Ustekinumab and Guselkumab Don't Work in RA

Josef Smolen presented a Phase 2 study evaluating the efficacy and safety of ustekinumab and guselkumab for the treatment of RA.

IL12 and IL-23 are composed of two subunits but they both contain identical larger subunits called p40. Ustekinumab is an antibody to the common p40 subunit of IL-12 and 23. Guselkumab is an antibody to the the p19 subunit of IL-23.

IL-12 is important in the activation of TH1 cells and the resulting release of IFN-gamma whereas IL-23 induces TH17 cells that make IL-17. This results in an upregulation in inflammation.

The question posed is if either or both IL-12 or IL-23 is involved in the pathogenesis of RA? To answer this question, this study randomized 250 patients to ustekinumab 80 mg q8 or 12 weeks, guselkumab 30 or 200 mg q8 weeks, and placebo. The primary endpoint was ACR 20 at week 28.

The patients in this study were about 50 years of age, 87-90% were RF-positive, they had a disease duration of 6 years, a swollen joint count of 16-17, and a HAQ of 1.7 to 1.8. They had active disease.

The primary endpoint failed for both ustekinumab and guselkumab at week 28 with an ACR 20 of 40% in the PBO group vs 40-55% in the active treatment groups. The ACR 50 and 70 were far from reaching the levels seen with TNF inhibitors and were not different from PBO.

This was a disappointing study but it is still important to discuss negative studies. On a positive note, the safety data was reassuring as both medications were well tolerated with no new or unexpected safety signals identified.

In the immunopathogenesis of RA, IL-12 and IL-23 do not appear to play a major role. This points to a different pathogenesis than what is seen with psoriatic arthritis.

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