Plasma exchange for anti-MDA5 antibody-positive dermatomyositis-associated rapidly progressive interstitial lung disease: A case report and literature review

Abstract

The prognosis of anti-MDA5-positive dermatomyositis (DM)-associated rapidly progressive interstitial lung disease (RPILD) is extremely poor and effective treatment options are limited. In addition, the risk of infection during immunosuppressive treatment is a major challenge. We report here, a case of RPILD in a 31-year-old man with anti-MDA5 antibody-positive DM. Despite treatment with methylprednisolone and human immunoglobulin, his lung condition worsened and his serum ferritin levels increased. Six cycles of plasma exchange (PE) adjuvant treatment significantly mitigated his symptoms and he was discharged from hospital two months later. We suggest that PE may be a promising therapeutic option for patients with anti-MDA5-positive DM-associated RPILD. However, randomized, controlled studies are required to confirm our findings.

Background

Inflammatory myopathies, collectively known as myositis, are a heterogeneous group of rare diseases that affect multiple organs and systems, including muscles, skin, lungs, and joints. ¹ There are five main types of inflammatory myopathies: dermatomyositis (DM); immune-mediated necrotizing myopathy; sporadic inclusion-body myositis; overlap myositis (including anti-synthetase syndrome); polymyositis. ¹ Inflammatory myopathy-specific autoantibodies are often used to identify patients with inflammatory myopathies. ² The anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody was first reported as a specific autoantibody to clinically amyopathic dermatomyositis (CADM) and termed anti-CADM-140; its target autoantigen was later identified as MDA5. ² CADM is a type of DM characterized by typical skin lesions but no obvious myositis symptoms. ³ Patients with CADM may develop rapidly progressive interstitial lung disease (RPILD), and anti-MDA5 antibody is closely associated with RPILD in CADM patients, especially in East Asia.^4,5 The prognosis of patients with CADM that develop RPILD remains poor. ⁶ RPILD is not unique to CADM and is also seen in some patients with DM. ⁵

Combination therapy including corticosteroids plus a calcineurin inhibitor or triple therapy including intravenous cyclophosphamide should initially be used in patients with anti-MDA5-positive DM-associated RPILD. ⁷ However, despite intensive immunosuppressive therapy, approximately 40% patients still have a poor prognosis. ⁸ If calcineurin antagonists are contraindicated or treatment fails, other immunosuppressive agents may be substituted or added on an individualized basis. For example, plasma exchange (PE), polymyxin B hemoperfusion and/or intravenous immunoglobulin may be used as rescue options. ⁸ In life-threatening situations, Extra Corporeal Membrane Oxygenation (ECMO) should be considered. ⁸

We report here a case of RPILD in a patient with anti-MDA5-positive DM. Importantly, although treatment with corticosteroids did not prevent the development of RPILD, short-term PE significantly improved the condition.

Case presentation

A 31-year-old male patient with a three-week history of cough and sputum, and a two-week history of muscle weakness and myalgia was admitted to our hospital. He had developed a cough with white sputum without any obvious cause and felt discomfort and feverish, although he had not measured his body temperature. He experienced muscle weakness and bilateral arm myalgia, which had not occurred previously. Subsequently, his symptoms spread to both legs. He had no history of other illnesses or long-term medication. The patient had been admitted to a local hospital due to myalgia exacerbation following exertion. His initial treatment with ceftriaxone and moxifloxacin had not alleviated his symptoms. Accordingly, the patient was transferred to our hospital for further treatment.

Tenderness and weakness in the proximal muscles of his limbs were observed on physical examination. Additionally, the patient had erythema-resembling skin lesions on his nail circumference, upper eyelids, and dorsal and palm sides around the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints, suggesting a heliotropic rash. Laboratory findings were as follows: white blood cell (WBC) count, 3.0 × 10⁹/l (physiological range, 3.5–9.5 × 10⁹/l); neutrophils, 62%; haemoglobin, 129 g/l (physiological range, 130–175 g/l); platelets, 159 × 10⁹/l (physiological range, 125–350 × 10⁹/l); high-sensitivity C-reactive protein (CRP), 10.0 mg/l (physiological range, 0.0–5.0 mg/l); lactate dehydrogenase (LDH), 252 IU/l (physiological range, 120–250 IU/l); ferritin, 881 µg/l (physiological range, 30–400 µg/l); creatine kinase, 365 IU/l (physiological range, 50–310 IU/l). Chest computed tomography (CT) showed patchy ground-glass opacities in the periphery of both upper lobes, with interlobular septal thickening, consolidation of the left lower lobe, and a slightly smaller area of consolidation of the right lower lobe.

Although moxifloxacin (0.4 g per day for 13 days) and low-dose methylprednisolone (40 mg per day) were prescribed, no satisfactory improvement of symptoms was observed. Urinalysis, and tests of liver function, and renal function showed no abnormal findings. In addition, tests were negative for, rheumatoid factor, antinuclear antibody, anti-neutrophil cytoplasmic autoantibodies, hepatitis B antibodies, hepatitis C antibodies, and T-SPOT tuberculosis. Muscle biopsy findings suggested mild myogenic damage, while enhanced magnetic resonance imaging (MRI) of the right leg muscle showed mild oedema in the right sartorius muscle and biceps femoris. Electromyography (EMG) showed no evident myogenic damage. Lung function was not assessed due to treatment tolerability concerns. However, analysis of myositis-specific autoantibodies showed presence of anti-MDA5 antibodies.

Based on clinical presentation and laboratory findings, a diagnosis of anti-MDA5 antibody-positive DM was established. The patient was treated with methylprednisolone (500 mg per day for three days) and human immunoglobulin (20 g per day for five days); the dose of methylprednisolone was gradually reduced. Piperacillin (4.5 g every 8 hours for two weeks), caspofungin (50 mg per day for one week), and sulfamethoxazole (0.48 g twice daily) were also administered to prevent infection. The patient’s chest congestion and cough did not improve, and his oxygen saturation was 90% which led to dyspnoea after exertion. His chest CT indicated RPILD (Figure 1).

Figure 1.

Chest computed tomography (CT) scans taken weekly showed enlargement of lung exudative lesions (a–e).

Since interstitial pneumonia progressed rapidly and infection could not be completely ruled out, we initiated PE as adjuvant therapy (three times per week, fresh frozen plasma 2000 ml/time). PE was completed in six sessions and followed by prednisolone (60 mg/day), tacrolimus (1 mg bd), and pirfenidone (100 mg tds). The patient’s symptoms gradually improved, and he was discharged from hospital two months later. At his follow-up examination five months after discharge from hospital, he was stable and on low-dose prednisone (7.5 mg/day) combined with calcium tablets. Treatment with tacrolimus and pirfenidone was maintained.

The reporting of this study conforms to CARE guidelines. ⁹ Written informed consent was obtained from the patient to publish his anonymised data. Ethical committee approval was not required because this was a case report based on clinical data recorded during the patient’s hospitalization.

Discussion

Anti-MDA5 antibodies were first identified as autoantibodies in 2005. ¹⁰ Investigators reported that the antibodies were associated with DM, particularly patients with CADM. ¹⁰ In subsequent studies, levels of anti-MDA5 have been shown to be associated with several clinicopathological characteristics and prognosis of DM. ¹¹ Moreover, the presence of anti-MDA5 antibodies in patients with CADM has been suggested to be a predictor of RPILD, a leading cause of death in patients with CADM. ¹¹ In one retrospective study, three patients were successfully treated with PE, and the anti-MDA5 Ab titre decreased significantly over the course of the therapy. ¹² Elevated levels of serum ferritin and anti-MDA5 antibody levels have also been correlated with the severity of RPILD in patients with DM.^13,14

In the case study reported here, the patient presented with cough, myalgia, and a skin rash. Laboratory tests showed a slight increase in creatine kinase and a muscle biopsy showed mildly myogenic damage. Following a chest CT examination that showed exudative lesions in the lungs and the presence of myositis-specific autoantibodies, anti-MDA5 antibodies, a diagnosis of anti-MDA5-positive DM with RPILD was confirmed. The patient was treated with methylprednisolone combined with human immunoglobulin but his RPILD worsened. However, six cycles of PE adjuvant treatment significantly mitigated his symptoms. He was subsequently treated with prednisolone, tacrolimus, and pirfenidone and was discharged from hospital two months later.

Although anti-MDA5-positive patients with DM and RPILD are often treated with a cocktail of immunosuppressants,^15–17 intensive immunosuppressive therapy in these patients can increase risk of death due to severe infection. Therefore, establishing a balance between immunosuppression and infection prevention is critical in their management. In our patient, the combination of methylprednisolone pulse therapy and immunoglobulin failed to mitigate his symptoms, but we decided to avoid more potent immunosuppressive agents because of infection concerns. We decided to use PE because of his disease exacerbation. By removing pathological substances (e.g., autoantibodies, immune complexes, and cytokines), PE can improve symptoms in patients with refractory or severe autoimmune diseases. ¹⁸ Interestingly, from a search of the PubMed database for studies published between 2010 to 2020, using the terms “anti-MDA5 antibody AND (plasmapheresis OR plasma exchange)”, we identified five studies that reported successful treatment of anti-MDA5-positive CADM patients with RPILD using PE.^19–23 In addition, a study from Japan reported that PE improved the one-year survival rate in patients with anti-MDA5-positive RPILD. ²⁴ Moreover, this study showed that PE therapy can be used in the setting of active infection. ²⁴ Importantly, the results of a recent retrospective study showed that any PE related adverse events can be resolved with appropriate interventions. ²⁵ Nevertheless, some studies have suggested PE has limited therapeutic value in patients with anti-MDA5-positive RPILD.^26,27 Although we did not evaluate anti-MDA5 antibody titres before and after treatment, we found that PE considerably improved our patient’s respiratory symptoms. However, randomized, controlled studies are required to confirm the efficacy and safety of PE in patients with anti-MDA5-positive RPILD.

The prognosis of anti-MDA5-positive DM-associated RPILD is extremely poor, and effective treatment options are limited. The risk of infection during immunosuppressive treatment is another challenge. Our findings, and those from several other previous studies, support the concept that PE is a promising adjuvant therapy for patients with anti-MDA5-positive DM-associated RPILD.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231198742 - Supplemental material for Plasma exchange for anti-MDA5 antibody-positive dermatomyositis-associated rapidly progressive interstitial lung disease: A case report and literature review

Supplemental material, sj-pdf-1-imr-10.1177_03000605231198742 for Plasma exchange for anti-MDA5 antibody-positive dermatomyositis-associated rapidly progressive interstitial lung disease: A case report and literature review by Ci Lu, Cheng Xu, Xiaoying Zhu and Yongmei Han in Journal of International Medical Research