What is the evidence for the benefit of alternative agents, including rituximab, in treating cardiac sarcoidosis refractory to steroid, methotrexate, mycophenolate (Cellcept), and infliximab (Remicade)?

From the Guidelines

For refractory cardiac sarcoidosis after failure of steroids, methotrexate, mycophenolate, and infliximab, rituximab shows promising evidence as a next-line agent. The most recent and highest quality study, published in 2024 in the journal Arthritis and Rheumatology 1, conditionally recommends rituximab as a first-line RP-ILD treatment option. Rituximab, typically administered at 1000 mg IV on days 1 and 15 (or 375 mg/m² weekly for 4 weeks), has demonstrated efficacy in several case series and small studies. Patients often require repeated courses every 6-12 months based on clinical response. Other potential options include cyclophosphamide (typically 500-1000 mg/m² IV monthly for 6 months), adalimumab (40 mg subcutaneously every 1-2 weeks), or repository corticotropin injection (80 units subcutaneously twice weekly). Leflunomide (10-20 mg daily) has also shown some benefit. When initiating rituximab, premedicate with acetaminophen, diphenhydramine, and methylprednisolone to prevent infusion reactions. Monitor for infections, particularly in combination with other immunosuppressants. The rationale for rituximab's efficacy lies in its depletion of CD20+ B cells, which play a crucial role in granuloma formation and maintenance in sarcoidosis. Consider PET/CT imaging before and after treatment to objectively assess cardiac inflammatory activity and treatment response.

Key Points

• Rituximab is a promising next-line agent for refractory cardiac sarcoidosis
• The recommended dose is 1000 mg IV on days 1 and 15 (or 375 mg/m² weekly for 4 weeks)
• Patients may require repeated courses every 6-12 months based on clinical response
• Other potential options include cyclophosphamide, adalimumab, and repository corticotropin injection
• Leflunomide has also shown some benefit
• Monitor for infections and infusion reactions when initiating rituximab

Treatment Considerations

• Rituximab should be considered as a first-line RP-ILD treatment option 1
• Upfront combination therapy (triple therapy for those with confirmed or suspected MDA-5 and double or triple therapy for those without confirmed or suspected MDA-5) is conditionally recommended over monotherapy as first-line treatment 1
• Early referral for lung transplantation is conditionally recommended over later referral after progression on optimal medical management 1

From the Research

Treatment Options for Cardiac Sarcoidosis

• Cardiac sarcoidosis is a rare cause of cardiomyopathy characterized by granulomatous inflammation involving the myocardium, and its treatment often involves corticosteroids and steroid-sparing agents such as methotrexate and azathioprine 2.
• In cases where patients are refractory to steroid, methotrexate, micophenolate, and infliximab, other agents such as rituximab may be considered as a therapeutic option 3, 4.

Evidence for Rituximab

• A single-center experience study published in 2022 found that rituximab decreased inflammation as assessed by cardiac FDG PET/CT in 6 out of 7 patients with active cardiac sarcoidosis, and improved or stabilized left ventricular ejection fraction in 4 patients 3.
• Another study published in 2015 reported the successful use of rituximab in refractory sarcoidosis with lung, eye, lymph nodes, and skin involvement, suggesting its potential benefit in treating cardiac sarcoidosis as well 4.

Other Treatment Approaches

• Infliximab, a tumor necrosis factor alpha inhibitor, has been found to play a vital role in stabilizing refractory cardiac sarcoidosis by stemming clinical deterioration, arrhythmia burden, and even reducing steroid requirements 5.
• A review of the existing literature on the use of infliximab in cardiac sarcoidosis highlighted the need for further prospective trial data to validate its findings 5.

Current State of Treatment

• The current treatment of cardiac sarcoidosis involves corticosteroid-based, tiered immunosuppression to control myocardial inflammation, with medical and device-based therapy for symptomatic atrioventricular block, ventricular tachyarrhythmias, and heart failure 6.
• Recent outcome data indicate a 90% to 96% 5-year survival rate in manifest cardiac sarcoidosis, with 10-year figures ranging from 80% to 90% 6.