Early referral of patients with suspected polymyalgia rheumatica - A systematic review.

INTRODUCTION: Prompt diagnosis and treatment of polymyalgia rheumatica (PMR) is crucial to prevent long-term complications and improve patient outcomes. However, there is currently no standardized approach to referral of suspected PMR patients to rheumatologists, leading to inconsistent management practices. The objective of this systematic review was to clarify the existing evidence regarding the following aspects of early management strategies in patients with suspected PMR: diagnostic strategies, GCA screening, glucocorticoid initiation prior to referral, value of shared care and value of fast track clinic. METHODS: Two authors performed a systematic literature search, data extraction and risk of bias assessment independently. The literature search was conducted in Embase, MEDLINE (PubMed) and Cochrane. Studies were included if they contained cohorts of suspected PMR patients and evaluated the efficacy of different diagnostic strategies for PMR, screening for giant cell arteritis (GCA), starting glucocorticoids before referral to secondary care, shared care, or fast-track clinics. RESULTS: From 2,437 records excluding duplicates, 14 studies met the inclusion criteria. Among these, 10 studies investigated the diagnostic accuracy of various diagnostic strategies with the majority evaluating different clinical approaches, but none of them showed consistently high performance. However, 4 studies on shared care and fast-track clinics showed promising results, including reduced hospitalization rates, lower starting doses of glucocorticoids, and faster PMR diagnosis. CONCLUSION: This review emphasizes the sparse evidence of early management and referral strategies for patients with suspected PMR. Additionally, screening and diagnostic strategies for differentiating PMR from other diseases, including concurrent GCA, require clarification. Fast-track clinics may have potential to aid patients with PMR in the future, but studies will be needed to determine the appropriate pre-referral work-up.

EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.

In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.

Standardized grip strength as an outcome measure in early rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) suffer progressive loss of hand function and have weaker hand grip than the healthy population. In this study we aimed to validate hand grip strength standardized by age and gender (z score) against currently accepted clinical measures of disease activity. METHOD: Electronic records of patients with a diagnosis of RA seen between April 2007 and December 2011 were screened for the documentation of tender and swollen joint counts, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), along with patient global activity score and grip strength. Bilateral grip strengths were converted to z scores on the basis of previously published age- and gender-corrected normative data for grip strength. The z scores were then correlated against components of disease activity scores. RESULTS: Ninety patients diagnosed with RA had been seen 602 times within 2 years of diagnosis. Hand grip data were available for 204 visits. There was a statistically significant inverse correlation between grip strength z scores and the tested variables. The sensitivity and specificity of a hand grip z score of -1.5 for predicting remission were, respectively, 70% and 76% for the right hand and 82% and 69% for the left hand. CONCLUSIONS: Hand grip testing and subsequent conversion to z scores corrected for age and gender correlate with disease activity in early RA. We have shown that the grip strength z scores can discriminate between various disease states, and the strength seems to return to near normative data when the disease is in remission.

EULAR recommendations for the management of large vessel vasculitis.

OBJECTIVES: To develop European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis. METHODS: An expert group (10 rheumatologists, 3 nephrologists, 2 immunolgists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search through a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of large vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. RESULTS: Seven recommendations were made relating to the assessment, investigation and treatment of patients with large vessel vasculitis. The strength of recommendations was restricted by the low level of evidence and EULAR standardised operating procedures. CONCLUSIONS: On the basis of evidence and expert consensus, management recommendations for large vessel vasculitis have been formulated and are commended for use in everyday clinical practice.

EULAR recommendations for the management of primary small and medium vessel vasculitis.

OBJECTIVES: To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis. METHODS: An expert group (consisting of 10 rheumatologists, 3 nephrologists, 2 immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. RESULTS: In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures. CONCLUSIONS: On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.

Modification and validation of the Birmingham Vasculitis Activity Score (version 3).

BACKGROUND: Comprehensive multisystem clinical assessment using the Birmingham Vasculitis Activity score (BVAS) is widely used in therapeutic studies of systemic vasculitis. Extensive use suggested a need to revise the instrument. The previous version of BVAS has been revised, according to usage and reviewed by an expert committee. OBJECTIVE: To modify and validate version 3 of the BVAS in patients with systemic vasculitis. METHODS: The new version of BVAS was tested in a prospective cross-sectional study of patients with vasculitis. RESULTS: The number of items was reduced from 66 to 56. The subscores for new/worse disease and persistent disease were unified. In 313 patients with systemic vasculitis, BVAS(v.3) correlated with treatment decision (Spearman's r(s) = 0.66, 95% CI 0.59 to 0.72), BVAS1 of version 2 (r(s) = 0.94, 95% CI 0.92 to 0.96), BVAS2 of version 2 in patients with persistent disease (r(s) = 0.60, 95% CI 0.21 to 0.83), C-reactive protein levels (r(s) = 0.43, 95% CI 0.31 to 0.54), physician's global assessment (r(s) = 0.91, 95% CI 0.89 to 0.93) and vasculitis activity index (r(s) = 0.88, 95% CI 0.86 to 0.91). The intraclass correlation coefficients for reproducibility and repeatability were 0.96 (95% CI 0.95 to 0.97) and 0.96 (95% CI 0.92 to 0.97), respectively. In 39 patients assessed at diagnosis and again at 3 months, the BVAS(v.3) fell by 17 (95% CI 15 to 19) units (p<0.001, paired t test). CONCLUSION: BVAS(v.3) demonstrates convergence with BVAS(v.2), treatment decision, physician global assessment of disease activity, vasculitis activity index and C-reactive protein. It is repeatable, reproducible and sensitive to change. The new version of BVAS is validated for assessment of systemic vasculitis.

Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force.

OBJECTIVES: We undertook a systematic literature review as a background to the European League Against Rheumatism (EULAR) recommendations for conducting clinical trials in anti-neutrophil cytoplasm antibody associated vasculitis (AAV), and to assess the quality of evidence for outcome measures in AAV. METHODS: Using a systematic Medline search, we categorised the identified studies according to diagnoses. Factors affecting remission, relapse, renal function and overall survival were identified. RESULTS: A total of 44 papers were reviewed from 502 identified by our search criteria. There was considerable inconsistency in definitions of end points. Remission rates varied from 30% to 93% in Wegener granulomatosis (WG), 75% to 89% in microscopic polyangiitis (MPA) and 81% to 91% in Churg-Strauss syndrome (CSS). The 5-year survival for WG, MPA and CSS was 74-91%, 45-76% and 60-97%. Relapse (variably defined) was common in the first 2 years but the frequency varied: 18% to 60% in WG, 8% in MPA, and 35% in CSS. The rate of renal survival in WG varied from 23% at 15 months to 23% at 120 months. METHOD: used to assess morbidity varied between studies. Ignoring the variations in definitions of the stage of disease, factors influencing remission, relapse, renal and overall survival included immunosuppressive therapy used, type of organ involvement, presence of ANCA, older age and male gender. CONCLUSIONS: Factors influencing remission, relapse, renal and overall survival include the type of immunosuppressive therapy used, pattern of organ involvement, presence of ANCA, older age and male gender. Methodological variations between studies highlight the need for a consensus on terminology and definitions for future conduct of clinical studies in AAV.

Disease-specific quality indicators, guidelines, and outcome measures in vasculitis.

Measuring quality of care in the anti neutrophil cytoplasm antibody (ANCA) associated vasculitides (AAV) has become more complex, because the introduction of immunosuppressive therapy has resulted in a substantial improvement in survival. Early diagnosis remains a problem, because many patients are seen by non-specialists who may not recognize vasculitis or fail to initiate therapy promptly. A comprehensive assessment to determine the pattern and severity of organ involvement allows a specialist to plan a therapeutic regimen, and to manage co-morbidity effectively. Recent guidelines from the European League Against Rheumatism (EULAR) address the conduct of high-quality clinical trials in vasculitis. Risk factors for poor outcome in vasculitis are probably similar in the different forms of AAV. The risk factors are discussed in the context of failing to achieve remission, relapse, organ failure, and death. Factors indicating a poor prognosis include: the presence of high disease activity at diagnosis (which increases mortality risk even though it is associated with a greater likelihood of response to therapy); the pattern of organ involvement, for example with cardiac features carrying an adverse outcome in Wegener's granulomatosis; significant damage; renal impairment; persistence of ANCA; elderly age at diagnosis; under-use of cyclophosphamide and glucocorticoids in the first 3 months of treatment; persistent nasal carriage of Staphylococcus aureus; and the increased risk of bladder cancer in patients who are given large amounts of cyclophosphamide.

Remission in antineutrophil cytoplasmic antibody-associated systemic vasculitis.

The definition of remission in patients with systemic vasculitis must be distinguished from the term "cure," which implies that patients are well and not requiring ongoing therapy. Remission should be defined using a standardised approach to measuring clinical disease activity, and the definition should be qualified by the duration of the remission and the type of maintenance therapy required to sustain remission. Remission is an important goal of management in the systemic vasculitides and is achievable in most patients. Maintenance of remission is a more difficult target, and evidence from studies of patients with antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis indicates that durable, lasting remission is unlikely to occur. Despite good disease control, damage or scarring from disease or its treatment is a common finding and is a separate outcome from remission. Future studies of vasculitis therapies should address the concept of rapid and sustained disease control, so that patients spend most of their time in a state of good health, with minimal damage.

Clinical and biological assessment in systemic necrotizing vasculitides.

The systemic vasculitides are multi-system disorders with significant mortality and morbidity and frequent relapses. Treatment is usually effective but fraught with potentially serious effects. Disease Assessment is important to ensure that patients receive the appropriate treatment. Disease Assessment should comprise measurement of disease activity, chronic irreversible damage and impairment of function. Serological markers can be helpful in assessing disease activity but lack sufficient sensitivity and specificity to be used on their own. Radiological techniques such as Magnetic Resonance Imaging, Ultrasound and Positron Emission Tomography show promise in the large vessel vasculitides but require validation in large studies. Clinical Assessment tools are the current gold standard for the assessment of disease activity, damage and function.

The role of biologic therapies in the management of systemic vasculitis.

The recent development of biologic therapies capable of selectively targeting components of the immune system has revolutionised the treatment of inflammatory arthritides. The steady increase in use of biologic agents coupled with the expansion in the knowledge of the pathogenesis of vascular inflammation has led to their application in the treatment of primary systemic vasculitis. These agents may have a role in addition to or in place of conventional immunosuppression and also be effective when the latter fails to induce remission. The use of biologics as targeted therapies has also, in reverse, improved our understanding of the pathophysiology of vascular inflammation. While the advent of biologics heralds a new era in the management of the systemic vasculitis, evidence for their efficacy is still in its infancy and has yet to match that of conventional immunosuppressants. In this review, we examine the up-to-date evidence for the use of biologics in systemic vasculitis, including TNF-alpha inhibitors, and highlight the challenges facing their use. We examine the rationale for using biologics based on the pathophysiology of vasculitis. Issues of toxicity and pharmacovigilance with the use of biologics are also discussed. Finally, future directions and predictions are presented.

Current state of tumour necrosis factor {alpha} blockade in Wegener's granulomatosis.

Tumour necrosis factor alpha (TNFalpha) is likely to be involved in the pathogenesis of Wegener's granulomatosis. This paper reviews published clinical trials of the anti-TNFalpha agents etanercept and infliximab with regard to their efficacy and safety in the treatment of Wegener's granulomatosis. On the basis of the high rate of adverse events, particularly an increased incidence of cancers, the use of etanercept in the management of Wegener's granulomatosis is not justified. However, the potential role for infliximab or the as yet untested adalimumab cannot be discounted. The development of novel approaches focusing on blockade of specific molecules including TNFalpha in the treatment of Wegener's granulomatosis is awaited.