Genetically proxied TYK2 inhibition is associated with reduced sarcoidosis susceptibility

Sarcoidosis is a multisystem inflammatory disorder of unknown aetiology that can affect any organ, including the lung, joints and skin. Clinical presentation can be highly heterogeneous and lead to significant morbidity and mortality.1 Glucocorticoids remain the cornerstone of pharmacological therapy but are limited by toxicities with long-term use. Although steroid-sparing agents are available, there are no licensed therapeutics for sarcoidosis. Many cytokines implicated in sarcoidosis (eg, gamma interferon and other type 1 cytokines) signal via the JAK-STAT pathway, and inhibition of this pathway has proved successful in several immune-mediated inflammatory diseases (IMIDs). Interestingly, tofacitinib, a JAK-STAT inhibitor, was associated with skin improvement and suppression of type 1 cytokines in an open-label trial of 10 patients with cutaneous sarcoidosis.2 However, these preliminary findings await confirmation by phase III trials and are caveated by tofacitinib’s potential adverse cardiovascular profile. Inhibition of TYK2, one member of the JAK family, has shown promise for IMIDs (eg, deucravcitinib for psoriasis and psoriatic arthritis (PsA)).3 Germline mutations causing loss-of-function of genes encoding drug targets have been used to correctly predict the effect of their pharmacological inhibition4; therefore, we used a naturally occurring loss-of-function mutation to evaluate the therapeutic potential …