What is the evidence for using Janus kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) or baricitinib (Olumiant), in the treatment of noncutaneous sarcoidosis?

Evidence for JAK Inhibitors in Noncutaneous Sarcoidosis

There is limited but promising evidence for JAK inhibitors in noncutaneous sarcoidosis, with tofacitinib showing efficacy in small studies for multiorgan disease, though it is not yet recommended as first-line therapy for most forms of noncutaneous sarcoidosis.

Current Evidence for JAK Inhibitors in Noncutaneous Sarcoidosis

• JAK inhibitors have shown efficacy in small studies for multiorgan sarcoidosis, with tofacitinib demonstrating resolution of PET-avid lesions in internal organs and normalization of disease biomarkers in case reports 1
• In an open-label trial of 10 patients with cutaneous sarcoidosis treated with tofacitinib, improvement in internal organ involvement was also observed, suggesting potential benefit beyond skin manifestations 2
• JAK inhibition appears to work by suppressing type 1 immunity, particularly CD4+ T cell-derived IFN-γ, which is a central cytokine mediator of macrophage activation in sarcoidosis 2
• Current guidelines mention tofacitinib primarily for cutaneous sarcoidosis, listing it as an "additional agent" to be used on a case-by-case basis rather than as part of the standard treatment algorithm 3, 4

Guideline Recommendations for Noncutaneous Sarcoidosis

• For inflammatory myopathy-associated interstitial lung disease (IIM-ILD), JAK inhibitors are conditionally recommended as a first-line ILD treatment option according to the 2023 ACR/CHEST guidelines 3
• For systemic autoimmune rheumatic disease-associated ILD (SARD-ILD) other than IIM-ILD, JAK inhibitors are conditionally recommended against as first-line therapy 3
• For neurosarcoidosis, current guidelines recommend a stepwise approach starting with glucocorticoids, followed by methotrexate and then TNF inhibitors (particularly infliximab), with no specific mention of JAK inhibitors 3
• For cardiac sarcoidosis, guidelines strongly recommend glucocorticoids (with or without other immunosuppressives) for patients with functional cardiac abnormalities 3

Treatment Algorithm for Noncutaneous Sarcoidosis

• First-line therapy: Glucocorticoids remain the mainstay of initial treatment for most forms of noncutaneous sarcoidosis 3
• Second-line therapy: Methotrexate is the most supported second-line agent for most forms of noncutaneous sarcoidosis, particularly for neurosarcoidosis 3, 5
• Third-line therapy: TNF inhibitors, particularly infliximab, have substantial evidence for efficacy in refractory noncutaneous sarcoidosis 6, 3
• Fourth-line or experimental therapy: JAK inhibitors may be considered in patients with refractory disease who have failed conventional therapies 2, 1

Special Considerations for Specific Organ Involvement

• Pulmonary sarcoidosis: JAK inhibitors are not currently recommended as first-line therapy, with conventional immunosuppressants and TNF inhibitors having more established evidence 5
• Neurosarcoidosis: The treatment algorithm typically progresses from glucocorticoids to methotrexate to infliximab, with no specific recommendation for JAK inhibitors 3
• Cardiac sarcoidosis: Strong recommendation for glucocorticoids with or without other immunosuppressives, with no specific mention of JAK inhibitors 3
• IIM-ILD: JAK inhibitors are conditionally recommended as a first-line option, which may be relevant for sarcoidosis patients with myopathy and ILD features 3

Potential Benefits and Limitations of JAK Inhibitors

• Benefits: JAK inhibitors target multiple cytokine pathways implicated in sarcoidosis pathogenesis, including IFN-γ, IL-6, IL-12, IL-15, and GM-CSF 2
• Limitations: Limited evidence from small studies, lack of inclusion in major treatment guidelines for most forms of noncutaneous sarcoidosis 3
• Safety considerations: JAK inhibitors have known risks including increased susceptibility to infection, which must be balanced against potential benefits 3

Future Research Directions

• Larger controlled trials are needed to establish the efficacy and safety of JAK inhibitors in various forms of noncutaneous sarcoidosis 2, 7
• Studies comparing JAK inhibitors to established therapies such as TNF inhibitors would help determine their relative place in treatment algorithms 5
• Investigation of specific JAK inhibitors beyond tofacitinib, including more selective agents like Tyk2 inhibitors, may yield additional therapeutic options 3