No Effect of Low-Dose Glucocorticoid Maintenance Therapy on Damage in SLE Patients in Prolonged Remission: A Propensity Score Analysis of the Longitudinal Lupus-Cruces-Bordeaux Inception Cohort.

Background/Objectives: Prolonged remission on low-dose glucocorticoids (GC) is a main goal in patients with systemic lupus erythematosus (SLE). The aim of this study is to assess whether GC ≤ 5 mg/d increases the risk of damage accrual in patients with SLE in prolonged remission. Methods: Observational study of routine clinical care data of the inception Lupus Cruces-Bordeaux cohort. Only patients in DORIS remission during five consecutive yearly visits were included. The endpoint was damage accrual during the 5-year follow-up, either global or specific damage: GC-induced, cardiovascular (CV), lupus and other. Patients no longer on GC therapy by year 5 (GC5-Off) were compared with those who continued GC therapy (GC5-On). Comparisons were made by Cox and Poisson regressions, which were adjusted with propensity score (PE) in order to control for confounding by indication. Results: 132 patients were included, 56 in the GC5-On and 76 in the GC5-Off groups. All patients were on GC ≤ 5 mg/d for the whole follow-up, the mean prednisone dose in the GC5-On group being 2.96 mg/d during the whole study period and 2.6 mg/d during the 5th year. Fourteen patients (10.6%) accrued damage. More patients in the GC5-On group accrued global damage, 16% vs. 7% in the GC5-Off group, p = 0.08, mainly at CV domains (7% vs. 1%, respectively, p = 0.16). In the PS-adjusted Cox and Poisson regressions, the GC5-On group was not significantly associated with global (p = 0.39) or CV damage accrual (p = 0.62), nor with the absolute (p = 0.40) or CV-restricted final SDI scores (p = 0.63). The C-index of the propensity score model was 0.79. Conclusions: Maintaining doses of prednisone < 5 mg/d in lupus patients in prolonged remission is not associated with an increased risk of damage accrual.

Elucidating the mechanisms and efficacy of antimalarial drugs in systemic lupus erythematosus.

INTRODUCTION: Antimalarials (AMs) are old drugs with a wide range of beneficial effects in systemic lupus erythematosus (SLE) beyond the control of activity. The most recent debate is focused on defining the optimal doses to assure the best benefit/risk ratio. AREAS COVERED: We have reviewed the pharmacological basis underlying the various therapeutic effects of AMs and the beneficial and toxic effects of HCQ, also discussing the role of mepacrine not only as a substitute in cases of maculopathy, but also as a very effective therapy combined with HCQ. We searched PubMed and Embase for articles published in English at any time. We used the terms "hydroxychloroquine" or "mepacrine" or "chloroquine" or "antimalarials", "pharmacokinetics", "efficacy", "remission", "toxicity", "adherence". We reviewed original research articles, large observational studies, systematic reviews, and expert consensus statements. Additionally, studies were identified through the assessment of the reference lists of the evaluated manuscripts. EXPERT OPINION: We advocate for the widespread use of HCQ at stable doses of 200 mg/d (≤4 mg/kg/d for most patients) and also for the early combination therapy with mepacrine to assure a good control of SLE activity, and also a durable and safe use of these essential drugs for the management of SLE.

Thrombotic antiphospholipid syndrome: From guidelines to clinical management.

Thrombotic manifestations, mainly venous thromboembolism (VTE) and stroke, are the most common and potentially life-threatening presentations of antiphospholipid syndrome (APS). The management of APS requires the assessment of the antiphospholipid antibodies (aPL) profile, of concurrent systemic lupus erythematosus or other systemic autoimmune diseases and the presence of risk factors for cardiovascular disease and bleeding. Anticoagulation with vitamin K antagonists (VKA) remains the cornerstone of therapy for thrombotic APS. As platelets play a central role in APS, low-dose aspirin is the first option for primary thromboprophylaxis in asymptomatic aPL carriers, and also plays a role as combination therapy with VKAs in arterial thrombosis. Treatment with direct oral anticoagulants (DOACs) could be considered in certain low-risk situations, although they are not recommended in patients with arterial thrombosis or triple positive aPL. Adjuvant therapies such as hydroxychloroquine and statins may be useful in complex settings such as thrombotic recurrences or high risk of bleeding. In this article, we review the evidence and the recommendations of the guidelines for the treatment of APS, and provide a critical and practical approach of its management from our clinical perspective.

Use of Glucocorticoids in SLE: A Clinical Approach.

Glucocorticoids (GCs) are one of the most effective first-line treatments for systemic lupus erythematosus (SLE). However, GC burden is associated with damage. The initial GC dose and tapering schedule should be tailored to the severity of the clinical scenario. As lupus therapy should prompt remission while minimising damage, recent guidelines recommend a more accurate approach to the use of GCs, setting lower starting doses and rapid tapering schemes, and encouraging maintenance prednisolone doses <5 mg/day. Methylprednisolone pulses (MP) help to reduce the dose of oral GCs and improve the clinical response in both severe and non-severe manifestations, without significant side effects. Fixed-tapering GC scheme provides a useful strategy to reduce GCs exposure. Long-term antimalarial treatment and early initiation of immunosuppressive drugs improve clinical efficacy while reducing GC toxicity. Besides, withdrawal of GCs is an achievable goal in patients in prolonged remission on stable treatment, and recent studies have attempted to identify the most suitable candidates. In this article, we review the pharmacological basis, clinical evidence of efficacy, dose-related harms, and potential withdrawal of GCs. We also review guidelines recommendations and finally give a personal and practical approach to dealing with the use of GCs in SLE patients.

Methylprednisolone Pulses and Prolonged Remission in Systemic Lupus Erythematosus: A Propensity Score Analysis of the Longitudinal Lupus-Cruces-Bordeaux Inception Cohort.

OBJECTIVE: The objective of this study was to analyze the effect of methylprednisolone pulses (MP), given during the first year after the diagnosis of systemic lupus erythematosus (SLE), in achieving prolonged remission according to the degree of lupus activity at presentation. METHODS: We conducted an observational study of routine clinical care data from the Lupus-Cruces-Bordeaux cohort. The end point was prolonged remission (ie, during five consecutive yearly visits). The effect of MP on remission during the first year was analyzed in the whole cohort and according to the baseline Systemic Lupus Erythematosus Disease Activity Index 2000 score: <6, 6 to 12, and >12, reflecting mild, moderate, and severe activity, respectively. For adjustment, logistic regression with propensity score (PS) and other therapeutic covariates was performed. RESULTS: Two hundred thirty-three patients were included. Prolonged remission was achieved by 132 patients (57%). MP were associated with prolonged remission (PS-adjusted odds ratio [OR] 2.50, 95% confidence interval [CI] 1.04-623, P = 0.042). A strong clinical effect was seen among patients with moderate (adjusted OR 5.28, 95% CI 1.27-21.97, P = 0.022) and moderate-severe SLE activity (adjusted OR 4.07, 95% CI 1.11-14.82, P = 0.033). The administration of MP resulted in reduced average dosages of prednisone during the first year among patient with moderate (mean 6.6 vs 10.2 mg/day, P = 0.017) and severe activity (mean 14 vs 28 mg/day, P = 0.015). The odds of prolonged remission were increased by longer-term use of hydroxychloroquine (HCQ) and decreased by higher initial doses of prednisone. CONCLUSION: This study supports the use of MP to induce prolonged remission in patients with SLE, particularly in those with moderate and severe activity. The extended use of HCQ also contributes to achieve prolonged remission.

Balancing risks and benefits in the use of hydroxychloroquine and glucocorticoids in systemic lupus erythematosus.

INTRODUCTION: Hydroxychloroquine (HCQ) and glucocorticoids (GCs) constitute the oldest and more used drugs in the treatment of systemic lupus erythematosus (SLE). Despite this long experience, both are still subject to a number of uncertainties, mainly regarding the dose. AREAS COVERED: We review the main mechanisms of action, the clinical and toxic effects of HCQ and GCs and analyze the recommendations for the use of both in guidelines published since 2018. We offer a set of recommendations based on the pharmacology, mechanisms of action and clinical evidence. EXPERT OPINION: HCQ is the backbone therapy for SLE, and a judicious use must be accomplished, using doses that allow a good control of lupus without compromising the safety of treatments very much prolonged over the time. Stable doses of 200 mg/day seem to accomplish both conditions. GCs should be used more judiciously, with methyl-prednisolone pulses as the main therapy for inducing rapid remission and doses ≤5-2.5 mg/day be never exceeded in long-term maintenance treatments.

Systemic lupus erythematosus and glucocorticoids: A never-ending story?

Glucocorticoids (GCs) continue to be essential agents for the management of systemic lupus erythematosus, since there are no other drugs able to active remission of active disease so rapidly. However, their potential for causing irreversible damage greatly limit their use. Fortunately, some strategies may help take advantage of their huge anti-inflammatory power while limiting GC-induced side effects. This article reviews the pharmacological basis of GC action and their translation into the clinical ground. We also offer the practical approach for the use of GC in induction and maintenance therapy as well as the strategies for GC withdrawal of the respective practice of the authors. The three main basic principles are a) using methyl-prednisolone pulses to induce remission not only in severe disease; b) limiting initial doses of prednisone to ≤30 mg/d, with rapid tapering to ≤5 mg/d, which should be the dose for maintenance therapy; and c) individualizing the decision and the strategy to withdraw GCs. Long-term therapy with HCQ and the early introduction of immunosuppressive treatment would help achieve these objectives.

Multidisciplinary management in chronic myeloid leukemia improves cardiovascular risk measured by SCORE.

Introduction: Cardiovascular events are one of the main long-term complications in patients with chronic myeloid leukemia (CML) receiving treatment with tyrosine kinase inhibitors (TKIs). The proper choice of TKI and the adequate management of risk factors may reduce cardiovascular comorbidity in this population. Methods: This study evaluated the cardiovascular risk of a cohort of patients with CML at diagnosis and after follow-up in a specialized cardiovascular risk consultation. In order to do this, we performed data analysis from 35 patients who received TKIs and were referred to the aforementioned consultation between 2015 and 2018 at our center. Cardiovascular risk factors were analyzed separately, as well as integrated into the cardiovascular SCORE, both at diagnosis and at the last visit to the specialized consultation. Results: At the time of diagnosis, 60% had some type of risk factor, 20% had a high or very high risk SCORE, 40% had an intermediate risk, and 40% belonged to the low risk category. During follow-up, the main cardiovascular adverse event observed was hypertension (diagnosed in 8 patients, 23%). 66% of patients quit smoking, achieving control of blood pressure in 95%, diabetes in 50%, weight in 76%, and dyslipidemia in 92%. 5.7% of patients suffered a thrombotic event and a significant percentage of patients showed a reduction in their SCORE. Conclusion: Our study shows the benefit of controlling cardiovascular risk factors through follow-up in a specialized consultation for patients with CML treated with TKI.

[Cytomegalovirus reactivation in patients with immune-mediated gastritis]. / Reactivación de citomegalovirus en pacientes con gastritis inmunomediada.

INTRODUCTION: Reactivation of cytomegalovirus can complicate the evolution of patients with gastritis induced by immune checkpoint inhibitors. METHODS: The experience in our center is described and a review of the literature is performed. RESULTS: A case of severe gastritis induced by treatment with a programmed cell death receptor-1 (anti-PD1) inhibitor, associated with reactivation of cytomegalovirus (CMV) is described. In the systematic review, we identified 5 cases of immune-related gastritis associated with CMV reactivation. Ganciclovir treatment contributed to clinical improvement in most patients. CONCLUSION: The early identification of a CMV infection in patients with severe or refractory immune-related gastritis will allow the initiation of targeted treatment, and may avoid increasing immunosuppressive therapy.

Clinical Differences and Outcomes of COVID-19 Associated Pulmonary Thromboembolism in Comparison with Non-COVID-19 Pulmonary Thromboembolism.

(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been reported to increase the risk of pulmonary thromboembolism (PTE). The aim of this study is to elucidate whether Coronavirus disease COVID-19-associated PTE has a different clinical expression than non-COVID-19 PTE due to a different pathophysiology. (2) Methods: retrospective study of PTE episodes conducted at our hospital between January 2019 and December 2020, comparing the group of COVID-19-associated PTE patients with a control group of non-COVID-19 PTE patients. (3) Results: A total of 229 patients with PTE were registered, 79 of whom had COVID-19. Cancer (15.2% vs. 39.3%; p < 0.001), previous surgery (0% vs. 8%; p = 0.01), previous VTE (2.5% vs. 15.3%; p = 0.003), signs and/or symptoms of deep venous thrombosis (DVT) (7.6% vs. 22.7%; p = 0.004) and syncope (1.3% vs. 8.1%; p = 0.035) were less frequent in the COVID-19 group. Central thrombosis was more frequent in the control group (35.3% vs. 13.9%; p = 0.001). No VTE recurrent episodes were observed in the COVID-19 group, whereas four (2.7%) episodes were recorded for the control group. One-month bleeding rate was higher in the COVID-19 group (10.1% vs. 1.3%; p = 0.004). (4) Conclusion: COVID-19-associated PTE has clinical characteristics that differ from those of PTE without COVID-19, including inferior severity and a lower rate of VTE recurrence. Physicians should be aware of the high risk of bleeding in the first month of COVID-19-associated PTE.

Ustekinumab for corticodependent immune-mediated colitis by pembrolizumab, an alternative for patients with concomitant liver injury.

Pembrolizumab, a programmed cell death receptor (PD-1) inhibitor, have improved the prognosis in several types of cancer. Despite the important clinical benefits, checkpoint inhibition have been associated with inflammatory and immune-related side effects (irAE).

Clinical Features and Risk Factors for Mortality Among Long-term Care Facility Residents Hospitalized Due to COVID-19 in Spain.

BACKGROUND: COVID-19 severely impacted older adults and long-term care facility (LTCF) residents. Our primary aim was to describe differences in clinical and epidemiological variables, in-hospital management, and outcomes between LTCF residents and community-dwelling older adults hospitalized with COVID-19. The secondary aim was to identify risk factors for mortality due to COVID-19 in hospitalized LTCF residents. METHODS: This is a cross-sectional analysis within a retrospective cohort of hospitalized patients ≥75 years with confirmed COVID-19 admitted to 160 Spanish hospitals. Differences between groups and factors associated with mortality among LTCF residents were assessed through comparisons and logistic regression analysis. RESULTS: Of 6 189 patients ≥75 years, 1 185 (19.1%) were LTCF residents and 4 548 (73.5%) were community-dwelling. LTCF residents were older (median: 87.4 vs 82.1 years), mostly female (61.6% vs 43.2%), had more severe functional dependence (47.0% vs 7.8%), more comorbidities (Charlson Comorbidity Index: 6 vs 5), had dementia more often (59.1% vs 14.4%), and had shorter duration of symptoms (median: 3 vs 6 days) than community-dwelling patients (all, p < .001). Mortality risk factors in LTCF residents were severe functional dependence (adjusted odds ratios [aOR]: 1.79; 95% confidence interval [CI]: 1.13-2.83; p = .012), dyspnea (1.66; 1.16-2.39; p = .004), SatO2 < 94% (1.73; 1.27-2.37; p = .001), temperature ≥ 37.8°C (1.62; 1.11-2.38; p = .013); qSOFA index ≥ 2 (1.62; 1.11-2.38; p = .013), bilateral infiltrates (1.98; 1.24-2.98; p < .001), and high C-reactive protein (1.005; 1.003-1.007; p < .001). In-hospital mortality was initially higher among LTCF residents (43.3% vs 39.7%), but lower after adjusting for sex, age, functional dependence, and comorbidities (aOR: 0.74, 95%CI: 0.62-0.87; p < .001). CONCLUSION: Basal functional status and COVID-19 severity are risk factors of mortality in LTCF residents. The lower adjusted mortality rate in LTCF residents may be explained by earlier identification, treatment, and hospitalization for COVID-19.

Incidence of venous thromboembolism in patients with non-hematological cancer admitted for COVID-19 at a third-level hospital in Madrid.

An increased risk of venous thromboembolism (VTE) in hospitalized patients with COVID-19 has been reported. We aimed to describe the incidence rate of VTE on patients with non-hematological cancer who required hospitalization due to COVID-19 at our center. In this prospective study, non-hematological cancer patients hospitalized for confirmed COVID-19 at our institution from 1st March to 30th April 2020, were evaluated daily for VTE complications during their hospital stay, and after discharge until 30th June 2020. Furthermore, Doppler ultrasound of lower limbs was routinely performed in asymptomatic patients based on D-dimer levels and current active cancer therapy. The primary outcome of this study was the cumulative incidence of VTE. Secondary outcomes were the cumulative incidence of bleeding and mortality. A total of 58 hospitalized non-hematological cancer patients and confirmed COVID-19 were identified. Median follow-up since initial symptoms of COVID-19 was 91 days (IQR 19-104). Pulmonary embolism was diagnosed in three (5%) patients. Symptomatic catheter-related deep vein thrombosis (DVT) was observed in one patient. Doppler ultrasound of lower limbs was done in 11 asymptomatic patients, showing distal DVT in two of them (18%). The cumulative incidence of VTE on day 14 after admission was 10%, without new VTE events after hospital discharge and up to 90 days follow-up. No bleeding complication was observed. Seventeen patients (29%) died in the first 14 days after COVID-19 diagnosis. Four patients died after discharge due to malignancy progression. The cumulative incidence of VTE in non-hematological cancer patients under active treatment was 10% at day 14 after admission, with no further new events in the following 12 weeks.

Clinical Characteristics and Risk Factors for Mortality in Very Old Patients Hospitalized With COVID-19 in Spain.

BACKGROUND: Advanced age is a well-known risk factor for poor prognosis in COVID-19. However, few studies have specifically focused on very old inpatients with COVID-19. This study aims to describe the clinical characteristics of very old inpatients with COVID-19 and identify risk factors for in-hospital mortality at admission. METHODS: We conducted a nationwide, multicenter, retrospective, observational study in patients ≥ 80 years hospitalized with COVID-19 in 150 Spanish hospitals (SEMI-COVID-19) Registry (March 1-May 29, 2020). The primary outcome was in-hospital mortality. A uni- and multivariate logistic regression was performed to assess predictors of mortality at admission. RESULTS: A total of 2772 consecutive patients (49.4% men, median age 86.3 years) were analyzed. Rates of atherosclerotic cardiovascular disease, diabetes mellitus, dementia, and Barthel Index < 60 were 30.8%, 25.6%, 30.5%, and 21.0%, respectively. The overall case-fatality rate was 46.9% (n: 1301) and increased with age (80-84 years: 41.6%; 85-90 years: 47.3%; 90-94 years: 52.7%; ≥95 years: 54.2%). After analysis, male sex and moderate-to-severe dependence were independently associated with in-hospital mortality; comorbidities were not predictive. At admission, independent risk factors for death were: oxygen saturation < 90%; temperature ≥ 37.8°C; quick sequential organ failure assessment (qSOFA) score ≥ 2; and unilateral-bilateral infiltrates on chest x-rays. Some analytical findings were independent risk factors for death, including estimated glomerular filtration rate < 45 mL/min/1.73 m2; lactate dehydrogenase ≥ 500 U/L; C-reactive protein ≥ 80 mg/L; neutrophils ≥ 7.5 × 103/µL; lymphocytes < 0.8 × 103/µL; and monocytes < 0.5 × 103/µL. CONCLUSIONS: This first large, multicenter cohort of very old inpatients with COVID-19 shows that age, male sex, and poor preadmission functional status-not comorbidities-are independently associated with in-hospital mortality. Severe COVID-19 at admission is related to poor prognosis.