We determined the tissue distribution of cartilage oligomeric matrix protein (COMP) in man and evaluated COMP in synovial fluid (SF) and serum. COMP was purified from human articular cartilage. Polyclonal antibodies were used to detect COMP in tissue cryosections an. protein extracts. COMP was determined quantitatively and qualitatively in SF and serum by competitive enzyme-linked immunosorbent assay and immunoblotting, Knee joint SF was taken from nine cadaveric and six living controls, 52 patients with osteoarthritis (OA), 85 patients with rheumatoid arthritis (RA! and GO patients with other forms of inflammatory arthritis. The degradative potential of SF on native COMP was tested in vitro. The highest concentrations of COMP were measured in articular cartilage and meniscus, the lowest in rib and trachea. Compared with controls, the concentrations of COMP in SF and serum were elevated in 36 and 50% of the patients. A total of 84% of patients with RA and 60% of patients with other forms of inflammatory arthritis showed significant amounts of low-molecular-weight COMP fragments (50-70 kDa) in SF. In contrast, SF fragments were present in only 21% of the OA patients. Furthermore, 13% of SF taken from patients with RA or other forms of inflammatory arthritis were able to degrade COMP in vitro. Using inhibitors, the involvement of serine proteinases could be demonstrated in only 8% of the cases. Based on these results, the absolute levels of COMP in SF and serum, and its fragmentation pattern in SF, seem to be promising as markers of joint tissue metabolism.
Objective. Skin temperature and skin blood flow were studied above different tender points in 20 patients with fibromyalgia (FM) and 20 healthy controls. Methods. Blood flow was measured by laser Doppler flowmetry and skin temperature was measured with an infrared thermometer. Results. In the skin above the five tender points examined in each subject, we found an increased concentration of erythrocytes, decreased erythrocyte velocity and a consequent decrease in the flux of erythrocytes. A decrease in temperature was recorded above four of the five tender points. Conclusion. Vasoconstriction occurs in the skin above tender points in FM patients, supporting the hypothesis that FM is related to local hypoxia in the skin above tender points.
Methods. Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, we compared the risk of SI between 11 798 anti-TNF-treated patients and 3598 non-biologic DMARD (nbDMARD)-treated patients. Results. A total of 1808 patients had at least one SI (anti-TNF: 1512; nbDMARD: 296). Incidence rates were: anti-TNF 42/1000 patient-years of follow-up (95% CI 40, 44) and nbDMARD 32/1000 patient-years of follow-up (95% CI 28, 36). The adjusted hazard ratio (adjHR) for SI in the anti-TNF cohort was 1.2 (95% CI 1.1, 1.5). The risk did not differ significantly between the three agents adalimumab, etanercept and infliximab. The risk was highest during the first 6 months of therapy [adjHR 1.8 (95% CI 1.3, 2.6)]. Although increasing age was an independent risk factor for SI in both cohorts, there was no difference in relative risk of infection in patients on anti-TNF therapy in the older population. There was no difference in hospital stay for SI between cohorts. Mortality within 30 days of SI was 50% lower in the anti-TNF cohort [odds ratio 0.5 (95% CI 0.3, 0.8)]. Conclusions. These data add to currently available evidence suggesting that anti-TNF therapy is associated with a small but significant overall risk of SI. This must be balanced against the risks associated with poor disease control or alternative treatments.
Objective. To assess the immediate and long-term efficacy and safety of percutaneous vertebroplasty with polymethylmethacrylate (PMMA) for the treatment of refractory pain resulting from osteoporotic vertebral fractures. Methods. A retrospective, open study of percutaneous vertebroplasty (PV) was conducted with long-term follow-up. PV with PMMA was carried out between 1990 and 1996 in 40 patients with symptomatic osteoporotic vertebral fracture(s) that had not responded to maximum medical therapy. In 1997, each patient was asked to come back to our institution for a physical and spinal X-ray examination. Efficacy was assessed by changes over time in pain on Huskisson's visual analogue scale (VAS). Results. Thirty-four vertebrae treated by PV in 25 patients were evaluated with long-term follow-up. The mean duration of follow-up was 48 months (range 12-84 months). Pain assessed by the VAS significantly (P < 0.05) decreased from a mean of 80 mm +/- 16 (S.D.) before PV to 37 +/- 24 mm after 1 month and 34 +/- 28 mm at the time of maximal follow-up. There was no severe complication related to this treatment, and no progression of vertebral deformity in any of the injected vertebrae. However, there was a slight but significantly increased risk of vertebral fracture in the vicinity of a cemented vertebra (odds ratio 2.27, 95% confidence interval 1.1-4.56). The odds ratio of a vertebral fracture in the vicinity of an uncemented fractured vertebra was 1.44 (0.82-2.55). Conclusion. PV appears to be a safe and useful procedure for the treatment of focal back pain secondary to osteoporotic vertebral fracture when conservative treatment has failed.
Objective. MTX is widely used to treat synovitis in PsA without supporting trial evidence. The aim of our study was to test the value of MTX in the first large randomized placebo-controlled trial (RCT) in PsA. Methods. A 6-month double-blind RCT compared MTX (15 mg/week) with placebo in active PsA. The primary outcome was PsA response criteria (PsARC). Other outcomes included ACR20, DAS-28 and their individual components. Missing data were imputed using multiple imputation methods. Treatments were compared using logistic regression analysis (adjusted for age, sex, disease duration and, where appropriate, individual baseline scores). Results. Four hundred and sixty-two patients were screened and 221 recruited. One hundred and nine patients received MTX and 112 received placebo. Forty-four patients were lost to follow-up (21 MTX, 23 placebo). Twenty-six patients discontinued treatment (14 MTX, 12 placebo). Comparing MTX with placebo in all randomized patients at 6 months showed no significant effect on PsARC [odds ratio (OR) 1.77, 95% CI 0.97, 3.23], ACR20 (OR 2.00, 95% CI 0.65, 6.22) or DAS-28 (OR 1.70, 95% CI 0.90, 3.17). There were also no significant treatment effects on tender and swollen joint counts, ESR, CRP, HAQ and pain. The only benefits of MTX were reductions in patient and assessor global scores and skin scores at 6 months (P = 0.03, P < 0.001 and P = 0.02, respectively). There were no unexpected adverse events. Conclusions. This trial of active PsA found no evidence for MTX improving synovitis and consequently raises questions about its classification as a disease-modifying drug in PsA.
Objective. To determine nephritis outcomes in a prospective multi-ethnic/racial SLE inception cohort. Methods. Patients in the Systemic Lupus International Collaborating Clinics inception cohort (<= 15 months of SLE diagnosis) were assessed annually for estimated glomerular filtration rate (eGFR), proteinuria and end-stage renal disease (ESRD). Health-related quality of life was measured by the Short Form (36 questions) health survey questionnaire (SF-36) subscales, mental and physical component summary scores. Results. There were 1827 patients, 89% females, mean (S.D.) age 35.1 (13.3) years. The mean (S.D.) SLE duration at enrolment was 0.5 (0.3) years and follow-up 4.6 (3.4) years. LN occurred in 700 (38.3%) patients: 566/700 (80.9%) at enrolment and 134/700 (19.1%) during follow-up. Patients with nephritis were younger, more frequently men and of African, Asian and Hispanic race/ethnicity. The estimated overall 10-year incidence of ESRD was 4.3% (95% CI: 2.8%, 5.8%), and with nephritis was 10.1% (95% CI: 6.6%, 13.6%). Patients with nephritis had a higher risk of death (HR = 2.98, 95% CI: 1.48, 5.99; P = 0.002) and those with eGFR <30 ml/min at diagnosis had lower SF-36 physical component summary scores (P<0.01) and lower Physical function, Physical role and Bodily pain scores. Over time, patients with abnormal eGFR and proteinuria had lower SF-36 mental component summary (P <= 0.02) scores compared to patients with normal values. Conclusion. LN occurred in 38.3% of SLE patients, frequently as the initial presentation, in a large multi-ethnic inception cohort. Despite current standard of care, nephritis was associated with ESRD and death, and renal insufficiency was linked to lower health-related quality of life. Further advances are required for the optimal treatment of LN.
Objectives. The prevalence of interstitial lung disease (ILD) in RA is similar to 5%. Previous work identified increasing age, active articular disease and articular damage as risk factors for RA-associated ILD (RA-ILD). The roles of high-resolution CT (HRCT) and lung function testing in defining the nature and extent of pulmonary involvement have recently been explored. This study is the first to examine predictive and prognostic factors for the development of RA-ILD and to report on the physiological and radiological characteristics of the condition from a large multicentre UK network. Methods. We collected data from centres across the UK on patients with both RA and ILD (proved on HRCT) diagnosed over a 25-year period from 1987 to 2012 using a standard pro forma. Potential predictors of RA-ILD were analysed. Baseline lung function data were recorded and related to HRCT findings. We analysed HRCT for subtype and extent of lung involved and examined the relationship between these and both all-cause and pulmonary mortality. We compared our results with case controls matched for age and gender using computer-generated selection from the RA population from one contributing centre. Results. A total of 230 patients were identified from across the UK with proven RA-ILD diagnosed over 25 years. Median age at diagnosis was 64 years and the male: female ratio was 1:1.09. Univariate analysis showed anti-CCP antibody titres to be the single most strongly associated predictor of RA-ILD. Male gender, age at onset, smoking and RF were all independently associated with RA-ILD on multivariate analysis. Vital capacity (VC) was preserved in limited disease but reduced in extensive disease, while gas transfer was reduced in both. Usual interstitial pneumonia (UIP) was the most common subtype on HRCT and both this and extensive disease were associated with increased all-cause mortality. Conclusion. This is the largest study of RA-ILD in the UK. Anti-CCP antibodies were strongly associated with RA-ILD in both sexes. Smoking was strongly associated with ILD in males, which may explain the higher frequency of RA-ILD in men. The predominant HRCT pattern was UIP and most patients had limited disease at presentation. The presence of UIP and extensive disease are associated with increased mortality. Baseline gas transfer is a useful screening tool for ILD, while the preservation of VC at baseline might predict limited disease on HRCT.
Objective. To identify pre-operative predictors of patient-reported outcomes of primary total knee replacement (TKR) surgery. Methods. The Elective Orthopaedic Centre database is a large prospective cohort of 1991 patients receiving primary TKR in south-west London from 2005 to 2008. The primary outcome is the 6-month post-operative Oxford Knee Score (OKS). To classify whether patients had a clinically important outcome, we calculated a patient acceptable symptom state (PASS) for the 6-month OKS related to satisfaction with surgery. Potential predictor variables were pre-operative OKS, age, sex, BMI, deprivation, surgical side, diagnosis, operation type, American Society of Anesthesiologists grade and EQ5D anxiety/depression. Regression modelling was used to identify predictors of outcome. Results. The strongest determinants of outcome include pre-operative pain/function-those with less severe pre-operative disease obtain the best outcomes; diagnosis in relation to pain outcome-patients with RA did better than those with OA; deprivation-those living in poorer areas had worse outcomes; and anxiety/depression-worse pre-operative anxiety/depression led to worse pain. Differences were observed between predictors of pain and functional outcomes. Diagnosis of RA and anxiety/depression were associated with pain, whereas age and gender were specifically associated with function. BMI was not a clinically important predictor of outcome. Conclusion. This study identified clinically important predictors of attained pain/function post-TKR. Predictors of pain were not necessarily the same as functional outcomes, which may be important in the context of a patient's expectations of surgery. Other predictive factors need to be identified to improve our ability to recognize patients at risk of poor TKR outcomes.
Objective. Treatment of large-vessel vasculitis (LVV) remains challenging. Patients usually respond to glucocorticoid (GC) therapy, but often relapse on tapering of the GC dose or after GC withdrawal. In addition, GCs are fraught with numerous adverse events. The aim of this study was to assess the efficacy and safety of the anti-IL-6 receptor (IL-6R) antibody tocilizumab (TCZ) in patients with LVV. Methods. Four patients with active LVV (two with GCA and two with Takayasu arteritis) received monthly TCZ infusions (8 mg/kg bodyweight) for 6 consecutive months. Two patients were treatment naïve, while two had relapsing disease. Disease activity and drug tolerability were assessed clinically and by laboratory tests at study entry and subsequently every month for 6 months of TCZ treatment, while an [18F]fluorodeoxyglucose PET (PET/CT) scan was performed before and after treatment. In addition, a semi-quantitative clinical evaluation was performed at baseline and at 3 and 6 months using the Indian Takayasu activity score and the Kerr indices. After TCZ, MTX was used as maintenance therapy. Results. All patients treated with TCZ therapy had a satisfactory clinical and laboratory response, while PET/CT findings significantly improved in all cases. No serious adverse events were noted. Only one patient had a transient increase in liver enzymes. Conclusions. In this small group of patients with LVV, treatment with TCZ was effective and well tolerated. Further, larger studies are required to confirm our findings.
Objective. To analyse the clinical relevance of the production of anti-infliximab antibodies (anti-infliximab Abs) in patients with RA undergoing infliximab treatment over a prolonged period of time. Methods. Clinical characteristics, serum trough infliximab and antibody levels were evaluated in 85 RA patients treated with infliximab for a median of 4.42 (interval 0.4-10.2) years. DAS in 28 joints (DAS-28), EULAR response criteria and survival of treatment were assessed at 3 time points (6 months, 12 months and >4 years). Results. Antibodies against infliximab were detected in 28 (32.9%) patients and were present in all EULAR non-responder patients. Antibody levels were higher in EULAR non-responders throughout the study period (P = 0.05 at 6 months, P = 0.02 at 1 year, P = 0.003 at >4 years) compared with EULAR (good and moderate) responders. Nine (10.5%) patients, all of them with high-serum anti-infliximab Ab levels, developed infusion-related reactions. Patients with anti-infliximab Abs more often required increased infliximab doses (51.7%) (P = 0.032) and median survival time on treatment was shorter (4.15 vs 8.89 years) (P = 0.0006). MTX co-therapy was not associated with lower proportion of anti-infliximab Ab-positive patients, but those receiving both infliximab and MTX had lower levels of anti-infliximab Abs (P = 0.073) and longer survival (P = 0.015) on treatment. Conclusion. The formation of anti-infliximab Abs during treatment with infliximab is associated with a loss of clinical response, the appearance of infusion reactions and discontinuation of treatment.
Objectives. There are no valid instruments to measure disease activity in Takayasu arteritis (TA). We aim to provide a valid measure to assess clinical disease activity with or without incorporating acute phase reactants. Methods. The Indian Takayasu Clinical Activity Score (ITAS) was initially derived from disease manifestations scored in the Disease Extent Index (DEI. Tak). The ITAS was validated by a group of physicians scoring both live and paper cases for inter-rater reliability (IRR), convergence with BVAS, correlation with the Physician's Global Assessment (PGA) and ESR/CRP. It was further validated at a single centre in 177 patients for its ability to discriminate between active and inactive disease state at first visit and sensitivity to change in 132 active patients measured serially at two follow-up visits. ITAS-A also included graded scores for ESR/CRP. Results. The final ITAS2010 contains 44 items with 33 features arising from the cardiovascular system. Seven key items are weighted to score 2 and all others score 1 only. Inter-observer variability was highly satisfactory (IRR 0.97). The ITAS showed superior inter-rater agreement compared with the BVAS (IRR 0.9) and PGA (IRR 0.82). In the single-centre study, median ITAS scores at first visit were significantly higher in active disease (5.62 +/- 3.14) compared with grumbling (3.36 +/- 1.96) and inactive disease (1.27 +/- 1.26, P < 0.0001). The therapy induced a significant decrease in the ITAS2010 but the higher ITAS-A scores remained elevated. Conclusion. The ITAS2010, validated in over 300 TA patients and sensitive to change, is a useful measure of clinical disease activity for patient monitoring. Higher ITAS-A scores suggest poor control of active disease by current therapy.
Objective. The aim of this study was to compare baseline variables, treatment and outcomes in patients with large-vessel GCA (LV-GCA), primarily of the upper extremities, with those with cranial disease (C-GCA). Methods. All patients >50 years of age with radiographic evidence of subclavian LV-GCA diagnosed between 1 January 1999 and 31 December 2008 were identified and compared with those with biopsypositive C-GCA diagnosed in the same period. Results. The study included 120 LV-GCA patients and 212 C-GCA patients. Compared with C-GCA, patients with LV-GCA were younger [68.2 years (S.D. 7.5) vs 75.7 (7.4), P<0.001] and had longer duration of symptoms at GCA diagnosis (median 3.5 vs 2.2 months, P<0.001). A history of PMR was more common in LV-GCA patients (26% vs 15%, P = 0.012), but a smaller proportion had cranial symptoms (41% vs 83%, P<0.001) and vision loss (4% vs 11%, P = 0.035). ACR classification criteria for GCA were satisfied in 39% of LV-GCA patients and 95% of C-GCA patients (P<0.001). Compared with C-GCA, patients with LV-GCA had more relapses (4.9 vs 3.0/10 person-years, P<0.001), higher cumulative corticosteroid (CS) doses at 1 year [11.4 g (S.D. 5.9) vs 9.1 (S.D. 3.7), P<0.001] and required longer treatment (median 4.5 vs 2.2 years, P<0.001). Conclusion. Although patients with LV-GCA had a lower rate of vision loss, they had a higher relapse rate and greater CS requirements. The ACR criteria for GCA are inadequate for the classification of patients with LV-GCA.
Methods. A total of 570 UA patients and 676 RA patients included in the Leiden Early Arthritis Clinic cohort were studied for baseline characteristics. The disease outcomes studied were fulfilment of the 1987 ACR-RA criteria and arthritis persistence in UA patients and the rate of radiological joint destruction and achieving sustained DMARD-free remission in RA patients. Results. Predictive factors for fulfilment of the 1987 ACR-RA criteria and for persistent arthritis in UA were largely similar. Risk factors for a severe rate of joint destruction were: older age (P < 0.001); male gender (P < 0.001); longer symptom duration at first visit (P = 0.048), involvement of lower extremities (P < 0.001); BMI (P < 0.001); high acute phase reactants, presence of IgM-RF (P < 0.001); anti-CCP2 antibodies (P < 0.001); anti-modified citrullinated vimentin antibodies (P < 0.001) and HLA-DRB1 shared epitope alleles (P = 0.001). A high BMI was associated with a lower rate of joint destruction but with a higher risk of disease persistence. The proportion of variance in joint destruction explained was 32% Conclusion. Predictors for RA development, previously used to develop a prediction rule in UA patients, are largely similar to predictors for arthritis persistency. Only part of the joint destruction level in RA is explained by the currently known risk factors. New factors need to be identified in order to guide pharmaceutical intervention at the level of individual RA patients.
Objectives. The osteochondral junction can be a source of pain in both RA and OA. Growth of blood vessels and nerves from the subchondral bone into articular cartilage may mediate the association between joint pathology and symptoms. We have investigated associations between angiogenesis, inflammation and neurovascular growth factor expression at the osteochondral junction in human arthritis. Methods. Osteochondral junctions from medial tibial plateaux of patients undergoing arthroplasty for RA (n = 10) or OA (n = 11), or from non-arthritic post-mortem controls (n = 11) were characterized by immunohistochemistry for CD34 and smooth muscle alpha-actin (blood vessels), CD68 (macrophages), CD3 (lymphocytes), proliferating cell nuclear antigen, vascular endothelial, platelet-derived and nerve growth factor (NGF). Results. Osteochondral angiogenesis was demonstrated as increased endothelial cell proliferation and vascular density in non-calcified articular cartilage, both in RA and OA. Osteochondral angiogenesis was associated with subchondral bone marrow replacement by fibrovascular tissue expressing VEGF, and with increased NGF expression within vascular channels. RA was characterized by greater lymphocyte infiltration and PDGF expression than OA, whereas chondrocyte expression of VEGF was a particular feature of OA. NGF was observed in vascular channels that contained calcitonin gene-related peptide-immunoreactive sensory nerve fibres. Conclusions. Osteochondral angiogenesis in RA and OA is associated with growth factor expression by cells within subchondral spaces, vascular channels and by chondrocytes. NGF expression and sensory nerve growth may link osteochondral angiogenesis to pain in arthritis.
Objective. The value of repeated ANCA measurements among patients with an established diagnosis of ANCA-associated vasculitis (AAV) remains controversial. The aim of this study was to explore whether either of the two distinct patterns of ANCA values during remission, a rise in ANCA or persistently positive ANCA, predicted future relapse. Methods. MEDLINE and EMBASE searches were performed. Studies with at least 10 subjects with AAV from which both sensitivity and specificity of a rise in ANCA and/or persistent ANCA for future disease relapse could be calculated were included. Likelihood ratios were calculated for each study and pooled to arrive at summary estimates. I 2-values were calculated as a measure of heterogeneity and meta-regression was used to explore sources of heterogeneity. Results. Nine articles on a rise in ANCA and nine articles on persistent ANCA were included. The summary estimates for positive likelihood ratio (LR+) and negative likelihood ratio (LR−) of a rise in ANCA during remission on subsequent relapse of disease were 2.84 (95% CI 1.65, 4.90) and 0.49 (95% CI 0.27, 0.87), respectively. The summary estimates for LR+ and LR− of persistent ANCA during remission for subsequent disease relapse were 1.97 (95% CI 1.43, 2.70) and 0.73 (95% CI 0.50, 1.06), respectively. There was substantial between-study heterogeneity, which was partially explained by the frequency of ANCA measurements. Conclusion. Among patients with AAV, a rise in or persistence of ANCA during remission is only modestly predictive of future disease relapse. There is limited use to serial ANCA measurements during disease remission to guide treatment decisions for individual patients with AAV.
Objectives. The epidemiological manifestations of ANCA-associated vasculitis (AAV) differ geographically. However, there have been no prospective studies comparing the incidence of AAV between Japan and Europe over the same time period using the same case definitions. Methods. The incidence of AAV was determined by a population-based method in Miyazaki prefecture, Japan, and Norfolk, UK, between 2005 and 2009. Patients with AAV were defined and classified according to the European Medicines Agency (EMEA) algorithm. Results. The number of incident cases of AAV in Japan and the UK were 86 and 50, respectively, and the average annual incidence over the 5-year period was 22.6/million (95% CI 19.1, 26.2) and 21.8/million (95% CI 12.6, 30.9) in Japan and the UK, respectively. The average age was higher in patients in Japan than in patients in the UK [mean (median), 69.7 (72) vs 60.5 (61) years]. Microscopic polyangiitis (MPA) was the predominant subtype in Japan (83%), while granulomatosis with polyangiitis (Wegener's) was more frequent in the UK (66%). As for the pattern of ANCA positivity, >80% of Japanese patients were pANCA/MPO positive, whereas two-thirds of UK patients were cANCA/PR3 positive. Renal involvement in MPA was very common in both countries, but was much less common in granulomatosis with polyangiitis in Japan compared with the UK. Conclusion. There was no major difference in AAV incidence between Japan and the UK, but this prospective study found MPA and MPO-ANCA to be more common in Japan and granulomatosis with polyangiitis and PR3-ANCA to be more common in the UK, in line with earlier reports.
Objective. To assess the efficacy of rituximab (RTX) in SSc. Methods. Fourteen patients with SSc were evaluated. Eight patients were randomized to receive two cycles of RTX at baseline and 24 weeks [each cycle consisted of four weekly RTX infusions (375 mg/m2)] in addition to standard treatment, whereas six patients (control group) received standard treatment alone. Lung involvement was assessed by pulmonary function tests (PFTs) and chest high-resolution CT (HRCT). Skin involvement was assessed both clinically and histologically. Results. There was a significant increase of forced vital capacity (FVC) in the RTX group compared with baseline (mean ± s.d.: 68.13 ± 19.69 vs 75.63 ± 19.73, at baseline vs 1-year, respectively, P = 0.0018). The median percentage of improvement of FVC in the RTX group was 10.25%, whereas that of deterioration in the controls was 5.04% (P = 0.002). Similarly, diffusing capacity of carbon monoxide (DLCO) increased significantly in the RTX group compared with baseline (mean ± s.d.: 52.25 ± 20.71 vs 62 ± 23.21, at baseline vs 1-year respectively, P = 0.017). The median percentage of improvement of DLCO in the RTX group was 19.46%, whereas that of deterioration in the control group was 7.5% (P = 0.023). Skin thickening, assessed with the Modified Rodnan Skin Score (MRSS), improved significantly in the RTX group compared with the baseline score (mean ± s.d.: 13.5 ± 6.84 vs 8.37 ± 6.45 at baseline vs 1-year, respectively, P < 0.001). Conclusion. Our results indicate that RTX may improve lung function in patients with SSc. To confirm our encouraging results we propose that larger scale, multicentre studies with longer evaluation periods are needed.