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1.
Clin Drug Investig ; 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31983056

RESUMO

BACKGROUND AND OBJECTIVE: Secukinumab, an anti-interleukin (IL)-17A monoclonal antibody, has demonstrated low radiographic progression over 4 years in patients with ankylosing spondylitis (AS). An adalimumab (tumor necrosis factor [TNF] inhibitor) biosimilar, GP2017 (SDZ-ADL; Sandoz), has been approved by the European Medicines Agency (July 2018) for use in all same indications as adalimumab, including AS. Adalimumab has also shown low long-term radiographic progression in patients with AS. Direct comparison of radiographic progression in AS between IL-17A and TNF inhibitors has not been studied. SURPASS is the first head-to-head, Phase IIIb, randomized, biologic-controlled study in AS to compare effects of secukinumab versus SDZ-ADL on spinal radiographic progression. METHODS: Overall, 858 biologic-naïve patients with AS with elevated high-sensitivity C-reactive protein (≥ 5 mg/L) and/or at least one syndesmophyte in the cervical/lumbar spine at baseline (without total ankylosis) were randomized (1:1:1) to subcutaneous (sc) secukinumab (300 or 150 mg) or SDZ-ADL (40 mg). Secukinumab will be administered at baseline, weeks 1, 2, 3, and 4, and then every 4 weeks until week 100. SDZ-ADL will be administered every 2 weeks from baseline until week 102. Patients and investigators will be unblinded to drug but blinded to secukinumab doses. Spinal X-rays will be obtained at baseline, and weeks 52 and 104, sacroiliac joint (SIJ) X-rays at baseline and week 104, and magnetic resonance imaging (MRI) of SIJs and spine at baseline, weeks 16, 52, and 104. The primary endpoint is to demonstrate superiority of secukinumab (300 or 150 mg) treatment versus SDZ-ADL regarding proportion of patients with no radiographic progression (change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score [mSASSS] ≤ 0.5) at week 104. Secondary endpoints include change from baseline in mSASSS, proportion of patients with syndesmophyte at baseline who develop no new syndesmophytes, reduction of osteitis on MRI of SIJs and spine (Berlin method). Assessment of SpondyloArthritis International Society (ASAS) 20/40 responses, ASAS partial remission, and AS Disease Activity Score (ASDAS) inactive disease (ASDAS < 1.3) in secukinumab- versus SDZ-ADL-treated patients at week 104. CONCLUSION: This is the first study designed to evaluate superiority of an IL-17A inhibitor, secukinumab, over a TNF inhibitor, SDZ-ADL, in reducing spinal radiographic progression in AS. STUDY REGISTRATION: ClinicalTrials.gov, NCT03259074.

2.
Lancet ; 395(10217): 53-64, 2020 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-31813637

RESUMO

BACKGROUND: Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to evaluate the efficacy and safety of ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X. METHODS: COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomly assigned (1:1:1) to receive subcutaneous 80 mg ixekizumab every 4 weeks (Q4W) or every 2 weeks (Q2W), or placebo. Changing background medications or switching to open-label ixekizumab Q2W, or both, was allowed after week 16 at investigator discretion. Primary endpoints were Assessment of SpondyloArthritis international Society-40 (ASAS40) response (defined as an improvement of 40% or more and an absolute improvement from baseline of 2 units or more [range 0-10] in at least three of the four domains [patient global, spinal pain, function, and inflammation] without any worsening in the remaining one domain) at weeks 16 and 52. Patients who switched to open-label ixekizumab were imputed as non-responders in logistic regression analysis. This trial is registered with ClinicalTrials.gov, number NCT02757352. FINDINGS: Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled (105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W). Both primary endpoints were met: ASAS40 at week 16 (ixekizumab Q4W: 34 [35%] of 96, p=0·0094 vs placebo; ixekizumab Q2W: 41 [40%] of 102, p=0·0016; placebo: 20 [19%] of 105) and ASAS40 at week 52 (ixekizumab Q4W: 29 [30%] of 96, p=0·0045; ixekizumab Q2W: 32 [31%] of 102, p=0·0037; placebo: 14 [13%] of 105). 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the ixekizumab Q4W group, and 79 (77%) of 102 in the ixekizumab Q2W group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events in the ixekizumab groups were nasopharyngitis and injection site reaction. Of the treatment-emergent adverse events of special interest, there was one case of serious infection in the ixekizumab Q4W group. The frequency of serious adverse events was low (four [1%] of 302) and similar across the three groups. There were no malignancies or deaths. No new safety signals were identified. INTERPRETATION: Ixekizumab was superior to placebo for improving signs and symptoms in patients with non-radiographic axial spondyloarthritis at weeks 16 and 52. Reports of adverse events were similar to those of previous ixekizumab studies. Ixekizumab offers a potential therapeutic option for patients with non-radiographic axial spondyloarthritis who had an inadequate response or were intolerant to NSAID therapy. FUNDING: Eli Lilly and Company.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Espondilite Anquilosante/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Ásia , Método Duplo-Cego , Esquema de Medicação , Europa (Continente) , Feminino , Humanos , Injeções Subcutâneas , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , América do Norte , América do Sul , Resultado do Tratamento
3.
Ann Rheum Dis ; 79(2): 176-185, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31685553

RESUMO

OBJECTIVES: To investigate the efficacy and safety of ixekizumab for up to 52 weeks in two phase 3 studies of patients with active radiographic axial spondyloarthritis (r-axSpA) who were biological disease-modifying antirheumatic drug (bDMARD)-naive (COAST-V) or tumour necrosis factor inhibitor (TNFi)-experienced (COAST-W). METHODS: Adults with active r-axSpA were randomised 1:1:1:1 (n=341) to 80 mg ixekizumab every 2 (IXE Q2W) or 4 weeks (IXE Q4W), placebo (PBO) or 40 mg adalimumab Q2W (ADA) in COAST-V and 1:1:1 (n=316) to IXE Q2W, IXE Q4W or PBO in COAST-W. At week 16, patients receiving ixekizumab continued their assigned treatment; patients receiving PBO or ADA were rerandomised 1:1 to IXE Q2W or IXE Q4W (PBO/IXE, ADA/IXE) through week 52. RESULTS: In COAST-V, Assessment of SpondyloArthritis international Society 40 (ASAS40) responses rates (intent-to-treat population, non-responder imputation) at weeks 16 and 52 were 48% and 53% (IXE Q4W); 52% and 51% (IXE Q2W); 36% and 51% (ADA/IXE); 19% and 47% (PBO/IXE). Corresponding ASAS40 response rates in COAST-W were 25% and 34% (IXE Q4W); 31% and 31% (IXE Q2W); 14% and 39% (PBO/IXE). Both ixekizumab regimens sustained improvements in disease activity, physical function, objective markers of inflammation, QoL, health status and overall function up to 52 weeks. Safety through 52 weeks of ixekizumab was consistent with safety through 16 weeks. CONCLUSION: The significant efficacy demonstrated with ixekizumab at week 16 was sustained for up to 52 weeks in bDMARD-naive and TNFi-experienced patients. bDMARD-naive patients initially treated with ADA demonstrated further numerical improvements after switching to ixekizumab. Safety findings were consistent with the known safety profile of ixekizumab. TRIAL REGISTRATION NUMBER: NCT02696785/NCT02696798.

4.
J Biopharm Stat ; 30(1): 160-177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31730441

RESUMO

Evaluating the association between diseases and the longitudinal pattern of pharmacological therapy has become increasingly important. However, in many longitudinal studies, self-reported medication usage data collected at patients' follow-up visits could be missing for various reasons. These pieces of missing or inaccurate/untenable information complicate determining the trajectory of medication use and its complete effects for patients. Although longitudinal models can deal with specific types of missing data, inappropriate handling of this issue can lead to a biased estimation of regression parameters especially when missing data mechanisms are complex and depend upon multiple sources of variation. We propose a latent class-based multiple imputation (MI) approach using a Bayesian quantile regression (BQR) that incorporates cluster of unobserved heterogeneity for medication usage data with intermittent missing values. Findings from our simulation study indicate that the proposed method performs better than traditional MI methods under certain scenarios of data distribution. We also demonstrate applications of the proposed method to data from the Prospective Study of Outcomes in Ankylosing Spondylitis (AS) cohort when assessing an association between longitudinal nonsteroidal anti-inflammatory drugs (NSAIDs) usage and radiographic damage in AS, while the longitudinal NSAID index data are intermittently missing.

5.
N Engl J Med ; 381(22): 2183-2184, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31774977
6.
Rheumatol Ther ; 6(4): 487-501, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31673975

RESUMO

Patients with axial spondyloarthritis (axSpA) frequently report pain, stiffness, fatigue, and sleep problems, which may lead to impaired physical activity. The majority of reported-on measures evaluating physical activity and sleep disturbance in axSpA are self-reported questionnaires, which can be impacted by patient recall (reporting bias). One objective measure, polysomnography, has been employed to evaluate sleep in patients with axSpA; however, it is an intrusive measure and cannot be used over the long term. More convenient objective measures are therefore needed to allow for the long-term assessment of both sleep and physical activity in patients' daily lives. Wearable technology that utilizes actigraphy is increasingly being used for the objective measurement of physical activity and sleep in various therapy areas, as it is unintrusive and suitable for continuous tracking to allow longitudinal assessment. Actigraphy characterizes sleep disruption as restless movement while sleeping, which is particularly useful when studying conditions such as axSpA in which chronic pain and discomfort due to stiffness may be evident. Studies have also shown that actigraphy can effectively assess the impact of disease on physical activity. More research is needed to establish the usefulness of objective monitoring of sleep and physical activity specifically in axSpA patients over time. This review summarizes the current perspectives on physical activity and sleep quality in patients with axSpA, and the possible role of actigraphy in the future to more accurately evaluate the impact of treatment interventions on sleep and physical activity in axSpA.Funding: Novartis Pharmaceuticals Corporation.Plain Language Summary: Plain language summary available for this article.

7.
Clin Exp Rheumatol ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31577217

RESUMO

OBJECTIVES: To compare the magnetic resonance imaging (MRI) morphology of inflammatory and chronic lesions in the sacroiliac joints (SIJs) and spine between patients with non-psoriatic and psoriatic non-radiographic axial spondyloarthritis (axSpA and p-axSpA, respectively). METHODS: Patients from the EMBARK trial (NCT01258738) with axSpA (n=179) and p-axSpA (n=24) who had MRI data available were compared in terms of baseline demographics, clinical characteristics, and the frequency (n/N [%]) and distribution of inflammatory and structural SIJ and spinal lesions. RESULTS: Patients with p-axSpA were on average older (35.1 years vs. 31.7 years, p=0.047), had a higher occurrence of asymmetric sacroiliitis (54.2% vs. 29.6%, p=0.042), and a lower occurrence of human leukocyte antigen (HLA)-B27 positivity (41.7% vs. 73.7%, p=0.010) than patients with axSpA. There were no significant differences in the frequency of lesions in any of the SIJ or spinal quadrants between the two subgroups. CONCLUSIONS: These data suggest that differences between axSpA and p-axSpA extend beyond presence of psoriasis, and include age, SI symmetry, and HLAB27 status. These findings may help explain the morphotype-phenotype relationship across axSpA, similar to those described in older radiographic studies.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31529687

RESUMO

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) increase blood pressure and potentially cardiovascular burden, which may limit their use in ankylosing spondylitis (AS). Our objective was to determine the association of NSAID use with incident hypertension in a longitudinal AS cohort. METHODS: Adults with AS were enrolled in a prospective cohort study of patient outcomes and examined every 4-6 months. Hypertension was defined by patient-reported hypertension; anti-hypertensive medication use; or, on two consecutive visits, systolic blood pressure ≥140 mm Hg or diastolic ≥90 mm Hg. Continuous NSAID use was dichotomized based on the validated NSAID index. We assessed the association of NSAID use as a time-varying exposure with the incidence of hypertension using Cox proportional hazards models. RESULTS: Of the 1282 patients in the cohort, 628 patients without baseline hypertension had at least one year of follow up, and were included in the analysis. Of these, 72% were male, the mean age at baseline was 39 ± 13 years, and 200 used NSAIDs continuously. On follow-up, 129 developed incident hypertension. After controlling for other variables, continuous NSAID use was associated with a hazard ratio (HR) of 1.12 for incident hypertension (95% CI, 1.04-1.20), compared to non-continuous or no use. The association did not differ in subgroups defined by age, body mass index, biologic use, or disease activity. CONCLUSION: In our prospective, longitudinal AS cohort, continuous NSAID use was associated with a 12% increased risk for the development of incident hypertension, as compared to non-continuous or no NSAID use.

10.
Arthritis Care Res (Hoboken) ; 71(10): 1285-1299, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31436026

RESUMO

OBJECTIVE: To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. RESULTS: Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. CONCLUSION: These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.

11.
Arthritis Rheumatol ; 71(10): 1599-1613, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31436036

RESUMO

OBJECTIVE: To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. RESULTS: Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. CONCLUSION: These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.

12.
Ann Rheum Dis ; 78(11): 1545-1549, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31362994

RESUMO

BACKGROUND: Patients with spondyloarthritis with radiographic sacroiliitis are traditionally classified according to the modified New York (mNY) criteria as ankylosing spondylitis (AS) and more recently according to the Assessment of SpondyloArthritis international Society (ASAS) criteria as radiographic axial spondyloarthritis (r-axSpA). OBJECTIVE: To investigate the agreement between the mNY criteria for AS and the ASAS criteria for r-axSpA and reasons for disagreement. METHODS: Patients with back pain ≥3 months diagnosed as axSpA with radiographic sacroiliitis (mNY radiographic criterion) were selected from eight cohorts (ASAS, Esperanza, GESPIC, OASIS, Reuma.pt, SCQM, SPACE, UCSF). Subsequently, we calculated the percentage of patients who fulfilled the ASAS r-axSpA criteria within the group of patients who fulfilled the mNY criteria and vice versa in six cohorts with complete information. RESULTS: Of the 3882 patients fulfilling the mNY criteria, 93% also fulfilled the ASAS r-axSpA criteria. Inversely, of the 3434 patients fulfilling the ASAS r-axSpA criteria, 96% also fulfilled the mNY criteria. The main cause for discrepancy between the two criteria sets was the reported age at onset of back pain. CONCLUSION: Almost all patients with axSpA with radiographic sacroiliitis fulfil both ASAS and mNY criteria, which supports the interchangeable use of the terms AS and r-axSpA.

13.
Clin Imaging ; 58: 70-73, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31252214

RESUMO

OBJECTIVE: Evaluate the MR distribution of inflammatory sacroiliac joint changes in axial spondyloarthritis phenotypes, including Ankylosing Spondylitis (AS) and non-radiographic Axial Spondyloarthritis (nrAxSpA). METHODS: A retrospective review of 94 patients seen for treatment of axial spondyloarthritis (SpA) who underwent sacroiliac joint MRI between January 2011 and December 2015 was performed. MR images from 68 patients (20 with AS and 48 with nrAxSpA) were reviewed independently by two radiologists. Images were scored on presence of active inflammatory and chronic structural lesions. These lesions were further categorized as unilateral, bilateral and asymmetric, or bilateral and symmetric. RESULTS: No statistically significant difference was found in the distribution (laterality or symmetry) of bone marrow edema or sclerosis between the AS and nr-axSpA groups. Osseous erosions were more commonly bilateral symmetric in AS than nr-axSpA (11/20 vs. 8/48, p = 0.01). No statistically significant difference was noted between bone marrow edema scores in the AS and nr-axSpA subgroups (2.6 vs 3.3, p = 0.514). Patients with AS had a significantly higher fat metaplasia score compared to patients with nr-axSpA (7.3 vs 1.1, p = 0.001). Patients with nr-axSpA had a higher mean score for erosions (11.6 vs 4.2, p = 0.001). Only patients classified as AS were found to have bony ankylosis. Inter-observer reliability was strong to excellent. CONCLUSION: Ankylosing spondylitis findings at the sacroiliac joints are classically described as bilateral and symmetric on radiographs. Our study demonstrates that distribution on MRI at an individual time point is variable. The variable distribution should be considered when radiologists evaluate MRI exams of AS patients.

15.
Arthritis Rheumatol ; 71(7): 1101-1111, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30848558

RESUMO

OBJECTIVE: The natural history of nonradiographic axial spondyloarthritis (SpA) is incompletely characterized, and there are concerns that nonsteroidal antiinflammatory drugs provide inadequate disease control in patients with active disease. This study was undertaken to investigate the effects of certolizumab pegol (CZP), an anti-tumor necrosis factor treatment, in patients with nonradiographic axial SpA with objective signs of inflammation. METHODS: In this ongoing parallel-group double-blind study, adults with active disease were recruited from 80 centers in Australia, Europe, North America, and Taiwan, and were randomized 1:1 to receive placebo or CZP (400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks) in addition to nonbiologic background medication (NBBM). Switching to open-label CZP (or other biologic) or making background medication changes was permitted at any point during the trial, although changes before week 12 were discouraged. The primary end point was the proportion of patients achieving major improvement (MI) (i.e., a ≥2.0-point decrease in the score from baseline or achievement of the lowest possible score [0.6]) in the Ankylosing Spondylitis Disease Activity Score (ASDAS) at week 52. RESULTS: A total of 317 patients were randomized to receive placebo plus NBBM (n = 158) or CZP plus NBBM (n = 159). ASDAS-MI at week 52 was achieved in 47.2% (75 of 159) of CZP plus NBBM patients, which was significantly greater (P < 0.0001) than the 7.0% (11 of 158) of placebo plus NBBM patients in whom ASDAS-MI was achieved. Of the placebo plus NBBM patients, 60.8% (96 of 158) switched to open-label treatment before week 52 compared to 12.6% (20 of 159) of the CZP plus NBBM patients. CONCLUSION: Adding CZP to background medication is superior to adding placebo in patients with active nonradiographic axial SpA. These results indicate that remission in nonradiographic axial SpA treated without biologics occurs infrequently, demonstrating the need for treatment beyond nonbiologic therapy.


Assuntos
Certolizumab Pegol/uso terapêutico , Sacroileíte/diagnóstico por imagem , Espondiloartropatias/tratamento farmacológico , /uso terapêutico , Adulto , Proteína C-Reativa/imunologia , Método Duplo-Cego , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Espondiloartropatias/diagnóstico por imagem , Espondiloartropatias/imunologia , Resultado do Tratamento
16.
Drug Saf ; 42(6): 751-768, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30739254

RESUMO

INTRODUCTION: Theoretical risks of biologic agents remain under study. OBJECTIVE: The aim of this study was to integrate 1-year safety data from 12 ustekinumab registrational trials. METHODS: Patients had moderate-to-severe plaque psoriasis, active psoriatic arthritis (PsA) (± methotrexate), or moderate-to-severe Crohn's disease (CD; failed/intolerant of immunomodulators/corticosteroids). Psoriatic patients received subcutaneous ustekinumab 45/90 mg or placebo, generally at week 0, week 4, then every 12 weeks thereafter, while those with CD received a single intravenous ustekinumab dose (130 mg or weight range-based dosing of approximately 6 mg/kg) or placebo induction dose at week 0, followed by subcutaneous ustekinumab 90 mg at week 8 and every 8/12 weeks thereafter. The incidence rates of a priori-defined safety events were integrated post hoc (adjusted for duration of follow-up, reported per 100 patient-years [PYs]). RESULTS: Among 6280 enrolled patients, 5884 ustekinumab-treated patients (psoriasis: 3117; PsA: 1018; CD: 1749) contributed 4521 PYs versus 674 PYs in placebo-treated patients through year 1 (829 PYs and 385 PYs during 8- to 16-week controlled periods). Combined across diseases among ustekinumab- versus placebo-treated patients, respective incidences/100 PYs (95% confidence intervals) of infections were 125.4 (122.2-128.7) versus 129.4 (120.9-138.3) through year 1, and not meaningfully increased in patients who did versus those who did not receive methotrexate (92.5 [84.2-101.5] vs. 115.3 [109.9-121.0]), or significantly increased in patients who did versus those who did not receive corticosteroids (116.3 [107.3-125.9] vs. 107.3 [102.0-112.8]) at baseline. Major adverse cardiovascular events (0.5 [0.3-0.7] vs. 0.3 [0.0-1.1]), malignancies (0.4 [0.2-0.6] vs. 0.2 [0.0-0.8]), and deaths (0.1 [0.0-0.3] vs. 0.0 [0.0-0.4]) were rare across indications. CONCLUSIONS: Ustekinumab demonstrated a favorable and consistent safety profile across registrational trials in approved indications. TRIAL REGISTRATIONS: ClinicalTrials.gov identifier: NCT00320216, NCT00267969, NCT00307437, NCT00454584, NCT00267956, NCT01009086, NCT01077362, NCT00265122, NCT00771667, NCT01369329, NCT01369342, and NCT01369355.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Psoríase/tratamento farmacológico , Ustekinumab/efeitos adversos , Ustekinumab/uso terapêutico , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Feminino , Humanos , Masculino , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento
17.
Arthritis Rheumatol ; 71(2): 258-270, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30225992

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of ustekinumab in 3 randomized, placebo-controlled studies in patients with axial spondyloarthritis (SpA). Studies 1 and 2 included patients with radiographic axial SpA (anti-tumor necrosis factor [anti-TNF]-naive patients and patients with inadequate response or intolerance to anti-TNF, respectively); study 3 patients had nonradiographic axial SpA. METHODS: In all 3 studies, patients were randomly assigned (1:1:1) to receive subcutaneous ustekinumab at 45 mg or 90 mg or placebo up to 24 weeks, after which placebo-treated patients were rerandomized to receive ustekinumab at 45 mg or 90 mg. The primary end point in studies 1 and 2 was the proportion of patients who met the Assessment of SpondyloArthritis international Society criteria for 40% improvement in disease activity (achieved an ASAS40 response). The primary end point in study 3 was the proportion of patients who achieved an ASAS20 response. Other disease activity and safety measures were also evaluated. A week 24 analysis of study 1 was preplanned to determine continuation of studies 2 and 3. RESULTS: For study 1, the primary and major secondary end points were not met, and the study was discontinued. As a result, studies 2 and 3 were prematurely discontinued before they were fully enrolled. For all 3 studies, neither ustekinumab dose group demonstrated clinically meaningful improvement over placebo on key efficacy end points. The proportion of patients experiencing adverse events in the ustekinumab groups was consistent with that in previous studies. CONCLUSION: In these 3 placebo-controlled trials, efficacy of ustekinumab in the treatment of axial SpA was not demonstrated. The safety profile was consistent with that of studies in other indications.


Assuntos
Antirreumáticos/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Ustekinumab/uso terapêutico , Adulto , Anticorpos Monoclonais/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Reação no Local da Injeção/epidemiologia , Masculino , Pessoa de Meia-Idade , Espondiloartropatias/diagnóstico por imagem , Espondiloartropatias/tratamento farmacológico , Espondilite Anquilosante/diagnóstico por imagem , Resultado do Tratamento
18.
Ann Rheum Dis ; 78(1): 66-73, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30341055

RESUMO

OBJECTIVE: To examine associations of HLA class I and class II alleles with ankylosing spondylitis (AS) in three cohorts of patients of European, Asian and African ancestry. METHODS: HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1 alleles were genotyped in 1948 unrelated white and 67 African-American patients with AS from the Prospective Study of Outcomes in Ankylosing Spondylitis cohort, the North American Spondylitis Consortium and Australo-Anglo-American Spondyloarthritis Consortium, 990 white and 245 African-American Controls and HLA-B alleles in 442 Han Chinese patients with AS and 346 controls from Shanghai and Gansu, China. In addition to the case:control analyses, HLA-B*27-negative patients with AS were analysed separately, and logistic regression and 'relative predispositional effects' (RPE) analyses were carried out to control for the major effect of HLA-B*27 on disease susceptibility. RESULTS: Although numerous associations were seen between HLA alleles and AS in whites, among HLA-B*27-negative patients with AS , positive associations were seen with HLA-A*29, B*38, B*49, B*52, DRB1*11 and DPB1*03:01 and negative associations with HLA-B*07, HLA-B*57, HLA-DRB1*15:01, HLA-DQB1*02:01 and HLA -DQB1*06:02. Additional associations with HLA-B*14 and B*40 (B60) were observed via RPE analysis, which excludes the HLA-B*27 alleles. The increased frequency of HLA-B*40:01 and decreased frequency of HLA-B*07 was also seen in Han Chinese and African-Americans with AS. HLA-B*08 was decreased in whites with acute anterior uveitis. CONCLUSIONS: These data, analysing the largest number of patients with AS examined to date in three ethnic groups, confirm that other HLA class I and II alleles other than HLA-B*27 to be operative in AS predisposition.


Assuntos
Grupos de Populações Continentais/genética , Predisposição Genética para Doença/genética , Antígenos de Histocompatibilidade Classe II/análise , Antígenos de Histocompatibilidade Classe I/análise , Espondilite Anquilosante/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Masculino , Espondilite Anquilosante/etnologia
19.
Lancet ; 392(10162): 2378-2387, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30360970

RESUMO

BACKGROUND: At present, biological disease-modifying anti-rheumatic drugs (DMARDs) are the only treatment recommended for patients with ankylosing spondylitis who have not responded to first-line treatment with non-steroidal anti-inflammatory drugs (NSAIDs). The TORTUGA trial investigated the efficacy and safety of filgotinib, an oral selective Janus kinase 1 (JAK1) inhibitor, for the treatment of patients with active ankylosing spondylitis. METHODS: In this completed, randomised, double-blind, placebo-controlled, phase 2 trial, we enrolled adult patients from 30 sites in seven countries (Belgium, Bulgaria, Czech Republic, Estonia, Poland, Spain, and Ukraine). Eligible patients had active ankylosing spondylitis and an inadequate response or intolerance to two or more NSAIDs. Patients were randomly assigned (1:1) with an interactive web-based response system to receive filgotinib 200 mg or placebo orally once daily for 12 weeks. Randomisation was stratified by current use of conventional synthetic DMARDs and previous receipt of anti-tumour necrosis factor therapy. The patients, study team, and study sponsor were masked to treatment assignment. The primary endpoint was the change from baseline in ankylosing spondylitis disease activity score (ASDAS) at week 12, which was assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug). Safety was assessed according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT03117270. FINDINGS: Between March 7, 2017, and July 2, 2018, 263 patients were screened and 116 randomly assigned to filgotinib (n=58) or placebo (n=58). 55 (95%) patients in the filgotinib group and 52 (90%) in the placebo group completed the study; three (5%) patients in the filgotinib group and six (10%) in the placebo group discontinued treatment. The mean ASDAS change from baseline to week 12 was -1·47 (SD 1·04) in the filgotinib group and -0·57 (0·82) in the placebo group, with a least squares mean difference between groups of -0·85 (95% CI -1·17 to -0·53; p<0·0001). Treatment-emergent adverse events were reported in 18 patients in each group, the most common being nasopharyngitis (in two patients in the filgotinib group and in four patients in the placebo group). Treatment-emergent adverse events led to permanent treatment discontinuation in two patients (a case of grade 3 pneumonia in the filgotinib group and of high creatine kinase in the placebo group). No deaths were reported during the study. INTERPRETATION: Filgotinib is efficacious and safe for the treatment of patients with active ankylosing spondylitis who have not responded to first-line pharmacological therapy with NSAIDs. Further investigation of filgotinib for ankylosing spondylitis is warranted. FUNDING: Galapagos and Gilead Sciences.


Assuntos
Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/uso terapêutico , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nasofaringite/induzido quimicamente , Infecções Oportunistas/etiologia , Pneumonia/etiologia , Índice de Gravidade de Doença , Resultado do Tratamento
20.
Ann Rheum Dis ; 77(9): 1311-1317, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29858176

RESUMO

OBJECTIVES: To evaluate construct validity, interpretability, reliability and responsiveness as well as determination of cut-off points for good and poor health within the original English version and the 18 translations of the disease-specific Assessment of Spondyloarthritis international Society Health Index (ASAS HI) in 23 countries worldwide in patients with spondyloarthritis (SpA). METHODS: A representative sample of patients with SpA fulfilling the ASAS classification criteria for axial (axSpA) or peripheral SpA was used. The construct validity of the ASAS HI was tested using Spearman correlation with several standard health outcomes for axSpA. Test-retest reliability was assessed by intraclass correlation coefficients (ICCs) in patients with stable disease (interval 4-7 days). In patients who required an escalation of therapy because of high disease activity, responsiveness was tested after 2-24weeks using standardised response mean (SRM). RESULTS: Among the 1548 patients, 64.9% were men, with a mean (SD) age 42.0 (13.4) years. Construct validity ranged from low (age: 0.10) to high (Bath AnkylosingSpondylitisFunctioning Index: 0.71). Internal consistency was high (Cronbach's α of 0.93). The reliability among 578 patients was good (ICC=0.87 (95% CI 0.84 to 0.89)). Responsiveness among 246 patients was moderate-large (SRM=-0.44 for non-steroidal anti-inflammatory drugs, -0.69 for conventional synthetic disease-modifying antirheumatic drug and -0.85 for tumour necrosis factor inhibitor). The smallest detectable change was 3.0. Values ≤5.0 have balanced specificity to distinguish good health as opposed to moderate health, and values ≥12.0 are specific to represent poor health as opposed to moderate health. CONCLUSIONS: The ASAS HI proved to be valid, reliable and responsive. It can be used to evaluate the impact of SpA and its treatment on functioning and health. Furthermore, comparison of disease impact between populations is possible.


Assuntos
Índice de Gravidade de Doença , Espondilartrite/reabilitação , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Progressão da Doença , Feminino , Indicadores Básicos de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espondilartrite/tratamento farmacológico , Espondilartrite/fisiopatologia , Traduções , Fator de Necrose Tumoral alfa/antagonistas & inibidores
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