Pulmonary Function Tests in Idiopathic Inflammatory Myopathy: Association With Clinical Parameters in Children

Authors


  • Presented in part at the 75th Annual Scientific Meeting of the American College of Rheumatology, Chicago, IL, November 2011.

225 East Chicago Avenue, Box #43, Chicago, IL 60611. E-mail: aprestridge@luriechildrens.org

Abstract

Objective

To determine the association of decreased lung function in children with idiopathic inflammatory myopathies (IIMs) with specific clinical parameters.

Methods

This study of 38 children ages 6–23 years diagnosed with definite/probable IIM evaluated the association of myositis-specific/-associated antibodies (MSAs/MAAs), duration of untreated disease at diagnosis, Disease Activity Score for muscle (DAS-M), muscle-derived enzymes (aldolase, lactate dehydrogenase [LDH], aspartate transaminase, and creatine phosphokinase [CPK]), neopterin and von Willebrand factor antigen, and the Childhood Myositis Assessment Scale (CMAS) scores with data from pulmonary function testing (PFT).

Results

Impaired PFTs were defined as total lung capacity (TLC) or diffusing capacity for carbon monoxide (DLCO) of <80% predicted. The PFTs documented that 37% of the children (14 of 38) had either decreased TLC or decreased DLCO; 5% (2 of 38) had both. Children with decreased TLC alone (7 [18%] of 38) were older both at the time of PFT and diagnosis, had anti–Jo-1 and anti–Scl-70 antibody, and had elevated levels of CPK and neopterin. Children with decreased DLCO alone (5 [13%] of 38) had a shorter duration of untreated disease at diagnosis, had higher DAS-M and total DAS, were positive for anti-Ro and anti–PL-12, had increased LDH, and had elevated levels of neopterin and aldolase, with low CMAS scores for items 1, 3, 10, 11, and 14.

Conclusion

Assessment of PFTs in children with IIMs should be considered, since more than one-third of patients were found to be impaired. The presence of MSAs/MAAs, an elevated serum neopterin level (mean ± SD 12.4 ± 9.6 nmoles/liter, normal value <10.5), older age at diagnosis, and shorter duration of untreated disease at diagnosis suggest the presence of potential lung pathology.

INTRODUCTION

Reports of pulmonary involvement in children with idiopathic inflammatory myopathies (IIMs) range from 18–50% ([1-3]). The IIMs are a rare group of systemic connective tissue disorders characterized by immune-mediated muscle damage ([4]). Myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) are often obtained to aid in the diagnosis and classification of patients with IIMs ([5-7]). Patients with many MSAs/MAAs have specific clinical features that contribute to the prognosis of pulmonary dysfunction. For example, in adults with IIMs, the presence of anti–Jo-1 is closely associated with pulmonary involvement manifesting as interstitial lung disease (ILD).

Adults with IIMs have been reported to have pulmonary damage as often as 46% of the time ([1]). The damage includes respiratory muscle weakness leading to respiratory failure, aspiration pneumonia, infections, ILD, and hypersensitivity pneumonitis secondary to medications ([8, 9]). Pulmonary involvement is present in many of the pediatric forms of IIM, including juvenile dermatomyositis (DM) ([9]). Although data are available for adults, the relationship of pulmonary dysfunction to clinical parameters commonly obtained for case management has not been evaluated in children. Furthermore, there are no guidelines for specific testing of children with IIMs for possible pulmonary abnormalities. Pulmonary function tests (PFTs) are the gold standard for screening patients suspected of pulmonary abnormalities. Recommendations for routine screening with PFTs are available for adult patients with IIMs ([2, 10, 11]), but it is not clear that these guidelines also apply to children with IIMs.

The most common finding on pulmonary testing of patients with IIMs is decreased total lung capacity (TLC) and/or abnormal diffusing capacity of the lung to carbon monoxide (DLCO) ([8]). Decreased TLC can be secondary to muscle weakness or occur as part of the spectrum of ILD ([12]). Furthermore, patients with decreased DLCO are at increased risk of ILD ([13]).

Early definition of the pulmonary problems is important because there is evidence that early aggressive treatment of ILD can lead to improved outcomes ([10]). Adults prospectively followed with PFTs had normalization of TLC and DLCO over time in one-third of patients after treatment ([14]). Similarly, resolution of PFT and chest high-resolution computed tomography (HRCT) abnormalities after aggressive therapy has been described in a pediatric patient with IIM and anti–PL-12 ([15]). Based on this evidence, it is imperative to identify those children at risk for pulmonary damage, most specifically ILD, early in their disease course. The purpose of this report was to review our experience with PFTs in children with IIMs and to identify clinical parameters that might alert the clinician that pulmonary testing was indicated.

Box 1. Significance & Innovations

  • Pulmonary function abnormalities are frequent in children with idiopathic inflammatory myopathies.
  • Myositis-specific/-associated antibodies, the Childhood Myositis Assessment Scale parameters, and serologic tests, such as neopterin, may help identify patients at increased risk of pulmonary complications.
  • In as much as early treatment can reverse pulmonary abnormalities, screening of children with idiopathic inflammatory myopathies with these features should be considered.

PATIENTS AND METHODS

Patient population

After obtaining approval from the Ann & Robert H. Lurie Children's Hospital of Chicago Institutional Review Board, a retrospective cross-sectional study of children with IIMs ages 6–23 years who had PFTs between 2008 and 2011 at the Ann & Robert H. Lurie Children's Hospital was performed. At the time of the first PFT, other clinical data, including muscle enzyme levels, MSAs/MAAs, and the Childhood Myositis Assessment Scale (CMAS) scoring, were obtained.

Patient testing

Disease Activity Scores (DAS).

For all time points, the DAS for involvement of skin (DAS-S) and muscle performance (DAS-M) were assessed by a single physician (LMP). Scores range from 0–9 for the DAS-S and from 0–11 for the DAS-M. Scores of 0 indicate absence of disease activity and scores >0 are considered abnormal ([16]). The DAS-M was confirmed by an independent physical therapy evaluation using the CMAS ([17]).

CMAS

The CMAS was administered using an examining table, stopwatch, step stool, chair, and pen. The 14 items were tested one after the other in the order listed on the CMAS scoring sheet. Scoring was completed based on the subject's ability to meet defined goals. This assessment was performed by a team of trained physical therapists in the Juvenile Myositis Clinic at each visit ([18]).

Laboratory testing

Serologic testing for muscle-derived enzymes, creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aldolase, aspartate transaminase (AST), and von Willebrand factor antigen was performed in the diagnostic laboratory using standard methodology ([19]). Neopterin testing was performed as described previously ([20]). Testing for MSAs/MAAs was performed in the laboratory of the Oklahoma Research Foundation using immunodiffusion and immunoprecipitation techniques ([5]).

PFT

PFTs were performed as outlined in the guidelines set forth by the American Thoracic Society and the European Respiratory Society ([21-23]).

Statistical analysis

Children who had abnormal PFTs were compared to those with normal PFTs. Comparisons were made between groups using Wilcoxon's rank sum test for continuous variables and the chi-square test for dichotomous variables.

RESULTS

Patient characteristics

Thirty-eight children with IIMs were included in this study. Their demographic characteristics are shown in Table 1. None of the children had amyopathic disease. The mean age at diagnosis for all patients was 9.76 years (range 2.91–19.74 years). The mean duration of untreated disease for all patients was 12.96 months (range 0–111.01 months). Of the 38 patients, 61% (n = 23) had definite/probable juvenile DM ([24]), 8% (n = 3) had juvenile polymyositis (PM), and 32% (n = 12) had overlap syndrome.

Table 1. Demographics of children with idiopathic inflammatory myopathies*
 DM (n = 23)PM (n = 3)Overlap (n = 12)Total (n = 38)
  1. DM = dermatomyositis; PM = polymyositis.
Age at diagnosis, mean ± SD years8.5 ± 3.815.5 ± 3.210.8 ± 4.39.8 ± 4.3
Male/female sex, no.4/191/24/89/29
Race, no.    
White182828
African American1113
Hispanic3025
Other1012

Laboratory abnormalities in children with IIMs

A total of 36 patients had MSA/MAA testing performed as part of routine clinical care. MSAs/MAAs were found to be positive or indeterminate in 56% of the children (n = 20), with some patients having more than one positive MSA/MAA (Table 2). Clinical laboratory evaluation was performed as part of routine care. Laboratory testing was performed at the same time as the PFT. Elevated values for CPK occurred in 38% of encounters, while an increase in aldolase, AST, and LDH was present in 26%, 13%, and 22%, respectively. Neopterin, which indicates T lymphocyte–dependent macrophage activation, was increased in 30% of the encounters and von Willebrand factor antigen, an indicator of damage to endothelial cells, was elevated in 19%. The CMAS was performed at the time of the PFTs, yielding a mean score of 43 points of muscle strength/function (range 5–52).

Table 2. Distribution of myositis-specific/-associated antibodies in children with idiopathic inflammatory myopathies*
 Juvenile DMJuvenile PMOverlapTotal, no./ total (%)
  1. DM = dermatomyositis; PM = polymyositis.
Anti–Jo-11102/36 (5.5)
Anti-Ku1001/36 (2.8)
Anti–Mi-23025/36 (13.8)
Anti–U1 RNP0156/36 (16.6)
Anti–U2 RNP0033/36 (8.3)
Anti-Ro4048/36 (22.2)
Anti–PL-120011/36 (2.8)
Anti-p155/1405027/34 (20.6)
Anti–PM-Scl0055/36 (13.8)
Anti–Scl-700022/36 (5.5)

PFTs

Of the 38 patients, abnormal PFTs (defined as TLC or DLCO corrected for alveolar volume [DLCO/VA] <80%) were present in 37% (n = 14); 24% (n = 9) had abnormal TLC and 18% (n = 7) had abnormal DLCO/VA. Only 5% (n = 2) had both abnormal TLC and abnormal DLCO/VA. PFTs were performed at the discretion of the treating rheumatologist based on changes in clinical status. All patients were receiving treatment for their IIM at the time of the PFT.

Abnormal TLC

Table 3 shows clinical data comparing patients with and without impaired TLC. Patients with decreased TLC were diagnosed at an older age (P = 0.008) and were also older at the time of their PFTs (P = 0.012). There was no difference in the number of nailfold end row capillary loops between the children with and without normal TLC. Children with decreased TLC had higher CPK (P = 0.019) and neopterin (P = 0.028) values at the time of their PFT. Children with MSAs/MAAs positive for anti–Jo-1 (P = 0.015) and anti–Scl-70 (P = 0.015) were more likely to have decreased TLC.

Table 3. Comparison of children with idiopathic inflammatory myopathies with or without decreased TLC*
 Normal TLC (n =29)Abnormal TLC (n =9)P
  1. Values are the mean ± SD unless otherwise indicated. TLC = total lung capacity; PFT = pulmonary function testing; DUD = duration of untreated disease at diagnosis; DAS = Disease Activity Score; ERL = end row loop; CPK = creatine phosphokinase; AST = aspartate transaminase; LDH = lactate dehydrogenase; vWF:Ag = von Willebrand factor antigen; NK = absolute CD3–CD16CD56+ natural killer cells; MSAs = myositis-specific autoantibodies; MAAs = myositis-associated autoantibodies; CMAS = Childhood Myositis Assessment Scale.
  2. aSignificant at P < 0.05.
Age at diagnosis, years8.57 ± 3.4213.57 ± 4.900.008a
Age at time of PFT, years12.29 ± 4.5916.56 ±3.720.012a
DUD, months14.98 ± 23.485.67 ± 5.890.28
DAS skin5.03 ± 2.153.00 ± 2.920.10
DAS muscle2.36 ± 2.403.88 ± 3.080.24
DAS total7.40 ± 3.787.25 ± 4.190.91
ERL, mm5.32 ± 1.625.26 ± 1.060.63
Laboratory tests   
CPK, IU/liter282.1 ± 755.92,489.8 ± 4,525.00.019a
CPK increased, no./total (%)10/29 (34)4/8 (50)0.42
Aldolase, units/liter8.36 ± 6.7129.47 ± 53.320.055
Aldolase increased, no./total (%)6/25 (24)3/7 (43)0.34
AST, units/liter37.4 ± 25.9133.8 ± 166.70.21
AST increased, no./total (%)2/26 (7.6)2/6 (33)0.12
LDH, units/liter237.6 ± 100.9443.7 ± 455.00.15
LDH increased, no./total (%)5/29 (17)3/8 (38)0.23
Neopterin, nmoles/liter7.64 ± 3.3014.6 ± 10.80.028a
Neopterin increased, no./total (%)7/28 (25)4/8 (50)0.18
vWF:Ag, %138.7 ± 62.9217.2 ± 125.50.10
vWF:Ag increased, no./total (%)4/28 (14)3/8 (38)0.16
NK antibodies,/mm3186.7 ± 99.6283.0 ± 217.60.27
MSAs/MAAs, no./total (%)   
Positive anti–Jo-10/27 (0)2/9 (22)0.015a
Indeterminate anti-Ku1/27 (3.7)0/9 (0)0.44
Positive anti–Mi-25/27 (18)0/9 (0)0.08
Positive anti–U1 RNP4/27 (15)2/9 (22)0.61
Positive anti–U2 RNP2/27 (7.4)1/9 (11)0.73
Positive anti-Ro6/26 (23)1/9 (11)0.41
Positive anti–PL-120/27 (0)1/9 (11)0.09
Positive anti–PM-Scl2/27 (7.4)3/9 (33)0.07
Positive anti–Scl-700/27 (0)2/9 (22)0.015a
CMAS   
CMAS item 13.41 ± 1.282.85 ± 2.030.51
CMAS item 22.00 ± 0.001.85 ± 0.370.076
CMAS item 34.08 ± 1.173.14 ± 1.860.22
CMAS item 42.91 ± 0.282.57 ± 1.130.61
CMAS item 53.75 ± 2.412.71 ± 2.490.38
CMAS item 62.87 ± 0.442.42 ± 1.130.16
CMAS item 72.95 ± 0.202.71 ± 0.750.34
CMAS item 84.08 ± 0.403.42 ± 1.390.27
CMAS item 92.69 ± 0.761.85 ± 1.460.11
CMAS item 103.82 ± 0.832.85 ± 1.950.07
CMAS item 113.21 ± 1.272.42 ± 1.980.31
CMAS item 123.78 ± 0.423.14 ± 1.460.22
CMAS item 132.95 ± 0.202.57 ± 1.130.36
CMAS item 142.95 ± 0.202.28 ± 1.250.059
CMAS total44.7 ± 7.3836.8 ± 17.80.49

Abnormal DLCO.

Table 4 compares the clinical variable in children with IIMs with and without decreased DLCO. Patients who had abnormal DLCO were not significantly different in age at diagnosis or age at time of PFT; however, they did have a significantly shorter duration of untreated disease at diagnosis (P = 0.033). The total DAS did differ (P = 0.039), with the DAS-M (P = 0.022) in children with decreased DLCO having a higher score, indicating weakness. There was no difference between the patients with respect to the number of nailfold end row loops/mm. Laboratory testing was significantly higher with respect to both aldolase (P = 0.006) and percentage of those with elevated aldolase (P = 0.007), LDH (P = 0.013), and percentage of patients with an elevated neopterin level (P = 0.043) in children with decreased DLCO. The CMAS scores were significantly lower in patients with decreased DLCO for head lift (CMAS item 1; P = 0.019), straight leg lift (CMAS item 3; P = 0.034), all fours maneuver (CMAS item 10; P = 0.04), floor rise (CMAS item 11; P = 0.035), and pick-up (CMAS item 14; P = 0.05). Patients with MSAs/MAAs positive for anti-Ro (P = 0.029) and anti–PL-12 (P = 0.042) were more likely to have abnormal DLCO.

Table 4. Comparison of children with idiopathic inflammatory myopathies with or without decreased DLCO*
 Normal DLCO (n = 31)Abnormal DLCO (n = 7)P
  1. Values are the mean ± SD unless otherwise indicated. DLCO = diffusing capacity for carbon monoxide; PFT = pulmonary function testing; DUD = duration of untreated disease at diagnosis; DAS = Disease Activity Score; ERL = end row loop; CPK = creatine phosphokinase; AST = aspartate transaminase; LDH = lactate dehydrogenase; vWF:Ag = von Willebrand factor antigen; NK = absolute CD3–CD16CD56+ natural killer cells; MSAs = myositis-specific autoantibodies; MAAs = myositis-associated autoantibodies; CMAS = Childhood Myositis Assessment Scale.
  2. aSignificant at P < 0.05.
Age at diagnosis, years9.77 ± 4.609.68 ± 3.030.70
Age at time of PFT, years13.84 ± 4.9210.93 ± 2.910.16
DUD, months13.71 ± 21.578.63 ± 19.200.033a
DAS skin4.39 ± 2.645.29 ± 1.380.60
DAS weakness2.13 ± 2.235.07 ± 2.860.022a
DAS total6.67 ± 3.5310.36 ± 3.770.039a
ERL, mm5.41 ± 1.354.88 ± 2.090.64
Laboratory tests   
CPK, IU/liter481.4 ± 1,271.02,196.1 ± 5,032.70.88
CPK increased, no./total (%)11/31 (35)3/6 (50)0.50
Aldolase, units/liter8.34 ± 6.7238.02 ± 62.620.006a
Aldolase increased, no./total (%)5/27 (19)4/5 (80)0.007a
AST, units/liter51.1 ± 79.574.3 ± 89.70.10
AST increased, no./total (%)3/26 (11)1/6 (17)0.74
LDH, units/liter232.5 ± 104.1494.8 ± 464.80.013a
LDH increased, no./total (%)5/30 (17)3/7 (43)0.15
Neopterin, nmoles/liter8.61 ± 5.5612.11 ± 9.690.36
Neopterin increased, no./total (%)7/30 (23)4/6 (67)0.043a
vWF:Ag, %150.0 ± 76.2187.3 ± 126.40.71
vWF:Ag increased, no./total (%)5/30 (17)2/6 (33)0.37
NK antibodies,/mm3192.4 ± 106.2285.6 ± 235.40.36
MSAs/MAAs, no./total (%)   
Positive anti–Jo-12/31 (6.4)0/5 (0)0.43
Indeterminate anti-Ku1/31 (3.2)0/5 (0)0.58
Positive anti–Mi-25/31 (16)0/5 (0)0.20
Positive anti–U1 RNP5/31 (16)1/5 (20)0.83
Positive anti–U2 RNP2/31 (6.4)1/5 (20)0.36
Positive anti-Ro4/30 (13)3/5 (60)0.029a
Positive anti–PL-120/31 (0)1/5 (20)0.042a
Positive anti–PM-Scl4/31 (13)1/5 (20)0.68
Positive anti–Scl-701/31 (3.2)1/5 (20)0.20
CMAS   
CMAS item 13.60 ± 1.352.00 ± 1.260.019a
CMAS item 21.96 ± 0.202.00 ± 0.000.68
CMAS item 34.08 ± 1.353.00 ± 1.260.03a
CMAS item 42.84 ± 0.622.83 ± 0.400.59
CMAS item 53.92 ± 2.191.83 ± 2.850.07
CMAS item 62.84 ± 0.622.50 ± 0.830.12
CMAS item 72.92 ± 0.402.83 ± 0.400.31
CMAS item 84.00 ± 0.763.66 ± 0.810.27
CMAS item 92.70 ± 0.751.66 ± 1.500.058
CMAS item 103.83 ± 0.812.66 ± 2.060.04a
CMAS item 113.33 ± 1.231.83 ± 1.830.035a
CMAS item 123.62 ± 0.873.66 ± 0.510.76
CMAS item 132.87 ± 0.612.83 ± 0.400.33
CMAS item 142.87 ± 0.612.50 ± 0.830.05a
CMAS total44.6 ± 10.035.8 ± 12.00.063

DISCUSSION

IIM affects 2.5–5 juvenile patients per one million children per year ([4]). Abnormalities in PFTs were found in 78% of a group of 21 patients with juvenile DM who had a significant restrictive decrease in ventilatory capacity ([25]). In another small group (n = 12) of patients with juvenile DM followed prospectively, approximately half were found to have decreased lung function on PFTs, despite being asymptomatic ([13]). In a retrospective analysis of a larger group (n = 59) of patients with juvenile DM, the children had lower TLC and DLCO than age- and sex-matched controls ([9]). Testing those patients with HRCT of the chest showed radiologic abnormalities, including ILD, chest wall calcinosis, and airway disease, that were associated with low TLC ([9]). In our study, 37% of patients had decreased pulmonary function, with TLC or DLCO of <80%. Therefore, pulmonary function abnormalities are common in pediatric patients with IIMs, and assessment of PFTs in children with IIMs should be strongly considered.

Autoantibodies have emerged as playing a significant role in the evaluation of people with IIMs because they are useful in distinguishing subsets of patients, some of whom have a much worse prognosis than others ([26]). Autoantibodies can be classified into 2 groups: MAAs, which are most common in patients with IIMs who have characteristics of other connective tissue disease, and MSAs, which are restricted to people with IIMs ([27]). MSAs may be found in up to 70% of all patients with juvenile DM if full serologic testing is utilized ([10]). This is higher than in our study, in which we found 56% of children had MSAs/MAAs that were positive or indeterminate.

Specific literature assessing the association of ILD in children with IIMs who are positive for MSAs is not common, since most of the evidence includes juvenile patients mixed with the more prevalent adult data ([28]). In adults, MSAs, the anti–aminoacyl–transfer RNA synthetase autoantibodies (anti-aaRS), have been associated with lung disease, specifically ILD ([8, 29]). Although the association of antisynthetase syndrome with ILD is well described in adults, little has been published specific to the juvenile forms of IIMs. Anti-aaRS autoantibodies were only present in 2.6% of juvenile cases of children with myositis or overlap syndrome ([26]). Similarly, a low prevalence of anti-aaRS autoantibodies in juvenile DM was also evident in additional studies ([30, 31]), as well as in our report, in which only 2 patients (5.5%) had antibodies to either Jo-1 or PL-12.

Additional studies reviewing the association of specific MSAs in juvenile patients with ILD are sparse. Dyspnea and ILD were described in an analysis of 48 patients with anti–Mi-2 ([32]). Anti–Mi-2 is present in 4–10% of patients with juvenile DM or juvenile DM overlap syndrome ([6]), consistent with data from our group, in which 14% of patients had Mi-2 antibody. A novel MSA anti-p155/140 has recently been identified ([33]) that is also designated as anti–transcription intermediary factor 1γ ([34]). In adult patients, the anti-p155/140 protein was present in 13–21% ([27]) of patients and associated with increased risk of malignancy ([7, 27]). In contrast, in children with juvenile DM, although this antibody is present in up to 29% of patients, it does not appear to be associated with cancer risk ([27]). A child with a DM-like presentation and an ovarian teratoma was negative for p155/140 ([35]).

In our study, of the patients that were tested for anti-p155/140, 20% had evidence of this antibody, which is similar to previous reports. Both adult and pediatric patients with this autoantibody have more severe dermatologic manifestations of disease ([7, 27]); however, no pulmonary abnormalities have been described to date. None of the children with anti-p155/140 in our study had evidence of pulmonary disease based on PFT.

It is important to examine the relationship of MSAs/MAAs in pediatric patients to determine if the same pattern of clinical characteristics is associated with specific autoantibodies as in adult patients. As new autoantibodies are identified, it will be of interest to fully characterize their clinical significance and relationship to ILD. Identifying patients with ILD early in their disease course will facilitate the institution of aggressive therapeutic intervention and potentially resolution of the ILD. In our study, anti–Jo-1, anti–PL-12, anti-Ro, and anti–Scl-70 were associated with decreased function on PFT, either in TLC or DLCO (Figure 1). Other studies from our group had documented that the specific Ro antibody was anti–Ro 52 ([36]).

Figure 1.

Percentage of children with idiopathic inflammatory myopathy (IIM) with abnormal total lung capacity (TLC) or diffusing capacity for carbon monoxide (DLCO), categorized by myositis-specific or -associated antibodies.

These data document that the identification of specific MSAs/MAAs in sera of children with IIMs increases the requirement for screening for pulmonary complications of IIM. Of note, the classification of IIM includes amyopathic conditions (i.e., without muscle involvement but having typical skin changes). None of the patients in this study were amyopathic; all had evidence of both skin and muscle involvement. In patients with amyopathic disease, there is an increased association with antibody to CADM140 (melanoma differentiation–associated protein 5 [MDA-5]) and ILD ([37]).

The muscle enzymes, specifically CPK, aldolase, AST, and LDH, are the gold standard used to confirm diagnosis, determine the extent of disease activity, and follow progress. In our study, patients with abnormal lung function, defined by decreased TLC, had significantly higher levels of both CPK and neopterin than those patients with normal lung function. Laboratory abnormalities in those patients with decreased DLCO/VA had higher levels of aldolase and LDH and a higher percentage of abnormal aldolase and neopterin. Few data are available about the association of laboratory abnormalities with pulmonary disease in IIM. One study of diffuse ILD in 7 of 15 patients with either PM or DM found that affected patients had higher CPK and aldolase ([38]), which is similar to our findings. A case report of a child with fatal ILD also observed elevated aldolase levels ([39]). Elevation in aldolase is an indicator of increased risk of pulmonary disease in patients with IIMs, as evidenced by our evaluation showing that patients with both abnormal DLCO and abnormal TLC had significantly higher aldolase levels. With respect to neopterin, a review of 50 children with juvenile DM documented an elevated mean ± SD neopterin level at diagnosis of 21.5 ± 10.13 nmoles/liter (10.5 is the upper limit of normal) ([20]), and the association of ILD with neopterin at the lung macrophage level had been previously established ([40]).

Many physicians use the CMAS clinically as an index of muscle strength and endurance. The CMAS is a 14-item scale based on observation of performance that evaluates muscle strength, physical function, and endurance in pediatric patients with IIMs ([18]). Muscle weakness in the chest wall muscles (items 7 and 8) and core strength (items 3 and 5) can lead to restrictive lung disease, as evidenced by low TLC; however, the link between CMAS and PFTs has not been studied in pediatric patients with IIMs. Our study revealed that children with abnormal TLC had no differences in CMAS scores compared to patients with normal PFTs (Table 3). Those with abnormal DLCO had significantly lower scores on items 1, 3, 10, 11, and 14 (Table 4). One study evaluating anti–p155/140 showed a trend toward low CMAS scores in pediatric patients with IIMs ([41]). This weakness puts the children who have this autoantibody at a higher risk of pulmonary dysfunction. Of interest, none of the patients in our study with anti-p155/140 had documented muscle weakness or either restrictive lung disease or low TLC.

There is evidence that early aggressive treatment of ILD can lead to improved outcomes ([10]). In adult cases of IIM with ILD, longer duration of untreated disease at diagnosis is associated with higher rates of complications ([10]). This differs from our data, which show that those pediatric patients with abnormal DLCO and TLC had a shorter duration of untreated disease at diagnosis. Adults prospectively followed with PFTs had normalization of TLC and DLCO over time in one-third of patients ([14]). Case reports also support this reversibility with treatment: a case of acute respiratory distress syndrome secondary to ILD in IIM was resolved with aggressive treatment with tacrolimus ([42]). Similarly, resolution of PFT and chest HRCT abnormalities after aggressive therapy has been described in a pediatric patient with IIM and the presence of anti–PL-12 ([15]). Based on this evidence, it is imperative to identify those patients with risk of pulmonary abnormalities, most specifically ILD, early in their disease course.

In a small pediatric study of 10 patients with juvenile DM, 5 were diagnosed with ILD based on PFT and computed tomography scan findings ([43]). The authors report the improvement in lung function after treatment with cyclosporine despite the fact that the patients had minimal symptoms ([43]). One case report of anti–PL-12 in a pediatric patient documented reversibility of ILD with aggressive treatment ([15]). Early corticosteroid therapy sufficient to normalize enzymes apparently led to better resolutions of ILD ([38]). A case report of an adult with ILD also demonstrated that the patient had elevated aldolase and CPK that improved with therapy ([44]).

Our study is limited by the fact that it is a retrospective evaluation of patients who had obtained PFT. All patients with IIMs did not have routine testing for PFTs. This may falsely elevate our numbers of abnormal PFTs, since the patients were referred clinically for PFTs. Evaluation of the patients who had abnormal PFTs with HRCT of the chest would have strengthened the study by correlating PFT abnormalities with ILD. None of the children were amyopathic, and correspondingly, no testing was performed for anti-CADM140 (MDA-5).

In conclusion, it is important to establish guidelines for the clinician to obtain screening for pulmonary disease in children, since pulmonary function abnormalities were identified in more than 30% of pediatric patients with IIMs. This study provides the suggestions for some of these useful indicators; MSAs/MAAs, the CMAS parameters, and routine laboratory tests may help identify children at increased risk of pulmonary complications. Elevation in neopterin is also a clue that the child should be screened with PFTs, since our study suggests that higher values were associated with impaired PFTs. Screening of pediatric patients with IIMs should be strongly considered to assess for pulmonary complications, since early aggressive medical therapy appears to have the capacity to reverse these potentially life-threatening complications.

AUTHOR CONTRIBUTIONS

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 published. Dr. Prestridge 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. Prestridge, Morgan, Pachman.

Acquisition of data. Prestridge, Morgan, Ferguson, Pachman.

Analysis and interpretation of data. Prestridge, Morgan, Huang, Pachman.

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