What is the role of inhibiting the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway in granuloma formation and maintenance in sarcoidosis?

From the Guidelines

Inhibiting the JAK-STAT pathway is a promising therapeutic approach for sarcoidosis, particularly for patients who have failed conventional treatments like corticosteroids and methotrexate, as it targets the central pathway mediating granuloma formation and maintenance. Sarcoidosis is a multisystem inflammatory disorder characterized by the formation of granulomas, which develop when the immune system overreacts, causing clusters of inflammatory cells to form in various organs, most commonly the lungs and lymph nodes. The JAK-STAT pathway is crucial in this process as it mediates cytokine signaling that drives granuloma formation and maintenance, as discussed in the European Respiratory Journal guidelines 1.

According to the European Respiratory Journal guidelines published in 2021 1, the use of JAK inhibitors, such as tofacitinib, baricitinib, and ruxolitinib, should be considered on a case-by-case basis for pulmonary sarcoidosis. These medications work by blocking the intracellular signaling that activates inflammatory cells and cytokine production. The rationale behind targeting this pathway stems from its central role in mediating signals from inflammatory cytokines like IL-6, IFN-γ, and IL-2, which are elevated in sarcoidosis and contribute to granuloma persistence.

Key points to consider when using JAK inhibitors for sarcoidosis include:

• Treatment duration typically extends for at least 3-6 months before assessing efficacy, with some patients requiring long-term therapy
• Regular monitoring of blood counts, liver function, and lipid profiles is essential due to potential side effects including increased infection risk, anemia, and elevated cholesterol
• JAK inhibitors are particularly valuable for patients who have failed conventional treatments like corticosteroids and methotrexate, as noted in the guidelines 1
• The approach for pulmonary sarcoidosis should be individualized, taking into account the need for treatment based on low risk, intermediate risk but impaired quality of life, or high risk, as discussed in the European Respiratory Journal guidelines 1.

From the Research

Role of JAK-STAT Pathway in Sarcoidosis

• The JAK-STAT pathway is constitutively active in sarcoidosis, contributing to the formation and maintenance of granulomas 2, 3, 4.
• Inhibiting the JAK-STAT pathway has been shown to be a promising therapeutic strategy in the treatment of sarcoidosis, particularly in patients who are refractory to traditional therapies 2, 3, 5, 6.

Effects of JAK Inhibition on Granuloma Formation and Maintenance

• JAK inhibition has been shown to induce disease remission in cutaneous sarcoidosis and granuloma annulare, with significant improvements in clinical symptoms and histologic resolution of disease 3, 5.
• Tofacitinib, a JAK inhibitor, has been used to treat patients with recalcitrant sarcoidosis, resulting in dramatic improvements in cutaneous and pulmonary symptoms 3, 5, 6.
• The use of JAK inhibitors, such as tofacitinib, may prevent critical laryngeal stenosis from progressing to tracheostomy and induce regression of cutaneous lesions in patients with severe multi-systemic sarcoidosis 6.

Potential Therapeutic Targets

• The JAK-STAT pathway is a potential therapeutic target for the prevention of organ damage in chronic pulmonary sarcoidosis, along with other targets such as mTOR, PPARγ pathways, the NRP2 receptor, and MMP-12 4.
• Further exploration of these targets is needed to develop effective therapeutic strategies for the treatment of sarcoidosis 4.