Review: A Contemporary, Multifaced Insight into Psoriasis Pathogenesis.

Psoriasis is a chronic recurrent inflammatory autoimmune pathology with a significant genetic component and several interferences of immunological cells and their cytokines. The complex orchestration of psoriasis pathogenesis is related to the synergic effect of immune cells, polygenic alterations, autoantigens, and several other external factors. The major act of the IL-23/IL-17 axis, strongly influencing the inflammatory pattern established during the disease activity, is visible as a continuous perpetuation of the pro-inflammatory response and keratinocyte activation and proliferation, leading to the development of psoriatic lesions. Genome-wide association studies (GWASs) offer a better view of psoriasis pathogenic pathways, with approximately one-third of psoriasis's genetic impact on psoriasis development associated with the MHC region, with genetic loci located on chromosome 6. The most eloquent genetic factor of psoriasis, PSORS1, was identified in the MHC I site. Among the several factors involved in its complex etiology, dysbiosis, due to genetic or external stimulus, induces a burst of pro-inflammatory consequences; both the cutaneous and gut microbiome get involved in the psoriasis pathogenic process. Cutting-edge research studies and comprehensive insights into psoriasis pathogenesis, fostering novel genetic, epigenetic, and immunological factors, have generated a spectacular improvement over the past decades, securing the path toward a specific and targeted immunotherapeutic approach and delayed progression to inflammatory arthritis. This review aimed to offer insight into various domains that underline the pathogenesis of psoriasis and how they influence disease development and evolution. The pathogenesis mechanism of psoriasis is multifaceted and involves an interplay of cellular and humoral immunity, which affects susceptible microbiota and the genetic background. An in-depth understanding of the role of pathogenic factors forms the basis for developing novel and individualized therapeutic targets that can improve disease management.

Microbiota-Accessible Boron-Containing Compounds in Complex Regional Pain Syndrome.

The microbiota-gut-brain axis has garnered increasing attention in recent years for its role in various health conditions, including neuroinflammatory disorders like complex regional pain syndrome (CRPS). CRPS is a debilitating condition characterized by chronic neuropathic pain, and its etiology and pathophysiology remain elusive. Emerging research suggests that alterations in the gut microbiota composition and function could play a significant role in CRPS development and progression. Our paper explores the implications of microbiota in CRPS and the potential therapeutic role of boron (B). Studies have demonstrated that individuals with CRPS often exhibit dysbiosis, with imbalances in beneficial and pathogenic gut bacteria. Dysbiosis can lead to increased gut permeability and systemic inflammation, contributing to the chronic pain experienced in CRPS. B, an essential trace element, has shown promise in modulating the gut microbiome positively and exerting anti-inflammatory effects. Recent preclinical and clinical studies suggest that B supplementation may alleviate neuropathic pain and improve CRPS symptoms by restoring microbiota balance and reducing inflammation. Our review highlights the complex interplay between microbiota, inflammation, and neuropathic pain in CRPS and underscores the potential of B as a novel therapeutic approach to target the microbiota-gut-brain axis, offering hope for improved management of this challenging condition.

Preliminary Study on the Antioxidant Effect of Natural Based Products with Potential Application in Complex Regional Pain Syndrome.

Complex regional pain syndrome (CRPS) is a complex condition characterized by chronic pain and various sensory, motor, and autonomic symptoms. It involves a complex interplay of mechanisms in the nervous system, including neuroinflammation, sensitization of pain pathways, and dysfunction of the sympathetic nervous system. Antioxidants may play a role in CRPS by helping to counteract oxidative stress, which is an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defences. CRPS involves inflammation and tissue damage, which can lead to increased ROS production and oxidative stress. Our paper represents a preliminary study on various commercially available natural-based products regarding their antioxidant effect. Several natural products with antioxidant properties, such as vitamins C and E, polyphenols, flavonoids, and botanical extracts, have shown promise in preclinical studies for their potential to alleviate pain and reduce inflammation associated with CRPS. The potential use of natural-based products with antioxidant effects for mitigating CRPS symptoms is still an area of ongoing research and investigation, but nonetheless it holds promise.

MMP-13, VEGF, and Disease Activity in a Cohort of Rheumatoid Arthritis Patients.

Identifying certain serum biomarkers associated with the degree of rheumatoid arthritis (RA) activity can provide us with a more accurate view of the evolution, prognosis, and future quality of life for these patients. Our aim was to analyze the presence and clinical use of matrix metalloproteinase-13 (MMP-13), along with vascular endothelial growth factor (VEGF) and well-known cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) for patients with RA. We also wanted to identify the possible correlations between MMP-13 and these serological markers, as well as their relationship with disease activity indices, quality of life, and ultrasonographic evaluation. For this purpose, we analyzed serum samples of 34 RA patients and 12 controls. In order to assess serum concentrations for MMP-13, VEGF, TNF-α, and IL-6, we used the enzyme-linked immunosorbent assay (ELISA) technique. Our results concluded that higher levels of MMP-13, VEGF, TNF-α, and IL-6 were present in the serum of RA patients compared to controls, with statistical significance. We furthermore identified moderately positive correlations between VEGF, MMP-13, and disease activity indices, as well as with the ultrasound findings. We also observed that VEGF had the best accuracy (97.80%), for differentiating patients with moderate disease activity. According to the data obtained in our study, that although MMP-13, TNF-α and C-reactive protein (CRP) have the same sensitivity (55.56%), MMP-13 has a better specificity (86.67%) in the diagnosis of patients with DAS28(4v) CRP values corresponding to moderate disease activity. Thus, MMP-13 can be used as a biomarker that can differentiate patients with moderate or low disease activity. VEGF and MMP-13 can be used as additional parameters, along with TNF-α and IL-6, that can provide the clinician a better picture of the inflammatory process, disease activity, and structural damage in patients with RA. Our data can certainly constitute a start point for future research and extended studies with multicenter involvement, to support the selection of individualized and accurate therapeutic management strategies for our patients.

Time to redefine hyperuricemia? The serum uric acid cut-off level for precipitation might be lower: a pilot study.

BACKGROUND: Hyperuricemia is classically defined as serum uric acid (SUA) value higher than 6.8 mg∕dL; between hyperuricemic patients, only 15-20% will develop gout. Our first goal was to find if there is a specificity of the "snowstorm" feature on ultrasound (US) for hyperuricemia. Moreover, we aimed to determine if there is a level of SUA from which the urates tend to appear in the synovial fluid, without generating a typical clinical gouty flare. PATIENTS, MATERIALS AND METHODS: We conducted a cross-sectional, transverse study, including 108 consecutive patients that displayed a set of clinical and imaging features, such as swollen knee and US proof for knee joint effusion. RESULTS: Performing binary logistic regression, the relation between the explanatory variable (hyperechogenic spots) and the response variable (SUA) was demonstrated to be a significant one (p=0.005). The value of 0.397 for the statistical phi coefficient suggests a medium intensity association between the diagnosis of gout or asymptomatic hyperuricemia and whether the patients have hyperechogenic spots or not. We found the cut-off value for SUA equal to 4.815 mg∕dL, regardless of gender, from which, the urate starts to precipitate. Values for men tend to be higher in comparison to the ones found for women (4.95 mg∕dL vs. 3.9 mg∕dL). CONCLUSIONS: The "snowstorm" aspect of the fluid might be the result of an increased level of SUA and more than this, the cut-off level for SUA to precipitate might be lower than the fore used values.

Antibiotic Resistance, Still a Global Challenge.

The use of antibiotics represents a major health problem worldwide because they are often administered without medical prescription. This has led to different situations starting from a large use in inappropriate cases without medical recommendation, to a major issue that represents antimicrobial resistance. Our aim was to identify the opinion of healthcare workers (physicians and pharmacists) about the most effective solution at reducing antimicrobial resistance, helping the policy makers to take a decision. The present study was conducted from March 15th, 2021 to April 15th, 2021, using a virtual questionnaire. A total of 397 respondents provided a complete response to our questionnaire: 313 physicians and 84 pharmacists. Our results provided valuable insights that can be used to inform the development of a national health policy, resulting in population health gains. Our work provided an indication of physicians' preferences toward solutions as "A tax on antibiotic consumption, which could be used to fund innovation strategies." (41.53%) and "An educational program for patients that highlights the causes and effects of antimicrobial resistance." (42.49%). The pharmacists preferred the solutions as "An educational program for patients that highlights the causes and effects of antimicrobial resistance." (52.38%) and "Elimination of antibiotics from the list of the emergency pharmaceutical services." (42.86%). A small number of physicians (2.24%) and pharmacists (3.57%) recommended as the most effective solution at reducing antimicrobial resistance "Restrain antibiotic use in the food industry."

Entheseal involvement in a group of psoriatic arthritis patients: An ultrasonographic study.

Psoriatic arthritis (PsA) is an inflammatory potentially destructive disease that requires early diagnosis and therapeutic approach. Its main pathogenic event and the condition's hallmark is considered to be enthesitis. Clinical examination of the enthesis can be a challenge in the clinical practice; thus, ultrasonography (US) has emerged as an indispensable imaging tool for evaluating both structural and inflammatory changes of this structure. In the present study, we aimed to analyze the type and frequency of entheseal involvement in PsA patients by US examination, performing a retrospective study on 41 patients diagnosed with PsA. Ultrasonographically confirmed enthesitis, identified according to Outcome Measures in Rheumatology group (OMERACT, initially Outcome Measures in Rheumatoid Arthritis Clinical Trials) definitions, was present in 26 of the included patients, Achilles enthesis being the most common site involved. The prevalence of tendon structure abnormalities and the presence of entesophytes underlines the importance of chronic inflammation on entheseal sites. US examination has proven to be a reliable imaging method, with significant and continuous improvement, which is clearly a requisite part for current understanding and diagnosis of enthesitis and more than this, for the patient follow-up algorithm.

Staphylococcus aureus-induced septic arthritis of the ankle related to malum perforans in a diabetes patient.

Septic arthritis (SA) is a less common joint pathology with potentially fatal outcome. It is considered a medical emergency, in which prompt diagnosis and differentiation of bacterial etiology is essential for appropriate management. The knee is the most prevalent site for SA (~50% of cases), followed by hip, shoulder, and elbow. Early intervention requires an accurate diagnosis and imaging techniques enable both a positive diagnosis, as well as arthrocentesis and liquid analysis, the "gold standard" criteria. We report the case of a 70-year-old patient, with history of rheumatoid arthritis (RA), diabetes mellitus (DM) and persistent left malum perforans in the last year, with development of a severe and debilitating Staphylococcus aureus-related SA of the left ankle, which posed significant therapeutic challenges. He developed a plantar lesion at the ball of the left foot, in the past one year, which was labeled as malum perforans in the setting of DM. Musculoskeletal ultrasound was the primary imaging technique used to define the location and extent of the infectious process. Cultures drawn from the tissue were positive for S. aureus. After an antibiotic course, the apparent infectious features were remitted but the long-lasting open wound failed to improve. Antibiotic therapy was initiated in accordance with culture sensibility tests but short- and long-term outcome was unfavorable with both treatment unresponsiveness and comorbidity burden posing considerable difficulties. The association and interrelation between different comorbidities (such as hypertension, diabetes, or obesity), chronic systemic inflammation (e.g., C-reactive protein level, disease activity), and RA medication is sometimes difficult to understand and to address in daily practice, and this case report highlights multiple toils encountered in a SA patient with RA on immunosuppressive therapy and complicated DM.

Facing the Unseen - Metabolic Syndrome in Psoriatic Arthritis.

Psoriatic arthritis (PsA) is a heterogeneous multifaceted inflammatory artropathy, associated or not with psoriasis, part of the spondyloarthropaties group. Beyond articular and skin manifestations, patients with psoriatic disease are prone to associated comorbidities, including cardiovascular disease (CVD), obesity and metabolic syndrome, diabetes, or fatty liver disease; in order to improve the prognosis and the quality of life for these patients, it is mandatory to prevent, identify and properly manage any of the comorbidities. We aimed to assess the presence of traditional CV risk factors and MetS in a group of PsA patients, compared to controls and their possible inter-relation. We performed an observational study on 41 consecutive patients diagnosed with PsA based on CASPAR established criteria. Our subjects met the criteria of MetS in a percentage of 43.90% of the cases and AHT, frequently reported in higher percentages for PsA or psoriasis patients, compared to general population was also revealed in significant percentages by our data. Regarding dyslipidemia, it is confirmed and validated by several studies that patients diagnosed with PsA or psoriasis associate an altered lipid metabolism and our study noticed data accordingly. As PsA is a condition characterized by chronic inflammation, a non-traditional CV risk factor, each patient should benefit from a periodic close evaluation in order to approach a compete and early therapeutic intervention and reduce further CV morbidity and mortality rates.

New insights into IL-17/IL-23 signaling in ankylosing spondylitis (Review).

Ankylosing spondylitis (AS) is a progressive common autoimmune inflammatory disease, part of the spondylarthritis group, characterized, besides clinical spinal and peripheral joint inflammation, by enthesitis and new bone formation, that can lead to severe functional impairment. Beyond intensive and continuous research on the pathogenic process extensively performed in recent years, their impact on therapeutic management remains open to future development. Better knowledge of AS pathogenesis have shown results progressively and studies are being performed to advance our current understanding of the disease. It is well known that tumor necrosis factor (TNF) exerts a central role, along with interleukin-17 (IL-17) and interleukin-23 (IL-23), demonstrated by several clinical studies. Similar to other rheumatic inflammatory conditions, SA is associated with an early process of systemic bone loss, both trabecular and cortical, consecutive osteopenia, osteoporosis, and high fracture risk. Current personalized therapeutic options benefit from new published data, to prevent future complications and to improve quality of life.

JAK/STAT pathway in pathology of rheumatoid arthritis (Review).

Rheumatoid arthritis (RA) is classified as an inflammatory, chronic autoimmune and disabling disease based on the intricate interplay between environmental and genetic factors. With a prevalence ranging from 0.3 to 1%, RA is the most prevalent inflammatory joint disease observed in adults. Disruption of immune tolerance becomes evident when abnormal stimulation of the innate and adaptive immune system occurs. This cascade of events causes persistent joint inflammation, proliferative synovitis and, ultimately, damage of the underlying cartilage as well as the subchondral bone, leading to permanent joint destruction, deformity and subsequent loss of function. With cytokines being the key to a multitude of biological processes, including inflammation, hematopoiesis and overall immune response, one must inevitably look at the main pathways through which a significant number of those molecules exert their function. Janus kinase/signal transducers and activators of transcription (JAK/STATs) represent one such pathway and, recently, JAK inhibitors (JAKinibs) have shown promise in the treatment of several inflammatory diseases, including RA. This narrative review focuses on the intricate signaling pathways involved as well as on the clinical aspects and safety profiles of JAKinibs approved for the treatment of RA.

Host immune response in chronic hepatitis C infection: involvement of cytokines and inflammasomes.

Chronic liver disease is a major health issue worldwide and chronic hepatitis C (CHC) is associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC). There is evidence that the hepatitis C virus (HCV) infection is correlated with immune senescence by way of immune activation and chronic inflammation, which lead to increased metabolic and cardiovascular risk, as well as progressive liver damage. Both the innate and adaptive immunity are firmly tied to the prognosis of an infection with HCV and its response to antiviral therapy. HCV is therefore associated with increased pro-inflammatory status, heightened production of cytokines, prolonged systemic inflammation, as well as increased morbidity and mortality, mainly due to the progression of hepatic fibrosis and HCC, but also secondary to cardiovascular diseases. Viral hepatic pathology is increasingly considered a disease that is no longer merely limited to the liver, but one with multiple metabolic consequences. Numerous in vitro studies, using experimental models of acute or chronic inflammation of the liver, has brought new information on immunopathological mechanisms resulting from viral infections and have highlighted the importance of involving complex structures, inflammasomes complex, in these mechanisms, in addition to the involvement of numerous proinflammatory cytokines. Beyond obtaining a sustained viral response and halting the aforementioned hepatic fibrosis, the current therapeutic "treat-to-target" strategies are presently focused on immune-mediated and metabolic disorders, to improve the quality of life and long-term prognosis of CHC patients.

Inflammatory and Oxidative Stress Markers-Mirror Tools in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease, associated with significant morbidity, mainly due to progressive damage and consequent disability. Oxidative stress is an important part of RA pathophysiology, as in autoimmune disease the interaction between immune response and endogenous/exogenous antigens subsequently induce the production of reactive oxygen species. The oxidative stress process seems to be positively strongly correlated with inflammation and accelerated joint destruction. We were asking ourselves if the oxidative stress biomarkers are the mirror tools of disease activity, outcome, and inflammation level in a group of RA patients under standard or biological therapy compared to healthy age-matched controls. In order to do this, the oxidative stress damage biomarkers (lipids peroxide and protein carbonyl level), antioxidant defense capacity, and pro-inflammatory status of plasma were quantified. In this study, we took into account the complete picture of RA diseases and assessed, for the first time, the inflammatory level in correlation with the oxidative stress level and antioxidant capacity of RA patients. Our results revealed that protein oxidation through carbonylation is significantly increased in RA groups compared to controls, and both protein carbonyl Pcarb and thiobarbituric acid reactive substance (TBARS) are reliable markers of ROS damage. Therefore, it is unanimous that neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio ( MLR), platelet/lymphocyte ratio (PltLR) correlated with Pcarb, and TBARS can provide a view of the complex phenomenon represented by proteins/lipids damage, key contributors to disease outcome, and an increased awareness should be attributed to these biomarkers.

Neuroinflammation in systemic lupus erythematosus - a review.

Neuroinflammation is a complex process that contributes to the pathogenesis of both immune mediated and neurodegenerative pathologies. Systemic lupus erythematosus (SLE) is the prototype of connective tissue diseases that can present the complete spectrum of neurological and psychiatric dysfunctions. The precise etiological diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) is rather difficult to be established and it is still controversial the exact timing of neuropsychiatric (NPS) events: either central nervous system (CNS) is the initial target of autoimmune abnormalities, either NPS symptoms are a part of multisystem involvement. Ischemic and inflammatory mechanisms have an important input on NPSLE pathogenesis. Neuroinflammation, consequent to blood-brain barrier (BBB) damage, local and systemic production of autoantibodies, determine neuronal injury and apoptosis, further responsible for diffuse cerebral events, mostly cognitive dysfunction and psychotic disorder. Moreover, SLE complications or therapy complications can interfere and contribute to complex clinical manifestations that can be present in SLE patients. Understanding the role of each pathogenic way can provide not only an early diagnosis, but a more accurate therapeutic approach of these patients.

The role of skin and muscle biopsy in the diagnosis of main connective tissue diseases.

Systemic involvement in autoimmune diseases is often unclear and organ changes are confounding, thus making it difficult to have an early accurate diagnosis. In those situations, both clinical and paraclinical findings might orientate the diagnosis, but only histological or immunohistochemistry changes might be accurate enough. The skin histological changes are relevant and sometimes might have a tremendous role in the accurate diagnosis of autoimmune rheumatic diseases, due to the correlation with the clinical systemic manifestations of the diseases and through the accessibility of biopsy. In the same time, muscle biopsy can provide important support for physicians improving diagnosis and optimizing management of connective tissue diseases.

High frequency ultrasonography of the hand versus anti-RA33 evaluation in early rheumatoid arthritis - a pilot study.

AIM: Accurate diagnosis and early treatment in rheumatoid arthritis (RA) can lead to a good outcome and a correct management of the disease. We aimed toinvestigate the prognostic value of anti-RA33 antibodies, by evaluating the relationship with ultrasonographic (US) findings in patients with early RA. MATERIAL AND METHODS: We performed a prospective study which included 29 patients, diagnosed with early RA according to the ACR/EULAR 2010 criteria and 21 sex and age-matched control subjects. All patients underwent clinical and biological assessment, followed by US examination in grayscale (GS) and power Doppler (PD) at baseline and after 12 months [from the second to the fifth metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints and wrists (RCC), in dorsal aspect]. The second and fifth MCP joints were scanned also in lateral aspects. RESULTS: The initial GS evaluation revealed the presence of synovitis in all 29 patients; PD found at least one joint with a PD grade higher than 1 in 23 patients, higher than 2 in 20 patients, and grade 3 in 6 patients; at 12 months, we revealed the presence of GSUS synovitis in 25 patients and PDUS examination found active synovitis in 12 subjects. In those patients, the anti-RA33 titre was significantly lower compared to those without PDUS active synovitis (p=0.031), with a moderately negative correlation (r=-0.519, p=0.0039). CONCLUSIONS: The current study shows that anti-RA33 antibodies might constitute an additional tool for diagnosing early RA patients and can help identify patients with mild disease and a low level of activesynovitis.

Intramuscular hemangioma of the arm: ultrasonography and pathology features.

Hemangiomas are between the most frequent soft tissue masses and despite the vascular origin, they do not generate metastases and do not have malignant evolution. They are frequent in childhood and female sex is more frequently affected. If deeply located, these tumors are difficult to diagnose and thus an imaging method is often needed, but conventional radiology is not sufficient. If superficially located, it frequently involves the skin and subcutaneous tissues, but in the deeper layer, they are often intramuscular. Clinical findings of intramuscular hemangioma include swelling, pain and sometimes loss of muscle function.

Ultrasonography in the diagnosis and management of non inflammatory conditions of the hand and wrist.

High resolution ultrasonography has already become an important tool in the diagnosis and management of inflammatory arthritis of the hand and wrist but lately it has been proven to be the method of choice in the evaluation of traumatic lesions of tendons, annular pulleys, nerves, and ligaments and at the same time in detecting foreign bodies. The objective of this paper is to review and describe the current knowledge on these US findings and to highlight the ultrasonography role in the evaluation of non-inflammatory conditions of the hand and wrist.

Vascular endothelial growth factor in systemic lupus erythematosus - correlations with disease activity and nailfold capillaroscopy changes.

Our study aimed to quantify serum VEGF (vascular endothelial growth factor) and its inter-relation with the severity of microvascular damage, assessed by nailfold capillaroscopy (NC), and to establish the possible relationship with disease activity score. We included 18 patients, diagnosed with systemic lupus erythematosus (SLE) and 17 gender and age-matched control subjects. For determining serum VEGF, we used a Human VEGF Assay kit-IBL. NC was performed, according to the standard method, using a video-capillaroscope Videocap 3.0, DS Medica, by the same examiner, blinded to clinical and laboratory data. Serum VEGF registered a mean value of 68.99±71.06 pg/mL for SLE patients and 31.84±11.74 pg/mL for controls, differences statistically significant; depending on disease activity, we found a mean value of 60.11±57.74 pg/mL, for patients with moderate disease activity vs. 30.96±11.51 pg/mL for the ones with a low activity (p=0.014). We found a moderately positive correlation, statistically significant (p=0.015), between serum level of VEGF and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Performing NC, we found changes in 88.88% of the patients; the most frequent were increased tortuosity, dilated capillaries, an increased length and a prominent subpapillary plexus. The presence of nailfold capillaroscopy changes and serum level of VEGF, correlated moderately, positive. Since serum levels of VEGF are higher in SLE patients, compared to controls, significantly different according to disease activity degree, and directly inter-related to abnormal NC patterns and a more active disease, we can include these accessible parameters in the routine evaluation, in order to better quantify the systemic damage, individualize the treatment, improve the outcome and life quality for these patients.