Confusions and challenges in the diagnosis of IgG4‐related disease

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a multi-organ immune-mediated fibroinflammatory disorder characterized by elevated serum IgG4 levels and tissue infiltration of IgG4-positive plasma cells. IgG4-RD affects nearly every organ, particularly lacrimal glands, major salivary glands, pancreas, bile ducts, lungs, kidneys, aorta, and retroperitoneum.1-3 Less commonly, it can also involve the meninges, pituitary gland, thyroid gland, pericardium, mediastinum, testicles, and coronary arteries.4 Timely diagnosis and treatment are crucial to prevent severe organ dysfunction and failure. The diagnosis of IgG4-RD lacks a "gold standard", which necessitates a comprehensive approach that integrates representative clinical manifestations, specific histopathological findings, typical laboratory and radiological aspects, and appropriate clinical context. The complexity increases owing to the heterogeneity in clinical and imaging manifestations of the disease, which necessitates differentiation from various other conditions. Notably, neither the elevation of serum biomarker IgG4 nor the infiltration of IgG4+ plasma cells or storiform fibrosis is a unique feature in this disease, as those manifestations lack specificity. The diagnostic journey for IgG4-RD is thus full of numerous challenges and potential pitfalls. Currently, instances of underdiagnosis and overdiagnosis coexist. Tumor-like changes in IgG4-RD are one of the primary causes of underdiagnosis. In addition, underdiagnosis may occur when patients present with non-specific manifestations, atypical single lesions, or normal serum IgG4 levels, complicating recognition of the disease. On the other hand, overdiagnosis has become a more prominent problem in recent years because IgG4-RD is one of the greatest mimickers by other diseases, rendering accurate diagnosis profoundly challenging. These include but are not limited to, tumors (eg, lymphoma, solid tumors, and inflammatory myofibroblastic tumor5), connective tissue diseases (eg, anti-neutrophilic cytoplasmic antibody [ANCA]-associated vasculitis6 and Sjögren's syndrome7), hematological diseases (eg, Castleman's disease,8 Rosai-Dorfman disease,9 and Kimura's disease10), sarcoidosis, Erdheim-Chester disease11 and chronic infections (eg, chronic fungal infection12). To mitigate the risk of misdiagnosis and overdiagnosis, a comprehensive consideration of various factors, including clinical symptoms, radiologic findings, serologic results, and pathologic features, is necessary. The following principles can enhance diagnostic accuracy, as shown in Figure 1. The initial step toward understanding IgG4-RD involves mastering its common manifestations, particularly the typical features and patterns characterized by the combination of 2 or more standard symptoms. The 2020 revised comprehensive diagnostic (2020 RCD) criteria13 and the 2019 American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) classification criteria (2019 AECC)14 for IgG4-RD offer insightful perspectives into the frequently observed symptoms of IgG4-RD. These guidelines provide detailed information for the identification and further exploration of this complex disease. According to 2019 AECC, there are typical and atypical manifestations of IgG4-RD. In the context of the head and neck gland involvement, typical manifestation consists of one or more pairs of symmetrical lacrimal, submandibular and parotid enlargement, while atypical manifestations include unilateral enlargement of the lacrimal and salivary gland, and ocular muscle involvement. For pancreas and biliary tree involvements, diffuse enlargement of the pancreas with or without biliary involvement characterizes typical manifestations, while atypical manifestations include focal and multifocal pancreatic enlargement and isolated biliary system involvement. With regard to thoracic involvement, peribronchovascular and septal thickening along with paravertebral band-like soft tissue in the thorax are the typical manifestations, whereas atypical manifestations include solid nodules, masses, round ground glass nodule in the lungs, pleural thickening or nodules and pleural effusions. For kidney involvement, typical manifestations involve hypocomplementemia, renal pelvic wall thickening and low-density areas in both renal cortices, while atypical manifestations include swollen kidneys, perirenal soft tissue density rings and proteinuria. In the case of retroperitoneum involvement, typical manifestations encompass diffuse thickening of the abdominal aortic wall and the surrounding soft tissue as well as iliac vessels below the renal artery, while atypical manifestations involve soft tissue around the aorta above the renal artery. Patients exhibiting typical manifestations, especially those corresponding to distinct patterns, are highly indicative of IgG4-RD. However, the presence of atypical manifestations necessitates a careful differential diagnosis to rule out other diseases. We recently evaluated the validity of the 2019 AECC and 2020 RCD classification criteria for IgG4-RD.15 This study included 875 IgG4-RD and 302 non-IgG4-RD cases, which included 213 mimickers and 89 patients with other diseases. The findings demonstrated that the 2019 AECC exhibited a sensitivity of 76.6% and a specificity of 98.0%, which were higher in the presence of pathological data. The 2020 RCD criteria proved particularly valuable in the cases lacking the involvement of typical organs of IgG4-RD defined by the 2019 AECC as characteristic of IgG4-RD, such as the pituitary gland and dura mater. These findings suggest that, in a clinical setting, there is a necessity to amalgamate these 2 criteria for a more accurate diagnosis of IgG4-RD. Second, it is crucial to emphasize the exclusion criteria. According to the 2019 AECC, exclusion criteria include clinical, serologic, radiologic, and pathologic characteristics suggesting IgG4-RD mimics.12 Clinical features that meet the exclusion criteria involve fever and no objective response to glucocorticoids; serologic characteristics include leukopenia and thrombocytopenia without alternative explanation, peripheral eosinophilia, positive ANCA, positive antibodies, and cryoglobulinemia; radiologic characteristics consist of known radiologic findings suspicious for malignancy or infection, rapid radiologic progression, long bone abnormalities consistent with Erdheim-Chester disease and splenomegaly; pathologic characteristics include cellular infiltrates suspicious for malignancies, markers consistent with inflammatory myofibroblastic tumor, prominent neutrophilic inflammation, necrotizing vasculitis, prominent necrosis, primary granulomatous inflammation and pathologic features of a macrophage/histiocytic disorder. The application of these exclusion criteria demands consistent vigilance to avert the risk of overdiagnosing IgG4-RD in the presence of the aforementioned conditions. Third, it is essential to be familiar with the distinctive characteristics of IgG4-RD and pay attention to the detailed features of the disease. Typically, IgG4-RD presents with a chronic and subtle onset with the absence of systemic symptoms, such as high fever or musculoskeletal pain, or very high inflammatory parameters, although some patients exhibit symptoms such as weakness and weight loss. The majority of IgG4-RD patients may present with multiple-organ involvement. Pathologically, this disease is characterized by chronic inflammation infiltrated with lymphoplasmacytic and storiform fibrosis. Therefore, acute onset, obvious hyperinflammatory state, and less common single-organ involvement are not supportive of the diagnosis of IgG4-RD. It is important to note that the 2019 AECC and 2020 RCD criteria emphasize that lymph node involvement alone does not fulfill one of the criteria for IgG4-RD. In addition, pathology from lymph nodes, or skin or gastrointestinal system is not considered under the 2019 AECC guidelines. Fourth, the response to treatment should be closely monitored. Glucocorticoids are the first-line treatment of IgG4-RD, which are always very effective. Therefore, if a patient is not responsive to moderate to high doses of glucocorticoids, it is necessary to re-evaluate the diagnosis. Finally, for atypical or difficult cases, a multidisciplinary discussion is recommended, to remain vigilant to any unusual presentations and responses. It is crucial to correct any possible misdiagnosis during follow-up period. By adopting these strategies, the misdiagnosis and overdiagnosis of IgG4-RD can be substantially reduced. Nianyi Zhang drafted the manuscript, and Wen Zhang revised the manuscript. None. This work was supported by the National Key Research and Development Program of China (2022YFC2703104), National High Level Hospital Clinical Research Funding 2022-PUMCH-C-006, 2022-PUMCH-B-013. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.