German guidelines for the sequential medical treatment of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs

The German Society of Rheumatology approved new German guidelines for the sequential medical treatment of rheumatoid arthritis (RA) based on the European League Against Rheumatism (EULAR) recommendations for the management of RA published in 2010. An update of the EULAR systematic literature research was performed in Medline, Embase, and Cochrane databases. Meta-analyses, controlled trials, cohort studies, and registry data addressing traditional and biologic disease-modifying antirheumatic drugs, glucocorticoids, and treatment strategies published between January 2009 and August 2011 were included. Two reviewers independently evaluated and compared the additional data that had been published after the time limit set by the EULAR recommendations. A national guideline working group developed an adapted set of recommendations. The new German guidelines were accepted by vote using an informal Delphi approach. Twelve recommendations and the resulting updated treatment algorithm were developed and approved as a practical orientation for rheumatologists. These recommendations are based on a successive treatment with traditional and biologic disease-modifying drugs depending on the individual progress of the disease and distinct patient characteristics. The German guidelines have been developed on the basis of the internationally well-recognized EULAR recommendations. In addition, more recent evidence from a systematic literature research was considered. They have been developed and approved by a group of national experts aiming at guidance for rheumatologists to reach best medical practice.     

Cardiovascular comorbidity and its risk factors in rheumatoid arthritis

Rheumatoid arthritis (RA) is still associated with an increased mortality mainly due to an increase in cardiovascular risk. This increase is not solely explained by traditional cardiovascular risk factors but also by disease characteristics, e.g. inflammation, positive rheumatoid factor and anti-citrullinated peptide antibodies (ACPA). Control of disease activity with disease-modifying drugs (DMARDs) was shown to reduce cardiovascular risk in RA patients. Use of non-steroidal antirheumatic drugs (NSAIDs) and glucocorticoids might be associated with an increased risk. The EULAR recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis have been established. These recommendations are based on national guidelines regarding control of traditional cardiovascular risk factors.     

The need to better classify and diagnose early and very early rheumatoid arthritis

Early rheumatoid arthritis (RA) and very early RA are major targets of research and clinical practice. Remission has become a realistic goal in the management of RA, particularly in early disease. The 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) RA classification criteria, the EULAR treatment recommendations for RA, and the EULAR recommendations for the management of early arthritis focus on early disease and translate the knowledge related to early RA into classification and management. Nevertheless, there is a need for further improvement and progress. Results from 6 recent studies are summarized, evaluating the performance of the 2010 ACR/EULAR RA classification criteria. The data show a significant risk of misclassification, and highlight that overdiagnosis and underdiagnosis may become important issues if the criteria recommend synthetic and biological disease-modifying antirheumatic drugs. Therefore, some considerations are presented on how the current problems and limitations could be overcome in clinical practice and future research. A consensus is needed to better define the early phase of RA and differentiate from other early arthritis. The possible effect of misclassification on spontaneous and drug-induced remission of early and very early RA awaits further elucidation. Such research will eventually lead to more reliable diagnostic and classification criteria for new-onset RA.     

Evidence-based management of systemic sclerosis: Navigating recommendations and guidelines

ObjectivesSystemic sclerosis (SSc) is a rare heterogeneous connective tissue disease. Recommendations addressing the major issues in the management of SSc including screening and treatment of organ complications are needed.MethodsThe updated European League Against Rheumatism/European Scleroderma Trial and Research (EULAR/EUSTAR) and the British Society of Rheumatology (BSR) and British Health Professionals in Rheumatology (BHPR) guidelines were compared and contrasted.ResultsThe updated EULAR/EUSTAR guidelines focus specifically on the management of SSc features and include data on newer therapeutic modalities and mention a research agenda. These recommendations are pharmacologic, with few guidelines regarding investigations and non-pharmacologic management. Recommendations from BSR/BHPR are similar to the organ manifestations mentioned in the EULAR/EUSTAR recommendations, and expand on several domains of treatment, including general measures, non-pharmacologic treatment, cardiac involvement, calcinosis, and musculoskeletal features. The guidelines usually agree with one another. Limitations include the lack of guidance for combination or second-line therapy, algorithmic suggestions, the absence of evidence-based recommendations regarding the treatment of specific complications (i.e., gastric antral ectasia and erectile dysfunction). Consensus for when to treat interstitial lung disease in SSc is lacking. There are differences between Europe and North American experts due to access and indications for certain therapies.ConclusionsCare gaps in SSc have been demonstrated so the EULAR/EUSTAR and BSR/BHP guidelines can promote best practices. Certain complications warrant active investigation to further improve outcomes in SSc and future updates of these recommendations.Care gaps in SSc have been demonstrated so the EULAR/EUSTAR and BSR/BHP guidelines can promote best practices. Certain complications warrant active investigation to further improve outcomes in SSc     

Discrepancies between the EULAR response criteria and the NICE guidelines for continuation of anti-TNF therapy in RA: a cause for concern?

OBJECTIVES: A discrepancy exists between the National Institute for Health and Clinical Excellence (NICE) guidelines for continuation of TNF therapy in RA and EULAR response criteria. We performed a retrospective study of patients starting anti-TNF therapy to establish how many NICE non-responders would have met EULAR response criteria, and whether this may increase. METHOD: We calculated the percentage of NICE non-responders who would have met EULAR moderate response criteria. We then compared the mean decrease in disease activity score (DAS28) for patients with low and high baseline scores. We analysed trends for treating RA in Derby with anti-TNF to address whether we were treating less active disease over time. RESULTS: At 3 months (n = 271 patients), 7.7% of NICE non-responders would have met EULAR moderate response criteria. At 6 months (n = 240 patients) this was 23.7%. Patients starting with a higher DAS28 had a significantly greater absolute drop in score. The mean decrease between the 1st and 3rd tertiles of patients divided by baseline DAS28 was significant at 3 and 6 months (P < 0.001). Derby rheumatologists were treating less active RA over time. Comparing the mean DAS28 baseline between the 1st and 3rd tertiles of patients divided by anti-TNF commencement date was significant (P < 0.001). CONCLUSIONS: A significant minority of NICE non-responders would fall within the moderate EULAR response criteria. This is likely to increase in future due to the increasing tendency to initiate anti-TNF in patients with less active disease. Consequently, NICE guidelines should be brought in line with EULAR response criteria.     

Remission in rheumatoid arthritis: wishful thinking or clinical reality?

OBJECTIVES: To review the concept of remission in rheumatoid arthritis (RA), as defined by the Food and Drug Administration (FDA), the American College of Rheumatology (ACR), and the European League Against Rheumatism (EULAR). To delineate differences between significant clinical improvements, very low disease activity, and the achievement of true remission. To evaluate the prevalence of these outcomes with biologic therapy and traditional disease-modifying antirheumatic drugs (DMARD) regimens. METHODS: The MEDLINE database was searched for the key words "remission" and "rheumatoid arthritis." Efficacy data of RA clinical trials from 1985 to 2004 are based on a literature review of medical journals and abstracts from rheumatology meetings. We review 3 well-defined sets of criteria established by the ACR, EULAR, and the FDA for measuring remission. RESULTS: Defining remissions in clinical trials and clinical practice requires appropriate standardized and objective outcome measures, such as the ACR and EULAR remission criteria. Traditional DMARDs often provide symptom relief, improvements in physical function, and the slowing of radiographic progression in patients with RA, but rarely lead to the complete cessation of RA activity. Remission, as defined by the ACR criteria, has been observed in 7 to 22% of patients treated with traditional DMARD monotherapy (ie, gold, penicillamine, methotrexate [MTX], cyclosporine A, or sulfasalazine), but these remissions have often been short-lived. Treatments with DMARD combinations, biologic monotherapy, and biologic combination therapy with MTX offer greater hope and may facilitate the higher rates of remission. Clinical trial results have shown that newer DMARDs such as leflunomide or the combination of multiple DMARDs can generally elicit greater EULAR remission rates (ranging from 13 to 42%) than monotherapies. Biologic combinations with MTX have also been shown to induce significant remission (as defined by the EULAR criteria) in RA patients, with a 31% rate observed with infliximab plus MTX at 54 weeks, a 50% rate observed for adalimumab plus MTX after 2 years of therapy, and a 41% rate observed for etanercept plus MTX after 2 years of therapy. CONCLUSIONS: In the era of biologics and combination therapy, identifying remission or at least very low disease activity as the ultimate goal in RA therapy should become the new standard for the outcome of all RA trials. The criteria established by the FDA, the ACR, and the EULAR represent an important step toward achieving this goal.     

Prioritization of clinical questions for the Australian Living Guideline for the Pharmacological Management of Inflammatory Arthritis

Aim

Living guidelines aim to reduce delays in translating new knowledge into practice by updating individual recommendations as soon as relevant new evidence emerges. We surveyed members of the Australian Rheumatology Association (ARA) to develop a list of priority questions for the Australian Living Guideline for the Pharmacological Management of Inflammatory Arthritis (ALG) and to explore clinicians' use of clinical practice guidelines.

Methods

An electronic survey of ARA members was performed in two phases. The first survey contained questions about current guideline use and beliefs and invited participants to submit at least three questions relevant to the management of rheumatoid arthritis (RA). In the second round, participants selected 10 questions they considered to be the highest priority from the collated list and ranked them in priority order. The sum of ranks was used to generate a final priority list.

Results

There were 115 (21%) and 78 (14%) responses to the first and second survey rounds respectively. 87% of respondents use existing rheumatology guidelines in their usual practice, primarily EULAR guidelines. Most respondents favored the development of Australian rheumatology guidelines. In total, 34 potential recommendation topics were identified and ranked in order of priority.

Conclusion

A list of 34 clinical questions about RA management, ranked in order of importance by clinicians, has informed the development of the ALG. Similar prioritization exercises in other contexts may permit guidelines to be tailored to the needs of guideline users in their specific context, which may facilitate international collaboration and promote efficient translation of evidence to practice.     

Optimal use of non-biologic therapy in the treatment of rheumatoid arthritis

With the evolution of therapies for RA, new treatment strategies and goals of therapy have evolved. Recent European League Against Rheumatism (EULAR) guidelines on the treatment of RA proposed three phases of therapy: phase I comprising first-line synthetic DMARD with or without glucocorticoid; phase II comprising second-line synthetic DMARD with or without glucocorticoid, or combination synthetic DMARD therapy, or (if prognostic factors are poor) first-line biologic DMARD; and phase III comprising alternative biologic DMARDs. In all phases, the key principle is tight control: striving to achieve a predefined goal of remission or low disease activity (treat to target) with frequent dose and medication adjustments tailored to the individual patient, preferably within the window of opportunity during early RA. In all phases, MTX is recognized as an anchor drug; it is characterized by proven efficacy in combination DMARD strategies, relatively low cost, relatively rapid onset of action, proven beneficial impact on radiological progression and mortality and a wide dose range that facilitates dose adjustments. Prednisone and its active metabolite, prednisolone, have similar characteristics, making them ideal anchor drugs too. The EULAR guidelines reserve a place for MTX and glucocorticoids in all phases of treatment. The second CAMERA (Computer Assisted Management in Early Rheumatoid Arthritis) study in early RA has demonstrated that including prednisone from the start in an MTX-based tight control strategy aimed at remission improves disease activity variables, time to remission, functional disability and radiological joint damage compared with the same strategy without prednisone. In conclusion, both MTX and prednisone play key roles in modern RA treatment strategies.     

Tapering biologics in rheumatoid arthritis: a pragmatic approach for clinical practice

Optimal rheumatoid arthritis (RA) therapy in daily clinical practice is based on the treat-to-target strategy. Quicker escalation of therapy and earlier introduction of biological disease-modifying anti-rheumatic drugs have led to improved outcomes in RA. However, chronic immunosuppressive therapy is associated with adverse events and higher costs. In addition, our patients frequently express a desire for lower dosing and drug holidays. Current clinical practice guidelines from the American College of Rheumatology and European League Against Rheumatism suggest that rheumatologists consider tapering treatment after achieving remission. However, the optimal approach for tapering therapy in RA, specifically de-escalation of biologics, remains unknown. This clinical review discusses biologic tapering strategies in RA. We draw our recommendations for everyday clinical practice from the most recent observational, pragmatic, and controlled clinical trials on de-escalation of biologics in RA. For each biologic, we highlight clinically relevant outcomes, such as flare rates, recapture of the disease control with retreatment, radiographic progression, side effects, and functional impact. We discuss the use of musculoskeletal ultrasound to select patients for successful tapering. In conclusion, we provide the reader with a practical guide for tapering biologics in the rheumatology clinic.     

Managing HIV-infected patients on antiretroviral therapy in Rio de Janeiro, Brazil: do providers follow national guidelines?

The objective of the paper was to compare provider practices in prescribing antiretroviral (ARV) drug regimens and use of laboratory monitoring at three health care facilities and to determine whether Brazilian national guidelines are being followed. A retrospective, cross-sectional survey was employed. We selected a sequential sample of patients on ARV therapy who registered at three health care facilities in Rio de Janeiro, Brazil, during 2001. We abstracted 2001 patient visit data from medical records using standardized data forms. Provider practice was compared to the 2000 Brazil national guidelines for ARV use. Providers who prescribed recommended or acceptable regimens were considered as having conformed to guidelines. Only 2% of patient records (N=984) reported use of inappropriate regimens as defined by the Brazil 2000 national ARV guidelines. Forty-nine per cent of patients at the Evandro Chagas hospital, 17% of those at Hospital Geral, and 57% of those at Centro da Saude were prescribed recommended therapies. Twenty per cent of patients seen at the public district hospital received dual ARV therapy, an acceptable regimen at the time. Although the national guidelines do not provide recommendations on laboratory monitoring, during the 1 year study period a majority of patients had at least one CD4+ cell count (92%) or viral load measurement (86%). Providers' practices in prescribing ARV regimens at these Rio de Janeiro facilities conform to national guidelines. Physicians would benefit from Brazilian ARV guidelines which incorporate the international consensus on the frequency of laboratory monitoring appropriate for patients in resource-constrained settings.     

Recommendations for the management of cardiovascular risk in patients with rheumatoid arthritis: Scientific evidence and expert opinion

Objectives

Last recommendations regarding cardiovascular risk (CVR) in rheumatoid arthritis (RA) patients were developed by the EULAR group in 2010. The aim is to update evidence-based recommendations about this worrying health problem.

Methods

We assembled a multidisciplinary workgroup (rheumatologists, endocrinologist, cardiologist, and epidemiologist) and a panel of 28 expert rheumatologists. The study was carried out in two big phases: identifying key areas in the prevention and management of CVR and developing a set of recommendations based on a review of the available scientific evidence and use of the Delphi consensus technique. All this has been developed according to an updating process of evidence-based recommendations.

Results

Overall, 25 recommendations were made addressing three complementary areas: CVR assessment tools, patient eligibility for assessment, and treatment strategies for control of CVR. The grade of the recommendations was not substantially modified compared to the original EULAR recommendations, except in two of them, which were upgraded from C to B. These two recommendations are the ones related to the use of corticosteroids and smoking cessation. The new developed recommendations address these two areas: CVR assessment and treatment strategies for control of CVR.

Conclusions

There are substantial gaps in the current knowledge that do not allow classifying properly RA patients based on their actual CVR and to accurately identify those patients who would benefit from CVR assessment. Consequently, studies designed to determine the causal effects of RA disease characteristics on cardiovascular morbidity/mortality and to identify patients at high risk of cardiovascular disease are still needed.     

Wie früh würden wir Biologika wirklich einsetzen?

According to a survey carried out during the annual congress of the German Society for Rheumatology (DGRh) last year, many rheumatologists would like to initiate TNF-alpha inhibitors earlier than suggested in the EULAR recommendations. While most of the survey participants agreed with the initial MTX monotherapy favored therein, more than half would prefer to combine MTX with a biologic instead of a second DMARD after failure of this option. This decision seems to be based mainly on clinical experience. Although international therapy guidelines allow an earlier use of biologic therapy in special cases, particularly in Germany an extensive documentation and justification is needed for this treatment strategy. Future guidelines may allow several parallel drug sequences based on prognostic factors and individual biomarkers.     

Management of rheumatoid arthritis: consensus recommendations from the Hong Kong Society of Rheumatology

Given the recent availability of novel biologic agents for the treatment of rheumatoid arthritis (RA), the Hong Kong Society of Rheumatology has developed consensus recommendations on the management of RA, which aim at providing guidance to local physicians on appropriate, literature-based management of this condition, specifically on the indications and monitoring of the biologic disease-modifying anti-rheumatic drugs (DMARDs). The recommendations were developed using the European League Against Rheumatism (EULAR) recommendations for the management of early arthritis as a guide, along with local expert opinion. As significant joint damage occurs early in the course of RA, initiating therapy early is key to minimizing further damage and disability. Patients with serious disease or poor prognosis should receive early, aggressive therapy. Because of its good efficacy and safety profile, methotrexate is considered the standard first-line DMARD for most treatment-naïve RA patients. Patients with a suboptimal response to methotrexate monotherapy should receive step-up (combination) therapy with either the synthetic or biologic DMARDs. In recent years, combinations of methotrexate with tocilizumab, abatacept, or rituximab have emerged as effective therapies in patients who are unresponsive to traditional DMARDs or the anti-tumor necrosis factor (TNF)-α agents. As biologic agents can increase the risk of infections such as tuberculosis and reactivation of viral hepatitis, screening for the presence of latent tuberculosis and chronic viral hepatitis carrier state is recommended before initiating therapy.     

Evidenzbasierte Empfehlungen zum Management einer undifferenzierten peripheren entzündlichen Arthritis (UPIA)

Introduction

Peripheral arthritis is the most common presenting complaint in clinical rheumatology. Unequivocal identification of the underlying entity can be difficult, particularly at an early stage. Such cases are commonly referred to as undifferentiated peripheral inflammatory arthritis (UPIA). Since evidence-based recommendations for the clinical management of UPIA are lacking, this international 3e initiative convened 697 rheumatologists from 17 countries to develop appropriate recommendations.

Methods

Based on a systematic literature research in Medline, EMBASE, Cochrane Library, and the ACR/EULAR abstracts of 2007/2008, 10 multinational recommendations were developed by 3 rounds of a Delphi process. In Germany, a national group of experts worked on 3 additional recommendations using the same method. The recommendations were discussed among the members of the 3e initiative and the degree of consensus was analyzed as well as the potential impact of the recommendations on clinical practice.

Results

A total of 39,756 references were identified, of which 250 were systematically reviewed for the development of 10 multinational recommendations concerning differential diagnosis, diagnostic and prognostic value of clinical assessments, laboratory tests and imaging techniques, and monitoring of UPIA. In addition, 3 national recommendations on the diagnostic and prognostic value of a response to anti-inflammatory therapy on the analysis of synovial fluid and on enthesitis were developed by the German experts based on 35 out of 5542 references.

Conclusions

The article translates the 2011 published original paper of the international 3e initiative (Machado et al., Ann Rheum Dis 70:15–24, 2011) and reports the methods and results of the national vote and the additional 3 national recommendations.     

Italian consensus on Eular 2003 recommendations for the treatment of knee osteoarthritis

The recommendations for the management of osteoarthritis (OA) of the knee firstly proposed by the EULAR in 2000, have been updated in 2003. One of the most important objectives of the expert charged to provide these recommendations was their dissemination. Thus, the information generated may be used by each individual country to produce their own set of management guidelines and algorithms for treatment in primary care. The Italian Society of Rheumatology (SIR) and the Italian League against Rheumatism (LIMAR) have organised a Consensus on the EULAR recommendations 2003 with the aim to analyse their acceptability and applicability according to our own experience and local situations in the Italy. The results of this Consensus have demonstrated that a large majority of the EULAR recommendations are endorsed by the Italian experts. Furthermore, the final document of the Italian Consensus clearly indicated the need that specialists involved in the management of knee OA strongly encourage the dissemination of the EULAR 2003 recommendations also in Italy.     

Italian consensus on EULAR recommendations 2005 for the management of hip osteoarthritis

The recommendations for the management of osteoarthritis (OA) of the hip were proposed by EULAR in 2005. Among the most important objectives of the expert charged to provide these recommendations were their wide dissemination and implementation. Thus, the information generated can be used by each individual country to produce their own set of management guidelines and algorithms for treatment in primary care. According with that previously executed for the EU-LAR recommendation 2003 for the knee, the Italian Society of Rheumatology (SIR) has organised a Consensus on the EULAR recommendations 2005 for the management of hip OA. To obtain an acceptability as large as possible, the group of experts was composed by many physicians interested in the management of hip OA, including Orthopaedics, Rheumatologists, Physiatrists, and General Practitioners. Main aim of the Consensus was to analyse the acceptability and applicability of the recommendations according to own experience and local situations in the Italy. The results of this Consensus have demonstrated that a large majority of the EULAR recommendations are endorsed by the Italian experts. Furthermore, the final document of the Italian Consensus clearly indicated the need that the specialists involved in the management of hip OA strongly encourage the dissemination of the EULAR 2005 recommendations also in Italy.     

Rituximab or a second anti–tumor necrosis factor therapy for rheumatoid arthritis patients who have failed their first anti–tumor necrosis factor therapy? Comparative analysis from the British Society for Rheumatology Biologics Register

Objective

To compare the effectiveness of rituximab (RTX) or a second anti–tumor necrosis factor (anti‐TNF) therapy in rheumatoid arthritis (RA) patients who had failed their first anti‐TNF and switched to either RTX or a second anti‐TNF, in routine clinical practice.

Methods

RA patients were registered with the British Society for Rheumatology Biologics Register. Response to treatment 6 months after switching was assessed using European League Against Rheumatism (EULAR) criteria and improvements in a Health Assessment Questionnaire (HAQ) score (0.22 unit or more). Regression analyses were used to compare EULAR response and improvement in HAQ score between the 2 groups, adjusting for propensity scores.

Results

In total, 1,328 patients were included in the analysis of EULAR response, and 937 patients were included in the analysis of HAQ scores. Six months after switching, 54.8% of patients who switched to RTX were EULAR responders compared to 47.3% of those who switched to a second anti‐TNF. A total of 38.4% of RTX patients achieved a clinically important improvement in HAQ score compared to 29.6% in anti‐TNF patients. After adjustment using propensity scores, patients who switched to RTX were significantly more likely to achieve EULAR response (odds ratio [OR] 1.31; 95% confidence interval [95% CI] 1.02, 1.69) compared to those who switched to an alternative anti‐TNF. RTX patients were also significantly more likely to achieve improvements in HAQ score (OR 1.49; 95% CI 1.07, 2.08).

Conclusion

The results suggest that switching to RTX may be of more benefit than switching to an alternative anti‐TNF therapy after failing the first anti‐TNF therapy in RA patients.