Predictive factors for dose reduction and discontinuation of nintedanib in fibrotic interstitial lung diseases: Real life data.

Nintedanib, an intracellular inhibitor targeting multiple tyrosine kinases, has emerged as a standard treatment for various fibrotic lung diseases. Despite its efficacy, side effects such as nausea, diarrhea, and hepatotoxicity often lead to dose reduction or discontinuation. In this retrospective analysis at an university hospital's interstitial lung disease clinic, we aimed to identify baseline characteristics associated with dose adjustment or treatment discontinuation. Of the 58 patients included, 41.4% maintained the full nintedanib dose, while 31.0% required dosage reduction, and 27.6% discontinued treatment due to adverse events, predominantly gastrointestinal and hepatotoxic effects. Multivariate analysis revealed body surface area (BSA) as an independent and significant baseline risk factor (adjusted Odds Ratio [aOR] 0.22), suggesting a 78% decreased chance of requiring dose modification for every decimal point increase in BSA. A BSA cutoff of ≤1.73 m [2] exhibited a sensitivity of 73% and specificity of 91.7%, with significant impact on one-year survival under full-dose treatment (p < 0.001). Lower BSA was associated with early onset adverse effects, particularly gastrointestinal, supporting the need for regular clinical monitoring. The study emphasizes the importance of recognizing baseline factors to ensure the safety and tolerability of nintedanib, thereby preventing the progression of pulmonary fibrosis. These findings contribute to the evolving understanding of nintedanib management in fibrotic interstitial lung diseases, guiding clinicians in personalized treatment approaches.

Systematic literature review to inform the Portuguese recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

OBJECTIVE: To perform a systematic literature review (SLR) aimed at evaluating the efficacy and safety of pharmacological and non-pharmacological treatments for Raynaud's phenomenon (RP) and digital ulcers (DU) in patients with systemic sclerosis (SSc) and other connective tissue diseases (CTD), in order to inform the Portuguese recommendations for managing RP and DU in these patients. METHODS: A SLR was conducted until May 2022 to identify studies assessing the efficacy and safety of pharmacological and non-pharmacological interventions for RP and DU in SSc and other CTD. Eligible study designs included randomized controlled trials (RCTs), controlled clinical trials, and their extensions for assessing efficacy and safety of interventions. Observational studies with a comparator were included for evaluating the efficacy and safety of non-pharmacological interventions and safety of pharmacological interventions. The risk of bias of each study was assessed using standard tools. RESULTS: Out of 71 publications meeting the inclusion criteria, 59 evaluated pharmacological and 12 non-pharmacological interventions. We found moderate quality evidence supporting the efficacy of calcium channel blockers, phosphodiesterase-5 inhibitors, and intravenous prostacyclin analogues in reducing RP frequency, severity, and duration. Intravenous iloprost had a small to moderate effect size in improving DU healing. Phosphodiesterase-5 inhibitors were effective in reducing total DU count, new DU occurrence, and enhancing DU healing. Bosentan effectively prevented new DU in SSc patients. No new safety concerns were associated with these treatments. The studies on non-pharmacological interventions were, in general, of low quality, and had a small sample size. Warming measures decreased frequency and duration of RP attacks; laser therapy improved RP-related outcomes; local oxygen-ozone therapy improved RP outcomes as an add-on therapy; bone marrow mononuclear cell implantation improved DU-associated pain; periarterial sympathectomy and vascular bypass reduced DU number and finger amputation risk. CONCLUSION: The available evidence supports the efficacy and safety of pharmacological interventions, namely nifedipine, sildenafil, iloprost, and bosentan in treating RP and DU in patients with SSc and other CTD. Scarce and low-quality evidence does support the use of some non-pharmacological interventions but with only a modest effect size. This SLR underscores the limited availability of high-quality evidence for determining the optimal treatment.

Genes, inflammatory response, tolerance, and resistance to virus infections in migratory birds, bats, and rodents.

Normally, the host immunological response to viral infection is coordinated to restore homeostasis and protect the individual from possible tissue damage. The two major approaches are adopted by the host to deal with the pathogen: resistance or tolerance. The nature of the responses often differs between species and between individuals of the same species. Resistance includes innate and adaptive immune responses to control virus replication. Disease tolerance relies on the immune response allowing the coexistence of infections in the host with minimal or no clinical signs, while maintaining sufficient viral replication for transmission. Here, we compared the virome of bats, rodents and migratory birds and the molecular mechanisms underlying symptomatic and asymptomatic disease progression. We also explore the influence of the host physiology and environmental influences on RNA virus expression and how it impacts on the whole brain transcriptome of seemingly healthy semipalmated sandpiper (Calidris pusilla) and spotted sandpiper (Actitis macularius). Three time points throughout the year were selected to understand the importance of longitudinal surveys in the characterization of the virome. We finally revisited evidence that upstream and downstream regulation of the inflammatory response is, respectively, associated with resistance and tolerance to viral infections.

Barriers and alternatives to pediatric rheumatology referrals: a survey of family doctors and pediatricians in Portugal.

BACKGROUND: Access to pediatric rheumatology (PR) is not well described in Portugal. The main goal of this study was to ascertain barriers to PR referrals and subsequent alternative referral patterns among family doctors and pediatricians. METHODS: A web-based survey was e-mailed to family doctors and pediatricians practicing in Portugal, in order to investigate access to PR care issues. Descriptive and comparative analysis was performed. RESULTS: Two hundred and ninety-two responses were obtained, 24.7% from pediatricians and 75.3% from family doctors. Only 12% claimed to have had specific education on PR. Nearly 70% worked less than one hour away from a PR center. Twenty eight percent had referred a patient to PR at least once, and 9.3% experienced a situation in which they considered referring to PR but ultimately did not. Many referred to other specialties, primarily pediatrics, adult rheumatology, and pediatric orthopedics. Pediatricians encountered more diversified rheumatic diseases. Fifty five percent had no opinion on PR centers' support, while 24% found it sufficient. Having specific training on PR, being a pediatrician and a specialist were associated with greater referrals to PR. The most rated measure for PR referrals' improvement was promoting education. Regional access to PR's discrepancies were documented. CONCLUSION: Mainly lack of education on PR, but also uneven national coverage and greater distances to some PR centers were the main barriers to PR referrals, in Portugal. Pediatricians seem to have better education, greater experience and more referrals to PR. The current alternatives for referral are pediatrics, adult rheumatology and pediatric orthopedics. Educational consolidation was the biggest and most rewarding inconsistency to battle against.

Molecular Changes in the Brain of the Wintering Calidris pusilla in the Mangroves of the Amazon River Estuary.

Migrant birds prepare differently to fly north for breeding in the spring and for the flight to lower latitudes during autumn, avoiding the cold and food shortages of the Northern Hemisphere's harsh winter. The molecular events associated with these fundamental stages in the life history of migrants include the differential gene expression in different tissues. Semipalmated sandpipers (Calidris pusilla) are Arctic-breeding shorebirds that migrate to the coast of South America during the non-breeding season. In a previous study, we demonstrated that between the beginning and the end of the wintering period, substantial glial changes and neurogenesis occur in the brain of C. pusilla. These changes follow the epic journey of the autumn migration when a 5-day non-stop transatlantic flight towards the coast of South America and the subsequent preparation for the long-distance flight of the spring migration takes place. Here, we tested the hypothesis that the differential gene expressions observed in the brains of individuals captured in the autumn and spring windows are consistent with the previously described cellular changes. We searched for differential gene expressions in the brain of the semipalmated sandpiper, of recently arrived birds (RA) from the autumnal migration, and that of individuals in the premigratory period (PM) in the spring. All individuals were collected in the tropical coastal of northern Brazil in the mangrove region of the Amazon River estuary. We generated a de novo neurotranscriptome for C. pusilla individuals and compared the gene expressions across libraries. To that end, we mapped an RNA-Seq that reads to the C. pusilla neurotranscriptome in four brain samples of each group and found that the differential gene expressions in newly arrived and premigratory birds were related with neurogenesis, metabolic pathways (ketone body biosynthetic and the catabolic and lipid biosynthetic processes), and glial changes (astrocyte-dopaminergic neuron signaling, astrocyte differentiation, astrocyte cell migration, and astrocyte activation involved in immune response), as well as genes related to the immune response to virus infections (Type I Interferons), inflammatory cytokines (IL-6, IL-1ß, TNF, and NF-κB), NLRP3 inflammasome, anti-inflammatory cytokines (IL-10), and cell death pathways (pyroptosis- and caspase-related changes).

Hypokalemic paralysis due to renal tubular acidosis: uncommon initial manifestation of primary Sjögren´s syndrome.

Primary Sjögren´s Syndrome is an immune-mediated disease characterized by exocrine glands dysfunction due to lymphoplasmacytic infiltration with sicca symptoms being one of its main features. The disease may, however, present as distal renal tubular acidosis due to renal involvement, which can range from asymptomatic to life-threatening. We describe the case of a 33-year-old woman with hypokalemic paralysis and metabolic acidosis secondary to distal renal tubular acidosis, leading to the diagnosis of primary Sjögren´s Syndrome. Although rare, recognizing primary Sjögren´s Syndrome as a possible cause of distal renal tubular acidosis may elicit an earlier diagnosis and treatment, improving the patient´s prognosis.

Myocardial Injury and Prognosis in Hospitalized COVID-19 Patients in Brazil: Results From The Brazilian COVID-19 Registry. / Lesão Miocárdica e Prognóstico em Pacientes Hospitalizados com COVID-19 no Brasil: Resultados do Registro Nacional de COVID-19.

BACKGROUND: Cardiovascular complications of COVID-19 are important aspects of the disease's pathogenesis and prognosis. Evidence on the prognostic role of troponin and myocardial injury in Latin American hospitalized COVID-19 patients is still scarce. OBJECTIVES: To evaluate myocardial injury as independent predictor of in-hospital mortality and invasive mechanical ventilation support in hospitalized patients, from the Brazilian COVID-19 Registry. METHODS: This cohort study is a substudy of the Brazilian COVID-19 Registry, conducted in 31 Brazilian hospitals of 17 cities, March-September 2020. Primary outcomes included in-hospital mortality and invasive mechanical ventilation support. Models for the primary outcomes were estimated by Poisson regression with robust variance, with statistical significance of p<0.05. RESULTS: Of 2,925 patients (median age of 60 years [48-71], 57.1% men), 27.3% presented myocardial injury. The proportion of patients with comorbidities was higher among patients with cardiac injury (median 2 [1-2] vs. 1 [0-2]). Patients with myocardial injury had higher median levels of brain natriuretic peptide, lactate dehydrogenase, creatine phosphokinase, N-terminal pro-brain natriuretic peptide, and C-reactive protein than patients without myocardial injury. As independent predictors, C-reactive protein and platelet counts were related to the risk of death, and neutrophils and platelet counts were related to the risk of invasive mechanical ventilation support. Patients with high troponin levels presented a higher risk of death (RR 2.03, 95% CI 1.60-2.58) and invasive mechanical ventilation support (RR 1.87, 95% CI 1.57-2.23), when compared to those with normal troponin levels. CONCLUSION: Cardiac injury was an independent predictor of in-hospital mortality and the need for invasive mechanical ventilation support in hospitalized COVID-19 patients.

FUNDAMENTO: As complicações cardiovasculares da COVID-19 são aspectos importantes da patogênese e do prognóstico da doença. Evidências do papel prognóstico da troponina e da lesão miocárdica em pacientes hospitalizados com COVID-19 na América Latina são ainda escassos. OBJETIVOS: Avaliar a lesão miocárdica como preditor independente de mortalidade hospitalar e suporte ventilatório mecânico em pacientes hospitalizados, do registro brasileiro de COVID-19. MÉTODOS: Este estudo coorte é um subestudo do registro brasileiro de COVID-19, conduzido em 31 hospitais brasileiros de 17 cidades, de março a setembro de 2020. Os desfechos primários incluíram mortalidade hospitalar e suporte ventilatório mecânico invasivo. Os modelos para os desfechos primários foram estimados por regressão de Poisson com variância robusta, com significância estatística de p<0,05. RESULTADOS: Dos 2925 pacientes [idade mediana de 60 anos (48-71), 57,1%], 27,3% apresentaram lesão miocárdica. A proporção de pacientes com comorbidades foi maior nos pacientes com lesão miocárdica [mediana 2 (1-2) vs. 1 (0-20)]. Os pacientes com lesão miocárdica apresentaram maiores valores medianos de peptídeo natriurético cerebral, lactato desidrogenase, creatina fosfoquinase, N-terminal do pró-peptídeo natriurético tipo B e proteína C reativa em comparação a pacientes sem lesão miocárdica. Como fatores independentes, proteína C reativa e contagem de plaquetas foram relacionados com o risco de morte, e neutrófilos e contagem de plaquetas foram relacionados ao risco de suporte ventilatório mecânico invasivo. Os pacientes com níveis elevados de troponina apresentaram um maior risco de morte (RR 2,03, IC95% 1,60-2,58) e suporte ventilatório mecânico (RR 1,87;IC95% 1,57-2,23), em comparação àqueles com níveis de troponina normais. CONCLUSÃO: Lesão cardíaca foi um preditor independente de mortalidade hospitalar e necessidade de suporte ventilatório mecânico em pacientes hospitalizados com COVID-19.

Lesão Miocárdica e Prognóstico em Pacientes Hospitalizados com COVID-19 no Brasil: Resultados do Registro Nacional de COVID-19 / Myocardial Injury and Prognosis in Hospitalized COVID-19 Patients in Brazil: Results From The Brazilian COVID-19 Registry

Resumo Fundamento As complicações cardiovasculares da COVID-19 são aspectos importantes da patogênese e do prognóstico da doença. Evidências do papel prognóstico da troponina e da lesão miocárdica em pacientes hospitalizados com COVID-19 na América Latina são ainda escassos. Objetivos Avaliar a lesão miocárdica como preditor independente de mortalidade hospitalar e suporte ventilatório mecânico em pacientes hospitalizados, do registro brasileiro de COVID-19. Métodos Este estudo coorte é um subestudo do registro brasileiro de COVID-19, conduzido em 31 hospitais brasileiros de 17 cidades, de março a setembro de 2020. Os desfechos primários incluíram mortalidade hospitalar e suporte ventilatório mecânico invasivo. Os modelos para os desfechos primários foram estimados por regressão de Poisson com variância robusta, com significância estatística de p<0,05. Resultados Dos 2925 pacientes [idade mediana de 60 anos (48-71), 57,1%], 27,3% apresentaram lesão miocárdica. A proporção de pacientes com comorbidades foi maior nos pacientes com lesão miocárdica [mediana 2 (1-2) vs. 1 (0-20)]. Os pacientes com lesão miocárdica apresentaram maiores valores medianos de peptídeo natriurético cerebral, lactato desidrogenase, creatina fosfoquinase, N-terminal do pró-peptídeo natriurético tipo B e proteína C reativa em comparação a pacientes sem lesão miocárdica. Como fatores independentes, proteína C reativa e contagem de plaquetas foram relacionados com o risco de morte, e neutrófilos e contagem de plaquetas foram relacionados ao risco de suporte ventilatório mecânico invasivo. Os pacientes com níveis elevados de troponina apresentaram um maior risco de morte (RR 2,03, IC95% 1,60-2,58) e suporte ventilatório mecânico (RR 1,87;IC95% 1,57-2,23), em comparação àqueles com níveis de troponina normais. Conclusão Lesão cardíaca foi um preditor independente de mortalidade hospitalar e necessidade de suporte ventilatório mecânico em pacientes hospitalizados com COVID-19.

Abstract Background Cardiovascular complications of COVID-19 are important aspects of the disease's pathogenesis and prognosis. Evidence on the prognostic role of troponin and myocardial injury in Latin American hospitalized COVID-19 patients is still scarce. Objectives To evaluate myocardial injury as independent predictor of in-hospital mortality and invasive mechanical ventilation support in hospitalized patients, from the Brazilian COVID-19 Registry. Methods This cohort study is a substudy of the Brazilian COVID-19 Registry, conducted in 31 Brazilian hospitals of 17 cities, March-September 2020. Primary outcomes included in-hospital mortality and invasive mechanical ventilation support. Models for the primary outcomes were estimated by Poisson regression with robust variance, with statistical significance of p<0.05. Results Of 2,925 patients (median age of 60 years [48-71], 57.1% men), 27.3% presented myocardial injury. The proportion of patients with comorbidities was higher among patients with cardiac injury (median 2 [1-2] vs. 1 [0-2]). Patients with myocardial injury had higher median levels of brain natriuretic peptide, lactate dehydrogenase, creatine phosphokinase, N-terminal pro-brain natriuretic peptide, and C-reactive protein than patients without myocardial injury. As independent predictors, C-reactive protein and platelet counts were related to the risk of death, and neutrophils and platelet counts were related to the risk of invasive mechanical ventilation support. Patients with high troponin levels presented a higher risk of death (RR 2.03, 95% CI 1.60-2.58) and invasive mechanical ventilation support (RR 1.87, 95% CI 1.57-2.23), when compared to those with normal troponin levels. Conclusion Cardiac injury was an independent predictor of in-hospital mortality and the need for invasive mechanical ventilation support in hospitalized COVID-19 patients.

Clinical characterisation of a multicentre nationwide cohort of patients with antisynthetase syndrome.

BACKGROUND: Antisynthetase syndrome (ASyS) is characterised by the association of inflammatory myopathy, interstitial lung disease (ILD), arthritis, Raynaud's phenomenon (RP) or mechanic's hands (MH), with the presence of anti-aminoacyl-tRNA-synthetase antibodies (anti-ARS). It has been suggested that different anti-ARS may be associated with distinct clinical pictures. OBJECTIVE: To characterise the clinical and immunological features of a multicentric nationwide cohort of ASyS patients. METHODS: This is a multicentre retrospective cohort study including patients with ASyS from nine Portuguese rheumatology centres. Data on patients' demographics, signs and symptoms, laboratory results, pulmonary imaging findings and treatment with immunomodulators were collected. Comparison between patients with different anti-ARS antibodies was made using the Chi-square test for categorical variables and Student's t-test or Man-Whitney test for continuous variables, considering anti-Jo1 positive patients as the reference group. RESULTS: Seventy patients were included (70% female) with a median age in years at disease onset of 52 (15-75) years and median follow-up time of 3 years (range 0-32). The three most common clinical manifestations were ILD (n=53, 75.7%), followed by arthritis (n=43, 61.4%) and myositis (n=37, 52.9%). Forty-three patients were positive for anti-Jo1 (61.4%), 11 for anti-PL12 (15.7%), 10 for anti-PL7 (14.3%), 4 for anti-EJ (5.7%), and 2 for anti-OJ (2.9%) antibodies. Antibody co-positivity with anti-Ro52 antibodies was found in 15 patients (21.4%) and was more prevalent in anti-Jo1 patients. ILD prevalence was similar in the different anti-ARS subgroups, without statistically significant differences. Patients positive for anti-PL7 antibodies had significantly lower risk of presenting arthritis (p =< 0.05) and those positive for anti-PL-12 antibodies had a significantly lower risk of presenting myositis than the reference group of anti-Jo1 positive patients (p =< 0.05). RP was more frequently found in patients positive for anti-PL-12 than in anti-Jo1-positive patients (p =< 0.05). Malignancies were reported in four (5.7%) patients, none of whom were anti-Ro52-positive, and one of such patients had a double malignancy. Only three deaths were reported. Corticosteroids were the most frequently prescribed therapy and the use of immunosuppressive drugs was decided according to the type of predominant clinical manifestation. CONCLUSION: The three most common clinical manifestations were ILD, followed by arthritis and myositis. Patients positive for anti-PL7 antibodies had significantly lower risk of presenting arthritis and those positive for anti-PL-12 antibodies had a significantly lower risk of presenting myositis than the reference group of anti-Jo1 positive patients. RP was more frequently found in patients positive for anti-PL-12 than in anti-Jo1-positive patients. Corticosteroids were the most frequently prescribed therapy. These results are generally concordant with data retrieved from international cohorts.

Clinical features and outcome of 1054 patients with Systemic Sclerosis: analysis of Reuma.pt/SSc registry.

BACKGROUND: Systemic sclerosis (SSc) is a rare connective tissue disorder with heterogeneous manifestations and outcomes. Besides differences in disease characteristics among distinct ethnic groups and geographical regions, several questions regarding the impact of the disease and the effectiveness of treatments remain unanswered. To address these questions, the Rheumatic Diseases Portuguese Register (Reuma.pt) launched a specific protocol for the prospective follow-up of SSc patients. OBJECTIVES: To describe the baseline characteristics, disease subsets, treatments used and survival of SSc patients registered in Reuma.pt/SSc. METHODS: Data from adult patients with SSc included in Reuma.pt up to November 2020 were analysed. Demographic features, SSc subsets, fulfilment of classification criteria, main clinical and immunological features, comorbidities, treatments used and survival data were described and compared between diffuse cutaneous (dc) and limited cutaneous (lc) disease subsets. Survival was calculated for patients included in Reuma.pt within the first two years of diagnosis. RESULTS: In total, 1054 patients were included, 87.5% female, with a mean age at diagnosis of 52.7 +/- 14.8 years. The most common subset was lcSSc (56.3%), followed by dcSSc (17.5%), preclinical SSc (13%), overlap syndrome (9.8%) and SSc sine scleroderma (3.3%). Raynaud's phenomenon (93.4%) and skin thickening (76.9%) were the most frequently observed clinical manifestations. Gastrointestinal (62.8% versus 47.8%), pulmonary (59.5% versus 23%) and cardiac (12.8% versus 6.9%) involvements were significantly more prevalent in dcSSc than lcSSc. Ninety per-cent of patients were Antinuclear antibody positive, 52.5% were Anti-centromere antibody positive and 21% anti-topoisomerase positive, with significant differences between lcSSc and dcSSc. One-third of patients were treated with immunomodulators, 53.6% with vasodilators, 23% with glucocorticoids and 2.3% with biologics. During follow-up, 83 deaths (7.9%) were reported. The overall 1-, 2- and 5-year survivals were 98.0%, 96.8% and 92.6%, respectively, without significant differences between lcSSc and dcSSc. CONCLUSION: Reuma.pt/SSc data highlights the importance of registries in improving knowledge about rare and complex diseases, such as SSc. Clinical features of Portuguese SSc patients are similar to those of other populations. In recently diagnosed patients, 5-year survival is over 92%. To the best of our knowledge, this is the first study showing that clinical features of Portuguese SSc are similar to those of other cohorts.

Photosensitivity and cGAS-Dependent IFN-1 Activation in Patients with Lupus and TREX1 Deficiency.

The exonuclease TREX1 safeguards the cells against DNA accumulation in the cytosol and thereby prevents innate immune activation and autoimmunity. TREX1 mutations lead to chronic DNA damage and cell-intrinsic IFN-1 response. Associated disease phenotypes include Aicardi‒Goutières syndrome, familial chilblain lupus, and systemic lupus erythematosus. Given the role of UV light in lupus pathogenesis, we assessed sensitivity to UV light in patients with lupus and TREX1 mutation by phototesting, which revealed enhanced photosensitivity. TREX1-deficient fibroblasts and keratinocytes generated increased levels of ROS in response to UV irradiation as well as increased levels of 8-oxo-guanine lesions after oxidative stress. Likewise, the primary UV-induced DNA lesions cyclobutane pyrimidine dimers were induced more strongly in TREX1-deficient cells. Further analysis revealed that single-stranded DNA regions, frequently formed during DNA replication and repair, promote cyclobutane pyrimidine dimer formation. Together, this resulted in a strong UV-induced DNA damage response that was associated with a cGAS-dependent IFN-1 activation. In conclusion, these findings link chronic DNA damage to photosensitivity and IFN-1 production in TREX1 deficiency and explain the induction of disease flares on UV exposure in patients with lupus and TREX1 mutation.