Hydroxychloroquine-induced toxic myopathy causing respiratory failure

Chloroquine and hydroxychloroquine (HCQ) are commonly prescribed antimalarial agents used for a variety of systemic diseases. HCQ neuromyotoxicity is a rare complication characterized by proximal muscle weakness, normal creatinine kinase levels, and characteristic ultrastructural changes on muscle biopsy of curvilinear body formation. In this report, we describe a patient with rheumatoid arthritis and respiratory failure associated with proximal myopathy secondary to HCQ. Characteristic changes on muscle biopsy were present. Patients treated with HCQ in whom proximal myopathy, neuropathy, or cardiomyopathy develop should be evaluated for possible HCQ toxicity. Clinicians should be aware of this unusual complication of antimalarials, as discontinuation of the agent may result in clinical improvement.     

Targeting autophagy in cancer

Autophagy is a conserved, self‐degradation system that is critical for maintaining cellular homeostasis during stress conditions. Dysregulated autophagy has implications in health and disease. Specifically, in cancer, autophagy plays a dichotomous role by inhibiting tumor initiation but supporting tumor progression. Early results from clinical trials that repurposed hydroxychloroquine for cancer have suggested that autophagy inhibition may be a promising approach for advanced cancers. In this review of the literature, the authors present fundamental advances in the biology of autophagy, approaches to targeting autophagy, the preclinical rationale and clinical experience with hydroxychloroquine in cancer clinical trials, the potential role of autophagy in tumor immunity, and recent developments in next‐generation autophagy inhibitors that have clinical potential. Autophagy is a promising target for drug development in cancer. Cancer 2018. © 2018 American Cancer Society.     

Long term follow-up of infliximab efficacy in pulmonary and extra-pulmonary sarcoidosis refractory to conventional therapy

Introduction

Infliximab, a humanized, chimeric, monoclonal antibody against tumor necrosis alpha (TNF-α), has been shown to reduce the pulmonary and extra-pulmonary manifestations of sarcoidosis, however, there is little information regarding sustained efficacy with long-term use of infliximab. We retrospectively investigate whether a reduction in disease response is maintained, over a prolonged course of therapy (up to 85 months) with infliximab, and report on adverse events associated with its use.

Methods

Subjects with multi-organ sarcoidosis were prescribed infliximab, between January 2000 to June 2010 due to failure of conventional therapy and were identified from the Drexel University College of Medicine sarcoidosis clinic. Retrospective patient reported symptom and objective clinical data analyses of pulmonary and extra-pulmonary findings were evaluated pre-infliximab and post or concurrent infliximab therapy. Any adverse events or reasons for discontinuation during infliximab therapy were reported.

Results

Twenty-six patients with biopsy proven sarcoidosis received anti-TNF therapy and met the criteria for study inclusion. Clinical evidence of sustained resolution or improvement was demonstrated in 58.5% of all organs assessed (p =<0.001). No clinical change in disease activity was seen in 35.8% of all organs evaluated. Despite infliximab treatment, 5.7% had progressive disease activity. Adverse events were seen in 57.7% of patients treated with infliximab over a 46.2 month average duration of therapy. Three (12%) patients had an adverse event that required permanent discontinuation.

Conclusions

Infliximab is efficacious in the treatment of extra-pulmonary sarcoidosis and the efficacy is maintained with prolonged treatment. In patients with pulmonary sarcoid, sustained improvement in pulmonary imaging was seen after initiation of infliximab, however, post-treatment pulmonary function testing was not conclusive. Long-term infliximab therapy was well tolerated for our study group.     

Influence of hydroxychloroquine on the bioavailability of oral metoprolol

AIMS: Hydroxychloroquine (HCQ) is used widely in the treatment of chronic inflammatory diseases such as rheumatoid arthritis. Since there is great interindividual variability in the pharmacokinetics of HCQ and chloroquine is a potent inhibitor of CYP2D6-catalysed pathways in vitro, we wished to study the interaction of HCQ with CYP2D6-mediated metabolism of other drugs in vivo. METHODS: Metoprolol and dextromethorphan (DM) were selected as probe drugs because they are well-studied and widely used test substrates of CYP2D6. In this randomized, double-blind crossover study, seven healthy volunteers with extensive metabolizer phenotype for CYP2D6 ingested either 400 mg hydroxychloroquine or placebo daily for 8 days after which single oral dose pharmacokinetics of metoprolol were investigated. Dextromethorphan metabolic ratio (DM-MR) was also determined at baseline and after the ingestion of HCQ or placebo. RESULTS: Concomitant administration of HCQ increased the bioavailability of metoprolol, as indicated by significant increases in the area under the plasma concentration-time curve (65 +/- 4.6%) and maximal plasma concentrations (72 +/- 6.9%) of metoprolol. While the DM-MR values were not significantly changed, the phenotypic classification of one individual, who was heterozygous for a mutant CYP2D6 allele, was converted to a poor metabolizer by HCQ administration. CONCLUSIONS: HCQ inhibits metoprolol metabolism most probably by inhibiting its biotransformation by CYP2D6. The inhibitory effect of HCQ on dextromethorphan metabolism was not apparent when DM-MR was used as an indicator, except in an individual with limited CYP2D6 capacity.     

Targeting autophagy during cancer therapy to improve clinical outcomes

Autophagy is a catabolic process that turns over long-lived proteins and organelles and contributes to cell and organism survival in times of stress. Current cancer therapies including chemotherapy and radiation are known to induce autophagy within tumor cells. This is therefore an attractive process to target during cancer therapy as there are safe, clinically available drugs known to both inhibit and stimulate autophagy. However, there are conflicting positive and negative effects of autophagy and no current consensus on how to manipulate autophagy to improve clinical outcomes. Careful and rigorous evaluation of autophagy with a focus on how to translate laboratory findings into relevant clinical therapies remains an important aspect of improving clinical outcomes in patients with malignant disease.     

Broad Concepts in Management of Systemic Lupus Erythematosus

Systemic lupus erythematosus is a multisystem autoimmune disease with protean manifestation. Although commonly seen in young women, it can affect men as well as elderly patients. Approach to treatment is multidisciplinary, involves defining the extent of organ involvement, and distinguishing between active manifestations and damage. The mainstay of therapy is judicious use of immunosuppressive medications. Long-term follow-up to address morbidity arising from treatment complications, disease damage, and increased cardiovascular risk is essential.     

Systemic lupus erythematosus and systemic sclerosis: All roads lead to platelets

Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are two phenotypically distincts inflammatory systemic diseases. However, SLE and SSc share pathogenic features such as interferon signature, loss of tolerance against self-nuclear antigens and increased tissue damage such as fibrosis. Recently, platelets have emerged as a major actor in immunity including auto-immune diseases. Both SLE and SSc are characterized by strong platelet system activation, which is likely to be both the witness and culprit in their pathogenesis. Platelet activation pathways are multiple and sometimes redundant. They include immune complexes, Toll-like receptors activation, antiphospholipid antibodies and ischemia-reperfusion associated with Raynaud phenomenon. Once activated, platelet promote immune dysregulation by priming interferon production by immune cells, providing CD40L supporting B lymphocyte functions and providing a source of autoantigens. Platelets are actively implicated in SLE and SSc end-organ damage such as cardiovascular and renal disease and in the promotion of tissue fibrosis. Finally, after understanding the main pathogenic implications of platelet activation in both diseases, we discuss potential therapeutics targeting platelets.