Real-world efficacy of baricitinib among patients with severe and critical COVID-19 pneumonia admitted in Ospital ng Makati from December 2020 to May 2021: A case-control study

Background@#Management of COVID--19 patients during surges have been a challenge as hospitals have to deal with staff, room, and medication shortages. Among these medications is tocilizumab which is given to patients with severe/critical conditions. In Ospital ng Makati, patients are given baricitinib as alternative immunomodulator to prevent possible cytokine storm during tocilizumab shortages. The current recommendation for baricitinib is to give it in addition to dexamethasone and remdesivir for hospitalized COVID-19 patients requiring low to high-flow oxygen, and non-invasive ventilation. However, there is not enough evidence to recommend it as an alternative to tocilizumab in COVID--19 patients. This study aims to find out the real-world efficacy of baricitinib in addition to standard of care among admitted patients with severe COVID-19 pneumonia admitted in Ospital ng Makati.@*Methods@#This is a retrospective, case control study that reviewed records of adult patients admitted at Ospital ng Makati from December 2020 to May 2021 due to severe COVID-19. Patients who were given standard of care was compared to those who were given baricitinib by measuring the duration of clinical improvement, in-hospital all-cause mortality, number of hospital stay, and progression to acute respiratory distress syndrome (ARDS) and need for mechanical ventilator.@*Results@#The use of baricitinib led to a faster improvement time (10 vs 12 days) however did not reach level of significance (p=0.069). There was also no significant difference in the mortality, number of hospital days, and progression to ARDS between the two groups.@*Conclusion@#There is not enough evidence to recommend baricitinib as an alternative to tocilizumab in patients with severe COVID--19 infection.

Crosstalk between the JAK2 and TGF-β1 signaling pathways in scleroderma-related interstitial lung disease targeted by baricitinib

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.

Efficacy and safety of different Janus kinase inhibitors combined with methotrexate for the treatment of rheumatoid arthritis: a single-center randomized trial

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.

Baricitinib improves pulmonary fibrosis in mice with rheumatoid arthritis-associated interstitial lung disease by inhibiting the Jak2/ Stat3 signaling pathway

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.

COVID-19 and mortality in patients with systemic lupus erythematosus

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).

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).

Efficacy and safety of baricitinib in the treatment of moderate-to-severe atopic dermatitis: a clinical observation / 中华皮肤科杂志

Objective:To evaluate the efficacy and safety of baricitinib in the treatment of moderate-to-severe atopic dermatitis (AD) .Methods:From June 2020 to June 2021, patients with moderate-to-severe AD who were insensitive or intolerant to topical agents were enrolled from Department of Dermatology, Peking University First Hospital. Before treatment, the patients were evaluated by 4 scales, including the Investigator′s Global Assessment (IGA), Eczema Area and Severity Index (EASI), Itch Numeric Rating Scale (NRS), and Dermatology Life Quality Index (DLQI) ; meanwhile, photos of skin lesions were taken, routine blood test was performed, blood biochemical indices and total IgE levels were measured. After exclusion of contraindications, the patients were treated with oral baricitinib at a dose of 2 mg/d for 16 weeks. Regular follow-up was conducted at weeks 1, 2, 4, 8, 12, 16 and 20 after the start of treatment, clinical evaluation was carried out with the above 4 scales, and adverse events were recorded during the treatment.Results:A total of 24 patients were enrolled in the study, and all completed 16-week oral treatment and 20-week follow-up. All the 4 scale scores showed a continuous downward trend within 20 weeks after the start of treatment. At week 20, the patients′ IGA, EASI, NRS, and DLQI scores significantly decreased from 4.13 ± 0.61, 37.59 ± 14.86, 6.83 ± 2.26 and 18.67 ± 8.64 points respectively at baseline to 1.12 ± 0.49, 4.53 ± 3.78, 0.72 ± 0.58 and 1.39 ± 0.85 points respectively ( t = 22.70, 10.55, 10.69, 8.40, respectively, all P < 0.001). During the follow-up period, no serious adverse reactions were observed; 3 patients experienced gastric discomfort at the start of oral treatment, but the symptoms disappeared after the treatment continued; 3 developed acute allergic manifestations (1 case of allergic conjunctivitis, 2 cases of acute urticaria), which resolved rapidly after the use of antihistamines without recurrence. Conclusion:Baricitinib can provide a safer and more effective treatment option for patients with moderate-to-severe AD, especially those who are insensitive or intolerant to topical agents and need systemic treatments.

The Role of the JAK/STAT Signaling Pathway in Steroid-induced Necrosis of Femoral Heads in MRL/lpr Iupus Mice / 中国生物化学与分子生物学报

Osteonecrosis of femoral head (ONFH) is one of the complications of systemic lupus erythematosus (SLE), which is characterized by complex pathogenesis and difficult treatment, and is the main cause of SLE-induced disability. Previous studies have confirmed that the JAK/STAT signaling pathway is involved in the pathological process of SLE, and the activation of JAK/STAT has also been found to be related to the occurrence of ONFH. Therefore, we speculated that the JAK/STAT signaling pathway may play an important role in the occurrence and development of SLE-ONFH. 30 female MRL/lpr mice were randomly divided into three groups: the model group (Lipopolysaccharide/24 hours, twice + Methylprednisolone/24 hours, 3 times), the control group (equal amount of PBS) and the treatment group (the model group + JAK1/2 inhibitors Baricitinib/day, 6 weeks), with 10 mice in each group. The results showed that the grip value of the model group was significantly lower than that of the control group at the 4th and 6th week (P < 0. 05), and that of the treatment group was better than that of the model group at the 6th week (P < 0. 05). At the 6th week, the mice were sacrificed to take the bilateral femoral head, and the morphology and HE staining pathological changes of the femoral head were observed. The results showed that the femoral head of the control group was spherical, transparent, hard and without cartilage defects, while that of the model group was irregular, rough, gray in color and partial defects of the femoral head. The performance of the mice in the treatment group was basically similar to that in the model group. And the overall appearance of the femoral head was more irregular than that in the control group. The color was darker than that in the control group, and there was a partial defect of the femoral head, but the degree was not as serious as that in the model group. The empty bone lacuna rate in the model group and treatment group were significantly higher than that in the control group (P < 0. 05), and the empty bone lacuna rate in the treatment group was lower than that in the model group (P < 0. 05). Western blotting, ELISA and RT-qPCR were used to detect the protein expression, phosphorylation levels, mRNA expression of the JAK/STAT pathway (JAK1, JAK2, JAK3, STAT3) in local bone tissues, and the expression of IL-6 and TNF- α in serum and local tissues. The mRNA expression of IL-6, TNF-α and STAT3 in bone tissues of the model group were significantly higher than that of the control group and treatment group, and the content of serum IL-6 and TNF- α of the model group were significantly higher than that of the treatment group and control group. The cartilage catabolic metabolites ADAMTS-4, MMP-13 and JAK/STAT pathway related proteins JAK1, p-JAK1, JAK2, p-JAK2, STAT3 and pSTAT3 in the model group were significantly higher than those in the control group and treatment group. In summary, the JAK/STAT signaling pathway is involved in the pathogenesis of ONFH in MRL/lpr lupus erythematosus mice. Selective JAK1/2 inhibitors can effectively inhibit ONFH inflammation, improve bone structures and joint functions, and may become an effective therapeutic drug for SLE ONFH.

Research progress on pathogenesis of skin graft-versus-host disease / 器官移植

Graft-versus-host disease (GVHD) is a major cause that prevents widespread application of allogeneic hematopoietic stem cell transplantation. GVHD is a complication that can affect all systems of the body, such as skin, liver, lung and gastrointestinal tract, among which skin is the most vulnerable organ. At present, the pathogenesis of skin GVHD has not been fully elucidated, and no effective treatment has been established. Severe or extensive chronic GVHD significantly affects the quality of life of the recipients. Consequently, it is urgent to unravel the pathogenesis of skin GVHD and explore novel therapeutic treatment. Cytokines, such as interleukin (IL)-22, IL-17, IL-6 and interferon (IFN)-γ, have been proven to play pivotal roles in the progression of skin GVHD. Nevertheless, the specific mechanism remains elusive. In this article, research progresses at home and abroad on the mechanism underlying the roles of these cytokines in skin GVHD were reviewed, aiming to provide novel ideas for the prevention and treatment of skin GVHD.

Uso de antirreumáticos en covid-19 desde la hidroxicloroquina hasta la anakinra pasando por tocilizumab y baricitinib: Una revisión de la literatura / Use of antirheumatic drugs in covid-19 from hydroxychloroquine to anakinra through tocilizumab and baricitinib: A review of the literature

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.

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

Uso de antirreumáticos en covid-19 desde la hidroxicloroquina hasta la anakinra pasando por tocilizumab y baricitinib: Una revisión de la literatura / Use of antirheumatic drugs in covid-19 from hydroxychloroquine to anakinra through tocilizumab and baricitinib: A review of the literature

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.

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.

Nuevas opciones de tratamiento para el paciente con COVID-19. La experiencia hematológica / New therapeutic options for the COVID-19 patient. The experience from the hematologist

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.

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.