JAK inhibition by methotrexate (and csDMARDs) may explain clinical efficacy as monotherapy and combination therapy

Abstract

Methotrexate (MTX) is recognized as the anchor drug in the algorithm treating chronic arthritis (RA, psoriatic arthritis), as well as a steroid sparing agent in other inflammatory conditions (polymyalgia rheumatica, vasculitis, scleroderma). Its main mechanism of action has been related to the increase in extracellular adenosine, which leads to the effects of A2A receptor in M1 macrophages that dampens TNFα and IL12 production and increases IL1Ra and TNFRp75. By acting on A2B receptor on M2 macrophages it enhances IL10 synthesis and inhibits NF‐kB signaling. MTX has also been shown to exert JAK inhibition of JAK2 and JAK1 when tested in Drosophila melanogaster as a model of kinase activity and in human cell lines (nodular sclerosis Hodgkin's lymphoma and acute myeloid leukemia cell lines). These effects may explain why MTX leads to clinical effects similar to anti‐TNFα biologics in monotherapy, but is less effective when compared to anti‐IL6R in monotherapy, which acting upstream exerts major effects downstream on the JAK1‐STAT3 pathway. The MTX effects on JAK1/JAK2 inhibition also allows to understand why the combination of MTX with Leflunomide, or JAK1/JAK3 inhibitor leads to better clinical outcomes than monotherapy, while the combination with JAK1/JAK2 or JAK1 specific inhibitors does not seem to exert additive clinical benefit.

JAK Inhibition as a New Treatment Strategy for Patients with COVID-19

“…Therefore, researchers believe that MTX has an efficacy equal to that of anti-TNFα monotherapy through adenosine and JAK inhibition. These effects possibly explain why MTX monotherapy results in good clinical outcomes resembling those of anti-TNF-α biologics alone but is less effective in comparison to anti-IL6-R alone [40]. MTX plus tofacitinib showed clinical effects similar to those of MTX plus adalimumab [41], suggesting that the specific inhibition of tofacitinib in combination with the JAK1/JAK2 inhibition capability of MTX may exert synergistic effects.…”

Efficacy and safety of tofacitinib for immune-mediated inflammatory rheumatic diseases (Part I)

“…При выборе ТОФА в качестве препарата «второго» или «третьего» ряда при РА следует иметь в виду удобный пероральный прием (в отличие от ГИБП, которые применяются в виде парентеральных инъекций), быстрое развитие анальгетического эффекта, высокую эффективность монотерапии, что имеет особое значение для лечения пациентов, имеющих противопоказания (или непереносимость) для применения МТ [73,74]. Следует подчеркнуть, что МТ также обладает способностью ингибировать JAK [184], т. е. проявляет «частично перекрещивающийся» механизм действия с ингибиторами JAK, что предоставляет теоретические обоснования эффективности монотерапии этими препаратами. Следует обратить внимание на низкую частоту инфекционных осложнений (в том числе реактивацию туберкулезной инфекции), за исключением герпеса, и особенно на эффективность ТОФА у пациентов с РА, резистентных к ГИБП.…”

From Cancer to Immune-Mediated Diseases and Tolerance Induction: Lessons Learned From Immune Oncology and Classical Anti-cancer Treatment

“…The drug has long since become the standard of treatment for rheumatoid arthritis, but at the relatively low doses used, its mechanism of action is thought to be due to enhanced conversion of AMP to extracellular adenosine, an endogenous anti-inflammatory substance which reduces macrophage cytokine release. Recently, though, it has been shown to inhibit JAK1/2 kinases, which are involved in inflammatory cell signaling ( 25 ).…”