Positive disease-specific autoantibodies have limited clinical significance in diagnosing IgG4-related disease in daily clinical practice

Abstract

Objectives The 2019 ACR/EULAR classification criteria for IgG4-related disease (IgG4-RD) have exclusion criteria including positive disease-specific autoantibodies, and these have been documented to have a high specificity. This study aimed to further validate these criteria as well as identify characteristics of patients showing false-negative results. Methods We retrospectively analysed 162 IgG4-RD patients and 130 mimickers. The sensitivity, specificity and fulfilment rates for each criterion were calculated, and intergroup comparisons were performed to characterize the false-negative cases. Results Both the IgG4-RD patients and mimickers were aged ≥65 years with male predominance. The final diagnoses of mimickers were mainly malignancy, vasculitis, sarcoidosis and aneurysm. The classification criteria had a sensitivity of 72.8% and specificity of 100%. Of the 44 false-negative cases, one did not fulfil the entry criteria, 20 fulfilled one exclusion criterion and 27 did not achieve sufficient inclusion criteria scores. The false-negative cases had fewer affected organs, lower serum IgG4 levels, and were less likely to have received biopsies than the true-positive cases. Notably, positive disease-specific autoantibodies were the most common exclusion criterion fulfilled in 18 patients, only two of whom were diagnosed with a specific autoimmune disease complicated by IgG4-RD. In addition, compared with the true-positive cases, the 18 had comparable serum IgG4 levels, number of affected organs, and histopathology and immunostaining scores despite higher serum IgG and CRP levels. Conclusions The ACR/EULAR classification criteria for IgG4-RD have an excellent diagnostic specificity in daily clinical practice. Positive disease-specific autoantibodies may have limited clinical significance for the diagnosis of IgG4-RD.

IgG4‐related disease presenting as severely symptomatic hypercalcemia: A case report and review of literature

“…However, although biopsies are essential in many settings to establish the diagnosis of IgG4‐RD and exclude mimickers, the new classification criteria 6 showed that an important strength of this criteria set is that a patient may be classified accurately as having IgG4‐RD in many cases on the basis of clinical, serological, and radiological findings even in the absence of a biopsy. Mizushima et al's research 7 also showed that the above classification criteria had a sensitivity of 72.8% and specificity of 100%, and even when the exclusion and inclusion criteria related to biopsy results were removed from the classification algorithm, the sensitivity drastically decreased to 42.6%, while the specificity was still maintained (100%).…”

“…The literature showed that although the serum IgG4 levels could elevate in non-IgG4-RD patients, the elevated levels were slight. 7,10 Hypercalcemia occurring in patients with IgG4-RD is not common. A literature review showed that only 5 definitely [11][12][13][14][15] (including 1 conference abstract 15 ) and 2 possible (not biopsied) IgG4-RD 16,17 associated hypercalcemia had been reported (Table 1).…”

“…For differential diagnosis, the literature 7,8 showed that mimickers of IgG4-RD were mainly malignancy, vasculitis, Sjögren's syndrome, sarcoidosis, multicentric Castleman's disease, and infections.…”

Hypertrophic Pachymeningitis with Characteristics of Both IgG4-related Disorders and Granulomatosis with Polyangiitis

“…A previous study in Japan reported that MPO-ANCA and PR3-ANCA seropositivity for GPA was 54.6% and 45.5%, respectively ( 12 ). A recent report concluded that the presence of ANCA does not influence the pathomechanisms of IgG4-related diseases ( 13 ). However, an overlap of ANCA-associated vasculitis and IgG4-related disease has been reported ( 14 ).…”

IgG4-related hypertrophic pachymeningitis with ANCA-positivity: A case series report and literature review

“…They had elevated serum IgG4 levels (>135 mg/dl for most patients) and positive ANCA. Although AAV is an important differential diagnosis of IgG4-RD in both the 2019 ACR/EULAR classification criteria ( 19 ) and CDC for IgG4-RD, a recent report concluded that the presence of ANCA might not influence the pathomechanisms of IgG4-RD ( 20 ). Furthermore, an overlap of AAV and IgG4-RD has been reported in some clinical patterns, such as tubulointerstitial nephritis, periaortitis, and prevertebral fibrosis ( 21 , 22 ).…”