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OBJECTIVES: To update the EULAR recommendations for the use of imaging modalities in primary large vessel vasculitis (LVV). METHODS: A systematic literature review update was performed to retrieve new evidence on ultrasound, MRI, CT and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) for diagnosis, monitoring and outcome prediction in LVV. The task force consisted of 24 physicians, health professionals and patients from 14 countries. The recommendations were updated based on evidence and expert opinion, iterating until voting indicated consensus. The level of agreement was determined by anonymous votes. RESULTS: Three overarching principles and eight recommendations were agreed. Compared to the 2018 version, ultrasound is now recommended as first-line imaging test in all patients with suspected giant cell arteritis, and axillary arteries should be included in the standard examination. As an alternative to ultrasound, cranial and extracranial arteries can be examined by FDG-PET or MRI. For Takayasu arteritis, MRI is the preferred imaging modality; FDG-PET, CT or ultrasound are alternatives. Although imaging is not routinely recommended for follow-up, ultrasound, FDG-PET or MRI may be used for assessing vessel abnormalities in LVV patients with suspected relapse, particularly when laboratory markers of inflammation are unreliable. MR-angiography, CT-angiography or ultrasound may be used for long-term monitoring of structural damage, particularly at sites of preceding vascular inflammation. CONCLUSIONS: The 2023 EULAR recommendations provide up-to-date guidance for the role of imaging in the diagnosis and assessment of patients with LVV.
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OBJECTIVE: To develop international consensus-based recommendations for early referral of individuals with suspected polymyalgia rheumatica (PMR). METHODS: A task force including 29 rheumatologists/internists, 4 general practitioners, 4 patients and a healthcare professional emerged from the international giant cell arteritis and PMR study group. The task force supplied clinical questions, subsequently transformed into Population, Intervention, Comparator, Outcome format. A systematic literature review was conducted followed by online meetings to formulate and vote on final recommendations. Levels of evidence (LOE) (1-5 scale) and agreement (LOA) (0-10 scale) were evaluated. RESULTS: Two overarching principles and five recommendations were developed. LOE was 4-5 and LOA ranged between 8.5 and 9.7. The recommendations suggest that (1) each individual with suspected or recently diagnosed PMR should be considered for specialist evaluation, (2) before referring an individual with suspected PMR to specialist care, a thorough history and clinical examination should be performed and preferably complemented with urgent basic laboratory investigations, (3) individuals with suspected PMR with severe symptoms should be referred for specialist evaluation using rapid access strategies, (4) in individuals with suspected PMR who are referred via rapid access, the commencement of glucocorticoid therapy should be deferred until after specialist evaluation and (5) individuals diagnosed with PMR in specialist care with a good initial response to glucocorticoids and a low risk of glucocorticoid related adverse events can be managed in primary care. CONCLUSIONS: These are the first international recommendations for referral of individuals with suspected PMR, which complement the European Alliance of Associations for Rheumatology/American College of Rheumatology management guidelines for established PMR.
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OBJECTIVES: To develop an Outcome Measures in Rheumatology (OMERACT) ultrasonography score for monitoring disease activity in giant cell arteritis (GCA) and evaluate its metric properties. METHODS: The OMERACT Instrument Selection Algorithm was followed. Forty-nine members of the OMERACT ultrasonography large vessel vasculitis working group were invited to seven Delphi rounds. An online reliability exercise was conducted using images of bilateral common temporal arteries, parietal and frontal branches as well as axillary arteries from 16 patients with GCA and 7 controls. Sensitivity to change and convergent construct validity were tested using data from a prospective cohort of patients with new GCA in which ultrasound-based intima-media thickness (IMT) measurements were conducted at weeks 1, 3, 6, 12 and 24. RESULTS: Agreement was obtained (92.7%) for the OMERACT GCA Ultrasonography Score (OGUS), calculated as follows: sum of IMT measured in every segment divided by the rounded cut-off values of IMTs in each segment. The resulting value is then divided by the number of segments available. Thirty-five members conducted the reliability exercise, the interrater intraclass correlation coefficient (ICC) for the OGUS was 0.72-0.84 and the median intrareader ICC was 0.91. The prospective cohort consisted of 52 patients. Sensitivity to change between baseline and each follow-up visit up to week 24 yielded standardised mean differences from -1.19 to -2.16, corresponding to large and very large magnitudes of change, respectively. OGUS correlated moderately with erythrocyte sedimentation rate, C reactive protein and Birmingham Vasculitis Activity Score (corrcoeff 0.37-0.48). CONCLUSION: We developed a provisional OGUS for potential use in clinical trials.
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Arteritis de Células Gigantes , Humanos , Arteritis de Células Gigantes/diagnóstico por imagen , Grosor Intima-Media Carotídeo , Reproducibilidad de los Resultados , Estudios Prospectivos , Arterias Temporales/diagnóstico por imagen , Ultrasonografía/métodosRESUMEN
OBJECTIVES: To explore current management practices for PMR by general practitioners (GPs) and rheumatologists including implications for clinical trial recruitment. METHODS: An English language questionnaire was constructed by a working group of rheumatologists and GPs from six countries. The questionnaire focused on: 1: Respondent characteristics; 2: Referral practices; 3: Treatment with glucocorticoids; 4: Diagnostics; 5: Comorbidities; and 6: Barriers to research. The questionnaire was distributed to rheumatologists and GPs worldwide via members of the International PMR/Giant Cell Arteritis Study Group. RESULTS: In total, 394 GPs and 937 rheumatologists responded to the survey. GPs referred a median of 25% of their suspected PMR patients for diagnosis and 50% of these were returned to their GP for management. In general, 39% of rheumatologists evaluated patients with suspected PMR >2 weeks after referral, and a median of 50% of patients had started prednisolone before rheumatologist evaluation. Direct comparison of initial treatment showed that the percentage prescribing >25 mg prednisolone daily for patients was 30% for GPs and 12% for rheumatologists. Diagnostic imaging was rarely used. More than half (56%) of rheumatologists experienced difficulties recruiting people with PMR to clinical trials. CONCLUSION: This large international survey indicates that a large proportion of people with PMR are not referred for diagnosis, and that the proportion of treatment-naive patients declined with increasing time from referral to assessment. Strategies are needed to change referral and management of people with PMR, to improve clinical practice and facilitate recruitment to clinical trials.
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Médicos Generales , Arteritis de Células Gigantes , Polimialgia Reumática , Humanos , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/tratamiento farmacológico , Polimialgia Reumática/diagnóstico , Polimialgia Reumática/tratamiento farmacológico , Reumatólogos , Glucocorticoides/uso terapéutico , Prednisolona/uso terapéutico , Encuestas y CuestionariosRESUMEN
Giant cell arteritis (GCA) represents the most common form of primary systemic vasculitis and is frequently associated with comorbidities related to the disease itself or induced by the treatment. Systematically collected data on disease course, treatment and outcomes of GCA remain scarce. The aim of this EULAR Task Force was to identify a core set of items which can easily be collected by experienced clinicians, in order to facilitate collaborative research into the course and outcomes of GCA. A multidisciplinary EULAR task force group of 20 experts including rheumatologists, internists, epidemiologists and patient representatives was assembled. During a 1-day meeting, breakout groups discussed items from a previously compiled collection of parameters describing GCA status and disease course. Feedback from breakout groups was further discussed. Final consensus was achieved by means of several rounds of email discussions after the meeting. A three-round Delphi survey was conducted to determine a core set of parameters including the level of agreement. 117 parameters were regarded as relevant. Potential items were subdivided into the following categories: General, demographics, GCA-related signs and symptoms, other medical conditions and treatment. Possible instruments and assessment intervals were proposed for documentation of each item. To facilitate implementation of the recommendations in clinical care and clinical research, a minimum core set of 50 parameters was agreed. This proposed core set intends to ensure that relevant items from different GCA registries and databases can be compared for the dual purposes of facilitating clinical research and improving clinical care.
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Investigación Biomédica/normas , Atención a la Salud/normas , Arteritis de Células Gigantes/terapia , Guías de Práctica Clínica como Asunto , Reumatología/normas , Sociedades Médicas , Europa (Continente) , HumanosRESUMEN
OBJECTIVES: To determine whether whole-body MRI defines clinically relevant subgroups within polymyalgia rheumatica (PMR) including glucocorticoid responsiveness. METHODS: 22 patients with PMR and 16 with rheumatoid arthritis (RA), untreated and diagnosed by consultant rheumatologists, underwent whole-body, multiple-joint MRI, scored by two experts. Patients with PMR reported whether they felt 'back to normal' on glucocorticoid therapy and were followed for a median of 2â years. RESULTS: All patients with PMR were deemed to respond to glucocorticoids clinically. A characteristic pattern of symmetrical, extracapsular inflammation, adjacent to greater trochanter, acetabulum, ischial tuberosity and/or symphysis pubis, was observed in 14/22 of the PMR cases. In PMR, this pattern was associated with complete glucocorticoid response (p=0.01), higher pretreatment C-reactive protein (CRP) and serum interleukin-6 (IL-6), and better post-treatment fatigue and function. Only 1/14 in the extracapsular group could stop glucocorticoids within 1â year, compared with 4/7 of the others. A score derived from the five sites discriminating best between PMR and RA correlated with IL-6 (p<0.002). IL-6 levels ≥16.8â pg/mL had 86% sensitivity and 86% specificity for the extracapsular MRI pattern. CONCLUSIONS: A subset of patients with rheumatologist-diagnosed PMR had a characteristic, extracapsular pattern of MRI inflammation, associated with elevated IL-6/CRP and with complete patient-reported glucocorticoid responsiveness.
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Imagen por Resonancia Magnética , Polimialgia Reumática/diagnóstico , Prednisolona/uso terapéutico , Imagen de Cuerpo Entero/métodos , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Glucocorticoides/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Polimialgia Reumática/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Glucocorticoids are often required for adequate control of inflammation in many serious inflammatory diseases; common indications for long-term treatment include polymyalgia rheumatica, giant cell arteritis, asthma and chronic obstructive pulmonary disease. Long-term glucocorticoid therapy is, however, associated with many adverse effects involving skin, gastro-intestinal, eye, skeletal muscle, bone, adrenal, cardio-metabolic and neuropsychiatric systems. This balance between benefits and risks of glucocorticoids is important for clinical practice and glucocorticoid-related adverse effects can significantly impair health-related quality of life. Understanding the nature and mechanisms of glucocorticoid-related adverse effects may inform how patients are monitored for toxicity and identify those groups, such as older people, that may need closer monitoring. For clinical trials in diseases commonly treated with glucocorticoids, standardised measurement of glucocorticoid-related adverse effects would facilitate future evidence synthesis and meta-analysis.
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Arteritis de Células Gigantes/tratamiento farmacológico , Glucocorticoides/efectos adversos , Polimialgia Reumática/tratamiento farmacológico , Erupciones por Medicamentos/etiología , Monitoreo de Drogas/métodos , Oftalmopatías/inducido químicamente , Glucocorticoides/uso terapéutico , Humanos , Enfermedades Musculares/inducido químicamente , Osteoporosis/inducido químicamente , Calidad de Vida , Úlcera Gástrica/inducido químicamente , Cicatrización de Heridas/efectos de los fármacosRESUMEN
OBJECTIVES: To review the literature in order to estimate how many previously unknown thoracic aortic aneurysms (TAAs) and thoracic aortic dilatations (TADs) might be detected by systematic, cross-sectional aortic imaging of patients with giant cell arteritis (GCA). METHODS: A systematic literature review was performed using Ovid Medline, Embase and the Cochrane Library. Studies potentially relevant to TAA/TAD were evaluated by two authors independently for relevance, bias and heterogeneity. Meta-analysis was performed using a random-effects model to estimate pooled prevalence. RESULTS: Two analyses of routinely collected administrative data suggested a threefold risk of TAA/dissection in GCA compared with controls. In GCA cohorts without systematic imaging, 2-8% had TAA. In the two best-reported studies, aneurysm dissection/rupture occurred in 1% and 6% of GCA cases. Aortic imaging studies had a variety of TAA/TAD definitions, imaging methods and time points. There were limited data on age-matched controls. Three studies suggested that male sex may be a risk factor for TAA/TAD in GCA. On average, five to ten patients with GCA would need aortic imaging to detect one previously unknown TAA/TAD. CONCLUSIONS: The data support an association between GCA and TAA/TAD compared with age-matched controls, but the true relative risk, and the time course of that risk, remains unclear. It is also unclear whether chest radiography is a sufficiently sensitive screening tool. Clinicians should retain a high index of suspicion for aortic pathology in patients with GCA. Before ordering imaging, clinicians should consider whether, and how, detecting aortic pathology would affect a patient's management.
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Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Arteritis de Células Gigantes/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Aneurisma de la Aorta Torácica/epidemiología , Arteritis de Células Gigantes/epidemiología , Humanos , Prevalencia , Factores de RiesgoRESUMEN
Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory rheumatic diseases that may present to a variety of disciplines and specialities. The mainstay of treatment is glucocorticoids (steroids); together PMR and GCA now represent one of the most common reasons for medium-to-high dose, long-term glucocorticoid treatment in primary care. However, adverse effects of glucocorticoids are common in these patients. Management of both diseases involves balancing the symptoms and risks of the disease against the adverse effects and risks of glucocorticoids. The crucial first step in management is to make a firm, well-documented diagnosis, since once glucocorticoids are started they can mask the symptoms of a number of other diseases. Diagnosis however can be challenging and there are still substantial gaps in the evidence for treatment.
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Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/tratamiento farmacológico , Polimialgia Reumática/diagnóstico , Polimialgia Reumática/tratamiento farmacológico , Diagnóstico Diferencial , Monitoreo de Drogas , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , HumanosRESUMEN
OBJECTIVES: To update the evidence on imaging for diagnosis, monitoring and outcome prediction in large vessel vasculitis (LVV) to inform the 2023 update of the European Alliance of Associations for Rheumatology recommendations on imaging in LVV. METHODS: Systematic literature review (SLR) (2017-2022) including prospective cohort and cross-sectional studies (>20 participants) on diagnostic, monitoring, outcome prediction and technical aspects of LVV imaging. Diagnostic accuracy data were meta-analysed in combination with data from an earlier (2017) SLR. RESULTS: The update retrieved 38 studies, giving a total of 81 studies when combined with the 2017 SLR. For giant cell arteritis (GCA), and taking clinical diagnosis as a reference standard, low risk of bias (RoB) studies yielded pooled sensitivities and specificities (95% CI) of 88% (82% to 92%) and 96% (95% CI 86% to 99%) for ultrasound (n=8 studies), 81% (95% CI 71% to 89%) and 98% (95% CI 89% to 100%) for MRI (n=3) and 76% (95% CI 67% to 83%) and 95% (95% CI 71% to 99%) for fluorodeoxyglucose positron emission tomography (FDG-PET, n=4), respectively. Compared with studies assessing cranial arteries only, low RoB studies with ultrasound assessing both cranial and extracranial arteries revealed a higher sensitivity (93% (95% CI 88% to 96%) vs 80% (95% CI 71% to 87%)) with comparable specificity (94% (95% CI 83% to 98%) vs 97% (95% CI 71% to 100%)). No new studies on diagnostic imaging for Takayasu arteritis (TAK) were found. Some monitoring studies in GCA or TAK reported associations of imaging with clinical signs of inflammation. No evidence was found to determine whether imaging severity might predict worse clinical outcomes. CONCLUSION: Ultrasound, MRI and FDG-PET revealed a good performance for the diagnosis of GCA. Cranial and extracranial vascular ultrasound had a higher pooled sensitivity with similar specificity compared with limited cranial ultrasound.
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Fluorodesoxiglucosa F18 , Arteritis de Células Gigantes , Humanos , Estudios Transversales , Estudios Prospectivos , Arteritis de Células Gigantes/diagnóstico por imagen , Tomografía de Emisión de PositronesRESUMEN
The temporal artery biopsy (TAB) is regarded as the gold-standard test in the diagnosis of giant cell arteritis (GCA). There is a lack of agreement among experienced pathologists regarding the diagnostic features and classification of inflammation observed in TAB sections in the diagnosis of GCA. AIMS: The aim of this research study was to establish consensus on the key parameters which should be included in a standardised reporting proforma for TAB specimens. We specifically investigated factors pertaining to clinical information, specimen handling and microscopic pathological features. METHODS: A modified Delphi process, comprising three survey rounds and three virtual consensus group meetings, was undertaken by 13 UK-based pathology or ophthalmology consultants, with a 100% response rate across the three rounds. Initial statements were formulated after a literature review and participants were asked to rate their agreement using a nine-point Likert scale. Consensus was defined a priori as an agreement of ≥70% and individual feedback was provided after each round, together with data on the distribution of group responses. RESULTS: Overall, 67 statements reached consensus and 17 statements did not. The participants agreed on the core microscopic features to be included in a pathology report and felt that a proforma would facilitate consistent reporting practices. CONCLUSIONS: Our work revealed uncertainty surrounding the correlation between clinical parameters (eg, laboratory markers of inflammation and steroid therapy duration) and microscopic findings, and we propose areas for future research.
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BACKGROUND: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are almost always treated with glucocorticoids (GCs), but long-term GC use is associated with diabetes mellitus (DM). The absolute incidence of this complication in this patient group remains unclear. OBJECTIVE: To quantify the absolute risk of GC-induced DM in PMR and GCA from published literature. METHODS: We identified literature from inception to February 2017 reporting diabetes following exposure to oral GC in patients with PMR and/or GCA without pre-existing diabetes. A random-effects meta-analysis was performed to summarise the findings. RESULTS: 25 eligible publications were identified. In studies of patients with GCA, mean cumulative GC dose was almost 1.5 times higher than in studies of PMR (8.2 g vs 5.6 g), with slightly longer treatment duration and longer duration of follow-up (6.4 years vs 4.4 years). The incidence proportion (cumulative incidence) of patients who developed new-onset DM was 6% (95% CI 3% to 9%) for PMR and 13% (95% CI 9% to 17%) for GCA. Based on UK data on incidence rate of DM in the general population, the expected background incidence rate of DM over 4.4 years in patients with PMR and 6.4 years in patients with GCA (follow-up duration) would be 4.8% and 7.0%, respectively. Heterogeneity between studies was high (I2=79.1%), as there were differences in study designs, patient population, geographical locations and treatment. Little information on predictors of DM was found. CONCLUSION: Our meta-analysis produced plausible estimates of DM incidence in patients with PMR and GCA, but there is insufficient published data to allow precise quantification of DM risk.
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OBJECTIVES: To explore patients' concepts of stiffness in polymyalgia rheumatica (PMR), and how they think stiffness should be measured. METHODS: Eight focus groups were held at three centres involving 50 patients with current/previous PMR. Each group had at least one facilitator and one rapporteur making field notes. An interview schedule was used to stimulate discussion. Interviews were recorded, transcribed and analysed using an inductive thematic approach. RESULTS: Major themes identified were: symptoms: pain, stiffness and fatigue; functional impact; impact on daily schedule; and approaches to measurement. The common subtheme for the experience of stiffness was "difficulty in moving", and usually considered as distinct from the experience of pain, albeit with a variable overlap. Some participants felt stiffness was the "overwhelming" symptom, in that it prevented them carrying out "fundamental activities" and "generally living life". Diurnal variation in stiffness was generally described in relation to the daily schedule but was not the same as stiffness severity. Some participants suggested measuring stiffness using a numeric rating scale or a Likert scale, while others felt that it was more relevant and straightforward to measure difficulty in performing everyday activities rather than about stiffness itself. CONCLUSIONS: A conceptual model of stiffness in PMR is presented where stiffness is an important part of the patient experience and impacts on their ability to live their lives. Stiffness is closely related to function and often regarded as interchangeable with pain. From the patients' perspective, visual analogue scales measuring pain and stiffness were not the most useful method for reporting stiffness; participants preferred numerical rating scales, or assessments of function to reflect how stiffness impacts on their daily lives. Assessing function may be a pragmatic solution to difficulties in quantifying stiffness.
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Articulaciones/fisiopatología , Polimialgia Reumática/patología , Actividades Cotidianas/psicología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Polimialgia Reumática/psicología , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES: To review the evidence for accuracy of imaging for diagnosis of polymyalgia rheumatica (PMR). METHODS: Searches included MEDLINE, EMBASE and PubMed. Evaluations of diagnostic accuracy of imaging tests for PMR were eligible, excluding reports with <10 PMR cases. Two authors independently extracted study data and three authors assessed methodological quality using modified QUADAS-2 criteria. RESULTS: 26 studies of 2370 patients were evaluated: 10 ultrasound scanning studies; 6 MRI studies; 1 USS and MRI study; 7 18-fluorodeoxyglucose-positron emission tomography (PET) studies; 1 plain radiography and 1 technetium scintigraphy study. In four ultrasound studies, subacromial-subdeltoid bursitis had sensitivity 80% (95% CI 55% to 93%) and specificity 68% (95% CI 60% to 75%), whereas bilateral subacromial-subdeltoid bursitis had sensitivity 66% (95% CI 43% to 87%) and specificity 89% (95% CI 66% to 97%). Sensitivity for ultrasound detection of trochanteric bursitis ranged from 21% to 100%. In four ultrasound studies reporting both subacromial-subdeltoid bursitis and glenohumeral synovitis, detection of subacromial-subdeltoid bursitis was more accurate than that of glenohumeral synovitis (p=0.004). MRI and PET/CT revealed additional areas of inflammation in the spine and pelvis, including focal areas between the vertebrae and anterior to the hip joint, but the number of controls with inflammatory disease was inadequate for precise specificity estimates. CONCLUSIONS: Subacromial-subdeltoid bursitis appears to be the most helpful ultrasound feature for PMR diagnosis, but interpretation is limited by study heterogeneity and methodological issues, including variability in blinding and potential bias due to case-control study designs. Recent MRI and PET/CT case-control studies, with blinded readers, yielded promising data requiring validation within a diagnostic cohort study.
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OBJECTIVE: To identify the instruments used to assess polymyalgia rheumatica (PMR) in published studies. METHODS: A systematic literature review of clinical trials and longitudinal observational studies related to PMR, published from 1970 to 2014, was carried out. All outcome and assessment instruments were extracted and categorized according to core areas and domains, as defined by the OMERACT (Outcome Measures in Rheumatology) Filter 2.0. RESULTS: Thirty-five articles (3221 patients) were included: 12 randomized controlled trials (RCT); 3 nonrandomized trials; and 20 observational studies. More than 20 domains were identified, measured by 29 different instruments. The most frequently used measures were pain, morning stiffness, patient global assessment and physician global assessment, erythrocyte sedimentation rate, and C-reactive protein. The definition of outcomes varied considerably between studies. CONCLUSION: The outcome measures and instruments used in PMR are numerous and diversely defined. The establishment of a core set of validated and standardized outcome measurements is needed.
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Antirreumáticos/uso terapéutico , Inmunosupresores/uso terapéutico , Evaluación de Resultado en la Atención de Salud , Polimialgia Reumática/tratamiento farmacológico , Calidad de Vida , Actividades Cotidianas , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Conferencias de Consenso como Asunto , Ensayos Clínicos Controlados como Asunto , Femenino , Humanos , Masculino , Estudios Observacionales como Asunto , Dimensión del Dolor , Polimialgia Reumática/diagnóstico , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
INTRODUCTION: Giant cell arteritis (GCA) is an autoimmune disease commonest in Northern Europe and Scandinavia. Previous studies report various associations with HLA-DRB1*04 and HLA-DRB1*01; HLA-DRB1 alleles show a gradient in population prevalence within Europe. Our aims were (1) to determine which amino acid residues within HLA-DRB1 best explained HLA-DRB1 allele susceptibility and protective effects in GCA, seen in UK data combined in meta-analysis with previously published data, and (2) to determine whether the incidence of GCA in different countries is associated with the population prevalence of the HLA-DRB1 alleles that we identified in our meta-analysis. METHODS: GCA patients from the UK GCA Consortium were genotyped by using single-strand oligonucleotide polymerization, allele-specific polymerase chain reaction, and direct sequencing. Meta-analysis was used to compare and combine our results with published data, and public databases were used to identify amino acid residues that may explain observed susceptibility/protective effects. Finally, we determined the relationship of HLA-DRB1*04 population carrier frequency and latitude to GCA incidence reported in different countries. RESULTS: In our UK data (225 cases and 1378 controls), HLA-DRB1*04 carriage was associated with GCA susceptibility (odds ratio (OR) = 2.69, P = 1.5×10(-11)), but HLA-DRB1*01 was protective (adjusted OR = 0.55, P = 0.0046). In meta-analysis combined with 14 published studies (an additional 691 cases and 4038 controls), protective effects were seen from HLA-DR2, which comprises HLA-DRB1*15 and HLA-DRB1*16 (OR = 0.65, P = 8.2×10(-6)) and possibly from HLA-DRB1*01 (OR = 0.73, P = 0.037). GCA incidence (n = 17 countries) was associated with population HLA-DRB1*04 allele frequency (P = 0.008; adjusted R(2) = 0.51 on univariable analysis, adjusted R(2) = 0.62 after also including latitude); latitude also made an independent contribution. CONCLUSIONS: We confirm that HLA-DRB1*04 is a GCA susceptibility allele. The susceptibility data are best explained by amino acid risk residues V, H, and H at positions 11, 13, and 33, contrary to previous suggestions of amino acids in the second hypervariable region. Worldwide, GCA incidence was independently associated both with population frequency of HLA-DRB1*04 and with latitude itself. We conclude that variation in population HLA-DRB1*04 frequency may partly explain variations in GCA incidence and that HLA-DRB1*04 may warrant investigation as a potential prognostic or predictive biomarker.