Safety and Efficacy of Adeno-Associated Viral Gene Therapy in Patients With Retinal Degeneration: A Systematic Review and Meta-Analysis.

Purpose: This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV). Methods: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched systematically for controlled or non-controlled interventional gene therapy studies using key words related to retinal diseases, gene therapy, and AAV vectors. The primary outcome measure was safety, based on ocular severe adverse events (SAEs). Secondary outcome measures evaluated efficacy of the therapy based on best corrected visual acuity (BCVA) and improvements in visual sensitivity and systemic involvement following ocular delivery. Pooling was done using a DerSimonian Laird random effects model. Risk of bias was assessed using the Cochrane Risk of Bias Tool, version 1. Results: Our search identified 3548 records. Of these, 80 publications met eligibility criteria, representing 28 registered clinical trials and 5 postmarket surveillance studies involving AAV gene therapy for Leber congenital amaurosis (LCA), choroideremia, Leber hereditary optic neuropathy (LHON), age-related macular degeneration (AMD), retinitis pigmentosa (RP), X-linked retinoschisis, and achromatopsia. Overall, AAV therapy vectors were associated with a cumulative incidence of at least one SAE of 8% (95% confidence intervals [CIs] of 5% to 12%). SAEs were often associated with the surgical procedure rather than the therapeutic vector itself. Poor or inconsistent reporting of adverse events (AEs) were a limitation for the meta-analysis. The proportion of patients with any improvement in BCVA and visual sensitivity was 41% (95% CIs of 31% to 51%) and 51% (95% CIs of 31% to 70%), respectively. Systemic immune involvement was associated with a cumulative incidence of 31% (95% CI = 21% to 42%). Conclusions: AAV gene therapy vectors appear to be safe but the surgical procedure required to deliver them is associated with some risk. The large variability in efficacy can be attributed to the small number of patients treated, the heterogeneity of the population and the variability in dosage, volume, and follow-up. Translational Relevance: This systematic review will help to inform and guide future clinical trials.

Kaposi's sarcoma in a patient with pemphigus vulgaris mimicking exacerbation of pemphigus.

BACKGROUND: Kaposi's sarcoma (KS) is a rare multifocal angiogenic tumor often seen in immunocompromised setting such as acquired immunodeficiency syndrome (AIDS) or organ transplantation recipients. Pemphigus vulgaris (PV) is a rare blistering disorder with mucocutaneous involvement for which immunosuppressive therapy has long been the core of treatment. Iatrogenic form of KS has been reported infrequently in pemphigus patients as a result of long-term immunosuppressive therapy. CASE: We describe a 39-year-old male patient with confirmed diagnosis of PV who developed KS after receiving immunosuppressive agents for his pemphigus. KS was initially localized to the oral cavity with features mimicking exacerbation of his pemphigus. CONCLUSION: This interesting case of KS suggests that dermatologists visiting patients with pemphigus with discomfort in the oral cavity should have a high degree of awareness and consider other differential diagnoses along with merely an exacerbation of PV.

Safety and efficacy of autologous cell vaccines in solid tumors: a systematic review and meta-analysis of randomized control trials.

We conducted a systematic review and meta-analysis of randomized control trials to formally assess the safety and efficacy of autologous whole cell vaccines as immunotherapies for solid tumors. Our primary safety outcome was number, and grade of adverse events. Our primary efficacy outcome was clinical responses. Secondary outcomes included survival metrics and correlative immune assays. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for studies published between 1946 and August 2020 using any autologous whole cell product in the treatment of any solid tumor. The Cochrane Randomized Controlled Trial risk of bias tool was used to assess risk of bias. Eighteen manuscripts were identified with a total of 714 patients enrolled in control and 808 in vaccine arms. In 698 patients receiving at least one dose of vaccine, treatment was well tolerated with a total of 5 grade III or higher adverse events. Clinical response was reported in a minority (n = 2, 14%) of studies. Autologous cell vaccines were associated with improved overall (HR 1.28, 95% CI 1.01-1.63) and disease-free survival (HR 1.33, 95% CI 1.05-1.67) over thirteen and ten trials respectively. Where reported, immune assays correlated well with clinical outcomes. Our results suggest that autologous whole cell vaccination is safe and efficacious in increasing survival in patients undergoing treatment for solid tumors.Registration: PROSPERO CRD42019140187.

Identifying effect modifiers of CAR-T cell therapeutic efficacy: a systematic review and individual patient data meta-analysis protocol.

BACKGROUND: Chimeric antigen receptor T cell therapy (CAR-T) represents a promising and exciting new therapy for hematologic malignancies, where prognosis for relapsed/refractory patients remains poor. Encouraging results from clinical trials have often been tempered by heterogeneity in response to treatment among patients, as well as safety concerns including cytokine release syndrome. The identification of specific patient or treatment-specific factors underlying this heterogeneity may provide the key to the long-term sustainability of this complex and expensive therapy. An individual patient data meta-analysis (IPMDA) may provide potential explanations for the high degree of heterogeneity. Therefore, our objective is to perform a systematic review and IPDMA of CAR-T cell therapy in patients with hematologic malignancies to explore potential effect modifiers of CAR-T cell therapy. METHODS AND ANALYSIS: We will search MEDLINE, Embase, and the Cochrane Central Register of Controlled Clinical Trials. Studies will be screened in duplicate at the abstract level, then at the full-text level by two independent reviewers. We will include any prospective clinical trial of CAR-T cell therapy in patients with hematologic malignancies. Our primary outcome is complete response, while secondary outcomes of interest include overall response, progression-free survival, overall survival, and safety. IPD will be collected from each included trial and, in the case of missing data, corresponding authors/study sponsors will be contacted. Standard aggregate meta-analyses will be performed, followed by the IPD meta-analysis using a one-stage approach. A modified Institute of Health Economics tool will be used to evaluate the risk of bias of included studies. ETHICS AND DISSEMINATION: Identifying characteristics that may act as modifiers of CAR-T cell efficacy is of paramount importance and can help shape future clinical trials in the field. Results from this study will be submitted for publication in a peer-reviewed scientific journal, presented at relevant conferences and shared with relevant stakeholders.

The second family affected with a PRDM8-related disease.

INTRODUCTION: Lafora disease (LD) is a severe form of progressive myoclonus epilepsy characterized by generalized seizures, myoclonus, intellectual decline, ataxia, spasticity, dysarthria, visual loss, and in later stages, psychosis and dementia. To date, mutations in the EPM2A and EPM2B/NHLRC1 genes have been identified as the common causes of LD. However, a mutation in PRDM8 has been reported only once in a Pakistani family affected with early-onset Lafora disease. In the present study, we report the second family with a PRDM8 mutation. METHODS: Two affected individuals of an Iranian family initially diagnosed as complicated hereditary spastic paraplegia (HSP) underwent careful neurologic examination. Homozygosity mapping and whole-exome sequencing were performed. Based on the results of genetic analysis to detection of Lafora bodies, a skin biopsy was done. RESULTS: The clinical features of the patients were described. Linkage to chromosome 4 and a mutation in the PRDM8 gene were identified, suggesting the patients may be affected with early-onset LD. However, like the Pakistani family, the search for Lafora bodies in their skin biopsies was negative. Their electroencephalograms showed generalized epileptiform discharges in the absence of clinical seizures. CONCLUSIONS: The current study increases the number of PRDM8-related cases and expands the phenotypic spectrum of mutations in the PRDM8 gene. Both reported PRDM8-related families presented intra and inter-familial heterogeneity and they have originated from the Middle East. Thus, it seems the PRDM8 mutations should be considered not only in LD but also in other neurodegenerative disorders such as a complicated HSP-like phenotype, especially in this region.

Pemphigus scalp lesions: is trichoscopy helpful in clinical diagnosis?

BACKGROUND: Pemphigus is an autoimmune intraepidermal bullous disease which can affect skin and∕or mucous membranes. Trichoscopy is a non-invasive tool that can help in the clinical diagnosis especially if the patient is presented with only scalp lesions. We conducted this study to investigate the trichoscopic features of pemphigus scalp lesions. METHODS: A total of 100 patients with confirmed diagnosis of pemphigus entered the study; Seventy-nine patients were diagnosed as pemphigus vulgaris (PV) and 21 as pemphigus foliaceus (PF). Trichoscopy of the scalp lesions was performed, and three dermatologists examined separately the trichoscopic images of each patient. The results were re-checked simultaneously by the examiners. Association between variables was analyzed by using different tests including: chi-square test or Fischer's exact test, independent T-Test or Mann-Whitney nonparametric test and logistic regression model when applicable. RESULTS: Mean age of the patients was 45.41 ± 11.13 years, and 58% of cases were male. The most common trichoscopic features observed among all cases were diffuse scaling (71/100), presence of any types of vessels (67/100), and extravasation (63/100). Positive anagen pull test, extravasation, yellow hemorrhagic crust, and polymorphic vessels were more commonly seen in PV than PF cases (P value < 0.05), and by having data of these variables, we can differentiate between PV and PF scalp lesions with 74% sensitivity and 91% specificity. CONCLUSION: Trichoscopy can help in clinical diagnosis of pemphigus scalp lesions but should be followed by other modalities such as biopsy and direct immunofluorescence for definite diagnosis.

Evaluation of Autoimmune Bullous Diseases in Elderly Patients in Iran: A 10-Year Retrospective Study.

Autoimmune bullous diseases (ABDs) are uncommon but significant skin disorders with relatively high morbidity and mortality. Some surveys have been carried out to describe the spectrum of ABDs in a region, but this is the first that has focused on ABDs in elderly patients. This study was conducted to determine the clinicoepidemiologic features of ABDs in elderly patients. Medical records of all ABD patients with disease onset after the age of 60 years who presented to the Autoimmune Bullous Diseases Research Center, Tehran, Iran between April 2003 and March 2013 were reviewed. Patients with dermatitis herpetiformis were not included. During the 10-year period studied, 296 patients with ABD and disease onset after 60 years of age were diagnosed. Bullous pemphigoid (BP) was observed to be the most common ABD (48.3%), followed by pemphigus vulgaris (45.3%), pemphigus foliaceus (3.7%), mucous membrane pemphigoid (1.4%), paraneoplastic pemphigus (0.7%), epidermolysis bullosa acquisita (0.3%), and linear IgA bullous disease (0.3%). A predominance in women was observed for total ABDs, BP, and pemphigus vulgaris. Although Iran is known to have a high prevalence of pemphigus, BP is the most frequent ABD among elderly patients in Iran, highlighting the importance of the clinical diagnosis of BP in elderly patients.

Trauma-induced pemphigus: a case series of 36 patients.

BACKGROUND AND OBJECTIVES: Pemphigus is a group of autoimmune diseases characterized by intraepidermal acantholytic blisters. Isomorphic responses, or Koebner phenomenon (KP), defined as the appearance of typical lesions of a disease following trauma are rarely reported in pemphigus. Our aim was to present patients who developed new pemphigus lesions as a result of skin trauma. PATIENTS AND METHODS: The medical files of pemphigus patients from the Autoimmune Bullous Diseases Research Center, who had a history of trauma before the onset or flare of their disease, between 1999 and 2013 were reviewed. RESULTS: Thirty-six pemphigus vulgaris (PV) patients had a history of trauma. Thirteen patients developed new-onset PV and the other 23 had previously been diagnosed with PV. Pemphigus lesions developed most often following major surgeries including abdominal, orthopedic, and chest surgeries as well as dental procedures, blunt physical trauma, and skin surgeries. Moreover, post-cataract laser surgery, burns, radiation therapy, and physiotherapy were also shown to induce pemphigus. Mean time between trauma and lesions was 4.7 weeks for recurrent PV and 15.0 weeks for new-onset PV. CONCLUSIONS: Unnecessary surgery and blunt trauma should be avoided in pemphigus patients. Furthermore, posttraumatic pemphigus should be suspected in poorly healing surgical wounds and confirmatory biopsies are mandatory.

Evaluation of the effect of disease duration in generalized vitiligo on its clinical response to narrowband ultraviolet B phototherapy.

BACKGROUND/PURPOSE: Narrowband ultraviolet B (NB-UVB) has been accepted as an effective therapy for generalized vitiligo. On the other hand, different factors seem to contribute to a good response. The purpose of this study is to evaluate the influence of disease duration on its clinical response to NB-UVB phototherapy. METHODS: In this open and uncontrolled study, vitiligo was considered 'recent' when the duration of disease was less than or equal to 4 years and 'long standing' when it was greater than 4 years. The patients received NB-UVB thrice weekly with an initial dose of 200 mJ/cm(2) and 10% increments at each subsequent treatment. After categorizing the clinical response to four groups (mild, moderate, good, and excellent), duration of disease and clinical response to NB-UVB were correlated statistically using the t-test. RESULTS: There were 63 patients: 34 women and 29 men, aged 6-60 years. The mean of disease duration was 10.13 ± 9.1 years. Vitiligo was 'recent' in 26 and 'long standing' in 37 patients. The mean of overall response was 51.94 ± 18.48%. Higher grades of response were more prevalent in patients with recent vitiligo than those with long-standing disease, and there was also statistically significant difference in overall response between these two groups of disease duration (P = 0.023). CONCLUSION: The early treatment of generalized vitiligo may enhance the chance of successful repigmentation.

Psoriasis and increased prevalence of hypertension and diabetes mellitus.

BACKGROUND: Psoriasis is an autoimmune skin disease and associated with other diseases such as cardiovascular, hypertension, and diabetes mellitus. AIM: Our aim was to explore the prevalence of diabetes mellitus and hypertension in psoriatic patients. MATERIALS AND METHODS: Between April 2008 and May 2010, a total of 304 psoriatic and 300 nonpsoriatic patients were enrolled in this cross sectional study. Data were obtained on age, sex, weight, heights, etc; documented medical history of diabetes mellitus and hypertension; family history of diabetes mellitus and hypertension in first relatives, history of smoking. RESULTS: There was no significant difference in age and gender distribution between two groups. There was also no difference in body mass index between two groups. Within psoriatic group, 79.3% of patients present with plaque type of the disease and 20.7% present with other types. The results showed that within psoriatic patients, the prevalence of diabetes in women is significantly higher than in men (OR=1.93, CI95%: 1.1-3.6, P=0.004) but this difference is not present in nonpsoriatic patients. The results also showed that the prevalence of diabetes in psoriatic patients is significantly higher than nonpsoriatic patients (OR=1.76, CI95%: 1.11-2.8, P=0.015). The data showed that psoriatic patients were more likely to develop hypertension compared with nonpsoriatic patients (OR=2.2, CI95%: 1.2-4.6, P=0.003). According to results, although smoking rate within psoriatic patients is higher than the other group but the difference was not significant. CONCLUSION: Psoriatic patients have an increased risk of developing metabolic syndrome and hypertension in comparison to nonpsoriatic patients.

Diffuse cutaneous mastocytosis: report of a severe case with fatal outcome.

Diffuse cutaneous mastocytosis (DCM) is a rare variant of mastocytosis. We describe a case of DCM with a very severe presentation at birth and fatal outcome.

Comparison of efficacy of azithromycin vs. doxycycline in the treatment of rosacea: a randomized open clinical trial.

BACKGROUND: Rosacea is a common inflammatory disorder of the skin. Systemic antibiotics currently used in the treatment of rosacea are sometimes associated with uncomfortable side effects. Therefore, a need for an effective agent with few side effects and good patient compliance exists. Azithromycin, a macrolide antibiotic with prolonged mode of action, has recently been found to be an effective alternative in the treatment of inflammatory acne. METHODS: For evaluation of the efficacy of azithromycin in the treatment of rosacea, we planned a randomized, open, clinical trial study to compare the efficacy of azithromycin with doxycycline in the treatment of this disease. Sixty-seven patients were randomized to receive either azithromycin 500 mg thrice weekly (on Monday, Wednesday, and Saturday) in the first, 250 mg thrice weekly (on Monday, Wednesday, and Saturday) in the second, and 250 mg twice weekly (on Tuesday, and Saturday) in the third month. The other group was given doxycycline 100 mg/day for the three months. Clinical assessment was made at baseline, at the end of first, second, third, and 2 months after treatment. Side affects were recorded. The limitation of this study is that there was no blindness. RESULTS: Statistically significant improvement was obtained with both drugs. Neither drug was shown to be more effective than the other. In the azithromycin group four patients had diarrhea, while epigastric burning was seen in two patients using doxycycline. CONCLUSION: This study indicates that azithromycin is at least as effective as doxycycline in the treatment of rosacea.

Two unusual cases of dental (periapical) infection.

Cutaneous sinus tracts of dental origin are often a diagnostic challenge. A delay in correct diagnosis can result in inappropriate treatments. We describe two unusual cases of periapical infection. The first patient presented with a fistulized tumoral mass under the chin present for 1 year. The patient had only one tooth, and that was anatomically unrelated to the tumor. Radiological examination showed a dormant tooth that was infected periapically. The second case was a man who complained of asymmetry and change in his left nasolabial fold of 4-5 week's duration. On examination, the nasolabial folds were asymmetric without any sign of facial palsy. On intraoral examination, there was a severely decayed tooth on the same side. Radiological survey confirmed periapical infection. A few weeks after proper treatment, the nasolabial folds became symmetric.

Calcinosis cutis complicating liver transplantation.

We report a case of calcinosis cutis in a 41-year-old man developing after liver transplantation at sites where no intravenous calcium had been administered. The cutaneous lesions developed on his right upper arm 10-days post-transplantation. The patient had received calcium chloride solution intravenously after surgery. We excluded other causes of ectopic calcification such as hyperparathyroidism, renal failure, and extravasation of calcium chloride.