Key Research in Vasculitis Encapsulated

WASHINGTON, D.C.—Multiple game-changing studies on the assessment and management of systemic vasculitis were presented at ACR Convergence 2024. Here, we highlight important points from seven of these studies. They focus on new treatment strategies for a range of diseases, including giant cell arteritis (GCA), anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis and IgG4-related disease (immunoglobulin G4-RD).

1. Upadacitinib for GCA

Abstracts 0770 & 1695: Merkel et al.^1,2

Upadacitinib (UPA) is an oral Janus kinase (JAK) inhibitor that was recently approved by the U.S. Food & Drug Administration (FDA) for the treatment of giant cell arteritis, based on the data presented in these abstracts. It had previously been approved by the FDA for several other indications, including rheumatoid arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis and psoriatic arthritis.

SELECT-GCA is a double-blind trial that randomized 428 patients with new (70%) or relapsing (30%) GCA to receive treatment with upadacitinib (UPA; 7.5 mg or 15 mg daily with a 26-week glucocorticoid taper) or placebo with a 52-week glucocorticoid taper.³

Patients treated with the higher dose of UPA were significantly more likely to achieve sustained remission (defined as the absence of disease activity from week 12 through week 52) and adherence to the glucocorticoid taper than patients treated with placebo (46% vs. 29%, P=0.002). They were also more likely to have a decrease in flare rate, fatigue and cumulative glucocorticoid exposure. Patients treated with the lower dose of UPA did not achieve any of these end points. This was true across subgroups based on age, sex, new-onset disease and history of polymyalgia rheumatica.

Patients treated with 15 mg of UPA had higher rates of herpes zoster, lympho­­penia, anemia and nonmelanoma skin cancer (NMSC), but did not have higher rates of venous thrombotic events, non-NMSC malignancies or major adverse cardiovascular events (MACE).

When I was in training, I was taught that GCA could only be treated with glucocorticoids. Clearly, this is no longer the case. Tocilizumab, the first biologic approved by the FDA for the treatment of GCA, has dramatically changed outcomes for many patients afflicted with this common cause of systemic vasculitis.⁴ However, many patients are reluctant to use tocilizumab because of contraindications, payer issues or a hesitancy to use an injectable drug. For patients in all of these groups, upadacitinib, an orally administered JAK inhibitor, may represent a welcome option.

Upadacitinib, like all JAK inhibitors, has a boxed warning indicating an association with MACE (e.g., cardiovascular death, myocardial infarction, stroke), venous thrombotic events and malignancies; some studies indicate these risks may be higher among older patients.⁵ It is, therefore, reassuring that SELECT-GCA did not detect an association between UPA and any of these adverse events. However, longer-term follow-up will be required before we can completely dismiss these concerns.

2. Inebilizumab for IgG4-Related Disease

Abstract 0775: Stone et al.⁶

Inebilizumab is a humanized mono­clonal antibody directed against CD-19, which is a marker present on a broad range of B cells, including plasmablasts and plasma cells. It is currently FDA approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD), a neuroinflammatory disorder that affects the optic nerves and spinal cord.

MITIGATE was a phase 3 study that randomized 135 patients with IgG4-RD to receive treatment with either inebilizumab (300 mg intravenous infusions on days 1 and 15, and week 26) or placebo, in addition to glucocorticoids, which were tapered over eight weeks.⁷

At the end of 52 weeks of observations, patients treated with inebilizumab were significantly less likely to experience relapse than patients treated with placebo (hazard ratio 0.13, 95% confidence interval [CI] 0.06, 0.28). The most common adverse events included COVID-19, lymphopenia and urinary tract infections. Serious and/or opportunistic infections were more common among patients treated with inebilizumab than placebo (9% vs. 3%).

B cell depletion with rituximab (a monoclonal antibody directed against CD20) has long been a standard therapy for the treatment of IgG4 RD. CD19 is present on a broader range of cells in the B cell lineage than CD20. Therefore, a monoclonal antibody directed against CD19 should result in deeper depletion of the B cell compartment. There are already data indicating that inebilizumab may be more effective than rituximab for NMOSD.⁸ Whether the same will be true for IgG4 RD has not yet been established.

3. Low-Dose Glucocorticoids for GPA

Abstract 0774: Merkel et al.⁹

This study identified 143 patients with granulomatosis with polyangiitis (GPA) who had active disease in the past year and were able to taper their prednisone to 5 mg daily. Patients were randomized to continue taking prednisone 5 mg daily for six months or to taper their prednisone dose to 0 over a period of four weeks.

Overall, patients who remained on low-dose prednisone had a reduced rate of relapse at month 6 (16% vs. 4%; OR 4.2; 95% CI 1.1–15.8). However, subgroup analysis demonstrated this benefit was restricted to patients not using rituximab for remission maintenance (20% vs. 6%; OR 9.5, 95% CI 1.1-81.7). There was no difference between the two arms in patient-reported outcomes, including Patient Reported Outcomes Measure­ment Information System (PROMIS) Fatigue, Pain Interference and Physical Function scales and the SF-36.

There has been a long-standing debate over the value of using low-dose prednisone for remission-maintenance among patients with GPA. Recent data demonstrating that even low-dose gluco­corticoids may have side effects has renewed interest in this debate.¹⁰

This study demonstrates that patients likely do benefit from the use of low-dose prednisone; however, this benefit is not seen in patients who receive rituximab for remission maintenance. We often continue low-dose prednisone in patients with long-standing GPA to prevent symptoms of glucocorticoid withdrawal or adrenal insufficiency; it is, therefore, interesting that patients who remained on low-dose prednisone did not seem to feel better than patients who were tapered off of glucocorticoids entirely.

However, the spectrum of disease manifestations associated with GPA is broad, and a study of this size may not be able to identify specific disease phenotypes (e.g., chronic sinusitis) that may benefit disproportionately from low-dose glucocorticoids.

4. Mepolizumab for EGPA

Abstracts 0827 & 2482: Khoury et al. & Merkel et al.^11,12

Mepolizumab is a monoclonal antibody directed against interleukin 5. In 2017, mepolizumab became the first drug approved by the FDA for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). These two studies examine what we know about the long-term effects of using mepolizumab for EGPA.

MIRRA was a phase 3, double-blind, placebo-controlled trial that randomized 136 patients with EGPA to receive treatment with either subcutaneous mepolizumab (300 mg monthly) or placebo; 100 patients who continued to require at least 5 mg of prednisolone daily to remain in remission were subsequently enrolled in a long-term access program, which allowed them to continue to receive mepolizumab 300 mg monthly until it became commercially available.¹³

Patients in this study received mepolizumab for a mean of 38.5 months. By months 16–18, 66% of patients were able to decrease their oral glucocorticoid requirement by greater than 50% (i.e., from a median prednisolone dose of 10 mg daily to 5.1 mg daily), and they were able to remain on the lower dose of glucocorticoids as long as they continued to receive treatment with mepolizumab. The most common serious adverse event reported was worsening asthma. However, no new safety concerns were identified.

Interleukin 5 blockade is exceptionally effective for addressing the sino­pulmonary manifestations of EGPA. These studies demonstrate that even after prolonged use, mepolizumab continues to be both safe and effective for patients with EGPA.

Benralizumab, a monoclonal antibody directed against the interleukin 5 receptor, was recently approved by the FDA for the treatment of EGPA;¹⁴ long-term studies of benralizumab demonstrate it is similarly safe and effective when used for up to five years for the treatment of patients with severe eosinophilic asthma.

Taken together, these studies demonstrate that patients with EGPA may safely use interleukin 5 blockade long term to keep their symptoms under control.

5. Clinical Characteristics of DADA2

Abstract 2647: Sharma et al.¹⁵

Deficiency of adenosine deaminase 2 (DADA2) is a monogenetic disorder characterized by systemic vasculitis, bone marrow failure and immunodeficiency.

Sharma et al. conducted a retrospective study of 101 patients with DADA2. The median age of disease onset was 17 years (range six months to 59 years), and it most commonly affected the skin (60%), central nervous system (including stroke in 35%), and gastrointestinal system (including mesenteric ischemia in 14%). Rare manifestations included amyloidosis, optic neuritis, pancreatic infarction and focal myocarditis. Risk factors for mortality included mesenteric ischemia, stroke and not receiving tumor necrosis factor inhibitor therapy.

Although DADA2 is often considered a pediatric diagnosis, this study highlights that over half of patients first become symptomatic as adults. This study also confirms the importance of using tumor necrosis factor inhibitors preferentially for the treatment of patients with DADA2, particularly for patients presenting with ischemic symptoms.

Philip Seo, MD, MHS, is an associate professor of medicine at Johns Hopkins University School of Medicine. He served as the third physician editor of The Rheumatologist.

Author’s Note

For those interested in the diagnosis and treatment of vasulitis and the latest research on the topic, the 22nd International Vasculitis Workshop will be hosted by the Australia and New Zealand Vasculitis Society (https://vasculitis-melbourne2026.com) on Feb. 21–25, 2026, in Melbourne.

References

1. Merkel P, Penn S, Setty A, et al. Efficacy and safety of upadacitinib in patients with giant cell arteritis (SELECT-GCA): A double-blind, randomized controlled phase 3 trial [abstract]. Arthritis Rheumatol. 2024;76(suppl 9). https://tinyurl.com/msm2srve.
2. Merkel P, Setty A, Blanco-Alonso R, et al. Efficacy of upadacitinib in patients with giant cell arteritis: Subgroup analysis of the SELECT-GCA phase 3 trial [abstract]. Arthritis Rheumatol. 2024;76(suppl 9). https://tinyurl.com/ykhtsbc3.
3. Blockmans D, Penn SK, Setty AR, et al. A phase 3 trial of upadacitinib for giant-cell arteritis. N Engl J Med. 2025 May 29;392(20):2013–2024.
4. Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritis. N Engl J Med. 2017 Jul 27;377(4):317–328.
5. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer Risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022 Jan 27;386(4):316–326.
6. Stone J, Culver E, Khosroshahi A, et al. A phase 3, randomized, double-blind, multicenter, placebo-controlled study of inebilizumab in IgG4-related disease (MITIGATE): Primary efficacy and safety findings [abstract]. Arthritis Rheumatol. 2024;76(suppl 9). https://tinyurl.com/mr3c4abb.
7. Stone JH, Khosroshahi A, Zhang W, et al. Inebilizumab for treatment of IgG4-related disease. N Engl J Med. 2025 Mar 27;392(12):1168–1177.
8. Lou CY, Wang Y, Xing JY, et al. Comparison of inebilizumab or rituximab in addition to glucocorticoid therapy for neuromyelitis optica spectrum disorders. Int J Ophthalmol. 2024 Jun 18;17(6):1073–1078.
9. Merkel P, Pagnoux C, Khalidi N, et al. A multicenter, randomized, controlled trial to evaluate the effects of low-dose glucocorticoids compared to stopping glucocorticoids to maintain remission of granulomatosis with polyangiitis: The TAPIR trial [abstract]. Arthritis Rheumatol. 2024;76(suppl 9). https://tinyurl.com/mfp7fh9w.
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11. Khoury P, Silver J, Wolff G, et al. Oral corticosteroid-sparing effects of mepolizumab in eosinophilic granulomatosis with polyangiitis (EGPA): Results up to 7.4 years from the long-term access programme [abstract]. Arthritis Rheumatol. 2024;76(suppl 9). https://tinyurl.com/33357jvu.
12. Wolff G, Wechsler M, Silver J, et al. Long-term safety of mepolizumab in eosinophilic granulomatosis with polyangiitis (EGPA): Pooled results from two open-label extension studies [abstract]. Arthritis Rheumatol. 2024;76(suppl 9). https://tinyurl.com/bdhfkd4t.
13. Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017 May 18;376(20):1921–1932.
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15. Sharma A, Bhowmick N, Naidu S, et al. Clinical characteristics, treatment outcomes and predictors of mortality in a DADA2 cohort of 101 patients [abstract]. Arthritis Rheumatol. 2024;76(suppl 9). https://tinyurl.com/9y23m2wr.