[CUHK Medical Grand Rounds] Anti-MDA5 dermatomyositis: A deadly disease
Idiopathic inflammatory myopathies (IIMs) are a heterogenous group of disorders characterized by muscle weakness and inflammation. In adults, they can be classified into major subgroups including dermatomyositis (DM), polymyositis (PM) and inclusion‐body myositis.1 Necrotizing autoimmune myositis is a subtype of polymyositis.
Diagnosis of IIMs is made based on a combination of clinical, histological and laboratory features. The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2017 classification criteria for IIMs, currently the most widely used classification criteria, adopted a probability score model of classifying patients with “definite”, “probable” or “possible” IIM based on clinical features, laboratory findings and muscle biopsy characteristics.1
Myositis-specific antibodies (MSAs) are specific for DM and PM. However, except for anti-histidyl-tRNA synthetase antibody (anti-Jo1), MSAs are not included in the classification criteria of IIMs. MSAs are pivotal biomarkers for predicting clinical manifestations and disease prognosis in IIMs.1 For example, anti-transcription intermediary factor 1 gamma (anti-TIF1γ) antibody is highly associated with malignancy, anti-M2 antibody is associated with steroid-responsive DM, and anti-signal recognition particle (anti-SRP) antibody is associated with treatment-resistant PM. Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody–related DM is a growing disease entity. Increased awareness of anti-MDA5 DM is related to its association with rapidly progressive interstitial lung disease (RP-ILD) and high mortality.
Case presentation and management
A 40-year-old male security guard, who had enjoyed good past health, was admitted to our hospital for shortness of breath and decreased exercise tolerance. He complained of pain at multiple joints and oral ulcers. No muscle weakness or dysphagia was reported. Physical examination showed heliotrope rash and Gottron papules over the elbows as well as proximal and distal interphalangeal joints. A small ulcer was noted over the Gottron papule atop the metacarpophalangeal joint of the left middle finger. (Figure 1) There were also swelling and tenderness over multiple proximal and distal interphalangeal joints of both hands, wrists, elbows and shoulders. However, muscle power of the limbs was full.
Chest examination showed fine crepitations over bilateral lung bases. Oxygen supplementation at 3 L/min was given. Laboratory investigations demonstrated mildly raised creatine kinase level (516 U/L; normal range, 39–308 U/L), high ferritin level (4,867 pmol/L; normal range, 67–889 pmol/L), and normal C-reactive protein level. MSA testing revealed strongly positive anti-MDA5 antibody. High-resolution CT scan showed ground glass opacity over bilateral lung bases. Bronchoalveolar lavage was performed, which ruled out infection. The patient was diagnosed with anti-MDA5–positive DM with RP-ILD.
The patient was treated with pulse methylprednisolone (1 g daily) for 3 days, followed by oral prednisolone (1 mg/kg/day). Intravenous (IV) rituximab (1 g, 2 doses, 2 weeks apart) and oral cyclosporin were also given. The treatment provided gradual improvement in the patient’s condition, and he was discharged with 2 L/min of long-term oxygen supplementation.
Two months later, the patient complained of sudden-onset shortness of breath with neck swelling. CT scan showed small pneumothorax with gross pneumomediastinum and subcutaneous emphysema. (Figure 2) He was treated with high-flow oxygen, with good recovery, and was discharged. Steroid was gradually tapered during follow-up visits at the clinic. With gradual improvement in lung function, oxygen supplementation was weaned down to 1 L/min.
Most patients with anti-MDA5 DM are clinically amyopathic. As such, anti-MDA5 antibody was formerly known as anti-clinically amyopathic dermatomyositis (CADM)-140 antibody. Anti-MDA5 DM is associated with RP-ILD, with a significantly lower 6-month survival rate than anti-MDA5–negative DM (approximately 50 percent vs >97 percent), making the presence of anti-MDA5 antibody an independent risk factor of poorer prognosis.2,3
Patints with anti-MDA5 DM have distinctive cutaneous ulcerations with predilection at sites of Gottron papules, as well as Gottron signs over digital pulps, periungual area, palmar papules and elbows.4 Cutaneous ulceration is highly associated with the development of interstitial lung disease (ILD). The exact mechanism of cutaneous ulceration in anti-MDA5 DM is uncertain, and may be related to underlying occlusive vasculopathy. Other mucocutaneous features of anti-MDA5 DM include oral ulcers, panniculitis, non-scarring hyperkeratosis at the thenar and lateral aspects of fingers, and diffuse alopecia. Polyarthritis and polyarthralgia are also common.
RP-ILD is defined as progressive ILD within 3 months of onset of respiratory symptoms. It is more common in Chinese and Japanese patients with anti-MDA5 DM, and is the leading cause of death with a mortality rate of up to 45 percent. Therefore, all patients with anti-MDA5 DM should be screened for ILD. High-resolution CT (HRCT) scan of thorax, lung function test, 6-minute walk test and echocardiogram should be performed to assess disease severity. Typically, HRCT findings show lower consolidation or ground glass opacities in the lower lobe of lung or a random pattern, without intralobular reticular opacities.5 Spontaneous pneumomediastinum is a rare complication that occurs in 2.2 percent of patients with anti-MDA5 DM and RP-ILD.6 Cutaneous ulcer is an independent risk factor of spontaneous pneumomediastinum.
High serum ferritin level (≥1,500 ng/mL) is associated with RP-ILD in anti-MDA5 DM, and confers a poor prognosis.7 Both serum ferritin level and anti-MDA5 antibody titre are correlated with disease activity and could therefore be used to monitor treatment response.3 Krebs von den Lungen‐6 (KL‐6) serum levels may also be used to monitor disease response and relapse.8
Aggressive and timely treatment of anti-MDA5 DM with RP-ILD is crucial. Early initiation of combination therapy with high-dose corticosteroid, IV cyclophosphamide and cyclosporin is recommended.9 However, some studies have shown suboptimal treatment response with combination therapy in some patients.10 With case series reporting promising results with IV rituximab,11 the anti-CD20 monoclonal antibody is also being used in treatment of anti-MDA5 DM with RP-ILD.
In conclusion, high clinical awareness of anti-MDA5 DM is of paramount importance. Prompt and aggressive treatment could potentially reduce morbidity and mortality in patients with RP-ILD.