Efficacy and Safety of Lenalidomide in Patients With IgG4-Related Disease

Immunoglobulin G4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disorder characterized by lymphoplasmacytic infiltration, IgG4-positive plasma cell accumulation, storiform fibrosis, and involvement of multiple organs. Although glucocorticoids remain the standard first-line therapy for induction of remission, a substantial proportion of patients experience disease relapse during glucocorticoid tapering or after treatment discontinuation. In addition, prolonged glucocorticoid exposure is associated with clinically significant adverse effects, including metabolic complications, osteoporosis, cardiovascular risks, and increased susceptibility to infection. Therefore, effective and well-tolerated maintenance therapies are urgently needed to sustain remission and reduce relapse risk in patients with IgG4-RD.

Accumulating evidence indicates that persistent immune dysregulation contributes to disease recurrence in IgG4-RD even after clinical remission has been achieved. Aberrant B-cell activation, expansion of plasmablasts and plasma cells, dysregulated T-cell responses, and remodeling of the immune microenvironment are considered key components underlying disease persistence and relapse. Therapeutic strategies targeting pathogenic immune pathways, particularly those involving B-cell and plasma cell responses, have shown potential clinical benefits, supporting the concept that immune modulation during the remission phase may prevent disease recurrence.

Lenalidomide is an immunomodulatory agent with established clinical activity in plasma cell disorders and emerging applications in immune-mediated diseases. Through binding to cereblon (CRBN), lenalidomide promotes the degradation of specific immune regulatory transcription factors, including IKZF1 and IKZF3, thereby modulating B-cell activation, plasma cell differentiation, inflammatory cytokine production, and T-cell function. Given the central role of B-cell/plasma cell dysregulation in IgG4-RD pathogenesis, these immunomodulatory properties provide a scientific rationale for evaluating lenalidomide as a maintenance therapy in patients with IgG4-RD who have achieved sustained clinical remission.

This is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial designed to evaluate the efficacy and safety of lenalidomide as maintenance therapy for relapse prevention in patients with IgG4-RD in sustained clinical remission.

Approximately 146 participants will be enrolled. Eligible participants are adults with IgG4-RD who meet the 2019 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria and have achieved sustained disease control following glucocorticoid therapy. Participants must have no documented disease relapse within the preceding year, an IgG4-RD Responder Index (IgG4-RD RI) score of 0, and be receiving a stable low-dose glucocorticoid regimen before randomization.

Participants will be randomly assigned in a 1:1 ratio to receive either lenalidomide 5 mg orally once daily or matching placebo for 52 weeks. During the initial treatment period, all participants will undergo standardized glucocorticoid tapering according to the predefined protocol. The study adopts a double-blind design, with participants, investigators, outcome assessors, and relevant study personnel blinded to treatment allocation.

The primary objective of this study is to determine whether lenalidomide can reduce the risk of IgG4-RD relapse compared with placebo during the maintenance phase. The primary endpoint is the cumulative relapse rate at week 52 after randomization, defined as the proportion of participants experiencing at least one protocol-defined IgG4-RD relapse event.

Secondary objectives include evaluation of the effect of lenalidomide on time to first relapse, maintenance of remission, disease activity changes, quality of life, and safety outcomes. Secondary endpoints include time to first IgG4-RD relapse, changes in IgG4-RD Responder Index scores, health-related quality of life assessments, and the incidence of adverse events, serious adverse events, and treatment discontinuations.

Exploratory objectives include characterization of immunological and biological changes associated with lenalidomide treatment during the remission maintenance phase. Exploratory endpoints include changes from baseline in serum IgG4, IgG, IgE, complement components (C3 and C4), inflammatory markers, peripheral blood immune cell subsets, transcriptomic profiles, and gut microbiota characteristics.

Safety monitoring will focus on known and potential risks associated with lenalidomide treatment, including hematologic toxicity, thromboembolic events, infections, skin reactions, hepatic and renal abnormalities, and reproductive safety risks. Adverse events and serious adverse events will be continuously monitored throughout the study. An independent data monitoring committee will periodically review accumulated safety data to ensure participant safety and evaluate the overall benefit-risk profile of the intervention.

This study aims to determine whether lenalidomide can serve as an effective and safe glucocorticoid-sparing maintenance therapy for patients with IgG4-RD in sustained clinical remission, with the potential to reduce disease recurrence, prolong remission duration, and minimize long-term glucocorticoid exposure.

Inclusion criteria

• Adults aged 18 to 75 years at the time of screening.
• Diagnosis of IgG4-related disease according to the 2019 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria.
• Patients with IgG4-related disease who have achieved sustained clinical remission following glucocorticoid therapy.
• No documented IgG4-related disease relapse within the previous 12 months before screening.
• IgG4-related disease Responder Index (IgG4-RD RI) score of 0 at screening.
• Receiving stable low-dose glucocorticoid therapy with prednisone-equivalent dose ≤7.5 mg/day for at least 6 months before randomization.
• Ability to provide written informed consent and comply with study procedures.

Exclusion criteria

• Active IgG4-related disease requiring induction therapy or escalation of immunosuppressive treatment at screening.
• Previous treatment with lenalidomide or known hypersensitivity to lenalidomide or related compounds.
• Requirement for prohibited concomitant medications during the study period.
• Significant uncontrolled infection or active severe infection.
• Clinically significant hematologic abnormalities, including severe neutropenia or thrombocytopenia.
• Significant hepatic or renal dysfunction that may affect study participation or drug safety evaluation.
• History of thromboembolic events or conditions associated with unacceptable thrombotic risk according to investigator assessment.
• Pregnancy, breastfeeding, or unwillingness to use effective contraception when applicable.
• Malignancy or other severe medical conditions that may interfere with study participation or outcome assessment.
• Any condition that, in the investigator's opinion, may compromise participant safety or affect the reliability of study results.