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2.
Adv Rheumatol ; 64(1): 21, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38515177

RESUMO

BACKGROUND: Psoriatic arthritis (PA) is a chronic inflammatory systemic arthritis that can result in loss of functional capacity and joint deformation. This systematic review assessed the effectiveness and safety of biological and target synthetic drugs for treating PA. METHODS: We searched for randomized clinical trials (RCTs) that evaluated the use of Adalimumab, Etanercept, Infliximab, Golimumab, Secukinumab, Certolizumab Pegol and Tofacitinib in the main general databases and clinical trial registers databases. The primary outcomes were ACR 50, PsARC, and serious adverse events. Two independent reviewers performed study selection and data extraction. Network meta-analyses were conducted using a random effects model and frequentist approach. The CINeMA software was used to assess the certainty of evidence. RESULTS: We included 33 RCTs (n = 11,034). The results from the network meta-analysis for the ACR 50 at 6-months follow-up showed that all drugs were superior to placebo, with Secukinumab (high certainty of evidence), Infliximab (very low certainty of evidence) and Adalimumab (high certainty of evidence) ranking the highest. Regarding the PsARC (at 6-months follow-up), all drugs, except for Golimumab (very low certainty of evidence), were superior to placebo, with Etanercept (low certainty of evidence), Infliximab (low certainty of evidence) and Certolizumab Pegol (low certainty of evidence) being the most effective drugs. There were no significant differences in the risk of serious adverse events between the drugs and placebo. Golimumab (very low certainty of evidence), Secukinumab (low certainty of evidence), and Adalimumab (very low certainty of evidence) ranked the highest for safety. CONCLUSIONS: In conclusion, based on the balance between efficacy and safety, Secukinumab and Adalimumab may be the preferred options among the evaluated drugs for treating patients with PsA. However, caution is necessary when interpreting the safety findings, as they are supported by evidence of low to very low certainty. Consequently, the balance between benefits and potential risks may change as new safety evaluation studies become available. PROTOCOL REGISTRATION: PROSPERO: CRD42022315577.


Assuntos
Artrite Psoriásica , Humanos , Artrite Psoriásica/tratamento farmacológico , Infliximab/uso terapêutico , Etanercepte/uso terapêutico , Adalimumab/efeitos adversos , Metanálise em Rede , Certolizumab Pegol/efeitos adversos
3.
Arthritis Res Ther ; 26(1): 61, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38444034

RESUMO

BACKGROUND: Disease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient's response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression. Nevertheless, the influence of DMARDs on prostanoid biosynthesis in RA patients remains poorly understood. This study aims to assess the impact of various DMARDs on urinary prostanoids levels and to explore whether urinary prostanoid profiles correlate with disease activity or response to therapy. METHODS: This study included 152 Swedish female patients with early RA, all rheumatoid factor (RF) positive, enrolled in the NORD-STAR trial (registration number: NCT01491815). Participants were randomized into four therapeutic regimes: methotrexate (MTX) combined with (i) prednisolone (arm ACT), (ii) TNF-α blocker certolizumab pegol (arm CZP), (iii) CTLA-4Ig abatacept (arm ABA), or (iv) IL-6R blocker tocilizumab (arm TCZ). Urine samples, collected before start of treatment and at 24 weeks post-treatment, were analyzed for tetranor-prostaglandin E metabolite (tPGEM), tetranor-prostaglandin D metabolite (tPGDM), 2,3-dinor thromboxane B2 (TXBM), 2,3-dinor-6-keto prostaglandin F1a (PGIM), leukotriene E4 (LTE4) and 12-hydroxyeicosatetraenoic acid (12-HETE) using liquid chromatography-mass spectrometry (LC-MS). Generalized estimating equation (GEE) models were used to analyze the change in urinary eicosanoids and their correlations to clinical outcomes. RESULTS: Patients receiving MTX combined with CZP or TCZ exhibited significant elevations in urinary tPGEM and TXBM levels after 24 weeks of treatment. Other eicosanoids did not show significant alterations in response to any treatment. Baseline urinary eicosanoid levels did not correlate with baseline clinical disease activity index (CDAI) levels, nor with changes in CDAI from baseline to week 24. Their levels were also similar between patients who achieved CDAI remission and those with active disease at week 24. CONCLUSIONS: Treatment with anti-TNF or anti-IL6R agents in early RA patients leads to an increased systemic production of proinflammatory and prothrombotic prostanoids. However, urinary eicosanoid levels do not appear to be predictive of the response to DMARDs therapy.


Assuntos
Antirreumáticos , Artrite Reumatoide , Dimaprit/análogos & derivados , Humanos , Feminino , Prostaglandinas , Antirreumáticos/uso terapêutico , Inibidores do Fator de Necrose Tumoral , Artrite Reumatoide/tratamento farmacológico , Metotrexato , Certolizumab Pegol
4.
Immunotherapy ; 16(5): 273-285, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38319071

RESUMO

Psoriasis pathogenesis involves TNF-α, IL-23 and IL17, against which biologics have been highly effective. Among the five TNF-α inhibitors available for psoriasis, namely infliximab, adalimumab, etanercept, golimumab and certolizumab pegol (CZP), CZP has a unique mechanism of action due to its structure. As CZP lacks the Fc region, it does not cross the placenta and can be safely used in pregnant women. Its PEGylated nature allows for longer distribution time in tissues, potentially leading to a longer-lasting effect compared with other TNF-α inhibitors. In clinical trials, the efficacy of CZP on psoriasis skin symptoms and joint symptoms was comparable to other TNF-α inhibitors, with no discernible differences in safety profiles.


Psoriasis is a skin condition that affects the skin and causes joint problems. There are some medicines called TNF-α inhibitors that work well, especially for the joint issues. There are currently five TNF-α inhibitors available for treating psoriasis. One of these, certolizumab pegol, is different from the others. It lacks a specific part, which makes it less likely to pass through the placenta. This means it's safer for pregnant and breastfeeding women. Clinical trials have shown that certolizumab pegol is just as effective as other TNF-α inhibitors for treating the skin and joint symptoms of psoriasis. It's also equally safe.


Assuntos
Psoríase , Fator de Necrose Tumoral alfa , Humanos , Feminino , Gravidez , Certolizumab Pegol/uso terapêutico , Psoríase/tratamento farmacológico , Adalimumab/uso terapêutico , Infliximab/uso terapêutico , Resultado do Tratamento
5.
RMD Open ; 10(1)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38395455

RESUMO

OBJECTIVE: To assess whether the retention rate of certolizumab pegol (CZP) was longer than that of other tumour necrosis factor inhibitors (TNFi) based on baseline rheumatoid factor (RF) levels. METHODS: Longitudinal, retrospective and multicentre study including patients with RA who were treated with any TNFi (monoclonal antibodies (mAB), etanercept (ETA) or CZP). Log-rank test and Cox regressions were conducted to evaluate the retention rate in the three groups according to the level of RF, with the third quartile of the baseline levels used as cut-off: <200 (

Assuntos
Artrite Reumatoide , Inibidores do Fator de Necrose Tumoral , Humanos , Estudos Retrospectivos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator Reumatoide , Resultado do Tratamento , Artrite Reumatoide/tratamento farmacológico , Certolizumab Pegol/uso terapêutico , Etanercepte/uso terapêutico , Anticorpos Monoclonais/uso terapêutico
6.
Arthritis Res Ther ; 26(1): 44, 2024 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-38331930

RESUMO

OBJECTIVES: Machine learning models can support an individualized approach in the choice of bDMARDs. We developed prediction models for 5 different bDMARDs using machine learning methods based on patient data derived from the Austrian Biologics Registry (BioReg). METHODS: Data from 1397 patients and 19 variables with at least 100 treat-to-target (t2t) courses per drug were derived from the BioReg biologics registry. Different machine learning algorithms were trained to predict the risk of ineffectiveness for each bDMARD within the first 26 weeks. Cross-validation and hyperparameter optimization were applied to generate the best models. Model quality was assessed by area under the receiver operating characteristic (AUROC). Using explainable AI (XAI), risk-reducing and risk-increasing factors were extracted. RESULTS: The best models per drug achieved an AUROC score of the following: abatacept, 0.66 (95% CI, 0.54-0.78); adalimumab, 0.70 (95% CI, 0.68-0.74); certolizumab, 0.84 (95% CI, 0.79-0.89); etanercept, 0.68 (95% CI, 0.55-0.87); tocilizumab, 0.72 (95% CI, 0.69-0.77). The most risk-increasing variables were visual analytic scores (VAS) for abatacept and etanercept and co-therapy with glucocorticoids for adalimumab. Dosage was the most important variable for certolizumab and associated with a lower risk of non-response. Some variables, such as gender and rheumatoid factor (RF), showed opposite impacts depending on the bDMARD. CONCLUSION: Ineffectiveness of biological drugs could be predicted with promising accuracy. Interestingly, individual parameters were found to be associated with drug responses in different directions, indicating highly complex interactions. Machine learning can be of help in the decision-process by disentangling these relations.


Assuntos
Antirreumáticos , Artrite Reumatoide , Produtos Biológicos , Humanos , Antirreumáticos/uso terapêutico , Etanercepte/uso terapêutico , Adalimumab/uso terapêutico , Abatacepte/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Áustria , Produtos Biológicos/uso terapêutico , Certolizumab Pegol/uso terapêutico , Sistema de Registros , Inteligência Artificial
7.
Sci Rep ; 14(1): 1374, 2024 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-38228719

RESUMO

The objectives of our study were to assess retention rate, safety, and predictive factors for retention of subcutaneous (SC) TNF inhibitors (TNFi) (adalimumab (ADA), etanercept (ETN), golimumab (GOL), and certolizumab pegol (CZP)) in axial spondyloarthritis (axSpA) depending on the line of treatment in real-life conditions. A multicentre retrospective observational study was conducted including 552 patients fulfilling the ASAS criteria for axSpA followed in the RIC-France register who began SC-TNFi between 01/01/13 and 08/31/2018 for a total of 824 prescriptions. Taking all lines of treatment into account, GOL had a significantly higher retention rate compared with ADA, ETN, and CZP with a mean retention length of 59 months. As first-line bDMARDs, GOL had a significantly higher retention rate compared with ADA and ETN. ETN had the best retention rate when prescribed as at least 3rd bDMARD. Taking all lines of treatment into account, female sex, peripheral disease, BASDAI at initiation, and line of treatment were predictive factors for treatment cessation. Primary inefficiency was the most frequent reason for treatment cessation. In conclusion, GOL showed the highest retention rate in axSpA. Male sex, absence of peripheral disease, and early line of prescription were associated with better SC-TNFi retention in axSpA.


Assuntos
Antirreumáticos , Espondiloartrite Axial , Espondilartrite , Feminino , Humanos , Masculino , Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Certolizumab Pegol/uso terapêutico , Etanercepte/uso terapêutico , França , Espondilartrite/tratamento farmacológico , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/uso terapêutico , Estudos Retrospectivos
8.
J Pharmacokinet Pharmacodyn ; 51(1): 65-75, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37943398

RESUMO

Biological therapies may act as immunogenic triggers leading to the formation of anti-drug antibodies (ADAs). Population pharmacokinetic (PK) models can be used to characterize the relationship between ADA and drug disposition but often rely on the ADA bioassay results, which may not be sufficiently sensitive to inform on this characterization.In this work, a methodology that could help to further elucidate the underlying ADA production and impact on the drug disposition was explored. A mixed hidden-Markov model (MHMM) was developed to characterize the underlying (hidden) formation of ADA against the biologic, using certolizumab pegol (CZP), as a test drug. CZP is a PEGylated Fc free TNF-inhibitor used in the treatment of rheumatoid arthritis and other chronic inflammatory diseases.The bivariate MHMM used information from plasma drug concentrations and ADA measurements, from six clinical studies (n = 845), that were correlated through a bivariate Gaussian function to infer about two hidden states; production and no-production of ADA influencing PK. Estimation of inter-individual variability was not supported in this case. Parameters associated with the observed part of the model were reasonably well estimated while parameters associated with the hidden part were less precise. Individual state sequences obtained using a Viterbi algorithm suggested that the model was able to determine the start of ADA production for each individual, being a more assay-independent methodology than traditional population PK. The model serves as a basis for identification of covariates influencing the ADA formation, and thus has the potential to identify aspects that minimize its impact on PK and/or efficacy.


Assuntos
Antirreumáticos , Artrite Reumatoide , Humanos , Certolizumab Pegol/farmacocinética , Certolizumab Pegol/uso terapêutico , Anticorpos , Artrite Reumatoide/tratamento farmacológico , Algoritmos , Antirreumáticos/uso terapêutico
9.
Arthritis Rheumatol ; 76(3): 363-376, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37846618

RESUMO

OBJECTIVE: We investigated methotrexate safety and the influence of dose on efficacy outcomes in combination with three different biologic treatments and with active conventional treatment (ACT) in early rheumatoid arthritis (RA). METHODS: This post hoc analysis included 812 treatment-naïve patients with early RA who were randomized (1:1:1:1) in the NORD-STAR trial to receive methotrexate in combination with ACT, certolizumab-pegol, abatacept, or tocilizumab. Methotrexate safety, doses, and dose effects on Clinical Disease Activity Index (CDAI) remission were assessed after 24 weeks of treatment. RESULTS: Compared with ACT, the prevalence of methotrexate-associated side effects was higher when methotrexate was combined with tocilizumab (hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.20-1.84) but not with certolizumab-pegol (HR 0.99, 95% CI 0.79-1.23) or with abatacept (HR 0.93, 95% CI 0.75-1.16). With ACT as the reference, the methotrexate dose was significantly lower when used in combination with tocilizumab (ß -4.65, 95% CI -5.83 to -3.46; P < 0.001) or abatacept (ß -1.15, 95% CI -2.27 to -0.03; P = 0.04), and it was numerically lower in combination with certolizumab-pegol (ß -1.07, 95% CI -2.21 to 0.07; P = 0.07). Methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the treatment combinations. CONCLUSION: Methotrexate was generally well tolerated in combination therapies, but adverse events were a limiting factor in receiving the target dose of 25 mg/wk, and these were more frequent in combination with tocilizumab versus ACT. On the other hand, methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the four treatment combinations at 24 weeks.


Assuntos
Antirreumáticos , Artrite Reumatoide , Humanos , Metotrexato/uso terapêutico , Antirreumáticos/efeitos adversos , Abatacepte/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/induzido quimicamente , Certolizumab Pegol/uso terapêutico , Quimioterapia Combinada , Resultado do Tratamento
10.
Int J Rheum Dis ; 27(1): e14854, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37522716

RESUMO

Tumor necrosis factor alpha (TNFα) inhibitors are now widely used to treat immune-mediated inflammatory diseases. Although they have a good safety profile, they are also associated with adverse cutaneous events. Pigmented purpuric dermatoses (PPD) include a variety of skin diseases characterized by multiple petechial hemorrhages due to capillaritis. Five major clinical types of PPD have been described and purpura annularis telangiectodes of Majocchi (PATM) is a rare subtype of PPD. The cause of PPD is unknown, but drugs are implicated in a minority of cases. There are very few cases in the literature triggered by TNFα inhibitors. We present a case of PATM induced by certolizumab pegol and perform a review including 4 articles in the literature reporting 5 PPD cases induced by TNFα inhibitors. When purpuric eruptions develop in patients treated with TNFα inhibitors, PPD and vasculitis should be differentiated. Thus, patients are not exposed to unnecessary evaluations and treatments.


Assuntos
Transtornos da Pigmentação , Púrpura , Humanos , Certolizumab Pegol/efeitos adversos , Fator de Necrose Tumoral alfa , Pele/patologia , Púrpura/induzido quimicamente , Púrpura/diagnóstico , Púrpura/complicações
11.
Farm Hosp ; 48(2): T51-T56, 2024.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-38148255

RESUMO

OBJECTIVE: To provide evidence of the effectiveness of certolizumab pegol (CZP) in real clinical practice in adult patients with moderate-to-severe plaque psoriasis (PsO) in the context of a risk-sharing agreement (RSA). METHODS: Retrospective observational study based on variables collected in the RSA for treatment with CZP of adult patients with moderate-severe plaque PsO. Ten Spanish hospitals where the RSA was implemented participated. The percentage of patients who achieved the target clinical response of the RSA at the follow-up visit (week 16) was evaluated: absolute Psoriasis Area and Severity Index (PASI) value ≤3 for biologic naïve population, and ≤5 in case of previous failure to a single biologic drug. In addition, the improvement in the scores of other scales included in the study was analysed: Body Surface Area (BSA), Dermatology Life Quality Index (DLQI), Physician's Global Assessment (PGA), and Nail Psoriasis Severity Index (NAPSI). A descriptive analysis was performed for the total population and by patient subgroups (naive vs. non-naive to biologic, male vs. female, and with vs. without discontinuation). RESULTS: Sixty-six patients were included, 12 men and 54 women. 90.9% achieved the target clinical response, with a mean reduction of 8 (-78.4%) absolute PASI points. Improvement was observed in BSA, PGA, NAPSI, and DLQI, with a reduction of 11.3 (-80.6%), 1.9 (-65.5%), 3.3 (-30.7%), and 9.0 (-66.4%) absolute value points, respectively. Despite not achieving the therapeutic target set in the RSA in 6 patients (9%) (the cost of the drug was assumed by the laboratory), only 2 (3%) discontinued treatment. CONCLUSION: Our study shows that CZP is effective in real clinical practice in patients with moderate-severe plaque PsO, with an improvement in absolute PASI and DLQI, as well as other scales, both for the total population and in the subgroups analysed. Nearly 91% of patients reached the therapeutic target fixed in the RSA. Implementing this type of agreement can provide a direct or indirect benefit for all the agents involved in the process, providing valuable information for decision-making.


Assuntos
Produtos Biológicos , Psoríase , Adulto , Feminino , Humanos , Masculino , Certolizumab Pegol/uso terapêutico , Resultado do Tratamento , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , Produtos Biológicos/uso terapêutico , Índice de Gravidade de Doença
12.
Ther Umsch ; 80(9): 378-385, 2023 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-38095250

RESUMO

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory bowel disease that can affect the entire gastrointestinal tract. The pathophysiology of CD includes a disrupted interplay of intestinal bacteria, the intestinal immune system and the intestinal surface in genetically susceptible individuals, which remains incompletely understood. Conventional therapies include steroids, but numerous advanced therapies are also available. Three tumor necrosis factor (TNF) inhibitors (infliximab, adalimumab and certolizumab pegol (Switzerland)) have been approved for MC. Additional treatment options include the interleukin (IL)-12/23 inhibitors ustekinumab and the integrin inhibitors vedolizumab. With risankizumab, a first selective IL-23 inhibitor for CD has been approved by the EMA in 2022. Moreover, the Janus kinase-1 inhibitor upadacitinib has been available for the treatment of CD in the EU since 2023. For localized CD, elective surgical resection also remains a valid option with good long-term outcomes. Perianal and fistulizing CD are difficult to treat and require a close interdisciplinary collaboration between gastroenterologists and colorectal surgeons. Surgical fistula treatment with curative intent should only be performed in well-controlled CD. The recent increase in therapeutic options in CD is encouraging, since more safe and effective therapies are now available to patients. Nevertheless, CD remains an incurable disease and so far, for all existing treatments only a fraction of patients responds to the therapy. Therefore, the development of new therapies should continue.


Assuntos
Doença de Crohn , Humanos , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Fator de Necrose Tumoral alfa/uso terapêutico , Infliximab/efeitos adversos , Certolizumab Pegol/efeitos adversos , Adalimumab/efeitos adversos , Resultado do Tratamento
13.
J Dermatolog Treat ; 34(1): 2276044, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37905433

RESUMO

THE PURPOSE OF THE ARTICLE: Pyoderma gangrenosum (PG) is an ulcerating neutrophilic dermatosis with an incidence of 3-10 patients per million. PG equally affects patients of both sexes and of any age. Of these patients, 50-75% are associated with auto-immune disease. The lower extremities are the most commonly affected body parts. Minor trauma to the skin may result in the development of new lesions. Patients complain of chronic, nonhealing ulcers with associated pain. Treatment starts with systemic or intralesional corticosteroids, however, no official treatment protocol currently exists. Recent success has been found with biologic agents such as TNF-a inhibitor, although the treatment efficacy in these reports is limited. As for the pregnant patient, the drug selection is difficult. In this report, we want to assess the efficiency of certolizumab in the pregnant patient. RESULTS: We report a case of a patient with PG, who responded well to certolizumab, 400 mg as a booster dose, followed by 200 mg biweekly for 8 weeks. The lesions gradually resolved and followed up for 5months without side effect. In addition, we reviewed the literature and compared the current treatment efficiency in the treatment of PG. CONCLUSION: Certolizumab may be a promising therapeutic option for patients with severe PG.


Assuntos
Pioderma Gangrenoso , Masculino , Gravidez , Feminino , Humanos , Pioderma Gangrenoso/tratamento farmacológico , Pioderma Gangrenoso/patologia , Certolizumab Pegol/uso terapêutico , Pele/patologia , Corticosteroides/uso terapêutico , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/uso terapêutico
14.
Front Immunol ; 14: 1212981, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37809085

RESUMO

Background: Psoriasis is a chronic immune-mediated inflammatory systemic disease with skin manifestations characterized by erythematous, scaly, itchy and/or painful plaques resulting from hyperproliferation of keratinocytes. Certolizumab pegol [CZP], a PEGylated antigen binding fragment of a humanized monoclonal antibody against TNF-alpha, is approved for the treatment of moderate-to-severe plaque psoriasis. Patients with psoriasis present clinical and molecular variability, affecting response to treatment. Herein, we utilized an in silico approach to model the effects of CZP in a virtual population (vPop) with moderate-to-severe psoriasis. Our proof-of-concept study aims to assess the performance of our model in generating a vPop and defining CZP response variability based on patient profiles. Methods: We built a quantitative systems pharmacology (QSP) model of a clinical trial-like vPop with moderate-to-severe psoriasis treated with two dosing schemes of CZP (200 mg and 400 mg, both every two weeks for 16 weeks, starting with a loading dose of CZP 400 mg at weeks 0, 2, and 4). We applied different modelling approaches: (i) an algorithm to generate vPop according to reference population values and comorbidity frequencies in real-world populations; (ii) physiologically based pharmacokinetic (PBPK) models of CZP dosing schemes in each virtual patient; and (iii) systems biology-based models of the mechanism of action (MoA) of the drug. Results: The combination of our different modelling approaches yielded a vPop distribution and a PBPK model that aligned with existing literature. Our systems biology and QSP models reproduced known biological and clinical activity, presenting outcomes correlating with clinical efficacy measures. We identified distinct clusters of virtual patients based on their psoriasis-related protein predicted activity when treated with CZP, which could help unravel differences in drug efficacy in diverse subpopulations. Moreover, our models revealed clusters of MoA solutions irrespective of the dosing regimen employed. Conclusion: Our study provided patient specific QSP models that reproduced clinical and molecular efficacy features, supporting the use of computational methods as modelling strategy to explore drug response variability. This might shed light on the differences in drug efficacy in diverse subpopulations, especially useful in complex diseases such as psoriasis, through the generation of mechanistically based hypotheses.


Assuntos
Farmacologia em Rede , Psoríase , Humanos , Certolizumab Pegol/uso terapêutico , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Doença Crônica
15.
BMJ Case Rep ; 16(9)2023 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-37748817

RESUMO

We report a case of a woman in her 30s with a history of cholecystectomy, hypertension, type 2 diabetes and rheumatoid arthritis on methotrexate and certolizumab who presented with epigastric pain radiating to the right upper quadrant. Laboratory findings revealed significantly elevated liver enzymes consistent with hepatocellular liver injury. The hepatocellular pattern of liver injury, negative autoimmune serologies and improvement on cessation of certolizumab were consistent with drug-induced hepatotoxicity. We used Roussel Uclaf Causality Assessment Method to assess the likelihood of drug-induced liver injury that showed a score of 7, this was in line with a probable causality grading. Although the patient had a history of methotrexate use, the onset of symptoms and transaminitis coincided with the recent initiation of certolizumab, which was the trigger of hepatocellular injury. Liver enzymes also remained normal after the reinitiation of methotrexate on follow-up.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas , Diabetes Mellitus Tipo 2 , Feminino , Humanos , Metotrexato/efeitos adversos , Certolizumab Pegol/efeitos adversos , Dor Abdominal , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia
16.
Adv Ther ; 40(10): 4504-4522, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37566157

RESUMO

INTRODUCTION: Biologic disease-modifying anti-rheumatics drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) are important treatments for rheumatoid arthritis (RA). As more of these drugs become available, there is a greater need to assess their real-world adherence and drug survival. METHODS: Treatment-naïve and treatment-experienced patients with RA who initiated treatment with bDMARDs and tofactinib during 2015-2018 in a large Israeli health maintenance organization were included. Adherence and time to treatment suspension were recorded. Odds for adherence were estimated using a multivariable logistic regression model. Risk for treatment suspension was estimated using a mixed-effect Cox proportional hazard model. RESULTS: The analysis included 753 eligible patients (61.8% treatment-naïve) treated with 1287 treatment episodes (tofacitinib 24.2%, tocilizumab 17.5%, etanercept 16.0%, adalimumab 10.4%, abatacept 9.9%, rituximab 9.0%, golimumab 6.9%, certolizumab pegol 3.6%, infliximab 1.9%, and sarilumab 0.5%). Good adherence was measured for almost all drugs, yet over 50% of all treatment episodes were suspended. Older age was associated with reduced risk for treatment suspension while higher number of primary care visits and higher Charlson's comorbidity score were associated with increased risk. Compared to etanercept, treatment with adalimumab, certolizumab, or rituximab was associated with increased risk for treatment suspension (HR 1.68 95% CI 1.27-2.22, HR 1.62 95% CI 1.00-2.60, and HR 2.72 95% CI 2.02-3.67, respectively). CONCLUSION: Treatment choice primarily depends on disease activity and prognosis. Real-world data, showing differences in drug survival of bDMARDs and tsDMARD, can also be used in the variety of considerations when choosing treatment. Future studies could separate patients with RA into subgroups, which would also account for potential drug survival differences and enable personalized therapy.


Assuntos
Antirreumáticos , Artrite Reumatoide , Produtos Biológicos , Humanos , Adulto , Etanercepte/uso terapêutico , Adalimumab/uso terapêutico , Rituximab/uso terapêutico , Metotrexato/uso terapêutico , Produtos Biológicos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Antirreumáticos/uso terapêutico , Certolizumab Pegol/uso terapêutico
17.
Ann Rheum Dis ; 82(10): 1286-1295, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37423647

RESUMO

BACKGROUND: The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action. METHODS: Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naïve early RA with moderate-severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI ≤2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni's and Dunnet's procedures adjusted for multiple testing (significance level: 0.025). RESULTS: Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences.The proportions of patients with serious adverse events were abatacept, 8.3%; certolizumab, 12.4%; tocilizumab, 9.2%; and active conventional therapy, 10.7%. CONCLUSIONS: Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments. TRIAL REGISTRATION NUMBER: NCT01491815.


Assuntos
Antirreumáticos , Artrite Reumatoide , Humanos , Certolizumab Pegol/uso terapêutico , Abatacepte/uso terapêutico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/induzido quimicamente , Metotrexato/uso terapêutico , Quimioterapia Combinada , Resultado do Tratamento
18.
Clin Ther ; 45(8): 770-777, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37442653

RESUMO

PURPOSE: Nonresponse to an anti-tumor necrosis factor (TNF) agent in patients with Crohn disease (CD) is often managed by either a switch to a different class of biologic (ie, ustekinumab, vedolizumab) or by cycling to another anti-TNF agent (ie, adalimumab, infliximab, certolizumab pegol). Persistence after a switch to a different biologic class or after cycling within the anti-TNF class was assessed in patients with nonresponse to an anti-TNF agent. METHODS: Adults with CD who discontinued from an anti-TNF agent and either switched to a different class of biologic (ie, anti-interleukin/integrin; the switching cohort) or cycled within the anti-TNF class (the cycling cohort) between September 23, 2016, and August 1, 2019, were selected from a commercial database. The index date was defined as the date of the first claim of the subsequent-line biologic (index biologic) after an anti-TNF. The switching and cycling cohorts were balanced with regard to baseline characteristics, using inverse probability of treatment weights-average treatment effect (IPTW-ATE). Persistence with the index biologic was defined as consistent use with no gaps of >120 days (ustekinumab, vedolizumab, infliximab) or of >60 days (adalimumab, certolizumab pegol) in biologic supply. Composite end points were persistence while being corticosteroid-free (defined as no use of corticosteroids with ≥14 days of supply after day 90 post-index) and persistence while on monotherapy (no immunomodulators/nonindex biologics). Weighted Kaplan-Meier and Cox models were used to assess outcomes at 12 months post-index. FINDINGS: There were 444 patients in the weighted switching cohort (mean age, 40.4 years; 56.3% female) and 441 in the weighted cycling cohort (mean age, 39.5 years; 58.4% female). At 12 months post-index, the rate of persistence with the index biologic was 75.7% in the switching cohort compared to 67.5% in the cycling cohort (log-rank P = 0.023); the rate of persistence while on monotherapy was 58.2% compared to 44.2%, respectively (log-rank P < 0.001). The rate of persistence was 44% greater in the switching compared to that in the cycling cohort (hazard ratio [HR] = 1.44; 95% CI, 1.11-1.88; P = 0.007); the rate of persistence while on monotherapy was 56% greater in the switching cohort (HR = 1.56; 95% CI, 1.28-1.90; P < 0.001). The between-cohort difference in persistence while being corticosteroid-free was not statistically significant (HR = 1.08; 95% CI, 0.89-1.32; P = 0.426). IMPLICATIONS: Patients with CD who switched to a different biologic class were more persistent than were patients who cycled to another anti-TNF agent. These findings may be useful for physicians when considering the treatment of patients who have experienced nonresponse or loss of response to the first-line anti-TNF agent.


Assuntos
Doença de Crohn , Adulto , Humanos , Feminino , Masculino , Doença de Crohn/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Infliximab/uso terapêutico , Adalimumab/uso terapêutico , Fatores Biológicos , Certolizumab Pegol/uso terapêutico , Ustekinumab , Estudos Retrospectivos , Fator de Necrose Tumoral alfa , Necrose/induzido quimicamente
19.
Int J Rheum Dis ; 26(7): 1248-1259, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37195063

RESUMO

AIM: Certolizumab pegol (CZP), an Fc-free, PEGylated tumor necrosis factor inhibitor (TNFi), has shown rapid and sustained reduction in signs and symptoms of rheumatoid arthritis (RA). Elevated rheumatoid factor (RF) level has been associated with RA disease progression and poorer TNFi response. We assessed the efficacy of CZP in patients with early and established RA across baseline RF levels. METHODS: This post-hoc analysis included data from 6 trials: C-OPERA (NCT01451203), pooled RAPID trials (RAPID-1 [NCT00152386], RAPID-2 [NCT00160602], J-RAPID [NCT00791999], RAPID-C [NCT02151851]), and EXXELERATE (NCT01500278). Patients who received CZP or placebo/comparator with methotrexate (MTX) were categorized by baseline RF quartiles. Efficacy was assessed with Disease Activity Score-28 erythrocyte sedimentation rate (DAS28-ESR). RESULTS: Overall, 316, 1537, and 908 patients were included in C-OPERA, pooled RAPID trials, and EXXELERATE, respectively. Patient demographics and baseline disease characteristics were similar between treatment groups and across RF quartiles. DAS28-ESR low disease activity (LDA) and remission (REM) rates were numerically higher in the CZP + MTX group than PBO + MTX group at weeks 12 and 24, across RF quartiles. LDA and REM rates in the CZP + MTX groups were comparable across RF quartiles at weeks 12 and 24. Mean DAS28-ESR decreased from week 0 to week 24 in the CZP + MTX groups, across RF quartiles. CONCLUSION: CZP showed steady efficacy across baseline RF quartiles in patients with early and established RA, over 24 weeks. CZP treatment may be considered in patients with RA irrespective of baseline RF levels and time from diagnosis.


Assuntos
Antirreumáticos , Artrite Reumatoide , Humanos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Certolizumab Pegol/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Metotrexato/efeitos adversos , Fator Reumatoide , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/uso terapêutico
20.
Int J Mol Sci ; 24(9)2023 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-37175894

RESUMO

Anti-tumour necrosis factor (TNF)-α agents have been increasingly used to treat patients affected by inflammatory bowel disease and dermatological and rheumatologic inflammatory disorders. However, the widening use of biologics is related to a new class of adverse events called paradoxical reactions. Its pathogenesis remains unclear, but it is suggested that cytokine remodulation in predisposed individuals can lead to the inflammatory process. Here, we dissect the clinical aspects and overall outcomes of autoimmune diseases caused by anti-TNF-α therapies.


Assuntos
Doenças Autoimunes , Doenças Inflamatórias Intestinais , Humanos , Adalimumab/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Certolizumab Pegol/uso terapêutico , Etanercepte/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fator de Necrose Tumoral alfa/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/induzido quimicamente , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/induzido quimicamente , Necrose/tratamento farmacológico , Infliximab/uso terapêutico
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