Interleukin-6 Levels Predict Severe Relapses in ANCA Vasculitis Patients on Rituximab, Study Reports

Although serum levels of the pro-inflammatory molecule interleukin (IL)-6 do not predict who will achieve complete remission, increases during periods of no disease activity are associated with subsequent severe relapses in patients with ANCA-associated vasculitis (AAV) on rituximab, according to an exploratory study.

The research, “The association of serum interleukin-6 levels with clinical outcomes in antineutrophil cytoplasmic antibody-associated vasculitis,” appeared in the Journal of Autoimmunity.

High levels of IL-6 have been implicated in inflammatory and antibody-mediated autoimmune diseases, including rheumatoid arthritis. However, the role of IL-6 in AAV has not been studied in detail, despite studies showing overproduction of IL-6 also in this disease and data in mice indicating a link between this molecule and disease severity.

Aiming to better understand this association, the team used serum samples from participants in the RAVE Phase 2/3 trial (NCT00104299), which involved 197 patients receiving either rituximab (brand name Rituxan, Truxima, Ruxience, and others) or standard immunosuppressant cyclophosphamide followed by azathioprine.

Among other assessments, the investigators measured disease activity and organ manifestations with the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) at baseline, at two weeks, and at 1, 2, 4, 6, 9, 12, 15, and 18 months after enrollment. The patients, all with active disease, were followed until month 24. Levels of both IL-6 and the inflammatory marker C-reactive protein (CRP) were determined at each study visit.

Among the 78 patients included in this study, 58 had granulomatosis with polyangiitis, while the remaining 20 had microscopic polyangiitis. In turn, 57 patients had anti-PR-3 antibodies and 21 had anti-MPO-ANCA antibodies.

Regarding disease status, 46% of patients had relapsing disease and 54% were newly diagnosed. Baseline serum IL-6 levels were detectable in 81% of participants.

Also, 45 patients were treated with rituximab and 33 with cyclophosphamide and azathioprine.

Levels of serum IL-6 at baseline were higher in patients with granulomatous inflammatory manifestations and those with both granulomatous disease and capillaritis — inflammation in tiny blood vessels — compared to participants with capillaritis only. Also, IL-6 was increased in people with anti-PR3-ANCA in comparison to those anti-MPO-ANCA antibodies at baseline, but not at subsequent timepoints.

Still, at baseline, the higher the levels of anti-PR3-ANCA, the greater the serum IL-6 levels. When evaluating specific manifestations, the scientists found that fever, conductive deafness, lung nodules or cavities, and not having red cell blood casts were associated with higher serum levels of IL-6.

At month 6, levels of IL-6 were reduced in response to remission-induction therapy, with 76% of patients achieving complete remission. The rate of patients achieving this goal did not differ between disease or antibody types, nor between treatments. Also, IL-6 levels were not associated with achieving complete remission within six months.

As for the patients experiencing relapses, no differences were found comparing treatments up to nine months of follow-up. Overall, no correlation was found between increased IL-6 levels and subsequent relapses. However, within the group of patients treated with rituximab, increases in IL-6 were associated with subsequent severe relapses, most of which within six months.

In turn, no links were found between CRP levels and relapses, either overall or within each treatment group.

Despite the well-known effect of serum IL-6 on immune B-cell proliferation, the researchers found no link between IL-6 levels and B-cell reappearance after depletion with rituximab. Also, increases in IL-6 did not predict changes in ANCA antibodies’ levels.

The data further showed that all 15 patients on rituximab who experienced a severe relapse had a prior increase in B-cell levels (back to detectable levels), 12 of those before or after the IL-6 increase.

“We cannot conclude that IL-6 is the central molecular mediator driving the disease relapse in AAV, but — according to our results — it appears to precede it … suggesting a possible pathogenic role,” the scientists said. “Further investigation into the mechanistic role of IL6 in AAV might lead to identifying this pathway as a potential therapeutic target in this disease.”