Let’s Discuss Part 2: More Insights from the ACR Convergence 2025 Review Course

Dr. Schulert explained that interleukin-18 (IL-18) is markedly elevated in patients with AOSD who develop MAS, and it is thought to be a key driver of MAS. IL-18 is produced by activated monocytes/macrophages via inflammasome-dependent processing, and its pathogenic role in MAS is mediated by the induction of interferon-γ and amplification of Th1-type immune responses, which lead to hyperinflammation and tissue damage. Recent studies have shown that chronic elevation of free, bioactive IL-18 is strongly associated with the risk and severity of MAS in patients with AOSD and, clinically, serum IL-18 levels can serve as a biomarker for disease activity.⁶

Vasculitis

Dr. Stone

At the final talk of the session, John Stone, MD, MPH, professor of medicine at Harvard Medical School, Boston, and the Edward A. Fox Chair in Medicine at Massachusetts General Hospital, Boston, provided an update on vasculitis. Dr. Stone began by discussing IgG4-related disease (IgG4-RD), which he said might strike some audience members as odd for a talk on vasculitis. However, he explained that IgG4-RD can be described as a vasculitis in that histopathology demonstrates obliterative phlebitis, which is evidence of small vessel vasculitic involvement, and patients can manifest with aortitis, tender temporal arteries or coronary artery aneurysms. Dr. Stone provided the clinical pearl that, in a patient with giant coronary artery aneurysms and no history of Kawasaki disease, IgG4-RD should be high on the differential. Although glucocorticoids are often used to treat IgG4-RD, these should be thought of as an induction rather than maintenance therapy because patients often have pancreatic involvement, which can be further complicated by the effects of prolonged steroid use. Inebilizumab, a monoclonal antibody targeting CD19⁺ B cells, was recently evaluated in a 52-week randomized, double-blind, placebo-controlled phase 3 trial. Among 135 participants with IgG4-RD, only 10% of those receiving inebilizumab experienced a treated disease flare compared with 60% in the placebo group. Secondary end points also favored inebilizumab, with markedly lower annualized flare rates and significantly higher odds of achieving flare-free, treatment-free or glucocorticoid-free remission.⁷ Based on these results, inebilizumab became the first U.S. Food & Drug Administration (FDA) approved treatment for IgG4-RD earlier this year.

On the subject of giant cell arteritis (GCA), Dr. Stone discussed the significant role that tocilizumab now plays in the management of most patients, who he advised should be started on this therapy at the time of diagnosis. A recent phase 3 trial evaluated upadacitinib, a selective Janus kinase inhibitor, combined with a 26-week glucocorticoid taper vs. placebo with a 52-week taper. Among the randomized patients (n=209 receiving 15 mg, n=107 receiving 7.5 mg and n=112 receiving placebo), approximately 70% had new-onset disease. Sustained remission at week 52 was achieved in about 46% of those on 15 mg of upadacitinib compared with 29.0% on placebo; the 7.5 mg dose did not show significant benefit. In addition, secondary outcomes, including reduced flare rates, lower glucocorticoid exposure and improved patient-reported measures, favored the 15 mg dose, and overall safety over 52 weeks was comparable between treatment and placebo groups.⁸ On the basis of this data, earlier this year upadacitinib became the second FDA approved treatment for GCA.