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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 Tratamento

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Background: Janus kinase inhibitors (jakinibs) are immunomodulators used for treating malignancies, autoimmune diseases, and immunodeficiencies. However, they induce adverse effects such as thrombosis, lymphocytosis, and neutropenia that could be mediated by extracellular vesicles (EVs). These particles are cell membrane-derived structures that transport cellular and environmental molecules and participate in intercellular communication. Jakinibs can modify the content of EVs and enable them to modulate the activity of different components of the immune response. Objective: to evaluate the interactions between immune system components of healthy individuals and EVs derived from monocytic and lymphoid lineage cells generated in the presence of baricitinib (BARI) and itacitinib (ITA) and their possible effects. Methods: EVs were isolated from monocytes (M) and lymphocytes (L) of healthy individuals, as well as from U937 (U) and Jurkat (J) cells exposed to non-cytotoxic concentrations of BARI, ITA, and dimethyl sulfoxide (DMSO; vehicle control). The binding to and engulfment of EVs by peripheral blood leukocytes of healthy individuals were analyzed by flow cytometry using CFSE-stained EVs and anti-CD45-PeCy7 mAb-labeled whole blood. The effect of EVs on respiratory burst, T-cell activation and proliferation, cytokine synthesis, and platelet aggregation was evaluated. Respiratory burst was assessed in PMA-stimulated neutrophils by the dihydrorhodamine (DHR) test and flow cytometry. T-cell activation and proliferation and cytokine production were assessed in CFSE-stained PBMC cultures stimulated with PHA; expression of the T-cell activation markers CD25 and CD69 and T-cell proliferation were analyzed by flow cytometry, and the cytokine levels were quantified in culture supernatants by Luminex assays. Platelet aggregation was analyzed in platelet-rich plasma (PRP) samples by light transmission aggregometry. The EVs' fatty acid (FA) profile was analyzed using methyl ester derivatization followed by gas chromatography. Results: ITA exposure during the generation of EVs modified the size of the EVs released; however, treatment with DMSO and BARI did not alter the size of EVs generated from U937 and Jurkat cells. Circulating neutrophils, lymphocytes, and monocytes showed a 2-fold greater tendency to internalize ITA-U-EVs than their respective DMSO control. The neutrophil respiratory burst was attenuated in greater extent by M-EVs than by L-EVs. Autologous ITA-M-EVs reduced T-cell proliferation by decreasing IL-2 levels and CD25 expression independently of CD69. A higher accumulation of pro-inflammatory cytokines was observed in PHA-stimulated PBMC cultures exposed to M-EVs than to L-EVs; this difference may be related to the higher myristate content of M-EVs. Platelet aggregation increased in the presence of ITA-L/M-EVs by a mechanism presumably dependent on the high arachidonic acid content of the vesicles. Conclusions: Cellular origin and jakinib exposure modify the FA profile of EVs, enabling them, in turn, to modulate neutrophil respiratory burst, T-cell proliferation, and platelet aggregation. The increased T-cell proliferation induced by BARI-L/M-EVs could explain the lymphocytosis observed in patients treated with BARI. The higher proportion of arachidonic acid in the FA content of ITA-L/M-EVs could be related to the thrombosis described in patients treated with ITA. EVs also induced a decrease in the respiratory burst of neutrophils.

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BACKGROUND: Randomized controlled trials (RCT) established the mortality reduction by tocilizumab (Actemra), baricitinib (Olumiant), and sarilumab (Kevzara) in hospitalized COVID-19 patients. However, uncertainty remains about which treatment performs best in patients receiving corticosteroids. OBJECTIVES: To estimate probabilities of noninferiority between baricitinib and sarilumab compared to tocilizumab in patients treated with corticosteroids. DATA SOURCES: PubMed, Embase, Cochrane Library, and MedRxiv. STUDY ELIGIBILITY CRITERIA: Eligible RCTs assigning hospitalized adults with COVID-19 treated with corticosteroids to tocilizumab or baricitinib or sarilumab versus standard of care or placebo (control). METHODS: Reviewers independently abstracted published data and assessed study quality with the Risk of Bias 2 tool. Unpublished data, if required, were requested from authors of included studies. The outcome of interest was all-cause mortality at 28 days. PARTICIPANTS: Twenty-seven RCTs with 13 549 patients were included. Overall, the risk of bias was low. Bayesian pairwise meta-analyses were used to aggregate results of each treatment versus control. The average odds ratio for mortality was 0.78 (95% credible interval [CrI]: 0.65, 0.94) for tocilizumab; 0.78 (95% CrI: 0.56, 1.03) for baricitinib; and 0.91 (95% CrI: 0.60, 1.40) for sarilumab. The certainty of evidence (GRADE) ranged from moderate to low. Bayesian meta-regressions with multiple priors were used to estimate probabilities of noninferiority (margin of 13% greater effect by tocilizumab). Compared to tocilizumab, there were ≤94% and 90% probabilities of noninferiority with baricitinib and sarilumab, respectively. RESULTS: All but two studies included data with only indirect evidence for the comparison of interest. CONCLUSIONS: Among hospitalized COVID-19 treated with corticosteroids, there are high probabilities that both baricitinib and sarilumab are associated with similar mortality reductions in comparison to tocilizumab.

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COVID-19 , Adulto , Humanos , Tratamento Farmacológico da COVID-19 , Corticosteroides/uso terapêutico

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Abstract Background and objective Systemic sclerosis (SSc) is an immune-mediated rheumatic disease characterized by fibrosis and vascular lesions. Interstitial lung disease is an early complication of SSc and the main cause of death from SSc. Although baricitinib shows good efficacy in a variety of connective tissue diseases, its role in systemic sclerosis-related interstitial lung disease (SSc-ILD) is unclear. The objective of our study was to explore the effect and mechanism of baricitinib in SSc-ILD. Methods We explored crosstalk between the JAK2 and TGF-β1 pathways. In vivo experiments, SSc-ILD mice model were constructed by subcutaneous injection of PBS or bleomycin (7.5 mg/kg) and intragastric administration of 0.5% CMC-Na or baricitinib (5 mg/kg) once every two days. We used ELISA, qRT-PCR, western blot and immunofluorescence staining to evaluate the degree of fibrosis. In vitro experiments, we used TGF-β1 and baricitinib to stimulate human fetal lung fibroblasts (HFLs) and assessed protein expression by western blot. Results The vivo experiments showed that baricitinib notably alleviated skin and lung fibrosis, decreased the concentration of pro-inflammatory factors and increased those of the anti-inflammatory factors. Baricitinib affected the expression of TGF-β1 and TβRI/II inhibitiing JAK2. In the vitro experiments, following the culture of HFLs with baricitinib or a STAT3 inhibitor for 48 h, the expression levels of TβRI/II decreased. Conversely, with successful inhibition of TGF-β receptors in HFLs, JAK2 protein expression decreased. Conclusions Baricitinib attenuated bleomycin-induced skin and lung fibrosis in SSc-ILD mice model by targeting JAK2 and regulating of the crosstalk between the JAK2 and TGF-β1 signaling pathways.

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Abstract Objective The study explored improvements in pulmonary inflammation and fibrosis in a bovine type II collagen-induced rheumatoid arthritis-associated interstitial lung disease mouse model after treatment with baricitinib and the possible mechanism of action. Methods A rheumatoid arthritis-associated interstitial lung disease mouse model was established, siRNA Jak2 and lentiviral vectors were transfected with human embryonic lung fibroblast cells. And the levels of relevant proteins in mouse lung tissue and human embryonic lung fibroblasts were detected by Western blotting. Results The levels of JAK2, p-JAK2, p-STAT3, p-SMAD3, SMA, TGFβR2, FN and COL4 were increased in the lung tissues of model mice (P < 0.5) and decreased after baricitinib intervention (P < 0.05). The expression levels of p-STAT3, p-SMAD3, SMA, TGFβR2, FN and COL4 were reduced after siRNA downregulation of the JAK2 gene (P < 0.01) and increased after lentiviral overexpression of the JAK2 gene (P < 0.01). Conclusion Baricitinib alleviated fibrosis in the lung tissue of rheumatoid arthritis-associated interstitial lung disease mice, and the mechanism of action may involve the downregulation of Smad3 expression via inhibition of the Jak2/Stat3 signaling pathway, with consequent inhibition of the profibrotic effect of transforming growth factor-β1.

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Abstract Objective To compare the efficacy and safety between baricitinib (BARI) and tofacitinib (TOFA) for the treatment of the rheumatoid arthritis (RA) patients receiving methotrexate (MTX) in clinical practice. Methods This retrospective study recruited 179 RA patients treated with BARI (2-4 mg/d) or TOFA (10 mg/d) at The First Affiliated Hospital of Guangxi Medical University from September 2019 to January 2022. The rate of low disease activity (LDA) was used as the primary end point. Secondary end points included the Disease Activity Scale-28 (DAS-28)-C-reactive protein (CRP); the rate of DAS28-CRP remission; visual analogue scale (VAS) for pain, swollen joint, and tender joint counts; and adverse events at the 6-month follow-up. Several factors affecting LDA achievement were also analyzed. Results Seventy-four patients were treated with BARI and 105 were treated with TOFA, including 83.24% females, with a median (IQR) age of 56.0 (53.0-56.0) years old and disease duration of 12.0 (6.0-12.0) months. There was no difference of the rate of LDA between the BARI and TOFA treatment groups. All disease indices in the two groups were significantly improved, including a significantly lower VAS in the BARI group (P < 0.05), reflecting the drug efficacy after 1 and 6 months of treatment. The incidence of adverse reactions was similar in these two groups. Conclusion The treatment efficacy and safety of BARI and TOFA in the RA patients were similar, but BARI was more effective in pain relief than TOFA. An older baseline age was more likely to achieve LDA in the BARI group, while a low baseline erythrocyte sedimentation rate (ESR) was more likely to achieve LDA in the TOFA group.

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In december 2019, a new disease erupted in Wuhan, China, caused by coronavirus 2019 (CO-VID-19), which produces severe acute respiratory syndrome (SARS-CoV-2). Some cases associate COVID-19 with autoimmune disorders; the role of this virus in autoimmunity is poorly understood. Systemic lupus erythematosus (SLE) is an autoimmune disorder. Baricitinib is a Janus kinase inhibitor (JAK) approved for the treatment of autoimmune and inflam matory disorders, recently used for treating severe COVID-19 disease. We discuss four cases of SLE with COVID-19, two of whom were admitted to the intensive care unit and died, with a history of lupus nephritis; the following two cases survived. The risk fac tors which increase mortality in SLE are not yet known; however, lupus nephritis was associated with COVID-19 mortality. More studies are needed to understand the risk between autoimmune disorders and COVID-19. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2551).

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Desde diciembre de 2019 estalló en Wuhan, China, una nueva enfermedad causada por corona-virus 2019 (COVID-19), causante del síndrome respiratorio agudo severo (SARS-CoV-2). Algunos casos asocian al COVID-19 a trastornos autoinmunes, el papel de este virus en la autoinmunidad está poco dilucidada. El lupus eritematoso sistémico (LES) es una enfermedad autoinmune. El baricitinib es una molécula inhibidora de quinasa de Janus (JAK) aprobada para el tratamiento de trastornos autoinmunitarios e inflamatorios, recientemente utilizado para el manejo de la enfermedad grave por COVID-19. Se trata de cuatro casos de LES con COVID-19, dos de las cuales ingresaron a la unidad de cuidados intensivos y fallecieron con antecedente de nefritis lúpica, los dos casos siguientes so brevivieron. Aún se desconocen los factores de riesgo que incrementan la mortalidad en LES; sin embargo, se asoció nefritis lúpica con mortalidad en COVID-19. Se requieren más estudios para comprender el riesgo entre las enfermedades autoinmunes y COVID-19. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2551).

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Alopecia areata (AA) is a chronic, immune-mediated form of nonscarring alopecia that is multifactorial and results in localized patches. It is often described as a self-limiting condition that results in the spontaneous regrowth of hair in most cases. However, this regrowth may take several months or years to occur in some patients, leading to the development of psychoemotional trauma in those that are affected. Although several therapies for AA have been developed and tested, there is no specific treatment that has been approved, leading to the availability of many off-label conventional treatment options, with very limited responses. More recently, with the advancement of pre-clinical and genetic studies, a greater understanding of the pathomechanisms involved in the development of AA has been uncovered. This has resulted in the introduction of targeted therapies that use small molecules to block specific pathways involved in AA pathophysiology. As such, the use of janus kinase (JAK) inhibitors for treatment of AA has emerged. JAK inhibitors block the T-cell mediated inflammatory response thought to be the driving factor behind AA pathogenesis, by inhibiting the janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathway, leading to a reversal of hair loss in AA patients. Thus, in an effort to demonstrate the efficacy of JAK inhibitors in the treatment of AA, several studies have been published within recent years. However, the question remains, "Are JAK inhibitors effective and safe in the management of Alopecia Areata?". This review aims to provide a comprehensive report on the role, efficacy, and outcomes of using JAK inhibitors in the treatment of AA. To competently answer the research question highlighted, the most recent, quality articles published over a 10-15-year period were sourced using PubMed, NCBI, Research gate, Medline, Cochrane Central Register of Controlled Trials, EMBASE and Google scholar. The literature search was primarily focused on randomized controlled trials (RCTs); however, in the absence of such, only the most recently published case reports, case series, clinical trials and open-label studies published to date were included.

RESUMO

OBJECTIVE: We aimed to analyze clinical outcomes from patients with severe COVID-19 pneumonia that received either baricitinib plus dexamethasone or dexamethasone monotherapy. METHODOLOGY: We performed a retrospective comparative study. Data from hospitalized patients with severe COVID-19 pneumonia (saturation <93%, bilateral pulmonary infiltrates) that were treated with baricitinib plus dexamethasone or dexamethasone were collected. Our primary objective was to compare overall mortality and secondly to compare progression to mechanical ventilation and over infection rates. RESULTS: A total of 793 patients were assessed for inclusion criteria, 596 were excluded and 197 were analyzed for primary outcome: 123 in the baricitinib plus dexamethasone group and 74 in the dexamethasone monotherapy group. The mean age was 59.9 years (SD ± 14.5) and 62.1% (123/197) were male. 42.9% (85/197) of the cases required ICU admission and 25.8% (51/197) underwent invasive mechanical ventilation (IMV). Overall thirty-day mortality was 27.9% (55/197); Mortality was significantly lower in the baricitinib plus dexamethasone group compared to the dexamethasone monotherapy group (20.3% vs 40.5%, P = <.05). There was no difference in hospital acquired infections between both groups. CONCLUSION: Thirty-day mortality was significantly lower in patients with COVID-19 pneumonia treated with baricitinib plus dexamethasone versus dexamethasone monotherapy. No difference was observed in progression to invasive mechanical ventilation and hospital acquired infections.

Assuntos

Azetidinas/uso terapêutico , Tratamento Farmacológico da COVID-19 , Dexametasona/uso terapêutico , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2/efeitos dos fármacos

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Pyoderma gangrenosum manifests as an ulceration of the skin often associated with several systemic diseases. The diagnosis is usually made by exclusion criteria with suggestions made by clinical findings and histological features. It can occur any site but more common in the legs. Advances in translational medicine led to the development of new forms of therapy in chronic inflammatory diseases by the oral administration of Janus kinase inhibitors. We report two cases of chronic ulceration of the skin consistent with the diagnosis of Pyoderma Gangrenosum that went into complete remission after the use of baricitinib.

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Actualmente nos encontramos en una pandemia mundial causada por el coronavirus 2019 o COVID­19, presentando diferentes desafíos para el sistema de salud debido a que no se cuenta aún con alguna vacuna ni con un tratamiento que haya demostrado su eficacia en totalidad, siendo el manejo actual preventivo y de soporte. Por lo que, en esta revisión se estudiará a los fármacos antirreumáticos más resaltantes que tengan un probable efecto farmacológico, como son la hidroxicloroquina, el tocilizumab, el anakinra y el baricitinib, frente al COVID­19. Se espera que brinde apoyo para futuros tratamientos e investigaciones sobre la enfermedad.

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We are currently in a global pandemic caused by the coronavirus 2019 or COVID-19, presenting different challenges for the health system due to the fact that there is still no vaccine or a treatment that has proven its effectiveness in its entirety, being the management current preventive and supportive. Therefore, this review will study the most prominent antirheumatic drugs that have a probable pharmacological effect, such as hydroxychloroquine, tocilizumab, anakinra and baricitinib, against COVID-19. It is expected that they will provide support for future treatments. and research on the disease

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RESUMEN Actualmente nos encontramos en una pandemia mundial causada por el coronavirus 2019 o COVID-19, presentando diferentes desafíos para el sistema de salud debido a que no se cuenta aún con alguna vacuna ni con un tratamiento que haya demostrado su eficacia en totalidad, siendo el manejo actual preventivo y de soporte. Por lo que, en esta revisión se estudiará a los fármacos antirreumáticos más resaltantes que tengan un probable efecto farmacológico, como son la hidroxicloroquina, el tocilizumab, el anakinra y el baricitinib, frente al COVID-19. Se espera que brinde apoyo para futuros tratamientos e investigaciones sobre la enfermedad.

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ABSTRACT We are currently in a global pandemic caused by the coronavirus 2019 or COVID- 19, presenting different challenges for the health system due to the fact that there is still no vaccine or a treatment that has proven its effectiveness in its entirety, being the management current preventive and supportive. Therefore, this review will study the most prominent antirheumatic drugs that have a probable pharmacological effect, such as hydroxychloroquine, tocilizumab, anakinra and baricitinib, against COVID-19. It is expected that they will provide support for future treatments. and research on the disease.

RESUMO

Resumen En la actual pandemia de enfermedad por coronavirus 2019 (COVID-19) se ha observado que las principales complicaciones se presentan como resultado de la liberación de múltiples citocinas como interleucina (IL) 1, IL-6, factor de necrosis tumoral alfa e interferones de tipo 1 que generan un estado proinflamatorio caracterizado por lesión tisular pulmonar y subsecuentemente falla orgánica múltiple. En el campo de la hematología se cuenta con experiencia en el uso de diversos fármacos diseñados para limitar estas citocinas los cuales se han utilizado ya en pacientes con COVID-19 entre los que se encuentran los inhibidores de la IL-6 como el tocilizumab, el sarilumab y el siltuximab, el inhibidor de IL-1 anakinra y los inhibidores de la janus cinasa ruxolitinib y baricitinib. Al conocer la base fisiopatológica de la COVID-19, la utilidad de este tipo de fármacos muestra resultados alentadores para los cuadros moderados a graves de la enfermedad y extender su uso en ensayos clínicos mayores.

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Abstract In the current SARS-CoV-2 pandemic, it has been observed that the main complications arise as a result of the release of multiple cytokines such as IL-1, IL-6, TNF-α and type 1 interferons that generate a proinflammatory state characterized by lung tissue injury and subsequently multiple organ failure. In the hematology field, there is experience in the use of various drugs designed to limit these cytokines which have already been used in patients with COVID-19 including IL-6 inhibitors such as tocilizumab, sarilumab, and siltuximab; the IL-1 inhibitor anakinra; and the janus kinase inhibitors ruxolitinib and baricitinib. Knowing the pathophysiological basis of COVID-19, the usefulness of this type of drugs show encouraging results for moderate to severe symptoms of the disease and encourages its use in larger clinical trials.