Sleep behaviour differs in women and men with psoriatic arthritis and axial spondyloarthritis with impact on quality of life and depressive symptoms.

OBJECTIVES: Axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) may have a profound impact on sleep and health-related quality of life. The aim of this study was to assess sleep quality and quality of life and determine associated factors in patients treated with spondyloarthritides (SpA). METHODS: Cross-sectional questionnaire-based assessment of sleep behaviour, quality of life, functional impairment and depression (Regensburg Insomnia Scale, WHO Quality of Life questionnaire, Funktionsfragebogen Hannover questionnaire, Beck Depression Inventory II, Patient health questionnaire 9) and retrospective medical chart analysis of a monocentric cohort of 330 patients with SpA (n=168 PsA and n=162 axSpA). RESULTS: 46.6% of patients with SpA demonstrated abnormal sleep behaviour. Linear regression models showed HLA-B27 positivity, Bath Ankylosing Spondylitis Disease Activity Index, depressive symptoms, functional capacity and disease duration to be predictive of insomnia symptoms in axSpA, respectively, depressive symptoms, female sex and Disease Activity Score 28 in patients with PsA. Patients with unrestful sleep had a significantly reduced health-related quality of life (p<0.001) as well as significantly more depressive symptoms (p<0.001). Satisfaction with health was rated significantly lower (p<0.001), indicating poor sleep as a burden on general well-being.In particular, female patients had a significantly worse sleep quality with a prolonged sleep latency (p=0.009), increased sleep disturbances (p=0.014) and unrestful sleep (p<0.001) as well as a reduced physical and mental health-related quality of life (p=0.015, p<0.001) and more depressive symptoms (p=0.015). CONCLUSION: Despite treatment, many patients with SpA demonstrate abnormal sleep behaviour with symptoms of insomnia and a reduced quality of life with significant differences between male and female patients. An interdisciplinary and holistic approach may be needed to address unmet needs.

Role of pyrimidine depletion in the mitochondrial cardiotoxicity of nucleoside analogue reverse transcriptase inhibitors.

OBJECTIVE: Long-term antiretroviral treatment with nucleoside analogue reverse transcriptase inhibitors (NRTI) may result in a cardiomyopathy due to mitochondrial DNA (mtDNA) depletion. An intact mitochondrial function is required for the synthesis of intramyocardial pyrimidine nucleotides, which in turn are building blocks of mtDNA. We investigated if NRTI-related cardiomyopathy can be prevented with pyrimidine precursors. METHODS: Mice were fed with zidovudine or zalcitabine with or without simultaneous Mitocnol, a dietary supplement with high uridine bioavailability. Myocardia were examined after 9 weeks. RESULTS: Both NRTI induced a cardiomyopathy with mitochondrial enlargement, a disrupted cristal architecture on electron microscopy and diminished myocardial mtDNA copy numbers. The myocardial mtDNA-encoded cytochrome c-oxidase I subunit was impaired more profoundly than the nucleus-encoded cytochrome c-oxidase IV subunit. The myocardial formation of reactive oxygen species and mtDNA mutations was enhanced in zidovudine and zalcitabine treated animals. Mitocnol attenuated or normalized all myocardial pathology when given with both NRTI, but by itself had no intrinsic effects and no apparent adverse effects. CONCLUSIONS: Zidovudine and zalcitabine induce a mitochondrial cardiomyopathy, which is antagonized with uridine supplementation, implicating pyrimidine pool depletion in its pathogenesis. Pyrimidine pool replenishment may be exploited clinically because uridine is well tolerated.

Uridine abrogates mitochondrial toxicity related to nucleoside analogue reverse transcriptase inhibitors in HepG2 cells.

OBJECTIVE: To assess in vitro if uridine may be suitable to prevent or treat mitochondrial toxicity related to nucleoside analogue reverse transcriptase inhibitors (NRTIs). METHODS: Human HepG2-hepatocytes were exposed to NRTIs with or without uridine for 25 days. Cell growth, lactate production, intracellular lipids, mitochondrial DNA (mtDNA) and the ratio between the respiratory chain components COX II (mtDNA-encoded) and COX IV (nuclear-encoded) were measured. RESULTS: HepG2 cells exposed to zalcitabine (177 nM) without uridine developed a severe depletion of mtDNA (to 8% of wild-type mtDNA levels), resulting in a decline of cell proliferation and COX II levels, with increased lactate and lipid accumulation. Uridine fully abrogated the adverse effects of zalcitabine on hepatocyte proliferation and normalized lactate synthesis, intracellular lipids and COX II levels by adjusting mtDNA levels to about 65% of NRTI-unexposed control cells. This effect was dose-dependent, with a maximum at 200 microM of uridine. Uridine also rapidly and fully restored cell function when added to cells with established mitochondrial dysfunction (zalcitabine for 15 days) despite continued zalcitabine exposure. Uridine also normalized cell proliferation in HepG2 cells exposed to 36 microM of stavudine and protected HepG2-cells exposed to 7 microM of zidovudine + 8 microM of lamivudine (pyrimidine analogues), but failed to improve cell function or mtDNA in cells exposed to 11.8 or 118 microM of didanosine (a purine analogue). CONCLUSIONS: The pyrimidine precursor uridine may attenuate the mitochondrial toxicity of antiretroviral pyrimidine NRTIs in vitro, and its supplementation may represent a promising strategy in the prevention or treatment of mitochondrial toxicities in HIV-infected patients.