Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations

Abstract

Brief Summary: Treatment of the autoimmune and immune-dysregulatory features of patients with STAT1 GOF or STAT3 GOF disease remains challenging. Jakinibs have been used to treat the severe immune-dysregulation in patients with either STAT1 GOF or STAT3 GOF mutations.

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case‐based review

“…In STAT1 and STAT3 ‐GOF, treatment with JAK inhibitors (i.e., ruxolitinib, tofacitinib, and baricitinib) may reduce the burden of autoimmune disease (e.g., immune cytopenias) and IL‐6 R antagonists (i.e., tocilizumab) used alone or in combination with JAK inhibitors in STAT3 ‐GOF reduces the burden of autoimmune disease, lymphoproliferation, and hyperinflammation . Increased risk of invasive fungal infections needs to be considered when considering addition of JAK inhibitors for the management of immune dysregulation …”

“…In STAT1 and STAT3-GOF, treatment with JAK inhibitors (i.e., ruxolitinib, tofacitinib, and baricitinib) [48][49][50] may reduce the burden of autoimmune disease (e.g., immune cytopenias) and IL-6 R antagonists…”

“…(i.e., tocilizumab)51 used alone or in combination with JAK inhibitors in STAT3-GOF reduces the burden of autoimmune disease, lymphoproliferation, and hyperinflammation 49. Increased risk of invasive fungal infections needs to be considered when considering addition of JAK inhibitors for the management of immune dysregulation.…”

Birds of a feather

“…There may be additional benefit to adding a jakinib, such as ruxolitinib, in patients with disease resistant to tocilizumab monotherapy. 56 Cytotoxic T-lymphocyteeassociated protein 4 (CTLA4) regulates T-cell proliferation by tempering T-cell receptor signal strength and by outcompeting CD28 for coactivating B7 ligands (Fig 2). Heterozygous loss of CTLA4 in humans causes autoimmune lymphoproliferative syndrome type 5 (ALPS5).…”

Immunosuppression for immunodeficiency: Getting smarter

“…A different therapeutic strategy was recently used for patients with activating autosomal dominant gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) or STAT3. 8 Patients with STAT1 GOF mutations experience chronic mucocutaneous candidiasis, susceptibility to fungal and viral infections, humoral and cellular immunodeficiency, inflammation, and autoimmunity. Similarly, patients with STAT3 GOF mutations often present early in life with a wide spectrum of lymphoproliferative and autoimmune symptoms, opportunistic infections, hypogammaglobulinemia, and lymphopenia.…”