What is the Type I Interferon (IFN) driven hypothesis in the pathogenesis of sarcoidosis?

From the Guidelines

The Type I interferon (IFN) driven hypothesis in sarcoidosis pathogenesis involves excessive Type I IFN signaling, particularly in a subset of patients with more severe disease, as suggested by recent studies 1. The researchers found that sarcoidosis patients exhibit a complex immune response, with some patients showing an upregulated Type I IFN gene signature in their blood, similar to what's seen in other autoimmune diseases like systemic lupus erythematosus.

• Key points to consider:
  • The IFN signature correlates with more severe clinical manifestations, including higher rates of organ involvement beyond the lungs, greater need for immunosuppressive therapy, and worse lung function.
  • Sarcoidosis patients' monocytes produce excessive amounts of Type I IFNs when stimulated, and that this overproduction is linked to dysregulation of the cGAS-STING pathway, which normally detects cytosolic DNA and triggers IFN production.
  • The researchers also identified that sarcoidosis patients' monocytes have impaired mitophagy (removal of damaged mitochondria), leading to accumulation of mitochondrial DNA in the cytosol, which activates the cGAS-STING pathway and drives Type I IFN production.
• The European Respiratory Journal study 1 provides the most recent and highest quality evidence on the treatment of sarcoidosis, and suggests that inhibiting the Type I IFN pathway may be a potential therapeutic target for sarcoidosis treatment, particularly in patients with the IFN signature.
• The study highlights the importance of considering the clinical phenotype of sarcoidosis patients, including stage, activity, and acute versus chronic disease, when making treatment decisions.
• The committee found insufficient information to make recommendations for other organ involvement, such as eye involvement, and suggests that further studies are needed to determine the effectiveness of adalimumab for ocular sarcoidosis.
• The study also emphasizes the need for a personalized approach to treatment, taking into account the individual patient's symptoms, disease severity, and response to therapy.
• Overall, the evidence suggests that the Type I IFN driven hypothesis is a key aspect of sarcoidosis pathogenesis, and that inhibiting the Type I IFN pathway may be a promising therapeutic strategy for patients with severe disease.

From the Research

Type I Interferon (IFN) Driven Hypothesis in Sarcoidosis

• The Type I Interferon driven hypothesis in the pathogenesis of sarcoidosis suggests that type 1 IFNs, such as IFN-alpha and IFN-beta, play a role in the development and progression of the disease 2.
• However, studies have shown that type 1 IFNs do not exacerbate sarcoidosis in remission, and their use is possible if indicated 2.
• A study published in 2022 found that inhibition of type 1 immunity with tofacitinib, a Janus kinase inhibitor, is associated with marked improvement in longstanding sarcoidosis, suggesting that type 1 IFNs may contribute to the pathogenesis of the disease 3.
• Another study found that CD4+ T cell-derived IFN-γ is a central cytokine mediator of macrophage activation in sarcoidosis, and suppression of its activity correlates with clinical improvement 3.

Role of Type 1 IFNs in Sarcoidosis

• Type 1 IFNs have been shown to induce sarcoidosis in some cases, with the clinical presentation being insidious and often confused with common constitutional side effects of IFN therapy 4.
• The age of onset of IFN-induced sarcoidosis is later than that of naturally occurring sarcoidosis, and the most common organs involved are the lungs and skin 4.
• A review of 65 cases of IFN-induced sarcoidosis reported in the literature found that the majority of cases follow a benign course, with complete resolution after discontinuation of IFN therapy expected 4.

JAK Inhibitors and Sarcoidosis

• JAK inhibitors, which can block the signals of inflammatory cytokines such as IFN-γ, have resulted in dramatic improvement in several patients with sarcoidosis 5.
• The use of JAK inhibitors in sarcoidosis and other inflammatory disorders with macrophage activation is supported by clinical evidence, and ongoing efforts are being made to evaluate their role in these disorders 5.
• The role of JAK dependent cytokines in macrophage activation and granuloma formation is being studied, with the goal of developing more effective, molecularly targeted therapies for sarcoidosis and other inflammatory disorders 5.