Differences in Clinical Characteristics of IgG4-Related Disease Across Age Groups

A Prospective Study of 737 Patients

Hui Lu; Fei Teng; Panpan Zhang; Yunyun Fei; Linyi Peng; Jiaxin Zhou; Mu Wang; Xiaowei Liu; Liang Zhu; Liwen Wang; Xuan Luo; Zheng Liu; Jieqiong Li; Yan Zhao; Wen Zhang; Xiaofeng Zeng


Rheumatology. 2021;60(6):2635-2646. 

In This Article


To our knowledge, this is the largest prospective study that revealed the age disparities of IgG4-RD. We focused on demographic features, organ involvement, laboratory tests, disease activity, treatment agents and outcomes among different age groups.

The demographic features of the five groups were different. Our work revealed male predominance in older groups, which was consistent with other reports.[24,28] IgG4-RD has long been considered to be accompanied with allergic conditions.[34,35] Although we found the frequencies of allergy history were significantly different across age groups, we did not find any statistical discrepancies in eosinophils and T-IgE that related to allergic inflammation. Of note, Yamamoto et al.[24] reported that both level of serum IgE and peripheral count of eosinophils were significantly lower or tended to be lower in the elderly-onset (>70) group.

IgG4-RD is a systemic disease characterized by multiple site involvement. Superficial organ involvements such as lacrimal gland and sinus were less common with advancing age, while the involvements of submandibular gland, parotid gland and skin showed no difference across age groups. As for internal organs, the proportions of pancreas, biliary tract, retroperitoneum, prostate and lung involvement increased with age, indicating that these internal organs were more likely to be damaged by IgG4-RD in the older patients. Besides, the phenomenon that the proportion of internal organ involvement increased with age was more prominent in male patients. Therefore, extra attention is needed and it is particularly necessary to perform a comprehensive and systemic evaluation to obtain a full view of organ involvement in clinical practice, especially for elderly men.

A comparison of laboratory tests revealed that ESR, CRP, serum IgG, IgM, IgG1, IgG3 and IgG4 levels were significantly different across age groups. Besides, ESR, CRP, serum IgG, IgG1, IgG3 and IgG4 levels were positively correlated with age. Consistent with our data, Wallace et al.[36] reported that patients with elevated serum IgG4 concentration tend to be older, with more organ involvements, with higher serum IgG, IgG1, IgG2 and IgG3 levels and lower complement levels. An age-dependent physiological process might contribute to the observed age-related increase in ESR, CRP and IgG subclasses. It has been reported that the production of acute-phase proteins, pro-inflammatory cytokines, such as IL-6 and TNF-α, reactive oxygen species and autoantibodies increased in multiple tissues with advancing age.[13,37] Yamamoto et al.[24] found no significant difference in serum IgG, IgG4 level and CRP between older (>70) and younger (≤70) patients. The discrepancy between the two studies possibly derived from different grouping criteria, different ethnic groups or relatively smaller sample size in the other study. Multiple linear regression analysis revealed that older age, male sex, lacrimal gland involvement and more involved organs were independently associated with higher serum IgG4 level, while artery involvement was independently associated with lower serum IgG4 level. The standardized β-coefficient indicated that the number of involved organs showed the strongest association with serum IgG4 level. Consistently, Wang et al.[28] revealed higher IgG4 level was associated with older age, male sex, higher baseline IgG4 RI and Mikulicz's disease. Besides, Wallace et al.[36] reported that patients with elevated serum IgG4 concentration tend to be older, with more organ involvements, with higher serum IgG subclass levels and lower complement levels. Zhang and Stone[21] mentioned in a review article that IgG4-RD of a 'proliferative type' affecting epithelial gland and tissues (dacryoadenitis, sialadenitis and pancreatitis, etc.) tends to have higher serum IgG1, IgG4 and IgE levels than that of a 'fibrotic type' originating from extra-glandular sites (such as aortitis). Our study (Peng et al.)[38] revealed IgG4-RD with aortitis/periaortitis and periarteritis (PAO/PA) had a lower level of serum IgG4 than IgG4-RD without PAO/PA.

The serum IgG1, IgG3, IgG4 and T-IgE levels peaked at 60–69 years of age, which was in accord with IgG4-RD RI. It was reported that healthy populations aged between 18 and 39 had the highest levels of IgG2 and IgG4, and those aged between 10 and 17 had the highest level of IgE,[39] indicating that age-related changes of immunoglobulins in IgG4-RD patients may also derived from disease severity. In addition, the probability of total internal organ involvement as well as single internal organ involvement (biliary tract, retroperitoneum, lung, kidney and artery) peaked at 60–69 years of age, suggesting that extra attention and comprehensive evaluation were required in this population.

In our clinical practice, the treatment approaches (the proportion of patients treated with GC or GC combined with IM) were not significantly different across age groups. Kaplan–Meier survival analysis suggested that younger age at onset was associated with relapse. Moreover, the result of multivariate Cox analysis revealed that age was associated with relapse, which was in accordance with two studies that focused on predictors of recurrence in Mikulicz's disease or IgG4-RD.[22,23] Multivariate Cox analysis also identified that higher proportions of eosinophils were a risk predictor associated with relapse, which was in accord with other studies.[40–41]

As for paediatric patients of IgG4-RD, our cohort showed a male dominance, which was different from that of 64% girls in a systematic review.[42] The most commonly affected organ in that review was orbital disease, followed by IgG4-related pancreatitis, cholangitis and pulmonary disease. By comparison, our patients showed that Mikulicz's disease was the most common manifestation, followed by lymphadenopathy, autoimmune pancreatitis and IgG4-related sclerosing cholangitis. Consistent with a previous report, the proportion of the IgG4-RD paediatric patients with elevated IgG4 serum concentration was 70%.[42]

Why the disease phenotypes differ depending on age of diagnosis remains a matter of conjecture. IgG4-RD is a multifactorial disease, and the different characteristics of age groups might originate from immunosenescence, inflammaging and difference of hormone levels, such as oestrogen. Immunosenescence was involved in both innate and adaptive immune systems.[37] Chronic antigenic stimulants accumulated as people got older, which remodelled the immune system by there being fewer naïve cells and increased dysfunctional memory cells. It was reported that the number of T regulatory cells increased with age though function degenerated.[13] Besides, there was a progressive reduction of the TCR repertoire and decreased proliferation of T cells in vitro with age.[43–46] As for B cells, the number of B regulatory cell as well as their functions were decreased with age.[13] In the innate immune system, previous studies have demonstrated that myeloid skewing, impairment of neutrophil chemotaxis and effector function, defects in NK cells and monocyte dysregulation were associated with age.[13,47] Inflammaging was characterized by a variety of senescence-associated secretory phenotypes, such as proinflammatory cytokines, chemokines, growth factors and proteases, secreted by senescent cells.[48] Both the dysregulation of the immune system and cellular senescence contributed to the proinflammatory environment.

There were a few limitations in this study. First, though PSM was performed between young and elderly patients, it could only control known variables, which might cause residual confounding in some degree. Second, pathology tests were carried out in 58.9% of patients; the rest of the patients were diagnosed based on typical clinical presentations, imaging studies and serum IgG4 level. Third, a different sex ratio might affect superficial or internal organ involvement across age groups. As a result, we compared the proportions of affected organs separately in both male and female patients (Supplementary Figure S2 available at Rheumatology online) and the results were consistent with that in the whole population.

In conclusion, our study revealed the differences in demographic features, organ involvements, laboratory tests, treatment agents and outcomes across age groups. The proportions of superficial organ involvement (lacrimal gland and sinus) decreased with age while the percentages of internal organ involvement (pancreas, biliary tract, retroperitoneal, lung and prostate) increased with age. Younger age at onset (≤56) was an independent risk factor of relapse in IgG4-RD patients based on GC therapy. Therefore, evaluation and treatment strategies should be given according to the clinical characteristics of different age groups.