Abstract
Objective
We examined features of clinically amyopathic JDM (CAJDM), in which patients have characteristic rashes with little to no evidence of muscle involvement, to determine whether this is a distinct phenotype from JDM.
Methods
Demographic, clinical, laboratory and treatment data from 12 (9 hypomyopathic, 3 amyopathic) patients meeting modified Sontheimer criteria for CAJDM and from 60 matched JDM patients meeting Bohan and Peter criteria were examined. Differences were evaluated by Fisher’s exact and Mann–Whitney tests, random forests and logistic regression analysis.
Results
Nine (75%) CAJDM patients had anti-p155/140 (transcriptional intermediary factor 1), one (8.3%) anti-melanoma differentiation-associated gene 5 autoantibodies and two (16.7%) were myositis autoantibody negative. CAJDM patients were younger at diagnosis and frequently had mild disease at onset. CAJDM patients had less frequent myalgias, arthritis, contractures, calcinosis, dysphagia, abdominal pain and fatigue. The muscle, skeletal and overall clinical scores were lower in CAJDM. Serum muscle enzymes were less frequently increased in CAJDM, and peak values were lower. CAJDM patients received fewer medications compared with JDM patients. Only 50% of CAJDM patients received oral prednisone, but the maximum dose and treatment duration did not differ from JDM. At a median follow-up of 2.9 years, CAJDM patients had no documented functional disability, and none developed weakness, calcinosis, interstitial lung disease or lipodystrophy. Multivariable modelling revealed a lower skeletal score and less frequent myalgias as the most important factors in distinguishing CAJDM from JDM.
Conclusion
CAJDM may be distinguished from JDM, in that they often have p155/140 (transcriptional intermediary factor 1) autoantibodies, have fewer systemic manifestations and receive less therapy.
Keywords: juvenile dermatomyositis, clinically hypomyopathic dermatomyositis, clinically amyopathic dermatomyositis, classification criteria, outcome, treatment
Rheumatology key messages
Patients with clinically amyopathic JDM frequently have anti-p155/140 (transcriptional intermediary factor 1) autoantibodies.
Clinically amyopathic JDM patients have less frequent systemic features compared with patients with JDM.
Clinically amyopathic JDM patients receive less therapy and have more favourable outcomes compared with JDM.
Introduction
Clinically amyopathic DM (CADM) is a subgroup of DM representing patients with hypomyopathic and amyopathic DM [1, 2]. Amyopathic DM is characterized by classic cutaneous manifestations of DM occurring for at least 6 months with no proximal muscle weakness or evidence of muscle disease. Hypomyopathic DM has been described as a group of patients with clinically amyopathic DM who have characteristic DM rashes and no weakness, but who have evidence of subclinical myositis based on laboratory testing, including elevation of serum muscle enzymes, EMG consistent with myositis, muscle oedema on MRI or inflammatory changes on muscle biopsy [1, 3, 4].
In adults, CADM represents ∼10–20% of the DM population [1, 5]. In children, CAJDM constituted 22% of patients with JDM in one clinic population [6], although relatively few cases of CAJDM in other reports suggests that the frequency may be lower in children [3, 4]. Melanoma differentiation-associated gene 5 (MDA5) autoantibodies are associated with amyopathic DM and rapidly progressing lung disease in Asian juvenile and Caucasian adult DM patients [7–10]. Anti-transcriptional intermediary factor 1 (TIF-1) (anti-p155/140) and anti-aminoacyl-tRNA synthetase autoantibodies have been less commonly reported in adult CADM patients [11–13].
The aims of our study were to examine demographic, clinical, laboratory and outcome features as well as therapies of CAJDM patients, and to determine the findings that distinguish CAJDM from JDM.
Methods
Patients
Twelve (nine hypomyopathic and three amyopathic DM) patients meeting modified Sontheimer criteria for CAJDM with a diagnosis before 18 years of age were identified. Patients had Gottron’s papules or sign and/or heliotrope rash without clinically detectable muscle weakness for at least 6 months [4]. Hypomyopathic patients also had subclinical muscle involvement with elevated serum muscle enzyme levels, muscle oedema on MRI and/or myopathic changes on EMG or muscle biopsy [4]. Skin biopsies were performed in three children (25%), and the Sontheimer criteria were modified in not requiring a skin biopsy to confirm a diagnosis of CAJDM.
CAJDM patients were matched at a ratio of one CAJDM patient to five patients who met probable or definite Bohan and Peter criteria for JDM [14] with the same myositis-specific autoantibodies (MSA). The 60 JDM patients were randomly selected from a cohort of 453 JDM patients. Both CAJDM and JDM patients were enrolled from 1994 to 2014 into at least one of four National Institutes of Health Clinical Center or Food and Drug Administration investigational review board-approved natural history protocols examining natural history of disease, genetic and environmental factors, and disease assessment. The study was also approved by the Institutional Review Board of the George Washington University Office of Human Research. Patients were referred for enrolment from throughout the USA [15]. Patients provided written informed consent/assent according to the standards of the Declaration of Helsinki.
A standardized physician questionnaire including demographics, illness onset characteristics, environmental exposures within 6 months of illness onset, clinical and laboratory features (muscle enzymes, EMG, MRI, and muscle and skin biopsy), therapies received and outcome information was completed [15, 16]. Scores for each organ system were based on the number of signs/symptoms present at diagnosis vs the number assessed [16]. Environmental factors within 6 months of diagnosis were recorded based on medical record review [17]. Ultraviolet (UV) index based on residential location for 30 days prior to the date of myositis symptom onset was determined using the National Weather Service UV Index Cities Forecast Archive determining average daily and maximum UV index data based on the closest city monitored by the National Oceanic and Atmospheric Administration, as previously described [18].
Sera were tested for MSA and myositis-associated autoantibodies using validated immunoprecipitation and immunoprecipitation-immunoblotting methods [19, 20].
Sixty-three of 72 patients (87.5%) (10 CAJDM and 53 JDM) had evaluable treatment information. A treatment trial was defined as beginning of administration of a medication or combination of medications to termination [21–23]. For prednisone, this was until the dose was reduced to 25% of the original dose or reached a stable dose that was the objective of the taper. A new treatment trial consisted of the addition of a new medication or discontinuation of a medication, an increase or decrease in the dose by ⩾25% of the original dose, or if the route of administration changed (i.e. oral vs parenteral MTX). Medication escalation included the addition of a new medication or increase in the dose related to increased disease activity based on clinical and/or laboratory features. Complete clinical response and remission were evaluated according to the consensus definitions of the International Myositis Assessment and Clinical Studies group [24].
Statistical analysis
GraphPad Prism version 7.0 for Windows (GraphPad Software, San Diego, CA, USA), SAS Enterprise Guide version 5.1 and JMP for Windows, version 11.0.0 (SAS Institute, Cary, NC, USA) were used for statistical analyses. Summary data were expressed as median and interquartile ranges (IQR), and P-values for differences between patient groups were obtained by the Mann–Whitney Rank Sum test. Fisher’s exact test was used to compare proportions between the groups. A P ⩽ 0.05 was considered significant. Random forests classification and logistic regression analyses were performed to further evaluate significant univariate differences between CAJDM patients and those with JDM. The random forests classification analysis was performed using the learning machine RandomForest and statistical language R (version 3.4.2, 2017; http://stat-www.berkeley.edu/users/breiman/RandomForests/). The statistical model had 500 forests and 20 000 trees per run and the mean decrease in accuracy (MDA) was used to rank the relative importance of the variables. MDA quantifies the relative contribution of the variable to the prediction accuracy of the statistical model [25].
Results
Of 453 JDM patients in the registry, twelve (nine with hypomyopathic and three with amyopathic JDM) were identified who met modified Sontheimer criteria for CAJDM. Disease duration at enrolment was a median of 2.9 (IQR: 1.2–6.0) years for CAJDM and 4.0 (IQR: 2.1–7.8) years for JDM patients. The three amyopathic JDM patients had classic cutaneous manifestations of DM with Gottron’s papules and/or heliotrope rash (one also had a skin biopsy consistent with DM) with no evidence of proximal muscle weakness and no serum muscle enzyme abnormalities. Among these three amyopathic patients, one had an EMG, two had thigh muscle MRIs and two had a muscle biopsy performed; all these test results were confirmed negative. The nine hypomyopathic patients had characteristic DM rashes, no detectable weakness on exam, but the presence of subclinical evidence of myositis, as all nine patients had elevation of one or more serum muscle enzymes. In five out of nine hypomyopathic patients, MRI was performed and demonstrated muscle oedema in four patients. Two hypomyopathic patients had an EMG, and myopathic changes were present in one patient. Muscle biopsy was performed in two other hypomyopathic patients and was normal in both patients. Skin biopsies were performed in two of nine hypomyopathic patients, and were consistent with DM.
Compared with JDM patients, CAJDM were younger at the time of diagnosis (median 4.1 vs 7.3 years) and frequently had mild illness severity at onset. CAJDM patients did not differ in other demographic features from those with JDM (Table 1). Serum muscle enzyme levels, including creatine kinase, aldolase, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase, were lower and less frequently elevated in CAJDM compared with JDM patients. The median ANA titre for CAJDM did not differ from that for JDM (Table 1). Ten of 12 (83.3%) CAJDM patients had MSAs, including nine patients (75%) with anti-p155/140 (TIF-1) autoantibodies and one patient (8.3%) with anti-MDA5 autoantibodies; 2 patients were MSA negative. CAJDM patients more frequently had p155/140 (TIF-1) autoantibodies than the full cohort of 453 JDM patients (75 vs 37.4%, P = 0.038). There was no difference in the frequency of anti-MDA5 autoantibodies between CAJDM and JDM (8.3 vs 7.7%).
Table 1.
Summary of demographic and laboratory features of patients with CAJDM and JDM
| Demographic and laboratory features | CAJDM (n = 12) | JDM (n = 60) | ||
|---|---|---|---|---|
| Age at diagnosis, median (IQR), years | 4.1 (2.2–6.1) | 7.3 (4.4–11.9)*** | ||
| Delay in diagnosis, median (IQR), months | 5.0 (1.0–9.5) | 4.0 (1.0–9.5) | ||
| Female gender, n (%) | 10 (83.3) | 43 (71.7) | ||
| Race, n (%) | ||||
| Caucasian | 9 (75.0) | 49 (81.7) | ||
| African-American | 0 (0) | 4 (6.7) | ||
| Hispanic | 1 (8.3) | 2 (3.3) | ||
| Asian | 0 (0) | 3 (5.0) | ||
| Illness severity at onset, n (%) | ||||
| Mild illness severity at onset | 9 (75) | 7 (11.7)**** | ||
| Moderate illness severity at onset | 3 (25) | 37 (61.7)* | ||
| Median (IQR) | n (%) | Median (IQR) | n (%) | |
| Highest serum muscle enzyme values (U/l) | ||||
| CK (upper limit normal 252 U/l) | 176 (104–292) | 3 (25.0) | 479 (186–2239)** | 38 (66.7)* |
| Aldolase (upper limit normal 6 U/l) | 6 (4.0–7.0) | 5 (41.7) | 9.9 (7.0–17.3)*** | 43 (82.7)** |
| LDH (upper limit normal 226 U/l) | 226 (185–242) | 4 (40.0) | 397 (266–574)**** | 39 (84.8)** |
| AST (upper limit normal 34 U/l) | 31 (27–39) | 2 (18.2) | 66 (43–177)**** | 42 (87.5)**** |
| ALT (upper limit normal 41 U/l) | 21 (16–51) | 2 (22.2) | 62 (23–108) | 32 (71.1)** |
| ANA positive | 9 (81.8) | 38 (70.4) | ||
| ANA titre | 320 (80–640) | 320 (0–640) | ||
| Myositis autoantibody status, n (%) | ||||
| Anti-p155/140 (TIF-1) | 9 (75.0) | 45 (75.0) | ||
| Anti-MDA5 | 1 (8.3) | 5 (8.3) | ||
| Myositis autoantibody negative | 2 (16.7) | 10 (16.7) | ||
Note that percentages may not reflect the number divided by the total number of subjects, when data are missing. Significant differences in CAJDM vs JDM:
P ≤ 0.05,
P ≤ 0.01,
P ≤ 0.005,
P ≤ 0.001. CAJDM: clinically amyopathic JDM; IQR: interquartile range; CK: creatine kinase; LDH: lactate dehydrogenase; AST: aspartate aminotransferase; ALT: alanine aminotransferase; TIF-1: transcription intermediary factor 1; MDA5: melanoma differentiation-associated gene 5.
There were no differences in the type and frequency of documented exposures within the 6 months preceding CAJDM and JDM diagnosis, including infections (36.4% in CAJDM patients vs 37.9% in JDM), immunizations (27.3 vs 24.1%), unusual sun exposure (9.1 vs 8.6%), medications (9.1 vs 15.5%) and stressful life events (27.3 vs 19%). The median UV index in the month prior to diagnosis based on residential location did not differ between CAJDM and JDM [average UV index for CAJDM 4.9 (IQR: 3.3–6.0) vs 4.7 (IQR: 1.9–6.4) for JDM, and highest UV index 6.0 (IQR: 5.4–7.2) for CAJDM vs 6.7 (IQR: 3.2–8.1) for JDM].
The frequencies of some signs and symptoms and severity of organ system scores at diagnosis differed between CAJDM and JDM, as shown in Table 2. As expected, the muscle system score at diagnosis was lower in CAJDM than in JDM patients. Skeletal and overall total system scores were also lower in CAJDM than in JDM patients, while other organ system scores at diagnosis did not differ between the two groups. Myalgias, arthralgias, arthritis and contractures were present less frequently in CAJDM than in JDM patients (Table 2).
Table 2.
Signs and symptoms of illness by organ system for patients with CAJDM and JDM
| Symptom/sign | CAJDM (n = 12) | JDM (n = 60) |
|---|---|---|
| Musculoskeletal system | ||
| Muscle system score, median (IQR) | 0 (0–0) | 0.29 (0.17–0.48)*** |
| Proximal muscle weakness | 0 (0.0) | 60 (100.0)*** |
| Distal muscle weakness | 0 (0.0) | 28 (46.7)** |
| Myalgias | 1 (8.3) | 37 (61.7)*** |
| Skeletal system score, median (IQR) | 0 (0–0) | 0.5 (0–1.0)** |
| Arthralgia | 2 (16.7) | 33 (55.0)* |
| Arthritis | 0 (0.0) | 29 (48.3)* |
| Contractures | 1 (8.3) | 37 (61.7)** |
| Cutaneous system | ||
| Cutaneous system score, median (IQR) | 0.31 (0.18–0.39) | 0.29 (0.22–0.37) |
| Gottron’s papules | 12 (100.0) | 56 (93.3) |
| Heliotrope rash | 9 (75.0) | 52 (86.7) |
| Malar rash | 10 (83.3) | 51 (85.0) |
| Periungual capillary abnormalities | 10 (83.3) | 47 (78.3) |
| Photosensitivity | 5 (45.5) | 33 (55.0) |
| Cuticular overgrowth | 4 (33.3) | 20 (33.9) |
| Linear extensor erythema | 3 (25.0) | 26 (44.1) |
| ‘V’-sign or ‘Shawl’-sign rash | 2 (16.7) | 18 (30.0) |
| ‘Mechanic’s hands’ | 1 (8.3) | 1 (1.7) |
| Mucous membrane involvement | 1 (9.1) | 24 (40.0)** |
| RP | 0 (0.0) | 5 (8.3) |
| Erythroderma | 0 (0.0) | 7 (11.7) |
| Skin ulcers | 0 (0.0) | 12 (20.0) |
| Lipodystrophy | 0 (0.0) | 3 (5.0) |
| Calcinosis | 0 (0.0) | 20 (33.3)* |
| Pulmonary system | ||
| Pulmonary system score, median (IQR) | 0 (0–0) | 0 (0–0) |
| Dysphonia | 1 (8.3) | 19 (31.7) |
| Dyspnoea at rest | 0 (0.0) | 6 (10.0) |
| Abnormal pulmonary function testing | 0 (0.0) | 8 (21.1) |
| Dyspnoea on exertion | 0 (0.0) | 9 (15.3) |
| Interstitial lung disease | 0 (0.0) | 3 (5.0) |
| Gastrointestinal system | ||
| Gastrointestinal system score, median (IQR) | 0 (0–0.08) | 0 (0–0.11) |
| Dysphagia | 0 (0.0) | 19 (31.7)* |
| Abdominal pain | 0 (0.0) | 22 (36.7)* |
| Constitutional system | ||
| Constitutional system score, median (IQR) | 0 (0–0.44) | 0.25 (0.25–0.5) |
| Fatigue | 4 (33.3) | 49 (81.7)** |
| Fever | 3 (25.0) | 17 (28.3) |
| Weight loss | 2 (16.7) | 24 (40.0) |
| Overall clinical system score, median (IQR) | 0.063 (0.034–0.12) | 0.21 (0.13–0.28)*** |
Values are n (%) unless otherwise stated. Note that percentages may not reflect the number divided by the total number of subjects, when data are missing. Frequency of cardiac system signs and symptoms and cardiac system score did not differ between the two groups (data not shown). Organ system scores are at time of diagnosis [15] and signs/symptoms are ever present. Significant differences between CAJDM and JDM:
P ≤ 0.05;
P ≤ 0.005,
P ≤ 0.001. CAJDM: clinically amyopathic DM; IQR: interquartile range.
Most skin rashes were present with similar frequency in CAJDM and JDM patients. CAJDM patients had a high frequency of malar rash and periungual capillary changes, but also frequent photosensitivity, cuticular overgrowth and linear extensor erythema. CAJDM patients had less frequent mucus membrane involvement than JDM and had no documented calcinosis, compared with 33.3% of JDM patients who developed calcinosis. CAJDM patients also had no cutaneous ulcers, erythroderma, lipodystrophy or RP (Table 2). CAJDM patients had a median of 5 (3.2–6.0) rashes compared with 6 (4.2–8.0) in JDM patients.
CAJDM patients had no documented dysphagia, abdominal pain or other gastrointestinal features. They had less frequent fatigue than JDM patients, and of note, none had documented interstitial lung disease (Table 2).
The total treatment duration did not differ between CAJDM and JDM (Table 3). CAJDM patients received fewer medications compared with JDM patients (median 2 vs 3). Only 50% of CAJDM patients received oral prednisone as compared with 100% of JDM patients (P < 0.0001), but the maximum daily dose of oral prednisone and corticosteroid treatment duration did not differ between the two groups. The frequency of usage of most medications did not differ between CAJDM and JDM, except that three or more medications in combination was significantly less frequent in CAJDM compared with JDM. Five of 10 CAJDM patients were treated with HCQ and/or MTX, 3 patients were treated with topical steroids or tacrolimus, 2 CAJDM patients received i.v. methylprednisolone and 1 patient received IVIG. None of the CAJDM patients received other immunosuppressive drugs, CYC or biologic therapies. Four of 10 CAJDM patients were treated with a combination of two medications, which included prednisone and MTX (2 patients), prednisone and HCQ (1 patient) and MTX and i.v. methylprednisolone (1 patient). One patient was treated with a combination of three medications, including oral prednisone, MTX and HCQ. There was no significant difference between CAJDM and JDM in the proportion of patients requiring an escalation of therapy, in the proportion of patients who discontinued corticosteroid therapy, or who achieved complete clinical response or remission.
Table 3.
Medications used and treatment responses in patients with CAJDM and JDM
| Medications used and treatment responses | CAJDM | JDM |
|---|---|---|
| Median number or duration of treatment, median (IQR) | n = 10 | n = 53 |
| Total treatment duration, months | 22.1 (8.0–52.1) | 32.6 (14.0–66.7) |
| Total number of medications per patient | 2.0 (1.0–3.0)** | 3.0 (2.0–5.0) |
| Steroid treatment duration, months | 17.4 (4.5–27.1) | 24.0 (12.0–42.5) |
| Maximum daily dose of oral prednisone | 2.0 (1.4–2.2) | 1.8 (1.0–2.0) |
| Number and percent of medication used, n (%) | ||
| Oral prednisone | 5 (50.0) | 53 (100.0)*** |
| MTX | 5 (50.0) | 35 (66.0) |
| HCQ | 5 (50.0) | 29 (54.7) |
| Topical corticosteroids or tacrolimus | 3 (30.0) | 7 (13.2) |
| i.v. methylprednisone | 2 (20.0) | 27 (50.9) |
| IVIG | 1 (10.0) | 15 (28.3) |
| Oral DMARDS | 0 (0.0) | 10 (18.9) |
| Cytotoxic/biologics | 0 (0.0) | 4 (7.6) |
| Two medications in combination | 4 (40.0) | 37 (69.8) |
| Three or more medications in combination | 1 (10.0) | 25 (47.2)* |
| Number and percent achieving outcomes, n (%) | ||
| Treatment escalation | 3 (30.0) | 32 (60.4) |
| Discontinuation of corticosteroid therapy | 4 (66.7) | 32 (60.4) |
| Complete clinical response | 4 (44.4) | 17 (32.7) |
| Remission | 2 (20.0) | 14 (26.4) |
Note that percentages may not reflect the number divided by the total number of subjects, when data are missing. Two medications in combination included oral prednisone and MTX, or oral prednisone and HCQ, or MTX and i.v. methylprednisone; three or more medications in combination included oral prednisone, MTX and HCQ. Significant differences between CAJDM and JDM:
P ≤ 0.05;
P ≤ 0.01,
P ≤ 0.001. CAJDM: clinically amyopathic JDM; IQR: interquartile range.
In terms of outcomes, disease course and mortality did not differ between CAJDM and JDM patients (Table 4). CAJDM patients tended to be hospitalized less often than JDM (25 vs 56.9%, P = 0.059). None of the 72 patients had a documented malignancy. At the most recent evaluation, all 12 CAJDM patients had no documented functional disability by ACR functional status classification, compared with 69% of JDM patients, and the CAJDM group had a lower median ACR Functional Class. In addition, none of the CAJDM patients had muscle weakness or calcinosis, in contrast to 45.8 and 24.1% of JDM patients, respectively. The frequency of skin rashes and periungual capillary changes at last evaluation was similar between CAJDM and JDM (Table 4).
Table 4.
Outcomes of patients with CAJDM and JDM
| Outcomes | CAJDM (n = 12) | JDM (n = 60) |
|---|---|---|
| Disease duration from diagnosis to final evaluation, median (IQR), years | 2.9 (1.2–6.0) | 4.0 (2.1–7.8) |
| Disease course | ||
| Chronic | 3 (42.9) | 30 (60.0) |
| Polycyclic | 2 (16.7) | 7 (11.7) |
| Monocyclic | 2 (16.7) | 13 (21.7) |
| Undefined | 5 (41.7) | 10 (16.7) |
| Ever hospitalized | 3 (25.0) | 33 (56.9) |
| Outcomes at last evaluation | ||
| Median ACR functional class (IQR) | 1 (1–1) | 1 (1–2)* |
| Skin rash present | 7 (58.3) | 31 (53.4) |
| Periungual capillary abnormalities | 6 (50.0) | 18 (33.3) |
| Muscle weakness | 0 (0.0) | 27 (45.8)** |
| Calcinosis | 0 (0.0) | 14 (24.1) |
| Lipodystrophy | 0 (0) | 1 (1.7) |
| Malignancy | 0 (0) | 0 (0) |
| Death | 0 (0) | 1 (1.7) |
Data are n (%) unless otherwise specified. Undefined disease course when patients have <2 years of follow-up. Note that percentages may not reflect the number divided by the total number of subjects, when data are missing. Significant differences between CAJDM and JDM:
P ≤ 0.05,
P ≤ 0.001. CAJDM: clinically amyopathic DM; IQR: interquartile range.
Twenty-one variables were used as potential predictors in the random forest model comparing CAJDM to JDM based on their significance in the univariable analysis using the 63 JDM with complete data. Proximal and distal weakness were removed from the analysis since their absence is part of the criteria for CAJDM [4]. In the random forests classification model that was pruned to include the top 10 variables, the most important predictors of CAJDM compared with JDM were lower skeletal system score (MDA 100.0), less frequent myalgia (MDA 61.6), lower overall clinical system score (MDA 29.6), absence of arthritis (MDA 24.7), mild illness severity at onset (MDA 22.9), less frequent contractures (MDA 22.5) and lower muscle system score (MDA 19.0), with an out-of-bag error rate of 5.6%. Seven top variables from the pruned random forest model were entered into logistic regression. The final logistic regression model revealed lower skeletal system score [odds ratio (OR) = 27.9, 95% CI: 3.4, 647.0; P = 0.009] and less frequent myalgia (OR = 0.042, 95% CI: 0.002, 0.264; P = 0.005) were significant predictors of CAJDM compared with JDM.
Discussion
CAJDM is a mild clinical phenotype of JDM in which patients often have characteristic JDM rashes with little to no indication of muscle involvement. We examined multiple characteristics of patients with CAJDM and compared them with a group of MSA-matched JDM patients to identify specific features of this condition.
In our study, nine hypomyopathic patients had characteristic DM rashes and no detectable muscle weakness on exam. Subclinical muscle involvement in these patients was confirmed by laboratory testing results, with elevation of one or more serum muscle enzymes in all nine patients, but the elevation was lower than in JDM patients. Of those with additional laboratory investigations to detect muscle involvement, four patients had abnormal MRI or EMG studies, indicative of subclinical muscle disease. Three patients, additionally, had amyopathic JDM, with no weakness or serum enzyme elevation, and two of these had EMG, MRI or muscle biopsy examinations, with negative findings. One of the three had a skin biopsy consistent with DM, and two had detectable MSAs [p155/140 (TIF-1)], so while they had no clinical or laboratory evidence of muscle involvement, they had other testing consistent with myositis in addition to their characteristic skin rashes.
In the CAJDM patients, 75% had anti-p155/140 (TIF-1) autoantibodies as the most frequent MSA present, and this was more frequent than in the full cohort of JDM patients. There was one patient with anti-MDA5 autoantibodies and two patients had no detectable MSAs. This contrasts with adult-onset CADM, which has been primarily associated with anti-MDA5 autoantibodies, and less commonly with anti-TIF-1γ and anti-synthetase autoantibodies [11–13]. Previous reports have suggested anti-p155/140 (TIF-1) autoantibodies to be associated with more severe photosensitive skin disease, lipodystrophy and a chronic course of illness [16, 26, 27]. The reason that the same MSA is associated with CAJDM, a more mild clinical phenotype, is not understood, but could potentially relate to differences in the autoantigenic epitopes or in autoantibody titres, as well as differences in genetic or environmental factors between these subgroups.
The clinical phenotype of CAJDM is milder than JDM patients and dominated by cutaneous manifestations. The median muscle, skeletal system and overall system scores were lower in our CAJDM patients, and notably there is an absence of pulmonary (particularly interstitial lung disease), cardiac and gastrointestinal disease in CAJDM. In addition, we found that CAJDM patients have less frequent myalgias, arthralgias and fatigue than JDM patients, and none of our patients developed arthritis, in contrast to other reports [3].
We found a similar distribution in the cutaneous manifestations of CAJDM and JDM patients, as reported by others [1, 6]. Importantly, calcinosis, vasculitis and lipodystrophy were absent in CAJDM patients, also as previously reported [1, 6], although calcinosis was uncommonly seen in one series of CAJDM patients [3]. Mucous membrane involvement was less frequent and the total number of rashes at presentation were fewer in the CAJDM patients. We also saw no malignancies in this subgroup of patients, as also previously reported [3, 6]. This differs from CADM in adults, who have a higher frequency of interstitial lung disease, associated malignancy and cutaneous vasculitis [2].
A North American group of paediatric rheumatologists has developed consensus treatment guidelines for JDM patients with skin-predominant disease, which suggests use of HCQ alone or in combination with MTX and/or prednisone [28]. Compared with JDM, CAJDM patients received fewer medications, and less frequently used prednisone or multiple combination therapies. However, many required systemic therapy, most frequently with prednisone, MTX and/or HCQ. Also, the duration of therapy and rate of achievement of inactive disease was not superior to JDM patients.
A strength of our study is the comprehensive examination of multiple characteristics of CAJDM compared with JDM patients with similar MSAs to determine distinguishing features of the two groups. However, our study has some limitations, one of which is that it is a retrospective observational study with a relatively small sample size. We also cannot estimate the frequency of CAJDM in this study, as probable or definite Bohan and Peter criteria were part of the eligibility criteria for many of our research studies, and thus the majority of patients with CAJDM would have been excluded. As some patients with CAJDM may have thus been excluded from our studies, this may have influenced the phenotype of CAJDM patients. That many of our findings were similar to other reports [1, 6], however, is reassuring.
In conclusion, CAJDM may be distinguished from JDM in that this subgroup of patients more likely has anti-p155/140 (TIF-1) autoantibodies, mild illness severity at onset, and less frequent myalgias and fatigue. They have more favourable outcomes than JDM patients, with less functional disability and weakness; an absence of calcinosis, malignancy, interstitial lung disease and other organ involvement; and require less systemic therapy.
Acknowledgements
We thank Drs Rachel Rosenstein and Sara Sabbagh for critical reading of the manuscript. Members of the Childhood Myositis Heterogeneity Collaborative Study Group who contributed to this study are: Leslie S. Abramson, Bita Arabshahi, Victoria Cartwright, Elizabeth J. Chalom, Barbara Anne Eberhardt, William Hannan, Gloria C. Higgins, Robert C. Fuhlbrigge, Jerry C. Jacobs (deceased), Lawrence Jung, Yukiko Kimura, Carol B. Lindsley, Alan L. Martin, Frederick W. Miller, Diana Milojevic, Barbara E. Ostrov, Maria D. Perez, Rafael F. Rivas-Chacon, Margalit Rosenkranz, David D. Sherry, Jennifer Soep, Sangeeta Sule and Scott A. Vogelgesang.
Funding: This work was supported in part by the Intramural Research program of the National Institute of Environmental Health Sciences (project ES101074 and ES1010081).
Disclosure statement: G.M. and R.V.C. were supported by the Cure JM Foundation. T.K. was supported by The Myositis Association. I.N.T. is a consultant to the Oklahoma Medical Research Foundation Clinical Immunology Laboratory. All other authors have declared no conflicts of interest.
Contributor Information
Childhood Myositis Heterogeneity Collaborative Study Group:
Leslie S Abramson, Bita Arabshahi, Victoria Cartwright, Elizabeth J Chalom, Barbara Anne Eberhardt, William Hannan, Gloria C Higgins, Robert C Fuhlbrigge, Jerry C Jacobs, Lawrence Jung, Yukiko Kimura, Carol B Lindsley, Alan L Martin, Frederick W Miller, Diana Milojevic, Barbara E Ostrov, Maria D Perez, Rafael F Rivas-Chacon, Margalit Rosenkranz, David D Sherry, Jennifer Soep, Sangeeta Sule, and Scott A Vogelgesang
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