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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.

Purpose of the study. To provide demographic, clinical, laboratory, ultrasound, radiological, morphological/ immunomorphological phenotype of IgG4-related ophthalmic diseases, which allowsmaking a differential diagnosis with granulomatous, autoimmune, inflammatory, endocrine and hematologic diseases affecting the eye and orbits. Materials and methods. From 2004 to 2016 108 (78.2%) of the 138 patients were diagnosed with non-tumoral lesions of eye and orbits. In 48 patients (35%) at admission and 5 patients in the follow were diagnosed IgG4-related ophthalmic disease. In the analysis of 82 (f-44, m-38) patients with IgG4-related disease, localization of lesions in orbit observed in 53 (f-36, m-17) and it was the most frequent involvement in patients with IgG4-related disease (64.5%). Only 7 patients had isolated IgG4-related ophthalmic disease, whereas 46 patients (87%) had involvement of 2-7 locations, as a manifestation of IgG4-related systemic disease.During the examination, the average age of patients with IgG4-related ophthalmic disease was 47.5 years (19-73 years). Median time to diagnosis was 52.8 months before 2004 and 36 months 2004-2016. Results. We noted the predominance of females in the ratio 2: 1 inthe group of patients with IgG4-related ophthalmic disease. Edema of the eyelids, nasal congestion (55-60%), tumor-like formations of the upper eyelids and increased lacrimation prevailed at the onset of the disease, whereas such functional impairment like limited mobility and pain in eyeballs, exophthalmos, ptosis and diplopia appeared later at 15-38% with a loss visual acuity in one case. Bilateral lesion (86%), mainly affecting the lacrimal glands (93.5%), infiltration of the extraocular muscles (83.5%) and retrobulbar tissue with a thickening of the optic nerve in one third of patients were the main localizations IgG4-related ophthalmic disease. Clinical symptoms were accompanied by the appearance of moderate inflammatory activity (38%), increased levels IgG (44%), IgG4(88%) and IgE (61%). Indicators of autoimmune disorders observed in 6-22% of patients, most often in patients with simultaneous involvement of the salivary glands. Significant lymphoplasmacytic infiltration (94%) with a ratio of plasma cells (IgG4/IgG) secreting IgG4> 40% (90%) with fibrosis formation (94%) and follicle formation (71%) with a moderate amount of eosinophils (34%) were the major morphological / immunomorphological manifestations of IgG4-related ophthalmic disease. Signs of vasculitis and obliterative phlebitis were found in a small amount of patients. Conclusion. Determination of elevated levels of IgG-4 / IgE in patients with edema, pseudotumor of the eyelid, sinusitis and increase of the palpebral lobe of the lacrimal gland suggests the presence of IgG4-related ophthalmic disease. Minimally invasive incisional biopsy of lacrimal glands and salivary glands followed by morphological / immunomorphological research is needed for the correct diagnosis. Diagnostic orbitotomy in ophthalmic hospitals in such cases is inexpedient, since it leads to the development of dry eye. Massive lymphoplasmacytic infiltration with IgG4 / IgG ratio more than 40%, advanced fibrosis in biopsiesof the orbits tissue or salivary glands when combined lesions are required for the making the diagnosis of IgG4-related ophthalmic disease.

We describe the first case of diagnosis of generalized calcifying aponeurotic fibroma in 52 year-old man receiving long-term therapy for seronegative rheumatoid arthritis with rheumatoid nodules. The prevalence of lesions (presence of multiple subcutaneous nodules in the aponeuroses and fascia of the head, neck, trunk, upper and lower extremities with massive deposition of calcium salts), and a combination with monoclonal secretion (IgGκ serum, BJκ in the urine), raised inflammation markers, suggest that this case of the disease is unique, so both in domestic and foreign literature contains no description of this unusual course of this type of mesenchymal tumor. We have shown that subcutaneous nodules biopsy followed by morphological and immunohistochemical study is required in the diagnosis of the disease. We have given the literature data on the clinical manifestations, methods of diagnosis and differential diagnosis of this disease with a variety of pathologies, accompanied by the development of multiple calcification.

The authors have described the world’s first case of necrotizing sarcoid granulomatosis (NSG) in a 22-year-old woman with the clinical presentations of acute abdomen, which are associated with abdominal lymph nodal infiltration and necrosis, obvious constitutional disturbances (fever, nocturnal sweats, and significant weight loss), high inflammatory activity (anemia, leukocytosis, high erythrocyte sedimentation rates and C-reactive protein levels), the gradual appearance of splenic and hepatic necrotic foci, and infiltration into the lung and lacrimal glands with the development of unilateral uveitis. The patient underwent five surgical interventions, several needle biopsies for recurrent abdominal syndrome, and long-term antibiotic treatment for presumed sepsis, which had caused drug-induced hepatitis. Bacteriological examination of blood, puncture samples, and removed abdominal cavity tissues, serological tests, and immunomorphogical study of biopsy samples and removed tissues yielded negative results for the presence of bacterial, fungal, and tuberculosis infections. NSG was diagnosed on the basis of the systemic nature of the lesion, the presence of granulomas with severe abdominal lymph nodal necrosis and necrotizing granulomatous/lymphocytic vasculitis in the mesentery and removed spleen, as well as the absence of granulomas in the spleen, appendix, and biopsy materials of the liver, colonic mucosa, and parotid gland. Fludarabine therapy was first used in world practice due to the inefficient treatment with high-dose glucocorticoids and cyclophosphamide and to a disease relapse when reducing their doses. The paper gives a detailed review of the literature on the clinical, laboratory, radiological, and morphological manifestations of the disease, which allow the differential diagnosis of NSG with different variants of granulomatous lesions. Based on the 5-year follow-up of the patient and on the analysis of clinical, laboratory, radiological, and morphological changes, the authors uphold the concept that the disease is an independent nosological entity: necrotizing angiitis with sarcoid reactions, rather than the entity of nodular or classic sarcoidosis.

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.

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.

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)/MATERIAL 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.

Antisynthetase syndrome encompassing a symptom complex with severe interstitial lung disease is the severest subtype of polymyositis and dermatomyositis. The characteristic feature of antisynthetase syndrome is the insufficient efficiency of traditional therapy with glucocorticosteroids and cytostatics, which determines the prognosis of the disease and the need for new therapeutic approaches to treating these patients.

Aim. To analyze clinical and laboratory features of cryoglobulinemic vasculitis (CGEV) associated with HCV infection. Material and methods. We examined 61 patients with clinical manifestation of CGEV in 2006-2011. CGEV was associated with autoimmune diseases in 31 patients (51 %), with HCV infection in 21 patients (34,4 %), essential (idiopathic) cryoglobulinemia in 8 patients (13 %) and lymphoproliferative diseases in 1 patient (1,6 %). 21 patients with HCV-associated CGEV were studied for main clinical and laboratory manifestations of the disease. Kidney and liver involvement was confirmed morphologically and immunomorphologically. Electroneurophysiological investigation evaluated peripheral nervous system involvement. Biopsy of parotid, lacrimal glands, peripheral lymph nodes, splenectomy and bone marrow trephine biopsy with morphological study and immunohistochemistry were used to identify type of lymphoma. Characteristics of monoclonal secretion were assessed with high-resolution electrophoresis in agarose gel with subsequent immunofixation of sera and concentrated urine. Results. Liver involvement was detected in 66 % of patients with HCV-associated CGEV., 34% patients were chronic HCV carriers with persistently normal liver function tests. Common rheumatologic manifestations of HCV-associated CGEV were skin lesions (90%), arthralgia (85%), frequent peripheral nervous system involvement (52%) and glomerulonephritis (38%). Prevalent immunological markers of CGEV associated with HCV were mixed monoclonal cryoglobulinemia with rheumatoid factor activity (62%), rare polyclonal (34%) and olygoclonal (4%) cryoglobulinemia, low levels of С4 compliment fraction (80%). Patients with mixed monoclonal cryoglobulinemia often developed clinical manifestations of Sjögren s syndrome (23 %) and malignant lymphoproliferative diseases (14 %). CGEV is a prognostically adverse sign in HCV infected patients and caused death of 14% patients even in a short period of follow-up (1-2 years).

Objective: to consider clinical practice problems in the differential diagnosis of different types of plasma cell dyscrasias (PCD). Subjects and methods. Fourteen patients (8 men and 6 women) aged 52±12 years, in whom rheumatic diseases (RD) were ruled out and who were diagnosed as having primary PCD: different types of myeloma in 7 patients, myeloma + AL-amyloidosis in 2, AL-amyloidosis in 3, and Waldenstrom’s macroglobulinemia in 2, were examined. Results and discussion. The most common maldiagnosed RDs in patients with PCD were seronegative rheumatoid arthritis (RA), systemic lupus erythematosus, Sjogren’s disease, and different forms of vasculitis. The most frequent masks of RD were kidney (78%) and osteoarticular system (64%) lesions, vascular disorders (36%), peripheral polyneuropathies (36%), and enlarged salivary glands with xerostomia (28.5%). Serum and urine immunochemical study should be performed in all patients who have clinical manifestations of seropositive RA, spondyloarthritis, intensive bone pain syndrome, ulceronecrotic vasculitis, enlarged submandibular salivary glands with macroglossia in the absence of markers of autoimmune disease for the timely diagnosis of PCD and the exclusion of RD. The paper estimates the sensitivity and specificity of main methods used to diagnose different types of PCD.

The paper describes two patients (a 50-year woman and a 72-year man) in whom the clinical manifestations of ulceronecrotic vasculitis had long preceded before the diagnosis of multiple myeloma was made. In the former, monoclonal cryoglobulinemia type I induced ulcerative lesions with the development of dry toe gangrene and paraproteinemic renal lesion. In the latter, ulceronecrotic vasculitis with the development of dry toe gangrene was a manifestation of monoclonal paraproteinemia without signs of cryoglobulinemia. Both patients were found to have monoclonal blood secretion (РIgGλ и РIgGκ) and urine Bence Jones protein (BJλ+BJκ, BJκ) in the absence of immunological markers of vasculitis developing in patients with rheumatic diseases. Immunochemical study of serum/urine and, when monoclonal secretion of PIg+BJ is detected, further examination for plasma cell dyscrasia should be performed in all cases of vascular disorders (cold allergy, Raynaud's syndrome, purpura, ulcers of cruses, and gangrene of distal phalanxes of the hands/feet) in patients with atypical vasculitis. The timely immunochemical study of blood and urine will make it possible to diagnose plasma cell dyscrasia (different types of myelomic disease, Waldenstrцm macroglobulinemia, primary amyloidosis) at the early stage of the disease and to rule out unjustifiably diagnosed vasculitis in patients with atypical vascular lesions.

Plasma cell dyscrasias (PCD) present certain difficulties in differentially diagnosing with autoimmune rheumatic diseases (RD) as they have some clinical and laboratory manifestations that are characteristic of the latter. Objective: to generalize the experience in diagnosing PCD at the Research Institute of Rheumatology (RIR), Russian Academy of Medical Sciences (RAMS). Subjects and methods. Nineteen patients admitted to the RIR, RAMS, for rheumatological referral diagnoses were diagnosed as having different types of PCD, both PCD in the presence of RD (n = 10) and primary PCD without RD (n = 9). Immunochemical studies of serum and urinary proteins and bone marrow trepanobiopsy were performed in all the patients. Histological studies were made of the minor salivary glands (n = 12), lymph nodes (n = 3), parotid salivary glands - PSG (n = 5), spleen (n = 1), cranial bones (n = 2) and humerus (n = 1). The immunophenotype of tumor lymphocytes in the biopsy and trepanobiopsy specimens were determined by an immunoflurenscence method with standard monoclonal antibody panels and the paraffin sections of biopsy specimens were examined by an immunoperoxidase technique. Biopsy and trepanobiopsy speciments and myelograms were assessed by the researchers of the N.N. Blokhin Russian Cancer Research Center, RAMS. Results. Over 10 years of follow-up, 19 patients (13 females and 6 males) were diagnosed as having different types of PCD: multiple myeloma (MM) (n = 9), extramedullary plasmacytoma of lymph nodes (n = 2), solitary plasmacytoma (SP) of bone (n = 2), Bence-Jones myeloma (BJM) (n = 2), primary amyloidosis (PA) (n = '), lymphoplasmacytic lymphoma (n = '), Waldenström's macroglobulinemia (WM) (n = 2). In the presence of RA, '0 patients with PCD developed Sjogren's disease (SD) (n = 7), rheumatoid arthritis (RA) + SD (n = 2), RA (n = '); and 9 patients had primary PCD (MM (n = 5), BJM (n = '), WM (n = '), SP (n = '), and PA (n = ')). These 9 patients with different rheumatological diagnoses were long followed up and referred to the RIR, RAMS, to specify these. One third of the patients had recurrent conjunctivitis, enlarged PSG and xerostomia (55%). Arthralgias, arthritis of minor and large joints, flexion contractures of hands, ossalgias, and pains in the lumbar spine and ribs were present in '0-45% of the patients. Vascular lesions, such as Reynaud's phenomenon, recurrent purpuras, lower extremity ulcerative lesions, and toe gangrenes, were observed in '0-35% of the patients with PCD. Lesions in the reticuloendothelial system, such as lymphadenopathy, splenomegaly ('5%), hepatomegaly (45%), and fever (25%), were also detected. Conclusion. Many clinical and laboratory manifestations of primary PCD and RD are similar and only the absence of classical laboratory markers of autoimmune disease, as well as the presence of serum monoclonal immunoglobulins and urinary Bence Jones protein suggest the presence of PCD, both primary PCDs and those with RD.

Plasma cell dyscrasias (PCD) present certain difficulties in differentially diagnosing with autoimmune rheumatic diseases (RD) as they have some clinical and laboratory manifestations that are characteristic of the latter. Objective: to generalize the experience in diagnosing PCD at the Research Institute of Rheumatology (RIR), Russian Academy of Medical Sciences (RAMS). Subjects and methods. Nineteen patients admitted to the RIR, RAMS, for rheumatological referral diagnoses were diagnosed as having different types of PCD, both PCD in the presence of RD (n = 10) and primary PCD without RD (n = 9). Immunochemical studies of serum and urinary proteins and bone marrow trepanobiopsy were performed in all the patients. Histological studies were made of the minor salivary glands (n = 12), lymph nodes (n = 3), parotid salivary glands - PSG (n = 5), spleen (n = 1), cranial bones (n = 2) and humerus (n = 1). The immunophenotype of tumor lymphocytes in the biopsy and trepanobiopsy specimens were determined by an immunoflurenscence method with standard monoclonal antibody panels and the paraffin sections of biopsy specimens were examined by an immunoperoxidase technique. Biopsy and trepanobiopsy speciments and myelograms were assessed by the researchers of the N.N. Blokhin Russian Cancer Research Center, RAMS. Results. Over 10 years of follow-up, 19 patients (13 females and 6 males) were diagnosed as having different types of PCD: multiple myeloma (MM) (n = 9), extramedullary plasmacytoma of lymph nodes (n = 2), solitary plasmacytoma (SP) of bone (n = 2), Bence-Jones myeloma (BJM) (n = 2), primary amyloidosis (PA) (n = '), lymphoplasmacytic lymphoma (n = '), Waldenström's macroglobulinemia (WM) (n = 2). In the presence of RA, '0 patients with PCD developed Sjogren's disease (SD) (n = 7), rheumatoid arthritis (RA) + SD (n = 2), RA (n = '); and 9 patients had primary PCD (MM (n = 5), BJM (n = '), WM (n = '), SP (n = '), and PA (n = ')). These 9 patients with different rheumatological diagnoses were long followed up and referred to the RIR, RAMS, to specify these. One third of the patients had recurrent conjunctivitis, enlarged PSG and xerostomia (55%). Arthralgias, arthritis of minor and large joints, flexion contractures of hands, ossalgias, and pains in the lumbar spine and ribs were present in '0-45% of the patients. Vascular lesions, such as Reynaud's phenomenon, recurrent purpuras, lower extremity ulcerative lesions, and toe gangrenes, were observed in '0-35% of the patients with PCD. Lesions in the reticuloendothelial system, such as lymphadenopathy, splenomegaly ('5%), hepatomegaly (45%), and fever (25%), were also detected. Conclusion. Many clinical and laboratory manifestations of primary PCD and RD are similar and only the absence of classical laboratory markers of autoimmune disease, as well as the presence of serum monoclonal immunoglobulins and urinary Bence Jones protein suggest the presence of PCD, both primary PCDs and those with RD.

The paper describes a case of Mikulicz's disease (MD) in a young woman (aged 19 years) with symmetrical large salivary gland lesion concurrent with the enlarged lacrimal glands. Immunomorphological and molecular studies of parotid gland biopsy specimens revealed the formation of MALT tissue without signs of B-cell clonality of an infiltrate. The diagnosis of lacrimal sac lymphoma was ruled out. MD was diagnosed. The use of rituximab in therapy for MD has first demonstrated a positive result in Russian and worldwide practice.