Clinical features of immunoglobulin-G4-related spinal pachymeningitis

Bingxue Zhang¹Lenan Kang²Xiaohong Li^3*

• ¹Dalian Municipal Friendship Hospital, Dalian, China
• ²齐齐哈尔市第一医院, 齐齐哈尔, China
• ³大连医科大学附属友谊医院, 大连市, China

IgG4-related disease (IgG4-related disease, IgG4-RD) is a systemic chronic inflammatory, fibrotic disease related to the immune system that can affect various parts of the body [1] ,However, neurological involvement is rare, particularly in reports of the dura mater [2] .Currently, both domestically and internationally, research on IgG4-RSP is mostly limited to case reports. There is a lack of research on the clinical features of this disease. This study retrospectively analyzed the individual case reports of IgG4-RSP published in the PubMed, Web of Science and Embase databases from 2009 to the present. The study then summarized and analyzed the clinical features of IgG4-RSP. The specific content is reported below.Using the search terms "immunoglobulin G4," "hypertrophic spinal pachymeningitis," "IgG4-related disease," and "IgG4-related spinal pachymeningitis," case reports and single-center studies published in PubMed, Web of Science, and Embase databases were retrieved from domestic and international sources until September 2024. A total of 362 articles were retrieved: 162 from PubMed, 98 from Web of Science, and 102 from the Embase databases. Of these, 140 were duplicates. After reading the full texts, irrelevant medical records and incomplete literature were excluded. Finally, 50 articles were obtained, including 55 patients. All patients were diagnosed with IgG4-RSP by a specialist clinician, and they had relatively complete clinical records.The articles were read in detail, and the following information was extracted: patient gender, age of onset, initial symptoms, clinical manifestations, laboratory tests, sites of lesions, pathological results, treatment methods, prognosis, and situations of misdiagnosis (Table 1).The data were analyzed by SPSS 26.0 statistical software. The measurement data approximately conforming to the normal distribution and the skewed distribution were respectively represented by the mean ± standard deviation (x ± s) and the median (the first quartile, the third quartile) [M(Q1, Q3)], and a P value < 0.05 was considered statistically significant.1. General Information: Of the 55 patients, 29 were male and 26 were female, resulting in a male-to-female ratio of approximately 1.1:1. The mean age of onset was 48.29 years, ranging from 17 to 79 years. For 44 patients, the time from symptom onset to IgG4-RSP diagnosis upon admission was 7.93 (range 0.50-6.00) months. Enhanced images were observed in 43 patients, including 29 cases of diffuse linear enhancement, 14 cases of focal or nodular enhancement, and 8 cases exhibiting both diffuse linear and focal or nodular enhancements. All spinal cord segments could be involved; the highest incidence was in the thoracic spine (n = 41, 74.5%), followed by the cervical spine (n = 31, 56.4%), the lumbar spine (n = 10, 18.2%), and the sacral spine (n = 2, 3.6%). Combined involvement of the cervical and thoracic spines was relatively common (n = 22, 40%). Ten patients had dura mater involvement in the brain. IgG4-related disease (IgG4-RD) is an inflammatory fibrotic disorder that affects multiple organs.It is mainly characterized by elevated serum IgG4 levels and the enlargement of affected organs and tissues. The glands most frequently affected include the pancreas, submandibular gland, and lacrimal gland. Involvement of the nervous system is rare [3] .In the nervous system, the dura and pituitary gland are most frequently affected. Previous studies have statistically shown that the incidence of IgG4-related pachymeningitis is 1.9% [4] , and the incidence of hypophysitis is between 1.7% and 2.3% [5, 6] . However, IgG4-RSP is primarily reported as individual cases. This disease primarily affects middle-aged individuals, with a male-to-female ratio of approximately 1.1:1.The clinical manifestations are complex and diverse, posing significant challenges to diagnosis. This paper summarizes the clinical and pathological characteristics of patients with IgG4-RSP to enhance neurologists' awareness of this disease and enable early diagnosis and treatment.The clinical manifestations of IgG4-RSP are nonspecific and associated with the affected spinal cord regions. They mainly manifest as radicular pain and symptoms of spinal cord compression. Among the 53 cases described symptoms in this paper, 38 patients reported pain as the initial symptom. Of those patients, 47% experienced dorsalgia and approximately 21% experienced cervicalgia. The most prevalent symptoms were weakness and/or sensory abnormalities in the trunk or limbs (75.5%), trunk or limb pain (75.5%), and disorders of urination and defecation (28.3%).The symptoms of IgG4-RSP are attributed to compression of the spinal nerve roots and spinal cord by thickened and hyperplastic dura mater. Spinal cord imaging examinations are essential for diagnosis. Magnetic resonance imaging (MRI) of the spinal cord is the preferred examination method for IgG4-RSP because it can accurately display the location, range, and degree of spinal cord compression of the lesion, as well as its evolution during follow-up. The condition is manifested by uneven thickening of the affected dura mater, which presents as a low signal on T1WI and a low or isointense signal on T2WI. Cross-sectional images show that the thickened dura mater compresses the adjacent spinal cord, causing it to become thinner. An enhanced scan reveals dura mater enhancement [7] . The spinal cord involvement of IgG4-RSP patients summarized in this article most commonly occurs in the thoracic spine, followed by the cervical spine. This finding is consistent with previous studies [8] . If a patient exhibits symptoms of spinal cord compression and an MRI of the spinal cord shows the aforementioned manifestations, the possibility of IgG4-RSP should be considered. Additional examinations should be performed to assist in the diagnosis.There are no separate diagnostic criteria for IgG4-RSP.The diagnosis primarily depends on the diagnosis of IgG4-related disease and involvement of the spinal dura mater. The Comprehensive Diagnostic Criteria for IgG4-Related Diseases (2011) [9] , formulated in Japan in 2011, was the earliest comprehensive diagnostic criterion for IgG4-RD. It encompasses three aspects: clinical manifestations, serum IgG4 levels, and pathological features. The criteria were updated and discussed in 2020 [10] . Simple lymph node enlargement does not meet the requirements for clinical and imaging features. Typical tissue fibrosis, especially mat fibrosis, and obliterative phlebitis have been added to the pathological diagnosis. Serum IgG4 levels are elevated in up to 90% of patients with IgG4-RD, but this estimate varies substantially depending on the types of patients included in studies [11] . A 2016 Japanese survey revealed that 84.5% of patients with type 1 autoimmune pancreatitis (AIP) had high serum levels of IgG4 [12] . Alessia Buglioni's research demonstrated that serum IgG4 levels were increased in 81% of patients with IgG4-related kidney disease (IgG4-RKD) [13] . Xia Ronghui et al [14] recruited a cohort of 40 patients diagnosed with IgG4-related sialadenitis (IgG4-RS), all exhibited elevated serum IgG4 levels.While elevated serum IgG4 levels are important for diagnosing IgG4-RD, some patients with IgG4-RSP do not have elevated levels. The case results summarized in this article show that approximately two-thirds of patients have normal serum IgG4 levels, which is consistent with previous research results [15] . Therefore, elevated serum IgG4 levels are not a specific to the diagnosis of IgG4-RD.However, clinical studies have shown [4,6] , that serum IgG4 levels can reflect disease activity to some extent and are positively correlated with the number of affected organs and the degree of organ fibrosis. In 2019, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) jointly promulgated the first international classification standard for IgG4-RD [16] emphasizing the typical clinical manifestations of the affected organs and changes in laboratory and imaging studies. This standard assigns weighted scores to each assessment indicator. This addresses the issue of diagnosing IgG4-RD when the serum IgG4 level is normal and pathological results are lacking. It is also more applicable to patients with IgG4-RD involving multiple organs.A diagnosis of IgG4-RSP still depends on pathological alterations. The characteristic histological manifestations of IgG4-RD are as follows: 1) massive lymphoplasmacytic infiltration, 2) mat fibrosis, and 3) obliterative phlebitis [17] . For immunoglobulin-G4-related hypertrophic pachymeningitis (IgG4-RHP), immunohistochemical staining requires more than 10 IgG4+positive plasma cells per high-power field (HPF), and the IgG4+positive/IgG+positive plasma cell ratio must be greater than 40% [18] . The pathological diagnosis of IgG4-RSP mainly refers to that of IgG4-RHP.IgG4-RD is an immune-mediated chronic inflammatory disease. Currently, drug treatment is based on glucocorticoids, supplemented by immunosuppressants and even biological agents [19] .When IgG4-RSP causes progressive neurological symptoms due to spinal cord compression, surgical decompression is effective. IgG4-RD patients respond well to glucocorticoids [20] , but there are no clear standards for the dosage, tapering schedule, or duration of maintenance treatment.Clinical experience is the main guide. While nearly all IgG4-RD patients respond to glucocorticoids, approximately 40% do not achieve complete remission and relapse within one year [21] . When used in combination with glucocorticoids, immunosuppressants such as methotrexate, cyclophosphamide, azathioprine, tacrolimus, and mycophenolate mofetil can improve outcomes, reduce recurrence, accelerate the taper process, and reduce glucocorticoid side effects [22][23][24][25] . They can accelerate the taper process and reduce glucocorticoid side effects. If the aforementioned treatments are ineffective, biological agents can be considered. Rituximab (RTX) is the earliest and most widely used biological agent for treating IgG4-RD. It can significantly reduce IgG4 levels [26] . RTX has a significant therapeutic effect on IgG4-RD remission [27] , and regular use can reduce IgG4-RD recurrence [28] . Of the 55 patients discussed in this article, 48 took glucocorticoids, 14 took immunosuppressants, and 12 took rituximab. While most patients showed short-term improvement, there was no long-term improvement or recurrence during follow-up.Because the data set is based on case reports and small-scale studies, there may be inconsistencies in the descriptions of clinical symptoms, laboratory and imaging examinations, and treatment plans.IgG4-related sarcoidosis (IgG4-RSP) is relatively uncommon in clinical settings. Its clinical symptoms and imaging results are not specific and depend on the affected area. Symptoms include local pain and spinal cord compression, which can result in progressive neurological impairment and paralysis. In patients with normal serum IgG4 levels and no other systemic involvement, the possibility of IgG4-RSP should be considered, and a dural biopsy should be performed promptly. Once the diagnosis is confirmed, early treatment is necessary; the prognosis for most treated patients is relatively good. The gold standard for diagnosing the disease is a spinal cord biopsy, but obtaining the sample is difficult and highly invasive. Some scholars have proposed using the quantitative concentration of IgG4 and the IgG4 index in the cerebrospinal fluid as an alternative to biopsy. However, there are few case reports on IgG4 concentrations in cerebrospinal fluid, so its clinical application is limited. This could be a focus of future research.