IgG4-RD Treatment Guidelines Favor Steroid Sparing, B-cell Therapies

Development of the IgG4ward! Foundation treatment guidelines

An international panel convened by the IgG4ward! Foundation has issued 28 statements on the treatment of IgG4-related disease. The panel recommends glucocorticoid-sparing therapy for most patients during remission induction and identifies B-cell directed therapies as effective for maintenance.¹ The guidelines were published November 9, 2026, in The Lancet Rheumatology, and investigators reached consensus on 22 of the 28 statements.¹

The 2015 international consensus statement covered diagnosis, treatment, and management in a single paper and included only five treatment statements.¹ ² The authors said new, dedicated guidelines were justified by an expanded evidence base. This includes 2 double-blind, placebo-controlled phase 3 trials: MITIGATE of inebilizumab, published in 2025, and INDIGO of obexelimab, published in 2026.¹ ³ ⁴

“We hope that management guidelines will also be published, and they will begin to educate clinicians about how to use these therapies, both during the remission induction period and in remission maintenance period,” John H. Stone, MD, MPH, said in an interview at ACR Convergence 2026, held November 6-11 in Orlando, Florida. Stone is with the Division of Rheumatology, Inflammation, and Immunity at Mass General Brigham, founded the IgG4ward! Foundation, and is a coauthor of the guidelines.

The group included 62 investigators from 15 countries across six continents: 52 physicians (48 clinicians and 4 radiologists), 1 medical reference librarian, eight patients, and 1 caregiver.¹ Rheumatology was the largest physician specialty (n = 22), followed by gastroenterology (n = 11), nephrology (n = 4), and radiology (n = 4).¹ Investigators generated 183 candidate questions. These were consolidated into 40 questions for a systematic literature search, which identified 114 eligible studies.¹

Evidence was graded with the 2011 Oxford Centre for Evidence-Based Medicine framework. The 52 physicians voted on each statement using a seven-point Likert scale.¹ Consensus was defined as more than 80% of voters agreeing or strongly agreeing, and disagreement did not exceed 7% for any statement.¹

Remission induction recommendations for IgG4-related disease

Panelists agreed most patients with clinically active disease should receive remission induction therapy (98% agreement).¹ They also agreed the starting glucocorticoid dose should not exceed 30 to 40 mg/day of prednisone (86%). Glucocorticoid monotherapy for induction should not last longer than three months (88%).¹ According to the authors, a lack of meaningful response after three months raises the possibility of a fibrotic disease manifestation or an alternative diagnosis.¹

Glucocorticoid-sparing therapy is recommended during induction for most patients, especially those at high risk of glucocorticoid toxicity or relapse (81%).¹ The authors noted inebilizumab and obexelimab reduce cumulative glucocorticoid exposure over the first year of treatment.¹

Several induction statements fell short of consensus:

• Glucocorticoid monotherapy for non-severe disease (67%)
• B-cell depletion or inhibition as monotherapy in selected patients (65%)
• Combined glucocorticoids and B-cell targeted therapy for severe disease or high relapse risk (79%)
• Combined glucocorticoids and conventional immunosuppressants for severe, refractory, or relapsing disease (79%)

The combination statement for severe disease (79%) carried a level 1b/grade A rating, 1 of the strongest evidence grades in the guidelines.¹

B-cell targeted therapy and remission maintenance

Panelists agreed B-cell directed therapies reduce relapse risk and are effective for maintenance (93%; level 1b/grade A).¹ In MITIGATE, inebilizumab was associated with an 87% reduction in flare risk vs placebo. Glucocorticoid-free remission at 1 year was 59% vs 22%.¹ ³ In INDIGO, obexelimab reduced flare risk by 56% and lowered cumulative glucocorticoid dose and toxicity at 1 year vs placebo.¹ ⁴

The guidelines recommend maintenance therapy selectively rather than routinely for all patients (86%).¹ When it is used, it should continue long enough to sustain remission, with periodic assessment of whether to discontinue (95%). The authors noted many experts continue maintenance for at least 12 to 36 months before trialing discontinuation.¹ Choice among targeted therapies should be individualized by mechanism, prior response, safety, access, and patient preference (95%). This statement rests on expert opinion alone.¹

Dose, interval, and duration of B-cell depletion for maintenance should be individualized (84%). The authors noted the optimal dosing interval has not been studied prospectively.¹ Stone said future management guidance is expected to take up this question directly.

"Should patients be maintained on continuous B-cell depletion by retreating them every 6 months with inebilizumab, or is it reasonable to treat patients on a more as-needed basis, perhaps guided by the serum IgG4 concentrations?" Stone said.

Monitoring, vaccination, and remaining evidence gaps

All voting physicians agreed relapse risk, treatment response, and maintenance of remission should be evaluated with a combination of clinical assessments, imaging, and laboratory tests (100%).¹ The authors wrote serum IgG4 trends over time are more informative than a single value. They added normalizing serum IgG4 is not a goal of therapy.¹ Long-term follow-up after remission is recommended regardless of treatment status (91%).¹

Vaccinations should be completed before starting B-cell depleting therapy whenever possible (86%).¹ The authors noted non-depleting B-cell inhibition with obexelimab might allow an adequate vaccine response after a brief treatment interruption.¹

"Does the medication need to be stopped completely, or as the early data show, can patients simply be immunized after a very short pause, or even while they're still on therapy?" Stone said, referring to obexelimab.

Panelists agreed antifibrotic agents currently have no defined role in IgG4-related disease (90%). They also agreed special considerations apply to treating children (96%).¹ Statements on organ-specific situations covered several areas: biliary stenting, pancreatic enzyme replacement, asthma, cardiovascular involvement, ureteral stenting, and chronic kidney disease. Most of these rest on level 4 evidence.¹ The authors listed unanswered questions to guide future research, including how on-demand and fixed maintenance strategies compare.¹

The IgG4ward! Foundation sponsored the guidelines. According to the authors, the foundation receives partial pharmaceutical support, but industry had no input into the guidelines and investigators were not compensated.¹

References

1. Perugino CA, Alexander T, Baker MC, et al. The IgG4ward! Foundation guidelines on the treatment of IgG4-related disease. Lancet Rheumatol. Published online November 9, 2026. doi:10.1016/S2665-9913(26)00312-7

2. Khosroshahi A, Wallace ZS, Crowe JL, et al. International consensus guidance statement on the management and treatment of IgG4-related disease. Arthritis Rheumatol. 2015;67:1688-1699.

3. Stone JH, Khosroshahi A, Zhang W, et al. Inebilizumab for treatment of IgG4-related disease. N Engl J Med. 2025;392:1168-1177.

4. Della-Torre E, Baker MC, Zhang W, et al. Obexelimab for the treatment of IgG4-related disease. N Engl J Med. 2026;395:1273-1284.