Search Results (297)

Childhood-onset lupus nephritis (cLN) should no longer be framed as a smaller version of adult lupus nephritis. It is a high-stakes pediatric kidney disease in which immune injury, treatment toxicity, growth, puberty, fertility, adherence, and transition to adult care intersect over decades. Approximately 10–20% of systemic lupus erythematosus begins in childhood, and 40–60% of affected children develop lupus nephritis. Regional cohorts report even higher renal involvement in some populations, including 65–73% among Saudi children with SLE. Contemporary guidance has moved from prolonged high-dose glucocorticoids and cyclophosphamide-dominant treatment toward biopsy-driven, treat-to-target care built around mycophenolic acid analogues, hydroxychloroquine, nephroprotection, rapid steroid tapering, and selected belimumab- or calcineurin-inhibitor-based triple therapy. This Viewpoint argues that the central question in cLN is no longer simply how to induce remission, but how to produce a durable kidney response early enough, with sufficiently low cumulative toxicity, to preserve kidney function and childhood development. Pediatric practice must therefore combine adult trial evidence with child-specific caution, explicit adherence strategies, fertility and growth protection, and structured transition planning. The aim should be efficacy without toxicity: not undertreatment, but intelligent, sustainable, developmentally informed treatment. Full article

Background: Acute rejection (AR) is an established risk factor for kidney allograft loss, but whether the timing of the first AR episode adds prognostic information independent of secular changes in immunosuppression remains incompletely defined. We re-examined this question in a cohort restricted to the contemporary calcineurin-inhibitor (CNI) era and explicitly accounted for the maintenance CNI (tacrolimus vs. cyclosporine). Methods: We studied 2470 recipients of an isolated kidney transplant performed between 2000 and 2018 at a single academic center. Recipients were classified by the timing of the first AR episode as AR-free, Early AR (≤6 months), Intermediate AR (6–12 months), or Late AR (>12 months). Co-primary outcomes were estimated glomerular filtration rate (eGFR) and death-censored graft survival. Multivariable Cox regression adjusted for recipient and donor age, recipient sex, HLA mismatch, donor type, ABO incompatibility, diabetes, retransplantation, transplant year, and maintenance CNI. A pre-specified secondary analysis evaluated whether the observed AR-timing association was explained by the maintenance CNI. Results: AR occurred in 294 of 2470 recipients (11.9%): 253 Early, 10 Intermediate, and 31 Late. Median follow-up was 105 months. Mean 5-year eGFR was 67.1 (AR-free), 56.5 (Early), 47.5 (Intermediate), and 47.2 mL/min/1.73 m² (Late) (p < 0.001). Kaplan–Meier 10-year death-censored graft survival was 90.5%, 80.7%, 77.8%, and 52.2%, respectively (log-rank p < 0.001). After adjustment, the hazard of graft failure relative to AR-free recipients was 2.25 (95% CI 1.68–3.01) for Early AR and 7.03 (4.28–11.54) for Late AR (both p < 0.001). The Intermediate AR estimate was directionally consistent but imprecise because of the small number of cases. Tacrolimus use was associated with a lower observed incidence of AR (8.5% vs. 20.0%, p < 0.001), but the observational CNI comparison was confounded by era and follow-up duration and did not explain the AR-timing gradient. Conclusions: Within a contemporary CNI-era cohort and after adjustment for maintenance immunosuppression and transplant year, late-onset AR—particularly onset beyond the first post-transplant year—provided strong prognostic information for long-term graft dysfunction and graft failure. Full article

Lichen planus (LP) is a chronic T-cell-mediated interface dermatitis. Genital involvement is frequently refractory to topical corticosteroids and calcineurin inhibitors and may lead to fibrosis, architectural distortion, and substantial impairment in quality of life. We report the case of a 39-year-old male with a 15-year history of biopsy-confirmed genital LP unresponsive to high-potency topical corticosteroids and tacrolimus 0.1%, who received topical Rosa damascena stem cell-derived exosomes (RSCEs) at biweekly sessions for four months. Each session combined 2 mL of in-office application with superficial microneedling in hyperkeratotic areas, followed by 3 mL of the same-day home application. No concomitant topical corticosteroid or calcineurin inhibitor was used during the treatment period. Paired pre- and post-treatment 4 mm punch biopsies were obtained from the same anatomical region, processed using identical protocols, stained with hematoxylin and eosin, and reviewed by a board-certified dermatopathologist. After four months, we observed clinical resolution of pruritus and fissuring, progressive desquamation of hyperkeratotic plaques, and improved tissue elasticity. The post-treatment biopsy showed reduced hyperkeratosis and hypergranulosis, attenuation of the band-like lymphohistiocytic infiltrate, partial restoration of the dermoepidermal interface, and reduced basal vacuolar degeneration relative to baseline. No dysplastic changes or treatment-related adverse events were observed. These observations are based on a single uncontrolled case and cannot establish causality, isolate the contribution of microneedling, or demonstrate disease modification beyond the descriptive level. Histological assessment was qualitative; no semi-quantitative or immunohistochemical analysis was performed. The exosome preparation was used as a standardized commercial product and was not independently characterized in our laboratory. The findings are intended solely as hypothesis-generating. Independent characterization of the exosome preparation, immunohistochemical and ideally transcriptomic profiling of paired tissue, and prospective controlled studies are required before any therapeutic claim can be supported. Full article

Background/Objectives Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family of amine oxidases involved in collagen cross-linking, has emerged as a key mediator of pathological extracellular matrix remodeling and tissue fibrosis. Dysregulated LOXL2 activity has been implicated in various fibrotic diseases; however, its role in fibrosis-driven chronic kidney injury, particularly in the context of calcineurin inhibitor-induced kidney toxicity, remains incompletely defined. Methods To investigate the contribution of LOXL2 inhibitor to cyclosporine A (CsA)-induced nephropathy, a well-established model of progressive tubulointerstitial fibrosis, male CD-1 mice were administered either saline or CsA (15 mg/kg/day, intraperitoneally) for 8 weeks. After 4 weeks of CsA exposure, CsA-treated mice were further divided into two groups and received either vehicle or a LOXL2 inhibitor (10 mg/kg/day, oral gavage) for an additional 4 weeks. Kidney function, albuminuria, histological fibrosis, inflammatory cell infiltration, and profibrotic gene expression were assessed. Results In a murine model of CsA-induced nephropathy, pharmacological inhibition of LOXL2 markedly improved kidney outcomes. LOXL2 inhibition significantly reduced albuminuria and ameliorated kidney dysfunction. In parallel, tubulointerstitial fibrosis was substantially attenuated, accompanied by reduced myofibroblast activation and extracellular matrix accumulation. These protective effects were associated with downregulation of profibrotic and inflammatory mediators and inhibition of TGF-β-related downstream signaling pathways activated by CsA. Conclusions The present preclinical findings suggest that Compound #765-mediated LOXL2 inhibition may offer a potential therapeutic benefit in CsA-induced fibrosis, though further validation is warranted. Full article

Cardiovascular disease remains the leading cause of mortality in kidney transplant recipients (KTRs). Arterial hypertension is present in a vast majority of patients after kidney transplantation, constituting the most prevalent cardiovascular comorbidity, and is a significant modifiable risk factor for other cardiovascular complications and graft loss. The 2024 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines do not address blood pressure control strategies in KTRs, and the prior 2021 KDIGO recommendations targeting values below 130/80 mmHg rely primarily on data extrapolated from non-KTR populations. This represents an existing evidence gap in the management of post-transplant hypertension. Dihydropyridine calcium channel blockers and angiotensin receptor blockers remain first-line antihypertensive medications, although most studies assessing their effectiveness in KTRs date back more than 15 years. The current treatment guidelines are based largely on limited and outdated data. Optimal selection and individualization of immunosuppressive therapy and—when feasible—its modification in some KTRs may be important in improving blood pressure control. This includes, for example, a reduction in the calcineurin inhibitor or steroid dose, as well as the use of mTOR inhibitors or belatacept. The lack of large, up-to-date randomized trials in the KTR population underscores the pressing need for further extensive research focused on this patient group. Full article

Atopic dermatitis (AD) is a common chronic inflammatory condition of the skin that has increased dramatically over the past decade and significantly impacts individual quality of life. Corticosteroids are still the primary therapy for AD, but there are limitations to their continued use due to potential adverse effects, particularly when used in sensitive areas. Topical calcineurin inhibitors (CNIs), such as tacrolimus and pimecrolimus, are available as a safe, steroid-sparing alternative that directly inhibit calcineurin-mediated activation of T cells and have been shown to be efficacious according to varying clinical study designs including randomized controlled trials, registry studies and meta-analyses. Although there was controversy regarding the safety of CNIs subsequent to the FDA’s black-box warning in 2006, the preponderance of evidence supports their continued safety when used as directed. In contrast to biologics and JAK inhibitors, CNIs occupy an inherently unique therapeutic niche for use in pediatric patients, have demonstrated historical efficacy, and can provide localized affordable treatment in sensitive areas including the face, eyelids and intertriginous surfaces. Furthermore, the role of CNIs in the context of precision dermatology continues to be defined through new innovations including barrier-repair strategies used in combination with topical medications, microneedle systems, and nanocarrier formulations. Hence, the role of CNIs in the current AD treatment paradigm is crucial and lies at the interface between topical corticosteroids and systemic immunomodulatory agents. The narrative review discusses recent advances in formulation strategies, combination approaches, and targeted delivery systems, underscoring how CNIs continue to bridge established practice and emerging therapeutic innovation in AD. Full article

Introduction: Steroid-resistant nephrotic syndrome (SRNS) represents a severe and challenging form of pediatric nephrotic syndrome and is associated with a high risk of progression to end-stage kidney disease. Calcineurin inhibitors (CNIs) are the standard second-line therapy; however, their use is limited by frequent relapses and long-term nephrotoxicity. Mycophenolate mofetil (MMF) offers a more favorable safety profile and a complementary mechanism of action; however, the clinical utility of combining MMF with CNIs remains largely under-explored in this population. Case Presentation: We describe a series of nine pediatric patients with steroid-resistant or steroid-dependent nephrotic syndrome who were refractory to cyclosporine monotherapy. These patients were treated with a combination regimen of cyclosporine (4–5 mg/kg/day; target trough levels of 75–150 ng/mL) and MMF (600 mg/m²/day). This therapeutic approach was associated with a reduction in corticosteroid dosage and a decrease in the annual number of relapses in most patients. Conclusions: In this small case series of pediatric patients with corticosteroid-dependent or steroid-resistant nephrotic syndrome refractory to cyclosporine monotherapy, the addition of mycophenolate mofetil was associated with a reduction in relapse frequency and corticosteroid requirements. Despite the limited sample size, these findings suggest that combination therapy may be a therapeutic option in difficult-to-treat pediatric nephrotic syndrome and warrant further evaluation in controlled studies. Full article

Background: Lichen planus (LP) is a chronic inflammatory dermatosis with multiple clinical variants involving the skin, mucous membranes, nails, and hair follicles. Methods: We conducted a retrospective, descriptive study of patients diagnosed with LP at a tertiary referral center from January 2011 to December 2024. Inclusion required concordance between clinical presentation and histopathologic findings. Demographic characteristics, LP subtypes, anatomical involvement, comorbidities, therapeutic approaches, and treatment outcomes were extracted from electronic health records. In addition, an exploratory sensitivity analysis restricted to patients with a single LP subtype was performed to allow for independent subgroup comparisons, and a modified Charlson Comorbidity Index (CCI) based on available comorbidity domains was calculated. Pairwise multivariable logistic regression models adjusted for age, sex, and outcome-specific modified CCI were performed for selected comorbidities. Results: A total of 754 patients were included (mean age 53.1 years), with cutaneous LP (cLP), oral LP (oLP), genital LP (gLP), and lichen planopilaris (LPP) being the most frequent subtypes; a total of 620 had a single major LP subtype and were included in the mutually exclusive analysis. In these groups, modified CCI, age-adjusted modified CCI, and overall comorbidity count differed significantly across subtypes (Kruskal–Wallis p < 0.001). After adjustment in pairwise models, cLP-only showed higher odds of malignancy compared with oLP-only, gLP-only, and LPP-only and higher odds of diabetes mellitus compared with all other pure subtypes. Most other comorbidity comparisons were non-significant or imprecise because of low event numbers. Topical glucocorticoids were the most frequently used treatment, and treatment responses varied by subtype, being more effective in cLP and gLP compared to LPP. Topical calcineurin inhibitors demonstrated the highest response rates in gLP. Acitretin was most effective in cLP, whereas isotretinoin showed favorable responses in oLP. Conclusions: This large, histopathologically confirmed cohort highlights distinct differences in comorbidity patterns, anatomical involvement, and therapeutic response across LP subtypes. Treatment outcomes vary substantially by subtype, underscoring the need for individualized management strategies. Prospective studies are warranted to further elucidate subtype-specific disease associations and optimize treatment approaches. Full article

Immune checkpoint inhibitors (ICIs) have substantially improved outcomes in advanced melanoma but are frequently linked to immune-related adverse events (irAEs). Vitiligo is a common cutaneous irAE and has been consistently associated with improved patient outcome, including prolonged progression-free and overall survival. It also represents significant visual stigma, particularly when the face is involved. Traditional treatment comprises topical steroids, calcineurin inhibitors, laser, and phototherapy which often have insufficient effects. Since 2023, the first approved drug for non-segmental vitiligo (NSV) with facial involvement, the topical Janus kinase inhibitor ruxolitinib, has been available. However, experience with its use in ICI-induced vitiligo remains limited. In this exploratory analysis, three patients who developed facial vitiligo following ICI therapy applied 1.5% ruxolitinib cream to affected facial areas twice daily. After six (two patients), and twelve months (one patient), extensive repigmentation was observed, quantified at 95.7%, 78.9%, and 99.1% using a novel semi-automatic tool. Quality-of-life questionnaires showed mean reductions of 57.6% (Vitiligo DLQI) and 68.2% (Vitiligo-specific Quality of Life) in disease burden. Treatment was associated with substantial repigmentation without observed side effects. Further evaluation in larger, prospective cohorts is warranted to better define treatment effects, clinical applicability, and long-term safety. Full article

Mineralocorticoid receptor antagonists (MRAs) are the cornerstone of the management of heart failure and chronic kidney disease. A well-known adverse event, hyperkalemia, is associated with fatal arrhythmia and discontinuation of MRA. Our narrative review discusses the personalized treatment of MRAs, focusing on the pharmacological profile and drug–drug interactions to address safety concerns related to hyperkalemia. Clinicians should scrupulously monitor potassium levels, especially during dose titration, and review each patient’s medication list. Cytochrome P450 3A4 (CYP3A4) inhibitors are pharmacokinetic precipitators that interact with most MRAs, except spironolactone, and adversely affect the risk of hyperkalemia, although suggestive evidence is scarce. Potassium-elevating drugs synergistically increase serum potassium levels when co-administered with an MRA (e.g., renin-angiotensin aldosterone inhibitors, co-trimoxazole, non-steroidal anti-inflammatory drugs, calcineurin inhibitors, and β blockers). Additional approaches include correction of metabolic acidosis using sodium bicarbonate, potassium-lowering therapy using loop and thiazide diuretics, and sodium-glucose cotransporter 2 inhibitors. Novel potassium binders enable patients to receive the maximum-tolerated MRA with fewer gastrointestinal side effects. Individualized interventions for hyperkalemia risk are important in treatment using MRA. Full article

Peripheral nerve injuries cause profound medical and socioeconomic consequences. Despite substantial microsurgical advances, including nerve autografting, nerve transfers, and the commercial availability of effective conduits, functional recovery remains incomplete for most patients. Current outcomes underscore the need for novel adjunctive therapies capable of enhancing axonal regeneration, accelerating reinnervation, and mitigating denervation-induced target atrophy. Tacrolimus, a calcineurin inhibitor widely used in organ transplantation, has emerged as a potent immunomodulatory and neuroregenerative agent. However, its systemic use is constrained by severe dose-limiting toxicities and metabolic derangements. This limitation has driven a paradigm shift toward localized tacrolimus delivery, leveraging biomaterials to achieve therapeutic drug concentrations at the repair site while minimizing systemic toxicity. This review synthesizes the state-of-the-art advances in biomaterial-based tacrolimus local delivery systems. We highlight biological mechanisms underlying tacrolimus-mediated neuroregeneration and immunomodulation. Engineering strategies including nerve conduits, wraps, injectable hydrogels, electrospun scaffolds, and stimuli-responsive carriers are discussed, with attention to polymeric composition, fabrication technologies, degradation kinetics, and pharmacological performance. We also explored the regulatory, manufacturing, and scalability challenges inherent to drug–device combination products. Finally, we identify emerging directions including multimodal biomaterials that integrate tacrolimus with trophic factors, extracellular vesicles, or bioelectrical stimulation. Collectively, biomaterial-enabled tacrolimus delivery represents a transformative strategy to bridge traditional nerve surgical repair and functional recovery. This review provides a roadmap for future interdisciplinary innovation at the interface of biomaterials science, neurobiology, pharmacology, and surgery. Full article

Background: Lupus nephritis (LN), a major complication of systemic lupus erythematosus, remains a key determinant of morbidity and mortality despite therapeutic progress. Objective: An expert report aims to present multidisciplinary insights from leading Italian centers on current LN management and future perspectives. Methods: Seven specialists—including nephrologists and rheumatologists with expertise in lupus nephritis—addressed key aspects of LN management, including treatment goals, available therapeutic options, treatment selection across disease stages, and emerging strategies. Results: The authors highlight evolving treatment paradigms—shifting from traditional induction–maintenance strategies to early combination regimens integrating biologics such as belimumab and calcineurin inhibitors like voclosporin—aligned with updated EULAR and KDIGO guidelines. Regional experiences underscore individualized therapy tailored by histology, disease activity, and patient profile. Multidisciplinary collaboration between nephrologists and rheumatologists, equitable access to innovative therapies, and integration of registries and digital records are identified as priorities. Conclusions: Emerging agents, including obinutuzumab, anifrolumab, and CAR-T cell therapies, represent promising advances toward steroid-sparing and potentially curative strategies. Continued research, biomarker development, and application of artificial intelligence are pivotal to optimizing outcomes and achieving personalized LN management. Full article

Background: Treatment options for vulvar lichen sclerosus (VLS) remain limited; therefore, therapies that improve quality of life and reduce neoplastic risk are needed. Photodynamic therapy (PDT) is a potential option. This study aimed to evaluate quality of life and sexual function in patients treated according to the protocol used at our institution. Methods: Forty patients with refractory VLS underwent PDT using a 10% 5-aminolevulinic acid nanoemulsion (Ameluz^®) applied to lesions under an occlusive aluminum foil dressing. Patients received 1–6 sessions of 10 min illumination (LED: 37 J/cm², ~77 mW/cm²) at 4–6-week intervals. The Dermatology Life Quality Index (DLQI) and Female Sexual Function Index (FSFI) were used for assessment. Results: Thirty-seven participants answered DLQI, while 20 declared themselves to be sexually active and were included in the analysis. Greater number of PDT sessions was associated with a lower DLQI score (τ = −0.583; adjusted p < 0.001). The number of PDT sessions and the total FSFI score (p = 0.014), as well as desire (p = 0.016), arousal (p = 0.020), orgasm (p = 0.020), and satisfaction (p = 0.016) domains were significantly correlated. Age correlated positively with DLQI scores (p = 0.016), indicating greater disease burden in older patients. Longer disease duration was also associated with poorer quality of life (p = 0.020). Conclusions: PDT can be considered an effective treatment for patients with VLS refractory to standard topical corticosteroid and calcineurin inhibitor therapies when delivered using a refined, patient-centered protocol. This optimized approach used in our institution is based on short irradiation time and precise light delivery, providing a favorable balance between therapeutic efficacy, patient comfort, and treatment feasibility. Our findings also suggest that the cumulative number of PDT sessions is a key factor for clinical response. Further studies should address long-term outcomes. Full article

Vitiligo is a chronic autoimmune disease characterized by the destruction of epidermal melanocyte, resulting in well-demarcated white patches on the skin. Despite the established use of corticosteroids and calcineurin inhibitors and the recent introduction of Janus kinase (JAK) inhibitors, a breakthrough targeted therapy that interrupts the IFN-γ signaling pathway, stable repigmentation remains a major clinical challenge, necessitating deeper investigation into its pathogenesis. Among the factors contributing to vitiligo, including genetic predisposition and autoimmunity, oxidative stress is a central driver of melanocyte damage and the subsequent autoimmune response. Chronic oxidative disequilibrium (high ROS level and impaired mitochondrial activity) and reduced antioxidant capacity (Nrf2/ARE pathway and catalase deficiency) function as triggering factors upstream of most other pathogenic pathways. Consequently, targeting oxidative stress, either as a monotherapy or in synergy with emerging targeted treatments, remains a pivotal area of therapeutic interest even in the current era of targeted therapies. Still, a significant gap remains the lack of standardized oxidative biomarkers to monitor disease activity and therapeutic response. Identifying these indicators is essential for personalized clinical management in vitiligo. This review examines how chronic oxidative disequilibrium and a reduced antioxidant capacity initiate and sustain the autoimmune cascade, leading to disease onset and progression. Full article

Background/Objectives: Asymptomatic hyperuricemia has been associated with increased cardiovascular risk; it is related to factors such as diet, genetic predisposition, and drug-related side effects. Impairment of uric acid control has been associated with the calcineurin inhibitors cyclosporin and tacrolimus, although available studies did not reach the same conclusions. Their widespread use in solid organ transplantation potentially exposes this population to higher cardiovascular risk. This systematic review aimed to assess their role in hyperuricemia risk compared with other immunosuppressive treatments and to clarify potential differences between cyclosporin and tacrolimus. Methods: The search was conducted in MEDLINE and Embase, limited to adult subjects, using the following terms: ((cyclosporin) OR (cyclosporine) OR (tacrolimus) OR (calcineurin inhibitor)) AND ((uric acid) OR (urate) OR (hyperuricemia)) AND ((transplant) OR (transplantation)). We assessed the quality of the studies according to the Critical Appraisal Skills Programme checklist. Results: After screening 639 manuscripts, we selected 36 studies that were relevant to our focus: 28 evaluated kidney transplant patients, while only eight focused on other solid organ transplants. Specifically, 20 studies compared calcineurin inhibitors with other immunosuppressants, while 15 assessed the impact of cyclosporin versus tacrolimus, and one study contributed to both scenarios. The prevalence of hyperuricemia ranged from 30 to 80% among patients receiving calcineurin inhibitors, with a slightly higher prevalence with cyclosporin than with tacrolimus (51–61% vs. 36–42%, respectively). The overall quality of the included studies was generally rated as low to moderate, with only ten studies focusing on uric acid control. Conclusions: Given the heterogeneity and overall quality of the available studies, no definitive conclusions can be drawn. In particular, the comparative effect of cyclosporin and tacrolimus remains uncertain because of conflicting findings across studies. Although calcineurin inhibitors may adversely affect uric acid control in transplant recipients, this association may be influenced by several confounding factors. Full article