Pulmonary sarcoidosis is characterized by the accumulation of immune cells that form granulomas affecting the lungs. Efzofitimod (ATYR1923), a novel immunomodulator, selectively binds neuropilin 2, which is upregulated on immune cells in response to lung inflammation. What is the tolerability, safety, and effect on outcomes of efzofitimod in pulmonary sarcoidosis? In this randomized, double-blind, placebo-controlled study evaluating multiple ascending doses of efzofitimod administered intravenously every 4 weeks for 24 weeks, randomized patients (2:1) underwent a steroid taper to 5 mg/d by week 8 or < 5 mg/d after week 16. The primary end point was the incidence of adverse events (AEs); secondary end points included steroid reduction, change in lung function, and patient-reported outcomes on health-related quality-of-life scales. Thirty-seven patients received at least one dose of study medication. Efzofitimod was well tolerated at all doses, with no new or unexpected AEs and no dose-dependent AE incidence. Average daily steroid doses through end of study were 6.8 mg, 6.5 mg, and 5.6 mg for the 1 mg/kg, 3 mg/kg, and 5 mg/kg groups compared with 7.2 mg for placebo, resulting in a baseline-adjusted relative steroid reduction of 5%, 9%, and 22%, respectively. Clinically meaningful improvements were achieved across several patient-reported outcomes, several of which reached statistical significance in the 5 mg/kg dose arm. A dose-dependent but nonsignificant trend toward improved lung function also was observed for 3 and 5 mg/kg. Efzofitimod was safe and well tolerated and was associated with dose-dependent improvements of several clinically relevant end points compared with placebo. The results of this study support further evaluation of efzofitimod in pulmonary sarcoidosis. ClinicalTrials.gov; No.: NCT03824392; URL: www.clinicaltrials.gov

Sarcoidosis is a systemic granulomatous inflammatory disease of unknown etiology. It affects the lungs in over 90% of patients yet extra-pulmonary and multi-organ involvement is common. Spontaneous remission of disease occurs commonly, nonetheless, over 50% of patients will require treatment and up to 30% of patients will develop a chronic progressive non-remitting disease with marked pulmonary fibrosis leading to significant morbidity and death. Guidelines outlining an immunosuppressive treatment approach to sarcoidosis were recently published, however, the strength of evidence behind many of the guideline recommended drugs is weak. None of the drugs currently used for the treatment of sarcoidosis have been rigorously studied and prescription of these drugs is often based on off-label” indications informed by experience with other diseases. Indeed, only two medications [prednisone and repository corticotropin (RCI) injection] currently used in the treatment of sarcoidosis are approved by the United States Food and Drug Administration. This situation results in significant reimbursement challenges especially for the more advanced (and often more effective) drugs that are favored for severe and refractory forms of disease causing an over-reliance on corticosteroids known to be associated with significant dose and duration dependent toxicities. This past decade has seen a renewed interest in developing new drugs and exploring novel therapeutic pathways for the treatment of sarcoidosis. Several of these trials are active randomized controlled trials (RCTs) designed to recruit relatively large numbers of patients with a goal to determine the safety, efficacy, and tolerability of these new molecules and therapeutic approaches. While it is an exciting time, it is also necessary to exercise caution. Resources including research dollars and most importantly, patient populations available for trials are limited and thus necessitate that several of the challenges facing drug trials and drug development in sarcoidosis are addressed. This will ensure that currently available resources are judiciously utilized. Our paper reviews the ongoing and anticipated drug trials in sarcoidosis and addresses the challenges facing these and future trials. We also review several recently completed trials and draw lessons that should be applied in future.

Sarcoidosis is a complex systemic granulomatous disease that can affect multiple organs, with pulmonary involvement being the most common. Its pathogenesis involves genetic predisposition and chronic immune dysregulation, which increase susceptibility to environmental or endogenous triggers, leading to an aberrant immune response. Imaging plays a central role in diagnosis and has evolved from traditional chest radiography Scadding staging to a computed tomography-based classification and radiomics that improves disease phenotyping. Due to its variable presentation, diagnosing sarcoidosis and attributing symptoms to the disease can be challenging; therefore, awareness and consideration of alternative diagnoses remain essential. The clinical course of sarcoidosis is unpredictable; many patients do not require therapy. Treatment decisions must be individualised, balancing disease severity, risk of organ damage, quality of life and potential toxicity of medication. However, the lack of both reliable prognostic tools and clear criteria for high-risk cases contributes to substantial heterogeneity in disease management. While the guidelines still recommend corticosteroids as first-line treatment, recent data show that methotrexate and prednisone have comparable effects on pulmonary function, although differ in side-effect profiles and time to efficacy. For refractory cases, second-line therapy involves combining or switching drugs, with anti-tumour necrosis factor agents representing third-line options, ideally in expert hands. Novel therapies targeting pathways involved in disease pathogenesis are under investigation. There is growing consensus on the need to revise current treatment algorithms to minimise corticosteroid use and adopt more evidence-based approaches. Future priorities include identifying prognostic biomarkers, refining trial design and establishing meaningful end-points to improve individualised care for the heterogeneous population of patients with sarcoidosis.