Autoimmunity and Autoinflammation: Relapsing Polychondritis and VEXAS Syndrome Challenge.

Relapsing polychondritis is a chronic autoimmune inflammatory condition characterized by recurrent episodes of inflammation at the level of cartilaginous structures and tissues rich in proteoglycans. The pathogenesis of the disease is complex and still incompletely elucidated. The data support the important role of a particular genetic predisposition, with HLA-DR4 being considered an allele that confers a major risk of disease occurrence. Environmental factors, mechanical, chemical or infectious, act as triggers in the development of clinical manifestations, causing the degradation of proteins and the release of cryptic cartilage antigens. Both humoral and cellular immunity play essential roles in the occurrence and perpetuation of autoimmunity and inflammation. Autoantibodies anti-type II, IX and XI collagens, anti-matrilin-1 and anti-COMPs (cartilage oligomeric matrix proteins) have been highlighted in increased titers, being correlated with disease activity and considered prognostic factors. Innate immunity cells, neutrophils, monocytes, macrophages, natural killer lymphocytes and eosinophils have been found in the perichondrium and cartilage, together with activated antigen-presenting cells, C3 deposits and immunoglobulins. Also, T cells play a decisive role in the pathogenesis of the disease, with relapsing polychondritis being considered a TH1-mediated condition. Thus, increased secretions of interferon γ, interleukin (IL)-12 and IL-2 have been highlighted. The "inflammatory storm" formed by a complex network of pro-inflammatory cytokines and chemokines actively modulates the recruitment and infiltration of various cells, with cartilage being a source of antigens. Along with RP, VEXAS syndrome, another systemic autoimmune disease with genetic determinism, has an etiopathogenesis that is still incompletely known, and it involves the activation of the innate immune system through different pathways and the appearance of the cytokine storm. The clinical manifestations of VEXAS syndrome include an inflammatory phenotype often similar to that of RP, which raises diagnostic problems. The management of RP and VEXAS syndrome includes common immunosuppressive therapies whose main goal is to control systemic inflammatory manifestations. The objective of this paper is to detail the main etiopathogenetic mechanisms of a rare disease, summarizing the latest data and presenting the distinct features of these mechanisms.

Inflammatory Bowel Disease as a Paradoxical Reaction to Anti-TNF-α Treatment-A Review.

TNF-α inhibitors (TNFis) have revolutionized the treatment of certain chronic immune-mediated diseases, being widely and successfully used in rheumatic inflammatory diseases, and have also proved their efficacy in the treatment of inflammatory bowel disease (IBD). However, among the side effects of these agents are the so-called paradoxical effects. They can be defined as the appearance or exacerbation of a pathological condition that usually responds to this class of drug while treating a patient for another condition. A wide range of paradoxical effects have been reported including dermatological, intestinal and ophthalmic conditions. The causal mechanism of occurrence may implicate an imbalance of cytokines, but is still not fully understood, and remains a matter of debate. These paradoxical reactions often show improvement on discontinuation of the medication or on switching to another TNFi, but in some cases it is a class effect that could lead to the withdrawal of all anti-TNF agents. Close monitoring of patients treated with TNFis is necessary in order to detect paradoxical reactions. In this study we focus on reviewing IBD occurrence as a paradoxical effect of TNFi therapy in patients with rheumatological diseases (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and juvenile idiopathic arthritis).

Lifestyle Patterns in Patients with Type 2 Diabetes.

Modern lifestyles have led to sedentary behavior, lower participation in active movement and physical activities during leisure time, unhealthy diets, and increased exposure to stress. It is important to examine the interaction of several lifestyle risk factors instead of focusing on one alone. The purpose of this study was to identify lifestyle patterns in a group of patients with type 2 diabetes and the associations of its components with certain metabolic parameters. Using principal component analysis, we identified three dietary patterns: the prudent pattern (fat, oil, cereals, potatoes, vegetables, fish, nuts, seeds and fruits), the Western pattern (meat and meat products, eggs and soft drinks) and the traditional pattern (milk and its derivatives, soups and sauces, with a low intake of sugar/snacks). In addition, using the same method of analysis, we identified two lifestyle patterns: the inadequate lifestyle pattern (Western dietary pattern, increased hours of sleep and lower levels of stress) and the traditional lifestyle pattern (traditional dietary pattern, increased physical activity (PA) and non-smoking status). The inadequate lifestyle pattern was associated with younger age, hypertension and diabetic neuropathy. The traditional lifestyle pattern was related to lower postprandial blood glucose levels. Sedentary individuals were more likely to be over 65 years old and to have higher glycated hemoglobin (HbA1c). Smokers were also more likely to have inadequate glycemic and lipid profile control.

Interstitial Lung Disease in Systemic Lupus Erythematosus and Systemic Sclerosis: How Can We Manage the Challenge?

Interstitial lung disease (ILD) is a severe and frequent manifestation of connective tissue diseases (CTD). Due to its debilitating potential, it requires serious evaluation and treatment. The prevalence of ILD in systemic lupus erythematosus (SLE) is still controversial. Therefore, in order to establish the diagnosis of ILD, an overlap syndrome must be excluded. Increasing the identification of SLE-associated ILD cases should become a target. To treat this complication, various therapies are now being proposed. To date, no placebo-controlled studies were conducted. Regarding another CTD, systemic sclerosis (SSc), SSc-associated ILD is considered one of the leading causes of mortality. The incidence of ILD varies among disease subtypes, being influenced by diagnostic method, but also by disease duration. Due to the high prevalence of this complication, all SSc patients should be investigated for ILD at the time of SSc diagnosis and during the course of the disease. Fortunately, progress was made in terms of treatment. Nintedanib, a tyrosine kinases inhibitor, showed promising results. It appeared to decrease the rate of progression of ILD compared to placebo. This review aimed to provide up-to-date findings related to SLE-associated ILD and SSc-associated ILD, in order to raise awareness of their diagnosis and management.

Adult-Onset Still's Disease-A Complex Disease, a Challenging Treatment.

Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder with an unknown cause characterized by high-spiking fever, lymphadenopathy, hepatosplenomegaly, hyperferritinemia, and leukocytosis. The clinical course can be divided into three significant patterns, each with a different prognosis: Self-limited or monophasic, intermittent or polycyclic systemic, and chronic articular. Two criteria sets have been validated. The Yamaguchi criteria are the most generally used, although the Fautrel criteria offer the benefit of adding ferritin and glycosylated ferritin values. AOSD's pathogenesis is not yet completely understood. Chemokines and pro-inflammatory cytokines, including interferon (IFN)-γ, tumor necrosis factor α (TNFα), interleukin (IL)-1, IL-6, IL-8, and IL-18, play a crucial role in the progression of illness, resulting in the development of innovative targeted therapeutics. There are no treatment guidelines for AOSD due to its rarity, absence of controlled research, and lack of a standard definition for remission and therapy objectives. Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids (CS), and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are used in AOSD treatment. Biological therapy, including IL-1, IL-6, IL-18, and IL-17 inhibitors, as well as TNFα or Janus-kinases (JAKs) inhibitors, is administered to patients who do not react to CS and csDMARDs or achieve an inadequate response.

Why Do We Need JAK Inhibitors in Systemic Lupus Erythematosus?

Systemic lupus erythematosus (SLE) is a chronic, multifactorial autoimmune disease with complex pathogenesis characterized by the imbalance of pro-inflammatory and anti-inflammatory cytokines. Janus kinases (JAKs), intracellular non-receptor tyrosine kinases, are essential for signal pathways of many cytokines. The JAK signal transducers and activators of transcription (STAT) pathways consist of four JAK kinases and seven STATs family members. The dysregulation of JAK-STAT pathways represents an important process in the pathogenesis of SLE. Thus, the use of therapies that target specific signaling pathways would be a challenge in SLE. It is well known that JAK inhibitors have real potential for the treatment of rheumatic diseases, but their efficacy in the treatment of SLE remains to be determined. JAK inhibitors are currently being investigated in phase II and III trials and are considered to become the next stage in SLE therapy. In this review, we report the current data regarding the efficacy of JAK inhibitors in SLE. The development of clinically useful kinase inhibitors might improve upon traditional therapeutic strategies.

The Involvement of Smooth Muscle, Striated Muscle, and the Myocardium in Scleroderma: A Review.

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by heterogeneous changes involving numerous organs and systems. The currently available data indicate that muscle injury (both smooth and striated muscles) is widespread and leads to significant morbidity, either directly or indirectly. From the consequences of smooth muscle involvement in the tunica media of blood vessels or at the level of the digestive tract, to skeletal myopathy (which may be interpreted strictly in the context of SSc, or as an overlap with idiopathic inflammatory myopathies), muscular injury in scleroderma translates to a number of notable clinical manifestations. Heart involvement in SSc is heterogenous depending on the definition used in the various studies. The majority of SSc patients experience a silent form of cardiac disease. The present review summarizes certain important features of myocardial, as well as smooth and skeletal muscle involvement in SSc. Further research is needed to fully describe and understand the pathogenic pathways and the implications of muscle involvement in scleroderma.

The Therapeutic Potential of the Endocannabinoid System in Age-Related Diseases.

The endocannabinoid system (ECS) dynamically regulates many aspects of mammalian physiology. ECS has gained substantial interest since growing evidence suggests that it also plays a major role in several pathophysiological conditions due to its ability to modulate various underlying mechanisms. Furthermore, cannabinoids, as components of the cannabinoid system (CS), have proven beneficial effects such as anti-inflammatory, immunomodulatory, neuromodulatory, antioxidative, and cardioprotective effects. In this comprehensive review, we aimed to describe the complex interaction between CS and most common age-related diseases such as neuro-degenerative, oncological, skeletal, and cardiovascular disorders, together with the potential of various cannabinoids to ameliorate the progression of these disorders. Since chronic inflammation is postulated as the pillar of all the above-mentioned medical conditions, we also discuss in this paper the potential of CS to ameliorate aging-associated immune system dysregulation.

Non-Traditional Pro-Inflammatory and Pro-Atherosclerotic Risk Factors Related to Systemic Lupus Erythematosus.

Cardiovascular diseases (CVD) are one of the leading causes of high mortality in patients with systemic lupus erythematosus (SLE). The Framingham risk score and other traditional risk factors do not fully reflect the CVD risk in SLE patients. Therefore, in order to stratify these high-risk patients, additional biomarkers for subclinical CVD are needed. The mechanisms of atherogenesis in SLE are still being investigated. During the past decades, many reports recognized that inflammation plays a crucial role in the development of atherosclerosis. The aim of this report is to present novel proinflammatory and pro-atherosclerotic risk factors that are closely related to SLE inflammation and which determine an increased risk for the occurrence of early cardiovascular events.

Predictors Associated with Adverse Pregnancy Outcomes in a Cohort of Women with Systematic Lupus Erythematosus from Romania-An Observational Study (Stage 2).

Background: Pregnancy in women with systemic lupus erythematosus (SLE) is accompanied by adverse pregnancy outcomes (APOs). We aimed to investigate the association between clinical, sonographic, and laboratory parameters and APOs (preeclampsia, intrauterine growth restriction, premature birth, and maternal mortality). Methods: This observational retrospective study included all pregnancies in women with SLE who attended two tertiary maternity hospitals from Romania between January 2013 and December 2020. Clinical, sonographic, and laboratory variables were examined. Bivariate associations of APO status and each predictor variable were evaluated, and significant predictors were further included in a classification model based on discriminant analysis. Results: Predictors of APOs included BMI > 25 kg/m2, personal history of lupus nephritis or chronic hypertension, proteinuria, low C3, SLE Disease Activity Index 2000 (SLEDAI-2k score ≥ 4 and physician's global-assessment (PGA) score ≥ 1 throughout pregnancy, increased mean uterine arteries pulsatility index in the first and second trimesters, cerebroplacental ratio < 1 in the second and third trimesters, and small fetal abdominal circumference in the third trimester. Glucocorticoids, methyldopa, and aspirin use appeared to be protective against APOs. Conclusions: This study provides a comprehensive analysis of the most important predictors for APOs in pregnant patients with SLE, which could constitute a basis for further research.

Targeting Systemic Sclerosis from Pathogenic Mechanisms to Clinical Manifestations: Why IL-6?

Systemic sclerosis (SS) is a chronic autoimmune disorder, which has both cutaneous and systemic clinical manifestations. The disease pathogenesis includes a triad of manifestations, such as vasculopathy, autoimmunity, and fibrosis. Interleukin-6 (IL-6) has a special role in SS development, both in vascular damage and in the development of fibrosis. In the early stages, IL-6 participates in vascular endothelial activation and apoptosis, leading to the release of damage-associated molecular patterns (DAMPs), which maintain inflammation and autoimmunity. Moreover, IL-6 plays an important role in the development of fibrotic changes by mediating the transformation of fibroblasts into myofibroblasts. All of these are associated with disabling clinical manifestations, such as skin thickening, pulmonary fibrosis, pulmonary arterial hypertension (PAH), heart failure, and dysphagia. Tocilizumab is a humanized monoclonal antibody that inhibits IL-6 by binding to the specific receptor, thus preventing its proinflammatory and fibrotic actions. Anti-IL-6 therapy with Tocilizumab is a new hope for SS patients, with data from clinical trials supporting the favorable effect, especially on skin and lung damage.

Temporomandibular Joint Osteoarthritis: Pathogenic Mechanisms Involving the Cartilage and Subchondral Bone, and Potential Therapeutic Strategies for Joint Regeneration.

The temporomandibular joint (TMJ) is a specialized synovial joint that is crucial for the movement and function of the jaw. TMJ osteoarthritis (TMJ OA) is the result of disc dislocation, trauma, functional overburden, and developmental anomalies. TMJ OA affects all joint structures, including the articular cartilage, synovium, subchondral bone, capsule, ligaments, periarticular muscles, and sensory nerves that innervate the tissues. The present review aimed to illustrate the main pathomechanisms involving cartilage and bone changes in TMJ OA and some therapeutic options that have shown potential restorative properties regarding these joint structures in vivo. Chondrocyte loss, extracellular matrix (ECM) degradation, and subchondral bone remodeling are important factors in TMJ OA. The subchondral bone actively participates in TMJ OA through an abnormal bone remodeling initially characterized by a loss of bone mass, followed by reparative mechanisms that lead to stiffness and thickening of the condylar osteochondral interface. In recent years, such therapies as intraarticular platelet-rich plasma (PRP), hyaluronic acid (HA), and mesenchymal stem cell-based treatment (MSCs) have shown promising results with respect to the regeneration of joint structures or the protection against further damage in TMJ OA. Nevertheless, PRP and MSCs are more frequently associated with cartilage and/or bone repair than HA. According to recent findings, the latter could enhance the restorative potential of other therapies (PRP, MSCs) when used in combination, rather than repair TMJ structures by itself. TMJ OA is a complex disease in which degenerative changes in the cartilage and bone develop through intricate mechanisms. The regenerative potential of such therapies as PRP, MSCs, and HA regarding the cartilage and subchondral bone (alone or in various combinations) in TMJ OA remains a matter of further research, with studies sometimes obtaining discrepant results.

Diet in Scleroderma: Is There a Need for Intervention?

Systemic sclerosis (SSc) patients exhibit a plethora of risk factors for nutritional decline, including the presence of chronic inflammation and the progressive nature of disease-related multisystem involvement. The prevalence and consequences of nutritional decline in scleroderma are frequently underestimated, its management currently remaining a subject of debate. The main objective of the present study was to perform a detailed assessment of scleroderma patients' diet as well as their eating habits and to describe the relationships with weight loss and malnutrition risk in the absence of professional nutritional counseling. METHODS: We used a translated and validated version of the EPIC-Norfolk FFQ (European Prospective Investigation into Cancer and Nutrition Norfolk Food Frequency Questionnaire) to evaluate the patients' diet and MUST (Malnutrition Universal Screening Tool) to investigate the risk of malnutrition. Disease activity was estimated using the EUSTAR-AI (European Scleroderma Trials and Research group Activity Index). RESULTS: We included 69 patients with SSc, of which 42 underwent a detailed dietary assessment. Dietary factors were connected to body composition and digestive symptoms. We found high sodium intake and frequent suboptimal energy consumption in our study group, including patients with cardiopulmonary involvement. Liver transaminases were inversely correlated with the consumption of nuts and seeds. Malnutrition and weight loss were significantly associated with pulmonary hypertension, heart failure, albumin levels, and the extent of skin fibrosis, but not advanced age. Although the patients with EUSTAR-AI ≥ 2.5 were more frequently included in the moderate and high malnutrition risk categories, these results did not reach statistical significance. CONCLUSIONS: Currently, there is an unmet need for longitudinal and interventional research focusing on the long-term significance, ramifications, and management of nutritional impairment in SSc patients with various clinical manifestations. Our results indicate that scleroderma patients could benefit from personalized nutritional counseling in an interdisciplinary setting.

Ischemic Heart Disease and Rheumatoid Arthritis-Two Conditions, the Same Background.

Rheumatoid arthritis (RA) is one of the most frequent inflammatory rheumatic diseases, having a considerably increased prevalence of mortality and morbidity due to cardiovascular disease (CVD). RA patients have an augmented risk for ischemic and non-ischemic heart disease. Increased cardiovascular (CV) risk is related to disease activity and chronic inflammation. Traditional risk factors and RA-related characteristics participate in vascular involvement, inducing subclinical changes in coronary microcirculation. RA is considered an independent risk factor for coronary artery disease (CAD). Endothelial dysfunction is a precocious marker of atherosclerosis (ATS). Pro-inflammatory cytokines (such as TNFα, IL-1, and IL-6) play an important role in synovial inflammation and ATS progression. Therefore, targeting inflammation is essential to controlling RA and preventing CVD. Present guidelines emphasize the importance of disease control, but studies show that RA- treatment has a different influence on CV risk. Based on the excessive risk for CV events in RA, permanent evaluation of CVD in these patients is critical. CVD risk calculators, designed for the general population, do not use RA-related predictive determinants; also, new scores that take into account RA-derived factors have restricted validity, with none of them encompassing imaging modalities or specific biomarkers involved in RA activity.

Characteristics of the intestinal microbiome in ankylosing spondylitis.

The importance of intestinal microbiota in the development of various systemic diseases has been highlighted over time. Ankylosing spondylitis (AS) is a systemic disease with a complex pathogenesis involving a particular genetic marker and distinctive environmental triggers such as a specific gut dysbiosis. We conducted a prospective case-control study which included 60 subjects from Iasi Rehabilitation Hospital: 28 AS cases and 32 healthy controls. Intestinal microbiota analysis was performed by real-time polymerase chain reaction (qPCR) in stool samples. We performed the quantitative analysis of gut microbiome, focusing both on anti-inflammatory (Bifidobacterium, Lactobacillus, Faecalibacterium prausnitzii) and pro-inflammatory (Bacteroides, Escherichia coli) species. Overall, intestinal bacterial diversity in the AS group was decreased compared to that noted in the control. A significantly decreased level of Clostridium leptum was observed, associated with an increased level of Escherichia coli. We showed correlations between laboratory tests (liver and kidney functional tests, inflammatory syndrome), the presence of HLA-B27, smoker status, the forms of AS with peripheral arthritis vs. pure axial forms and bacterial structures. No significant correlations were shown for disease activity scores, radiological stage of sacroiliitis or for body mass index. Our findings support that the intestinal microbiome in AS patients has a special signature characterized by an inflammatory status. Numerous environmental, genetical, clinical and paraclinical factors can lead to changes in gut bacterial diversity in these cases.

From Pathogenesis to Therapy in Knee Osteoarthritis: Bench-to-Bedside.

Osteoarthritis (OA) is currently the most widespread musculoskeletal condition and primarily affects weight-bearing joints such as the knees and hips. Importantly, knee OA remains a multifactorial whole-joint disease, the appearance and progression of which involves the alteration of articular cartilage as well as the synovium, subchondral bone, ligaments, and muscles through intricate pathomechanisms. Whereas it was initially depicted as a predominantly aging-related and mechanically driven condition given its clear association with old age, high body mass index (BMI), and joint malalignment, more recent research identified and described a plethora of further factors contributing to knee OA pathogenesis. However, the pathogenic intricacies between the molecular pathways involved in OA prompted the study of certain drugs for more than one therapeutic target (amelioration of cartilage and bone changes, and synovial inflammation). Most clinical studies regarding knee OA focus mainly on improvement in pain and joint function and thus do not provide sufficient evidence on the possible disease-modifying properties of the tested drugs. Currently, there is an unmet need for further research regarding OA pathogenesis as well as the introduction and exhaustive testing of potential disease-modifying pharmacotherapies in order to structure an effective treatment plan for these patients.

Idazoxan and Efaroxan Potentiate the Endurance Performances and the Antioxidant Activity of Ephedrine in Rats.

Background and objectives: The connections between the imidazoline system and multiple other neurotransmitter systems in the brain (adrenergic, dopaminergic, serotoninergic, glutamatergic, opioid) indicate the complexity of the mechanisms underlying motor activity and behavior. The aim of the present research was to investigate the effects of the combination of ephedrine (EPD) and imidazoline antagonists idazoxan (IDZ) and efaroxan (EFR) on the endurance performance in the treadmill test in rats. Materials and Methods: We used Wistar rats distributed as follows: Group 1 (Control) receiving distilled water 0.3 mL/100 g body weight; Group 2 (EPD) receiving 20 mg/kg ephedrine; Group 3 (EPD + IDZ) receiving 20 mg/kg ephedrine + 3 mg/kg idazoxan; Group 4 (EPD + EFR) receiving 20 mg/kg ephedrine + 1 mg/kg efaroxan. An additional group (C) of animals receiving 0.3 mL/100 g body weight distilled water (but not subjected) to effort was used. Endurance capacity was evaluated using a treadmill running PanLAB assay. The evaluation of the substances' influence on oxidative stress was performed by spectrophotometric determination of superoxide dismutase (SOD) and glutathione peroxidase (GPX) activity. Results: Treatment with EPD-IDZ and EPD-EFR were correlated with a longer distance traveled on the belt and with a decrease in the necessary electric shocks to motivate the animal to continue running in the forced locomotion test. Additionally, an increase in the activity of antioxidant enzymes was found. Conclusions: Idazoxan and efaroxan potentiated the physical effort-related effects of ephedrine with regard to endurance capacity and antioxidant activity in rats.

Gut microbiota changes in inflammatory bowel diseases and ankylosing spondilytis.

BACKGROUND AND AIMS: Both inflammatory bowel diseases (IBD) and ankylosing spondylitis (AS) can be considered chronic immune disorders sharing common etiopathogenetic mechanisms. Changes in the composition of the intestinal microbiota, which can lead to an abnormal mucosal response, could be the missing link between these two diseases. Our study evaluate the composition of intestinal microbiota and to characterize gut dysbiosis in patients with IBD and AS. METHODS: We conducted a prospective case-control study that enrolled 124 patients [20 Crohn's disease (CD), 27 ulcerative colitis (UC), 28 AS, 17 IBD + AS and 32 controls). Intestinal microbiota analysis was performed by real-time polymerase chain reaction in stool samples. RESULTS: The total quantity of bacteria was decreased in all investigated groups compared to the control group. In studied groups, we noticed an increased percentage of Bacteroides and Escherichia coli (E.coli) and a decreased percentage of Clostridium coccoides, Clostridium leptum, and Faecalibacterium prausnitzii compared to the control group. The percentages of Bifidobacterium (p=0.010) as well as Lactobacillus group (p=0.023) were higher in the L3 form of CD patients. In the E2 form of UC, the quantity of Bacteroides was much higher compared to the E3 form (p=0.004). In AS patients, significant correlations were observed only for the Bifidobacterium species, significantly increased in the axial form compared to peripheral disease (p=0.035). Statistically significant correlations were demonstrated between the Crohn Disease Activity Index score and the total bacterial group (p=0.023, r=-0.507), respectively Bacteroides (p=0.021, r=-0.511) and between the Mayo score and Lactobacillus (p=0.001), respectively E. coli (p=0.001). In IBD + AS group, the Crohn Disease Activity Index score was inversely correlated with the total bacterial group (p=0.010) and directly correlated with Lactobacillus (p=0.047). CONCLUSIONS: Intestinal dysbiosis is associated with both IBD and AS. In the association of IBD with AS, dysbiosis is intermediate, but it is associated with the more severe articular disease. Bifidobacterium and Lactobacillus (commonly used as probiotics!) were found to be increased in the association between active IBD and active AS. Further studies are needed to understand how dysbiosis regulates the gut immune system and contributes to intestinal and articular inflammation.

Adult-onset Still's disease and the role of dermatological manifestations: A case report and literature review.

Adult-onset Still's disease (AOSD) is a rare inflammatory systemic disease with unknown etiology, characterized by spiking fever, evanescent rash, arthralgia and arthritis, leukocytosis and possible multi-organ involvement. Based on a case report of a 19-year-old man who was admitted to hospital for an influenza-like syndrome associated with a transient and recurrent pale-red disseminated non-specific rash, we performed a PubMed database search for cases and reviews of Adult's Onset Still's Disease published in English in the last 5 years. Due to its heterogeneous clinical manifestations, of which skin rash is an important sign, and the lack of a specific laboratory test, the diagnosis requires the exclusion of a wide range of mimicking disorders and the use of specific scoring systems. The high ferritin levels, major leukocytosis with neutrophilia, absence of typical antibodies for other systemic autoimmune diseases and other markers of infectious disease were the milestones that led to the positive diagnosis. The first line of treatment remains corticosteroid therapy in association with disease-modifying anti-rheumatic drugs.

A patient-centered approach to the burden of symptoms in patients with scleroderma treated with Bosentan: A prospective single-center observational study.

Systemic sclerosis (SSc) is a rare and complex autoimmune disease associated with poor vital and functional outcomes. The functional hindrance in patients derives from various disease-specific manifestations, including Raynaud's phenomenon and digital ulcers (DUs). Bosentan is an endothelin receptor antagonist capable of preventing the appearance of new DUs in patients with scleroderma. The present study aimed to evaluate the effects of Bosentan on the severity of Raynaud's phenomenon, DU-related symptoms and functional impairment during the first year of treatment. A prospective study that included adult patients with SSc admitted to the Rheumatology Department between January 2016 and January 2017 that were candidates for Bosentan therapy, was performed. All patients were asked to evaluate the burden of symptoms secondary to Raynaud's and DUs using a visual analogue scale (VAS), whereas functional hindrance was assessed via Health Assessment Questionnaire Disability Index (HAQ-DI). The outcomes were assessed at baseline and every 3 months during 1 year of therapy. Among the 41 patients included initially, 2 participants discontinued the treatment after 1 month due to adverse events (elevation of liver enzymes). The study cohort exhibited a significant improvement in HAQ-DI, VAS-R and VAS-DU scores in response to Bosentan therapy over the 1-year follow-up period. Higher scores at baseline predicted a weaker treatment-related improvement, with the risk of a poor outcome being increased by 220% for VAS-R, 116% for VAS-DU, whereas no increase was observed for HAQ-DI. The post-treatment improvement in VAS-DU levels was associated with a better outcome for HAQ-DI (R=0.44; P=0.005). This association was not identified for VAS-R (R=0.24; P=0.137). Throughout the follow-up period, patients with dyspnea presented with significantly higher HAQ-DI scores compared with non-dyspneic patients. Bosentan therapy may indirectly influence functionality and quality of life in patients with scleroderma by reducing the burden of Raynaud's and DU-related symptoms. Nonetheless, patients with SSc with a decreased symptom burden at baseline exhibited improved outcomes.