Johannes W. J. Bijlsma

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs

Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.

Treating rheumatoid arthritis to target: recommendations of an international task force

Background Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension. Such targets have not been defined for rheumatoid arthritis (RA). Objective To develop recommendations for achieving optimal therapeutic outcomes in RA. Methods A task force of rheumatologists and a patient developed a set of recommendations on the basis of evidence derived from a systematic literature review and expert opinion; these were subsequently discussed, amended and voted upon by >60 experts from various regions of the world in a Delphi-like procedure. Levels of evidence, strength of recommendations and levels of agreement were derived. Results The treat-to-target activity resulted in 10 recommendations. The treatment aim was defined as remission with low disease activity being an alternative goal in patients with long-standing disease. Regular follow-up (every 1–3 months during active disease) with appropriate therapeutic adaptation to reach the desired state within 3 to a maximum of 6 months was recommended. Follow-up examinations ought to employ composite measures of disease activity which include joint counts. Additional items provide further details for particular aspects of the disease. Levels of agreement were very high for many of these recommendations (≥9/10). Conclusion The 10 recommendations are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA based on evidence and expert opinion.

Osteoarthritis: an update with relevance for clinical practice.

Osteoarthritis is thought to be the most prevalent chronic joint disease. The incidence of osteoarthritis is rising because of the ageing population and the epidemic of obesity. Pain and loss of function are the main clinical features that lead to treatment, including non-pharmacological, pharmacological, and surgical approaches. Clinicians recognise that the diagnosis of osteoarthritis is established late in the disease process, maybe too late to expect much help from disease-modifying drugs. Despite efforts over the past decades to develop markers of disease, still-imaging procedures and biochemical marker analyses need to be improved and possibly extended with more specific and sensitive methods to reliably describe disease processes, to diagnose the disease at an early stage, to classify patients according to their prognosis, and to follow the course of disease and treatment effectiveness. In the coming years, a better definition of osteoarthritis is expected by delineating different phenotypes of the disease. Treatment targeted more specifically at these phenotypes might lead to improved outcomes.

Effect of Collagen Turnover on the Accumulation of Advanced Glycation End Products

Collagen molecules in articular cartilage have an exceptionally long lifetime, which makes them susceptible to the accumulation of advanced glycation end products (AGEs). In fact, in comparison to other collagen-rich tissues, articular cartilage contains relatively high amounts of the AGE pentosidine. To test the hypothesis that this higher AGE accumulation is primarily the result of the slow turnover of cartilage collagen, AGE levels in cartilage and skin collagen were compared with the degree of racemization of aspartic acid (% d-Asp, a measure of the residence time of a protein). AGE (N ε-(carboxymethyl)lysine,N ε-(carboxyethyl)lysine, and pentosidine) and % d-Asp concentrations increased linearly with age in both cartilage and skin collagen (p < 0.0001). The rate of increase in AGEs was greater in cartilage collagen than in skin collagen (p < 0.0001). % d-Asp was also higher in cartilage collagen than in skin collagen (p< 0.0001), indicating that cartilage collagen has a longer residence time in the tissue, and thus a slower turnover, than skin collagen. In both types of collagen, AGE concentrations increased linearly with % d-Asp (p < 0.0005). Interestingly, the slopes of the curves of AGEs versus% d-Asp, i.e. the rates of accumulation of AGEs corrected for turnover, were identical for cartilage and skin collagen. The present study thus provides the first experimental evidence that protein turnover is a major determinant in AGE accumulation in different collagen types. From the age-related increases in % d-Asp the half-life of cartilage collagen was calculated to be 117 years and that of skin collagen 15 years, thereby providing the first reasonable estimates of the half-lives of these collagens.

EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis

The objective was to develop evidence -based recommendations and a research and educational agenda for the non-pharmacological management of hip and knee osteoarthritis (OA). The multidisciplinary task force comprised 21 experts: nurses, occupational therapists, physiotherapists, rheumatologists, orthopaedic surgeons, general practitioner, psychologist, dietician, clinical epidemiologist and patient representatives. After a preliminary literature review, a first task force meeting and five Delphi rounds, provisional recommendations were formulated in order to perform a systematic review. A literature search of Medline and eight other databases was performed up to February 2012. Evidence was graded in categories I–IV and agreement with the recommendations was determined through scores from 0 (total disagreement) to 10 (total agreement). Eleven evidence-based recommendations for the non-pharmacological core management of hip and knee OA were developed, concerning the following nine topics: assessment, general approach, patient information and education, lifestyle changes, exercise, weight loss, assistive technology and adaptations, footwear and work. The average level of agreement ranged between 8.0 and 9.1. The proposed research agenda included an overall need for more research into non-pharmacological interventions for hip OA, moderators to optimise individualised treatment, healthy lifestyle with economic evaluation and long-term follow-up, and the prevention and reduction of work disability. Proposed educational activities included the required skills to teach, initiate and establish lifestyle changes. The 11 recommendations provide guidance on the delivery of non-pharmacological interventions to people with hip or knee OA. More research and educational activities are needed, particularly in the area of lifestyle changes.

The Effectiveness of Early Treatment with “Second-Line” Antirheumatic Drugs: A Randomized, Controlled Trial

In recent years, therapeutic strategies for patients with rheumatoid arthritis have been discussed in detail [1-8]. Traditional therapy, usually referred to as the pyramid model, begins with nonsteroidal anti-inflammatory drugs (NSAIDs). If these are insufficiently effective, they are later replaced or supplemented with second-line antirheumatic drugs, which are distinguished from NSAIDs primarily by their assumed disease-modifying potential and delayed onset of action. These second-line drugs are also referred to as slow-acting antirheumatic drugs (SAARDs) or disease-modifying antirheumatic drugs (DMARDs). Traditionally, the SAARDs of first choice have been hydroxychloroquine or intramuscular gold followed by D-penicillamine, methotrexate, or azathioprine. The traditional therapeutic pyramid is based on the principle of primum non nocere: Because of their potential toxicity, SAARDs should only be given when milder therapies have failed. Recently, the beneficial effects of the pyramid strategy have been questioned because the long-term outcome of rheumatoid arthritis continues to be disappointing. Patients with rheumatoid arthritis have increased mortality [9, 10], and their quality of life is seriously affected by functional impairment and loss of employment [11, 12]. The pyramid model might be undesirable because administering SAARDs only after milder regimens prove to be insufficiently effective delays the suppression of inflammation. It is preferable that the disease process be controlled as soon as possible, because radiologic abnormalities appear in the joints early in the course of the disease [13, 14] and are related to the extent of inflammation [15, 16]. Toxicity indices for NSAIDs and most SAARDs have recently been shown to be similar; thus, exposure of patients to possible adverse reactions is probably not in itself a reason to withhold treatment with SAARDs [17]. However, the ability of SAARDs to modify the course of disease and prevent radiologic damage is often questioned [18, 19]. The poor long-term outcome of rheumatoid arthritis might be caused not by a delay in effective treatment but by the low disease-modifying power of both first- and second-line drugs. The short courses of SAARDs (short because of adverse reactions or impatience with a delay in effect) might also play a role [20, 21]. Combinations of SAARDs have not been shown to be superior to single drugs [21, 22]. Current clinical practice is shifting toward the earlier introduction of second-line treatment for rheumatoid arthritis, but thus far no clinical trials have shown this strategy to be beneficial. We investigated the consequences of ignoring the treatment pyramid for patients with recent-onset rheumatoid arthritis. In this report, we describe the first-year results of a randomized clinical trial in which the delayed and the immediate introduction of SAARDs were compared. Effectiveness was measured by disease activity and progression of radiologic abnormalities. The various SAARDs are considered as a single group in this report; comparisons among the second-line therapies will be reported in detail later. Methods Patients As of January 1990, all patients with recent-onset rheumatoid arthritis (diagnosed according to the 1987 American College of Rheumatology criteria [[23]] from six rheumatologic centers in the region of Utrecht, the Netherlands, were asked to participate in a randomized, prospective clinical trial. Disease duration had to have been less than 1 year, and most patients were enrolled shortly after diagnosis. The following exclusion criteria were applied: 1) age younger than 17 years, 2) comorbid conditions that might interfere with one of the therapeutic strategies, 3) previous or current treatment with any SAARDs, glucocorticosteroids, or cytotoxic or immunosuppressive therapy, 4) the possibility of pregnancy or breast feeding, and 5) psychiatric or mental disturbances that would make adherence to the study protocol unlikely. All patients gave informed consent before study entry and were told that the study was intended to compare the unsure outcome of treatment with NSAIDs alone with that of treatment with NSAIDs and a SAARD for rheumatoid arthritis at an early stage. The study design was approved by the ethical committees of all participating hospitals. The baseline characteristics of patients who were eligible for the study but who objected to randomization were compared with those of randomly assigned patients to determine whether any selection bias had occurred. Treatment Patients entering the study were randomly assigned to one of two therapeutic groups. All randomization procedures were done by drawing sealed envelopes from blocks of 100 with equal numbers of patients for each of the four treatments per hospital; the person doing the procedures was blinded to treatment assignments. This method was used because eligible patients were not distributed equally among the centers. The assigned therapeutic strategy was continued for at least 1 year. In the non-SAARD group, patients began receiving NSAID therapy, the dose and type of which could be modified at any time. For this group, initiation of SAARD treatment during the study was regarded as discontinuation of the therapeutic strategy. In the SAARD group, patients were randomly assigned (by persons blinded to treatment assignments) to treatment with one of the following SAARDs: hydroxychloroquine (400 mg/d), intramuscular gold (aurothioglucose, 50 mg/wk), or oral methotrexate (7.5 to 15 mg/wk). Therapy with the initial SAARD was continued for 12 months unless adverse reactions necessitated discontinuation; if this occurred, another SAARD was given. Hydroxychloroquine was followed by auranofin (6 to 9 mg/d); intramuscular gold was followed by D-penicillamine (500 to 750 mg/d); and methotrexate was followed by sulfasalazine (2000 to 3000 mg/d). Discontinuation of therapy with the second SAARD was regarded as discontinuation of the therapeutic strategy. Use of NSAIDs was allowed in the SAARD group; as in the non-SAARD group, the dose and type could be changed at any time. Patients were assigned to the non-SAARD group and the SAARD group in a ratio of 1:3, and power calculations for the primary end point disability ( equals 0.05; equals 0.20; difference to be detected, 25%) indicated that group sizes of 40 and 120, respectively, would be sufficient. The ratio of 1:3 was chosen to enable later comparisons of results within the SAARD group, which were thought to be similar. The use of analgesics was allowed in both groups; the use of oral glucocorticosteroids was avoided if possible; and intraarticular injections were not allowed within 2 months of a scheduled visit. Criteria for discontinuation or dose adjustment of a SAARD because of adverse reactions were described in detail in the study protocol. Discontinuation of any treatment because of sustained disease activity was done only if the patient and the attending physician (who had to discuss the patient with a colleague) judged it to be unavoidable. Primary End Points Assessments were done at the start of the trial and were repeated every 3 months. Clinical variables were assessed by the same physician or research nurse for each patient on each occasion. Primary end points were functional disability, pain, joint score, erythrocyte sedimentation rate, and radiologic abnormalities [24]. Radiologic abnormalities and erythrocyte sedimentation rate were determined by persons blinded to treatment assignments; functional disability and pain were self-assessed scores; and determination of the joint score was not blinded to treatment. Functional disability was assessed using a validated Dutch version of the Health Assessment Questionnaire Disability Score [25-27]. The questionnaire scores range from 0 to 3; 0 is the best score (no problems), and 3 is the worst. Pain was measured on two horizontal visual analog scales of 100 mm; the mean of the scores for pain during the night and pain during the morning was calculated. The joint score according to Thompson and colleagues [28, 29] assessed the simultaneous presence of joint tenderness and swelling in a selection of joints weighed for joint size (range, 0 to 534) [28, 29]. Erythrocyte sedimentation rate (mm/h) was measured using Westergren method. Radiography of hands and feet was done at the start of the study and at 12 months. A modified version of the method of Sharp and coworkers [30, 31] was used to score radiologic abnormalities. According to this method, erosions and joint space narrowing in hand and foot joints are scored and added together to obtain a total radiologic damage score (range, 0 to 448). All radiographs were evaluated by two investigators who were blinded to treatment assignments. The scores of the first investigator were used in the analyses, and the scores of the second investigator were used to validate the scores of the first. Correlation between the two sets of scores was satisfactory (Spearman correlation coefficients for scores at baseline and at 12 months were 0.84 for both); the second investigator was found to have given lower scores (means at baseline were 4.2 and 3.4, respectively; means at 12 months were 11.2 and 9.7, respectively). Therefore, in individual cases, differences in total scores of 25% or more were discussed until an agreement was reached on the appropriate score. That score was then used in the analyses. Additional Assessments Secondary end points were grip strength (mean of three measurements of each hand with a vigorimeter [Martin, Tuttlingen, Germany] in kPa), duration of morning stiffness (maximum, 720 min), and general well-being (horizontal visual analog scale of 100 mm). Additional laboratory variables were serum level of C-reactive protein (mg/L), hemoglobin concentration (mmol/L), and platelet count (times 109/L). Rheumatoid factor status was determined to be positive or negative, as indicated by either the Latex

Effectiveness of exercise therapy in patients with osteoarthritis of the hip or knee: A systematic review of randomized clinical trials

OBJECTIVE To review the effectiveness of exercise therapy in patients with osteoarthritis (OA) of the hip or knee. METHODS A computerized literature search of Medline, Embase, and Cinahl was carried out. Randomized clinical trials on exercise therapy for OA of the hip or knee were selected if treatment had been randomly allocated and if pain, self-reported disability, observed disability, or patients global assessment of effect had been used as outcome measures. The validity of trials was systematically assessed by independent reviewers. Effect sizes and power estimates were calculated. A best evidence synthesis was conducted, weighting the studies with respect to their validity and power. RESULTS Six of the 11 assessed trials satisfied at least 50% of the validity criteria. Two trials had sufficient power to detect medium-sized effects. Effect sizes indicated small-to-moderate beneficial effects of exercise therapy on pain, small beneficial effects on both disability outcome measures, and moderate-to-great beneficial effects according to patients global assessment of effect. CONCLUSION There is evidence of beneficial effects of exercise therapy in patients with OA of the hip or knee. However, the small number of good studies restricts drawing firm conclusions.

Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: A possible mechanism through which age is a risk factor for osteoarthritis

OBJECTIVE Age is an important risk factor for osteoarthritis (OA). During aging, nonenzymatic glycation results in the accumulation of advanced glycation end products (AGEs) in cartilage collagen. We studied the effect of AGE crosslinking on the stiffness of the collagen network in human articular cartilage. METHODS To increase AGE levels, human adult articular cartilage was incubated with threose. The stiffness of the collagen network was measured as the instantaneous deformation (ID) of the cartilage and as the change in tensile stress in the collagen network as a function of hydration (osmotic stress technique). AGE levels in the collagen network were determined as: Nepsilon-(carboxy[m]ethyl)lysine, pentosidine, amino acid modification (loss of arginine and [hydroxy-]lysine), AGE fluorescence (360/460 nm), and digestibility by bacterial collagenase. RESULTS Incubation of cartilage with threose resulted in a dose-dependent increase in AGEs and a concomitant decrease in ID (r = -0.81, P < 0.001; up to a 40% decrease at 200 mM threose), i.e., increased stiffness, which was confirmed by results from the osmotic stress technique. The decreased ID strongly correlated with AGE levels (e.g., AGE fluorescence r = -0.81, P < 0.0001). Coincubation with arginine or lysine (glycation inhibitors) attenuated the threose-induced decrease in ID (P < 0.05). CONCLUSION Increasing cartilage AGE crosslinking by in vitro incubation with threose resulted in increased stiffness of the collagen network. Increased stiffness by AGE crosslinking may contribute to the age-related failure of the collagen network in human articular cartilage to resist damage. Thus, the age-related accumulation of AGE crosslinks presents a putative molecular mechanism whereby age is a predisposing factor for the development of OA.

Age-related accumulation of Maillard reaction products in human articular cartilage collagen.

Non-enzymic modification of tissue proteins by reducing sugars, the so-called Maillard reaction, is a prominent feature of aging. In articular cartilage, relatively high levels of the advanced glycation end product (AGE) pentosidine accumulate with age. Higher pentosidine levels have been associated with a stiffer collagen network in cartilage. However, even in cartilage, pentosidine levels themselves represent <1 cross-link per 20 collagen molecules, and as such cannot be expected to contribute substantially to the increase in collagen network stiffness. In the present study, we investigated a broad range of Maillard reaction products in cartilage collagen in order to determine whether pentosidine serves as an adequate marker for AGE levels. Not only did the well-characterized AGEs pentosidine, N(epsilon)-(carboxymethyl)lysine, and N(epsilon)-(carboxyethyl)lysine increase with age in cartilage collagen (all P<0.0001), but also general measures of AGE cross-linking, such as browning and fluorescence (both P<0.0001), increased. The levels of these AGEs are all higher in cartilage collagen than in skin collagen. As a functional measure of glycation the digestibility of articular collagen by bacterial collagenase was investigated; digestibility decreased linearly with age, proportional to the extent of glycation. Furthermore, the arginine content and the sum of the hydroxylysine and lysine content of cartilage collagen decrease significantly with age (P<0.0001 and P<0. 01 respectively), possibly due to modification by the Maillard reaction. The observed relationship between glycation and amino acid modification has not been reported previously in vivo. Our present results indicate that extensive accumulation of a variety of Maillard reaction products occurs in cartilage collagen with age. Altogether our results support the hypothesis that glycation contributes to stiffer and more brittle cartilage with advancing age.

Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells

Anergic/suppressive CD4+CD25+ T cells have been proposed to play an important role in the maintenance of peripheral tolerance. Here we demonstrate that in humans these cells suppress proliferation to self antigens, but also to dietary and foreign antigens. The suppressive CD4+CD25+ T cells display a broad usage of the T cell receptor Vβ repertoire,suggesting that they recognize a wide variety of antigens. They reside in the primed/memory CD4+CD45RO+CD45RBlow subset and have short telomeres, indicating that these cells have the phenotype of highly differentiated CD4+ T cells that have experienced repeated episodes of antigen‐specific stimulation in vivo. This suggests that anergic/suppressiveCD4+CD25+ T cells may be generated in the periphery as a consequence of repeated antigenic encounter. This is supported by the observation that highly differentiated CD4+T cells can be induced to become anergic/suppressive when stimulated by antigen presented by non‐professional antigen‐presenting cells. We suggest that besides being generated in the thymus, CD4+CD25+ regulatory T cells may also be generated in the periphery. This would provide a mechanism for the generation of regulatory cells that induce tolerance to a wide array of antigens that may not be encountered in the thymus.