Treatment Approaches to IgG4-related Systemic Disease

Arezou Khosroshahi; John H. Stone


Curr Opin Rheumatol. 2011;23(1):67-71. 

In This Article

Immunosuppressive Agents and Biologic Therapies

Immunosuppressive agents have been employed in patients with refractory or recurrent AIP. However, data regarding their efficacy are few and recommendations must be based primarily on small, retrospective case series and case reports.[23,24]

Azathioprine and Mycophenolate Mofetil

The immunosuppressive therapies used have been extrapolated from their effectiveness in other autoimmune conditions (e.g. autoimmune hepatitis) or in organ transplantation patients.

The approach at the Mayo Clinic is to employ immunosuppressive agents in AIP patients who have failed their prednisone taper at least once. The agents of choice are azathioprine (2.0–2.5 mg/kg/day) or mycophenolate mofetil (750 mg twice daily).[3] The follow-up periods reported for patients treated with these regimens remain short, for example, a mean of 6 months (range: 2–19 months) in the Mayo series. Anecdotal experience suggests that lower doses of these medications are not efficacious. Other medications employed as steroid-sparing agents include 6-mercaptopurine and cyclophosphamide, but limited to no data are available about their efficacy.


Some patients with AIP and IgG4-RSD have incomplete responses to treatment with glucocorticoids and traditional immunosuppressive agents. With longer follow-up of such patients, disease relapses, refractoriness to tapering regimens, and a variety of predictable adverse effects related to glucocorticoids occur.

B-lymphocyte depletion with rituximab is now regarded as an effective therapeutic strategy for pemphigus vulgaris, an autoimmune condition mediated by autoantibodies of the IgG4 subclass.[25] The first suggestion that rituximab might be efficacious in IgG4-RSD stemmed from the use of this agent in a patient with IgG4-associated cholangitis, AIP, and ocular involvement whose disease had proven refractory to glucocorticoids and 6-mercaptopurine.[26]

We subsequently reported the successful treatment of four patients whose disease had become refractory to several immunosuppressive medications. The patients had a variety of IgG4-RSD manifestations including AIP, IgG4-associated cholangitis, aortitis, IgG4-related sialadenitis, and dacryoadenitis.[27] All four patients demonstrated swift clinical and serological responses. The prompt declines observed in serum IgG4 concentration contrast sharply with the effects of rituximab in other autoimmune diseases such as rheumatoid arthritis. Moreover, IgG4 appeared to be the only IgG subglass affected to a significant degree by rituximab therapy.

Confirmation and refinement of these findings in large studies are required in order to clarify this potential improvement in IgG4-RSD. Mechanistic studies in patients with rituximab, aiming to understand how rituximab achieves its effectiveness in this condition, may elucidate some aspects of pathogenesis of IgG4-RSD. The optimal regimen and frequency of rituximab treatment are not clear and require larger prospective studies of patients with different IgG4-RSD presentations.


Bortezomib is a proteasome inhibitor, first developed as an antineoplastic agent. Cytotoxicity against plasma cells is a major feature of bortezomib, and the drug is approved for the treatment of multiple myeloma. Because of the central role played by plasma cells in the inflammatory infiltrates of IgG4-RSD, the application of bortezomib in this condition would appear to be a rational treatment strategy. Bortezomib was reported to be successful in treatment of a patient with recurrent IgG4-lung disease and orbital pseudotumor.[28,29] Further studies are required to confirm the effectiveness of bortezomib and to understand its potential adverse effects in this condition.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: