A long-term extension trial reported a case of lymphoma in a

patient treated with tofacitinib, but the rate of lymphoproliferative disease was consistent with the rate seen in all patients with RA, including those treated with biologics.[28] Similarly, occurrences of basal cell cancer, non-Hodgkin’s lymphoma, stomach adenocarcinoma, Ibrutinib mouse breast mucinous adenocarcinoma and bone squamous cell carcinoma were reported in phase 3 trials.[31] Further investigation has pooled phase 2 and 3 data to reflect 5651 patient-years of tofacitinib treatment. The most common malignancies reported were lung and breast cancer. Three cases of lymphoma were identified. The incidence for all malignancies (excluding non-melanoma skin cancer) is consistent with that of RA patients taking traditional small-molecule DMARDs and biologic agents.[33] Laboratory abnormalities were observed with tofacitinib treatment. Neutrophil levels decreased and studies showed suppressed hemoglobin Dasatinib ic50 levels (contrary to the rise in hemoglobin typically seen with biologic therapy). Since JAK2 is integral in the signaling of erythropoietin and colony stimulating factors, these

cytopenias are felt to be a consequence of JAK2 inhibition.[28] Notably, low density lipoprotein (LDL) and high DL (HDL) levels increased in tofacitinib study groups. While analyses of phase 3 trials and long-term open label extension studies have not demonstrated an increased risk of cardiovascular events compared

to control RA patients, it may be too soon to conclude that these changes in lipid levels are inconsequential.[34] Small, but statistically significant elevations in serum creatinine and infrequent increases in serum transaminase levels were also demonstrated. While long-term trials of tofacitinib are still ongoing, the available data regarding the safety profile of tofacitinib is encouraging and in keeping with the safety profile seen in biologic therapy. Additional JAK inhibitors are under clinical investigation ID-8 in RA (Table 5). Baricitinib (INCBO28050) is a selective inhibitor of JAK1 and JAK2. Baricitinib is similar to ruxolitinib in its inhibition of JAK1 and JAK2. Ruxolitinib was the first JAK inhibitor approved by the United States FDA in November of 2011 for treatment of myelofibrosis. Phase 2a trials for ruxolitinib in RA demonstrated significantly improved ACR response criteria, spurring on further investigation of baricitinib.[35] In preclinical trials of baricitinib, inhibition of JAK1 and JAK2 interfered with signaling of inflammatory cytokines such as IL-6 and IL-23.[36] Indeed, baricitinib was found to be effective in several rodent models of inflammatory arthritis without evidence of immunosuppression. The risk of bone marrow suppression expected with JAK1 and JAK2 inhibition was avoided by using periodic and incomplete inhibition.