[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.

[IgG4-related disease: patient group characterization and rituximab therapy].

AIM: To characterize a group of patients with IgG4-related disease (IgG4-RD) in a Russian population and to evaluate the efficiency of rituximab therapy. SUBJECTS AND METHODS: In 2009 to 2011, at the Research Institute of Rheumatology, Russian Academy of Medical Sciences, 30 patients (16 men and 14 women; mean age 44 years) were diagnosed with IgG4-RD that was confirmed by determination of serum IgG4 levels and immunohistochemical study of biopsy samples stained for IgG4-positive plasma cells. Seven patients received rituximab therapy. RESULTS: It was assumed at baseline that there were different types of neoplasias in 12 (40%), non-Hodgkin's and Hodgkin's lymphomas in 10 (33.3%), Sjögren's syndrome in 5 (16.7%), and Wegener's granulomatosis in 3 (10%). When 2 or more locations were involved, the condition was regarded as multifocal fibrosclerosis (33.3%). Localized forms were revealed in 20 (66.7%) patients. Among them, the largest number of patients was those who had orbital pseudotumor, Mikulicz's disease, or retroperitoneal fibrosclerosis. The most common sites of involvement were orbits (66.7%), salivary glands (70%) and lymph nodes (36.7%). Comparison of serum IgG4 levels in 28 patients with IgG4-RD, 22 patients with Sjögren's disease, salivary and lacrimal gland lymphomas, and 10 healthy controls showed that the concentration of IgG4 was significantly higher in Group 1 (median 2.6 g/I; IQR 1.22-4.65 (p < 0.001). Tissue IgG4/IgG ratio varied from 25 to 50% and averaged 38%. A moiré-like pattern of varying fibrosis was noted in 83% of cases. Analysis of laboratory data revealed elevated C-reactive protein concentrations (46.7% with a mean of 39.5 mg/l; normal values < 5.0 mg/l), increased erythrocyte sedimentation rate (60% with a mean of 37.6 mm/h), hypergammaglobulinemia (30% with a mean of 29.4%; normal range 13-22%), and rheumatoid factor (23.3%). After rituximab therapy, all the patients showed a decrease of IgG4 levels to the normal levels and positive changes evidenced by visualization techniques (computed tomography, magnetic resonance imaging). CONCLUSION: IgG4-RD is a novel problem in modern medicine, which requires a multidisciplinary approach and further study. Rituximab therapy is a promising treatment.

[Differential diagnosis of Wegener's granulomatosis and extranodal NK/T-cell lymphoma, nasal type].

Men aged over 40 years more commonly develop NK/T-cell lymphomas (NK/T-CL). The paper describes a case of NK/T-CL in a 20-year-old man. Despite the fact that the disease (nasal septum perforation, hard palate bone destruction, recurrent nasopharyngeal bleeding, considerable weight loss, and high erythrocyte sedimentation rate,) progressed rapidly for 5 months, the patient was found to be diagnosed as having Wegener' granulomatosis (WG). Repeated incisional biopsies showed massive necrotic changes with no clear histological verification of the diagnosis. The absence of lung and kidney lesions typical of WG, the lack of antineutrophil antibodies, and the detection of Epstein-Barr virus DNA in blood could presume NK/T-CL and confirm it by extended biopsy to have materials sufficient for morphological and immunomorphological studies. This observation shows that the disease may occur at a young age and rapidly progress; only early diagnosis can improve prognosis in patients with this type of lymphomas.

[Rituximab therapy for systemic manifestations and MALT lymphomas of the parotid gland in Sjögren's disease: preliminary data].

AIM: To evaluate the efficacy of rituximab (RT) in cryoglobulinemic vasculitis (CGV) and MALT lymphomas of the parotid gland (PG) in patients with Sjögren's disease (SD). SUBJECTS AND METHODS: RT therapy was performed in 13 patients with SD and CGV and in 17 with SD and PC MALT lymphoma. Eleven patients with SD received RT monotherapy and 19 with this disease had combined therapy with RT and cyclophosphan (CP). RT was used intravenously dropwise at a dose of 500 mg weekly or once every two weeks in combination with intravenous dropwise CP 1000 mg the next day with 4-6 per course. For the diagnosis of MALT lymphomas, all the patients with SD underwent incisional PG biopsy under local anesthesia at the Research Institute of Rheumatology, Russian Academy of Medical Sciences. PG biopsy specimens were histologically and immunohistochemically studied at the Russian Cancer Research Center, Russian Academy of Medical Sciences. In 11 cases, B-cell clonality was identified from immunoglobulin (Ig) heavy chain genes rearrangements, by using polymerase chain reaction at the Hematology Research Center, Ministry of Health and Social Development of the Russian Federation. RESULTS: Cutaneous manifestations of vasculitis disappeared in 75% of cases after monotherapy with RT and in 100% of cases after combination therapy with RT and CP. At 6-month follow-up, a complete response to therapy remained in 25% of the patients after a course of monotherapy and in 83% after combined therapy. Serum monoclonal Ig cryoglobulins and their urinary light chains ceased to be detectable in 75% of the patients in both groups at 3 months. At 6 months, a recurrence of mixed monoclonal cryoglobulinemia was seen in 50 and 43% of cases after monotherapy and combined therapy, respectively. The clinical and laboratory response of cryoglobunemic glomerulonephritis to combined therapy with RT and CP was complete in 60% of cases at 6-month follow-up. After RT monotherapy, the patients with SD and PG MALT lymphoma achieved a complete clinical response in 88%, of whom histological and immunohistochemical reexaminations of PG biopsy specimens revealed no signs of MALT lymphoma in 71% of cases. B-cell clonality remained in the PG biopsy specimens following RT monotherapy. After the combination of RT and CP, a complete clinical response to therapy was observed in 100% of the patients, a complete histological response and a complete molecular one were seen in 83 and 60%, respectively. CONCLUSION: RT showed its efficacy in treating SD patients with CGV and PG MALT lymphomas.

[The first experience of using rituximab in Mikulicz disease].

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.

[The role of parotid gland biopsy in early detection of lymphoma in primary Sjogren's syndrome].

AIM: To investigate the incidence of MALT-lymphoma in Sjogren's disease by means of biopsy of the enlarged parotid glands. MATERIAL AND METHODS: The incisional parotid biopsy was performed in 57 primary Sjogren's syndrome (pSS) patients with existing parotid enlargement. The median age was 54 years (range 19-75 years). The median pSS duration was 7 years (range 1-30 years). The palpable parotid enlargement was defined as grade 1 and massive (visional) enlargement of the parotid glands was defined as grade 2. Histologic and immunohistochemical examinations for diagnosis of lymphoma were made. High resolution electrophoresis and immunofixation were performed for detection of monoclonal immunoglobulins in the serum and their free light chains in the urine. RESULTS: Biopsy of the enlarged parotid glands identified MALT-lymphoma in 37 of 57 (64.9%) pSS patients. Of 37 pSS patients with parotid enlargement of grade 2, diagnosis of MALT-lymphoma was made in 89.2%. Of 20 pSS patients who had parotid enlargement of grade 1, MALT-lymphoma was diagnosed in 20%. In patients with grade 1 enlarged parotid glands MALT-lymphoma was identified only in cases with the presence of monoclonal immunoglobulins in the serum and their free light chains in the urine (3 of 4 patients) or in case of disseminated disease (lymphoma involved regional lymph nodes and soft tissues of the face)--1 of 4 patients. In patients with grade 2 enlargement of parotid glands MALT-lymphoma located most frequently in affected parotid glands (69.6%). CONCLUSION: The incisional biopsy of enlarged parotid glands is necessary for detection of MALT lymphoma in pSS patients.

[First experience with the application of rituximab for the treatment of patients with Sjogren's syndrome and disease].

Efficiency and tolerability of rituximab therapy were assessed in 13 patients with Sjogren's syndrome and disease (10) (SLE-1, RA-2). Nine patients (SD-8, PA-1) presented with lymphomas and 4 with systemic manifestations of the disease. Complete and partial remission of lymphoma was achieved in 7 (78%) and 2 (22%) patients respectively. Beneficial effect of therapy on systemic manifestations of the disease was recorded in 3 (75%) of the 4 cases and only 1 patient had cryoglubulinemic glomerulonephritis resistant to rutiximab. Subjective improvement of glandular manifestations was reported by 12 (92%) patients. Objective improvement of salivation and lacrimation was documented in 7 (54%) and 6 (48%) patients who had residual secretion before therapy. Positive outcome of therapy in 12 patients was associated with complete depletion of CD20+ lymphocytes in peripheral blood. These cells were found in a patient who died despite the treatment. Rutiximab significantly decreased medians of ESR, IgG, IgA, IgM, gamma-globulin, and RF levels (p = 0.05-0.002). In 8 patients, therapy resulted in the disappearance of blood cryoglobulins. Intravenous premedication with 500 mg methylprednisolone prevented side effects of rutiximab. The study showed high efficiency and good tolerability of rituximab in combination with pulsed therapy with alkylating cytostatics and courses of polychemotherapy for the treatment of lymphoma and cryoglobuliemic vasculitis in patients with Sjorgen's syndrome and disease. Combination of rutiximab and pulsed therapy was more efficient than rutiximab monotherpy in patients with grade I-IIE MALT-type lymphomas. Rutiximab decreased systemic and glandular manifestations of Sjogren's disease and syndrome in 75 and 48-54% of the patients respectively.

[MALT-lymphomas in Sjogren's disease].

AIM: To develop algorithm of early diagnosis of extranodal lymphoma arising in patients with Sjorgen's disease (SD). MATERIAL AND METHODS: SD diagnosis was made in 457 patients treated in Rheumatology Institute clinic in 1999-2004, 38 (8.3%) females aged 19-82 had lymphoproliferative diseases. MALT-lymphomas were diagnosed in 15 (42.2%) patients. All the patients have undergone morphological, immunomorphological investigations of the salivary glands, postoperative material was analysed in some patients. In addition, the following investigations were made: ultrasonography of the salivary glands, lymph nodes, viscera; scintigraphy; trephine biopsy of the bone marrow; myelograms; CT of the chest, abdomena and brain; tests for monoclonal immunoglobulins in the serum and light chains in urine; biopsy of the parotid gland. Clinical, morphological and immunophenotypical characteristics of MALT-lymphomas were assessed by WHO classification. Lymphoma stages were classified according to Ann Arbor. RESULTS: Parotid glands were affected with MALT-lymphoma most frequently. Predominant were extranodal lymphomas of the parotid submandibular, minor salivary glands of the lip and lacrimal glands of stage I E-II E. Extranodal lymphoma with nodal lesion of stage IV occurred less frequently. Untreated long existing MALT-lymphomas of the parotid glands may transform into B-large cell lymphomas deteriorating SD prognosis. The presence of long-term (> 12 months) massive enlargement of parotid/submandibular salivary and lacrimal glands, massive infiltration, monoclonal immunoglobulins in blood serum and their light chains in the urine predict development of MALT-lymphoma in SD. CONCLUSION: In SD, MALT-lymphomas develop primarily in target organs--salivary and lacrimal glands. SD patients with persistent enlargement of the parotid glands need biopsy for early detection of malignant lymphoproliferation.

[Sicca syndrome in sarcoidosis and involvement of the salivary and lacrymal glands].

AIM: To present differential-diagnostic signs of sarcoidosis with affection of the salivary and lacrymal glands and Sjogren's disease. MATERIAL AND METHODS: The examination of 620 patients with affection of the salivary and lacrymal glands revealed sarcoidosis in 19 of them. The diagnosis was verified histologically. Clinical, serological and histological characteristics of sarcoidosis patients were compared to those of 200 patients with Sjogren's disease (SD) detected among the examinees. RESULTS: Sarcoidosis patients vs those with SD (p < 0.001) had massive enlargement of the salivary glands (84.3%) with severe xerostomy which appeared rather early (78.9%), affection of the lacrymal glands manifesting with enlargement of the palpebral region, edema of the upper eyelids (57.9%), pulmonary lesion (78.9%), cranial nerves (47.4%), skin (42%), enlargement of the intrathoracic lymph nodes (100%). CONCLUSION: In spite of the presence of mucosal dryness simulating SD, sarcoidosis of the lacrymal and salivary glands has some specific features allowing differentiation of sarcoidosis.

[Prognostic implications of mixed monoclonal cryoglobulinemia in Sjogren's disease]. / Prognosticheskoe znachenie smeshannoi monoclonal'noi krioglobulinemii pri bolezni Shegrena.

AIM: To specify the risk of severe systemic manifestations and transformation into malignant lymphoma in Sjogren's disease (SD) patients with monoclonal mixed cryoglobulinemia (MMC). MATERIAL AND METHODS: A prospective study performed in 1985-1990 included 248 SD patients followed up after the initial detection of monoclonal immunoglobulins (Ig) with serum active rheumatoid factor (RF). The patients' cryoglobulins (CG) were examined. The type of CG was determined by electrophoresis in agarose gel combined with immunofixation and immunoelectrophoresis with mono-specific antisera to heavy and light Ig chains. Biopsies of the lower lip salivary glands and skin were made in all the patients with MMC and 40 patients without CG. The biopsies were studied histologically, histochemically and immunomorphologically. Clinical symptoms and prognosis were studied in all the patients observed in 1985-2000 after the initial diagnosis of MMC. In suspected lymphoma development, histological and immunophenotypical studies of lymph node, bone marrow biopsies, trephine biopsies were made as well as myelograms, Ga-67 scintigraphy, CT of the thoracic and abdominal cavities. The total of clinical, morphological, immunophenotypical and cytogenetic characteristics of lymphoma was estimated by REAL classification. RESULTS: CG at first examination was detected in 50 (20.2%) of 248 patients with SD. 20 (40%) of 50 patients were diagnosed to have MMC with monoclonal IgMchi (19) and IgA (1) in the serum with RF activity. Ten (50%) patients with MMC developed lymphoma after 10.9 +/- 3.3 years, on the average. In the absence of CG lymphoma developed in 5.5% (p < 0.001). B-cell intoxication in patients with diffuse lymphadenopathy, foci of lymphoid infiltration in the lungs, ulcers of the crus and such indices as stab neutrophilic shift, monocytosis, hypoproteinemia with hypogammaglobulinemia, disappearance of the RF, CG, low CIC level, immunodeficiency of monoclonal Ig and appearance of the protein BJ in the urine are markers of developing large B-cell immunosecreting lymphomas. Highly aggressive diffuse LCL resulted in death of 70% SD patients with MMC; 30% died of immunocomplex cryoglobulinemic vasculitis. 10-15-year survival of SD patients after detection of MMC was 50%, free of CG - 97% (p < 0.001). CONCLUSION: MMC is a definite serological marker of developing lymphoma and ulcerative-necrotic vasculitis in SD. In detection of MMC in SD patients it is necessary to prescribe early pathogenetically validated treatment before development of life threatening manifestations.