From Rituximab to Ianalumab: The Evolution of Targeted Therapy in Sjögren Disease

For the better part of 2 decades, clinicians treating Sjögren disease operated in something close to therapeutic darkness. While the immunopathology was increasingly understood — a B cell-expanded, chronically activated state marked by elevated BAFF levels, hypergammaglobulinemia, and progressively destructive glandular inflammation — that understanding never translated into approved targeted treatment. Patients arrived in clinic with debilitating dryness, fatigue, pain, and neurologic symptoms, and left with tear substitutes, saliva support, hydroxychloroquine, and in some cases off-label methotrexate.

In January 2026, that era began to end when the FDA granted Breakthrough Therapy designation to ianalumab (Novartis) for Sjögren disease, recognizing it as a potential first targeted treatment for the condition.¹ The designation was built on the strength of NEPTUNUS-1 and NEPTUNUS-2, the first global Phase 3 trials ever to demonstrate statistically significant reductions in disease activity in Sjögren — themselves a milestone that many in the field had spent careers working toward.¹⁻²

Sjögren disease is the second most prevalent rheumatic autoimmune condition, affecting an estimated 1 to 4 million Americans, approximately 90% of whom are women.¹ Despite this burden, the condition has long been undertreated and underrecognized — shaped in part by diagnostic barriers that have kept patients waiting years for answers. An estimated 30 to 40% of patients are seronegative, and a constellation of multi-system symptoms — dry eye, oral dryness, fatigue, autonomic dysfunction, and neuropathic pain — often presents across multiple subspecialties before a unifying diagnosis is reached.³

"The breakdown often isn't a single missed moment," said Kara Wada, MD, a quadruple board-certified allergist, immunologist, and lifestyle medicine physician at The Ohio State University Wexner Medical Center, who lives with Sjögren disease herself. "Someone may be seeing an ophthalmologist for dry eye, a dental hygienist notices reduced saliva, they're talking to their primary care doctor about fatigue or gastrointestinal symptoms… but finding the connecting thread that unites all of those as an immune-mediated process affecting the entire body often gets missed for years."

That diagnostic fragmentation has compounded the challenge of building a treatment evidence base. For years, the B cell-depleting agent rituximab represented the primary off-label option for systemic disease — a drug extracted from the lymphoma field and deployed, with persistent uncertainty about its benefit in Sjögren. Two large randomized trials, TEARS and TRACTISS, failed to meet their primary endpoints in fatigue and dryness, respectively, though both showed secondary signals including improvement in salivary flow rates in patients with residual glandular function.⁴⁻⁵ The failures reflected both mechanistic limitations and, increasingly recognized in retrospect, problems with trial design — a high placebo response rate, poorly calibrated endpoints, and difficulty distinguishing active inflammation from chronic glandular damage that medications could not reverse.

"We've consistently found a placebo response of like 50% sometimes, and that makes it very hard to demonstrate an effect in the intervention group," said Thomas Grader-Beck, MD, Associate Professor of Clinical Medicine at Johns Hopkins University School of Medicine and Associate Director of Research at the Jerome L. Greene Sjögren Disease Center. "As our knowledge expands on how to design these trials, composite outcomes such as STAR or CRES will become more important to try to separate out the placebo response from the intervention response."

The mechanistic picture has become substantially clearer over this same period. The centrality of the BAFF pathway to Sjögren pathology — BAFF, or B cell activating factor, sustaining survival of transitional B cells into mature, autoreactive states, with excess BAFF expression seen consistently in Sjögren disease — provided a rational therapeutic target.⁶ Belimumab, which blocks the BAFF cytokine itself, showed promising signals but never reached approval in Sjögren. Rituximab, which depletes B cells but does not address BAFF, was shown to paradoxically trigger a surge in BAFF levels following B cell depletion — driving repopulation of the autoreactive B cell pool and potentially contributing to post-treatment flares.

"Once you deplete with rituximab, the natural physiological homeostasis is for B cells to be repopulated, and BAFF does that — but we know that BAFF tilts you toward auto-reactivity," said Lucy Carter, MD, PhD, Consultant Rheumatologist at Newcastle upon Tyne NHS Foundation Trust and Honorary Clinical Senior Lecturer at Newcastle University. "So one of the things that came through is that it's not enough to just deplete the B cells. You've really got to focus on what's coming back after repopulation."

Ianalumab addresses precisely that gap. A fully human monoclonal antibody with a dual mechanism of action, it depletes B cells via antibody-dependent cellular cytotoxicity and, simultaneously, blocks the BAFF receptor — preventing BAFF-induced B cell maturation and proliferation from driving disease re-emergence after depletion. In vitro data have suggested B cell depletion up to 70-fold greater than that seen with rituximab.² In the NEPTUNUS-1 and NEPTUNUS-2 trials, both studies met their primary endpoint of statistically significant improvement in ESSDAI score from baseline to week 48, with score reductions of 6.4 versus 5.1 points and 6.5 versus 5.5 points versus placebo, respectively.² Patient global assessment and physician global assessment were also significantly improved versus placebo in both trials — the first time patient global was reported positive in a Phase 3 Sjögren trial, a distinction Grader-Beck called notable. The safety profile across both studies was favorable, with adverse events broadly similar to placebo and no unexpected signals in infection rates or malignancy.²

"The most striking aspect is the overall trajectory — when you look at all the different outcomes, it's not that here placebo is better, here ianalumab is better. It's a consistent signature across 2 separate trials," Grader-Beck said. "I think that, really, for me, is very promising."

The breakthrough designation arrives against a backdrop of a rapidly expanding Sjögren pipeline. Phase 3 readouts are anticipated in 2026 or early 2027 for additional agents including telitacicept, nipocalimab, and dacidilimab, each targeting different aspects of disease biology.⁷ For Wada, who describes having watched the asthma field transform over her career through increasingly targeted precision medicine, the trajectory in Sjögren feels unmistakably familiar. "We're not only seeing an increase in the number of therapies in development, but that is shifting how we understand the disease," she said. "I really envision that happening for Sjögren… and my hope is that it is guided in part by better diagnostics, too."

Diagnostic gaps — particularly the challenge of identifying seronegative patients, who may require salivary gland biopsy for confirmation — remain an important parallel priority. Salivary gland ultrasound is gaining traction as a potential stratification tool for both clinical and trial settings, and additional biomarker development is underway.

The field is not without remaining questions. The modest absolute ESSDAI differences between ianalumab and placebo in the NEPTUNUS trials, secondary endpoints not all reaching statistical significance after the primary, and the persistent challenge of improving the cardinal symptoms of dryness and fatigue in a patient population with longstanding glandular damage will all require further data. Novartis plans to submit ianalumab to global regulatory authorities beginning in 2026.¹

"It's really exciting to have ianalumab now with a breakthrough designation and positive Phase 3 trials," Grader-Beck said, "and really, it's a great time to be treating Sjögren patients. If I compare this to just a few years ago, there was not really as much on the horizon. We've made a lot of progress over this time."

References

1. Novartis. Novartis ianalumab receives FDA Breakthrough Therapy designation for Sjögren's disease. Press release. Published January 16, 2026. https://www.novartis.com/news/media-releases/novartis-ianalumab-receives-fda-breakthrough-therapy-designation-sjogrens-disease

2. Novartis. Novartis ianalumab first drug to reduce disease activity and patient burden in Sjögren's disease Phase III trials. Press release. Published October 29, 2025. https://www.novartis.com/news/media-releases/novartis-ianalumab-first-drug-reduce-disease-activity-and-patient-burden-sjogrens-disease-phase-iii-trials

3. Negrini S, et al. Sjögren's syndrome: a systemic autoimmune disease. Clin Exp Med. 2022;22(1):9-25.

4. Devauchelle-Pensec V, et al. Treatment of primary Sjögren syndrome with rituximab: a randomized trial. Ann Intern Med. 2014;160(4):233-242. doi:10.7326/M13-1085

5. Bowman SJ, et al. Randomized controlled trial of rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjögren's syndrome. Arthritis Rheumatol. 2017;69(7):1440-1450.

6. Mariette X, Criswell LA. Primary Sjögren's syndrome. N Engl J Med. 2018;378(10):931-939. doi: 10.1056/NEJMcp1702514.

7. Novartis announces both ianalumab Phase III clinical trials met primary endpoint in patients with Sjögren's disease. Press release. Novartis. Published August 11, 2025. https://www.novartis.com/news/media-releases/novartis-announces-both-ianalumab-phase-iii-clinical-trials-met-primary-endpoint-patients-sjogrens-disease