Cross-sectional survey of the undergraduate rheumatology curriculum in European medical schools: a EULAR School of Rheumatology initiative.

OBJECTIVES: To survey the undergraduate rheumatic and musculoskeletal diseases (RMDs) curriculum content in a sample of medical schools across Europe. METHODS: The undergraduate musculoskeletal diseases and disability curriculum of University of Nottingham, UK, was used as a template to develop a questionnaire on curriculum content. The questionnaire elicited binary (yes/no) responses and included the option to provide additional information as free text. The survey was mailed to members of the European League Against Rheumatism (EULAR) School of Rheumatology (Undergraduate Classroom) and to EULAR Standing Committee on Education and Training members in January 2017, with a reminder in February 2017. RESULTS: Responses were received from 21 schools belonging to 11 countries. Assessment of gait, hyperalgesic tender site response and hypermobility were not included in many curricula. Similarly, interpretation of investigations undertaken on synovial fluid was taught in only 16 schools. While disease-modifying anti-rheumatic drugs and biological agents, and urate-lowering treatment were included in the curricula of 20 and 21 institutions, respectively, only curricula from 18 schools included core non-pharmacological interventions. Osteoarthritis, gout, rheumatoid arthritis, spondyloarthropathy, polymyalgia rheumatica and lupus were included in the curriculum of all institutions. However, common RMDs such as calcium pyrophosphate deposition, fibromyalgia, giant cell arteritis and bone and joint infection were included in 19 curricula. CONCLUSION: This survey highlights areas of similarities and differences in undergraduate curricula across Europe. It is hoped that the results of this survey will catalyse the development and agreement of a minimum core European Curriculum for undergraduate education in RMDs.

The ability of systemic biochemical markers to reflect presence, incidence, and progression of early-stage radiographic knee and hip osteoarthritis: data from CHECK.

OBJECTIVE: To relate systemic biochemical markers of joint metabolism to presence, incidence, and progression of early-stage radiographic knee and/or hip osteoarthritis (OA). METHOD: The cartilage markers uCTX-II, sCOMP, sPIIANP, and sCS846, bone markers uCTX-I, uNTX-I, sPINP, and sOC, and synovial markers sHA and sPIIINP were assessed by enzyme-linked immunosorbent assay or radioactive immunoassay in baseline samples of CHECK (Cohort Hip and Cohort Knee), a cohort study of early-stage symptomatic knee and/or hip OA. Knee and hip radiographs were obtained at baseline and 5-year follow-up. Presence of OA at baseline was defined as Kellgren and Lawrence (K&L) = 1 (maximum observed). Incidence of OA was defined as K&L = 0 at baseline and K&L ≥ 1 at 5-year follow-up. Progression of OA was defined as K&L = 1 at baseline and K&L ≥ 2 at 5-year follow-up. RESULTS: Data were available for 801 subjects at baseline and for 723 subjects at both baseline and 5-year follow-up. Multiple cartilage and synovial markers showed positive associations with presence and progression of knee and hip OA and with incidence of hip OA, except for negative associations of uCTX-II and sCOMP with incidence of knee OA. uCTX-II and sCOMP showed multiple interactions with other biomarkers in their associations with knee and hip OA. Bone markers were positively associated with presence of radiographic knee OA, but negatively associated with progression of radiographic hip OA. CONCLUSION: Especially metabolism in cartilage and synovial matrix appear to be of relevance in knee and hip OA. The role of bone metabolism appears to differ between knee and hip OA.

Association between serum levels of the proinflammatory protein S100A8/A9 and clinical and structural characteristics of patients with established knee, hip, and hand osteoarthritis.

OBJECTIVES: To explore the association between S100A8/A9 serum levels with clinical and structural characteristics of patients with established knee, hip, or hand osteoarthritis (OA). METHOD: A cross-sectional exploratory study was conducted with 162 OA patients. Measures for pain, stiffness, and function included the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) questionnaire or the Australian Canadian Osteoarthritis Hand (AUSCAN) Index and for structural abnormalities, osteophytes and joint space narrowing grades. The association between S100A8/A9 and clinical or structural characteristics was analysed using linear regression or logistic regression where appropriate. RESULTS: The mean age of the OA patients was 56 years, 71% were female, and 61% had a Kellgren and Lawrence (K&L) score ≥ 2. The serum S100A8/A9 level did not differ between knee, hip, and hand OA patients and no association was found between serum S100A8/A9 and clinical characteristics. The serum S100A8/A9 level was negatively associated with the sum score of osteophytes after adjusting for sex and body mass index (BMI) [adjusted ß -0.015, 95% confidence interval (CI) -0.030 to 0.001, p = 0.062] and positively associated with erythrocyte sedimentation rate (ESR) > 12 mm/h (adjusted OR 1.002, 95% CI 1.000-1.004 p = 0.049) for each increase in S100A8/A9 of 1 ng/mL. For hand OA patients, a negative association of S100A8/A9 with sum score of joint space narrowing was found (adjusted ß -0.007, 95% CI -0.016 to 0.001, p = 0.099). CONCLUSIONS: The results from this cross-sectional exploratory study do not support an important role for serum S100A8/A9 levels as a biomarker for clinical and structural characteristics in established knee, hip, and hand OA patients. The inverse association with structural abnormalities and the positive association with ESR may reflect inflammatory synovial processes in patients with OA before structural abnormalities occur.

The efficacy of abatacept in reducing synovial T cell activation by CD1c myeloid dendritic cells is overruled by the stimulatory effects of T cell-activating cytokines.

OBJECTIVE: To investigate whether the potential of abatacept to inhibit vigorous CD1c myeloid dendritic cell (MDC)-driven activation of naive and memory CD4 T cells is abrogated in the presence of T cell-activating cytokines. METHODS: CD4 T cell subsets (naive [Tn], central memory [Tcm], and effector memory [Tem] T cells) were isolated from the peripheral blood (PB) of healthy controls and the PB and synovial fluid (SF) of rheumatoid arthritis (RA) patients. CD4 T cells were cocultured with autologous, thymic stromal lymphopoietin (TSLP)-primed CD1c MDCs in the presence or absence of abatacept (CTLA-4Ig) and/or interleukin-7 (IL-7) or IL-15. Subsequently, T cell proliferation and cytokine production were measured. RESULTS: The percentages of each CD4 T cell subset from the circulation of healthy controls and RA patients were comparable and mainly consisted of Tn and Tcm cells, whereas the SF of RA patients mainly consisted of Tcm and Tem cells. Activation of CD4 T cell subsets by TSLP-primed MDCs from the RA PB was completely blocked by abatacept. Addition of IL-7 or IL-15 to the cocultures strongly increased CD4 T cell activation and overruled the inhibitory capacity of abatacept. IL-7-induced reversal was associated with robust induction of interferon-γ, tumor necrosis factor α, and IL-17 secretion. Similarly, CD4 T cell proliferation induced by TSLP-primed MDCs from the SF of RA patients was strongly blocked by abatacept, but this inhibitory effect was vigorously overruled in the presence of IL-7. CONCLUSION: These findings indicate that the presence of T cell-activating cytokines such as IL-7 or IL-15 in the joints of RA patients reduces the capacity of abatacept to inhibit MDC-driven CD4 T cell activation. This mechanism may be one explanation for the partial, and sometimes absent, response to abatacept therapy in a subset of patients.

The course of ultrasonographic abnormalities in knee osteoarthritis: 1 year follow up.

OBJECTIVE: Imaging of (peri)articular structures and inflammation with Ultrasonography (US) during the course of osteoarthritis (OA) might contribute to knowledge about early diagnosis of OA, prognosis and possibly the effect of disease modifying drugs. Our goal was to identify the prevalence of distinct patterns (stable vs fluctuating) in a set of US features in a cohort of patients receiving standard multimodal treatment for knee OA at T = 0, T = 3 months and T = 12 months. DESIGN: This was a prospective, explorative study including 55 patients fulfilling the American College of Rheumatology clinical criteria for knee OA. Six US features were investigated including: effusion, synovial proliferation, infrapatellar bursitis, meniscal protrusion, Baker's cyst and cartilage thickness at three time points during 1 year. A composite inflammatory score was composed. Overall prevalence was assessed as well as individual patterns which were appointed as stable or unstable. RESULTS: Inflammation like effusion and synovial hypertrophy does occur in over 40% of patients at some time in the year of follow up and shows a fluctuating pattern. Meniscal protrusion and Baker's cyst however are more stable features. CONCLUSIONS: Our study gives insight in the prevalence and course of US abnormalities in patients with knee OA and contributes to the knowledge on the possible role of this imaging modality in research.

Embitterment in patients with a rheumatic disease after a disability pension examination: occurrence and potential determinants.

OBJECTIVES: Health care and vocational professionals regularly encounter patients with rheumatic diseases who are embittered after a disability pension examination. People who are embittered typically feel victimised, experience resentment and injustice, resist help, and have difficulty coping. Our objective was to examine the occurrence of embitterment in patients with rheumatic diseases after a disability pension examination and the association of embitterment with its possible determinants helplessness and illness invalidation at work. METHODS: The Illness Cognition Questionnaire (ICQ), Illness Invalidation Inventory (3*I), and Bern Embitterment Inventory were completed by patients who had 9 to 12 weeks earlier received the result of a disability pension examination. Diagnoses were fibromyalgia (n=103), rheumatoid arthritis (n=46), osteoarthritis (n=158), another rheumatic disease (n=62), and more than one rheumatic disease (n=187). Scores were compared to scores of reference groups. Hierarchical regression analyses were conducted. RESULTS: Eighteen to 27 percent of patients had high levels of embitterment with no differences between diagnostic groups (p=0.71). Helplessness (p<0.001), the two invalidation dimensions discounting and lack of understanding (p<0.001), and the combination of helplessness with these invalidation dimensions (p<0.01), were predictive of more embitterment. CONCLUSIONS: Our results suggest that, after a disability pension examination, embitterment is present in about one out of five patients with a rheumatic disease. This is problematic insofar as embitterment limits well-being, functioning, and the potential to reintegrate to work. To the extent that helplessness and invalidation at work are causal determinants of embitterment, interventions targeting these aspects may be key to reduce embitterment.

Are changes in bone mineral density different between groups of early rheumatoid arthritis patients treated according to a tight control strategy with or without prednisone if osteoporosis prophylaxis is applied?

UNLABELLED: Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early rheumatoid arthritis (RA) patients receiving preventive treatment for osteoporosis. A small increase in lumbar bone mineral density (BMD) during the first year of treatment was recorded, regardless of use of glucocorticoids. INTRODUCTION: This study aims to describe effects on BMD of treatment according to EULAR guidelines with a methotrexate-based tight control strategy including 10 mg prednisone daily versus the same strategy without prednisone in early RA patients who received preventive therapy for osteoporosis. METHODS: Early RA patients were included in the CAMERA-II trial: a randomized, placebo-controlled, double-blind 2-year trial, in which effects of addition of 10 mg prednisone daily to a methotrexate-based tight control strategy were studied. All patients received calcium, vitamin D and bisphosphonates. Disease activity was assessed every 4 weeks. Radiographs of hands and feet and dual-energy X-ray absorptiometry of lumbar spine and left hip were performed at baseline and after 1 and 2 years of treatment. RESULTS: BMD increased significantly over time in both treatment groups at the lumbar spine with a mean of 2.6% during the first year (p<0.001), but not at the hip; at none of the time points did BMD differ significantly between the prednisone and placebo group. Higher age and lower weight at baseline and higher disease activity scores during the trial, but not glucocorticoid therapy, were associated with lower BMD at both the lumbar spine and the hip in mixed-model analyses. CONCLUSION: Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early RA patients on bisphosphonates. A small increase in lumbar BMD during the first year of treatment was found, regardless of use of glucocorticoids.

Ultrasonographic analysis in knee osteoarthritis: evaluation of inter-observer reliability.

OBJECTIVES: Evidence for the validity of US in detecting structural joint pathology in OA is increasing. However, despite the rapidly emerging field of US in OA, few studies have reported on the inter-observer reliability of US to date. The objective of this study was to assess inter-observer reliability of ultrasonography (US) in the evaluation of specifically defined features in osteoarthritis (OA) of the knee. METHODS: US was performed independently by two rheumatologists in 60 outpatients fulfilling the American College of Rheumatology clinical criteria for knee OA. The acquisition protocol comprised medial meniscus protrusion, synovial hypertrophy, effusion, infrapatellar bursitis and cartilage thickness. Cartilage thickness and meniscal protrusion (if >3 mm) were measured on a continuous scale, all other variables were scored dichotomously. RESULTS: Inter-observer agreement (κ-value) was moderate for protrusion of the medial meniscus (0.54), good for infrapatellar bursitis (0.66) and effusion (0.74), excellent for Bakers' cyst (0.85) and poor for the detection of synovial hypertrophy (-0.08). Inter-observer reliability was good for the measurement of medial meniscus protrusion (correlation coefficient 0.80, 95% limits of agreement -1.93 to 1.94 mm) and cartilage thickness (correlation coefficient 0.62 and 0.68, 95% limits of agreement -0.87 to 0.84 mm and -0.77 to 0.96 mm at the medial and lateral condyle respectively). CONCLUSIONS: This study demonstrated good reproducibility of US in the assessment of the majority of the investigated mechanical, inflammatory and degenerative features of knee OA, and contributes to exploring the use of US in knee OA as a useful tool in research as well as in clinical practice.

Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage.

OBJECTIVE: Adipose tissue is an endocrine tissue releasing adipokines suggested to be involved in the pathogenesis of osteoarthritis (OA). Nevertheless, their relative contribution and exact mechanisms are still ambiguous. The aim of this study is to compare serum adipokine levels between end-stage knee OA patients and controls and to relate these serum levels to local parameters of cartilage damage and synovial inflammation. METHODS: Serum was collected from 172 severe knee OA patients, shortly before total knee replacement (TKR) surgery and from 132 controls without radiographic knee OA [Kellgren & Lawrence (K&L) = 0]. Serum adiponectin, leptin, and resistin levels were measured by enzyme-linked immunosorbent assay (ELISA). Cartilage and synovial tissue were collected at TKR surgery and assessed for cartilage degeneration and synovial inflammation by histochemistry and biochemical analyses. RESULTS: The adipokine levels were all distinctly higher in OA patients as compared to controls. Especially adiponectin and leptin were associated with female gender (stand beta = 0.239 and 0.467, respectively, P < 0.001) and body mass index (BMI) (stand beta = -0.189 and 0.396, respectively, P < 0.001). No associations between serum levels of adipokines and cartilage damage (histochemistry, proteoglycan content) were found whereas weak but positive associations with synovial inflammation were found [adiponectin and interleukin-1ß (IL-1ß), stand beta = 0.172, P = 0.02; resistin and histology, stand beta = 0.183, P = 0.034, adjusted for demographics]. CONCLUSION: This study suggests an important involvement of adipokines in OA patients considering their high serum levels compared to controls. Associations of systemic adipokines with local synovial tissue inflammation were found, although not represented by similar relations with cartilage damage, suggesting that adipokines are of relevance in the inflammatory component of OA.

Increased interleukin (IL)-7Rα expression in salivary glands of patients with primary Sjogren's syndrome is restricted to T cells and correlates with IL-7 expression, lymphocyte numbers and activity.

OBJECTIVE: To identify interleukin (IL)-7Rα expression in the labial salivary gland (LSG) of patients with primary Sjögren's syndrome (pSS) and non-Sjögren's syndrome sicca (nSS-sicca) and to study its correlation with glandular inflammation and IL-7 expression. METHODS: The presence of infiltrating immune cells and IL-7Rα cells in inflamed LSG of patients with pSS (n=12) and nSS-sicca controls (n=7) was studied by immunohistochemistry and fluorescence activated cell sorting analysis upon tissue digestion (n=15 and n=13, respectively). Additionally, the correlations of IL-7Rα cells with hallmark disease parameters of pSS, major infiltrating inflammatory cells and IL-7 were assessed. RESULTS: In the LSG of patients with pSS increased numbers of IL-7Rα cells were found as compared with nSS-sicca patients. IL7Rα cells strongly correlated with the lymphocytic focus score, IL-7 expression, the decrease in percentage of IgA plasma cells and numbers of CD3 T cells, CD20 B cells, and CD1a and CD208 myeloid dendritic cells. Analysis of isolated cells from the LSG demonstrated strongly increased percentages of IL-7Rα CD3 T cells in pSS as compared with nSS, showing abundant IL-7Rα expression on both CD4 and CD8 T cells. Other CD45 leucocytes and CD45- tissue cells scarcely expressed IL-7Rα. Percentages of IL-7Rα T cells also significantly correlated with glandular inflammation. CONCLUSIONS: This study shows the presence of increased IL-7Rα T cells in the LSG of patients with pSS and their association with the severity of sialadenitis, disease parameters and IL-7 expression. Considering the immunostimulatory ability of IL-7Rα T cells and IL-7, this suggests that IL-7(R)-dependent T cell-driven immune activation plays an important role in inflammation in pSS.

Suppression of bone turnover by B-cell depletion in patients with rheumatoid arthritis.

UNLABELLED: The role of B cells in inflammatory bone formation and resorption is controversial. We investigated this in patients with rheumatoid arthritis (RA) treated with rituximab, a B-cell depleting antibody. We found a significant suppression in bone turnover, possibly a direct effect or as a consequence of a reduction in inflammation and disease activity. INTRODUCTION: RA is the most prevalent inflammatory joint disease, in which B cells play an important role. However, the role of B cells in bone turnover is controversial and RA subjects treated with rituximab, a B-cell depleting monoclonal antibody, provide an ideal model for determining the role of B cells in inflammatory bone resorption. METHODS: Serum from 46 RA patients, collected pre- and post-rituximab therapy, was analysed for biomarkers of bone turnover (procollagen type I amino-terminal propeptide [P1NP], osteocalcin, ß-isomerised carboxy-terminal telopeptide of type 1 collagen [ßCTX] and osteoprotegerin [OPG]). RESULTS: A significant decrease in bone resorption was observed 6 months after rituximab (median change ßCTX -50 ng/L, 95%CI -136, -8 p < 0.001, this equates to -37%; 95%CI -6, -49), mirrored by a reduction in disease activity. Similarly, there was a significant increase in P1NP, a marker of bone formation (median change P1NP 5.0 µg/L, 95%CI -1.0, 11.2, p = 0.02; 13%; 95%CI -3, 39), but no significant change in osteocalcin or OPG levels. The percentage change from baseline of ßCTX in a subgroup of patients (not on prednisolone or bisphosphonate) was significantly correlated with the percentage reduction in DAS28 score (r (s) = 0.570, p = 0.014). CONCLUSIONS: In conclusion, we have found that B-cell depletion increases bone formation and decreases bone resorption in RA patients; this may be a direct effect on osteoblasts and osteoclasts, respectively, and be at least partially explained by the decreased inflammation and disease activity.

Multinational evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative.

OBJECTIVE: To develop evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis (UPIA). METHODS: 697 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2008-9 consisting of three separate rounds of discussions and modified Delphi votes. In the first round 10 clinical questions were selected. A bibliographic team systematically searched Medline, Embase, the Cochrane Library and ACR/EULAR 2007-2008 meeting abstracts. Relevant articles were reviewed for quality assessment, data extraction and synthesis. In the second round each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. RESULTS: A total of 39,756 references were identified, of which 250 were systematically reviewed. Ten multinational key recommendations about the investigation and follow-up of UPIA were formulated. One recommendation addressed differential diagnosis and investigations prior to establishing the operational diagnosis of UPIA, seven recommendations related to the diagnostic and prognostic value of clinical and laboratory assessments in established UPIA (history and physical examination, acute phase reactants, autoantibodies, radiographs, MRI and ultrasound, genetic markers and synovial biopsy), one recommendation highlighted predictors of persistence (chronicity) and the final recommendation addressed monitoring of clinical disease activity in UPIA. CONCLUSIONS: Ten recommendations on how to investigate and follow-up UPIA in the clinical setting were developed. They are evidence-based and supported by a large panel of rheumatologists, thus enhancing their validity and practical use.

Post-approval trials of new medicines: widening use or deepening knowledge? Analysis of 10 years of etanercept.

OBJECTIVE: To investigate the main aims of the post-approval randomized controlled trials (RCTs) on etanercept and the extent to which they were designed to gain more comparative information. METHODS: A search of the literature (Medline, Embase), trial registries (Clinical Trials.gov, Controlled Trials.com), and market authorization reports from the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) was carried out to identify all RCTs. A comparison of trial data identified unpublished trials and multiple publications relating to the same study. All RCTs completed and/or published after initial market approval was regarded as post-approval. RESULTS: Up until 2008, we found 84 post-approval trials, 11 (13%) trials on approved extensions of indication, another 30 (36%) trials on the approved indications, and 43 (51%) trials on indications not (yet) approved. Nearly half of the studies on indications not yet approved were initiated and funded by independent sponsors. After the initial approval of etanercept, six head-to-head trials were conducted on the approved indications. Overall, the main objectives of post-approval trials with etanercept were found to confirm efficacy and safety in new indications, and to gather additional information for optimal use on the approved indications. CONCLUSION: Post-approval RCTs on etanercept focus more on studies searching for new indications than on deepening knowledge about use. Ten years after the market entry of etanercept, one of the reasonable demands of clinical practice, for more comparative information, still remains unanswered.

Patient and spouse appraisals of health status in rheumatoid arthritis and fibromyalgia: discrepancies and associations with invalidation.

OBJECTIVES: The health problems of patients with rheumatoid arthritis and fibromyalgia are mostly invisible to others, which can lead to a discrepancy between patients' and spouses' appraisals of the severity of the health problems. As a consequence, some patients may feel 'invalidation' from their spouse, such as not being understood and believed. Aim of this study was to compare patients' and spouses' appraisals of the health status of patients with rheumatoid arthritis and patients with fibromyalgia, and to examine whether discrepancies in these appraisals are associated with invalidation experiences of the patient. METHODS: Eighty-four patients with rheumatoid arthritis and 95 patients with fibromyalgia filled out a health status questionnaire (MOS short-form general health survey, SF-20) and a questionnaire on invalidation by the spouse (Illness Invalidation Inventory, 3*I). The spouses appraised the patients' health status independently from the patients using a spouse version of the SF-20. RESULTS: Patients with fibromyalgia and their spouses appraised the patients' health status significantly worse than patients with rheumatoid arthritis and their spouses. The agreement between patients and spouses was generally fair with somewhat more agreement in rheumatoid arthritis than in fibromyalgia. Patient-spouse discrepancies in health status appraisals were not associated with invalidation experiences. CONCLUSIONS: The invisibility of health problems in fibromyalgia and rheumatoid arthritis is not accompanied by large patient-spouse discrepancies of health status appraisals, which suggests that invalidation by spouses is not dependent on observable evidence such as clinical signs of damage or pathology.

Lack of understanding in fibromyalgia and rheumatoid arthritis: the Illness Invalidation Inventory (3*I).

BACKGROUND: Patients with rheumatic diseases may face 'discounting' (denying and patronising) or 'lack of understanding' because of having symptoms without external clinical signs, but instruments to assess such invalidation experiences are lacking. OBJECTIVES: To develop and evaluate the Illness Invalidation Inventory (3*I), to compare invalidation experiences of two groups of patients who differ in visual signs and laboratory findings-rheumatoid arthritis (RA) and fibromyalgia-and to examine the association of invalidation with health status. METHODS: A questionnaire (eight items with respect to five sources: spouse, family, medical professionals, work environment and social services) was constructed. It was completed by 142 patients with RA and 167 patients with fibromyalgia. RESULTS: Principal axis factoring with oblimin rotation yielded two factors with high internal consistency (α>0.70): 'discounting' (five items) and 'lack of understanding' (three items). Patients with fibromyalgia experienced significantly more discounting and lack of understanding from their family, medical professionals, colleagues and social services than did patients with RA. Both patient groups experienced more invalidation from social services, colleagues and family than from medical professionals and spouses. More discounting and lack of understanding correlated with poorer mental well-being and social functioning in both patient groups. Discounting correlated with more physical disability and pain in patients with RA. CONCLUSIONS: The 3*I is a brief, reliable instrument for assessing patients' perceptions of invalidation from different sources, which differ between patient groups and are associated with health status. Future validation research should clarify the clinical impact of invalidation on treatment adherence and outcome.

Increased expression of interleukin-7 in labial salivary glands of patients with primary Sjögren's syndrome correlates with increased inflammation.

OBJECTIVE: To study the expression levels and immunostimulatory capacities of interleukin-7 (IL-7) in primary Sjögren's syndrome. METHODS: Labial salivary gland (LSG) IL-7 expression was determined by immunohistochemistry, using a quantitative scoring system, in 30 patients with sicca syndrome: 15 patients with primary Sjögren's syndrome (SS) and 15 patients with non-SS sicca syndrome. The correlation of IL-7 expression in LSGs with parameters of local and peripheral disease was studied, and serum and salivary IL-7 levels were determined. Additionally, the effects of IL-7 on cytokine production by peripheral blood mononuclear cells (PBMCs) from patients with primary SS were determined in vitro by Luminex multicytokine assay and compared with the effects in control subjects. RESULTS: The expression of IL-7 in LSGs was higher in patients with primary SS compared with that in patients with non-SS sicca syndrome. IL-7 was observed primarily in the vicinity of lymphocytic infiltrates. Salivary IL-7 levels in patients with primary SS were higher than those in control subjects. In all 30 patients with sicca syndrome, IL-7 expression in LSGs correlated with parameters of both local and peripheral disease. Furthermore, IL-7 stimulated T cell-attracting and T cell-differentiating cytokines (monokine induced by interferon-gamma [IFNgamma], IFNgamma-inducible 10-kd protein, IL-12, and IL-15), as well as Th1 (IFNgamma), Th2 (IL-4), Th17 (IL-17A), proinflammatory (tumor necrosis factor alpha and IL-1alpha), and regulatory (IL-10 and IL-13) cytokine production by PBMCs. All of these cytokines were previously shown to be associated with primary SS. The IL-7-induced increase in IL-10 production in patients with primary SS was reduced compared with that in control subjects. CONCLUSION: The correlation between LSG IL-7 expression and (local) disease parameters in primary SS as well as the IL-7-mediated induction of inflammatory cytokines indicate that IL-7 might contribute to the immunopathology of primary SS.

Cartilage proteoglycan aggrecan epitopes induce proinflammatory autoreactive T-cell responses in rheumatoid arthritis and osteoarthritis.

OBJECTIVES: To explore potential T-cell epitopes of the core protein of human cartilage proteoglycan aggrecan (PG) in patients with rheumatoid arthritis (RA) or osteoarthritis. METHODS: Peptide-specific T-cell proliferation and cytokine/chemokine production in response to PG-specific peptides were measured in RA and osteoarthritis patients and in healthy controls. RESULTS: Peptides representing amino acid regions 16-39 and 263-282 of PG were most frequently recognised by T cells in a subset of patients with RA or osteoarthritis. Peripheral blood mononuclear cells from these PG-reactive RA and osteoarthritis patients showed increased production of proinflammatory cytokines/chemokines in response to PG peptide stimulation. As PG p263-282 was found to show high sequence homology with Yersinia Yop protein, the corresponding bacterial (Yersinia) peptide was also tested. Remarkably, RA and osteoarthritis patients responding to the Yersinia peptide also responded to p263-282 of PG suggesting a possibility of molecular mimicry in these patients. CONCLUSIONS: These results indicate that PG-specific peptides, located in the G1 domain of PG, can induce (auto)antigenic T-cell responses in RA and osteoarthritis patients. These peptides might thus be involved in the immune pathogenesis and/or cartilage degradation in RA and osteoarthritis.

Radiation synovectomy with (90)Yttrium, (186)Rhenium and (169)Erbium: a systematic literature review with meta-analyses.

OBJECTIVE: To perform a systemic review and meta-analysis on the effectiveness of radiosynoviorthesis (RSO). METHODS: A search of medical databases was conducted. Criteria for inclusion: articles in English, minimum follow-up of 6 months, specification of joint disease, reported outcome of at least 5 RSOs. The studies were scored for quality by the Oxford Centre of Evidenced-based Medicine Levels of Evidence, from 1 to 4. RESULTS: Twenty-one (21) studies were included (3 quality 1b, 5 2b and 13 4), analysing 169Erbium/186Rhenium-RSO used predominantly in small joints and 49 (1 quality 1b, 10 2b and 38 4) on 90Yttrium-RSO used predominantly in knee joints. The reported success rates of 169Erbium/186Rhenium-RSO ranged from 69-100% at 6 months, and from 54-100% at > or =12 months; for 90Yttrium they were 24-100% and 29-94%, res-pectively. Studies comparing the effect of RSO with that of glucocorticoid (GC) or saline injection alone were pooled. At 6 months, the pooled odds ratio favouring RSO of the knee with Yttrium over control is 4 (confidence interval (CI) 95% 1.2-14), p=0.02, but at 12 months the ratio was 1.7 (CI95% 0.69-4), p=0.26. For RSO of small joints with Erbium/Rhenium compared to controls, the pooled odds ratio at 6 months is 2 (CI95% 0.66-6), p=0.22 and at 12 months 2 (CI95% 1.09-3.5), p=0.03. CONCLUSION: Reported success rates of RSO are high, but differences in effect with GC injection are less evident, although there is marked heterogeneity in study design of the (small number of) comparative studies.

The chondroprotective effect of selective COX-2 inhibition in osteoarthritis: ex vivo evaluation of human cartilage tissue after in vivo treatment.

OBJECTIVE: Recent in vitro studies showed that celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, protects human osteoarthritic cartilage tissue from degeneration. The objective was to substantiate these beneficial effects in an in vivo (clinical) study with celecoxib treatment of patients with severe knee osteoarthritis (OA) and subsequent evaluation of cartilage tissue ex vivo. METHODS: Patients with knee OA were treated 4 weeks prior to total knee replacement surgery with either celecoxib 200mg b.d., indomethacin 50mg b.d., or received no treatment. During surgery cartilage and synovium were collected and analyzed in detail ex vivo. RESULTS: When compared to non-treated patients, patients treated with celecoxib showed significant beneficial effects on proteoglycan synthesis, -release, and -content, confirming the in vitro data. In the indomethacin group, no significant differences were found compared to the control group. On the contrary, a tendency towards a lower content and lower synthesis rate was found. In the treated groups prostaglandin-E(2) levels were lower than in the control group, indicating COX-2 inhibition. Ex vivo release of interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha by synovial tissue was decreased by treatment with celecoxib, whereas in the indomethacin group only IL-1 beta release was decreased. CONCLUSION: Using this novel approach we were able to demonstrate an in vivo generated chondrobeneficial effect of celecoxib in patients with end stage knee OA.

Helicobacter pylori eradication in patients on long-term treatment with NSAIDs reduces the severity of gastritis: a randomized controlled trial.

BACKGROUND: Maintenance use of nonsteroidal anti-inflammatory drugs (NSAIDs) is often complicated by gastropathy. In non-NSAID users, eradication of Helicobacter pylori is associated with decreased mucosal inflammation, and may halt the progression to atrophy and intestinal metaplasia, but the continuous use of NSAIDs may interfere with these processes. GOAL: To investigate the effect of H. pylori eradication on gastric mucosal histology during long-term NSAID use, with and without gastroprotective therapy. STUDY: Patients were eligible for inclusion if they were on long-term NSAIDs and were H. pylori-positive on serologic testing. Patients were randomly assigned to either eradication or placebo. Gastritis was assessed according to the updated Sydney classification for activity, chronic inflammation, gastric glandular atrophy, intestinal metaplasia, and H. pylori density. RESULTS: Biopsy specimens were available for histology of 305 patients. Of these, 48% were on chronic gastroprotective medication. Significant less active gastritis, inflammation, and H. pylori density was found in the eradication group compared with the placebo group in both corpus and antrum (P<0.001). In the corpus, less atrophy was found in the eradication group compared with the placebo group. CONCLUSIONS: H. pylori eradication in patients on long-term NSAID therapy leads to healing of gastritis despite ongoing NSAID therapy.