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.

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.

A New Approach to Postoperative Rehabilitation following Mosaicplasty and Bone Marrow Aspiration Concentrate (BMAC) Augmentation.

BACKGROUND: Chondral defects in the knee present a significant challenge due to their limited self-healing capacity, often leading to joint degeneration and functional disability. Current treatments, including surgical approaches like mosaicplasty and regenerative therapies such as bone marrow aspirate concentrate (BMAC) augmentation, aim to address these defects and improve patient outcomes. MATERIALS AND METHODS: This study conducted a single-center, randomized controlled trial to evaluate the efficacy of different treatment approaches and rehabilitation protocols for chondral defects. Thirty-seven subjects presenting with symptomatic chondral or osteochondral defects (>3 cm2) in the weight-bearing region of the femoral condyle were partitioned into three groups, and underwent mosaicplasty with or without BMAC augmentation, followed by either a 6-week or 12-week rehabilitation program. Group 1 (n = 10) received mosaicplasty combined with BMAC augmentation and engaged in a twelve-week two-phase rehabilitation protocol. Group 2 (n = 15) underwent mosaicplasty alone and participated in the same twelve-week two-phase rehabilitation regimen. Meanwhile, Group 3 (n = 12) underwent mosaicplasty and underwent a shorter six-week one-phase rehabilitation program. Clinical assessments were performed using the visual analog scale (VAS) for pain, goniometry for the knee's range of motion (ROM), manual muscle testing (MMT) for quadricep strength, and the Western Ontario and McMaster University Arthritis Index (WOMAC) for functional evaluation in three test phases. RESULTS: Significant differences in WOMAC scale scores were observed between the three groups at the intermediate (F(2, 34) = 5.24, p < 0.010) and final (F(2, 34) = 111, p < 0.000) stages, with post hoc Tukey tests revealing variations shared among all three groups. The between-group analysis of the VAS scale demonstrated no statistically significant difference initially (F(2, 34) = 0.18, p < 0.982), but significant differences emerged following the intermediate (F(2, 34) = 11.40, p < 0.000) and final assessments (F(2, 34) = 59.87, p < 0.000), with post hoc Tukey tests revealing specific group variations, notably between Group 1 and both Group 2 and Group 3, and also between Group 3 and Group 2. The between-group analysis of quadricep muscle strength using MMT scores revealed no statistically significant differences initially (F(2, 34) = 0.376, p < 0.689) or following the intermediate assessment (F(2, 34) = 2.090, p < 0.139). The one-way ANOVA analysis showed no significant difference in the knee ROM initially (F(2, 34) = 1.037, p < 0.366), but significant differences emerged following intermediate (F(2, 34) = 9.38, p < 0.001) and final assessments (F(2, 34) = 11.60, p < 0.000). Post hoc Tukey tests revealed significant differences between Groups 1 and 2, Groups 1 and 3, and Groups 2 and 3 at intermediate and final assessments. CONCLUSIONS: The patients who received BMAC augmentation and completed a 12-week rehabilitation protocol had significantly better outcomes in pain relief, knee function, and ROM when compared to those who did not receive BMAC augmentation or those who completed a shorter rehabilitation period. Our findings suggest that combining mosaicplasty with BMAC augmentation and a comprehensive rehabilitation program can lead to superior clinical outcomes for patients with chondral defects in the knee.

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.