|Ahead of print publication
Clinical characteristics, therapeutics, and treatment outcomes of adult patients with anti-melanoma differentiation-associated gene 5 dermatomyositis: A single-center experience from South India
Shivraj Padiyar1, Aswin M Nair2, Bijesh Yadav3, Prathyusha Manikuppam1, Avanish Jha1, Abhilasha Arvind Manwatkar1, John Mathew1
1 Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Rheumatology, Travancore Medical College Hospital, Kollam, Kerala, India
3 Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||09-Jul-2022|
|Date of Acceptance||09-Aug-2022|
|Date of Web Publication||20-Sep-2022|
Department of Clinical Immunology and Rheumatology, Christian Medical College Vellore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Introduction: To study the clinical characteristics and treatment outcomes of patients with anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis (DM).
Methods: This was a retrospective study done between 2019 and 2021 in a tertiary care center in South India. All consecutive patients, presenting to the adult rheumatology department, classified as idiopathic inflammatory myositis (IIM), and positive for anti-MDA5 antibodies, were included in the study. Baseline characteristics of anti-MDA5 patients were compared with the data of non-MDA5 patients over the last 10 years. Clinical, biochemical, and treatment responses were assessed on follow-up. Complete and partial responders were identified using predefined criteria. Factors predicting mortality were determined by logistic regression analysis. Data were analyzed using the Statistical Package for the Social Sciences (SPSS) version 25.
Results: A total of 29 adult patients of IIM were positive for anti-MDA5 antibody during the study period. The mean (±standard deviation) age of the patients was 40.3 (±13.02) years with a female:male ratio of 1.4:1. Panniculitis, calcinosis, palmar papules, and ulcerated Gottron's were the specific cutaneous manifestations, seen in 3 (10%), 7 (24%), 4 (13.4%), and 7 (24%) patients, respectively. A total of 14 patients (48.1%) had clinically amyopathic DM and 17 patients (60.7%) had interstitial lung disease (ILD) diagnosed by high-resolution computerized tomography scan, of which organizing pneumonia was the predominant pattern. Complete response was seen in 10 patients (43.4%), while a partial response was seen in 8 patients (34.7%). Five patients died on follow-up, accounting for mortality of 21%. Age >50 years was significantly associated with mortality (P = 0.025). Gottron's sign (P < 0.001), panniculitis (P < 0.001), calcinosis (P < 0.001), cutaneous ulcerations (P < 0.001), inflammatory arthritis (P < 0.001), and ILD (P < 0.02) were present more commonly in the anti-MDA5 IIM group, whereas myopathy (P < 0.001), elevated creatine phosphokinase (P < 0.001), and lactate dehydrogenase (P < 0.001) were more frequently present in the non-anti-MDA5 IIM group (n = 421).
Conclusions: Anti-MDA5 DM represents a distinct and unique subset of IIM with characteristic clinical manifestations. Elderly age is a poor prognostic factor of mortality.
Keywords: Anti-melanoma differentiation-associated gene 5, palmar papules, panniculitis, rapidly progressive interstitial lung disease, ulcerated Gottron's
|How to cite this URL:|
Padiyar S, Nair AM, Yadav B, Manikuppam P, Jha A, Manwatkar AA, Mathew J. Clinical characteristics, therapeutics, and treatment outcomes of adult patients with anti-melanoma differentiation-associated gene 5 dermatomyositis: A single-center experience from South India. Indian J Rheumatol [Epub ahead of print] [cited 2022 Oct 3]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=356477
| Introduction|| |
An idiopathic inflammatory myositis (IIM) group of disorders are characterized by a spectrum of cutaneous, pulmonary, and musculoskeletal manifestations. The diagnosis is usually concluded based on a clinical picture aided by muscle enzymes, electromyography, and muscle biopsies. The advent of myositis-specific (MSA) and associated autoantibodies (MAA) has revolutionized the understanding of the disease. Over the last three decades, these autoantibodies are being increasingly used to classify IIM into phenotypic subgroups and to predict an outcome or therapeutic response. Although substantial overlap exists between various autoantibodies and their phenotype, certain manifestations strongly stand in favor of a particular autoantibody. Although gold standard assays to detect these MSA are immunoprecipitation and immunodiffusion assays, these are not widely available. The availability of enzyme-linked immunosorbent assays and line immunoblot assays has increased the utility of MAA/MSA in day-to-day clinical practice.
Melanoma differentiation-associated gene 5 (MDA5), an RNA-specific helicase, recognizes double-stranded RNA viruses. Anti-MDA5 antibodies are one of the unique antibodies with a characteristic presentation, seen in about 10%–35% of patients with dermatomyositis (DM). In 2005, Sato et al. originally reported anti-MDA5 antibody in Japanese patients with clinically amyopathic DM (CADM) and rapidly progressive interstitial lung disease (RP-ILD). Patients with anti-MDA5-positive DM have characteristic clinical presentations such as RP-ILD, ulcerated Gottron's papules, CADM, and panniculitis with higher mortality. However, these phenotypes vary largely with ethnicity; the Asian population shows a higher incidence of RP-ILD and higher mortality compared to better outcomes in Caucasians., The Indian population, on the other hand, is ethnically diverse with regional differences in genetic composition. There is very little literature reported on anti-MDA5 from the Indian subcontinent due to the rarity of presentation and inadequate identification. A recent study published in India showed high mortality (38%) and a high incidence of ILD (50%) in this group.
In this study, we aim to study the clinical profile and treatment outcomes of anti-MDA5 DM patients from our cohort. A comparison has been made with the historic cohorts of IIM to determine the pathognomonic characteristics in anti-MDA5 DM.
| Methods|| |
This was a retrospective study of prospectively collected data conducted at a tertiary care teaching institute in Southern India. Patients presenting from October 2019 to April 2021, to the adult rheumatology department satisfying the 2017 American College of Rheumatology/European League Against Rheumatism classification criteria for IIM or Peter and Bohan's criteria or Sontheimer's classification criteria for amyopathic DM with positive anti-MDA5 antibodies by immunoblot (EUROIMMUN 16 Antigen Kit, Lubeck, Germany) were included. Those patients who had titers of 2+ or more for anti-MDA5 antibody without any other MSA positivity were included in the study. Patients satisfying the classification criteria of any other connective tissue diseases were excluded from the study.
Details on demography, clinical presentation, family history, malignancy, treatment details (immunosuppressants), laboratory results, and chest imaging were retrieved from the institutional electronic medical records (EMRs). All IIM patients at our institution undergo routine cross-sectional chest imaging to rule out ILD. They also undergo a detailed malignancy evaluation. Muscle disease was evaluated clinically by strength assessment using the Medical Research Council 5-point scale in addition to electrophysiologic testing and laboratory testing for serum muscle enzymes. Radiographic assessment by muscle magnetic resonance imaging and muscle biopsy was done whenever necessary. Follow-up of the patients is usually done every 3 months in our department, the data of which were retrieved from the EMR. Those patients who were lost to follow-up due to the COVID-19 pandemic and who could not have an in-person visit to the hospital were contacted via telephone/video consultation. Appropriate blood investigations were done in their hometown, during September–October 2021, and that time point was taken as the last follow-up visit. Only those patients who were continuing the treatment were included in the outcome analysis. For the comparison cohort of non-MDA5 patients, patients of IIM over the last 10 years in our institution, who had either a positive MSA or MAA, were selected. The study was approved by the institutional review board (IRB) no.: 14532. Being a retrospective design, waiver of consent was obtained from the IRB.
Assessment of treatment response was done as follows. Only those patients with at least 1 follow-up visit, 3 months after initiation of medications, were included for outcome analysis. The clinical and biochemical response during the follow-up period was assessed. Clinical response was defined by the improvement in muscle power and extramuscular manifestations (musculoskeletal, cutaneous, and pulmonary). Laboratory response was defined by the reduction in the level of at least two of the 3 muscle enzymes (creatine phosphokinase [CPK], lactate dehydrogenase [LDH], and aspartate transaminase) to < 2 times the upper limit of normal (<2 × ULN). Patients with ILD were followed up by lung function tests at each follow-up visit. The American Thoracic Society guidelines for assessing lung function were used. For those patients who did not have spirometry at follow-up, clinical improvement as noted down by the physician was taken for assessing response to therapy. Patients were categorized into complete responders (CR) and partial responders based on the cumulative improvement in musculoskeletal, cutaneous, and pulmonary manifestations.
- Complete responders: Those patients with the muscle power of ≥4+/5 and/or Manual muscle power testing (MMT) 8 of ≥76/80, complete resolution of skin and articular involvement, muscle enzymes (two out of three, AST, LDH, and CPK) ≤2 × ULN, and stable/improved lung function during the follow-up period
- Partial responders: Those patients with some improvement in muscle power and extramuscular manifestations but not meeting the criteria for CR
- Relapses: Defined as worsening in any organ manifestation (muscle, skin, joint, or ILD) either clinically or biochemically and not occurring as a result of the discontinuation of therapy after achieving initial response
- Rapidly progressive interstitial lung disease: Defined as acute onset and rapid worsening of dyspnea within 3 months of the onset of respiratory symptoms leading to severe hypoxia ≤60 mmHg.
Descriptive statistics were reported using mean ± standard deviation (SD) for normally distributed data or median ± interquartile range for nonnormal distribution. A comparison of means was done using two independent-sample t-tests. Association between the categorical variables and outcome was established using Chi-square/Fisher's exact test. P < 0.05 was considered to be statistically significant. SPSS Statistics version 25 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.).
| Results|| |
Baseline characteristics of anti-melanoma differentiation-associated gene 5-positive dermatomyositis patients
A total of 29 adult patients of DM were positive for anti-MDA5 antibody from January 2019 to April 2021. The mean (±SD) age of the patients was 40.3 (±13.02) years with a female: male ratio of 1.4:1. The mean (±SD) disease duration was 15.6 (±22.79) months. The clinical features of these patients are summarized in [Table 1].
|Table 1: Clinical and demographic characteristics of individuals with anti-melanoma differentiation-associated gene 5 antibody dermatomyositis|
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The pathognomonic cutaneous manifestations, namely Gottron's sign and heliotrope rash, were present in 20 patients (69%) and 13 patients (44.8%), respectively. Apart from the classical cutaneous manifestations of DM, panniculitis and calcinosis were present in 3 (10%) and 7 (24.1%) of our patients, respectively. Ulcerated Gottron's [Figure 1] was present in 7 (24.1%) patients. Palmar papules were noted in 4 (13.8%) of our patients. One-fourth of the patients also presented with pyrexia of unknown origin. ILD by computerized tomography scan [Figure 2] was reported in 17 patients (60.7%). However, dyspnea was present at the time of initial presentation in only 14 (48.3%) patients. The predominant patterns of ILD were organizing pneumonia (OP) and nonspecific interstitial pneumonitis-OP overlap, which were seen in 6 (24.1%) patients each. RP-ILD was present only in 2 (6.8%) patients. Left ventricular dysfunction was seen in 2 (6.8%) patients. Clinical muscle weakness was reported in 15 (51.7%) patients, whereas 10 (34.6%) patients were hypomyopathic DM and 4 (13.7%) patients were amyopathic.
|Figure 2: Multiple confluent ground glass opacities and consolidations with dependent and basal segment predominance-probable NSIP ILD. NSIP ILD: Nonspecific interstitial pneumonitis interstitial lung disease|
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Antinuclear antibody positivity by immunofluorescence was seen only in 2 (6%) patients. Anti-Ro52 positivity was seen in 7 (24.1%) patients and anti-Ku was positive in 1 patient. No patient in our cohort had malignancy at presentation or follow-up.
Comparison between anti-melanoma differentiation-associated gene 5 dermatomyositis cohort and nonanti-melanoma differentiation-associated gene 5 myositis cohort
The clinical features of these anti-MDA-5 DM patients were compared with 421 non-MDA-5 myositis patients and are summarized in [Table 1]. There were no statistically significant differences in gender, age at diagnosis, or disease duration. Among the cutaneous manifestations, Gottron's sign (P < 0.001), panniculitis (P < 0.001), calcinosis (P < 0.001) [Figure 3], and cutaneous ulcerations (P < 0.001) were significantly present in the anti-MDA5 group. Among the systemic manifestations, inflammatory arthritis (P < 0.001) and ILD (P < 0.02) were present more commonly in the anti-MDA5 IIM group, whereas myopathy (P < 0.001), elevated CPK (P < 0.001), and LDH (P < 0.001) were more frequently present in the non-anti-MDA5 IIM group.
|Figure 3: Plain radiograph anteroposterior view of the pelvis and hip with femur showing extensive calcinosis|
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Glucocorticoids were started in 27 (93%) patients. Eleven patients (37.9%) and 16 patients (55.1%) received 0.5 mg/kg and 1 mg/kg prednisolone equivalent of steroids, respectively. Mycophenolate was the most common steroid-sparing agent used in our cohort (16 patients, 55.2%). Methotrexate was used in 8 patients (27.6%), cyclophosphamide in 3 (10.3%), and azathioprine in 1 (3.4%). Rituximab was administered in 6 patients (20.6%), indications being cutaneous disease (2 patients), refractory panniculitis (1 patient), calcinosis (1 patient), RP-ILD (1 patient), and to facilitate faster steroid tapering in 1 patient.
Among 29 patients, 6 patients did not have even a single follow-up and were not considered for outcome analysis. The mean (±SD) follow-up duration was 15.5 (±13.9) months. Complete response was seen in 10 patients (43.4%), while a partial response was seen in 8 patients (34.7%). Five patients died on follow-up, accounting for mortality of 21.7%. Relapses were seen in 4 patients – worsening calcinosis (2 patients), cutaneous (1 patient), and arthritis (1 patient). The refractory calcinosis in one patient responded to rituximab, whereas the other patient [Figure 4] was refractory to rituximab, tofacitinib, and pamidronate.
Response to immunosuppression in interstitial lung disease
The initial presentation of RP-ILD was seen in two patients. The first patient died at the initial presentation. The second patient was given methylprednisolone pulse with rituximab and mycophenolate, however, succumbed due to progressive respiratory failure within 1 week. All the patients were treated with mycophenolate. All the patients were given 0.5 mg− 1 mg/kg prednisolone equivalent of glucocorticoids at the discretion of the treating physician. Improvements in spirometry/clinical improvement were seen in all patients. The mean (±SD) forced vital capacity% at baseline was 66.6 (±19.19) and on follow-up was 81.6 (±29.45). Two of these patients died on follow-up: one due to sepsis and the other due to diabetic ketoacidosis.
Mortality during follow-up
Overall, five patients died during the follow-up period. The cause of death is shown in [Table 2]. The median duration between onset of symptoms and death was 12 months (range: 3–12). A logistic regression analysis [Table 3] was done to identify the predictors of mortality. Age more than 50 years was significantly associated with mortality (P = 0.025). The presence of Anti-Ro52 antibodies and ulcerated Gottron's was not associated with mortality (P = 0.99 and 0.45, respectively) in our cohort.
|Table 3: Logistic regression analysis predicting the mortality in anti-melanoma differentiation-associated gene 5 dermatomyositis|
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| Discussion|| |
The presentation of anti-MDA5 IIM varies across various cohorts with the RP-ILD phenotype in the Japanese and Chinese populations to arthritis, rash, and amyopathic presentation in Caucasians [Table 4]. In this study, we present the clinical characteristics and treatment outcomes from our cohort of anti-MDA-5 DM. The clinical characteristics which were significantly more in the anti-MDA5 group were Gottron's sign, panniculitis, calcinosis, palmar papules, cutaneous ulcers with ulcerated Gottron's, inflammatory arthritis, amyopathy, and presence of ILD. Palmar papules and ulcerated Gottron's, which are one of the unique manifestations previously reported in the Caucasian cohort, were seen in 13.4% and 24.1% of our patients, respectively. Clinicians need to be aware of these presentations, as they could be the sole and initial manifestations of the disease. Inflammatory arthritis closely mimics rheumatoid arthritis, and it could lead to misdiagnosis in early cases. Around one-fourth (24.1%) of our patients had anti-Ro52 positivity, which was slightly less than the previously reported., Relatively low CK and LDH levels observed in our study are consistent with the previous studies., This goes in line with a high percentage of the amyopathic pattern of muscle involvement and the muscle biopsy findings of sparse inflammation, focal or absent Major histocompatibility complex (MHC-I) expression, and membrane attack complex.
|Table 4: Comparison of prominent cohorts of adult anti-melanoma differentiation-associated gene 5 dermatomyositis|
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OP was the most common type of ILD seen in our cohort. All of our ILD patients with non-RP-ILD presentations were treated with steroids and mycophenolate as the second-line agent. Among those who had to follow up data, all patients had improvement either clinically or in lung function tests. This is to emphasize that all patients with ILD in anti-MDA5 DM may not need aggressive immunosuppression. There is a wide disparity in the presentation of ILD and RP-ILD between Asians and Caucasians. While ILD and RP-ILD are seen in 82%–90% and 39%–100% of Japanese and Southeast Asian cohorts, respectively,,, the prevalence is only 38%–73% and 20%–57%, respectively, in Caucasian series., Our cohort was behaving more like a Caucasian cohort, with ILD being present in 17 (60.7%) patients and RP-ILD in only 2 patients (6.8%). Surprisingly, we had a lower number of RP-ILD in our cohort. One of the explanations may be that they might have succumbed to the disease even before they reached our center. However, considering the other series from India, it looks like the percentage of RP-ILD is lesser than that of the Southeast Asian population.
Five patients (21%) succumbed to the disease. Of these two were due to RP-ILD which is known to have over 80% mortality. This was consistent with the other studies from India which had 30% mortality at 1 year. Among the predictors of mortality, age > 50 years was significantly associated with mortality. This finding was similar to previous cohorts.,
Ro52 and MDA-5 are cytoplasmic proteins that are involved in the interferon pathway. An unknown viral trigger can stimulate the receptors like MDA-5 and can lead to interferon production. A co-existence of these antibodies may theoretically increase the interferon signature burden leading to severe disease. The presence of anti-Ro52 is a known poor prognostic factor in anti-Jo-1-positive antisynthetase syndrome. Anti-Ro52 positivity was associated with higher odds of mortality (odd ratio: 17.5 [95% confidence interval: 2.19–173.49]) in a retrospective cohort study by Dunga et al. Our study, however, did not show increased mortality with the presence of anti-Ro52. [Table 4] shows the comparison of the salient characteristics of anti-MDA5 + patients from various cohorts.
Infectious complications were less in our cohort. This may be because of the robust antibiotic prophylaxis with co-trimoxazole (one double-strength tablet thrice weekly) commonly followed in our center in all patients on long-term immunosuppression, apart from pneumococcal and influenza vaccinations.
There was no malignancy detected during follow-up of the patients. Cancer has been reported in French and Japanese cohorts in 7%–9% of patients. However, a Spanish cohort has reported higher rates of malignancy (28%).
Major limitations in our study were the small sample size and the retrospective nature of the study. All patients did not have CT scan at follow-up leading to missing data. Since this study was done around the COVID era, six patients were lost to follow-up. Furthermore, we did not include juvenile patients in our study. Although this is a single-center study, our tertiary care setup caters to populations across the country with diverse ethnic backgrounds.
| Conclusions|| |
Anti-MDA5 DM behaves as a distinct entity in inflammatory myositis with characteristic clinical patterns. A combination of high-dose steroids with mycophenolate led to improvement in all the patients with anti-MDA5 antibodies and non-RP-ILD presentations. Increasing age is a poor prognostic factor for mortality.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]