IgG4-RD patients with or without ophthalmic involvement showed different baseline demographic features. Patients with ocular involvement were younger than patients with extra-ophthalmic IgG4-RD in this cohort. IgG4-RD primarily developed in a middle-aged population. Although pediatric cases are rare, IgG4-RD is now increasingly recognized to occur in children. Dozens of pediatric cases have been described[11]. Compared with adult patients, orbital manifestations are more frequently observed in children[12]. In this study, we included 10 pediatric cases, the youngest was 6 years old. However, we found no differences in organ involvement between children and adults. Larger pediatric cohorts are needed to confirm whether there are potential unique characteristics in certain age group.
Previous study has also revealed different clinical characteristics between female and male IgG4-RD patients[7]. IgG4-RD typically affects patients with a male to female ratio ranging from 1.6:1 to 4:1[13, 14]. The sex ratio changes with patterns of organ involvement[15]. IgG4-related head and neck lesions seems to exhibit a more even sex distribution, while involvement of internal organs such as pancreas may be more frequent in male[16].Here our data demonstrated that the male predominance tended to be more significant in patients with extra-ophthalmic IgG4-RD. But patients with IgG4-ROD exhibited a male-to-female ratio of 1:1, which was consistent with reports of other case series[17, 18].
In this cohort, the median time from onset to diagnosis was much longer in patients with IgG4-ROD (24 months). A longer delay in diagnosis was also reported in patients with major salivary gland involvement[19]. Patients with predominantly orbital involvement were more frequently misdiagnosed by ophthalmologists due to the lack of awareness of this rare disease. Furthermore, our multivariate analysis suggested that involvement of orbital tissue was negatively associated with autoimmune pancreatitis, sclerosing cholangitis, retroperitoneal fibrosis and other internal organ diseases, which might come with obvious symptoms that may remind patients to see a doctor. On the other hand, orbital manifestations are usually mild and not urgent, which may lead to a delay in seeking medical advice.
Organ involvement varies among different published case series. In studies of Thailand and India, orbits are commonly affected organs (34-58.6%)[6, 20]. While the leading affected organs reported in other populations include the pancreas in Singapore[21], Japan[22] and Italy[23],lymph nodes in Mexico[24] and France[5], and submandibular gland in China[19]and United States[14]. In this study, salivary gland was the most commonly affected organ (64.6%), followed by orbital tissues (54.8%). The submandibular, parotid and sublingual gland are often affected, with a frequency of 20–30% in Europe and 60–80% in Asia[8]. High frequency of lacrimal gland involvement is often associated with the involvement of salivary gland in the context of Mikulicz’s disease[15],[24].
With regard to ocular lesions, lacrimal gland was the most frequently involved anatomic location of IgG4-ROD. Most studies reported that the frequency of lacrimal gland involvement varies form 66%-83%[2, 5], which concurred with our results. Nevertheless, lesions in areas other than lacrimal gland were not uncommon. Extraocular muscles and trigeminal nerve branch enlargements were affected in 19–55% of patients with IgG4-ROD in previous studies[3, 5, 17] and 27.7% in this study. Some authors suggested that lesions in these areas might represent a progressive condition of IgG4-ROD and be refractory to systemic corticosteroid treatment[3]. Our data showed that involvement of areas other than lacrimal gland was associated with a high frequency of multiple types of lesions. This might indicate higher immune activity and a worse ocular condition. Besides, lacrimal gland involvement seemed to be negatively related to other types of lesions. This suggested that instead of secondary infiltrations from affected lacrimal gland, lesions in these areas might be de novo lesions.
Serum IgG4 elevation was found in 93.8% IgG4-RD patients in this study. Published data also showed serum IgG4 elevation occurred in 55–97% of cases, especially in Asian patients[6],[17, 18]. The median IgG4 level in our patients with IgG4-ROD was 12.3g/L, much higher than that of patients with extra-ophthalmic IgG4-RD of our cohort and patients with IgG4-ROD in literature[17, 18]. Although widely used as diagnosis criteria, elevation of serum IgG4 has poor diagnostic specificity. It can occur in a broad spectrum of systemic conditions, including infectious, neoplastic and autoimmune diseases[16]. Increased ratio of serum IgG4/IgG (> 10%) can increase diagnostic specificity[22], especially when IgG4 concentrations are only slightly raised. It is still controversial that whether serum IgG4 levels correlate with extra-ophthalmic involvement or higher relapse risk [17, 18]. However, our data suggested that higher IgG4/IgG ratio would be a better parameter indicating orbital involvement.
Other serological findings in patients with IgG4-RD are largely non-specific. Although patients with IgG4-ROD were found to have lower C3, C4, ESR, CRP and IgA levels than patients with extra-ophthalmic IgG4-RD, multivariate analysis detected no statistical significance. Hypocomplementemia at baseline may suggest kidney involvement[14]. An association between very low levels of C3 (< 50 mg/dl) and kidney involvement in IgG4-RD has been reported[15]. However, in our study, although C3 was lower in IgG4-RD patients with kidney involvement and IgG4-ROD, we did not detect any association between ophthalmic disease and kidney disease.
Histopathologic findings of IgG4-RD include three characteristic features: dense lymphocytic infiltration, storiform fibrosis and obliterative phlebitis[16]. In this study, dense lymphocytic infiltration was a general pathologic finding; while storiform fibrosis and obliterative phlebitis were described in only one skin specimen. Storiform fibrosis is a unique pattern associated with IgG4-RD[1]. However, it sometimes escapes from detection because the histological appearance is not always similar for all organs. Storiform fibrosis is absent within lacrimal gland, and the frequency of obliterative phlebitis is low in salivary gland and lacrimal gland[1, 16]. This can explain the low report rate of obliterative phlebitis and storiform fibrosis in our samples.
High number of IgG4 + plasma cells on immunohistochemistry is a disease hallmark[1]. Similar to histopathologic findings, the absolute number of IgG4 + plasma cells/HPF should be interpreted according to specific organs. For example, the cutoff value for salivary gland and lacrimal gland is recommended to be at least 100 cells/HPF; while that in the pancreas can be more than 50 cells/HPF and in lung > 20 cells/HPF[1, 16]. The ratio of IgG4+/IgG + plasma cells must be at least 40% to support a histopathologic diagnosis of IgG4-RD. And higher numbers of IgG4 + plasma cells (typically 70% or higher) suggest a greater likelihood of IgG4-RD[1]. Thirty-two orbital specimens met the prevalent immunohistochemistry criteria in this study. However, only seven cases fulfilled the more restricted criteria (> 100/HPF). Higher cutoff value decreased diagnostic sensitivity dramatically in this study. Nevertheless, positive immunohistochemistry alone does not necessarily indicate IgG4-RD and should be correlated with other histologic and clinical features. Non-specific presence of IgG4 + cells in other inflammatory and neoplastic disorders was not uncommon[25, 26]. Finally, a IgG4/IgG ratio < 40% does not rule out the diagnosis of IgG4-RD, for the majority of samples from other organs in this study, including pancreas, lung, liver and paranasal sinus, IgG4/IgG ratios were less than 40%.
This study has limitations. Although it is based on a prospective cohort, the analysis itself is retrospective in nature. Some laboratory and histopathologic information was not available. And 44.9% of patients with IgG4-ROD needed additional orbital imaging studies to identify exact anatomic locations in detail. Finally, not all patients underwent thorough examinations of the whole body, some affected organs might remain undetected at initial evaluation.
In conclusion, we have described demographic, clinical, laboratory and histopathologic differences between patients with IgG4-ROD and extra-ophthalmic IgG4-RD based on a large cohort. Patients with IgG4-ROD were more even in gender and consisted of younger people with longer time from onset to diagnosis. Allergic history and multi-organ involvement were more common in the IgG4-ROD group. IgG4-ROD was positively associated with higher serum IgG4/IgG ratio and more frequent salivary gland involvement, but less internal organ involvement was observed. Lacrimal gland involvement was the most common manifestation of IgG4-ROD. But other anatomic areas were also frequently affected. These features might indicate potential differences in pathogenesis of these two subgroups.