New therapeutic options in sarcoidosis

Corticosteroids remain the cornerstone of sarcoidosis treatment but are associated with significant toxicities and impaired quality of life. Second-line and third-line treatments include hydroxychloroquine or immunosuppressants (methotrexate, azathioprine, leflunomide and mycophenolate mofetil), and anti-TNF-α agents (infliximab and adalimumab), respectively. The latest identification of significant key cellular pathways in sarcoidosis pathogenesis has led to the development of new therapeutic strategies described in this review.

JAK inhibitors, mainly tofacitinib, exhibited encouraging results in case reports, small retrospective series, and two prospective open-label trials for skin and pulmonary sarcoidosis. mTOR inhibitors demonstrated efficacity in one cross-over study on skin involvement. Promising findings were obtained with efzofitimod, an inhibitor of neuropilin-2 receptor, in a pilot study on pulmonary sarcoidosis, which needs to be confirmed. Other drugs with potentially relevant mechanisms of action have been used in case reports or small series or are under investigation: CTLA-4 inhibitors, IL-6 inhibitors, NLRP3 inflammasome inhibitors, GM-CSF inhibitors, PDE-4 inhibitors, and statins. There is very little data available on antifibrotic agents for fibrotic pulmonary sarcoidosis.

Despite many challenges, well designed studies are warranted to investigate new therapeutic options in sarcoidosis, particularly in patients with refractory forms or unacceptable side-effects with third-line treatment.