Onset of Sarcoidosis in Patients on Biologic Therapy: A Systematic Review

Sarcoidosis is an autoimmune disease that initially presents as red-brown violaceous annular plaques and papules. Systemic manifestations occur in 90% of patients, most commonly fibrosis of lung parenchyma, congestive heart failure, heart conduction defects, lymphadenopathy, hepatic disease, and uveitis. While immunosuppressive agents are the first-line treatment, there have been recent paradoxical reports of sarcoidosis-like reactions in patients on biologic therapy. ¹ Given the increasing use of biologics worldwide, the goal of this systematic review is to identify and summarize such reports.

EMBASE and MEDLINE search was conducted on October 5, 2020 in accordance with PRISMA guidelines (Supplemental Files 1 and 2) . The quality of evidence was assessed using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence and Naranjo criteria were used for probability of causation analysis.

The 134 identified studies (Supplemental Figure 1, Supplemental Table 1) included 1,157 patients with a mean age of 46.8 years. Of the 1,157 patients diagnosed with sarcoidosis, 7.4% (n = 86/1,157) exhibited cutaneous sarcoidosis, 3.7% (n = 43/1,157) had both cutaneous and systemic involvement, 25.7% (n = 29/1,157) had only systemic involvement, and the remaining 63.2% (n = 731/1,157) patients did not have the location of sarcoidosis identified. TNF-α inhibitors were the most common associated biologics (88.9%), followed by anti-CD20 antibody (3.5%) and anti-IL-17 inhibitors (2.0%) (Supplemental Table 2). Diagnoses were made between 0.75 month to 6.7 years after biologic initiation. Of the 194 patients with a reported resolution reported, 130 patients had complete resolution within a mean of 7.6 months (Supplemental Table 3) and 4 had partial resolution (Supplemental Table 4). Most common treatments that led to complete resolution were biologic discontinuation in 31.5% (n = 41/130) and oral corticosteroid in 50% (n = 65/130) of patients.

While the mechanisms of pathogenesis of sarcoidosis is largely unknown, the disease is characterized by hyperactivity of the immune system, specifically of the T helper-1 cells (Th1). ² The granuloma formation characteristics of sarcoidosis is thought to be a result of an increased production of interferon-γ (IFN- γ), interleukin-2 (IL-2), and release of TNF-α, which promotes a Th1 immune response that may contribute to onset of a sarcoid reaction. ³ Given that TNF-α inhibitors were the most common biologic agent class reported to be associated with onset of sarcoidosis, it is possible that inhibition of TNF-α causes a cytokine imbalance that impacts the above-described pathways. ⁴ Additionally, TNF-α inhibition is thought to alter the pathways involved with p38 kinase, adenosine A2A and A3 receptors, which may disrupt the balance in CD4 cell activity, specifically T helper-17 leading to the onset of sarcoidosis. ⁵

Important limitations of our review include the observational nature of included studies, lack of reported re-challenge tests and a resulting mean Naranjo score of 5.6, which indicates only a probable adverse drug reaction. Additionally, a large proportion of patients included in this review had comorbidities that may increase the risk of developing sarcoidosis, such as rheumatoid arthritis, psoriatic arthritis and spondyloarthropathy. Ultimately, further mechanistic studies with larger sample sizes are warranted to elucidate the causality, pathophysiology, and management strategies for sarcoidosis-like reactions that onset during biologic therapy.

Supplemental Material

Online supplementary file 1 - Supplemental material for Onset of Sarcoidosis in Patients on Biologic Therapy: A Systematic Review

Supplemental material, Online supplementary file 1, for Onset of Sarcoidosis in Patients on Biologic Therapy: A Systematic Review by Yuliya Lytvyn, Asfandyar Mufti, Muskaan Sachdeva, Abrahim Abduelmula, Ahmed Bagit and Jensen Yeung in Journal of Cutaneous Medicine and Surgery

Supplemental Material

Online supplementary file 2 - Supplemental material for Onset of Sarcoidosis in Patients on Biologic Therapy: A Systematic Review

Supplemental material, Online supplementary file 2, for Onset of Sarcoidosis in Patients on Biologic Therapy: A Systematic Review by Yuliya Lytvyn, Asfandyar Mufti, Muskaan Sachdeva, Abrahim Abduelmula, Ahmed Bagit and Jensen Yeung in Journal of Cutaneous Medicine and Surgery

Supplemental Material

Online supplementary file 3 - Supplemental material for Onset of Sarcoidosis in Patients on Biologic Therapy: A Systematic Review

Supplemental material, Online supplementary file 3, for Onset of Sarcoidosis in Patients on Biologic Therapy: A Systematic Review by Yuliya Lytvyn, Asfandyar Mufti, Muskaan Sachdeva, Abrahim Abduelmula, Ahmed Bagit and Jensen Yeung in Journal of Cutaneous Medicine and Surgery

Supplemental Material

Figure S1 - Supplemental material for Onset of Sarcoidosis in Patients on Biologic Therapy: A Systematic Review

Supplemental material, Figure S1, for Onset of Sarcoidosis in Patients on Biologic Therapy: A Systematic Review by Yuliya Lytvyn, Asfandyar Mufti, Muskaan Sachdeva, Abrahim Abduelmula, Ahmed Bagit and Jensen Yeung in Journal of Cutaneous Medicine and Surgery