Abstract
Background:
IgG4-related disease (IgG4-RD) is a multi-organ fibroinflammatory disease considered to have an autoimmune origin. Case series describing individual organ involvement have suggested differences in phenotypic expression between males and females. We aimed to characterize differences in IgG4-RD manifestations between male and female patients in a large single-center cohort.
Methods:
Patients were recruited 2008–2023 and classified according to the ACR/EULAR Classification Criteria. Age at diagnosis, organ involvement at baseline, treatment status, and pre-treatment laboratory values were collected. Circulating plasmablasts and B cell subsets were quantitated by flow cytometry. Active disease was defined by an IgG4-RD Responder Index score >0. Laboratory values were analyzed for patients who were untreated at baseline and had active IgG4-RD.
Results:
Of the 564 participants enrolled in the MGH IgG4-RD Registry, 328 fulfilled ACR/EULAR Classification Criteria and were included. There was a strong male predominance (male:female ratio = 2·2:1), which contrasted markedly with our general rheumatology clinic population (0·4:1)(p < 0·001). The male predominance increased with each decade of life starting at age 40. On average, male patients were 5·5 years older at diagnosis (63·7 years versus 58·2 years; p=0·003). Males were also disproportionately more likely to have pancreas and kidney involvement, to present with extremely elevated serum IgG4 concentrations, and to have expansions of both plasmablasts and B cells derived from extra-follicular activation.
Conclusions:
IgG4-RD is unusual among autoimmune diseases in that it is more likely to affect males and to present with a striking sex-dependent organ distribution and degree of B cell response.
INTRODUCTION
IgG4-related disease (IgG4-RD) is a multi-organ immune-mediated fibrotic disease that typically presents with diffuse enlargement of target organs1, 2. Glandular tissues such as the pancreas, lacrimal, submandibular, parotid, thyroid, pituitary and prostate are often affected by IgG4-RD3. In addition, IgG4-RD has classic manifestations in both the intra- and extra-hepatic bile ducts4; the orbits (particularly extra-ocular muscles)4; and the lungs, kidneys, aorta, and retroperitoneum4. The disease also tends to involve blood vessels of essentially any size, suggesting that classification as a variable-vessel vasculitis is appropriate5. The full scope of these potential disease manifestations justifies its reputation among the most protean of immune-mediated disorders.
The etiology of IgG4-RD and the events surrounding the observed loss of tolerance in this disease remain to be defined6. The immune response observed in IgG4-RD has been defined by the accumulation of plasmablasts, double-negative (DN)3 B cells, DN4 B cells, CD4+ cytotoxic T lymphocytes (CTLs), and CD8+ CTLs in both the blood and lesional tissues7, 8. In addition, it has been demonstrated that disease-associated dominant plasmablast clones express self-reactive IgG4 antibodies8. The disease has a predilection for middle-aged to elderly individuals, but cases with classic disease phenotypes have also been reported in people of all ages, including children9. Case series on specific organ manifestations of IgG4-RD have suggested that the pancreatic, renal, retroperitoneal, meningeal, large-vessel, and coronary artery manifestations exhibit a strong male predilection 4, 10, 11. As an example, only 13% of reported cases of coronary artery involvement reported in the literature are females. Other organ manifestations of IgG4-RD (e.g., salivary gland disease) do not show any such sex-dependent enrichment12, 13, 14.
Such male predominance is uncommon in an autoimmune condition15, 16, 17, 18, 19. We therefore examined our large single-center experience with IgG4-RD, accumulated over fifteen years, to identify and understand differences in disease phenotypes across the sexes. We focused on baseline differences in organ involvement, laboratory values, disease activity, and circulating B cell subsets implicated in the disease mechanism.
METHODS
This study was approved by the Mass General Brigham institutional review board. Patients were recruited from the MGH Rheumatology Clinic between January, 2008 and May, 2023. All patients provided informed consent for follow-up in the longitudinal cohort and review of their medical records. Patients were evaluated according to standardized clinical and laboratory assessments. Data were recorded in both the electronic medical record and a RedCap database20, 21.
Patients were classified according to the American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) Classification Criteria44. The ACR/EULAR Classification Criteria include two entry criteria. The entry criteria consist of either the involvement IgG4-RD of an organ considered typical for the disease or the identification of pathology findings compatible with IgG4-RD in an organ regarded as atypical. The ACR/EULAR Classification Criteria also address four categories of exclusion criteria, referring to clinical, serological, radiological, or pathological findings. Patients who fulfill the entry criteria and have none of the exclusion criteria are then scored in nine weighted inclusion domains. A minimum score of 20 points is required for classification of an individual patient as an IgG4-RD patient. Only patients satisfying the ACR/EULAR Classification Criteria were included in this study. Data collection included self-reported sex, age at diagnosis, disease activity, treatment status, organ involvement, clinical laboratory values, and the results of flow cytometry analyses.
Active disease, defined by the treating rheumatologist, corresponded to an IgG4-RD-Responder Index (IgG4-RD-RI) score >0, based on clinical, laboratory, and imaging findings. Disease activity status was determined at the time of the baseline visit. The baseline visit was defined as the first visit for which data were collected after the completion of informed consent. There were no exclusion criteria based on the presence of activity at baseline, treatment status, or the involvement of specific organs. However, for analyses of laboratory values and B cell subset quantitation by flow cytometry, only patients with active and untreated disease were included. At the baseline visit, laboratory values, disease activity, and treatment status were collected.
Flow cytometry studies were performed at the Ragon Institute of MGH, the Massachusetts Institute of Technology, and Harvard University (Cambridge, MA). We interrogated our repository database to identify patients who: 1) fulfilled the ACR/EULAR Classification Criteria; 2) had active disease but were on no immunosuppressive treatment; and, 3) had peripheral blood mononuclear cells sampled between the dates of interest. This yielded the numbers we studied. The patients who fulfilled criteria included 17 female patients, 38 male patients, and 28 age-matched healthy donors for quantitation of B cell subsets by flow cytometry. The flow cytometry experiments were conducted between February 13 and March 10, 2020.
Fc receptors were blocked using Human TruStain FcX (BioLegend) for 20 minutes on ice. PBMCs were then stained with antibodies optimized to provide the maximal separation of positive and negative populations. The antibody panel included the following anti-human antibodies: CD38-BUV661 (BD, clone HIT2), CD20-BUV805 (BD, clone 2H7), CD21-BV480 (BD, clone B-ly4), CD11c-BV605 (BD, clone B-ly6), IgD-BV785 (BioLegend, clone 1A6–2), CXCR5-A488 (BD, clone RF8B2), CD27-PE/Dazzle (BioLegend, clone M-T271), CD19-APC/R700 (BD, clone SJ25C1). After a 30-minute incubation on ice, protected from light, stained cells were washed twice and incubated with DRAQ7 (BioLegend) to stain non-viable cells. All flow cytometry studies were executed on freeze-thawed PBMCs in batches using rainbow tracking beads to control for day-to-day variation in laser output. A BD Symphony cytometer was used for all flow cytometry studies. FlowJo version 10.9 was used for hierarchical gating and flow cytometric data output. Graphpad Prism version 10 was used for plotting flow cytometry data. After excluding non-viable lymphocytes and gating on CD19+ B cells, B cell subsets were defined by the following: plasmablasts as CD19+IgD−CD27+CD38HiCD20−; DN B cells as CD19+IgD−CD27−; DN2 as CD19+IgD−CD27−CXCR5−CD11c+; DN3 as CD19+IgD−CD27−CXCR5−CD11c−; DN4 as CD19+IgD−CD27−CXCR5+CD11c+; naive as CD19+IgD+CD27−; unswitched memory as CD19+IgD+CD27+; canonical memory as CD19+IgD−CD27+CXCR5+CD11c− (after the exclusion of plasmablasts); and age-associated B cells as CD19+IgD−CD27+CXCR5−CD11c+.
Statistical methods
Statistical analyses were performed through the use of SAS (Version 9.4). We presented numbers and percentages for categorical variables and medians with interquartile ranges (IQRs) for continuous variables that were not normally distributed. We compared the differences in the characteristics (i.e., baseline demographic factors, clinical symptoms, and laboratory results) between men and women using Chi-square tests for categorical variables (and Fisher’s Exact test for cells in which n < 5) and Wilcoxon rank sum tests for continuous variables. We analyzed differences in circulating B cell subsets across male and female patients using the Mann-Whitney test. Statistical comparisons were regarded as significant if P < 0.05.
Role of the Funding Source
The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all of the data and the final responsibility to submit for publication.
RESULTS
Patient Cohort
From the 564 patients with possible IgG4-RD that were consented into the cohort, 328 fulfilled the ACR/EULAR Classification Criteria and were included in this study. Of these 328 patients, 226 (69%) were male and 102 (31%) were female. The baseline features of the study population are shown in Table 1. The male patients were 5·5 years older on average at the time of diagnosis compared with their female counterparts. The median age at diagnosis among the male patients was 63·7 years (IQR 17·8 years), as opposed to 58·2 years (IQR 23·9 years) for the females (P = 0·003). Seventy-eight percent of the patients were diagnosed after the age of 50 (Figure 1A). A balanced sex distribution was noted among patients diagnosed prior to the age of 40, but a male predominance became evident with each decade of life corresponding to age at diagnosis (Figure 1B). For individuals diagnosed after age 69, 77% were male (p = 0·026). No significant differences were observed between female and male patients with regard to distributions of race and ethnicity.
Table 1.
Demographics and Baseline Laboratory Values, By Sex.
| Male | Female | P-Value | |
|---|---|---|---|
| Demographics | |||
| Subjects – N (%) | 226 (69%) | 102 (31%) | <0.001 |
| Age at Diagnosis – median (IQR) | 63.7 (53.9–71.7) | 58.2 (44.1–68.0) | 0.003 |
| Age at Diagnosis – N (%) | |||
| < 40 | 15 (6.6) | 17 (16.7) | 0.03 |
| 40– <50 | 26 (11.5) | 14 (13.7) | |
| 50– <60 | 50 (22.1) | 25 (24.5) | |
| 60– <70 | 64 (28.3) | 25 (24.5) | |
| ≥ 70 | 71 (31.4) | 21 (20.6) | |
| Race – N (%) | |||
| White | 164 (72.6) | 74 (72.6) | 0.60 |
| Asian | 32 (14.2) | 12 (11.8) | |
| Black or African American | 10 (4.4) | 4 (3.9) | |
| American Indian/ Alaskan Native | 0 (0.0) | 1 (1.0) | |
| Unknown | 9 (4.0) | 7 (6.9) | |
| Other | 10 (4.4) | 3 (2.9) | |
| Ethnicity – N (%) | |||
| Hispanic or Latino | 27 (12.0) | 16 (15.7) | 0.06 |
| Not Hispanic or Latino | 187 (82.7) | 74 (72.6) | |
| Unknown/Not Reported | 12 (5.3) | 12 (11.8) | |
| Laboratory Values - median (IQR) | |||
| IgG4 (3.9–86.4 mg/dl)(F: N=25, M: N=71) | 402.6 (146.2–807.5) | 201.4 (93.3–542.9) | 0.08 |
| Normal range (3.9–86.4 mg/dL) – N (%) | 10 (14.1) | 6 (24.0) | 0.31 |
| > ULN but ≤ 2x ULN – nN(%) | 11 (15.5) | 6 (24.0) | |
| > 2x ULN but ≤ 5x ULN – N (%) | 16 (22.5) | 6 (24.0) | |
| > 5x ULN – N (%) | 34 (47.9) | 7 (28.0) | |
| IgG1 (382.4–928.6 mg/dl) (F: n=25, M: n=71) | 753.0 (603.0–990.0) | 679.0 (528.0–848.0) | 0.20 |
| IgE (0–100 IU/ml) (F: n=33, M: n=78) | 199.0 (60.0–449.0) | 128.0 (35.5–255.5) | 0.20 |
| C3 (81–157 mg/dl) (F: n=23, M: n=63) | 112.0 (92.0–135.0) | 129.0 (108.0–157.0) | 0.25 |
| C3 hypocomplementemic – N (%) | 12 (15.4) | 7 (23.3) | 0.33 |
| *C4 (12–39 mg/dl)(F: n=23, M: n=64) | 23.2 (11.3) | 23.3 (9.4) | 0.97 |
| C4 hypocomplementemic – N (%) | 16 (20.5) | 6 (20.0) | 0.95 |
| Eosinophils (0–8%) (F: n=32, M: n=82) | 3.8 (2.1–6.2) | 3.2 (1.9–5.2) | 0.56 |
| Creatinine (0.60–1.50mg/dL) (M: n=76; F: n=28,) | 1.01 (0.90–1.29) | 0.73 (0.69–0.84) | <0.001 |
| Creatinine (renal involvement) M=31, F=5 | 1.31 (0.94–1.96) | 0.82 (0.73–0.97) | 0.10 |
| Lipase (13–60 U/L) (F: n=20, M: n=58) | 24.5 (10.0–41.0) | 33.5 (23.0–68.0) | 0.03 |
| Lipase (pancreatic involvement) M=38, F=9 | 16.5 (7.0–32.0) | 27.0 (19.0–141.0) | 0.04 |
The distribution of C4 was normal and therefore we report the mean (SD) for C4 instead of the median (IQR). The other continuous variables did not have normal distributions.
Figure 1A. Age at Diagnosis in the MGH IgG4-RD Cohort.
Note: Upper limited is not inclusive
Age is reported in years.
Figure 1B. Age at Diagnosis by Sex.
Age is reported in years.
Baseline ACR/EULAR Classification Criteria score
The ACR/EULAR Classification Criteria provide an overview of specific clinical, radiological, and histopathological features of IgG4-RD. We therefore used these criteria to compare specific and important disease characteristics across sexes. We observed male patients to have higher ACR/EULAR Classification Criteria scores at baseline with a median score of 35 (IQR 28–46), compared with 29·5 (IQR 25–39) for females (p < 0·001). The higher scores among male patients were driven largely by an observed predilection for specific organ manifestations as well as higher serum IgG4 values (Table 2). More specifically, the male IgG4-RD cohort was enriched for pancreatic, renal, and retroperitoneal involvement. No specific organ manifestations appeared to be more common among female patients. Some distinctive but unusual manifestations of IgG4-RD such as paravertebral soft tissue masses (5 patients) and inflammatory masses at the ureteropelvic junction (12 patients) occurred exclusively in males.
Table 2.
Fulfillment of ACR/EULAR Classification Criteria items, Males versus Females.
| ACR/EULAR Classification Criteria Domain | Male N (%) | Female N (%) | P-Value |
|---|---|---|---|
| Total Score – median (IQR) | 35.0 (28.0–46.0) | 29.5 (25.0–39.0) | <0.001 |
| Histopathology – N (%) | 0.03 | ||
| Uninformative Biopsy | 44 (19.5) | 22 (21.6) | |
| Dense Lymphoplasmacytic Infiltrate | 44 (19.5) | 34 (33.3) | |
| Dense Lymphoplasmacytic Infiltrate and Obliterative Phlebitis | 3 (1.3) | 1 (1.0) | |
| Dense Lymphoplasmacytic Infiltrate and Storiform Fibrosis with or without Obliterative Phlebitis | 131 (58.0) | 45 (44.1) | |
| Immunostaining performed – N (%) | 157 (69.5) | 70 (69.3) | 0.98 |
| Immunostaining Weight – median (IQR) | 14.0 (7.0–14.0) | 7.2 (7.0–14.0) | 0.19 |
| Immunostaining Weight – N (%) | |||
| 0 | 2 (1.3) | 1 (1.4) | 0.36 |
| 7 | 76 (48.4) | 39 (55.7) | |
| 14 | 47 (29.9) | 22 (31.4) | |
| 16 | 32 (20.4) | 7 (10.0) | |
| 29 | 0 (0.0) | 1 (1.4) | |
| Serum IgG4 Concentration – N (%) | 0.005 | ||
| Normal or Not Checked | 34 (15) | 27 (27) | 0.01 |
| > Normal but <2x ULN | 31 (13.7) | 22 (21.6) | 0.07 |
| 2x to 5x ULN | 56 (24.8) | 23 (22.6) | 0.66 |
| ≥ 5x ULN | 105 (47) | 30 (29) | 0.004 |
| Bilateral Lacrimal, Parotid, Sublingual, and Submandibular Glands | 0.21 | ||
| No set of glands is involved | 104 (46.0) | 38 (37.3) | |
| One set of glands is involved | 57 (25.2) | 27 (26.5) | |
| Two or more sets of glands are involved | 62 (27.4) | 37 (36.3) | |
| Chest and Thoracic Area | 0.38 | ||
| Neither of the items listed is present | 204 (90.3) | 94 (92.2) | |
| Peribronchovascular and septal thickening | 7 (3.1) | 4 (3.9) | |
| Paravertebral Band-Like Soft Tissue in the Thorax | 5 (2.2) | 0 (0.0) | |
| Pancreas and Biliary Tree | 0.05 | ||
| None of the items listed is present | 141 (62.4) | 76 (74.5) | |
| Diffuse pancreas enlargement (loss of lobulations) | 19 (8.4) | 5 (4.9) | |
| Diffuse pancreas enlargement and capsule-like rim with decreased enhancement | 26 (11.5) | 4 (3.9) | |
| Pancreas (either of above) and biliary tree involvement | 38 (16.8) | 14 (13.7) | |
| Renal | * | ||
| None of the items listed is present | 121 (53.5) | 65 (63.7) | 0.09 |
| Hypocomplementemia | 69 (30.5) | 29 (28.4) | 0.70 |
| Renal pelvis thickening/soft tissue | 11 (4.9) | 0 (0.0) | 0.02 |
| Bilateral renal cortex low density areas | 44 (19.5) | 11 (10.8) | 0.05 |
| Retroperitoneum | 0.10 | ||
| Neither of the items listed is present | 178 (78.8) | 86 (84.3) | |
| Diffuse thickening of the abdominal aortic wall | 3 (1.3) | 3 (2.9) | |
| Circumferential or antero-lateral soft tissue around the infra-renal aorta or iliac arteries | 40 (17.7) | 10 (9.8) |
The categories of all variables except the renal variable are mutually exclusive. This is because although the renal components are not mutually exclusive in practice, only the highest point value is counted in the criteria. Many patients have both hypocomplementemia and bilateral renal cortex low density areas, so reporting such patients as not having hypocomplementemia (as would be required by the classification criteria) would lead to a falsely low estimate of hypocomplementemia.
Males were also more likely than females to have a history of hypocomplementemia at some point in their courses and to have hypodense lesions within the renal cortices on CT imaging of the abdomen, the latter of which characterizes patients with IgG4-related renal involvement. Male patients were also twice as likely as females to demonstrate the classic radiologic findings of retroperitoneal fibrosis, i.e., circumferential or anterolateral soft tissue infiltration around the infra-renal abdominal aorta, frequently extending caudally to the iliac arteries. Nearly 18% of the male patients demonstrated this finding, compared with fewer than 10% of the female patients.
Organ involvement
Male subjects were substantially more likely to have major organ involvement compared with the female subjects (Figure 2). The enrichment for internal organ involvement among male patients was most pronounced for pancreatic and kidney disease. The proportion of male patients with pancreatic and renal involvement by IgG4-RD was approximately double the proportions observed in female patients. Fifty percent of the male patients had pancreatic involvement, compared to only 27% of the female patients (p < 0·001). The higher likelihood of pancreatic disease among males was consistent with the finding that male patients had lower lipase levels at the time of the baseline assessment, compatible with IgG4-RD-induced injury to the pancreas (exocrine pancreatic failure is associated with hypolipasemia) (Table 1). The median baseline serum lipase concentration among male patients was 25 U/L (IQR 10–41 U/L), compared to 34 U/L (IQR 23–6 U/L) (normal range: 13–60 U/L) for the females (p = 0·033). Male patients were also more likely to have a history of renal involvement or to have renal involvement at baseline (males 39%, females 18%; p < 0·001).
Figure 2. Organ involvement in female and male patients with IgG4-RD.
* = p-value of <0.001
Consistent with our findings of more extensive internal organ involvement and higher serum IgG4 levels among male patients with IgG4-RD, we also observed a sex-dependent enrichment for lymphadenopathy found in 29% of male patients versus 16% of female patients (p < 0·011). Lymphadenopathy is a finding typically associated with widespread disease and higher serum IgG4 concentrations, compatible with a more robust or long-standing underlying immune response.
Female patients had numerically higher frequencies of disease affecting certain organs or regions of the head and neck, e.g., the lacrimal, parotid, and submandibular glands as well as the orbits. None of those comparisons, however, achieved statistical significance across the sexes.
Baseline laboratory values
Laboratory values were examined for a subset of patients who had active disease and were untreated at baseline. Male patients were more likely to have serological abnormalities at baseline. The distribution of IgG4 values differed significantly across the sexes, favoring higher values in males (p = 0·005) (Table 2). Forty-seven percent of the male patients had an IgG4 serum concentration ≥ 5 times the upper limit of normal (ULN), compared with 29% of the female patients (p = 0·004). Twenty-seven percent of the female patients had normal serum IgG4 concentrations at baseline, compared with only 15% of the males (p = 0·014).
We also examined a subset of patient samples from our IgG4-RD repository, collected during a time of active disease but before the institution of treatment, to understand if the increased serum IgG4 concentrations observed among male patients corresponded to more prominent circulating B cell responses among males compared to females. We found that male patients with IgG4-RD were more likely to have observable, active B cell responses in the blood as defined by proportional expansions of plasmablasts (p = 0.009) (Figure 3A). We also quantified other class-switched extrafollicular activated B cell subsets implicated in the mechanism of IgG4-RD6, including DN2 and DN3 B cells. We found statistical trends towards greater expansions of DN2 (p = 0.06) and DN3 (p = 0.16) B cells among male patients with IgG4-RD compared to female patients. We did not observe significant perturbations among naïve, unswitched memory, DN4 B cells, canonical CD27+ memory, or age-associated B cells (data not shown).
Figure 3:
Proportional quantitation of activated B cell subsets in the blood of males vs female patients with lgG4-RD. Dot plots displaying the proportions of each activated B cell subset as a % of total CD19+ B cells among PBMCs from 17 females and 38 males with lgG4-RD. Panel A) plasmablasts; B) DN2 B cells; C) DN3 B cells. For all analyses, Mann-Whitney U test was used to calculate p-values. ** = p-value of <0.01.
The error bars refer to the median and interquartile ranges.
DISCUSSION
IgG4-RD is a multi-organ inflammatory condition recognized to be a unique disease only in 200344. The chronic, relapsing nature of this disease; its responsiveness to immunosuppression; and the presence of self-reactivity among dominantly-expanded plasmablasts suggest that IgG4-RD has an autoimmune etiology. The accumulation of IgG4+ class-switched plasma cells and B cells at sites of disease provide direct evidence for the chronic activation of the adaptive immune system in IgG4-RD, and potential autoantigenic triggers for the disease have been identified7. Targeted immune-based therapies to date have suggested substantial efficacy of approaches focusing on B cell depletion or modulation.
The data provided in this manuscript demonstrate, however, that IgG4-RD is highly atypical of autoimmune diseases in at least one important aspect. Whereas the great majority of diseases considered to have autoimmune etiologies demonstrate striking tendencies to occur in females, IgG4-RD has a strong predilection for affecting males. Well-known examples of this female predilection in autoimmune diseases include systemic lupus erythematosus, Sjögren’s syndrome, and rheumatoid arthritis, estimated to be nine, four, and three times more likely to affect females than males, respectively16, 17, 22. Even inflammatory rheumatologic conditions that do not have clearcut autoimmune bases, e.g., giant cell arteritis and Takayasu’s arteritis, have unequivocal preferences for affecting women, with female to male ratios of 3:1 and 9:1, respectively23, 24. Although phenotypic sex differences have been reported in IgG4-RD12, 13, to date no comprehensive assessment of these purported differences has been performed in a cohort of patients defined by the ACR/EULAR Classification Criteria for IgG4-RD.
The male patients in our cohort were more likely than their female counterparts to exhibit organ involvement typically associated with IgG4-RD. Significant differences were observed, for example, in the pancreas, an organ in which 50% of males exhibited IgG4-RD involvement compared to only 26% of females (p <0·001). Renal involvement also exhibited a similar difference, observed in 39% of males but only 18% of females (p <0·001).
Furthermore, male patients were more likely to be serologically active at baseline. The more extensive organ involvement observed in males corresponds to the more profound serological abnormalities observed in the male population. The greater burden of disease among the male patients in our cohort was reflected in the higher serum IgG4 concentrations in males and the larger number of affected organs in males. In addition, the greater disease burden in males was associated with increases in males relative to females in the both numbers of plasmablasts and increases in the peripheral blood concentrations of B cells activated through extra-follicular pathways such as DN2 and DN3 B cells.
The sex predilection in IgG4-RD resembles that of ANCA-associated vasculitis – specifically, that of granulomatosis with polyangiitis (GPA)25. Among patients in the Wegener’s Granulomatosis Etanercept Trial (WGET), a trial that enrolled 180 patients, those with “severe”, i.e., disseminated disease, were more likely to be male. In contrast, those with “limited” disease, a term that connoted disease more likely to affect the upper respiratory tract and sinuses but tending to spare the kidneys26, were more likely to be young and female. These sex distribution patterns in GPA and IgG4-RD illustrate another way that these two conditions resemble each other. Both diseases commonly affect the lungs, kidneys, orbits, and sinuses, and both can also affect the pachymeninges and pituitary glands. In both diseases, the more severe “proliferative” or “disseminated” forms of the diseases appear to be more likely to affect males than females. Nevertheless, there is no question that these severe forms of the diseases can also occur in female patients, albeit in lower percentages compared with males.
Our cohort represents the largest study to date with the ACR/EULAR Classification Criteria applied to a population of patients suspected of having IgG4-RD. Male patients were more likely to fulfill ACR/EULAR Classification Criteria than females. Of the 349 males enrolled in our cohort, 65% fulfilled the ACR/EULAR criteria. In contrast, only 47% of the 215 females fulfilled these same criteria. The female patients in our cohort were more likely to be categorized as having “probable” or “possible” IgG4-RD.
A number of explanations have been offered to explain the discrepancies between males and females with regard to the occurrence of autoimmune disease. Some of these explanations include the potential impact of hormonal changes in women15, the role of X inactivation (which only affects women)27, and upregulation of transcription factors that predispose to autoimmunity19. Sex differences within the microbiome have also been observed in several autoimmune diseases13, 28. In general, these explanations offer some potential insights into why autoimmunity preferentially affects women. This is quite the opposite of what we have observed in IgG4-RD. It remains possible that IgG4-RD is not an autoimmune disorder and that further investigations will reveal alternative insights that explain the male predilection observed.
It is possible that the differences in phenotypic expression in our cohort relate in part to delays in diagnosis among men. The male patients in our cohort were, on average, more than five years older than their female counterparts at the time of diagnosis. Women are more likely to have regular visits for health care than are men and this is perhaps particularly true in young adulthood and early middle age, when issues pertaining to contraception, cervical cancer screening, pregnancy, childbirth, and menopause are more likely to bring female patients to medical attention. This may explain the lack of gender discrepancy among the patients diagnosed when younger than age 40. Conversely, it is also possible that the ways in which IgG4-RD tends to express itself in men, with potentially asymptomatic involvement of internal organs, is more likely to be associated with delays in diagnosis compared to the head and neck manifestations of the disease.
Differential environmental exposures may also explain the apparently higher incidence of IgG4-RD among men, particularly older men. Blue-collar work has been linked to an increased risk of IgG4-RD29. The underlying mechanisms of this association between blue-collar work and IgG4-RD, if representative of a true relationship, are unclear. Another potential explanation for these data pertains to cigarette smoking. In many societies, the percentage of individuals who smoke is higher among males than females. Cigarette smoking has been offered as one potential risk factor for IgG4-RD, but the majority of this risk pertains only to patients with retroperitoneal fibrosis30. In this regard, it is worth noting that the percentage of male patients with RPF was higher than that of female patients, though this comparison did not achieve statistical significance.
Our study has both strengths and weaknesses. It is the largest cohort of patients reported from a Western country and the largest study to examine questions of phenotypic differences among males and females in a cohort of patients who fulfill the ACR-EULAR Classification Criteria for IgG4-RD. It is also the largest cohort of patients in which the ACR-EULAR Classification criteria have been applied. One weakness, however, is that only a relatively small percentage of patients in our cohort had their initial assessments at a time before they received any immunosuppressive treatment. Therefore, the number of patients with active disease and on no treatment whose laboratory values we were able to analyze was relatively small compared to the size of the overall cohort. Although the IQRs for many laboratory comparisons were wide, the data consistently supported greater serological activity among the male patients.
In summary, in this large single-center cohort from North America, we observed major differences between females and males. Investigators addressing questions of pathogenesis and etiology must bear in mind these differences in phenotypic disease expression. Further investigation is needed to understand why these discrepancies occur across various manifestations of the disease.
Supplementary Material
Research In Context.
Evidence before this study:
IgG4-related disease (IgG4-RD) is a multi-organ fibroinflammatory disease considered to be of autoimmune origin. Case series generally focusing on specific organ manifestations of the disease have suggested that there might be a predilection for males among patients with IgG4-RD. We reviewed this literature through PubMed searches covering the period between 1January 2003 and 17 February 2023. Terms used included, “IgG4-RD organ involvement”, “IgG4-RD sex distribution”, “sex differences in autoimmune diseases”, “IgG4-RD manifestation”. Results yielded peer-reviewed studies including case-series and various cohort studies. These studies suggested that IgG4-RD might have a predilection for middle-aged to elderly individuals. Nevertheless, cases with classic disease phenotypes have been reported in both sexes and among individuals of all ages, including children. Case series have suggested predilections for males among patients with pancreatic, renal, retroperitoneal, meningeal, large-vessel, and coronary artery manifestations, but not in other manifestations. No studies to date have used validated criteria for the classification of patients with IgG4-RD.
Added value of this study:
The findings of our study of 328 patients, all of whom fulfilled the ACR/EULAR Classification Criteria for IgG4-RD, confirms the sense from the literature on this disease extending back for two decades. Although IgG4-RD can occur in both sexes, IgG4-RD has a predilection for males and the disease is more likely to be severe in males, associated with widespread organ involvement and substantial evidence of serologically active disease.
Implications of all the available evidence:
Substantial differences in risk of disease and in disease expression appear to exist between males and females. Investigators addressing questions of pathogenesis and etiology must bear in mind these differences in phenotypic disease expression. Further investigation is needed to understand why these discrepancies occur across various manifestations of the disease.
Funding sources:
This work was supported by an Autoimmunity Center of Excellence award from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID), UM1AI144295 (Professor Stone) and U19AI 11095 (Professor Pillai); a Scientist Development Award (998547) from the Rheumatology Research Foundation (Dr. Katz); the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), K08 AR079615 (Dr. Perugino) and T32 AR007258 (Dr. Katz).
Footnotes
Disclosure of interests:
Yasmin G. Hernandez-Barco reports honorarium for CME and Grand Rounds lectures on autoimmune pancreatitis [A: honorarium from who?]. ZSW reports consulting fees from Viela Bio, Zenas, Horizon, Sanofi, MedPace, BioCryst, and Amgen; and participation on a Data Safety Monitoring Board or Advisory Board for Sanofi, Horizon, Novartis, Shionogi, and Otsuka/Visterra. SP reports consultancy fees from Be Bio Pharma, Paratus Inc, and Octagon Therapeutics; and stock options [A: correct?] for Ab Pro Inc, Be Bio Pharma, Paratus Inc. JHS reports consultancy fees from Acepodia, Alexion, BMS, Connect Biopharma, Horizon, iCell Gene Therapeutics, Q32, Sanofi, and ZenasBio; and has a leadership or fiduciary role in other board, society, committee or advocacy group [A: please specify the role] for Horizon Therapeutics. None of the other authors has any interests to disclose.
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