Tuesday, 23 Apr 2019

You are here

Why TNF Inhibitors May Work in Some Autoinflammatory Patients

The NLRP3 inflammasome is a critical component of the innate immune system and activation of NLRP3 inflammasome results in caspase-1–dependent secretion of the proinflammatory cytokines IL-1β and IL-18. Gain-of-function missense mutations in NLRP3 is thought to drive many of the autoinflammatory diseases, especially the cryopyrin-associated periodic syndromes (CAPS).

Despite these advances, some autoinflammatory and CAPS patients demonstrate partial responses to IL-1 inhibition. The current issue of the Journal of Clinical Investigation reports that TNF-α, in addition to IL-1β, plays an important role in promoting the NLRP3 inflammasomopathies.

Specifically, this multicenter research study took advantage of mutant Nlrp3-knockin mouse lines deficient in both IL-1β and IL-18 to investigate these alternate pathways. They found TNF to be an important transcriptional regulator of the NLRP3 inflammasome murine models of autoinflammatory disease. 

Using both genetic knock outs (KO) and targeted etanercept treatment they were able to show a significant role for TNF in the development and progression of murine inflammasomopathies.

They generated Nlrp3-knockin mice on various KO backgrounds including Il1b/Il18-, caspase-1–, caspase-11– (Casp1/11-), and Tnf-deficient strains. The Nlrp3L351P Il1b–/– Il18–/– mutant mice survived and grew normally until adulthood and, at 6 months of age, exhibited marked splenomegaly and leukophilia.

When they treated the Nlrp3A350V mice with the TNF inhibitor etanercept resulted in all pups surviving to adulthood, with normal body and spleen/body weight ratios. Nlrp3A350V Tnf–/– mice showed a similar phenotypic rescue, with marked reductions in serum IL-1β and IL-18, reduced myeloid inflammatory infiltrate in the skin and spleen, and substantial decreases in splenic mRNA expression of both inflammasome components (Nlrp3, Pycard, pro-Casp1) and pro-cytokines (Il1b, Il18).

These findings suggest that TNF may be responsible for partial responses to IL-1–targeted therapies in CAPS patients and that TNF inhibition may provide additional clinical benefit in such patients. 

Disclosures: 
The author has no conflicts of interest to disclose related to this subject

Add new comment

More Like This

FDA Approves Cimzia for Non-Radiographic Axial Spondyloarthritis

The U.S. Food and Drug Administration today approved Cimzia (certolizumab pegol) injection for treatment of adults with a certain type of inflammatory arthritis called non-radiographic axial spondyloarthritis (nr-axSpA), with objective signs of inflammation. This is the first time that the FDA has approved a treatment for nr-axSpA.

Lower TNF Inhibitor Persistence in Spondylitis

A claims data analysis shows that only one-third of ankylosing spondylitis (AS) treated with tumor necrosis factor inhibitors (TNFi) therapy remain on their initial drug in the 2 years post initiation.

The Risk of Tuberculosis with TNF Inhibitors

A study from Turkey shows that among 2117 patients treated with a TNF inhibitor (TNFi) the risk of developing TB was 6 fold higher in those treated with a TNFi compared to non-users.

This retrospective cohort study included patients with rheumatoid arthritis (RA), ankylosing spondylitis, juvenile idiopathic arthritis or psoriatic arthritis (PsA) that treated with or without TNFI. The calculated the 2-year RR of TB after TNFi.

Higher Infection Rates for Infliximab in Psoriasis

A prospective study of psoriasis patients from the British Association of Dermatologists Biologic Interventions Register demonstrated that infliximab therapy yielded 2-3 times more serious infection than seen in those treated with non-biologic DMARDs or methotrexate (MTX).

Biomarker Combo Predicts TNF Inhibitor Responses

Based on clinical trial data, patients starting tumour necrosis factor-alpha inhibitors (TNFi) have roughly a two-thirds chance of achieiving a good clinical response. French investigators have studied a series of potential biomarkers and surmised that the combination of baseline prealbumin, platelet factor 4 and S100A12 can predict a 78% response to TNFi in rheumatoid arthritis (RA) patients.