Why JAK Inhibitors Work and Anti-inflammatory Drugs Often Don't


Reviews describe the JAK/STAT pathway that has proven successful against rheumatoid arthritis and inflammatory conditions, and the many other pathways that govern inflammation, often to the detriment of anti-inflammatory strategies.

Last week's articles on rheumatology in the major nonspecialty journals:



Review Article: Mechanisms of Disease. JAKs and STATs in Immunity, Immunodeficiency, and Cancer N Engl J Med, Jan 10, 2013 (Full text $15)

The new biological modifiers tofacitinib, baricitinib, and ruxolitinib are all targeted at the same cellular pathway. This review describes the biology of this JAK/STAT pathway in detail, including the mechanisms by which JAK drives gene expression and the effects of its receptor proteins JAK3 and TYK2, both of which are critical to immune response. It also reviews the effects of interleukins on STATs, and their associations with rheumatologic disorders including lupus, rheumatoid arthritis, and Sjogren's syndrome. The first generation of JAK inhibitors targeted all the JAKs; a second generation will be more selective. There are no useful STAT inhibitors, but research goes on.

Anti-Inflammatory Therapy in Chronic Disease: Challenges and OpportunitiesScience, Jan. 11, 2013 (Full text $20)

Anti-inflammatory drugs are successful but limited. This article reviews the reasons for these limitations: Redundancies, compensatory pathways, and feedback mechanisms, as well as the risks of reduced immune response to infections. For example, anti-TNFα compounds were successful therapy for antibody to citrinullated protein (ACPA)–positive rheumatoid arthritis (RA), because TNFα was the proximal trigger and because many of the inflammatory mediators were downstream in the same pathway. In contrast, targeting the mitogen-activated protein kinase p38 was unsuccessful. It describes strategies to circumvent these limitations, among them inhibiting inflammatory molecules or stimulating innate anti-inflammatory responses. 


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