Differences in clinical characteristics of IgG4-related disease across age groups: a prospective study of 737 patients.

OBJECTIVE: The aim of this study was to compare the clinical characteristics of IgG4-related disease (IgG4-RD) among different age groups. METHODS: We conducted a prospective study of 737 patients who were newly diagnosed with IgG4-RD and compared detailed demographic features, organ involvements, laboratory tests, treatments and outcomes across age groups. The patients were divided into five groups according to their age at diagnosis: ≤39, 40-49, 50-59, 60-69 and ≥70 years. The clinical characteristics of paediatric patients were also described. RESULTS: Sex ratio, disease duration, allergy history and clinical symptoms were significantly different across age groups. Besides, the proportions of superficial organ involvement (lacrimal gland and sinus) decreased with age, while the proportions of internal organ involvement (pancreas, biliary tract, retroperitoneal tissue, lung and prostate) increased with age, which was more prominent in male patients. Mikulicz's disease was the most common manifestation (70%) in paediatric IgG4-RD patients. Multiple Cox analysis identified that age ≤56 years at diagnosis was an independent risk factor of relapse. CONCLUSION: We revealed the impact of age on clinical characteristics of IgG4-RD, which indicated that different management might be required among different age groups.

A Case Report of Mikulicz Syndrome.

Mikulicz Syndrome (MS) is a rare chronic condition characterized by the abnormal enlargement of glandular tissue in the head and neck. Patients usually present with enlarged lacrimal and parotid glands. While this can be a benign self-limiting condition, other complex systemic diseases, such as sarcoidosis, may represent other underlying etiologies. We present a case of MS in a patient with a history of Crohn's disease.

Complement System in the Pathogenesis of Benign Lymphoepithelial Lesions of the Lacrimal Gland.

OBJECTIVE: We aimed to examine the potential involvement of local complement system gene expression in the pathogenesis of benign lymphoepithelial lesions (BLEL) of the lacrimal gland. METHODS: We collected data from 9 consecutive pathologically confirmed patients with BLEL of the lacrimal gland and 9 cases with orbital cavernous hemangioma as a control group, and adopted whole genome microarray to screen complement system-related differential genes, followed by RT-PCR verification and in-depth enrichment analysis (Gene Ontology analysis) of the gene sets. RESULTS: The expression of 14 complement system-related genes in the pathologic tissue, including C2, C3, ITGB2, CR2, C1QB, CR1, ITGAX, CFP, C1QA, C4B|C4A, FANCA, C1QC, C3AR1 and CFHR4, were significantly upregulated while 7 other complement system-related genes, C5, CFI, CFHR1|CFH, CFH, CD55, CR1L and CFD were significantly downregulated in the lacrimal glands of BLEL patients. The microarray results were consistent with RT-PCR analysis results. Immunohistochemistry analysis of C3c and C1q complement component proteins in the resected tissue were positive in BLEL patients, while the control group had negative expression of these proteins. Gene ontology (GO) analysis revealed that activation of the genes of complement system-mediated signaling pathways were the most enriched differential gene group in BLEL patients. CONCLUSIONS: Local expression of complement components is prominently abnormal in BLEL, and may well play a role in its pathogenesis.

Clinical characteristics of immunoglobulin G4-related disease: a prospective study of 118 Chinese patients.

OBJECTIVE: To characterize the clinical features of IgG4-related disease (IgG4-RD) in China. METHODS: A prospective cohort study of IgG4-RD was carried out in Peking Union Medical College Hospital between 2011 and 2013. Patients with newly diagnosed IgG4-RD were enrolled. RESULTS: A total of 118 patients with IgG4-RD were enrolled, including 82 males and 36 females, aged 53.1 (s.d. 13.6) years. The most common symptom at onset was lacrimal gland swelling (38/32.2%). A range of organs were involved: 77 patients (65.3%) had lymphadenopathy, 76 (64.4%) had sialadenitis, 60 (50.8%) had dacryoadenitis, 45 (38.1%) had autoimmune pancreatitis, 32 (27.1%) had pulmonary involvement, 31 (26.3%) had periaortitis/retroperitoneal fibrosis, 29 (35.4% of male patients) had prostatitis and 29 (24.6%) had renal involvement. In addition, there were 21 (17.8%) cases of sclerosing cholangitis, 15 (12.7%) of sinusitis and 10 (8.5%) of inflammatory pseudotumour. Uncommon manifestations included mediastinal fibrosis, skin involvement, sclerosing thyroiditis, hypophysitis, orchitis and colitis. Multiple organ involvement was observed in 93 patients, whereas only 4.2% had only a single organ involved. A history of allergy was reported in 73 (61.9%) patients. The serum IgG4 level was elevated in 97.5% and was correlated with the number of organs involved. Most patients were treated with glucocorticoids alone or in combination with immunosuppressive drugs, and the majority usually improved within 3 months. CONCLUSION: IgG4-RD is a systemic inflammatory and sclerosing disease. Parotid and lacrimal involvement (formerly called Mikulicz's disease), lymphadenopathy and pancreatitis are the most common manifestations. Patients with IgG4-RD showed favourable responses to treatment with glucocorticoids and immunosuppressive agents.

[Comparative study of clinical features between unilateral and bilateral orbital IgG4-related disease]. / Estudio comparativo de los hallazgos clínicos en la enfermedad orbitaria asociada a IgG4 con afectación unilateral vs. bilateral.

OBJECTIVE: Descriptive and comparative study of patients with orbital IgG4-related disease. MATERIAL AND METHODS: A review and analysis of the cases diagnosed with inflammatory orbital lesion related to IgG4 by the Ophthalmic Pathology Service in the Dr. Luis Sánchez Bulnes Hospital. RESULTS: A total of 9 cases were found, in which 66% were women, and with a mean age of 48 years and time to diagnosis of 2 years. Unilateral involvement was observed in 56% of cases. All the females experienced pain, and there was an optimal response to corticosteroid treatment in 100% of patients who required medical treatment (one case showed spontaneous resolution). In bilateral cases (44%), only 25% were female, and none had pain as a presenting symptom. Furthermore, 25% of these patients required a combination with immunosuppressants to control inflammation. CONCLUSIONS: Clinical presentation of patients with unilateral orbital IgG4-related disease differs from those with bilateral involvement.

[IGg4 related autoimmune hepatitis].

A 50-year-old man was investigated for painless jaundice. The histologic pattern on the liver biopsy study met the criteria of autoimmune hepatitis. Further clinical and laboratory investigation revealed multi-organ involvement, including Mikulicz's disease of the salivary glands and pancreatic insufficiency. The diagnosis of IgG4-related disease was suggested by a finding of elevated blood levels of IgG4. IgG4-related disease is an inflammatory fibrosing condition characterized by T-cell infiltration of affected organs, presence of IgG4-positive plasma cells, and elevated levels of IgG4 in serum. In the present case, the liver histopathology was compatible with one of several well-defined types of liver involvement in IgG4-related disease. IgG4-related disease may mimic malignant tumors of the biliary tract, pancreas, or liver. Undiagnosed patients may progress to end-stage fibrosis or undergo unnecessary surgery. It is highly important that IgG4-related disease be recognized because it is a treatable condition that responds well to steroids.

A case of immunoglobulin 4-related disease with bilateral mass-forming lesions in the nasolacrimal ducts.

This case study describes a 58-year-old man with watery eyes, bilateral swelling of the ala nasi and submandibular glands, and a swollen right parotid gland. Computed tomography revealed mass-forming lesions in both nasolacrimal ducts, extending bilaterally to the lacrimal sac and inferior meatus in the nose. Pathologic investigation showed marked infiltrates of immunoglobulin 4 (IgG4)-positive plasma cells in the nasolacrimal duct lesion, which led us to diagnose IgG4-related disease. Oral prednisolone improved the symptoms of watery eyes and the bilateral swelling of the nasolacrimal duct and salivary gland enlargement. To the best of our knowledge, this is the first report of IgG4-related disease involving mass-forming lesions in the nasolacrimal ducts.

Lacrimal gland function in autoimmune pancreatitis.

OBJECTIVE: Autoimmune pancreatitis (AIP) may be a pancreatic lesion of IgG4-related systemic disease. Lacrimal gland swelling is a rare extrapancreatic lesion of AIP. The aim of the present study was to investigate lacrimal gland function in AIP patients, and to determine changes after steroid therapy. PATIENTS AND METHODS: Schirmer's test and sialochemistry were done prospectively in 11 AIP patients. These tests were also performed after steroid therapy in 7 patients. RESULTS: Dysfunction of tear secretion was found in at least one eye in 7 (64%) patients. The average lower level in both eyes was 4.3+/-1.5 mm in the 7 patients with lacrimal gland dysfunction, which was significantly lower than the 8.2+/-2.4 mm in patients with normal lacrimal gland function (p=0.005). There were no significant differences between the two groups in age at diagnosis of AIP, sex ratio, and the presence of swelling of the lacrimal glands and the salivary glands. Although there was no significant difference, mean serum IgG4 levels and mean salivary Na+ and beta2 microglobulin levels were lower in patients with normal lacrimal gland function. After steroid therapy, lacrimal gland function improved in 3 of 5 patients with impaired lacrimal gland function, though the degree of improvement was not marked compared to the improvement of salivary gland function. CONCLUSION: Lacrimal gland function was frequently impaired in AIP patients, even when no lacrimal gland swelling was observed clinically. Lacrimal gland function impairment appears to be similar to impairment of salivary gland function in AIP patients.

[A case of Mikulicz's syndrome associated with sarcoidosis].

A 29-year-old woman with symmetrical bilateral swelling of the parotid, submandibular, and lacrimal glands--also called Mikulicz's symptoms--showed skin rash and pedal erythema. Serum IgG4 was within the normal range but serum ACE and lysozome were elevated. Incisional biopsy of the parotid glands and histopathological examination indicated sarcoidosis. This was complicated by uveitis and a low-grade fever. No facial nerve palsy was observed. Based on these findings, the definitive diagnosis was Mikulicz's syndrome associated with sarcoidosis. An alternative diagnosis was incomplete Heerfordt syndrome. The administration of steroid hormones, caused parotid, submandibular, and lacrimal glands swelling to disappear.

Mikulicz syndrome associated with a malignant large cell gastric lymphoma: a case report and review of the literature.

There is much confusion in the literature regarding the differences between Mikulicz disease and Mikulicz syndrome. This may be because there seems to be a connection between the disease and disease processes associated with the syndrome. This article provides historical data discussing the emergence of Mikulicz disease, confusions regarding its definition, and finally offers an explanation to the interrelationships of these two entities. This case report hypothesizes that the non-Hodgkin's lymphoma (NHL), which in association with Sjögren's syndrome and Mikulicz disease in this patient comprised the Mikulicz syndrome, may have transformed into his malignant large-cell gastric lymphoma. It supports conclusions in the literature that Mikulicz disease, benign lymphoepithelial lesion, and Sjögren's syndrome may all be a part of the same disease process as graduated variants of one another, with malignant lymphoma being a recognized complication of these entities.

Pathological features of lymphoid proliferations of the salivary glands: lymphoepithelial sialadenitis versus low-grade B-cell lymphoma of the malt type.

Lymphoid proliferations of the salivary glands can be either reactive or neoplastic. Reactive lesions include the lymphoepithelial sialadenitis (LESA; also known as myoepithelial sialadenitis [MESA]) of Sjogren's syndrome. Lymphomas of the salivary glands are predominantly B-cell type and include extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type. The spectrum of histopathologic features of LESA/MESA includes 1) "fully benign lymphoid infiltrate," with or without an associated lymphoid follicular structure, without immunoglobulin (Ig) light chain restriction in B-cells, and without any features of aggressive behavior, and 2) "lymphoproliferative lesions," with or without areas of Ig light chain restriction in B-cells, with the usual presence of centrocyte-like cells. A more or less pronounced lymphoepithelial aggressiveness may be present without definite evidence of malignancy. B-cell clones are detected in over 50% of cases of LESA/MESA by molecular genetic methods, but this does not correlate with morphological or clinical evidence of overt lymphoma. On the other hand, "marginal zone B-cell lymphoma of the MALT type" of the salivary glands produces a dense lymphoid infiltrate diffusely involving the gland, with obliteration of acini. The centrocyte-like cells form broad "halos" around the epithelial cell nests and broad strands between lymphoepithelial lesions, often linking together several lymphoepithelial lesions. Further, lymphoma cells express monotypic surface Ig, and in the majority of the cases, the plasma cells are also monoclonal. In conclusion, the diagnosis of LESA/MESA versus marginal zone B-cell lymphoma of the MALT type still relies on the evaluation of morphological features. It seems that molecular genetic analysis has little or no practical role in the clinical diagnosis of salivary gland lymphoma in a setting of LESA/MESA and Sjögren's syndrome.

[A tuberculous etiology in Mikulicz's syndrome]. / Etiologia tuberculoasa în sindromul Mikulicz.

A patient 20 years old presents bilateral hypertrophy of the lacrimal glands with discreet exophthalmos and conjunctival injection at the upper supero-external fornix level. The ocular affection appeared 6 weeks before as a painless tumefaction initially at the right eye and after that at the left eye also, with palpebral fold reduction. From childhood the patient has a ganglionary tuberculosis confirmed by the biopsy of a lateral cervical ganglion. Under the rim of the orbit on palpate the lacrimal gland as a depressible, painless mass, which is continued in the orbit. A lacrimal gland biopsy, effected at the left eye, shows the presence of dispersed nodules with round cells in the whole fragment of lacrimal gland, and epithelioid and giant cells in the center. The inflammatory phenomenon yield slowly with tuberculostatics generally and hydrocortisone in local instillations.

Chemotherapy of progressive hairy-cell leukaemia.

5 patients with hairy-cell leukaemia were treated with chemotherapy. 3 of them received multiple courses of CHOP (cyclophosphamide-doxorubicin-vincristine-prednisolone); 1 patient received cyclophosphamide monotherapy for 6 months. The 5th patient developed a Mikulicz's syndrome after splenectomy and was initially treated with cyclophosphamide monotherapy, then received 1 course of CHOP, and finally 9 courses of intermediate-dose methotrexate. 1 complete remission (45 months+) and 3 partial remissions (75+, 68, 32+ months) were observed, while 1 patient had progressive disease. Our results indicate that chemotherapy may be a valuable alternative to alpha-interferon in the treatment of hairy-cell leukaemia progressing after splenectomy.

[Autoimmune diseases of the salivary glands]. / Autoimmunye zabolevaniia sliunnykh zhelez.

The structural and functional features of the salivary glands and their function associated with the immunocompetent system are described. The disturbance of such association, in the author's opinion, is conducive to the development of a peculiar tumour pathology (adenolymphomas) and autoimmune processes (Sjögren syndrome autoimmune parotitis). Based on the data from the literature two forms of this disease are distinguished: (1) a distinct nosological form developing as a result of various exo- and endogenous injuries, and (2) manifestations of other diseases, as a rule, of the autoimmune genesis accompanied by the secondary involvement of the salivary glands. The morphological picture in both forms is identical. It is suggested that in systemic involvement of the salivary, lacrimal and other glands and some autoimmune disease the term "Sjögren syndrome" be used, and the distinct disease be termed "autoimmune parotitis".

Mikulicz's disease and Mikulicz's syndrome.

The pathogenesis, clinical manifestations, and historical development of Mikulicz's disease and Mikulicz's syndrome are given. It is recommended that the term "Mikulicz's syndrome" be dropped to avoid confusion with the rare and well defined entity "Mikulicz's disease."