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Pathophysiology-Based Approaches to Treatment

  • Cory A. Perugino
  • John H. Stone
Chapter

Abstract

IgG4-related disease (IgG-RD) is capable of causing great morbidity and even mortality if the condition remains undiagnosed or poorly treated yet is typically a treatment-responsive disorder. Glucocorticoids have not been studied rigorously, and practices with regard to dosing and duration of treatment remain largely empiric. In addition, IgG4-RD patients are often particularly susceptible to and intolerant of the deleterious effects of glucocorticoid therapy. B cell depletion with anti-CD20 monoclonal antibodies appears to be a rapid, effective means of obtaining disease control and limiting patients’ glucocorticoid exposure, but this option is frequently available. Other therapies targeting the B cell lineage may also be efficacious, and one is under study. The means by which depletion or inhibition of B cells and their progeny ameliorate IgG4-RD are coming into focus now through careful mechanistic studies of samples from treated patients.

The mechanistic understanding of IgG4-RD will bring an array of specific targets for therapeutic intervention. Plasmablast-directed therapy with a CD19 monoclonal antibody is currently in clinical trials. CD4+ cytotoxic T lymphocytes and fibrosis, both observed nearly universally in the tissue of IgG4-RD patients, present two unexploited vulnerabilities in controlling and even reversing the effects of the disease. Further development of such therapies is a major goal for the next few years.

References

  1. 1.
    Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366(6):539–51.CrossRefPubMedGoogle Scholar
  2. 2.
    Ebbo M, Daniel L, Pavic M, et al. IgG4-related systemic disease: features and treatment response in a French cohort: results of a multicenter registry. Medicine (Baltimore). 2012;91:49–56.CrossRefGoogle Scholar
  3. 3.
    Raina A, Yadav D, Krasinskas A, et al. Evaluation and Management of Autoimmune Pancreatitis: experience at a large US Center. Am J Gastroenterol. 2009;104:2295–306.CrossRefPubMedGoogle Scholar
  4. 4.
    Chari S, Smyrk T, Levy M. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol. 2006;4:1010–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Kamisawa T, Shimosegawa T, Okazaki K. Standard steroid treatment for autoimmune pancreatitis. Gut. 2009;58:1504–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Ghazale A, Chari S, Zhang L, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008;134:706–15.CrossRefPubMedGoogle Scholar
  7. 7.
    Khosroshahi A, Wallace ZA, Crowe JL, Akamizu T, Azumi A, Carruthers MN, et al. International consensus guidance statement on the management and treatment of IgG4-related disease. Arthritis Rheum. 2015;67:1688–99.CrossRefGoogle Scholar
  8. 8.
    Kamisawa T, Okazaki K, Kawa S, et al. Amendment of the Japanese consensus guidelines for autoimmune pancreatitis, 2013 III. Treatment and prognosis of autoimmune pancreatitis. J Gastroenterol. 2014;49:961–70.CrossRefPubMedGoogle Scholar
  9. 9.
    Masaki Y for the All-Japan IgG4-RD Team; abstract presentation at the 2014 Second International Symposium on IgG4-Related Disease and Associated Conditions.Google Scholar
  10. 10.
    Hart PA, Topazian MD, Witzig TE, Clain JE, Gleeson FC, Klebig RR, et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience. Gut. 2013;62:1607–15.CrossRefPubMedGoogle Scholar
  11. 11.
    Mattoo H, Della-Torre E, Mahajan VS, Stone JH, Pillai S. Circulating Th2 memory cells in IgG4-related disease are restricted to a defined subset of subjects with atopy. Allergy. 2014;69:399–402.CrossRefPubMedGoogle Scholar
  12. 12.
    Mattoo H, Mahajan V, Della-Torre E, et al. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J Allergy Clin Immunol. 2014;134:679–87.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wallace ZS, Mattoo H, Carruthers M, Mahajan VS, Della Torre E, Lee H, Kulikova M, Deshpande V, Pillai S, Stone JH. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann Rheum Dis. 2015;74:190–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Mattoo H, Mahajan VS, Maehara T, Deshpande V, Della-Torre E, Wallace ZS, et al. Clonal expansion of CD4+ cytotoxic T lymphocytes in patients with IgG4-related disease. J Allergy Clin Immunol. 2016;138(3):825–38.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Khosroshahi A, Carruthers MN, Deshpande V, et al. Rituximab for the treatment of IgG4-related disease lessons from 10 consecutive patients. Medicine. 2012;91:57–66.CrossRefPubMedGoogle Scholar
  16. 16.
    Khosroshahi A, Bloch D, Deshpande V, et al. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG-related systemic disease. Arthritis Rheum. 2010;62:1755–62.CrossRefPubMedGoogle Scholar
  17. 17.
    Carruthers M, Topazian M, Khosroshahi A, et al. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis. 2015;74:1171–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Chu SY, Yeter K, Kotha R, Pong E, Miranda Y, Phung S, Chen H, et al. Suppression of rheumatoid arthritis B cells by XmAb5871, an anti-CD19 antibody that coengages B cell antigen receptor complex and Fcγ receptor IIb inhibitory receptor. Arthritis Rheum. 2014;66(5):1153–64.CrossRefGoogle Scholar
  19. 19.
    Horton HM, Chu SY, Ortiz EC, Pong E, Cemerski S, Leung IW, Jacob N, et al. Antibody-mediated coengagement of FcγRIIb and B cell receptor complex suppresses humoral immunity in systemic lupus erythematosus. J Immunol. 2011;186(7):4223–33.CrossRefPubMedGoogle Scholar
  20. 20.
    Della-Torre E, Feeney E, Deshpande V, Mattoo H, Mahajan V, et al. B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease. Ann Rheum Dis. 2015;74(12):2236–43.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Singapore 2019

Authors and Affiliations

  1. 1.Division of Rheumatology, Allergy, and ImmunologyMassachusetts General HospitalBostonUSA
  2. 2.Department of MedicineHarvard Medical SchoolBostonUSA
  3. 3.Rheumatology ClinicMassachusetts General HospitalBostonUSA

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