Assuntos
Antirreumáticos , Artrite Reumatoide , Azetidinas , Purinas , Pirazóis , Sulfonamidas , Humanos , Artrite Reumatoide/tratamento farmacológico , Feminino , Purinas/efeitos adversos , Purinas/uso terapêutico , Purinas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Azetidinas/uso terapêutico , Azetidinas/efeitos adversos , Azetidinas/administração & dosagem , Pessoa de Meia-Idade , Adulto , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Masculino , Estudos de Coortes , Adulto Jovem , Adolescente , Antirreumáticos/uso terapêutico , Antirreumáticos/efeitos adversos , Gravidez , Países Escandinavos e Nórdicos/epidemiologia , Sistema de Registros , Tuberculose/epidemiologia , Tuberculose/prevenção & controle , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/epidemiologia , IdosoRESUMO
BACKGROUND: Glioblastoma cells preferentially use de-novo purine synthesis pathway, whereas normal brain prefers salvage pathway. Mycophenolate mofetil (MMF), a commonly used oral immunosuppressant that inhibits inosine-5'-monophosphate dehydrogenase (IMPDH), a key enzyme in the de-novo purine pathway. Pre-clinical suggested MMF can improve radiation and temozolomide efficacy in glioblastoma which led to this phase 0/1 trial (NCT04477200) to assess MMF's tolerability with chemoradiation in glioblastoma, mycophenolic acid accumulation, and purine synthesis inhibition in tumor. METHODS: In the phase 0 study, eight recurrent glioblastoma patients received MMF at doses ranging 500-2,000 mg BID for 1-week before surgery. The tissues were analyzed using mass spectrometry for drug accumulation and purine synthesis inhibition. In the phase 1 study, adult patients were given MMF starting at 1,000 mg orally (PO) twice daily (BID), with the possible dose ranging 500-2,000 PO BID. Nineteen recurrent glioblastoma patients (target N=30) received MMF 1-week prior to and concurrently with re-irradiation (40.5 Gy). Thirty newly diagnosed glioblastoma patients received MMF 1-week prior to and concurrently with chemoradiation, followed by MMF 1-day before and during 5 days of each adjuvant temozolomide cycle. RESULTS: Both enhancing and non-enhancing tumors from phase 0 subjects yielded >1 µM active drug metabolite, and the guanosine triphosphate: inosine monophosphate ratio was decreased by 75% in enhancing tumors in MMF-treated patients compared to untreated controls (P=0.009), indicating effective target engagement and inhibition of purine synthesis. In the phase 1 study, no dose-limiting toxicities (DLTs) were observed at the interim analysis at MMF 1,000-1,500 mg BID combined with chemoradiation. At 2,000 mg BID, there was no DLT combined with temozolomide alone, however, there were four DLTs noted (hemiparesis, cognitive disturbance, fatigue, thrombocytopenia) when combined with radiotherapy and temozolomide together, though all were reversible. Interim median overall survival in recurrent phase 1 is 15.6 months, and not reached yet in newly diagnosed phase 1. CONCLUSIONS: MMF with chemoradiation has been reasonably well tolerated and showed promising evidence of brain tumor target engagement and drug accumulation. This study led to a recommended phase 2 dose of MMF 1,500 mg BID and will provide a preliminary efficacy estimate for a randomized phase 2/3 trial through the Alliance for Clinical Trials in Oncology.
Assuntos
Quimiorradioterapia , Glioblastoma , Purinas , Humanos , Glioblastoma/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Quimiorradioterapia/métodos , Purinas/farmacologia , Purinas/uso terapêutico , Idoso , Recidiva Local de Neoplasia , Neoplasias Encefálicas/tratamento farmacológicoRESUMO
Janus Kinase (JAK) inhibitors have emerged as a novel category of medications to treat a variety of immune-mediated conditions. However, limited insight exists regarding the impact of safety concerns on their usage and prescribing practices. Therefore, the objective of this study was to describe the utilization of JAK-inhibitors in Canada, both nationally and within individual provinces. We used data from IQVIA's Compuscript database. We conducted a repeated cross-sectional study of all JAK-inhibitor units dispensed in retail pharmacies (tofacitinib, ruxolitinib, baricitinib, and upadacitinib) within the ten Canadian provinces from July 1, 2016, to June 30, 2022. Throughout Canada, outpatient pharmacies dispensed an estimated total of 26,126,409 JAK-inhibitor units between 2016 and 2022, averaging 9,431 units dispensed per 100,000 population. All provinces had increasing rates of JAK-inhibitor units dispensed over time, whereby between July 2021 to June 2022, New Brunswick exhibited the highest rates (27,696 units per 100,000), and Prince Edward Island demonstrated the lowest rates (10,065 units per 100,000). In this study, utilization of JAK-inhibitors increased in Canada over the study period, evident at both provincial and national levels. Variability in JAK-inhibitor utilization between provinces underscores the necessity for further investigations to ascertain appropriate usage practices. Key Points ⢠From 2016 to 2022, an estimated total of 26,126,409 JAK-inhibitor units were dispensed in retail pharmacies across Canada, with an average rate of 9,431 units dispensed for every 100,000 people in the population. ⢠Tofacitinib was the most dispensed JAK-inhibitor during the entire study period, making up 76% of all units dispensed. Ruxolitinib, upadacitinib, and baricitinib made up 16%, 7.9%, and 1.1% of the JAK-inhibitor units dispensed, respectively. ⢠The variance in provincial adoption of JAK-inhibitors across Canada might be influenced by several factors, including drug coverage availability, disease prevalence, and physician prescribing patterns.
Assuntos
Azetidinas , Inibidores de Janus Quinases , Piperidinas , Padrões de Prática Médica , Purinas , Pirazóis , Pirimidinas , Pirróis , Sulfonamidas , Humanos , Estudos Transversais , Canadá , Padrões de Prática Médica/estatística & dados numéricos , Inibidores de Janus Quinases/uso terapêutico , Sulfonamidas/uso terapêutico , Pirazóis/uso terapêutico , Azetidinas/uso terapêutico , Pirimidinas/uso terapêutico , Piperidinas/uso terapêutico , Purinas/uso terapêutico , Pirróis/uso terapêutico , Nitrilas/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Benzamidas/uso terapêuticoRESUMO
PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have demonstrated significant clinical benefits in progression-free and overall survival. This study investigates the outcomes associated with two kinds of CDK4/6i in patients with hormone receptor (HR)-positive metastatic and relapsed breast cancer to inform real-world evidence of treatment strategies. METHODS: This retrospective study included 340 Taiwanese patients with HR-positive advanced breast cancer from the Taipei Veterans General Hospital, between 2018 and 2023. We analyzed patient characteristics, treatment strategies and outcomes associated with two CDK4/6i. The efficacy of patients who experienced economic burden and interrupted CDK4/6i treatment after 2 years of National Health Insurance (NHI) reimbursement was also investigated. RESULTS: Patients receiving ribociclib and palbociclib showed no significant differences in age, histology, body mass index(BMI), or pathologic status. The distribution of disease status and endocrine therapy partners was comparable between the two groups. Dose reduction was similar, while patients with palbociclib tended to discontinue CDK4/6i usage, and those with ribociclib tended to switch to the other CDK4/6i or endocrine partners. There was no significant difference in progression-free survival (PFS) between the two CDK4/6i in the first-line setting. Adverse prognostic factors were increasing HER2 IHC score, higher Ki-67 levels, visceral and liver metastasis, prior chemotherapy, and endocrine therapy resistance, while higher BMI, bone-only metastasis, and letrozole treatment were associated with a lower risk of progression. The limited follow-up time in our study was insufficient to assess the outcomes of patients treated with interrupted CDK4/6i for up to two years under the NHI reimbursement policy. CONCLUSION: Treatment outcomes between the two types of CDK4/6i did not differ significantly, indicating the safety and efficacy of CDK4/6i for the Asian population. Ribociclib and palbociclib showed similar efficacy in PFS in the real-world setting.
Assuntos
Aminopiridinas , Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Piperazinas , Inibidores de Proteínas Quinases , Purinas , Piridinas , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Pessoa de Meia-Idade , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Piridinas/uso terapêutico , Estudos Retrospectivos , Idoso , Piperazinas/uso terapêutico , Aminopiridinas/uso terapêutico , Purinas/uso terapêutico , Taiwan , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Resultado do Tratamento , Metástase Neoplásica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Povo AsiáticoRESUMO
Cardiac fibrosis is characterized by the over-proliferation, over-transdifferentiation and over-deposition of extracellular matrix (ECM) of cardiac fibroblasts (CFs). Cardiac sympathetic activation is one of the leading causes of myocardial fibrosis. Meanwhile, cardiac fibrosis is often together with cardiac inflammation, which accelerates fibrosis by mediating inflammatory cytokines secretion. Recently, the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling pathway has been confirmed by its vital role during the progression of cardiac fibrosis. Thus, JAK/STAT3 signaling pathway is thought to be a potential therapeutic target for cardiac fibrosis. Baricitinib (BR), a novel JAK1/2 inhibitor, has been reported excellent effects of anti-fibrosis in multiple fibrotic diseases. However, little is known about whether and how BR ameliorates cardiac fibrosis caused by chronic sympathetic activation. Isoproterenol (ISO), a ß-Adrenergic receptor (ß-AR) nonselective agonist, was used to modulate chronic sympathetic activation in mice. As expected, our results proved that BR ameliorated ISO-induced cardiac dysfunction. Meanwhile, BR attenuated ISO-induced cardiac fibrosis and cardiac inflammation in mice. Moreover, BR also inhibited ISO-induced cardiac fibroblasts activation and macrophages pro-inflammatory secretion. As for mechanism studies, BR reduced ISO-induced cardiac fibroblasts by JAK2/STAT3 and PI3K/Akt signaling, while reduced ISO-induced macrophages pro-inflammatory secretion by JAK1/STAT3 and NF-κB signaling. In summary, BR alleviates cardiac fibrosis and inflammation caused by chronic sympathetic activation. The underlying mechanism involves BR-mediated suppression of JAK1/2/STAT3, PI3K/Akt and NF-κB signaling.
Assuntos
Azetidinas , Fibroblastos , Fibrose , Camundongos Endogâmicos C57BL , Purinas , Pirazóis , Sulfonamidas , Animais , Fibrose/tratamento farmacológico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Masculino , Fibroblastos/efeitos dos fármacos , Purinas/farmacologia , Purinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Camundongos , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Miocárdio/patologia , Isoproterenol , Células Cultivadas , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , NF-kappa B/metabolismo , Inflamação/tratamento farmacológico , Citocinas/metabolismo , Humanos , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: To analyze the efficacy and safety of Janus kinase inhibitors (JAKi) in the treatment of pediatric AD. RECENT FINDINGS: Adolescents with moderate and severe atopic dermatitis (AD) need systemic therapies, as stated several recent practice guidelines. (JAKi) have shown their efficacy in the treatment of adult AD, however, there is a lack of information concerning efficacy and safety of their use in pediatric AD. We found that the JAKi's abrocitinib (ABRO), baricitinib (BARI), and upadacitinib (UPA), are all an effective treatment option with a very fast onset of action for adolescents with moderate-to-severe AD. BARI was not effective in children between 2 and 10 years with moderate-to-severe AD. Fortunately, major safety issues with JAKi in adolescents with AD have not been documented in the trials, so far, contrasting with the reports in adults with AD, where these events have very rarely occurred. There are some reports of herpes zoster (HZ) infection in adolescents on JAKi, but it is not a major safety concern. Acne is a relatively common AE with UPA in adolescents; however, it is responsive to standard treatment. This review will help the clinician to choose among the JAKi according to the needs and clinical features of patients with moderate and severe AD. In the following years, with the advent of new biologicals and JAKi, these therapies will fall into place in each phase of the evolution of patients with AD.
Assuntos
Dermatite Atópica , Inibidores de Janus Quinases , Humanos , Dermatite Atópica/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/administração & dosagem , Criança , Adolescente , Purinas/uso terapêutico , Administração Oral , Azetidinas/uso terapêutico , Azetidinas/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Resultado do TratamentoRESUMO
Lichen planus is a chronic auto-inflammatory disease that primarily affects mucocutaneous regions. There are many variants of lichen planus including cutaneous, oral, nail, follicular, and erosive forms. Without any disease-specific treatment options, multi-variant lichen planus can be a challenging disease to manage. We present a 61-year-old woman with multivariant lichen planus that was refractory to numerous systemic and topical therapies. Subsequently, her cutaneous and vulvovaginal lesions improved with the use of oral baricitinib and the erosive oral lesions improved with topical ruxolitinib.
Assuntos
Azetidinas , Líquen Plano , Nitrilas , Purinas , Pirazóis , Pirimidinas , Sulfonamidas , Humanos , Feminino , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Nitrilas/uso terapêutico , Pessoa de Meia-Idade , Purinas/uso terapêutico , Purinas/administração & dosagem , Azetidinas/uso terapêutico , Azetidinas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Líquen Plano/tratamento farmacológico , Líquen Plano/patologia , Administração OralAssuntos
Anticorpos Monoclonais Humanizados , Azetidinas , Tratamento Farmacológico da COVID-19 , Pirazóis , Respiração Artificial , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Feminino , Estudos de Coortes , Pirazóis/uso terapêutico , Pessoa de Meia-Idade , Idoso , Azetidinas/uso terapêutico , Azetidinas/administração & dosagem , Purinas/uso terapêutico , Sulfonamidas/uso terapêutico , COVID-19RESUMO
PURPOSE: Heterozygous STAT1 Gain-of-Function (GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC) among Inborn Errors of Immunity. Clinically, these mutations manifest as a broad spectrum of immune dysregulation, including autoimmune diseases, vascular disorders, and malignancies. The pathogenic mechanisms of immune dysregulation and its impact on immune cells are not yet fully understood. In treatment, JAK inhibitors have shown therapeutic effectiveness in some patients. METHODS: We analyzed clinical presentations, cellular phenotypes, and functional impacts in five Taiwanese patients with STAT1 GOF. RESULTS: We identified two novel GOF mutations in 5 patients from 2 Taiwanese families, presenting with symptoms of CMC, late-onset rosacea, and autoimmunity. The enhanced phosphorylation and delayed dephosphorylation were displayed by the patients' cells. There are alterations in both innate and adaptive immune cells, including expansion of CD38+HLADR +CD8+ T cells, a skewed activated Tfh cells toward Th1, reduction of memory, marginal zone and anergic B cells, all main functional dendritic cell lineages, and a reduction in classical monocyte. Baricitinib showed therapeutic effectiveness without side effects. CONCLUSION: Our study provides the first comprehensive clinical and molecular characteristics in STAT1 GOF patient in Taiwan and highlights the dysregulated T and B cells subsets which may hinge the autoimmunity in STAT1 GOF patients. It also demonstrated the therapeutic safety and efficacy of baricitinib in pediatric patient. Further research is needed to delineate how the aberrant STAT1 signaling lead to the changes in cellular populations as well as to better link to the clinical manifestations of the disease.
Assuntos
Candidíase Mucocutânea Crônica , Mutação com Ganho de Função , Imunofenotipagem , Pirazóis , Fator de Transcrição STAT1 , Humanos , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/terapia , Masculino , Feminino , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Azetidinas/uso terapêutico , Purinas/uso terapêutico , Criança , Adolescente , Taiwan , AdultoRESUMO
Covid-19 disease is implicated in increased mortality among immunocompromised patients. The JAK inhibitor, baricitinib (bar), or the IL-6 inhibitor, tocilizumab (toc), demonstrated a survival benefit in patients with severe disease.However, evidence supporting their use in immunocompromised patients with severe Covid-19 is scarce.We aimed to assess clinical outcomes of bar/toc treatment in immunocompromised patients. A multi-center registry of consecutive immunocompromised patients hospitalized due to severe Covid-19 during the Omicron variant dominance period. After excluding patients who did not require high oxygen supply, patients treated with bar/toc were compared to patients treated by standard of care (SOC). Primary outcome was in hospital mortality. Secondary outcomes were 30 and 60 day mortality, super-infection and thromboembolic events. Among an overall 228 immunocompromised patients hospitalized in six Israeli hospitals with severe Covid-19, 112 patients required high oxygen support, of whom 48 (43%) were treated with bar/toc. In-hospital mortality rates were exceptionally high and did not significantly differ between bar/toc and SOC treated patients (62.5% vs. 64.1%, p = 1.0). A logistic regression analysis revealed that advanced age and incomplete vaccination were predictors of in-hospital mortality. Patients treated with bar/toc had no excess of suspected super-infection (62.8% vs. 60.7%, p = 0.84) or thromboembolic events (8.3% vs 3.1%, p = 0.39). In immunocompromised patients with severe Covid-19 and a high oxygen demand, bar/toc therapy was not associated with reduced mortality or with a higher rate of associated complications, compared to SOC. Larger prospective studies should better address efficacy and safety.
Assuntos
Anticorpos Monoclonais Humanizados , Azetidinas , Tratamento Farmacológico da COVID-19 , COVID-19 , Mortalidade Hospitalar , Hospedeiro Imunocomprometido , Purinas , Pirazóis , SARS-CoV-2 , Sulfonamidas , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , COVID-19/imunologia , COVID-19/mortalidade , COVID-19/terapia , Sulfonamidas/uso terapêutico , Azetidinas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Pirazóis/uso terapêutico , SARS-CoV-2/imunologia , Purinas/uso terapêutico , Resultado do Tratamento , Imunomodulação/efeitos dos fármacos , Idoso de 80 Anos ou maisAssuntos
Azetidinas , Purinas , Pirazóis , Sulfonamidas , Vitiligo , Humanos , Azetidinas/uso terapêutico , Azetidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Vitiligo/terapia , Vitiligo/tratamento farmacológico , Purinas/administração & dosagem , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Masculino , Feminino , Adulto , Administração Oral , Pessoa de Meia-Idade , Terapia Combinada , FototerapiaRESUMO
INTRODUCTION: Epidermolysis Bullosa Pruriginosa (EBP) is a persistent, recurring disease that seriously affects quality of life. Fewer than 100 cases of EBP have been reported to date. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling, and inhibition of this pathway using Janus kinase (JAK) inhibitors might be a useful therapeutic strategy for these diseases. PATIENT CONCERNS: A male patient, 28 years of age, was admitted to our hospital because of recurrent papules, nodules, and intense itching on the trunk and extremities for 12 years. Repeated large and intense itching has seriously affected the patient normal life. DIAGNOSIS: The patient was diagnosed with EBP based on examination results. INTERVENTIONS: Oral baricitinib tablets (2 mg, once a day)â +â Oral desloratadine citrate disodium tablets (8.8 mg, once a day) combined with topical compound flumethasone ointment and Fucidin cream. OUTCOMES: The patient skin rashes had subsided and flattened remarkable, and his itching was markedly relieved. The visual analogue scale (VAS) itching score of the patient gradually declined from 8 to 9 points to 2 to 3 points. CONCLUSION: This study confirms that baricitinib is effective and feasible in treating EBP, especially in remarkable relieving itching, which rendered new ideas for therapeutic approaches for EBP in the future.
Assuntos
Azetidinas , Purinas , Pirazóis , Sulfonamidas , Humanos , Purinas/uso terapêutico , Masculino , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Azetidinas/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Administração OralRESUMO
BACKGROUND: Janus kinase (JAK) inhibitors (JAKis) are effective therapeutic agents against rheumatoid arthritis (RA). However, patients having RA with particular risk factors may have a higher incidence of adverse effects (AEs), including major cardiovascular events (MACE) and infections. In this multicenter cohort study, we aimed to clarify the risk factors affecting the drug retention of JAKis in patients with RA. METHODS: We retrospectively evaluated patients with RA who received their first JAKi (tofacitinib, baricitinib, upadacitinib, or filgotinib) at our institute. The clinical outcomes, including AEs, were recorded, particularly MACE and serious infections. The drug retention rates were analyzed using the Kaplan-Meier method, and risk factors affecting drug retention rates were determined using a multivariable Cox regression hazards model. RESULTS: Overall 184 patients with RA receiving their first use of baricitinib (57.6%), tofacitinib (23.9%), upadacitinib (12.0%), or filgotinib (6.5%) were included in this study. Fifty-six (30.4%) patients discontinued JAKi treatment owing to ineffectiveness (9.2%) or AEs, including infections (21.2%). The overall drug retention rates were significantly lower in patients treated with pan-JAKi than in those treated with JAK1 inhibitors (p = 0.03). In the Cox regression model, the presence of baseline high RA disease activity, use of glucocorticoid and treatments with pan-JAKis were associated with reduced drug retention rates of JAKis (p < 0.001, p = 0.01 and 0.04, respectively). Pan-JAKi treated patients with high disease activity had significantly lower drug retention rates (p < 0.001). CONCLUSIONS: In a real-world setting, the drug retention rates of JAKis were reduced mainly by treatment discontinuation owing to AEs. Treatment with pan-JAKis and high baseline RA disease activity were identified as predictive factors for the discontinuation of JAKis. Lower drug retention rates were found in patients receiving pan-JAKis with high disease activity than in those without high disease activity.
Assuntos
Artrite Reumatoide , Azetidinas , Inibidores de Janus Quinases , Piperidinas , Purinas , Pirazóis , Sulfonamidas , Humanos , Artrite Reumatoide/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Azetidinas/uso terapêutico , Azetidinas/efeitos adversos , Estudos Retrospectivos , Idoso , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Purinas/uso terapêutico , Purinas/efeitos adversos , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Antirreumáticos/uso terapêutico , Antirreumáticos/efeitos adversos , Triazóis/uso terapêutico , Triazóis/efeitos adversos , Fatores de Risco , Adulto , PiridinasRESUMO
Hyperinflammatory Coronavirus disease 2019 (COVID-19) and rapidly-progressive interstitial lung diseases (RP-ILD) secondary to inflammatory myopathies (IIM) present important similarities. These data support the use of anti-rheumatic drugs for the treatment of COVID-19. The aim of this study was to compare the efficacy of combining baricitinib and pulse steroids with the Standard of Care (SoC) for the treatment of critically ill COVID-19 patients. We retrospectively enrolled consecutive patients admitted to the Intensive Care Unit (ICU) with COVID-19-pneumonia. Patients treated with SoC (dexamethasone plus remdesivir) were compared to patients treated with baricitinib plus 6-methylprednisolone pulses (Rheuma-group). We enrolled 246 patients: 104/246 in the SoC and 142/246 in the Rheuma-group. All patients presented laboratory findings suggestive of hyperinflammatory response. Sixty-four patients (26.1%) died during ICU hospitalization. The mortality rate in the Rheuma-group was significantly lower than in the SoC-group (15.5 vs. 40.4%, p < 0.001). Compared to the SoC-group, patients in the Rheuma-group presented significantly lower inflammatory biomarker levels after one week of treatment. Higher ferritin levels after one week of treatment were strongly associated with mortality (p < 0.001). In this large real-life COVID-19 cohort, baricitinib and pulse steroids led to a significant reduction in mortality, paralleled by a prompt reduction in inflammatory biomarkers. Our experience supports the similarities between hyperinflammatory COVID-19 and the IIM-associated RP-ILD.
Assuntos
Azetidinas , Tratamento Farmacológico da COVID-19 , COVID-19 , Quimioterapia Combinada , Unidades de Terapia Intensiva , Metilprednisolona , Purinas , Pirazóis , SARS-CoV-2 , Sulfonamidas , Humanos , Purinas/uso terapêutico , Purinas/administração & dosagem , Masculino , Feminino , Azetidinas/uso terapêutico , Azetidinas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Metilprednisolona/uso terapêutico , Metilprednisolona/administração & dosagem , COVID-19/mortalidade , COVID-19/complicações , Dexametasona/uso terapêutico , Dexametasona/administração & dosagem , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Monofosfato de Adenosina/administração & dosagem , Resultado do Tratamento , Alanina/análogos & derivados , Alanina/uso terapêutico , Alanina/administração & dosagemRESUMO
Myasthenia gravis (MG) is an autoimmune disease that targets neuromuscular junctions. While immunotherapy remains the cornerstone of treatment, the effects of Janus kinase (JAK) inhibitors on MG remain underexplored. In this report, we describe the case of a 58-year-old woman with ocular myasthenia gravis who received treatment with the JAK inhibitor, baricitinib for alopecia areata. The patient presented with left eyelid ptosis and an inadequate response to steroids and pyridostigmine, along with symptoms of alopecia areata. Following diagnosis, we initiated a treatment regimen consisting of baricitinib for six months. After initiation of baricitinib, we observed a complete resolution of the patient's MG symptoms, accompanied by hair regrowth, even when steroids were tapered and pyridostigmine was discontinued. Furthermore, the titer of the anti-acetylcholine receptor antibody was decreased. This report represents the first reported case of anti-acetylcholine receptor antibody-positive MG that was successfully treated through the inhibition of JAK activity.
Assuntos
Azetidinas , Miastenia Gravis , Purinas , Pirazóis , Sulfonamidas , Humanos , Miastenia Gravis/tratamento farmacológico , Azetidinas/uso terapêutico , Feminino , Pessoa de Meia-Idade , Sulfonamidas/uso terapêutico , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Resultado do Tratamento , Receptores Colinérgicos/imunologiaRESUMO
CDK4/6 inhibitors are oral agents inhibiting key molecules of the cell cycle regulation. In patients with endocrine receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer, the combination of CDK4/6 inhibitors with endocrine therapy is an effective treatment in the metastatic setting. Now, two studies in the adjuvant setting - MonarchE (2 years of abemaciclib) and NATALEE (3 years of ribociclib) - report positive invasive disease-free survival. Here, we re-evaluate these seminal trials. First, an excess drop-out or loss-to-follow up occurred early in the control arms of both studies. Since both trials are open-label, there is concern that the patients who drop-out do not do so at random but based on socioeconomic factors and alternative options. Is it possible that the results merely appear favorable due to loss to follow up? Based on re-constructed Kaplan-Meier curves, we concluded the results of these studies remain fragile, being prone to informative censoring. Secondly, adverse events were notably higher in both trials, and some of them, like COVID-19 related deaths in NATALEE, raise serious concerns. Third, the potential costs associated with CDK4/6 inhibition given as adjuvant therapy are unprecedented. The NATALEE strategy, in particular, could affect up to 35 % of patients with newly diagnosed breast cancer, which is the cancer with the highest incidence worldwide. Without confirmatory data based on a placebo-controlled trial, or better identification of patients that would benefit from the addition of CDK4/6 inhibitors in the adjuvant setting, we argue against their routine use as adjuvant therapy in ER+ /HER2- early breast cancer.
Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Inibidores de Proteínas Quinases , Feminino , Humanos , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/uso terapêutico , Benzimidazóis/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/uso terapêutico , Purinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Background: Acquired reactive perforating collagenosis (ARPC) poses a clinical challenge with an unclear pathogenesis. This disease has been frequently proven resistant to immunosuppressive treatments, significantly affecting the quality of life of patients. In this report, we highlight the efficacy of baricitinib as a viable option for maintenance therapy in ARPC. Case summary: An 81-year-old woman presented to our hospital with recurrent pruritus and cup-like ulcerated lesions on her trunk and limbs persisting for 1 year. She exhibited limited response to oral antihistamines and topical steroids. Past medical history revealed a prolonged history of coronary heart disease and type 2 diabetes spanning several years to decades. Histopathological examination revealed cup-shaped depressions filled with necrotic inflammatory debris. In the dermis, a mixed inflammatory infiltrate composed of lymphocytes and histiocytes was observed. Van Gieson staining indicated the elimination of fibrous tissue extending from the dermis into the epidermis. Consequently, a diagnosis of ARPC was established. Due to the inadequate response to conventional treatments and the severe itching, we initiated baricitinib therapy for ARPC, resulting in gradual symptom improvement. Follow-up assessments showed no adverse reactions and normal laboratory findings. Conclusion: The case report suggests that baricitinib might offer significant therapeutic benefits for ARPC.
Assuntos
Azetidinas , Doenças do Colágeno , Purinas , Pirazóis , Sulfonamidas , Humanos , Feminino , Azetidinas/uso terapêutico , Azetidinas/efeitos adversos , Sulfonamidas/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Idoso de 80 Anos ou mais , Purinas/uso terapêutico , Purinas/efeitos adversos , Doenças do Colágeno/tratamento farmacológico , Resultado do Tratamento , Pele/patologia , Pele/efeitos dos fármacosRESUMO
Patients with rheumatoid arthritis (RA) who receive immunosuppressive medications have a heightened risk of infection. The goal of our study was to calculate the pooled cumulative incidence and risk of infection in patients with RA treated with Janus kinase inhibitors (JAKi). The PubMed and EMBASE databases were queried for randomized controlled trials comparing patients with RA treated with JAKi (upadacitinib, baricitinib, tofacitinib, peficitinib, or filgotinib), defined as the treatment group, compared with control subjects, defined as participants receiving placebo or treatment regimen that was similar to that of participants in the treatment group, with the exception of JAKi. The primary study endpoint was the relative risk (RR) of any-grade and severe infection. The secondary endpoints were RR and cumulative incidence of opportunistic infections, herpes zoster, and pneumonia. The Stata v17 software was used for all data analysis. Results showed that treatment with baricitinib was associated with an increased risk of any-grade (RR 1.34; 95% CI: 1.19-1.52) and opportunistic (RR 2.69; 95% CI: 1.22-5.94) infection, whereas treatment with filgotinib (RR 1.21; 95% CI: 1.05-1.39), peficitinib (RR 1.40; 95% CI: 1.05-1.86) and upadacitinib (RR 1.30; 95% CI: 1.09-1.56) was associated with increased risk of any-grade infection only. Analysis based on type of infection showed a pooled cumulative incidence of 32.44% for any-grade infections, 2.02% for severe infections, 1.74% for opportunistic infections, 1.56% for herpes zoster, and 0.49% for pneumonia in patients treated with any JAKi during the follow-up period. Treatment with specific JAKi in patients with RA is associated with an increased risk of any-grade and opportunistic infections but not severe infection. Close clinical monitoring of patients with RA treated with JAKi is required to establish the long-term infection risk profile of these agents.
Assuntos
Artrite Reumatoide , Azetidinas , Inibidores de Janus Quinases , Piperidinas , Purinas , Pirazóis , Pirimidinas , Sulfonamidas , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/complicações , Humanos , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/uso terapêutico , Azetidinas/efeitos adversos , Azetidinas/uso terapêutico , Incidência , Purinas/efeitos adversos , Purinas/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Herpes Zoster/epidemiologia , Herpes Zoster/induzido quimicamente , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/induzido quimicamente , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Niacinamida/análogos & derivados , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Infecções/epidemiologia , Infecções/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como Assunto , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Adamantano/análogos & derivados , PiridinasAssuntos
Artrite Reumatoide , Azetidinas , Síndrome de Behçet , Purinas , Pioderma Gangrenoso , Pirazóis , Sulfonamidas , Humanos , Pirazóis/uso terapêutico , Azetidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/tratamento farmacológico , Purinas/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Pioderma Gangrenoso/tratamento farmacológico , Pioderma Gangrenoso/etiologia , Pioderma Gangrenoso/diagnóstico , Resultado do Tratamento , Feminino , Masculino , Pessoa de Meia-IdadeRESUMO
The aim of this study is to share real-life data on the increase in creatinine due to CDK 4/6 inhibitor treatment and patients diagnosed with HR+/HER2-MBC and treated with ribociclib or palbociclib combined with ET were included in the study. While creatinine increase was observed in 17.9% (n = 19) of the 106 patients in the study population, 8.5% (n = 9) had Grade 1, 8.5% (n = 8) had Grade 2, and % 0.9 (n = 1) had Grade 3 creatinine elevation. The increase in creatinine occurred in 25% (n = 12) of ribociclib users and 12.1% (n = 7) of palbociclib users. No patient required a dose reduction or discontinuation of treatment due to elevated creatinine. Of the patients with high creatinine levels, 36.8% (n = 7) were over 65 years of age. Those with multiple comorbidities, blood urea nitrogen (BUN) >13.5 mg/dl, creatinine >0.66 mg/dl, BUN/creatinine ratio >19.95, glomerular filtration rate (GFR) >96.05 ml/min, and uric acid >4.69mg/dl. It was observed that the increase in the creatinine level was statistically significant (p <0.001). In conclusion, this study revealed that the increase in the serum creatinine secondary to ribociclib and palbociclib treatments is associated with kidney function tests and the number of concomitant diseases. Key Words: CDK 4/6 inhibitor, Creatinine elevation, Palbociclib, Ribociclib.