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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Objective

To assess the efficacy of therapies in healing and preventing digital ulcers (DUs) in systemic sclerosis (SSc; scleroderma).

Methods

Medline and EMBASE databases, and American College of Rheumatology and European League Against Rheumatism abstracts, were searched. Randomized controlled trials (RCTs) with outcomes investigating healing or prevention of DUs in SSc and comparing a pharmacologic therapy with placebo or an active agent were included. The pooled risk ratios (RRs) using the fixed-effects model were calculated and heterogeneity was tested using the I2 statistic.

Results

Sixty studies were found; 19 were not randomized, and 10 did not give DU quantitative data or no comparison of a different drug, leaving 31 RCTs with a total of 1,989 patients. Quality was 3 of 5 or less for 11 trials. DUs were not the primary outcome in many RCTs. Phosphodiesterase type 5 (PDE-5) inhibitors were significant for DU healing (RR 3.28 [95% confidence interval (95% CI) 1.32, 8.13], P = 0.01). Two large bosentan trials were significant for mean number of new DUs (standardized mean difference [SMD] −0.34 [95% CI −0.57, −0.11], P = 0.004). Oral prostacyclins were not statistically different from placebo, but intravenous (IV) iloprost prevented new DUs (SMD 0.77 [95% CI −1.46, −0.08], P = 0.03). Single trials for atorvastatin and vitamin E were positive in the prevention and healing of DU, respectively. There were many negative trials: antiplatelet therapy, oral N-acetylcysteine, heparin, dimethyl sulfoxide, ketanserin, prazosin, prostaglandin E1, cyclofenil, quinapril, and topical nitroglycerin formulation.

Conclusion

Small sample sizes, few comparative trials, and heterogeneity limits the conclusions. The results suggest a role for PDE-5 inhibitors in the healing of DUs; bosentan and IV iloprost may prevent new DUs.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Systemic sclerosis (SSc; scleroderma) is a connective tissue disease with fibrosis and vascular abnormalities in the majority of patients ([1]). Raynaud's phenomenon (RP) occurs in more than 90% of patients with SSc and results from an excessive, vasoconstrictive response to low temperatures and other stimuli, as well as fixed arterial defects due to hypertrophy and occlusion of the vasculature. The characteristic pallor and cyanosis of RP most frequently affects the distal extremities (fingers and toes). In its most severe form, RP can lead to digital ulcers (DUs) ([1]). DUs occur in 15% of SSc patients at any given visit and in 50% of SSc patients ever. They typically present with painful ulcers on fingertips, but can also have skin break down at skin creases, over the proximal interphalangeal joints, or in association with calcinosis ([2]). Complications of DUs include local infection, osteomyelitis, gangrene, or amputation. Disability and reduced hand function may occur, resulting from fibrosis and tissue loss ([2]).

Given that DUs carry high clinical impact, it is very important for health care providers who treat DUs in SSc to have knowledge of potential healing and prevention modalities. The European League Against Rheumatism (EULAR) has published evidence-based guidelines for treatment of RP and DUs, but relative benefits of the treatment strategies described have not been meta-analyzed ([3]). The guidelines did not include more recent studies of phosphodiesterase type 5 (PDE-5) inhibitors. Several trials have investigated the effects of pharmacologic agents on healing and preventing DUs in SSc, often in RP trials where DU treatment was not the primary outcome. A meta-analysis to estimate the effects of drugs for both healing and prevention was performed in order to summarize the clinical trials for SSc DUs.

Box 1. Significance & Innovations

  • There have been several, mostly small random controlled trials studying treatment for prevention and healing of digital ulcers (DUs) in systemic sclerosis, and many studies did not have DU treatment as the primary outcome, as they were trials in Raynaud's phenomenon.
  • Phosphodiesterase-type inhibitors showed healing of DUs.
  • Two bosentan trials and intravenous iloprost showed a reduction of new DUs.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Identification of studies

A comprehensive literature search of the Medline, PubMed, and EMBase databases from 1980 to February 29, 2012, and of the American College of Rheumatology and EULAR abstracts, was conducted using the following search terms: Digital Ulcers (DU) and Raynaud's Phenomenon (RP)/ or Scleroderma/ or Systemic Sclerosis (SSc). Furthermore, key references were hand searched to identify other potentially relevant studies. Studies met inclusion criteria if they were randomized controlled trials (RCTs); had primary, secondary, or exploratory outcomes investigating healing or prevention of DUs in SSc; and compared a pharmacologic therapy with placebo or another active agent. Studies were excluded if there were insufficient data on DUs, including lack of quantitative data. Recent abstracts that did not have full manuscripts published were included if there were sufficient data obtained from the registration of the clinical trial protocol and published abstract(s). Full text articles were retrieved if review of titles and abstracts did not obviously exclude the studies. Two reviewers (TT and JS) separately identified papers for inclusion into the meta-analysis. If there was disagreement, the full papers were read and agreement was achieved by consensus of authors.

Quality assessment

The quality of the studies was assessed using the methods described by Jadad et al ([4]). Quality score was based on randomization, blinding, statistical methods, intent-to-treat analysis, and method of randomization. If an article did not explain/discuss a quality item, it was assumed a “0” (zero) score for that item.

Data extraction

Data extraction was performed using a standardized data extraction form. The following data were extracted from each study: first author, year of publication, pharmacologic agent(s) studied, study design (crossover or parallel), total sample size and number with ulcers, specific clinical outcome relating to DUs in SSc, and primary study outcome, noting that many studies were trials of RP where DU outcome measures were secondary or exploratory. Where possible, data on the following outcomes were extracted: the number of new DUs in each group overall and/or the number of patients with new DUs, number of patients with DUs at the beginning and end of the study, improvement in or full or partial healing of DUs, adverse events, and functional assessment using standardized outcomes, such as the Scleroderma Health Assessment Questionnaire ([5]).

Statistical analysis

Raw numerical data, such as event rates, and pre- and post-number of DUs for within- and between-groups differences were extracted from studies, and the risk ratio (RR) and standardized mean difference (SMD) were calculated where appropriate. RR was done for proportions (such as the proportion of patients with ulcers in 2 groups at the study beginning and end) and the SMD was performed when there were numerical data (such as the number of ulcers that healed in each group or the number of patients who became ulcer free in each group). Studies within the same class of drug were combined if similar outcomes were provided. The random-effects model, as described by DerSimonian and Laird ([6]), was used to calculate the pooled RRs or differences between groups. In this model, the weight of the study is proportional to the inverse of the within-study variance. The I2 statistic was used to examine the between-study heterogeneity ([7]). Values <30% indicate mild heterogeneity, whereas values >50% indicate notable heterogeneity. All statistical analyses were completed using Review Manager software, version 5.0.11.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Search results

The electronic database search and initial screening for eligibility identified 60 studies for full text review (see Figure 1 for full search strategy). There were 31 RCTs ([8-37]) that met inclusion criteria for the meta-analysis, with a total of 1,989 participants enrolled (Table 1), but all did not have baseline DUs and, in some trials of RP in SSc, only a few patients had an ulcer even throughout the trial. All patients had a diagnosis of SSc, and 811 patients had a baseline DU (Table 1). Most trials studied RP, with secondary or exploratory outcomes documenting either DU healing or prevention of new DUs. The trial duration ranged from 4 weeks to 3 years (Table 1). Included trials had a mean quality score of 3.65 out of a maximum score of 5 (range 1–5) (Table 1) ([4]). One trial contained SSc and other patients with other autoimmune diseases and RP ([28]).

image

Figure 1. Illustration of the search strategy for studies meeting inclusion criteria to be included in the meta-analysis. RCTs = randomized controlled trials; DU = digital ulcer; ACR = American College of Rheumatology; EULAR = European League Against Rheumatism.

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Table 1. Meta-analysis of pharmacologic agents for DU healing and prevention in RP for SSc patients: data extraction*
Author, year (ref.)ComparisonClinical outcome of DUsNumber of participantsNumber of participants with baseline DUsStudy quality (Jadad score)Trial duration
  1. a

    DUs = digital ulcers; RP = Raynaud's phenomenon; SSc = systemic sclerosis (scleroderma); ASA = acetylsalicylic acid; PGE = prostaglandin E; DMSO = dimethyl sulfoxide; IV = intravenous; NAC = N-acetylcysteine.

  2. b

    American College of Rheumatology Annual Scientific Meeting abstract (applies to Herrick et al, 2009 [32]).

Blom-Bulow et al, 1981 ([8])Cyclofenil vs. placeboHealingTotal 27; placebo 27; cyclofenil 2714412 months (2 × 6 months)
Roald and Seem, 1984 ([38])Ketanserin vs. placeboHealingTotal 10; placebo 10; ketanserin 10539 weeks
Beckett et al, 1984 ([10])Dipyridamole and aspirin vs. placeboHealingTotal 28; placebo 28; ASA and dipyridamole 281051–2 years
Belch et al, 1985 ([11])CL 115,347 PGE2 analog vs. placeboSeverityTotal 29; placebo 14; PGE2 15Total 8; placebo 3; PGE2 546 weeks
Lukac et al, 1985 ([12])Ketanserin vs. placeboHealingTotal 15; placebo 7; ketanserin 8Total 7; placebo 3; ketanserin 443 months
Mohrland et al, 1985 ([13])PGE1 vs. placeboHealing, newTotal 55; placebo 28; PGE1 27Total 14; placebo 10; PGE1 434 weeks
Williams et al, 1985 ([14])Topical DMSO vs. placebo50% healingTotal 84; placebo 31; 2% DMSO 25; 70% DMSO 2884312 weeks
Wollersheim et al, 1986 ([15])Prazosin vs. placeboHealingTotal 24; placebo 24; prazosin 24928 weeks (2 weeks × 4)
Meyrick Thomas et al, 1987 ([16])Nifedipine vs. placeboNewTotal 10; placebo 10; nifedipine 10Not given420 weeks (6 weeks in each arm, 4 week washout × 2)
McHugh et al, 1988 ([17])IV iloprost vs. placeboHealingTotal 20; placebo 9; IV iloprost 118/29 at some stage37 weeks (6 hours × 3 days in each arm, 6 week washout)
Rademaker et al, 1989 ([18])IV iloprost vs. oral nifedipineHealing (change in mean number of DUs)Total 23; placebo 23; IV iloprost 12; nifedipine 11Not given416 weeks (iloprost 8 hours × 3 days then 8 hours × 1 at 8 weeks, oral nifedipine 4–16 weeks)
Wigley et al, 1992 ([19])IV iloprost vs. placeboHealing, newTotal 35; placebo 35; IV iloprost 35Total 11; placebo 4; IV iloprost 7410 weeks (iloprost 6 hours × 5 days, 2 week outpatient washout)
Lau et al, 1993 ([20])Oral cicaprost vs. placeboHealingTotal 49; placebo 16; cicaprost 33Total 5; placebo 2; cicaprost 334 months
Wigley et al, 1994 ([37])IV iloprost vs. placeboHealing, newTotal 131; placebo 67; IV iloprost 64Total 73; placebo 38; IV iloprost 35412 weeks (14 day pretreatment, 5 day treatment, 9 week followup)
Black et al, 1998 ([21])Oral cicaprost vs. placeboHealingTotal 103; placebo 35; oral iloprost 68Total 28; placebo 9; oral iloprost 1956–12 weeks
Vayssairat, 1999 ([22])Beraprost vs. placeboNewTotal 107; placebo 52; beraprost 550 (must heal more than 1 month before inclusion, but history of DU in last 3 years)5179–184 days of treatment, 5-month surveillance
Denton et al, 2000 ([23])Heparin vs. placeboHealingTotal 30; placebo 14; heparin 16Not given (baseline mean 2.0 heparin, control 1.0)224 weeks
Scorza et al, 2001 ([24])Cyclic IV iloprost vs. nifedipineImprovementTotal 46; nifedipine 17; IV iloprost 29Total 17; IV iloprost 14; nifedipine 3312 months (IV iloprost 8 hours × 5 days then 8 hours × 1 every 6 weeks, nifedipine × 12 months)
Korn et al, 2004 ([25])Oral bosentan vs. placeboHealing (total population, if baseline); newTotal 122; placebo 43; bosentan 79Total 77; placebo 24; bosentan 53416 weeks
Marasini et al, 2004 ([26])IV iloprost vs. alprostadilImprovement and healingTotal 21; IV iloprost 11; alprostadil 10Total 7; IV iloprost 5; alprostadil 2160 days (treatment loading × 5 days, maintenance × 2 every 30 days, alprostadil 3 hours/day, iloprost 6 hours/day)
Fries et al, 2005 ([27])Sildenafil vs. placeboImprovement and healingTotal 16; placebo 16; sildenafil 16649 weeks (treatment 4 weeks in each arm, 1 week washout)
Gliddon et al, 2007 ([28])Quinapril vs. placeboNewTotal 210; placebo 106; quinapril 1045052–3 years
Abou-Raya et al, 2008 ([29])Atorvastatin vs. placeboNew, healing (decrease in mean no. of DUs)Total 84; placebo 28; atorvastatin 56Not given (baseline mean 3.4 placebo, 3.3 atorvastatin)44 months
Chung et al, 2009 ([30])Nitroglycerin topical formulation vs. placeboNewTotal 219; placebo 108; nitroglycerin 111Not given44 weeks
Fiori et al, 2009 ([31])Vitamin E vs. placeboMean time to healingTotal 27; placebo 12; vitamin E 15271Unclear, 20 weeks (treated twice a week)
Herrick et al, 2009 ([32]), 2011 ([33])aSildenafil vs. placeboHealingTotal 45; placebo 25; sildenafil 20Total 8; placebo 3; sildenafil 5328 days
Shenoy et al, 2010 ([34])Tadalafil vs. placeboHealing, newTotal 24; placebo 24; tadalafil 24Total 7; placebo 5; tadalafil 2513 weeks (6 week treatment in each arm, 1 week washout)
Correa et al, 2010 ([9])bOral NAC vs. placeboNewTotal 42; placebo 21; oral NAC 21Not given34 weeks (3 times daily)
Matucci-Cerinic et al, 2011 ([35])Bosentan vs. placeboHealing, newTotal 188; placebo 90; bosentan 98188532 weeks (24 week treatment, 8 week followup)
Seibold et al, 2011 ([36])bTreprostinil vs. placeboHealing, new; time to healingTotal 148; placebo 76; treprostinil 72148420 weeks (primary end point 16 weeks)
Bali et al, 2011 ([48])IV iloprost vs. placeboHealing, newTotal 17; placebo 7; IV iloprost 7Not given54 months (once monthly)

Statistical analyses for relevant outcomes pertaining to the healing or prevention of DUs are shown for all 31 included studies (Table 2). However, there were only 10 studies ([19, 21, 22, 25, 27, 32-37]) whose outcomes could be combined in forest plots (Figures 2, 3, and 4), displaying pooled RRs or SMDs.

Table 2. Meta-analysis of pharmacologic agents for DU healing and prevention in RP for SSc patients: statistical data extraction and recalculation*
Author, year (ref.)ComparisonStatistic (95% CI)P
  1. DUs = digital ulcers; RP = Raynaud's phenomenon; SSc = systemic sclerosis (scleroderma); 95% CI = 95% confidence interval; RR = risk ratio; N/A = not applicable; PGE = prostaglandin E; SMD = standardized mean difference; DMSO = dimethyl sulfoxide; IV = intravenous; NAC = N-acetylcysteine.

  2. a

    P value or RR extracted from original study (all other P values are recalculated).

  3. b

    American College of Rheumatology Annual Scientific Meeting abstract (applies to Herrick et al, 2009 [32]).

Blom-Bulow et al, 1981 ([8])Cyclofenil vs. placeboDU healing: RR 2.00 (0.62, 6.45)0.25
Roald and Seem, 1984 ([38])Ketanserin vs. placeboN/A0.14a
Beckett et al, 1984 ([10])Dipyridamole and aspirin vs. placeboDU healing: RR 0.71 (0.38, 1.33)0.29
Belch et al, 1985 ([11])CL 115,347 PGE2 analog vs. placeboDU severity: SMD 0.81 (−0.72, 2.35)0.3
Lukac et al, 1985 ([12])Ketanserin vs. placeboDU healing: RR 5.60 (0.39, 79.70)0.2
Mohrland et al, 1985 ([13])PGE1 vs. placeboDU healing: RR 0.89 (0.27, 2.90) New DU: RR 0.31 (0.03, 2.78)DU healing: 0.85 New DU: 0.29
Williams et al, 1985 ([14])Topical DMSO vs. placebo50% DU healing: RR 1.07 (0.62, 1.85)0.8
Wollersheim et al, 1986 ([15])Prazosin vs. placeboDU healing: RR 15 (0.98, 228.9)0.05
Meyrick Thomas et al, 1987 ([16])Nifedipine vs. placeboNew DU: RR 0.50 (0.18, 1.40) SMD −0.62 (−0.57, 1.33)0.19 (RR) 0.20 (SMD)
McHugh et al, 1988 ([17])IV iloprost vs. placeboInsufficient data (nonsignificant difference)P not given
Rademaker et al, 1989 ([18])IV iloprost vs. oral nifedipineDU healing: SDM 0.00 (−0.82, 0.82)1
Wigley et al, 1992 ([19])IV iloprost vs. placeboDU healing: RR 3.00 (0.76, 11.81) New DU: RR 1.18 (0.30, 4.72) SMD: −0.77 (−1.46, −0.08)DU healing: 0.12 New DU: 0.81 (RR), 0.03 (SMD)
Lau et al, 1993 ([20])Oral cicaprost vs. placeboInsufficient data (nonsignificant difference)Not given
Wigley et al, 1994 ([37])IV iloprost vs. placeboDU healing: RR 1.40 (0.58, 3.35) New DU: RR 0.76 (0.44, 1.31)DU healing: 0.45 New DU: 0.33 (RR) 0.03 (SMD)
Black et al, 1998 ([21])Oral iloprost vs. placeboDU healing: RR 1.87 (0.25, 13.78)0.54
Vayssairat, 1999 ([22])Beraprost vs. placeboNew DU: SSc subgroup: RR 0.66 (0.37, 1.18) Total population: RR 0.82 (0.57, 1.18)SSc subgroup: 0.16 Total population: 0.28
Denton et al, 2000 ([23])Heparin vs. placeboDU healing: SMD 0.38 (−0.34, 1.11)0.3
Scorza et al, 2001 ([24])Cyclic IV iloprost vs. nifedipineDU improvement: RR 0.95 (0.62, 1.47)0.83
Korn et al, 2004 ([25])Oral bosentan vs. placeboDU healing: RR 0.94 (0.70, 1.26) New DU: total population: RR 0.95 (0.70, 1.30) SMD −0.42 (−0.80, −0.04) If baseline DU: RR 0.32 (0.14, 0.75) SMD −0.57 (−1.06, −0.08)DU healing: 0.68 (RR) New DU: total population 0.76 (RR) 0.03 (SMD) If baseline DU: 0.008 (RR) 0.02 (SMD)
Marasini et al, 2004 ([26])IV iloprost vs. alprostadilDU healing: RR 2.50 (0.17, 37.26) DU improvement: RR 0.95 (0.62,1.47)DU healing: 0.51 DU improvement: 0.83
Fries et al, 2005 ([27])Sildenafil vs. placeboDU healing: RR 5.00 (0.29, 86.43) DU improvement: RR 13.00 (0.89, 89.39)DU healing: 0.27 DU improvement: 0.06
Gliddon et al, 2007 ([28])Quinapril vs. placeboNew DU: RR −0.08 (−0.23, 0.06)aNot given
Abou-Raya et al, 2008 ([29])Atorvastatin vs. placeboNew DU: RR −0.85 (−1.32, −0.38) Healing DU: RR 0.30 (−0.15, 0.76)New DU: 0.0004 Healing DU: 0.20
Chung et al, 2009 ([30])Nitroglycerin topical formulation vs. placeboNew DU: RR 0.69 (0.32, 1.50)0.35
Fiori et al, 2009 ([31])Vitamin E vs. placeboMean time of DU healing: SMD −2.37 (−3.39, −1.35)< 0.00001
Herrick et al, 2009 ([32]), 2011 ([33])bSildenafil vs. placeboDU healing: RR 3.33 (0.21, 52.68)0.39
Shenoy et al, 2010 ([34])Tadalafil vs. placeboDU healing: RR 2.67 (0.80, 8.86) New DU: RR 0.20 (0.03, 1.59)DU healing: 0.11 New DU: 0.13
Correa et al, 2010 ([9])bOral NAC vs. placeboInsufficient data (nonsignificant difference)Not given
Matucci-Cerinic et al, 2011 ([35])Bosentan vs. placeboDU healing: RR 0.94 (0.65, 1.35) SMD 0.19 (−0.10, 0.47) New DU: RR 0.93 (0.76, 1.13)DU healing: 0.73 (RR) 0.20 (SMD) New DU: 0.45 (RR)
Seibold et al, 2011 ([36])bTreprostinil vs. placeboDU healing: RR 1.21 (0.84, 1.73) New DU: RR 0.95 (0.71, 1.26) Time to DU healing: SMD −0.19 (−0.51, 0.14)DU healing: 0.30 New DU: 0.72 Time to DU healing: 0.26
Bali et al, 2011 ([48])IV iloprost vs. placeboInsufficient data (nonsignificant difference)Not given
image

Figure 2. Forest plots showing the risk ratios or standardized (Std.) mean differences (SMDs; difference in number of ulcers between active and placebo) for clinical trials comparing bosentan to placebo treatment, using the Mantel-Haenszel (M-H) method (fixed-effects model) for clinical outcomes. A, Number of patients with digital ulcer (DU) healing, B, Number of patients with new DUs (total population including those with baseline ulcers), C, Reduction in mean number of new DUs per patient, D, Reduction in mean number of new DUs per patient only if already with baseline DUs. A negative SMD is a reduction in number of DUs comparing active versus placebo. Total risk ratio with 95% confidence interval (95% CI) or SMD with 95% CI is given. Heterogeneity is present if chi2 has a P value < 0.05 or I2 > 50%. Test for overall effect is statistically significant if P < 0.05.

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image

Figure 3. Forest plots showing the risk ratios for clinical trials comparing phosphodiesterase type 5 (PDE-5) inhibitors to placebo treatment, using the Mantel-Haenszel (M-H) method (fixed-effects model) for clinical outcomes. A, Number of patients with digital ulcer (DU) improvement, B, Number of patients with complete DU healing. Total risk ratio with 95% confidence interval (95% CI) is given. Heterogeneity is present if chi2 has a P value < 0.05 or I2 > 50%. Test for overall effect is statistically significant if P < 0.05. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/acr.22018/abstract.

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image

Figure 4. Forest plots showing the risk ratios or standardized (Std.) mean differences (SMDs; difference in number of ulcers between active and placebo) for clinical trials, comparing prostacyclin analogs to placebo treatment, using the Mantel-Haenszel (M-H) method (fixed-effects model) for clinical outcomes. A, number of patients with digital ulcer (DU) improvement or healing, B, number of patients with new DUs, C, number of patients with new DUs (intravenous [IV] iloprost only). A negative SMD is a reduction in number of DUs comparing active versus placebo. Total risk ratio with 95% confidence interval (95% CI) or SMD with 95% CI is given. Heterogeneity is present if chi2 has a P value < 0.05 or I2 > 50%. Test for overall effect is statistically significant if P < 0.05. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/acr.22018/abstract.

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PDE-5 inhibitors

We analyzed 3 RCTs comparing various PDE-5 inhibitors to placebo treatment on DU improvement (defined or not within each paper) and healing. The first trial compared sildenafil (50 mg) to placebo (n = 16) in a crossover trial ([27]); the second compared modified-release sildenafil (100 mg initially then increased to 200 mg once daily) versus placebo (n = 45) ([32, 33]); and the third studied tadalafil (20 mg) and placebo (n = 24) in a crossover trial ([34]) (Table 1). One publication did not provide DU data, but the data were obtained from a presented abstract. Although the 3 trials were individually underpowered to detect a statistically significant benefit, the pooled effect showed a definite benefit of PDE-5 inhibitors on the number of patients with both DU healing (RR 3.28 [95% confidence interval (95% CI) 1.32, 8.13], P = 0.01) and DU improvement (RR 4.29 [95% CI 1.73, 10.66], P = 0.002) (Figure 2). There were significant serious adverse events with PDE-5 inhibitors, and a total of 7 patients from the 3 trials withdrew as a result of potential treatment-related adverse events, including headaches, myalgias, nonpainful erections, allergic reaction, chest pain, palpitations, and facial edema ([27, 32-34]).

Endothelin receptor antagonists (ERAs).

There were 2 RCTs comparing the effect of bosentan to placebo on DU healing and prevention ([25, 35]). Both trials began with 62.5 mg of bosentan or matched placebo twice daily for 4 weeks, but the duration of the subsequent increased dosage (125 mg twice daily) was 12 weeks in the first trial (n = 122) ([25]) and 20 weeks in the second trial (n = 188) ([35]). There was no statistically significant difference in DU healing for both trials. A meta-analysis of these 2 trials showed that bosentan was successful in DU prevention, with a statistically significant reduction in the mean number of new DUs per patient (SMD −0.34 [95% CI −0.57, −0.11], P = 0.004) (Figure 3). The effect seemed similar for patients who already had baseline DUs (SMD −0.36 [95% CI −0.61, −0.11], P = 0.005) compared to the overall group, but the second trial had all patients enrolled with a baseline DU and approximately half of the first trial enrolled patients with a current DU. The reduction for new DUs in patients without a current DU was smaller (data not shown). The reduction in the number of patients with a new DU was not statistically significant. The proportion of patients experiencing at least 1 adverse event was similar in both bosentan and treatment groups ([35]). The most common significant adverse events within those treated with bosentan included abnormal liver enzymes and edema/fluid retention ([25, 35]).

Prostacyclin analogs

There were 11 RCTs with a total of 700 patients comparing iloprost to placebo or another active pharmacologic agent, but the trials were for treatment of RP, so many did not have a DU during the trials ([17-22, 24, 26, 36, 37]). The active treatment in most trials was iloprost; 4 studies compared intravenous (IV) iloprost to placebo ([17, 19, 37]). One study compared oral iloprost to placebo ([21, 36]), 2 studies compared IV iloprost to nifedipine ([18, 24]), and 1 study compared IV iloprost to alprostadil ([26]). Three other studies compared beraprost ([22]), cicaprost ([20]), and treprostinil ([36]) to placebo. None of the studies showed a statistically significant difference in DU healing or improvement individually or pooled in forest plots (Table 2 and Figure 4). Only IV iloprost prevented new DUs (SMD −0.77 [95% CI −1.46, −0.08], P = 0.03) (Table 2). There were insufficient data in 3 trials to extract DU data ([17, 20]). The 2 trials comparing IV iloprost to nifedipine ([18, 24]) could not be combined into a forest plot due to heterogeneity in clinical outcomes, as well as study duration (16 weeks [18] and 12 months [24]) (Table 1).

Calcium-channel blockers (CCBs).

In our meta-analysis, there was only 1 study comparing nifedipine to placebo ([16]) that found no statistically significant difference in the prevention of new DUs, but the data were from a trial of RP and few ulcers occurred (which means the trial is underpowered) (Table 1). There were 2 other studies ([18, 24]) that compared 2 active pharmacologic treatments against each other, namely IV iloprost versus nifedipine, but did not compare CCBs to placebo (Table 1).

Single trials

Single trials investigated DUs in patients with RP using cyclofenil ([8]), aspirin ([10]), dipyridamole ([9]), prostaglandin E2 (PGE2) analog ([11]), PGE1 ([13]), low molecular weight heparin ([23]), prazosin ([15]), ketanserin (2 trials, but only 1 [12] had data to extract on both active and placebo groups for DUs [[12, 38]]), topical vitamin E ([31]), a topical nitroglycerin formulation ([30]), quinapril ([28]), atorvastatin ([29]), oral N-acetylcysteine ([9]), and topical dimethyl sulfoxide ([14]) were all compared to placebo. There were 2 trials, vitamin E ([31]) and atorvastatin ([29]), that showed statistically significant differences in clinical outcomes in comparison to placebo. The mean time to DU healing with vitamin E gel was significantly less than placebo (P < 0.00001) (Table 2). Although there were no statistically significant differences in DU healing, atorvastatin treatment did prevent new DUs in comparison to placebo, with mean ± SD 1.6 ± 0.9 DUs in atorvastatin versus 2.5 ± 1.3 (P < 0.0004) in 56 treated with active and 28 treated with placebo, with an SMD (in fewer new DUs) of 0.85 (95% CI [of reduced number of DUs] 1.32, 0.38) favoring atorvastatin. Funnel plots did not suggest publication bias (see Supplementary Figure 1, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22018/abstract).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

As DU complications in SSc are common ([2]), several treatments for healing and prevention of both RP and DUs have been explored, including CCBs, antiplatelet and anticoagulant therapies, ERAs, PDE-5 inhibitors, and statins ([39]). This meta-analysis of RCTs summarizes the treatment effect of various pharmacologic agents in the healing and prevention of DUs in RP.

CCBs, which have a direct effect on vascular smooth muscles and inhibit platelet activation, are considered first-line treatment for RP in SSc patients ([3]). They have been tested in several small trials with a significant clinical improvement in the frequency and severity of RP attacks. However, data were insufficient to support a role in reducing new DUs ([40]), given the small sample size in a single study, so larger RCTs are required to estimate the role of CCBs on DUs. Years ago, a trial was performed comparing nifedipine to placebo in RP, including SSc patients, which helped to provide the standard of care in RP treatment with nifedipine; but there was not extractable data on digital ulcers in this landmark trial ([41]). The EULAR Scleroderma Trial and Research SSc guidelines suggest that nifedipine be used as a first-line treatment in RP for SSc patients ([3]) and experts have suggested that nifedipine be used as initial treatment of DUs ([42]).

There was a strong statistically significant difference (P < 0.002) in the healing or improvement of DUs with PDE-5 inhibitors compared to placebo in 3 RCTs ([27, 32-34]). These are small studies where RP was the primary outcome, so results can only be interpreted with caution. PDE-5 inhibitors are approved for pulmonary arterial hypertension (PAH) and modulate cGMP ([43]). Randomization was not stratified according to baseline ulcer presence or absence, which is a potential bias. There is a completed registered trial of sildenafil in DUs, but the results were not available at the time of the search for this meta-analysis. The EULAR Scleroderma Trial and Research guidelines do not include PDE-5 inhibitors for DU treatment ([3]), but PDE-5 inhibitors were frequently chosen by SSc experts in the treatment and prevention of DUs after failure of CCBs ([42]).

Bosentan, an endothelin receptor antagonist, reduces the number of new DUs in SSc patients, especially if there is a baseline DU at trial entry. Elevated levels of endothelin have been found in the serum of patients with SSc and may be a marker of severe vascular injury ([44]). Bosentan has relatively good tolerability and is given orally ([45]). Previous smaller, uncontrolled studies suggested some benefit in the number of healed DUs ([46]), but the 2 RCTs did not. There is no effect on healing of DUs. A factor-limiting use of bosentan for DU prevention is access, as it is costly and not approved in North America for this indication, although it is approved in Europe.

Iloprost, a prostacyclin analog given intravenously, is a potent vasodilator with platelet inhibitor properties, as well as efficacy in severe RP in SSc ([37]). The standard administration of IV iloprost is for 6-hour infusions of 0.5–2 ng/kg/minute daily for 5 days ([43, 47, 48]). Our meta-analysis also examined oral prostacyclins (including oral iloprost, beraprost, cicaprost, and treprostinil; the latter had not been published at time of search). Only IV iloprost was found to have a statistically significant effect in preventing new DUs ([19]), but many of the trials were likely underpowered for DUs.

Overall, there are many limitations to this meta-analysis. Given the small sample size in many studies, small treatment effects, and inclusion of many RP trials that studied DU less systematically, a large trial (yet to be performed) or a missed trial could have changed the results. There could also be publication bias where studies with positive findings are more likely to be published (however, the funnel plots did not demonstrate publication bias). The definitions of DU healing, partial healing, and number of DUs (in total, per person, or number of people with DUs) and variable length of the trials all could affect results. For instance, a short trial may have had less opportunity for healing, whereas a longer trial could have more healing and new ulcers. Examining time to healing and time to ulcer development may be better outcomes in future trials. Additionally, the small number of studies for each drug class and heterogeneity of the studies limit conclusions.

Furthermore, we had to exclude 10 RCTs: 8 did not include DU subanalyses and 2 compared the same pharmacologic agent at different doses. Of the 31 RCTs meeting inclusion criteria, 5 had insufficient data to analyze. Most drug classes were only represented by a single trial and were unable to be pooled. This may contribute to the lack of statistical significance in clinical outcomes for DU healing or prevention with various treatments ([8-16, 23, 26, 28, 30]). Although topical vitamin E ([31]) and atorvastatin ([29]) showed statistically significant benefits, each had a single, small RCT, so results may not be reproducible or generalizable. The 2 trials comparing IV iloprost to oral nifedipine could not be combined because of different definitions for DU healing: Rademaker et al ([18]) used the change in mean number of DUs per patient, whereas Scorza et al ([24]) used the number of people with DU improvement. All results were also re-analyzed using a fixed-effects model that yielded similar results (data not shown).

It could be beneficial to examine the role of combination therapies in DUs, such as sildenafil and bosentan, which have been shown to potentially be of benefit in PAH, and in a case report to have had a possible synergistic effect ([49]). DU end points are not standardized and are somewhat subjective (i.e., when to classify an ulcer as partially healed versus fully healed; the depth and size are difficult to measure). The data may be helpful in designing future (better) studies and informing clinicians about both the lack of data and positive, but potentially flawed, results. For instance, PDE-5 inhibitors may be important in SSc DU treatment, and statins may be a class worth exploring further for the prevention of SSc-associated DUs.

In summary, our meta-analysis of randomized trials for the pharmacologic management of DUs in SSc patients (mostly subanalyes of RP trials) identified 31 RCTs, with 10 RCTs whose outcomes could be combined in forest plots. In comparison to placebo, statistically significant improvements in DU healing and/or improvement have been shown with PDE-5 inhibitors and vitamin E, whereas bosentan and IV iloprost prevented new DUs. There was a great degree of heterogeneity among the trials, and several were underpowered, as DU outcomes were not part of the primary analyses within most trials. Standardized outcome measures and larger, multicenter, randomized trials of high quality may be helpful in defining healing and prevention strategies for DUs in SSc with several potentially effective classes of drugs.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Pope had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Tingey, Shu, Smuczek, Pope.

Acquisition of data. Tingey, Shu, Smuczek, Pope.

Analysis and interpretation of data. Tingey, Shu, Smuczek, Pope.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information
  • 1
    Pope JE.The diagnosis and treatment of Raynaud's phenomenon: a practical approach.Drugs2007;67:51725.
  • 2
    Steen V, Denton CP, Pope JE, Matucci-Cerinic M.Digital ulcers: overt vascular disease in systemic sclerosis.Rheumatology (Oxford)2009;48 Suppl 3:iii1924.
  • 3
    Kowal-Bielecka O, Landewe R, Avouac J, Chwiesko S, Miniati I, Czirjak L, et al.EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research Group (EUSTAR).Ann Rheum Dis2009;68:6208.
  • 4
    Jadad A, Moore R, Carroll D, Jenkinson C, Reynolds D, Gavaghan D, et al.Assessing the quality of reports of randomized clinical trials: is blinding necessary?Control Clin Trials1996;17:112.
  • 5
    Steen VD, Medsger TA Jr.The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time.Arthritis Rheum1997;40:198491.
  • 6
    DerSimonian R, Laird N.Meta-analysis in clinical trials.Control Clin Trials1986;7:17788.
  • 7
    Higgins JP, Thompson SG.Quantifying heterogeneity in a meta-analysis.Stat Med2002;21:153958.
  • 8
    Blom-Bulow B, Oberg K, Wollheim FA, Persson B, Jonson B, Malmberg P, et al.Cyclofenil versus placebo in progressive systemic sclerosis: a one-year double-blind crossover study of 27 patients.Acta Med Scand1981;210:41928.
  • 9
    Correa MJ, Mariz HA, Andrade LE, Kayser C.Oral n-acetylcysteine in the treatment of Raynaud's phenomenon secondary to systemic sclerosis: a randomized, double-blind, placebo-controlled clinical trial [abstract].Arthritis Rheum2010;62 Suppl:S242.
  • 10
    Beckett VL, Conn DL, Fuster V, Osmundson PJ, Strong CG, Chao EY, et al.Trial of platelet-inhibiting drug in scleroderma: double-blind study with dipyridamole and aspirin.Arthritis Rheum1984;27:113743.
  • 11
    Belch JJ, Madhok R, Shaw B, Leiberman P, Sturrock RD, Forbes CD.Double-blind trial of cl115,347, a transdermally absorbed prostaglandin e2 analogue, in treatment of Raynaud's phenomenon.Lancet1985;1:11803.
  • 12
    Lukac J, Rovensky J, Tauchmannova H, Zitnan D.Effect of ketanserin on Raynaud's phenomenon in progressive systemic sclerosis: a double-blind trial.Drugs Exp Clin Res1985;11:65963.
  • 13
    Mohrland JS, Porter JM, Smith EA, Belch J, Simms MH.A multiclinic, placebo-controlled, double-blind study of prostaglandin e1 in Raynaud's syndrome.Ann Rheum Dis1985;44:75460.
  • 14
    Williams HJ, Furst DE, Dahl SL, Steen VD, Marks C, Alpert EJ, et al.Double-blind, multicenter controlled trial comparing topical dimethyl sulfoxide and normal saline for treatment of hand ulcers in patients with systemic sclerosis.Arthritis Rheum1985;28:30814.
  • 15
    Wollersheim H, Thien T, Fennis J, van Elteren P, van 't Laar A.Double-blind, placebo-controlled study of prazosin in Raynaud's phenomenon.Clin Pharmacol Ther1986;40:21925.
  • 16
    Meyrick Thomas RH, Rademaker M, Grimes SM, MacKay A, Kovacs IB, Cook ED, et al.Nifedipine in the treatment of Raynaud's phenomenon in patients with systemic sclerosis.Br J Dermatol1987;117:23741.
  • 17
    McHugh NJ, Csuka M, Watson H, Belcher G, Amadi A, Ring EF, et al.Infusion of iloprost, a prostacyclin analogue, for treatment of Raynaud's phenomenon in systemic sclerosis.Ann Rheum Dis1988;47:437.
  • 18
    Rademaker M, Cooke ED, Almond NE, Beacham JA, Smith RE, Mant TG, et al.Comparison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis: a double blind randomised study.BMJ1989;298:5614.
  • 19
    Wigley FM, Seibold JR, Wise RA, McCloskey DA, Dole WP.Intravenous iloprost treatment of Raynaud's phenomenon and ischemic ulcers secondary to systemic sclerosis.J Rheumatol1992;19:140714.
  • 20
    Lau CS, Belch JJ, Madhok R, Cappell H, Herrick A, Jayson M, et al.A randomised, double-blind study of cicaprost, an oral prostacyclin analogue, in the treatment of Raynaud's phenomenon secondary to systemic sclerosis.Clin Exp Rheumatol1993;11:3540.
  • 21
    Black CM, Halkier-Sorensen L, Belch JJ, Ullman S, Madhok R, Smit AJ, et al.Oral iloprost in Raynaud's phenomenon secondary to systemic sclerosis: a multicentre, placebo-controlled, dose-comparison study.Br J Rheumatol1998;37:95260.
  • 22
    Vayssairat M.Preventive effect of an oral prostacyclin analog, beraprost sodium, on digital necrosis in systemic sclerosis: French microcirculation society multicenter group for the study of vascular acrosyndromes.J Rheumatol1999;26:21738.
  • 23
    Denton CP, Howell K, Stratton RJ, Black CM.Long-term low molecular weight heparin therapy for severe Raynaud's phenomenon: a pilot study.Clin Exp Rheumatol2000;18:499502.
  • 24
    Scorza R, Caronni M, Mascagni B, Berruti V, Bazzi S, Micallef E, et al.Effects of long-term cyclic iloprost therapy in systemic sclerosis with Raynaud's phenomenon: a randomized, controlled study.Clin Exp Rheumatol2001;19:5038.
  • 25
    Korn JH, Mayes M, Matucci Cerinic M, Rainisio M, Pope J, Hachulla E, et al.Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist.Arthritis Rheum2004;50:398593.
  • 26
    Marasini B, Massarotti M, Bottasso B, Coppola R, Papa ND, Maglione W, et al.Comparison between iloprost and alprostadil in the treatment of Raynaud's phenomenon.Scand J Rheumatol2004;33:2536.
  • 27
    Fries R, Shariat K, von Wilmowsky H, Bohm M.Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy.Circulation2005;112:29805.
  • 28
    Gliddon AE, Dore CJ, Black CM, McHugh N, Moots R, Denton CP, et al.Prevention of vascular damage in scleroderma and autoimmune Raynaud's phenomenon: a multicenter, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril.Arthritis Rheum2007;56:383746.
  • 29
    Abou-Raya A, Abou-Raya S, Helmii M.Statins: potentially useful in therapy of systemic sclerosis-related Raynaud's phenomenon and digital ulcers.J Rheumatol2008;35:18018.
  • 30
    Chung L, Shapiro L, Fiorentino D, Baron M, Shanahan J, Sule S, et al.MQX-503, a novel formulation of nitroglycerin, improves the severity of Raynaud's phenomenon: a randomized, controlled trial.Arthritis Rheum2009;60:8707.
  • 31
    Fiori G, Galluccio F, Braschi F, Amanzi L, Miniati I, Conforti ML, et al.Vitamin E gel reduces time of healing of digital ulcers in systemic sclerosis.Clin Exp Rheumatol2009;27:514.
  • 32
    Herrick A, ven den Hoogen F, Gabrielli A, Tamimi N, Reid C, O'Connell D, et al.Modified-release sildenafil reduces Raynaud's attack frequency in systemic sclerosis [abstract].Arthritis Rheum2009;60 Suppl:S174.
  • 33
    Herrick AL, van den Hoogen F, Gabrielli A, Tamimi N, Reid C, O'Connell D, et al.Modified-release sildenafil reduces Raynaud's phenomenon attack frequency in limited cutaneous systemic sclerosis.Arthritis Rheum2011;63:77582.
  • 34
    Shenoy PD, Kumar S, Jha LK, Choudhary SK, Singh U, Misra R, et al.Efficacy of tadalafil in secondary Raynaud's phenomenon resistant to vasodilator therapy: a double-blind randomized cross-over trial.Rheumatology (Oxford)2010;49:24208.
  • 35
    Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Hsu VM, Carpentier P, et al.Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial.Ann Rheum Dis2011;70:328.
  • 36
    Seibold JR, Wigley FM, Schiopu E, Denton CD, Silver RM, Steen VD, et al.Digital ischemic ulcers in scleroderma treated with oral treprostinil diethanolamine: a randomized, double-blind, placebo-controlled, multicenter study [abstract].Arthritis Rheum2011;63 Suppl:S968.
  • 37
    Wigley FM, Wise RA, Seibold JR, McCloskey DA, Kujala G, Medsger TA Jr, et al.Intravenous iloprost infusion in patients with Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study.Ann Intern Med1994;120:199206.
  • 38
    Roald OK, Seem E.Treatment of Raynaud's phenomenon with ketanserin in patients with connective tissue disorders.Br Med J1984;289:5779.
  • 39
    Galluccio F, Matucci-Cerinic M.Two faces of the same coin: Raynaud's phenomenon and digital ulcers in systemic sclerosis.Autoimmun Rev2011;10:2413.
  • 40
    Thompson AE, Shea B, Welch V, Fenlon D, Pope JE.Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis.Arthritis Rheum2001;44:18417.
  • 41
    Rodeheffer RJ, Rommer JA, Wigley F, Smith CR.Controlled double-blind trial of nifedipine in the treatment of Raynaud's phenomenon.N Engl J Med1983;308:8803.
  • 42
    Walker K, Pope J.Treatment of systemic sclerosis (SSc) complications: what to use when first-line treatment fails. A consensus of SSc experts.Semin Arthritis Rheum2012;42:4255.
  • 43
    Botzoris V, Drosos AA.Management of Raynaud's phenomenon and digital ulcers in systemic sclerosis.Joint Bone Spine2011;78:3416.
  • 44
    Biondi ML, Marasini B, Bassani C, Agastoni A.Increased plasma endothelin levels in patients with Raynaud's phenomenon.N Engl J Med1991;324:113940.
  • 45
    Dhillon S.Bosentan: a review of its use in the management of digital ulcers associated with systemic sclerosis.Drugs2009;69:200524.
  • 46
    Garcia de la Pena-Lefebvre P, Rodriguez Rubio S, Valero Exposito M, Carmona L, Gamir Gamir ML, Beltran Gutierrez J, et al.Long-term experience of bosentan for treating ulcers and healed ulcers in systemic sclerosis patients.Rheumatology (Oxford)2008;47:4646.
  • 47
    Fishman AP.Pulmonary hypertension: beyond vasodilator therapy.N Engl J Med1998;338:3212.
  • 48
    Bali SG, Aberer F, Kraenke B, Aberer E.Discontinuing long-term iloprost treatment for Raynaud's phenomenon and systemic sclerosis: a single center, randomized, placebo-controlled, double-blind study.Acta Derm Venereol2011;20:1321.
  • 49
    Ambach A, Seo W, Bonnekoh B, Gollnick H.Low-dose combination therapy of severe digital ulcers in diffuse progressive systemic sclerosis with the endothelin-1 receptor antagonist bosentan and the phosphodiesterase v inhibitor sildenafil.J German Soc Dermatol2009;7:88891.

Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
ACR_22018_sm_SupplFig1.doc27KSupplementary Figure 1. Funnel plots of comparisons: A) bosentan versus placebo in reduction in mean number of new digital ulcer (DU) per patient; B) phosphodiesterase type 5 (PDE5) inhibitor versus placebo in complete DU healing; C) prostacyclin versus placebo in number of patients with new DU; D) prostacyclin versus placebo in number of patients with new DU. SMD Standard Mean Difference, RR is Relative Risk, SE is Standard Mean Difference or log of Relative Risk No publication bias was found when examining the Funnel plots.

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