Benzonatate Exposure Trends and Adverse Events.

BACKGROUND AND OBJECTIVES: Adverse events (AE), including death, occur in children with benzonatate use. This study aims to understand recent trends in benzonatate exposure and clinical consequences in pediatric patients. METHODS: This retrospective analysis of data from IQVIA pharmacy drug dispensing, National Poison Data System, National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance Project, FDA Adverse Event Reporting System, and the medical literature evaluated exposure trends and medication-related AEs with benzonatate. Trends for comparator narcotic and nonnarcotic antitussive medications were analyzed where possible for context. RESULTS: During the study period, pediatric benzonatate prescription utilization increased but remained low compared with pediatric utilization of dextromethorphan-containing prescription antitussive medications. Among the 4689 pediatric benzonatate exposure cases reported to US poison control centers from 2010 to 2018, 3727 cases (80%) were for single-substance exposures. Of these, 3590 cases (77%) were unintentional exposures and most involved children 0 to 5 years old (2718 cases, 83%). Cases involving intentional benzonatate exposure increased among children 10 to 16 years old with a more pronounced increase for multiple-substance exposures. Most benzonatate cases involving misuse or abuse were for children 10 to 16 years old (59 cases, 61%). The proportion of cases with serious adverse effects was low. There were few cases annually of serious AEs with benzonatate in children. CONCLUSIONS: There were rising patterns of unintentional ingestion of benzonatate in children 0 to 5 years old and intentional benzonatate ingestion in children 10 to 16 years old. Rational prescribing and improved provider and caregiver awareness of benzonatate toxic effects may reduce risks associated with benzonatate exposure.

Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus.

Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study's primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, -26.5), cholesterol efflux capacity (p = 0.08, CI 95%: -0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.

A case series analysis of serious exacerbations of viral hepatitis and non-viral hepatic injuries in tocilizumab-treated patients.

BACKGROUND AND AIMS: Reports of moderate to severe liver injury associated with tocilizumab, an interleukin-6 (IL-6) receptor antagonist, have been reported in the post-marketing setting. This case series aims to characterize cases of tocilizumab-associated clinically significant hepatic injury. METHODS: We analysed cases of severe acute liver injury associated with tocilizumab reported in the FDA Adverse Event Reporting System and the medical literature. RESULTS: We identified 12 cases in which tocilizumab was a suspected primary cause of liver injury and eight cases in which serious sequelae of underlying or coincident viral hepatitis were temporally associated with its use. Using the Drug-Induced Liver Injury Network (DILIN) severity scale, five of 12 cases were Grade 5 (two liver transplants, three deaths), one was Grade 4 (liver failure) and six were Grade 3 (serious events with elevated bilirubin). Two cases reported liver atrophy with low hepatocellular expression of Ki-67, a marker of cellular proliferation. Among the eight cases of tocilizumab-associated viral hepatitis exacerbation, three were scored as DILIN severity Grade 5 (one liver transplant, two deaths), one was Grade 4 (liver failure), and four were Grade 3. The reported viral hepatitis events were hepatitis B virus (HBV) reactivation (n = 3), hepatitis C virus (HCV) flare (n = 1), cytomegalovirus (CMV)-induced liver failure (n = 1), Epstein-Barr virus hepatitis (n = 1), acute hepatitis E (HEV, n = 1) and HEV-induced macrophage activation syndrome (n = 1). CONCLUSION: Tocilizumab may be a primary cause of severe liver injury, as well as exacerbate underlying viral hepatitis. The disruption by tocilizumab of IL-6-mediated immune protection and hepatocyte regeneration may aggravate clinical outcomes in some cases.

2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. RESULTS: Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. CONCLUSION: These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.

2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. RESULTS: Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. CONCLUSION: These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.

Safety and Tolerability of Omalizumab: A Randomized Clinical Trial of Humanized Anti-IgE Monoclonal Antibody in Systemic Lupus Erythematosus.

OBJECTIVE: Autoreactive IgE antibodies have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). We hypothesize that omalizumab, a monoclonal antibody binding IgE, may improve SLE activity by reducing type I interferon (IFN) production by hampering plasmacytoid dendritic cells and basophil activation. This study was undertaken to assess the safety, tolerability, and clinical efficacy of omalizumab in mild to moderate SLE. METHODS: Sixteen subjects with SLE and a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥4 and elevated autoreactive IgE antibody levels were randomized to receive omalizumab or placebo (2:1) for 16 weeks, followed by 16 weeks of open-label treatment and a 4-week washout period. The SLEDAI-2K score, British Isles Lupus Assessment Group index (BILAG 2004) score, and physician's global assessment of disease activity were recorded at each visit. The type I IFN-induced gene signature was determined using quantitative polymerase chain reaction. RESULTS: Omalizumab was well tolerated with no allergic reactions, and mostly mild adverse events comparable to those experienced with placebo treatment. SLEDAI-2K scores improved in the omalizumab group compared to the placebo group at week 16 (P = 0.038), as well as during the open-label phase in subjects initially receiving placebo (P = 0.02). No worsening in BILAG scores or the physician's global assessment was detected. There was a trend toward a reduction in IFN gene signature in subjects treated with omalizumab (P = 0.11), especially in subjects with a high baseline IFN signature (P = 0.052). CONCLUSION: Our findings indicate that omalizumab is well tolerated in SLE and is associated with improvement in disease activity. Larger randomized clinical trials will be needed to assess the efficacy of omalizumab in patients with SLE.

Pharmacotherapy Pearls in Rheumatology for the Care of Older Adult Patients: Focus on Oral Disease-Modifying Antirheumatic Drugs and the Newest Small Molecule Inhibitors.

Providing safe and effective pharmacotherapy to geriatric patients with rheumatologic disorders is challenging. Multidisciplinary care involving rheumatologists, primary care physicians, and other specialties can optimize benefit and reduce adverse outcomes. Oral disease-modifying antirheumatic drugs, including methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide, and the small molecule inhibitors tofacitinib and apremilast have distinctive monitoring requirements and specific adverse reaction profiles. This article provides clinically relevant pearls for use of these interventions in older patients.

Low incidence of opportunistic Infections in Lupus Patients treated with Cyclophosphamide and Steroids in a Tertiary care setting.

BACKGROUND: Infection is common cause of morbidity and mortality in systemic lupus erythematosus (SLE). Our objective was to determine incidence and types of infections, particularly opportunistic infections, in SLE patients receiving cyclophosphamide, and to identify contribution of variables like demographics, steroid, other immunosuppressives, white blood cell and absolute neutrophil count to infection risk. PATIENTS AND METHODS: We did retrospective chart review of SLE patients in our institute over last 10 years, who received minimum six cyclophosphamide infusions. Types of infection, cumulative steroid dose, and maintenance medications were recorded. Statistical analyses were done using SAS software. RESULTS: 87.1% of the 31 patients were female. Mean age was 37.9 years, 48.4% Hispanic, 25.8% African American, 6.4% Asian and 19.4% were Caucasian. No one was on pneumocystis jirovecii pneumonia (PJP) prophylaxis. There were 42 episodes of infection in 31 patients. Different infections were urinary tract infections (UTI), upper respiratory infections (URI), line sepsis, bacterial pneumonia, PJP, mucocutaneous infections and viral gastroenteritis. Infection frequency was significantly higher among Asians compared to Caucasians (p =0.0152). Infection rate was significantly higher during cyclophosphosphamide induction phase (65.9%) compared to maintenance phase (34.1%) (p value=0.0041). Infection rate was higher with higher cumulative steroid dose and in patients on quarterly cyclophosphamide infusion compared to those on oral azathioprine or mycophenolate mofetil. No association found among baseline white blood cell (WBC) or absolute neutrophil count (ANC) and infection rate. CONCLUSION: We found higher infection rates among Asians and in patients with higher cumulative steroid dose. Single incidence of PJP noted despite absence of prophylaxis. Quarterly cyclophosphamide was associated with higher infection rates. Larger prospective studies are needed to confirm our results.

JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects.

The Janus kinase/signal transduction and activator of transcription (JAK-STAT) signaling pathway is implicated in the pathogenesis of inflammatory and autoimmune diseases including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Many cytokines involved in the pathogenesis of autoimmune and inflammatory diseases use JAKs and STATs to transduce intracellular signals. Mutations in JAK and STAT genes cause a number of immunodeficiency syndromes, and polymorphisms in these genes are associated with autoimmune diseases. The success of small-molecule JAK inhibitors (Jakinibs) in the treatment of rheumatologic disease demonstrates that intracellular signaling pathways can be targeted therapeutically to treat autoimmunity. Tofacitinib, the first rheumatologic Jakinib, is US Food and Drug Administration (FDA) approved for rheumatoid arthritis and is currently under investigation for other autoimmune diseases. Many other Jakinibs are in preclinical development or in various phases of clinical trials. This review describes the JAK-STAT pathway, outlines its role in autoimmunity, and explains the rationale/pre-clinical evidence for targeting JAK-STAT signaling. The safety and clinical efficacy of the Jakinibs are reviewed, starting with the FDA-approved Jakinib tofacitinib, and continuing on to next-generation Jakinibs. Recent and ongoing studies are emphasized, with a focus on emerging indications for JAK inhibition and novel mechanisms of JAK-STAT signaling blockade.

Pharmacotherapy Pearls for the Geriatrician: Focus on Oral Disease-Modifying Antirheumatic Drugs Including Newer Agents.

Providing safe and effective pharmacotherapy to the geriatric patients with rheumatological disorders is an ongoing struggle for the rheumatologist and geriatrician alike. Cohesive communication and partnership can improve the care of these patients and subvert adverse outcomes. Disease-modifying antirheumatic drugs, including methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide, and the newest oral agent for treatment of rheumatoid arthritis, tofacitinib, have distinctive monitoring and adverse effect profiles. This article provides the general practitioner or geriatrician with clinically relevant pearls regarding the use of these interventions in older patients.

Integrating a Patient Safety Conference into Graduate Medical Education.

OBJECTIVES: The Institute of Medicine has established aims for improvement in patient care that emphasize safe, timely, effective, efficient, equitable, and patient-centered medicine. This goal is echoed by the Accreditation Council for Graduate Medical Education (ACGME). METHODS: The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) graduate medical education program implemented a Clinical Learning Environment Review (CLER) project whose aim is to support a patient and trainee safety environment. An ongoing biannual patient and learner safety conference is able to capture close calls, safety attitudes, potential learner mistreatment, and trainee fatigue in a nonpunitive manner that supports answering the question, "What was learned and what needs to be improved?" RESULTS: Group recommendations were captured at a quality improvement conference. We documented a shift in attitudes away from one where the institution is perceived to be weakest at supporting safety reporting. CONCLUSIONS: This project is designed to serve as a mechanism for insuring care that is respectful and responsive to patient needs and values. It identifies keys to avoiding wasted re-sources or harmful delay while also seeking to improve care based upon scientific knowledge.

Glucose acts in the CNS to regulate gastric motility during hypoglycemia.

Our purposes were to 1) develop an animal model where intravenously (iv) administered d-glucose consistently inhibited antral motility, and 2) use this model to assess whether iv glucose acts to inhibit motility from a peripheral or a central nervous system site and to elucidate the factor(s) that determine(s) whether stomach motor function is sensitive to changes in blood glucose. Rats were anesthetized with alpha-chloralose-urethane, and antral motility was measured by a strain-gauge force transducer sutured to the antrum. In some cases, antral motility and gastric tone were measured by monitoring intragastric balloon pressure. Increases in blood glucose were produced by continuous iv infusion of 25% d-glucose at 2 ml/h. Inhibition of antral motility and gastric tone was observed when gastric contractions were induced by hypoglycemia (subcutaneously administered insulin, 2.5 IU/animal). In contrast, no inhibition of gastric motor function was observed when glucose infusion was tested on gastric contractions that were 1) spontaneously occurring, 2) evoked by iv administered bethanechol in vagotomized animals, and 3) evoked by the TRH analog RX77368, microinjected into the dorsal motor nucleus of the vagus. Using the model of insulin-induced hypoglycemia to increase gastric motor activity, we found that neither sectioning the hepatic branch of the vagus (n = 5), nor treating animals with capsaicin to destroy sensory vagal afferent nerves (n = 5) affected the ability of iv d-glucose to inhibit gastric motor function. Our results indicate that an important factor determining whether stomach motor function will be sensitive to changes in blood glucose is the method used to stimulate gastric contractions, and that the primary site of the inhibitory action of iv glucose on gastric motility is the central nervous system rather than the periphery.