Prognostic significance of lymphocytic foci composition in minor salivary gland biopsies for severe disease flare and severity in Sjögren's syndrome: a 3-year follow-up cohort study.

Introduction: This was an ambispective cohort study evaluating the prognostic significance of lymphocytic foci and its lymphoid composition in minor salivary gland biopsy (MSGB) for short-term disease flare and severity in Sjögren's syndrome (SS). Methods: The inclusion criteria comprised individuals meeting the ACR/EULAR 2016 criteria who underwent MSGB with an infiltration of more than 50 lymphocytes and received clinical diagnosis between September 2017 and December 2018. Patients with inadequate biopsy samples were excluded. The number of lymphocytic foci and their lymphoid composition in MSGB were assessed using immunofluorescence staining. Major organ damage and improvements in the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) were measured. Statistical analyses, including Cox and linear regressions, were conducted. Results: A total of 78 patients with at least one lymphocytic focus were included in the study. The presence of higher T-cell counts in lymphocytic foci in MSGB was associated with severe disease flare, and a logarithmic transformation of T-cell count indicated increased risk (HR 1.96, 95% CI 0.91-4.21). Improvements in the ESSDAI were associated with higher total lymphocyte count and T- and B-cell numbers in the lymphoid composition of the lymphocytic foci. Seropositive patients exhibited higher T CD4+ cell numbers. Correlation analysis showed negative associations between age and lymphocytic foci and the T-cell count. Positive correlations were observed between antinuclear antibody (ANA) titers and total lymphocyte numbers. Discussion: Patients with a higher number of T cells in the lymphocytic infiltrates of lymphocytic foci may have a two-fold risk of severe disease flare. The number of B cells and T CD4+ cells in the lymphocytic infiltrates of lymphocytic foci showed a weak but positive relation with the ESSDAI improvement during follow-up. Age and seropositivity appeared to influence the lymphoid composition of the lymphocytic foci.

Impact of IL6R genetic variants on treatment efficacy and toxicity response to sarilumab in rheumatoid arthritis.

BACKGROUND: Sarilumab, an IL-6 receptor antagonist, is a first-line biologic disease-modifying anti-rheumatic drug for rheumatoid arthritis. The identification of genetic biomarkers as predictors of response to sarilumab could allow for a personalized treatment strategy to improve clinical outcomes. METHODS: We conducted a retrospective cohort study of 62 patients treated with sarilumab to determine whether single-nucleotide polymorphisms (SNP) in the IL6R gene could predict efficacy and toxicity responses. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples obtained from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Treatment response was assessed six months after treatment initiation. Satisfactory response was based on EULAR criteria. Low disease activity was determined according to DAS28 and CDAI and quantitative improvements in DAS28 and CDAI scores. RESULTS: Three SNPs (rs4845625, rs4329505 and rs11265618) were significantly associated with response outcomes. All of the SNPs, except for rs12083537, had at least one significant association with dyslipidemia or hepatotoxicity. CONCLUSIONS: These findings support the potential clinical value of SNPs, particularly rs4845625, as potentially useful biomarkers to predict response to sarilumab in patients with RA.

Indoor falls and number of previous falls are independent risk factors for long-term mortality after a hip fracture.

BACKGROUND: Hip fractures are almost always the result of a fall. Causes and circumstances of falls may differ between frail and vigorous patients. AIM: To describe the circumstances of falls causing hip fractures, number of falls during the previous year, and their association with long-term mortality. PATIENTS AND METHODS: The study is a retrospective review conducted in a tertiary university hospital serving a population of 425,000 inhabitants in Barcelona. All patients admitted with hip fractures with medical records describing the circumstances and number of previous falls were included. The number of falls in the previous 12 months was recorded, including the one causing the fracture. The circumstances of the index fall were dichotomized according to whether it was from the patient's own height or above; day or night; indoors or outdoors, due to intrinsic or extrinsic causes. Cumulative mortality was recorded for almost 5 years after hip fracture. RESULTS: Indoor falls were strongly associated with shorter survival. Falling more than once in the previous year was also a risk factor for long-term mortality (hazard ratio 1.461, p < 0.001 and hazard ratio 1.035, p = 0.008 respectively). CONCLUSION: Indoor falls and falling more than once in the previous year are long-term risk factors for mortality after hip fractures. It is always essential to take a careful patient history on admission to determine the number of falls and their circumstances, and special care should be taken to reduce mortality in patients at high risk.

A 37-Year-Old Man with Familial Hereditary Hemorrhagic Telangiectasia and Pulmonary Arteriovenous Malformations Presenting with Seizures and a Diagnosis of Brain Abscesses.

BACKGROUND Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant genetic disease associated with arteriovenous malformations involving diverse organs. Neurological complications from brain abscesses (BA) secondary to pulmonary arteriovenous malformations (PAVMs) is a serious and recognized, albeit infrequent, medical problem. We report the case of a 37-year-old man with familial HHT and PAVMs who presented with seizures as a manifestation of BA. CASE REPORT A 37-year-old man was admitted for first tonic-clonic seizures. He had a history of recurrent epistaxis and recurrent gastrointestinal bleeds treated with fulguration and oral iron therapy. A diagnosis of HHT was made because the patient met 3 of 4 Curaçao criteria. Physical examination revealed hypoxemia without dyspnea. A chest X-ray detected nodular pulmonary lesions in both lower lobes. Cranial computed tomography (CT) revealed 3 space-occupying lesions. Antiepileptics and dexamethasone were started. Cranial magnetic resonance and positron emission tomography suggested that lesions were BA. Thoracoabdominal CT with contrast revealed several bilateral PAVMs. Blood cultures were repeatedly negative. With the presumptive diagnosis of septic-embolic BA, empirical antibiotic therapy was started for 8 weeks. Neurological symptoms resolved and malformations >2 cm were selectively embolized. A genetic study revealed exon5 mutations in the ENG gene. CONCLUSIONS This report highlights the association between PAVMs in a patient with HHT and development of BA. Clinicians should be aware of this association so that diagnosis and treatment can be provided as fast as possible to ensure the best outcome for the patient. Embolization was performed as preventive treatment, and a genetic study was conducted as it is potentially useful for primary prevention in the patient's offspring.

Role of IL6R Genetic Variants in Predicting Response to Tocilizumab in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic arthritis that may lead to irreversible joint damage and significant disability. Patients with RA are commonly treated with Tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, but many patients refractorily respond to this therapy. Identifying genetic biomarkers as predictors of TCZ response could be a key to providing a personalized medicine strategy. We aimed to evaluate whether functional single nucleotide polymorphisms (SNPs) in the IL6R gene could predict TCZ response in patients with RA. We retrospectively included 88 RA patients treated with TCZ. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Responses to treatments were assessed at six months using three variables: a quantitative improvement in Disease activity score including 28 joints (DAS28), a satisfactory European League Against Rheumatism (EULAR) response, and low disease activity (LDA) achievement. The three response variables studied were associated with genetic variant rs4845625, and no association was found with the other five SNPs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for TCZ response.

Krebs von den Lungen-6 glycoprotein circulating levels are not useful as prognostic marker in COVID-19 pneumonia: A large prospective cohort study.

Coronavirus disease 2019 (COVID-19) has rapidly expanded worldwide. Currently, there are no biomarkers to predict respiratory worsening in patients with mild to moderate COVID-19 pneumonia. Small studies explored the use of Krebs von de Lungen-6 circulating serum levels (sKL-6) as a prognostic biomarker of the worsening of COVID-19 pneumonia. We aimed at a large study to determine the prognostic value of sKL-6 in predicting evolving trends in COVID-19. We prospectively analyzed the characteristics of 836 patients with COVID-19 with mild lung disease on admission. sKL-6 was obtained in all patients at least at baseline and compared among patients with or without respiratory worsening. The receiver operating characteristic curve was used to find the optimal cutoff level. A total of 159 (19%) patients developed respiratory worsening during hospitalization. Baseline sKL-6 levels were not higher in patients who had respiratory worsening (median {IQR} 315.5 {209-469} vs. 306 {214-423} U/ml p = 0.38). The last sKL-6 and the change between baseline and last sKL-6 were higher in the respiratory worsening group (p = 0.02 and p < 0.0001, respectively). The best sKL-6 cutoff point for respiratory worsening was 497 U/ml (area under the curve 0.52; 23% sensitivity and 85% specificity). sKL-6 was not found to be an independent predictor of respiratory worsening. A conditional inference tree (CTREE) was not useful to discriminate patients at risk of worsening. We found that sKL-6 had a low sensibility to predict respiratory worsening in patients with mild-moderate COVID-19 pneumonia and may not be of use to assess the risk of present respiratory worsening in inpatients with COVID-19 pneumonia.

Early differentiated CD28+ CD27+ T lymphocytes as a biomarker for short and long-term outcomes in older patients with pneumonia.

This study tested the hypothesis that a more senescent immune system would predict a worse outcome in older patients hospitalized for community-acquired pneumonia (CAP). CAP has long been responsible for high rates of mortality and readmissions among older people. Although immunosenescence is a key factor in the increased susceptibility to infections, there are no related biomarkers currently available in clinical practice. In this context, the aim of this prospective study was to identify immunosenescence-related biomarkers to predict outcomes in patients older than 65 years hospitalized for CAP. We evaluated 97 patients admitted to our hospital for CAP in 2019 and 2020. All patients were followed for 1 year. Our findings showed that elevated levels of early differentiated CD28+ CD27+ T cells at admission were associated with better short (2 months) and long-term (1 year) outcomes in terms of mortality and readmissions. Early differentiated CD28+ CD27+ CD4+ T cell counts were even better long-term predictors. In conclusion, early differentiated CD28+ CD27+ T cells could be useful biomarkers to identify high-risk older patients with CAP, helping clinicians with risk stratification and follow-up.

Clinical Value of IL6R Gene Variants as Predictive Biomarkers for Toxicity to Tocilizumab in Patients with Rheumatoid Arthritis.

Tocilizumab is a first-line biologic disease-modifying anti-rheumatic drug (bDMARD) that inhibits the interleukin-6 (IL-6) pathway by antagonizing the IL-6 receptor (IL-6R). Tocilizumab is widely used to treat rheumatoid arthritis (RA), a prevalent autoimmune disease that can cause irreversible joint damage and disability. Although many bDMARDs have been developed for RA, there is a lack of validated biomarkers which could guide personalized medicine strategies. To evaluate whether single-nucleotide polymorphisms (SNPs) in the IL6R gene could predict tocilizumab toxicity in patients with RA, we conducted a retrospective cohort study of 88 patients treated with tocilizumab. Six SNPs previously described in the IL6R gene were genotyped (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625). Using parametric tests, we studied the association between the SNPs and hepatotoxicity, infection, hypersensitivity, gastrointestinal, hematological, and dyslipidemia adverse events (AEs). We found associations between dyslipidemia and rs4845625 and between hematological AEs and rs11265618 and rs4329505. No further associations were found for the remaining SNPs and other AEs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for toxicity to tocilizumab in patients with RA.

Sarilumab (IL-6R antagonist) in critically ill patients with cytokine release syndrome by SARS-CoV2.

ABSTRACT: Blocking IL-6 pathways with sarilumab, a fully human anti-IL-6R antagonist may potentially curb the inflammatory storm of SARS-CoV2. In the present emergency scenario, we used "off-label" sarilumab in 5 elderly patients in life-threatening condition not candidates to further active measures. We suggest that sarilumab can modulate severe COVID-19-associated Cytokine Release Syndrome.

Hip fracture and mortality: study of specific causes of death and risk factors.

The leading causes of mortality in our study were pneumonia, diseases of the circulatory system, and dementias. In patients with hip fractures, the emphasis should be placed not only on measures to prevent falls and osteoporosis, but also on preventing functional decline and pneumonia. PURPOSE: To describe the specific causes of death in patients who died up to 2 years after sustaining a hip fracture, how many of those deaths were directly related to the hip fracture, and the risk factors for mortality. METHODS: A retrospective review of the clinical data of all patients admitted with hip fractures between December 2009 and September 2015. Cause of death was classified according to the International Statistical Classification of Diseases and Related Health Problems (ICD10) RESULTS: In the first 2 years after hip fracture, 911 patients (32.7%) died. The leading causes of mortality were pneumonia 177 (19.4%), diseases of the circulatory system 146 (16%), and dementias 126 (13.9%). Thirty patients (3.2%) died from causes directly related to hip fracture or surgery. Mortality risk factors with a higher relative risk were advanced age, male sex, higher comorbidity, delirium, and medical complications during admission. CONCLUSIONS: Pneumonia and circulatory system diseases were the commonest causes of death in our study. In patients with hip fractures, emphasis should be placed on preventing functional decline and pneumonia. In a few patients, death was directly related to the hip fracture, although decompensation of chronic illness as a result of hip fracture and fracture-related functional decline may have been indirect causes. Patients with worse conditions at admission had the highest risk of mortality.

Effectiveness and safety of intravenous tocilizumab to treat COVID-19-associated hyperinflammatory syndrome: Covizumab-6 observational cohort.

Although the starting event in COVID-19 is a viral infection some patients present with an over-exuberant inflammatory response, leading to acute lung injury (ALI) and adult respiratory distress syndrome (ARDS). Since IL-6 plays a critical role in the inflammatory response, we assessed the efficacy and safety of tocilizumab (TCZ) in this single-centre, observational study in all Covid-19 in-patient with a proven SARS-CoV-2 rapidly progressing infection to prevent ALI and ARDS. 104 patients with COVID-19 treated with TCZ had a lower mortality rate (5·8%) compared with the regional mortality rate (11%), hospitalized patient's mortality (10%), and slightly lower than hospitalized patients treated with our standard of care alone (6%). We found that TCZ rapidly decreased acute phase reactants, ferritin and liver release of proteins. D-Dimer decreased slowly. We did not observe specific safety concerns. Early administration of IL6-R antagonists in COVID-19 patients with impending hyperinflammatory response, may be safe and effective treatment to prevent, ICU admission and further complications.

Effect of bosentan in pulmonary hypertension development in systemic sclerosis patients with digital ulcers.

Systemic sclerosis is a disease where microcirculation damage is critical in their beginning and vascular complications have similar pathogenic findings. Digital ulcers are a frequent complication in systemic sclerosis patients and pulmonary hypertension is one of the leading causes of death. The use of bosentan has been shown to be useful for the treatment of pulmonary arterial hypertension and to prevent new digital ulcers. However, is unknown if bosentan can prevent pulmonary hypertension. Our objective was to determine if bosentan is useful to prevent pulmonary hypertension in SSc patients. A retrospective study in 237 systemic sclerosis patients with digital ulcers history treated or not with bosentan to prevent it was made. We analyzed the occurrence of pulmonary hypertension defined by an echocardiogram pulmonary arterial pressure > 40 mmHg in the entire cohort. Demographic, clinical, and treatment variables were recorded for all patients. Statistical significance was denoted by p values < 0.05. Fifty-nine patients were treated with bosentan a median of 34 months. 13.8% of treated patients had pulmonary hypertension vs 23.7% of untreated patients (p 0.13) during the follow up. In multivariate analysis patients not treated with bosentan had 3.9fold-increased risk of pulmonary hypertension compared with patients under bosentan treatment (p < 0.02). Moreover the percentage carbon monoxide diffusing capacity (DLCO) in bosentan treated patients did not decrease from baseline to the end of follow-up (61.8±14% vs 57±20.1%, p = 0.89). We concluded that Systemic sclerosis patients with digital ulcers treated with bosentan seems to have less risk to develop pulmonary hypertension and to stabilize DLCO.

Pulmonary Thrombosis or Embolism in a Large Cohort of Hospitalized Patients With Covid-19.

Objective: We set out to analyze the incidence and predictive factors of pulmonary embolism (PE) in hospitalized patients with Covid-19. Methods: We prospectively collected data from all consecutive patients with laboratory-confirmed Covid-19 admitted to the Hospital de la Santa Creu i Sant Pau, a university hospital in Barcelona, between March 9 and April 15, 2020. Patients with suspected PE, according to standardized guidelines, underwent CT pulmonary angiography (CTPA). Results: A total of 1,275 patients with Covid-19 were admitted to hospital. CTPA was performed on 76 inpatients, and a diagnosis of PE was made in 32 (2.6% [95%CI 1.7-3.5%]). Patients with PE were older, and they exhibited lower PaO2:FiO2 ratios and higher levels of D-dimer and C-reactive protein (CRP). They more often required admission to ICU and mechanical ventilation, and they often had longer hospital stays, although in-hospital mortality was no greater than in patients without PE. High CRP and D-dimer levels at admission (≥150 mg/L and ≥1,000 ng/ml, respectively) and a peak D-dimer ≥6,000 ng/ml during hospital stay were independent factors associated with PE. Prophylactic low molecular weight heparin did not appear to prevent PE. Increased CRP levels correlated with increased D-dimer levels and both correlated with a lower PaO2:FiO2. Conclusions: The 2.6% incidence of PE in Covid-19 hospitalized patients is clearly high. Higher doses of thromboprophylaxis may be required to prevent PE, particularly in patients at increased risk, such as those with high levels of CRP and D-dimer at admission. These findings should be validated in future studies.

The four horsemen of a viral Apocalypse: The pathogenesis of SARS-CoV-2 infection (COVID-19).

The pathogenesis of coronavirus disease 2019 (COVID-19) may be envisaged as the dynamic interaction between four vicious feedback loops chained or happening at once. These are the viral loop, the hyperinflammatory loop, the non-canonical renin-angiotensin system (RAS) axis loop, and the hypercoagulation loop. Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 lights the wick by infecting alveolar epithelial cells (AECs) and downregulating the angiotensin converting enzyme-2 (ACE2)/angiotensin (Ang-1-7)/Mas1R axis. The viral feedback loop includes evading the host's innate response, uncontrolled viral replication, and turning on a hyperactive adaptative immune response. The inflammatory loop is composed of the exuberant inflammatory response feeding back until exploding in an actual cytokine storm. Downregulation of the ACE2/Ang-(1-7)/Mas1R axis leaves the lung without a critical defense mechanism and turns the scale to the inflammatory side of the RAS. The coagulation loop is a hypercoagulable state caused by the interplay between inflammation and coagulation in an endless feedback loop. The result is a hyperinflammatory and hypercoagulable state producing acute immune-mediated lung injury and eventually, adult respiratory distress syndrome.

Reflexiones de un docente ante la situación de pandemia de COVID-19 / No disponible

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Rituximab levels are associated with the B cell homeostasis but not with the clinical response in patients with rheumatoid arthritis.

OBJECTIVE: To study the levels of rituximab (RTX) and anti-RTX antibodies (ARAs) in patients with rheumatoid arthritis (RA) at 30, 90, and 180 days after the first infusion, in relation to clinical and serological parameters and B cell homeostasis. METHODS: Thirty-four patients with RA who failed to respond to anti-tumor necrosis factor therapy received RTX. At baseline, 4, 12, and 24 weeks after the first infusion of RTX, we performed a clinical assessment and determined the levels of RTX, ARAs, B cells, rheumatoid factors, anti-cyclic citrullinated peptide antibodies, immunoglobulins, and complements. RESULTS: RTX levels varied widely among patients. No ARAs were detected during the follow-up. Patients with lower levels of RTX presented with higher decreases in erythrocyte sedimentation rate, immunoglobulins, and complement 6 months after the first infusion. Patients with higher levels of RTX showed a higher B cell depletion at 90 days but an earlier B cell recovery than those with lower levels of RTX. No differences in clinical response were observed between the two groups at 6 months after starting the treatment. CONCLUSION: Our findings suggest that RTX levels in the serum of patients with RA are related to B cell homeostasis and the severity of immunological parameters but not to the clinical response at 6 months.