Is there evidence in support of the use of intra-articular hyaluronate in treating rheumatoid arthritis of the knee? A meta-analysis of the published literature

Intra-articular hyaluronate (HA) injections for treating rheumatoid knee are still debatable, and this meta-analysis aims to elucidate the effectiveness of HA injection for rheumatoid knee. The meta-analysis comprised randomized clinical trials (RCTs) that compared the efficacy of HA injections with that of a placebo. The articles were retrieved after systematic searches of databases, including MEDLINE, EMBASE, and Japana Centra Revuo Medicina. The outcomes were classified into four categories: evaluation of reduction in the intensity of pain, evaluation of reduction in the intensity of inflammation, overall evaluation of therapeutic efficacy, and evaluation of adverse effects. Effect sizes were calculated from the risk ratio (RR) of each of the above-mentioned outcome categories. Five RCTs (720 participants) were pooled for the meta-analysis. The pooled effect sizes were 1.64 (p = 0.01) for pain reduction, 1.61 (p = 0.001) for reduction in inflammation, and 1.50 (p = 0.004) for the overall evaluation of treatment effectiveness. No serious side-effects were reported, while minor adverse effects were reported in patients after HA treatment (RR 0.98, p = 0.32). The results indicated that intra-articular HA is an effective and safe alternative therapy for the rheumatoid knee.     

Is the prevention of rheumatoid arthritis possible?

Clinical Rheumatology - Preclinical phases of rheumatoid arthritis (RA) have been described, genetic and environmental risk factors for RA development have been identified, and several biomarkers...     

Does practice mirror the evidence base in the treatment of rheumatoid arthritis?

A large base of evidence exists regarding treatments for rheumatoid arthritis (RA) and how they may be used to preserve long-term function and improve patient outcomes. However, little is known about whether real-life rheumatology practice reflects the evidence base. This survey aimed to capture differing perceptions among rheumatologists in the identification and treatment of patients and to understand how their management of and treatment decisions for patients with RA may be influenced by the current published literature. Rheumatologists from five European countries and Canada participated in a survey between April and May 2006 to establish how rheumatologists identify and treat particular patient types in everyday practice. In total, 458 rheumatologists responded to the online and telephone survey. Rapidly progressing disease was overwhelmingly recognized (97%) as a distinct subtype among patients with RA, and the majority (88%) of respondents make treatment decisions based on this distinction. Most rheumatologists use measures including C-reactive protein, erythrocyte sedimentation rate, tender/swollen joint counts, and X-ray progression to diagnose and monitor this particular group of patients; a minority (30%) used magnetic resonance imaging to identify and monitor patients with rapidly progressing disease. Although treatment goals for these patients were similar among rheumatologists, the treatment approach varied considerably across countries. Overall, rheumatologists agree on the management goals for patients with rapidly progressing RA; however, their treatment patterns have some dissimilarities.     

Anomalies of intra-synovial citrullination: Is there any interest in the diagnosis of early rheumatoid arthritis?

Autoantibodies to citrullinated proteins (ACPA) are specifically associated with rheumatoid arthritis (RA) and seem to play an important role in its pathogenesis. The specific immunological conflict between ACPA and citrullinated fibrin plays a major role in the self-maintenance of synovial inflammation by forming fibrin deposits in the synovial tissue. These deposits, secondarily citrullinated by a local peptidylarginine deiminase (PADI) enzyme activity, seem to maintain the immunological conflict and the inflammation. Our objective in this work is to study the anomalies of citrullination in a group of patients with early RA, in comparison with a control group of patients suffering from undetermined inflammatory arthritis, osteoarthritis and spondyloarthropathy. For this purpose, we used an enzyme-linked immunosorbent assay (ELISA) to determine the levels of ACPA in serum and synovial fluid. By immunohistochemistry, subtype 4 of PADI was also sought in the synovial biopsies taken from all our patients. We found that the ACPA levels in serum and synovial fluid were significantly higher in patients with RA. The enzyme PADI4 was found only in the group with RA and was statistically correlated with ACPA mean levels in sera and synovial fluid. The expression of PADI4 seems to correlate with intra-synovial deposits of fibrin in RA. However, determination of synovial ACPA levels and detection of intra-synovial PADI4 deposits are of no additional benefit compared with assessment of ACPA levels in serum for the diagnosis of early RA.     

Is there any evidence to support the use of anti-depressants in painful rheumatological conditions? Systematic review of pharmacological and clinical studies

The aim of this study was to review the evidence supporting the use of anti-depressants in painful rheumatological conditions. A systematic review of papers published between 1966 and 2007, in five European languages, on anti-depressants in rheumatological conditions was performed. Papers were scored using Jadad method and analgesic ES was calculated. We selected 78 clinical studies and 12 meta-analyses, from 140 papers. The strongest evidence of an analgesic effect of anti-depressants has been obtained for fibromyalgia. A weak analgesic effect is observed for chronic low back pain, with an efficacy level close to that of analgesics. In RA and AS, there is no analgesic effect of anti-depressants, but these drugs may help to manage fatigue and sleep disorders. There is no clear evidence of an analgesic effect inOA, but studies have poor methodological quality. Analgesic effects of anti-depressants are independent of their anti-depressant effects. Tricyclic anti-depressants (TCAs), even at low doses, have analgesic effects equivalent to those of serotonin and noradrenalin reuptake inhibitors (SNRIs), but are less well tolerated. Selective serotonin reuptake inhibitors (SSRIs) have modest analgesic effects, but higher doses are required to achieve analgesia. Anti-depressant drugs, particularly TCAs and SNRIs, have analgesic effects in chronic rheumatic painful states in which analgesics and NSAIDs are not very efficient, such as fibromyalgia and chronic low back pain. In inflammatory rheumatic diseases, anti-depressants may be useful for managing fatigue and sleep disorders. Further studies are required to compare anti-depressants with other analgesics in the management of chronic painful rheumatological conditions.     

Is there a rationale to using leflunomide in early rheumatoid arthritis?

The efficacy of leflunomide in the treatment of early rheumatoid arthritis (RA) patients might be attributed to the fact that it acts at several levels, including the anti-inflammatory and anti-destructive pathways. This is in addition to its inhibition of the L-dihydro-orotate dehydrogenase (DHOH) enzyme and pyrimidine de novo synthesis which decreases cell proliferation and more specifically early activated CD4+ T cells, as well as monocyte interaction with T cells leading to cytokine and anticytokine production. Recent studies clearly indicate the rationale of an early administration of leflunomide in RA patients, particularly in the light of the results of previously reported clinical studies showing its rapid onset of action when compared to other DMARDs. The early efficacy and safety of leflunomide in patients with early RA is sustained over a long period, and the long-term safety profile of leflunomide does not seem to be different from that observed in phase III trials.     

Diet and the risk of rheumatoid arthritis – A systematic literature review

ObjectivesDiet has received attention as a factor possibly contributing to the development of Rheumatoid arthritis (RA). Several dietary exposures have been examined in various populations using different diet assessment methods. The aim of this study was to systematically assess the literature on the relation between dietary patterns, different food and food groups, macronutrients, non-alcoholic beverages and the risk of developing RA.MethodsA systematic literature search was performed to identify relevant articles on diet and the risk of developing RA. The selection of articles and overall quality assessment of all included studies were performed independently by two examiners. Overall study quality was evaluated using the Newcastle-Ottawa Scales. We excluded all articles where the temporal relation between dietary data collection and time of RA diagnosis was not presented. Main findings were summarized for cohort-based studies and case-control studies separately.ResultsA total of 984 articles were screened. Nineteen relevant cohort-based studies, and eight case-control studies, were included in our review. Two articles were excluded due to lacking data on the relation between RA diagnosis and time of dietary data collection and one due to incorrect outcome. Identified studies suggested protective effects of fish, vegetables and Mediterranean-style diets, although study results and methods were heterogenous. An issue in some case-control studies was that unvalidated diet assessment methods were used. A vast majority of the cohort-based studies used validated diet assessment methods, although the definitions of exposures studied varied.ConclusionThere is lack of consistent evidence on the role of diet in the development of RA, partly due to differences in study quality and methodology Limited evidence suggests that some healthy eating habits may reduce the risk of RA. More high-quality studies in the area are needed for a deeper understanding of the effect of diet, and to enable strategies to prevent RA.     

Is there evidence for the use of FLT3 inhibitors as maintenance therapy in AML?

It is often assumed that all patients with FLT3 (FMS-Like Tyrosine kinase-3)-mutated AML who undergo an allogeneic transplant should receive maintenance therapy with a FLT3 inhibitor. The validity of this assumption is controversial.     

Is early rheumatoid arthritis the same disease process as late rheumatoid arthritis?

Thoughts on treatment for the early control of synovitis have stimulated research on pathobiological events at the site of inflammation in patients with early rheumatoid arthritis. Several studies have thus been conducted to examine synovial biopsy samples at various stages of the disease. The most important conclusion from these studies is that all features of chronic synovial inflammation can be observed in so-called early rheumatoid arthritis. This suggests that no arguments exist for the effect of therapeutic intervention on synovitis varying in different phases of rheumatoid arthritis. In end-stage rheumatoid arthritis, factors that are secondary to the disease may contribute to the perpetuation of synovial inflammation. Mutations in key regulatory genes could play a role in the autonomous progression of the disease. In addition, it is conceivable that the release of bone and cartilage fragments might elicit an inflammatory response in patients with destructive rheumatoid arthritis.     

Is there evidence to support the inclusion of viscosupplementation in the treatment paradigm for patients with hip osteoarthritis?

OBJECTIVE: Viscosupplementation with hyaluronic acid (HA) or its derivatives for the symptomatic relief of osteoarthritis (OA) of the hip joint has never been studied in placebo-controlled, double-blinded trials and conflicting results have been obtained from the published open trials. The aim of this study was to review the literature on viscosupplementation as a symptomatic treatment of hip OA. METHODS: Data sources: Clinical trials in Medline (1966-2005) and Cochrane Controlled Trials Register using the key words: hip osteoarthritis AND hyaluronic acid or HA preparation trade name. All trials aimed to assess intra-articular hyaluronic acid injection for the treatment of hip OA were analyzed. In the absence of placebo-controlled trials, and because of the very wide variety of the study designs it was not possible to apply strictly the conventional rules of meta-analysis. RESULTS: Nine studies, including a total of 287 patients, were identified. Eight studies were uncontrolled-open trials. One was a randomized double blind study comparing two HA preparations. Five open-label prospective studies, including a total of 141 patients with symptomatic hip OA, assessed the safety and efficacy of 1 to 3 x 2mL intra-articular (IA) injections of hylan G-F 20 under fluoroscopic or ultrasound guidance. The overall success rate was about 50% at 3 to 12 month follow-up. In 31 subjects with symptomatic hip OA who received 1 x 3mL IA injection of non animal stabilized hyaluronic acid (NASHA) under fluoroscopy, pain and disability were reduced by 59% and 47% respectively at month 3. Six to 11 months after treatment the results remained satisfactory (42% and 39%). Hyaluronan injections, performed 3 to 5 times at weekly intervals in 44 patients, were effective in controlling pain in 68% of the patients over the 6 month follow-up period. In contrast, 1 to 3 ultrasound guided IA injections of HA preparations with 0.5-0.75 or 1.0 million MW induced only a very weak benefit in 28 patients. In all studies IA injections of HA were safe and well tolerated. Transient pain at the injection site and mild increase in hip pain for a few days was more frequent with NASHA. In the only double blind controlled trial no difference between hyaluronan and hylan was found regarding both efficacy and safety. CONCLUSION: To date, in the absence of placebo-controlled studies, the efficacy of IA injections of HA or its derivatives in the symptomatic treatment of hip OA cannot be determined conclusively. Nevertheless the published data suggest that viscosupplementation may be effective. Double-blind, controlled studies are required to confirm these data, before viscosupplementation should be included into the treatment paradigm for patients with hip osteoarthritis.     

Is rheumatoid factor still a superior test for the diagnosis of rheumatoid arthritis?

The diagnosis of rheumatoid arthritis (RA) is based primarily on the 1987 revised American College of Rheumatology criteria for RA, which considers mainly the clinical symptoms. But typical clinical symptoms of RA are not manifested completely in early disease course. On the other hand, appreciable advantages have been made in the therapeutic strategy of RA in the last decade and highly effective disease-modifying anti-rheumatic drugs are available now for the control of RA. The treatment strategy for the control of early RA is aggressive. Thus, a highly specific and early diagnostic marker is needed for the detection of RA. Our study is an attempt to see the role of anti-CCP2 antibody (claimed to be highly specific and early diagnostic tool) in the diagnosis of RA. We studied 119 cases of RA in terms of clinical symptoms, disease duration and various autoantibody [including rheumatoid factor (RF), anti-CCP2 antibody, antinuclear antibody, anti-dsDNA] and C-reactive protein status. All the tests were also performed in 26 age and sex-matched healthy controls. Estimation of antibodies was done by quantitative ELISA. IgM RF was positive in 47.89% cases (p value = 0.000), followed by IgG RF (42.01%, p = 0.000) and IgA RF (36.97%, p = 0.000). RF was positive in 64.7% RA cases (p value = 0.000) when all three isotypes were tested together. RF was also detected in one healthy control. In 92 cases, anti-CCP2 Ab was done, hence other data were analyzed further in 92 cases only. Anti-CCP2 Ab was positive (cut-off = 15.0 U/ml) in only 50% RA patients but none of the healthy controls was positive for it. Swelling of joints was seen in 82.6% anti-CCP2 Ab positive cases (p value = 0.092) when compared with anti-CCP2 Ab negative cases (67.4%) while among RF positive cases, only 65.4% ((p value = 0.010) cases had swelling of joints. Out of 39 RA cases presenting with disease duration less than 1 year, only 48.71% patients were anti-CCP2 Ab positive while RF was positive in 61.53% patients. Utility of various combined autoantibody tests revealed that if one does all isotypes of RF (IgG, IgA and IgM) only, then 64.7% RA cases can be diagnosed and if anti-CCP2 Ab is added to it, the sensitivity increases to 75.56%. Thus, our study concludes that anti-CCP2 Ab is not a sensitive test for the diagnosis of RA neither it is useful in early diagnosis of RA, but it increases the sensitivity if added with all RF isotypes.     

Is the disease course of rheumatoid arthritis becoming milder? Time trends since 1985 in an inception cohort of early rheumatoid arthritis

OBJECTIVE: Based on comparisons of short-term cohort studies or cross-sectional samples of patients from different calendar times, it has been suggested that present patients with rheumatoid arthritis (RA) have a milder disease course compared with that of patients in past decades. This study was undertaken to investigate whether the course of disease activity and functional disability in patients with RA has become milder over the past several years. METHODS: We used the Nijmegen inception cohort of early RA, which included all patients with newly diagnosed RA who had attended the department of rheumatology at Radboud University Nijmegen Medical Centre since 1985. Patients were assessed for disease activity by the Disease Activity Score in 28 joints (DAS28) every 3 months and for functional disability by the Health Assessment Questionnaire (HAQ) disability index (DI) every 6 months. Within the total cohort, 4 subcohorts were defined, based on the date of inclusion of the patients (1985-1990, 1990-1995, 1995-2000, 2000-2005). To investigate whether the course of disease activity and functional disability (over time) was different between the subcohorts, longitudinal regression analysis (linear mixed models) was used, with the DAS28 and HAQ DI over time as outcome variables, respectively, and subcohort as the independent variable, correcting for baseline demographic and clinical characteristics. The treatment strategy was compared between the subcohorts. RESULTS: The DAS28 at baseline and over the first 5 years of disease was lower in the more recent subcohorts. The HAQ DI did not show improvement but instead a trend toward worsening functional disability. Using longitudinal regression it was shown that disease activity improved early in the disease course and stabilized thereafter, and that this improvement was greater in patients in the more recent subcohorts and in patients with a higher baseline DAS28. Initially, the HAQ DI also improved but stabilized thereafter, and this initial improvement was less pronounced in patients in the more recent subcohorts and was greater for patients with a higher baseline HAQ DI. The treatment strategy was more aggressive in the more recent subcohorts, as shown by a shorter duration from diagnosis to the start of treatment with prednisone or disease-modifying antirheumatic drugs (DMARDs), and a greater prevalence of DMARD therapy. CONCLUSION: The course of disease activity in RA patients has become milder in more recent years. The reason for this improving trend remains to be elucidated, although the trend coincides with a more aggressive treatment strategy.