Low Rheumatoid Arthritis Activity Research Articles

Tofacitinib as a means of optimizing the treatment of rheumatoid arthritis at the outpatient stage (clinical cases)

Two clinical cases of tofacitinib use in the management of rheumatoid arthritis (RA) patients by a rheumatologist at the outpatient stage within the framework of the “Treatment to Target” strategy are presented. The first clinical case describes the case history of a female patient (age 48 years, RA duration 20 years), which demonstrates the difficulties in selecting pathogenetic therapy for late-stage RA. Consecutively prescribed four synthetic baseline anti-inflammatory drugs (methotrexate, sulfasalazine, cyclophosphamide, leflunomide) and two genetically engineered biological drugs (infliximab, rituximab) failed to achieve remission of the disease in the patient. Decrease in disease activity was noted after connection of the third biological drug – etanercept, treatment with which had to be interrupted due to pregnancy planning. The return to the combined treatment after childbirth did not lead to repeated “success”. A positive result was achieved 12 weeks after tofacitinib at a dose of 10 mg/day, which provided a decrease in RA activity to moderate and complete withdrawal of glucocorticoids. Given the incomplete clinical effect, tofacitinib dose was increased to 20 mg/day by the outpatient rheumatologist, which resulted in achieving low RA activity persisting for 5 years. The second case demonstrates the effectiveness of tofacitinib inclusion in the RA treatment regimen as a “second-line” drug. A patient (age 46 years, RA duration 10 years) with long-term drug (methotrexate 25 mg/week) clinical and laboratory remission of RA after an upper respiratory tract infection developed an exacerbation of the disease. Despite three-component therapy with baseline anti-inflammatory drugs, the patient had persistence of high RA activity, which led to the revision of pathogenetic therapy – tofacitinib at a dose of 10 mg/day with clinical effect of the drug after 4 weeks. The achieved clinical and laboratory remission of the disease has been maintained for two years. In outpatient practice tofacitinib can be an effective tool for optimizing RA treatment.

Menopause and rheumatoid arthritis as factors associated with osteoporosis development

The aim of the research. To study the role of menopause, glucocorticoids (GCs) intake and characteristics of rheumatoid arthritis (RA) in development of osteoporosis (OP) and osteoporotic fractures. Material and methods. A total of 73 female RA patients in menopause were examined. The control group included 29 female RA patients in premenopause. In addition to standard clinical and laboratory examinations, P1NP, 25(OH)D, CTX-1 were measured, dual-energy x-ray absorptiometry and x-ray of the thoracic and lumbar spine were performed. Statistical analysis was performed using the “Statistica 12.0” software package. Results. Premenopausal patients had lower BMI. Patients in postmenopause had higher rate of OP (42 patients) than the controls (8 patients) (57.5% vs 27.6%, respectively). Among patients in postmenopause, OP was associated with lower BMI (27.6 vs 30.5 kg/m2), higher cumulative dose of GCs (6.9 vs 1.65 g), higher duration of GCs intake (32 vs 18 months), lower RA activity (3.37 vs 3.9 according to DAS28-CRP) and lower CTX-1 level (0.52 vs 0.7 ng/ml). In the same group, osteoporotic fractures were only associated with longer GCs intake (32 vs 24 months). In premenopause patients, OP was associated with longer RA duration (21 vs 6 months), cumulative dose of GCs (13.9 vs 0.45 g), duration of GCs intake (48 vs 3 months), higher level of hs-CRP (46 vs 8 mg/l) and lower P1NP level (51.8 vs 43.8 ng/ml). Osteoporotic fractures in premenopause were associated with RA duration (28 vs 6 months), cumulative dose of GCs (12.5 vs 1.2 g) and lower BMD in all examined areas. Conclusion. The OP rate was higher in postmenopause patients. In both groups, the duration of GCs intake and accumulated dose of GCs were associated with OP. In postmenopause, OP was also associated with lower BMI. In premenopause, OP and osteoporotic fractures were associated with longer RA duration, cumulative dose of GCs and lower BMD in all studied areas.

Evaluation of the effectiveness of Tofacitinib in rheumatoid arthritis in real clinical practice: The relationship between pain relief in the first 4 weeks and disease activity after 3–6 months

The JAK inhibitor tofacitinib (TOFA) blocks the intracellular signaling pathway that activates the synthesis of cytokines and mediators involved in the development of pain and central sensitization (CS), which determines the rapid analgesic effect. However, it is not clear how pain reduction is associated with achieving low activity in rheumatoid arthritis (RA).The aim of the studywas to assess the relationship between the early clinical response to tofacitinib and a decrease in rheumatoid arthritis activity after 3 and 6 months.Material and methods.The study group consisted of 88 RA patients (age – 53±11.5 years; 79.3% of women) who received basic anti-inflammatory drugs (59.5% – methotrexate, 19.8% – leflunomide) and who were prescribed TOFA in a dose 10 mg/day. Seropositivity for rheumatoid factor was 89.8%; the value of the DAS28 index is 5.2±1.2. The severity of pain was assessed using the Brief Pain Inventory questionnaire, the neuropathic component of pain (NCP) – using the PainDETECT questionnaire, signs of CS – using the Central Sensitization Inventory (CSI) questionnaire in the early stages after the administration of TOFA, RA activity – using the DAS28-CRP index after 3 and 6 months.Results.The mean severity of pain at baseline was 5.3±2.0 on the visual analogue scale (VAS); 51.1% of patients had signs of CS (CSI>40), 15.9% had NCP (PainDETECT>18). 7 days after the start of therapy, there was a significant decrease in pain – to 4.1±1.8 according to VAS (p<0.05) and CS – 40.4±13.5 to 36.5±12.5 according to CSI (p=0.01). After 28 days, the effect was even more significant: the level of pain according to the VAS was 2.8±1.6 (p=0.000), the NCP decreased from 11.8±5.6 to 6.8±3.1 (p=0.000), CS – up to 31.6±13.9 (p=0.000). The value of the DAS28-CRP index after 3 and 6 months was 3.7±1.3 and 3.6±1.2, respectively. The number of patients with pain relief ≥50% after 28 days was 59.9%, low RA activity after 3 months. (DAS28-CRP≤3.2) was acieved in 64.4% of patients. There was a clear correlation between the number of patients with a pain reduction of ≥50% at 28 days and the number of patients who achieved low RA activity at 3 and 6 months. (rS=0.548, p=0.000 and rS=0.790, p=0.000). 6 patients dropped out of the study due to inefficiency or social reasons. No serious adverse reactions were noted.Conclusions.The use of the JAK inhibitor TOFA allows achieving a quick analgesic effect and reducing the signs of CS. An early clinical response to TOFA (pain relief) predicts a decrease in RA activity after 3 and 6 months of therapy.

AB0135 A VERY EARLY CLINICAL RESPONSE TO TOFACITINIB IS ASSOCIATED WITH LOW RHEUMATOID ARTHRITIS ACTIVITY AFTER 3 AND 6 MONTHS

Background:JAK inhibitors block intracellular signaling pathways responsible for the synthesis of cytokines and mediators involved in the development of chronic pain and central sensitization (CS). This determines a very rapid clinical response to JAK inhibitors. However, it is not clear how the significant pain reduction in the first weeks of therapy is associated with the achievement of low rheumatoid arthritis (RA) activity.Objectives:to assess the relationship between the early clinical response to tofacitinib and the decrease in RA activity after 3 and 6 months.Methods:Study group included 88 patients with RA, their age was 53±11,5, 79.3% of women, 89.8% of RF “+”, DAS28 5.2±1.2, receiving DMARDs (methotrexate 59.5% and leflunomide 19.8%), who were administered with tofacitinib 5 mg 2 times a day due to inefficacy or intolerance of biological DMARDs. There were assessed the pain severity using Brief pain inventory (BPI) questionnaire, the presence of neuropathic pain component (NPC) using PainDETECT questionnaire and signs of CS using Central Sensitisation Inventory (CSI) questionnaire at early time after tofacitinib administration, RA activity using DAS28 after 3 and 6 months.Results:The mean pain severity at baseline was 5.3±2.0 according to the visual analogue scale (VAS 0-10), 51.1% of patients had signs of central sensitization (CSI ≥ 40), 15.9% had NPC (PainDETECT ≥18). 7 days after tofacitinib intake there was statistically reliable reduction of pain severity – up to 4.1±1.8 (р<0.05) and CS – CSI from 40.4±13.5 to 36.5±12.5 (р=0.01). After 28 days, the effect was higher: the pain level (VAS) was 2.8±1.6 (p=0.000), PainDETECT decreased from 11.8±5.6 to 6.8±3.1 (p=0.000), CSI – to 31.6±13.9 (p=0.000). DAS28 after 3 and 6 months was 3.7±1.3 and 3.6±1.2. The number of patients with pain decrease of ≥50% after 28 days of therapy was 59.9%. Low RA activity after 3 months. (DAS28 ≤3.2) was achieved in 64.4% of patients. There was a clear correlation between the number of patients with significant pain reduction at 28 days and the number of patients with low RA activity after 3 and 6 months (rS=0.548, p=0.000; rS=0.790, p=0.000). Six patients withdrew from the study due to inefficacy or social reasons. There were no serious adverse reactions.Conclusion:The application of JAK inhibitor tofacitinib allows to reach a fast analgesic effect and reduce CS signs. An early clinical response to tofacitinib (pain relief) predicts a decrease in RA activity after 3 and 6 months of the therapy.Limitation: Open-label observatory study.Disclosure of Interests:None declared

Is There a Feasible Link between Vitamin D Receptor Genotypic and Allelic Frequencies with Analytical Biomarkers of Rheumatoid Arthritis Disease?

Rheumatoid arthritis (RA) is one of the most widespread autoimmune disorders and it has a genetic background with a variety of genes affecting the degradation of the immune system. Along these lines, we assessed the relationship between the BsmI, and FokI VDR polymorphisms and inflammable records identified with infections activity. Such as interleukins (IL-6, IL-8), hypoxia inducible factor-alpha (HIF-α), soluble receptor of advanced glycation end product (sRAGE), oxidized low-density lipoprotein cholesterol (oxLDL), neutrophil gelatinase-associated lipocalin (NGAL) and procollagen N-propeptide of type III collagen (P3NP) and the allelic frequencies of BsmI VDR rs1544410 and FokI VDR rs2228570 polymorphism on the RA. Total of 131 subjects [70 RA patients and 61 age and sex matched apparently healthy controls (HC)] were monitored for inflammatory biomarkers using ELISA. All patients were screened for the BsmI and FokI using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The all biomarkers were significantly higher in RA patients in comparison with HC. There were positive correlations between NGAL, oxLDL and s-RAGE, oxLDL. On BsmI, 'GG' and 'AG' genotypes were significantly associated with high RA activity as well as the frequency of genotypes 'AG & GG" were higher in high activity RA as compared to low RA activity. However on FokI, was observed that in high activity patients the frequency of 'CC' & 'CT' was more prevalent as compared to low activity ones. These outcomes support the immunoregulatory role of vitamin D which is associated with several inflammatory diseases, signifying a credible anti-inflammatory role in perturbation of the RA.

Fibrinogen-Like Protein 1 Is a Novel Biomarker for Predicting Disease Activity and Prognosis of Rheumatoid Arthritis.

Rheumatoid arthritis (RA), afflicting over 1% of the population, is an inflammatory joint disease leading to cartilage damage and ultimately impaired joint function. Disease-modifying anti-rheumatic drugs are considered as the first-line treatment to inhibit the progression of RA, and the treatment depends on the disease status assessment. The disease activity score 28 as clinical gold standard is extensively used for RA assessment, but it has the limitations of delayed assessment and the need for specialized expertise. It is necessary to discover biomarkers that can precisely monitor disease activity, and provide optimized treatment for RA patients. A total of 1,244 participants from two independent centers were divided into five cohorts. Cohorts 1–4 constituted sera samples of moderate to high active RA, low active RA, RA in remission and healthy subjects. Cohort 5 consisted of sera of RA, osteoarthritis (OA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), primary Sjogren's syndrome (pSS) and healthy subjects. Biomarkers were found from cohorts 1–2 (screening sets), cohort 3 (discovery and external validation sets), cohort 4 (drug intervention set) and cohort 5 (biomarker-specific evaluation set). We found 68 upregulated and 74 downregulated proteins by TMT-labeled proteomics in cohort 1, and fibrinogen-like protein 1 (FGL1) had the highest area under the receiver operating characteristic curve (AUC) values in cohort 2. In cohort 3, in cross-comparison among moderate/high active RA, low active RA, RA in remission and healthy subjects, FGL1 had AUC values of approximately 0.9000 and predictive values of 90%. Additionally, FGL1 had a predictive value of 91.46% for moderate/high active RA vs. remission/low active RA and 80.77% for RA in remission vs. low active RA in cohort 4. Importantly, FGL1 levels had no significant difference in OA and AS compared with healthy persons. The concentrations in SLE and pSS were improved, but approximately 3-fold lower than that in active RA in cohort 5. In summary, FGL1 is a novel and specific biomarker that could be clinically useful for predicting progression of RA.

Superficial Ulcerating Rheumatoid Necrobiosis Associated with Methotrexate Use in a Patient with Rheumatoid Arthritis

Methotrexate, a disease-modifying antirheumatic drug, is fundamental to limiting progression in several rheumatic diseases such as rheumatoid arthritis (RA). However, methotrexate is also associated with various significant adverse effects. Of note, there are several dermatologic manifestations attributed to methotrexate therapy. In particular, accelerated nodulosis and panniculitis are linked to methotrexate therapy in the current literature. The authors present the case of a 55-year-old Caucasian female with seropositive erosive RA who developed superficial ulcerating rheumatoid necrobiosis (SURN), secondary to methotrexate therapy. The patient’s treatment consisted of methotrexate discontinuation, topical clobetasol, and initiation of leflunomide as a replacement of methotrexate. Follow-up evaluation confirmed resolution of SURN over time and maintained low disease RA activity with leflunomide.Few cases describe SURN in the setting of RA and there are currently no cases published that suggest methotrexate’s possible role in SURN. Methotrexate-induced SURN is plausible in this case because of the correlation with therapy initiation and remission after therapy discontinuation. SURN has significant histological overlap with other methotrexate-induced dermatologic manifestations, allowing for a possible correlation. Most dermatological side effects of methotrexate are linked to a genetic predisposition of the HLA-DRB1 gene. Additionally, methotrexate’s mechanism of action for rheumatologic disease paradoxically stimulates adenosine-1 receptors and activates neutrophil chemotaxis and phagocytosis. Adenosine-1 receptor stimulation is hypothesised to be the source of rheumatoid-accelerated nodulosis and possibly SURN. Furthermore, the location of manifestation, genetic predisposition, and comorbid features in the patient all possibly have a role in this unique dermatological side effect.

The course of chronic heart failure in patients with early rheumatoid arthritis on the anti-rheumatic therapy

Objective: To evaluate the effect of the “treat to target” anti-rheumatic therapy on the course of chronic heart failure (CHF) in patients with early rheumatoid arthritis (RA). Materials and methods: The study included 22 patients (17, or 77% female) with CHF with valid diagnosis of RA (ACR/EULAR criteria, 2010), median (Me) age of 60 years, and median disease duration of 7 months. Ten patients (45%) were seropositive for IgM rheumatoid factor and 22 (100%) had antibodies to cyclic citrulline peptide. Their median (1st; 3rd quartiles) DAS28 was 5.6 [4.8; 6.5]. The diagnosis of CHF was confirmed in accordance with the guidelines on the diagnosis and treatment of CHF by the Russian Society of Specialists in Heart Failure (2013). NT-proBNP levels were measured by electrochemiluminescence (Elecsys proBNP II, Roche Diagnostics, Switzerland). All patients were started on subcutaneous methotrexate (MT) with rapid dose titration to 30 mg weekly. If the MT was insufficiently effective, a biological disease-modifying antirheumatic drug (bDMARD) was added to the therapy after 3 months, mainly a TNF-alpha inhibitor. After 18 months, 10 (45%) patients were in remission and had low disease activity, 6 (60%) patients underwent MT therapy in combination with bDMARDs. Results: At baseline, 21 (95%) patients were diagnosed with CHF with preserved ejection fraction and one patient had CHF with reduced ejection fraction. After 18 months there was an improvement of clinical symptoms, echocardiographic parameters (reduction of the left atrium diameter and the left atrium end-systolic volume index, IVRT, E'LV), and diastolic function of the left ventricle (LV). No episodes of acute CHF deterioration were registered. LV diastolic function normalized in 7 (32%) patients who reached the target level of blood pressure, remission (n=5) and low disease activity (n=2), mainly under the treatment with MT and bDMARDs. In patients with RA and CHF, the NT-proBNP levels decreased from 192.2 [151.4; 266.4] to 114.0 [90.4; 163.4] pg/ml (p<0.001) and became normal in 16 of 22 (73%) patients (p<0.001) with remission or low RA activity. In 5 (22%) patients, clinical CHF manifestations resolved, LV diastolic function and NT-proBNP levels were normalized. Conclusion: In the patients with early RA and CHF anti-rheumatic therapy improves the clinical course of CHF, LV diastolic function and reduces NT-proBNP levels.

Insulin resistance in rheumatoid arthritis: relationship to lipid metabolism disorders and metabolic syndrome

Objective:to determine the incidence of insulin resistance (IR) in patients with rheumatoid arthritis (RA) and to assess the relationship of IR to blood lipid profile changes and the presence of metabolic syndrome (MS).Subjects and methods.The investigation enrolled 47 RA patients (41 women and 6 men) without a history of diabetes mellitus (DM) and with normal fasting glucose levels during examination. The patients' median age was 56 [39; 62] years; disease duration – 6 [5; 14] years. Most of the patients had low (40.4%) or moderate (42.6%) RA activity (DAS28). IR was diagnosed using the Homeostastic Model Assessment of Insulin Resistance (HOMA-IR) index 2.77. The presence of MS was assessed by the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII) criteria and the International Diabetes Federation (IDF) criteria.Results and discussion.The median HOMA-IR value in RA patients was 1.7 [1.1; 3.2]. The HOMA-IR index correlated with age (r=0.3; p=0.04), body mass index (r=0.6; p<0.001), waist circumference (r=0.6; p<0.001), and the concentrations of total cholesterol (r=0.3; p=0.02) and triglycerides (TG) (r=0.5; p<0.001). All the patients were divided into two groups: 1) 15 patients with IR; 2) 32 patients without IR. The patients of both groups were matched for sex, age, RA duration and activity, and therapy, but the RA patients with IR more often had abdominal obesity (100.0 and 37.5%), hypertriglyceridemia (33.3 and 6.3%) and the atherogenic index >3.0 (40.0 and 6.3%, respectively; p<0.05 in all cases). MS was diagnosed using the NCEP/ATPIII criteria in 46.7% of cases with RI and in 6.3% of those without IR; MS was identified by the IDF criteria in 60.0 and 12.5% of cases, respectively (p<0.01 in all cases). There were no differences between groups in the incidence of hypertension, myocardial infarction, or in the frequency of surgeries for myocardial revascularization.Conclusion.More than 30% of RA patients without DM have IR (HOMA-IR ≥2.77). IR in RA is associated with obesity, elevated blood TG levels, and a proatherogenic lipid profile. The use of the criteria for MS could not always allows suspect IR in patients with RA.

Carotid atherosclerosis in females with low-activity rheumatoid arthritis and its predictors

Carotid atherosclerosis in females with low-activity rheumatoid arthritis and its predictors

THE PLACE OF TOFACITINIB IN THE TREATMENT STRATEGY OF RHEUMATOID ARTHRITIS

Objective: to determine the efficiency and safety of therapy with tofacitinib (TOFA) in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) after insufficient previous therapy in real clinical practice. Subjects and methods. The investigation enrolled a total of 33 patients with RA who met the 1987 American College of Rheumatology (ACR) and/or the 2010 ACR/European League Against Rheumatism (EULAR) criteria. All the patients received TOFA 5–10 mg administered orally twice daily in combination with MTX; 30 patients took TOFA 10 mg/day and 3 patients had TOFA 20 mg/day. Every 6 weeks, the patients were examined by a rheumatologist and laboratory-instrumental tests. RA activity changes were assessed with DAS28-CRP, SDAI, and CDAI. Results and discussion . Results were assessed at weeks 12, 54, and 114. A significant decrease in DAS28-CRP, SDAI, and CDAI values was noted just at 12-week follow-up; at week 54, the mean values of these indices were 3.7±1.0, 14.9±8.8, and 13.4±9.0, respectively. There was a substantial decline in the levels of rheumatoid factor in 27% of the patients; while one third of them had a 60% decrease in its level and four patients achieved a negative seroconversion. Neither serious adverse events (AEs) no AEs that had not previously been described in the literature were observed during the follow-up study. Nine non-serious AEs were recorded in 8 (25.0%) patients. Conclusion. The investigation shows that TOFA makes it possible to control the activity of the inflammatory process and, with its sufficient safety and generally good tolerance, to achieve low RA activity in 49% of cases, including patients with multidrug resistance. The high efficacy of TOFA and, in particular, its combination with MTX used in patients with refractory RA give grounds for wider use of this drug, as confirmed by our investigation.

Association Between Atrial, Ventricular and Vascular Morphofunctional Alterations in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) represents a risk of non-fatal and cardiovascular events. The aim of the present study was to evaluate simultaneously left and right atrial and ventricular function, as well as arterial stiffness, in RA patients. This cross-sectional study included 55 consecutive RA patients and 55 healthy age and gender-matched controls. Blood pressure and arterial stiffness were assessed in all participants, who also underwent a complete echocardiographic examination. RA patients were treated with steroid therapy (52.7%), methotrexate (66.6%) and biological therapy (54.5%). Disease activity score revealed low average RA activity. Augmentation index was significantly higher in RA patients (32.2±8.6 vs. 28.4±8.9%, P=0.02). Left atrial volume was also higher among RA patients (23.1±8.2 vs. 20.1±7.1ml/m2, P=0.04), whereas mitral and tricuspid E/A ratios were significantly lower in RA individuals (0.90±0.24 vs. 1.03±0.35, P=0.02; 1.07±0.31 vs. 1.27±0.35, P=0.003, respectively). Tissue Doppler systolic and diastolic velocities were similar between the observed groups. Arterial stiffness index showed significant correlation with disease duration (r=0.29; P=0.03). Tissue Doppler-derived transmitral late diastolic velocity (A') showed significant correlation with index of disease activity in the RA patients. Our results showed that left and right ventricular diastolic function and arterial stiffness were significantly deteriorated in the RA patients comparing with controls. The assessment of left and right ventricular diastolic function, as well as vascular function, should be an essential part of clinical evaluation in the RA patients.

THE EFFECT OF ABATACEPT ON BLOOD BIOMARKERS IN PATIENTS WITH RHEUMATOID ARTHRITIS

Objective: to estimate changes in the cytokine profile in patients receiving abatacept (ABC).Subjects and methods. The investigation enrolled 44 patients with rheumatoid arthritis (RA) who had been unsuccessfully treated with disease-modifying antirheumatic drugs and biological agents. A control group included 16 healthy donors. The majority of patients were women who were positive for rheumatoid factor (RF) (80%) and antibodies to cyclic citrullinated peptide (ACCP) (79.5%); the mean age was 49.6±13.9 years; the median disease duration was 2 [1.4; 3] years with high RA activity (mean DAS28, 5.2±0.8). The serum concentrations of interleukin (IL) 1β, IL-6, IL-17AF, tumor necrosis factor-α (TNF-α), VEGF-A, IP-10, and YKL-40 were measured by enzyme immunoassay before and 6 months after ABC therapy. Disease activity was assessed using DAS28 every 3 months. ABC was infused intravenously according to the standard regimen.Results and discussion. The patients with RA as compared with the control group had significantly elevated levels of IL-6 (2.4 [1.1; 6.4] and 0.7 [0.62; 1.0] pg/ml; p=0.0002), YKL-40 (97 [68.4; 97.9] and 64 [52.4; 107.5] pg/ml; p=0.03), IP-10 (21 [12.9; 49.8] and 14 [9.2; 15.2] pg/ml, respectively; p=0.005). ABC caused a significant decrease in RA activity after 3 months of therapy (p<0.05). Following 6 months, 86% of the patients achieved good and moderate EULAR responses; low RA activity according to DAS28 was recorded in 52%. ABC induced significant decreases in the concentrations of IL-6 to 1.29 [0.9; 2.2] pg/ml (p=0.0006) and IP-10 to 14 [7.5; 28] pg/ml (p=0.007) after 6 months of therapy. A similar trend was observed when assessing changes in the concentration of matrix metalloproteinase 3 (MMP-3), which reduced from 30.1 [13; 82] to 10 [7.4; 55] pg/ml (p=0.0003), and in that of RF, which declined from 218 [9.6; 187] to 159 [9.7; 155] pg/ml (p=0.02). The lower levels of IL-6 (r=0.5) and IP-10 (r=0.32) significantly correlated with a decrease in DAS28 (p<0.05). There was a trend towards a more pronounced reduction in disease activity in patients positive for ACCP and antibodies to modified citrullinated vimentine (AMCV). The percentage of non-responders to therapy in the ACCP- and AMCV-negative groups was nearly twice as high as in those who were positive for these antibodies (27.2 and 16%; 26.7 and 14.8%, respectively), but these differences failed to reach significance. However, after 6-month of follow-up, the percentage of non-respondents in the AMCV-negative group was significantly higher than in the AMCV-positive group (20% and 0%, respectively; p=0.03). The patients who did not respond to ABC therapy had higher baseline levels of IL-6 (p=0.03) and YKL-40 (p=0.02). Conclusion. ABC therapy results in a substantial reduction in the concentration of the proinflammatory cytokines IL-6 and IP-10, as well as MMP-3 and RF. The lower levels of IL-6 and IP-10 significantly correlated with a decrease in RA activity. There was a tendency towards a more pronounced reduction of disease activity in ACCP- and AMCV-positive patients. The high baseline levels of IL-6 and YKL-40 and the absence of AMCV may suggest that ABC therapy can be ineffective.

Relationship Between Vitamin D and Rheumatoid Arthritis Activity

Objectives: Deficiency of vitamin D has been involved in the pathogenesis of many auto-immune diseases, as diabetes mellitus type 1 and multiple sclerosis. Reduction of the intake of vitamin D has been associated with high susceptibility of the development of rheumatoid arthritis (RA) and also with increased disease activity in patients with RA. The objective of this study was to evaluate the status of vitamin D in patients with RA, assess the correlation between serum level of vitamin D and disease activity and its association to the pathogenesis of RA. Methods: 60 female patients with RA, 25-hydroxyvitamin D3 [25(OH)D3] levels, Para-thyroid hormone levels, Creactive protein (CRP) and erythrocyte sedimentation rate (ESR) were measured. Disease activity was evaluated by calculating the 28-joint Disease Activity Score (DAS28). A control group (n=30), matched for age, was evaluated as well. Results: There is a significant decrease in the mean vitamin D serum levels in RA patients compared to control group (F test, p 0.031). We did not find any correlation between DAS28 score and vitamin D levels in controls (p=0.871), low active RA patients (p=0.722) and high active RA patients (P=0.428). Conclusion: No association was found between vitamin D and disease activity. However, the deficiency of vitamin D may have a negative impact on bone health in patients in the course of the disease. Vitamin D supplementation may be needed to prevent the osteoporosis and for the relief of pain in patients with RA.

Association Between Genetic Variation in FOXO3 and Reductions in Inflammation and Disease Activity in Inflammatory Polyarthritis.

ObjectiveGenetic variation in FOXO3 (tagged by rs12212067) has been associated with a milder course of rheumatoid arthritis (RA) and shown to limit monocyte‐driven inflammation through a transforming growth factor β1–dependent pathway. This genetic association, however, has not been consistently observed in other RA cohorts. We sought to clarify the contribution of FOXO3 to prognosis in RA by combining detailed analysis of nonradiographic disease severity measures with an in vivo model of arthritis.MethodsCollagen‐induced arthritis, the most commonly used mouse model of RA, was used to assess how Foxo3 contributes to arthritis severity. Using clinical, serologic, and biochemical methods, the arthritis that developed in mice carrying a loss‐of‐function mutation in Foxo3 was compared with that which occurred in littermate controls. The association of rs12212067 with nonradiographic measures of RA severity, including the C‐reactive protein level, the swollen joint count, the tender joint count, the Disease Activity Score in 28 joints, and the Health Assessment Questionnaire score, were modeled longitudinally in a large prospective cohort of patients with early RA.ResultsLoss of Foxo3 function resulted in more severe arthritis in vivo (both clinically and histologically) and was associated with higher titers of anticollagen antibodies and interleukin‐6 in the blood. Similarly, rs12212067 (a single‐nucleotide polymorphism that increases FOXO3 transcription) was associated with reduced inflammation, both biochemically and clinically, and with lower RA activity scores.ConclusionConsistent with its known role in restraining inflammatory responses, FOXO3 limits the severity of in vivo arthritis and, through genetic variation that increases its transcription, is associated with reduced inflammation and disease activity in RA patients, effects that result in less radiographic damage.

IMPACT OF PREGNANCY ON THE ACTIVITY OF RHEUMATOID ARTHRITIS AND ITS THERAPY ACCORDING TO PROSPECTIVE FOLLOW-UP DATA

Rheumatoid arthritis (RA) frequently affects women of child-bearing age, which determines long-standing interest in studying the mutual impact of pregnancy and RA. The first observation described about 80 years ago has shown decrease of disease activity in the absolute majority of pregnant women. Later prospective studies have demonstrated that only 48–66% of women have clinical improvement during pregnancy, postpartum exacerbation of RA develops in 70% of cases, and most patients need drug therapy. Objective: to assess changes of RA activity with DAS28-CRP during pregnancy and postpartum; to examine the impact of RA activity during early pregnancy on further course of the disease; and to determine drug therapy requirement in pregnant women with RA. Subjects and methods. Thirty-two pregnancies were prospectively followed up during each trimester and within 12 months postpartum in 29 women with RA who fulfilled the 1987 ACR criteria and had been examined at the V.A. Nasonova Research Institute of Rheumatology from February 2011 to August 2014. Results and discussion . 46% of the patients with RA showed reduction of disease activity during pregnancy. Exacerbation of RA was observed in 75% of the patients within 12 months at 1.5 months postpartum on average. In patients who were in remission and had low disease activity during early pregnancy, activity of RA throughout pregnancy and 1 month postpartum remained lower than that in those with moderate and high activity in the first trimester (p = 0.0008–0.04). A similar trend was also seen in patients without active arthritis at the moment of conception (according to survey data). In 23 (71.9%) patients with signs of disease activity during pregnancy, anti-inflammatory therapy was enhanced and DAS28-CRP decreased (p = 0.008) while it tended to increase in the remaining 9 (28.9%) patients with low disease activity who did not received medication. After delivery, patients with high and moderate disease activity showed earlier improvement (p = 0.008), as they more early resumed therapy with diseasemodifying antirheumatic drugs (DMARDs) and biologics than those who were in remission and had low disease activity during pregnancy. In the latter, a tendency for higher disease activity persisted for 3 months after delivery. Disease activity during the first-to-third trimester was significantly higher in 12 (37.5%) patients who had conceived while taking DMARDs or biologics and urgently withdrew them due to their pregnancy than in 20 (62.5%) cases when DMARDs and/or biologicalshad not been used or had been discontinued in advance when they started planning pregnancy (p < 0.04). Conclusion . Remission or low activity of RA during early pregnancy is a predictor for low disease activity and for minimizing drug therapy to the point of its refusal throughout pregnancy. Without drug therapy, RA activity may tend to increase. A postpartum RA exacerbation is also noted in patients who have been in remission and had low RA activity antepartum. Dramatic withdrawal of DMARDs or biologics because of an unplanned pregnancy contributes to higher RA activity just in the first trimester of pregnancy. Pregnancy should be planned, by choosing stable anti-inflammatory therapy in advance.

T-Helper Cell Cytokine Expression Profiling in Rheumatoid Arthritis Patients by Flow Cytometric Bead Array Analysis

Background: Rheumatoid arthritis (RA) is the most common chronic autoimmune disease affecting multiple joints. A chronic imbalance in cytokine production by T-helper (Th) cells is likely a key factor in RA development. Our objective was to profile the serum cytokine expression from three key Th cell types (Th1, Th2, and Th17) in RA patients in order to correlate the resulting cytokine expression profiles with RA activity. Material and Methods: From a population of RA patients (n = 71) and healthy controls (n = 18), the serum concentra- tions of seven cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, and TNF-α) were analyzed by flow cytometric bead array (CBA). Results: The serum concentrations of all seven cytokines were significantly higher in RA patients than in healthy controls. Interestingly, the serum concentration profiles varied with the 28-joint Disease Activity Score (DAS28), a measure of RA activity derived from joint indices (tender joints and swollen joints count) and the erythrocyte sedimentation rate. In the high RA activity group (DAS28 > 5.1), all seven cytokines were significantly elevated. In the moderate RA activity group (DAS28 between 3.2 and 5.1), only IL-2, IL-6, IL-10, and IL-17A were significantly increased. In the low RA activity group (DAS28 ≤ 3.2), only IL-2, IL-4, and TNF-α were significantly elevated. Conclusions: The Th cell-derived cytokine expression profile significantly changes across varying levels of RA activity. Th1/Th17 cell-derived TNF-α and Th2 cell-derived IL-4 appear to play more important roles in the early stages of RA, while all seven cytokines derived from Th1, Th2, and Th17 cells (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, and TNF-α) are overtly involved in the advanced stages of RA.

TRENDS IN DISEASE ACTIVITY, FUNCTIONAL STATUS, AND RADIOGRAPHIC CHANGES IN EARLY RHEUMATOID ARTHRITIS: RESULTS OF A 5-YEAR FOLLOW-UP WITHIN THE RUSSIAN RADIKAL PROGRAM

Objective: to assess trends in disease activity, functional status, and radiographic changes, and their relationships in patients with early rheumatoid arthritis (RA). Subjects and methods. The investigation enrolled 200 patients with early RA included in the RADIKAL (Early arthritis: diagnosis, outcomes, criteria, active treatment) program in the period 2003 to 2007. The duration of the disease at inclusion was <2 years. RA diagnosis fulfilled the 1987 American College of Rheumatology (ACR) criteria. Rheumatoid factor was found in 67.5% of the patients and anti-cyclic citrullinated peptide antibodies were detected in 57%. 86.5% of patients were female; median age was 49 [40; 58] years. The patients received traditional disease-modifying antirheumatic drugs and biological agents (24%). Monitoring was made according to the tight control principle. Determination of main clinical and laboratory parameters, DAS28, HAQ disability index (DI) and functional class, as well as hands and feet X-ray were done every year. Results. There was stabilization of RA activity and functional status over 5 years. Median DAS28 at inclusion was 5.1 [4.49; 5.85], that after 1, 2, 3, 4, and 5 years was 3.05 [2.25; 4.43], 3.04 [2.07; 4.23], 2.55 [1.86; 3.74], 2.48 [1.78; 3.77], and 3.12 [1.86; 4.32], respectively. Median HAQ DI was 1.125 [0.625; 1.75], 0.5 [0.125; 1.0], 0.5 [0; 1.0], 0.5 [0; 1.0], 0.5 [0; 1.0], and 0.75 [0.125; 1.125], respectively. During the entire follow-up period, there was a stable positive correlation between DAS28 and HAQ DI (r = 0.61–0.77). Despite reductions in DAS28 and HAQ DI, destruction progressed. Joint erosions were seen in 16% of the patients at inclusion; and in 27.5, 38.5, 49.5, 58, and 73% at 1-, 2-, 3-, 4-, and 5-year of follow-up, respectively. Conclusion. The found positive correlation between DAS28 and HAQ DI suggests that lower RA activity has a favorable impact on the functional status of patients. However, irreversible structural joint changes continue to develop in the presence of persistent RA course, which can cause a higher HAQ score that may be noted after 5 years of follow-up.

USE OF MULTIPARAMETER ANALYSIS OF LABORATORY BIOMARKERS TO ASSESS RHEUMATOID ARTHRITIS ACTIVITY

The key component in the management of patients with rheumatoid arthritis (RA) is regular control of RA activity. The quantitative assessment of a patient’s status allows the development of standardized indications for anti-rheumatic therapy. Objective: to identify the laboratory biomarkers able to reflect RA activity. Subjects and methods. Fifty-eight patients with RA and 30 age- and sex-matched healthy donors were examined. The patients were divided into high/moderate and mild disease activity groups according to DAS28. The serum concentrations of 30 biomarkers were measured using immunonephelometric assay, enzyme immunoassay, and xMAP technology. Results and discussion . Multivariate analysis could identify the factors mostly related to high/moderate RA activity according to DAS28, such as fibroblast growth factor-2, monocyte chemoattractant protein-1, interleukins (IL) 1α, 6, and 15, and tumor necrosis factor-α and could create a prognostic model for RA activity assessment. ROC analysis has shown that this model has excellent diagnostic efficiency in differentiating high/moderate versus low RA activity. Conclusion. To create a subjective assessment-independent immunological multiparameter index of greater diagnostic accuracy than the laboratory parameters routinely used in clinical practice may be a qualitatively new step in assessing and monitoring RA activity.

Shared care or nurse consultations as an alternative to rheumatologist follow-up for rheumatoid arthritis (RA) outpatients with stable low disease-activity RA: cost-effectiveness based on a 2-year randomized trial

Objectives: To compare the cost-effectiveness of three types of follow-up for outpatients with stable low-activity rheumatoid arthritis (RA).Method: In total, 287 patients were randomized to either planned rheumatologist consultations, shared care without planned consultations, or planned nurse consultations. Effectiveness measures included disease activity (Disease Activity Score based on 28 joint counts and C-reactive protein, DAS28-CRP), functional status (Health Assessment Questionnaire, HAQ), and health-related quality of life (EuroQol EQ-5D). Cost measures included activities in outpatient clinics and general practice, prescription and non-prescription medicine, dietary supplements, other health-care resources, and complementary and alternative care. Measures of effectiveness and costs were collected by self-reported questionnaires at inclusion and after 12 and 24 months. Incremental cost-effectiveness rates (ICERs) were estimated in comparison with rheumatologist consultations.Results: Changes in disease activity, functional status, and health-related quality of life were not statistically significantly different for the three groups, although the mean scores were better for the shared care and nurse care groups compared with the rheumatologist group. Shared care and nurse care were non-significantly less costly than rheumatologist care. As both shared care and nurse care were associated with slightly better EQ-5D improvements and lower costs, they dominated rheumatologist care. At EUR 10 000 per quality-adjusted life year (QALY) threshold, shared care and nurse care were cost-effective with more than 90% probability. Nurse care was cost-effective in comparison with shared care with 75% probability.Conclusions: Shared care and nurse care seem to cost less but provide broadly similar health outcomes compared with rheumatologist outpatient care. However, it is still uncertain whether nurse care and shared care are cost-effective in comparison with rheumatologist outpatient care.