Systemic sclerosis associated myopathy: how to treat.

Purpose of review: Systemic sclerosis (SSc) and myositis are two different entities that may coexist as an overlap syndrome. Immunological biomarkers such as anti-PM/Scl or anti-Ku reinforce the syndrome. This review is focused on the treatment of different and characteristic manifestations of this syndrome. Recent findings: Among the different phenotypes of muscle involvement in patients with SSc, the fibrotic pattern and the sporadic inclusion body myositis must be identified early to avoid a futile immunosuppressive treatment. Other forms such as dermatomyositis, non-specific myositis and immune-mediated necrotizing myopathy need to receive conventional immunosuppressive therapy considering that high dose of glucocorticoids may induce a scleroderma renal crisis in patients with SSc. Physicians must be aware of the existence of a "double trouble" association of hereditary myopathy with an autoimmune phenomenon. Several autoantibodies, mainly anti-PM/Scl and anti-Ku may help to define specific phenotypes with characteristic clinical manifestations that need a more specific therapy. Vasculopathy is one of the underlying mechanisms that link SSc and myositis. Recent advances in this topic are reviewed. Summary: Current treatment of SSc associated myopathy must be tailored to specific organs involved. Identifying the specific clinical, pathological, and immunological phenotypes may help to take the correct therapeutic decisions.

Rituximab for Inflammatory Myopathies in a Colombian Cohort.

INTRODUCTION/OBJECTIVES: Rituximab (RTX) is a treatment for refractory inflammatory myopathies, such as dermatomyositis (DM) and polymyositis (PM). This study describes the characteristics of patients receiving RTX for myositis in our institution to evaluate its efficacy. METHOD: We collected demographic data from all patients diagnosed with DM or PM who received RTX between 2011 and 2018. Clinical and serological variables (including creatine phosphokinase [CPK] levels) were analyzed. Remission of disease was defined as no evidence of disease activity (active myositis) for longer than a 6-month continuous period while undergoing myositis therapy or no medication. RESULTS: Eighteen patients who had received first-line immunosuppressants were included. Fifteen (83%) had DM, 2 (11%) had PM, 1 had juvenile dermatomyositis, and 14 (77%) were women. All patients received glucocorticoids. Three patients (16.6%) were treated with RTX as monotherapy, and 15 (83.3%) were treated with RTX combined with other immunosuppressants. On average, there were 2 RTX treatment cycles. Improved muscular weakness was found in 13 cases (72%), and improved serum CPK levels were found in 15 cases (83%). Twelve patients (66%) achieved remission. CONCLUSIONS: Most patients experienced an objective improvement, as reflected in their serum CPK values and degree of muscular weakness. This suggests that RTX could be helpful in treating refractory myositis.

Cardiac and placental mitochondrial characterization in a rabbit model of intrauterine growth restriction.

BACKGROUND: Intrauterine growth restriction (IUGR) is associated with cardiovascular remodeling persisting into adulthood. Mitochondrial bioenergetics, essential for embryonic development and cardiovascular function, are regulated by nuclear effectors as sirtuins. A rabbit model of IUGR and cardiovascular remodeling was generated, in which heart mitochondrial alterations were observed by microscopic and transcriptomic analysis. We aimed to evaluate if such alterations are translated at a functional mitochondrial level to establish the etiopathology and potential therapeutic targets for this obstetric complication. METHODS: Hearts and placentas from 16 IUGR-offspring and 14 controls were included to characterize mitochondrial function. RESULTS: Enzymatic activities of complexes II, IV and II + III in IUGR-hearts (-11.96 ±â€¯3.16%; -15.58 ±â€¯5.32%; -14.73 ±â€¯4.37%; p < 0.05) and II and II + III in IUGR-placentas (-17.22 ±â€¯3.46%; p < 0.005 and -29.64 ±â€¯4.43%; p < 0.001) significantly decreased. This was accompanied by a not significant reduction in CI-stimulated oxygen consumption and significantly decreased complex II SDHB subunit expression in placenta (-44.12 ±â€¯5.88%; p < 0.001). Levels of mitochondrial content, Coenzyme Q and cellular ATP were conserved. Lipid peroxidation significantly decreased in IUGR-hearts (-39.02 ±â€¯4.35%; p < 0.001), but not significantly increased in IUGR-placentas. Sirtuin3 protein expression significantly increased in IUGR-hearts (84.21 ±â€¯31.58%; p < 0.05) despite conserved anti-oxidant SOD2 protein expression and activity in both tissues. CONCLUSIONS: IUGR is associated with cardiac and placental mitochondrial CII dysfunction. Up-regulated expression of Sirtuin3 may explain attenuation of cardiac oxidative damage and preserved ATP levels under CII deficiency. GENERAL SIGNIFICANCE: These findings may allow the design of dietary interventions to modulate Sirtuin3 expression and consequent regulation of mitochondrial imbalance associated with IUGR and derived cardiovascular remodeling.

Influence of Mitochondrial Genetics on the Mitochondrial Toxicity of Linezolid in Blood Cells and Skin Nerve Fibers.

The antibiotic linezolid is a ribosomal inhibitor with excellent efficacy. Although the administration period has been reduced to 28 days, side effects, usually of hematologic or neuropathic origin, are still reported due to secondary inhibition of mitochondrial protein synthesis. Susceptibility to linezolid toxicity remains unknown. Therefore, the objective of this study was to gain an understanding of clinical heterogeneity in response to identical linezolid exposures through exhaustive examination of the molecular basis of tissue-dependent mitotoxicity, consequent cell dysfunction, and the association of mitochondrial genetics with adverse effects of linezolid administered for the recommended period. Peripheral blood mononuclear cells (PBMC) and skin nerve fibers from 19 and 6 patients, respectively, were evaluated before and after a 28-day linezolid treatment in order to assess toxic effects on mitochondria and cells. Mitochondrial DNA haplotypes and single nucleotide polymorphisms (SNPs) in ribosomal sequences where linezolid binds to mitochondrial ribosomes were also analyzed to investigate their genetic contributions. We found that linezolid reduced mitochondrial protein levels, complex IV activity, and mitochondrial mass in PBMC and was associated with a trend toward an increase in the rate of apoptosis. In skin tissue, mitochondrial mass increased within nerve fibers, accompanied by subclinical axonal swelling. Mitochondrial haplogroup U, mutations in 12S rRNA, and the m.2706A→G, m.3197T→C, and m.3010G→A polymorphisms in 16S rRNA showed a trend toward an association with increased mitochondrial and clinical adverse effects. We conclude that even when linezolid is administered for a shorter time than formerly, adverse effects are reported by 63% of patients. Linezolid exerts tissue-dependent mitotoxicity that is responsible for downstream cellular consequences (blood cell death and nerve fiber swelling), leading to adverse hematologic and peripheral nervous side effects. Multicentric studies should confirm genetic susceptibility in larger cohorts.

Colonic Oxidative and Mitochondrial Function in Parkinson's Disease and Idiopathic REM Sleep Behavior Disorder.

OBJECTIVE: To determine potential mitochondrial and oxidative alterations in colon biopsies from idiopathic REM sleep behavior disorder (iRBD) and Parkinson's disease (PD) subjects. METHODS: Colonic biopsies from 7 iRBD subjects, 9 subjects with clinically diagnosed PD, and 9 healthy controls were homogenized in 5% w/v mannitol. Citrate synthase (CS) and complex I (CI) were analyzed spectrophotometrically. Oxidative damage was assessed either by lipid peroxidation, through malondialdehyde and hydroxyalkenal content by spectrophotometry, or through antioxidant enzyme levels of superoxide dismutase-2 (SOD2), glutathione peroxidase-1 (Gpx1), and catalase (CAT) by western blot. The presence of mitochondrial DNA (mtDNA) deletions was assessed by long PCR and electrophoresis. RESULTS: Nonsignificant trends to CI decrease in both iRBD (45.69 ± 18.15; 23% decrease) and PD patients (37.57 ± 12.41; 37% decrease) were found compared to controls (59.51 ± 12.52, p: NS). Lipid peroxidation was maintained among groups (iRBD: 27.46 ± 3.04, PD: 37.2 ± 3.92, and controls: 31.71 ± 3.94; p: NS). Antioxidant enzymes SOD2 (iRBD: 2.30 ± 0.92, PD: 1.48 ± 0.39, and controls: 1.09 ± 0.318) and Gpx1 (iRBD 0.29 ± 0.12, PD: 0.56 ± 0.33, and controls: 0.38 ± 0.16) did not show significant differences between groups. CAT was only detected in 2 controls and 1 iRBD subject. One iRBD patient presented a single mtDNA deletion.

Clinical characteristics of adult patients with inborn errors of metabolism in Spain: A review of 500 cases from university hospitals.

Patients with inborn errors of metabolism (IEMs) have become an emerging and challenging group in the adult healthcare system whose needs should be known in order to implement appropriate policies and to adapt adult clinical departments. We aimed to analyze the clinical characteristics of adult patients with IEMs who attend the most important Spanish hospitals caring for these conditions. A cohort study was conducted in 500 patients, categorized by metabolic subtype according to pathophysiological classification. The most prevalent group of IEMs was amino acid disorders, with 108 (21.6%) patients diagnosed with phenylketonuria. Lysosomal storage disorders were the second group, in which 32 (6.4%) and 25 (5%) patients had Fabry disease and Gaucher disease respectively. The great clinical heterogeneity, the significant delay in diagnosis after symptom onset, the existence of some degree of physical dependence in a great number of patients, the need for a multidisciplinary and coordinated approach, and the lack of specific drug treatment are common features in this group of conditions.

The diagnosis and classification of polymyositis.

Polymyositis is classified as a separate entity among idiopathic inflammatory myopathies but it is considered as the least common since it is an exclusion diagnosis. This myopathy usually presents with subacute-chronic symmetric proximal limb weakness, although some extramuscular manifestations are common. Creatine kinase values may be increased up to 50-fold in active disease. Muscle biopsy is characterized by endomysial inflammatory infiltrate consisting predominantly of CD8+ T cells that invade healthy muscle fibres expressing the MHC-I antigen. Although serum autoantibodies, EMG and imaging techniques can help in diagnosis, muscle histopathology is a pivotal value. The clinical picture together with the pathological findings confers the also called PM pattern. A broad differential diagnosis is needed before concluding a diagnosis of pure PM. Sporadic inclusion-body myositis, toxic, endocrine and metabolic myopathies as well as muscular dystrophies are the major categories to be ruled out. Finally, a diagnostic algorithm for suspected cases of PM is also proposed.