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Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts
  1. Zachary S Wallace1,2,3,
  2. Yuqing Zhang1,2,3,
  3. Cory A Perugino1,3,
  4. Ray Naden4,
  5. Hyon K Choi1,2,3,
  6. John H Stone1,3
  7. for the ACR/EULAR IgG4-RD Classification Criteria Committee
    1. 1 Rheumatology Unit, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts, USA
    2. 2 Clinical Epidemiology Unit, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts, USA
    3. 3 Harvard Medical School, Boston, Massachusetts, USA
    4. 4 Department of Medicine, McMaster University, Hamilton, Ontario, Canada
    1. Correspondence to Dr Zachary S Wallace, Rheumatology Unit, Clinical Epidemiology Unit, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital Harvard Medical School, Boston, Massachusetts, USA; zswallace{at}


    Objective IgG4-related disease (IgG4-RD) is a heterogeneous, multiorgan condition of unclear aetiology that can cause organ failure. Difficulty recognising IgG4-RD contributes to diagnostic delays. We sought to identify key IgG4-RD phenotypes.

    Methods We used two cross-sectional studies assembled by an international, multispecialty network of IgG4-RD specialists who submitted 765 cases to derive and replicate phenotypic groups. Phenotype groups of disease manifestations and key covariate distributions across the identified groups were measured using latent class analysis.

    Results In the derivation cohort (n=493), we identified four groups with distinct manifestations: Group 1 (31%), Pancreato-Hepato-Biliary disease; Group 2 (24%), Retroperitoneal Fibrosis and/or Aortitis; Group 3 (24%), Head and Neck-Limited disease and Group 4 (22%), classic Mikulicz syndrome with systemic involvement. We replicated the identification of four phenotype groups in the replication cohort. Compared with cases in Groups 1, 2 and 4, respectively, cases in Group 3 were more likely to be female (OR 11.60 (95% CI 5.39 to 24.98), 10.35 (95% CI 4.63 to 23.15) and 9.24 (95% CI 3.53 to 24.20)) and Asian (OR 6.68 (95% CI 2.82 to 15.79), 7.43 (95% CI 2.97 to 18.56) and 6.27 (95% CI 2.27 to 17.29)). Cases in Group 4 had a higher median serum IgG4 concentration (1170 mg/dL) compared with groups 1–3 (316, 178 and 445 mg/dL, respectively, p<0.001).

    Conclusion We identified four distinctive IgG4-RD phenotypes according to organ involvement. Being Asian or female may predispose individuals to head and neck-limited disease. These phenotypes serve as a framework for identifying IgG4-RD and studying its aetiology and optimal treatment.

    • IgG4-related disease
    • epidemiology
    • cluster analysis

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    • HKC and JHS contributed equally.

    • Handling editor Josef S Smolen

    • Presented at This work was previously presented at the European League Against Rheumatism 2018 Annual Meeting (Ann Rheum Dis, volume 77, supplement Suppl, year 2018, page A91) and the American College of Rheumatology Annual Meeting (Arthritis Rheumatol. 2018; 70 (suppl 10)).

    • Correction notice This article has been corrected since it published Online First. The collaborators statement has been corrected.

    • Collaborators Takashi Akamizu; Mitsuhiro Akiyama; Adrian Bateman; Daniel Blockmans; Pilar Brito-Zeron; Corrado Campochiaro; Mollie Carruthers; Suresh Chari; Tsutomu Chiba; Andreu Fernandez Codina;Lynn Cornell; Emma Culver; Emanuel Della-Torre; Vikram Deshpande; Jean-Francois Dicaire; Lingli Dong; Mikael Ebbo; Judith A Ferry; George Fragkoulis; Fabian Frost; Luca Frulloni; Phil A Hart; Gabriela Hernandez-Molina; Dai Inoue; Karuna Keat;Terumi Kamisawa; Shigeyuki Kawa; Mitsuhiro Kawano; Arezou Khosroshahi; Hiroshi Kobayashi; Yuzo Kodama; Satoshi Kubo; Kensuke Kubota; Marco Lanzillotta; Markus M Lerch; Yanying Liu; Matthias Löhr; Chiara Marvisi; Ferran Martinez-Valle; Eduardo Martin-Nares; Yasufumi Masaki; Shoko Matsui; Ichiro Mizushima; Seiji Nakamura; Jan Nordeide; Kenji Notohara; Kazuichi Okazaki; Sergio Paira; Jovan Popovic; Manel Ramos-Casals; James Rosenbaum; Jay Ryu; Yasuharu Sato; Amita Sharma; Takako Saeki; Hiroshi Sekiguchi; Nicolas Schleinitz; Evgeniya V Sokol; James R Stone; Hiroki Takahashi; Naoki Takahashi; Masayuki Takahira; Yoshiya Tanaka; Hisanori Umehara; Augusto Vaglio; Alejandra Villamil; Yoko Wada; George Webster; Kazunori Yamada; Motohisa Yamamoto; Joanne Yi; Giuseppe Zamboni; Yoh Zen; Wen Zhang

    • Contributors All named authors contributed to planning, conduct and reporting of the work. Members of the IgG4-Related Disease Classification Criteria Working Group contributed to conduct of the study because they contributed detailed information regarding cases.

    • Funding ZSW received grant support through a Scientist Development Award from the Rheumatology Research Foundation and from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS/NIH; Loan Repayment Award and K23 AR073334). JHS received funding for development of the IgG4-RD Classification Criteria from the American College of Rheumatology and the European League Against Rheumatism.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval This study was approved by the Partners HealthCare Institutional Review Board.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Investigators interested in collaboration or using the data from the IgG4-Related Disease Classification Criteria Working Group can contact Dr John H Stone ( Requests will be considered on a case-by-case basis.