T. Pham

International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis

Objective: To obtain an international consensus about the use of anti-tumour necrosis factor α (anti-TNFα) for treating patients with ankylosing spondylitis (AS). Methods: These recommendations were developed by a review of published reports in combination with expert opinion, including a Delphi exercise, and a consensus meeting of the ASsessments in AS (ASAS) Working Group. Results: The final consensus comprises the following requirements: (1) For the initiation of anti-TNFα therapy: (a) a diagnosis of definitive AS; (b) presence of active disease for at least four weeks as defined by both a sustained Bath AS Disease Activity Index (BASDAI) of at least 4 and an expert opinion based on clinical features, acute phase reactants, and imaging modalities; (c) presence of refractory disease defined by failure of at least two non-steroidal anti-inflammatory drugs during a single three month period, failure of intra-articular steroids if indicated, and failure of sulfasalazine in patients with peripheral arthritis; (d) application and implementation of the usual precautions and contraindications for biological therapy. (2) For the monitoring of anti-TNFα therapy: both the BASDAI and the ASAS core set for clinical practice should be followed regularly. (3) For the discontinuation of anti-TNFα therapy: in non-responders, consideration should be made after 6–12 weeks’ treatment. Response is defined as improvement of (a) at least 50% or 2 units (on a 0–10 scale) of the BASDAI, (b) expert opinion that treatment should be continued. Conclusion: This consensus statement on anti-TNFα treatment in AS may be used for guidance in clinical decision making and as the basis for the development of guidelines. Evaluation of the healthcare consequences of this consensus is subject to further research by the ASAS group.

Comparison of Tripterygium wilfordii Hook F Versus Sulfasalazine in the Treatment of Rheumatoid Arthritis: A Randomized Trial

Context In Chinese medicine, extracts of Tripterygium wilfordii Hook F (TwHF, known as lei gong teng or thunder god vine) are used to treat autoimmune and inflammatory conditions. Small clinical trials suggest that TwHF may benefit patients with rheumatoid arthritis. Contribution This trial compared TwHF extract with sulfasalazine in 121 patients with active rheumatoid arthritis who could continue oral prednisone and nonsteroidal anti-inflammatory drugs but not disease-modifying antirheumatic drugs. Among patients who continued treatment for 24 weeks, achievement of 20% improvement in American College of Rheumatology criteria was greater with TwHF than with sulfasalazine. Adverse event rates were similar. Caution Only 62% and 41% of patients continued TwHF and sulfasalazine treatment, respectively, and provided 24 weeks of data. The Editors Rheumatoid arthritis is characterized by chronic inflammation of the joint lining (synovial membrane) (1), which causes pain and swelling of diarthrodial joints. Over time, uncontrolled disease results in progressive joint damage, disability, and increased mortality (2). The evolving understanding of the immune mechanisms that perpetuate the inflammatory response has led to effective targeted therapies, including inhibitors of inflammatory cytokines (tumor necrosis factor, interleukin-1, and interleukin-6), modulators of activation of CD4+ T cells and dendritic cells, and agents that deplete B cells (3, 4). Despite the clinical efficacy of these therapies, many patients have no clinically meaningful response or discontinue treatment because of adverse events. Furthermore, the limited availability of effective biologics in developing countries, the need for parenteral administration of the biologics, and the relatively high cost all restrict access to these therapies in many patients with rheumatoid arthritis around the world (5). In traditional Chinese medicine, extracts of the roots of the medicinal vine Tripterygium wilfordii Hook F (TwHF) (known in China as lei gong teng or thunder god vine) have shown therapeutic promise in treating autoimmune and inflammatory conditions as well as cancer (68). More recently, different extracts of TwHF have been used in Chinese allopathic medicine for the treatment of autoimmune and inflammatory diseases, and small controlled trials reported good responses with TwHF extracts in patients with cadaveric kidney transplants (9, 10) and Crohn disease (11). Of the approximately 380 metabolites isolated from the plant, 95% are terpenoids (12, 13). Three diterpenoidstriptolide, tripdiolide, and triptonide (13)are the most abundant and account for the immunosuppressive and anti-inflammatory effects observed with the root extracts in both in vitro and in vivo studies (6). In 2 previous single-center trials of patients with rheumatoid arthritis, the extract was standardized by the content of triptolide and tripdiolide (14). This made it possible to use optimal doses identified in an open-label trial (15) for the design of a subsequent small placebo-controlled study (16). Although the number of patients was small, the apparent clinical impact and experimental results indicating potent inhibition of the expression of proinflammatory genes both in vitro and in vivo in animal models (1721) provided the rationale for our multicenter, double-blind, active comparator trial of a standardized TwHF extract in patients with active rheumatoid arthritis. Methods Design Overview This randomized, controlled, 24-week study was conducted between March 2004 and October 2005. All participants provided written informed consent to enter the trial, and the institutional review boards at the participating sites approved the protocol. All investigators and outcome assessors were blinded to group assignment of the patients. Our objective was to determine whether therapy with TwHF extract, 180 mg/d, was statistically significantly better than therapy with sulfasalazine, 2 g/d, over 24 weeks in patients with rheumatoid arthritis by using standard outcome measures. Setting and Participants Our study was conducted at 11 U.S. centers: 2 academic centers (National Institutes of Health, Bethesda, Maryland, and University of Texas, Dallas, Texas) and 9 rheumatology subspecialty clinics (1 each in Dallas and Austin, Texas; Tampa and Fort Lauderdale, Florida; Arlington, Virginia; Duncanville, Pennsylvania; Wheaton and Greenbelt, Maryland; and Lansing, Michigan). Eligible patients had to be at least 18 years of age and have established rheumatoid arthritis, defined by the American College of Rheumatology (ACR) classification criteria (22) as rheumatoid arthritis lasting longer than 6 months. Eligible patients had active disease, defined as 6 or more painful and swollen joints, a visual analogue scale score for pain of at least 3 (on a scale of 1 to 10, with 1 being mild), and a C-reactive protein (CRP) level of 57.14 nmol/L or greater (0.6 mg/dL) or an erythrocyte sedimentation rate (ESR) greater than 25 mm/h. Patients who were taking any disease-modifying antirheumatic drug at screening underwent a 28-day washout period. The use of oral prednisone, at stable doses up to 7.5 mg/d, and nonsteroidal anti-inflammatory drugs were allowed as long as the dose was not changed for 28 days before randomization and the patient agreed to continue to take the medication during the study. Table 1 lists baseline patient characteristics. Table 1. Patient Characteristics at Baseline Randomization and Interventions We used a computer-generated, pseudo-random code (with random, permuted blocks) to assign patients to treatment groups across all centers. We assigned eligible patients at a 1:1 ratio to receive either TwHF extract, 180 mg/d, or sulfasalazine, 2 g/d. In the event of gastrointestinal intolerance, the protocol allowed for temporary dose reduction of 50%. As described elsewhere (15, 16), the triptolide and tripdiolide content of the ethanol and ethylacetate extract (measured by high-performance liquid chromatography [22]) was used to standardize the drug preparation for this study. On the basis of data on in vitro activity and in vivo toxicity, 30 mg of TwHF extract were formulated per capsule. Our study was conducted under the U.S Food and Drug Administrationapproved Investigational New Drug application 39191. Outcomes and Measurements Patients were evaluated clinically and by laboratory measures at baseline, 2 weeks, and every 4 weeks for a total of 24 weeks. A rheumatologist or trained staff member masked to treatment allocation assessed the patients. Serum or plasma specimens were obtained from the patients at baseline, 4 weeks, and 24 weeks and stored at 80C until analysis. Radiographs of hands and feet were obtained at baseline and 24 weeks or at study discontinuation. The primary end point was a 20% improvement at 24 weeks, as defined by ACR criteria (ACR 20) (23). To meet criteria, a patient must have 20% or greater improvement in both tender and swollen joints (68 tender and 66 swollen joints were assessed) and 20% or greater improvement in 3 or more of the following: the physicians or patients assessment of global health status, the patients assessment of pain on a visual analogue scale, the patients assessment of function (using a modified version of the Health Assessment Questionnaire [HAQ]), and the serum CRP level. Secondary end points included the efficacy of TwHF in achieving ACR 50 and ACR 70 responses at 24 weeks, the improvement in the European League Against Rheumatism Disease Activity Score 28 (DAS 28) measure, and a change in the Sharpvan der Heijde score of the hand and foot radiographs (24). Radiographs were obtained at baseline and at the end of the study and were scored by 2 independent readers who were blinded to the randomization schedule and the radiograph sequence. Drug adherence was assessed by using a daily diary and by pill counts. Body weight, blood pressure, and serum glucose level were measured at each visit. Laboratory assessments included ESR (Westergren method); high-sensitivity CRP with normal levels up to 38.1 nmol/L (0.4 mg/dL), which was analyzed in a central laboratory; and interleukin-6 levels, which were measured at baseline, 4 weeks, and 24 weeks by using high-sensitivity enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, Minnesota). Rheumatoid factor was measured by immunonephelometry with a BNII analyzer (Siemens Medical Solutions Diagnostics, Newark, Delaware), cortisol and adrenocorticotropic hormone levels by immunochemiluminescence methods with an Immulite 2500 (Siemens Medical Solutions Diagnostics, Los Angeles, California), and plasma lipids by Synchron LX-20 automated analyzers (Beckman Coulter, Brea, California). Safety assessments consisted of all patients marking adverse events in their drug diaries, which were reviewed on each visit. Vital signs and safety laboratory measures, including a complete blood count and a chemistry profile (electrolyte and liver and kidney function tests), were recorded at each visit. Adverse events were graded by severity according to the National Cancer Institute Common Toxicity Criteria guidelines. An electrocardiogram (ECG) was obtained from all patients at baseline, 2 weeks, and the end of study. After 24 weeks, no follow-up was conducted. Statistical Analysis We designed our study to detect differences in the primary end point with greater than 90% power at a 2-sided level of significance of 0.05. To properly account for missing end point data due to dropouts, we used mixed-effects analyses to predict each patients ACR response at the end of study visit and to properly account for uncertainty in that prediction. The response was categorized according to the ACR 20, ACR 50, and ACR 70 criteria. In a similar manner, we compared changes in DAS 28 from baseline visit between treatment groups. We modeled the treatment group, visit number (2 random-effect terms for visit number and visit nu

Dissemination and evaluation of the ASAS/EULAR recommendations for the management of ankylosing spondylitis : results of a study among 1507 rheumatologists

Background: Ten ASAS/EULAR recommendations for the management of ankylosing spondylitis (AS) were published in 2006. Objectives: (a) To disseminate and (b) to evaluate conceptual agreement with, and (c) application of, these recommendations as well as (d) potential barriers to the application. Methods: A questionnaire was sent to rheumatologists in 10 countries. It included (a) the text of the recommendations; (b) rheumatologists’ demographic variables; (c) two numerical rating scales from 1 to 10 for each recommendation: conceptual agreement with, and application of, the recommendation (10 indicates maximal agreement and maximal application); and (d) a list of potential barriers to the application of the recommendation. Statistical analysis included descriptive and multivariate analyses. Results: 7206 questionnaires were sent out; 1507 (21%) were returned. Of the 1507 answering rheumatologists, 62% were men, mean (SD) age 49 (9) years, and 34% had an academic position. Conceptual agreement with the recommendations was high (mean (SD) for all recommendations 8.9 (0.9)). Self-reported application was also high (8.2 (1.0)). The difference between agreement and application varied across recommendations and countries. The most pronounced discrepancies were reported for use of anti-tumour necrosis factor drugs in a few countries, with funding as the most commonly reported barrier for application of this recommendation. Conclusion: This large project has helped the dissemination of the ASAS/EULAR recommendations for the management of AS and shows that conceptual agreement with the recommendations is very high. The project also highlights inequalities in access to healthcare for European citizens with AS.

An international study on starting tumour necrosis factor-blocking agents in ankylosing spondylitis

Objectives: To determine the type and proportion of patients with ankylosing spondylitis who rheumatologists consider to be candidates for treatment with tumour necrosis factor (TNF)-blocking agents, and to what extent this is in agreement with the ASsessment in Ankylosing Spondylitis (ASAS) international working group recommendations on initiation of treatment with anti-TNF agents. Methods: Participants were rheumatologists from 10 different countries, who were considered to be experts in treating patients with ankylosing spondylitis and in the use of anti-TNF treatment, but were unaware of the ASAS recommendations (unpublished at the time of study in 2003). The first 10 consecutive patients with ankylosing spondylitis seen by the rheumatologist were evaluated as to whether the patient was a candidate for anti-TNF treatment. Thereafter, a metrologist assessed the patient for disease activity and severity, and collected data on demographics and treatment. Results: Complete data were available for 1207 of the 1284 patients and were used for analysis. Overall, the rheumatologists indicated that they would initiate TNF-blocking agents in 49.3% of patients, ranging from 37.2% patients in Canada to 78.3% in Australia. These candidates had higher disease activity, higher levels of acute-phase reactants, worse spinal mobility, worse function, more often hip involvement and a higher prevalence of sick leave. Of all patients considered to be candidates, 40% did not fulfil ASAS recommendations with respect to previous use of non-steroidal anti-inflammatory drugs (NSAIDs; at least two NSAIDs) or Bath Ankylosing Spondylitis Disease Activity Index (⩾4). Conversely, 36% of patients who did not fulfil the NSAID or BASDAI recommendations were still considered to be candidates for TNF-blocking treatment. Objective variables, such as C reactive protein, erythrocyte sedimentation rate or magnetic resonance activity, were considered less important than disease activity in the decision on starting TNF-blocking drugs. The only important objective criterion was rapid radiographic progression. Conclusion: Rheumatologists wanted to initiate TNF-blocking drugs in roughly half of the patients with ankylosing spondylitis. However, there was a wide variation across countries and doctors. Rheumatologists considered both disease activity and severity to be determinants of starting TNF blockers, but their decision was often in disagreement with ASAS recommendations.

Initiation of biological agents in patients with ankylosing spondylitis: results of a Delphi study by the ASAS Group

Background: There is ample evidence of important symptomatic efficacy of tumour necrosis factor α (TNFα) inhibition in ankylosing spondylitis (AS). Moreover, studies suggest that anti-TNF could be considered as the first disease controlling antirheumatic treatment (DC-ART) for AS. Objective: To determine precisely which patients with AS are most likely to benefit from anti-TNFα treatment because of the cost and possible long term side effects of such treatment. Methods: Assessment in Ankylosing Spondylitis (ASAS) members were asked to use a Delphi technique to name the characteristics of patients with AS for whom they would start DC-ART, in three different clinical presentations (isolated axial involvement, peripheral arthritis, enthesitis). Results: Among the 62 invited ASAS members, more than 50% actively participated in the four phases of definition according to the Delphi technique. For each of the three clinical presentations, a combination of five to six domains was proposed, with an evaluation instrument and a cut off point defining a minimum level of activity for each domain. Conclusion: This study provides a profile for a patient with AS for considering initiation of biological agents that reflects the opinion of the ASAS members, using a Delphi exercise. Further studies are required to assess their relevance and their consistency with clinical practice.

The serum and cerebrospinal fluid pharmacokinetics of anakinra after intravenous administration to non-human primates

Anakinra improves the central nervous system manifestations of neonatal-onset multisystem inflammatory disease, which is mediated by IL-1beta oversecretion. The cerebrospinal fluid (CSF) penetration of the IL-1 receptor antagonist anakinra was studied in rhesus monkeys after intravenous doses of 3 and 10 mg/kg. Drug exposure (area under concentration-time curve) in CSF was 0.28% of that in serum. The average CSF concentration at 3 mg/kg was 1.8 ng/mL, which is 30-fold higher than endogenous CSF levels of IL-1Ra. The CSF penetration was not dose-dependent, indicating that the CSF penetration was not saturated in the 3 to 10 mg/kg dose range.

SAT0163 Long Term Treatment with Abatacept or Tocilizumab Does Not Increase Epstein-Barr Virus Load in Patients with Rheumatoid Arthritis

Background Epstein-Barr Virus (EBV) is a widely disseminated lymphotrophic herpes virus implicated in a lot of benign and malignant disorders. In transplant patients, EBV load is enhanced because of immunosuppressive drugs (cyclosporine) and in a few cases, it can lead to lymphoproliferative disorders (LPD). An EBV load higher than 500 copies per 500 ng of DNA is a predictive factor of post transplant lymphoma [1,2] Similarly, immunity against EBV is particular in RA patients: the level of antibodies against EBV is higher in RA than in healthy controls [3], RA patients have a defective EBV specific supressor T cell function [4].The risk to develop a lymphoma is higher in RA patients than in controls. We have previously shown that: 1/ EBV load is 10 fold higher in RA patients than in controls [5] and 2/ Methotrexate and TNF alpha antagonists (immunosuppressive drugs used in RA patients) do not increase EBV load in RA [6]. Objectives Here, we monitored EBV load over 3 years in patients with RA treated by 2 more recent biologics, Abatacept (CTLA4 Ig) a T cell activation inhibitor, or Tocilizumab, an anti IL6 receptor antibody. Methods EBV load in the peripheral blood mononuclear cells (PBMCs) from 55 patients under Abatacept (+/− Methotrexate) and 35 patients under Tocilizumab (+/− Methotrexate) was monitored from 6 months up to 3 years, by real time PCR. The influences of treatment duration and disease activity score 28 (DAS28) index on EBV load were analyzed. Results Neither Abatacept nor Tocilizumab significantly enhanced EBV load over time. None of our patients developed EBV associated lymphoma. Conclusions Long term usage of Methotrexate with Abatacept or Tocilizumab in patients with RA does not significantly influence EBV load in PBMCs. References Baldanti F et al. High levels of Epstein Barr virus DNA in blood of solid organ transplant recipients and their value in predicting postransplant lymphoproliferative disorders. Journal of Clinical Microbiology 38: 613–619, 2000 Morito M,et al. Quantitative analysis of Epstein Barr virus load by using a real time PCR assay. Journal of Clinical Microbiology 37: 132–136, 1999 Alspaugh M et al. Elevated levels of antibodies to Epstein Barr virus antigens in sera and synovial fluids of patients with rheumatoid arthritis. Journal of Clinical Investigation 67: 1134–1140, 1981 Tosato G et al. Defective EBV specific suppressor T cell function in rheumatoid arthritis. New England Journal of Medicine 305: 1238–1243, 1981 Balandraud N et al. Epstein-Barr Virus Load in the peripheral blood of patients with Rheumatoid arthritis. accurate quantification using re[2] Kimura H, al time Polymerase chain reaction. Arthritis and Rheumatism 2003;48:1223–1228. Balandraud N et al. Long-term treatment with methotrexate or tumor necrosis factor alpha inhibitors does not increase epstein-barr virus load in patients with rheumatoid arthritis. Arthritis and Rheumatism 57(5): 762–767, 2007 Acknowledgement This work was supported by AORC AP-HM, INSERM and Chugai. Disclosure of Interest E. Massy: None declared, O. Muis-Pistor: None declared, M. Martin: None declared, I. Auger: None declared, M.-C. Guzian: None declared, S. Guis: None declared, J. Roudier: None declared, T. Pham: None declared, N. Balandraud Grant/research support from: This work has been partially supported by Chugai group