The role of anti-citrullinated protein antibody reactivities in an inception cohort of patients with rheumatoid arthritis receiving treat-to-target therapy.

BACKGROUND: Anti-citrullinated protein antibody (ACPA) reactivities precede clinical onset of rheumatoid arthritis (RA), and it has been suggested that ACPA reactivities towards distinct target proteins may be associated with differences in RA phenotypes. We aimed to assess the prevalence of baseline ACPA reactivities in an inception cohort of patients with early RA, and to investigate their associations with disease activity, treatment response, ultrasound findings and radiographic damage. METHODS: Disease-modifying antirheumatic drug (DMARD)-naïve patients with early RA, classified according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria, were included in the ARCTIC trial and assessed in the present analysis. During follow up, patients were monitored frequently and treatment was adjusted according to a predetermined protocol, starting with methotrexate monotherapy with prednisolone bridging. Analysis of 16 different ACPA reactivities targeting citrullinated peptides from fibrinogen, alpha-1 enolase, vimentin, filaggrin and histone was performed using a multiplex chip-based assay. Samples from 0, 3, 12 and 24 months were analysed. Controls were blood donors with similar characteristics to the patients (age, gender, smoking status). RESULTS: A total of 217 patients and 94 controls were included. Median [25, 75 percentile] number of ACPA reactivities in all patients was 9 [4, 12], and were most prevalent in anti-cyclic citrullinated peptide /rheumatoid factor-positive patients 10 [7, 12]. Disease activity measures and ultrasound scores at baseline were lower in ACPA reactivity-positive compared to ACPA reactivity-negative patients. ACPA reactivity levels decreased after 3 months of DMARD treatment, most pronounced for fibrinogenß 60-74 to 62% of baseline antibody level, with least change in filaggrin 307-324 to 81% of baseline antibody level, both p < 0.001. However, outcomes in disease activity measures, ultrasound and radiographic scores after 12 and 24 months were not associated with baseline levels or changes in ACPA reactivity levels and/or seroreversion after 3 months. CONCLUSIONS: The clinical relevance of analysing ACPA reactivities in intensively treated and closely monitored early RA was limited, with no apparent associations with disease activity, prediction of treatment response or radiographic progression. Further studies in larger patient materials are needed to understand the role of ACPA reactivities in patients with RA classified according to the 2010 ACR/EULAR criteria and treated according to modern treatment strategies. TRIAL REGISTRATION: www.ClinicalTrials.gov, NCT01205854 . Registered on 21 September 2010.

Calprotectin as a marker of inflammation in patients with early rheumatoid arthritis.

OBJECTIVES: Calprotectin is an inflammatory marker of interest in rheumatoid arthritis (RA). We evaluated whether the level of calprotectin was associated with disease activity, and if it was predictive of treatment response and radiographic progression in patients with early RA. METHODS: Plasma from disease-modifying antirheumatic drug (DMARD)-naïve patients with RA fulfilling 2010 American College of Rheumatology/European League Against Rheumatism classification criteria with symptom duration <2 years was analysed for calprotectin at baseline, and after 1, 3 and 12 months. All patients received treat-to-target therapy, as part of a randomised controlled strategy trial (ARCTIC). The association between calprotectin, erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) and measures of disease activity were assessed by correlations. We used likelihood ratios and logistic regression models to assess the predictive value of the baseline inflammatory markers for treatment response and radiographic damage. RESULTS: 215 patients were included: 61% female, 82% anti-citrullinated peptide antibody positive, mean (SD) age 50.9 (13.7) years and median (25, 75 percentile) symptom duration 5.8 (2.8, 10.5) months. Calprotectin was significantly correlated with Clinical Disease Activity Index (r=0.32), ESR (r=0.50) and ultrasonography power Doppler (r=0.42) before treatment onset. After 12 months of treatment, calprotectin, but not ESR and CRP, was significantly correlated with power Doppler (r=0.27). Baseline levels of calprotectin, ESR and CRP were not predictive of treatment response, but high levels of calprotectin were associated with radiographic progression in multivariate models. CONCLUSIONS: Calprotectin was correlated with inflammation assessed by ultrasound before and during DMARD treatment, and was also associated with radiographic progression. The data support that calprotectin may be of interest as an inflammatory marker when assessing disease activity in different stages of RA. TRIAL REGISTRATION NUMBER: NCT01205854; Post-results.

Patients with seronegative RA have more inflammatory activity compared with patients with seropositive RA in an inception cohort of DMARD-naïve patients classified according to the 2010 ACR/EULAR criteria.

OBJECTIVES: To compare the presentation of seropositive and seronegative early rheumatoid arthritis (RA) in disease-modifying antirheumatic drug (DMARD)-naïve patients classified according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria. METHODS: All patients had symptom duration from first swollen joint <2 years and were DMARD naïve with an indication for DMARD treatment. Patients were stratified as seropositive (positive rheumatoid factor (RF)+ and/or anticitrullinated peptide antibody (ACPA)+) or seronegative (RF- and ACPA-), and disease characteristics were compared between groups. RESULTS: A total of 234 patients were included, and 36 (15.4%) were seronegative. Ultrasonography (US) scores for joints (median 55 vs 25, p<0.001) and tendons (median 3 vs 0, p<0.001), number of swollen joints (median 17 vs 8, p<0.001), disease activity score (DAS; mean 3.9 vs 3.4, p=0.03) and physician global assessment (mean 49.1 vs 38.9, p=0.006) were significantly higher in seronegative patients compared with seropositive. Total van der Heijde-modified Sharp score, Richie Articular Index and patient-reported outcome measures were similar between groups. CONCLUSIONS: Seronegative patients had higher levels of inflammation, assessed both clinically and by US, than seropositive patients. These differences may reflect the high number of involved joints required for seronegative patients to fulfil the 2010 ACR/EULAR classification criteria for RA. TRIAL REGISTRATION NUMBER: NCT01205854; Pre-results.

Sexually transmitted herpes simplex viruses.

Herpes simplex virus type 2 (HSV-2) is the dominant primary causative agent in genital ulcerative infections. Since infections with HSV-2 usually are acquired through sexual contacts, antibodies are rarely found before the age of onset of sexual activity. Although most genital infections are caused by HSV-2, a rising proportion has become attributable to primary type 1 herpes simplex virus (HSV-1) infection. Genital HSV-1 infections are usually both less severe clinically and less prone to recur. HSV-1 infection might render a certain protection against an HSV-2 infection and seems to mitigate the HSV-2 illness. It is not yet clear whether the advent of HSV-1 genitally will reduce the general occurrence of HSV-2. Increased efforts to protect against sexual transmission of the herpes viruses should have an effect on the transmission of other chronic diseases, such as the human immunodeficiency virus (HIV). In conclusion, it seems that increased sexual promiscuity and more advanced sexual techniques contribute to an unnecessary rise in prevalence of genital HSV infections, thus also affecting transmission of other genitally manifested diseases in targeted populations.