Dermatomyositis with positive anti-MDA5 antibody has a distinct phenotype in terms of skin, joint, muscle, and lung involvement in both children and adults. It is associated with mucocutaneous ulceration, symmetrical polyarthritis of small joints of the hands. It is also found to be associated with painful palmar papules in adults [7–9]. For muscle involvement, most adult patients are clinically amyopathic, although the distribution varies with the ethnic group where CADM occurred in 82% of Japanese and 45% of Caucasian [6, 10]. CADM was not commonly reported in JDM with anti-MDA5 antibody, but it has a milder muscle involvement compared to those without [7]. For lung involvement, ILD overall occurs rarely in only 8% of JDM [11], while it occurs at a higher frequency in those with anti-MDA5 antibody. In a Japanese study, all 11 out of 35 JDM patients (31%) who possessed the antibody had ILD, of whom 6 had RP-ILD. It was concluded that JDM patients with the antibody were significantly more likely to have RP-ILD [12]. Ethnic difference in the severity of ILD in anti-MDA5 antibody-positive dermatomyositis is observed, where ILD is in general not rapidly progressive in Caucasians in both children and adults [7, 10].
It was a diagnostic challenge with our patient’s presenting symptoms mimicking juvenile idiopathic arthritis or vasculitis, leading to a one-month delay in diagnosis as pathognomonic cutaneous features and muscle weakness did not appear at first presentation. In retrospect, the patient was first presented with the typical phenotype of anti-MDA5 antibody-positive dermatomyositis with cutaneous ulceration, palmar papules, and small hand joint arthritis. Other than these features, the interphalangeal joint hyperpigmentation and calcinosis over external ears should alert one to dermatomyositis. An awareness of less common signs of dermatomyositis and a high index of suspicion are required to make the diagnosis. The diagnosis of dermatomyositis in our patient was supported by positive anti-MDA5 antibody and evidence of inflammatory myopathy on MRI without performing muscle biopsy and electromyography described in the widely used Bohan and Peter’s criteria [13]. Anti-MDA5 antibody is one of the MSA that is dermatomyositis-specific, which is not found in other inflammatory myopathies or connective tissue disorders [2, 8]. Although negative MSA does not exclude the diagnosis, the test is non-invasive and is helpful in patients with cutaneous features not specific to dermatomyositis. Anti-MDA5 antibody is particularly important to be performed in patients presenting with skin ulcers of unknown diagnosis even without muscle weakness because of its essential prognostic value. Referencing on the high mortality rate due to respiratory failure in RP-ILD from adult data, one can anticipate a rapid disease progression and complications in those with positive anti-MDA5 antibody. It is valuable as ILD can occur very early in the disease course as in our patient, where an early diagnosis allows a window for aggressive treatment such that progression into RP-ILD may be avoided. New classification criteria by the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) for adult and juvenile idiopathic inflammatory myopathies were recently published, in an effort to include one MSA – anti-Jo1 antibody [14]. It is expected that other MSA may be incorporated in the classification criteria in the future after MSA is more widely used.
Due to rarity of the disease hence a lack of randomized controlled trials, the current treatment for JDM is largely based on consensus guidelines. The treatment for JDM with ILD or anti-MDA5 antibody is not well established. It could also be attributed to the lack of ILD grading parameters to guide further studies. In 2010, the Childhood Arthritis & Rheumatology Research Alliance (CARRA) in North America reached consensus on the treatment of moderately severe JDM, using a combination of steroid and MTX with or without IVIG [15]; however patients with pulmonary involvement and skin ulceration were excluded. In 2017, the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative proposed a treatment recommendation for JDM with major organ involvement, using cyclophosphamide in addition to steroid and MTX, and consider the use of IVIG, cyclosporine A, infliximab, rituximab etc. in cases with poor response [16]. However, the decision to intensify treatment is based solely on clinician’s opinion. Owing to high mortality, treatment for anti-MDA5 antibody-positive JDM should be individualized as early intensification of therapy in those with a poor response may be vital. In adults, the recommended initial treatment for ILD with anti-MDA5 antibody is at least dual therapy with steroid and calcineurin inhibitor with or without cyclophosphamide [17, 18]. We followed this recommendation as the patient was in her adolescence and the fact that there was a lack of paediatric recommendation. It has been debated whether to use cyclophosphamide in view of the risk of gonadotoxicity for young females. However, her disease was steroid-resistant with rapid progression of ILD and was complicated with PNM. It was alarming as a recent study suggested that PNM in adult anti-MDA5 antibody-positive dermatomyositis patients was associated with significantly higher mortality [19]. Multiple immunosuppressants including cyclophosphamide and rituximab were required to induce disease remission. It is difficult to conclude the efficacy of rituximab, a chimeric monoclonal anti-CD20 antibody that depletes B-cell, as multiple agents were added in proximity. The use of rituximab in RP-ILD with positive anti-MDA5 antibody appeared promising in an adult case series [20], however there are few reports on its use in paediatric groups.
To improve the survival rate of refractory dermatomyositis, there is a need for novel mechanism-based treatment in the era of molecular medicine. It has been reported that the type I interferon (IFN) pathway is involved in the pathogenesis of juvenile and adult dermatomyositis [21]. Ladislau et al. demonstrated in 2018 that type I IFN pathway activation in vitro reproduces the main dermatomyositis pathological findings including muscle atrophy and vasculopathy, and the pathogenic effects in vitro were abolished by a Janus kinase (JAK) inhibitor ruxolitinib that targets the IFN pathway [22]. Sabbagh et al. in 2019 reported the use of tofacitinib, a JAK inhibitor, leading to clinical improvement within six months in two anti-MDA5 antibody-positive JDM refractory to multiple agents including rituximab [23]. Further studies are required to shed light on the use of JAK inhibitor as adjuvant or rescue treatment for this subset of JDM.