Even though glucocorticoid is the current first line medication for IgG4-RD, it is well accepted in the field that excessive dosage of GC, especially accumulative dosage, is associated with increasing organ damage. Although B cell depletion with rituximab has been verified to be an effective treatment for IgG4-RD, even without concomitant GC therapy, rituximab can increase the risk of infection during the treatment. Belimumab is an IgG1-lambda monoclonal antibody that prevents the survival of B lymphocytes by blocking the binding of soluble human B lymphocyte stimulator protein (BLyS) to receptors on B lymphocytes. Previous studies and trails suggested that the activity of B-cell mediated immunity and autoimmune responses were ameliorated after belimumab without increasing rates of adverse events when compared to standard of care . However, the efficacy and tolerability of belimumab in IgG4-RD patients have not been examined before. This randomized, control clinical trial aimed to evaluate the tolerability and the efficacy of Belimumab for maintenance treatment for IgG4-RD.

IgG4-RD is associated with substantial morbidity and mortality, but there is no established therapy other than GCs for an acute flare. Up to date, no randomized prospective controlled studies have been performed for this disease, and no approved therapy is available. Although GCs are widely and effectively used for treatment of initial disease and flare, they are associated with substantial toxicity which limits their long-term use. Disease flares also occur in many patients either during the GC taper or after GC discontinuation. Patients need a treatment that will more effectively control their disease and avoid GC toxicity. This study will establish the safety and tolerability of Belimumab in IgG4-RD and its ability to reduce the risk of disease flares. There are currently no medicinal products approved for the treatment of IgG4-RD. The majority of cases follow a relapsing course that can lead to permanent tissue damage with attendant morbidity and potential mortality. Glucocorticoids are widely and effectively used for treatment of initial disease and of flare, but they do not prevent recurrence of active disease after their discontinuation and are associated with substantial toxicity. Patients also continue to relapse on the off-label steroid-sparing immunosuppressive medications used by some physicians to manage patients with IgG4-RD; thus, there is a high unmet medical need for more effective therapies in this patient population.

The pathogenesis of IgG4-RD suggests that B-cell depletion may be an effective avenue for therapeutic intervention. Therapeutic depletion of B cells with rituximab reduces disease-relevant biomarkers and appears to have clinical benefit in uncontrolled, retrospective and prospective clinical studies. This study aims to define the efficacy and safety of Belimumab for the prevention of flares of this rare disease. In addition, the potential of Belimumab for minimizing GC exposure could limit the well-known adverse effects of GCs on bone, skin, muscle, adrenal gland, and eyes, and GC association with weight gain, diabetes, hypertension, and neuropsychiatric effects.

Inclusion Criteria:

1. Male or female adults, ≥ 18 years of age at time of informed consent.
2. Written informed consent.
3. Fulfillment of the 2019 ACR/EULAR classification criteria, involving at least one of the following organs: pancreas, lacrimal glands, salivary glands, bile ducts/biliary, orbits, lungs, retroperitoneum, aorta, kidneys, or thyroid gland.
4. New onset or experiencing an IgG4-RD flare that requires initiation or continuation of GC treatment at the time of informed consent. This GC therapy can either be newly initiated or be increased from a maintenance dose of ≤ 10 mg/day of prednisone or equivalent.

Exclusion Criteria:

1. Severe organ dysfunction.
2. Severe infection.
3. Having known immunodeficiency disorder.
4. History of malignancy within the last 10 years.
5. Receipt of any biologic therapy, including B cell-depleting therapy (eg, rituximab, ocrelizumab, obinutuzumab, ofatumumab, inebilizumab) or other biologic immunomodulatory agent (abatacept) in the 6 months prior to screening.
6. Non-biologic DMARDs or immunosuppressive agent other than GCs (eg, Leflunomide, Cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, others) have been used withing 12 weeks before screening.
7. Being pregnant, lactating, or planning to become pregnant within 6 months of the test.
8. Positive test for hepatitis B or HIV infection. Positive test for hepatitis B include detection of hepatitis B surface antigen (HBsAg) or HBV-DNA.
9. Chest image ,PPD or TB-ELISPOT results show active tuberculosis.