[IgG4-related disease: what do we know after 20 years].

IgG4-related disease is immunomediated fibroinflammatory condition, characterized by tumefective lesions in different organs with distinctive pathomorphological features and IgG4 hypersecretion in serum and tissues in the majority of patients. IgG4-RD has been established as a separate clinical in the early 2000s. In the review we focus on the evolution of views on ethiopathogenesis of the disease, therapeutic and diagnostic options and classification of the disease.

[Clinical and laboratory characteristics of IgG4-realated disease and its diagnostic algorithm].

AIM: to propose diagnostic algorithm of IgG4-related disease (IgG4-RD). MATERIALS AND METHODS: One center retrospective research. 52 pts with IgG4-RD were included. The diagnosis was proved histologically and immunohistochemically. 48 out of 52 pts received treatment. Treatment included one of the following schemes (along with low oral glucocorticoids): rituximab monotherapy, cyclophosphamide monotherapy or their combination. RESULTS: The mean age was 47.4±5.9 years, the mean age of the disease onset was 43.9±16.0 years. Median time before the diagnosis was 24 months. The most often sites of IgG4-RD were lacrimal (63.5%), salivary (46.2%) glands, lungs (48%), lymph nodes (34.6%) and retroperitoneum (17.3%). In clinical picture the leading complain was organ enlargement, but not its dysfunction. Pain was characteristic for retroperitoneum localization. In 56.8% of pts with IgG4-related syalo - and/or dacryoadenitis there was association with ear - nose - throat organs affection. In 4 pts (7.7%) IgG4-RD was combined with some malignant disease, including MALT-lymphoma of lacrimal glands. Irreversible organ damage as an IgG4-RD outcome had 15.4% of pts. The main laboratory markers of IgG4-RD were ESR elevation (38.5%), blood eosinophilia (9.6%), immunological disturbances (serum total IgG and IgG4 elevation, IgE elevation, antinuclear antibodies, rheumatoid factor detection, hypocomplementemia). Serum IgG4 level >1.35 g/l was elevated in 88% of pts and correlated with the number of affected organs (Spearman correlation coefficient 0.39, Student's test, р=0.0056). Monoclonal serum secretion and B-cell clonality in the tissue was detected in 4 (23.5%) out of 17 pts, but not all of them had both signs. CONCLUSION: Based on the analysis of clinical and laboratory characteristics of IgG4-RD a diagnostic algorithm was proposed that enhances the detection and examination of the patients with suspected IgG4-RD.

[The differential diagnosis of Erdheim-Chester disease and IgG4-related diseases].

The paper describes Russia's first diagnosed case of Erdheim--Chester disease (systemic histiocytosis) in a 65-year-old man who has been long treated for Ormond's disease (idiopathic retroperitoneal fibrosis). It also gives the data available in the literature on the pathogenetic components of these diseases and on the similarity of many clinical, laboratory, and morphological characteristics of these two immunoinflammatory diseases and covers the issues of their differential diagnosis. Invasive procedures with a careful morphological/immunomorphological examination of biopsy specimens obtained from affected tissues are shown to be necessary for accurate diagnosis.

[IgG4-related disease and clonal B-cell lymphoid proliferation: Description of two clinical cases and a review of literature].

IgG4-related disease (IgG4-RD) is a systemic immune-related disease that may involve the pancreas, liver, retroperitoneal space, biliary tract, salivary and lacrimal glands, eye socket, lung, and kidney. In term of pathomorphogenesis, it is a fibroinflammatory disease manifesting as a tumor-like lesion of organs, elevated serum IgG4 levels, and a morphofunctional substrate - the development of marked fibrosis and lymphoplasmacytic infiltration in the tissues with the high content of IgG4-positive plasma cells. The detection of a tumor-like nodule frequently leads to that the patients with IgG4-RD undergo major traumatic surgery for presumed cancer. At the same time, a number of investigations show the association of IgG4-RD with the development of cancer and lymphoproliferative diseases. The paper describes two clinical cases: Russia's first diagnosis of MALT lymphoma of the lacrimal gland, IgG4-positive and IgG4-RD with a rare onset with a destruction focus in the cervical vertebrae, multiple organ dysfunction, B-cell clonality in salivary gland tissue and PIgMκ secretion. It also reviews world literature on the development of lymphoproliferative diseases in the presence of IgG4-RD.

[IgG4-related salivary gland lesions]. / Svyazannye s IgG-4 porazheniya slyunnykh zhelez.

AIM: To provide the demographic, clinical, laboratory, radiological, morphological, and immunomorphological characteristics of IgG4-related sialoadenitis (IgG4-S), which allow the differential diagnosis with neuroendocrine, granulomatous, blood cancer lesions of the salivary gland (SG). SUBJECTS AND METHODS: In the period 2004 to 2014, IgG4-S was diagnosed in 32 (11%) out of 289 patients with significantly enlarged parotid and submandibular glands (PG and SMG). Only 4 (9%) patients had isolated IgG4-related disease (IgG4-D) whereas involvement of a few organs ran as an IgG4-SD systemic disease in 29 (91%) patients. RESULTS: There was a slight preponderance of women with a median onset age of 42 years. Enlargement of the SMG (52.7%), lesions of the nasal cavity and paranasal sinuses (37.2%), and enlargement of the lacrimal gland and orbital pseudotumors (31%) are the most common clinical manifestations at disease onset. A follow-up study indicated that along with involvements of SMG (97%), PG (72%), eye sockets (72%), nasal cavity and paranasal sinuses (56%), one third of the patients were found to have generalized lymphadenopathy, to frequently develop pulmonary, hepatic, pancreatic, renal injuries; and the disease ran within IgG4-SD. The laboratory manifestations were characterized by moderate eosinophilia and elevated blood IgE levels in one-third of the patients and by moderately higher erythrocyte sedimentation rate and hypergammaglobulinemia in 50%. The increased blood level of IgG (84%) and its subclass IgG4 (86.4%) is an indication for further verification of IgG4-D in patients with involvement of the major SG. Immunohistochemical examination, by measuring the concentration of IgG4-secreting plasma cells (PCs), and determination of B-cell clonality in biopsy specimens should be done to verify a diagnosis with IgG4-D. CONCLUSION: The determination of blood IgG4 (>2 g/l) in patients with considerably enlarged major SG may suggest the presence of IgG4-S. Minimally invasively incised PG and SMG biopsies with their subsequent morphological and immunomorphological examinations should be performed to make an accurate diagnosis. More than 40% of IgG4-secreting PCs detected in SG tissue is evidence to diagnose IgG4-D.

[Differential diagnosis of rheumatic diseases and blood cancers involving the nasal cavity and accessory sinuses].

AIM: To provide the clinical, laboratory, radiological, morphological, and immunomorphological signs that permit the differential diagnosis to be made in patients with involvement of the nasal cavity and accessory sinuses (NCAS). SUBJECTS AND METHODS: In the period 2009 to 2013, the Laboratory for Intensive Therapy for Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences, associated the disease onset with NCAS involvement in 39 (7.6%) of 512 examinees. NCAS involvement was present at disease onset in 100% of the patients with natural killer (NK) cell lymphoma (NK/T lymphoma), in 84.5% of those with Wegener granulomatosis (WG), in 29.5% of those with IgG4-related disease (IgG4-RD), and in 17.5% of those with sarcoidosis. Such an onset could be extremely rarely observed in histiocytosis. RESULTS: Despite the similar clinical manifestations, NCAS involvements in NK/T lymphoma of nasal type and WG at disease onset show clear differences in the laboratory and systemic manifestations of these diseases. The patients with lymphoma have no characteristic laboratory abnormalities at disease onset, except the 100% presence of Epstein-Barr virus (EBV) DNA in blood and, only as a tumor grows, fever appears and there are elevated C-reactive protein and lactate dehydrogenase levels and pronounced destructive changes in the facial bones with mandatory hard palate destruction; at the same time the signs of systemic involvement are virtually absent. The patients with WG at disease onset have fever, high erythrocyte sedimentation rate, elevated C-reactive level, significant anemia, leukocytosis and 90% are found to have anti-neutrophil cytoplasmic antibodies with the rapid development of systemic manifestations: involvements of the lung, kidney, and peripheral nervous system. Destructive changes in the facial bones are minimal and hard palate destructions are absent. The patients with IgG4-RD, sarcoidosis, and juvenile xanthogranuloma have similar clinical and laboratory manifestations in the absence of hemorrhagic nasal discharge, nasal septal perforation, and facial bone destruction, with the practically involvement of the salivary/lacrimal glands and orbital regions. A third of the patients are observed to have different allergic manifestations, moderate eosinophilia, and signs of autoimmune disorders (the presence of rheumatoid and antinuclear factors, hypergammaglobulinemia). Elevated serum IgG4 levels are characteristic of IgG4-RD. CONCLUSION: Blood anti-neutrophil cytoplasmic antibodies, EBV DNA, and IgG4 levels should be determined in all patients with NCAS involvement. Mini-invasive incision biopsies of the nasal mucosa, orbital regions, and major salivary glands should be done, by morphologically verifying the diagnosis of sarcoidosis, histiocytosis, and WG and by making an immunomorphological examination to diagnose NK/T lymphoma and IgG4-RD.

[Features of ontogenesis of uroliths].

The aim of the study was investigation of urolith growth process using the method of ontogenetic analysis. A total of 435 autochtonic uroliths obtained after surgery or spontaneous elimination from 422 patients with urolithiasis were studied with roentgenophasic analysis on diffractometer DRON-3, IR-spectroscopy, electron-probe. The concrements incorporate several zones with a nucleus as one of the zones. In some cases spherolith consisted of several splitted individuums with different orientation. Their nuclei contained phosphates and organic substance resultant from renal inflammation. In the other cases lithogenesis of the spherolith started from monocrystal microscopic nucleus which arrived from the kidney. The number of spherolith emergences can be interpreted as a rhythmic course of the disease. A prolonged macrorhythm characterizes stable disease. Formation of cut surfaces of the spherolith defines interruption of rhythmic zonality. A change in the composition of the crystal medium does not stop concrement growth, it provokes replacement of one mineral phase for the other. The ontogenetic analysis has detected that in the position of the concrement in the kidney mineral substance of its deep zones undergoes phasic transformations and morphological alterations. In changing medium conditions there are recovery of surfaces of solution with a change of a mineral phase, formation of new growth rhythms, aggregation and compression of the particles. This explains mixed composition of most of uroliths.