Challenges in Treating Statin-Associated Necrotizing Myopathy.

Myalgia and mild elevation in muscle enzymes are common side effects of statin therapy. While these symptoms are generally self-limited, in rare cases, statin use is associated with an immune-mediated necrotizing myopathy caused by development of autoantibodies against HMG-CoA reductase. The primary presenting symptom of this condition is progressive symmetric proximal weakness that does not abate or worsens even after cessation of statin therapy and is associated with markedly elevated creatine kinase (CK) levels. To date, no randomized controlled trials have been conducted to identify the most effective treatment for statin-associated autoimmune myopathy. Treatment recommendations involve a combination of steroids and immunosuppressive drugs. This single-center case series highlights the clinicopathologic features diagnostic for statin-associated autoimmune myopathy as well as treatment challenges for the patient population. The series highlights a range of potential presentations, from mildly symptomatic despite highly elevated CK, to severe muscle weakness including dysphagia. Multiple patients required several immunosuppressant medications as well as intravenous immunoglobulin (IVIG) to achieve disease control. In this case series, marked improvement was noted in several diabetic patients with IVIG.

IgA Vasculitis Nephritis: A Case Series and Comparison of Treatment Guidelines.

Immunoglobulin A (IgA) vasculitis nephritis (IgAVN) and IgA nephropathy (IgAN) share many pathological parallels and are viewed as related diseases by many groups. Current treatment guidelines remain vague, controversial, and without consensus, especially regarding the role of immunosuppressive medications. We present five cases of IgAVN encountered at our tertiary care center between 2016 and 2020, which were treated with different immunosuppression regimens. Infection was the leading cause of death in this series. These cases provide evidence that IgAVN should be distinguished from IgAN on a spectrum of IgA-associated glomerulonephritis. The outcomes presented herein suggest that the morbidity and systematic involvement IgAVN is greater than previously believed and that these substantial risks should be reflected in contemporary treatment guidelines.

Correlation of High-Density Lipoprotein-Associated Paraoxonase 1 Activity With Systemic Inflammation, Disease Activity, and Cardiovascular Risk Factors in Psoriatic Disease.

OBJECTIVE: To compare the activity of high-density lipoprotein (HDL)-associated paraoxonase 1 (PON1) in patients with psoriasis (PsO) and patients with psoriatic arthritis (PsA), and to evaluate the association of PON1 activity with the extent of disease activity and severity of the cardiovascular disease (CVD) burden in these patients. METHODS: Serum levels of paraoxonase and arylesterase activity (both measures of PON1 function in humans) were measured in patients with PsA (n = 198, 51.0% male) and patients with PsO (n = 145, 50.3% male) who were enrolled in a longitudinal psoriatic disease biorepository. Data on PsA disease activity (using the Disease Activity Score in 28 joints [DAS28], Clinical Disease Activity Index, and painful/swollen joint counts), preexistent CVD and CVD risk factors (including diabetes, dyslipidemia, hypertension, and smoking), Framingham Risk Scores for CVD, quality of life measures, and laboratory test findings (erythrocyte sedimentation rate, C-reactive protein level, and lipid profiles) were recorded. RESULTS: Serum arylesterase activities were significantly lower in patients with PsO and patients with PsA (mean ± SD 111.1 ± 25.5 µmoles/minute/ml and 124.4 ± 33.4 µmoles/minute/ml, respectively) compared to healthy controls (144.3 ± 33.4 µmoles/minute/ml) (each P < 0.001 versus healthy controls). Serum arylesterase activity decreased in parallel with increasing levels of disease activity (DAS28 scores, P = 0.012), older age (P = 0.013), higher body mass index (P = 0.042), greater incidence of metabolic syndrome (P = 0.004) and hypertension (P = 0.014), and worsening Framingham Risk Scores (P = 0.001). However, no correlation was seen between serum arylesterase activity and the extent of disease activity or CVD burden in patients with PsO. Serum paraoxonase activity trended lower both in patients with PsO and in patients with PsA (each P = 0.073 versus healthy controls). However, no association was seen between serum paraoxonase activity and the extent of disease activity or CVD burden in either of the patient cohorts. CONCLUSION: PON1 activity is decreased in psoriatic diseases. In the PsA cohort, decreases in arylesterase activity correlated with increasing severity of joint disease and CVD burden. Arylesterase activity, as compared to paraoxonase activity, appeared to serve as a more sensitive predictor of preexisting CV risk factors in the PsA cohort. However, this correlation was not observed in the PsO population.

Fulminant Infectious Aortitis With Ascending Aortic Rupture.

Infectious aortitis is associated with a high rate of acute aortic adverse events. However, the nonspecificity of symptoms and low sensitivity of blood cultures may delay early recognition of this condition. A 77-year-old man was incidentally found to have aortitis. His disease took a fulminant course and was complicated by dissection and rupture only 4 days after the diagnosis. Serial computed tomographic angiography provided valuable information about the development of aortitis into dissection and rupture. Postdissection histologic analysis revealed gram-positive cocci in the aortic wall.

Triple threat in pregnancy.

A woman aged 22 years with a history of lupus presented in the 18th week of pregnancy with hypertensive emergency and flash pulmonary oedema. Bedside echocardiogram revealed severe left ventricular (LV) dysfunction with an ejection fraction (EF) of 25% and pericardial effusion. Laboratories revealed hypocomplementemia, proteinuria, elevated C reactive protein and anti-DS-DNA, raising concern for a lupus flare. Cardiac MRI showed an acute intramyocardial oedematous process, consistent with lupus carditis, and further worsening of LVEF to 13%. Shared-decision-making with the patient included discussion of maternal risks of continuation of pregnancy in the setting of worsening heart function and the fetal risks of definitive treatment with cyclophosphamide for a lupus flare and the patient decided to proceed with medical termination of pregnancy. Treatment with immunosuppressants, including cyclophosphamide, and steroids, was then initiated. 2 months after discharge, cardiac MRI showed marked improvement in LVEF to 50% and the patient remains clinically free of heart failure.

The impact of identifying carotid plaque on addressing cardiovascular risk in psoriatic arthritis.

BACKGROUND: Patients with psoriatic arthritis (PsA) are at an increased risk for cardiovascular (CV) disease.  The aim of this study was to identify the frequency of carotid plaque in asymptomatic patients with psoriatic arthritis at baseline and follow-up screening, and to assess for the impact of demonstrating plaque on management of traditional cardiovascular risk factors. METHODS: Eighty-seven PsA patients underwent carotid duplex ultrasound screening. Repeat carotid duplex ultrasound was offered to all patients between 12 and 30 months. Preventive cardiology referrals were generated for all patients through the electronic health record. Traditional cardiovascular risk factors, medication use, and rates of utilization of preventive cardiology services were compared between patients with and without plaque. RESULTS: Carotid plaque was identified in 34/87 (39 %) of PsA patients. Age and triglyceride levels were predictors of plaque presence. Patients with plaque trended toward higher rates of smoking and diabetes, and higher low-density lipoprotein levels. Only 9/87 (10 %) patients completed at least one visit with preventive cardiology after enrollment despite referral. Low use of statin (21 %) and antiplatelet (27 %) medication was observed. Rates of biologic medication use for PsA were higher (75 %) than studies in similar cohorts of patients with carotid plaque. No association was seen between disease duration or activity and the presence of carotid plaque. CONCLUSION: Despite demonstration of high cardiac risk by the presence of carotid plaque, implementation of preventive cardiovascular services and rates of statin and antiplatelet use remained low. Age and triglyceride levels were significant variables in predicting plaque presence. There is no evidence that demonstration of plaque resulted in further evaluation or changes in treatment regimens to address heightened cardiovascular risk.

Advances in primary angiitis of the central nervous system.

Primary angiitis of the central nervous system (PACNS) is a rare idiopathic inflammatory syndrome targeting the vessels of the brain and spinal cord. Clinical presentation is variable, insidious, and non-specific; headache and encephalopathy are the most common symptoms. Multiple strokes affecting numerous vascular territories may be seen, and both focal and diffuse neurologic dysfunction may be present. Cerebrospinal fluid (CSF) analysis is crucial; a normal CSF along with normal brain parenchymal imaging carries a high negative predictive value in excluding PACNS. The role of imaging continues to evolve, and most patients have abnormal vascular imaging; however, the specificity of imaging for PACNS has historically been poor. Cerebral and meningeal biopsy is a valuable tool in confirming the diagnosis and excluding mimics. PACNS generally responds to immunosuppressive therapy. Failure to respond should prompt evaluation for an alternative diagnosis. Given the rarity of this disorder, exclusion of mimics such as the reversible cerebral vasoconstriction syndromes (RCVS) and infectious processes is essential.

Regulation of the Caenorhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase-3.

Oxidative stress plays a central role in many human diseases and in aging. In Caenorhabditis elegans the SKN-1 protein induces phase II detoxification gene transcription, a conserved oxidative stress response, and is required for oxidative stress resistance and longevity. Oxidative stress induces SKN-1 to accumulate in intestinal nuclei, depending on p38 mitogen-activated protein kinase signaling. Here we show that, in the absence of stress, phosphorylation by glycogen synthase kinase-3 (GSK-3) prevents SKN-1 from accumulating in nuclei and functioning constitutively in the intestine. GSK-3 sites are conserved in mammalian SKN-1 orthologs, indicating that this level of regulation may be conserved. If inhibition by GSK-3 is blocked, background levels of p38 signaling are still required for SKN-1 function. WT and constitutively nuclear SKN-1 comparably rescue the skn-1 oxidative stress sensitivity, suggesting that an inducible phase II response may provide optimal stress protection. We conclude that (i) GSK-3 inhibits SKN-1 activity in the intestine, (ii) the phase II response integrates multiple regulatory signals, and (iii), by inhibiting this response, GSK-3 may influence redox conditions.