Regulatory B cells in rheumatoid arthritis: Alterations in patients receiving anti-TNF therapy.

Cytokines, including tumor necrosis factor alpha (TNFα) are involved in Rheumatoid arthritis (RA) pathogenesis by augmenting autoimmunity, sustaining long term inflammation in the synovium, and promoting joint damage. Anti-TNF therapy is one of the most efficient and widely used therapies for RA, although its mechanism is not clarified yet. Earlier we demonstrated that RA patients have a reduced number of IL-10 producing regulatory B cells (B10 cells) as compared to healthy individuals and they are functionally impaired. Our aim was to study the influence of anti-TNF therapy on B10 cells in RA, to follow the alteration of B cell activation markers (CD25, CD69) and to monitor the level of citrullinated peptid-specific antibodies and the secreted IL-10 in patients' sera during the therapy. We have observed that at six month after starting the therapy the frequency of B10 cells remarkably increased, while the expression of the activation marker, CD69 decreased on B cells. In contrast, serum levels of IL-10 and anti-citrullinated peptide antibodies did not change post-treatment. CONCLUSION: The reduced activation state of B cells and the increasing number of regulatory B10. cells might contribute to the therapeutic efficacy of anti-TNF agents in RA.

The development of candidate composite disease activity and responder indices for psoriatic arthritis (GRACE project).

OBJECTIVE: To develop new composite disease activity indices for psoriatic arthritis (PsA). METHODS: Data from routine clinic visits at multiple centres were collected in a systematic manner. Data included all domains identified as important in randomised controlled trials in PsA. Decisions to change treatment were used as surrogates for high disease activity. New indices were developed by multiple linear regression (psoriatic arthritis disease activity score: PASDAS) and empirically, utilising physician-defined cut-offs for disease activity (arithmetic mean of desirability functions: AMDF). These were compared with existing composite measures: Composite Psoriatic arthritis Disease Activity Index (CPDAI), Disease Activity for PSoriatic Arthritis (DAPSA), and Disease Activity Score for rheumatoid arthritis (DAS28). RESULTS: 161/503 (32%) subjects had treatment changes. Although all measures performed well, compared with existing indices, PASDAS was better able to discriminate between high and low disease activity (area under receiver operating curves (ROC)) curve with 95% CI: PASDAS 0.773 (0.723, 0.822); AMDF 0.730 (0.680, 0.780); CPDAI 0.719 (0.668, 0.770); DAPSA 0.710 (0.654, 0.766); DAS28 0.736 (0.680, 0.792). All measures were able to discriminate between disease activity states in patients with oligoarthritis, although area under the receiver operating curves (AUC) were generally smaller. In patients with severe skin disease (psoriasis area and severity index>10) both nonparametric and AUC curve statistics were nonsignificant for all measures. CONCLUSIONS: Two new composite measures to assess disease activity in PsA have been developed. Further testing in other datasets, including comparison with existing measures, is required to validate these instruments.

Disease burden of psoriatic arthritis compared to rheumatoid arthritis, Hungarian experiment.

The objectives of this study were to assess the costs of psoriatic arthritis (PsA) in Hungary and to identify key cost drivers among demographic and clinical variables and to compare cost-of-illness of PsA and rheumatoid arthritis (RA). Cross-sectional retrospective survey of 183 consecutive patients from eight rheumatology centres was conducted. Mean direct medical, direct non medical, indirect and total costs were 1,876, 794, 2,904 and 5,574 euros/patient/year, respectively. Total costs were in significant linear relationship with health assessment questionnaire score and psoriatic area severity index. Costs of RA were higher in all domains than of PsA. Our study was the first from the Eastern European region that provides cost-of-illness data on PsA. Our study revealed that functional status and severity of skin symptoms were the key cost drivers. The costs of PsA in Hungary were lower than in the high-income European countries.

Physician's Global Assessment in Psoriatic Arthritis: A Multicenter GRAPPA Study.

OBJECTIVE: Physician's global assessment (PGA) of disease activity is a major determinant of therapeutic decision making. This study assesses the reliability of the PGA, measured by means of 0-100 mm visual analog scale (VAS), and the additional use of separate VAS scales for musculoskeletal (PhysMSK) and dermatologic (PhysSk) manifestations in patients with psoriatic arthritis (PsA). METHODS: Sixteen centers from 8 countries enrolled 319 consecutive patients with PsA. PGA, PhysMSK, and PhysSk evaluation forms were administered at enrollment (W0) and after 1 week (W1). Detailed clinical data regarding musculoskeletal (MSK) manifestations, as well as dermatological assessment, were recorded. RESULTS: Comparison of W0 and W1 scores showed no significant variation (intraclass correlation coefficients were PGA 0.87, PhysMSK 0.86, PhysSk 0.78), demonstrating the reliability of the instrument. PGA scores were dependent on PhysMSK and PhysSk (p < 0.0001) with a major effect of the MSK component (B = 0.69) compared to skin (B = 0.32). PhysMSK was correlated with the number of swollen joints, tender joints, and presence of dactylitis (p < 0.0001). PhysSk scores were correlated with the extent of skin psoriasis and by face, buttocks or intergluteal, and feet involvement (p < 0.0001). Finally, physician and patient assessments were compared showing frequent mismatch and a scattered dot plot: PGA versus patient's global assessment (r = 0.36), PhysMSK versus patient MSK (r = 0.39), and PhysSk versus patient skin (r = 0.49). CONCLUSION: PGA assessed by means of VAS is a reliable tool to assess MSK and dermatological disease activity. PGA may diverge from patient self-evaluation. Because MSK and skin/nail disease activity may diverge, it is suggested that both PhysMSK and PhysSk are assessed.

[The role of biological agents in the treatment of psoriatic arthritis, literature review]. / A biológiai terápia szerepe az arthritis psoriatica gyógykezelésében (irodalmi attekintés).

INTRODUCTION: The recognition of the key pathogenetic role of TNF-alpha in psoriatic arthritis has made it possible to introduce new drugs in the treatment. TNF-alpha inhibitors available in Hungary (infliximab, etanercept, adalimumab) are potential therapies for patients who have not adequately responded to traditional disease-modifying antirheumatic drugs. OBJECTIVE: The aim of the study was to present the epidemiology and progression of psoriatic arthritis in Hungary based on national and international data, to assess the target population for biological therapy and to analyze their effectiveness, reviewing the available literature of randomized controlled trials. METHODS: The prevalence of psoriatic arthritis in Hungary was estimated using international data. Characteristics of psoriatic arthritis population were studied using the database of a rheumatology ward. A systematic literature search was performed to identify each relevant trial. A synthesis and comparison of the results from the 5 identified trials was performed and the average effect of biological agents was calculated. Both the fixed and the random effect model were used for the data synthesis; the results were probed with Mantel-Haenzel test. RESULTS: The prevalence of psoriatic arthritis is about 10.000-20.000 in Hungary. Average disease-duration was 10 years in the sample (n = 189), the most frequent was polyarticular form (51%). Regarding functional status the mean HAQ score was 1.46, with an average progression of 0.05 points/year. The trial data confirmed that biological agents are superior to placebo in improving symptoms (achieving ACR20); risk difference between biological treatments and placebo is 47% (RD = 0.47, 95% CI: 0.42-0.53). The biological treatment of 2 patients improves the status of 1 patient (NNT = 2.1 95% CI 1.9-2.4). There is no significant difference in efficacy between the three biological agents. CONCLUSIONS: TNF-alpha inhibitors are effective treatments of psoriatic arthritis and are safe under strict medical control. The principles of indications, contraindications, administration and control have been worked out by the Rheumatology and Physical Medicine Board.

Acceptability of less than perfect health states in rheumatoid arthritis: the patients' perspective.

Some health problems are considered by many individuals as a 'normal' part of ageing. Our aim was to investigate whether patients with rheumatoid arthritis (RA) consider different types and levels of health losses as acceptable beyond a certain age. A multicenter cross-sectional survey was performed involving RA patients at the initiation of the first biological therapy. The EQ-5D and the Health Assessment Questionnaire Disability Index (HAQ-DI) questionnaires were used to describe domain-specific health states. Patients were asked to indicate for each domain from what age and onward (between ages 30 and 80 years in 10 year intervals) they considered moderate and severe problems acceptable or alternatively never acceptable. Seventy-seven RA patients (females 86%, mean age 50.3, disease duration 9.1 years) completed the questionnaire. Disease activity (DAS28), EQ-5D and HAQ-DI scores were mean 6.00 (SD 0.85), 0.35 (SD 0.36), 1.48 (SD 0.66), respectively. The majority of the patients considered age 70 and beyond as acceptable to have some health problems (EQ-5D: self-care 42%, pain/discomfort 34%, mobility 33%, usual activities 33%, anxiety/depression 27%), whilst at ages 30 and 40 as not acceptable. Severe health problems were mostly (57-69%) considered never acceptable, except the 'Usual activities' domain (acceptable from age 80 by 50.6%). The great majority of the patients (77-96%) were younger than what they indicated as the acceptability age limit. Similar results were found for the HAQ-DI. This small experimental study suggests that RA patients consider some health problems acceptable. This acceptability is age related and varies by health areas. Further larger studies are needed to explore explanatory variables and to compare with other diseases. Owing to the impact acceptability might have on RA patients' self-evaluation of current health state and decision-making, the topic deserves methodological improvement and further investigation.

Patient global assessment in psoriatic arthritis: a multicenter GRAPPA and OMERACT study.

OBJECTIVE: During OMERACT 8, delegates selected patient global assessment (PGA) of disease as a domain to be evaluated in randomized controlled trials in psoriatic arthritis (PsA). This study assessed the reliability of the PGA, measured by means of 0-100 mm visual analog scale (VAS), and the additional utility of separate VAS scales for joints (PJA) and skin (PSA). METHODS: In total, 319 consecutive patients with PsA (186 men, 133 women, mean age 51 ± 13 yrs) were enrolled. PGA, PJA, and PSA were administered at enrolment (W0) and after 1 week (W1). Detailed clinical data, including ACR joint count, Psoriasis Area and Severity Index (PASI), and Hospital Anxiety and Depression Scale, were recorded. RESULTS: Comparison of W0 and W1 scores showed no significant variations (intraclass correlation coefficients for PGA 0.87, PJA 0.86, PSA 0.78), demonstrating the reliability of the instrument. PGA scores were not influenced by patient anxiety or depression, but were dependent on PJA and PSA (p = 0.00001). PJA was dependent on the number of swollen and tender joints (p < 0.00001). PSA scores were influenced by the extent of skin psoriasis and by hand skin involvement (p = 0.00001). Joint and skin disease were found not to correlate in terms of disease activity as evidenced by the swollen joint count compared to PASI (r = 0.11) and by the PJA compared to PSA (r = 0.38). CONCLUSION: PGA assessed by means of VAS is a reliable tool related to joint and skin disease activity. Because joint and skin disease often diverge it is suggested that in some circumstances both PJA and PSA are also assessed.

Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study.

INTRODUCTION: Gender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA). METHODS: The cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents. RESULTS: Women had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but the statistical significance was marginal. Similar proportions of females and males were taking different therapies. CONCLUSIONS: In this large multinational cohort, RA disease activity measures appear to be worse in women than in men. However, most of the gender differences in RA disease activity may originate from the measures of disease activity rather than from RA disease activity itself.

Natural autoantibodies reactive with glycosaminoglycans in rheumatoid arthritis.

INTRODUCTION: Although natural autoantibodies make up the majority of circulating immunoglobulins and are also present in high numbers in therapeutically used intravenous immunoglobulin preparations, they have received little attention and their precise role remains largely unknown. An increasing awareness of the importance of posttranslational autoantigen modifications and glycobiology led us to explore carbohydrate-reactive natural autoantibodies in patients with rheumatoid arthritis. This study examined systematic antibodies reactive to glycosaminoglycans (GAGs), the carbohydrate components of proteoglycans that are released in large amounts from degrading cartilage. METHODS: To measure antibodies reactive to six different types of GAGs, a specialised ELISA was used in which the carbohydrates were covalently linked to the plastic surface through a 2 nm spacer. Sera from rheumatoid arthritis patients (n = 66), umbilical cord serum samples (n = 11) and adult controls (n = 54) were studied. In order to explore cross-reactivity with microbial antigens, bacterial peptidoglycans and fungal polysaccharides were used. Sera and synovial fluid samples were also tested using a GlycoChip carbohydrate array to characterise individual carbohydrate recognition patterns. We followed a multistep statistical screening strategy for screening GAG-reactive antibodies as predictive disease markers. RESULTS: While anti-GAG antibodies were absent in the umbilical cord sera, they were readily detectable in adult controls and were significantly elevated in patients with rheumatoid arthritis (p < 0.001). Anti-GAG antibodies showed significant cross-reactivity among different types of GAGs. They also reacted with bacterial peptidoglycans and fungal polysaccharides. Interestingly, anti-chondroitin sulphate C IgM antibody levels showed inverse correlation both with the Disease Activity Score (DAS) 28 scores and C-reactive protein (CRP) levels in rheumatoid arthritis. CONCLUSION: The highly abundant and cross-reactive, GAG-specific natural autoantibodies in serum may serve as novel disease-state markers in patients with rheumatoid arthritis.

Clinical and genetic registries in psoriatic disease.

Clinical and genetic registries are an important tool in studying psoriasis and psoriatic arthritis (PsA). They assist in delineating disease features and are crucial in defining phenotype and identifying genetic and other markers of disease expression. At the 2007 Annual Meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), members of the clinical registries and genetics committees described several ongoing registries, including their construction, protocols, and some results from their analyses. In breakout groups, members discussed data issues, including identification of core datasets, ownership, and how to share data; and ethical issues and possible sources of funding for registries. Proceedings of these meetings are summarized.