RESUMEN
PURPOSE OF REVIEW: Limited data is available for tapering or discontinuation of biologic therapy in patients with axSpA who are in disease remission. The current review concentrates on published studies regarding dose tapering or withdrawal of biologics in axSpA. RECENT FINDINGS: Recent evidence in light of randomized controlled trials suggests that tapering of b-DMARDs is a feasible strategy to maintain remission or low disease activity in axSpA patients. TNF inhibitors were the studied biologics in most of these trials. The disease flare rates were comparable to those maintained on standard dose in most of these studies, although with variable tapering strategies and follow-up. Additionally, the duration of disease in remission prior to tapering, studied primary outcome, and flare definitions were heterogeneous. Female sex, HLA-B*27 negativity, high physician global score, and high CRP were negative predictors of successful tapering, but not consistently reported in all the trials. Although designed to address efficacy, there were no safety concerns with b-DMARD tapering. Withdrawal or complete discontinuation of biologics met with increased risk of flares compared to standard dosing. Tapering of TNF inhibitors may be feasible in certain axSpA patients with an acceptable disease state; however, discontinuation is not currently recommended owing to increased risk of flare. Future studies with axSpA patients with longer remission duration prior to taper and different doses and types of b-DMARDs may provide more guidance.
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Antirreumáticos , Productos Biológicos , Reducción Gradual de Medicamentos , Humanos , Antirreumáticos/administración & dosificación , Antirreumáticos/uso terapéutico , Productos Biológicos/administración & dosificación , Productos Biológicos/uso terapéutico , Reducción Gradual de Medicamentos/métodos , Espondiloartritis/tratamiento farmacológico , Privación de Tratamiento , Inducción de Remisión/métodos , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Inhibidores del Factor de Necrosis Tumoral/uso terapéuticoRESUMEN
BACKGROUND/OBJECTIVE: To assess safety/efficacy of tofacitinib and tumor necrosis factor inhibitors (TNFi) in patients from Latin America (LATAM) in ORAL Surveillance. METHODS: In ORAL Surveillance, 4362 patients with rheumatoid arthritis aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily or TNFi. This post hoc analysis stratified patients by geographical location (LATAM, n = 1202; non-LATAM, n = 3160). Incidence rates (IRs; patients with first event/100 patient-years) and hazard ratios for adverse events of special interest were reported. Efficacy outcomes included Clinical Disease Activity Index and American College of Rheumatology 20/50/70 responses. RESULTS: Risk factors associated with cardiovascular disease and malignancies were less prevalent in the LATAM cohort compared with the non-LATAM cohort. IRs for patients receiving tofacitinib (combined doses) versus TNFi were 0.54 versus 0.28 (LATAM) and 1.14 versus 0.92 (non-LATAM) for major adverse cardiovascular events; 0.58 versus 0.27 (LATAM) and 1.33 versus 0.95 (non-LATAM) for malignancies excluding nonmelanoma skin cancer; and 0.69 versus 0.35 (LATAM) and 0.63 versus 0.33 (non-LATAM) for all-cause death. IRs for nonmelanoma skin cancer and venous thromboembolism were also numerically higher with tofacitinib versus TNFi and in the non-LATAM cohort versus LATAM. Efficacy was similar across treatment groups within each cohort. CONCLUSIONS: Adverse events of special interest were generally less frequent in LATAM versus non-LATAM patients, reflecting differences in baseline characteristics, and higher with tofacitinib versus TNFi in both cohorts, consistent with the overall findings of ORAL Surveillance. Our findings emphasize the importance of assessing individual risk factors to guide benefit/risk assessment and treatment decisions. CLINICAL TRIAL REGISTRATION NUMBER: NCT02092467.
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Artritis Reumatoide , Enfermedades Cardiovasculares , Neoplasias , Piperidinas , Pirimidinas , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antirreumáticos/efectos adversos , Antirreumáticos/administración & dosificación , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Incidencia , América Latina/epidemiología , Neoplasias/epidemiología , Neoplasias/tratamiento farmacológico , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Pirroles/efectos adversos , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral/efectos adversos , Inhibidores del Factor de Necrosis Tumoral/administración & dosificaciónRESUMEN
BACKGROUND AND AIMS: VARSITY (An Efficacy and Safety Study of Vedolizumab Intravenous [IV] Compared to Adalimumab Subcutaneous [SC] in Participants With Ulcerative Colitis) showed superior clinical remission and endoscopic improvement in ulcerative colitis with vedolizumab vs adalimumab. This analysis compared histologic outcomes. METHODS: Patients in VARSITY were randomized 1:1 to maintenance with vedolizumab IV 300 mg every 8 weeks or adalimumab SC 40 mg every 2 weeks (both following standard induction). Geboes Index and Robarts Histopathology Index (RHI) scores were used to assess prespecified histologic exploratory end points of histologic remission (Geboes <2 or RHI ≤2) and minimal histologic disease activity (Geboes ≤3.1 or RHI ≤4) at weeks 14 and 52. RESULTS: In total, 769 patients received vedolizumab (n = 383) or adalimumab (n = 386). Mean baseline histologic disease activity was similar between vedolizumab and adalimumab groups. Vedolizumab induced greater histologic remission than adalimumab at week 14 (Geboes: 16.7% vs 7.3%, Δ9.4% [95% confidence interval {CI}, 4.9%-13.9%], P < .0001; RHI: 25.6% vs 16.1%, Δ9.5% [95% CI, 3.8%-15.2%], P = .0011) and week 52 (Geboes: 29.2% vs 8.3%, Δ20.9% [95% CI, 15.6%-26.2%], P < .0001; RHI: 37.6% vs 19.9%, Δ17.6% [95% CI, 11.3%-23.8%], P < .0001) overall and in both anti-tumor necrosis factor (TNF)-naïve and -failure subgroups. Results were similar for minimal histologic disease activity. Histologic outcomes were generally better in anti-TNF-naïve vs -failure patients. At week 52, rates of mucosal healing (composite end point of histologic plus endoscopic improvement) were also higher with vedolizumab than adalimumab (Geboes: 25.6% vs 6.7%; RHI: 30.5% vs 14.5%). CONCLUSIONS: Higher rates of histologic remission, minimal histologic disease activity, and combined histologic plus endoscopic outcomes were observed with vedolizumab than with adalimumab in ulcerative colitis in both anti-TNF-naïve and -failure subgroups. REGISTRATION: ClinicalTrials.gov NCT02497469; EudraCT 2015-000939-33.
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Adalimumab/administración & dosificación , Antiinflamatorios/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Colitis Ulcerosa/tratamiento farmacológico , Colon/efectos de los fármacos , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Cicatrización de Heridas/efectos de los fármacos , Adalimumab/efectos adversos , Adulto , Antiinflamatorios/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Colitis Ulcerosa/patología , Colon/patología , Colonoscopía , Método Doble Ciego , Femenino , Humanos , Infusiones Intravenosas , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Inducción de Remisión , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral/efectos adversosRESUMEN
BACKGROUND: Data on outcomes following de-escalation of intensified anti-TNF therapy in inflammatory bowel disease (IBD) are limited and concerns about relapse limit willingness to de-escalate. AIMS: To evaluate rates of successful de-escalation at 12 months and to determine factors that may predict success. METHODS: Single-centre experience of IBD patients that were de-escalated following deep remission on dose-intensified infliximab (IFX) or adalimumab (ADA) for secondary loss of response. Patients were classified as 'successes' if remaining on reduced anti-TNF or 'failures' if requiring re-escalation, steroids, surgery or enrolment into a clinical trial at 12 months. Patient demographics, disease characteristics, biomarkers (faecal calprotectin, C-reactive protein, albumin) and anti-TNF drug levels were collected 6-monthly. RESULTS: Of 25 patients (20 CD, 5 UC), 16 (64%) were successes 12 months post-de-escalation. Median time to failure was 6 months. Six of the nine failures required anti-TNF re-escalation and three entered a clinical trial. Re-escalation recaptured response in all six patients. There was no significant difference in baseline biomarker activity between the two groups. There was no difference in infliximab levels between successes and failures at the time of de-escalation (5.5 vs. 5.3, p = 0.63) as well as 6 months (3.1 vs. 4.6, p = 0.95) and 12 months (3.2 vs. 4.5, p = 0.58) post-de-escalation. CONCLUSION: Nearly two-thirds of patients remained on reduced anti-TNF dosing 12 months after de-escalation. All patients who failed de-escalation were recaptured after dose re-escalation. De-escalation with close monitoring may be considered in patients on intensified anti-TNF therapy in sustained remission.
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Adalimumab , Colitis Ulcerosa , Enfermedad de Crohn , Monitoreo de Drogas , Infliximab , Adalimumab/administración & dosificación , Adalimumab/inmunología , Adulto , Biomarcadores/análisis , Proteína C-Reactiva/análisis , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/inmunología , Relación Dosis-Respuesta Inmunológica , Monitoreo de Drogas/métodos , Monitoreo de Drogas/estadística & datos numéricos , Reducción Gradual de Medicamentos/métodos , Reducción Gradual de Medicamentos/estadística & datos numéricos , Duración de la Terapia , Femenino , Humanos , Infliximab/administración & dosificación , Infliximab/inmunología , Masculino , Recurrencia , Inducción de Remisión/métodos , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Inhibidores del Factor de Necrosis Tumoral/inmunologíaRESUMEN
BACKGROUND: Inflammatory bowel diseases (IBD) are often treated with anti-tumor necrosis factor alpha (anti-TNFα) medications. Concomitant treatment of IBD with anti-TNFα agents and immunomodulators appears to be associated with an increased risk for lymphoma. METHODS: Patients who developed lymphoma while on monotherapy with an anti-TNFα agent were identified at three centers. Institutional Review Board approval was obtained. RESULTS: Five adolescents and young adult patients with pediatric-onset IBD who were treated with infliximab (IFX) without exposure to thiopurines were subsequently diagnosed with lymphoma. Three of the five patients had bone involvement at presentation. Epstein-Barr virus was positive in 2 cases. Median time from diagnosis of IBD and exposure to IFX prior to diagnosis of lymphoma was 5 and 4.3 years, respectively. CONCLUSIONS: This case series reports long-term follow-up for young patients with IBD who were treated with IFX monotherapy and developed lymphoma. Three of the five patients had bone involvement. In general, the risk of lymphoma following exposure to anti-TNFα medications alone remains low, but the incidence of primary bone lymphomas in IBD has not been reported. Studies examining longer exposure times may be needed to determine the true lymphoma risk in patients treated with IFX monotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Colitis Ulcerosa , Enfermedad de Crohn , Sustitución de Medicamentos/métodos , Infliximab , Linfoma , Adolescente , Edad de Inicio , Huesos/diagnóstico por imagen , Huesos/patología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/epidemiología , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/epidemiología , Femenino , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Infliximab/administración & dosificación , Infliximab/efectos adversos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Linfoma/diagnóstico , Linfoma/etiología , Linfoma/fisiopatología , Linfoma/terapia , Masculino , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Inhibidores del Factor de Necrosis Tumoral/efectos adversos , Adulto JovenRESUMEN
OBJECTIVE: We sought to evaluate COVID-19 clinical course in patients with IBD treated with different medication classes and combinations. DESIGN: Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) is a large, international registry created to monitor outcomes of IBD patients with confirmed COVID-19. We used multivariable regression with a generalised estimating equation accounting for country as a random effect to analyse the association of different medication classes with severe COVID-19, defined as intensive care unit admission, ventilator use and/or death. RESULTS: 1439 cases from 47 countries were included (mean age 44.1 years, 51.4% men) of whom 112 patients (7.8%) had severe COVID-19. Compared with tumour necrosis factor (TNF) antagonist monotherapy, thiopurine monotherapy (adjusted OR (aOR) 4.08, 95% CI 1.73 to 9.61) and combination therapy with TNF antagonist and thiopurine (aOR 4.01, 95% CI 1.65 to 9.78) were associated with an increased risk of severe COVID-19. Any mesalamine/sulfasalazine compared with no mesalamine/sulfasalazine use was associated with an increased risk (aOR 1.70, 95% CI 1.26 to 2.29). This risk estimate increased when using TNF antagonist monotherapy as a reference group (aOR 3.52, 95% CI 1.93 to 6.45). Interleukin-12/23 and integrin antagonists were not associated with significantly different risk than TNF antagonist monotherapy (aOR 0.98, 95% CI 0.12 to 8.06 and aOR 2.42, 95% CI 0.59 to 9.96, respectively). CONCLUSION: Combination therapy and thiopurines may be associated with an increased risk of severe COVID-19. No significant differences were observed when comparing classes of biologicals. These findings warrant confirmation in large population-based cohorts.MKH should be changed to MDK for co-last author line.
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Azatioprina , COVID-19 , Enfermedades Inflamatorias del Intestino , Mercaptopurina , SARS-CoV-2 , Inhibidores del Factor de Necrosis Tumoral , Adulto , Antiinflamatorios/farmacología , Azatioprina/administración & dosificación , Azatioprina/efectos adversos , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/inmunología , Quimioterapia Combinada/métodos , Quimioterapia Combinada/estadística & datos numéricos , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/virología , Cooperación Internacional , Masculino , Mercaptopurina/administración & dosificación , Mercaptopurina/efectos adversos , Sistema de Registros/estadística & datos numéricos , Ajuste de Riesgo , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/aislamiento & purificación , Índice de Severidad de la Enfermedad , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Inhibidores del Factor de Necrosis Tumoral/efectos adversosRESUMEN
OBJECTIVES: Treatment with golimumab monotherapy in early peripheral SpA (pSpA) results in higher rates of clinical remission compared with treatment in more longstanding disease. When reaching remission, treat-to-target recommendations suggest tapering of treatment. We therefore explored whether addition of MTX would permit discontinuation of golimumab in patients with pSpA in sustained clinical remission. METHODS: After a 2-year extension phase with golimumab treatment, patients with pSpA reaching clinical remission in the CRESPA trial were offered a tapering strategy leading to discontinuation of golimumab and replacement by MTX monotherapy. Patients were prospectively followed to assess the rate of sustained biologic-free clinical remission. In case of relapse of arthritis, enthesitis or dactylitis under MTX monotherapy, golimumab was restarted. RESULTS: Of the original 60 pSpA patients, 25 entered the step-down strategy. Currently, only 4 patients (16%) are still in sustained remission under MTX monotherapy. In 21 patients (84%), golimumab was reinstalled because of relapse of disease activity (n = 19) or development of adverse events related to MTX (n = 2). Restarting golimumab treatment promptly restored clinical remission in all patients within 12 weeks. CONCLUSION: In patients with early pSpA achieving clinical remission after 2 years of golimumab treatment, step-down therapy to monotherapy with MTX led to high rates of clinical relapse. This underscores the overall weak efficacy of MTX in maintaining clinical remission in pSpA. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01426815.
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Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Metotrexato/uso terapéutico , Espondiloartritis/tratamiento farmacológico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Antirreumáticos/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Metotrexato/administración & dosificación , Estudios Prospectivos , Recurrencia , Inducción de Remisión , Factores de Tiempo , Inhibidores del Factor de Necrosis Tumoral/administración & dosificaciónRESUMEN
BACKGROUND: Adherence to adalimumab in inflammatory bowel disease (IBD) patients is reported to be below par. Non-adherence may result in loss-of-response and increased hospitalization. We analyzed the effect of an electronic needle container (ENC) on adherence to adalimumab. METHODS: In this multicenter, 12-months observational study, we included adalimumab treated IBD patients. All patients were invited to receive an ENC. Patients who declined or did not complete the registration for an ENC served as controls. Primary endpoint was whether an ENC increased adherence, calculated from pharmacy refills as proportion of days covered (PDC). Secondary endpoints were clinical outcomes, including loss-of-response, identification of predictors of adherence and correlation between different modalities for measuring adherence. Loss-of-response was defined as a disease flare, dose-escalation or IBD-related hospitalization or surgery. RESULTS: The pharmacies' records identified 198 eligible patients, of whom 32 were excluded. The ENC was supplied to 69 patients, the remaining 97 patient formed the control group. Median baseline PDC (98.4% vs. 96.1%, p = 0.047) and the proportion of adherent (PDC ≥ 86%) patients (87.0% vs. 74.2%, p = 0.045) was higher for the ENC group. The ENC did not improve the adherence of patients during follow-up (odds ratio 1.26, 95% CI 0.55-2.86). During follow-up, five (7.2%) patients in the ENC group and 13 (13.4%) in the control group discontinued adalimumab (log-rank p = 0.22). Loss-of-response occurred in 12 (17.4%) and 14 (14.4%) patients, respectively (log-rank p = 0.66). CONCLUSIONS: Our results show no beneficial effect of a reminder-based intervention on adherence or treatment outcomes.
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Adalimumab/administración & dosificación , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Cumplimiento de la Medicación , Sistemas Recordatorios/instrumentación , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Adulto , Esquema de Medicación , Femenino , Humanos , Inyecciones , Masculino , Persona de Mediana Edad , Países Bajos , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: To study the safety of extended monthly intravitreal infliximab injections in patients with active posterior uveitis in Behcet's disease. METHODS: This is a prospective, interventional, noncomparative, open-label, pilot study of 9 monthly intravitreal infliximab injections (1 mg/0.05 mL) for 22 eyes of 16 patients with active posterior uveitis in Behcet's disease. Control of inflammation and visual outcomes were assessed, and ocular complications were monitored during the study period. RESULTS: Successful treatment was achieved in 7 eyes (35%), and failure was encountered in 13 eyes (65%). Only seven eyes of six patients (35%) had completed the study and achieved complete resolution of inflammation with improved best-corrected visual acuity and no complications. Failure was either because of inability to control the inflammation in nine eyes (45%) or development of exacerbation of inflammation in four eyes (20%). Four eyes developed severe immunological reaction from the drug after first (n = 1), second (n = 2), and third (n = 1) injections and had to discontinue the injections. Kaplan-Meier survival analysis showed that the mean estimated time to failure was 3.3 ± 0.2 months, and all failed eyes required revision of their systemic immunotherapy to control the ocular inflammation. CONCLUSION: Intravitreal infliximab for active posterior uveitis in Behcet's disease was associated with a high complication rate and failure to control inflammation in most eyes. It should not be considered a substitute to systemic therapy.
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Síndrome de Behçet/tratamiento farmacológico , Infliximab/administración & dosificación , Uveítis Posterior/etiología , Agudeza Visual , Adulto , Síndrome de Behçet/complicaciones , Síndrome de Behçet/diagnóstico , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Inyecciones Intravítreas , Masculino , Proyectos Piloto , Estudios Prospectivos , Factores de Tiempo , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Uveítis Posterior/diagnóstico , Uveítis Posterior/tratamiento farmacológico , Adulto JovenRESUMEN
Lupus miliaris disseminatus faciei (LMDF) is a chronic inflammatory dermatosis of unknown aetiology, most often seen in young adults. Although many treatments for LMDF exist, treatment guidelines have not been developed, and response to therapy is generally unpredictable. We present the results of transcriptomic analysis of LMDF lesional skin, which revealed a variety of differentially expressed genes linking LMDF to alterations in innate and adaptive T helper 1 immunity. Immunohistochemical analysis was also performed, identifying similar changes in T-cell immune responses. Given evidence for increased tumour necrosis factor (TNF) pathway activity, our patient, who had previously been refractory to multiple treatments, was initiated on TNF inhibitor therapy with excellent response. This characterization of the LMDF immune response may lead to improved treatment of this condition.
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Dermatosis Facial/inmunología , Granuloma/tratamiento farmacológico , Infliximab/uso terapéutico , Rosácea/tratamiento farmacológico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Administración Intravenosa , Enfermedad Crónica , Quimioterapia Combinada/métodos , Dermatosis Facial/genética , Dermatosis Facial/patología , Perfilación de la Expresión Génica/métodos , Granuloma/diagnóstico , Granuloma/inmunología , Humanos , Inmunidad Celular/inmunología , Inmunohistoquímica/métodos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Infliximab/administración & dosificación , Masculino , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Rosácea/diagnóstico , Rosácea/inmunología , Linfocitos T/inmunología , Células TH1/inmunología , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Adulto JovenRESUMEN
To determine the prevalence of clonal T-large granular lymphocyte (T-LGL) cells in patients with spondyloarthritis (SpA) and psoriatic arthritis (PsA) and to define possible risk factors for this condition. We present a cross-sectional analysis with retrospective and prospective aspects. 115 SpA patients, 48 PsA patients and 51 controls were recruited between December 28, 2017 and January 23, 2019. Flow cytometry (FACS) was performed to screen for aberrant T-LGL cells. Molecular analysis was then employed to confirm the diagnosis in patients with suggestive FACS findings. Patients with clonal T-LGL populations were followed prospectively by FACS analysis. Electronic patient files were retrospectively analyzed to determine risk factors. Median age was 49 years for SpA, 55.5 years for PsA, and 54 years for controls. Median disease duration of SpA and PsA was 15 years and 11 years, respectively. 79.8% of patients had received biologics at some point, 75.5% had ever received tumor necrosis factor (TNF) inhibitors. 59.5% were treated with TNF inhibitors at the time of study inclusion. We identified clonal T-LGL expansions in 13 individuals equaling a prevalence of 6% (13/214). T-LGL patients were taking TNF inhibitors more frequently at the time of study inclusion (p = 0.022) and were more likely to have ever been treated with TNF inhibition (p = 0.046). Clonal T-LGL expansions can be detected in patients with SpA, PsA and also in healthy controls. Confirming earlier results, exposure to TNFα-blocking agents appears to increase the risk of developing clonal expansions of T-LGL cells.
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Artritis Psoriásica/sangre , Espondiloartritis/sangre , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Adulto , Anciano , Artritis Psoriásica/tratamiento farmacológico , Estudios de Casos y Controles , Estudios Transversales , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Espondiloartritis/tratamiento farmacológico , Linfocitos T/metabolismo , Inhibidores del Factor de Necrosis Tumoral/efectos adversosRESUMEN
The hypothesis of the study was that polymorphisms in promoter regions -238 and -308 of TNF-α could be associated with different clinical outcomes in inflammatory bowel diseases (IBD) and immune-mediated rheumatic diseases (IMRD). The aim was to examine the possible association of both polymorphisms with concentration of C-reactive protein (CRP) and fecal calprotectin (fCAL), onset of the remission and development of the ADA in patients on therapy with anti-TNF inhibitors. The prospective study was done in patients with IBD and IMRD on infliximab (IFX) or adalimumab (ADM). Patients were genotyped for TNF-α -238 and -308 polymorphisms. The concentration of CRP, fCAL, IFX or ADM and antibodies to drugs were measured according to manufacturer's instructions and followed-up for 6 or 12 months. Out of all patients (N = 112), number of patients in remission did not differ according to genotypes (for IBD patients P = 0.509 vs 0.223; for IMRD patients P = 0.541 vs 0.132 for TNF-α -238 and -308, respectively). Initial CRP concentration was higher in IBD patients with TNF-α -308 GG than GA/AA genotypes in patients who failed to achieve remission [11.8 (4.4-39.6) vs 3.1 (1.5-6.5), P = 0.033]. In IBD patients with remission, fCAL concentration after at least 6 months of therapy was higher in TNF-α-308 GG than in GA genotype [52 (25-552) vs 20 (20-20) µg/g, P = 0.041]. Our results showed the association of TNF-α -308 GG genotype with a higher concentration of CRP and fecal calprotectin in patients with inflammatory bowel diseases on IFX or ADM therapy. Clinical remission and development of antibodies to anti-TNF drugs were not associated with TNF-α -238 and -308 polymorphisms.
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Adalimumab/administración & dosificación , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/administración & dosificación , Enfermedades Reumáticas/tratamiento farmacológico , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Adulto , Anciano , Biomarcadores/análisis , Proteína C-Reactiva/análisis , Femenino , Humanos , Complejo de Antígeno L1 de Leucocito/análisis , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Inducción de Remisión , Factor de Necrosis Tumoral alfaRESUMEN
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by articular and extra-articular manifestations. Among extra-articular involvement, rheumatoid meningitis (RM) is a rare condition, which may exhibit variable symptoms including headache, focal and/or generalized neurologic deficits. It may develop as the preceding manifestation of RA or occur at any time of the disease course. Some drugs used for the treatment of RA may give rise to aseptic meningitis or create a tendency to infectious meningitis due to their immunosuppressive effect. All these possibilities may lead to difficulties in the differential diagnosis. Achieving a diagnosis in a short time is crucial in terms of prognosis. Here, we would like to report a case with longstanding RA manifested by left-sided weakness and seizure shortly after initiating etanercept (ETA) therapy. ETA-induced meningitis was confirmed with appropriate diagnostic tools. Our aim with this case-based review is to attract the attention of this rare condition and discuss diagnostic challenges.
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Artritis Reumatoide/tratamiento farmacológico , Meningitis Aséptica/inducido químicamente , Inhibidores del Factor de Necrosis Tumoral/efectos adversos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Femenino , Humanos , Persona de Mediana Edad , Tomografía Computarizada por Rayos X , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Inhibidores del Factor de Necrosis Tumoral/inmunologíaRESUMEN
Tumor necrosis factor inhibitor (TNFi) therapies are often the first biologic therapy used to treat rheumatoid arthritis (RA) patients. However, a substantial fraction of patients do not respond adequately to TNFi therapies. A test with the ability to predict response would inform therapeutic decision-making and improve clinical and financial outcomes. A 32-question decision-impact survey was conducted with 248 rheumatologists to gauge the perceived clinical utility of a novel test that predicts inadequate response to TNFi therapies in RA patients. Participants were informed about the predictive characteristics of the test and asked to indicate prescribing decisions based on four result scenarios. Overall, rheumatologists had a favorable view of the test: 80.2% agreed that it would improve medical decision-making, 92.3% said it would increase their confidence when making prescribing decisions, and 81.5% said it would be useful when considering TNFi therapies. Rheumatologists would be more likely to prescribe a TNFi therapy when the test reported that no signal of non-response was detected (79.8%) and less likely to prescribe a TNFi therapy when a signal of non-response was detected (11.3%-25.4%). Rheumatologists (84.7%) agreed that payers should provide coverage for such a test. This study shows that rheumatologists support the clinical need for a test to predict inadequate response to TNFi therapies. Test results were perceived to lead to changes in prescribing behaviors as results instill confidence in the ordering rheumatologist.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Técnicas de Apoyo para la Decisión , Reumatología/métodos , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Actitud del Personal de Salud , Estudios Transversales , Femenino , Humanos , Masculino , Pautas de la Práctica en Medicina , Medicina de Precisión , Encuestas y Cuestionarios , Inhibidores del Factor de Necrosis Tumoral/efectos adversosRESUMEN
Over the past two decades, tumor necrosis factor-α (TNF-α) inhibitors became one of the most important drugs in the treatment of patients with psoriatic arthritis. Unfortunately, some of the patients exhibit unwanted side effects of the treatment. We describe a patient with psoriasis, psoriatic arthritis and uveitis who was treated with adalimumab and after 4 months of the treatment developed clinical and neuroradiological signs of demyelinating disease of the central nervous system. She experienced no signs and symptoms of neurological disease prior to adalimumab administration. After a detailed neurological work-up she was diagnosed with relapsing-remitting type of multiple sclerosis and treated with oral and pulse glucocorticoids and later with dimethyl fumarate. Adalimumab was discontinued. The question remains was the demyelination induced by the TNF-α blockade or was it unmasked by the introduction of the cytokine blocking agent. In patients suffering from inflammatory arthritis, treating disease to target as well as a close follow-up and knowledge of potential side effects of treatment remains crucial in good clinical practice.
Asunto(s)
Adalimumab/efectos adversos , Artritis Psoriásica/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inducido químicamente , Inhibidores del Factor de Necrosis Tumoral/efectos adversos , Adalimumab/administración & dosificación , Adalimumab/farmacología , Femenino , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Inhibidores del Factor de Necrosis Tumoral/farmacologíaRESUMEN
Biological disease-modifying antirheumatic drugs (bDMARDs) monotherapy may enhance adherence and decrease adverse events compared to combination therapy with conventional synthetic DMARDs (csDMARDs); however, persistence with bDMARD monotherapy has not been extensively studied. We explore persistence of etanercept monotherapy and monotherapy with other tumor necrosis factor inhibitors (TNFis) among patients first achieving remission/low disease activity (LDA) while on combination therapy with csDMARDs and a TNFi. Using Corrona registry data, the percentage of patients persistent with the index TNFi (etanercept versus other TNFis) over 6 and 12 months was determined. Factors influencing persistence and treatment patterns at 6 and 12 months were examined. Among 617 eligible patients, 56% of 182 patients on etanercept and 45% of 435 patients on other TNFis persisted with monotherapy at 6 months, 46% and 33%, respectively, at 12 months. Across first-line and subsequent biologic DMARDs, etanercept persistence was greater than other TNFi persistence by 10.8% (95% CI 2.1%, 19.6%) at 6 months and 11.4% (95% CI 0.9%, 21.9%) at 12 months. Patients on other TNFis were more likely to require reintroduction of csDMARD after 6 months (45% versus 35% for etanercept). Remission was the key predictor of persistence for both etanercept and other TNFi monotherapies. This retrospective, cohort study of registry data reflecting real-world practice indicates patients who achieve remission/LDA with combination csDMARD and TNFi therapy may successfully transition to TNFi monotherapy. Patients on etanercept monotherapy experienced greater persistence and less frequent reintroduction of a csDMARD than was observed for patients on other TNFi monotherapies.
Asunto(s)
Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Productos Biológicos/administración & dosificación , Etanercept/administración & dosificación , Metotrexato/administración & dosificación , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Anciano , Antirreumáticos/efectos adversos , Productos Biológicos/efectos adversos , Quimioterapia Combinada , Etanercept/efectos adversos , Femenino , Humanos , Masculino , Cumplimiento de la Medicación , Metotrexato/efectos adversos , Persona de Mediana Edad , Sistema de Registros , Inducción de Remisión , Estudios Retrospectivos , Inhibidores del Factor de Necrosis Tumoral/efectos adversosRESUMEN
OBJECTIVES: The effect of vedolizumab on postoperative outcomes in patients with inflammatory bowel disease (IBD) remains unclear. We aimed to determine the relation between preoperative vedolizumab and early postoperative complications in patients with IBD undergoing abdominal surgery. METHODS: A search of databases and abstracts from gastroenterology conferences was performed. Primary outcomes included overall and infectious postoperative complication rates as well as surgical site infections. Studies that compared Crohn disease, ulcerative colitis, or patients with IBD-undefined with preoperative vedolizumab treatment undergoing abdominal surgery with controls with preoperative antitumor necrosis factor-α (anti-TNF-α) treatment or no preoperative biologic treatment were included. A meta-analysis was completed using the Mantel-Haenszel and DerSimonian and Laird models. RESULTS: Six studies totaling 1201 patients were included; 281 patients were treated preoperatively with vedolizumab, 327 patients were treated preoperatively with anti-TNF-α agents, and 593 patients were not treated preoperatively with any biologics. There was no significant difference in overall complications (odds ratio [OR] 1.04, 95% confidence interval [CI] 0.48-2.24, P = 0.92, I2 =77%) between the vedolizumab and no-biologic groups. There also was no significant difference in infectious complications (OR 1.00, 95% CI 0.37-2.69, P = 1.00, I2 = 78%), which persisted after sensitivity analysis (OR 0.71, 95% CI 0.31-1.60, P = 0.41, I2 = 46%). Furthermore, there was no significant difference in overall complications (OR 0.77, 95% CI 0.24-2.46, P = 0.66, I2 = 85%) and infectious complications (OR 0.89, 95% CI 0.20-3.94, P = 0.87, I2 = 86%) between the vedolizumab and anti-TNF-α groups. After sensitivity analysis, differences in overall and infectious complications remained insignificant (OR 0.54 and 0.50, 95% CI 0.24-1.17 and 0.22-1.15, P = 0.12 and 0.10, I2 = 39% and 18%, respectively). Vedolizumab was also not associated with a significant increase in surgical site infections compared with the no-biologic (OR 1.45, 95% CI 0.33-6.32, P = 0.62, I2 = 75%) and anti-TNF (OR 1.30, 95% CI 0.22-7.60, P = 0.77, I2 = 81%) groups. CONCLUSIONS: Preoperative treatment with vedolizumab in patients with IBD undergoing abdominal surgery is not associated with increases in overall or infectious postoperative complications compared with preoperative anti-TNF-α treatment and no preoperative biologic treatment. Large, prospective studies are needed to further assess the impact of preoperative vedolizumab treatment on postoperative complications, particularly with respect to IBD subtype.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Fármacos Gastrointestinales/efectos adversos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Complicaciones Posoperatorias/epidemiología , Inhibidores del Factor de Necrosis Tumoral/efectos adversos , Abdomen/cirugía , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/cirugía , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/cirugía , Femenino , Fármacos Gastrointestinales/administración & dosificación , Humanos , Enfermedades Inflamatorias del Intestino/cirugía , Masculino , Oportunidad Relativa , Complicaciones Posoperatorias/inducido químicamente , Periodo Preoperatorio , Infección de la Herida Quirúrgica/inducido químicamente , Infección de la Herida Quirúrgica/epidemiología , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral/administración & dosificaciónRESUMEN
Importance: Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy. Objective: To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM. Design, Setting, and Participants: Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020. Interventions: Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230). Main Outcome and Measures: The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period. Results: Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively. Conclusions and Relevance: Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach. Trial Registration: ClinicalTrials.gov Identifier: NCT03074656.
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Artritis/tratamiento farmacológico , Monitoreo de Drogas , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Adulto , Algoritmos , Femenino , Humanos , Infliximab/administración & dosificación , Infliximab/efectos adversos , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Psoriasis/tratamiento farmacológico , Nivel de Atención , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Inhibidores del Factor de Necrosis Tumoral/efectos adversosRESUMEN
BACKGROUND & AIMS: Some patients develop anti-drug antibodies (ADAs), which reduce the efficacy of infliximab, a monoclonal antibody against tumor necrosis factor (TNF), in the treatment of immune-mediated diseases, including inflammatory bowel diseases. ADAs arise inconsistently, and it is not clear what factors determine their formation. We investigated features of the immune system, the infliximab antibody, and its complex with TNF that might contribute to ADA generation. METHODS: C57BL/6 mice were given injections of infliximab and recombinant human TNF or infliximab F(ab')2 fragments. Blood samples were collected every 2-3 days for 2 weeks and weekly thereafter for up to 6 weeks; infliximab-TNF complexes and ADAs were measured by enzyme-linked immunosorbent assay (ELISA). Intestinal biopsy and blood samples were obtained from patients having endoscopy who had received infliximab therapy for inflammatory bowel diseases; infliximab-TNF complexes were measured with ELISA. Infliximab-specific plasma cells were detected in patient tissue samples by using mass cytometry. We studied activation of innate immune cells in peripheral blood mononuclear cells (PBMCs) from healthy donors incubated with infliximab or infliximab-TNF complexes; toll-like receptors (TLRs) were blocked with antibodies, endocytosis was blocked with the inhibitor PitStop2, and cytokine expression was measured by real-time polymerase chain reaction and ELISAs. Uptake of infliximab and infliximab-TNF complexes by THP-1 cells was measured with confocal microscopy. RESULTS: Mice given increasing doses of infliximab produced increasing levels of ADAs. Blood samples from mice given injections of human TNF and infliximab contained infliximab-TNF complexes; complex formation was associated with ADA formation with an area under the curve of 0.944 (95% confidence interval, 0.851-1.000; P = .003). Intestinal tissues from patients, but not blood samples, contained infliximab-TNF complexes and infliximab-specific plasma cells. Incubation of PBMCs with infliximab-TNF complexes resulted in a 4.74-fold increase in level of interleukin (IL) 1ß (IL1B) messenger RNA (P for comparison = .005), increased IL1B protein secretion, and a 2.69-fold increase in the expression of TNF messenger RNA (P for comparison = 0.013) compared with control PBMCs. Infliximab reduced only IL1B and TNF expression. Antibodies against TLR2 or TLR4 did not block the increases in IL1B or TNF expression, but endocytosis was required. THP-1 cells endocytosed higher levels of infliximab-TNF complexes than infliximab alone. CONCLUSIONS: In mice, we found ADA formation to increase with dose of infliximab given and concentration of infliximab-TNF complexes detected in blood. Based on studies of human intestinal tissues and blood samples, we propose that infliximab-TNF complexes formed in the intestine are endocytosed by and activate innate immune cells, which increase expression of IL1B and TNF and production of antibodies against the drug complex. It is therefore important to optimize the infliximab dose to a level that is effective but does not activate an innate immune response against the drug-TNF complex.
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Anticuerpos/sangre , Fragmentos Fab de Inmunoglobulinas/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Infliximab/inmunología , Intestinos/inmunología , Inhibidores del Factor de Necrosis Tumoral/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Estudios de Casos y Controles , Endocitosis , Femenino , Humanos , Inmunidad Innata , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/administración & dosificación , Inyecciones Intravenosas , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Células THP-1 , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Factor de Necrosis Tumoral alfa/administración & dosificación , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
INTRODUCTION: De-escalation of biologic therapy is a commonly encountered clinical scenario. Although biologic discontinuation has been associated with high rates of relapse, the effectiveness of dose de-escalation is unclear. This review was performed to determine the effectiveness of dose de-escalation of biologic therapy in inflammatory bowel disease. METHODS: We searched EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials from inception to October 2019. Randomized controlled trials and observational studies involving dose de-escalation of biologic therapy in adults with inflammatory bowel disease in remission were included. Studies involving biologic discontinuation only and those lacking outcomes after dose de-escalation were excluded. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: We identified 1,537 unique citations with 20 eligible studies after full-text review. A total of 995 patients were included from 18 observational studies (4 prospective and 14 retrospective), 1 nonrandomized controlled trial, and 1 subgroup analysis of a randomized controlled trial. Seven studies included patients with Crohn's disease, 1 included patients with ulcerative colitis, and 12 included both. Overall, clinical relapse occurred in 0%-54% of patients who dose de-escalated biologic therapy (17 studies). The 1-year rate of clinical relapse ranged from 7% to 50% (6 studies). Eighteen studies were considered at high risk of bias, mostly because of the lack of a control group. DISCUSSION: Dose de-escalation seems to be associated with high rates of clinical relapse; however, the quality of the evidence was very low. Additional controlled prospective studies are needed to clarify the effectiveness of biologic de-escalation and identify predictors of success.