IgG4-RD Classification Criteria Scouting Report

Written By: Guy Katz, MD; Ian Cooley, MD; Duncan F Moore, MD; Naomi Patel, MD; Massachusetts General Hospital Rheumatology Fellowship

Based on: Wallace ZS et al; American College of Rheumatology/European League Against Rheumatism IgG4-Related Disease Classification Criteria Working Group. The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol. 2020 Jan;72(1):7-19.

Topic Overview

IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease first described in the early 2000’s. Many of its manifestations have long been recognized and thought to represent idiopathic single organ system diseases. These are now unified by this underlying diagnosis, primarily on the basis of a common histopathology (characterized by storiform fibrosis, obliterative phlebitis, and an IgG4-rich lymphoplasmacytic infiltrate). While some clinical features can be quite suggestive, manifestations can be protean, and the disease is notoriously difficult to differentiate from other mimicking conditions (such as sarcoidosis, Sjogren’s syndrome, ANCA-associated vasculitis, and lymphoma). Both because it is a recently recognized disease, and because of the frequently challenging nature of arriving at the diagnosis, the development of effective classification criteria is invaluable for research and clinical purposes. These criteria were developed by a large multispecialty international group and feature a robust list of exclusion criteria in addition to inclusion criteria as well as a weighted scoring system, which yielded a sensitivity of 82.0-85.5% and specificity 97.8-99.2% in validation cohorts.

Implications for Patients, Providers, & Researchers

Current implications: These are the first-ever classification criteria for IgG4-RD. Researchers can immediately begin using them to generate standardized cohorts for prospective clinical trials and epidemiologic studies that will allow for robust, replicable, and generalizable research in this disease. Like other classification criteria, despite the fact that these criteria were developed primarily for research purposes, they have demonstrated remarkable clinical utility as well. The criteria present a user-friendly and comprehensive framework with which to approach the diagnosis of this rare, under-recognized, and treatable disease. The publication alone has already helped raise awareness and understanding of this disease.

Future implications: These criteria are likely to benefit clinicians, researchers, and patients for quite some time. Study of the pathophysiology of the disease itself has led to a broader understanding of autoimmunity and fibrosis. With these classification criteria, larger-scale study of this pathophysiology is likely to further our understanding of not only the disease itself but also many other autoimmune and fibrotic conditions, ranging from systemic sclerosis to cirrhosis. Additionally, these criteria feature exclusion criteria that are strongly associated with IgG4-RD mimickers rather than the disease itself. This focus on exclusion criteria is novel in rheumatology classification criteria, and future criteria in our field can make use of this framework both to improve specificity of the criteria themselves and to heighten clinicians’ awareness of specific features that should make them question a given diagnosis.

Will IgG4-RD Classification Criteria Win its First Round Match-up?

In its first round match-up, the IgG4-RD criteria will compete with the study describing three subtypes of relapsing polychondritis (RP). The excellent study on RP subtypes demonstrated that the most common forms of RP lack many of its characteristic features, thereby leading to significant delays in diagnosis. While this is tremendously important in the field of RP, the IgG4-RD classification criteria achieve a similar goal on a much larger scale in a disease that arguably has less widespread recognition and understanding. Additionally, the classification criteria have many implications that reach beyond the disease itself. Both because of its novelty and its potential impact, IgG4-RD Classification Criteria is likely to beat RP Subtypes in its first round match-up.

Could IgG4-RD Classification Criteria Win it All?

Alas, storiform fibrosis alone is not enough to confirm the ever-elusive diagnosis of IgG4-RD. As it can mimic many other conditions and be difficult to confirm, classification criteria are essential to identify patients and allow them to be properly treated. Drs. Stone and Wallace have both been leaders in the understanding of IgG4-RD and have again come through with criteria that have a whopping specificity of greater than 98%. It will likely win against RP subtypes in its first bracket, though it is hard to predict how it will fare against VEXAS, a worthy challenger that is so unlike the rest. As prednisone is a mainstay of therapy in IgG4-RD, it may be tough to compete with Avacopan, which demonstrated an unmatched steroid-sparing effect, and belimumab and anifrolumab, which show promise as new options in the treatment of SLE. However, once it makes it past the initial rounds, its novelty combined with its widespread applicability will likely lead it to win against more bread-and-butter topics like gout and rheumatoid arthritis.


  1. Wallace ZS, Naden RP, Chari S, Choi H, Della-Torre E, Dicaire JF, Hart PA, Inoue D, Kawano M, Khosroshahi A, Kubota K, Lanzillotta M, Okazaki K, Perugino CA, Sharma A, Saeki T, Sekiguchi H, Schleinitz N, Stone JR, Takahashi N, Umehara H, Webster G, Zen Y, Stone JH; American College of Rheumatology/European League Against Rheumatism IgG4-Related Disease Classification Criteria Working Group. The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol. 2020 Jan;72(1):7-19. doi: 10.1002/art.41120. Epub 2019 Dec 2. PMID: 31793250.
  2. Ferrada M, Rimland CA, Quinn K, Sikora K, Kim J, Allen C, Sirajuddin A, Goodspeed W, Chen M, Grayson PC. Defining Clinical Subgroups in Relapsing Polychondritis: A Prospective Observational Cohort Study. Arthritis Rheumatol. 2020 Aug;72(8):1396-1402. doi: 10.1002/art.41270. Epub 2020 Jul 8. PMID: 32249511.

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