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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 March 2017. The reasons behind this delay were unresolved safety concerns (mainly infections) and doubts about reduction of structural progression. Pooled data from studies of tofacitinib in patients with RA showed that the overall risk of infection (including serious infection) and mortality rates in RA patients treated with tofacitinib were similar to those observed in RA patients treated with biologic agents. 11 Regarding joint damage, a subsequent trial showed that tofacitinib monotherapy was superior to MTX in preventing radiological progression. 12 The overall rates and types of malignancies observed in the tofacitinib clinical programme remained stable over time with increasing tofacitinib exposure and were in line with what is expected in patients with moderate to severe RA. 13 The EMA approved tofacitinib at a dose of 5mg twice daily, being indicated in combination with MTX for the treatment of moderate to severe active RA in adult patients who have had an inadequate response to MTX. It also can be used as monotherapy in cases of intolerance to MTX or when continued treatment with MTX is inappropriate. JAK1/2 inhibitors Baricitinib is a JAK1/2 inhibitor with moderate activity on TYK2 and no influence on JAK3. Phase III studies demonstrated that baricitinib alone or in combination with MTX had superior efficacy to MTX monotherapy as initial treatment for patients with active RA. 7 In patients with inadequate response to 38 | Issue 90 | 2018 | hospitalpharmacyeurope.com MTX, baricitinib was superior when compared with placebo and adalimumab. 14 It also demonstrated clinical improvement and inhibition of progression of radiographic joint damage in patients who failed to respond to csDMARDs 15 and clinical improvement in patients with inadequate response to bDMARDs. 16 Baricitinib was approved by the EMA in March 2017 at a dose of 4 or 2mg once daily. It is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to, one or more DMARDs. It can be used as monotherapy or in combination with MTX. Baricitinib approval was initially rejected by the FDA, on the basis that additional clinical data were needed to determine the most appropriate doses and to further characterise safety concerns across treatment arms. A major reason behind this decision was the presence of thromboembolic events in five patients receiving baricitinib in clinical trials. It just has been approved by the FDA at a dose of 2mg once daily in adult patients with moderately- to-severely active RA who have had an inadequate response to one or more tumor necrosis factor (TNF) inhibitor therapies. It may be used as monotherapy or in combination with MTX or other csDMARDs. Baricitinib was approved with a Boxed Warning for the risk of serious infections, malignancies and thrombosis. As part of the approval, the sponsor has agreed to conduct a randomised controlled clinical trial to evaluate the long-term safety of baricitinib in patients with RA. JAK1 inhibitors Filgotinib is a selective inhibitor of JAK1 over JAK2, JAK3 and TYK2. The rationale for the development of more selective inhibitors such as filgotinib is that less selective JAK inhibitors lead to pan-JAK inhibition that might generate dose-limiting side effects. Published results of Phase II studies in patients with insufficient response to MTX showed that filgotinib was superior to placebo with an acceptable safety profile. 17,18 It has also shown efficacy as monotherapy. 19 Upadacitinib is another selective inhibitor of JAK1. It has also demonstrated efficacy in Phase II trials, with a favorable safety and tolerability profile in patients with inadequate response to MTX and to bDMARDs. 20,21 Phase III clinical trials are currently ongoing. JAK3 inhibitors Decernotinib selectively inhibits JAK3 over the other JAKs. Taking this into account it would be expected that some of the side effects seen with less specific JAK inhibitors might be avoided. Decernotinib has shown superiority compared with placebo in a Phase II study. 22 Development is currently on hold. Peficitinib inhibits all of the JAKs, having a moderate selectivity for JAK3. Its milder effect on JAK2 suggests that effects on red blood cells and platelets caused by JAK2 inhibition might be less intense. Results from Phase II trials have demonstrated an acceptable response in patients with inadequate response to csDMARDs. 23,24 Phase III trials are underway. Safety profile Information from clinical trials is creating a characteristic safety profile for this new class of molecules. What is difficult to answer at this moment is whether the different selectivities of each JAK inhibitor will establish distinctions