Anti-cyclic Citrullinated Peptide Antibody Status Research Articles

A Case of Posterior Scleritis with Negative Rheumatoid Factor and Positive Anti-Cyclic Citrullinated Peptide Antibody Status: Case Report

Background: Posterior scleritis is a potentially vision threatening condition which is often underdiagnosed due to varied clinical presentation, several non-infectious inflammatory diseases can cause this disorder, although infectious diseases should be ruled out. Case presentation: A 56 years-old-female with acute unilateral decreased vision in right eye and positive history for rheumatoid arthritis (RA) was referred, based on ophthalmic examination the diagnosis of posterior scleritis was considered. The only positive inflammatory marker was found is high serum titer of Anti-Cyclic Citrullinated Peptide (Anti-CCP). Conclusion: This is the first case of posterior scleritis with only positive Anti-CCP. Elevated serum Anti-CCP titer may be considered as risk factor for inflammatory scleritis in patient with RA.

Peripheral distributions of IL-4-producing CD4 + T cells and CD4 + CD25 + FoxP3 + T cells (Tregs) in rheumatoid arthritis patients with poor response to therapy are associated with HLA shared epitope alleles and ACPA status.

Specific profiling of CD4 + T cell subsets in the circulation and inflamed joints of rheumatoid arthritis (RA) patients may have therapeutic implications. This study aimed to evaluate the peripheral distributions of Th2 and Treg cells in relation to HLA-shared epitope (SE) alleles and anti-cyclic citrullinated peptide antibody (ACPAs) status in patients with good response (GR) and poor response (PR) to treatment. The frequencies of IL-4-producing CD4 + T cells (Th2) and CD4 + CD25 + Foxp3 + T cells (Tregs) were determined by flow cytometry in 167 RA patients including 114 GR and 53 PR cases. CD4 + T cell subsets were also analyzed based on HLA-SE and ACPAs statuses. One hundred nine of 167 patients were positives for HLA-SE, 63.4% for ACPAs, 43.7% for SE/ACPAs and 14.9% were negatives for SE/ACPAs. Higher frequencies of Th2 (P = 0.001) and Treg cells (P = 0.03) were found in the patients versus controls. Increased and decreased frequencies of Th2 and Tregs cells were observed in the PR versus GR patients respectively (P = 0.003 and P = 0.004). Higher proportions of Th2 cells were observed in the SE+RA versus SE-RA (P = 0.001), in ACPA+RA versus ACPA-RA (P = 0.005) and in the SE+ACPA+RA versus SE-ACPA-RA patients (P = 0.002). Treg cells frequencies decreased in the SE+RA versus SE-RA (P = 0.03) and in SE+ACPA+RA versus SE-ACPA-RA (P = 0.02). ACPA+GR and SE+PR patients showed higher proportions of Th2 cells than ACPA-GR and SE-PR patients respectively (P = 0.02 and P = 0.01). Analysis of the CD4 + T cell subsets profiles in conjunction with genetic background and autoantibodies patterns can be useful for precise therapeutic response monitoring in the RA patients.

Soluble programmed death molecule 1 (sPD-1) as a predictor of interstitial lung disease in rheumatoid arthritis

BackgroundPrevious studies have indicated that the programmed death molecule 1 (PD-1) signaling pathway may play a key role in rheumatoid arthritis (RA). However, the pathogenesis of rheumatoid arthritis-related interstitial lung disease (RA-ILD) is not clear. We examined the serum levels of soluble PD-1 in patients with RA and its relationship with RA-ILD.MethodsBlood samples were obtained from 87 patients with RA (58 with ILD and 29 without ILD) and 45 healthy controls. Serum sPD-1 was measured by Enzyme-Linked Immunosorbent Assay. The pulmonary interstitial disease score was completed by a pulmonary physician and a radiologist through chest high-resolution computed tomography. Patients with RA-ILD were tested for lung function [e.g., forced vital capacity (FVC%), diffusing capacity of lungs for carbon monoxide (DLCO%)]. Associations between ILD and various markers, including sPD-1 and confounding factors, were investigated by logistic regression analysis. Diagnostic values of sPD-1 for the presence of ILD were investigated using receiver operating characteristic curve analysis.ResultsSerum sPD-1 levels were higher in RA patients with ILD than in RA patients without ILD and healthy controls (185.1 ± 109.0 pg/ml vs. 119.1 ± 77.5 pg/ml vs. 52.1 ± 21.7 pg/ml, P < 0.05). Serum sPD-1 levels were positively correlated with RF titer (P = 0.02, r = 0.249), anti-cyclic citrullinated peptide antibody status (P = 0.02, r = 0.243), and serum IgG levels (P < 0.001, r = 0.368), negatively associated with FVC% (P = 0.02, r = − 0.344), forced expiratory volume (FEV1%) (P = 0.01, r = − 0.354), total lung capacity (TLC%) (P = 0.046, r = − 0.302), and was independently associated with the presence of ILD in RA patients by multivariate logistic regression analysis. The sensitivity and specificity of sPD-1 levels for the detection of ILD in RA patients were 58.6% and 75.9%, respectively. The area under the curve was 0.689.ConclusionSerum sPD-1 levels were increased in RA patients with ILD. Increased sPD-1 may be a valuable biomarker to predict the presence of ILD in patients with RA.

Efficacy and safety of sarilumab in combination with csDMARDs or as monotherapy in subpopulations of patients with moderately to severely active rheumatoid arthritis in three phase III randomized, controlled studies

BackgroundThe interleukin-6 receptor inhibitor sarilumab demonstrated efficacy in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or as monotherapy in patients with moderately to severely active rheumatoid arthritis (RA) with an inadequate response (IR) or intolerant (INT) to methotrexate (MTX) or tumour necrosis factor (TNF)-α inhibitors. This analysis investigated the efficacy and safety of sarilumab in patient subgroups.MethodsData were included from phase III studies: two placebo-controlled studies of subcutaneous sarilumab 150/200 mg every 2 weeks (q2w) either + MTX in MTX-IR patients (52 weeks) or + csDMARDs in TNF-IR/INT patients (24 weeks), and a monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w in MTX-IR/INT patients (24 weeks). Prespecified and post hoc subgroups included patient demographics, disease characteristics, and prior treatments. Prespecified and post hoc endpoints included clinical, radiographic, and physical function measures, and p values are considered nominal. Safety was assessed during double-blind treatment.ResultsThe superiority of sarilumab (either as monotherapy vs. adalimumab or in combination with csDMARDs vs. placebo + csDMARDs) across clinical endpoints was generally consistent across subgroups defined by patient demographics, disease characteristics, and prior treatments, demonstrating the benefit of sarilumab treatment for a wide range of patient types. Interaction p values of < 0.05 were consistently observed across studies only for baseline anti-cyclic citrullinated peptide antibody (ACPA) status for American College of Rheumatology 20% response, but not American College of Rheumatology 50% or 70% response. Adverse events and worsening laboratory parameters occurred more frequently in sarilumab-treated vs. placebo-treated patients and were more frequent in the small number of patients ≥ 65 years (n = 289) vs. patients < 65 years (n = 1819). Serious infections occurred in six patients aged ≥ 65 years receiving sarilumab, although the incidence of serious infections was generally higher in patients aged ≥ 65 years regardless of treatment.ConclusionsApart from ACPA status, there were no consistent signals indicating differential effects of sarilumab in any of the subpopulations assessed. Sarilumab demonstrated consistent efficacy and safety across a wide range of patients with RA.Trial registrationClinicalTrials.gov NCT01061736, registered on February 03, 2010; ClinicalTrials.gov NCT01709578, registered on October 18, 2012; ClinicalTrials.gov NCT02332590, registered on January 07, 2015

Glycation marker glucosepane increases with the progression of osteoarthritis and correlates with morphological and functional changes of cartilage in vivo

BackgroundChanges of serum concentrations of glycated, oxidized, and nitrated amino acids and hydroxyproline and anticyclic citrullinated peptide antibody status combined by machine learning techniques in algorithms have recently been found to provide improved diagnosis and typing of early-stage arthritis of the knee, including osteoarthritis (OA), in patients. The association of glycated, oxidized, and nitrated amino acids released from the joint with development and progression of knee OA is unknown. We studied this in an OA animal model as well as interleukin-1β-activated human chondrocytes in vitro and translated key findings to patients with OA.MethodsSixty male 3-week-old Dunkin-Hartley guinea pigs were studied. Separate groups of 12 animals were killed at age 4, 12, 20, 28 and 36 weeks, and histological severity of knee OA was evaluated, and cartilage rheological properties were assessed. Human chondrocytes cultured in multilayers were treated for 10 days with interleukin-1β. Human patients with early and advanced OA and healthy controls were recruited, blood samples were collected, and serum or plasma was prepared. Serum, plasma, and culture medium were analyzed for glycated, oxidized, and nitrated amino acids.ResultsSeverity of OA increased progressively in guinea pigs with age. Glycated, oxidized, and nitrated amino acids were increased markedly at week 36, with glucosepane and dityrosine increasing progressively from weeks 20 and 28, respectively. Glucosepane correlated positively with OA histological severity (r = 0.58, p < 0.0001) and instantaneous modulus (r = 0.52–0.56; p < 0.0001), oxidation free adducts correlated positively with OA severity (p < 0.0009–0.0062), and hydroxyproline correlated positively with cartilage thickness (p < 0.0003–0.003). Interleukin-1β increased the release of glycated and nitrated amino acids from chondrocytes in vitro. In clinical translation, plasma glucosepane was increased 38% in early-stage OA (p < 0.05) and sixfold in patients with advanced OA (p < 0.001) compared with healthy controls.ConclusionsThese studies further advance the prospective role of glycated, oxidized, and nitrated amino acids as serum biomarkers in diagnostic algorithms for early-stage detection of OA and other arthritic disease. Plasma glucosepane, reported here for the first time to our knowledge, may improve early-stage diagnosis and progression of clinical OA.

The impact of anti-cyclic citrullinated peptide antibody status on the management of patients with early rheumatoid arthritis: observational study results from Lithuania.

Background.To provide data on the use of anti-cyclic citrullinated peptide antibody (anti-CCP) and other routinely used clinical parameters and to assess the impact of anti-CCP status on therapeutic decisions, an observational study was conducted in patients with rheumatoid arthritis (RA).Methods.Sixty-seven adult patients with a recent diagnosis of RA were recruited from four rheumatology centres in Lithuania and were prospectively observed for 12 months. Data collection was based on the review of medical records and routine examination of patients. Patients completed the Health Assessment Questionnaire – Disability Index and Patient Global Assessment of disease activity using a visual analogue scale. Physicians were asked about the importance of the anti-CCP results and other factors important for therapeutic decisions.Results.Of the 67 patients enrolled, 54 (80.6%) completed the study. At the beginning of the study, physicians considered anti-CCP results to be important for decision-making in 87.0% of patients. The perceived importance of anti-CCP results did not change significantly throughout the study. After one year of treatment, factors that were considered more important than the anti-CCP results included the presence of erosions, significantly increased C-reactive protein, duration of morning stiffness, multi-articular expanding, and rheumatoid factor status. For nearly half of the patients (n = 26; 48.1%), physicians would not change the treatment strategy if the patient had the opposite anti-CCP results at baseline.Conclusions.The study revealed that decision-making in the management of RA was based on multifactorial data. The role of anti-CCP as a single test in treatment decisions needs further investigation.

Comparative evaluation of treatment patterns and healthcare utilization of newly-diagnosed rheumatoid arthritis patients by anti-cyclic citrullinated peptide antibody status

Background: Anti-cyclic citrullinated peptide (CCP) antibody positivity is an established diagnostic factor for severe disease activity and joint damage and a prognostic factor for aggressive disease in rheumatoid arthritis (RA).Objective: To compare RA-related treatment, healthcare utilization, and joint erosion between anti-CCP-positive and anti-CCP-negative RA patients.Methods: Newly-diagnosed RA patients were identified from the Henry Ford Health System database between January 1, 2009 and December 31, 2014; the date of the first RA diagnosis within the study period was the index date. Baseline anti-CCP test was used to categorize patients as anti-CCP-positive or anti-CCP-negative, and outcomes were evaluated in the 6 months post-index.Results: There were 217 anti-CCP-positive and 191 anti-CCP-negative RA patients included in the study. A higher proportion of anti-CCP-positive patients were initiated on RA treatment than anti-CCP-negative patients (70.5% vs 23.0%; p < .0001). More anti-CCP-positive patients received methotrexate (73.2% vs 56.8%; p = .0374), while more anti-CCP-negative patients received hydroxychloroquine (31.8% vs 13.1%; p = .0037) in first-line therapy. A higher proportion of anti-CCP-negative patients were tested for rheumatoid factor (RF) and erythrocyte sedimentation rate (ESR). Of those tested, there were more positive test results in the anti-CCP-positive cohort compared to the anti-CCP-negative cohort (RF: 84.4% vs 18.2%, p < .0001; C-reactive protein [CRP]: 69.7% vs 48.3%, p = .0008; and ESR: 89.5% vs 53.9%, p < .0001). Outpatient utilization predominated, with more anti-CCP-positive patients having any outpatient physician office visit (96.3% vs 77.5%, p < .0001) and a higher mean number of visits (5.3 vs 2.5, p < .0001) than anti-CCP-negative patients. Among anti-CCP-positive (n = 113) and anti-CCP-negative (n = 58) patients with imaging results, more anti-CCP-positive patients had joint erosion compared to anti-CCP-negative patients (18.6% vs 8.6%; p = .0858); however, statistical significance was not reached.Conclusion: RA patients with positive anti-CCP antibodies had higher degrees of inflammation and disease activity as indicated by laboratory results, which likely contributed to their higher rates of healthcare utilization, joint erosion, and proportions of RA treatment.

Left ventricular function at two-year follow-up in treatment-naive rheumatoid arthritis patients is associated with anti-cyclic citrullinated peptide antibody status: a cohort study

Objectives: In rheumatoid arthritis (RA), the role of autoimmunity, especially anti-cyclic citrullinated peptide antibody (anti-CCP) level, and the time-course of left ventricular (LV) function is unknown. The objective was to assess LV function and the amount of coronary calcium in relation to anti-CCP levels in a cohort of treatment-naive RA patients, and to assess changes in these parameters during a 2 year follow-up period.Method: Sixty-six steroid- and disease-modifying anti-rheumatic drug-naive RA patients were treated with methotrexate according to the Danish national guidelines. We assessed LV function by conventional echocardiography and speckle-tracking echocardiography. We estimated the amount and progression of coronary calcium by coronary computed tomography. Patients were examined at the time of diagnosis and after 2 years.Results: Patients with elevated anti-CCP at baseline and after 2 years, compared to those with non-persistently elevated anti-CCP, had significantly less improvement in S´ (1 ± 1.4 cm/s vs 0.2 ± 0.9 cm/s; p = 0.04) and a worsening in global longitudinal systolic strain (GLS) (0.6 ± 1.8% vs −1 ± 2.8%; p = 0.04). There was a significant correlation between ΔGLS over 2 years and anti-CCP at 2 year follow-up (r = 0.36; p = 0.006). We observed a small progression of coronary calcium score during the 2 year follow-up period. No differences in progression were found between patients with high anti-CCP titres at baseline and 2 year follow-up (n = 12) and patients with normal/low anti-CCP titres (n = 32) (23.8 ± 40.3 vs 22.6 ± 68.9; p = 0.96).Conclusions: Deformation analysis by speckle-tracking echocardiography is a valuable tool to detect early development of myocardial dysfunction despite normal ejection fraction in RA.

AB0440 What effect does the presence of bronchiectasis have on CCP antibody levels in patients with rheumatoid arthritis?

BackgroundIt is well established that anti cyclic citrullinated peptide (CCP) antibodies are a marker of rheumatoid arthritis (RA) and are associated with greater articular damage [1]. There is increasing evidence...

AB0362 Tight control of disease activity by conventional DMARDs could minimize the use of biological therapies in patients with early rheumatoid arthritis: Data from an early arthritis clinic in hong kong

ObjectivesTo examine the treatment outcome at 1 year of patients treated with tight control of the disease in a prospective cohort of patients with newly diagnosed rheumatoid arthritis (RA).MethodsAll patients...

A systematic review and meta-analysis of pregnancy as a protective factor against rheumatoid arthritis

Backgroundand objectivesThe female preponderance of rheumatoid arthritis (RA) implies that reproductive factors may play an important role in its pathogenesis. Although several studies have shown an inverse association between previous...

Long-term stability of anti-cyclic citrullinated peptide antibody status in patients with early inflammatory polyarthritis

IntroductionThe utility of reassessing anti-cyclic citrullinated peptide (anti-CCP) antibody status later in disease in patients presenting with early undifferentiated inflammatory polyarthritis, particularly in those who test negative for both anti-CCP and rheumatoid factor (RF) at baseline, remains unclear. We aimed therefore to determine the stability of CCP antibody status over time and the prognostic utility of repeated testing in subjects with early inflammatory polyarthritis (IP).MethodsAnti-CCP and RF were measured at baseline and 5 years in 640 IP patients from the Norfolk Arthritis Register, a primary care-based inception cohort. The relation between change in anti-CCP status/titer and the presence of radiologic erosions, the extent of the Larsen score, and Health Assessment Questionnaire (HAQ) score by 5 years was investigated.ResultsWith a cut-off of 5 U/ml, 28% subjects tested positive for anti-CCP antibodies, 29% for RF, and 21% for both at baseline. Nine (2%) anti-CCP-negative patients seroconverted to positive, and nine (4.6%) anti-CCP-positive individuals became negative between baseline and 5 years. In contrast, RF status changed in 17% of subjects. However, change in RF status was strongly linked to baseline anti-CCP status and was not independently associated with outcome. Ever positivity for anti-CCP antibodies by 5 years did not improve prediction of radiographic damage compared with baseline status alone (accuracy, 75% versus 74%). A higher baseline anti-CCP titer (but not change in anti-CCP titer) predicted worse radiologic damage at 5 years (P < 0.0001), even at levels below the cut-off for anti-CCP positivity. Thus, a titer of 2 to 5 U/ml was strongly associated with erosions by 5 years (odds ratio, 3.6 (1.5 to 8.3); P = 0.003).ConclusionsRepeated testing of anti-CCP antibodies or RF in patients with IP does not improve prognostic value and should not be recommended in routine clinical practice.

Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA–DRB1 shared epitope, regardless of rheumatoid factor or anti–cyclic citrullinated peptide antibody status

Smoking is associated with rheumatoid arthritis (RA) in individuals with the HLA-DRB1 shared epitope (SE). SE alleles have been shown to be predominantly associated with anti-cyclic citrullinated peptide (anti-CCP)-positive RA. These risk factors have not been identified for anti-CCP-negative RA. The aim of this study was to investigate whether SE-containing HLA-DRB1 alleles, smoking, or the combination of these factors contributes to the development of RA, depending on the presence or absence of serologic markers, in a Korean population. All of the patients with RA (n =1,482) and all of the control subjects (n = 1,119) were Korean. Four-digit HLA-DRB1 typing was performed by a conventional polymerase chain reaction-sequence-based typing method. Information about smoking history was obtained through a questionnaire. The patients with RA were tested for anti-CCP antibodies and rheumatoid factor (RF). The SE alleles had significant effects on anti-CCP antibody and RF formation. The DRB1*0901 allele was associated with the presence of anti-CCP antibodies (odds ratio [OR] 2.49) and RF (OR 2.09). SE alleles and smoking were associated with both anti-CCP-positive and anti-CCP-negative RA. The combination of smoking and double copies of the SE allele increased the risk of anti-CCP-positive RA 36.11-fold and increased the risk of anti-CCP-negative RA 12.29-fold, compared with the risk among nonsmokers not carrying SE alleles. Interactions between SE alleles and smoking were observed for both anti-CCP-positive and RF-positive RA, although the associations of RF-positive RA could be consequences of the underlying anti-CCP antibody status. We demonstrated that the combination of SE alleles and smoking is associated with RA susceptibility regardless of anti-CCP antibody or RF status, but that the combination shows stronger effects in anti-CCP-positive/RF-positive patients with RA than in anti-CCP-negative/RF-negative patients with RA. The SE-smoking interactions were present in anti-CCP-positive and RF-positive RA.