Drug-Induced Sarcoid-like Reactions Associated to Targeted Therapies and Biologic Agents

Abstract

Background: Sarcoidosis is a multisystem inflammatory disease characterized by the immune-mediated formation of non-necrotizing epithelioid granulomas. Several commonly used medications can induce similar granulomatous reactions, known as drug-induced sarcoid-like reactions (DISRs), which closely mimic sarcoidosis. Despite their specificity in targeting molecular pathways, certain therapies-particularly targeted treatments-have increasingly been linked to DISRs. Methods: This narrative review was based on a PubMed search using the terms "SARCOID LIKE REACTION" and "DRUG". A cross-check was performed with "SARCOID" combined with each identified drug to identify misclassified cases. Drugs with limited evidence or weak pathogenetic plausibility were excluded, leaving only molecularly targeted therapies for consideration. Sources included case reports, case series, and reviews selected based on their clinical and scientific relevance, without any restrictions on time or language. Results: In light of the available data, five main pharmacological groups were found to be associated to DISR: immune checkpoint inhibitors, TNF-α antagonists, BRAF inhibitors, monoclonal antibodies, and miscellaneous agents. Each group has distinct mechanisms of action and clinical indications, which likely affect the frequency, presentation, and timing of DISRs. Conclusions: Diagnosing DISRs is challenging, and a structured approach is crucial for differentiating them from other conditions. To support clinicians, we propose a diagnostic algorithm to guide decision-making in suspected cases. Management should be individualized, as most DISRs either resolve spontaneously or improve after the discontinuation of the causative drug. Important factors influencing therapeutic decisions include the severity of the underlying disease, the availability of alternative treatments, and the extent of DISR manifestations.

Keywords: BRAF inhibitors; TNF-α antagonists; drug-induced sarcoid like reactions; immune checkpoint inhibitors; monoclonal antibodies; sarcoidosis.

Figure 1

Mechanism of granuloma formation. An unknown antigen (Ag) activates alveolar macrophages (AMs), which begin to produce TNF-α, and dendritic cells (DCs), which migrate to the draining lymph nodes and secrete IL-12 and IL-1. These cytokines promote the differentiation and expansion of Th1 and Th17 lymphocytes, producers of IFN-γ and IL-2, further amplifying the immune response. TNF-α also stimulates natural killer (NK) cells to release IFN-γ, enhancing macrophage activation. Activated macrophages upregulate adhesion molecules (e.g., ICAM-1) and secrete a wide array of pro-inflammatory mediators, including IL-1β, TNF-α, CCL20, IL-12, IL-18, IL-23, IL-17, and TGF-β, contributing to a sustained inflammatory environment. This cytokine-rich environment recruits and organizes specific immune cells, such as Th1 and Th17 cells, B cells, monocytes, and regulatory T cells (Tregs), promoting the formation and maintenance of the granuloma. Created in BioRender. Rubini, S. (2025) https://BioRender.com/c1p8l3p (accessed on 8 May 2025).

Figure 2

Mechanism of action of immune checkpoint inhibitors (ICIs). ICIs work by blocking inhibitory pathways that suppress immune responses. Ipilimumab targets CTLA-4, which is expressed on activated T cells in lymphoid organs. Nivolumab and Pembrolizumab target PD-1, which is found on T cells in peripheral tissues. Atezolizumab, Durvalumab, and Avelumab target PD-L1, which is expressed on both tumor cells and immune cells. Created in BioRender. Rubini, S. (2025) https://BioRender.com/0s4w3t6 (accessed on 9 May 2025).

Figure 3

Mechanism of action of anti-tumor necrosis factor (Anti-TNF) agents. Anti-TNF agents selectively bind to TNF-α, inhibiting its interaction with TNFR1 (p55) and thereby preventing the activation of NF-kB, MAPK, and apoptotic pathways. Additionally, they block TNF-α from binding to TNFR2 (p75), leading to a significant increase in Treg cells, which can produce TGF-β, contributing to immune regulation and granuloma formation.

Figure 4

Mechanism of action of BRAF and MEK inhibitors. BRAF inhibitors, often combined with MEK inhibitors, target the mutant BRAF^V600E protein, blocking the MAPK signaling pathway. This leads to altered cytokine profiles, increased expression of immune-stimulatory molecules (e.g., CD40L, IFNγ), and reduced levels of immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells (MDSCs). Created in BioRender. Rubini, S. (2025) https://BioRender.com/6eaaz3x (accessed on 9 May 2025).

Figure 5

Diagnostic algorithm.