IgG4-related disease (IgG4-RD) has only existed as a unique disease entity since 2003, yet remarkable progress has already been achieved in describing the essential features of the disease. A framework for systematic clinical studies has been created by the development of a quantitative disease activity tool (the IgG4-RD Responder Index) and the validation of classification criteria, both of which were the products of international, multi-centre investigations. In addition, substantial strides have been made in understanding the pathophysiology of IgG4-RD. In particular, the central role of B cells in the disease has been demonstrated by both the robust clinical responsiveness of IgG4-RD to B cell depletion and by the identification of multiple self-antigens that promote B cell expansion. CD4+ T cells have also been investigated in detail; CD4+ cytotoxic T lymphocytes (suspected of promoting disease) and a specific T follicular helper cell subset that contributes to IgG4 isotype switching have both been defined by multiple groups. The mechanisms by which these immune cells converge on target tissues, interact with fibroblasts and promote tissue remodelling are beginning to be understood and will be an important research focus in the coming years. Over the past few years, considerable advances have been made in understanding the pathogenesis of IgG4-related disease. Our increased knowledge of the important roles of B cells and T cells is now starting to make its way into the clinic.

IgG4-related disease: an update on pathophysiology and implications for clinical care.

IgG4-related disease (IgG4-RD) is a fascinating clinical entity first reported in this century in Japan, and includes a wide variety of diseases, such as formerly named Mikulicz's disease (MD), autoimmune pancreatitis (AIP), interstitial nephritis, prostatitis and retroperitoneal fibrosis. The Japanese IgG4 team organized by the Ministry of Health, Labor and Welfare (MHLW) of Japan has published the first criteria, comprehensive diagnostic (CD) criteria for IgG-RD 2011. Thereafter, IgG4-RD has been accepted widely and many cases have been reported from all over the world. Several problems have arisen in clinical practice, however, including the difficulty obtaining biopsy samples, and the sensitivity and specificity in cut off level of serum IgG4 and impaired immunostaining of IgG4. Given these situations, the Japanese IgG4 team has updated the 2011 comprehensive diagnostic criteria for IgG4-RD and propose the 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD, which consists of 3 domains; 1) Clinical and radiological features, 2) Serological diagnosis and 3) Pathological diagnosis. In addition, the new pathological diagnosis is composed by three sub-items including storiform fibrosis and obliterative phlebitis.

The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD.

IgG4 related disease was recognized as a unified disease entity only 15 years ago. Awareness of IgG4 related disease has increased worldwide since then, and specialists are now familiar with most of its clinical manifestations. Involvement of the pancreato-biliary tract, retroperitoneum/aorta, head and neck, and salivary glands are the most frequently observed disease phenotypes, differing in epidemiological features, serological findings, and prognostic outcomes. In view of this multifaceted presentation, IgG4 related disease represents a great mimicker of many neoplastic, inflammatory, and infectious conditions. Histopathology remains key to diagnosis because reliable biomarkers are lacking. Recently released classification criteria will be invaluable in improving early recognition of the disease. IgG4 related disease is highly treatable and responds promptly to glucocorticoids, but it can lead to end stage organ failure and even death if unrecognized. Prolonged courses of corticosteroids are often needed to maintain remission because the disease relapses in most patients. Rapid advancement in our understanding of the pathophysiology of IgG4 related disease is leading to the identification of novel therapeutic targets and possible personalized approaches to treatment.

Advances in the diagnosis and management of IgG4 related disease

IgG4-related disease (IgG4-RD) is characterized by lymphoplasmacytic infiltration enriched in IgG4-positive plasma cells and variable degrees of fibrosis with a characteristic storiform pattern. Since fibrosis is an important feature of IgG4-RD, we performed a prospective cohort study to evaluate the performance of 68Ga-FAPI, a recently introduced PET agent targeting fibroblast activation protein, in IgG4-RD. 
Methods: Twenty-six patients with IgG4-RD were recruited. All patients underwent both 68Ga-FAPI and 18F-FDG PET/CT. The positive rates of the PET/CT scans in the involved organs and the uptake values were compared. 
Results: In a total of 136 organ involvements in the 26 patients, 68Ga-FAPI PET/CT additionally detected 18/136 (13.2%) organ involvements in 13/26 (50.0%) patients compared with 18F-FDG PET/CT. 68Ga-FAPI PET/CT had a higher positive rate than 18F-FDG PET/CT in detecting involvement in the pancreas, bile duct/liver, and lacrimal gland. 68Ga-FAPI also demonstrated significantly higher uptake than 18F-FDG in the matched disease in the pancreas, bile duct/liver, and salivary gland (P < 0.01). However, lymph node involvements with flip-flop uptake of 18F-FDG were not accumulating 68Ga-FAPI. 
Conclusion:68Ga-FAPI might be a promising imaging agent for the assessment of IgG4-RD.

https://jnm.snmjournals.org/content/jnumed/62/2/266.full.pdf

Fibroblast Activation Protein-Targeted PET/CT with 68Ga-FAPI for Imaging IgG4-Related Disease: Comparison to 18F-FDG PET/CT.

The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6-0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2-4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added.

European Guideline on IgG4-related digestive disease – UEG and SGF evidence-based recommendations:

IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serological, radiological and pathological data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4-RD. An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises; existing literature; derivation and validation cohorts of 1879 subjects (1086 cases, 793 mimickers); and multicriterion decision analysis to identify, weight and test potential classification criteria. Two independent validation cohorts were included. A three-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least one of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serological, radiological and pathological items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, eight weighted inclusion criteria domains, addressing clinical findings, serological results, radiological assessments and pathological interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% CI 97.2% to 99.8%) and a sensitivity of 85.5% (95% CI 81.9% to 88.5%). In the second, the specificity was 97.8% (95% CI 93.7% to 99.2%) and the sensitivity was 82.0% (95% CI 77.0% to 86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. ACR/EULAR classification criteria for IgG4-RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiological and basic science investigations.

https://ard.bmj.com/content/annrheumdis/79/1/77.full.pdf

The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease

We thank Yamamoto and colleagues1 for their response to our paper2 and their description of their experience with rituximab (RTX) in IgG4-related disease (IgG4-RD) in three patients. Their letter raises a number of important points pertaining to the management of IgG4-RD, in general, and to the use of B-cell-depletion strategies, specifically.

First, their patients are exemplary of the fact a sizeable subset of IgG4-RD patients has a propensity to disease relapse over time. This point has been underappreciated from early reports of the use of glucocorticoids to treat IgG4-RD because those reports were characterised by short follow-up periods. Although the great majority of patients respond to glucocorticoids initially, repeated disease flares are the rule for many.

Second, patients with IgG4-RD endure substantial morbidity from the requirement for repeated courses (or continuous on treatment) with glucocorticoids. The three patients described by Yamamoto and colleagues are reported to have experienced bilateral avascular necrosis of the hips and glucose intolerance (severe diabetes mellitus in one case). Our general sense is that the toxicities of prolonged glucocorticoid use in this and other diseases are underestimated. Moreover, patients …

https://ard.bmj.com/content/annrheumdis/74/8/e47.full.pdf

Response to: ‘Is rituximab effective for IgG4-related disease in the long term? Experience of cases treated with rituximab for 4 years’ by Yamamoto et al

Phillip A. Hart

Papers

The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease

Response to: ‘Is rituximab effective for IgG4-related disease in the long term? Experience of cases treated with rituximab for 4 years’ by Yamamoto et al