Monday, 22 Jan 2018

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

Infliximab Does Not Increase Perioperative Infection

Staying on a TNF inhibitor (TNFi) throughout major surgery has generatlly been associated with higher rates of perioperative infection (https://buff.ly/2iBFVjp).  On the other hand, discontinuation of the TNFi prior to surgery is associated with lower rates of  infection (https://buff.ly/2iAFZQf)

CALM Study: Tight Control with Anti-TNF Wins in Crohn's Disease

Not unlike rheumatoid arthritis and other inflammatory disorders, therapeutic efficacy in Crohn's disease (CD) is often assessed clinically. There is growing use and interest in biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein. But Lancet has now reported a clinical trial has shown that a tight control strategy can yield better responses to TNF inhibitors when compared to usual care. 

Amgen-Abbvie Settle Humira Biosimilar Patent Dispute

Amgen's biosimilar version of adalimumab (Humira) was FDA-approved in September 2016 and given the trade name Amjevita (generic: adalimumab-atto). This new TNF inhibitor biosimilar has not yet been to market because of legal wranglings over patent issues by Abbvie's Humira.

Another Adalimumab Biosimilar Approved

On Friday August 25th, the FDA approved another adalimumab biosimilar: Cyltezo (generic name: adalimumab-adbm).

Adalimumab Biosimilars Adding Up

Reuters reports that yet another adalimumab biosimilar has been approved by European Union regulators.

The new drug is named Imraldi, and is manufactured by Samsung Bioepis, a company who has several biosimilars approved or in development for worldwide use.