A Fulminant Case of Refractory Sarcoidosis Triggered by Infliximab-Neutralizing Antibodies

Sarcoidosis is a multisystem granulomatous disorder, commonly involving the lungs, heart, and skin. Despite recent dramatic advancements in the field, the exact cause remains an enigma; yet, we believe the pathogenesis represents an interplay between environmental, infectious, and genetic factors. An abnormal T regulatory response, in parallel with an enhanced Th1 response, results in the release of cytokines, including IL-2, IL-12, IL-18, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), which initiates granuloma formation. Meanwhile, enhanced Th17 production stimulates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, ultimately leading to granuloma expansion. The recent evolution in understanding the immunologic pathogenesis of sarcoidosis has led to the introduction of advanced treatment modalities for refractory cases resistant to steroids, methotrexate, and leflunomide, which are often used as first-line treatments. TNF-α inhibitors are considered a pioneering treatment with promising effects in advanced sarcoidosis, especially for neurosarcoidosis, cardiac, cutaneous, and refractory pulmonary cases. We present a very rare case of refractory pulmonary sarcoidosis that progressed to fulminant cardiac sarcoidosis, manifesting as heart failure and malignant arrhythmia despite high-dose infliximab treatment. This refractory course was attributed to the emergence of infliximab-neutralizing antibodies, which rendered infliximab ineffective. This case raises awareness about a preventable progression of disease that may otherwise have a fatal outcome, mandating strict follow-up for the emergence of neutralizing antibodies and the need for concomitant low-dose methotrexate, prednisone, and/or azathioprine to prevent such life-threatening sequelae.