rheumatology and musculoskeletal
JAK inhibitors in the treatment of rheumatoid arthritis
Progress in treating rheumatoid arthritis has been achieved with Janus kinase inhibitors , orally available disease-modifying anti-rheumatic drugs targeting the intracellular kinase JAK and having similar efficacies to biologics
Manuel Pombo-Suarez MD Rheumatology Department , Complejo Hospitalario Universitario de Santiago de Compostela . Spain
Juan Gomez-Reino MD Fundación Ramón Domínguez Complejo Hospitalario Universitario de Santiago de Compostela , Spain
Rheumatoid arthritis ( RA ) is a systemic autoimmune disease characterised by inflammation , synovitis and progressive destruction of the articular cartilage and underlying bone , along with various extraarticular manifestations . Cytokines act as soluble mediators responsible for the inflammatory process , activating endothelial cells and attracting immune cells to accumulate within the synovial compartment . 1
The basis of RA treatment is the use of disease-modifying anti-rheumatic drugs ( DMARDs ). There are two major classes of DMARDs : synthetic ( sDMARDs ) and biological ( bDMARDs ). Furthermore , sDMARDs are divided into conventional synthetic ( csDMARDs ) and targeted synthetic ( tsDMARDs ). 2 This classification is based on the development process . The use of csDMARDs has evolved empirically , as their modes of action are largely unknown . By contrast , tsDMARDs have been developed to target specific molecules that are known to play a role in RA pathogenesis . This is the case of the subjects of this review , being designed to inhibit molecules of the Janus kinase ( JAK ) transduction pathway .
The JAK inhibitors are a recent class of drugs for the treatment of RA . Unlike previous therapies that were based on blocking different cytokines outside the cell , JAK inhibitors act by disrupting signalling pathways within the cell . In recent years , intracellular signalling proteins , as kinases , have emerged as potential targets for regulating the immune system in arthritis . JAKs are intracellular transducers of signals from many extracellular cytokines . There are four types of JAKs : JAK1 ; JAK2 ; JAK3 ; and non-receptor tyrosine protein kinase , TYK2 . Distinct cytokine receptors are paired with different JAKs , which are activated upon cytokine binding . This triggers the regulation of gene expression through activation of various signalling molecules . 3 Suppressing the cytokine effect through JAK inhibition seems a feasible approach to treat RA . Each JAK inhibitor has specific affinities to different JAKs ; therefore distinctive cytokines and other soluble factors are blocked and particular effects are expected .
Treatment recommendations Present recommendations for the treatment of RA suggest that therapy should be initiated with a csDMARD , methotrexate ( MTX ) being the most commonly used . Until the advent of tsDMARDs ,
8 HHE 2018 | hospitalhealthcare . com bDMARDs were the single available option in patients who failed to respond to csDMARDs . The arrival of bDMARDs meant a dramatic step forward in the treatment of RA and made it possible to increase the level of demand , supporting a ‘ treat to target ’ strategy aimed at lowering disease activity or remission . However , up to one third of patients do not adequately respond to bDMARDs and more lose response over time or experience adverse events . 5 Thus there is a demand for new therapies to fill the gap and that is where tsDMARDs , specifically JAK inhibitors , come into play . Presently , tsDMARDs are recommended for the treatment of patients who failed with csDMARD added to the csDMARD in a similar way than bDMARDs . 4 Interestingly , if the use of csDMARD as comedication is contraindicated , tsDMARDs are preferred over all bDMARDs , because JAK inhibitors have shown better efficacy on monotherapy compared with MTX . 6 , 7
JAK inhibitors A large number of clinical trials have already demonstrated the efficacy of different JAK inhibitors ; To date , tofacitinib and baricitinib have been approved by the European Medicines Agency ( EMA ) and by the Food and Drug Administration ( FDA ). Tofacitinib has been marketed in a number of countries , including the USA , in the last five years . Many JAK inhibitors with different specificities are being developed , and a number of these are expected to be launched in the coming years .
JAK1 / 3 inhibitors Tofacitinib is a selective inhibitor with a high affinity for JAK1 and 3 and for JAK2 , to a lesser extent . Phase III trials have shown efficacy for tofacitinib in RA patients who have failed DMARDs , both as monotherapy 6 and in combination with MTX . 8 A study has demonstrated that tofacitinib plus MTX was non-inferior to adalimumab plus MTX , and that tofacitinib monotherapy was not non-inferior relative to the two combination groups . 9 Tofacitinib also demonstrated higher rates of response when compared with placebo in patients with insufficient response to bDMARDs . 10
Tofacitinib was the first JAK inhibitor to reach the market , being approved in the USA and 44 other countries in 2012 . It took longer to obtain approval from the EMA , and this was granted in