Association of polymorphisms of HLA-DRB1 and TNF-308 G/A with radiographic joint damage in patients with early rheumatoid arthritis with high inflammatory activity, treated according to the principle of "Treat to target" (REMARKA study).

AIM: To clarify the association between HLA-DRB1 and TNFα (-308G>A) genes polymorphism and joint destruction/further progression during 12 months of the follow-up period (FUP) in patients with early (<6 months), active, predominantly antibodies to cyclic citrullinated peptide (ACCP) and rheumatoid factor (RF)-positive rheumatoid arthritis (RA) treated according to "Treat to target" strategy. MATERIALS AND METHODS: The study included 85 patients with early RA and duration of symptoms <6 months. All patients were initially assigned to subcutaneous methotrexate (MTX) with rapid dose escalation to 20-25 mg/week. Combination MTX + biological therapy, mainly adalimumab, was used when MTX was ineffective. Joint destruction was assessed by Sharp-Van der Heijde modification scoring method at baseline and after 12 months FUP. Real time polymerase chain reaction (PCR-RT) was used for TNFα gene polymorphism (-308G>A) genotyping. Low resolution PCR-RT with subsequent sequence-based typing of *04 were performed to study HLA-DRB1 gene polymorphism. The HLA-DRB1*01, *04:01, *04:04, *04:05, *04:08, *10 alleles were categorized as SE+ (Shared Epitope) alleles. RESULTS: As for TNFα gene polymorphism, it was demonstrated that the number of narrowings and total Sharp score values were almost twice as high at baseline in GG genotype carriers as compared to GA genotype carriers (р<0,005, and р<0,004 respectively). Similar association was found after 12mo FUP. The progression of joint destruction, assessed as the change (∆) in the number of erosions, joint space narrowings and the total score, was statistically significantly associated with HLA-DRB1*(SE) genotypes: the carriers of SE (SE+/SE+) double-dose had more advanced progression as compared to (SE+/SE-)/(SE-/SE-) carriers (р<0,028, р<0,019, р<0,035 respectively). CONCLUSION: Our data suggest that HLA-DRB1 (SE+) gene and TNFα (-308G>A) polymorphisms are associated with the progression of radiographic joint destruction in early, active RA patients managed according to "Treat to target" stratagy.

[N-terminal pro-brain natriuretic peptide levels and diastolic dysfunction in patients with early rheumatoid arthritis before the administration of disease-modifying antirheumatic drugs].

AIM: To determine N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with early rheumatoid arthritis (RA) before the use of disease-modifying antirheumatic drugs (DMARDs); to compare NT-proBNP values with traditional risk factors (TRF), cardiovascular diseases (CVD), inflammatory markers, and left ventricular (LV) diastolic dysfunction (DD). SUBJECTS AND METHODS: The investigation enrolled 74 patients with a valid RA diagnosis (the 2010 ACR/EULAR criteria), 56 (74%) women, median (Me) age, 54 years; disease duration, 7 months; seropositive for IgM rheumatoid factor (87%) and/or anti-cyclic citrullinated peptide antibodies (100%) with no history of the use of DMARDs and glucocorticosteroids. Duplex scanning and echographic findings were used to assess TRF for CVD and carotid artery atherosclerosis (CAA) in all the patients with early RA prior to therapy. An E/A ratio was used as a criterion for LVDD. RESULTS: NT-proBNP concentrations in patients with early RA proved to be higher than those in the control group (p<0.0001). Higher-than-normal NT-proBNP levels were seen in 36 (49%) patients. The patients with early RA and elevated NT-proBNP values were older and had a higher body mass index (BMI) than those with normal NT-proBNP levels. Those with elevated NT-proBNP concentrations were more frequently found to have CAA, coronary calcification, and coronary heart disease; their intima-media thickness was also larger and C-reactive protein (CRP) levels higher than in those with normal NT-proBNP values. There were correlations between NT-proBNP levels and erythrocyte sedimentation rate, CRP, simplified disease activity index, and clinical disease activity index. Multivariate analysis revealed that chronic heart failure (CHF), CAA, CRP and low-density lipoprotein (LDL) levels, and BMI correlated with NT-proBNP concentrations. LVDD was detected in 35 (48%) patients with early RA. The level of NT-proBNP in patients with DD was higher than in those without DD. Higher-than-normal NT-proBNP values were observed in 23 (65%) and 12 (32%) patients with and without LVDD, respectively. The optimal NT-proBNP level for CHF detection was equal to 237.4 pg/ml (86% sensitivity and 85% specificity); the area under the ROC curve was 0.879. CONCLUSION: Just at the early disease stage, the patients are noted to have a high NT-proBNP level that is influenced by higher BMI, low LDL levels, CAA, CHF, and high CRP values. In the patients with early RA, the diagnostically significant NT-proBNP concentration for CHF detection was higher (237 pg/ml) than in those without RA (125 pg/ml). The patients with early RA should undergo NT-proBNP determination, LVDD screening, correction of TRF for CVD, atherosclerosis treatment, and remission achievement.

[Immunogenetic aspects of early rheumatoid arthritis].

The study is aimed to investigate the distribution of alleles of HLA-DRB1 gene in patients with early rheumatoid arthritis and healthy individuals in Russian population, and evaluate their significance as molecular genetic markers of rheumatoid arthritis predisposition and protection. The association between alleles of HLA-DRB1 genes, antibodies to cyclic citrullinated peptides and IgM rheumatoid factor was also studied. Low and high resolution HLA-DRB1 genotyping were compared. In the cohort of patients with early rheumatoid arthritis, the alleles of HLA-DRB1 gene were found to be markers of rheumatoid arthritis protection/risk, especially in the homozygous state. They determined production of antibodies to cyclic citrullinated peptides but were not associated with rheumatoid factor IgM levels. These findings support different autoimmune mechanisms of rheumatoid arthritis pathogenesis.

[Clinical and immunological aspects of early-stage rheumatoid arthritis].

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by a systemic inflammatory and destructive joint lesion that is manifested by the involvement of various organs and systems into the pathological process. Whether the variants of the course and outcomes of RA may be predicted early is the most important inadequately studied problem. HLA-DRB1* genotypes affect disease severity; however, different alleles encoding the identical amino acid sequence have a varying association with the disease and their combinations can differently increase the risk of RA. Total epitope (SE) is associated not only with the risk of RA as a whole, but also with the development of the severe course of the disease to a greater extent. A number of studies have demonstrated that if a patient has concurrently antibodies to cyclic citrullinated peptide (CCP) and rheumatoid factor, as well as HLA-DRB1 alleles, the likelihood of rapid X-ray progression is 10 times greater than that in a patient without these markers. The paper considers the course of early RA depending on the combined determination of immunological and immunogenetic markers (SE and CCP antibodies). Each of them makes a substantial contribution to the development of a destructive process in early RA, which necessitates the assessment of a combination of the factors.

[Anticitrulline antibodies and wrist joint MRI parameters in patients with early arthritis].

AIM: To examine correlations between immunological markers, clinical parameters and MRI data in patients with early rheumatoid arthritis (RA) and undifferentiated arthritis (UDA). MATERIAL AND METHODS: The study was made of 211 patients with early RA (43 males, 168 females) and 47 patients with early UDA (mean age 48.6 +/- 13.4 years), duration of the symptoms 5.5 +/- 4.5 months). RF-positive were 136 (64.5%) patients. X-ray erosions were detected in 45 (21.3%) patients. RA activity was estimated by the integral DAS28 index (by 3 parameters), function--by HAO questionnaire (Russian version). The immunonephelometric analyzer (BN-100, Dade Behring, Germany) determined concentration of C-reactive protein (CRP), IgM. Anticitrulline antibodies (ACAB) were estimated by enzyme immunoassay, the upper limit of the norm was 5.0 U/ml. MR imaging (MRI) of both the wrists in RA patients was made on the 0.2 T Artoscan unit, the assessment was made with the reference atlas OMERACT-RAMRIS. RESULTS: IgM and ACAB levels were much higher in RA than in UDA. Among the patients positive by both tests (RF+ACAB) 95.2% had a typical clinical picture and RA diagnosis while 60% patients negative by RF and ACAB had UDA (p < 0.001); among patients positive by one of the tests the ratio UDA to RA was 1:2 (32.6 and 67.4%). In RA patients with very high ACAB (> 100 U/ml) CRP reached 38.10 +/- 48.29 mg/l while in negative ACAB--17.07 +/- 19.34 mg/l (p = 0.016). Wrist MRI detected synovitis and bone erosions in 93 and 66% cases, respectively. High ACAB level (> 100 U/ml) and CRP levels were associated with high DAS28, RF IgM and MRI erosions number. CONCLUSION: RF and ACAB patients are characterized by a typical RA picture in the disease onset (specificity 93.6%). MRI detects synovitis in the wrist joints in 93 and erosions in 66% early RA patients. Combination of high ACAB and CRP levels is associated with high RA activity, RF IgM and great number of erosions according to MRI and may serve a marker of a severe disease course.

[Diagnostic value of antibodies to modified citrullinized vimentin in early rheumatoid arthritis].

A hundred and two patients (18 males, 84 females; mean age, 50.3 +/- 12.3 years) diagnosed as having early rheumatoid arthritis (RA) were examined. A control group consisted of 189 patients with various rheumatic diseases and 30 healthy donors. The serum concentrations of antibodies to modified citrullinized vimentin (MCVA) and to cyclic citrullinized peptide2 (CCTP2A) were measured by enzyme immunoassay (EIA); rheumatoid factor (RF) IgM was determined by nephelometric immunoassay. In early RA, the level of MCVA (median, 49.6 U/ml; interquartile range, 0.9-249.3) was significantly higher than in the control group 1.65 U/ml; 0.3-19.7). There was a direct significant correlation between the levels of MCVA and CCTP2A (p = 0.9), as well as RF IgM (p = 0.6). The diagnostic efficiency of MCVA (area under the curve, 0.705; 95% confidence interval, 0.607-0.803) was higher than that of CCTP, (0.590; 0.467-0.714), but lower than that of RF IgM (0.813; 0.736-0.889). MCVA was comparable with CCTP, and RF IgM in sensitivity; however, it ranked below them in specificity (71%). Choice of the optimum upper normal range (30 U/ml) permits up to an 88% increase in MCVA specificity and the concurrent consideration of results of testing MCVA, CCTP2A, and RF IgM is attended by up to a 78% increase in sensitivity. EIA of MCVA is a sensitive and specific serological test for the diagnosis of early RA.

[Early diagnosis of rheumatoid arthritis in modern clinical practice (results of a follow-up of a Moscow cohort of early arthritis patients participating in the program RADICAL)].

AIM: To estimate potentialities of early diagnosis of rheumatoid arthritis (RA) diagnosis in clinical practice in the course of the RADICAL program. MATERIAL AND METHODS: Of 366 patients participating in the trial 61 (16.7%) were males and 305 (83.3%) were females at the age of 47.76 +/- 14.1 years. The longest duration of the symptoms before consulting a doctor was 51 weeks, mean duration--5.7 weeks, 55% patients had the symptoms for 3 weeks. All the patients have undergone laboratory examination including leukocyte count, platelet count, estimation of ESR, concentration of C-reactive protein (CRP), rheumatoid factor (RF) and antibodies to a cyclic citrullated peptide (ACCP); roentgenography of the wrists and feet. On demand, antinuclear factor (ANF) and HLA-B27 were investigated. RA was diagnosed on the basis of ACR classification criteria. If the criteria were not complete at the moment of the study, the patient was referred to the group of "undifferentiated arthritis" (UA). The patients were examined before the treatment, 6 and 12 months later. The treatment was made according to Russian clinical recommendations. RESULTS: Prior to admission to hospital, 58% patients were suspected for RA, 18.3%--osteoarthrosis (OA), 14%--reactive arthritis. 18.9% were not diagnosed, other diagnoses were considered in 12.6% patients. At primary examination RA was diagnosed in 212 (57.9%) patients, UA was in 133 (36.3%) patients, 21 (5.7%) patients had other diagnoses. Twelve months later RA, UA and other diseases were diagnosed in 256 (69.9%), 70 (19.1%) and 40 (10.9%) patients, respectively. CONCLUSION: A 3-stage algorithm of early RA diagnosis is proposed. At the stage of the first contact with the patient in an outpatient clinic a valid RA suspition with consideration of modified EULAR criteria must be formulated. At the second stage a district rheumatologist must examine the patient outpatiently with determination of ACR classification criteria. In diagnosis verification the treatment must be started according to APP and EULAR clinical recommendations. If RA diagnosis can not be verified or rejected, the patient must be refered to hospital (stage 3). If verification of RA diagnosis is impossible, the diagnosis should be formulated as UA.

[Biochemical diagnosis of liver damage in patients with hemophilia]. / Biokhimicheskaia diagnostika porazheniia pecheni u bo'lnykh gemofiliei.

The complexes of the controlling and informative biochemical tests are offered. They are scientifically validated criteria for early identification of the disorders of renal function and differentiation between the syndromes of its damage in the course of the disease.

[Characteristics of the functional status of the liver in hemophilia]. / Osobennosti funktsional'nogo sostoianiia pecheni pri gemofilii.

The liver function was studied in 135 patients with severe hemophilia A and B. It has been established that in hemophilia the liver is naturally involved into the pathological process. The liver function disorders are manifested as inflammatory and cytolytic syndromes. The incidence rate and degree of the shifts manifestation correlate with the disease duration.