Ali Nili

Pemphigus vulgaris is a B cell–mediated autoimmune disease characterized by autoantibodies targeting desmoglein-3 (Dsg3), a critical adhesion molecule in epithelial tissues. Current treatments rely on broad immunosuppression, highlighting the need for more targeted therapeutic approaches in pemphigus vulgaris and other autoantibody-driven disorders. We engineered a therapeutic fusion protein consisting of the pathogenic domains of Dsg3 linked to either human immunoglobulin G1 (IgG1) or mouse IgG2a (Dsg3-Fc). In vitro, Dsg3-Fc selectively eliminated Dsg3-autoreactive B cells. In vivo, Dsg3-Fc effectively depleted human B cells expressing patient-derived anti-Dsg3 B cell receptors, even in the presence of circulating autoantibodies. Moreover, Dsg3-Fc inhibited both disease initiation and progression in a polyclonal, active pemphigus vulgaris model in immunocompetent mice. In addition, Dsg3-Fc rapidly neutralized pathogenic autoantibodies without inducing systemic toxicity. These findings demonstrate that targeting pathogenic B cells and neutralizing autoantibodies through autoantigen-Fc fusion proteins may represent a promising therapeutic strategy for pemphigus vulgaris and potentially other autoantibody-mediated diseases without the need for global immunosuppression.

Although chimeric antigen receptor (CAR) T cell therapies have demonstrated promising clinical outcomes, durable remissions remain limited. To extend the efficacy of CAR T cells, we develop a CAR enhancer (CAR-E), comprising a CAR T cell antigen fused to an immunomodulatory molecule. Here we demonstrate this strategy using B cell maturation antigen (BCMA) CAR T cells for the treatment of multiple myeloma, with a CAR-E consisting of the BCMA fused to a low-affinity interleukin 2 (IL-2). This selectively induces IL-2 signaling in CAR T cells upon antigen–CAR binding, enhancing T cell activation and antitumor activity while reducing IL-2-associated toxicities. We show that the BCMA CAR-E selectively binds CAR T cells and increases CAR T cell proliferation, clearance of tumor cells and development of memory CAR T cells. The memory cells retain the ability to re-expand upon restimulation, effectively controlling tumor growth upon rechallenge. Mechanistic studies reveal the involvement of both CAR and IL-2 receptor endodomains in the CAR-E mechanism of action. The CAR-E approach avoids the need for specific engineering and enables CAR T cell therapy with lower cell doses.

Rituximab (RTX) combined with short‐term glucocorticoids (GC) is an effective therapeutic option for pemphigus. The newly developed Glucocorticoid Toxicity Index (GTI) tool provides the possibility to measure GC toxicities over time. To compare 1‐year GTI between two groups of RTX‐treated and RTX‐naïve patients with pemphigus. The responsiveness of the GTI was also investigated. A prospective cohort of 129 adults with newly diagnosed pemphigus was conducted. GC‐related toxicities were assessed at 3‐month intervals according to Composite and Specific lists of the GTI. Of the patients, 76.7% ( n = 99) received RTX. Throughout the time intervals, RTX‐treated patients had lower GTI compared to RTX‐naïve ones ( p = 0.036). The mean GTI at 1‐year was 34.3 in the RTX‐treated group and 50.8 in the RTX‐naïve group ( p = 0.04). The most commonly observed GC‐related toxicity was neuropsychiatric manifestations for 34% (224 events). The relapse rate of RTX‐treated patients (1%) was significantly lower than RTX‐naïve patients (10%) ( p = 0.037). The GTI showed no correlation with cumulative GC consumption in both groups ( p > 0.05, both). Patients treated with GC alone had remarkably higher GTI than patients treated with GC plus RTX. The GTI is an applicable tool to quantitatively capture GC toxicities at the patient level in pemphigus.

Purpose Dislocation following total hip arthroplasty (THA) is a well-known complication. However, there is little data on its rate and predictors in patients with developmental dysplasia of the hip (DDH). The current study is aimed to determine the rate and specific risk factors of dislocation following THA in DDH patients. Methods All the medico-surgical records of primary THAs from January 2014 to January 2019 were retrospectively reviewed. They were categorized into three main groups: primary OA, DDH, and others. Pre-operative and post-operative radiographs, past medical and surgical history, and surgical notes were reviewed in DDH cases. Results In a total of 171 patients with DDH, 21 suffered from dislocation after THA (12%) which was significantly more frequent than those with primary OA. In univariate analysis, higher grade of dysplasia, smaller head size, intra-operative fracture, Wagner Cone stem, failure of offset restoration, and implanting the cup outside the Lewinnek’s safe zone were identified as predictors of dislocation. In multiple regression analysis, however, only higher Crowe grade, intra-operative fracture, and post-operative acetabular offset less than 16 mm were independent predictors of dislocation. Conclusion Dysplastic hips can be more prone to post-THA dislocation than those with primary OA. Higher grades of dysplasia, failure of offset restoration, and intra-operative fracture can increase the rate of dislocation in this group of patients.

Introduction: Pemphigus vulgaris (PV) is an intraepidermal autoimmune bullous disease (AIBD) characterized by autoantibodies against desmosomal adhesion proteins, most commonly desmoglein (Dsg)3, leading to the suprabasal cleft formation and acantholysis. Areas covered: Direct immunofluorescence (DIF) and indirect immunofluorescence (IIF) studies display the intercellular deposition of IgG/C3 throughout the epidermis and presence of circulating autoantibodies respectively, as a net-like pattern. However, the target antigen remains unknown using immunofluorescence techniques. Thanks to the development of Dsg ELISA, using recombinant technology, circulating antibodies against Dsg1 and 3 could be detected sensitively. It is possible to differentiate PV from pemphigus foliaceus (PF) using this assay. BIOCHIP mosaic and multivariant ELISA are two novel serologic methods with the added value of the ability to screen several AIBDs simultaneously. Non-Dsg1/3 antigens are also involved in the pathogenesis of PV and investigated more deeply thanks to the protein microarrays technique. Additionally, patients with high values of anti-Dsg1/3 may be lesion-free, suggesting the presence of nonpathogenic autoantibodies. Expert opinion: Newer diagnostic methods to replace traditional techniques should possess high sensitivity and specificity and be widely available, noninvasive, and relatively cheap. The newly developed methods need to be further evaluated before being recommended for routine use.

Pemphigus Vulgaris (PV) is a rare autoimmune blistering disease, which mainly causes mucosal and/or cutaneous lesions. In June 2018, FDA approved Rituximab (RTX)‐ a B‐cell depleting agent‐ for the management of patients with moderate‐to‐severe pemphigus. Although the majority of patients respond well to this drug, some do not reach complete remission with a single cycle of RTX. In this review, following an overview of RTX and its clinical outcomes, we have focused on the possible outcomes after RTX therapy in patients with PV. The response is defined into four main categories; complete responders, partial responders, non‐responders, and paradoxical reactions, based on three possibilities of reaching the consolidation phase after three months, reaching remission until six months, and the ability of corticosteroid tapering in six months after RTX administration. Concerning the safety of RTX, three categories of infusion reactions, short and long‐term side effects are discussed. Additionally, we have suggested approaches for the evaluation of clinical and serological responses at different critical time‐points, including one, two, three, and six months after RTX administration. Finally, available markers to predict the response to RTX and research gaps in the field of RTX therapy have been summarized.

Background: Port Wine Stain (PWS) is a congenital capillary malformation. Although multiple treatments are required, the gold standard treatment for PWS is Pulsed Dye Laser (PDL). Given its anti‐angiogenic effects, sirolimus can be considered as an adjuvant to PDL in PWS.Aim: To evaluate the efficacy and safety of topical sirolimus (Rapamycin) 0.2% cream as adjuvant therapy for PDL for PWS.Methods: In this randomized double‐blind placebo‐controlled trial, 15 patients with PWS were enrolled. Each lesion was divided into upper and lower parts, and each part was assigned randomly to receive PDL (4 sessions, 2 months apart) plus sirolimus vs PDL and placebo. The response was evaluated using colorimetry, investigator global assessment (IGA), and patient global assessment (PGA) every two months for eight continuous months.Results: According to the colorimetric analysis, medial and lateral sides of the treatment and placebo parts did not differ significantly (both P‐value > .05). However, according to PGA and IGA, there was a significant difference in favor of sirolimus (P‐values = .041 and .039, respectively). Itching and dryness (86.7%), contact dermatitis (20%) were the most common adverse effects in the sirolimus group, while none of them were observed in placebo.Conclusion: Although the improvement was significant subjectively, topical sirolimus 0.2% as an adjuvant to PDL does not appear to improve PWS erythema using calorimetric assessment.