Leonardo Punzi

Eular evidence based recommendations for the management of hand osteoarthritis - report of a task force of the Eular Standing Committee for International Clinical Studies Including Therapeutics(ESCISIT)

Objectives: To develop evidence based recommendations for the management of hand osteoarthritis (OA). Methods: The multidisciplinary guideline development group comprised 16 rheumatologists, one physiatrist, one orthopaedic surgeon, two allied health professionals, and one evidence based medicine expert, representing 15 different European countries. Each participant contributed up to 10 propositions describing key clinical points for management of hand OA. Final recommendations were agreed using a Delphi consensus approach. A systematic search of Medline, Embase, CINAHL, Science Citation Index, AMED, Cochrane Library, HTA, and NICE reports was used to identify the best available research evidence to support each proposition. Where possible, the effect size and number needed to treat were calculated for efficacy. Relative risk or odds ratio was estimated for safety, and incremental cost effectiveness ratio was used for cost effectiveness. The strength of recommendation was provided according to research evidence, clinical expertise, and perceived patient preference. Results: Eleven key propositions involving 17 treatment modalities were generated through three Delphi rounds. Treatment topics included general considerations (for example, clinical features, risk factors, comorbidities), non-pharmacological (for example, education plus exercise, local heat, and splint), pharmacological (for example, paracetamol, NSAIDs, NSAIDs plus gastroprotective agents, COX-2 inhibitors, systemic slow acting disease modifying drugs, intra-articular corticosteroids), and surgery. Of 17 treatment modalities, only six were supported by research evidence (education plus exercise, NSAIDs, COX-2 inhibitors, topical NSAIDs, topical capsaicin, and chondroitin sulphate). Others were supported either by evidence extrapolated from studies of OA affecting other joint sites or by expert opinion. Strength of recommendation varied according to level of evidence, benefits and harms/costs of the treatment, and clinical expertise. Conclusion: Eleven key recommendations for treatment of hand OA were developed using a combination of research based evidence and expert consensus. The evidence was evaluated and the strength of recommendation was provided.

EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee For International Clinical Studies Including Therapeutics (ESCISIT)

Objective: To develop evidence based recommendations for the management of gout. Methods: The multidisciplinary guideline development group comprised 19 rheumatologists and one evidence based medicine expert representing 13 European countries. Key propositions on management were generated using a Delphi consensus approach. Research evidence was searched systematically for each proposition. Where possible, effect size (ES), number needed to treat, relative risk, odds ratio, and incremental cost-effectiveness ratio were calculated. The quality of evidence was categorised according to the level of evidence. The strength of recommendation (SOR) was assessed using the EULAR visual analogue and ordinal scales. Results: 12 key propositions were generated after three Delphi rounds. Propositions included both non-pharmacological and pharmacological treatments and addressed symptomatic control of acute gout, urate lowering therapy (ULT), and prophylaxis of acute attacks. The importance of patient education, modification of adverse lifestyle (weight loss if obese; reduced alcohol consumption; low animal purine diet) and treatment of associated comorbidity and risk factors were emphasised. Recommended drugs for acute attacks were oral non-steroidal anti-inflammatory drugs (NSAIDs), oral colchicine (ES = 0.87 (95% confidence interval, 0.25 to 1.50)), or joint aspiration and injection of corticosteroid. ULT is indicated in patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes of gout. Allopurinol was confirmed as effective long term ULT (ES = 1.39 (0.78 to 2.01)). If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, allopurinol desensitisation, or a uricosuric. The uricosuric benzbromarone is more effective than allopurinol (ES = 1.50 (0.76 to 2.24)) and can be used in patients with mild to moderate renal insufficiency but may be hepatotoxic. When gout is associated with the use of diuretics, the diuretic should be stopped if possible. For prophylaxis against acute attacks, either colchicine 0.5–1 mg daily or an NSAID (with gastroprotection if indicated) are recommended. Conclusions: 12 key recommendations for management of gout were developed, using a combination of research based evidence and expert consensus. The evidence was evaluated and the SOR provided for each proposition.

Autophagy in human health and disease.

From the Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston (A.M.K.C., S.W.R.); and the Howard Hughes Medical Institute and Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas (B.L.). Address reprint requests to Dr. Choi at the Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, or at amchoi@rics.bwh.harvard.edu.

2016 updated EULAR evidence-based recommendations for the management of gout

Background New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations. Methods The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach. Results Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 µmol/L) and <5 mg/dL (300 µmol/L) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended. Conclusions These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease.

European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis

Objectives To agree terminology and to develop recommendations for the diagnosis of calcium pyrophosphate deposition (CPPD). Methods The European League Against Rheumatism (EULAR) CPPD Task Force, comprising 15 experts from 10 countries, agreed the terms and recommendations for diagnosis of CPPD using a Delphi consensus approach. Evidence was systematically reviewed and presented in terms of sensitivity, specificity and positive likelihood ratio (LR) to support diagnosis; ORs were used for association. Strength of recommendation (SOR) was assessed by the EULAR visual analogue scale. Results It was agreed that ‘CPPD’ should be the umbrella term that includes acute calcium pyrophosphate (CPP) crystal arthritis, osteoarthritis (OA) with CPPD and chronic CPP crystal inflammatory arthritis. Chondrocalcinosis (CC) defines cartilage calcification, most commonly due to CPPD and detected by imaging or histological examination. A total of 11 key recommendations were generated on the topics of clinical features, synovial fluid (SF) examination, imaging, comorbidities and risk factors. Definitive diagnosis of CPPD relies on identification of SF CPP crystals. Rapid onset inflammatory symptoms and signs are suggestive but not definitive for acute CPP crystal arthritis. Radiographic CC is not highly sensitive or specific, whereas ultrasonography appears more useful (LR=24.2, 95% CI 3.51 to 168.01) for peripheral joints. Recognised risk factors for CPPD include ageing, OA and metabolic conditions such as primary hyperparathyroidism, haemochromatosis and hypomagnesaemia; familial forms are rare. SORs varied from 53 to 99 (maximum 100). Conclusion New terms for CPPD were agreed and 11 key recommendations for diagnosis of CPPD were developed using research evidence and expert consensus.

Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate

Infliximab, a humanised, mouse derived, genetically engineered, monoclonal antibody to tumour necrosis factor α (TNFα), is successfully used in association with low dose methotrexate in the treatment of rheumatoid arthritis (RA).1 Serious infections have been reported to be associated with infliximab treatment.1,2 However, the safety of infliximab is unknown or has not been yet established in chronic viral infections, including human immunodeficiency virus, hepatitis B virus (HBV) or hepatitis C virus infections. We describe a case, from our cohort of 102 patients treated with infliximab plus methotrexate, who carried hepatitis B surface antigen (HBsAg) and subsequently developed acute hepatitis due to HBV reactivation after 16 months of treatment with infliximab. A 49 year old man was diagnosed as having RA in January 1990. HBsAg, and HBe and HBc antibodies were positive, while HBe antigen and HBs …

Gout: why is this curable disease so seldom cured?

Gout is the most common inflammatory arthritis and one in which pathogenesis and risk factors are best understood. One of the treatment objectives in current guidelines is ‘cure’. However, audits show that only a minority of patients with gout receive adequate advice and treatment. Suboptimal care and outcomes reflect inappropriately negative perceptions of the disease, both in patients and providers. Historically, gout has been portrayed as a benign and even comical condition that is self-inflicted through overeating and alcohol excess. Doctors often focus on managing acute attacks rather than viewing gout as a chronic progressive crystal deposition disease. Urate-lowering treatment is underprescribed and often underdosed. Appropriate education of patients and doctors, catalysed by recent introduction of new urate-lowering treatments after many years with no drug development in the field, may help to overcome these barriers and improve management of this easily diagnosed and curable form of potentially severe arthritis.

Reliability and validity of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index in Italian patients with osteoarthritis of the knee.

OBJECTIVE The Western Ontario and McMaster Universities (WOMAC) Osteoarthritis (OA) Index is a tested questionnaire to assess symptoms and physical functional disability in patients with OA of the knee and the hip. We adapted the WOMAC for the Italian language and tested its metric properties in 304 patients with symptomatic OA of the knee. METHODS Three hundred and four consecutive patients, attending 29 rheumatologic outpatient clinic in northern, central, and southern Italy, were asked to answer two disease-specific questionnaires (WOMAC and Lequesne algofunctional index) and one generic instrument (Medical Outcomes Study SF-36 Health Survey-MOS SF-36). A sample of 258 patients was readministered the WOMAC 7-10 days after the first visit and the structured interview, which also assessed demographic and other characteristics. Internal consistency was assessed using Cronbachs alpha, reliability using intraclass correlation coefficients (ICCs), and construct and discriminant validity using Spearmans correlations, Wilcoxon rank sum test, and Kruskal-Wallis test. RESULTS All WOMAC subscales (pain, stiffness, and physical function) were internally consistent with Cronbachs coefficient alpha of 0.91, 0.81, and 0.84, respectively. Test-retest reliability was satisfactory with ICCs of 0.86, 0.68, and 0.89, respectively. In comparison with the SF-36, the expected correlations were found when comparing items measuring similar constructs, supporting the concepts of convergent construct validity. Very high correlations were also obtained between WOMAC scores and Lequesne OA algofunctional index. WOMAC physical function, but not WOMAC stiffness and pain subscales, was weakly associated with radiological OA severity (P=0.03). Also, WOMAC pain score was inversely correlated (P=0.01) with years of formal education. Examination of discriminant validity showed that the scores on the WOMAC and SF-36 followed hypothesized patterns: the WOMAC discriminated better among subjects with varying severity of knee problems, whereas the SF-36 discriminated better among subjects with varying levels of self-reported health status and comorbidity. CONCLUSION The Italian version of WOMAC is a reliable and valid instrument for evaluating the severity of OA of the knee, with metric properties in agreement with the original, widely used version.

Long-term anti-TNF therapy and the risk of serious infections in a cohort of patients with rheumatoid arthritis: Comparison of adalimumab, etanercept and infliximab in the GISEA registry

OBJECTIVE To evaluate the risk of serious infections (SIs) in RA patients receiving anti-TNF therapy on the basis of the data included in the GISEA register. METHODS The study involved 2769 adult patients with long-standing RA (mean age 53.2±13.4 years; mean disease duration 9.0±8.3 years) enrolled in the GISEA register, who had been treated for at least 6 months with TNF inhibitors or had discontinued therapy due to SI: 837 (30%) treated with infliximab (IFN), 802 (29%) with adalimumab (ADA), and 1130 (41%) with etanercept (ETN). RESULTS 176 patients had experienced at least one of the 226 Sis during the 9 years of treatment with an anti-TNF agent, an overall incidence of 31.8/1000 patient-years (95% CI 25.2-38.3): 23.7/1000 patient-years (95% CI 13.1-34.2) on ADA; 12.8/1000 patient-years (95% CI 6.3-19.4) on ETN and 65.1/1000 patient-years (95% CI 48.4-81.8) on IFN. The risk was higher in the first than in the second year of treatment, but this difference was not statistically significant (p=0.08) (38.9% of the SIs were recorded in the first 12 months of treatment). The risk of SI was significantly different among the three treatment groups (p<0.0001). Multivariate models confirmed that the use of steroids (p<0.046), concomitant DMARD treatment during anti-TNF therapy (p=0.004), advanced age at the start of anti-TNF treatment (p<0.0001), and the use of IFN or ADA rather than ETN (respectively p<0.0001 and p=0.023) were strong and statistically significant predictors of infection. CONCLUSIONS Anti-TNF therapy is associated with a small but significant risk of SI that is associated with the concomitant use of steroids, advanced age at the start of anti-TNF treatment, and the type of anti-TNF agent.

EULAR recommendations for calcium pyrophosphate deposition. Part II: Management

Objectives To develop evidence-based recommendations for management of calcium pyrophosphate deposition (CPPD). Methods A multidisciplinary guideline development group of 15 experts, representing 10 European countries, generated key propositions for management of CPPD using a Delphi consensus approach. For each recommendation research evidence was searched systematically. Whenever possible, the effect size and number needed to treat for efficacy and RR or OR for side effects were calculated for individual treatment modalities. Strength of recommendation was assessed by the European League Against Rheumatism visual analogue scale. Results Nine key recommendations were generated, including topics for general management, treatment of acute attacks, prophylaxis against recurrent acute attacks and management of chronic symptoms. It was recommended that optimal treatment requires both non-pharmacological and pharmacological treatments. For acute CPP crystal arthritis, cool packs, temporary rest and joint aspiration combined with steroid injection are often sufficient. For prophylaxis or chronic inflammatory arthritis with CPPD, oral non-steroidal anti-inflammatory drugs with gastroprotective treatment and/or low-dose colchicine 0.5–1.0 mg daily may be used. Other recommendations included parenteral or oral corticosteroid for acute CPP arthritis in those unresponsive or unsuited to other measures, and low-dose corticosteroid, methotrexate or hydroxychloroquine for chronic inflammatory arthritis with CPPD. Asymptomatic CPPD requires no treatment. Strength of recommendations varies from 79% to 95%. Conclusion Nine key recommendations for management of CPP crystal associated arthritis were developed using both research evidence and expert consensus. Strength of recommendations was provided to assist the application of these recommendations.