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OBJECTIVE: Polymorphisms in the antifungal signalling molecule CARD9 are associated with ankylosing spondylitis (AS). Here, we investigated the cellular mechanism by which CARD9 controls pathogenic Th17 responses and the onset of disease in both experimental murine AS and patients. METHODS: Experiments in SKG, Card9-/-SKG, neutrophil-deplete SKG mice along with in vitro murine, neutrophil and CD4+ T cell cocultures examined Card9 function in neutrophil activation, Th17 induction and arthritis in experimental AS. In AS patients the neutrophil: Bath Ankylosing Spondylitis Functional Index relationship was analysed. In vitro studies with autologous neutrophil: T cell cocultures examined endogenous CARD9 versus the AS-associated variant (rs4075515) of CARD9 in T cellular production of IL-17A. RESULTS: Card9 functioned downstream of Dectin-1 and was essential for induction of Th17 cells, arthritis and spondylitis in SKG mice. Card9 expression within T cells was dispensable for arthritis onset in SKG mice. Rather, Card9 expression controlled neutrophil function; and neutrophils in turn, were responsible for triggering Th17 expansion and disease in SKG mice. Mechanistically, cocultures of zymosan prestimulated neutrophils and SKG T cells revealed a direct cellular function for Card9 within neutrophils in the potentiation of IL-17 production by CD4+ T cells on TCR-ligation. The clinical relevance of the neutrophil-Card9-coupled mechanism in Th17-mediated disease is supported by a similar observation in AS patients. Neutrophils from HLA-B27+ AS patients expanded autologous Th17 cells in vitro, and the AS-associated CARD9S12N variant increased IL-17A. CONCLUSIONS: These data reveal a novel neutrophil-intrinsic role for Card9 in arthritogenic Th17 responses and AS pathogenesis. These data provide valuable utility in our future understanding of CARD9-specific mechanisms in spondyloarthritis .
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Espondiloartritis , Espondilitis Anquilosante , Humanos , Ratones , Animales , Espondilitis Anquilosante/patología , Neutrófilos/metabolismo , Interleucina-17/metabolismo , Espondiloartritis/patología , Técnicas de Cocultivo , Células Th17 , Proteínas Adaptadoras de Señalización CARD/genéticaRESUMEN
OBJECTIVES: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin 17A (IL-17A), has shown significant efficacy in the treatment of psoriatic arthritis (PsA) and sustained long-term clinical response without unexpected new safety outcome for an IL-17A inhibitor. Here, we report the updated safety profile of ixekizumab up to 3 years in patients with PsA. METHODS: This is an integrated safety analysis from four clinical trials in patients with PsA who received at least one dose of ixekizumab. Treatment-emergent adverse events (TEAEs) and selected adverse events (AEs) exposure-adjusted incidence rates (EAIRs) per 100 patient-years up to 3 years of exposure are reported. RESULTS: A total of 1401 patients with a cumulative ixekizumab exposure of 2247.7 patient-years were included in this analysis. The EAIR of patients with ≥1 TEAE was 50.3 per 100 patient-years and most TEAEs were mild to moderate in severity. Serious AEs were reported by 134 patients (EAIR=6.0). The most reported TEAEs were nasopharyngitis (EAIR=9.0) and upper respiratory tract infection (EAIR=8.3). Infections in general and injection site reactions were the most common TEAEs; the incidence rates of serious cases were low (EAIR ≤1.2). The EAIRs of malignancies (EAIR=0.7), inflammatory bowel disease (EAIR=0.1) including ulcerative colitis and Crohn's disease, depression (EAIR=1.6), and major adverse cerebro-cardiovascular events (EAIR=0.5) were low. As assessed, based on year of exposure, incidence rates were decreasing or constant over time. CONCLUSIONS: In this analysis, the overall safety profile and tolerability of ixekizumab are consistent with the known safety profile in patients with PsA. No new or unexpected safety events were detected. TRIAL REGISTRATION NUMBER: NCT01695239, NCT02349295, NCT02584855, NCT03151551.
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Anticuerpos Monoclonales Humanizados , Artritis Psoriásica , Enfermedad de Crohn , Fármacos Dermatológicos , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Artritis Psoriásica/patología , Terapia Biológica , Enfermedad de Crohn/inducido químicamente , Fármacos Dermatológicos/efectos adversos , Fármacos Dermatológicos/uso terapéutico , Humanos , Interleucina-17 , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of an oral selective tyrosine kinase 2 (TYK2) inhibitor, deucravacitinib, in patients with active psoriatic arthritis (PsA). METHODS: In this double-blind, phase II trial, 203 patients with PsA were randomised 1:1:1 to placebo, deucravacitinib 6 mg once a day or 12 mg once a day. The primary endpoint was American College of Rheumatology-20 (ACR-20) response at week 16. RESULTS: ACR-20 response was significantly higher with deucravacitinib 6 mg once a day (52.9%, p=0.0134) and 12 mg once a day (62.7%, p=0.0004) versus placebo (31.8%) at week 16. Both deucravacitinib doses resulted in significant improvements versus placebo (p≤0.05) in the multiplicity-controlled secondary endpoints of change from baseline in Health Assessment Questionnaire-Disability Index and Short Form-36 Physical Component Summary score and in Psoriasis Area and Severity Index-75 response. Improvements were also seen in multiple exploratory endpoints with deucravacitinib treatment. The most common adverse events (AEs) (≥5%) in deucravacitinib-treated patients were nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, rash, headache and diarrhoea. There were no serious AEs and no occurrence of herpes zoster, opportunistic infections and major adverse cardiovascular events, or differences versus placebo in mean changes in laboratory parameters with deucravacitinib treatment. CONCLUSIONS: Treatment with the selective TYK2 inhibitor deucravacitinib was well tolerated and resulted in greater improvements than placebo in ACR-20, multiplicity-controlled secondary endpoints and other exploratory efficacy measures in patients with PsA. Larger trials over longer periods of time with deucravacitinib are warranted to confirm its safety profile and benefits in PsA. TRIAL REGISTRATION NUMBER: NCT03881059.
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Antirreumáticos , Artritis Psoriásica , Antirreumáticos/uso terapéutico , Artritis Psoriásica/inducido químicamente , Artritis Psoriásica/tratamiento farmacológico , Método Doble Ciego , Compuestos Heterocíclicos , Humanos , Índice de Severidad de la Enfermedad , TYK2 Quinasa , Resultado del TratamientoRESUMEN
BACKGROUND/OBJECTIVE: This post hoc analysis assessed efficacy and safety of intravenous (IV) golimumab in ankylosing spondylitis (AS) patients with early disease (ED) versus late disease (LD). METHODS: The phase 3, double-blind, GO-ALIVE study randomized patients to IV golimumab 2 mg/kg at weeks 0 and 4 and then every 8 weeks through week 52, or placebo at weeks 0, 4, and 12 with crossover to IV golimumab at week 16. Clinical efficacy was assessed by ≥20% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS20), ≥50% improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI 50), and Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3 (inactive disease). Using self-reported duration of inflammatory back pain (IBP), patients were grouped into quartiles: first = ED and fourth = LD. Descriptive statistics summarized efficacy and safety findings through 1 year. RESULTS: Early disease patients (n = 60) were ~10 years younger and had shorter median AS (IBP) symptom duration (2-3 years) versus LD patients (n = 52; 21-24 years). At week 16, numerically higher proportions of golimumab- than placebo-treated patients achieved ASAS20 (ED: 71% vs. 32%; LD: 67% vs. 21%), BASDAI 50 (ED: 40% vs. 12%; LD: 33% vs. 7%), and ASDAS <1.3 (ED: 17% vs. 4%; LD 8% vs. 0%) regardless of IBP duration. Efficacy was durable through 1 year of treatment; however, response rates were numerically higher in patients with ED versus LD. Through week 60, adverse events and serious adverse events, respectively, were reported by 46% and 3% of ED patients and 61% and 2% of LD patients. CONCLUSION: Prompt diagnosis of AS and early treatment with IV golimumab may yield more robust improvements in disease activity.
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Antirreumáticos , Espondiloartritis , Espondilitis Anquilosante , Anticuerpos Monoclonales , Método Doble Ciego , Humanos , Espondiloartritis/tratamiento farmacológico , Espondilitis Anquilosante/diagnóstico , Espondilitis Anquilosante/tratamiento farmacológico , Resultado del TratamientoRESUMEN
OBJECTIVES: Here, we present the reported incidence rates of inflammatory bowel disease (IBD) in patients receiving treatment with secukinumab for psoriasis (PsO), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), in a pooled analysis of 21 clinical trials. METHODS: Data from all patients who had received at least one dose of secukinumab were included. Safety analyses were conducted to evaluate cumulative IBD rates as well as per-year rates, by indication. Crohn's disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) events were analysed using exposure-adjusted incidence rates (patient incidence rates per 100 patient-years (PY)). RESULTS: A total of 7355 patients with a cumulative exposure of 16 226.9 PY were included in the pooled analysis. Among 5181 patients with PsO, there were 14 cases of UC, 5 cases of CD and 1 case of IBDU, with exposure adjusted incidence rates (EAIRs) of 0.13, 0.05 and 0.01, respectively. Of these 20 cases, 14 were new-onset. In 1380 patients with PsA, there were 3 cases of UC, 3 cases of CD and 2 cases of IBDU (EAIRs 0.08, 0.08 and 0.05); 7 of these represented new-onset cases. Among 794 patients with AS, there were 4 cases of UC, 8 cases of CD and 1 case of IBDU (EAIRs 0.2, 0.4 and 0.1); 9 were new-onset cases. In the per year analysis, the EAIRs for each indication did not increase over time with secukinumab treatment. CONCLUSIONS: In this pooled secukinumab safety analysis of 7355 patients across 21 clinical trials, cases of IBD events (including CD, UC and IBDU) were uncommon.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Productos Biológicos/efectos adversos , Enfermedades Inflamatorias del Intestino/inducido químicamente , Psoriasis/tratamiento farmacológico , Espondilitis Anquilosante/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Artritis Psoriásica/epidemiología , Productos Biológicos/uso terapéutico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/epidemiología , Enfermedad de Crohn/inducido químicamente , Enfermedad de Crohn/epidemiología , Humanos , Incidencia , Enfermedades Inflamatorias del Intestino/epidemiología , Vigilancia de Productos Comercializados , Psoriasis/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Estudios Retrospectivos , Medición de Riesgo/métodos , Espondilitis Anquilosante/epidemiologíaRESUMEN
OBJECTIVES: The Assessment of SpondyloArthritis international Society (ASAS) MRI working group (WG) was convened to generate a consensus update on standardised definitions for MRI lesions in the sacroiliac joint (SIJ) of patients with spondyloarthritis (SpA), and to conduct preliminary validation. METHODS: The literature pertaining to these MRI lesion definitions was discussed at three meetings of the group. 25 investigators (20 rheumatologists, 5 radiologists) determined which definitions should be retained or required revision, and which required a new definition. Lesion definitions were assessed in a multi-reader validation exercise using 278 MRI scans from the ASAS classification cohort by global assessment (lesion present/absent) and detailed scoring (inflammation and structural). Reliability of detection of lesions was analysed using kappa statistics and the intraclass correlation coefficient (ICC). RESULTS: No revisions were made to the current ASAS definition of a positive SIJ MRI or definitions for subchondral inflammation and sclerosis. The following definitions were revised: capsulitis, enthesitis, fat lesion and erosion. New definitions were developed for joint space enhancement, joint space fluid, fat metaplasia in an erosion cavity, ankylosis and bone bud. The most frequently detected structural lesion, erosion, was detected almost as reliably as subchondral inflammation (κappa/ICC:0.61/0.54 and 0.60/0.83) . Fat metaplasia in an erosion cavity and ankylosis were also reliably detected despite their low frequency (κappa/ICC:0.50/0.37 and 0.58/0.97). CONCLUSION: The ASAS-MRI WG concluded that several definitions required revision and some new definitions were necessary. Multi-reader validation demonstrated substantial reliability for the most frequently detected lesions and comparable reliability between active and structural lesions.
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Artropatías/diagnóstico por imagen , Imagen por Resonancia Magnética/normas , Reumatología/normas , Articulación Sacroiliaca/diagnóstico por imagen , Espondiloartritis/diagnóstico por imagen , Adulto , Femenino , Humanos , Artropatías/etiología , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sacroileítis/diagnóstico por imagen , Sacroileítis/etiología , Espondiloartritis/complicacionesRESUMEN
PURPOSE OF REVIEW: Majority of patients with axial spondyloarthritis (axSpA) report use of complementary and alternative medicine (CAM) therapies before and even after the diagnosis, due to perceived efficacy and wide-spread belief that these modalities lack side effects. In this review, we describe the available scientific evidence for the CAM therapies in axSpA. RECENT FINDINGS: Clinical trials of the CAM therapies in axSpA are generally hampered by small sample size, short duration, difficulties in blinding, lack of control groups and strong placebo effect. Nonetheless, exercise programs like Pilates and mind-body techniques such as Tai Chi may have favorable effect on the disease activity and function. Although not yet confirmed, the modulation of the microbiome with the help of probiotics or fecal transplant has face validity given the evolving scientific rationale. Diet has only limited role in the management of axSpA. Deep tissue massage, omega-3 fatty acids and Stanger bath were found to be useful in small studies. CAM therapies are not always entirely well tolerated, particularly the manipulative techniques like chiropractic and Tui-na in patients with advanced disease and osteoporosis. There are no trials of yoga in axSpA despite the wider acceptance and use of yoga as an effective mind-body technique. SUMMARY: Larger and better quality clinical trials of CAM therapies are needed to confirm their efficacy and safety in the management of axSpA and to include them in the 'mainstream' medicine.
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Espondiloartritis/tratamiento farmacológico , Terapias Complementarias , Humanos , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVES: Secukinumab, a fully human anti-IL-17A monoclonal antibody, provided rapid and sustained improvements in signs and symptoms of ankylosing spondylitis (AS) over 2 years in the Phase 3 MEASURE 1 trial. Here, we report efficacy and safety after 3 years of treatment. METHODS: AS subjects completing 2 years of treatment every 4 weeks with subcutaneous secukinumab 150 or 75 mg (following intravenous loading or initial placebo treatment to 16/24 weeks) entered a separate 3-year extension study (NCT01863732). Assessments included ASAS20/40, ASAS5/6, BASDAI, BASDAI 50, BASFI, BASMI, SF-36 physical component summary, ASAS partial remission and ASDAS-CRP. Results were also analysed by prior anti-TNF treatment status. RESULTS: Among 290 subjects completing the core trial, 274 entered the extension study, with 260 subjects (94.9%) completing 156 weeks of treatment. ASAS20/40 response (observed) was 80.2%/61.6% in the IVâ150 mg group and 75.5%/50.0% in the IVâ75 mg group after 156 weeks. Sustained improvements were also seen in BASDAI, BASFI, BASMI and across all other endpoints regardless of previous exposure to anti-TNF agents. Mean secukinumab exposure was 964.3 days (137.8 weeks). Discontinuation rates were low, and secukinumab had a favourable safety profile, consistent with previous reports. Exposure-adjusted incidence rates for serious infections, Candida infections, Crohn's disease, ulcerative colitis, malignant/unspecified tumours, and adjudicated major adverse cardiac events were 1.1, 0.4, 0.5, 0.1, 0.5 and 0.7 per 100 subject-years, respectively. CONCLUSIONS: Secukinumab provided sustained efficacy in signs, symptoms and physical function in subjects with AS over 3 years. No new safety signals were observed.
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Antiinflamatorios/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Interleucina-17/antagonistas & inhibidores , Espondilitis Anquilosante/tratamiento farmacológico , Administración Intravenosa , Adulto , Antiinflamatorios/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Femenino , Humanos , Inyecciones Subcutáneas , Interleucina-17/inmunología , Masculino , Persona de Mediana Edad , Inducción de Remisión , Espondilitis Anquilosante/diagnóstico , Espondilitis Anquilosante/inmunología , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE OF REVIEW: Axial spondyloarthritis (axSpA) is a chronic inflammatory condition with articular and extra-articular manifestations. Remission, a state of absence of clinical and imaging signs of disease activity over time, is the goal of management. This review addresses the concept of minimal disease activity (MDA) in axSpA, which is less stringent than remission, and is closer to patient and provider acceptable low disease state. RECENT FINDINGS: Existing axSpA treatments improve physical function and quality of life, and lead to remission in a minority of patients. A consistent MDA state decreases disease progression in rheumatoid arthritis and psoriatic arthritis. We argue a need to develop MDA in axSpA for clinical practice and clinical trials and propose methodology. Considering that MDA will be used in clinical practice, its elements must be easy to collect and cover both musculoskeletal and extra-articular domains. MDA will complement current disease activity measures in axSpA. SUMMARY: Defining an MDA target in axSpA would provide an outcome measure that is less stringent than remission, and will likely predict function and quality of life. We propose methods to develop MDA in axSpA and that further research be performed to determine if treating to an MDA target in axSpA improves patient outcomes.
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Antirreumáticos/uso terapéutico , Espondilitis Anquilosante/tratamiento farmacológico , Humanos , Evaluación de Resultado en la Atención de Salud , Planificación de Atención al Paciente , Calidad de Vida , Índice de Severidad de la Enfermedad , Espondiloartritis/tratamiento farmacológico , Espondiloartritis/fisiopatología , Espondilitis Anquilosante/fisiopatología , Resultado del TratamientoRESUMEN
PURPOSE OF REVIEW: The Assessment of Spondyloarthritis International Society (ASAS) axial spondyloarthritis (axSpA) classification criteria marked a major step forward in SpA research, distinguishing axial from peripheral disease, and allowing earlier identification through MRI. This facilitated all aspects of research including epidemiology, therapeutics and patient outcomes. RECENT FINDINGS: The ASAS axSpA classification criteria have been applied broadly in research, and were validated in a recent meta-analysis of international studies. Concerns arose because of clinical differences between the clinical and imaging arms, which imply different risk for radiographic progression, and perform differently in validation studies. Low specificity of the MRI finding of sacroiliac joint bone marrow edema may lead to misclassification in populations with low axSpA prevalence. We suggest methodology to improve upon the criteria, including rigorous assessment of potential candidate criteria sets, discrete choice experiments to allow consideration of feature weights, and validation. Separately, assessment of structural and inflammatory MRI abnormalities should be performed to refine the MRI definition of sacroiliitis. SUMMARY: The debate regarding the validation and modification of the ASAS axSpA classification criteria should lead to international efforts to build upon the gains made by these criteria, to further refine the axSpA population definitions for research and ultimately improve patient outcomes.
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Sacroileítis/clasificación , Espondiloartropatías/clasificación , Médula Ósea/diagnóstico por imagen , Progresión de la Enfermedad , Edema/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Prevalencia , Articulación Sacroiliaca/diagnóstico por imagen , Sacroileítis/diagnóstico por imagen , Sacroileítis/epidemiología , Sensibilidad y Especificidad , Sociedades Médicas , Espondiloartritis/epidemiología , Espondiloartropatías/diagnóstico por imagen , Espondiloartropatías/epidemiología , Espondilitis Anquilosante/clasificación , Espondilitis Anquilosante/diagnóstico por imagenRESUMEN
OBJECTIVE: We investigated the relationship between Staphylococcus aureus colonization and the use of immunosuppressive therapies in patients with immune-mediated inflammatory diseases (IMIDs). METHODS: We prospectively enrolled IMID patients from the rheumatology and dermatology departments of Oregon Health & Science University. At enrolment, we surveyed patients for S. aureus infection risk factors and those using immune-modulating therapies, and evaluated their colonization status with bilateral nares and inguinal fold cultures. Patients were asked to follow up 6-12 months later for reassessment of colonization status by repeat culture. S. aureus isolates were tested for the presence of methicillin resistance by PCR. RESULTS: We enrolled a total of 548 IMID patients. At enrolment, 219 (40.0%) patients were colonized with S. aureus, of which 27 (12.3%) were methicillin-resistant S. aureus (MRSA). Baseline colonization rates were similar between TNF-α inhibitor users and non-users (40.5% and 39.4%, P = 0.79), but were significantly higher for psoriasis patients compared with those with RA (43.5% and 31.8%, P = 0.02). A total of 384 patients were available for follow-up. Patients who were colonized at enrolment were more likely to be colonized at follow-up if they were treated with TNF-α inhibitors during the study as compared to patients without TNF-α inhibitor exposure [odds ratio (OR) = 2.2 (95% CI 1.1, 4.2), P = 0.02]. CONCLUSION: Patients with psoriasis are more likely to be colonized with S. aureus than patients with RA. Patients who are colonized with S. aureus are more likely to remain colonized if exposed to TNF-α inhibitors.
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Inmunosupresores/uso terapéutico , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Psoriasis/tratamiento farmacológico , Fiebre Reumática/tratamiento farmacológico , Infecciones Estafilocócicas/epidemiología , Staphylococcus aureus/aislamiento & purificación , Abatacept , Adalimumab , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Etanercept , Femenino , Estudios de Seguimiento , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , Inmunoglobulina G/efectos adversos , Inmunoglobulina G/uso terapéutico , Inmunosupresores/efectos adversos , Infliximab , Masculino , Persona de Mediana Edad , Análisis Multivariante , Prevalencia , Estudios Prospectivos , Psoriasis/complicaciones , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Factores de Riesgo , Rituximab , Infecciones Estafilocócicas/etiología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto JovenRESUMEN
OBJECTIVE: To evaluate golimumab's effect on MRI-detected spinal inflammation in ankylosing spondylitis (AS). METHODS: Patients were randomly assigned to subcutaneous injections of placebo (n=78), golimumab 50 mg (n=138), or golimumab 100 mg (n=140) every 4 weeks. An MRI substudy comprising 98 patients (placebo n=23, 50 mg n=37, 100 mg n=38) at eligible MRI substudy sites had serial spine MRI scans (sagittal plane, 1.5T scanners, T1 and short tau inversion recovery sequences) at baseline and weeks 14 and 104. Two blinded (treatment, image order) readers independently evaluated MRI spinal inflammation using AS spine MRI-activity (ASspiMRI-a) scores; reader scores were averaged. Changes from baseline to weeks 14 and 104 were compared among treatment groups using analysis of variance on van der Waerden normal scores both with (post-hoc) and without (prespecified) adjustment for baseline ASspiMRI-a scores. RESULTS: Median baseline ASspiMRI-a scores were lower in the 100 mg (3.5) than placebo (6.8) and 50 mg (7.8) groups. Median decreases in activity scores from baseline to week 14 were -0.5 for placebo, -3.5 for 50 mg (p=0.047 vs placebo), and -1.5 for 100 mg (p=0.14 vs placebo). After adjusting for baseline ASspiMRI-a score imbalance, significant improvements were observed with both 50 mg (p=0.011) and 100 mg (p=0.002) versus placebo. ASspiMRI-a scores improvement achieved with golimumab was maintained at week 104. Improvement in ASspiMRI-a scores correlated with improvement in the recently developed AS disease activity score (ASDAS) and C-reactive protein (CRP) levels but not with other key AS clinical outcomes. CONCLUSION: Golimumab significantly reduced MRI-detected spinal inflammation of AS; improvements were sustained to week 104 and correlated with improvement in ASDAS and CRP.
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Anticuerpos Monoclonales/administración & dosificación , Imagen por Resonancia Magnética , Espondilitis Anquilosante/tratamiento farmacológico , Espondilitis Anquilosante/patología , Adulto , Antirreumáticos/administración & dosificación , Proteína C-Reactiva/metabolismo , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Placebos , Índice de Severidad de la Enfermedad , Espondilitis Anquilosante/inmunología , Resultado del TratamientoRESUMEN
IMPORTANCE: Repository corticotropin injection is an expensive medication that was approved in 1952 for the treatment of many inflammatory conditions. The clinical evidence supporting the use of repository corticotropin (hereinafter referred to as corticotropin) has been weak, perhaps because its approval predated the modern review standards of the US Food and Drug Administration (FDA). OBJECTIVE: To characterize the clinical evidence supporting the use of corticotropin for its FDA-approved indications. EVIDENCE REVIEW: Studies were identified via electronic searches of Ovid MEDLINE, the Cumulative Index of Nursing and Allied Health Literature (CINAHL), and the Cochrane Central Register of Controlled Trials (CENTRAL) from database inception to May 12, 2021 (the MEDLINE search was updated on June 8, 2021). Bibliographies of retrieved articles were also reviewed through ClinicalTrials.gov, FDA documents, and the manufacturer's website. Search terms included HP Acthar, ACTH gel, repository corticotropin, and terms for specific diseases, such as multiple sclerosis, nephrotic syndrome, rheumatoid arthritis, and West syndrome (or spasms, infantile). The review included randomized clinical trials (RCTs), nonrandomized and single-arm clinical trials, and prospective cohort studies that compared corticotropin with an active comparator, placebo, or no treatment. Data were extracted by 1 reviewer and verified by a second. Disagreements were resolved through discussion. Studies were qualitatively synthesized by indication to summarize important design features and results. FINDINGS: Of 1059 records screened, 203 full-text articles were assessed for eligibility. A total of 41 studies involving 2235 participants met inclusion criteria; of those, 11 involved infantile spasms, 10 involved multiple sclerosis (MS), 11 involved rheumatological conditions, 7 involved nephrotic syndrome, 1 involved ocular conditions, and 1 involved sarcoidosis. Overall, 19 studies either included a single arm or exclusively compared different corticotropin dosing strategies. The evidence was most robust for the treatment of infantile spasms and MS. The largest number of studies comparing corticotropin with an active agent (n = 4) or placebo (n = 5) pertained to MS, with almost all studies finding that corticotropin performed better than placebo but no different than corticosteroids. For the treatment of infantile spasms, 8 controlled studies were identified (6 were randomized); of those, only 1 small RCT found corticotropin to be significantly superior to corticosteroids. Studies of patients with other conditions (n = 20) frequently lacked a control group (n = 12), were placebo-controlled (n = 5), or exclusively examined different corticotropin dosing strategies (n = 2). Placebo-controlled RCTs of rheumatoid arthritis, ankylosing spondylitis, optic neuritis, systemic lupus erythematosus, and nephrotic syndrome were generally small and did not consistently demonstrate that corticotropin was superior to placebo. Blinded RCTs showed a similar or greater number of adverse effects with corticotropin relative to corticosteroids. CONCLUSIONS AND RELEVANCE: In this scoping review, few RCTs supported the clinical benefit of corticotropin for most FDA-approved indications. Most RCTs found that corticotropin was not superior to corticosteroids for treating relapses of MS or infantile spasms.
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Artritis Reumatoide , Esclerosis Múltiple , Síndrome Nefrótico , Espasmos Infantiles , Corticoesteroides/uso terapéutico , Hormona Adrenocorticotrópica , Artritis Reumatoide/tratamiento farmacológico , Femenino , Humanos , Masculino , Esclerosis Múltiple/tratamiento farmacológico , Síndrome Nefrótico/tratamiento farmacológico , Espasmos Infantiles/tratamiento farmacológico , Estados Unidos , United States Food and Drug AdministrationRESUMEN
BACKGROUND: Psoriasis, psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) are chronic immune-mediated inflammatory diseases (IMIDs) associated with cardiovascular (CV) disease. High-sensitivity C-reactive protein (hsCRP) and, more recently, the neutrophil-lymphocyte ratio (NLR) are important inflammatory biomarkers predictive of CV disease and CV disease-associated mortality. Here, we report the effect of interleukin (IL)-17A inhibition with secukinumab on CV risk parameters in patients with psoriasis, PsA, and axSpA over 1 year of treatment. METHODS: This was a post hoc analysis of pooled data from phase 3/4 secukinumab studies in psoriasis, PsA, and axSpA. CV-related exclusion criteria included uncontrolled hypertension and congestive heart failure. Traditional risk factors assessed were body mass index (BMI) > 25, high fasting glucose and blood pressure (systolic and diastolic), and high cholesterol (low-density lipoproteins [LDL], total cholesterol/HDL ratio, and triglycerides). Inflammatory CV risk parameters assessed were hsCRP and NLR. Statistical analysis was descriptive. Subgroup analyses were performed in high-risk patients defined as having baseline hsCRP > 4 mg/L (patients with psoriasis) and > 10 mg/L (patients with PsA/axSpA). RESULTS: In total, 9197 patients from 19 clinical trials (8 in psoriasis, n = 4742; 5 in PsA, n = 2475; 6 in axSpA, n = 1980) were included. All traditional CV risk parameters remained stable in secukinumab-treated patients through 1 year. Secukinumab rapidly reduced both hsCRP and the NLR compared with placebo at week 12 (psoriasis) or week 16 (PsA/axSpA) in the overall population and in high-risk patients (all P < 0.01). This reduction was maintained for at least 1 year of secukinumab therapy in all indications. CONCLUSIONS: Secukinumab led to a rapid and sustained reduction in hsCRP and the NLR in patients with IMIDs with a high systemic inflammatory burden. Traditional CV risk factors remained stable for at least 1 year in patients with psoriasis, PsA, and axSpA. Taken together, secukinumab had a favorable effect on systemic inflammation without impact on traditional CV risk factors. TRIALS REGISTRATION: ClinicalTrials.gov, NCT01365455, NCT01358578, NCT01406938, NCT01555125, NCT01636687, NCT02752776, NCT02074982, NCT02826603, NCT01752634, NCT01989468, NCT02294227, NCT02404350, NCT02745080, NCT01863732, NCT01649375, NCT02008916, NCT02159053, NCT02896127, NCT02696031.
RESUMEN
Importance: Approximately one-quarter of the global population have latent tuberculosis infection (LTBI), and tuberculosis (TB) is accountable for more than 1.5 million deaths annually. Methotrexate, cyclosporine, and tumor necrosis factor inhibitors may be associated with increased risk of TB and LTBI reactivation, although data are limited on the risks of TB with use of newer biologics. Objective: To assess the association of secukinumab with reporting of active TB development, TB reactivation, and LTBI activation as an adverse event (AE) in patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis. Design, Setting, and Participants: This pooled cohort study pooled data from 28 clinical trials of secukinumab used in psoriasis (17 phase 3 or 3b and 2 phase 4 trials), psoriatic arthritis (5 phase 3 trials), and ankylosing spondylitis (4 phase 3 trials). A search of the Novartis Secukinumab Compound Pool Database was conducted for the 28 trials. All trial participants who had received at least 1 approved subcutaneous dose of secukinumab (150 mg or 300 mg) were included. Before randomization in these trials, patients underwent screening for TB. Patients with active TB were excluded, and patients with LTBI were treated according to local guidelines. Data were analyzed from the start of treatment in the individual studies through December 25, 2018. Main Outcomes and Measures: Reporting of active TB or LTBI as an AE over a 5-year period using exposure-adjusted incidence rates (EAIR; incidence rates per 100 patient-years). Results: A total of 12â¯319 patients were included, of whom 8819 patients had psoriasis (71.6%; 5930 men [67.2%]; mean [SD] age, of 44.9 [13.5] years), 2523 had psoriatic arthritis (20.5%; 1323 women [52.4%]; mean [SD] age, 48.8 [12.1] years), and 977 had ankylosing spondylitis (7.3%; 658 men [67.3%]; mean [SD] age, 42.3 [11.9] years). In the total population, 684 patients (5.6%) had tested positive for LTBI at screening. Over 5 years, LTBI as an AE during secukinumab treatment was reported in 13 patients (0.1% of 12â¯319). Of these 13 patients, 6 had a prior positive LTBI test result, and 7 were newly diagnosed as having LTBI. Four of the 7 patients had psoriasis (EAIR, 0.03; 95% CI, 0.01-0.07), 1 had psoriatic arthritis (EAIR, 0.02; 95% CI, 0.00-0.11), and 2 had ankylosing spondylitis (EAIR, 0.08; 95% CI, 0.01-0.28). No cases of active TB were reported. Conclusions and Relevance: This study found that LTBI reported as an AE after secukinumab treatment was uncommon and appeared to support the use of secukinumab in chronic systemic inflammatory conditions.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Artritis Psoriásica/tratamiento farmacológico , Tuberculosis Latente/epidemiología , Psoriasis/tratamiento farmacológico , Espondilitis Anquilosante/tratamiento farmacológico , Adulto , Artritis Psoriásica/inmunología , Conjuntos de Datos como Asunto , Femenino , Humanos , Incidencia , Interleucina-17/antagonistas & inhibidores , Interleucina-17/inmunología , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/inmunología , Masculino , Persona de Mediana Edad , Psoriasis/inmunología , Investigación Cualitativa , Ensayos Clínicos Controlados Aleatorios como Asunto , Espondilitis Anquilosante/inmunologíaRESUMEN
BACKGROUND: This analysis assessed improvements in patients with radiographic axial spondyloarthritis (r-axSpA) treated with ixekizumab in the Assessment of Spondyloarthritis International Society (ASAS) treatment response domains and additional patient-reported outcomes at 1 year of treatment. METHODS: COAST-V and COAST-W were 52-week, phase 3, randomized controlled trials evaluating the efficacy and safety of ixekizumab in biologic disease-modifying antirheumatic drug (bDMARD)-naïve and tumor necrosis factor inhibitor (TNFi)-experienced patients with radiographic spondyloarthritis, respectively. Patients were treated with 80-mg ixekizumab either every 2 weeks or every 4 weeks. Patient-reported outcomes included Patient Global Disease Activity, Spinal Pain, stiffness as measured by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Questions 5 and 6, function as measured by the Bath Ankylosing Spondylitis Functional Index, fatigue as measured by the Fatigue Numeric Rating Scale and BASDAI question 1, Spinal Pain at Night, and sleep quality as measured by the Jenkins Sleep Evaluation Questionnaire. Mixed-effects models for repeated measures were used to analyze changes from baseline in patient-reported outcomes from weeks 1 to 16, and descriptive statistics were reported from weeks 20 to 52. Analysis of covariance with Scheffé's method was used for the ASAS response association analyses. RESULTS: This study assessed 341 bDMARD-naïve and 316 TNFi-experienced patients in the placebo-controlled blinded treatment dosing period (weeks 1-16) as well as 329 bDMARD-naïve and 281 TNFi-experienced patients in the dose double-blind extended treatment period (weeks 20-52). bDMARD-naïve or TNFi-experienced patients treated with ixekizumab every 2 weeks and every 4 weeks reported improvements in patient global disease activity, spinal pain, function, stiffness, fatigue, spinal pain at night, and sleep quality through week 52. Greater correlations with improvements in all response domains were seen when comparing ASAS40 responders to ASAS20 non-responders (p < 0.001), with up to 10.5-fold greater improvements observed in ASAS40 responses compared with ASAS20 non-responders. Function and fatigue demonstrated the highest values. CONCLUSIONS: Ixekizumab-treated bDMARD-naïve and TNFi-experienced patients with radiographic axial spondyloarthritis achieving ASAS40 reported sustained and consistent improvement in all ASAS response domains and other patient-reported outcomes though week 52, with spinal pain, function, and stiffness as major drivers of the response. TRIAL REGISTRATION: NCT02696785 and NCT02696798 , March 2, 2016.