Autoimmune Liver Diseases and Rheumatoid Arthritis-Is There an Etiopathogenic Link?

Rheumatoid arthritis (RA) is a systemic immune-mediated disease that, in addition to the articular involvement, can have extra-articular manifestations. Even though liver damage in RA is not very common, associated autoimmune liver diseases (AILDs) may occur. The most common AILD associated with RA is primary biliary cirrhosis (PBC), followed by autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). There are common underlying mechanisms that play a role in the emergence of autoimmunity and inflammation in both rheumatic and autoimmune liver diseases. Genetic studies have revealed the existence of several common disease-associated genes shared between RA and AILDs, and infectious triggers, particularly those associated with recurrent or complicated urinary tract infections, are also speculated to be potential triggers for these conditions. Moreover, these diseases share common serologic patterns characterized by the presence of specific autoantibodies and hyper-gammaglobulinemia. In this study, we focus on reviewing the association between RA and AILDs regarding the prevalence and possible etiopathogenic link.

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.

Evaluation of Disease Activity in Inflammatory Bowel Disease: Diagnostic Tools in the Assessment of Histological Healing.

Inflammatory bowel disease (IBD) comprises two types of chronic intestinal disorders: Crohn's disease and ulcerative colitis. In long-standing ulcerative colitis disease activity, histological persistent inflammation has been linked to an increased risk of relapse, and long-term corticosteroid use, even when endoscopic remission is reached. In Crohn's disease, the discontinuous nature of lesions and transmural inflammation have limited the standardized histological assessment. The current evidence from research proposes that besides clinical and endoscopic healing, the achievement of histological healing constitutes an endpoint to assess disease activity and remission in IBD patients concerning better long-term disease outcomes. Histological alterations may persist even in the absence of endoscopic lesions. For these reasons, new advanced techniques promise to revolutionize the field of IBD by improving the endoscopic and histologic assessment, disease characterization, and ultimately patient care, with an established role in daily practice for objective assessment of lesions. This review outlines the importance of including microscopic evaluation in IBD, highlighting the clinical benefits of a deep state of disease remission using validated diagnostic methods and scoring systems for daily clinical practice.

Cytokines in Systemic Lupus Erythematosus-Focus on TNF-α and IL-17.

Systemic lupus erythematosus (SLE) is an autoimmune disorder known for its complex pathogenesis, in which cytokines play an essential role. It seems that the modulation of these cytokines may impact disease progression, being considered potential biomarkers. Thus, TNF (tumor necrosis factor)-α and IL (interleukin)-17 are molecules of great interest in SLE. TNF-α plays a dual role in SLE, with both immunosuppressive and proinflammatory functions. The role of IL-17 is clearly described in the pathogenesis of SLE, having a close association with IL-23 in stimulating the inflammatory response and consecutive tissue destruction. It appears that patients with elevated levels of these cytokines are associated with high disease activity expressed by the SLE disease activity index (SLEDAI) score, although some studies do not confirm this association. However, TNF-α and IL-17 are found in increased titers in lupus patients compared to the general population. Whether inhibition of these cytokines would lead to effective treatment is under discussion. In the case of anti-TNF-α therapies in SLE, the possibility of ATIL (anti-TNF-induced lupus) is a serious concern that limits their use. The use of anti-IL-17 therapies in SLE is a promising option, but not yet approved. Future studies of these cytokines in large cohorts will provide valuable information for the management of SLE.

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).

New onset severe ulcerative colitis following Ixekizumab therapy.

Ixekizumab is one of the three biologic agents including Secukinumab and Brodalumab that targets the Interleukin-17 (IL-17) pathway to reduce inflammation in psoriasis and ankylosing spondylitis. In this report we present the case of 42-year-old woman, who was diagnosed with psoriasis and psoriatic arthritis. One week after first administration of Ixekizumab, she developed diffuse abdominal pain, bloody diarrhea (7-8 stools/day) and fever. Following imaging (colonoscopy, computed tomography) and laboratory investigations, she was diagnosed with acute severe ulcerative colitis complicated with toxic megacolon. The medical treatment (first corticotherapy, then infliximab) has failed and the patient needed emergency colectomy. Based on the immunological mechanisms and the observation from other studies, Ixekizumab should be considered an etiology for new-onset inflammatory bowel disease.

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.

Correlations between clinics, dermoscopy and histopathology in a female with two dermatofibromas - a case report.

Dermatofibromas are benign fibrohistiocytic tumors that involve the dermis. They have often a polymorphous clinical aspect, being frequently confused with other lesions varying from vascular tumors to melanoma. An important tool in diagnosis is represented by dermoscopy, which facilitates the recognition of dermatofibromas' characteristic structures such as central white patch and peripheral pigment network. Although dermatofibromas are often solitary lesions, we report the case of a woman who presented two fibrohistiocytary masses, involving the calf and the thigh, the last one with an atypical aspect leading to the confusion with a malignant tumor. Furthermore, the lesions were different at both dermoscopic and histopathological examinations, needing a second histopathological opinion. The aim of our study is to emphasize the role of histopathology, which represents the diagnostic golden standard in suspicious cases and the possible connections between dermatoscopy and histology. Sometimes, even histopathology may be very difficult, needing repeated sections and even special stains.

An animal model of peripheral nerve regeneration after the application of a collagen-polyvinyl alcohol scaffold and mesenchymal stem cells.

Extensive nerve injuries often leading to nerve gaps can benefit, besides the gold standard represented by autologous nerve grafts, by the inciting field of tissue engineering. To enhance the role of biomaterials in nerve regeneration, the nerve conduits are associated with Schwann or Schwann-like cells. In this study, we evaluated rat sciatic nerve regeneration, by using a biodegradable nerve guide composed of Collagen (COL) and Polyvinyl Alcohol (PVA), associated with mesenchymal stem cells (MSC). After the exposure of the rat sciatic nerve, a nerve gap was created by excising 1 cm of the nerve. Three experimental groups were used for nerve gap bridging: autografts, nerve conduits filled with medium culture and nerve conduits filled with MSC. The methods of sensory and motor assessment consisted of the functional evaluation of sciatic nerve recovery - toe-spread, pinprick tests and gastrocnemius muscle index (GMI). The histological and immunocytochemical analysis of the probes that were harvested from the repair site was performed at 12 weeks. Successful nerve regeneration was noted in all three groups at the end of the 12th week. The functional and immunocytochemical results suggested that COL-PVA tubes supported with mesenchymal stem cells could be considered similar to autologous nerve grafts in peripheral nerve regeneration, without the drawbacks of the last ones. The functional results were better for the autografts and the ultrastructural data were better for the nerve conduits, but there were not noticed any statistical differences.

Case-control study to evaluate the link between immunosuppression and Candida spp. infection.

Candidiasis is one of the fungal infections with the highest incidence in the immunosuppressed host. The evolution of infection and the increase of antifungal medical drugs resistance could both contribute to the mortality attributable to Candida infection in the immunosuppressed host. Even though the data from international studies are well known, few studies have been published in Romania on this subject. In the case-control study we demonstrated the link between the immunosuppression and the presence of Candida infection. Further studies are to be carried out in order to identify more accurately this link and to extend the study to other fungi. There is a need to increase the microbiological diagnosis use at least at the hospital laboratory level in order to better identify the real situation of fungal infections and the link between them and the concrete status of different hosts. Continued surveillance for infections caused by C. albicans and other species of Candida among hospitalized patients is recommended. Control of antimicrobial resistance among nosocomial infections caused by C. albicans and other species of Candida requires rational policies for use of both antifungal and antibacterial agents and appropriate surveillance for the emergence of resistant strains and species.