nonTNF

Non-TNF inhibitors are therapies that reduce inflammatory activity through targets other than tumor necrosis factor alpha (TNF-α). They include biologic agents that block interleukins or their receptors, as well as small-molecule drugs that modulate intracellular signaling pathways. These therapies are used to treat autoimmune and autoinflammatory diseases, often as alternatives to TNF inhibitors or after TNF inhibitors have failed.

Mechanisms and representative agents span several targets. IL-1 pathway blockers such as anakinra (IL-1 receptor antagonist) and canakinumab (anti-IL-1β) are used in certain autoinflammatory conditions. The IL-6 axis is targeted by tocilizumab (IL-6 receptor blocker). IL-12/23 inhibitors like ustekinumab bind the p40 subunit shared by IL-12 and IL-23. IL-17 and IL-23 inhibitors include secukinumab and ixekizumab (IL-17A inhibitors), guselkumab and risankizumab (IL-23 inhibitors), and tildrakizumab (IL-23 p19 inhibitor). JAK inhibitors such as tofacitinib, upadacitinib, and baricitinib interfere with intracellular signaling used by multiple cytokines, while PDE4 inhibitors like apremilast offer oral, non-biologic modulation of inflammatory pathways.

Common indications include rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, axial spondyloarthritis, Crohn’s disease, ulcerative colitis, and certain autoinflammatory syndromes. Choice of non-TNF agent depends on disease type, prior response to therapies, comorbidities, and safety considerations.

Safety and monitoring vary by class. Risks include infections, liver enzyme abnormalities, lipid changes, and, for JAK inhibitors, thromboembolic events and herpes zoster. Baseline and periodic monitoring, vaccination planning, and TB screening are generally advised, with adjustments for pregnancy and lactation as appropriate.