A 40-year-old man presented with intermittent headache and diplopia. 6 years before admission, he had recurrent headache at top and frontal area. He had been diagnosed with tubercular meningitis in the local hospital and received HRZE regimen for 2 months followed by HRE regimen for 27 months. His headache was not alleviated and then he went to our hospital 3 years ago. Contrast-enhanced magnetic resonance imaging (MRI) demonstrated an enhancing mass overlying clivus with dural tail sign. The lesion was initially considered to be a meningioma based on its imaging appearance. The patient then received a gamma knife surgery. The headache mitigated a little but persisted to date. 7 months before returning to our institution, he developed diplopia, hoarseness, and dysphagia progressively. On examination, the patient had bitemporal hemianopsia and limited abduction of both eyes (Figure 1A, upper). He had no speech disturbance or motor dysfunction. Contrast-enhancing MRI showed a 3.8x2.9x2.9 cm mass overlying clivus with dural tail sign (Figure 1A, lower). The lesion oppresses brain stem, with bone erosion at the clivus and left talus cone region and part of the lesion protrudes into pharyngonasal cavity. Cerebrospinal fluid examination was generally normal and mycobacterium spp. and cryptococcus were not detected. He received a surgery with endoscope removing mass subtotally. The histopathological evaluation revealed fibro-connective tissue with mixed inflammation containing predominantly plasma cells. Immunostaining showed increased number of IgG4-positive plasma cells (>200/HPF) and elevated ratio of IgG4-positive cells to CD138-positive cells (approximately 55%, Figure 1C). No granuloma with caseous necrosis was noted. These findings were suggestive of an IgG4-RD and the patient was transferred to our department.
Immunoglobulin analysis revealed IgG 17.2 g/L (normal range 8.0-15.5 g/L), IgG4 subclass 1.9 g/L (normal range 0.035~1.5 g/L). Serum levels of IgA, IgM, C3, and C4 were normal. Antinuclear antibody revealed 1:100 titer, while anti-neutrophil cytoplasmic antibodies, anti-SS-A, anti-SS-B, anti-dsDNA, anti-Smith, anti-Scl-70 as well as other anti-ENA were all negative. HCV antibody, HBV surface antigen and HBV-DNA were negative. TST was positive (induration >=10mm) and TB-IGRA demonstrated significantly elevated IFN-gamma (414.21 pg/ml, normal range 0-14 pg/ml). Repeated sputum tests were negative. A computed tomography scan of her chest showed neither lung lesions suggestive of TB nor hilar or mediastinal lymph node swelling. Investigation of other systemic manifestation of IgG4-RD was negative. We diagnosed the patient with IgG4-RD complicated with LTBI. Treatment of corticosteroids combined with methotrexate (10mg/week) and cyclophosphamide (0.5g/m2/month for 3 months) was initiated and was well tolerated by the patient. Isoniazid was also started to prevent TB recurrence. In a follow-up of 3 months, he had attenuated bitemporal hemianopsia and better abduction of both eyes, and MRI showed the clivus mass shrank remarkably (Figure 1B). Serum IgG consecutively decreased to 8g/L and became stable, while IgG4 level decreased to between 0.4-0.6 g/L along 9 months follow-up (Figure 1D). In addition, the patient did not complain any TB related syndromes and the IFN-gamma level in the TB-IGRA test decreased gradually (Figure 1E).
The cause of IgG4-RD remains unclear, however, chronic infection such as TB was reported in IgG4-RD (summarized in Table 1). Notably, IgG4-RD occurs either after TB contact or diagnosis, or at the same time as TB confirmation. Among those patients, TB occurs in lung, urinary tract, lymph node and meninges.
China has always been one of the countries with the most serious TB epidemic all over the world. In 2017, about 60.08/100'000 cases of TB were reported in China. In addition, skin test positivity ranged from 15% to 42%, and IGRA positivity rate ranged from 13% to 20% in rural China. TB is closely related to patients with rheumatic diseases who are receiving immunosuppressive therapies, however, TB incidence in IgG4-RD patients remains unknown. We performed an additional retrospective study to explore the frequency of TB infection in IgG4-RD patients at our institute (Supplementary Figure S1). According to the 2011 comprehensive diagnostic criteria, we identified 83 subjects with a diagnosis of IgG4-RD who visited our hospital between February 2015 and September 2020. Among them, 47 were screened for TB infection. In 17/47 (36.2%) patient with IgG4-RD, a TB disease (positive signs of TB disease symptoms and chest computed tomography and positive TB tests) or LTBI diagnosis (negative signs of TB diseases and chest computed tomography (CT), M. tb was not isolated from a clinical specimen, but positive TB-IGRA and/or TST) was present (Supplementary Figure S1). Among the 17 subjects, 82.4% were male and the median age is 52.5 +- 14.3 years. Except two patients (No. 4 and 7), all other patients had high levels of IgG4 in the serum. Two patients (No. 2 and 15) had TB disease based on positive TB symptoms, chest CT, and TB blood test/TST, while others had LTBI. Organ involvement, laboratory examinations, and diagnosis in these patients are summarized in Table 2.