This prospective study enrolled patients with IgG4-RD at Peking Union Medical College Hospital between March 2011 and January 2020 (ClinicalTrials.gov ID: NCT01670695). Patients who satisfied the 2011 comprehensive criteria were included. Patients with malignancies, infectious diseases, comorbid rheumatoid diseases or conditions that could mimic IgG4-RD were excluded. Finally, newly diagnosed and untreated IgG4-RD patients were included in this study (n = 737). After taking age distribution of patients and balanced sample size into consideration, patients were divided into five groups according to the age at diagnosis (≤39, 40–49, 50–59, 60–69 and ≥70 years). Paediatric patients were identified as aged 17 years or younger at diagnosis. Patients' allergy history was collected by using the definitions of the European Academy of Allergy and Clinical Immunology, including allergic asthma, allergic rhinoconjunctivitis, allergic urticaria, atopic eczema, allergic contact dermatitis, food allergy and drug allergy. Detailed demographic parameters, organ involvements, laboratory tests, imaging studies, histological examinations, disease activity, treatment agents and outcomes were recorded. This study was approved by the Ethics Committee of Peking Union Medical College Hospital. All enrolled patients signed written informed consents.
Organ involvement was assessed by reviewing patients' past medical history, symptoms, signs, laboratory tests, imaging studies and histological examinations. Involved organs were classified into superficial and internal organs according to anatomical sides.[27,28] Superficial organs included submandibular gland, parotid gland, lacrimal gland, sinus, thyroid and skin. Internal organs referred to pituitary, lung, liver, biliary tract, pancreas, gastrointestinal tract, artery, retroperitoneal tissue, mediastinum, kidney and prostate. Lymph node was not included in either superficial or internal organs.
Laboratory Tests, Imaging Studies and Histological Examinations
Laboratory tests of complete blood count, ESR, CRP, serum immunoglobin (Ig) concentration, IgG subclasses, total IgE (T-IgE) level, complement (C3, C4), ANAs, RF, liver and renal function tests were performed and recorded at baseline (at the time of diagnosis without treatment) and in the follow-up. Proportions of B cell phenotypes were measured in 103 treatment naïve patients who were newly diagnosed by flow cytometry after staining with CD19, CD24 and CD38 as previously described. B cell subsets were defined as mature naïve B cells (CD19+CD24intCD38int), memory B cells (CD19+CD24+CD38−), regulatory B cells (CD19+CD24hiCD38hi) and CD19+CD24−CD38hi B cells according to literature reports.[30,31] All patients underwent image examinations, namely ultrasonography, CT, MRI or 18F-fluorodeoxyglucose PET/CT. Tissue biopsies were carried out on 434 patients according to pathology method reported before.
Disease Activity, Treatment Agents and Outcomes
Disease activity was evaluated by IgG4-RD responder index (RI). Treatment regime included GC monotherapy, IM monotherapy, GC combined with IM and watchful waiting (referring to no treatment or single injection of betamethasone). Relapse was defined as a recurrence or worsening of symptoms or imaging studies, with or without the re-elevation of serum IgG4 concentration. Re-elevation of serological IgG4 level alone was not considered to be a relapse. We included 310 patients treated with GC monotherapy or GC combined with IM and analysed their relapse in the follow-up of 36 months.
Continuous normally distributed data were presented as mean and standard deviation and continuous non-normally distributed data were presented as median and interquartile range. Multiple sets of measurement data were compared with a one-way analysis of variance or multiple independent samples non-parametric test (Kruskal–Wallis test). A post hoc Tukey test or Dunn's test was used for multiple comparisons (α = 0.05). Categorical variables were assessed by Fisher's exact test or the χ 2 test. The χ 2 trend test was used to test the statistical significance of changes in proportions of organ involvement with age. Correlations between variables were assessed using Pearson's rank test (normally distributed) or Spearman's rank correlation test (non-normally distributed). Stepwise multiple linear regression analysis was employed to identify the potential factors associated with serum IgG4 concentration. The receiver operating characteristic curve was used to determine the predictive ability of age for relapse and the cut-off value. Propensity score matching (PSM) was performed to eliminate confounding. Potential factors such as sex, disease duration, IgG4-RD RI, involvement of superficial (salivary gland, sinus) and internal organs (pancreas, biliary tract and lung) and whether an IM was used were included as independent variables. Kaplan–Meier survival curves and log-rank tests were performed to calculate the relapse rate. Univariate and multivariate Cox regression analysis was performed to estimate the risk factors of relapse in IgG4-RD and a backward stepwise method (likelihood ratio test) was used. Statistical analysis was performed with IBM SPSS Statistics version 22 (IBM Corp., Armonk, NY, USA). P-values <0.05 (two-tailed) were considered statistically significant.
Rheumatology. 2021;60(6):2635-2646. © 2021 Oxford University Press