Pharmacokinetic interactions between tacrolimus and Wuzhi capsule in liver transplant recipients: Genetic polymorphisms affect the drug interaction.

Wuzhi capsule (WZC), a commonly used Chinese patent medicine to treat various types of liver dysfunction in China, increases the exposure of tacrolimus (TAC) in liver transplant recipients. However, this interaction has inter-individual variability, and the underlying mechanism remains unclear. Current research indicates that CYP3A4/5 and drug transporters influence the disposal of both drugs. This study aims to evaluate the association between TAC dose-adjusted trough concentration (C/D) and specific genetic polymorphisms of CYP3A4/5, drug transporters and pregnane x receptor (PXR), and plasma levels of major WZC components, deoxyschisandrin and γ-schisandrin, in liver transplant patients receiving both TAC and WZC. Liquid chromatography-tandem-mass spectrometry was used to detect the plasma levels of deoxyschisandrin and γ-schisandrin, and nine polymorphisms related to metabolic enzymes, transporters and PXR were genotyped by sequencing. A linear mixed model was utilized to assess the impact of the interaction between genetic variations and WZC components on TAC lnC/D. Our results indicate a significant association of TAC lnC/D with the plasma levels of deoxyschisandrin and γ-schisandrin. Univariate analysis demonstrated three polymorphisms in the genes ABCB1 (rs2032582), ABCC2 (rs2273697), ABCC2 (rs3740066), and PXR (rs3842689) interact with both deoxyschisandrin and γ-schisandrin, influencing the TAC lnC/D. In multiple regression model analysis, the interactions between deoxyschisandrin and both ABCB1 (rs2032582) and ABCC2 (rs3740066), post-operative day (ß < 0.001, p < 0.001), proton pump inhibitor use (ß = -0.152, p = 0.008), body mass index (ß = 0.057, p < 0.001), and ABCC2 (rs717620, ß = -0.563, p = 0.041), were identified as significant factors of TAC lnC/D, accounting for 47.89% of the inter-individual variation. In summary, this study elucidates the influence of the interaction between ABCB1 and ABCC2 polymorphisms with WZC on TAC lnC/D. These findings offer a scientific basis for their clinical interaction, potentially aiding in the individualized management of TAC therapy in liver transplant patients.

Tacrolimus reverses pemphigus vulgaris serum-induced depletion of desmoglein in HaCaT cells via inhibition of heat shock protein 27 phosphorylation.

BACKGROUND: Glucocorticoids are the first-line treatment for Pemphigus vulgaris (PV), but its serious side effects can be life-threatening for PV patients. Tacrolimus (FK506) has been reported to have an adjuvant treatment effect against PV. However, the mechanism underlying the inhibitory effect of FK506 on PV-IgG-induced acantholysis is unclear. OBJECTIVE: The objective of this study was to explore the effect of FK506 on desmoglein (Dsg) expression and cell adhesion in an immortalized human keratinocyte cell line (HaCaT cells) stimulated with PV sera. METHODS: A cell culture model of PV was established by stimulating HaCaT cells with 5% PV sera with or without FK506 and clobetasol propionate (CP) treatment. The effects of PV sera on intercellular junctions and protein levels of p38 mitogen-activated protein kinase (p38MAPK), heat shock protein 27 (HSP27), and Dsg were assayed using western blot analysis, immunofluorescence staining, and a keratinocyte dissociation assay. RESULTS: PV sera-induced downregulation of Dsg3 was observed in HaCaT cells and was blocked by FK506 and/or CP. Immunofluorescence staining revealed that linear deposits of Dsg3 on the surface of HaCaT cells in the PV sera group disappeared and were replaced by granular and agglomerated fluorescent particles on the cell surface; however, this effect was reversed by FK506 and/or CP treatment. Furthermore, cell dissociation assays showed that FK506 alone or in combination with CP increased cell adhesion in HaCaT cells and ameliorated loss of cell adhesion induced by PV sera. Additionally, FK506 noticeably decreased the PV serum-induced phosphorylation of HSP 27, but had no effect on p38MAPK phosphorylation. CONCLUSION: FK506 reverses PV-IgG induced-Dsg depletion and desmosomal dissociation in HaCaT cells, and this effect may be obtained by inhibiting HSP27 phosphorylation.

Comparison of the efficacy of tacrolimus 0.1% ointment vs calcipotriol/betamethasone in combination with NBUVB in treatment of vitiligo.

Purpose: Vitiligo is an idiopathic depigmenting skin disorder. The study compares the efficacy of topical tacrolimus 0.1% with calcipotriol/betamethasone dipropionate in vitiligo patients receiving NB-UVB treatment.Materials and methods: Forty-one adult patients with generalized type vitiligo were recruited. Patients were assigned to phototherapy and then classified into either group one (20 patients), receiving calcipotriol/betamethasone dipropionate cream (D group), or group two (21 patients), receiving tacrolimus 0.1% ointment (T group). They were followed-up at 3 and 6 months.Results: The D group witnessed an increase in the repigmentation area from 35.4% in the third month to 54.7% in the sixth month (p = 0.001) and the T group from 32.2% to 45.6% (p = 0.011). However, the differences between the treatment groups were not statistically significant. Body sites demonstrated different levels of improvement ranging from the highest in the face to the lowest in the Hand & Feet with the other body sites in between. A negative correlation was identified between the duration since diagnosis and the response to D treatment (3 months: r = -0.612, p = 0.007; 6 months: r = -0.755, p = 0.001).Conclusions: Although both combinations are efficacious, they did not significantly differ in efficacy at three and six months follow-up points.Clinical trial registration: The study was registered at clinicaltrials.gov (NCT04440371).

Mapping children by ALT 4-5 years after liver transplant: Potential individual and population applications.

INTRODUCTION: Although clinicians repeatedly measure ALT to assess allograft health in children with liver transplants, they generally make decisions based on single values or qualitative trends without quantitative aggregation or synthesis. We therefore aimed to derive and test a holistic ALT metric for the 5th post-transplant year (Yr 4-5) that may better guide clinical decision-making and/or population comparisons. METHODS: We derived the "adjusted mean Yr 4-5 ALT" for children transplanted in 2005-2016 by averaging the median ALT from each month. Patients in quartiles (Q1-4) defined by the adjusted mean Yr 4-5 ALT were compared by clinical variables, Yr 5-8 outcomes, and tacrolimus standard deviation (MLVI). RESULTS: For 97 children [49 male; 77 deceased donors; median (IQR) age at LT 2.5 (0.8-11.7) years], the 25th, 50th, and 75th percentile thresholds for adjusted mean Yr 4-5 ALT were 19, 28, and 47 U/L, respectively. Age, donor type, LT indication, rejection history, and mean tacrolimus levels did not differ between quartiles (Q). Children in Q4 had more Yr 4-5 acute rejection episodes (p < .01), higher Yr 4-5 MLVI (p < .01), and more Yr 5-8 for-cause liver biopsies (p < .01) than those in Q1 + Q2. Children in Q3 also had higher Yr 4-5 MLVI than Q1 + Q2 (p = .047). Rates of chronic rejection and therapeutic liver-related procedures were higher in Q4 but the difference did not reach significance. CONCLUSION: An integrated ALT metric calculated utilizing all available ALT values correlates with MLVI and future for-cause biopsies. Further study of this novel ALT metric as a predictor of clinical outcomes and descriptor of populations is warranted.

Rare case of benign transient hyperphosphatasemia in a complicated multiorgan adult transplant patient: Case report and literature review.

BACKGROUND: Transient hyperphosphatasemia, characterized by isolated highly elevated alkaline phosphatase (ALP) activity in the absence of liver or bone disease, is typically seen in children but rarely in adults. Here we report highly elevated ALP activity in a complicated multiple-organ transplant patient due to benign transient hyperphosphatasemia. CASE REPORT: A 54-year-old male had a complicated past medical history including a bilateral lung transplant for cystic fibrosis in 2006, colonic resection due to colon cancer in December 2011 and subsequent chemotherapy which ended in June 2022. He also had combined liver and kidney transplant in 2022 at our academic medical center. Post-transplant, he was treated with triple drug immunosuppressant therapy (tacrolimus, mycophenolic acid, and prednisone). Although his alkaline phosphatase (ALP) activity was 83 U/L, it continued to increase three months after combined liver and kidney transplant even though other liver enzymes were mildly elevated but total bilirubin remained within their reference ranges. Flecainide was discontinued but his ALP remained high, peaking at 5904 U/L. Finally, lansoprazole, ergocalciferol (vitamin D2) and vitamin E supplement were discontinued as nonessential medications, and coincidently ALP activity started to decline. CONCLUSIONS: After ruling out all possibilities that may cause elevated ALP, we concluded that this is a rare case of benign transient hyperphosphatasemia in an adult transplant recipient.

A Potential Alternative Treatment for Vitiligo: An Observational Study on Tacrolimus 0.3% Lotion.

Vitiligo is a complex multifactorial disorder of depigmentation affecting 0.5 to 2% of the world's population without specific gender or racial prevalence.1 Though no treatments are FDA approved to repigment vitiligo, topical medications along with phototherapy alone or in combination remain the mainstay of therapy. While Janus Kinase inhibitors and other agents are in development, current topical options are mainly limited to steroid formulations of various potencies or immunomodulatory steroid-sparing agents such as tacrolimus 0.03% or 0.1%.

Successful treatment of Talaromyces marneffei pneumonia in a HIV-negative renal transplantation recipient: A case report.

RATIONALE: Talaromyces marneffei causes life-threatening opportunistic fungal infections in immunocompromised patients. It often has a poorer prognosis in non-human immunodeficiency virus (HIV)-infected than in HIV-infected individuals because of delayed diagnosis and improper treatment. PATIENT CONCERNS: A 51-year-old man presented with complaints of pyrexia, cough, and expectoration that had lasted for 15 day. This patient has been taking anti-rejection medication since kidney transplant in 2011. DIAGNOSIS: T marneffei pneumonia; post renal transplantation; renal insufficiency; hypertension. INTERVENTIONS: Intravenous moxifloxacin was administered on admission. After the etiology was established, moxifloxacin was discontinued and replaced with voriconazole. The tacrolimus dose was adjusted based on the blood concentration of tacrolimus and voriconazole. OUTCOMES: The patient was successfully treated and followed-up without recurrence for 1 year. LESSONS: A high degree of caution should be maintained for the possibility of T marneffei infection in immunodeficient non-HIV patients who live in or have traveled to T marneffei endemic areas. Early diagnosis and appropriate treatment can prevent progression of T marneffei infection and achieve a cure. Metagenomic next-generation sequencing (mNGS) can aid the physician in reaching an early pathogenic diagnosis. Close monitoring of tacrolimus and voriconazole blood levels during treatment remains a practical approach at this time.

Effect of treatment with Fufang Huangqi decoction on dose reductions and discontinuation of pyridostigmine bromide tablets, prednisone, and tacrolimus in patients with type I or II myasthenia gravis.

OBJECTIVE: To investigate the clinical efficacy of Fufang Huangqi decoction in combination with pyridostigmine bromide tablets, prednisone, and tacrolimus in the treatment of type I and II myasthenia gravis (MG) through changes in the clinical symptom scores of 100 patients with type I and II MG. This study also aimed to examine dose reductions and dis-continuation of these 3 Western medicines after administration of Fufang Huangqi decoction. METHODS: The clinical data on 100 patients with type I or II MG who were treated in the outpatient department of the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, China, between June 2017 and June 2020 were collected. The patients were divided into 4 groups based on whether they had taken pyridostigmine bromide tablets, prednisone, and/or tacrolimus at the time of their hospital visit: the Fufang Huangqi decoction group (group A), the pyridostigmine bromide tablets + Fufang Huangqi decoction group (group B), the pyridostigmine bromide tablets + prednisone + Fufang Huangqi decoction group (group C), and the pyridostigmine bromide tablets + tacrolimus + Fufang Huangqi decoction group (group D). The average treatment time was (15.6 ± 11.5) months (range: 0.5-55 months). Changes in the clinical symptom scores of the 4 groups of patients after medication administration and dose reductions and discontinuation of the 3 Western medicines were analyzed. RESULTS: An overall effectiveness rate of 86.00% was achieved in the 100 patients after treatment for (15.6 ± 11.5) months (range 0.5-55 months). The effectiveness rates were 85.71% in group A, 88.24% in group B, 76.92% in group C, and 80.00% in group D. The dosage of pyridostigmine bromide was reduced for 69.12% of the patients in group B for the first time after (4.2 ± 4.1) months, and 45.59% of the patients in group B discontinued pyridostigmine bromide after (8.8 ± 6.1) months. The dosage of pyridostigmine bromide was reduced for 46.15% of the patients in group C for the first time after (5.3 ± 3.4) months, and 23.08% of the patients in group C discontinued pyridostigmine bromide after (19.8 ± 11.0) months; 76.92% reduced hormone dosage after (2.8 ± 1.9) months, and 23.08% discontinued hormone treatment after (6.7 ± 2.9) months. The dosage of pyridostigmine bromide was reduced for 1 patient in group D after 1 month; this patient discontinued pyridostigmine bromide after 3 months and reduced tacrolimus dosage after 5 months. One patient in group D discontinued pyridostigmine bromide and tacrolimus on his own initiative at 0.5 months and took Fufang Huangqi decoction for 2 months without discontinuing Western medicine. CONCLUSION: Fufang Huangqi decoction is effective for the treatment of type I and II MG and improves the associated clinical symptoms. Moreover, this agent is conducive to dose reductions and discontinuation of basic Western medicines, thereby reducing the side effects experienced by patients.

[Long-term efficacy and safety of treatment with cinacalcet in hypercalcemic persistent secondary hyperparathyroidism in renal transplant].

Introduction: persistent hypercalcemic secondary hyperparathyroidism (PSHPT) in kidney transplantation (KTx) can expose renal transplant recipients (RTRs) to a series of complications. Cinacalcet has been shown to be effective in controlling hypercalcemic PSHPT. Therefore, we evaluated the efficacy and tolerability of cinacalcet, over a period of 3 years, in the treatment of hypercalcemic PSHPT in a group of RTRs. Patients and Methods: eight patients with a kidney transplant age > 12 months, parathyroid hormone (PTH) levels > 120 pg/ml and total serum calcium (TCa) levels > 10.5 mg/dl, were treated with cinacalcet at an initial dose of 30 mg/day. Hypercalcemic PSHPT picture must have been present for at least 6 months before the start of treatment with cinacalcet. Every 6-8 weeks were determined: estimated glomerular filtration rate (eGFR), PTH, TCa, serum phosphorus, fractional excretion of calcium (FECa), tubular maximum reabsorption rate of phosphate (TmP/GFR), serum tacrolimus. Annually all patients underwent to ultrasound control of the transplanted kidney. The main endpoints of the study were the reduction of PTH levels > 30% from baseline and the normalization of TCa levels (<10.2 mg/dl). Results: the results are shown as median ± interquartile range (IQR). At follow-up PTH levels decreased from 223 (202-440) to 135 pg/ml (82-156) (P < 0.01), with a percentage decrease of -54 (-68;-44), TCa levels decreased from 11.0 (10.7-11.7) to 9.3 mg/dl (8.8-9.5) (P < 0.001). Serum phosphorus levels increased from 2.7 (2.0-3.0) to 3.2 mg/dl (2.9-3.5) (P < 0.05). Fractional excretion of calcium did not change, while TmPO4/GFR increased even not significantly. Renal function and serum levels of tacrolimus did not change throughout the observation period. At end of the study the average cinacalcet dosages were 30 mg/day (30-30). Ultrasound scans of the transplanted kidney showed no development of nephrocalcinosis and/or nephrolithiasis. Conclusions: cinacalcet has proved effective and well tolerated in the treatment of hypercalcemic PSHPT in RTRs.

Oral lichen planus: comparative efficacy and treatment costs-a systematic review.

OBJECTIVE: To compare the reported efficacy and costs of available interventions used for the management of oral lichen planus (OLP). MATERIALS AND METHODS: A systematic literature search was performed from database inception until March 2021 in MEDLINE via PubMed and the Cochrane library following PRISMA guidelines. Only randomized controlled trials (RCT) comparing an active intervention with placebo or different active interventions for OLP management were considered. RESULTS: Seventy (70) RCTs were included. The majority of evidence suggested efficacy of topical steroids (dexamethasone, clobetasol, fluocinonide, triamcinolone), topical calcineurin inhibitors (tacrolimus, pimecrolimus, cyclosporine), topical retinoids, intra-lesional triamcinolone, aloe-vera gel, photodynamic therapy, and low-level laser therapies for OLP management. Based on the estimated cost per month and evidence for efficacy and side-effects, topical steroids (fluocinonide > dexamethasone > clobetasol > triamcinolone) appear to be more cost-effective than topical calcineurin inhibitors (tacrolimus > pimecrolimus > cyclosporine) followed by intra-lesional triamcinolone. CONCLUSION: Of common treatment regimens for OLP, topical steroids appear to be the most economical and efficacious option followed by topical calcineurin inhibitors. Large-scale multi-modality, prospective trials in which head-to-head comparisons interventions are compared are required to definitely assess the cost-effectiveness of OLP treatments.

Optimizing topical management of atopic dermatitis.

OBJECTIVE: Provide a review of atopic dermatitis management, focusing on optimizing topical therapy, creating a stepwise approach for treatment plans, and providing guidance on when to start systemic therapy. DATA SOURCES: PubMed search of articles in the English language regarding atopic dermatitis in all ages. STUDY SELECTION: Articles on the subject matter were selected and reviewed. RESULTS: Topical corticosteroids are the first-line treatment for managing atopic dermatitis. Topical nonsteroidal agents, calcineurin inhibitors, crisaborole, and recently, ruxolitinib, which cause no cutaneous atrophy, are options for reducing the use of topical corticosteroids, including on sensitive sites. Emerging topical agents are in clinical trials. Proactive management, with continued application 2 to 3 times weekly of a midpotency topical corticosteroid or tacrolimus, may maintain control for clear (or almost clear) localized sites of dermatitis that rapidly recur when topical anti-inflammatory medication is stopped. If topical therapy alone cannot control disease and quality of life is impacted, reevaluation to confirm the diagnosis, manage comorbid conditions, address compliance and patient-specific concerns, and optimize topical therapy must be undertaken before deciding to advance to systemic medication. Dupilumab, an interleukin-4 receptor inhibitor, has become first-line systemic therapy given its efficacy and safety, allowing long-term treatment without laboratory monitoring. Other biologics and Janus kinase inhibitors are emerging as alternatives that could eliminate the need for immunosuppressants with their higher risks. CONCLUSION: Several options are now available for topical treatment. A stepwise approach is needed to consider alternative therapies and diagnoses before advancing to systemic treatment, but the safety of newer immunomodulators will lower the threshold for more aggressive intervention.

Topical Tacrolimus 0.1% for treatment of cutaneous microcystic lymphatic malformations.

Microcystic lymphatic malformations as described in the international literature form a subgroup of low-flow congenital vascular malformations (VM) resulting from irregular embryological development. Microcystic lesions normally manifest as an accumulation of lymph- and blood-filled vesicles that, when externalized, cause skin maceration with consequent pain and potential infection resulting in the impairment of the patient's quality of life. There is no consensus on a standardized algorithm nor clear guidelines for successful treatment of this type of lymphatic malformation, and treatment options employed often result in ambivalent and transient outcomes with a high rate of recurrence. The topical formulation of tacrolimus is a well-known FDAapproved anti-T cell agent that was recently identified as a potent activator of ALK1, which is involved in several processes and functions including angiogenesis. We investigated if topical administration of tacrolimus may be an effective therapy for directly targeting cutaneous microcystic lymphatic malformations as a complement to systemic treatment. The study enrolled four patients with cutaneous microcystic lymphatic malformations: three male (ages: 13,15,18) and one female (age: 30). Two of the patients presented lesions on their backs, one patient on the left hand and one on the left lower limb. All four patients received treatment with topical tacrolimus 0.1% twice a day for 10 weeks on a previously selected area for application. Weekly clinical follow-ups were conducted along with close physician-patient contact. All patients displayed a satisfactory response after treatment. Lymphorrhea and bleeding were stopped in all cases and the esthetic aspect of lesions improved in two patients. To date, all patients presented no clinically significant changes to the size or extension of the lesion. Topical tacrolimus treatment is a promising and reasonable option for microcystic lymphatic malformations. Our results encourage further exploration in larger populations with the consideration that it is a safe and effective alternative or complementary therapy to systemic treatment.

Self-assembled tacrolimus-loaded lecithin-chitosan hybrid nanoparticles for in vivo management of psoriasis.

Lecithin-chitosan hybrid nanoparticles are emerging as a promising nanocarrier for topical drug delivery. They could achieve a maximized encapsulation of hydrophobic drugs due to the lipophilic nature of lecithin that comprises the core while enhancing retention in the upper skin layers using the positively charged polymeric coat of chitosan. The aim of this study is to incorporate tacrolimus; a hydrophobic anti-proliferative agent into lecithin chitosan hybrid nanoparticles by ethanolic injection technique using a suitable co-solvent to enhance encapsulation of the drug and allow a satisfactory release profile in the upper skin layers. Tacrolimus was successfully incorporated into the synthesized particles using olive oil and Tween 80 as co-solvents, with particle size (160.9 nm ± 15.9 and 118.7 nm ± 13.3, respectively) and EE (88.27% ± 4.3 and 66.72% ± 1.8, respectively). The in vitro drug release profile showed a faster release pattern for the Tween 80-containing particles over a 48-hour period (79.98% vs. 35.57%), hence, were selected for further investigation. The hybrid nanoparticles achieved significantly higher skin deposition than the marketed product (63.51% vs. 34.07%) through a 24-hour time interval, particularly, to the stratum corneum and epidermis skin layers. The in vivo results on IMQ-mouse models revealed superior anti-psoriatic efficacy of the synthesized nanoparticles in comparison to the marketed product in terms of visual observation of the skin condition, PASI score and histopathological examination of autopsy skin samples. Additionally, the in vivo drug deposition showed superior skin deposition of the nanoparticles compared to the marketed product (74.9% vs. 13.4%).

FK506 ameliorates osteoporosis caused by osteoblast apoptosis via suppressing the activated CaN/NFAT pathway during oxidative stress.

OBJECTIVE: Osteoporosis is affecting the health of postmenopausal women in the world. In case of that, we explored whether FK-506 could ameliorate osteoporosis by inhibiting the activated CaN/NFAT pathway during oxidative stress. METHODS: First, the castrated rat model is constructed through the bilateral ovariectomy. Hologic Discovery (S/N 80347) dual-energy X-ray absorptiometry assessed bone mineral density (BMD) implemented at left femur of rats. Next, hematoxylin-eosin (H&E) staining observed and calculated the changes of bone trabecular, mean trabecular plate separation (Tb.Sp), mean trabecular plate thickness (Tb.Th), and bone volume fraction (BV/TV). Then, CCK-8 assay, TUNEL assay, ALP kit and alizarin red staining detected the viability, apoptosis, alkaline phosphatase (ALP) activity, and capacity of mineralization respectively. At last, commercially available kits detected the levels of ROS and SOD in transfected MC3T3-E1 cells and bone tissues, and Western blot analysis detected proteins related to apoptosis and CaN/NFAT pathway. RESULTS: FK-506 increased the BMD and changes of bone trabecular in female castrated rats. FK-506 inhibited the oxidative stress and apoptosis by suppressing the activated CaN/NFAT pathway. Low dose of FK-506 improved the viability, ALP activity, and mineralization capacity. What's more, it suppressed the apoptosis of H2O2-induced MC3T3-E1 cells, which was deteriorated by the high dose of FK-506. Briefly, low dose of FK-506 inhibited the oxidative stress by suppressing the activated CaN/NFAT pathway, while high dose of that further inhibited the oxidative stress by suppressing the CaN/NFAT pathway. CONCLUSION: FK-506 ameliorates osteoporosis resulted from osteoblastic apoptosis which caused by suppressing the activated CaN/NFAT pathway during oxidative stress.

Anaphylaxis Induced by Intravenous Tacrolimus Administration During Kidney Transplant Surgery: A Case Report.

A 35-year-old male patient with end-stage renal disease due to vesicoureteral reflux preemptively received a renal graft from his father. The patient had a history of allergy to contrast-enhancing media. He received oral tacrolimus (TAC) and mycophenolate mofetil without any problems for 2 days before kidney transplantation. During the induction period of the surgery, his systolic blood pressure (sBP) decreased to 60 mmHg approximately 1 hour after initiating intravenous tacrolimus (TAC-IV) and intravenous piperacillin (PIPC), and the anesthesiologist suspected drug-induced anaphylaxis and stopped administration of the medications. Because TAC had been administered preoperatively without any adverse events, PIPC was suspected as the causative agent of the anaphylaxis. After the patient's hemodynamics returned to baseline, TAC-IV was restarted. However, his sBP rapidly decreased to 40 mmHg and the patient developed wheezing. He was diagnosed with drug-induced anaphylaxis due to castor oil derivatives in the TAC-IV formulation. The patient's sBP was restored with the administration of some vasopressors, and kidney transplantation was then performed without difficulty. Two days after kidney transplantation, oral TAC was administered without anaphylaxis. Clinicians should consider that not only the drug itself but also its additives or metabolites could induce anaphylaxis.

Dupilumab-Associated Ocular Surface Disease: Clinical Characteristics, Treatment, and Follow-Up.

PURPOSE: A consecutive case series of patients with dupilumab-associated ocular surface disease (DAOSD) that describes common ocular symptoms and signs, proposes a symptom disease severity grading system, and describes treatment strategies of DAOSD patients was evaluated. METHODS: A retrospective chart review of patients with concomitant dupilumab-treated atopic dermatitis and DAOSD with ophthalmic evaluation between January 2014 and May 2019 was conducted. RESULTS: Twenty-nine patients (mean age 46 years, M/F: 12/17) with 57 ophthalmic exams were identified. The most common ocular symptoms included irritation/pain (n = 28, 97%), redness (n = 24, 83%), pruritus (n = 18, 62%), discharge (n = 18, 62%), and light sensitivity (n = 6, 21%). The most frequent signs included conjunctival injection (n = 18, 62%), superficial punctate keratitis (n = 16, 55%), and papillary reaction (n = 8, 28%). Topical corticosteroids (TCS) (n = 23, 79%), tacrolimus (n = 6, 21%), and artificial tears (n = 7, 24%) were the most commonly used therapies. Of those with follow-up documentation (n = 21), 20 were noted to have partial or complete response with TCS based on symptoms and reduction of signs. Using our proposed symptom-based grading scale, scaled 1 to 5 based on the presence of common symptoms listed above, 66% (n = 19) requiring topical immunomodulating therapy were found in the 'severe' group (≥3 symptoms) and 17% (n = 5) were found in the 'mild' group (≤2 symptoms). CONCLUSIONS: This study provides insight into the commonly presenting ocular signs and symptoms associated with DAOSD and highlights the efficacy of TCS and other immunomodulators in improving symptoms associated with DAOSD. Based on our findings, we propose a symptom-based grading system that can guide nonophthalmic physicians regarding ophthalmology consult.

LRP1/CD91 is highly expressed in monocytes from patients with vitiligo - even after repigmentation.

Vitiligo pathophysiology is mediated by antigen-specific cytotoxic T cells. Environmental stressors cause susceptible melanocytes to secrete damage-associated molecular patterns (DAMPs). DAMPs are recognized by receptors such as the endocytic low-density lipoprotein receptor-related protein (LRP1/CD91), expressed in antigen-presenting cells, which activate self-reactive CD8+ T cells, leading to melanocyte destruction. Within this response, interferon gamma triggers production of cytokine CXCL10, recruiting more activated T cells causing further melanocytic damage. We hypothesized that expression of LRP1/CD91 was higher in vitiligo patients compared to non-vitiligo individuals. And further that levels/expression of CXCL10 in plasma were linked to disease severity. We enrolled forty individuals in this study: 18 patients with vitiligo and 22 healthy volunteers. We assessed LRP1/CD91 expression and plasma CXCL10 in patients with vitiligo and healthy volunteers. Additionally, vitiligo patients received combined treatment for 16 weeks following which the said parameters were reassessed. Vitiligo Area Scoring Index was calculated before and after treatment for these patients. Analysis of LRP1/CD91 MFI values in monocytes from vitiligo patients showed high surface levels of LRP1/CD91 than from healthy volunteers (10.50 ± 0.77 vs. 6.55 ± 0.77 MFI units, p < 0.001). This expression did not change after treatment. Plasma levels of CXCL10 were higher in vitiligo patients than healthy volunteers (93.78 ± 7.73 vs. 40.17 ± 6.25 pg/ml). The patients with a good clinical response to treatment had a parallel reduction in plasma CXCL10 levels (105.8 ± 18.44 vs. 66.13 ± 4.87 pg/ml) before and after treatment. LRP1/CD91 expression may reflect susceptibility to vitiligo. Plasma levels of CXCL10 can represent a biomarker for monitoring treatment response. LRP1 and CXCL10 may represent therapeutic targets.

A comparative study on the use of fractional CO2 laser with tacrolimus or calcipotriol or narrow band ultraviolet-B in treatment of stable nonsegmental vitiligo.

Conventional methods of treatment for vitiligo are often unsatisfactory to the patients and time consuming, new treatment modalities are needed. This study was conducted to evaluate the efficacy and safety of fractional carbon dioxide (CO2 ) laser therapy followed by narrow band ultraviolet-B (NB-UVB) phototherapy, topical tacrolimus or topical calcipotriol on stable nonsegmental vitiligo. Thirty patients with stable nonsegmental vitiligo were evaluated. All patients were subjected to three sessions of fractional CO2 laser 1 month apart. Patients were divided into three groups (each group 10 patients). Group (A) treated with tacrolimus ointment twice daily for 3 months, group (B) treated with calcipotriol ointment twice daily for 3 months, and group (C) treated with NB-UVB twice weekly for 3 months. Outcomes were evaluated by calculating vitiligo area scoring index (VASI) score change, percentage of repigmentation, patient satisfaction, and adverse effects. There was a statistical significant decrease in VASI score after treatment in the three groups. The VASI change and % of regimentation was higher in group (C) treated by laser and NB-UVB and this was significantly higher than group (B) treated with laser and calcipotriol. Otherwise, there was no statistical significant difference between other treatment groups. In concluion, NB-UVB phototherapy, topical tacrolimus, or topical calcipotriol in combination with fractional CO2 laser could be used effectively and safely as an alternative modality for treatment of vitiligo. The combination of fractional CO2 laser and NB-UVB was found to be more effective.

Successful treatment of erythematous-squamous disorders of the external auditory canal with tacrolimus and clotrimazole in otic oil: Our experience in 25 patients.

The external auditory canal (EAC) comprises a special area where erythematous-scaly diseases are located. Among the main dermatoses that can affect EAC seborrheic dermatitis, psoriasis, irritant or allergic contact dermatitis, chronic external otitis (atrial eczematoid dermatitis) and cutaneous lupus should be considered. In this study, 25 consecutive patients were recruited on our dermatological outpatient clinic, 9 men and 16 women, with a clinical diagnosis of localized erythematous-squamous dermatoses in EAC. The mean age was 48.8 years (16-83). The mean time of evolution of the dermatoses was 11.44 months (2-36). Regarding the diagnosis, 14 patients were diagnosed with seborrheic dermatitis (56%), 9 patients with psoriasis (36%), 1 patient with subacute cutaneous lupus (4%), and 1 patient with allergic contact dermatitis to corticosteroids (4%). The indicated treatment was tacrolimus 0.1% and clotrimazole 1% in otic oil, twice a day, for 1 month. The EAC had to be cleaned initially with saline solution impregnated on a swab from the ears. The IGA score and pruritus showed a high results, with important improvement of almost all patients. The satisfaction of the patients obtained with the TSQM-9 questionnaire was 95.2. Retreatment showed an equal efficacy observed during the first treatment period. The efficacy and the absence of side effects with the treatment make this magistral formula an adequate therapeutic option for these dermatoses.