Systemic sclerosis sine scleroderma: a time of re-appraisal.

OBJECTIVE: Systemic sclerosis sine scleroderma (ssSSc), formally described in 1962, is a subset of SSc which, unlike limited (lcSSc) and diffuse cutaneous (dcSSc) forms, lacks skin fibrosis. According to the 2013 ACR/EULAR criteria, SSc can be diagnosed in the absence of skin thickening, even if this is expected to develop later in disease course. Driven by a fatal case of ssSSc with cardiac involvement, we analysed published data on ssSSc prevalence and severity. METHODS: A systematic literature review and qualitative synthesis of SSc cohorts with data on ssSSc was performed. RESULTS: Thirty-five studies on a total of 25,455 SSc patients published between 1976 and 2023 were identified. The mean prevalence of ssSSc, albeit using different definitions, was almost 10% (range 0-23%), with the largest study reporting a cross-sectional prevalence of 13%. In 5 studies with a follow-up period of up to 9 years, reclassification of ssSSc into lcSSc or dcSSc ranged from 0% to 28%. Interstitial lung disease, pulmonary arterial hypertension, scleroderma renal crisis, and cardiac diastolic dysfunction were present in 46% (range 9.3-59.1%), 15% (range 5.9-24.6%), 5% (range 1.6-24.6%), and 26.5% (range 1.8-40.7%) of ssSSc patients, respectively. Survival across studies was comparable to lcSSc and better than dcSSc. CONCLUSION: Published data on ssSSc vary widely regarding prevalence, clinical expression and prognosis partly due to underdiagnosis and misclassification. Although classification criteria should not impact appropriate management of patients, updated ssSSc subclassification criteria, which will take into account time from disease onset, should be considered.

Pathophysiological Mechanisms and Clinical Associations of Non-Alcoholic Fatty Pancreas Disease.

Non-Alcoholic Fatty Pancreas disease (NAFPD), characterized by fat accumulation in pancreatic tissue, is an emerging clinical entity. However, the clinical associations, the underlying molecular drivers, and the pathophysiological mechanisms of NAFPD have not yet been characterized in detail. The NAFPD spectrum not only includes infiltration and accumulation of fat within and between pancreatic cells but also involves several inflammatory processes, dysregulation of physiological metabolic pathways, and hormonal defects. A deeper understanding of the underlying molecular mechanisms is key to correlate NAFPD with clinical entities including non-alcoholic fatty liver disease, metabolic syndrome, diabetes mellitus, atherosclerosis, as well as pancreatic cancer and pancreatitis. The aim of this review is to examine the pathophysiological mechanisms of NAFPD and to assess the possible causative/predictive risk factors of NAFPD-related clinical syndromes.

High-density lipoprotein cholesterol and multiple myeloma: A systematic review and meta-analysis.

Background and aims: To systematically investigate all relevant evidence on the association between high-density lipoprotein cholesterol (HDL-C) and multiple myeloma (MM). Methods: We searched PubMed and Cochrane library databases (up to 20 September 2022) for studies with evidence on HDL-C in patients with MM. A qualitative synthesis of published prospective and retrospective studies for the role of HDL-C and other lipid profile parameters in MM was performed. Additionally, a meta-analysis on HDL-C mean differences (MD) between MM cases and controls was performed. Results: Fourteen studies (3 prospective, 11 retrospective) including 895 MM patients were eligible for this systematic review. Ten studies compared HDL-C levels in MM patients with healthy controls. In these 10 studies (n = 17,213), pooled analyses showed that MM patients had significantly lower HDL-C levels compared to healthy controls (MD: -13.07 mg/dl, 95% CI: -17.83, -8.32, p < 0.00001). Regarding secondary endpoints, total cholesterol (TC) (MD: -22.19 mg/dl, 95% CI: -39.08, -5.30) and apolipoprotein A-I (apoA-I) (-40.20 mg/dl, 95% CI: -55.00, -25.39) demonstrated significant decreases, while differences in low-density lipoprotein cholesterol (LDL-C) (MD: -11.33 mg/dl, 95% CI: -36.95, 14.30) and triglycerides (MD: 9.93 mg/dl, 95% CI: -3.40, 23.26) were not shown to be significant. Conclusions: HDL-C, as well as TC and apoA-I, levels are significantly decreased in MM. Hence, lipid profile parameters should be taken into account when assessing such patients.

Lipoprotein(a), Interleukin-6 inhibitors, and atherosclerotic cardiovascular disease: Is there an association?

Background and aims: Lipoprotein(a) [Lp(a)] and interleuking-6 (IL-6), an inflammation biomarker, have been established as distinct targets of the residual atherosclerotic cardiovascular disease (ASCVD) risk. We aimed to investigate the association between them, and the potential clinical implications in ASCVD prevention. Methods: A literature search was conducted in PubMed until December 31st, 2022, using relevant keywords. Results: Elevated lipoprotein(a) [Lp(a)] levels constitute the most common inherited lipid disorder associated with ASCVD. Although Lp(a) levels are mostly determined genetically by the LPA gene locus, they may be altered by acute conditions of stress and chronic inflammatory diseases. Considering its resemblance with low-density lipoproteins, Lp(a) is involved in atherosclerosis, but it also exerts oxidative, thrombotic, antifibrinolytic and inflammatory properties. The cardiovascular efficacy of therapies lowering Lp(a) by >90% is currently investigated. On the other hand, interleukin (IL)-1b/IL-6 pathway also plays a pivotal role in atherosclerosis and residual ASCVD risk. IL-6 receptor inhibitors [IL-6(R)i] lower Lp(a) by 16-41%, whereas ongoing trials are investigating their potential anti-atherosclerotic effect. The Lp(a)-lowering effect of IL-6(R)i might be attributed to the inhibition of the IL-6 response elements in the promoter region of the LPA gene. Conclusions: Although the effect of IL-6(R)i on Lp(a) levels is inferior to that of available Lp(a)-lowering therapies, the dual effect of the former on both inflammation and apolipoprotein (a) synthesis may prove of equal or even greater significance when it comes ASCVD outcomes. More trials are required to establish IL-6(R)i in ASCVD prevention and elucidate their interplay with Lp(a) as well as its clinical significance.

The Effect of Upadacitinib on Lipid Profile and Cardiovascular Events: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Our aim was to systematically investigate the effect of upadacitinib, an oral JAK-1 selective inhibitor, on lipid profile and cardiovascular disease risk. METHODS: PubMed, PubMed Central and ClinicalTrials.gov databases were searched for relevant randomized controlled trials (RCTs) up to 31 July 2022. We performed a qualitative synthesis of published RCTs to investigate the associations of upadacitinib with lipoprotein changes, along with a quantitative synthesis of MACE and mean lipoprotein changes where there were available data. RESULTS: Nineteen RCTs were eligible for the present systematic review, which included 10,656 patients with a mean age of 51 years and a follow-up period of 12-52 weeks. Increases in low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were noted upon upadacitinib administration (3-48 mg/day) in 15 studies, while the LDL-C:HDL-C ratio remained unchanged. The pooled analyses of three placebo-controlled RCTs (n = 2577) demonstrated that upadacitinib at 15 mg increased the LDL-C by 15.18 mg/dL (95% CI: 7.77-22.59) and HDL-C by 7.89 mg/dL (95% CI: 7.08-8.69). According to the pooled analysis of 15 placebo-controlled RCTs (n = 7695), upadacitinib had no effect on MACE (risk ratio, RR: 0.62; 95% CI: 0.24-1.60). A sub-analysis focusing on upadacitinib at 15 mg (12 studies, n = 5395) demonstrated similar results (RR: 0.67; 95% CI: 0.19-2.36). CONCLUSIONS: Treatment with upadacitinib increases both LDL-C and HDL-C levels. Nevertheless, upadacitinib had no significant effect on the cardiovascular disease risk during a ≤52-week follow-up.

The role of the gut-brain axis in depression: endocrine, neural, and immune pathways.

The aim of this article is to summarize the pathways connecting the gut and the brain and to highlight their role in the development of depression as well as their potential use as therapeutic targets. A literature search was conducted in PubMed using relevant keywords and their combinations up to the end of March 2020. Previously seen as a disease pertaining solely to the central nervous system, depression is now perceived as a multifactorial condition that extends beyond neurotransmitter depletion. Central to our understanding of the disease is our current knowledge of the communication between the gut and the brain, which is bidirectional and involves neural, endocrine, and immune pathways. This communication is facilitated via stress-mediated activation of the HPA axis, which stimulates the immune system and causes a decrease in microbial diversity, also known as dysbiosis. This change in the intestinal flora leads, in turn, to bacterial production of various substances which stimulate both the enteric nervous system and the vagal afferents and contribute to additional activation of the HPA axis. Concomitantly, these substances are associated with an increase in intestinal permeability, namely, the leaky gut phenomenon. The bidirectional link between the gut and the brain is of great importance for a more inclusive approach to the management of depression. It can thus be deployed for the development of novel therapeutic strategies against depression, offering promising alternatives to limited efficacy antidepressants, while combination therapy also remains a potential treatment option.

Schwannoma of the Lateral Femoral Cutaneous Nerve, an Unusual Cause of Meralgia Paresthetica: A Case Report.

INTRODUCTION: Meralgia paresthetica (MP) is a clinical syndrome usually resulting usually from compression of the lateral femoral cutaneous nerve (LFCN). Tumors arising from this nerve could also be the cause of this syndrome. CASE REPORT: We present an unusual cause of MP in a 67-year-old Caucasian male. The cause of the syndrome appeared to be a schwannoma tumor of the LFCN. Such a cause of MP has not been reported previously in the literature. CONCLUSION: Medical practitioners should also consider other causes of MP syndrome, such as peripheral nerve tumors. Although diagnosis is considered to be clinical, ultrasound or magnetic resonance imaging (MRI) could be helpful to establish the diagnosis.

Renal Fibromuscular Dysplasia: A Not So Common Entity of Secondary Hypertension.

Fibromuscular dysplasia is a rare noninflammatory vascular disease characterized by nonatheroslerotic stenosis predominantly seen in young women, whereas the majority of cases involve the renal arteries causing secondary hypertension. Most noninvasive screening tests are not quite sensitive or reproducible to rule out renal artery stenosis, but renal angiography usually confirms the diagnosis. Percutaneous renal artery angioplasty is the treatment of choice; however, it may not result in normalization of blood pressure if diagnosis is delayed. Continued follow-up is necessary since stenosis reoccurs.

Resistant hypertension workup and approach to treatment.

Resistant hypertension is defined as blood pressure above the patient's goal despite the use of 3 or more antihypertensive agents from different classes at optimal doses, one of which should ideally be a diuretic. Evaluation of patients with resistive hypertension should first confirm that they have true resistant hypertension by ruling out or correcting factors associated with pseudoresistance such as white coat hypertension, suboptimal blood pressure measurement technique, poor adherence to prescribed medication, suboptimal dosing of antihypertensive agents or inappropriate combinations, the white coat effect, and clinical inertia. Management includes lifestyle and dietary modification, elimination of medications contributing to resistance, and evaluation of potential secondary causes of hypertension. Pharmacological treatment should be tailored to the patient's profile and focus on the causative pathway of resistance. Patients with uncontrolled hypertension despite receiving an optimal therapy are candidates for newer interventional therapies such as carotid baroreceptor stimulation and renal denervation.