[The relationship between Sjogren's syndrome, systemic sclerosis and lymphoproliferative diseases].

Despite the large number of studies devoted to the study of systemic sclerosis (SSc), the high risk of developing lymphomas in this disease, the relationship of their development with certain subtypes of SSc and specific SSc-associated autoantibodies is still debated in the literature. AIM: To study demographic, clinical, laboratory and immunological characteristics of patients with a combination of primary Sjogrens syndrome (pSS) and SSc and diagnosed lymphoproliferative diseases (LPDs); to characterize morphological/immunomorphological variants and course of non-Hodgkins lymphomas (NHL), developing in patients with these rheumatic diseases (RDs). MATERIALS AND METHODS: In 19982018 at the Nasonova Research Institute of Rheumatology, 13 patients with clinical and laboratory manifestations of pSS (12) and SSc (13) were diagnosed with various lymphoproliferative diseases (LPDs). In 3 cases, an induced RD was observed: 1 case of a diffuse, rapidly progressive form of SSc, 2 cases of pSS in combination with a limited form of SSc after chemotherapy and radiation therapy of Hodgkins lymphoma (1), B-cell NHL (1) and CR of the breast (1) respectively. The first 2 cases were excluded from the analysis, since the development of lymphomas is not pathogenetically associated with RD. RESULTS: Of 11 patients with LPDs, 10 after a long course of RDs were diagnosed with NHL [MALT lymphoma of the parotid salivary glands 7, disseminated MALT lymphoma 2, disseminated MALT lymphoma with transformation into diffuse large B-cell lymphoma (DLBCL) 1]. RDs debuted with Raynauds phenomenon (RP) in 64.5% and pSS manifestations in 45.5% of patients. Stomatological manifestations of pSS were characterized by recurrent parotitis in 36%, significant parotid gland enlargement with massive infiltration of labial salivary glands (focus score 4) in 100%, severe xerostomia in 70%, extraglandular manifestations and lymphadenopathy in 50% of patients. The course of the SSc was characterized by mild RP with various types of capillaroscopic changes and mild lung changes and non-significant progression during long-term follow-up (median 22 years). The entire spectrum of SSс specific antibodies (anticentromere antibodies 60%, antibodies to ribonucleoprotease III 30%, Pm/Scl 10%), excepting antibodies to topoisomerase I, as well as pSS specific autoantibodies (antiRo/La 70%, RF (rheumatoid factor) 90%), were detected in patients with a combination of these RDs. CONCLUSION: pSS is often combined with a limited form of SSc regardless of the type of autoantibodies detected. The presence of pSS, rather than SSc, is a high-risk factor for the development of NHL in this group of patients. The patients with pSS and SSc are characterized by a steady progression of pSS with a slow and mild course of SSc throughout the observation period. The development of severe stomatological manifestations and high immunological activity of pSS contribute to the development of localized MALT lymphomas (70%) and disseminated MALT lymphomas (30%) with primary lesions of the salivary glands and transformation into DLBCL in case of their late diagnosis. The optimal method for preventing the development of NHL in this group of patients is the early diagnosis of pSS, the appointment of alkylating cytotoxic agents and/or anti-B-cell therapy in the early stages of pSS. Given the possibility of transformation of localized NHL into DLBCL, for early diagnosis, minimally invasive surgical biopsies of significantly enlarged parotid salivary glands should be performed before glucocorticoids are prescribed. Detection of positive B-cell clonality and lymphoepithelial lesions in the parotid salivary gland is considered a predictor of MALT lymphoma development during follow-up. Localized and disseminated MALT lymphomas in patients with pSS and SSc respond well to therapy, in contrast to MALT lymphomas transformed into DLBCL.

[A case report of bilateral trigeminal sensory neuropathy as one of the initial manifestation of systemic scleroderma (the difficulties of early diagnosis of the primary disease)]. / Dvustoronnyaya trigeminal'naya sensornaya neiropatiya kak odno iz nachal'nykh proyavlenii sistemnoi sklerodermii (trudnosti rannego ustanovleniya diagnoza osnovnogo zabolevaniya).

The article describes the case of a patient with bilateral trigeminal sensory neuropathy (TSN), as a possible neurological manifestation of systemic scleroderma (SS). In this patient, intense non-paroxysmal facial pain caused by TSN, subjectively dominated over other manifestations of SS, including Raynaud's syndrome, for at least 1.5 years, thus hampering the diagnosis of the primary disease. In addition to pain, which was not relieved by analgesic medication, TSN was manifested by marked sensory deficit on the face (hypoesthesia / anesthesia) and bilateral sensory deficits in the oral cavity, including the anterior third of the tongue. TSN was also combined with disorders of taste perception. The assumption of rheumatic origin of TSN occurred during a primary neurological examination: a standard examination revealed generalized sensory polyneuropathy with bilateral involvement of the trigeminal nerve; the additional study identified no neurological signs of rheumatic diseases, including Raynaud's phenomenon. SS met all the criteria for the diagnosis (2013), high titers of nuclear ribonucleoprotein were determined as well. Thus, TSN as early and subjectively dominant manifestation of SS can complicate the diagnosis of primary rheumatic diseases. Therefore, in cases of distal sensory polyneuropathy with bilateral involvement of the trigeminal nerve, it is necessary to conduct an additional survey to identify the signs of possible rheumatic diseases: signs of vascular lesion (Raynaud's syndrome), lesions of skin, joints and muscles.

[The new possibilities in serologic diagnostic of Ixodes mite-borne borreliosis using ImmunoChip].

The new kit of reagents in format of the immunochip "ImmunoChip Borreliosis" for multiplex serologic analysis of mite-borne borreliosis demonstrated high diagnostic sensitivity and specificity. The percentage of detection of specific immunoglobulins was higher in "ImmunoChip Borreliosis" as compared with screening results in immune enzyme analysis. The high correlation between results of testing in immunochip and data of immune blotting is demonstrated to.

[Pleiotropic effects of statins in systemic sclerosis].

AIM: To study anti-inflammatory and angioprotective properties of statins in patients with systemic sclerosis (SS). MATERIAL AND METHODS: Fifty SS patients enrolled in the trial were divided into two groups: the study group included 30 patients who received standard therapy and atorvastatin in a dose 10-40 mg/day, the control group (n = 20) received standard therapy alone. The blood of the patients was studied with enzyme immunoassay for concentrations of highly sensitive C-reactive protein (hs-CRP), IL-6, VCAM-1, E-selectin, WF antigen, VEGF-A, VEGF-R2. The tests were made before the treatment and after 12 months of the treatment. RESULTS: The levels of hs-CRP, IL-6, VCAM-1, E-selectin, WF antigen, VEGF-A and VEGF-R2 were significantly higher in the study group than in healthy donors. The controls also had elevated levels of the above substances except IL-6 and VEGF-A which elevated but not significantly. A 12-month treatment in the study group resulted in a significant lowering of hs-CRP, IL-6, WF antigen, E-selectin, VEGF-A and VEGF-R2, the number of patients with elevated IL-6, WF antigen, VEGF-R2 also reduced while in the controls the parameters did not change. CONCLUSION: Atorvastatin has anti-inflammatory and angioprotective effects in SS patients.

[Significance of bone marrow endothelial progenitor cells in disturbance of angiogenesis and endothelial dysfunction in systemic scleroderma].

The study is aimed to investigate the process of endothelial repair related to endothelial progenitor cells (EPC) in systemic sclerosis (SS), and analyze the role of EPC abnormalities in endothelial dysfunction and impaired angiogenesis. Correlation between EPC circulating levels, measured by flowcytometry, and peripheral vascular manifestations, cardiac involvement, carotid artery disease, Framingham risk factor score, endothelial function and morphological signs of microangiopathy is explored. Our data demonstrate, that EPC reduction with disease progression is closely linked with endothelial dysfunction and destructive microangiopathy, and significantly contribute into development of severe cardiac disease and pulmonary hypertension in SS patients.

[Designing and clinical testing of immune-enzyme and immunofluorescence test systems for serodiagnosis of ixodes borreliosis]. / Razrabotka i klinicheskaia aprobatsiia immunofermentnykh i immunoliuminestsentnykh test-sistem dlia serodiagnostiki iksodovykh kleshchevykh borreliozov.

The methods of immune enzyme assay (MIEA) and of lanthanide immunofluorescence analysis (LIFA) were used to work out the test systems for the detection (in blood serum of patients) of specific IgM IgG antibodies to the B. burgdorferi spirochete--a causative agent of ixodic borrelioses. The test system was clinically tested versus the indirect immunofluorescence reaction (IIFR) and commercial immune enzyme test system (CIET). The results of antibodies' detection were shown to correlate with the analysis data for the same sera in IIFR and to be in line with a real presence or absence of the disease. Test systems based on LIFA were proven to be most sensitive and specific.

[Preparations for serodiagnosis of diseases due to causative agents of ixode tick-borne Borreliosis (Lyme disease). Communication 2. Comparative study of recombinant enzyme immunoassay test-systems (rELISA) for serological diagnosis of ixode tick-borne Borreliosis]. / Preparaty dlia serodiagnostiki zabolevanii, vyzyvaemykh vozbuditeliami iksodovykh kleshchevykh borreliozov (bolezn' Laima). Soobshchenie 2. Sravnitel'naia otsenka rekombinantnykh immunofermentnykh test-sistem (rELISA), ispol'zuemykh v serodiagnostike iksodovykh kleshchevykh borreliozov.

One foreign and two Russian recombinant enzyme immunoassay test-systems were comparatively investigated under conditions of an encoded experiment. Sensitivity in the experiment with the Russian test-systems Borreliosis-ELISA-IgG and Lyme Best was 63.8 and 68.8% respectively. As for the test-system Borrelia IgG Recombinant, it was 47.5%. All the test-systems were highly specific (94.4 to 99.5%). The test-systems Lyme Best and Borrelia IgG Recombinant revealed partial cross reactions with sera from patients with systemic lupus erythematosus and leptospirosis.

[Preparations for serodiagnosis of diseases due to causative agents of ixode tick-borne borreliosis (Lyme disease). Communication 1. Comparative study of the 1st generation enzyme immunoassay test-systems for detection of antibodies to Borrelia burkdorferi sensu lato]. / Preparaty dlia serodiagnostiki zabolevanii, vyzyvaemykh vozbuditeliami iksodovykh kleshchevykh borreliozov (bolezn' Laima). Soobshchenie!. cravnitel'noe izuchenie immunofermantnikh test sistem 1 pokoleniia, napravlennikh na vyiavlenie antitel k Borrelia burgdorferi sensu lato.

Four foreign and one Russian 1st generation test-systems for detecting class G antibodies or summary antibodies to Borrelia burkdorferi sensu lato were comparitively investigated with the use of the clinical material under conditions of an encoded experiment. Cross reactions with sera from patients with syphilis, Epstein-Barr infection, cytomegalovirus infection and systemic lupus erythematosus were observed. The best specificity and sensitivity parameters were provided by the Enzygnost Borreliosis test-system.

[Articular lesions in Ixodes tick-borne borreliosis (Lyme disease)]. / Porazhenie sustavov pri iksodovykh kleshchevykh borreliozakh (laimskoi bolezni).

Articular lesions in 157 patients infected with ixodes tick-borne borreliosis (ITB) in a central Russia's region set on, on the average, in 4 months after tick attack; they were associated with systemic signs of an early disseminated infection and set on less seldom in a late period. The most often encountered systemic signs were as follows: secondary erythema (32% of patients), neurological syndrome (13%), cardio-vascular lesions (22%), ocular lesions (13%) and hepatic lesions (8%). The articular syndrome manifested itself through arthralgia (53 patients) and arthritis (104 patients), which set on quite often in the tick-attack area. There was a peculiarity typical of articular lesions, which made it possible to distinguish them from other rheumatic disease. A dynamic follow-up revealed different clinical variations of Lyme's arthritis and peculiarities of the genetic profile, i.e. a higher prevalence of HLA A2, HLA-B15 and HLA-DR4 as well as of haplo-types HLA A2-B15 and HLAB15-DR4. The articular lesions were associated with an intensive specific humoral immune response. The instrumental examination methods, i.e. ultrasonography of joints as well as scintigraphy of bones and joints, did not reveal any qualitative differences between arthralgia and arthritis, which is indicative of a common nature different-intensity manifestations of arthropathy in thick-borne borreliosis.

[Comparative analysis of use of two strains of various genotypes of Borrelia burgdorferi sensu lato as antigens for antibody identification in Ixodes tick borreliosis by indirect immunofluorescence]. / Sravnitel'nyi analiz rezul'tatov ispol'zovaniia dvukh shtammov razlichnykh genovidov Borrelia burgdorferi sensu lato v kachestve antigenov dlia opredeleniia antitel pri iksodovykh kleshchevykh borreliozakh metodom nepriamoi immunofluorestsentsii.

The results of the indirect reaction of immune-fluorescence (IRIF) was studied in testing 49 sera of 19 patients with Lyme-borreliosis with antigens of genotypes Borrelia afzeli (strain Jp-21) and Borrelia burgdorferi sensu stricto (strain No. 17); rabbit fluorescini-sothiocyanate-marked conjugates to human immunoglobulins M and G as well as polyvalent conjugate were used of. No reliable differences were found between all positive and all negative results. The biggest portion of positive results was registered in tests with anti-G-conjugate (up to 92% with strain No 17).

[Comparative analysis of methods for laboratory diagnosis of Lyme's disease in early stages of infection]. / Sravnitel'nyi analiz metodov laboratornoi diagnostiki bolezni laima na rannei stadii infektsii.

Different methods of laboratory diagnostics were comparatively analyzed in examining 25 patients at the early infection stage. Sera were measured by using various serological reactions. Specific antibodies were determined by using the reaction of indirect immune-fluorescence (RIIF), the immune-enzyme analysis (IEA) and the complement-binding reaction (CBR) in 83.1%, 54.4% and 12.5% of cases, respectively. Essential differences in sensitivity were detected between the above methods. RIIF was proven to be a reliable and sufficiently sensitive method in the laboratory diagnostics of Lyma's disease. While the use of two methods, i.e. RIIF and IEA, ensures the highest percentage of detection of antibodies to the causative agent of Lyma's disease.

[Use of western-immunoblotting to determine serum IgG-antibodies to antigens of different genotypes of Borrelia--Borrelia burgdorferi sensu stricto, Borrelia afzelii, and Borrelia garinii]. / Ispol'zovanie vestern-immunoblotinga glia opredeleniia syvorotochnykh IgG-antitel k antigenam raznykh genovidov borrelii--Borrelia burgdorferi sensu stricto, Borrelia afzelii i Borrelia garinii.

The reaction of the sera from 86 patients with Lyme borreliosis was evaluated in the immunoblotting using three genotypes of pathogenic Borrelia strains. The Russian isolates of Borrelia afzelii (strain IP3) and B. garinii 20047T (strain IP90) were compared with the USA typical strain B31--B. burgdorferi sensu stricto. The results were assessed by the criteria recommended for the USA and developed for B. burgdorferi sensu stricto. Certain differences were shown in the reactions of serum IgG with major proteins of three Borrelia genotypes. The sera interacted with p37 of an I-90 isolate and with p39 of both Russian isolates significantly more frequently. The rate of positive results of a serum test using the strain B31 was 18.6% (16 patients); 13 patients were additionally identified when the Russian isolates were applied. It is expedient to use the genotypes circulating in Russia as an antigenic material for immunoblotting. Criteria for positive serum test results may be individual for each genotype of Borreliae.

[Detection of anti-Borrelia antibodies by immunoblotting in Lyme borreliosis]. / Opredelenie antiborrelioznykh antitel metodom immunoblottinga pri borrelioze Laima.

IgM and IgG were detected in the sera from 25 Russian patients with Lyme disease by immunoblotting test with Immunetics kit (USA). Early stage of the disease was diagnosed in 12 patients and late stage in 13. Specific protein lines were detected in virtually all patients but their number and combination in the sera were different. Eleven (43%) sera were regarded as positive according to the American criteria of seropositive test, 3 of them by IgM and 10 by IgG. In patients with short disease serum reaction was either negative or confined to 1-2 lines per strip. Patients with late stage showed a more manifest extensive reaction, which was the most pronounced in patients with a long lasting disease and articular involvement; the reaction was similar to that characteristic of chronic Lyme arthritis. Parallel testing of IgG antibodies in 25 sera from American patients with Lyme disease (confirmed by direct isolation of the agent) showed notable similarity of reactions of both American and Russian sera. More essential differences were observed only for low molecular weight proteins (p28, p23, p21).

[Morphology of the skin manifestations of Lyme disease]. / K morfologii kozhnykh proiavlenii bolezni Laima.

The paper describes a case of a long-lasting chronic migrant erythema (ME) in an 82-year-old female, which developed after the bite of an insect (a tick?). The specific feature of this case is an unusual duration (2 years) of a single focus of ME and autopsy of the skin revealed giant cells with centrally arranged 3-5 nuclei and cytoplam with PAS-positive inclusions as tiny (5 m) oblong formations, that may be Borelia.

[Age and symptoms of Lyme disease]. / Vozrast i techenie laimskoi bolezni.

AIM: Comparison of clinical symptoms in Lyme disease (LD) in various age groups. MATERIAL AND METHODS: 150 patients with verified LD were divided into 4 age groups: under 15 years (group 1), 16-40 years (group 2), 41-60 years (group 3), over 60 years (group 4). Antibodies to Borrelia burgdorteri were detected with indirect immunofluorescence and Western blot. RESULTS: LD clinical symptoms differed in the age groups. Patients of group 1 had more prevalent infectious syndrome with fever but they had no radiculoneuritis and polyneuritis. Patients of group 2 more frequently suffered of carditis and secondary erythema. Groups 3 and 4 were characterized by infectious syndrome, secondary erythema and aseptic meningitis, joint lesions being more frequent in group 3, nervous system lesions--in group 4. CONCLUSION: Age peculiarities of LD symptoms are very important. In particular, joint syndrome is responsible for lingering course of LD.

[Methods for the instrumental diagnosis and verification of Lyme arthritis]. / Metody instrumental'noi diagnostiki i verifikatsii Laim-artrita.

We used instrumental methods to characterise Lyme arthropathy in 79 patients with joint involvement and history of Lyme borreliosis. All of them had arthralgia and 45 of them also had arthritis. Radiological examination has established subchondral bone sclerosis in sacroiliac joints in 68% and sacroiliitis in 29% of the examinees. Scintigraphy revealed polyarticular lesions in many cases. Ultrasound investigation has found inflammation and edema of periarticular tissues in the knee, shoulders and hips. The level of antibodies against the causative agent Borrelia (in EIA) was significantly higher in patients with marked signs of inflammation in ultrasound examination. Thus, the combined methods of examination in the diagnosis of Lyme arthritis provide the most complete information.

[Use of fluoroquinolones in rheumatology]. / Primenenie ftorkhinolonov v revmatologii.

The efficacy and tolerance of 3 fluoroquinolones (ciprofloxacin, pefloxacin, lomefloxacin) were studied in 157 patients with rheumatic diseases concurrent with infection-induced abnormalities. Infection cure was achieved in 123 (78.6%) patients, as evidenced by clinical, microbiological, and serological studies. The tolerance of fluoroquinolones was regarded as good, satisfactory, and poor in 114 (72.6%), 37 (23.6%), and 6 (3.8%) patients, respectively. All representative drugs of the fluoroquinolones series produced typical adverse reactions. The authors consider it expedient to make further clinical studies to test the optimal treatment regimens and to expand indications for the use of fluoroquinolones in this group of patients.