Quality evaluation of the underlying evidence in the updated treatment recommendations for systemic lupus erythematosus.

OBJECTIVES: SLE is a multisystem autoimmune disorder known for its broad clinical spectrum. Recently, the European, British and Latin American rheumatology professional societies [EULAR, British Society for Rheumatology (BSR) and Pan-American League of Associations of Rheumatology (PANLAR)] published updated recommendations for SLE management. The objective of this study was to characterize the data supporting the updated recommendations, with the goal of highlighting areas that could benefit from additional high-quality research. METHODS: References were compiled from the recently published EULAR, BSR and PANLAR SLE treatment recommendations. Data collected from each study included publication year, treatment regimen, study design, sample size, inclusion and exclusion criteria and relevant SLE diagnostic criteria. Studies with less than 10 patients and those that did not specify the SLE diagnostic criteria used were excluded. RESULTS: Altogether, 250 studies were included in this study. The majority were prospective and retrospective cohorts (72%), with only a small percentage of randomized controlled trials (28%). The median (interquartile range) number of patients included was 37 (19-86). The revised ACR 1982 criteria were the most commonly used criteria for SLE diagnosis (52%), followed by the revised ACR criteria from 1997 (27%). Only a small proportion of studies included the use of disease activity scores when defining study population (15%). CONCLUSION: Our study has indicated a scarcity of sufficiently powered high-quality research referenced in the recently published SLE treatment guidelines. Well-designed large-scale studies utilizing the updated 2019 SLE diagnostic criteria are needed to better inform healthcare professionals caring for patients with SLE.

Exploring the Association between Legg-Calvé-Perthes Disease and Attention Deficit Hyperactivity Disorder in Children.

BACKGROUND: Legg-Calvé-Perthes disease (LCPD) is an idiopathic hip osteonecrosis prevalent in children < age 15 years. The etiology remains incompletely understood, partly because of multiple potential environmental risk factors and partly because of lack of genetic markers. It has been hypothesized that hyperactivity may induce mechanical stress and/or vascular damage at a fragile joint. OBJECTIVES: To assess children with LCPD for markers of attention deficit hyperactivity disorder (ADHD) relative to their unaffected comparably aged siblings to exclude the contribution of hyperactive behavior versus environmental and/or genetic factors in LCPD. METHODS: All children followed in the Pediatric Orthopedic Clinic, and their comparably aged siblings, were recruited. ADHD was assessed using the TOVA computerized test and DSM-IV criteria. Quality of life and sleep disorders as ancillary tests were assessed using the Child Health Questionnaire (Parent Form 50), Pediatric Outcomes Data Collection Instrument, and Pediatric Daytime Sleepiness Scale. RESULTS: Sixteen children with LCPD (age 9.1 ± 3.3, 75% males) were compared with their closest-aged siblings (age 9.3 ± 2.6, 30% males). Mean TOVA scores of children with LCPD (-3.79 ± 2.6) and of their non-LCPD siblings (-3.6 ± 4.04) were lower relative to the general population (0 ± 1.8, P < 0.0001). Both group means were in the ADHD range (≤ -1.8) implying that 73% of this LCPD cohort and 53% of their non-LCPD siblings performed in the ADHD range, relative to 3.6% incidence expected in the general population (P < 0.0001). Other test results were similar in both groups. CONCLUSIONS: Our findings in a small cohort of children with LCPD and their comparably aged siblings do not support an association between LCPD and ADHD. ADHD markers were equally high in the LCPD children and siblings.

Renal Tubular CD24 Upregulation Aggravates Folic Acid Induced Acute Kidney Injury: A Possible Role for T Regulatory Cells Inhibition in Mice.

Acute kidney injury (AKI) is characterized by cell death and inflammation. CD24 is a protein induced during tissue damage and is not expressed in mature renal tissue. We explored the role of CD24 in the pathogenesis of folic acid-induced AKI (FA-AKI) in mice. A single Intraperitoneal (IP) injection of folic acid induced AKI in WT and CD24-/- mice. Renal function tests, histological analysis, immunohistochemistry, Western blot analysis, and ELISA were performed to assess the severity of renal damage and the intensity of the inflammatory response. FA-AKI induced CD24 in the distal tubular epithelial cells. Compared to WT mice, FA-AKI CD24-/- mice exhibited an attenuated reduction in renal function and histological injury, lower serum IL-10 and interferon γ, and decreased expression of renal TNFα. In contrast, renal and systemic IL-33 upregulation were augmented. CD24-/- FA-AKI animals exhibited increased splenic margination and renal infiltration of regulatory T cells (Tregs). At day 7, FA-AKI CD24-/- mice exhibited increased expression of tubular pro-apoptotic and decreased anti-apoptotic proteins compared to WT animals. Anti-CD24 antibody administration to FA-AKI mice attenuated the decrease in renal function as well as the histological injury. Renal biopsies from patients with ATN stained strongly for CD24 in the distal tubules. In conclusion, during AKI, upregulation of CD24 promotes renal inflammation through inhibition of Treg infiltration and diversion of cell death towards necrosis rather than apoptosis. Neutralization of CD24 may prove a target for future therapies in AKI.

Twenty Years of Targeted and Biologic Immunomodulatory Drugs: Postmarketing Modifications of Drug Labels Approved by the US Food and Drug Administration.

OBJECTIVE: To determine the extent and characteristics of postmarketing safety issues associated with targeted and biologic immunomodulatory drugs. METHODS: We searched Drugs@FDA to identify immunomodulatory drugs approved between January 1, 1998, and December 31, 2017. Supporting studies characteristics, regulatory pathways, and label modifications from approval to May 2020 were collected from drug labels. RESULTS: The study cohort included 31 drugs, mostly (n=23, 74%) monoclonal antibodies. The most common indications were rheumatologic disorders (n=10, 32%). A total of 372 postmarketing safety-related label modifications were identified, with a median duration of 5 years (interquartile range [IQR], 32 to 105 months) following initial approval. Most drugs were affected by modifications of warnings and precautions (n=25, 81%), 10 drugs (32%) were affected by black box warnings, and 3 drugs (10%) were withdrawn from the market. The most common safety issues were related to infections (n=109, 27%) followed by immunologic phenomena (n=99, 24%). The most common data source was postmarketing reports to pharmacovigilance programs (n=205, 55%). Drugs approved by the FDA through expedited regulatory pathways (n=12, 39%) had more postmarketing safety issues compared with those approved through regular approval (15.5 vs 9.8 per drug, respectively), with longer durations from approval to identification (6 years; IQR, 38 to 111 months, vs 4 years; IQR, 28 to 95 months). CONCLUSION: Safety issues associated with targeted and biologic immunomodulatory drugs are often identified postmarketing, with substantial time intervals following initial approval. Clinicians should follow updates of the safety profiles of immunomodulatory drugs closely and be vigilant for previously unidentified adverse events.

Treatment with Ixekizumab Following Secukinumab Failure in Patients with Psoriatic Arthritis: Real-Life Experience from a Resistant Population.

OBJECTIVE: To assess the clinical response to ixekizumab following secukinumab failure in patients with psoriatic arthritis. METHODS: A retrospective multi-center observational study included psoriatic arthritis (PsA) patients with a history of treatment with secukinumab, further treated with ixekizumab. Primary endpoint was primary response to treatment (drug survival > 6 months); secondary endpoints were changes in disease activity indices from initiation of ixekizumab to 6 and 12 months later and overall drug survival. RESULTS: Of 23 PsA patients, 86% (n = 20) received more than two TNF inhibitors (TNFi). Median secukinumab treatment time was 15 months (IQR 10-21.5 months). Subsequently, 19 patients (83%) had a primary response to ixekizumab. Overall treatment duration during follow-up period for primary responders was 14 months (IQR 10-20.5). Reasons for ixekizumab cessation were worsening psoriasis (27%), peripheral arthritis (27%), both (47%), worsening of axial disease (13%), and adverse events (6%). Articular disease indices including Disease Activity Index for Psoriatic Arthritis (DAPSA), tender joints count (TJC) and Simplified Disease Activity Index (SDAI) were significantly lower at 6 and 12 months (DAPSA 1.5-2 levels reduction; p = 0.018 and 1-1.5 levels reduction; p = 0.031, respectively; TJC -2.16 [-4.0, -0.3]; p = 0.025 and -1.69 [-3.09, -0.28]; p = 0.022, respectively; SDAI -10.13 [-16.4, -3.8], p = 0.003 and -12.2 [-17.1, -7.2], p = 0.0002, respectively). PASI75 at 6 and 12 months was achieved by 63% and 57%, respectively, and PASI100 at 6 and 12 months by 31% and 21%, respectively. CONCLUSION: Patients with resistant PsA, including inadequate response to secukinumab, demonstrated a good response to ixekizumab, albeit limited on time. Within class switch from secukinumab to ixekizumab may be a plausible therapeutic option in PsA patients following secukinumab failure.

Characteristics of criminal cases against physicians charged with opioid-related offenses reported in the US news media, 1995-2019.

BACKGROUND: Pharmaceutical companies and drug distributors are intensely scrutinized in numerous lawsuits for their role in instigating the opioid epidemic. Many individual physicians have also been held accountable for activities related to prescribing opioid medications. The purpose of this study was to examine the epidemiologic patterns of criminal cases against physicians charged with opioid-related offenses reported in the US news media. METHODS: We searched the Nexis Uni® database for news media reports on physicians who had been arrested, indicted or criminally charged for illegally prescribing opioids between January 1995 and December 2019. Data collected from the news media reports include defendant's age, sex, clinical specialty, type of crime and legal consequences. RESULTS: The annual number of criminal cases against physicians charged with opioid-related offenses reported in the US news media increased from 0 in 1995 to 42 in 2019. Of the 372 physician defendants in these criminal cases, 90.1% were male, 27.4% were 65 years and older, and 23.4% were charged in Florida. Of the 358 physician defendants with known clinical specialty, 245 (68.4%) practiced in internal medicine, family medicine, or pain management. Drug trafficking was the most commonly convicted crime (accounting for 54.2% of all convicted cases), followed by fraud (19.1%), money laundering (11.0%) and manslaughter (5.6%). Of the 244 convicted physicians with known sentences, 85.0% were sentenced to prison with an average prison term of 127.3 ± 120.3 months. CONCLUSIONS: The US news media has reported on an increasing number of opioid-related criminal cases against physicians from a wide variety of clinical specialties. The most commonly convicted crime in these cases is drug trafficking, followed by fraud, money laundering, and manslaughter.