Showing papers in "Rheumatology in 2012"
TL;DR: T cells, B cells and the orchestrated interaction of pro-inflammatory cytokines play key roles in the pathophysiology of RA, including production of acute-phase proteins (such as CRP), anaemia of chronic disease, cardiovascular disease and osteoporosis and affect the hypothalamic-pituitary-adrenal axis, resulting in fatigue and depression.
Abstract: RA is a progressive inflammatory autoimmune disease with articular and systemic effects. Its exact cause is unknown, but genetic and environmental factors are contributory. T cells, B cells and the orchestrated interaction of pro-inflammatory cytokines play key roles in the pathophysiology of RA. Differentiation of naive T cells into Th 17 (T(H)17) cells results in the production of IL-17, a potent cytokine that promotes synovitis. B cells further the pathogenic process through antigen presentation and autoantibody and cytokine production. Joint damage begins at the synovial membrane, where the influx and/or local activation of mononuclear cells and the formation of new blood vessels cause synovitis. Pannus, the osteoclast-rich portion of the synovial membrane, destroys bone, whereas enzymes secreted by synoviocytes and chondrocytes degrade cartilage. Antigen-activated CD4(+) T cells amplify the immune response by stimulating other mononuclear cells, synovial fibroblasts, chondrocytes and osteoclasts. The release of cytokines, especially TNF-α, IL-6 and IL-1, causes synovial inflammation. In addition to their articular effects, pro-inflammatory cytokines promote the development of systemic effects, including production of acute-phase proteins (such as CRP), anaemia of chronic disease, cardiovascular disease and osteoporosis and affect the hypothalamic-pituitary-adrenal axis, resulting in fatigue and depression.
688 citations
TL;DR: The criteria were developed in a three-phase process, beginning with an analysis of patient cohorts to determine what disease characteristics had persuaded clinicians to initiate MTX therapy, followed by consensus-based decisions and the creation of a scoring system that would predict which patients would go on to develop persistent and/or erosive disease.
Abstract: Advances in our understanding of the pathogenesis of RA over the past two decades, particularly the identification of cytokines that promote synovial inflammation (e.g. TNF-α, IL-1 and IL-6), have led to treatment courses that affect the disease process itself, beyond alleviation of symptoms. In turn, emphasis has shifted to intervention early enough in the disease course to prevent the joint destruction that follows inflammation. Accordingly, in 2010 the ACR and the European League Against Rheumatism (EULAR) put forward revised classification criteria emphasizing RA characteristics that emerge early in the disease course, including ACPAs, a biomarker that predicts aggressive disease. These were in contrast with the 1987 ARA criteria, which distinguished established RA patients from those with other forms of arthritis, and identified patients with later disease. The categories of the 2010 ACR/EULAR criteria are grouped into four classifications, with point scores for each: joint symptoms; serology (including RF and/or ACPA); symptom duration, whether 6 weeks; and acute-phase reactants (CRP and/or ESR). The criteria were developed in a three-phase process, beginning with an analysis of patient cohorts to determine what disease characteristics had persuaded clinicians to initiate MTX therapy, followed by consensus-based decisions and the creation of a scoring system that would predict which patients would go on to develop persistent and/or erosive disease.
347 citations
TL;DR: The results confirm that SSc is a devastating condition as reflected by a pooled SMR of 3.5 and that SMR has not significantly changed over the past 40 years.
Abstract: Objective. SSc is known as the most severe connective tissue disorder, and to be associated with a high mortality risk. Some improvements in therapy for SSc have been achieved in recent years and some preliminary data have suggested an improvement in patient survival. Thus, we set out to determine whether mortality rate in SSc patients has decreased over the past 40 years through a meta-analysis of cohort studies. Methods. We performed a systematic review and a meta-analysis of literature in MEDLINE and Embase databases from January 1960 to June 2010. All cohort studies reporting on SSc mortality were analysed. We then calculated pooled standardized mortality ratios (SMRs) of SSc mortality and calculated their changes over time using meta-regression analysis. Results. Nine studies were included, corresponding to a total of 2691 SSc patients. The pooled SMR was 3.53 [95% CI 3.03, 4.11, P < 0.0001; I 2 = 93%, P(het) = 0.001]. Mid-cohort year ranged from 1977 to 1995 (before 1980: two studies; 198090: five studies; and after 1990: two studies): adjusted meta-regression analysis did not show significant change in SMR over time (P = 0.523). Among 732 deaths, heart involvement was the most frequent cause of deaths (29%) followed by lung involvement. Conclusion. Our results confirm that SSc is a devastating condition as reflected by a pooled SMR of 3.5. Additionally, SMR has not significantly changed over the past 40 years. Further studies are needed to assess the effect of the most recent available therapies on mortality in SSc.
329 citations
TL;DR: 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, but other predictive factors need to be identified to improve ability to recognize patients at risk of poor TKR outcomes.
Abstract: 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
307 citations
TL;DR: 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.
Abstract: 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.
299 citations
TL;DR: Among patients with AAV, a rise in or persistence of ANCA during remission is only modestly predictive of future disease relapse, and there is limited use to serial ANCA measurements during disease remission to guide treatment decisions for individual patientswith AAV.
Abstract: 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. I2-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.
270 citations
TL;DR: Anti-MDA5ab titre and ferritin and IL-18 concentrations are useful for the evaluation of the response to treatment and the status of ILD in patients with anti-MAD5ab-positive DM.
Abstract: Objective. The aim of this study was to investigate the precise clinical characteristics and to analyse the association between the anti-MDA5 antibody (anti-MDA5ab) titre and disease status in patients with anti-MDA5ab-positive DM. Methods. Twenty-seven patients who presented with DM and were positive for the anti-MDA5ab were enrolled. The association between the clinical manifestations and the clinical parameters, including the anti-MDA5ab, was analysed. Results. The complication of rapidly progressive interstitial lung disease (RP-ILD) occurred in 20 (74%) patients. The frequencies of fatal outcome, relapse and malignancy were 33, 4 and 4%, respectively. Remarkably, a fatal outcome occurred within the first 6 months. Compared with six non-RP-ILD patients, elderly age at onset, severely involved pulmonary function and high levels of serum ferritin were present in 20 RP-ILD patients with anti-MDA5ab. Alveolararterial oxygen difference (AaDO2) 532 mmHg and ferritin 5828 ng/ml at admission were poor prognostic factors in RP-ILD patients with anti-MDA5ab-positive DM. The median value of the anti-MDA5ab titre on admission was higher in patients who later died than in those who survived. The efficacy of treatment was indicated by the anti-MDA5ab, ferritin and IL-18 concentrations. The decline index of the anti-MDA5ab titre after treatment was lower in the subset of patients who died than in the subset of patients who lived. Sustained high levels of anti-MDA5ab, ferritin and IL-18 were present in the patients who died. Conclusion. Anti-MDA5ab titre and ferritin and IL-18 concentrations are useful for the evaluation of the response to treatment and the status of ILD in patients with anti-MAD5ab-positive DM.
242 citations
TL;DR: The presence of anti-MDA5 Ab identifies the characteristic skin, musculoskeletal, pulmonary and prognostic features in patients with DM and seems to predict a group of patients with CADM-complicated fatal RPILD.
Abstract: Objective Interstitial lung disease (ILD), especially rapidly progressive ILD (RPILD), is a major poor prognostic factor in patients with DM. We investigated the association of anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) with clinical characteristics and mortality in Japanese patients with DM. Methods Seventy-nine DM patients, comprising 58 classic DM and 21 clinically amyopathic DM (CADM) patients, were enrolled. Serum Abs were screened by immunoprecipitation assays, and an immunosorbent assay (ELISA) was used for MDA5. The relationships of clinical characteristics and mortality with each Ab were investigated. Results Anti-MDA5 Ab was detected in 17 patients. Anti-clinically amyopathic DM 140 kDa polypeptide Abs (anti-CADM-140 Abs) were found in 16 of the 17 anti-MDA5 Ab(+) patients. Skin ulcers, palmar papules, CADM, RPILD and mediastinal emphysema were widely distributed in anti-MDA5 Ab(+) patients. Mortality at 6 months as well as 5 years was also significantly higher in anti-MDA5 Ab(+) patients than in anti-MDA5 Ab(-) patients. In a multivariable Cox regression analysis, mortality was independently associated with anti-MDA5 Ab (relative hazard 6.33; 95% CI 1.43, 28.0). All of the deaths in anti-MDA5 Ab(+) patients were attributed to respiratory failure of RPILD; however, RPILD did not worsen in any of the anti-MDA5 Ab(+) patients who survived the first 6 months. Conclusion The presence of anti-MDA5 Ab identifies the characteristic skin, musculoskeletal, pulmonary and prognostic features in patients with DM. In addition, anti-MDA5 Ab seems to predict a group of patients with CADM-complicated fatal RPILD.
238 citations
TL;DR: In this small group of patients with LVV, treatment with TCZ was effective and well tolerated, and PET/CT findings significantly improved in all cases.
Abstract: 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 naive, 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 ( 18 F)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 toler- ated. Further, larger studies are required to confirm our findings.
223 citations
TL;DR: Applying algorithms to national administrative data sets provides a readily available method for estimating the prevalence of a chronic condition such as gout, where diagnosis and drug treatment are relatively specific for this disease.
Abstract: Objective. Previous small studies in Aotearoa New Zealand have indicated a high prevalence of gout. This study sought to determine the prevalence of gout in the entire Aotearoa New Zealand population using national-level health data sets. Methods. We used hospitalization and drug dispensing claims for allopurinol and colchicine for the entire Aotearoa New Zealand population from the Aotearoa New Zealand Health Tracker (ANZHT) to estimate the prevalence of gout in 2009, stratified by age, gender, ethnicity and socio-economic status (n = 4 295 296). Results were compared with those obtained from an independent large primary care data set (HealthStat, n = 555 313). Results. The all-ages crude prevalence of diagnosed gout in the ANZHT population was 2.69%. A similar prevalence of 2.89% was observed in the HealthStat population standardized to the ANZHT population for age, gender, ethnicity and deprivation. Analysis of the ANZHT population showed that gout was more
189 citations
TL;DR: Although no clinical trial has compared high vs low doses of GCs, some studies have shown the efficacy of medium doses in severe forms of SLE, and the dose below which treatment can be considered safe has not been defined, but daily doses <7.5 mg of prednisone seem to minimize adverse effects.
Abstract: Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressive agents. They act by two different mechanisms: the genomic and the non-genomic pathways. The genomic pathway is considered responsible for many adverse effects of GCs, most of them are time and dose dependent. Observational studies support a relationship between GCs and damage in SLE. GCs have been associated with the development of osteoporosis, osteonecrosis, cataracts, hyperglycaemia, coronary heart disease and cognitive impairment, among others. Although no clinical trial has compared high vs low doses of GCs, some studies have shown the efficacy of medium doses in severe forms of SLE. The dose below which treatment can be considered safe has not been defined, but daily doses <7.5 mg of prednisone seem to minimize adverse effects. Combination therapy with HCQ and the judicious use of immunosuppressive drugs help to keep prednisone therapy within those limits.
TL;DR: MPO is elevated in patients with RA and promotes oxidative stress through the production of hypochlorous acid and protein carbonyls in SF were associated with MPO protein concentration.
Abstract: Objective. To determine whether MPO contributes to oxidative stress and disease activity in RA and whether it produces hypochlorous acid in SF. Methods. Plasma and where possible SF were collected from 77 RA patients while 120 healthy controls supplied plasma only. MPO and protein carbonyls were measured by ELISAs. 3-Chlorotyrosine in proteins and allantoin in plasma were measured by mass spectrometry. Results. Plasma MPO concentrations were significantly higher in patients with RA compared with healthy controls [10.8 ng/ml, inter-quartile range (IQR): 7.214.2; P 3.2) and those with low disease activity (LDA; DAS-28 43.2) (HDA 27.9 ng/ml, 20.234.1 vs LDA 22.1 ng/ml, 16.934.9; P > 0.05). There was a significant relationship between plasma MPO and DAS-28 (r = 0.35; P = 0.005). Plasma protein carbonyls and allantoin were significantly higher in patients with RA compared with the healthy controls. MPO protein was significantly higher in SF compared with plasma (median 624.0 ng/ml, IQR 258.42433.0 vs 30.2 ng/ml, IQR 25.150.9; P < 0.0001). The MPO present in SF was mostly active. 3-Chlorotyrosine, a specific biomarker of hypochlorous acid, was present in proteins from SF and related to the concentration of MPO (r = 0.69; P = 0.001). Protein carbonyls in SF were associated with MPO protein concentration (r = 0.40; P = 0.019) and 3-chlorotyrosine (r = 0.66; P = 0.003).
TL;DR: The signalling mechanisms of Toll-like receptors, the central function of TLRs in the pathogenesis of RA, the role of endogenous danger signals in driving TLR activation within the context of RA and the current preclinical and clinical strategies available to date in therapeutic targeting ofTLRs in RA are discussed.
Abstract: RA is a debilitating disorder that manifests as chronic localized synovial and systemic inflammation leading to progressive joint destruction. Recent advances in the molecular basis of RA highlight the role of both the innate and adaptive immune system in disease pathogenesis. Specifically, data obtained from in vivo animal models and ex vivo human tissue explants models has confirmed the central role of Toll-like receptors (TLRs) in RA. TLRs are pattern recognition receptors (PRRs) that constitute one of the primary host defence mechanisms against infectious and non-infectious insult. This receptor family is activated by pathogen-associated molecular patterns (PAMPs) and by damage-associated molecular patterns (DAMPs). DAMPs are host-encoded proteins released during tissue injury and cell death that activate TLRs during sterile inflammation. DAMPs are also proposed to drive aberrant stimulation of TLRs in the RA joint resulting in increased expression of cytokines, chemokines and proteases, perpetuating a vicious inflammatory cycle that constitutes the hallmark chronic inflammation of RA. In this review, we discuss the signalling mechanisms of TLRs, the central function of TLRs in the pathogenesis of RA, the role of endogenous danger signals in driving TLR activation within the context of RA and the current preclinical and clinical strategies available to date in therapeutic targeting of TLRs in RA.
TL;DR: Examination of the role of T cells in SSc and key soluble profibrotic mediators secreted by Th2 cells and their interactions with fibroblasts suggest that Th2-polarized T cells and the fibroticmediators subsequently released directly induce fibrosis.
Abstract: SSc is an autoimmune disease characterized by inflammation and extracellular matrix deposition that ultimately leads to loss of organ function. T cells appear to play a prominent role in its pathogenesis. The evidence for this comes from their being at the site of fibrosis, their activated phenotype and alteration in their number and frequency in peripheral blood. This review examines the role of T cells in the pathogenesis of SSc and specifically examines the key soluble profibrotic mediators (IL-4, IL-6, IL-13) secreted by Th2 cells and their interactions with fibroblasts that deposit excess extracellular matrix leading to fibrosis. We finally examine possible therapeutic options in targeting T-cell mediators to disrupt the cellular interactions between T cells and fibroblasts that serve to drive the fibrotic response. One of the factors driving fibrosis is IL-6 and this can be neutralized in vivo not only to limit IL-6-driven tissue fibrosis but concomitantly to suppress switching of Tregs to Th17 T cells that will provide more IL-6, thus perpetuating the fibrosis. Taken together, these data implicate the role of T cells in SSc and suggest that Th2-polarized T cells and the fibrotic mediators subsequently released directly induce fibrosis. Targeting such cytokines may be therapeutic not only in SSc but more generally in diseases where fibrosis is directed by inflammatory signals.
TL;DR: This preliminary non-controlled prospective study supported the safety, tolerability and efficacy of PRP injections for pain relief and improved function in a limited number of patients with OA of the hip.
Abstract: Objective. To assess the safety and symptomatic changes of IA injections of platelet-rich plasma (PRP) in patients with OA of the hip. Methods. Forty patients affected by monolateral severe hip OA were included in the study. Each joint received three IA injections of PRP, which were administered once a week. The primary end point was meaningful pain relief, which was described as a reduction in pain intensity of at least 30% from baseline levels as evaluated by the WOMAC subscale at 6-months post-treatment. The visual analogue scale (VAS) and Harris hip score subscale for pain were used to verify the results. Secondary end points included changes in the level of disability of at least 30% and the percentage of positive responders, i.e. the number of patients that achieved a >30% reduction in pain and disability. Results. Statistically significant reductions in VAS, WOMAC and Harris hip subscores for pain and function were reported at 7 weeks and 6 months (P < 0.05). Twenty-three (57.5%) patients reported a clinically relevant reduction of pain (45%, range 3071%) as assessed by the WOMAC subscale. Sixteen (40%) of these patients were classified as excellent responders who showed an early pain reduction at 67 weeks, which was sustained at 6 months, and a parallel reduction of disability. Side effects were negligible and were limited to a sensation of heaviness in the injection site.
TL;DR: Patients with PsA have a poorer QoL compared with those with PsC as measured by all questionnaires except the DLQI, which revealed a lowerQoL in patients with Ps C.
Abstract: Objective. PsA is an inflammatory arthritis present in 30% of people with psoriasis (PsC). Both conditions have a significant impact on quality of life (QoL). Our objective was to test the hypothesis that people with PsA have poorer QoL than patients with PsC because of the added burden of arthritis, age and comorbidities. Methods. Consecutive patients with PsA (CASPAR criteria) and PsC were approached to participate in this study. Patients with PsC were examined by a rheumatologist using a standardized protocol to exclude PsA. Patients completed the HAQ, Medical Outcome Study 36-item Short Form Health Survey, Dermatology Life Quality Index (DLQI), EuroQoL 5 domains (EQ-5D) and Fatigue Severity Scale (FSS). Mean scores were compared and multivariate analyses were conducted to compare the QoL measures between the two patient groups. Results. Two hundred and one patients with PsC and 201 patients with PsA were studied. A significant decrease in QoL for patients with PsA compared with those with PsC was identified by all questionnaires except for the DLQI. This skin-specific questionnaire revealed a lower QoL in patients with PsC. Multivariate analyses for each QoL measure confirmed the results of these analyses. After adjusting for age, sex, duration of PsC, comorbidities, DMARDs and biologic therapy, HAQ and DLQI were independently associated with PsA in a logistic regression.
TL;DR: This large-scale epidemiological survey provides an estimate of the burden of rheumatic diseases in China.
Abstract: Objective. To investigate the prevalence of eight common rheumatic diseases in a large Chinese population. Methods. A population-based epidemiological investigation of the prevalence of eight common rheumatic diseases in a suburb of Beijing was conducted in 14 642 individuals. A community-based survey was carried out using a screening questionnaire. Positive responders were included in a clinical and laboratory examination. Diagnosis was based on the criteria of ACR or those used widely in literature. Results. A total of 10 556 inhabitants were interviewed. Forty-three cases of RA were identified with an age-adjusted prevalence of 0.28% (95% CI 0.19%, 0.41%). Gout was diagnosed with a crude prevalence of 0.09% (95% CI 0.05%, 0.17%). Psoriasis was reported in 28 individuals with a prevalence of 0.27% (95% CI 0.18%, 0.38%). This included two cases diagnosed with PsA, resulting in a prevalence of 7.14% (95% CI 0.88%, 23.5%) in psoriasis patients and 0.02% (95% CI 0%, 0.07%) in the general population. Three individuals were identified with SLE, with a prevalence of 0.03% (95% CI 0%, 0.06%). One individual was identified with SSc and the calculated prevalence was 0.01% (95% CI 0%, 0.05%). One case
TL;DR: In BD, HLA-B51/B5 carriage predominates in males and is associated with moderately higher prevalences of genital ulcers, ocular and skin manifestations, and a decreased prevalence of gastrointestinal involvement.
Abstract: Objective. To investigate comprehensively the relationships between Behcet's disease (BD) clinical features and HLA-B51 or HLA-B5 (HLA-B51/B5) status using meta-analyses. Methods. Relevant publications were identified by a systematic literature search. Eligible studies had to provide frequencies for one or more BD characteristics according to HLA-B51/B5 status. Pooled relative risks (RRs) were calculated by random-effects meta-analysis for those BD characteristics for which five or more relevant studies were identified. Between-study variability was assessed with I 2 and Q-statistics, and modelled using meta-regression. Results. Among the 859 publications evaluated, 72 (representing 74 study populations) met eligibility criteria. Pooled RRs (95% CIs) of the association of HLA-B51/B5 with the 14 analysed clinical character- istics were male sex 1.14 (1.05, 1.23); eye involvement 1.13 (1.06, 1.21); genital ulcers 1.07 (1.01, 1.14); skin involvement 1.10 (1.03, 1.16); erythema nodosum 1.11 (0.96, 1.29); pseudofolliculitis 1.07 (0.93, 1.23); positive pathergy test 1.05 (0.94, 1.17); joint involvement 0.94 (0.86, 1.04); neurological involvement 0.95 (0.71, 1.27); gastrointestinal involvement 0.70 (0.52, 0.94); thrombophlebitis 1.17 (0.77, 1.76); vascular involvement 1.00 (0.68, 1.47); chest involvement 1.55 (0.75, 3.20) and orchiepididymitis 1.13 (0.59, 2.15). For most of the analysed outcomes, between-study heterogeneity was low or absent and most of the meta-regression models were statistically non-significant. Conclusion. The results of these meta-analyses showed that, in BD, HLA-B51/B5 carriage predominates in males and is associated with moderately higher prevalences of genital ulcers, ocular and skin mani- festations, and a decreased prevalence of gastrointestinal involvement.
TL;DR: Although SRC prognosis has improved markedly, SRC remains a severe manifestation of SSc, despite treatment with angiotensin-converting enzyme inhibitor and dialysis, according to a study undertaken to describe SRC characteristics, prognosis and outcome.
Abstract: Objective. Scleroderma renal crisis (SRC) is a severe manifestation of SSc, whose prognosis remains severe, despite treatment with angiotensin-converting-enzyme inhibitor and dialysis. This study was undertaken to describe SRC characteristics, prognosis and outcome, and evaluate the responsibility of CSs in its occurrence.Methods. Analysis concerned 91 SSc patients with SRC who were compared with 427 non-SRC–SSc patients taken as controls.Results. Among the 91 SRC patients, 71 (78.0%) had high blood pressure, 53 (58.2%) hypertensive encephalopathy and 51 (56.0%) thrombotic microangiopathy; 64 (70.3%) had received CSs before or concomitantly with SRC vs 156 (36.5%) non-SRC–SSc patients (P < 0.001). Treated SRC patients also received more prednisone 29.3 (28.4) vs 3.6 (9.9) mg than controls (P < 0.001). SRC clinical outcomes were poor: 49 (53.8%) patients required dialysis, which was definitive for 38. Thirty-seven (40.7%) SRC patients died vs 10.8% of the controls (P < 0.001). Death was most frequent among dialysed patients who never recovered renal function (22 vs 2) and 13 never-dialysed SRC patients died.Conclusions. Although SRC prognosis has improved markedly, SRC remains a severe manifestation of SSc, despite treatment with angiotensin-converting enzyme inhibitor and dialysis. CSs contributed significantly to SRC occurrence.
TL;DR: Current therapy for RA is such that progression from symptom onset to significant disability is now no longer inevitable, and RA patients can anticipate comfortable and productive lives on medical therapy.
Abstract: Treatment for RA has changed profoundly over the past 25 years, evolving from a strategy of providing symptomatic relief, to implementation of therapeutic regimens that impact disease activity and ultimately have been shown to slow or arrest structural joint damage. Drug therapy for RA has evolved from salicylates, to NSAIDs, CSs, DMARDs, MTX, and finally to biologic response modifiers. MTX has become the initial drug of choice in most patients with RA, and some do well on MTX monotherapy without the addition of other agents. Combination regimens including MTX and other conventional DMARDs may be an effective early approach to treatment of RA. The biologic response modifiers (biologics) became available in the late 1990s, based on our understanding of the molecular mediators of synovial inflammation in RA. The first biologics inhibited TNF-a, a cytokine active in host defences against some infections and malignancies, but which also promotes inflammation and bone erosion. Inhibitors of TNF-a are mostly given with MTX, although some can be given as monotherapy. Studies consistently show that combination MTX + TNF-a inhibitor therapy leads to better outcomes than with either agent alone. Tight control strategies, employing objective measures, also lead to improved outcomes. When patients fail treatment with one or more TNF-a inhibitor + MTX, a number of other possible alternatives may be tried, including treatment with biologics having other mechanisms, such as antibodies to certain ILs, other cytokines and inflammatory mediators. Current therapy for RA is such that progression from symptom onset to significant disability is now no longer inevitable, and RA patients can anticipate comfortable and productive lives on medical therapy.
TL;DR: Investigation of the role of Th17 cells in sarcoidosis found enhanced IL-17A expression in granulomas and the presence of IL- 17A(+), IL-18A(+)IFN-γ(+) and IL-4(+)memory Th cells in the circulation and BAL indicate Th17 cell involvement ingranuloma induction or maintenance in sarCOidosis.
Abstract: Objective. Sarcoidosis is a systemic inflammatory disorder characterized by granulomas. Although the aetiology is unknown, sarcoidosis is thought to be mediated by Th1 lymphocytes. Recently, IL-17A has been implicated in granuloma formation in various diseases, including tuberculosis. Therefore, we hypothesized that Th17 cells play a role in sarcoidosis, paralleling recent findings in autoimmune diseases such as RA. The aim of our study was to investigate the role of Th17 cells in sarcoidosis.
Methods. T cells were investigated by intracellular flow cytometry and immunohistochemistry, in blood, bronchoalveolar lavages (BALs) and bronchial mucosal biopsies from a cohort of newly diagnosed sarcoidosis patients and healthy controls.
Results. Circulating memory CD4(+) T-cell populations of sarcoidosis patients contained significantly increased proportions of IL-17A(+) cells when compared with healthy controls. Interestingly, proportions of IL17A/IFN-gamma and IL-17A/IL-4 double-producing cells were significantly increased in blood of sarcoidosis patients and were present in substantial numbers in BAL. In granuloma-containing, but not in non-granulomatous sarcoidosis biopsies, we found significantly increased numbers of IL-17A(+) T cells, located in and around granulomas throughout the lamina propria. IL-22(+) T cells were increased in the subepithelial layer.
Conclusions. Enhanced IL-17A expression in granulomas and the presence of IL-17A(+), IL-17A(+) IFN-gamma(+) and IL-17A(+) IL-4(+) memory Th cells in the circulation and BAL indicate Th17 cell involvement in granuloma induction or maintenance in sarcoidosis. Therefore, neutralization of IL-17A activity may be a novel strategy to treat sarcoidosis.
TL;DR: Biologic treatments have provided effective therapeutic options for patients with RA with inadequate response to conventional DMARDs, but the fact that these agents are immune modulators has raised safety concerns, prompting careful evaluation in clinical trials and intensive post-marketing surveillance.
Abstract: Biologic treatments--including five TNF-α inhibitors, the IL-1 receptor antagonist anakinra, the IL-6 receptor inhibitor tocilizumab, the selective inhibitor of T-cell co-stimulation abatacept and the B-cell-directed mAb rituximab--have provided effective therapeutic options for patients with RA with inadequate response to conventional DMARDs. However, the fact that these agents are immune modulators has raised safety concerns, prompting careful evaluation in clinical trials and intensive post-marketing surveillance. Serious infections may arise, and diagnosis may be delayed by an atypical spectrum of signs and symptoms. Patients may experience reactivation of latent tuberculosis, hepatitis B or C or opportunistic infections. RA is a risk factor for cancer, and biologic therapy may modestly increase the risk of lymphoma and some solid tumours beyond background. During biologic therapy, demyelinating disorders of the CNS have been noted, and pre-existing disease manifestations may be aggravated. Hepatic transaminase levels may increase, although these elevations are usually mild to moderate, transient and without clinical consequence. Hyperlipidaemia, which is responsive to lipid-lowering therapy, may develop, and patients with congestive heart failure may experience symptom exacerbation. Safe use of biologic agents requires thorough risk assessment of potential candidates for treatment and careful monitoring during and after therapy.
TL;DR: Repetitive exposure to bending/straightening the elbow was a significant risk factor for medial and lateral epicondylitis and is associated with prolonged sickness absence in 5% of affected working-aged adults.
Abstract: Objective. To explore the relationship between occupational exposures and lateral and medial epicondylitis, and the effect of epicondylitis on sickness absence in a population sample of working-aged adults. Methods. This was a cross-sectional study of 9696 randomly selected adults aged 25?64 years involving a screening questionnaire and standardized physical examination. Age- and sex-specific prevalence rates of epicondylitis were estimated and associations with occupational risk factors explored. Results. Among 6038 respondents, 636 (11%) reported elbow pain in the last week. Of those surveyed, 0.7% were diagnosed with lateral epicondylitis and 0.6% with medial epicondylitis. Lateral epicondylitis was associated with manual work [odds ratio (OR) 4.0, 95% CI 1.9, 8.4]. In multivariate analyses, repetitive bending/straightening elbow >1 h day was independently associated with lateral (OR 2.5, 95% CI 1.2, 5.5) and medial epicondylitis (OR 5.1, 95% CI 1.8, 14.3). Five per cent of adults with epicondylitis took sickness absence because of their elbow symptoms in the past 12 months (median 29 days). Conclusion. Repetitive exposure to bending/straightening the elbow was a significant risk factor for medial and lateral epicondylitis. Epicondylitis is associated with prolonged sickness absence in 5% of affected working-aged adults.
TL;DR: Sensitivity of a first-time CCDS or an MRI for detection of GCA rapidly decreases under corticosteroid treatment, and imaging of patients with suspected GCA should be performed as soon as possible, preferably within the first days of treatment.
Abstract: Objective. To compare the impact of initial corticosteroid treatment on high-resolution MRI and colour-coded duplex sonography (CCDS) findings in patients with GCA (temporal). Methods. Sensitivity and specificity of CCDS and high-resolution contrast-enhanced MRI studies of 59 patients with suspected GCA were retrospectively analysed. Patients were grouped according to the duration of steroid treatment before imaging: 01 day, 24 days and >4 days. In 41 patients, imaging results were compared with findings of temporal artery biopsy (TAB). Results. Sixty-one per cent (36/59) of patients were diagnosed with GCA. TAB findings were positive in 59% (24/41). The compared results of TAB sensitivity of CCDS and MRI under steroid treatment of 01 day were 92% and 90%, 24 days 80% and 78% and >4 days 50% and 80%, respectively. The compared results of the final clinical diagnosis sensitivity of CCDS and MRI under steroid treatment of 01 day was 88% and 85%, 24 days 50% and 64% and >4 days 50% and 56%, respectively.
TL;DR: Medical follow-up with special attention to comorbidity providing information on possible chronic symptoms and giving support for potential depression and anxiety are recommended.
Abstract: OBJECTIVES: To measure the frequency of and risk factors for rheumatic manifestations after chikungunya virus (CHIKV) infection and to assess their impact on quality of life (QoL). METHODS: In a cohort study among 509 cases diagnosed in France, demographic and clinical characteristics were collected at baseline, and QoL status by 36-item short-form health survey (SF-36), a short form of the Arthritis Impact Measurement Scales 2 (AIMS2-SF) and General Health Questionnaire (GHQ-12) at follow-up. SF-36 scores were compared with population norms. Factors associated with QoL were identified in multivariate linear regression models. RESULTS: A total of 391 (77%) patients participated (53.5% female, mean age 50.2 years). Median time from onset at follow-up was 23.4 months. Among 176 recovered patients, a shorter duration of symptoms was observed in younger age groups and male patients. The probability of full recovery at 1 year was 0.39. Those not recovered were older, had more comorbidities and a longer acute stage with joint swelling. Scores of physical and mental components of the SF-36 and GHQ-12 were low. The AIMS2-SF was affected mainly in symptoms, psychological and social dimensions. Recovered patients did not differ significantly from age- and gender-matched population SF-36 norms. Older age (P = 0.01-0.002) was associated with lower SF-36 scores. Other factors associated with lower SF-36, lower GHQ12 scores and higher AIMS2-SF dimensions were lack of recovery (P = 0.017 to <0.0001), presence of comorbidity (P = 0.005 to <0.0001) and a longer duration of acute stage (P = 0.047 to <0.0001). CONCLUSION: Medical follow-up with special attention to comorbidity providing information on possible chronic symptoms and giving support for potential depression and anxiety are recommended.
TL;DR: CS treatment remains the standard therapy for EF, taken alone or in association with an ISD; MPPs at initiation of treatment are associated with a better outcome and a lower need of ISD use; an IsD, usually MTX, might be useful as a second-line therapy, mainly in patients with morphoea-like lesions.
Abstract: Objective. To analyse therapeutic management of eosinophilic fasciitis (EF). Methods. We reviewed 34 adult patients with biopsy-proven EF. Analyses focused on the therapeutic management, including treatment modalities, responses and associated or predictive factors. Results. Thirty-four patients were included with a diagnosis age of 53 (15) years. They were featured by cutaneous manifestations (88%) including morphoea (41%), myalgia (86%) and hypereosinophilia (85%). Thirty-two patients (94%) were eligible for treatment evaluation and all received CSs as a first-line therapy. Fifteen patients (47%) received methylprednisolone pulses (MPPs) at treatment initiation and 14 patients (44%) received an immunosuppressive drug (ISD), usually MTX (86%), as a second-line therapy. Complete remission was achieved for 69% of patients, remission with disability 19% and failure 12%. A poor outcome was associated with a diagnosis time delay of >6 months [odds ratio (OR) = 14.7] and the lack of MPPs (OR = 12.9). Conclusion. Our study reports new insights into the therapeutic management of EF: (i) CS treatment remains the standard therapy for EF, taken alone or in association with an ISD; (ii) MPPs at initiation of treatment are associated with a better outcome and a lower need of ISD use; (iii) an ISD, usually MTX, might be useful as a second-line therapy, mainly in patients with morphoea-like lesions. Naturally, these practical conclusions should be confirmed by a prospective and multicentre study.
TL;DR: Resistance exercise in RA is safe, and the improvement in most outcomes was statistically significant and possibly clinically relevant for RA disability.
Abstract: Objective. To evaluate the efficacy of resistance exercises in RA patients. Methods. A systematic literature search was done using Pubmed, Embase and Cochrane databases through November 2009 and in abstracts presented at rheumatology scientific meetings over the past 3 years. Randomized controlled trials (RCTs) comparing resistance exercise based therapy with interventions without resistance exercise for the treatment of RA patients were included. Outcomes studied were post-intervention disability on the HAQ, functional capacity assessed by walking speed, pain on the visual analogue scale (VAS), joint count, isometric, isokinetic and grip strength. Efficacy was assessed by weighted mean differences (WMDs) and tolerance was assessed by relative risk (RR). Data were pooled using the inverse of variance model, and heterogeneity was tested. Results. Ten RCTs, including 547 patients, met the study inclusion criteria. The mean (S.D.) Jadad score was 2.3 (0.6). Resistance exercises significantly improved isokinetic strength (WMD = 23.7%, P < 0.001), isometric strength (WMD = 35.8%, P < 0.001), grip strength (WMD = 26.4%, P < 0.001) and HAQ (WMD =0.22, P < 0.001). Exercise also had a positive impact on the 50-foot walking test (WMD =1.90 s, P < 0.001) and ESR (WMD =5.17, P = 0.005). Withdrawals [RR = 0.95, 95% confidence interval (CI) 0.61, 1.48] and adverse events (RR = 1.08, 95% CI 0.72, 1.63) were well balanced in both groups. Patient and exercise characteristics did not influence the results. Subgroup analysis revealed a trend towards higher efficacy associated with high-intensity programmes. Conclusion. Resistance exercise in RA is safe, and the improvement in most outcomes was statistically significant and possibly clinically relevant for RA disability.
TL;DR: Overall, the safety of biologic and non-biologic DMARDs appears to be reasonable, particularly compared with the risks associated with the disease itself.
Abstract: Safety data come from a number of sources. Randomized clinical trials tend to be relatively short, exclude patients with significant comorbidity, have limited numbers of subjects and are primarily powered for efficacy. The most useful post-marketing data come from large national registries, such as Britain's BSRBR, Sweden's ARTIS, Germany's RABBIT, France's DANBIO, Spain's BIODASER and North America's CORRONA. Among the most commonly used non-biologic DMARDs, MTX is associated with risks of hepatotoxicity and cytopenia, as well as pneumonitis, particularly during the first year of treatment. Regarding TNF inhibitors, there is an increased risk of infection (including serious infections) by bacterial pathogens, atypical fungi and opportunistic pathogens. When possible, pneumococcal and influenza vaccines should be given before initiation of treatment with any biologic DMARD. Screening for latent tuberculosis is recommended for all TNF inhibitors, and has been shown to reduce the risk of reactivation. Evidence from registries suggests that there is no increased risk of solid tumours with TNF inhibitor treatment; however, non-melanoma skin cancers are more common. Specific risks with other biologic DMARDs include gastrointestinal perforation with tocilizumab, progressive multifocal leucoencephalopathy with rituximab and pulmonary infections with abatacept. Overall, the safety of biologic and non-biologic DMARDs appears to be reasonable, particularly compared with the risks associated with the disease itself.
TL;DR: A concise summary of current evidence for non-pharmacological interventions and non-biologic drugs formed the basis for the update of the ASAS/EULAR recommendations for the management of AS.
Abstract: Objective. To perform a systematic literature review as a basis for the update of the Assessment in SpondyloArthritis International Society and European League Against Reumatism (ASAS/EULAR) recommendations for the management of AS with non-pharmacological interventions and non-biologic drugs. Methods. The search was performed in PubMed, EMBASE, PEDro and Cochrane between 1 January 2005 and 1 December 2009, and in abstracts of EULAR and ACR meetings (200709). Effect sizes for outcomes on pain, disease activity, spinal mobility and physical function and level of evidence were presented. Results. Of 2383 papers, 35 with complete data were included. Physical therapy exercises in various modalities have positive effects on BASFI, BASDAI, pain and mobility function. Various NSAIDs including coxibs improve BASDAI, disease activity and BASFI. No effect of SSZ and MTX on any variable was found. Surgical interventions of the spine and the hip can give excellent results by restoring function. Conclusion. This concise summary of current evidence for non-pharmacological interventions and non-biologic drugs formed the basis for the update of the ASAS/EULAR recommendations for the management of AS.
TL;DR: Patients with RA have episodes of worsening disease activity (flares) that prompt them to seek clinical review or medication change, which have implications for clinical practice and trials, therefore further research should establish a professional/patient consensus.
Abstract: Objective. People with RA have episodes of worsening disease activity (flares) that prompt them to seek clinical review or medication change. This study explored patients’ perspectives of flare that prompts them to seek medication review. Methods. Fourteen focus groups across five countries comprised 67 RA patients. Transcripts were analysed by several researchers and a patient, using inductive thematic analysis. Results. Patients use flare for five different scenarios, including flare that prompts medical help-seeking, where six themes were identified. In ‘Symptoms and early warnings’, pain is intense (wanting to die), constant and persistent and considered a key feature. Systemic features predominate, including fatigue, feeling generally ill (flu-like), physical and cognitive shut-down and social withdrawal. Warning signs (prodrome) comprise fatigue and flu-like symptoms. ‘Self-management of intensifying symptoms’ includes pacing, heat/cold, rest and increasing medication, often without medical advice. Patients ‘Define this as uncontrollable flare’ when clusters of unprovoked, persistent symptoms halt their ability to run daily life, until prompted into ‘Seeking help when symptoms can’t be contained’. Underpinning themes are ‘Individual context’ (e.g. different symptom clusters) and ‘Uncertainty’ (e.g. when to seek help). Patients report that the current patient global visual analogue scale (VAS) does not capture flare. Conclusion. Patients use flare for multiple events and seek help for complex clusterings of intense, unprovoked symptoms that defy self-management, not necessarily captured in joint counts or global VAS. Flare terminology and definition have implications for clinical practice and trials, therefore further research should establish a professional/patient consensus.