Arundathi Jayatilleke, MD
The association of RA and cardiovascular disease has been extensively described. Beta adrenergic receptors are not known to be involved in RA, though Abuhelwa et al. suggest a potential role in “immunologic balance” in their study of beta blocker use and RA remission. In a pooled analysis of five tocilizumab trials, use of beta blockers was associated with lower proportions of CDAI remission. However, without information on beta blocker dose or duration of therapy as well as potential confounding by indication, the significance of this finding is uncertain.
Another known association of RA and its treatment is malignancy, perhaps due to decrease in immunosurveillance; it remains a concern in choice of therapy and long-term effects. Solipuram et al. performed a systematic review of combination JAK inhibitor and methotrexate therapy in RA to evaluate the evidence regarding malignancy risk. Among the 13 trials included for analysis, 40 cases of malignancy were reported for over 3,600 patient-years in patients receiving combination therapy, compared to 7 cases among nearly 1,000 patient-years in patients receiving methotrexate alone; no change in relative risk was seen in non-melanomatous skin cancer or other cancers. While this information is reassuring, it does not eliminate the possibility of increased malignancy given variations in duration of followup in different studies. There is also a need for longer follow-up because of a potential latency period before the development of cancer. Ideally, long-term extension studies could help better define this risk, though those studies tend to be single-armed and without a control.
Though different JAK inhibitors generally are thought to have similar efficacy and class-associated side effects, few studies have compared immunomodulatory effects of the medications. Reddig et al compared the effects of baricitinib, upadicitinib, filgotinib, tofacitinib, and methotrexate on cell proliferation, cell activation, and apoptosis, as well as induction of DNA damage and repair in an in vitro study. The study authors used human peripheral blood monocytes treated with phytohemagglutinin to activate T cells and induce proliferation. Tofacitinib, baricitinib, and upadicitinib were associated with comparable dose-dependent inhibition of lymphocyte activation and proliferation. Higher doses of filgotinib were required to obtain the same effect. Filgotinib at high concentrations also were associated with higher levels of DNA damage markers. These findings are interesting as to the shared mechanism of action of JAK inhibitors, regardless of JAK specificity. However, given the lack of “universal” patterns in vitro, their clinical importance or relevance in distinguishing between the medications is unclear.
Kim et al. investigates the pathogenesis of RA in their in vitro study of mast cells. Though previously identified in RA synovial fluid and tissue and not in OA synovium, their role is not entirely clear. Though normally associated with allergic responses, mast cells have been postulated to have pro- and anti-inflammatory effects, and release inflammatory cytokines and mediators, such as histamine. Synovial fluid and serum samples from RA and OA patients, as well as healthy volunteers, were analyzed for tryptase, chymase, and histamine; serum levels of all three were higher in RA than in OA patients and healthy volunteers. Synovial fluid levels of histamine were higher in RA. Cell culture studies were performed using IL-33 to activate human mast cells, causing an increase in tryptase –positive cells, as well as an increased expression of RANKL and MMP-9. This suggests a role for mast cells in osteoclastogenesis and tissue degradation. In addition to providing more information about the involvement of mast cells in RA pathogenesis, these findings suggest mast cells as a potential therapeutic target.