An Unusual Case of Infection-Provoked Macrophage Activation Syndrome in Mixed Connective Tissue Disease

Background Compared to systemic lupus erythematosus and adult-onset Still’s disease, mixed connective tissue disease (MCTD) is rarely associated with macrophage activation syndrome (MAS). Viruses, including cytomegalovirus (CMV), may potentiate MAS,[1] often in conjunction with an underlying connective tissue disease.[1-3] Despite this, reports of infection-provoked MAS in adults with MCTD remain very rare.[2,3] Here we describe a case of MAS in a patient with MCTD and concurrent CMV viremia and Clostridioides difficile colitis.

Case Report A 65-year-old male was diagnosed with MCTD after presenting with pulmonary arterial hypertension, presumed glomerulonephritis, Raynaud’s phenomenon, and polyarthritis on a background of coronary artery disease and recent NSTEMI requiring stent placement. Investigation revealed a positive ANA (≥1:640, speckled pattern); high-positive anti-RNP-A, Sm/RNP, Ro60/SSA, Ro52/TRIM21, and SSB; and proteinuria. Right heart catheterization and renal biopsy were deferred given dual-antiplatelet therapy and spontaneous renal recovery. He received methylprednisolone prior to a prednisone taper and initiated mycophenolate mofetil (MMF), hydroxychloroquine, macicentan, and tadalafil. He subsequently presented with watery diarrhea, fever (38.5°C), malaise, weight loss and arthralgia. Infectious work-up revealed CMV viremia (serum viral load >4 million/mL) and C. difficile colitis, for which he initiated ganciclovir and oral vancomycin. He was found to have new bicytopenia (hemoglobin 78 g/L, platelet count 175 ×10^9/L), hyperferritinemia (peak 6751 μg/L), hypertriglyceridemia (3.47 mmol/L), hypofibrinogenemia (nadir 1.0 g/L), and elevated aspartate aminotransferase (101 units/L). His C-reactive protein was 21.0 mg/L (peak) and his complement C3 and C4 were normal. Both hematology and rheumatology were consulted, and the patient was diagnosed with MAS. Bone marrow biopsy was deferred given overwhelming evidence for MAS. His MMF was held for diarrhea, and he was initiated on methylprednisolone (250 mg daily for 3 consecutive days, followed by taper) and anakinra (100 mg subcutaneously daily, titrated to 3-times daily) with clinical and biochemical improvement.

Conclusion We found only 2 other published English-language adult cases of MAS in conjunction with MCTD in the context of infection. One case was related to histoplasmosis,[2] and the other to an unspecified infection. [3] It is well known that infections can trigger MAS,[1] and while rare, in the appropriate clinical context, MAS should be considered in patients with MCTD who present with an infection and are not improving with standard treatment and whose biochemical parameters suggest MAS.

References [1.] Atteritano M. Eur Rev Medi Pharmacol Sci 2012;16:1414-24. [2.] Kawashima H. Intern Med 2025;64:141-6. [3.] Dhote R. Arthritis Rheum 2003;49:633-9.