European League Against Rheumatism

Fibromyalgia Guidelines Released by EULAR

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Updated guidelines on fibromyalgia have been published by the European League Against Rheumatism (EULAR). The guidelines provide evidence-based recommendations, including nonpharmacologic and psychological interventions, for the management of patients with fibromyalgia, and were published online July 4 in the Annals of Rheumatic Diseases.

The new recommendations represent the first update to the EULAR guidelines for fibromyalgia management in more than a decade and include evidence to support pharmacologic, nonpharmacologic, complementary, and alternative medicines/therapies.

“[These recommendations] allow EULAR to move from recommendations that are predominantly based on expert opinion to ones that are firmly based on scientific evidence from high-quality reviews and meta-analyses,” write the authors.

The working group, which included 18 members from 12 European countries, reviewed data from 107 systematic reviews and/or meta-analyses. The authors found the strongest evidence for patient education and nonpharmacologic intervention (exercise) as part of initial therapy. Beyond this, the recommendations underscore the need for an individualized approach, which may include pharmacologic, psychological, and/or rehabilitative interventions, depending on the individual patient. The authors caution, however, that the “size of effect for many treatments is relatively modest,” and that further research is needed to determine optimal treatment strategies and improve patient outcomes.

“These new EULAR guidelines are based on the most up-to-date information and are in line with the thinking of most clinicians working in the area of [fibromyalgia],” Leslie J. Crofford, MD, director, Division of Rheumatology & Immunology at Vanderbilt University, Nashville, Tennessee, told Medscape Medical News.

Dr Crofford noted that although overall, the treatment recommendations made by EULAR are similar to how these patients are managed in the United States, there are some differences. For example, in the United States, “[t]here is a strong cultural pressure for pharmacologic over nonpharmacologic treatments.”

Dr Crofford explained that some of this pressure may come from “advertising by pharma suggesting that drugs work better than they actually do.” In addition, she posited that “a lack of knowledge of how to ‘prescribe’ nonpharmacologic treatments,” as well as a lack of availability or access to nonpharmacologic treatments in the United States (eg, a lack of insurance coverage for psychological interventions, communities without access to therapeutic pool facilities, etc), may also contribute to the bias toward pharmacologic intervention.
When evaluating the data, the working group took into account factors such as the number of trials, number of patients, outcomes assessed, and adverse events. The group then based recommendations on a 4-point scale (“strong for/weak for/weak against/strong against”), with the strength of the recommendation based on “the balance between desirable and undesirable effects (considering values and preferences), confidence in the magnitude of effects and resource use.”

In addition to the new recommendations, the committee highlighted five priority questions for research, including:

Is monotherapy better than a multimodal approach?

What type of exercise is most beneficial (strength or aerobic training)?

Do patient characteristics predict therapeutic response?

Does fibromyalgia with concurrent inflammatory joint disease require a different therapeutic approach?

Who is best equipped to manage patients with fibromyalgia?

The authors note that focus on these research priorities will help improve patient care by addressing “issues clarifying to whom certain interventions may best be delivered,” as well as helping ensure patients are managed by the right person or part of the healthcare system.

Q & A: Professor Johannes W.J. Bijlsma, president of the European League Against Rheumatism

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Professor Johannes W.J. Bijlsma, president of the European League Against Rheumatism (EULAR) spoke about the organisation’s ongoing projects and what’s new in rheumatology.

Radha Chitale spoke with Professor Johannes W.J. Bijlsma, president of the European League Against Rheumatism (EULAR), about the organisation’s ongoing projects and what’s new in rheumatology. 

What initiatives within EULAR have been working well and what would you like to continue during your tenure?

I’ve been working with education for quite some time and we’ve produced a lot of materials. We’re in the process of formalizing them into a virtual School of Rheumatology with continuing education materials not only for physicians but for health professionals and patients.

The School of Rheumatology would have different classrooms for different people. For patients the priority is to have lay summaries of all the important EULAR recommendations and publications. For health professionals, we’d like to gather different subspecialties like occupational therapy and physical therapy and see what their activities should be and how to certify them. For medical students, we’d like to establish the minimum things every medical student should know about rheumatology and make a primer available on the Internet.

What EULAR projects are planned for the coming year?

Another important thing to have would be more awareness for rheumatic disease in the public and a greater possibility for patients to visit a health professional.

We know that the most gain you can get in treating rheumatism is not only in the first year but in the first months, and improving the knowledge of general physicians and health professionals about rheumatic disease, and who they should refer patients to, will help let those patients into practices earlier on.

Next year, for the 70th meeting of EULAR in Madrid, Spain, we will launch a “time is joint” campaign, which says that if you make an early RA diagnosis, you can preserve the joints. But we also want to help people with joint problems to have good an easy access to people who can help them – a “joint over time” approach. I think that will keep me quite busy for the coming years.

What have been the most exciting developments in rheumatology in the last few years, and what will be the major themes in treatment and care moving forward?

More early diagnosis, which has been possible with new imaging and lab techniques, and also more personalized treatment. For the individual patient, checking them more often than we did in the past to see if they are doing well and adapting treatment modalities accordingly. We have more drugs, biologics and others, and so have more possibilities to act on those findings and improve patients at that moment.

We see different mechanisms, not just for RA, but for spondyloarthritis and there is a start in the fields of osteoarthritis and osteoporosis of new ways of treatment based on increased knowledge of the pathogenesis and the possibility to make targeted therapies. There’s been a lot of new drug development in the last 5 years, for example, new pathways targeting interleukin-17, that will benefit a lot of new patients.

But making the most optimal use of existing drugs and combinations of existing drugs before we go to other drugs is also important. Ten to 15 years ago we used only 7.5 mg of methotrexate per week because we were afraid to increase the dose. But when we started increasing the dose, instead of getting 20 percent of patients in good condition, we got 70 percent. You can gain a lot by looking at how patients are responding and adapting the dose.

Making Rational Treatment Decisions in Rheumatoid Arthritis When Methotrexate Fails.

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Advances in the treatment of rheumatoid arthritis in recent years have profoundly muted the destructive potential of this disease. The safety profile of methotrexate has made earlier treatment possible, and biologic therapies have opened the door to combination rather than sequential therapy, with the result that treatment recommendations now aim for disease remission.1,2 However, the evidence base guiding the treatment that should be given after a patient has an inadequate response to methotrexate monotherapy is weak, despite the armamentarium of efficacious agents.

O’Dell et al. now report in the Journal the results of their randomized clinical trial evaluating the safety and efficacy of adding sulfasalazine and hydroxychloroquine to methotrexate (triple therapy) as compared with adding etanercept (a tumor-necrosis-factor [TNF] receptor) to methotrexate in patients with rheumatoid arthritis who have active disease.3 If the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating greater disease activity) had not decreased by at least 1.2 units at 24 weeks, patients were switched in a blinded fashion to the alternative regimen. The primary outcome — the difference between the two groups in the change in the DAS28 at 48 weeks — showed the noninferiority of triple therapy to etanercept–methotrexate. The progression of radiographic joint damage (as assessed with the use of the van der Heijde modification of the Sharp score, which ranges from 0 to 380, with higher scores indicating more extensive disease) over 48 weeks also did not differ significantly between the groups (an increase of 0.54 Sharp score units in the triple-therapy group and 0.29 Sharp score units in the etanercept–methotrexate group, P=0.43). These results are certainly encouraging, but several caveats must be considered.

The noninferiority margin chosen by O’Dell et al. (0.6) is half the minimum clinically meaningful improvement of 1.2 in the DAS28, but justification that this margin is acceptable to clinicians and patients is not provided. This may be a moot concern, since improvement with triple therapy as compared with improvement with etanercept–methotrexate was much closer than 0.6. Furthermore, Table S2 in the Supplementary Appendix of the article (available with the full text of the article at NEJM.org) shows each component of the DAS28 improving similarly in the two regimens, suggesting equivalent efficacy across the DAS28 domains. Figure S2 in the Supplementary Appendix of the article indicates that the proportions of patients who continued with the originally assigned regimen and of patients who switched to the alternative regimen were similar in the two groups, as were the proportions of patients who withdrew or were lost to follow-up and of patients who completed the study — further reducing concerns that missing data or poor implementation biased the results toward a finding of noninferiority. Since a noninferiority margin was not specified for the secondary outcomes, the reader cannot determine whether P values for these outcomes, such as radiographic progression, identify triple therapy as noninferior to etanercept–methotrexate.

The study by O’Dell et al. is not the first to compare these treatment regimens. In the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study, patients were randomly assigned to methotrexate monotherapy, triple therapy, or methotrexate plus etanercept.4 No significant difference in the primary outcome (the change in DAS28 scores from week 48 to week 102) was observed between the two combination-treatment groups — similar to the results in the study by O’Dell et al.; however, the Sharp scores for radiographic progression increased more in the triple-therapy group than in the methotrexate–etanercept group (1.69 vs. 0.64, P=0.046). In the Swedish Pharmacotherapy (Swefot) study, in which patients who had not had an adequate response to methotrexate were randomly assigned to triple therapy or to infliximab (an anti-TNF antibody) plus methotrexate, the superiority of infliximab–methotrexate with respect to a good response according to European League against Rheumatism (EULAR) criteria was observed at 12 months but not at 18 or 24 months.5,6 The Sharp scores for radiographic progression increased more in the triple-therapy group than in the infliximab–methotrexate group (7.23 vs. 4.00, P=0.009) — a finding consistent with that in the TEAR study.

There are considerable methodologic differences across the studies. The study by O’Dell et al. and the TEAR study were double-blind studies that included observed data without imputation of missing data and used etanercept as the biologic therapy, whereas the Swefot study was not a blinded study, included persons who, for any reason, did not have a measurable response, and used infliximab as the alternative therapy to triple therapy. The Swefot and TEAR studies targeted early disease, whereas O’Dell et al. targeted established disease. The inclusion and exclusion criteria also varied among the studies. Even so, the results were remarkably consistent. The efficacy rates at the extended time points, as well as the frequencies of total and serious adverse events, were relatively similar with the two treatment regimens in all the studies. The TNF inhibitor–methotrexate regimen showed modest superiority over triple therapy in slowing radiographic progression, although the trend in the study by O’Dell et al. was not significant.

We have to consider, however, whether these findings have arrived too late to influence modern practice, in which arguably a TNF inhibitor is the preferred next step when methotrexate alone is inadequate.7,8 Whether third-party payers who currently require failure of methotrexate monotherapy before prescription of expensive biologic therapy will change this policy to require failure of the cheaper nonbiologic combination is an interesting question. The development of more affordable biosimilar agents may change the treatment choices yet again,9 potentially rendering the studies with nonbiologic agents cited above irrelevant. We hope that with the ever-increasing number of effective treatments for rheumatoid arthritis, future recommendations for treatment will be guided by additional comparative-effectiveness studies such as the study by O’Dell et al. In addition, future identification of biomarkers to identify the patients who are most likely to have a response to, or are least likely to have side effects with, specific therapies will be the next great leap in the treatment of rheumatoid arthritis.

 

Source: Editorial, NEJM

Gout Guidelines From ACR Include New Drugs, Diet.

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New gout guidelines from the American College of Rheumatology are meant to improve gout management by providing clinicians with clear, readily implemented guidance on urate-lowering therapy (including diet and lifestyle changes), chronic tophaceous gouty arthropathy (CTGA), analgesic and antiinflammatory management of acute gouty arthritis, and drug prophylaxis of acute attacks.

The guidelines, reported in the October issue of Arthritis Care & Research in two parts, and include guidance on the new drugs febuxostat and pegloticase, recently approved for gout management and not yet addressed in the European League Against Rheumatism or British Society for Rheumatology gout guidelines.

Senior author Robert Terkeltaub, MD, told Medscape Medical News,”This is the first time in the 78-year history of ACR that there have been guidelines for the management of gout. This indicates how seriously people in rheumatology take this and how common the problem has become, with more than 8 million cases in the US, affecting 3.9% of adults. What we have here is a disease that is very well understood but ridiculously poorly managed.” Dr. Terkeltaub is chief of rheumatology at the Veterans Affairs Medical Center in San Diego, California, and professor of medicine and associate division director at the University of California in San Diego.

Old Disease, New Management

Part 1 of the guidelines focuses on hyperuricemia and CTGA. The top recommendation is for more intensive education of patients on diet, lifestyle choices, treatment objectives, and management of concomitant diseases; this includes recommendations on specific dietary items to encourage, limit, and avoid.

“We provide a comorbidity check-list for the clinician that I expect will be very useful in day-to-day practice,” Dr. Terkeltaub said. “We have also provided a cohesive set of diet and lifestyle recommendations. This has been a problem because of the fact and fiction mixed in to diet and lifestyle approaches to gout. The guideline is an advance because it provides a more actionable set of recommendations for physicians to talk about with their patients.”

Table. Comorbidity Checklist for Patients with Gout

Obesity, dietary factors
Excessive alcohol intake
History of urolithiasis
Chronic kidney disease
Potential genetic or acquired causes of uric acid overproduction (inborn error of purine metabolism, psoriasis, myeloproliferative or lymphoproliferative disease)
Lead intoxication

 

Dr. Terkeltaub added, “Many patients feel that diet and moderation alone should be sufficient to manage their gout. Diet is important, but what is really important is getting the serum urate to a target appropriate for that patient. At a bare minimum it should be < 6 mg/dL. In clinical practice the serum uric acid level is no longer part of the routine metabolic panel, but it is inexpensive and should be monitored regularly in gout patients.”

Dr. Terkeltaub noted that dietary or alcohol excess can increase uric acid and trigger acute gout attacks in susceptible individuals, but he said that dietary restrictions alone may not reduce serum urate levels enough to prevent joint damage in gout patients.

“The average age gout patient in our clinical trials has a serum uric acid level between 9.5 and 10 mg/dL. Even ideal diet and alcohol intake will likely lower that by only 10% to 15%, which will not bring the typical gout patient to a serum uric acid of 6 mg/dL. Often people need urate-lowering drugs to get them to the target level and keep them there. People feel that if they have fewer gout attacks, they are better, but the disease will progress unless serum uric acid is reduced to a level where deposits of urate crystals in the joint tissues will disappear,” Dr. Terkeltaub said.

Start Low, Go Slow With Allopurinol

The ACR guidelines recommend treating patients with a xanthine oxidase inhibitor, such as allopurinol, as the first-line pharmacologic urate-lowering therapy approach. The recommended goal is to reduce serum urate to less than 6 mg/dL, and the initial allopurinol dosage should be no greater than 100 mg/d, the guidelines say. This should be followed by gradual increase of the maintenance dose, which can safely exceed 300 mg even in patients with chronic kidney disease.

“Clinicians often start allopurinol at doses that are too high but maintain allopurinol at doses that are too low,” Dr. Terkeltaub said. “We give specific guidance on start low, go slow dose escalation.”

To avoid allopurinol toxicity, the guidelines recommend considering HLA-B*5801 prescreening of patients at particularly high risk for severe adverse reaction to allopurinol (eg, Koreans with stage 3 or worse kidney disease and all patients of Han Chinese and Thai descent).

For CTGA, the guidelines recommend combination therapy, with 1 xanthine oxidase inhibitor (allopurinol or febuxostat) and 1 uricosuric agent, when target urate levels are not achieved. They advise using probenecid as an alternative first-line urate-lowering drug in the setting of contraindication or intolerance to at least 1 xanthine oxidase inhibitor (except in patients with creatinine clearance below 50 mL/min). They also recommend pegloticase in patients with severe gout disease who do not respond to standard, appropriately dosed urate-lowering therapy.

“We provide guidance for dose-escalation of urate-lowering therapy for specific case scenarios of mild, moderate, and severe disease including for patients with destructive joint disease that is chronic to their gout. These provide ways to assess the patient in an office setting on clinical findings alone, with serum uric acid. Pictorial representation of most severe patients should help identify who needs more intensive uric acid-lowering therapy,” Dr. Terkeltaub said.

Acute Gout Requires Prompt Treatment

Part 2 of the guidelines covers therapy and prophylactic antiinflammatory treatment for acute gouty arthritis. These guidelines recommend initiating pharmacologic therapy within 24 hours of onset of acute gouty arthritis attack while continuing urate-lower therapy without interruption.

Nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, or oral colchicine are the recommended first-line treatment for acute gout, and combinations of these medications can be used for severe or unresponsive cases.

To prevent the acute gout flares that may accompany the early stages of urate-lowering therapy, the guidelines recommend oral colchicine or low-dose NSAIDs as long as there is no medical contraindication or lack of tolerance.

Dr. Terkeltaub advised caution with colchicine dosing. “One of the major problems in quality of care is that people were getting drowned in colchicine for acute gout. We assessed the evidence and decided to go with the FDA [Food and Drug Administration]-approved regimen of low-dose colchicine for early acute gout flare. That is a major recommendation. When people get drowned in high doses of colchicine for a long time for acute gout, the rate of adverse events is quite high.”

The recommendations were prepared during a 2-year project by an ACR task force panel that included 7 rheumatologists, 2 primary care physicians, a nephrologist, and a patient representative. The draft guidelines then went through 3 rounds of peer review, Dr. Terkeltaub said.

“I’d like to see better education of physicians and other primary caregivers, including nurse practitioners and physician assistants, and then better education of gout patients. If we only accomplish that, we’ll have accomplished a lot. There has been a systematic failure of both quality of care and patient education in gout,” Dr. Terkeltaub said.

Doug Campos-Outcalt, MD, scientific analyst for the American Academy of Family Physicians, reviewed the new guidelines for Medscape Medical News. Dr. Capos-Outcalt is chair of the Department of Family Medicine at the University of Arizona College of Medicine in Phoenix.

Dr. Campos-Outcalt said, “This is a reasonable, limited number of guidelines that are implementable. You don’t like to see guidelines that have 50 recommendations. The ACR guidelines also present, from a family physician perspective, no major changes in standard-of-care.” However, Dr. Campos-Outcalt suggested that a broader effort to disseminate the guidelines to primary care physicians will be needed because few of them regularly read the journal in which the guidelines appear.

Dr. Campos-Outcalt told Medscape Medical News that the guidelines seem reasonable but that before being influenced by them, he would like to take a closer look at the level of evidence each recommendation is based on. “We don’t like to see recommendations based on low-level evidence,” he said. Only about 20% of the ACR recommendations were based on top-quality “level A” evidence (supported by more than 1 randomized clinical trial or meta-analysis). About half of the recommendations were based on level C evidence (consensus opinion of experts, case studies, or standard of care).

Source: Mescape.com