Targeted quadruple therapy in anti‐MDA5 positive dermatomyositis with orbital and pulmonary complications

Here, we present a case of anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis complicated by orbital cellulitis/ulceration and rapidly progressive interstitial lung disease (RP-ILD), successfully treated with quadruple therapy. A 40-year-old female patient with no significant past medical history presented to University of Texas Medical Branch, with periorbital swelling. She had previously experienced two episodes, each diagnosed as angioedema, at an outside hospital over the last 2 months. Upon admission, she was febrile, 38°C, tachycardic, 130 beats per minute, hypertensive, 137/94 mmHg, oxygen saturation 100%, and respiratory rate 14 breaths per minute. The physical examination revealed bilateral periorbital swelling, Gottron's sign (Figure 1A), Gottron's papules (Figure 1B), Holster sign (Figure 1C), and digits ulceration (Figure 1D). No synovitis or mouth ulcers were observed. The cardiorespiratory examination was negative for crackles and murmurs, and muscle strength was unremarkable. Laboratory tests showed elevated: white blood cell count (18.72 × 109 cells/L; reference < 10.8 × 109 cells/L), neutrophils (16.82 × 109 cells/L; reference < 7.8 × 109 cells/L), erythrocyte sedimentation rate (71 mm/1 h; reference < 20 mm/1 h), C-reactive protein (14.1 mg/L; reference < 8 mg/L). A comprehensive metabolic panel, creatinine kinase, and complement 1 esterase inhibitor were within normal ranges. The infectious workup revealed bacteremia with Group A Streptococcus (GAS). The autoimmune workup returned positive for elevated antinuclear antibody (1:320, speckled pattern), rheumatoid factor (94 IU/mL; negative < 14 IU/mL), and SSA-52 (80 AU/mL; negative < 40). The following autoantibodies were negative: anti-centromere, anti-SCL-70, anti-Smith, anti-ribonucleoprotein, anti-SSB, anti-dsDNA, anti-cyclic citrullinated peptide, anti-neutrophil cytoplasmic antibody. Complement levels (C3, C4) and tumor markers (carcinoembryonic antigen, CA19-9, CA-125) were also within normal limits. A computed tomography (CT) of the orbit showed preseptal cellulitis bilaterally and postseptal cellulitis in the left orbit (Figure 1E). The chest X-ray (CXR) was unremarkable. The electrocardiogram showed sinus tachycardia, and a transthoracic echocardiogram was negative for vegetations. She was started on intravenous (IV) ampicillin-sulbactam. Based on her clinical symptoms, a diagnosis of anti-MDA5 dermatomyositis was suspected and confirmed with serologic testing. She received IV immunoglobulin (IVIG; 2 g/kg divided over 3 days) on Day one. Due to concurrent bacteremia, immunosuppressive therapy was initially withheld. However, 5 days post-admission, she developed bilateral periorbital ulceration (Figure 1F) and hypoxemia requiring 6 liters per minute of oxygen. A repeat CT of the orbit again showed cellulitis without evidence of necrotizing fasciitis. A CT angiogram of the lungs was negative for pulmonary embolism but revealed multifocal bilateral consolidative opacities (Figure 1G). The absence of cough, dysphagia, and infiltration on the CXR at the time of admission argued against bacterial pneumonia, instead supporting RP-ILD associated with anti-MDA5 dermatomyositis. On Day 7, rituximab (375 mg/m² body surface area weekly for 4 weeks) and IV methylprednisolone (1000 mg, daily for 3 days) were initiated due to worsening hypoxemia and the resolution of bacteremia. By Day 10, the patient required high-flow oxygen, 40 L/min. A repeat CT thorax showed worsening infiltrates (Figure 1H). Concerns about the treatment's delayed efficacy led to the initiation of plasmapheresis. Twenty-four hours after one plasmapheresis session (Day 11), her oxygen requirements significantly decreased from 40 to 6 L/min. She underwent a total of five plasmapheresis sessions every 2 days. Her ferritin levels went down from 1200 to 402 ng/mL after one session of plasmapheresis, rituximab, and IV methylprednisolone. On Day 14, mycophenolate mofetil was initiated at 1000 mg twice daily. The patient completed four doses of rituximab and was discharged on 1000 mg of mycophenolate mofetil twice daily and 2 L/min of oxygen. Six months later, she remained stable on 1000 mg of mycophenolate mofetil twice daily and 2 L/min of oxygen during sleep. Her skin lesions and periorbital edema had healed well with no recurrence. Anti-MDA5 dermatomyositis is known to be associated with periorbital edema and cutaneous ulcerations, most often affecting the fingers, elbows, knees, and ears.1 A few cases describe periorbital ulceration following preseptal cellulitis due to GAS.2 We hypothesize that the periorbital swelling was secondary to MDA5, which disrupted the skin barrier, allowing the infection to take hold. Because bacteremia coincided with ulcer development, we cannot definitively attribute ulceration to MDA5 alone; rather, the combination of dermatomyositis-related vasculopathy and infection likely contributed to the lesion. Anti-MDA5 is also known to cause RP-ILD.3, 4 Given high mortality rate, the American College of Rheumatology guidelines recommend triple therapy.5 Those requiring supplemental oxygen or demonstrating radiographic progression over days to weeks should receive glucocorticoids plus two disease-modifying antirheumatic drug (DMARD). When oxygen requirements escalate precipitously or imaging reveals diffuse alveolar damage, a fourth modality such as plasmapheresis should be considered to achieve rapid disease control given lagging effect of DMARDs. Our patient's bacteremia initially precluded immunosuppression use, so we commenced treatment with IVIG. Following clearance of blood cultures, we escalated to methylprednisolone combined with mycophenolate mofetil and rituximab, the latter selected over cyclophosphamide to minimize risks of cytopenia and urotoxicity. Despite this triple regimen, her hypoxemia worsened rapidly. The introduction of plasmapheresis resulted in a marked improvement in oxygenation within 24 h. This sequential escalation from single to triple to quadruple therapy once infection was controlled highlights a practical strategy for balancing the urgency of immunosuppression against the risks posed by concomitant sepsis. This case is worthy of reporting for three principal reasons. First, it expands the clinical spectrum of anti-MDA5 dermatomyositis by suggesting that periorbital ulceration can occur when vasculopathy and infection intersect. Second, it offers a detailed, infection-conscious algorithm for managing RP-ILD, demonstrating that aggressive immunomodulation, including rituximab, mycophenolate, steroids, and plasmapheresis can be deployed safely after sepsis is addressed. Third, it illustrates that rituximab-centered triple and quadruple regimens can achieve rapid and sustained improvement without the toxicities traditionally associated with cyclophosphamide. By describing these novel observations and therapeutic considerations, we aim to inform clinicians of both a previously unrecognized cutaneous manifestation and a stepwise approach to immunosuppression in complex anti-MDA5 dermatomyositis. Lastly but not least, this case encourages general practitioners, ophthalmologists, and allergists to be aware of this entity, as the initial presentation can be orbital swelling. Enrique Medina contributed to the discussion sections of the case. In addition, he retrieved the references to support those sections and made the necessary edits to every part of the report. Sameen Zafar contributed to writing the introduction, drafting, and editing the report. Roopkiran Panesar wrote the case presentation and assisted with drafting and editing the report. Ronak Gandhi retrieved and discussed imaging and assisted with drafting the report. Vijaya Murthy edited each part of the case report and helped in the management of the case. All authors contributed intellectually to the case. We thank the patient and their family for trusting us with their care and management. The authors declare no conflicts of interest. All images are obtained with permission from the patient and family. Written consent was obtained from the patient for participation in research and publication. The data that support the findings of this study are available from the corresponding author upon reasonable request.