Reviews on Recent Clinical Trials - Volume 13, Issue 3, 2018

Background: A close relationship between rheumatic diseases and cardiovascular disease (CVD) has been reported, accounting for the higher mortality and morbidity observed in these patients. In the last years, it has been clearly reported that patients affected by primary Sjögren’s syndrome (pSS) experienced an increased risk of CVD. Objective: This review aimed at investigating CVD, traditional cardiovascular (CV) risk factors and possible targeted therapeutic strategies in pSS patients. Method: Available literature concerning CV risk factors in pSS patients has been selected and discussed. Conclusion: Disease-related characteristics and traditional CV risk factors contribute to observed atherosclerotic damage in pSS patients. The pro-inflammatory mediators together with hypertension and type 2 diabetes, which are more prevalent in pSS patients, determine the increased CV burden. Future studies are needed to fully elucidate the role of possible targeted therapies.

Atrial Fibrillation (AF) is the most commonly described cardiac arrhythmia found in the general population and can lead to adverse outcomes. Its onset and maintenance requires the presence of an arrhythmogenic substrate that predisposes the patient for risk of these types of arrhythmias and the occurrence of a trigger event. A major characteristic of AF-related structural remodelling is atrial fibrosis, a process closely related to inflammation. Autoimmune rheumatic diseases constitute systemic inflammatory disorders that can also present with cardiovascular manifestations, including a high incidence of AF, thus supporting the idea of a link between AF and inflammation. A vicious cycle exists in which inflammation leads to a higher prevalence of structural cardiovascular disease, which in turn leads to more inflammation and AF; in fact, inflammation is known to affect signalling pathways that lead to the development of AF. Therapy must first target systemic inflammation, since decreasing the inflammatory burden has consistently shown to positively ameliorate the prognosis. When this approach is not sufficient, rhythm or, when not feasible, rate control is indicated in addition to anticoagulant therapy. As far as the rhythm control strategy is concerned, antiarrhythmic drugs and/or catheter ablation should be considered. New mapping techniques allowing the characterization of the arrhythmic substrate have opened new perspectives and may help in the treatment of AF in these patients, since atrial tissue is the target of inflammation-induced arrhythmic alterations. In cases where the natural history of the arrhythmia itself is more advanced, in order to minimize the impact of AF on cardiac function as well as quality of life, a device-based therapy, including an “ablate and pace” approach could be adopted.

Background: Obesity is a debilitating growing condition and represents a challenge for every surgeon. It is associated with the activation of the inflammatory pathway and this may have a negative impact on the natural history of some rheumatic diseases. Bariatric surgery, reducing obesity, could bring to a minor activation of the well-known inflammatory pathway with improvement of these diseases. The aim of this review is to investigate the role of weight loss, achieved through bariatric surgery, in rheumatic diseases. Materials and Methods: A systematic review of literature was undertaken to evaluate weight loss subsequent to bariatric surgery in obese patients suffering from some rheumatic diseases (Rheumatoid Arthritis, Psoriasis, Psoriatic Arthritis, Fibromyalgia, Osteoarthritis, Systemic Lupus Erythematous). Three major databases (PUBMED, EMBASE and WEB OF SCIENCE) were searched. Results: Three-hundred studies were identified. After screening of titles, abstracts and inclusion criteria sixteen articles were included. Of the selected articles, seven were reviews, five were case reports, one was a clinical report, one was a retrospective study, one was a cohort study and one was an author manuscript. Conclusion: Weight loss, obtained through bariatric surgery, seems to reduce serum inflammatory markers as a consequence of the inflammatory pathway reduction and this is connected with both the improvement of some rheumatic diseases as well as with the reduction in the use of medicaments (steroids and immunosuppressors).

Background: Rheumatoid Arthritis (RA) has been associated with insulin resistance (IR), a well-established pathophysiological feature of Type 2 Diabetes (T2DM). Inconsistent literature evidence suggests that IR could be ameliorated by biological medications targeting TNFα. Objective: The aim of this systematic review was to evaluate the effect of TNFα inhibitors (TNFi) on IR in RA patients. Methods: We performed a systematic review in order to identify the available data on the effect of anti- TNFα medications on IR in RA patients. For this purpose, MedLine (via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL) and SCOPUS were searched up to December 2016. Results: The search strategy retrieved 209 individual records. Of these, only 12 articles were included in the systematic review. The pooled analysis under a random-effects model demonstrated a significant improvement of IR after treatment with TNFi quantified with the HOmeostasis Model Assessment of Insulin Resistance (HOMA-IR), with a standardized difference in means (SDM) of -0.847 (95%CI: -1.278 - 0.417, p < 0.0001). Heterogeneity across studies was high (Q = 65.00 with df = 9, p < 0.001, I2 = 89.15%). Conclusion: Our meta-analysis suggests that TNFα blockade might improve IR in RA patients.

Background: Systemic Lupus Erythematosus (SLE) is characterised by increased mortality secondary to Cardiovascular Diseases (CVD). Despite being common in SLE, traditional cardiovascular risk factors cannot entirely justify such increase in CVD-associated mortality. The endothelium is a key regulator of the vascular homeostasis; lupus-associated persistent systemic inflammation may impair endothelium functionality, thus initiating a cascade of events that, in concert with traditional CVD-risk factors, leads to atherosclerosis development and progression. Numerous methods have been used for the in vivo assessment of the endothelial function; among all, Flow- Mediated Dilatation (FMD) has been widely validated in clinical trials. Quantification of the endothelial dysfunction by FMD has been confirmed to be an early predictor of CVD in multiple studies involving both non-CVD and CVD-population and it may therefore represent a likewise efficient biomarker of CVD in SLE. Methods: Research and online content related to endothelial function in SLE is reviewed in this article with special attention to the pathophysiology and therapeutic opportunities. Results: To date, the vast majority of the available data, albeit not all, shows that endotheliumdependent FMD values are lower in SLE patients compared to healthy subjects; further studies, however, will be required in order to confirm the usefulness of the endothelial dysfunction quantification as CVD-predictor in the specific clinical setting of lupus. Notably, FMD variations can also be a sensitive marker for assessing specific therapeutic strategies ability of improving endothelial function in SLE patients. Conclusion: Endothelial function appears to be affected by SLE potentially contributing to the increased cardiovascular risk observed in SLE patients.

Background: Psoriatic arthritis is a chronic inflammatory arthropathy that affects 14%- 30% of patients with skin and/or nail psoriasis, leading to severe physical limitations and disability. It has been included in the group of spondyloarthropathy with which it shares clinical, radiologic, and serologic features in addition to familial and genetic relationship. Beyond skin and joint involvement, psoriatic arthritis is characterized by a high prevalence of extra-articular manifestation and comorbidities, such as autoimmune, infectious and neoplastic diseases. In particular, an increased risk of cardiovascular comorbidity has been observed in psoriatic arthritis patients. Methods: A systematic search was performed in the electronic databases (PubMed, Web of Science, Scopus, EMBASE) up until January 2017. Studies were included if they contained data on CV disease and/or risk factors in PsA and each article was then reviewed for quality and clinical relevance. After completing the literature search all screened literature was summarized and discussed in our study group (CaRDDs study group). All literature and comments were included in the systematic review. Results: The initial search produced 278 abstracts, which were narrowed to 83 potentially relevant articles by preliminary review of the titles and by excluding review articles and case report (n = 195). Thirty articles were deemed ineligible after examining the abstracts. Full texts of the remaining 53 articles were retrieved. The majority of articles excluded were due to only providing data on patients with psoriasis or due to being not relevant to the CV risk in PsA. In the end, 32 articles were deemed eligible for this review. Conclusion: Psoriatic arthritis appeared significantly associated with subclinical atherosclerosis and endothelial dysfunction and, in turn, with an increased cardiovascular risk. Thus, patients with psoriatic arthritis may benefit from a periodic assessment of surrogate markers of cardiovascular risk. This could help to establish more specific cardiovascular prevention strategies for these patients.

Background: Although in the past, prevention of the joint destruction and disability was strongly emphasised in Rheumatoid Arthritis (RA), at present, a growing body of evidence is focused at identifying the best management of associated comorbidities, such as Type 2 Diabetes (T2D). Recently, the hypothesis that blocking pro-inflammatory activity may be helpful in the treatment of some comorbidities has been proposed in RA patients. Objective: We reviewed the role of IL-1β during RA and T2D, the efficacy of IL-1 blocking agents in controlling both diseases and, possible, decreasing the concomitant enhanced atherosclerotic process. Method: After literature search, the available evidence has been selected and commented in the text. Results: During RA, it is well known that different inflammatory cytokines, such as interleukin-1β (IL-1β), are pivotal pathogenic mediators and their role has been largely confirmed in clinical settings. Similarly, it has been shown that the excess of nutrients, secondary to over-nutrition, may activate the immune system, leading to an increased production of inflammatory cytokines, including IL-1β, suggesting new possible therapeutic targets. Conclusion: Although further studies are needed to fully investigate the pathogenic interplay between inflammation and metabolic disorders, IL-1β has been implicated in both RA and T2D pathogenic mechanisms. Intriguingly, the potential role of anti-IL-1 drugs has been proposed in RA patients affected by T2D.

Background: Recent evidence demonstrated a potential role of complement C3 as a candidate biomarker of cardiometabolic risk in the general population. Objective: Aim of the present study was to investigate the correlation between complement C3 levels and comorbid Type 2 Diabetes (T2DM) in Rheumatoid Arthritis (RA) patients. Methods: For the present study, 40 consecutive diabetic RA patients (RA/T2DM+ group) and 80 consecutive RA patients without diabetes (RA/T2DM- group) were recruited. Results: Patients in the RA/T2DM+ group were significantly older (p < 0.0001), had a longer RA duration (p < 0.0001) and higher disease activity (p = 0.006) compared to controls. Moreover, patients in the RA/T2DM+ group had significantly higher levels of ESR (p < 0.0001), CRP (p < 0.0001) and complement C3 (p < 0.0001). A logistic regression model was built to ascertain the effect of selected variables (age, RA duration, BMI, ESR, C3, lnCRP, corticosteroid use) on the likelihood that patients have T2DM. Longer RA duration, ESR and C3 were associated with an increased likelihood of being classified as T2DM. Finally, we built ROC curves to evaluate the predictivity of RA duration, complement C3 and the combination of both variables on the likelihood of being diagnosed with T2DM. The area under the ROC curve was 0.79 (p < 0.0001) for RA duration, 0.71 (p < 0.0001) for complement C3 and 0.89 (p < 0.0001) for the combination of both variables. Conclusion: According to our data complement C3 levels can predict the presence of T2DM in RA patients.

Background: Takotsubo Cardiomyopathy (TC), also called transient left ventricular (LV) ballooning syndrome, resembles myocardial infarction and is characterized by LV dysfunction in the absence of coronary artery disease. Hypothesis described for TC has been an intense social stressor, pheochromocytoma, thyrotoxicosis among others. We performed this study to analyze the association of hypothyroidism with TC. Methods: We queried the Nationwide Inpatient Sample which represents 20% of all the United States hospital data for our study. We identified TC and hypothyroidism through their respective ICD9. Codes for years 2006-2012. SAS 9.4 was used to perform a chi-square analysis to find any statistical significance and p < 0.05 used to determine statistical significance. Significant differences were identified using odds ratio (OR) estimates. Results: A total of 19,713 cases with TC were identified of which 17,340 (87.96%) were females and 2,373 (12.04%) were males. 3,272 patients with TC had diagnosis of hypothyroidism. There is statistically significant evidence of an association between TC and hypothyroidism (OR 2.21 (95% CI: 2.11- 2.31); p<0.0001). There is evidence of increased statistical significance of females having TC 5.24 (95% CI: 4.96-5.53; (p<0.0001)) compared to males, with an increased statistically significance of females with hypothyroidism having TC, OR 6.65 (95% CI: 5.57-7.93; p< 0.001) compared to males. Conclusion: There is an increased association of hypothyroidism, especially hypothyroidism for females with TC.

Introduction: To compare the efficacy of abiraterone acetate, enzalutamide, cabazitaxel and Radium-223 in the treatment of castration-resistant, docetaxel-resistant metastatic prostate cancer. Methods: An indirect comparison of Overall Survival (OS) and time to PSA progression among abiraterone acetate, enzalutamide, cabazitaxel and Radium-223 was performed with a network metaanalysis. OS in the entire population of patients was the primary endpoint. OS in ECOG 0-1/2, BPISF≤ 4/>4, pretreated with 1 or 2 courses of chemotherapy, age≤65/>65 patients, patients with only bone metastases or bone and visceral metastases, and time to PSA progression were the secondary endpoints. An indirect comparison of the Hazard Ratio and the 95% Confidence Interval was performed, assuming an alpha error of 5% as an index of statistical significance. The among-the-trial heterogeneity was assessed using a qualitative methodological and clinical analysis. Results: Four trials were selected. In three trials, the comparator was placebo, in one trial it was mitoxantrone, the effect of which in improving survival was considered negligible. No significant difference in OS among abiraterone acetate, enzalutamide, cabazitaxel and radium 223 was observed in neither the entire population nor all the subgroups of patients. Enzalutamide resulted significantly better than abiraterone acetate, cabazitaxel or radium-223 in time to PSA progression. Conclusion: Since no significant difference in efficacy seems to exist between the four therapeutic options in the treatment of castration-resistant, docetaxel-resistant, metastatic prostate cancer, the safety of the treatment, patient's compliance and costs should represent the criteria to guide clinicians' choice in clinical practice.