JAK inhibitors to treat STAT3 gain-of-function: a single-center report and literature review

Abstract

Objective: The signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) syndrome (STAT3-GOF) is an inborn error of immunity (IEI) characterized by diverse manifestations of immune dysregulation that necessitate systemic immunomodulatory treatment. The blockade of the interleukin-6 receptor and/or the inhibition of the Janus kinases has been commonly employed to treat diverse STAT3-GOF-associated manifestations. However, evidence on long-term treatment outcome, especially in the case of adult patients, is scarce.

Methods: Clinical data, including laboratory findings and medical imaging, were collected from all seven patients, diagnosed with STAT3-GOF, who have been treated at the Hannover University School, focusing on those who received a Janus kinase (JAK) inhibitor (JAKi). Previously published cases of STAT3-GOF patients who received a JAKi were evaluated, focusing on reported treatment efficacy with respect to diverse STAT3-GOF-associated manifestations of immune dysregulation and safety.

Results: Five out of seven patients diagnosed with STAT3-GOF were treated with a JAKi, each for a different indication. Including these patients, outcomes of JAKi treatment have been reported for a total of 41 patients. Treatment with a JAKi led to improvement of diverse autoimmune, inflammatory, or lymphoproliferative manifestations of STAT3-GOF and a therapeutic benefit could be documented for all except two patients. Considering all reported manifestations of immune dysregulation in each patient, complete remission was achieved in 10/41 (24.4%) treated patients.

Conclusions: JAKi treatment improved diverse manifestations of immune dysregulation in the majority of STAT3-GOF patients, representing a promising therapeutic approach. Long-term follow-up data are needed to evaluate possible risks of prolonged treatment with a JAKi.

Keywords: JAK inhibitors; STAT3 gain-of-function; antiphospholipid syndrome; arthritis; baricitinib; ruxolitinib; tofacitinib; trachyonychia.

Figure 1

Summary of variants in STAT3, causing STAT3-GOF (A) and associated clinical manifestations as well as treatments (B) in seven patients (AIHA, autoimmune hemolytic anemia; CNS, central nervous system; Ig, immunoglobulin; ILD, interstitial lung disease; ITP, immune thrombocytopenia; T1D, type 1 diabetes).

Figure 2

Peripheral B cell (A-D) and T cell subsets (E-H) in patients with STAT3-GOF prior and after introduction of JAKi treatment (B, baricitinib; m, month; pat, patient; TCZ, tocilizumab)

Figure 3

Outcome of treatment with a JAKi in 5 patients with STAT3-GOF. Summary of treatment response (A) and adverse events of special interest (AESI) (B). Course of laboratory parameters, including C-reactive protein (CRP) (C), leukocyte (D) and platelet counts (E). For patient (pat.) 1 we indicate treatment, i.e. tocilizumab (TCZ), TCZ + ruxolitinib (R) and baricitinib (B), under which above mentioned laboratory values were measured. For patient 5 data from 1st year of treatment with ruxolitinib and TCZ are shown, prior to treatment suspension for lung transplantation. Sonographic evaluation of largest spleen dimension (F). Course of lung function during treatment, including measurements of vital capacity (VC) and diffusion capacity for carbon monoxide (DLCO) (G & H, respectively). Measurement of calprotectin in stool (I). For pat. 5 calprotectin was measured at diagnosis of chronic diarrhea, after suspending ruxolitinib treatment for suspected toxicity Evaluation of disease activity score 28 – CRP (DAS28-CRP) (J). Trachyonychia and its course at 3 months (m) and 6 m after introduction of baricitinib (K). Brain magnetic resonance imaging (MRI) showing cochlear inflammation (indicated by the white arrow) prior to starting baricitinib and 4 months (+4 m) after baricitinib introduction (L).

Figure 4

Summary of clinical manifestations (A) and review of response to a JAKi in 41 patients with STAT3-GOF (B) (AIH, autoimmune hepatitis; ILD, interstitial lung disease; n.a., not available; T1D, type 1 diabetes).