 = mild, 2 = moderate and 3 = severe), with the total score ranging 0–51. When scoring the skin, the evaluator pinches the skin between both thumbs, and the skin thickness and mobility with the under layer is evaluated. When the skin completely lacks mobility with the under layer, it is scored as 3; when there is no apparent hardening but the skin feels somewhat thickened, it is scored as 1; and thickening in between these two is scored as 2.

The skin thickening for each site is determined with the mRSS, as follows:

• Fingers: The mRSS is evaluated with the backs of the fingers between the PIP and MCP joints.
• Forearms/upper arms: Skin thickening on the extensor side is first evaluated over the flexor side.
• Face: The cheeks should be evaluated rather than the forehead (between the zygomatic arch and lower jaw).
• Chest: The chest should be evaluated from the superior end to the inferior end of the sternum, including the breasts, with the patient in the seated position.
• Abdomen: The patient should be evaluated in the supine position from the inferior end of the sternum to the superior margin of the pelvis.
• Thighs/lower legs/dorsum of feet: The patient should be evaluated in the supine position with the knees bent.

The mRSS is a semiquantitative method that may be affected by the subjectivity of the evaluator, but the mRSS interobserver variation in three facilities in the USA and UK was almost the same in each facility. Therefore, the accuracy of this evaluation method was thought to be maintained.⁴ Moreover, Clements et al.⁵ reported that the inter‐observer variation of mRSS was 25% and the intra‐observer variation was 12%. The former indicates the accuracy of the method, while the latter indicates its reproducibility. Considering that the percentages for similar indicators that are used to evaluate rheumatoid arthritis are 37% and 43%, respectively, the mRSS has sufficiently acceptable accuracy and reproducibility.

Furst et al.⁶ reported that the weight of skin biopsies from the forearm not only correlates with the skin scores for the biopsy section of the forearm, but it also correlates with the mRSS for the entire body. This demonstrates that mRSS reflects the histological, fibrotic changes in patients with SSc, indicating the validity of the mRSS.

Medsger et al.⁷ set the severity classification of the skin based on the mRSS in Western patients as 0 = normal, 1–14 = mild, 15–29 = moderate, 30–39 = severe, and more than 40 = end‐stage. However, when the Ministry of Health, Labor and Welfare's Scleroderma Research Team formulated treatment guidelines (2004, revised in 2007), they advocated a scoring system of 0 = normal, 1–9 = mild, 10–19 = moderate, 20–29 = severe and more than 30 = very severe for Japanese patients. This classification is considered valid for Japanese patients.

CQ2 What timing and degree of skin thickening should be considered for treatment?

Recommendation: Patients who satisfy two or more of the following items should be treated: (i) diffuse cutaneous SSc (dcSSc) within 6 years from the onset of skin thickening; (ii) rapid progression of skin thickening (progression in the range or severity of skin thickening within a period from a few months to 1 year); and (iii) edematous lesions are the main clinical presentation on palpation. Scleroderma‐specific antinuclear antibodies should also be referenced.

Recommendation level: 2D

Explanation: SSc skin thickening goes through the edematous, hardening and atrophy stages. Depending on the range of skin thickening, SSc is classified into two types: dcSSc, in which the lesions extend to the proximal part of the limbs (upper arms and thighs) or onto the trunk; and limited cutaneous SSc (lcSSc), in which the lesions are limited to the distal part of the limbs (forearms and lower legs) and face.⁸ In patients with dcSSc, skin thickening progresses within 6 years from onset, and progression of skin thickening matches the progression stage, with the development of visceral lesions in the lungs, gastrointestinal tract, kidneys and heart, as well as joint flexion contracture. Serious skin thickening is reported to develop in 70% of cases within 3 years of onset. It is rare for skin thickening to worsen again after the initial 6 years. Compared with this, in patients with lcSSc, skin thickening gradually develops after a long period of Raynaud's phenomenon (a few years to more than 10 years). Therefore, progressive dcSSc skin thickening should be treated, while lcSSc skin thickening does not require aggressive treatment. However, even lcSSc should be treated if skin thickening spreads rapidly over a broad area.

Table 6. Summary of clinical questions

Clinical question	Recommendation level	Recommendation
CQ1 Is the modified Rodnan total skin thickness score (mRSS) useful for determining skin thickening?	1B	The mRSS is useful for quantitatively evaluating skin thickening, and using this scoring system is recommended
CQ2 What timing and degree of skin thickening should be considered for treatment?	2D	Patients who satisfy two or more of the following items should be treated: (i) diffuse cutaneous systemic sclerosis (dcSSc) within 6 years from the onset of skin thickening; (ii) rapid progression of skin thickening (progression in the range or severity of skin thickening within a period from a few months to 1 year); and (iii) edematous lesions are the main clinical presentation on palpation. Scleroderma‐specific antinuclear antibodies should also be referenced
CQ3 Are corticosteroids effective for treating skin thickening?	2C	Oral corticosteroids should be administrated, because they are effective for cases in which there has been rapid progression at an early stage
CQ4 Do corticosteroids induce a renal crisis?	1C	Administration of oral corticosteroids is a risk factor for a renal crisis, so it is recommended to carefully monitor blood pressure and kidney function
CQ5 Is d‐penicillamine effective for treating skin thickening?	2B	It is thought that d‐penicillamine does not improve SSc skin thickening; therefore, its administration is not recommended
CQ6 Is cyclophosphamide effective for treating skin thickening?	2A	Cyclophosphamide is proposed as a treatment option for skin thickening
CQ7 Is methotrexate effective for treating skin thickening?	2D	Methotrexate (MTX) has been found to improve skin thickening, but the efficacy of this drug is not established
CQ8 Are other immunosuppressants effective for treating skin thickening?	Cyclosporin, 2C; tacrolimus, 2C; mycophenolate mofetil (MMF), 2C; azathioprine, 2D	Cyclosporin, tacrolimus and MMF are proposed as treatment options for skin thickening
CQ9 Is rituximab effective for treating skin thickening?	2B	The efficacy of rituximab has been demonstrated, but carefully selecting patients who are indicated for this treatment is proposed from a safety perspective
CQ10 Are other biologics effective for treating skin thickening?	1A; tumor necrosis factor (TNF) inhibitors, none; tocilizumab, none; interferon (IFN)‐γ, none; i.v. immunoglobulin G, none	Avoiding the use of IFN‐α is recommended. The efficacy of TNF inhibitors, tocilizumab, IFN‐γ and IVIG is unknown
CQ11 Is imatinib effective for treating skin thickening?	2A	The efficacy of imatinib for treating skin thickening is unknown, and it should not be administrated as treatment for skin thickening
CQ12 Are other drugs effective for treating skin thickening?	Minocycline, 1A; tranilast, none; bosentan, none; sildenafil, none	Administrating minocycline as a treatment for skin thickening is not recommended. The efficacy of tranilast, bosentan and sildenafil for treating skin thickening is unclear
CQ13 Is hematopoietic stem cell transplantation effective for treating skin thickening?	2A	The efficacy of hematopoietic stem cell transplantation for treating skin thickening has been demonstrated, but carefully selecting patients who are indicated for this treatment is proposed from a safety perspective
CQ14 Is phototherapy effective for treating skin thickening?	2C	Long‐wave ultraviolet light therapy can be effective for improving skin thickening, and this treatment has been proposed

Based on the above information, patients with two or more of the following items should be treated: (i) dcSSc within 6 years from the onset of skin thickening; (ii) rapid progression of skin thickening (progression in the range or severity of skin thickening within a period from a few months to 1 year); or (iii) edematous lesions are the main clinical presentation on palpation.

In patients with IcSSc, the scleroderma‐specific antinuclear antibody levels should be referenced to determine whether there will be extensive spread of skin thickening in the future.^{9, 10} When a patient is positive for anti‐topoisomerase I (Scl‐70) antibodies and/or anti‐RNA polymerase III antibodies, or when the presence of anti‐U3RNP antibodies is suspected, there is a high probability that lcSSc will progress to dcSSc. On the other hand, if a patient tests positive for anticentromere antibodies, it is highly likely that the condition will continue to be lcSSc.

CQ3 Are corticosteroids effective for treating skin thickening?

Recommendation: Oral corticosteroids should be administrated, because they are effective for cases in which there has been rapid progression at an early stage.

Recommendation level: 2C

Explanation: Few reports have proven the efficacy of corticosteroids for treating skin thickening in patients with SSc, but Sharada et al.¹¹ conducted a randomized, double‐blind study on 35 subjects and reported the efficacy of dexamethasone injection pulse therapy (100 mg once a month, for 6 months). In the treatment group (n = 17), the mRSS reduced from 28.5 ± 12.2 to 25.8 ± 12.8, while in the control group (n = 18), the mRSS increased from 30.6 ± 13.2 to 34.7 ± 10. Takehara conducted an uncontrolled prospective study on 23 patients presenting with early stage edematous and rapidly progressing skin thickening, and reported that due to the administration of low‐dose oral steroids, the mRSS reduced from 20.3 ± 9.3 to 12.8 ± 7.0 after 1 year.¹²

Therefore, although sufficient scientific data on the efficacy of steroids are lacking, steroids are thought to be empirically valid for patients with currently progressing skin thickening at an early stage, and the recommendation level is set as 2D, based on the consensus of the committee that created this guideline. Prednisolone (PSL) 20–30 mg/day is the standard initial dose for SSc patients who meet the indications for treatment that are stated in CQ2. The initial dose should be administered for 2–4 weeks while the extent of improvement in skin thickening is monitored. Thereafter, the dose should be slowly tapered by approximately 10% every 2 weeks to every few months, and then a dose of around 5 mg/day can be used as the maintenance dose for a considerable time. If the progression of skin thickening halts for a long time or the disease enters the atrophy stage, then the steroids may be discontinued.

Administration of corticosteroids may induce a renal crisis, which is a particular problem for SSc patients. Japanese people have a lower incidence of renal crisis than Westerners, but steroids should be administered with care, as described in CQ4.

CQ4 Do corticosteroids induce a renal crisis?

Recommendation: Administration of oral corticosteroids is a risk factor for a renal crisis; therefore, carefully monitoring blood pressure and kidney function is recommended.

Recommendation level: 1C

Explanation: While corticosteroids are effective for treating skin thickening, it has been indicated that they induce a renal crisis. In three retrospective studies that were conducted in Europe and the US, steroid use was associated with the onset of a renal crisis. Steen et al. reported that in a case‐controlled study, 36% of patients who were administered predonisone 15 mg/day or more of oral corticosteroids developed a renal crisis within 6 months, compared with 12% of patients in the control group (odds ratio [OR]: 4.4; 95% confidence interval [CI]: 2.1–9.4; P < 0.0001). Therefore, if possible, keeping predonisone <10 mg/day is recommended.¹³ DeMarco et al.¹⁴ reported that 61% of patients with a renal crisis had taken oral steroids within the past 3 months (relative risk: 6.2; 95% CI: 2.2–17.6). In 1989, Helfrich et al.¹⁵ reported that many patients had taken predonisone 30 mg/day or more oral steroids within the previous 2 months among patients with normal blood pressure who developed a renal crisis (64% vs. 16%, respectively). Penn et al.¹⁶ conducted a retrospective study on 110 patients with a renal crisis in a single facility and reported that there was no difference in the renal crisis prognosis based on the use or non‐use of steroids.

Patients who are positive for anti‐RNA polymerase III antibodies have a higher risk of developing a renal crisis than those who are negative for anti‐RNA polymerase III antibodies. In Japan, the rate of positive anti‐RNA polymerase III antibodies is estimated to be lower than that in Europe and the US,¹⁷ and the incidence of renal crisis is also lower in Japanese patients with SSc than in those in Europe and the US.

Given that steroid use is considered in patients who have severe or rapidly progressing skin thickening at an early stage of the disease, they also have a high risk of developing a renal crisis. As stated above, there is no clear evidence that corticosteroid use increases the risk of a renal crisis; but when administering steroids, it is beneficial to carefully monitor the patient's blood pressure and renal function. Care is particularly vital in patients who are thought to be positive for anti‐RNA polymerase III antibodies.

CQ5 Is D‐penicillamine effective for treating skin thickening?

Recommendation: It is thought that D‐penicillamine does not improve SSc skin thickening; therefore, its administration is not recommended.

Recommendation level: 2B

Explanation: In 1966, one report found that D‐penicillamine improved SSc skin thickening.¹⁸ Since then, many reports have evaluated the efficacy of D‐penicillamine,¹⁹ which has frequently been used to treat patients with SSc. However, in 1999, a double‐blind study compared high‐dose D‐penicillamine (750–1,000 mg/day) with low‐dose D‐penicillamine (125 mg/day, every other day) in patients with early‐stage dcSSc. There was no significant difference between the two groups in terms of skin thickening.²⁰ This study used low‐dose D‐penicillamine rather than a placebo for ethical reasons, but it introduced the idea that D‐penicillamine was ineffective. Conversely, in 2008, Derk et al.²¹ reported that D‐penicillamine was effective for treating skin thickening, based on the results of a retrospective randomized cohort study. However, D‐penicillamine is associated with a high incidence of adverse drug reactions, and today, many specialists deny its efficacy. Therefore, it should not be used actively.

CQ6 Is cyclophosphamide effective for treating skin thickening?

Recommendation: Cyclophosphamide (CYC) is proposed as a treatment option for skin thickening.

Recommendation level: 2A.

Explanation: In a multicenter double‐blind study on pulmonary fibrosis, Tashkin et al.²² reported that oral cyclophosphamide (1 mg/kg/day) significantly improved skin thickening after 12 months of treatment. The mRSS improved from 15.5 ± 1.3 to 11.9 ± 1.3 in 54 patients who were administered cyclophosphamide, while the change in the 55 patients in the placebo group was only 14.6 ± 1.4 to 13.7 ± 1.4. In the cyclophosphamide treatment group, a comparatively larger change was seen in the dcSSc group (from 21.7 ± 10.1 to 15.9 ± 11.0), than in the lcSSc group (from 6.1 ± 3.6 to 5.0 ± 4.3). However, when the authors evaluated these patients after 24 months, they found that there was no longer a significant difference in the improvement of the mRSS in the dcSSc group.²³

No reports have evaluated whether skin thickening is improved with cyclophosphamide intravenous pulse therapy. However, if we consider that the total dose increases with oral cyclophosphamide, there may be many instances in which it would be better to opt for intravenous pulse therapy.

Cyclophosphamide is mainly used to treat pulmonary lesions in patients with SSc, but improvement of skin thickening has also been demonstrated. Therefore, it may be administered to patients who did not respond to steroids or cannot take corticosteroids, and the patient should be monitored carefully for adverse drug reactions.

CQ7 Is methotrexate effective for treating skin thickening?

Recommendation: Methotrexate (MTX) has been found to improve skin thickening, but the efficacy of this drug is not established.

Recommendation level: 2D

Explanation: Two double‐blind studies have examined MTX. In a study by Van den Hoogen et al.²⁴ on 29 patients, skin thickening tended to improve with an MTX intramuscular injection of 15 mg/week for 24 weeks, but there was no significant difference in the effect (P = 0.06). In the MTX treatment group (n = 19), there was a 0.7% reduction in the mRSS, but there was a 1.2% increase in the placebo group (n = 12). In a multicenter, randomized, double‐blind study by Pope et al.²⁵ on 73 patients, the physician global assessment improved due to oral MTX (10 mg/week for 12 months), but there was no significant difference in the patient global assessment, and there was also no significant difference in the improvement of skin thickening. In the MTX group (n = 35), the mRSS changed from 27.7 ± 2.4 to 21.4 ± 2.8 after 12 months; and in the placebo group (n = 36), the mRSS changed from 27.4 ± 2.0 to 26.3 ± 2.1 (P < 0.17). However, when these data were analyzed using Bayesian statistics, a significant improvement was seen in the mRSS and other indices in the MTX group.²⁶ Therefore, although the efficacy of MTX is not currently established, this drug may be considered for patients who are unresponsive to other treatments. However, MTX poses a risk of inducing interstitial pneumonia, and care is needed during administration. Furthermore, MTX is not covered by insurance for treating SSc.

CQ8 Are other immunosuppressants effective for treating skin thickening?

Recommendation: Cyclosporine, tacrolimus, and mycophenolate mofetil (MMF) are proposed as treatment options for skin thickening.

Recommendation level: Cyclosporine: 2C, Tacrolimus: 2C, MMF: 2C, Azathioprine: 2D

Explanation: A double‐blind study reported that skin thickening improved after 1 year with oral cyclosporine (2 mg/kg/day).²⁷ According to this study, the mRSS improved from 15.2 ± 2.0 to 11.3 ± 1.8 after 1 year (P = 0.008). However, it was a small study, with only 10 subjects per group in a single facility, and the efficacy of this treatment cannot currently be established. Conversely, other reports have stated that oral cyclosporine induced a renal crisis, and other reports have found that a high incidence of hypertension is associated with using this drug.^{28, 29} Therefore, it is essential to take care regarding the onset of a renal crisis when administering this drug.

Oral tacrolimus (mean 0.07 mg/kg/day) improved skin thickening in four patients in an open‐label study with a small number of subjects (n = 8).²⁹ However, this report did not present specific data, including data on mRSS; and the details are unknown. Tacrolimus also requires due diligence regarding renal crisis, similar to cyclosporine.

In a study by Nadashkevich et al., cyclophosphamide (2 mg/kg/day for 12 months, followed by 1 mg/kg/day for 6 months) and azathioprine (2.5 mg/kg/day for 12 months, followed by 2 mg/kg/day for 6 months) were each administered to 30 subjects, and improvements in the mRSS were seen in the cyclophosphamide treatment group, but not in the azathioprine treatment group. This report found that azathioprine was inferior to cyclophosphamide.³⁰

Five reports have evaluated the use of MMF for treating skin thickening. In an open‐label study, Derk et al.³¹ administered MMF to 15 patients with early‐stage dcSSc (starting from 1000 mg/day, increasing to 2000 mg/day, and increasing again to 3000 mg/day if possible) for 12 months or longer, and conducted prospective observations. The mRSS decreased from 22.4 to 13.6 after 6 months, and to 8.4 at the end of the study. Mendoza et al. used MMF alone as a disease‐modifying drug in 25 patients with early‐stage, untreated SSc (median dose 2000 mg/day) in a prospective observation. After 18.2 ± 8.73 months, the mRSS had significantly decreased from 24.56 ± 8.62 to 14.52 ± 10.9 (P = 0.0004).³² In a pilot study on 13 patients with early‐stage SSc, Stratton et al. started treatment with MMF 0.5 g twice a day after administrating anti‐thymocyte globulin, and the dose was increased to 1 g twice a day and continued for 11 months. With this treatment, the mRSS decreased from 28 ± 3.2 to 17 ± 3.0 after 12 months, and there was a significant improvement in skin thickening (P < 0.01).³³ Vanthuyne et al.³⁴ reported that there was a significant improvement in skin thickening using combined MMF, steroid pulse therapy, and low‐dose oral steroids. On the other hand, in a 5‐year retrospective study comparing 109 patients who were treated with MMF and 63 patients who were treated with other immunosuppressants, there was no difference in the mRSS change.³⁵ Cyclosporine, tacrolimus, and MMF are not covered by insurance for treating SSc.

CQ9 Is rituximab effective for treating skin thickening?

Recommendation: The efficacy of rituximab has been demonstrated, but carefully selecting patients who are indicated for this treatment is proposed from a safety perspective.

Recommendation level: 2B

Explanation: In the first open‐label study the administration of rituximab (RTX) in 20 subjects, there was no improvement of skin thickening.³⁶ Subsequently, Daoussis et al.³⁷ conducted an open‐label study in which two courses of RTX were administered at 6‐month intervals to 14 patients, and they reported that the mRSS significantly reduced from 13.5 ± 6.84 before treatment to 8.37 ± 6.45 after 1 year. Another study found that the mRSS significantly improved after 2 years in 8 patients who were treated with four courses of treatment (4.87 ± 0.83 vs 13.5 ± 2.42, P < 0.0001).³⁸ Similarly, in an open‐label study, Smith et al.³⁹ administered two courses of RTX at 6‐month intervals to eight patients, and reported that the mRSS significantly reduced from 24.8 ± 3.4 to 14.3 ± 3.5 after 24 weeks, and then to 13 after 24 months. Bosello et al. administered one course of RTX to 20 patients and re‐administered it to eight patients. The mRSS significantly reduced from 22.3 ± 9.5 before treatment to 14.4 ± 8.4 after 6 months (P < 0.001), to 11.2 ± 7.5 after 12 months, to 9.95 ± 6.9 after 24 months, to 8.1 ± 5.2 after 36 months, and to 9.8 ± 7.2 after 48 months (P < 0.0001).⁴⁰ Furthermore, in a prospective study that was conducted by the EUSTAR group on 63 subjects,⁴¹ the improvement of the mRSS in the RTX treatment group was significantly greater than that in the control group (−24.0 ± 5.2% vs −7.7 ± 4.3%; P = 0.03), and the mean mRSS also reduced significantly (26.6 ± 1.4 vs 20.3 ± 1.8; P = 0.0001). This suggests that RTX effectively treats skin thickening, but there are also concerns regarding serious infections. Therefore, carefully using RTX is desirable. RTX is not covered by insurance for treating patients with SSc.

CQ10 Are other biologics effective for treating skin thickening?

Recommendation: Avoiding the use of interferon (IFN)‐α is recommended.

Recommendation level: 1A.

The efficacy of tumor necrosis factor (TNF) inhibitors, tocilizumab, IFN‐γ and i.v. immunoglobin (IVIG) is unknown.

TNF inhibitors, none; tocilizumab, none; IFN‐γ, none; IVIG, none.

Explanation: In a retrospective cohort study that was conducted by Lam et al.⁴² on 18 patients with SSc, etanercept was administrated at a dose of 25 mg twice a week or 50 mg once a week for a mean period of 30 months. The mRSS decreased from 6.63 ± 6.35 to 3.98 ± 2.38, but the change was not significant. Denton et al.⁴³ administrated infliximab at a dose of 5 mg/kg at 0, 2, 6, 14 and 22 weeks to 16 patients with dcSSc whose condition tended to deteriorate (the mean disease duration was 25.7 months), but there was no change in the mRSS (the mean before treatment, 26; after treatment, 22). Bosello et al. administrated infliximab at a dose of 3 mg/kg at 0, 2, 6 and 14 weeks concomitantly with MTX to four patients with SSc, followed by etanercept 25 mg twice a week. The mRSS improved in each case (35 to 16, 12 to 7, 16 to 7 and 8 to 3, respectively) but the changes were not significant.⁴⁴ As illustrated, there is insufficient evidence to support that TNF inhibitors effectively improve skin thickening.

A case report and case series study demonstrated that skin thickening improved due to tocilizumab, an anti‐interleuken‐6 receptor antibody.^{45, 46} An open‐label study⁴⁷ and case report⁴⁸ indicated that basiliximab, an anti‐CD25 antibody, was effective, and a case report found that a patient responded to alemtuzumab, an anti‐CD52 antibody.⁴⁹

Grassegger et al.⁵⁰ reported the results of a double‐blind study on 44 subjects in whom IFN‐γ was used. IFN‐γ 100 μg was administrated s.c. three times per week for 12 months. No significant improvement of skin thickening was seen, but restrictions in opening the mouth significantly improved in the IFN‐γ treatment group (from 38.46 to 47.66 mm between 13 and 18 months; the opening of mouths in participants in the control group increased from 40.18 to 43.65 mm, P < 0.01). Conversely, in a double‐blind study, Black et al.⁵¹ found that skin thickening did not improve in 35 subjects using IFN‐α. They reported that the patients had worse lung function; therefore, this treatment may be harmful.

Three reports have evaluated high‐dose IVIG. Levy et al.⁵² administrated IVIG to three patients with dcSSc and reported that the mRSS reduced in all three. In Japan, Ihn et al.⁵³ reported on their experience using IVIG in five patients with dcSSc, and found that the mRSS reduced in all patients. Furthermore, Nacci et al.⁵⁴ administrated IVIG to seven patients with SSc and reported that the mRSS significantly reduced from 29.2 ± 8.3 to 21.1 ± 4.6 after 6 months (P < 0.005) and joint symptoms also improved. Poelman⁵⁵ conducted a retrospective study in which the mRSS reduced from 29.6 ± 7.2 before treatment to 24.1 ± 9.6 after 6 months (n = 29, P = 0.0011), 22.5 ± 10.0 after 12 months (n = 25, P = 0.0001), 20.6 ± 11.8 after 18 months (n = 23, P = 0.0001) and 15.3 ± 6.4 after 24 months (n = 15, P < 0.0001). The symptoms of participants in the treatment group significantly improved compared with the symptoms of those in the control group in other clinical tests that were conducted after 12 months.⁵⁵ However, in a placebo‐controlled randomized study that was conducted in Japan (400 mg/kg per day × 5 days, single course dose), the mRSS change in the IVIG group was −3.3 ± 4.2, which was not significantly different from that in the placebo group (−4.2 ± 4.6).⁵⁶

CQ11 Is imatinib effective for treating skin thickening?

Recommendation: The efficacy of imatinib for treating skin thickening is unknown, and it should not be administrated to treat skin thickening.

Recommendation level: 2A.

Explanation: One case report and a case series report have examined the efficacy of imatinib, and the mRSS improved.^57-59 In an open‐label study by Gordon et al.⁶⁰ on 17 participants, the median mRSS reduced from 21 to 16 after 24 months (P = 0.002). Open‐label studies by Khanna et al. and Spiera et al. also reported a decline in the mRSS.^{61, 62}

On the other hand, a significant improvement in the mRSS was not seen in a 6‐month double‐blind study (200 mg/day) with 10 subjects by Pope et al., or in a 6‐month open‐label study (200 mg/day) with 30 subjects by Fraticelli et al.^{63, 64} Furthermore, a significant improvement in the mRSS was not seen in a 6‐month randomized double‐blind control study (imatinib 400 mg/day or placebo) with 28 subjects by Preyet al.⁶⁵ However, in terms of tolerability, there were significantly more adverse events in the imatinib group, including edema, than in the control group.

CQ12 Are other drugs effective for treating skin thickening?

Recommendation: Administrating minocycline as a treatment for skin thickening is not recommended.

Recommendation level: 1A.

The efficacy of tranilast, bosentan and sildenafil for treating skin thickening is unclear.

Tranilast, none; bosentan, none; sildenafil, none.

Explanation: In an open‐label study in 1998, oral minocycline was administrated to 11 subjects, whose skin thickening completely disappeared after 1 year.⁶⁶ Subsequently, a multicenter, double‐blind, open‐label study on minocycline was conducted on 36 early stage dcSSc patients, but there was no significant difference in the improvement of skin thickening after 1 year of administration of oral minocycline, compared with the improvement of thickening that followed a natural course of SSc patients treated with placebo in a clinical trial of D‐penicillamine.⁶⁷

Tranilast is effective for treating keloid and thickened scars, and it could be used to treat skin thickening in patients with SSc. However, to date, there have been no studies investigating its efficacy for treating this condition.

Two reports have evaluated the efficacy of bosentan, an endothelin receptor antagonist (ERA), for treating skin thickening. Kuhn et al.⁶⁸ administrated bosentan at a dose of 125 mg/day for 4 weeks and increased the dose to 250 mg/day for 20 weeks in an open‐label study with 10 subjects. The mRSS had significantly declined at the 12‐week and 24‐week points compared with before treatment. Giordano et al.⁶⁹ conducted a retrospective study and found that the mRSS significantly declined at the 24‐week and 48‐week points. Bosentan is not covered by insurance for SSc skin thickening.

Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, led to a reduction in the mRSS in a case report.⁷⁰ Sildenafil is not covered by insurance for SSc.

CQ13 Is hematopoietic stem cell transplantation effective for treating skin thickening?

Recommendation: The efficacy of hematopoietic stem cell transplantation for treating skin thickening has been demonstrated, but carefully selecting patients who are indicated for this treatment is proposed from a safety perspective.

Recommendation level: 2A.

Explanation: Since the 1990s, hematopoietic stem cell transplantation has been attempted for severe cases of SSc. In the early stages of clinical trials, skin thickening improved significantly, but the high rate of transplantation‐related deaths was problematic.⁷¹ Accordingly, after that point, patient selection and protocols relating to efficacy and safety were investigated. Improvement in skin thickening was also reported during allogeneic stem cell transplantation. However, recently, autologous stem cell transplantation has become the mainstay of treatment, and to date, the results of phase II and phase III clinical studies have been reported.

ASSIST, a phase II clinical study,⁷² was a randomized open‐label controlled study on reduced‐intensity autologous hematopoietic stem cell transplantation and CYC pulse therapy. The main inclusion criteria were patients with dcSSc, age younger than 60 years, an mRSS of 15 or above with organ damage or an mRSS of 14 or lower with pulmonary lesions. The main exclusion criteria were percentage vital capacity (VC) of less than 45%, left ventricular ejection fraction of less than 40%, symptomatic heart disease, serum creatinine of 177 mmol/L or higher, history of six or more CYC pulse therapy treatments and a disease duration of longer than 4 years. Nineteen subjects were included in the study. Stem cells were isolated from the granulocyte colony‐stimulating factor, and CYC was administrated. After pretransplantation treatment with CYC and anti‐thymocyte globulin, the investigators performed stem cell transplantation. The mRSS improved from 28 (before treatment) to 15 (after 1 year) in the 10 subjects who were initially allocated into the stem cell transplantation group, while these scores worsened from 16 to 22 in the nine subjects in the control group. Seven of the subjects in the control group, whose symptoms worsened, were reallocated to the stem cell transplantation group after 1 year, and the mRSS improved from 27 to 15 (after 1 year). Overall, in the stem cell transplantation group, the mRSS improved from 29 before treatment to 15 after 12 months and to 12 after 24 months. No patients died.

ASTIS, a phase III clinical study,⁷³ was a randomized open‐label controlled study on autologous hematopoietic stem cell transplantation and CYC pulse therapy (once a month, 12 courses in total) that was conducted in 28 facilities in Europe and Canada, following almost the same protocol as the ASSIST trial. One hundred and fifty‐six subjects were included in the study. There was a significant difference in the change in mRSS, of −19.9 in the stem cell transplantation group and −8.8 in the control group (P < 0.001). There were eight treatment‐related deaths out of the 79 subjects in the stem cell transplantation group within 1 year.

As stated above, autologous hematopoietic stem cell transplantation is effective for improving skin thickening, but there is a risk of transplantation‐related death. Therefore, it is essential to carefully select patients who are indicated for this treatment. From a safety perspective, using this treatment for targeting skin thickening alone is currently not recommended. This treatment is not covered by insurance for treating SSc.

CQ14 Is phototherapy effective for treating skin thickening?

Recommendation: Long‐wave ultraviolet (UV) light therapy can be effective for improving skin thickening, and this treatment has been proposed.

Recommendation level: 2C.

Explanation: UV therapy for treating skin thickening in patients with SSc has been studied in reports with a small number of subjects. Conventional psoralen and UV‐A (PUVA) were used, and recent reports have evaluated the efficacy of UV‐A1.

Four case reports have evaluated the use of PUVA to effectively treat SSc. Morita et al.⁷⁴ reported on one patient who responded to topical PUVA, Kanekura et al.⁷⁵ reported on three patients who responded to topical PUVA, and Hofer et al.⁷⁶ reported on four patients who responded to oral PUVA.

Morita et al.⁷⁷ evaluated four patients who were administrated a daily dose of UV‐A1 irradiation at 60 J/cm², using 9–29 irradiation, and reported that skin thickening and joint range of motion improved in all four subjects. Von Kobyletzki et al. found that one patient had mild improvement in these factors and seven patients had marked improvement. In a study with eight subjects in whom 30 J/cm² was administrated to digital lesions four times a week for 8 weeks, followed by three times a week for 6 weeks, for a total of 50 irradiation doses (a total of 1500 J/cm²), the severity score reduced from 21.5 to 16.0.⁷⁸ Kreuter et al.⁷⁹ treated 18 patients with digital lesions using a similar protocol as that used by von Kobyletzki et al., and reported that skin thickening improved in 16 patients, with a mean score improvement of approximately 25% (P < 0.0001). On the other hand, Draand et al.⁸⁰ conducted a randomized controlled study with blinded testers and nine subjects, and reported that there was no significant difference between the test groups. However, these studies had a very small number of patients, and it is necessary to conduct large‐scale studies in the future.

Based on the above information, there is insufficient evidence to support the efficacy of UV light therapy in treating patients with SSc, but there have been a number of reports in which the treatment was effective. Given that UV light does not lead to serious adverse reactions, using this method of treatment, particularly UV‐A1, is considered acceptable in select patients. However, it is vital to be aware of the risk of skin cancer when using this treatment concurrently with immunosuppressants.

Guidelines for the Treatment of the Lungs

Interstitial lung disease (ILD)

CQ1 Should ILD screening be performed at SSc diagnosis?

Recommendation: ILD screening with HRCT is recommended for all cases at diagnosis of SSc.

Recommendation level: 1C.

Explanation: The incidence of ILD in patients with SSc differs depending upon the detection methods, and ILD is detected with HRCT in 50–60% of unselected cases with SSc.^{81, 82} In contrast, the sensitivity of detection that is based on subjective symptoms, including shortness of breath, fine crackles on auscultation, chest X ray and restrictive ventilatory impairment with pulmonary function test (FVC predicted <80%) is less than 50%.⁸²

Figure 6

Algorithm for interstitial lung disease treatment. HRCT, high‐resolution computed tomography; ILD, interstitial lung disease; SSc, systemic sclerosis.

This demonstrates that some cases of ILD may be overlooked when auscultation and simple chest X ray are used alone. ILD is the most common cause of death in patients with SSc,^{83, 84} and information relating to the presence or absence of ILD is extremely important in terms of predicting the patient's prognosis. ILD is frequently present at an early stage of the disease, and the new appearance of ILD after a disease duration of more than 3 years is rare.⁸⁵ Therefore, ILD screening of patients who are diagnosed with SSc is useful for predicting prognosis and determining therapeutic indications, irrespective of the duration of disease. It is often difficult to evaluate the dorsal side of the lower lung field, in which SSc‐ILD commonly occurs, by HRCT in a supine position. This is due to the effects of gravitation, and taking HRCT with the patient in the prone position is preferable when aiming to detect ILD. Radiation exposure with HRCT is also a serious concern, but reducing the number of HRCT slices to nine has been shown to reduce radiation exposure to approximately 1/25th, without affecting the detection sensitivity or accuracy.⁸⁶

Table 7. Summary of clinical questions

Clinical question	Recommendation level	Recommendation
CQ1 Should interstitial lung disease (ILD) screening be performed at diagnosis of systemic sclerosis (SSc)?	1C	ILD screening with high‐resolution computed tomography (HRCT) is recommended for all cases at diagnosis of SSc
CQ2 Is there any useful indicators for predicting progression to end‐stage lung disease?	1C	Teatment decision should be made by predicting the risk of progression to end‐stage lung disease based on the presence or absence of fibrotic changes, or the extent of any interstitial lung disease‐related lesions on HRCT, and the forced vital capacity (FVC) measured with pulmonary function test
CQ3 Is cyclophosphamide effective?	1A	The use of cyclophosphamide (CYC) is recommended for the treatment of SSc‐ILD that is predicted to progress
CQ4 Is azathioprine effective?	2C	The use of azathioprine (AZ) has been proposed as maintenance therapy after CYC treatment for patients with SSc‐ILD, but using AZ as a first‐line monotherapy is not recommended
CQ5 Is mycophenolate mofetil effective?	2C	Mycophenolate mofetil (MMF) has been proposed as a substitute therapy for CYC for treating SSc‐ILD
CQ6 Are calcineurin inhibitors effective?	2D	Tacrolimus and cyclosporin should not be used as first‐line drugs for treating SSc‐ILD
CQ7 Are corticosteroids effective?	2D	The use of corticosteroids combined with immunosuppressants, such as CYC or MMF, for patients with SSc‐ILD is proposed; but steroid monotherapy, including pulse therapy, is not recommended
CQ8 Are endothelin receptor blockers effective?	2B	Bosentan, macitentan and ambrisentan should not be used to treat SSc‐ILD
CQ9 Is imatinib effective?	2C	Iimatinib is proposed as a treatment option for SSc‐ILD in CYC‐refractory cases, or when CYC cannot be administrated due to intolerance
CQ10 Are biologics (TNF inhibitors, abatacept or tocilizumab) effective?	None	The efficacy of TNF inhibitors, abatacept and tocilizumab for treating SSc‐ILD is unclear
CQ11 Is rituximab effective?	2C	Rituximab is proposed as a treatment option for SSc‐ILD in patients who are refractory to CYC or when CYC cannot be administrated due to intolerance
CQ12 Is pirfenidone effective?	2D	Pirfenidone is proposed as a treatment option for patients with SSc‐ILD who are refractory to CYC or when CYC cannot be administrated due to intolerance
CQ13 Is autologous hematopoietic stem cell transplantation effective?	2A	The use of autologous hematopoietic stem cell transplantation is proposed as a treatment option for patients with CYC‐refractory SSc‐ILD, but it is essential to carefully select patients who are indicated for this treatment due to the possibility of transplantation‐related deaths
CQ14 Are proton‐pump inhibitors effective?	2D	Use of proton‐pump inhibitors is propsed for patients with SSc‐ILD

CQ2 Are there any useful indicators for predicting progression to end‐stage lung disease?

Recommendation: Teatment decision should be made by predicting the risk of progression to end‐stage lung disease based on the presence or absence of fibrotic changes, or the extent of any ILD‐related lesions on HRCT and the FVC predicted measured by pulmonary function test.

Recommendation level: 1C.

Explanation: The progression of SSc‐ILD varies widely, from patients who have no progression at all after the initial diagnosis to patients who experience progression to respiratory failure within a few years. In a North American cohort study, the FVC fell to 75% or lower in only 40% of subjects with ILD throughout the entire course of the disease, and the FVC in only 13% fell to 50% or lower.^{87, 88} Progression is particularly common within the first 4 years after the onset of SSc; after that point, progression is slow in many cases, even without treatment.⁸⁷ A retrospective report that evaluated the changes in FVC over time in 254 patients found that 5.5% of patients with an FVC that was less than that at the initial measurement had slower subsequent decreases: 13.8% of patients with an FVC of less than 60% improved; 9.5% experienced a decrease between 60% and 80%; 19.7% levelled off between 60% and 80%; 31.1% improved to 60% or higher; 16.1% improved to 80% or higher; and 4.3% levelled off at 80% or higher.⁸⁹ In total, only 15% of patients experiemced a decline in the FVC over time. Therefore, even if ventilatory impairment is found initially, it does not necessarily mean that the function will continue to decline thereafter. Some patients experience progression of the disease and a poor prognosis, but the overall 5‐year survival rate for patients with SSc‐ILD is 85% and the 10‐year survival rate is between 60% and 70%.^{87, 90} Only 13–15% of SSc‐ILD patients have a poor prognosis in which their condition will progress to end‐stage lung disease requireg oxygen suppemmentation or lung transplantation. Therefore, not all patients with SSc‐ILD require treatment, and only patients in whom ILD is likely to progress to the end‐stage lung disease are indicated for undergoing treatment. Thus, predicting disease progression is extremely important in patients with SSc‐ILD.

Poor survival factors in SSc‐ILD reported include male sex and coexisting myocardial disease.⁸⁷ There is no difference in ILD prognosis based on dcSSc/lcSSc disease classification, severity of skin thickening based on the mRSS, and the presence or absence of autoantibodies, including anti‐topoisomerase I antibodies.^{87, 88} One study showed that there is a relationship between ILD with positive anti‐U11/U12RNP antibodies and poor prognosis,⁹¹ but this antibody is rare, with a positive rate in less than 5% of SSc, and it cannot be measured in routine clinical practice. Subjective shortness of breath is linked to a subsequent reduction of the FVC.⁸⁹ Although dyspnea indices (Mahler, Borg, Saint George, modified Medical Research Council [mMRC] and others), Health Assessment Questionnaire (HAQ)‐D1, 36‐Item Short Form Survey (SF‐36), and coughing frequency and severity are shown to correlate with the FVC, no reports have indicated the usefulness of these indices for predicting disease progression.^92-94 The 6‐min walking distance does not always correlate with the severity of ILD, and is a rather comprehensive evaluation of multiple factors, including PH, musculoskeletal disorders and others.⁹⁵ On the other hand, the minimum level of oxygen saturation during the 6‐min walking test is useful for predicting survival, and less than 89% or a decrease by 4% or more increases the mortality risk by 2.4 times.⁹⁶ However, because of peripheral vascular complications in patients with SSc, the reproducibility of oxygen saturation measurements using the fingers is poor. Therefore, measurements on the forehead are recommended.⁹⁷ The mortality risk is 2.1‐times higher in patients with FVC of less than 70%, showing that FVC is a useful predictor of survival.³ A HRCT of the chest can show varying degrees of ground‐glass opacities, reticular shadows, thickeness of alveolar septa, traction bronchiectasis, honeycombing and cystic lesions, which present as usual interstitial pneumonia (UIP) or non‐specific interstitial pneumonia (NSIP). Irreversible changes that are caused by secondary structural damage that is associated with fibrosis, such as traction bronchiectasis, are good indicators of decline in the FVC and diffusing capacity of the lungs for carbon monoxide (DLCO).⁹⁸ In the absence of PH, the correlation with the DLCO is more prominent.⁹⁹ Furthermore, the expansion of fibrosis‐related findings over time correlates with the progression of restrictive ventilatory impairment and shortness of breath,¹⁰⁰ and it is useful for predicting reduced pulmonary function.¹⁰¹ Conversely, ground‐glass opacities do not correlate with pulmonary function or the severity of shortness of breath, and are useless to predict ILD progression.^{98, 101-103} Various HRCT scoring systems are advocated for predicting the prognosis of patients with ILD,^{104, 105} but the extent of lesions (area ratio) is simple and useful. If the extent of lesions that encompasses all patterns is 20% or more, the mortality risk is increased by 2.5–3.0 times, while 35% or more increases the risk by 3.9 times.^{3, 84, 106} A widely used staging system that combines FVC and the extent of lesions on HRCT was proposed by a group in the UK.³ When lesions seen on HRCT exceed 20% or the FVC is less than 70%, the condition is referred to as an extensive disease, and it has a 3.5‐times higher mortality risk than limited disease, which does not satisfy the aforementioned criteria. On the other hand, the cell count and components in bronchoalveolar lavage (BALF) does not predict ILD progression.^107-109 The serum KL‐6 level and surfactant protein‐D are increased in more than half of SSc‐ILD cases, but SP‐D is not useful as a predictor of FVC decline,¹¹⁰ and there are no long‐term observational data on KL‐6. Instead, the elevation of these indicators is related to ground‐glass opacities on HRCT and inflammatory BALF features such as an elevated inflammatory cell ratio.¹¹¹ C‐reactive protein has been reported as a useful blood biomarker for predicting FVC reduction.¹¹² Lung biopsy pathology is not useful for predicting prognosis, but a report that enrolled lcSSc cases alone demonstrated that those with UIP tended to have a poorer prognosis than those with NSIP;¹¹³ and technetium‐99m diethylenetriamine‐pentaacetic acid pulmonary clearance,¹¹⁴ nitric oxide concentration in the breath¹¹⁵ and B‐line or comet sign on lung ultrasound^{116, 117} are reported to be useful for predicting a decline in the FVC, but there are no prospective observational data. A comprehensive review analyzing factors that predicted ILD progression and death demonstrated that age, reduced FVC, reduced DLCO and the extent of lesions on HRCT are related to poor prognosis. The study also showed that male sex, the extent of lesions and fibrotic findings on HRCT and elevated KL‐6 may predict ILD progression.¹¹⁸ However, the extent of lesions on HRCT was the only independent factor that was related to both ILD progression and poor survival.

CQ3 Is cyclophosphamide effective?

Recommendation: The use of CYC is recommended for the treatment of SSc‐ILD that is predicted to progress.

Recommendation level: 1A

Explanation: A retrospective study on a large‐scale cohort showed that oral CYC (1–2 mg/kg) delayed the progression of SSc‐ILD and improved survival.^{119, 120} Another retrospective study showed that CYC use may inhibit the decline of FVC.⁸⁹ A number of open‐label studies have been implemented on oral CYC or i.v. administration of CYC (IVCY) on small numbers of patients.^121-130 The IVCY dose varies depending upon the report, but generally the dose is 0.4–1 g/m² per dose or 0.5–1 g, administrated 1–24 times at intervals of 1–3 months. IVCY was often co‐administrated with low‐ to high‐dose PSL, and some patients were co‐administrated steroid pulse therapy. The longest observation period was 4 years, and there was no change or improvement of the FVC in 54–93% of cases, but a long‐term study found that ILD deteriorated in more than half the subjects within 5 years.¹³¹ A controlled study that used AZ (2.5 mg/kg) as the control drug reported that the decline of FVC was significantly suppressed in the CYC treatment group after 18 months compared with the AZ group.¹³² The only multicenter placebo‐controlled double‐blind study on CYC that has been implemented to date was the Scleroderma Lung Study.¹³³ The study included 158 patients with a disease duration of less than 7 years, shortness of breath on exertion, and ground‐glass opacity on HRCT or elevated inflammatory cell proportion in BALF; and the subjects were allocated into an oral CYC group (2 mg/kg) or a placebo group and observed for 1 year. The results showed that reduction of FVC was suppressed by 2.53% in participants in the CYC group compared with those in the placebo group. An extension observational study showed that the inhibitory effect of CYC on the decline of FVC disappears 1 year after discontinuation of CYC, demonstrating the necessity of maintenance therapy.¹³⁴ Around the same time, a randomized, prospective controlled study was conducted to investigate the effect of IVCY on 45 patients with early or mild SSc‐ILD with an FVC of 70% or higher.¹³⁵ In the IVCY group, CYC (600 mg/m²) was administrated six times a total, once a month after PSL 20 mg was administrated every other day, and AZ (2.5 mg/kg) was used as maintenance therapy after CYC therapy was completed. When patients who were administrated CYC were compared with patients in a non‐treated observation group, the reduction of FVC was suppressed by 4.2% in participants in the IVCY group, but there was no statistically significant difference between the two groups. The European League Against Rheumatism (EULAR) recommendations, which are based on these results, states that use of CYC should be recommended for treatment of SSc‐ILD while also considering its safety.¹³⁶ A meta‐analysis on CYC therapy for patients with SSc‐ILD found that CYC suppressed the reduction of FVC in the short‐term, but the results were limited and not sustainable.^137-139 Therefore, pulmonary function gradually declines in many patients. CYC also leads to many adverse events, including infection and cytopenia;¹⁴⁰ and in the long term, it increases the risk of malignancy, including bladder cancer and hematopoietic malignancy. Therefore, in a prediction formula that was based on the risk–benefit, 1‐year treatment with oral CYC does not significantly improve the quality‐adjusted life years.¹⁴¹ Fibrotic findings on HRCT, a high mRSS, low dyspnea index, mild reduction of FVC pretreatment (60–80%) and an elevated nitric oxide concentration in the breath are reported as predictors of the therapeutic effect of CYC.^{89, 101, 108, 133, 142, 143} Therefore, CYC treatment is indicated for patients who are predicted to have ILD progression (see CQ2), and it can be efficacious for treating patients with the above characteristics. However, given the concerns about long‐term safety, treatment should be limited to less than 1 year or limited to a total dose of less than 36 g;¹⁴⁴ and thereafter, the regimen should switch to another immunosuppressant with favorable safety profile, such as AZ as maintenance therapy. The evidence is more abundant on oral CYC than IVCY, but IVCY is advantageous because the total CYC dose can be reduced, potentially making this method safer than others.

CQ4 Is azathioprine effective?

Recommendation: The use of AZ has been proposed as maintenance therapy after CYC treatment for patients with SSc‐ILD, but using AZ as a first‐line monotherapy is not recommended.

Recommendation level: 2C.

Explanation: In a prospective comparative study of CYC and AZ, both the FVC and DLCO reduced by 10% or more in the AZ group (2.5 mg/kg) after 18 months.¹³² Therefore, AZ is not recommended as a first‐line treatment for patients with SSc‐ILD. However, a retrospective survey¹²⁷ and open‐label study¹⁴⁵ demonstrated that AZ may suppress the reduction of FVC when it was used as maintenance therapy after CYC treatment.

CQ5 Is mycophenolate mofetil effective?

Recommendation: MMF has been proposed as a substitute therapy for CYC for treating SSc‐ILD.

Recommendation level: 2C

Explanation: The inability to administrate long‐term CYC due to safety concerns is one of the reasons for the limited effect of CYC. Therefore, the efficacy of MMF for treating patients with SSc‐ILD has been extensively investigated, because MMF demonstrates a similar effect (non‐inferiority) to CYC for treating lupus nephritis and other rheumatic conditions. The stabilization of FVC and a favorable safety profiles have been shown through retrospective or open‐label studies on MMF (2–3 g),^146-149 but no placebo‐controlled studies have been reported to date. In a long‐term open‐label study exceeding 2 years, there was little FVC reduction and the treatment was well tolerated.¹⁵⁰ Conversely, improved FVC and DLCO were reported in an open‐label study of combined MMF with monthly steroid pulse therapy repeated 6 times.¹⁵¹ A case–control study that compared 10 patients who were treated with MMF and 10 subjects with matching backgrounds who were treated with CYC over a 2‐year period found no difference in the change in FVC, but the HRCT score worsened in the MMF group only.¹⁵² In the meta‐analysis of five retrospective studies and one prospective open‐label study that investigated the effect of MMF, 69 patients treated with MMF (62% had pretreatment with other immunosuppressants, mainly CYC) experienced no significant change of FVC or DLCO within 12 months, while no serious drug‐related adverse events were reported.¹⁵³ Thus, while the safety profile of MMF is superior to that of CYC, there is currently insufficient evidence to support whether it is equivalent to CYC in terms of efficacy and if it could therefore be used as an alternative option. A multicenter, double‐blind, controlled study on oral CYC and MMF is currently underway in the USA. MMF is not covered by health insurance for treating SSc.

CQ6 Are calcineurin inhibitors effective?

Recommendation: Tacrolimus and cyclosporin should not be used as first‐line drugs for treating SSc‐ILD.

Recommendation level: 2D

Explanation: There are several case series evaluating the efficacy of tacrolimus and cyclosporin for SSc,^{154, 155} but they were almost always used for treating skin thickening and arthritis. A retrospective report on patients with ILD associated with connective tissue disease, in which the patients were administrated cyclosporin, reported that one of four patients with SSc‐ILD died, one experienced a transitory effect and the remaining two had no progression of disease.¹⁵⁶ However, calcineurin inhibitors potentially induce a renal crisis,^{157, 158} and their use should be avoided in patients at high risk of developing renal crisis, such as those with early dcSSc. There are few reports on the efficacy of calcineurin inhibitors; therefore, from a risk–benefit perspective, it is not recommended to use them as a first‐line therapy for treating patients with SSc‐ILD. Tacrolimus and cyclosporin are not covered by health insurance for SSc.

CQ7 Are corticosteroids effective?

Recommendation: The use of corticosteroids combined with immunosuppressants, such as CYC or MMF, for patients with SSc‐ILD is proposed; but steroid monotherapy, including pulse therapy, is not recommended.

Recommendation level: 2D

Explanation: A retrospective cohort study has demonstrated that reduced FVC could not be inhibited with large‐dose steroid monotherapy, including pulse therapy.⁸⁷ On the other hand, a historical survey on 71 SSc‐ILD patients reported that prednisolone monotherapy at a mean dose of 30 mg had an equivalent effect of inhibiting FVC reduction to that of immunosuppressants.¹⁵⁹ Given that there is a high risk of renal crisis in patients with early dcSSc within 4 years of onset, which is the disease phase in which rapid FVC reduction occurs, administration of a moderate dose (>15 mg) or higher steroids cannot be recommended from a risk–benefit perspective.¹⁶⁰ However, an open‐label study indicated that concurrent administration of a moderate dose of steroids (PSL equivalent to ≤25 mg) may enhance the effect of CYC.^{124, 147} Another open‐label study demonstrated improvement and stability of FVC when steroid pulse therapy was combined with immunosuppressants such as CYC and MMF.^{151, 161-163} However, both were open‐label studies without control groups, and it is difficult to evaluate the effect of steroid monotherapy. Steroid pulse therapy is not covered by health insurance for treating SSc.

CQ8 Are endothelin receptor blockers effective?

Recommendation: Bosentan, macitentan and ambrisentan should not be used to treat SSc‐ILD.

Recommendation level: 2B

Explanation: A multicenter placebo‐controlled double‐blind study on bosentan for treating patients with SSc‐ILD without PH showed that this drug did not suppress FVC decline or worsening symptoms.¹⁶⁴ In a single center open‐label study in which bosentan was used on progressive ILD after CYC use, or in cases in which it was difficult to use CYC due to safety concerns, bosentan did not inhibit FVC decline and it could not demonstrate superiority over a historical control with similar backgrounds.¹⁶⁵ There are no clinical studies for assessing efficacy of macitentan or ambrisentan to treat SSc‐ILD, but in multicenter placebo‐controlled double‐blind studies on both drugs to treat idiopathic pulmonary fibrosis (IPF), these drugs failed to suppress FVC decline, acute exacerbation and/or death.^{166, 167} Conversely, statistically significantly more patients in the ambrisentan group experienced disease progression (reduced FVC and increased hospitalization or death due to respiratory deterioration) than those in the placebo group.¹⁶⁵ Based on these results, ambrisentan should be administrated with great care to patients with ILD. The pathophysiology of IPF is not the same as that of SSc‐ILD,¹⁶⁸ but ambrisentan may exacerbate SSc‐ILD. Therefore, in case of considering use of ambrisentan for patients with pulmonary arterial hypertension (PAH), careful decision‐making based on consideration of the risk–benefit of using this drug is mandatory. Bosentan, macitentan and ambrisentan are not covered by health insurance for treating SSc‐ILD.

CQ9 Is imatinib effective?

Recommendation: Low‐dose imatinib is proposed as a treatment for SSc‐ILD in CYC‐refractory cases, or when CYC cannot be administrated due to intolerance.

Recommendation level: 2C

Explanation: Imatinib, a tyrosine kinase inhibitor, was expected to have a therapeutic effect on SSc due to its transforming growth factor‐β/platelet‐derived growth factor signal inhibitory action; therefore, several open‐label studies evaluating imatinib's effect on SSc have been conducted, and two of those studies evaluated its effect in patients with SSc‐ILD. In a report by Spiera et al.,¹⁶⁹ in which imatinib (400–600 mg) was administrated for 1 year, six of the 30 subjects with dcSSc withdrew due to adverse drug reactions, but the remaining subjects completed the 1‐year treatment regimen and FVC improved by 6.4%. However, the improvement in FVC was more prominent in patients without ILD on imaging than in those with ILD, and the results might have reflected improvement in skin thickening of the thoracic wall. In a report by Khanna et al.,¹⁷⁰ seven out of 20 SSc‐ILD patients withdrew imatinib due to adverse reactions, and FVC improvement was only seen in 1.74%. In all studies, over half of the subjects presented with adverse drug reactions such as gastrointestinal symptoms and peripheral edema, and many patients withdrew due to adverse events. Therefore, high prevalence of intolerance was a major concern. A review of five open‐label studies on the use of imatinib for treating SSc found large variations in the results, and this is partly explained by intolerance due to adverse drug reactions.¹⁷¹ Therefore, low‐dose imatinib (200 mg) was trialed by considering tolerability, and case series with six patients reported that two patients with ILD had not experienced reduction of FVC, there were few adverse drug reactions and the patients were able to take the drug for a long period (2 years).¹⁷² Furthermore, an open‐label study was conducted to prove the effect of low‐dose imatinib (200 mg) on 26 patients with progressive ILD, despite CYC treatment. After 6 months, FVC increased by 15% or more in 15% of subjects, decreased by 15% or more in 27% of subjects and remained unchanged in 58% of subjects.¹⁷³ In another trial on imatinib 200 mg combined with IVCY that was administrated to five patients with SSc‐ILD, the treatment was well tolerated, but the FVC improved in only one patient.¹⁷⁴ Imatinib may inhibit the progression of SSc‐ILD, but to date there has been no study with a control group, such as a placebo group, which makes it difficult to evaluate the effect of the drug. The regular dose of imatinib is not recommended for treating patients with SSc‐ILD due to intolerance, but tolerabilty is favorable in low doses, and it could be considered as an alternative treatment option for patients who are refractory or non‐responsive to CYC. Imatinib is not covered by health insurance for treating SSc.

CQ10 Are biologics (TNF inhibitors, abatacept or tocilizumab) effective?

Recommendation: The efficacy of TNF inhibitors, abatacept and tocilizumab for treating SSc‐ILD is unclear.

Recommendation level: None

Explanation: Efficacy of biologics that are effective for treating rheumatoid arthritis (infliximab, etanercept, abatacept and tocilizumab) have been examined for skin thickening as well as joint and tendon involvement in SSc patients in observational and open‐label studies, but there have been no reports showing significant changes in pulmonary function, including FVC, during the course of treatment.^175-177 In case reports, improvement of FVC and HRCT findings has been shown in patients with dcSSc who were treated with abatacept in addition to treatment with CYC, MMF, MTX or corticosteroids.¹⁷⁸ In another report, pulmonary function and HRCT findings in patients with dcSSc did not worsen during the treatment with tocilizumab.¹⁷⁹ However, current information regarding the efficacy of biologics on SSc‐ILD is apparently insufficient, resulting in failure to reach any proposal. In addition, they are not covered by health insurance for treating patients with SSc.

CQ11 Is rituximab effective?

Recommendation: Rituximab is proposed as a treatment option for SSc‐ILD in patients who are refractory to CYC or when CYC cannot be administrated due to intolerance.

Recommendation level: 2C

Explanation: Since importance of B cells in the pathogenesis of SSc‐ILD has been speculated because of infiltration of B cells into the lung tissue at the early stage of the disease, efficacy of B‐cell depletion therapy for SSc‐ILD patients has been investigated.¹⁸⁰ Case reports have indicated that stabilization or mild improvement of pulmonary function is observed after treatment with rituximab in CYC‐refractory cases.^181-183 In an open‐label study in which 1000 mg of rituximab was administrated twice every 2 weeks to patients with early dcSSc, there was no reduction in the FVC and DLCO after 1 year.^{184, 185} The FVC and DLCO were also maintained after 1 year in an open‐label study on the use of 1000 mg of rituximab that was administrated twice every 2 weeks to nine patients with CYC‐refractory SSc‐ILD.¹⁸⁶ A prospective comparative study has been conducted in SSc‐ILD.¹⁸⁷ In this study, the enrolled subjects were randomly divided into two groups. Eight subjects were administrated 375 mg/m² of rituximab four times weekly as a regimen of treatment, followed by a second course after 24 months. In the control group, six subjects continued the ongoing treatment (CYC, MMF, low‐dose steroids or others). In the lung function test after 1 year, in the ritximab group, the FVC improved by 7.5% and DLCO improved by 9.75%, compared with FVC worsening by 4.3% and DLCO worsening by 5.2% in the control group. Patients in the rituximab group received retiximab treatment every 6 months and were observed until 2 years later. FVC improved by 9% and DLCO improved by 10.9% compared with baseline.¹⁸⁸ Few serious adverse events, including infection, were reported in these cases, suggesting good tolerability. In reports that collected data on patients using rituximab in the EULAR cohort, there was no change in the FVC in nine patients with an FVC of less than 70% at 4–12 months after treatment (from 60.6 ± 2.4% to 61.3 ± 4.1%), but there was mild improvement in the DLCO (from 41.1 ± 2.8% to 44.8 ± 2.7%).¹⁸⁹ FVC reduction was significantly suppressed in patients in the rituximab group compared with those of a control group with matched backgrounds. A placebo‐controlled double‐blind study has not yet been performed, but rituximab could be considered as alternative treatment for CYC‐refractory patients. Rituximab is not covered by health insurance for treating SSc.

CQ12 Is pirfenidone effective?

Recommendation: Pirfenidone is proposed as a treatment option for patients with SSc‐ILD who are refractory to CYC or when CYC cannot be administrated due to intolerance.

Recommendation level: 2D

Explanation: Pirfenidone is reported to be effective for inhibiting acute exacerbation and decline in pulmonary function in patients with IPF, but there are very few reports on the use of pirfenidone for treating SSc‐ILD. In a case series with five patients with SSc‐ILD who were treated with pirfenidone 600 mg, there was improvement in VC in all patients, and the drug was well tolerated. Furthermore, it was feasible to manage gastrointestinal symptoms, which were a concern, by dose‐escalating protocol.¹⁹⁰ There is currently no evidence that would enable an evaluation of pirfenidone's efficacy, but it could be considered as a treatment for patients with SSc‐ILD who are CYC‐refractory or cannot tolerate CYC. A multicenter double‐blind controlled study on the use of pirfenidone for patients with SSc‐ILD is currently underway in the USA. Pirfenidone is not covered by health insurance for treating SSc‐ILD.

CQ13 Is autologous peripheral hematopoietic stem cell transplantation effective?

Recommendation: The use of autologous hematopoietic stem cell transplantation is proposed as a treatment option for patients with CYC‐refractory SSc‐ILD, but it is essential to carefully select patients who are indicated for this treatment due to the possibility of transplantation‐related deaths.

Recommendation level: 2A

Explanation: Hematopoietic stem cell transplantation has been used for patients with severe SSc, in whom survival is expected to be poor. Inclusion and exclusion criteria and procedure protocols have been extensively investigated and modified; currently, the main indications are early dcSSc with progressive skin thickening and/or progressive ILD (FVC <70%) with restrictive ventilatory impairment. Recently, autologous peripheral blood hematopoietic stem cell transplantation, rather than allogeneic transplantation or bone marrow transplantion, has become the main form of treatment, and the protocols differ depending upon the institutions. The transplanted cells are hematopoietic stem cells or hematopoietic progenitor cells that are mobilized in the peripheral blood through high‐dose CYC or CYC in combination with G‐CSF, which are then recovered as CD34‐positive cells. However, some protocols include the T‐cell‐depletion protocol. Non‐myeloablative protocols adopt conditioning with high‐dose CYC monotherapy or anti‐thymocyte globulin, and myeloablative protocols combine total body irradiation or busulphan with high‐dose CYC. Phase I/II clinical trials that were initially conducted in Europe, in collaboration with the European Group for bone Marrow Transplantation/EULAR, enrolled 41 patients with early dcSSc, as well as lcSSc patients with progressive ILD or PH.¹⁹¹ Of these subjects, 69% had marked improvement of skin thickening (the mRSS improved by 25% or more) after transplantation, while 16% had 15% or more improvement of VC, 24% had 15% or more worsening of VC and 68% were unchanged. However, the rate of transplantation‐related deaths was as high as 17%. Furthermore, a follow‐up report that included an additional 25 patients found that the procedure did not improve pulmonary function, but the incidence of transplantation‐related deaths reduced to 8.7% through strict patient selection.¹⁹² An open‐label study in the USA enrolling 34 patients reported that this procedure is efficious for skin thickening, but FVC improved only 2.11% and DLCO even decreased by 6.0%.¹⁹³ However, the rate of transplantation‐related deaths in this study reached 23%. These studies were open‐label studies and there was no control group, which makes it difficult to evaluate the effect of transplantation on ILD progression. Subsequently, a randomized open‐label controlled study was conducted in the USA, comparing autologous peripheral hematopoietic stem cell transplantation combined with a non‐myeloablative protocol group with an IVCY group.¹⁹⁴ The FVC in the transplantation group (n = 10) was improved by 15% after 12 months, compared with a decrease of 9% in the IYCY group (n = 9), indicating a statistically significant difference, and the effect was maintained in 80% of the improved cases for up to 2 years after transplantation. Conversely, a randomized open‐label study was conducted in Europe and Canada comparing an autologous hematopoietic stem cell transplantation group with an IVCY group (monthly for a total of 12 doses), incorporating a larger number of subjects (n = 156).¹⁹⁵ When death or organ failure was the end‐point, there were more events in the transplantation group after 1 year than in the IVCY group. However, after 2 years, the event incidence was reversed between the two groups; and when the groups were followed up 7 years later, the incidence was statistically significantly lower in the transplantation group than it was in the IVCY group. The FVC in the transplantation group improved by 6.3% after 2 years, compared with a decrease of 2.8% in the IVCY group, indicating a statistically significant difference. Transplantation‐related deaths occurred in 10% of patients in the transplantation group, and there were significantly more serious adverse events, including infection and heart failure, in the transplantation group than in the IVCY group. Conversely, the rate of death due to disease was 11% in the transplantation group compared with 25% in the IVCY group. These controlled studies demonstrate that autologous hematopoietic stem cell transplantation suppresses the deterioration of pulmonary function, but given that the rate of transplantation‐related deaths was 5–10%, it is essential to carefully select patients for whom this treatment is indicated. This treatment is not covered by health insurance for treating SSc.

CQ14 Are proton‐pump inhibitors effective?

Recommendation: Use of proton‐pump inhibitors (PPI) is proposed for patients with SSc‐ILD.

Recommendation level: 2D

Explanation: A high prevalence of esophageal dilatation and GERD has been reported in patients with SSc‐ILD.^{196, 197} Evaluation of esophageal function revealed a high incidence of reflux that reached the upper esophagus.¹⁹⁸ Moreover, given that centrilobular fibrosis findings on HRCT and deposition of the basic substance is detected at a high rate by lung biopsies,¹⁹⁹ it has been supeculated that micro‐aspiration of the gastric contents may contribute to the progression of ILD.²⁰⁰ Currently, no prospective studies have found that PPI inhibit the progression of ILD, but because esophageal lesions frequently occur in patients with SSc beginning at an early stage of the disease, it is probably beneficial to use PPI in all SSc‐ILD patients, irrespective of the clinical presentation of GERD.²⁰¹ However, no PPI are covered by health insurance for SSc‐ILD.

Guidelines for the Treatment of the Gastrointestinal Tract

Gastrointestinal tract lesions

CQ1 Is improving lifestyle habits effective for the symptoms of upper gastrointestinal tract lesions?

Recommendation: Improving lifestyle habits is recommended for the symptoms of upper gastrointestinal tract lesions.

Recommendation level: 1C

Explanation: It is important for patients to improve everyday lifestyle habits, including: (i) avoiding high‐fat foods, sweet foods like chocolate, food seasoned with spices and alcohol;²⁰² smoking; and consuming a low‐residue diet; (ii) consuming small meals frequently; and (iii) avoiding eating before bed and lying down for a number of hours after eating.²⁰³

High‐fat meals and chocolate are known to reduce lower esophageal sphincter pressure, causing reflux of the gastric content, including gastric acid,^{204, 205} while meals with a high fat and high fiber content prolong digestion time in the stomach.²⁰⁶ Furthermore, care must be taken not to ingest a large amount of food at one time, and it is also preferable to avoid excessive exercise.²⁰⁶ Moreover, as well as avoiding lying down immediately after eating, it is also useful to raise the head when sleeping.²⁰⁷

Drugs such as anticholinergic drugs, calcium antangonists and beta‐blockers reduce gastric motility and can reduce the lower esophageal sphincter pressure; therefore, it is essential to take care when using these drugs concomitantly.²⁰⁸

No reports have a high level of evidence, but it is important for patients to improve their lifestyle habits to improve the symptoms of upper gastrointestinal tract lesions, and the recommendation level is set as 1C, based on the consensus of the committee that created this guideline.

CQ2 Are gastroprokinetic preparations effective for improving upper gastrointestinal tract hypomotility?

Recommendation: Treating the symptoms of gastrointestinal tract hypomotility including dysphagia, reflux esophagitis, abdominal distension and intestinal pseudo‐obstruction with gastroprokinetic preparations is recommended.

Recommendation level: Domperidone, mosapride, and erythromycin: 1B, metoclopramide: 2B, itopride, acotiamide, trimebutine: 2C

Explanation: No curative disease‐modifying drug exists for treating sclerosis, and there is no drug to prevent progression of gastrointestinal lesions. Therefore, by necessity, symptomatic treatment for gastrointestinal symptoms must constitute the main treatment.

The dopamine antagonist and cholinergic metoclopramide are known to promote peristalsis of the upper gastrointestinal tract,^{209, 210} but caution is essential for treating psychiatric symptoms.²⁰⁶ Domperidone is a peripheral dopamine antagonist and it is expected to have a similar effect to that of metoclopramide, but domperidone is advantageous because it does not cross the blood–brain barrier. Therefore, unlike metoclopramide, it is unlikely to cause psychiatric adverse drug reactions. The serotonin agonist mosapride is also expected to have a similar effect to that of metoclopramide.^211-213

The most proven peristaltic stimulant is the acetylcholine release stimulant called cisapride, but its sale has been discontinued due to adverse drug reactions. However, based on research on cisapride, which showed that concurrent administration with a PPI is more effective than monotherapy,²¹⁴ more effective therapy may be possible with the concurrent use of peristaltic stimulants and PPI.

Erythromycin is a macrolide antibiotic, but it has a motilin action to improve peristalsis of the stomach and small intestine.^{206, 215-217}

Itopride acts as a dopamine antagonist and inhibits acetylcholine esterase, acotiamide inhibits acetylcholinesterase and trimebutine has an opioid‐like action; therefore, these drugs are expected to exert a similar effect to those of other peristaltic stimulants, but there are no reports on their efficacy.

Figure 7

Algorithm from the treatment of gastrointestinal lesions.

CQ3 Are PPI effective for GERD?

Recommendation: Using PPI to treat GERD is strongly recommended.

Recommendation level: 1A.

Explanation: There is sufficient evidence to show that PPI are effective for treating patients with normal GERD,^{218, 219} and they are assumed to be effective for treating GERD in patients with SSc. Other reports have stated that PPI are effective for treating GERD in patients with SSc,^220-225 and a random‐sampling double‐blind study showed that PPI are effective for treating patients with SSc, although the sample size was small.^{226, 227} However, almost all the reports on the treatment of GERD in SSc patients used omeprazole, and some studies used lansoprazole.²²⁷ The efficacy of omeprazole at the maximum dose that is permitted under insurance coverage in Japan (20 mg/day) has been demonstrated; but the efficacy of 40 mg/day, which is not covered by insurance, has also been demonstrated.^{221, 224, 225} Symptoms have also been found to worsen during long‐term, continuous use; therefore, in clinical practice, using the highest PPI dose possible is recommended.^{222, 228}

Chronic GERD can cause esophageal stenosis and obstruction,²²⁹ as well as changes in the mucosa from the squamous epithelium to the columnar epithelium, known as Barrett's esophagus,^{220, 230, 231} which can then develop into adenocarcinoma. Therefore, when a patient develops Barrett's esophagus, it is essential that they have at least regular endoscopic examinations; and when necessary, undergo histological diagnosis with a biopsy. In addition, when the mucosal changes in Barrett's esophagus become widespread, it is preferable to investigate treatment with radiofrequency ablation (RFA) and endoscopic resection.^{208, 232}

CQ4 Is rikkunshito effective for upper gastrointestinal tract symptoms?

Recommendation: Rikkunshito is proposed as a treatment option for the symptoms of abnormalities in upper gastrointestinal tract motility.

Recommendation level: 2D

Explanation: There is insufficient evidence on the kampo formula rikkunshito (2.5 g × 3, before meals) for treating upper gastrointestinal tract symptoms associated with SSc, but one report on a small number of subjects demonstrated that this treatment was effective when used for patients with SSc.²³³ Rikkunshito promotes stomach mobility and improves symptoms such as heartburn, abdominal fullness and nausea; therefore, it is expected to improve upper gastrointestinal tract symptoms.^234-236

CQ5 Is surgical treatment effective for GERD?

Recommendation: Surgical treatment is proposed as an option for GERD, but only in certain cases and using an appropriate surgical technique.

Recommendation level: 2D

Explanation: Performing esophagocardioplasty for SSc patients with GERD can exacerbate symptoms such as abdominal distension²³⁷ and dysphagia; therefore, this surgery should be limited to patients with severe GERD or reflux esophagitis, and a decision on this procedure should also consider the experience of the surgeon.²³⁸

Esophagectomy has been reported to increase the mortality rate, and this procedure should be indicated with care.²³⁹

However, one report on a small number of patients found that symptoms improved with Roux‐en‐Y gastric bypass surgery, compared with patients who underwent endoscopic esophagocardioplasty.²³⁹ Therefore, this procedure may be considered, depending upon the patient's medical condition.

Pylorectomy to treat severe gastric hypomotility was initially considered to be effective, but it has proven to be ineffective in the long term.²⁴⁰

Table 8. Summary of clinical questions

Clinical Question	Recommendation Level	Recommendation
CQ1 Is improving lifestyle habits effective for symptoms of upper gastrointestinal tract lesions?	1C	Improving lifestyle habits is recommended for symptoms of upper gastrointestinal tract lesions
CQ2 Are gastroprokinetic preparations effective for upper gastrointestinal tract hypomotility?	Domperidone, mosapride and erythromycin,1B; metoclopramide, 2B; itopride, acotiamide, trimebutine, 2C	It is recommended to treat symptoms of gastrointestinal tract hypomotility, including dysphagia, reflux esophagitis, abdominal distension, and intestinal pseudo‐obstruction, with gastroprokinetic preparations
CQ3Are proton‐pump inhibitors (PPI) effective for gastroesophageal reflux disease?	1A	It is strongly recommended to use PPI to treat gastroesophageal reflux disease
CQ4 Is rikkunshito effective for upper gastrointestinal tract symptoms?	2D	Rikkunshito is proposed as a treatment option for symptoms of upper gastrointestinal tract motility abnormalities
CQ5 Is surgical treatment effective for gastroesophageal reflux disease?	2D	Recommendation: Surgical treatment is proposed as an option for gastroesophageal reflux disease, only in certain cases and using an appropriate surgical technique
CQ6 Is balloon dilatation effective for upper gastrointestinal tract obstruction?	2D	Balloon dilatation is proposed as an option for upper gastrointestinal tract obstruction
CQ7 Is tube feeding effective for upper gastrointestinal tract obstruction?	2D	Tube feeding using a jejunal feeding tube is proposed as an option for cases of gastrointestinal tract hypomotility when there is good motility beyond the jejunum with no obstruction, for cases of intestinal obstruction caused by upper gastrointestinal tract hypomotility or stenosis
CQ8 Are antibiotics effective for intestinal bacteria overgrowth?	1D	It is recommended to administrate antimicrobial preparations for intestinal bacteria overgrowth, while sequentially changing the preparations when there is malabsorption due to abnormal proliferation of bacteria
CQ9 Is dietary therapy effective for intestinal hypomotility?	2D	It has been proposed to use dietary therapy for intestinal hypomotility
CQ10 Are gastroprokinetic preparations effective for intestinal hypomotility?	1D	It is recommended to administrate gastroprokinetic preparations for intestinal hypomotility
CQ11 Is octreotide effective for intestinal hypomotility?	2B	Octreotide is proposed for intestinal hypomotility in patients non‐responsive to gastroprokinetic preparations
CQ12 Is daikenchuto effective for intestinal hypomotility?	2D	Daikenchuto is proposed as a treatment option for intestinal hypomotility
CQ13 Is pantothenic acid effective for intestinal hypomotility?	2D	Pantothenic acid is proposed as a treatment option for intestinal hypomotility
CQ14 Is oxygen therapy effective for intestinal hypomotility?	2D	Oxygen therapy is proposed as a treatment option for intestinal hypomotility
CQ15 Is hyperbaric oxygen therapy effective for pneumatosis cystoides intestinalis?	2D	Hyperbaric oxygen therapy is proposed as a treatment option for pneumatosis cystoides intestinalis
CQ16 Are parasympathomimetic drugs effective for intestinal hypomotility?	2D	The parasympathomimetic drugs neostigmine and besacolin are proposed as a treatment option for intestinal hypomotility
CQ17 Is surgical therapy effective for severe lower gastrointestinal lesions?	1D	Surgical therapy is not recommended for obstruction caused by severe lower gastrointestinal lesions, except in certain circumstances
CQ18 Is home total parenteral nutrition effective for severe lower gastrointestinal lesions?	2D	Home total parenteral nutrition is proposed as a treatment option for pseudo‐ileus and malabsorption due to intestinal hypomotility caused by severe lower gastrointestinal lesions

CQ6 Is balloon dilatation effective for upper gastrointestinal tract obstruction?

Recommendation: Balloon dilatation is a proposed option for treating upper gastrointestinal tract obstruction.

Recommendation level: 2D

Explanation: One report found that gastrointestinal tract obstruction improved due to balloon dilatation for esophageal stenosis,²⁴¹ and this procedure may be considered for severe cases. However, the stenosis site can be severely fibrotic or sclerotic, and forceful operations pose the risk of perforation. Therefore, this procedure should be performed with care. It is also essential to consider using drugs such as camostat, PPI and sodium alginate to reduce the effect on the mucosa due to reflux of digestive juices into the esophagus after dilatation.

This treatment often causes re‐stenosis; therefore, it is essential that the patient understands that it may be necessary to repeat the procedure a number of times.

CQ7 Is tube feeding effective for upper gastrointestinal tract obstruction?

Recommendation: Tube feeding using a jejunal feeding tube is proposed as an option for cases of gastrointestinal tract hypomotility when there is good motility beyond the jejunum with no obstruction, for cases of intestinal obstruction caused by upper gastrointestinal tract hypomotility or stenosis.

Recommendation level: 2D

Explanation: A low‐residue diet is recommended when there is reduced gastroesophageal peristalsis.²⁴² Furthermore, while there is no evidence to support the use of a jejunal feeding tube in patients with SSc, when there is reduced peristalsis proximal to the jejunum, as well as no obstruction and good peristalsis, placement of a jejunal feeding tube is generally often effective.^{206, 208, 243}

CQ8 Are antibiotics effective for intestinal bacteria overgrowth?

Recommendation: Administrating antibiotics for intestinal bacteria overgrowth while sequentially changing the preparations when there is malabsorption due to abnormal proliferation of bacteria is recommended.

Recommendation level: 1D

Explanation: Antibiotics are known to be effective for intestinal bacteria overgrowth and malabsorption that is caused by SSc, but no robust studies have used a placebo. However, generally, the broad‐spectrum antimicrobial quinolone or amoxicillin is used as the basis for treating intestinal bacteria overgrowth²⁰⁸ in patients who present with symptoms such as diarrhea, steatorrhea, chronic abdominal pain, abdominal distension, weight loss and vitamin B12 deficiency. The condition is often treated by sequentially changing the treatment.²⁴⁴ The efficacy of metronidazole,²⁴⁵ new quinolone norfloxacin, ciprofloxacin, levofloxacin, aminoglycoside gentamicin and sulfamethoxazole/trimethoprim combination²⁰⁸ have been reported, while the efficacy of tetracycline²⁴⁶ and neomycin²⁴⁷ monotherapy is considered to be slightly lower. Recently, there has been an increased use of non‐absorbable antibiotic rifaximin overseas (it has not been approved in Japan), and there have been a number of reports on its efficacy;^248-250 therefore, when this drug becomes available for use in Japan in the future, it may also be a treatment option.

In reality, there are no fixed opinions regarding a particular type of antimicrobial, the timing for starting treatment and the duration of treatment; therefore, judgment must be made based on each case.

The breath test, in which glucose or lactulose is used, is a simple method for diagnosing intestinal bacteria overgrowth.^{245, 247}

When the symptoms of diarrhea persist during treatment with antibiotics it is vital to consider the possibility of pseudomembranous colitis.

No reports have a high level of evidence, but this treatment is generally implemented, and the recommendation level is set as 1D, based on the consensus of the committee that created this guideline.

CQ9 Is dietary therapy effective for intestinal hypomotility?

Recommendation: Dietary therapy is proposed as an option for intestinal hypomotility.

Recommendation level: 2D

Explanation: Proactively increasing water intake and avoiding high‐fiber food is suggested to treat constipation.²⁵¹

Nutrition replacement therapy is important for treating malabsorption syndrome, and nutritional supplementation, including fat‐soluble vitamins, low‐residue diets, elemental diets and medium‐chain fats, is important.^{252, 253}

CQ10 Are gastroprokinetic preparations effective for intestinal hypomotility?

Recommendation: Administrating gastroprokinetic preparations to treat intestinal hypomotility is recommended.

Recommendation level: 1D

Explanation: Domperidone is effective for treating intestinal pseudo‐obstruction,^{240, 254} and metoclopramide is reported to improve peristalsis in both the small and large intestines.^{252, 255, 256} Mosapride is not only effective for treating the upper gastrointestinal tract, but reports indicate that it is also effective for treating the large intestine.²¹¹ One report has evaluated the efficacy of the prostaglandin F2α preparation called dinoprost.²⁵⁷

However, gastroprokinetic preparations are often ineffectual when symptoms frequently recur due to a long process of intestinal hypomotility. Instead, inhibiting the overgrowth of intestinal bacteria with antibiotics can be effective for treating intestinal pseudo‐obstruction and malabsorption syndrome.

No reports have a high level of evidence, but the recommendation level is set as 1D, based on the consensus of the committee that created this guideline.

CQ11 Is octreotide effective for intestinal hypomotility?

Recommendation: Octreotide is proposed for intestinal hypomotility in patients who are non‐responsive to gastroprokinetic preparations.

Recommendation level: 2B

Explanation: Octreotide is reported to promote intestinal peristalsis in both healthy individuals and patients with SSc.²⁵⁸ In some reports, octreotide was used in patients in whom gastroprokinetic preparations were ineffective, and the authors reported that octreotide effectively and safely improved small intestine peristalsis.²⁵⁹ When used as a monotherapy, octreotide only improves intestinal pseudo‐obstruction in the short‐term, but in some patients, a long‐term effect was achieved by combining octreotide with erythromycin.^{260, 261} However, because the evidence is not adequate, octreotide may be considered for refractory cases in which other drugs are ineffective. Octreotide is not covered by insurance for intestinal hypomotility in Japan.

CQ12 Is daikenchuto effective for intestinal hypomotility?

Recommendation: Daikenchuto is proposed as an option for intestinal hypomotility.

Recommendation level: 2D

Explanation: Basic research studies have demonstrated that daikenchuto improves gastrointestinal motility,²⁶² and clinical studies have evaluated patients with constipation due to various causes, indicating that daikenchuto improves the symptoms of intestinal hypomotility.^{263, 264} However, only one case report has evaluated the effect of daikenchuto for treating gastrointestinal hypomotility in a patient with SSc,²⁶⁵ and the research results on its efficacy are insufficient.

CQ13 Is pantothenic acid effective for intestinal hypomotility?

Recommendation: Pantothenic acid is proposed as a treatment option for intestinal hypomotility.

Recommendation level: 2D

Explanation: Pantothenic acid (s.c., i.m. or i.v. injection) is mainly used for treating postoperative intestinal paralysis, but other reports have found that pantothenic acid was also effective for treating gastrointestinal hypomotility in patients with SSc.^{266, 267} However, all the patients were concomitantly administrated antibiotics or other drugs, and pantothenic acid may not be an effective monotherapy. Research results have not demonstrated that it has adequate efficacy.

CQ14 Is oxygen therapy effective for intestinal hypomotility?

Recommendation: Oxygen therapy is proposed as a treatment option for intestinal hypomotility.

Recommendation level: 2D

Explanation: Reports on the use of oxygen therapy to improve postoperative gastrointestinal hypomobility indicated that hyperbaric oxygen therapy was a safe and effective therapy, even in elderly people.²⁶⁸

One case report found that intestinal peristalsis recovered due to transnasal oxygen therapy (2 L/min).²⁶⁹

CQ15 Is hyperbaric oxygen therapy effective for pneumatosis cystoides intestinalis?

Recommendation: Hyperbaric oxygen therapy is proposed as a treatment option for pneumatosis cystoides intestinalis.

Recommendation level: 2D

Explanation: In some reports, hyperbaric oxygen therapy was trialed for the treatment of treatment‐resistant pneumatosis cystoides intestinalis and pneumoperitoneum in patients with SSc,²⁷⁰ but facilities that can implement this therapy are limited.

Pneumatosis cystoides intestinalis can be improved by improving intestinal peristalsis and/or treating intestinal bacteria overgrowth; therefore, treatments for this condition should also be considered.

CQ16 Are parasympathomimetic drugs effective for intestinal hypomotility?

Recommendation: The parasympathomimetic drugs called neostigmine and besacolin are proposed as treatment options for intestinal hypomotility.

Recommendation level: 2D

Explanation: No reports have evaluated an anti‐cholinesterase preparation of neostigmine (s.c., i.m. or drip infusion) in patients with SSc, but some reports have examined the efficacy of this drug in patients with intestinal pseudo‐obstruction due to various causes, including surgery.²⁷¹

Bethanechol chloride, a cholinergic drug, is reported to be effective for intestinal hypomotility due to various causes, but in a study that compared 15 people who were administrated neostigmine and bethanechol chloride with 15 healthy volunteers, there was a higher gastrointestinal peristaltic promoting effect in the neostigmine group than in the control participants.²⁷² However, research results on both drugs regarding the improvement of intestinal hypomotility in patients with SSc are insufficient.

CQ17 Is surgery effective for severe lower gastrointestinal lesions?

Recommendation: Surgical therapy is not recommended for treating an obstruction that is caused by severe lower gastrointestinal lesions, except in certain circumstances.

Recommendation level: 1D

Explanation: The main source of obstruction that is caused by severe lower gastrointestinal lesions is reduced peristalsis, and exacerbated symptoms of intestinal obstruction are often seen postoperatively;²⁷³ therefore, it is preferable to opt for conservative treatment whenever possible. Patients who are recommended for surgical treatment are those who have treatment‐resistant, severe intestinal pseudo‐obstruction and gastrointestinal perforation at the site of pneumatosis cystoides intestinalis.^{252, 274} When performing surgical treatment, subtotal colectomy can sometimes be effective,²⁷⁵ but it is preferable to preserve the ileocecal valve.²⁷³

No reports have a high level of evidence, but the recommendation level is set as 1D, based on the consensus of the committee that created this guideline.

CQ18 Is home total parenteral nutrition effective for severe lower gastrointestinal lesions?

Recommendation: Home total parenteral nutrition (TPN) is proposed as a treatment option for pseudo‐ileus and malabsorption due to intestinal hypomotility that is caused by severe lower gastrointestinal lesions.

Recommendation level: 2D

Explanation: When abdominal symptoms do not improve with resting of the gastrointestinal tract, TPN is indicated to improve the abdominal symptoms and maintain good quality of life.^{242, 276-281} Intermittent administration of TPN alone during the night is possible by using a completely subcutaneous embedded type of implant (port). However, it is essential to take note of associated complications including catheter infection and heart failure.

Guidelines for the Treatment of the Kidneys

Kidney lesions

CQ1 Are there SSc renal disorders other than scleroderma renal crisis?

Recommendation: SSc renal disorders other than scleroderma renal crisis (SRC) exist, and differentiating these conditions from drug‐induced renal dysfunction and anti‐neutrophil cytoplasmic antibody‐associated glomerulonephritis is recommended.

Recommendation level: 1C

Explanation: SRC is the most serious SSc renal dysfunction because it affects the patient's life prognosis. SRC is reported to occur in 10–19% of SSc patients in Europe and the USA.^{282, 283} In a recent international SRC survey, the incidence was reported to be 4.2% in patients with dcSSc and 1.1% in those with lcSSc.²⁸⁴ This differs significantly from the previous incidence that was reported in North America, and SRC is considered to be a quite rare complication. In Japan, its incidence is 5% or lower.²⁸⁵

Unlike SRC, SSc that is complicated by crescentic glomerulonephritis is rare. In the 1990s, Japanese reports found that patients with SSc and renal dysfunction, without hypertension, were positive for the anti‐myeloperoxidase/anti‐neutrophil cytoplasmic antibody (MPO‐ANCA).^286-288 SSc was thought to be complicated by ANCA‐associated vasculitis. The incidence of SSc with ANCA is reported to be 7–13%, but SSc with ANCA‐associated vasculitis is extremely rare.^{286, 289, 290}

d‐Penicillamine was a therapeutic agent that causes drug‐induced renal dysfunction.^{291, 292} Until the 1990s, d‐penicillamine was widely used to treat SSc fibrotic disease, but the frequency of its use is declining, because its efficacy was doubted in a large‐scale clinical study. Calcineurin inhibitors that are used as immunosuppressants can lead to renal dysfunction; therefore, caution when using them is essential.²⁹³

On the other hand, in patients with SRC, renal dysfunction progresses acutely or subacutely; and plasma renin activity increases, causing hypertension. Pathologically, there are no vasculitis findings such as an immune complex deposition or neutrophil infiltration. Instead, the pathology presents as thickening of the inner membrane of the arterioles with proliferation of the vascular endothelial cells, vascular smooth muscle cells and fibroblasts.²⁹⁴ SRC is characterized by the sudden appearance of hypertension and acute or subacute progression of renal dysfunction. Clinical symptoms present as easy fatigue, hypertension‐related headaches, nausea and visual disturbances. Blood test findings include elevated serum creatinine and cystein, anemia and elevated plasma renin activity, while urinalysis findings include proteinuria and hematuria. If the condition progresses, the patient may present with hypertension, heart enlargement with kidney failure, pericardial effusion or hypertensive retinopathy.^{282, 295}

CQ2 How is normotensive SRC diagnosed?

Recommendation: Pathology that is not associated with hypertension is present in a small percentage of patients with SRC. The diagnosis should be made while referencing findings such as high plasma renin activity.

Recommendation level: 1C

Explanation: Normotensive SRC has been known to exist since before it was understood that plasma renin activity is high in patients with SRC and that angiotensin‐converting enzyme (ACE) inhibitors are effective for treating the condition.^{282, 296} In this condition, which is seen in a small percentage of patients who are diagnosed with SRC, some patients have elevated plasma renin activity and others have activity that is within the normal range. In other words, even in patients with renal dysfunction with normal plasma renin activity and normal blood pressure, if other diseases and drug‐induced renal dysfunction can be ruled out, then the condition is diagnosed as normotensive SRC. In this case, if possible, performing a kidney biopsy and conducting a pathology search are recommended. The pathology is unclear, but approximately 60% of patients also have thrombotic microangiopathy.^{296, 297} Studies investigating the prognosis of kidney function reported that the prognosis is worse for patients with normotensive SRC than for those with SRC and hypertension.²⁹⁸

CQ3 What are the prognostic factors or clinical symptoms of SRC?

Recommendation: A positive test for anti‐RNA polymerase antibodies should be considered as a predictor of the onset of SRC.

Diffuse cutaneous SSc within 4 years of onset, rapid progression of skin thickening, new anemia, new pericardial effusion, congestive heart failure and use of high‐dose corticosteroids should be considered.

Recommendation level: Anti‐RNA polymerase antibody positive, 1A; diffuse cutaneous SSc within 4 years of onset, rapid progression of skin thickening, new anemia, new pericardial effusion, congestive heart failure and use of high‐dose corticosteroids, 2C.

Explanation: The predictive factors and clinical symptoms of SRC were investigated in detail using clinical data from University of Pittsburgh.²⁸² The results indicate that the items listed in the recommendations predict the onset of SRC in patients with SSc. SRC can be induced with the use of high‐dose corticosteroids in patients with diffuse cutaneous systemic scleosis and rapidly progressing skin thickening who are positive for anti‐RNA polymerase III antibodies. This result has been reproduced by many clinical studies.^{296, 298, 299} With corticosteroids, a person who has used steroids with a PSL conversion 15 mg/day or more for 6 months or more is considered to have a history of high‐dose steroid use. On the other hand, even with the risk of diffuse cutaneous SSc, SRC is uncommon in patients who are positive for anti‐Scl70 antibodies.²⁸² However, while the incidence is unknown, SRC can develop in patients who are positive for anti‐Scl70 antibodies.

A basic research study extracted data on 90 SRC patients from a cohort study in Europe and the USA with 1519 patients, and a comparative investigation found that the human leukocyte antigen DRB1*0407 and DRB1*1304 genes are related to SRC onset.³⁰⁰ A study on Japanese patients reported that high levels of serum‐soluble CD147 are related to the onset of SRC.³⁰¹

The incidence of anti‐RNA polymerase antibody expression in SSc differs significantly, depending upon race and country (0–41%).³⁰² The anti‐RNA polymerase III antibody expression rate in Japanese was reported to be 6–10.7%.^{303, 304} The anti‐RNA polymerase III antibody enzyme‐linked immunosorbent assay (ELISA) technique has been developed, and the ELISA index level was reported to relate to the onset of SRC³⁰³

Figure 8

Kidney lesion treatment algorithm. *ACE, angiotensin‐converting enzyme.

Table 9. Summary of clinical questions

Clinical Question	Recommendation Level	Recommendation
CQ1 Are there SSc renal disorders other than scleroderma renal crisis (SRC)?	1C	There are systemic sclerosis (SSc) renal disorders other than SRC, and it is recommended to differentiate this condition from drug‐induced renal dysfunction and anti‐neutrophil cytoplasmic antibody‐associated glomerulonephritis
CQ2 How is normotensive SRC diagnosed?	1C	Pathology not associated with hypertension is present in a small percentage of SRC cases. It is recommended to make a diagnosis referencing findings such as high plasma renin activity
CQ3 What are the prognostic factors or clinical symptoms of SRC?	Anti‐RNA polymerase antibody positive, 1A; diffuse cutaneous systemic sclerosis within 4 years of onset, rapid progression of skin thickening, new anemia, new pericardial effusion, congestive heart failure, use of high‐dose corticosteroids, 2C	It is recommended to consider testing positive for anti‐RNA polymerase III antibodies as a risk factor that predicts onset of SRC. It is proposed to consider diffuse cutaneous systemic sclerosis within 4 years of onset, rapid progression of skin thickening, new anemia, new pericardial effusion, congestive heart failure, and use of high‐dose corticosteroids
CQ4 What factors determine severity and prognosis in SRC?	1C	It is recommended to evaluate the severity of SRC with serum creatinine levels at the start of treatment and estimated glomerular filtration rate (eGFR). The glomerular filtration rate calculated from the serum cystein levels is used to classify severity
CQ5 Are angiotensin‐converting enzyme (ACE) inhibitors effective for treating SRC?	1C	ACE inhibitors are effective for treating SRC and are recommended as first‐line drugs
CQ6 Are angiotensin receptor blockers effective as first‐line drugs for treating SRC?	2C	Angiotensin receptor blockers are not recommended for use as first‐line drugs for SRC
CQ7 What therapeutic agents are effective for treating ACE inhibitor‐resistant SRC?	2D	When normal blood pressure cannot be maintained with treatment using ACE inhibitors, calcium antagonists are proposed as an option for concomitant agents
CQ8 Are ACE inhibitors effective for preventing SRC?	1B	There are no reports of ACE inhibitors exerting an SRC preventative effect, and it is recommended to not use ACE inhibitors to prevent SRC
CQ9 Is hemodialysis effective for SRC?	1C	Some cases of SRC have rapid decline in kidney function and develop kidney failure. Hemodialysis is recommended for these cases
CQ10 Is kidney transplant treatment effective for SRC?	2C	Kidney transplant treatment is proposed as an option for patients undergoing hemodialysis for SRC

CQ4 What factors determine the severity and prognosis of SRC?

Recommendation: Evaluating the severity of SRC with serum creatinine levels and the estimated glomerural filtration rate (eGFR) at the start of treatment is recommended. The glomerular filtration rate calculated from the serum cystein levels is used to classify severity.

Recommendation level: 1C

Explanation: The patient's reponse to treatment differs depending upon their kidney function at diagnosis. In previous reports, the prognosis was good for patients whose serum creatinine did not exceed 3.0 mg/dL, did not have signs of heart failure, and blood pressure returned to normal within 3 days of starting treatment.^{305, 306} The serum creatinine levels, signs of heart failure and taking longer for blood pressure to normalize affects the prognosis of kidney function.

The eGFR (mL/min/1.73 m²)* is used to classify severity.

0 (normal)	≥90
1 (mild)	60 – 89
2 (moderate)	45 – 59
3 (severe)	30 – 44
4 (very severe)	≤29 or initiation of hemodialysis

When a disease other than SSc is identified as the cause of renal dysfunction, the disease is excluded from evaluation using these criteria.

*Loss of muscle mass can occur in patients with SSc, and the eGFR predictive equation using cystein C is used, because cystein C does not tend to be affected by muscle mass.

• Males: (104 × Cys‐C^−1.019 × 0.996^age) − 8
• Females: (104 × Cys‐C^−1.019 × 0.996^age × 0.929)−8
• Cys‐C: serum cysteine C concentration (mg/L)

CQ5 Are ACE inhibitors effective for treating SRC?

Recommendation: ACE inhibitors are effective for treating SRC and are recommended as first‐line drugs.

Recommendation level:1C

Explanation: When a patient is diagnosed with SRC, treatment with an ACE inhibitor should begin immediately.^{305, 307, 308} Captopril should be started at a low dose, and the systolic blood pressure should be reduced by 20 mmHg and diastolic blood pressure by 10 mmHg in 24 h. The treatment should be carefully controlled to ensure that the systolic blood pressure is 140 mmHg or lower within 3 days. Enalapril is similarly effective.³⁰⁹

CQ6 Are angiotensin receptor blockers effective as first‐line drugs for treating SRC?

Recommendation: Angiotensin receptor blockers (ARB) are not recommended for use as first‐line drugs for SRC.

Recommendation level: 2C

Explanation: ARB are widely used therapeutic agents for hypertension because they inhibit the action of angiotensin II in the same way as ACE inhibitors. However, these drugs inadequately treat hypertension and nephropathy due to SRC.^{282, 310} If treatment with ACE inhibitors alone normalize blood pressure inadequately, using ARB with ACE inhibitors is indicated to be effective.²⁸²

However, concomitant use can cause adverse drug reactions such as hyperkalemia, angioedema and renal dysfunction, and caution when using these drugs is essential.

CQ7 What therapeutic agents are effective for treating ACE inhibitor‐resistant SRC?

Recommendation: When normal blood pressure cannot be maintained with ACE inhibitors, calcium antagonists are proposed as an option for concomitant agents.

Recommendation level: 2D

Explanation: When blood pressure cannot be maintained within a normal range, even when using renin–angiotensin inhibitors (ACE inhibitors and ARB), it is necessary to use other antihypertensive drugs concomitantly. Calcium antagonists are the first‐line drugs for this purpose.²⁸² No reports have evaluated the efficacy of beta‐blockers and diuretics.

On the other hand, a case report has examined the efficacy of ERA and direct renin inhibitors.³¹¹

If blood pressure is not reduced even when using the maximum dose of ACE inhibitors concurrently with calcium blockers and ARB, alpha‐blockers may also be used.³¹²

CQ8 Are ACE inhibitors effective for preventing SRC?

Recommendation: No reports have found that ACE inhibitors prevent SRC, and not using ACE inhibitors to prevent SRC is recommended.

Recommendation level: 1B

Explanation: The QUINS trial investigated the effect of low‐dose ACE inhibitors to prevent SRC in patients with early SSc, but a preventive effect was not shown.³¹³ An SRC preventive effect was also not observed with low‐dose ACE inhibitors in a multicenter study using double‐blind testing methods.³¹⁴ Recently, life prognosis was demonstrated to be significantly worse after the onset of SRC in patients with SSc in whom low‐dose ACE inhibitors were administrated p.o. before the onset of SRC.³¹⁵

CQ9 Is hemodialysis effective for treating SRC?

Recommendation: Some patients with SRC have a rapid decline in kidney function and develop kidney failure. Hemodialysis is recommended for these patients.

Recommendation level: 1C

Explanation: The kidney function of some patients deteriorates within a short time frame, and even with treatment with ACE inhibitors, 30–60% of patients begin using hemodialysis.^{282, 298, 316} These studies on the frequency of hemodialysis were in the 2000s, when ACE inhibitors were used as therapeutic agents. Hemodialysis was only a temporary treatment for 20–50% of the patients who began using hemodialysis, and these patients were able to withdraw from treatment. More than half of the patients who begin hemodialysis require permanent hemodialysis treatment. Once hemodialysis begins, it must be continued if blood pressure is not reduced with ACE inhibitors. In these instances, dialysis with AN69 membranes has been reported to cause anaphylactic symptoms with concomitant administration of ACE inhibitors; therefore, concomitant use is contraindicated. It is essential to investigate different types of dialysis membranes that enable the ongoing use of ACE inhibitors.

No randomized controlled study has been implemented, but the recommendation level is set as 1C, based on the consensus of the committee that created this guideline.

CQ10 Is kidney transplantation effective for SRC?

Recommendation: Kidney transplantation is proposed as an option for patients undergoing hemodialysis for SRC.

Recommendation level: 2C

Explanation: Kidney transplantation is effective for treating patients with SRC.³¹⁷ SRC progresses rapidly, and patients who develop kidney failure, despite management of blood pressure with ACE inhibitors or other such drugs, are started on hemodialysis. Kidney transplantation is recommended for patients who are permanently on hemodialysis. In an investigation in Australia on end‐stage kidney failure patients,³¹⁸ SSc accounted for a miniscule 0.3% (n = 127) of the 40 238 patients who were included in the study over a period of approximately 40 years. Twenty‐two of the 127 patients underwent kidney transplantation. The 5‐year survival rate of the patients who did not undergo kidney transplantation was 40%, even after ACE inhibitor treatment was introduced. Conversely, the 5‐year survival rate of the patients who underwent kidney transplantation was 53%.

The recurrence rate of kidney dysfunction in patients who undergo kidney transplantation is approximately 20%, but it is unknown whether the kidney dysfunction is due to SRC or is vascular damage caused by the transplantation.³¹⁹

Guidelines for Treatment of the Heart

Cardiac lesions

CQ1 What is the incidence of cardiac diastolic dysfunction in patients with SSc?

Recommendation: Diastolic dysfunction is the most common heart lesion that occurs in patients with SSc, and is seen in approximately 20% of SSc patients; therefore, conducting screening is recommended.

Recommendation level: 1C

Explanation: Goote et al.³²⁰ reported that 17.7% of 570 SSc patients in a French cohort had diastolic dysfunction, based on the following definition: left ventricle relaxation delay (E/A ≤ 1 and left ventricle inflow deceleration time [DcT] >240 msec), or a restrictive ventricular filling pattern (E/A > 2 or E/A > 1 and DcT ≤ 140 ms). Hinchcliff et al.³²¹ analyzed the echocardiograms of 153 SSc patients and reported that 23% had diastolic dysfunction, based on the following definition: side wall mitral annulus velocity (e’) of less than 10 cm/s (in patients younger than 55 years), e’ of less than 9 cm/s (in patients aged 55–65 years) and e’ of less than 8 cm/s (in patients older than 65 years). On the other hand, Meune et al.³²² analyzed 100 SSc patients and found that 30% had diastolic dysfunction when dysfunction was defined as e’ less than 10 cm/s. However, given that the mean age of the target patients in this study was 54 ± 14 years, and the targeted patients included many patients who were 55 years and older, it is thought that some of the patients who Meune et al. defined as having diastolic dysfunction would not satisfy the definition of diastolic dysfunction by Hinchcliff et al. Recently, E/e’ that is not reliant on preload has become the preferred method for evaluating diastolic dysfunction over the preload‐dependent E/A; therefore, generally, E/e’ of more than 15 is defined as diastolic dysfunction. Lee et al.³²³ reported that E/e’ reflects diastolic dysfunction with a greater degree of sensitivity than E/A in SSc patients, and they also reported that the incidence of diastolic dysfunction in SSc patients was 17.1% (6/35); dysfunction was defined as E/e’ of more than 15. Therefore, the incidence of diastolic dysfunction differs slightly depending upon how it is defined, but approximately 20% of SSc patients are thought to have diastolic dysfunction.

CQ2 What other kinds of heart lesions are associated with SSc?

Recommendation: Heart lesions other than diastolic dysfunction that occur in patients with SSc include systolic dysfunction, coronary disease, conductive disorders, pericarditis and valvular disease (aortic valve, mitral valve), and testing is recommended.

Recommendation level: 1C

Explanation: Heart lesions other than diastolic dysfunction that occur alongside SSc include systolic dysfunction, coronary disease, conductive disorders, pericarditis and valvular disease (aortic valve, mitral valve). The incidence of these complications was reported to be 10–32% in patients with dcSSc and 12–23% in those with lcSSc.³²⁴ If conditions without subjective symptoms are included, almost all patients could have some kind of heart lesion. Even if the heart function is normal, almost all patients have diffuse myocardial fibrosis. If this condition progresses, it may present as systolic dysfunction, but even in patients with normal systolic function, many are found to have diastolic dysfunction (see CQ1). The complication rate of coronary disease is also high, and according to a meta‐analysis by Ungprasert et al.,³²⁵ the incidence of coronary disease in SSc patients was 1.82‐times higher than that in a control group matched by age and sex. Therefore, coronary disease should be suspected based on questioning, detailed testing including an exercise tolerance test and coronary artery computed tomography (CT) scans. Furthermore, various arrhythmias such as sick sinus, I° atrioventricular block, atrial fibrillation, supraventricular extrasystole, premature ventricular contraction, supraventricular tachycardia and ventricular tachycardia are found with fibrosis of the sinoatrial node and atrioventricular node.³²⁶ A report stated that pericardial effusion was found in 40% or more of SSc patients, but in many cases, it is not clinically problematic.³²⁷ Another report found that aortic regurgitation (AR) occurs in 18% of SSc patients, and mitral valve regurgitation (MR) occurs in 48%, but most cases are mild.³²⁸ The condition's onset is said to correlate with age, but the cause of frequent AR and MR in SSc patients is unknown.

CQ3 Are there serology indicators for heart lesions that are associated with SSc?

Recommendation: Measurement of the serology markers BNP or NT‐proBNP is proposed when screening patients for cardiac involvement and evaluating disease severity.

Figure 9

Cardiac lesion treatment algorithm. ACE, angiotensin‐converting enzyme; ARB, angiotensin‐receptor blocker; ECG, electrocardiogram; MRI, magnetic resonance imaging.

Table 10. Summary of clinical questions

Clinical question	Recommendation level	Recommendation
CQ1 What is the incidence of cardiac diastolic dysfunction in systemic sclerosis?	1C	Diastolic dysfunction is the most common heart lesion that occurs with SSc, and is seen in approximately 20% of SSc patients, so it is recommended to conduct screening
CQ2 What other kinds of heart lesions are associated with systemic sclerosis?	1C	Heart lesions that occur with SSc other than diastolic dysfunction include systolic dysfunction, coronary disease, conductive disorders, pericarditis, valvular disease (aortic valve, mitral valve), so testing is recommended
CQ3 Are there serology indicators for heart lesions associated with systemic sclerosis?	2C	Measurement of the serology markers BNP or NT‐proBNP is proposed when screening for cardiac involvement and evaluating severity
CQ4 What kinds of tests are used to detect heart lesions associated with systemic sclerosis?	2C	Cardiac magnetic resonance imaging and myocardial scintigraphy are proposed for detection of cardiac lesions associated with SSc
CQ5 Are calcium blockers effective for treating heart lesions associated with systemic sclerosis?	2C	Ca blockers are proposed as an option for treating heart lesions associated with systemic sclerosis
CQ6 Are ACE inhibitors and ARB effective for heart lesions associated with systemic sclerosis?	2C	ACE inhibitors and ARB are proposed as an option for treating heart lesions associated with SSc
CQ7 Is there other effective treatments for heart lesions associated with systemic sclerosis?	2C	There are no specific therapeutic agents for treating heart lesions associated with SSc, so it is proposed to implement treatment in accordance with the underlying disease
CQ8 Is immunotherapy effective for heart lesions associated with systemic sclerosis?	Steroid administration for pericarditis, 2D; immunosuppressant therapy for other cardiac lesions, none	Administration of steroids is proposed as a treatment for pericarditis associated with SSc. The efficacy of immunosuppressants for treatment of other heart lesions associated with SSc is unknown

Recommendation level: 2C

Explanation: BNP and NT‐proBNP increase in SSc PAH patients in correlation with the severity of the condition, and they are important serological markers for PH. However, these markers will increase in response to any myocardial damage, even in patients without PH, and they are important serological markers for cardiac lesions in general. Ivanovic et al.³²⁹ compared 50 SSc patients with age‐matched control patients and reported that BNP predicted left ventricular diastolic dysfunction. Moreover, when Allanoe et al. investigated 69 SSc patients, they reported that NT‐proBNP was significantly higher in patients with left ventricular or right ventricular systolic dysfunction than in those without. They found that a cut‐off of 125 pg/mL could predict systolic dysfunction with 92% sensitivity and 71% specificity.³³⁰ BNP is also reported to predict atrial fibrillation episodes.³³¹

CQ4 What kinds of tests are used to detect heart lesions that are associated with SSc?

Recommendation: Cardiac MRI and myocardial scintigraphy are proposed to detect cardiac lesions that are associated with SSc.

Recommendation level: 2C

Explanation: Cardiac MRI is useful to detect myocardial fibrosis. Some reports using delayed enhancement MRI found that myocardial fibrosis occurred in approximately two‐third of SSc patients.^332-334 In another study, patients who had a long history of Raynaud's phenomenon (15 years or longer) had a wider area of fibrosis than those without a long history of Raynaud's phenomenon.³³² In fact, patchy fibrosis that does not match the coronary artery region and biventricular necrosis of the contraction band has been found during autopsy of some cases, and thickening of the inner membrane of small coronary arteries has been found in histopathological examinations. Therefore, a small coronary artery vasospasm (cardiac Raynaud's phenomenon) is thought to be involved in myocardial fibrosis. Reduced accumulation can be seen on myocardial perfusion scintigraphy in SSc patients, even if significant stenosis is not seen on coronary angiography.³³⁵ Therefore, myocardial scintigraphy is also useful for detecting cardiac lesions. Papagoras et al.³³⁶ reported that reduced blood flow was found on stress myocardial perfusion scintigraphy in 60% (21/35) of asymptomatic SSc patients, and scintigraphy is considered useful for the early diagnosis of myocardial damage that is caused by SSc. Only a limited number of facilities are able to implement MRI and myocardial perfusion scintigraphy, but implementing these tests in the available facilities is recommended.

CQ5 Are calcium blockers effective for treating heart lesions that are associated with SSc?

Recommendation: Ca blockers are a proposed option for treating heart lesions that are associated with SSc.

Recommendation level: 2C

Explanation: Allanore et al.³³⁷ compared the background of 129 SSc patients with reduced left ventricle ejection fraction (LVEF) (<55%), with 256 SSc patients with normal LVEF (data on both groups taken from the EULAR Scleroderma Trial and Research Group database), and reported that administration of Ca blockers was an independent predictive factor for maintaining LVEF. Therefore, Ca blockers may be effective for treating cardiac lesions in patients with SSc. The type of Ca blockers was not mentioned in that report, but Vignaux et al. administrated nifedipine for 14 days to 18 SSc patients with no signs of cardiac insufficiency or PH and then evaluated the results before and after treatment with MRI and echocardiography. They reported that myocardial perfusion and cardiac function significantly improved.³³⁸ Kahan et al.³³⁹ administrated a single dose of nicardipine 40 mg to 20 SSc patients, and reported that the LVEF significantly increased.

CQ6 Are ACE inhibitors and ARB effective for treating heart lesions that are associated with SSc?

Recommendation: ACE inhibitors and ARB are a proposed option for treating heart lesions that are associated with SSc.

Recommendation level: 2C

Explanation: Kahan et al.³⁴⁰ administrated captopril to 12 SSc patients and reported that these patients had improved blood flow, seen on thallium myocardial scintigraphy. Lee et al.³²³ reported that of 35 SSc patients, those who were administrated ACE inhibitors or ARB (n = 12) had significantly better diastolic function than those who were not administrated these drugs (n = 23). However, ACE inhibitors do not exert a prophylactic effect, even if they are administrated before the onset of a renal crisis; conversely, they have been shown to worsen a patient's life prognosis after the onset of a renal crisis. Therefore, administration of ACE inhibitors to SSc patients requires care.

CQ7 Are there other effective treatments for heart lesions that are associated with SSc?

Recommendation: There are no specific therapeutic agents for treating heart lesions that are associated with SSc, and implementing treatment according to the underlying disease is recommended.

Recommendation level: 2C

Explanation: There are no specific therapeutic agents for treating cardiac lesions in patients with SSc, and treatment is generally administrated according to the underlying disease. Specifically, ACEs or ARB and beta‐blockers are administrated for systolic dysfunction, and coronary vasodilators are administrated for coronary disease. When necessary, catheterization or coronary bypass surgery is performed. Antiarrhythmic drugs, catheter ablation, or pacemakers are used for arrhythmia, and valvuloplasty or valve replacement is considered for patients with vavular disease. Currently, no drugs have been proven to treat diastolic dysfunction in general, not just SSc. One report found that bosentan improves myocardial blood flow and cardiac function,³⁴¹ but a double‐blind study on patients with left ventricular systolic dysfunction was unable to demonstrate the efficacy of bosentan.³⁴² Therefore, the administration of bosentan to patients with left ventricular systolic dysfunction should be investigated carefully.

CQ8 Is immunotherapy effective for heart lesions that are associated with SSc?

Recommendation: Administration of steroids is a proposed treatment for pericarditis that is associated with SSc. The efficacy of immunosuppressants for the treatment of other heart lesions that are associated with SSc is unknown.

Recommendation level: Steroid administration for pericarditis: 2D, immunosuppressant therapy for other cardiac lesions: none

Explanation: Only one case report has indicated that medium‐dose steroid therapy was effective for treating severe pericarditis in patients with SSc,³⁴³ and there are no reports on the utility of immunosuppressants for treating other types of cardiac lesions. Rather, there are reports that these drugs are ineffective,³⁴⁴ and administration of immunosuppressants for cardiac lesions other than pericarditis should be considered carefully.

Guidelines for the Treatment of The PH

PH

CQ1 What is the origin and incidence of PH in patients with SSc?

Recommendation: PH with SSc includes PAH, PH due to left heart disease (PVH) and PH due to interstitial lung disease (ILD‐PH). PAH occurs in approximately 10% of SSc patients, and the SSc‐PAH, PVH and ILD‐PH ratio is 10:10:2.5–3.

Recommendation level: None

Explanation: A meta‐analysis found that 9% of 3818 SSc patients had PAH.³⁴⁵ A number of reports have studied the prevalence of PAH in SSc patients. All rates ranged 7–12%,^346-349 and PAH was thought to be a complication in approximately 10% of SSc patients. On the other hand, in a multicenter prospective study in France, 384 SSc patients were followed for 3 years, during which the incidence of PH was reported as 1.37/100 patients per year, PAH was 0.61, PVH was 0.61 and ILD‐PH was 0.15.³⁵⁰ According to this study, the ratio of PAH to ILD‐PH was approximately 4:1, which is roughly the same as the figures reported in a North American registry (PHAROS) (49:15)³⁵¹ and an English cohort (343:86, but this includes collagen diseases other than SSc);³⁵² and the incidence of PAH and ILD‐PH can be considered to be roughly 10:2.5–3. On the other hand, the ratio of PAH to PVH is 1:1 according to the aforementioned survey; but in the PHAROS registry, the ratio of PAH to PVH was 49:7, which is significantly different. However, the PHAROS registry targeted high‐risk patients. In reality, Fox et al.³⁵³ have reported that the PAH to PVH ratio was 29:24; therefore, in SSc patients, the prevalence of PAH and PVH can be considered to be almost the same.

CQ2 What are the risk factors for developing SSc‐PAH?

Recommendation: lcSSc, anticentromere antibodies and anti‐U1RNP antibodies are risk factors for PAH, but regular screening once a year is recommended for all SSc patients.

Recommendation level: 1C

Explanation: In the USA and UK, PH without ILD (isolated PH, which corresponds to PAH in terms of its clinical classification) is often seen in patients with lcSSc that has a long disease duration.³⁵⁴ Sixty percent or more of lcSSc patients with isolated PH are positive for anticentromere antibodies, but there is no difference in the incidence of isolated PH in lcSSc patients who are positive for anticentromere antibodies and those with lcSSc who are negative for anticentromere antibodies.³⁵⁵ In subsequent reports, the incidence of isolated PH was equivalent between lcSSc patients who were positive for anticentromere antibodies and those with lcSSc who were positive for anti‐Th/To antibodies.³⁵⁶ Anti‐U3RNP antibodies are related to isolated PH in patients with dcSSc.³⁵⁷ Conversely, in Japan, isolated PH is common in patients with SSc who have overlapping anti‐U1RNP antibody‐positive symptoms.³⁵⁸ In a report from France that retrospectively investigated 78 SSc patients with PAH, 55% of the patients were diagnosed with early onset PAH within 5 years of SSc onset, and 16% of those patients had dcSSc.³⁵⁹ There was no difference in the distribution of the disease type and autoantibodies between early onset PAH and PAH that was diagnosed 5 years or more after the onset of SSc. Therefore, the risk factors for PAH differ based on race, and the results are not always reproducible. Therefore, all SSc patients should be regarded as at high risk for developing PAH, and regular annual screenings should be conducted.³⁶⁰

CQ3 What tests are effective for SSc‐PAH screening?

Recommendation: Physical findings (telangiectasia), serology tests (high serum BNP or NT‐proBNP and hyperuricemia), electrocardiogram (ECG; right axis deviation), respiratory function tests (high %FVC/%DLCO), and echocardiography are effective, and their implementation is recommended.

Recommendation level: 1C

Explanation: See CQ4 for information on ECG. According to a multicenter joint study (the DETECT study) that was conducted mainly in North America and Europe, of the many non‐invasive tests, those that are useful for SSc‐PAH screening include high %FVC/%DLCO in respiratory function tests, current or past telangiectasia, positivity for anticentromere antibodies, high serum NT‐proBNP, hyperuricemia and right axis deviation on ECG.³⁶¹ Among respiratory function tests, %DLCO reduction is important, and the entry criteria for the DETECT study were set as a disease duration of 3 years or more and %DLCO of less than 60%. Mukerjee et al.³⁶² reported that less than one‐sixth of SSc‐PAH patients have a %DLCO exceeding 60%. In the PHAROS registry, the criterion for the PH high risk group was %DLCO of less than 55% or %FVC/%DLCO of 1.6 or more.³⁵¹ In serology tests, both BNP and NT‐proBNP are useful for screening, and Cavagna et al.³⁶³ reported that BNP of more than 64 pg/mL can predict the presence of SSc‐PAH with a specificity of 87%, while NT‐proBNP of more than 239.4 pg/mL has a specificity of 80%. When BNP and NT‐proBNP were compared in the same report, BNP was slightly superior to NT‐proBNP for screening. It has been reported that serum uric acid levels are not only elevated in patients with SSc‐PAH, but they are also elevated in PAH patients due to various causes, but these are still useful for screening.^364-366 Despite the above information, no reports have a high level of evidence, but given the importance of screening, the recommendation level is set as 1C, based on the consensus of the committee that created this guideline.

Figure 10

Pulmonary hypertension treatment algorithm. *Prostacyclin analogs (beraprost, epoprostenol, treprostinil), endothelin receptor antagonists (bosentan, ambrisentan, macitentan), phosphodiesterase type 5 inhibitors (sildenafil, tadalafil), soluble guanylate cyclase stimulants (riociguat). **Combination of two or more pharmaceuticals with different action mechanisms from the following: prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors or soluble guanylate cyclase stimulants. WHO, World Health Organization.

CQ4 What is standard practice to implement right heart catheterization?

Recommendation: PH is highly likely when the tricuspid regurgitation velocity (TRV) on echocardiography exceeds 3.4 m/s, or the estimated right ventricular systolic pressure (RVSP) exceeds 50 mmHg. Therefore, implementing right heart catheterization is recommended. In the event that the RV is 3.4 m/s or less or the RVSP is 50 mmHg or less, if other findings indicate PH, right heart catheterization should be implemented.

Recommendation level: A TRV of more than 3.4 m/s or RVSP of more than 50 mmHg, 2A; TRV of 3.4 m/s or less or RVSP of 50 mmHg or less, 2B.

Explanation: According to the ESC, ERS and ISHLT joint guidelines, when the TRV is more than 3.4 m/s or the RVSP is more than 50 mmHg on echocardiography, then PH is highly likely to be present. Therefore, conducting right heart catheterization is proposed to obtain a definitive diagnosis. Even when the TRV is 3.4 m/s or less or RVSP is 50 mmHg or less, if findings such as an elevated blood flow rate of pulmonary artery valve regurgitation, shortened acceleration time of blood outflow from the right ventricle to the pulmonary artery, right heart enlargement, flattening of the ventricular septum, thickening of the right ventricular walls and enlargement of the main trunk of the pulmonary artery are found, then the patient may have PH.³⁶⁷ In particular, in the DETECT study, which was mentioned in CQ3, enlargement of the right atrium was an important echocardiography parameter other than the TRV. The RVSP that is referred to here assumes that the right atrial pressure is 5 mmHg, which corresponds to 45 mmHg in tricuspid regurgitation peak gradient. In fact, when screening using cardiac ultrasound was performed sequentially on 197 SSc patients in a retrospective study, of the 36 patients with a TRPG of 40 mmHg or more, PH was found in all 32 patients who were able to undergo right heart catheterization,³⁶⁸ and the aforementioned cut‐off was considered valid. On the other hand, Mukerjee et al.,³⁶² who targeted 137 SSc patients, compared the pulmonary artery systolic pressure (measured with echocardiography) with the mean pulmonary artery pressure (measured with right heart catheterization), and reported that although both demonstrated a positive correlation (r²=0.44), not only were there false positives, but also approximately 10% of the cases presented as false negatives; the TRPG did not exceed 31 mmHg on Doppler ultrasound, even though the patient had PH. Therefore, even if the TRV is 3.4 m/s or less or RVSP is 50 mmHg or less, if the aforementioned ultrasound findings suggest PH or other subjective findings or physical findings suggest PH, right heart catheterization should be considered.

Table 11. Summary of clinical questions

Clinical question	Recommendation level	Recommendation
CQ1 What is the origin and incidence of pulmonary hypertension (PH) in systemic sclerosis (SSc)?	None	PH with SSc includes pulmonary arterial hypertension (PAH), PH from left heart disease (PVH), and PH from interstitial lung disease (ILD‐PH). PAH occurs in approximately 10% of SSc patients, and the SSc‐PAH, PVH and ILD‐PH ratios are approximately 10:10:2.5–3
CQ2 What are the risk factors for pulmonary arterial hypertension from systemic sclerosis (SSc‐PAH)?	1C	lcSSc, anticentromere antibodies, and anti‐U1RNP antibodies are risk factors for PAH, but regular screening once a year is recommended for all SSc patients
CQ3 What tests are effective for SSc‐PAH screening?	1C	Physical findings (telangiectasia), serology tests (high serum BNP or NT‐proBNP, hyperuricemia), electrocardiogram (right axis deviation), respiratory function tests (high percentage forced vital capacity/percentage diffusing capacity of the lung for carbon monoxide) and echocardiography are effective, and implementation is recommended
CQ4 What is standard practice to implement right heart catheterization?	TRV >3.4 m/s or RVSP >50 mmHg, 2A; TRV≤3.4 m/s or RVSP ≤50 mmHg, 2B	PH is highly likely when the tricuspid regurgitation velocity (TRV) on echocardiography exceeds 3.4 m/s, or the estimated right ventricular systolic pressure (RVSP) exceeds 50 mmHg, so it is recommended to implement right heart catheterization. It is recommended to implement right heart catheterization if TRV ≤3.4 m/s or RVSP ≤50 mmHg, and there are other findings suggestive of PH
CQ5 What is the complication rate of pulmonary veno‐occlusive disease (PVOD) among systemic sclerosis PH? How is this differentially diagnosed?	2C	Approximately half of serious SSc‐PAH cases may also have PVOD‐like lesions. Definitive diagnosis requires histological testing, but it is recommended to suspect this condition if thickened alveolar septa, centrilobular ground‐glass opacities, or mediastinal lymphadenopathy are found on chest computed tomography
CQ6 What factors determine prognosis in systemic sclerosis PAH?	Age, cardiac index (CI), 1C; sex, subtype, WHOFC, pulmonary vascular resistance (PVR), 2C	Age and cardiac index are prognosticators for SSc‐PAH, so it is recommended to consider these factors. Sex (male), subtype (limited scleroderma), World Health Organization Functional Class (WHOFC) and pulmonary vascular resistance also determine prognosis, so it is proposed to also consider these factors
CQ7 Does SSc‐PAH require supportive therapy?	2C	It is proposed to use diuretics for right heart failure, and oxygen therapy to maintain PaO2 above 60 mmHg
CQ8 Is immunosuppressant therapy effective for systemic sclerosis PH?	2C	It has been proposed to not use immunosuppressant therapy for SSc‐PAH
CQ9 Should pharmaceutical intervention be provided to patients with borderline high pulmonary arterialpressure (21–24 mmHg) or patients who correspond to WHOFC I?	None	There is no evidence on the efficacy of pharmaceutical intervention for patients with borderline high pulmonary arterial pressure (21–24 mmHg) or patients who correspond to WHOFC I
CQ10 What pharmaceuticals are used for treating SSc‐PAH WHOFC II?	ERA, PDE5 inhibitors, sGC, stimulants, 1B; sustained‐release beraprost, 2C; normal beraprost tablet, 2D	Endothelin receptor antagonists (ERA) (bosentan, ambrisentan, macitentan), phosphodiesterase (PDE) 5 inhibitors (sildenafil, tadalafil), soluble guanylate cyclase (sGC) stimulants (riociguat) are recommended for WHOFC II SSc‐PAH. It is proposed to use beraprost and beraprost sustained release for WHOFC II SSc‐PAH
CQ11 What pharmaceuticals are used for treating SSc‐PAH WHOFC III?	ERA, PDE5 inhibitors, riociguat, epoprostenol i.v., treprostinil s.c. injection, iloprost inhalant, 1B; beraprost, treprostinil i.v., 2B; initial combination therapy, 2A	ERA (bosentan, ambrisentan, macitentan), PDE5 inhibitors (sildenafil, tadalafil), riociguat, epoprostenol i.v., treprostinil s.c. injection and inhaled iloprost recommended for WHOFC III SSc‐PAH
CQ12 What pharmaceuticals are used for treating SSc‐PAH WHOFC IV?	Epoprostenol i.v., 1A; initial combination therapy, 2A; ERA (bosentan, ambrisentan, macitentan), PDE5 inhibitors (sildenafil, tadalafil), riociguat, treprostinil s.c. injection and i.v., iloprost inhalant, 2C	Epoprostenol i.v. is recommended for WHOFC IV SSc‐PAH. It is also proposed to use ERA (bosentan, ambrisentan, macitentan), PDE5 inhibitors (sildenafil, tadalafil), riociguat, treprostinil s.c. injection and i.v., inhaled iloprost and use these drugs for initial combination therapy
CQ13 What are the treatment goals of SSc‐PAH?	1C	It is recommended to aim for WHOFC I or II, normalization of right ventricular function on echocardiography, right atrial pressure <8 mmHg and cardiac index >2.5 to 3.0 L/min per m^2 with right heart catheterization, 6‐min walking distance >380 to 440 m, and normalization of BNP or NT‐proBNP
CQ14 Should pulmonary vasodilators be used for interstitial lung disease PH (ILD‐PH)?	2C	It is proposed to use PAH therapeutic agents for PH with ILD with caution
CQ15 Is lung transplantation effective for SSc‐PAH and ILD?	2C	It is proposed to evaluate indication of lung transplantation for refractory SSc‐PAH and ILD
CQ16 Is imatinib effective for SSc‐PAH?	2B	Imatinib is sometimes effective for refractory PAH, but administration is not recommended for safety reasons
CQ17 Is rituximab effective for SSc‐PAH?	None	The efficacy of rituximab for SSc‐PAH is currently unknown

CQ5 What is the complication rate of pulmonary veno‐occlusive disease among patients with SSc‐PH? How is this differentially diagnosed?

Recommendation: Approximately half of patients with serious SSc‐PAH may also have pulmonary veno‐occlusive disease (PVOD)‐like lesions. A definitive diagnosis requires histological testing, but this condition should be suspected if the alveolar septum is thickened, centrilobular ground‐glass opacities are present or mediastinal lymphadenopathy is found on chest CT.

Recommendation level: 2C

Explanation: Overbeek et al.³⁶⁹ conducted pathohistological imaging on samples that were collected during lung transplantation in eight PAH patients with lcSSc, and pulmonary congestion was seen in the PVOD in four of the eight patients (50%). On the other hand, when Gunther et al.³⁷⁰ analyzed HRCT images of 26 SSc patients presenting with precapillary PH, they found a high rate of findings that were characteristic of PVOD, including enlarged hilar and bronchial lymph nodes, centrilobular ground‐glass opacity and a thickened alveolar septum, and reported that 16 (61.5%) of the patients had multiple findings. Furthermore, the clinical course of these patients resembled PVOD, with eight patients (50%) developing pulmonary edema with administration of pulmonary vasodilators. The 3‐year survival rate was 30% or lower, and the life prognosis was significantly worse for approximately 80% of patients with only one or less CT finding that was characteristic of PVOD. Based on this information, more than half of SSc‐PAH patients may have PVOD‐like lesions. However, the patients who were analyzed in the Overbeek et al. report required lung transplantation or died; therefore, this would be the complication rate in severe cases. The complication rate of PVOD‐like lesions would be much lower among all SSc‐PAH patients, because this would also include mild cases. However, PVOD‐like lesions occur at a certain rate in patients with SSc‐PAH. Futhemore, the PVOD diagnostic criteria that were defined by the study team on respiratory failure has the condition of “able to exclude chronic lung diseases such as interstitial lung disease, and connective tissue disorders”, and it is necessary to note that some SSc‐PAH patients develop PVOD‐like lesions, which are different from isolated PVOD.

Pulmonary veno‐occlusive disease‐like lesions should be suspected when patients present with the aforementioned findings of a thickened alveolar septum, centrilobular ground‐glass opacities or mediastinal lymphadenopathy on chest CT, and should also be suspected in extremely mild cases without ILD, when there is a severe reduction in arterial oxygen partial pressure at rest (70 mmHg or less) and/or a marked reduction in the pulmonary diffusion capacity on respiratory function tests (%DLCO <55%).

CQ6 What factors determine the prognosis of patients with SSc‐PAH?

Recommendation: Age and cardiac index (CI) are prognosticators for SSc‐PAH, and these factors should be considered. Sex (male), subtype (limited scleroderma), World Health Organization Functional Class (WHOFC) and pulmonary vascular resistance (PVR) may also determine the prognosis, and these factors should also be considered.

Recommendation level: Age, CI, 1C; sex, subtype, WHOFC, PVR, 2C.

Explanation: A univariate analysis of French registry data indicates that age and CI are SSc‐PAH prognosticators, while male sex, subtype (limited scleroderma), WHOFC and PVR may also determine the prognosis. In a multivariate analysis, only male sex was a significant factor for determining poor prognosis.³⁷¹ Humbert et al.³⁷² reported that almost 90% of patients with SSc‐PAH that was diagnosed after the appearance of symptoms were classified as WHOFC III or IV, whereas proactive screening with echocardiography enabled approximately half of the cases to be classified as WHOFC I or II, which also improved prognosis. Therefore, WHOFC is also considered a prognosticator. However, Hachulla et al.³⁷³ reported that even if the condition of SSc‐PAH patients is classified as WHOFC II at diagnosis, their condition often deteriorates thereafter, ultimately resulting in a poor prognosis. Thus, FC II does not always indicate a good prognosis. In terms of hemodynamics, Campo et al.³⁷⁴ reported that the stroke volume index (SVI) (the CI divided by the heart rate) and PVR are SSc‐PAH prognosticators, and an SVI of 30 mL and PVR of 7.22 Wood unit is the cut‐off.

CQ7 Does SSc‐PAH require supportive therapy?

Recommendation: The use of diuretics is proposed to treat right heart failure, and oxygen therapy to maintain PaO₂ above 60 mmHg.

Recommendation level: 2C

Explanation: When PAH is accompanied by signs of right heart failure, limiting sodium and water intake together with using diuretics is empirically effective for improving subjective symptoms, but no studies have investigated the effect of diuretics on the prognosis of patients with PAH. Hypoxia causes pulmonary blood vessel constriction, and oxygen therapy is widely used; but no controlled study has confirmed the effect of this therapy. The Fifth World Symposium on PH recommended introducing home oxygen therapy to maintain the arterial oxygen partial pressure at or above 60 mmHg.³⁷⁵ In terms of other supportive therapies, an i.v. injection of digitalis preparation has been reported to temporarily increase cardiac output,³⁷⁶ but no results have demonstrated the long‐term effect of an oral maintenance dose. A digitalis preparation is also used to control the pulse rate in patients with supraventricular tachycardia. It could be used in patients with signs of left heart failure as well as those with low cardiac output and supraventricular tachycardia. Furthermore, because microthrombus formation may be involved in the pathogenesis of PAH, anticoagulation therapy using warfarin has been used for a long time. To date, there has been one prospective study and six retrospective studies on idiopathic PAH (IPAH)/heritable PAH.³⁷⁷ Fuster et al. conducted a retrospective investigation of 115 IPAH patients, 78 of whom started warfarin within 12 months of diagnosis; the remaining 37 patients did not. The patients in the group that started warfarin early had a significantly higher 3‐year survival rate than those who did not (36% vs 7%).³⁷⁸ In a subgroup analysis by Rich et al.³⁷⁹ on the effect of high‐dose calcium antagonists on IPAH, they found that patients in the group that used anticoagulation therapy with warfarin had a higher 3‐year survival rate than those in the group that did not use warfarin, irrespective of the presence or absence of an acute vasoreactivity (62% vs 31%). On the other hand, an investigation by Frank et al.³⁸⁰ on IPAH reported that there was no difference in the survival rate, with or without anticoagulation therapy. Therefore, while the efficacy of anticoagulants has been demonstrated in five studies, it has been ruled out in two. Two studies investigated the efficacy of anticoagulants for treating SSc‐PAH, but the results of these studies were controversial. When Johnson et al.³⁸¹ analyzed SSc‐PAH and IPAH cohorts, 28% of SSc‐PAH patients and 59% of IPAH patients were administrated warfarin, but the patients’ prognoses did not improve in either group. On the other hand, a report that analyzed the prognosis of 117 connective tissue disease PAH patients (including 104 SSc‐PAH patients) claimed that concomitant administration of PAH therapeutic agents and warfarin improved prognosis.³⁸² The issue with these studies is that the anticoagulant was not randomly allocated. Bosentan reduces the blood concentration of warfarin, and concomitant administration of warfarin and epoprostenol increases the risk of bleeding. In particular, one report found that nine out of 31 patients (29%) who were co‐administrated epoprostenol and warfarin had alveolar hemorrhage.³⁸³ On the other hand, the ESC, ERS and ISHLT joint guidelines recommend that severe patients who require continuous i.v. therapy should be administrated warfarin with a prothrombin‐international normalized ratio of 1.5–2.5 or 2.0–3.0.³⁶⁷ Therefore, currently, PAH therapeutic agents that have a high evidence level should be prioritized, and anticoagulation agents should be used for patients at a high risk of developing venous thrombosis, such as bedridden patients or those who are positive for antiphospholipid antibodies, as well as for patients at a low risk of hemorrhage, such as those with high levels of secondary fibrinolysis markers in the blood.

CQ8 Is immunosuppressant therapy effective for treating SSc‐PH?

Recommendation: Immunosuppressant therapy should not be used for patients with SSc‐PAH.

Recommendation level: 2C

Explanation: Sanchez et al.³⁸⁴ treated 28 CTD‐PAH patients, including eight with SSc‐PAH, with an intermittent administration of CYC 600 mg/m² for 1 month combined with medium‐dose steroids (n = 22) or CYC monotherapy (n = 6), and reported that the progression of PAH was inhibited in the long term in eight of 20 patients with systemic lupus erythematosus or mixed connective tissue disease, whereas no patient in the SSc‐PAH group responded to the treatment. It was understood from these results that immunosuppressants are not effective for treating SSc‐PAH, and the efficacy of these drugs for treating SSc‐PAH has not been investigated further. However, a report by Miyamichi‐Yamamoto et al.³⁸⁵ on the effect of aggressive immunosuppressive therapy on 13 CTD‐PAH patients also included one SSc‐PAH patient, and as expected, the patient did not respond. Based on the above information, immunosuppressants are generally not recommended for treating SSc‐PAH patients.

CQ9 Should pharmaceutical intervention be provided to patients with borderline high PAH (21–24 mmHg) or patients whose condition corresponds to WHOFC I?

Recommendation: No evidence supports the efficacy of pharmaceutical intervention for patients with borderline high PAH (21–24 mmHg) or patients whose condition corresponds to WHOFC I.

Recommendation level: None

Explanation: PAH guideline both in Japan and overseas do not mention pharmaceutical intervention for patients with borderline high PAH (21–24 mmHg) or patients whose condition corresponds to WHOFC I, as there are currently no data available. However, this is because very few reports have investigated the effect of pharmaceutical intervention in these cases, and the recommendations may change if new evidence comes to light in the future. In fact, in a prospective open‐label study on sustained‐release beraprost that was conducted in Japan, the condition of six out of the 44 subjects was classified as FC I. Although a subgroup analysis by class was not implemented, patients with collagen diseases, including SSc, significantly improved their 6‐min walking distance after 12 weeks.³⁸⁶ Even if PH is not seen at rest, it developed in 19% of SSc patients whose PH was found only during exercise; and in one report, half the patients who developed PH died within 5 years.³⁵² Kovacs et al. observed 10 SSc patients whose mPAP was at the upper end of normal (15.5 ± 3.2 mmHg) for 12 months without treatment, and then administrated bosentan for 6 months. They reported that after 12 months, mPAP significantly increased to 18.0 ± 3.2 mmHg, but decreased to 15.5 ± 3.1 mmHg with the administration of bosentan.³⁸⁷ Therefore, if SSc‐PAH is considered a progressive pathology, early therapeutic intervention may improve its hemodynamics and prognosis, and we are awaiting the accumulation of further evidence.

CQ10 What pharmaceuticals are used for treating patients with SSc‐PAH WHOFC II?

Recommendation: ERA (bosentan, ambrisentan and macitentan), PDE5 inhibitors (sildenafil or tadalafil) and soluble guanylate cyclase (sGC) stimulants (riociguat) are recommended for treating patients with WHOFC II SSc‐PAH. Beraprost and sustained‐release beraprost are proposed for use in these patients.

Recommendation level: ERA, PDE5 inhibitors, sGC stimulants, 1B; sustained‐release beraprost, 2C; normal beraprost tablet, 2D.

Explanation: Bosentan, ambrisentan, macitentan, sildenafil, tadalafil and riociguat have all demonstrated efficacy in randomized controlled trials that include patients whose condition was classified as WHOFC II.^388-393 However, only bosentan has been used in a randomized controlled trial, which was limited to WHOFC II patients (the EARLY trial).³⁸⁸ In this study, the primary end‐point was pulmonary vascular resistance and changes in the 6‐min walking distance after 6 months. The 6‐min walking distance tended to be longer in the bosentan group than in the placebo group (+11.2 m vs −7.9 m, P = 0.07), but pulmonary vascular resistance was significantly improved in the bosentan group compared with that in the placebo group (−16.8% vs +7.5%, P < 0.0001). Studies on other drugs also included severe patients who were graded as other than FC II, and all drugs significantly improved regarding the primary end‐point compared with a placebo. The primary end‐point in studies on drugs other than bosentan and macitentan was change in the 6‐min walking distance after 12 or 16 weeks, and all participants demonstrated significant lengthening of the 6‐min walking distance compared with those who were given the placebo.^{389, 391-393} In the macitentan study, the primary end‐point was the time until clinical worsening of the condition, and the study demonstrated that the time until clinical worsening of the condition significantly lengthened compared with a placebo.³⁹⁰ However, none of these studies were limited to SSc‐PAH patients, and there was also no subgroup analysis on SSc patients only. In a study on sildenafil, 45% of the participants had SSc‐PAH. The investigators conducted a subgroup analysis on CTD‐PAH patients and found that after 12 weeks, the 6‐min walking distance lengthened by 55 m compared with those who were given a placebo, and the hemodynamics also significantly improved.³⁹⁴ On the other hand, a meta‐analysis investigating the efficacy of bosentan, sitaxentan (an ERA that inhibits both endothelin receptor A and B; development has currently stopped due to liver damage) and sildenafil on exercise tolerance found that there was no significant improvement in exercise tolerance in patients with CTD‐PAH, the majority of which had SSc‐PAH.³⁹⁵ As stated above, some studies recommend PDE5 inhibitors (sildenafil) as first‐line drugs for patients with SSc‐PAH that is classified as WHOFC II or III,³⁹⁶ but no study has directly compared each drug, and actual drug selection should comprehensively consider all aspects, including tolerance and safety. There have been two randomized controlled trials on beraprost in Europe and the USA, and in both studies, the efficacy was limited to improved exercise tolerance in the short term (3–6 months), and efficacy over the long term was not demonstrated. There was also no improvement in hemodynamics, and the recommendation level was low.^{397, 398} However, after that, the extended‐release formula became available, and a study in Japan on the efficacy of this formula found significant improvement in exercise tolerance and hemodynamics after 12 weeks compared with before starting treatment.³⁸⁶ This study was an open‐label study, and the evidence level is low, but the disease of 28 of the 44 subjects (63.6%) was graded as FC II. Therefore, beraprost (extended‐release) may be effective for FC II‐graded disease. A subgroup analysis on SSc‐PAH patients only was not performed, but in a subgroup analysis on 19 patients with CTD‐PAH, which included six SSc‐PAH patients, the 6‐min walking distance significantly lengthened after 12 weeks of treatment.

CQ11 What pharmaceuticals are used for treating patients with WHOFC III SSc‐PAH?

Recommendation: ERA (bosentan, ambrisentan, macitentan), PDE5 inhibitors (sildenafil, tadalafil), riociguat, i.v. injected epoprostenol, s.c. injected treprostinil and inhaled iloprost are recommended for patients with WHOFC III SSc‐PAH.

Beraprost and i.v. injected treprostinil are proposed for treating patients with WHOFC III SSc‐PAH.

The initial combined administration of these drugs is also proposed.

Recommendation level: ERA, PDE5 inhibitors, riociguat, epoprostenol i.v., s.c. injected treprostinil, iloprost inhalant, 1B; beraprost, treprostinil i.v., 2B; initial combination therapy, 2A.

Explanation: See CQ10 for information on drugs that are also used for treating patients with WHOFC II SSc‐PAH. A randomized controlled trial on bosentan to treat patients with WHOFC III and IV SSc‐PAH was implemented prior to the EARLY trial, demonstrating that the 6‐min walking distance significantly lengthened after 16 weeks in patients who were administrated the drug compared with that of participants who were given a placebo.³⁹⁹ No difference was seen when the results were limited to SSc‐PAH patients, but the number of patients was small because it was a subgroup analysis (test drug group, n = 33; placebo group, n = 14), and interpretation of the results requires caution. The efficacy of epoprostenol has been demonstrated in three randomized controlled trials on patients with WHOFC III or IV PAH,^400-402 and one of these studies examined CTD‐PAH patients.⁴⁰² These were open‐label randomized controlled trials that investigated the efficacy of adding epoprostenol IV to a basic regimen for 111 CTD‐PAH patients, including 78 SSc‐PAH patients and 87 patients whose condition was classified as WHOFC III. The group in which epoprostenol i.v. was added to the regimen significantly improved their exercise tolerance and hemodynamics after 12 weeks compared with the basic regimen group. See the explanation in CQ10 for information on beraprost. A randomized controlled trial of treprostinil s.c. injection included 469 subjects, comprising 90 CTD‐PAH patients (19%), 396 whose condition was considered WHOFC III (84%) and 34 patients whose condtion was graded as FC IV (7%). The 6‐min walking distance significantly lengthened after 12 weeks in patients who were administrated the treatment compared with those who were given a placebo.⁴⁰³ The improvement increased dose‐dependently. A similar randomized controlled trial was implemented for treprostinil i.v., and the results also showed that the 6‐min walking distance significantly lengthened after 12 weeks in the treatment group compared with the placebo group. However, many serious adverse events, including death, occurred; therefore, the study was terminated early.⁴⁰⁴ Therefore, taking care regarding the safety of treprostinil i.v. is recommended. A randomized controlled trial was implemented for an inhaled iloprost on patients with WHOFC III or IV PAH and those with chronic thromboembolic PH. The primary end‐points were improvement in WHOFC and lengthening of the 6‐min walking distance by 10% or more after 12 weeks. The iloprost group had a significant improvement effect compared with the placebo group⁴⁰⁵.

Conventionally, sequential combination therapy, in which the therapeutic effect of single drugs is observed for 3–6 months before adding other drugs, is recommended. However, other reports have examined the efficacy of an initial combination therapy in which multiple drugs are administrated from the start. Galie et al. combined ambrisentan and tadalafil from the start of treatment and compared this treatment with monotherapy using various drugs (combination group and ambrisentan monotherapy, tadalafil monotherapy allocated at ratios of 2:1:1). The risk of clinical failure (defined based on multiple end‐points: first occurrence of death, hospitalization for worsening PAH, disease progression or unsatisfactory long‐term clinical response) was reduced by 50% (AMBITION trial).⁴⁰⁶ Furthermore, in 2015, the EULAR published the results of a subgroup analysis of patients with CTD‐PAH in the AMBITION trial.⁴⁰⁷ According to this report, the risk of clinical failure was reduced by 57% in the combination group compared with the monotherapy group, even in the 187 CTD‐PAH patients, which included 118 SSc patients. The combination group also had improvement in the secondary end‐point (NT‐proBNP) compared with the monotherapy group. Therefore, using an initial combination therapy for patients with WHOFC III SSc‐PAH is recommended.

CQ12 What pharmaceuticals are used for treating patients with SSc‐PAH WHOFC IV?

Recommendation: Epoprostenol i.v. is recommended for treating patients with WHOFC IV SSc‐PAH. ERA (bosentan, ambrisentan and macitentan), PDE5 inhibitors (sildenafil and tadalafil), riociguat, treprostinil s.c. and i.v., and inhaled iloprost are also proposed. These drugs are also recommended for initial combination therapy.

Recommendation level: Epoprostenol i.v., 1A; initial combination therapy, 2A; ERA (bosentan, ambrisentan and macitentan), PDE5 inhibitors (sildenafil and tadalafil), riociguat, treprostinil s.c. and i.v., and inhaled iloprost, 2C.

Explanation: See CQ10 and CQ11 for evidence on these various pharmaceuticals. There are no randomized controlled trials on the efficacy of an initial combination therapy with these drugs. Therefore, the evidence level is low, but the efficacy of these phamaceuticals has been suggested in reports with a small number of patients and in retrospective analyses. Sitbon et al.⁴⁰⁸ used an initial combination therapy of epoprostenol i.v., bosentan and sildenafil in 19 patients (FC III n = 8, IV n = 11), and reported that after 4 months, the mPAP had reduced from 65.8 ± 13.7 to 45.7 ± 14.0 (P < 0.01), and the effect was maintained during the follow‐up period of 32 ± 19 months. Moreover, at the final follow up, the disease of all patients was classified as WHOFC II or lower, and the 3‐year survival rate was 100%. Bergot et al. performed a retrospective analysis of 78 patients with idiopathic, heritable or anorexigen‐associated PAH, who were registered in the French PH registry and treated with epoprostenol i.v. The authors reported that patients in the group who were administrated an initial combination therapy that included epoprostenol had the best prognosis (1‐year survival rate, 92%; 3‐year survival rate, 88%).⁴⁰⁹ These analyses did not include SSc‐PAH patients, but given that patients whose disease is classified as WHOFC III and IV have extremely poor prognosis, an initial combination therapy should be considered for severe cases of SSc‐PAH.

CQ13 What are the goals for treating SSc‐PAH?

Recommendation: It is recommended to aim for WHOFC I or II, normalization of right ventricular function on echocardiography, right atrial pressure of less than 8 mmHg and CI of more than 2.5–3.0 L/min per m² with right heart catherterization, 6‐min walking distance of more than 380 to 440 m, and normalization of BNP or NT‐proBNP.

Recommendation level: 1C

Explanation: The treatment goals of PAH that were decided at the Fifth World Symposium on PH have been listed.⁴¹⁰ However, these goals are not limited to individuals with SSc‐PAH, and it is essential to note that SSc is a systemic disease; therefore, factors such as WHOFC, 6‐min walking distance, and BNP do not simply reflect the severity of PAH. In reality, as described in CQ7, even if SSc‐PAH is classified as WHOFC II at diagnosis, the patient's condition often becomes more severe over time and their prognosis is poor.³⁷³ Mathai et al.⁴¹¹ reported that even with the same degree of severity in hemodynamics, SSc‐PAH patients have significantly higher NT‐proBNP than IPAH patients. In a separate report, Mathai et al.⁴¹² reported that the minimum improvement in the 6‐min walking distance with clinical significance was 33 m, and the goal from an exercise tolerance perspective would be to lengthen the 6‐min walking distance by 30 m or more. Mauritz et al.⁴¹³ reported that the prognosis improved for PAH patients if NT‐proBNP improved by 15% or more each year; therefore, it is good to set this as a goal for patients with NT‐proBNP. Normalization of the size of the right ventricle and contractile function is the goal for echocardiography, but recently, tricuspid annular plane systolic excursion (TAPSE) has gained importance as a simple indicator of right heart function, and reports show that TAPSE ≤ 1.7 cm predicts poor prognosis in patients with SSc‐PAH.⁴¹⁴ A TAPSE >1.7 is one of the treatment goals for echocardiography.

CQ14 Should pulmonary vasodilators be used for patients with ILD‐PH?

Recommendation: It is proposed to use PAH therapeutic agents for PH with ILD with caution.

Recommendation level: 2C

Explanation: Mathai et al.⁴¹⁵ retrospectively compared 39 SSc‐PAH patients and 20 ILD‐PH patients, and reported that the life prognosis was worse for ILD‐PH patients (P < 0.01) than it was for the SSc‐PAH patients, and the risk of death was 5 times higher. Therefore, treating the underlying disease with diuretics and oxygen therapy, is recommended, as well as treating the ILD⁴¹⁶; but no studies have demonstrated the efficacy of this treatment. On the other hand, there are not yet adequate data on the efficacy of PGI₂ preparations, bosentan, or sildenafil for treating ILD‐PH. Minai et al.⁴¹⁷ treated 19 ILD‐PH patients with moderate or worse ILD, including 4 SSc patients, using epoprostenol (n = 10) or bosentan (n = 9), and reported that 15 of these patients lengthened their 6‐min walking distance by 50 m or more. Ghofrani et al. randomly allocated 16 patients with moderate or worse ILD and PH with an mPAP of 35 mmHg or higher, including some with SSc, into two groups and treated each group with epoprostenol or sildenafil respectively. They reported that the gas exchange efficiency increased in the sildenafil group only.⁴¹⁸ Conversely, in the epoprostenol group, an increase in shunt blood flow increased the ventilation perfusion mismatch and decreased oxygen saturation. A similar worsening of gas exchange efficiency was reported for bosentan.⁴¹⁹ Drugs that are used to treat PAH may worsen oxygenation. Therefore, these drugs must be used with caution in patients with moderate or worse ILD. Furthermore, a double‐blind study on ambrisentan in patients with idiopathic pulmonary fibrosis (IPF) reported that there were a significantly higher number of hospitalizations that were related to respiratory insufficiency in the test drug group than in the placebo group, and there tended to be a large number of deaths; therefore, the study was discontinued early.⁴²⁰ Administration of ambrisentan to patients with moderate or worse ILD should be determined carefully. On the other hand, in a similar randomized, double‐blind study on sildenafil in IPF patients, the partial pressure of oxygen in arterial blood and subjective symptoms after 12 weeks, such as dyspnea, were significantly better in patients in the sildenafil group than in those in the placebo group, and sildenafil improved the ventilation perfusion mismatch.⁴²¹

CQ15 Is lung transplantation effective for treating SSc‐PAH and ILD?

Recommendation: It is proposed to evaluate indication of lung transplantation for refractory SSc‐PAH and ILD.

Recommendation level: 2C

Explanation: SSc patients often have GERD, which puts them at high risk of developing aspiration pneumonia post‐transplantation. These patients also frequently have renal dysfunction, and the use of immunosuppressant drugs may lead to renal toxicity. Therefore, patients with underlying SSc often have difficulty when undergoing lung transplantation, even if they have PAH or ILD. However, the survival rates for patients who have undergone lung transplantation to treat SSc‐PAH or SSc‐ILD are reported to be 69% to 91% at 30 days, 59% to 93% at 1 year, and 46% to 73% at 3 years. Although the figures differ depending upon the report, there is almost no difference in outcomes among these reports in patients who had lung transplantation due to underlying diseases other than SSc.⁴²² The indications for lung transplantation should be evaluated based on the patient's age (younger than 55 years for a bilateral lung transplant and younger than 60 years for a unilateral lung transplant).

CQ16 Is imatinib effective for treating SSc‐PAH?

Recommendation: Imatinib is sometimes effective for pattients with refractory PAH, but administration is not recommended for safety reasons.

Recommendation level: 2B

Explanation: Imatinib can be effective for severe cases, based on the results of a previous phase II clinical trial,⁴²³ and an international joint phase II/III study was implemented in patients with serious PAH who had pulmonary vascular resistance of ≥800 dyne/s/cm⁵, even when treated with two or more existing PAH therapeutic agents. There was a significant lengthening of the 6‐min walking distance in patients in the test drug group compared with those who were given a placebo (32 m, P = 0.002), after 24 weeks, but the use of imatinib was unable to lengthen the time until clinical worsening of the condition.⁴²⁴ Furthermore, the incidence of major adverse events and the rate of discontinuing medication were higher in the imatinib group (44% vs 30% and 33% vs 18% respectively) than they were in the placebo group. In particular, 8 patients taking a combination of warfarin and imatinib developed a problematic subdural hematoma. Therefore, while imatinib is sometimes effective for treating refractory PAH, administration is not recommended for safety reasons.

CQ17 Is rituximab effective for treating SSc‐PAH?

Recommendation: The efficacy of rituximab for SSc‐PAH is currently unknown.

Recommendation level: None

Explanation: In one case report, rituximab was effective for treating ILD‐PH,⁴²⁵ but no reports have demonstrated the efficacy of rituximab for treating SSc‐PAH. A phase II clinical trial is currently underway overseas to investigate the efficacy of rituximab for treating SSc‐PAH.⁴²⁶

Guidelines for The Treatment of The Digital Vasculopathy (Raynaud's Phenomenon and Digital Ulcers)

Digital vasculopathy

CQ1 Are there indicators for predicting the onset of digital vasculopathy?

Recommendation: Early disease onset, extensive skin thickening and positivity for anti‐topoisomerase I antibodies should be considered as risk factors for the development of digital ulceration.

Recommendation level: 2C

Explanation: Recently, there have been a number of research reports on the risk factors that lead to digital ulcers. Digital ulcers were found in 29 patients in an investigation on 85 SSc patients, and smoking, early disease onset, long disease duration, joint contracture and delay in beginning iliprost therapy were reported as risk factors.⁴²⁷ Futhermore, in a large‐scale analysis, 24.1% of 1881 SSc patients had digital ulcers, and male sex, PAH, esophageal dysfunction, diffuse skin sclerosis (only when PAH was present), positivity for anti‐topoisomerase I antibodies, young age at onset of Raynaud's phenomenon and elevated sedimentation rate were listed as risk factors.⁴²⁸ Of 267 Chinese patients, 29.6% had digital ulcers, and positivity for anti‐topoisomerase I antibodies, gastrointestinal involvement and young age at onset had a particularly strong correlation with the development of digital ulcers.⁴²⁹ Furthermore, the presence of joint synovitis was a predictor of the appearance of digital ulcers in 1301 patients with disease duration of 3 years or less.⁴³⁰

In an analysis by Silva et al.⁴³¹ in 2015, many study reports listed extensive skin fibrosis, eary onset of Raynaud's phenomenon or other symptoms, and positivity for anti‐topoisomerase I antibodies as risk factors. One report also listed a late SSc pattern and worsening of SSc patterns found via video capillaroscopy as risk factors.⁴³¹

CQ2 Does not smoking prevent or improve digital vasculopathy?

Recommendation: Smoking is a risk factor for the development of digital vasculopathy, and stopping smoking is recommended to prevent or improve digital vasculopathy.

Recommendation level: 1C

Explanation: One study evaluated digital ischemia in 101 SSc patients, depending on whether or not the individual smoked, to investigate the relationship between smoking and digital vasculopathy. The analysis found that the incidence of undergoing debridement (OR = 4.5) and the incidence of hospitalization for i.v. vasodilators (OR = 3.8) was significantly higher for smokers than for never‐smokers.⁴³² Digital ulcers were found in 29 patients in a study of 85 SSc patients, and the study reported that smoking, early disease onset, long disease duration, joint contracture and delay in beginning iliprost therapy were risk factors for digital ulcers.⁴²⁷ No reports have a high level of evidence, but not smoking or quitting smoking is one of the important lifestyle instructions that is given in routine medical practice, and the recommendation level is set as 1C, based on the consensus of the committee that created this guideline.

Figure 11

Digital vasculopathy treatment algorithm.

Table 12. Summary of clinical questions

Clinical question	Recommendation level	Recommendation
CQ1 Are there indicators for predicting the onset of digital vasculopathy?	2C	Early disease onset, extensive skin thickening and positivity for anti‐topoisomerase I antibodies should be considered as risk factors for the development of digital ulceration
CQ2 Does not smoking prevent or improve digital vasculopathy?	1C	Smoking is a risk factor for the development of digital vasculopathy, and stopping smoking is recommended to prevent or improve digital vasculopathy
CQ3 Are calcium antagonists effective for treating digital vasculopathy?	1A	Calcium antagonists are effective for treating Raynaud's phenomenon, and the use of this drug is recommended
CQ4 Are antiplatelet drugs or beraprost sodium effective for treating digital vasculopathy?	1C	Antiplatelet drugs and beraprost sodium are effective for treating Raynaud's phenomenon in patients with SSc, and the use of these drugs is recommended. Sarpogrelate hydrochloride is also effective for treating skin ulcers
CQ5 Are prostaglandin analogs effective for treating digital vasculopathy?	1C	Alprostadil is recommended for the treatment of Raynaud's phenomenon and digital ulcers
CQ6 Are angiotensin‐converting enzyme (ACE) inhibitors or angiotensin‐receptor blockers (ARB) effective for treating digital vasculopathy?	2D	The efficacy of ACE inhibitors and ARB for treating digital vasculopathy is unknown, and their use is not recommended
CQ7 Are anti‐thrombin drugs effective for treating digital vasculopathy?	1C	Anti‐thrombin drugs are effective for treating skin ulcers, and the use of these drugs is recommended
CQ8 Are endothelin receptor antagonists effective for treating digital vasculopathy?	Bosentan for prevention of new digital ulcers, 1A; other, 2C	Bosentan is a recommended treatment to prevent new digital ulcers. In some cases, it can have an effect on Raynaud's phenomenon, existing digital ulcers and ulcers at other sites. Ambrisentan is also proposed as a treatment for existing digital ulcers
CQ9 Are phosphodiesterase (PDE) 5 inhibitors effective for treating digital vasculopathy?	Sildenafil treatment for Raynaud's phenomenon, 2B; other, 2C	Of the PDE5 inhibitors, sildenafil is proposed to ease Raynaud's phenomenon, but it is essential to carefully consider its use. Sildenafil could have an effect on digital ulcers in some cases. Tadalafil and vardenafil are also proposed as treatment options for Raynaud's phenomenon in some cases
CQ10 Is hyperbaric oxygen therapy effective for treating digital vasculopathy?	2D	Hyperbaric oxygen therapy is considered to be effective for treating skin ulcers and is proposed as a treatment option
CQ11 Is surgical treatment effective for skin ulcers and/or gangrene?	1D	Split thickness skin grafting is effective for treating skin ulcers and gangrene, and the use of this treatment is recommended. Thoughtless amputation is not recommended to treat skin ulcers and gangrene
CQ12 Is sympathectomy effective for treating digital vasculopathy?	2D	The efficacy of sympathectomy for treating digital vasculopathy has not been demonstrated, and postoperative complications are also problematic; therefore, the use of this technique is not recommended
CQ13 Is a sympathetic nerve block effective for treating digital vasculopathy?	2D	A sympathetic nerve block is a proposed treatment option for digital vasculopathy
CQ14 Are statins effective for treating digital vasculopathy?	2B	Statins are a proposed treatment for digital vasculopathy, but it is essential to carefully consider its use
CQ15 What ointments effectively treat ulcers and/or gangrene?	1D	Trafermin, prostaglandin E1 ointment, sucrose povidone‐iodine ointment, and bucladesine sodium ointment effectively improve skin ulcers, and the use of these drugs is recommended
CQ16 Are any other therapies effective for treating digital vasculopathy (other than the above)?	Glyceryl nitrate and botulinum toxin, 2C; other, 2D	Reports have indicated that topical negative pressure therapy, intermittent pneumatic compression, platelet‐rich plasma, topical nitroglycerin and therapeutic vascular angiogenesis have an effect on digital vasculopathy. These are proposed as treatment options for refractory cases, but it is essential to carefully consider the use of these procedures

CQ3 Are calcium antagonists effective for treating digital vasculopathy?

Recommendation: Calcium antagonists are effective for treating Raynaud's phenomenon, and the use of this drug is recommended.

Recommendation level: 1A

Explanation: Twenty‐nine reports in English have investigated the efficacy of calcium antagonists for treating SSc Raynaud's phenomenon, but many of the reports were on a small number of patients, and no significant difference from placebo was shown. In a report on the efficacy of nifedipine in a randomized cross‐over study in 16 SSc patients, nifedipine significantly reduced the frequency, duration and severity of Raynaud's phenomenon.⁴³³ In a meta‐analysis of calcium antagonists for treating Raynaud's phenomenon in SSc patients, nifedipine (10–20 mg three times a day) was administrated for 2–12 weeks to 44 SSc patients in five different studies, and nifedipine significantly reduced the frequency and severity of Raynaud's phenomenon compared with a placebo.⁴³⁴ A study on nicardipine (60 mg/day) did not achieve a significant difference compared with a placebo, but this is thought to have been due to the small number of subjects in this study.⁴³⁴ Furthermore, the efficacy of calcium antagonists has been investigated only for Raynaud's phenomenon, and its efficacy for treating digital ulcers, skin ulcers and gangrene is unknown.

CQ4 Are antiplatelet drugs or beraprost sodium effective for treating digital vasculopathy?

Recommendation: Antiplatelet drugs and beraprost sodium are effective for treating Raynaud's phenomenon in patients with SSc, and the use of these drugs is recommended. Sarpogrelate hydrochloride is also effective for treating skin ulcers.

Recommendation level: 1C

Explanation: Many of the reports on the efficacy of antiplatelet drugs and beraprost sodium to treat digital vasculopathy in patients with SSc are case reports, and there were responders and non‐responders to the treatment.

In an investigation of 12 SSc patients who were administrated sustained‐release beraprost sodium, there was significant improvement in the Raynaud's condition score and subjective symptoms.⁴³⁵ On the other hand, in a multicenter double‐blind prospective trial on 107 SSc patients, beraprost sodium did not demonstrate a significant inhibitory effect on digital ulcers and Raynaud's phenomenon compared with a placebo, but digital ulcers tended to decrease, and there was significant improvement in the patients’ overall well‐being.⁴³⁶

Sarpogrelate hydrochloride was reported to improve peripheral coldness in 29% of 57 SSc patients, numbness in 35% and pain in 28%.⁴³⁷ It also reduced the frequency of Raynaud's phenomenon in 43% of patients, reduced its duration in 43%, and significantly reduced the frequency and duration of Raynaud's phenomenon compared with beraprost sodium. Sarpogrelate hydrochloride also significantly improved the area of skin ulcers and Skindex‐16 in a study on 11 SSc patients.⁴³⁸

The use of cilostazol led to a significant improvement of the Raynaud's condition score after 3 months of treatment in 10 SSc patients.⁴³⁹ Cilostazol before meals also improved the Raynaud's condition score after 4 weeks of treatment in 10 SSc patients.⁴⁴⁰ A randomized controlled trial was conducted to investigate the efficacy of cilostazol in patients with Raynaud's phenomenon, and it found that the cilostazol treatment group had significant increase in brachial artery diameter after 6 weeks of treatment.⁴⁴¹ No reports have demonstrated a high level of evidence regarding the direct action of cilostazol on skin ulcers and gangrene, but there is evidence relating to Raynaud's phenomenon, and the efficacy of cilostazol can be expected for skin ulcers and gangrene.

As stated above, no studies have a high level of evidence, but the recommendation level is set as 1C, based on the consensus of the committee that created this guideline.

CQ5 Are prostaglandin analogs effective for treating digital vasculopathy?

Recommendation: Alprostadil is recommended for the treatment of Raynaud's phenomenon and digital ulcers.

Recommendation level: 1C

Explanation: Thirty‐six SSc patients were administrated alprostadil for 5 days consecutively per week for 6 weeks during the winter to investigate the drug's effect on Raynaud's phenomenon and the healing of digital ulcers.⁴⁴² Treatment with alprostadil significantly reduced the incidence of Raynaud's phenomenon compared with before treatment (20% reduction after 1 week [P < 0.05], 41% reduction after 2 weeks [P < 0.005] and 53% reduction after 3 weeks [P < 0.0005]), and it reduced the severity of Raynaud's phenomenon. The study reported that after alprostadil was administrated, digital ulcers were completely healed in 12 of the 14 patients.⁴⁴² No studies have a high level of evidence, but the recommendation level is set as 1C, based on a consideration of the benefit and risk, and on the consensus of the committee that created this guideline.

A number of randomized controlled trials on iloprost have been conducted in Europe and the USA, and the drug has been found to be effective for treating Raynaud's phenomenon and digital ulcers,^{443, 444} but it is not yet released on the market in Japan.

CQ6 Are ACE inhibitors or ARB effective for treating digital vasculopathy?

Recommendation: The efficacy of ACE inhibitors and ARB for treating digital vasculopathy is unknown, and their use is not recommended.

Recommendation level: 2D

Explanation: A multicenter randomized controlled trial on quinapril investigated the effect of ACE inhibitors on digital vasculopathy.⁴⁴⁵ The study investigated the number of new ischemic ulcers appearing on the hands, frequency and severity of Raynaud's phenomenon in 210 patients with SSc or with Raynaud's phenomenon. Quinapril did not inhibit the occurence of new digital ulcers and did not improve the frequency or severity of Raynaud's phenomenon.⁴⁴⁵ Based on the above study, it is thought that ACE inhibitors are not effective for treating digital vasculopathy.

A randomized controlled trial using losartan was conducted to evaluate the effect of ARB.⁴⁴⁶ The study investigated the frequency and severity of Raynaud's phenomenon in 52 patients, including 27 SSc patients and 25 patients with primary Raynaud's phenomenon. The frequency (P < 0.009) and severity (P < 0.0003) of Raynaud's phenomenon were significantly improved in the oral losartan group compared with the nifedipine group. When only the SSc patients were analyzed, the frequency (P < 0.091) and severity (P < 0.064) of Raynaud's phenomenon tended to improve, but it was not a significant improvement. There are no reports on the efficacy of ARB for treating skin ulcers.

Furthermore, the administration of ACE inhibitors prior to the onset of a renal crisis does not prevent the onset of the crisis; in fact, this may be associated with an increased risk of death after the onset.⁴⁴⁷ Therefore, introducing ACE inhibitors and ARB for treating digital vasculopathy only may be problematic, and these drugs are not currently recommended (recommendation level 2D).

CQ7 Are anti‐thrombin drugs effective for treating digital vasculopathy?

Recommendation: Anti‐thrombin drugs are effective for treating skin ulcers, and the use of these drugs is recommended.

Recommendation level: 1C

Explanation: Anti‐thrombin drugs are used to treat skin ulcers due to SSc, but very few reports have evaluated the efficacy of this treatment.^448-450 Shimizu et al.⁴⁴⁸ have reported that refractory skin ulcers that are associated with SSc healed due to argatroban. A study on the efficacy of argatroban for treating skin ulcers, including that seen in SSc patients, observed that skin ulcers were significantly improved with the administration of argatroban.⁴⁵⁰ Based on the above information, while few reports have a high level of evidence, argatroban is considered to be effective for the treatment of SSc skin ulcers. The recommendation level is set as 1C, based on a consideration of the benefit and risk, and on the consensus of the committee that created this guideline.

CQ8 Are endothelin receptor antagonists effective for treating digital vasculopathy?

Recommendation: Bosentan is a recommended treatment to prevent new digital ulcers. In some cases, it can have an effect on Raynaud's phenomenon, existing digital ulcers and ulcers at other sites. Ambrisentan is also proposed as a treatment for existing digital ulcers.

Recommendation level: Bosentan for the prevention of new digital ulcers, 1A; other, 2C.

Explanation: Many case reports to date have used bosentan to treat digital vasculopathy, and in some reports, there were both responders and non‐responders. Treatment with bosentan reduced the frequency and severity of Raynaud's phenomenon in three patients with SSc,⁴⁵¹ and it significantly improved Raynaud's phenomenon in 14 patients in another study.⁴⁵² However, in studies with a higher level of evidence, including a multicenter joint randomized controlled trial by Korn et al.⁴⁵³ on 122 SSc patients and a randomized controlled trial on 17 patients,⁴⁵⁴ there was no significant improvement in the frequency or symptoms of Raynaud's phenomenon. In the trial by Korn et al.,⁴⁵³ bosentan did not improve existing digital uclers, but it significantly inhibited the development of new ulcers. A similar result was obtained in the RAPIDS‐2 randomized controlled trial on 188 patients,⁴⁵⁵ and bosentan's preventive effect has also been found in a meta‐analysis.⁴⁵⁶ These studies did not demonstrate a significant improvement in existing ulcers, but many reports have demonstrated the drug's efficacy;^457-460 therefore, the recommendation level for the treatment of existing digital ulcers is set as 2C. An investigation on five patients with ulcers that were not digital ulcers found that bosentan treatment accelerated the healing of existing ulcers.⁴⁶¹

A study of six patients and another study of 20 patients on the effect of ambrisentan reported that there was significant improvement in the number and diameter of digital ulcers,^{462, 463} but ambrisentan did not have a preventive effect on new digital ulcers. Currently, ambrisentan is not covered by insurance for the treatment of SSc vascular lesions.

CQ9 Are PDE5 inhibitors effective for treating digital vasculopathy?

Recommendation: Of the PDE5 inhibitors, sildenafil is proposed to ease Raynaud's phenomenon, but it is essential to carefully consider its use. Sildenafil could have an effect on digital ulcers in some cases. Tadalafil and vardenafil are also proposed as treatment options for Raynaud's phenomenon in some cases.

Recommendation level: Sildenafil treatment for Raynaud's phenomenon, 2B; other, 2C.

Explanation: A large number of case reports have evaluated the efficacy of sildenafil to treat digital vasculopathy; however, there is also a report with a more robust level of evidence on a randomized cross‐over study of 16 SSc patients, which investigated the efficacy of sildenafil for treating Raynaud's phenomenon.⁴⁶⁴ The study found that treatment with sildenafil significantly improved the frequency and duration of Raynaud's phenomenon, as well as the Raynaud's condition score. In a subsequent randomized controlled trial on 57 patients with lcSSc, modified release sildenafil significantly inhibited the frequency of Raynaud's phenomenon.⁴⁶⁵ Another study investigating 19 patients found that there was a significant improvement of digital ulcers by sildenafil treatment.⁴⁶⁶

A randomized cross‐over study on tadalafil for 39 patients did not show a significant improvement in the Raynaud's condition score, frequency or duration of Raynaud's phenomenon.⁴⁶⁷ However, these items were significantly improved in 24 patients of another randomized cross‐over study.⁴⁶⁸

No studies have a high level of evidence to support the efficacy of vardenafil for treating patients with SSc, but significant improvement was seen in a randomized cross‐over study on 53 patients with Raynaud's phenomenon, including 38 SSc patients,⁴⁶⁹ and this drug may be effective for treating Raynaud's phenomenon.

In summary, PDE5 inhibitors may be effective for easing digital vasculopathy, particularly Raynaud's phenomenon. However, there are virtually no reports in Japan demonstrating the effects. These drugs are also expensive; in Japan, they are an orphan drug and not covered by insurance for treating SSc digital vasculopathy. Therefore, the use of these drugs requires careful consideration.

CQ10 Is hyperbaric oxygen therapy effective for treating digital vasculopathy?

Recommendation: Hyperbaric oxygen therapy is considered to be effective for treating skin ulcers and is proposed as a treatment option.

Recommendation level: 2D

Explanation: A number of case reports have examined the efficacy of hyperbaric oxygen therapy for treating digital vasculopathy. Markus et al.⁴⁷⁰ used hyperbaric oxygen therapy to treat two SSc patients with skin ulcers on their limbs and reported that the skin ulcers improved. Hyperbaric oxygen therapy was also used in Japan for four SSc patients with refractory skin ulcers, and the skin ulcers are reported to be improved.⁴⁷¹

As indicated above, although no reports have a high level of evidence, hyperbaric oxygen therapy is considered effective to treat skin ulcers due to SSc.

CQ11 Is surgery effective for treating skin ulcers and/or gangrene?

Recommendation: Split thickness skin grafting is effective for treating skin ulcers and gangrene, and the use of this treatment is recommended.

Recommendation level: 1D

Recommendation: Thoughtless amputation is not recommended to treat skin ulcers and gangrene.

Recommendation level: 1D

Explanation: Many case reports have evaluated the efficacy of split thickness skin grafting for treating skin ulcers.^{472, 473} In these reports, the grafting was performed after the improvement of blood flow and granuloma formation by oral medication, topical medication and debridement, which results in the epithelialization of the ulcers.^{472, 473} Based on these reports, split thickness skin grafting is considered effective for skin ulcers.

On the other hand, Deguchi et al.⁴⁷⁴ reported the results of artery bypass surgery that was trialed in six SSc patients. Five out of the six patients had graft occlusion again, and underwent limb loss or developed persistent recurrent ulcer. Therefore, although this study only included a small number of patients, artery bypass surgery is not considered effective for skin ulcers.

In terms of amputation of the fingers, toes or lower limbs that are affected by ulcers, many reports have found that ulcers and gangrene develop again in the amputated stump. Therefore, the affected limb should not be amputated without careful consideration (i.e. there are other factors, such as whether the ulcers have caused sepsis).

Thus, as stated above, no studies have a high level of evidence, but the recommendation level is set as 1D, based on a consideration of the benefit and risk, and on the consensus of the committee that created this guideline.

CQ12 Is sympathectomy effective for treating digital vasculopathy?

Recommendation: The efficacy of sympathectomy for treating digital vasculopathy has not been demonstrated, and postoperative complications are also problematic; therefore, the use of this technique is not recommended.

Recommendation level: 2D

Explanation: All the reports to date on the efficacy of sympathectomy for treating Raynaud's phenomenon in patients with SSc have been case reports.^{475, 476} Many reports have discovered that this procedure improved the pain that is caused by Raynaud's phenomenon, but the skin temperature did not improve. Furthermore, another report found that postoperative sepsis, scar formation at the surgical wound site and postoperative finger and/or toe amputations occurred.⁴⁷⁵ Therefore, not only is the efficacy of this procedure unproven, but there are also postoperative complications; therefore, sympathectomy is not recommended.

CQ13 Is a sympathetic nerve block effective for treating digital vasculopathy?

Recommendation: A sympathetic nerve block is a proposed treatment option for digital vasculopathy.

Recommendation level: 2D

Explanation: Several case reports to date suggest that sympathetic nerve block is efficacious for treating digital vasculopathy in SSc patients.^{477, 478} One of them indicates that this procedure was effective for a patient who was resistant to conventional treatments. Therefore, although there is little evidence, sympathetic nerve block may be considered as a treatment option for digital vasculopathy.

CQ14 Are statins effective for treating digital vasculopathy?

Recommendation: Statins are a proposed treatment for digital vasculopathy, but it is essential to carefully consider their use.

Recommendation level: 2B

Explanation: The results of a randomized controlled trial on the efficacy of statins for treating digital vasculopathy in SSc patients have been reported.⁴⁷⁹ In this study, 40 mg of statins were administrated p.o. by 56 patients for 4 months, and 28 patients took an oral placebo drug. Patients with oral statin had lower Raynaud's phenomenon Visual Analog Scale scores, severity of digital ulcers and pain scales than those with placebo.⁴⁷⁹ However, the safety of using statins in patients without dyslipidemia has not been established, and serious adverse drug reactions have been reported; therefore, the use of this drug requires careful consideration.

CQ15 What ointments effectively treat ulcers and/or gangrene?

Recommendation: Trafermin, prostaglandin E1 ointment, sucrose povidone‐iodine ointment, and bucladesine sodium ointment effectively improve skin ulcers, and the use of these drugs is recommended.

Recommendation level: 1D

Explanation: Many case reports have evaluated the efficacy of trafermin for treating skin ulcers in patients with SSc,^480-482 and in some reports, trafermin was effective for skin ulcers that were refractory to other treatments.

In several case reports, prostaglandin E1 ointment was used for treating skin ulcers,⁴⁸³ but there is little description about the efficacy of the treatment.

No reports have examined the efficacy of sucrose povidone‐iodine ointment for treating SSc skin ulcers, and it has only been introduced as a specialist's opinion.⁴⁸⁴

Bucladesine sodium ointment has been used in two case reports,^{485, 486} which indicate that it works to epithelialize refractory SSc skin ulcers.

Thus, as stated above, no studies have a high level of evidence to support the efficacy of topical ointments. However, they are frequently used in clinical practise and are empirically effective for treating skin ulcers. On the other hand, this treatment has few adverse drug reactions compared with other drugs. Therefore, the recommendation level is set as 1D, based on a consideration of the benefit and risk, and on the consensus of the committee that created this guideline. Few reports have evaluated other ointments, but these may be considered for use depending upon the condition of the wound.

CQ16 Are any other therapies effective for treating digital vasculopathy (other than the above)?

Recommendation: Reports have indicated that topical negative pressure therapy, intermittent pneumatic compression, platelet‐rich plasma, topical nitroglycerin and therapeutic vascular angiogenesis have an effect on digital vasculopathy. These are proposed as treatment options for refractory cases, but it is essential to carefully consider the use of these procedures.

Recommendation level: Glyceryl nitrate and botulinum toxin, 2C; other, 2D.

Explanation: Currently, a wide variety of treatments have been tried for SSc digital vasculopathy. Few reports have evaluated the treatments listed below, and the level of evidence is low, but these regimens may be considered as treatment options. However, the patient should be carefully monitored for adverse drug reactions.^{487, 488}

Case reports indicate that topical negative pressure therapy is effective for treating SSc digital ulcers, ulcers on other parts of the body and gangrene.^489-491 One report demonstrated the efficacy of intermittent pneumatic compression on 26 patients with ulcers on their upper limbs, including some with SSc.⁴⁹² One case report showed that platelet‐rich plasma effectively treated scleroderma skin ulcers.⁴⁹³ The efficacy of topical nitroglycerin was demonstrated in a multicenter randomized controlled trial on 219 patients with primary or secondary Raynaud's phenomenon.⁴⁹⁴

The efficacy of therapeutic vascular angiogenesis through autologous bone marrow stem cell transplantation for refractory ulcers has been reported.^{495, 496} On the other hand, both cases with worsend and improved ulcers after percutaneous transluminal angioplasty has been reported.^{497, 498}

Botulinum toxin may have an effect on Raynaud's phenomenon by relieving symptoms of vasospasm,⁴⁹⁹ and the efficacy of this treatment was demonstrated in 12 SSc patients.⁵⁰⁰ Further investigation into its efficacy is warranted. Alpha‐receptor blockers were shown to have a mild effect on Raynaud's phenomenon in two randomized trials, but there was also a high frequency of adverse drug reactions.⁵⁰¹ Riociguat, a soluble guanylate cyclase stimulant, has demonstrated efficacy for treating Raynaud's phenomenon,⁵⁰² and a clinical trial in SSc patients is underway.

Guidelines for the Rehabilitation of the Treatment

Rehabilitation

CQ1 Which rating scales show the extent of dysfunction in patients with SSc?

Recommendation: The HAQ is generally used as a rating scale to show disability due to SSc, and this rating scale is recommended. The use of the SF‐36 is sometimes seen as a general quality of life (QOL) score. However, it does not fully cover the QOL of patients with SSc. Saint George's Respiratory Questionnaire is often used to evaluate respiratory function, and the use of this questionnaire is proposed. The chronic obstructive pulmonary disease assessment test (CAT) is simple to use, and its use is therefore proposed.

Recommendation level: HAQ, 1A; Saint George's Respiratory Questionnaire for respiratory function evaluation, 2C; CAT, 2C.

Explanation: Dysfunction that is caused by SSc results in limited joint range of motion, reduced muscle strength, and dexterity movement disorders, mainly in the fingers due to skin thickening and skin ulcers. When the lesions extend to the face, they can restrict muscle movement in the face and mouth opening. Furthermore, respiratory disorders can be seen if there is interstitial pneumonia or PH.

The most commonly used rating scale to evaluate the extent of dysfunction is the HAQ,⁵⁰³ which also has a Japanese version. The HAQ is widely used for determining the effect of therapy. Rating scales for different dysfunctions include the Hand Mobility in Scleroderma (HAMIS),⁵⁰⁴ Duruoz's Hand Index (DHI),⁵⁰⁵ Hand Functional Disability Scale,⁵⁰⁶ and ABILHAND^©.⁵⁰⁷ Furthermore, the Saint George's Respiratory Questionnaire⁵⁰⁸ and CAT⁵⁰⁹ have been used to evaluate respiratory function when the patient also has interstitial pneumonia. Permission is required to use the Japanese version of the Saint George's Respiratory Questionnaire. Moulthon et al.⁵¹⁰ have used the Mouth Handicap in Systemic Sclerosis (MHISS) to evaluate oral dysfunction, but there is no Japanese version of this questionnaire.

CQ2 Is rehabilitation effective for preventing or improving finger contracture?

Recommendation: Finger flexion and extension stretching and mobility are effective for preventing and improving finger contracture, and it is recommended. The use of splinting is not recommended due to peripheral circulatory disorders that are associated with SSc.

Recommendation level: Finger flexion and extension stretching and mobility, 1B; splinting, 2C.

Explanation: Severe skin thickening is seen on the fingers of patients with diffuse cutaneous SSc, making flexion and extension difficult and often resulting in difficulty performing routine daily activities.

Poole⁵¹¹ has reviewed the effect of finger flexion and extension mobility combined with heat therapy, as well as range of motion training with stretching, as advocated by Mugii et al.⁵¹²

Askew et al.⁵¹³ found that joint range of motion and grip strength significantly improved by using a combination of a paraffin bath and finger flexion and extension mobility in 10 patients. Pils et al. conducted a randomized controlled trial in which no paraffin bath was used as the control. Eight patients in each group performed the procedures for 3 months. They found that all subjects improved their joint range of motion, but there was no difference between patients who used the paraffin bath and those who did not.⁵¹⁴ Sandqvist et al. conducted a similar randomized controlled trial, in which no paraffin bath was used as the control. Seventeen patients in each group performed the procedures for 1 month. They found that all subjects had improved joint range of motion, and there was significant improvement in patients who used the paraffin bath.⁵¹⁵ Mancuso and Poole conducted a similar trial on three subjects for 8 weeks. All three subjects experienced improved joint range of motion.⁵¹⁶ The combined use of a paraffin bath and heat therapy is often reported, but depending on the condition of the skin ulcers, the risk of infection must also be considered. Therefore, it is essential to use heat therapy with care. Seeger et al. administrated splinting to 19 patients for 2 weeks, but the treatment did not have an effect, and more than half of the subjects withdrew from the study. Moreover, the risk of peripheral circulation disorders due to skin ulcers was high because of the sustained pressure and extension that is exerted on the skin).⁵¹⁷

Figure 12

Rehabilitation treatment algorithm. SSc, systemic sclerosis.

Table 13. Summary of clinical questions

Clinical question	Recommendation level	Recommendation
CQ1 What kind of rating scales show the extent of dysfunction in systemic sclerosis?	Health Assessment Questionnaire (HAQ), 1A; Saint George's Respiratory Questionnaire for respiratory function evaluation, 2C; chronic obstructive pulmonary disease assessment test (CAT), 2C	The HAQ is generally used as a rating scale to show disability due to SSc, and this rating scale is recommended. The use of the SF‐36 is sometimes seen as a general quality of life (QOL) score. However, it does not fully cover the QOL of patients with SSc. Saint George's Respiratory Questionnaire is often used to evaluate respiratory function, and the use of this questionnaire is proposed. CAT is simple to use, and its use is therefore proposed
CQ2 Is rehabilitation effective for preventing or improving finger contracture?	Finger flexion and extension stretching and mobility, 1B; splinting, 2C	Finger flexion and extension stretching and mobility are effective for preventing and improving finger contracture, and it is recommended. The use of splinting is not recommended due to peripheral circulatory disorders associated with systemic sclerosis
CQ3 Is pulmonary rehabilitation and cardiac rehabilitation effective for cardiopulmonary dysfunction caused by interstitial lung disease and pulmonary hypertension associated with systemic sclerosis?	Rehabilitation for interstitial pneumonia, 2C; cardiac rehabilitation for pulmonary hypertension, 2D	Rehabilitation is effective for interstitial lung disease and it is proposed as a therapeutic option. There are few reports on cardiac rehabilitation for pulmonary hypertension in systemic sclerosis and the efficacy has not been demonstrated, but it could be considered as a treatment option with the aim of preventing issues associated with disuse
CQ4 Is rehabilitation effective for improving restricted mouth opening and mask‐like faces caused by systemic sclerosis skin thickening due to SSc?	2C	Auto stretching exercises are effective for the face and mouth, and they are proposed as a therapeutic option

CQ3 Are pulmonary rehabilitation and cardiac rehabilitation effective for treating cardiopulmonary dysfunction that is caused by interstitial lung disease and PH that is associated with SSc?

Recommendation: Rehabilitation is effective for interstitial lung disease and it is proposed as a therapeutic option. There are few reports on cardiac rehabilitation for pulmonary hypertension in systemic sclerosis and the efficacy has not been demonstrated, but it could be considered as a treatment option with the aim of preventing issues associated with disuse. Recommendation level: Pulmonary rehabilitation for interstitial pneumonia, 2C; cardiac rehabilitation for pulmonary hypertension, 2D.

Explanation: Few reports have studied the efficacy of pulmonary rehabilitation for treating patients with interstitial pneumonia. Recently, a number of reports have found functional improvement using methods that were similar to rehabilitation in patients with obstructive pulmonary disorder. Mugii et al.⁵¹⁸ wrote case reports on the effect of short‐term (2 months) and mid‐term (7 months) rehabilitation intervention.⁵¹⁹ For pulmonary rehabilitation, interval training between breaks is effective, based on the characteristics of hypoxia during exercise that are seen in patients with interstitial pneumonia. Someya et al.⁵²⁰ implemented rehabilitation for a mean period of 55 days in 16 SSc patients with interstitial pneumonia and found that the 6‐min walking distance increased.

No reports have studied the use of cardiac rehabilitation for treating PH in patients with SSc only; therefore, the evidence for this therapy has not been established. The reports are limited to functional evaluation, including the 6‐min walking distance test. It is essential to prevent disuse syndrome, which is caused by excessive rest, through interval training between breaks. Hypoxia and heart rate should be monitored during exercise.

CQ4 Is rehabilitation effective for improving restricted mouth opening and mask‐like faces that are caused by skin thickening due to SSc?

Recommendation: Auto stretching exercises are effective for the face and mouth, and they are proposed as therapeutic options.

Recommendation level: 2C

Explanation: Melvin has introduced rehabilitation for the face and mouth, dividing various automatic muscle movements that make up facial expressions into 16 different categories.^{521, 522} Naylor has reported on manual stretches for oral exercises and using tongue depressors to stretch the inside of the mouth.^{523, 524} The auto stretching exercises that were advocated by Mugii et al. exercise the various muscles that create facial expressions, refining the program introduced by Melvin to enable patients to practice the exercises daily. Mugii et al. also incorporated many exercises for the area around the mouth, which is usually problematic. They investigated the effect of the exercises on the width of the mouth opening in 35 patients and found that auto stretching exercises affected the opening width over the short term of 1 month and the long term of 2 years.^{525, 526} Maddali‐Bongi et al.⁵²⁷ reported that the opening width, facial skin score, and MHISS improved with twice weekly manual therapy and voluntary practice for 9 weeks. Yuen et al.⁵²⁸ implemented a randomized controlled trial on 48 patients for 6 months, and reported that the mouth opening width improved after 3 months; but by the 6‐month mark, many patients withdrew from the study and others did not experience improvement.

Conflict of Interest

None declared.