Metabolic syndrome, dyslipidemia, hypertension and type 2 diabetes in youth: from diagnosis to treatment

Overweight and obesity in youth is a worldwide public health problem. Overweight and obesity in childhood and adolescents have a substantial effect upon many systems, resulting in clinical conditions such as metabolic syndrome, early atherosclerosis, dyslipidemia, hypertension and type 2 diabetes (T2D). Obesity and the type of body fat distribution are still the core aspects of insulin resistance and seem to be the physiopathologic links common to metabolic syndrome, cardiovascular disease and T2D. The earlier the appearance of the clustering of risk factors and the higher the time of exposure, the greater will be the chance of developing coronary disease with a more severe endpoint. The age when the event may occur seems to be related to the presence and aggregation of risk factors throughout life

Digital ulcers predict a worse disease course in patients with systemic sclerosis

Objective: Systemic sclerosis (SSc) is a systemic autoimmune disease with high morbidity and significant mortality. There is a great need of predictors that would allow risk stratification of patients with SSc and ultimately initiation of treatment early enough to ensure optimal clinical results. In this study, we evaluated whether a history of digital ulcers (HDU) at presentation may be a predictor of vascular outcomes and of overall clinical worsening and death in patients with SSc. Methods: Patients from the EULAR Scleroderma Trials and Research (EUSTAR) database, satisfying at inclusion the 1980 American College of Rheumatology classification criteria for SSc, who had a follow-up of at least 3 years since baseline or who have died, were included in the analysis. HDU at presentation as a predictor of disease worsening or death was evaluated by Cox proportional hazards regression analysis. Results :3196 patients matched the inclusion criteria (male sex 13.2%, 33.4% diffuse subset). At presentation, 1092/3196 patients had an HDU (34.1%). In multivariable analysis adjusting for age, gender and all parameters considered potentially significant, HDU was predictive for the presence of active digital ulcers (DUs) at prospective visits (HR (95% CI)): 2.41(1.91 to 3.03), p<0.001, for an elevated systolic pulmonary arterial pressure on heart ultrasound (US-PAPs):1.36 (1.03 to 1.80), p=0.032, for any cardiovascular event (new DUs, elevated US-PAPs or LV failure):3.56 (2.26 to 5.62), p<0.001, and for death (1.53 (1.16 to 2.02), p=0.003). Conclusions :In patients with SSc, HDU at presentation predicts the occurrence of DUs at follow-up and is associated with cardiovascular worsening and decreased survival

Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis.

Objectives Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database. Methods Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12\ub13 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression. Results Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model. Conclusions The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trial

Phenotypes Determined by Cluster Analysis and Their Survival in the Prospective European Scleroderma Trials and Research Cohort of Patients With Systemic Sclerosis

Objective: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained. / Methods: A total of 11,318 patients were registered in the EUSTAR database, and 6,927 were included in the study. Twenty‐four clinical and serologic variables were used for clustering. / Results: Clustering analyses provided a first delineation of 2 clusters showing moderate stability. In an exploratory attempt, we further characterized 6 homogeneous groups that differed with regard to their clinical features, autoantibody profile, and mortality. Some groups resembled usual dcSSc or lcSSc prototypes, but others exhibited unique features, such as a majority of lcSSc patients with a high rate of visceral damage and antitopoisomerase antibodies. Prognosis varied among groups and the presence of organ damage markedly impacted survival regardless of cutaneous involvement. / Conclusion: Our findings suggest that restricting subsets of SSc patients to only those based on cutaneous involvement may not capture the complete heterogeneity of the disease. Organ damage and antibody profile should be taken into consideration when individuating homogeneous groups of patients with a distinct prognosis

The Role Of Biological Agents For Rheumatoid Arthritis: Best Evidence And Guidelines For Clinical Decision [uso De Agentes Biológicos Para O Tratamento Da Artrite Reumatóide: Melhores Evidências E Recomendações Para A Prática Clínica]

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease of unknown etiology, which predominantly involves small joints and is more common in women. It has a high degree of morbidity and is an important health problem. The treatment of RA includes DMARDs (disease-modifying anti-rheumatic drugs) and more recently the so-called biological agents. Carry out a structured literature review to determine the best existing evidences in medical literature regarding the diagnosis and treatment of rheumatoid arthritis. Six questions on RA were prepared: 1) What are the diagnostic criteria for initial rheumatoid arthritis diagnosis?; 2) For patients with diagnosis of rheumatoid arthritis what are the prognosis markers and what are their clinical implications?; 3) For patients with rheumatoid arthritis, when should DMARDs (MTX, sulfasalazine, among others) be introduced? What is the initial choice drug?; 4) For patients with rheumatoid arthritis, when should biological agents be introduced? Should they be administered after the initial administration of methotrexate or at the time of diagnosis?; 5) What are the indications of the biological agents in early onset RA?; 6) Are biological agents effective and safe in the treatment of rheumatoid arthritis: Is there evidence of the relative superiority of any of the biological agents in terms of efficacy and safety? A structured literature review was carried out using different databases. In this review, the objective was to identify clinical studies which are methodologically more adequate that might respond to each of the questions. A committee of specialists evaluated literature data and prepared responses to each one of the questions. The respective evidence levels and degrees of recommendations were then established for each response and an evidence-based recommendation was made.624156165Harris Jr., E.D., Rheumatoid arthritis: Pathophysiology and implications for therapy (1990) N Engl J Med, 322, pp. 1277-1289Hochberg, M.C., Adult and juvenile rheumatoid arthritis: Current epidemiologic concepts (1981) Epidemiol, pp. 27-44. , Rev 3Marques Neto, J.F., Gonçalves, H.T., Langen, L.F.O.B., Estudo multicêntrico da prevalência da AR do adulto em amostras da população brasileira (1993) Rev Bras Reum, 33, pp. 169-173Senna, E.R., De Barros, A.L.P., Silva, E.O., Prevalence of Rheumatic diseases in Brazil: A study using the COPCORD approach (2004) J Rheumatol, 31, pp. 594-597Guyatt, G., Rennie, D., (2002) User's Guide to the Medical Literature - A Manual for Evidence-Based Clinical Practice 1 Ed., , Chicago-IL: AMA press;(2004), http://minerva.minervation.com/cebm/docs/levels.html, Centre for Evidence Based Medicine. 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A 10 year observational prospective study (2000) J Rheumatol, 27 (3), pp. 571-574Wassmuth, R., Wagner, U., Prognostic use of human leukocyte antigen genotyping for rheumatoid arthritis susceptibility, disease course, and clinical stratification (2002) Rheum Dis Clin North Am, 28 (1), pp. 17-37Meyer, O., Labarre, C., Dougados, M., Goupille, P., Cantagrel, A., Dubois, A., Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage (2003) Ann Rheum Dis, 62 (2), pp. 120-126Kroot, E.J., De Jong, B.A., Van Leeuwen, M.A., Swinkels, H., Van Den Hoogen, F.H., Van't Hof, M., The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis (2000) Arthritis Rheum, 43 (8), pp. 1831-1835Jansen, L.M., Van Schaardenburg, D., Van Der Horst-Bruinsma, I., Van Der Stadt, R.J., De Koning, M.H., Dijkmans, B.A., The predictive value of anti-cyclic citrullinated peptide antibodies in early arthritis (2003) J Rheumatol, 30 (8), pp. 1691-1695Bas, S., Genevay, S., Meyer, O., Gabay, C., Anti-cyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis (2003) Rheumatology (Oxford), 42 (5), pp. 677-680Vencovsky, J., Machacek, S., Sedova, L., Kafkova, J., Gatterova, J., Pesakova, V., Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis (2003) Ann Rheum Dis, 62 (5), pp. 427-430Huizinga, T.W., Machold, K.P., Breedveld, F.C., Lipsky, P.E., Smolen, J.S., Criteria for early rheumatoid arthritis: From Bayes' law revisited to new thoughts on pathogenesis (2002) Arthritis Rheum, 46 (5), pp. 1155-1159Quinn, M.A., Conaghan, P.G., Emery, P., The therapeutic approach of early intervention for rheumatoid arthritis: What is the evidence? (2001) Rheumatology (Oxford), 40 (11), pp. 1211-1220Nell, V.P., Machold, K.P., Eberl, G., Stamm, T.A., Uffmann, M., Smolen, J.S., Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis (2004) Rheumatology (Oxford), 43 (7), pp. 906-914Smolen, J.S., Aletaha, D., Patients with rheumatoid arthritis in clinical care (2004) Ann Rheum Dis, 63 (3), pp. 221-225Boers, M., Verhoeven, A.C., Markusse, H.M., Van De Laar, M.A., Westhovens, R., Van Denderen, J.C., Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis (1997) Lancet, 350 (9074), pp. 309-318Emery, P., Breedveld, F.C., Dougados, M., Kalden, J.R., Schiff, M.H., Smolen, J.S., Early referral recommendation for newly diagnosed rheumatoid arthritis: Evidence based development of a clinical guide (2002) Ann Rheum Dis, 61 (4), pp. 290-297Jones, G., Halbert, J., Crotty, M., Shanahan, E.M., Batterham, M., Ahern, M., The effect of treatment on radiological progression in rheumatoid arthritis: A systematic review of randomized placebo-controlled trials (2003) Rheumatology (Oxford), 42 (1), pp. 6-13Rau, R., Herborn, G., Menninger, H., Sangha, O., Radiographic outcome after three years of patients with early erosive rheumatoid arthritis treated with intramuscular methotrexate or parenteral gold. Extension of a one-year double-blind study in 174 patients (2002) Rheumatology (Oxford), 41 (2), pp. 196-204Van Aken, J., Lard, L.R., Le Cessie, S., Hazes, J.M., Breedveld, F.C., Huizinga, T.W., Radiological outcome after four years of early versus delayed treatment strategy in patients with recent onset rheumatoid arthritis (2004) Ann Rheum Dis, 63 (3), pp. 274-279Guidelines for the management of rheumatoid arthritis: 2002 Update (2002) Arthritis Rheum, 46 (2), pp. 328-346Gordon, P., West, J., Jones, H., Gibson, T., A 10 year prospective followup of patients with rheumatoid arthritis 1986-96 (2001) J Rheumatol, 28 (11), pp. 2409-2415Suarez-Almazor, M.E., Belseck, E., Shea, B., Homik, J., Wells, G., Tugwell, P., Antimalarials for treating rheumatoid arthritis (2000) Cochrane Database Syst Rev, (4). , CD000959Suarez-Almazor, M.E., Belseck, E., Shea, B., Wells, G., Tugwell, P., Sulfasalazine for rheumatoid arthritis (2000) Cochrane Database Syst Rev, (2). , CD000958Suarez-Almazor, M.E., Belseck, E., Shea, B., Wells, G., Tugwell, P., Methotrexate for rheumatoid arthritis (2000) Cochrane Database Syst Rev, (2). , CD000957Osiri, M., Shea, B., Robinson, V., Suarez-Almazor, M., Strand, V., Tugwell, P., Leflunomide for treating rheumatoid arthritis (2003) Cochrane Database Syst Rev, (1). , CD002047Suarez-Almazor, M.E., Spooner, C., Belseck, E., Azathioprine for treating rheumatoid arthritis (2000) Cochrane Database Syst Rev, (4). , CD001461Suarez-Almazor, M.E., Spooner, C., Belseck, E., Penicillamine for treating rheumatoid arthritis (2000) Cochrane Database Syst Rev, (4). , CD001460Clark, P., Tugwell, P., Bennet, K., Bombardier, C., Shea, B., Wells, G., Injectable gold for rheumatoid arthritis (2000) Cochrane Database Syst Rev, (2). , CD000520O'Dell, J.R., Paulsen, G., Haire, C.E., Blakely, K., Palmer, W., Wees, S., Treatment of early seropositive rheumatoid arthritis with minocycline: Four-year followup of a double-blind, placebo-controlled trial (1999) Arthritis Rheum, 42 (8), pp. 1691-1695Wells, G., Haguenauer, D., Shea, B., Suarez-Almazor, M.E., Welch, V.A., Tugwell, P., Cyclosporine for rheumatoid arthritis (2000) Cochrane Database Syst Rev, (2). , CD001083Quinn, M.A., Emery, P., Window of opportunity in early rheumatoid arthritis: Possibility of altering the disease process with early intervention (2003) Clin Exp Rheumatol, 21 (5 SUPPL. 31), pp. S154-S157Lard, L.R., Visser, H., Speyer, I., Vander Horst-Bruinsma, I.E., Zwinderman, A.H., Breedveld, F.C., Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: Comparison of two cohorts who received different treatment strategies (2001) Am J Med, 111 (6), pp. 446-451Emery, P., Breedveld, F.C., Dougados, M., Kalden, J.R., Schiff, M.H., Smolen, J.S., Early referral recommendation for newly diagnosed rheumatoid arthritis: Evidence based development of a clinical guide (2002) Ann Rheum Dis, 61 (4), pp. 290-297Breedveld, F.C., Kalden, J.R., Appropriate and effective management of rheumatoid arthritis (2004) Ann Rheum Dis, 63 (6), pp. 627-633St. Clair, E.W., Disease-modifying anti-rheumatic drugs (2001) Primer on the Rheumatic Diseases. 12th Edition, pp. 599-602. , ed. Atlanta: The Arthritis FoundationSmolen, J.S., Sokka, T., Pincus, T., Breedveld, F.C., A proposed treatment algorithm for rheumatoid arthritis: Aggressive therapy, methotrexate, and quantitative measures (2003) Clin Exp Rheumatol, 21 (5 SUPPL. 31), pp. S209-S210Galindo-Rodriguez, G., Avina-Zubieta, J.A., Russell, A.S., Suarez-Almazor, M.E., Disappointing longterm results with disease modifying antirheumatic drugs. A practice based study (1999) J Rheumatol, 26 (11), pp. 2337-2343Aletaha, D., Smolen, J.S., Effectiveness profiles and dose dependent retention of traditional disease modifying antirheumatic drugs for rheumatoid arthritis. An observational study (2002) J Rheumatol, 29 (8), pp. 1631-1638Bathon, J.M., A comparison of etarnecept e methotrexate in patients with early rheumatoid arthritis (2000) N Engl J Med, 343, pp. 1586-1593Smolen, J.S., Treatment of early rheumatoid arthritis with infliximabe plus methotrexate or methotrexate alone: Preliminary results of ASPIRE Trial (2003) Ann Rheum Dis, 62 (SUPPL. 1), p. 64Bredveld, F., BeST study: How should we use TNF antagonists best in RA? (2004) EULARMaini, R.N., Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis (1998) Arthritis Rheum, 41 (9), pp. 1552-1563Maini, R., Infliximabe (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: A randomised phase III trial (1999) Lancet, 354 (9194), pp. 1932-1939. , ATTRACT Study GroupLipsky, P.E., Infliximabe and methotrexate in the treatment of rheumatoid arthritis (2000) N Engl J Med, 343 (22), pp. 1594-1602. , Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study GroupMoreland, L.W., Etanercepte therapy in rheumatoid arthritis. A randomized, controlled trial (1999) Ann Intern Med, 130 (6), pp. 478-486Weinblatt, M.E., A trial of etanercepte, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate (1999) N Engl J Med, 340 (4), pp. 253-259Bathon, J.M., A comparison of etanercepte and methotrexate in patients with early rheumatoid arthritis (2000) N Engl J Med, 343 (22), pp. 1586-1593Genovese, M.C., Etanercepte versus methotrexate in patients with early rheumatoid arthritis: Two-year radiographic and clinical outcomes (2002) Arthritis Rheum, 46 (6), pp. 1443-1450Klareskog, L., Therapeutic effect of the combination of etanercepte and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: Double-blind randomised controlled trial (2004) Lancet, 363 (9410), pp. 675-681Keystone, E.C., Once-weekly administration of 50 mg etanercepte in patients with active rheumatoid arthritis: Results of a multicenter, randomized, double-blind, placebo-controlled trial (2004) Arthritis Rheum, 50 (2), pp. 353-363Weinblatt, M.E., Adalimumabe, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The ARMADA trial (2003) Arthritis Rheum, 48 (1), pp. 35-45Van De Putte, L.B., Efficacy and safety of adalimumabe as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed (2004) Ann Rheum Dis, 63 (5), pp. 508-516Furst, D.E., Adalimumabe, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: Results of STAR (Safety Trial of Adalimumabe in Rheumatoid Arthritis) (2003) J Rheumatol, 30 (12), pp. 2563-2571Keystone, E.C., Radiographic, clinical, and functional outcomes of treatment with adalimumabe (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: A randomized, placebo-controlled, 52-week trial (2004) Arthritis Rheum, 50 (5), pp. 1400-1411Jiang, Y., A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: Radiologic progression and correlation of Genant and Larsen scores (2000) Arthritis Rheum, 43 (5), pp. 1001-1009Cohen, S., Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: Results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial (2002) Arthritis Rheum, 46 (3), pp. 614-624Khanna, D., McMahon, M., Furst, D.E., Safety of tumour necrosis factor-alpha antagonists (2004) Drug Saf, 27 (5), pp. 307-324Keane, J., Tuberculosis associated with infliximabe, a tumor necrosis factor alpha-neutralizing agent (2001) N Engl J Med, 345 (15), pp. 1098-1104Gomez-Reino, J.J., Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: A multicenter active-surveillance report (2003) Arthritis Rheum, 48 (8), pp. 2122-2127(2004) Arthritis Res Ther, 6 (SUPPL. 2), pp. S19-S23Hochberg, M.C., Comparison of the efficacy of the tumour necrosis factor alpha blocking agents adalimumabe, etanercepte, and infliximabe when added to methotrexate in patients with active rheumatoid arthritis (2003) Ann Rheum Dis, 62 (SUPPL. 2), pp. ii13-ii1

Upadacitinib monotherapy improves patient-reported outcomes in rheumatoid arthritis: results from SELECT-EARLY and SELECT-MONOTHERAPY

OBJECTIVE: To evaluate the effect of upadacitinib (UPA) monotherapy vs MTX on patient-reported outcomes (PROs) in patients with RA who were MTX-naïve or who had an inadequate response to MTX (MTX-IR). METHODS: PROs from the SELECT-EARLY and SELECT-MONOTHERAPY randomized controlled trials were evaluated at Weeks 2 and 12/14. Patients were ≥18 years of age with RA symptoms for ≥6 weeks (SELECT-EARLY, MTX-naïve) or diagnosed RA for ≥3 months (SELECT-MONOTHERAPY, MTX-IR) and received UPA monotherapy (15 or 30 mg) or MTX. PROs included Patient Global Assessment of Disease Activity (PtGA), pain visual analogue scale, HAQ Disability Index (HAQ-DI), morning stiffness duration/severity, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (SELECT-EARLY), health-related quality of life (HRQOL) by the 36-iem Short Form Health Survey and Work Productivity and Activity Impairment (WPAI; SELECT-EARLY). Least square mean (LSM) changes and proportions of patients reporting improvements greater than or equal to the minimum clinically important differences and normative values were determined. RESULTS: In 945 MTX-naïve and 648 MTX-IR patients, UPA monotherapy (15 mg, 30 mg) vs MTX resulted in greater reported LSM changes from baseline at Weeks 12/14 in PtGA, pain, HAQ-DI, morning stiffness duration/severity, FACIT-F (SELECT-EARLY), HRQOL and WPAI (SELECT-EARLY). These changes were statistically significant with both doses of UPA vs MTX at Weeks 12/14 in both RCTs. Improvements were reported as early as week 2. Compared with MTX, more UPA-treated MTX-naïve and MTX-IR patients reported improvements greater than or equal to the minimum clinically important differences and scores greater than or equal to normative values. CONCLUSION: Among MTX-naïve and MTX-IR patients with active RA, UPA monotherapy at 15 or 30 mg for 12/14 weeks resulted in statistically significant and clinically meaningful improvements in pain, physical function, morning stiffness, HRQOL and WPAI compared with MTX alone. CLINICAL TRIAL REGISTRATION NUMBER: SELECT-EARLY (NCT02706873) and SELECT-MONOTHERAPY (NCT02706951) are registered with ClinicalTrials.gov