anti-CCP Research Articles

Association of Red Cell Distribution Width and Mean Platelet Volume With Disease Activity in Rheumatoid Arthritis Patients.

The inner layer of the synovial joints is the primary target of rheumatoid arthritis, or RA, a chronic systemic inflammatory disorder that is linked to increasing disability, early mortality, and economic hardships. The objective is to determine the association of red cell distribution width (RDW) and mean platelet volume (MPV) with disease activity in RA. A retrospective study was conducted between July 2021 and January 2022 in the outpatient rheumatology clinics at Gulab Devi Teaching Hospital. In this study, 100 consecutive participants with a diagnosis of RA fulfilling the ACR/EULAR 2010 classification criteria were enrolled. Patient's records were reviewed for age, gender, length of illness, smoking status, treatment history, current treatment regimen, concomitant medications, rheumatoid factor (RF), anti-cyclic citrulline peptide (anti-CCP) antibodies, and extra-articular manifestations. Laboratory investigations were reviewed for complete blood count including RDW and MPV, ESR, CRP, liver, and renal functions. Disease activity score DAS 28-ESR was used to quantify disease activity. To determine the relationship between different parameters and the RDW and MPV, linear regression research was conducted. According to the DAS28 score, 12% of patients were in remission, 9% had low, 34% had moderate, and 45% had high disease activity. DAS28 score was 5.01±1.72 (2.45-9.32) and RDW was 16.18±4.42. There was a strong positive correlation (r = 0.653) of RDW with the DAS28 score and it was statistically significant (p<0.001). MPV was 11.30±2.09 fL. There was a moderately positive correlation (r = 0.366) of MPV with the DAS28 score and it was statistically significant (p<0.001). Conclusively, both RDW and MPV are positively related to disease activity in patients with RA. These can be used as a simple tool for assessing disease activity and guiding the treatment.

Phytotherapeutic potential of compounds identified from fractionated extracts of Morus alba L., as an inhibitor of interleukin-6 in the treatment of rheumatoid arthritis: computational approach

The presence of HLA-DRB1 alleles that encode critical points associated with environmental interactions is associated with increased risk of rheumatoid arthritis caused by anti-citrullinated protein antibodies. Therefore, interleukin-6 (IL-6), a multifunctional cytokine that controls both local and systemic acute inflammatory responses through its ability to induce a phase response, plays a serious role. Its overexpression leads to pathological challenges such as rheumatoid arthritis and menopausal osteoporosis. However, targeting the IL-6 receptor and its region could be the major step in controlling the overexpression of this cytokine for therapeutic importance. Therefore, our research explored the computational insight needed to investigate the anti-RFA potential of phytochemicals from fractionated extracts of Morus alba L. against receptors, which have been implicated as druggable targets for the treatment of rheumatoid arthritis. In this study, fifty-nine (59) previously isolated and characterized phytochemicals from M. alba L. were identified from the literature and retrieved from the PubChem database. In silico screening was used to assess the mode of action of these phytochemicals from M. alba L. against receptors that may serve as therapeutic targets for rheumatoid arthritis. Molecular docking studies, toxicity prediction, drug visualization and molecular dynamics simulation (MD) of the ligands together with the receptor-identified target were carried out using the Schrodinger Molecular Drug Discovery Suite. The findings indicated that a selected group of ligands displayed significant binding strength to specific amino acid residues, revealing an important link between the building blocks of proteins (amino acids) and ligands at the inhibitor binding site through traditional chemical interactions, such as interactions between hydrophobic and hydrogen bonds. The binding affinities of the receptors were carefully checked via comparison with those of the approved ligands, and the results suggested structural and functional changes in the lead compounds. Therefore, the bioactive component from M. alba L. could be a lead foot interleukin-6 (IL-6) inhibitor and could be a promising lead compound for the treatment of rheumatoid arthritis and related challenges. Communicated by Ramaswamy H. Sarma

Identification of early risk factors for anti-citrullinated-protein-antibody positive rheumatoid arthritis-a prospective cohort study.

Individuals positive for anti-cyclic-peptide-antibodies (anti-CCP) and musculoskeletal complaints (MSK-C) are at risk for developing rheumatoid arthritis (RA). In this study we aimed to investigate factors involved in arthritis progression. Anti-CCP2-positive individuals with MSK-C referred to a rheumatologist were recruited. Individuals lacked arthritis at clinical and ultrasound examination and were followed for ≥three years or until clinical arthritis diagnosis. Blood samples from inclusion were analyzed for; nine anti-citrullinated-protein-antibody (ACPA) reactivities (citrullinated α-1-enolase, fibrinogen, filaggrin, histone, vimentin and tenascin peptides); 92 inflammation-associated proteins; and HLA-shared epitope alleles. Cox regression was applied to the data to identify independent predictors in a model. 267 individuals were included with median follow up of 49 months (IQR: 22-60). 101 (38%) developed arthritis after median 14 months (IQR: 6-27). The analysis identified that presence of at least one ACPA reactivity (HR 8.0, 95% CI 2.9-22), ultrasound detected tenosynovitis (HR 3.4, 95% CI 2.0-6.0), IL6 levels (HR 1.5, 95% CI 1.2-1.8) and IL15-Rα levels (HR 0.6, 95% CI 0.4-0.9) are significant independent predictors for arthritis progression in a prediction model (Harrell's C 0.76 [SE 0.02], AUC 0.82 [95% CI 0.76-0.89], cross-validated AUC 0.70 [95% CI 0.56-0.85]). We propose a high-Risk-RA phase characterized by presence of ACPA reactivity, tenosynovitis, IL6, and IL15-Rα and suggest that these factors need to be further investigated for their biological effects and clinical values, to identify individuals at particular low risk and high risk for arthritis progression.

Essential role of local antibody distribution in mediating bone-resorbing effects

The link between antibodies and bone mass is debated. Activated IgG, which interacts directly with Fc gamma receptors, stimulates osteoclastogenesis in vitro, and local injection in immune-activated mice leads to bone loss. Multiple myeloma patients with high serum IgG levels have induced osteoclast activation and display bone loss. In addition, bone loss has been linked to serum autoantibodies in autoimmune diseases, including anti-citrullinated protein antibodies (ACPA) in individuals with rheumatoid arthritis (RA). Whether serum IgG or autoantibodies regulate bone mass under healthy conditions is poorly studied. In elderly men, neither serum levels of polyclonal IgG nor autoantibody were associated with areal bone mineral density in the MrOS Sweden study. Repetitive systemic injections of high-dose polyclonal IgG complexes in mice did not exert any discernible impact on bone mineral density. However, repetitive local intra-articular injection of the same IgG complexes led to a localized reduction of trabecular bone density. These results indicate antibodies may only impact bone density when close to the bone, such as within the synovial joint.

Dynamics of modified cardiovascular risk factors in patients with rheumatoid arthritis on the background of 5-year therapy with an interleukin 6 receptor inhibitor

The effect of an inhibitor of interleukin (IL) 6 receptors on the state of the cardiovascular system in patients with rheumatoid arthritis (RA) remains poorly understood, especially with its long-term use.The aim – to study the effect of therapy with the IL-6 receptor inhibitor tocilizumab (TCZ) on the dynamics of modifiable risk factors (RF), total cardiovascular risk (CVR), structural changes in the carotid arteries (CA) and the incidence of cardiovascular complications (CVC) in patients with rheumatoid arthritis during the 260-week follow-up period.Material and methods. The study included 37 patients with active RA (32 women and 5 men) with ineffectiveness and/or intolerance to disease modifying anti-rheumatic drugs (DMARDs); median age was 56 [48; 68] years, disease duration was 92 [49; 158] months; DAS28 (Disease Activity Score 28) – 6.2 [5.5; 6.7] points; all patients were seropositive for rheumatoid factor (RF), 86% – for antibodies to cyclic citrullinated peptide (ACCP). Patients received TCZ therapy 8 mg/kg intravenously every 4 weeks; after 192 [176; 210] weeks, 60% of patients switched to subcutaneous administration of the drug at a dose of 162 mg once a week. In 51% of patients with RA, TCZ monotherapy was performed, in 49% – combination therapy of TCZ with DMARDs. Statins were received by 17 (46%) patients, including 7 patients before and 10 after inclusion in the study. All patients underwent an assessment of traditional risk factors, the total cardiovascular risk was calculated using the mSCORE scale, atherosclerotic vascular lesions were assessed by the detection of atherosclerotic plaques (ASP) of CA. The observation period was 260.4 [251.5; 283.4] weeks.Results. After 260 weeks of TCZ therapy, RA remission was observed in 32 (86%) patients, low activity – in 5 (14%) patients. During the observation period, the frequency of modified RF and the total CVR did not change significantly, an increase in body mass index (BMI) by 11% was recorded, the number of patients with hypercholesterolemia and a reduced level of HDL cholesterol (C) decreased. In patients without statin therapy, there were no significant changes in the blood lipid spectrum. In the group of patients receiving statins, there was an increase in HDL-C by 43%, a decrease in cholesterol levels by 15%, atherogenic index (AI) by 56% (p&lt;0.01 in all cases) and associations between the dynamics of ∆cholesterol and ∆CRP (r=0.35; p=0.04), ∆LDL-C and ∆CRP (r=0.41; p=0.03). Significant structural changes in CA in RA patients by the end of 260 weeks of TCZ therapy were not identified. Initially, intima-media thickness (IMT) CA positively moderately correlated with age (r=0.7; p&lt;0.01), BMI (r=0.37; p&lt;0.01), systolic blood pressure (SBP) (r=0.62; p&lt;0.01) and weakly with lipid spectrum parameters – cholesterol (r=0.29; p&lt;0.01), LDL-C (r=0.36; p&lt;0.01). No new associations of IMT CA by the end of the observation, as well as the relationship of the IMT CA value with the indicators of RA activity and the ongoing therapy, were identified. By the end of the study, the distribution of patients by mSCORE value and CVR level did not change significantly. The incidence of CVC was 0,54 per 100 patient-years over a 260-week period of TCZ use. Conclusion. Against the background of long-term TCZ therapy in RA patients, there was no increase in CVR and significant structural changes in CA. It is necessary to dynamically monitor the blood lipid profile and CVR in RA patients receiving TCZ therapy. Statin therapy can successfully control dyslipidemia in RA patients who receive long-term TCZ.

Macrophage extracellular traps require peptidylarginine deiminase 2 and 4 and are a source of citrullinated antigens bound by rheumatoid arthritis autoantibodies.

Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis, but the sources of citrullinated antigens as well as which peptidylarginine deiminases (PADs) are required for their production remain incompletely defined. Here, we investigated if macrophage extracellular traps (METs) could be a source of citrullinated proteins bound by APCAs, and if their formation requires PAD2 or PAD4. Thioglycolate-induced peritoneal macrophages from wild-type, PAD2-/-, and PAD4-/- mice or human peripheral blood-derived M1 macrophages were activated with a variety of stimulants, then fixed and stained with DAPI and either anti-citrullinated histone H4 (citH4) antibody or sera from ACPA+ or ACPA- rheumatoid arthritis subjects. METs were visualized by immunofluorescence, confirmed to be extracellular using DNase, and quantified. We found that ionomycin and monosodium urate crystals reliably induced murine citH4+ METs, which were reduced in the absence of PAD2 and lost in the absence of PAD4. Also, IgG from ACPA+, but not ACPA-, rheumatoid arthritis sera bound to murine METs, and in the absence of PAD2 or PAD4, ACPA-bound METs were lost. Finally, ionomycin induced human METs that are citH4+ and ACPA-bound. Thus, METs may contribute to the pool of citrullinated antigens bound by ACPAs in a PAD2- and PAD4-dependent manner, providing new insights into the targets of immune tolerance loss in rheumatoid arthritis.

Radiological Progression and Predictors of Radiological Progression in Early Rheumatoid Arthritis Treated with Conventional Synthetic Disease-modifying Agents

Aim: To study the clinical and serological predictors of radiological progression at one year in a cohort of Indian patients with early rheumatoid arthritis (RA). Methods: In this prospective open-label observational study, consecutive patients with early RA (&lt;six months) were examined at baseline and at each visit (0, 3, 6, 9 and 12 months) for disease activity, DAS ESR 28 and European League Against Rheumatism response. Radiography of the hands and feet was performed at baseline and at one year of treatment, and radiologic progression was assessed using van der Heijde’s Sharp score. The prognostic factors were evaluated using a logistic regression model. Results: Fifty-one eligible patients were analysed for disease outcomes, whereas 43 were eligible for radiographic progression. The mean duration of RA was 3.4 ± 1.85 months. At baseline, 96% of the patients had moderate to high disease activity. The proportion of patients with erosions increased from 16.3% to 37.2% at one year, whereas that of patients with joint space narrowing (JSN) increased from 21% to 39.5%. At one year, the mean increase in total Sharp’s score was 1.67, while 32.5% of patients had radiological progression. Age of onset, presence of erosions, JSN, anticitrullinated protein antibody (ACPA) titre and tender joint counts at baseline were associated with radiographic progression at one year. However, in the multivariate analysis, none of the variables predicted radiographic damage. Only JSN was positively associated with progression at one year. Conclusion: Age at onset, presence of erosions, JSN, ACPA titre and tender joint counts at baseline were associated with radiographic progression at one year, but further studies are required to confirm these results.

Reproductive Effect by Rheumatoid Arthritis and Related Autoantibodies.

Rheumatoid arthritis (RA) is a common inflammatory arthritis in women. The effects of RA on the reproductive system are usually overlooked, as RA is not diagnosed until later in reproductive age. Whether RA itself or its related rheumatoid antibodies have an impact on female reproductive function has long been a thought-provoking issue. In brief, relevant epidemiological evidence has shown that women affected by RA are more likely to have coexisting reproductive disorders, including infertility, endometriosis, and premature ovarian insufficiency (POI), or to subsequently develop them. Furthermore, linkage between RA and pregnancy loss (PL) as well as polycystic ovary syndrome (PCOS) is also well known, albeit controversial in available evidence. RA and reproductive disorders appear to share a similar inflammatory immune response and genetic background. The stress experienced by patients with RA may affect their reproductive choices to some extent. Notably, few studies have explored the impact of rheumatoid antibodies such as rheumatoid factors (RFs) and anti-citrullinated protein antibodies (ACPAs) on reproductive disorders. Although it has been mentioned that the rate of RF and/or ACPA positivity is higher in women with a history of PL and POI, the clinical relevance of this relationship and underlying mechanisms still need to be further clarified.

Predictors at diagnosis for start of biologic disease-modifying antirheumatic drugs in patients with early rheumatoid arthritis: a cohort study

ObjectivesTo investigate the relation between patient characteristics at rheumatoid arthritis (RA) diagnosis and subsequent initiation of treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs).DesignA retrospective cohort...

Limited Diagnostic and Prognostic Value of Routine Radiographs in Newly Presenting Arthritis Suspected of Rheumatoid Arthritis: A Retrospective Study.

Current recommendations suggest that patients with newly presenting arthritis suspected of rheumatoid arthritis (RA) should undergo routine radiographs of hands and feet (X-HF) as the presence of RA-associated erosions might be of diagnostic and prognostic value. Our objective was to investigate the prevalence, diagnostic, and prognostic value of RA-associated erosions seen on routine X-HF in a large, recent cohort of patients with newly presenting arthritis. A retrospective cohort study was performed between 2016 and 2019 in patients with newly presenting arthritis suspected of RA. Patients were included if arthritis was present at diagnosis, rheumatoid factor and anticitrullinated protein antibodies were measured, RA was noted in the differential diagnosis, and routine X-HF were conducted. Outcomes were the prevalence of one or more RA-associated erosion(s), and whether diagnostic or prognostic classification were changed by erosivity. Seronegative patients, patients without acute phase reactants, and patients with longer symptom duration were analyzed as subgroups. RA-associated erosions were found in 32 of 724 patients (4.4%, 95% confidence interval [95% CI] 3.1-6.2). Erosions led to a change of diagnostic classification in two patients (0.3%, 95% CI 0.01-1.1) and changed prognostic classification in three patients (0.4%, 95% CI 0.1-1.3). Seronegative patients and patients without elevated acute phase reactants had significantly lower prevalence of erosions (χ2 9.4, P = 0.002, χ2 6.5, P = 0.01). Longer symptom duration was not associated with a different prevalence of erosions (χ2 0.4, P = 0.81). The recommendation of conducting routine X-HF in patients with newly presenting arthritis suspected of RA might be reconsidered due to low prevalence of early erosive disease and lack of diagnostic and prognostic value.

Comparative effectiveness of abatacept versus TNF inhibitors in rheumatoid arthritis patients who are ACPA and shared epitope positive

BackgroundThe HLA-DRB1 shared epitope (SE) is a risk factor for the development of rheumatoid arthritis (RA) and the production of anti-citrullinated protein antibodies (ACPAs) in RA patients. Our objective was to examine the real-world effectiveness of abatacept versus tumor necrosis factor inhibitors (TNFi) in patients with RA who were SE and anti-cyclic citrullinated peptide antibody (anti-CCP3) positive.MethodsAbatacept or TNFi initiators who were SE + and anti-CCP3+ (> 20 U/mL) at or prior to treatment and had moderate or high CDAI score (> 10) at initiation were identified. The primary outcome was mean change in CDAI score over six months. Analyses were conducted in propensity score (PS)-trimmed and -matched populations overall and a biologic-experienced subgroup. Mixed-effects models were used.ResultsIn the overall PS-trimmed (abatacept, n = 170; TNFi, n = 157) and PS-matched cohorts (abatacept, n = 111; TNFi, n = 111), there were numerically greater improvements in mean change in CDAI between abatacept and TNFi but were not statistically significant. Similar trends were seen for biologic-experienced patients, except that statistical significance was reached for mean change in CDAI in the PS-trimmed cohort (abatacept, 12.22 [95% confidence interval (95%CI) 10.13 to 14.31]; TNFi, 9.28 [95%CI 7.08 to 11.48]; p = 0.045).ConclusionIn this real world cohort, there were numerical improvements in efficacy outcomes with abatacept over TNFi in patients with RA who were SE + and ACPA+, similar to results from a clinical trial population The only statistically significant finding after adjusting for covariates was greater improvement in CDAI with abatacept versus TNFi in the bio-experienced PS-trimmed cohort..

Search for predictors of methotrexate toxicity in rheumatoid arthritis

Aim. To determine prognostic markers of methotrexate (MT) toxicity in rheumatoid arthritis (RA).Materials and methods. The study included 294 patients with RA who were prescribed MT at a dose of 10 to 25 mg per week for the first time as basic anti-inflammatory therapy (BPVT). The following adverse events (AEs) were recorded: hepatotoxicity, toxicity from the gastrointestinal tract, blood system. Qualitative parameters were considered as possible predictors of MT intolerance: gender, obesity, smoking, systemic manifestations, as well as rheumatoid factor (RF), antibodies to cyclic citrullinated peptide (ACCP), intake of glucocorticosteroids (GCS), form of administration of MT; and quantitative: age of RA onset, baseline disease activity according to DAS28 (Disease Activity Score 28) and HAQ (Health Assessment Questionnaire), MT dose. Statistical processing was performed by one-factor methods using Pearson’s χ2 test with Yates correction, Fisher’s exact two-tailed test, Mann–Whitney U-test, and Student’s t-test. Multivariate analysis was carried out by binary logistic regression.Results. In a univariate analysis, significant results were obtained for hepatotoxicity: a direct correlation with the use of corticosteroids at the onset (odds ratio (OR) 2.0; 95 % confidence interval (CI) 1.1–3.8, p = 0.03), inversely correlated with MT tablet intake (OR 0.5, 95 % CI 0.2–0.95, p = 0.03). According to the results of multivariate analysis, hepatotoxicity was recorded more often when taking GCS in the debut 2.01 times (95 % CI 1.02–3.96, p = 0.043), and in the presence of ACCP – 3.16 times (95 % CI 1.06–9.45, p = 0.039); and less frequently when taking tableted MT by 2.62 times (95 % CI 0.17–0.84, p = 0.017). Gastrointestinal toxicity tends to be associated with a younger age of RA onset (p = 0.06) and greater RA HAQ activity at onset (p = 0.07).Conclusions. Hepatotoxicity is more expected in patients seropositive for ACCP and GCS treatment in the onset of RA, but is less common when taking MT tablets. AEs from the gastrointestinal tract are associated with a younger age of onset of the disease and a greater degree of activity according to the HAQ index.

Prognostic value of serum protein electrophoresis constituents for arthritis development in anti-citrullinated protein antibody-positive patients with musculoskeletal pain

Objective Predictors of arthritis development in patients with anti-citrullinated protein antibodies (ACPAs) and musculoskeletal symptoms are needed for risk stratification and to improve clinical outcomes. The aim of this study was to assess the relationship between serum protein electrophoresis (SPE) constituents and the development of clinical arthritis in ACPA-positive patients with musculoskeletal pain. Method We prospectively followed 82 ACPA-positive patients with musculoskeletal pain but no baseline arthritis during a median of 72 months (interquartile range 57–81 months). The primary outcome was arthritis development, as judged by clinical examination. SPE constituents were evaluated in baseline sera by immunoturbidimetric methods. Serum levels of the analysed proteins (albumin, orosomucoid, α1-anti-trypsin, haptoglobin, and immunoglobulins IgA, IgG, and IgM) were related to arthritis development by Cox regression analyses. Results During the follow-up period, 39/82 patients (48%) progressed to arthritis. Median baseline levels of orosomucoid and α1-anti-trypsin were higher in patients who developed arthritis than in those who did not (p = 0.04), while median albumin levels were significantly lower (p = 0.03). Immunoglobulin levels did not differ between the groups. Univariable analysis demonstrated a significantly increased risk of arthritis with elevated baseline haptoglobin [hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.32–4.85, p = 0.005] and orosomucoid levels (HR 2.63, 95% CI 1.09–6.31, p = 0.03). However, neither remained significant in multivariable analysis adjusting for elevated C-reactive protein (CRP) levels. Conclusion SPE does not add prognostic value for arthritis development in ACPA-positive patients with musculoskeletal pain.

Long-term mortality in treated-to-target RA and UA: results of the BeSt and IMPROVED cohort

ObjectivesTo study long-term (up to 20-year) mortality of two treat-to-target trial cohorts in undifferentiated arthritis (UA) and early rheumatoid arthritis (RA).MethodsThe BeSt (BehandelStrategieën) study (n=508, early RA) was performed between...

Clinical significance of behavioral type “a” in patients suffering from rheumatoid arthritis

According to modern concepts, rheumatoid arthritis is a classic psychosomatic disease that leads to a decrease in the quality of life of patients and their early disability. To date, few foreign and domestic studies have examined the relationship between behavioral type “A” and rheumatoid arthritis. The clinical significance of behavioral type A in patients with rheumatoid arthritis has been studied to determine new therapeutic and diagnostic approaches. As part of a one-stage (cross-sectional) study, 74 people suffering from rheumatoid arthritis were examined during the year, which were represented by two groups, in accordance with the diagnosed behavioral type. The first group consisted of 22 patients suffering from rheumatoid arthritis with behavioral type A, and the second group consisted of 52 patients suffering from rheumatoid arthritis with behavioral type B. All patients received standard basic and anti-inflammatory therapy in the form of methotrexate at a dose selected individually. The duration of adequate basic therapy corresponded to the incidence of rheumatoid arthritis in both groups. Patients with behavioral type A were characterized by lower immunological activity, manifested, among other things, by a lower level of antibodies to cyclic citrullinated peptide and C-reactive protein, whereas the frequency of erosive lesions was higher. The presence of behavioral type A in patients with rheumatoid arthritis is a risk factor for the development of atherosclerotic damage. A personal negative quality, i. e. , hostility, which is included as one of the characteristics of behavioral type “A,” has a reliable direct relationship with the number of erosions, and significantly, its value directly correlates with the incidence of rheumatoid arthritis. Thus, the stratification of patients suffering from rheumatoid arthritis, according to the presence of behavioral type “A,” demonstrates the clinical and laboratory features of the disease and may be important for the development of new therapeutic and diagnostic approaches and the provision of therapeutic and preventive interventions in these patients

Rheumatoid Arthritis and Pericardial Effusion - A Unique Major Manifestation.

Pericardial effusion is common in the setting of rheumatoid arthritis (RA); however, it is rarely its first manifestation. An 82-year-old male presented with abdominal pain, vomiting and fever. Blood analysis revealed elevated systemic inflammatory markers, and an abdominal computed tomography scan revealed non-specific alveolar condensation of the right pulmonary base and pericardial effusion subsequently quantified as medium size by transthoracic echocardiography. A large aetiological panel was requested, with the autoimmunity study revealing high levels of rheumatoid factor (RF) and anti-citrullinated cyclic peptide (anti-CCP) antibodies. Since the patient did not present articular involvement, the initial hypothesis was pericardial effusion due to pneumonia and no specific treatment for RA was started. At follow-up, the pericardial effusion recurred and a pericardiocentesis was performed. The pericardial fluid analysis was sterile, and no malignant cells were identified. A new serological study confirmed high levels of RF and anti-CCP antibodies, and immunomodulatory treatment was initiated. After one year, the pericardial effusion recurred due to non-compliance with immunomodulatory therapy. A surgical pleuro-pericardial window was performed, and the cytological study of the pericardial patch revealed submesothelial thickening and foci of perivascular lymphocytic infiltrate. The patient remained asymptomatic. After exclusion of a large spectrum of infectious and non-infectious causes and the relapse after suspension of immunomodulatory treatment, the most probable aetiology for the pericardial effusion remains RA. Pericardial syndromes can be the first manifestation of AR even in the absence of articular symptoms and this disease must be considered in the aetiological investigation. The occurrence of pericardial effusion in the setting of rheumatoid arthritis (RA) is a usual finding but this form of extra-articular manifestation is possibly the first and only presentation of the disease.In the case of recurrent pericardial effusion, the diagnosis of RA must be considered in the aetiological investigation even in the absence of more common manifestations of the disease.

Identification of circulating autoantibodies to non-modified proteins associated with ACPA status in early rheumatoid arthritis.

To discover autoantibodies to non-modified proteins associated with the presence/absence of anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA). The autoantibody repertoire of 80 ACPA negative and 80 ACPA positive RA subjects from the Swedish population-based Epidemiological Investigation of RA (EIRA) cohort was screened using a suspension bead array built on protein fragments earlier described as autoimmunity targets. Four autoantibodies positive in the initial screening were validated in another set of EIRA samples containing 317 ACPA-positive, 302 ACPA-negative and 372 age- and sex-matched controls. The relationship between the four autoantibodies and lung abnormalities on high-resolution computed tomography (HRTC) was examined in 93 early RA patients from LURA cohort. Association between the autoantibodies, smoking and MHC class II alleles was assessed by logistic regression analysis. : Anti-ANOS1 and anti-MURC IgG levels were associated with ACPA-positive status (OR = 3.02; 95% CI 1.87-4.89; and OR = 1.86; 95% CI 1.16-2.97, respectively) and increased in ACPA-positive patients compared with controls. Anti-ANOS1 IgG was associated with smoking habit (OR = 2.11; 95% CI 1.22-3.69) and anti-MURC IgG with the presence of the MHC class II "shared-epitope" genes (OR = 1.95; 95% CI 1.11-3.46). Anti-TSPYL4 IgG was associated with ACPA-negative (OR = 0.41; 95% CI 0.19-0.89). Anti-TSPYL4 IgG and anti-MAP2K6 IgG levels were increased in the ACPA-negative patients compared with controls. Presence of anti-MAP2K6 IgG and anti-TSPYL4 IgG correlated negatively with HRCT-defined lung abnormalities. These four autoantibodies may be useful in diagnostics and in predicting clinical phenotypes of RA.

Frequency of Positive Anti-CCP Antibodies in Rheumatoid Arthritis Patients with Negative Rheumatoid Factor

Background: Rheumatoid arthritis (RA) is a polyarticular autoimmune disease that affects about 1% of the adult population. The disease is characterized by synoviocyte hyperplasia, mainly synovial fibroblasts, resulting in bone and joint destruction. Recent studies have shown that cytokines and other systemic inflammation mediators have a key role in the development ofrheumatoid arthritis. Recently, Anti-Citrullinated Protein Antibodies (anti-CCP) have come into use for the diagnosis of rheumatoid arthritis (RA). It has been reported that anti-CCP has quite a high specificity for RA (98%), together with sensitivity similar to that for rheumatoid factor (RF). The study aimed to determine the frequency of positive anti-CCP antibodies in rheumatoid arthritis patients with negative rheumatoid factor.&#x0D; Methods: 91 patients (both male and females) aged 40-70years with negative RF were clinically diagnosed with rheumatoid arthritis. Patients with positive rheumatoid factor and joint injuries were disclaimed. The consultant pathologist used a second-generation enzyme-linked immunosorbent assay (ELISA) to assess the serum levels of anti-CCP antibodies, &gt;20IU/ ml is considered positive p-value of 0.05 were considered statistically significant.&#x0D; Results: In the study, the age range was 40 to 70 years, averaging 53.44 ± 7.16 years. 59 (64.84%) of the patients were between the ages of 40 and 55. Of 91 patients, 56 (61.54%) were women, and 35 (38.46%) were men with aratio of 1.6:1 man to women. In patients with negative rheumatoid factors, 27 (40.66%) patients were found to have the levels of positive anti-CCP antibodies.&#x0D; Conclusion: Patients with negative rheumatoid factor showed the high frequency of positive anti-CCP.

Synovial-tissue resident macrophages play proinflammatory functions in the pathogenesis of RA while maintaining the phenotypes in the steady state

Synovial tissue-resident macrophages (STRMs) maintain normal joint homeostasis in a steady state. However, it is unclear whether STRMs still play homeostatic roles or change the functions in the joint of rheumatoid arthritis (RA), where infiltrating peripheral blood monocyte-derived macrophages (PBMoMs) play proinflammatory roles. In the present study, we examined changes in the phenotypes and functions of STRMs in response to RA-related stimuli in vitro. STRMs were prepared from non-inflammatory osteoarthritis (OA) joint synovium, which is histologically indistinguishable from normal joint synovium. PBMoMs were prepared and used for comparison. After stimulation with plate-bound IgG, which mimics anti-citrullinated protein antibody immunocomplex formed in RA joints, or with combinations of RA-related inflammatory mediators, namely tumor necrosis factor-α (TNF-α) and prostaglandin E2 or interferon-γ, PBMoMs downregulated surface markers and genes associated with anti-inflammatory macrophages, and upregulated cytokine and marker genes of proinflammatory macrophages in RA. On the other hand, STRMs hardly changed the expression of surface molecules and marker genes but altered the pattern of cytokine gene expression after stimulation like PBMoMs. Furthermore, in vitro stimulated STRMs promote proinflammatory functions of cocultured synovial fibroblasts. Thus, STRMs might play proinflammatory roles in RA joints, while maintaining their phenotypes in the steady state.

Plasma TNF-α Elevation in Biologic Naive Rheumatoid Arthritis Patients Belonging to a Population with New Mutations in TLR4 and CYP51A1 genes without Association with Disease-Related Antibodies Levels.

In a system biology-based study, we previously reported that IL-6 and IL6R -specific m-RNA levels were elevated in leukocytes of patients with Rheumatoid arthritis (RA). Here, the association of toll-like receptor4 (TLR4) rs 141534085 and cytochrome P450 family 51 subfamily A member 1(CYP51A1) rs6 with tumor necrosis factor-α (TNF- α), rheumatoid factor (RF)- and Anti- cyclic citrullinated peptide (anti-CCP) antibody -positivity was investigated in almost the same subjects. Forty-six patients and 48 normal subjects were recruited in this study. The blood leucocytes TLR4 rs 141534085 and CYP51A1 rs6 -comprising DNA sequences were amplified by using tetra-primer amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR) technique and the PCR products were checked by Sanger DNA sequencing method. ELISA method was used to determine plasma levels of TNF- α, anti-CCP antibody and RF positivity of plasma was evaluated through a latex agglutination test. The TNF- α level was significantly higher in the patient group than control subjects (p= 0.001). Moreover, we were not able to find any correlation between TNF-α levels and RF as well as anti-CCP antibodies when we used the K2/ Fisher's exact test and Pearson test respectively. Our DNA sequencing data revealed the following new mutations in TLR4 rs141534085 comprising regions: A>T in position 1050, T>A in position 1052, and C>A in position 1054; and for CYP51A1 rs6 encompassing region, the new mutations were; G>A in position 21680, the T nucleotide was inserted in position 21762 and the G nucleotide was inserted in position 21763, G>T in position 21764. The data of this study showed that both TLR4 rs141534085 and CYP51A1 rs6 related DNA regions should be considered as hotspot areas in RA pathogenicity. Moreover, these data indicated that, TNF- α did not alter the production of anti-CCP and RF pathogenic antibodies in patients with long-term RA.