JAK/STAT Inhibitors: A New Treatment Target for Rheumatoid Arthritis

Rheumatoid arthritis in hip
Rheumatoid arthritis in hip
Janus kinase and signal transducers and activators of transcription inhibitors represent promising treatment targets in RA.

Numerous studies have implicated the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway in the pathogenesis and progression of rheumatoid arthritis (RA), making it an attractive target for drug development.1,2 

Charles Malemud, PhD, a professor in the department of rheumatology at Case Western University School of Medicine in Cleveland, Ohio, has conducted extensive research into the relationship between JAK/STAT signaling and inflammatory arthritis. In an interview with Rheumatology Advisor, he described key mechanisms by which JAK/STAT signaling contributes to RA progression.

Members of the JAK family (JAK1, JAK2, JAK3, and TYK2) are rapidly activated through the binding of cytokines or growth factors to cognate receptors at the cytoplasmic regions of the cell surface.3 Activated JAK phosphorylates the cytokine receptor, leading to the creation of a docking site for STAT proteins. 

Once recruited, the STAT proteins are themselves phosphorylated by the receptor-associated JAKs.3 The STAT proteins are then released and dimerize before being translocated into the nucleus, where they operate as transcription factors for target genes.3

“The downstream events that are activated by the JAK/STAT pathway include the increased gene expression of pro-inflammatory cytokines, such as interleukin-6 (IL-6), which contribute to the chronic inflammation characteristic of RA,” Dr Malemud explained. 

He added that activation of JAK/STAT, along with other signaling pathways, also induces chondrocyte apoptosis, synoviocyte “apoptosis resistance,” and upregulation of matrix metalloproteinase gene expression.4,5 Growing appreciation for the importance of the JAK/STAT pathway in inflammation has fueled interest in developing JAK inhibitors (also known as Jakinibs) for RA and other inflammatory arthritides.6

Tofacitinib in RA

In 2012, tofacitinib became the first Jakinib approved by the US Food and Drug Administration (FDA) for RA, and in 2016 the FDA approved an extended-release formulation. Tofacitinib is an oral small-molecule inhibitor of JAK1 and JAK3 and, to a lesser extent, JAK2.2 It has been studied for the treatment of RA in several phase 2 and phase 3 trials.

The randomized phase 3 ORAL Solo trial compared tofacitinib monotherapy with placebo in patients with moderate to severe RA who had an inadequate response to one or more disease-modifying antirheumatic drugs.7 After 3 months, patients treated with tofacitinib 5 mg or 10 mg were significantly more likely to meet the criteria for an American College of Rheumatology 20, 50, or 70 (ACR20, ACR50, ACR70) response than patients who took placebo.7 Patients given tofacitinib also had significantly greater reductions in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores and greater improvement in physical function, already evident by week 2 of the trial.7

The phase 3 ORAL Step trial compared tofacitinib plus methotrexate with placebo plus methotrexate in patients with moderate to severe RA and an inadequate response to tumor necrosis factor inhibitors.2 The tofacitinib/methotrexate combination was associated with significantly greater ACR20 response rates and improvement in HAQ-DI and disease activity-28 (DAS-28) scores.

The most common adverse events observed in clinical trials of tofacitinib are diarrhea, nasopharyngitis, upper respiratory infection, headache, and hypertension.8 Tofacitinib is also associated with an increased risk for serious infections, including pneumonia, cellulitis, herpes zoster, urinary tract infection, and tuberculosis.8 Tofacitinib may also increase levels of cholesterol, creatinine, and transaminases during therapy.2

A pooled analysis of data from 2 long-term extension studies in patients with RA showed tofacitinib had sustained efficacy over 4 years.9 Regarding long-term safety, analyses of data from 6194 patients with tofacitinib exposure of up to 8.5 years reported an incidence rate for serious adverse events of 9.4/100 patient-years10 and an incidence rate for serious infections of 2.7/100 patient-years. The investigators said the adverse event profile remained stable over time.10