JAK1/2 INHIBITOR BARICITINIB AS A POTENTIAL THERAPY IN A PATIENT WITH GAIN-OF-FUNCTION MUTATION IN SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1 (STAT1)

Kornvalee Meesilpavikkai1,2,3, Willem A. Dik1,4, Benjamin Schrijver1,4, Nicole M. A. Nagtzaam1,4, Sandra J. Posthumus-van Sluijs1,4, P. Martin van Hagen1,2, and Virgil A. S. H. Dalm1,2
1 Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands,
2 Department of Internal Medicine, Division of Clinical Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands,
3 Faculty of Medicine, Department of Microbiology, Chulalongkorn University, Bangkok, Thailand, 
4 Laboratory Medical Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands

In the past decade, patients with heterozygous signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations have been progressively reported worldwide. Chronic mucocutaneous candidiasis (CMC) is the hallmark of STAT1 GOF mutations, but bacterial infections, mainly caused by Staphylococcus aureus, viral infections, predominantly Herpesviridae, and autoimmune manifestations are also commonly present. Since curative treatment for these patients is still unavailable, most of the patients with STAT1 GOF mutations receive prolonged systemic antimicrobial therapy that could lead to drug resistance. Immunotherapies or immunosuppressive therapies are also considered in some patients, although the effectiveness still needs to be evaluated in more detail. Baricitinib is a novel JAK inhibitor that hampers interferon (IFN) induced JAK-STAT1 signalling by inhibiting JAK1 and JAK2 which are the upstream molecule of STAT1. Baricitinib is an orally available medication that was recently approved for treatment of rheumatoid arthritis. Based on its mechanisms of action, baricitinib could be a potential candidate for the treatment of patients with STAT1 GOF mutation.

Design and methods
The patient is a 25-year-old Dutch female diagnosed with heterozygous STAT1 GOF mutation at p.V653I of the SH2 domain. Over the years, main clinical problems included recurrent oral and esophageal Candida albicans infections and immune-mediated oral and vaginal ulcers. Candidiasis repetitively erupted within two weeks after termination of a course of antifungal therapy. Therefore, prophylactic antifungal therapy was required. In vitro study of baricitinib was performed before baricitinib treatment (2 mg once daily) was initiated in the patient. Blood samples, collected before start of baricitinib and every 2 – 4 weeks afterwards, were examined for STAT1/STAT3 phosphorylation, STAT1-regulated gene expression, and cytokine production. 

Results
The patient showed remarkable clinical improvement upon baricitinib treatment. Systemic prophylactic antifungal therapy and immunosuppressive treatment could be terminated, without reoccurrence of candidiasis or ulcers. Baricitinib reduced STAT1 hyperphosphorylation and STAT3 phosphorylation, and improved the capacity of PBMCs to produce IL-17A, IL-17F, and IL-22, cytokines crucial for antifungal immune responses. Baricitinib also reduced expression of the IL-27/STAT-1 regulated genes CXCL9, CXCL10, and PD-L1 (CD274) in long-term T lymphocyte cultures from the patient. PBMCs obtained from the patient during three months of baricitinib therapy also expressed CXCL9 and CXCL10 at levels approaching those of healthy controls.

Conclusions
We show for the first time therapeutic benefit of the clinically available baricitinib in a patient with GOF STAT1. Further studies are required to evaluate its clinical implications in other patients with STAT1 GOF mutation.

JAK1/2 INHIBITOR BARICITINIB AS A POTENTIAL THERAPY IN A PATIENT WITH GAIN-OF-FUNCTION MUTATION IN STAT1