Nasim Fazel

Cutaneous and Mucosal Lichen Planus: A Comprehensive Review of Clinical Subtypes, Risk Factors, Diagnosis, and Prognosis

Lichen planus (LP) is a chronic inflammatory disorder that most often affects middle-aged adults. LP can involve the skin or mucous membranes including the oral, vulvovaginal, esophageal, laryngeal, and conjunctival mucosa. It has different variants based on the morphology of the lesions and the site of involvement. The literature suggests that certain presentations of the disease such as esophageal or ophthalmological involvement are underdiagnosed. The burden of the disease is higher in some variants including hypertrophic LP and erosive oral LP, which may have a more chronic pattern. LP can significantly affect the quality of life of patients as well. Drugs or contact allergens can cause lichenoid reactions as the main differential diagnosis of LP. LP is a T-cell mediated immunologic disease but the responsible antigen remains unidentified. In this paper, we review the history, epidemiology, and clinical subtypes of LP. We also review the histopathologic aspects of the disease, differential diagnoses, immunopathogenesis, and the clinical and genetic correlations.

Oral candidiasis and angular cheilitis

Candidiasis, an often encountered oral disease, has been increasing in frequency. Most commonly caused by the overgrowth of Candida albicans, oral candidiasis can be divided into several categories including acute and chronic forms, and angular cheilitis. Risk factors for the development of oral candidiasis include immunosuppression, wearing of dentures, pharmacotherapeutics, smoking, infancy and old age, endocrine dysfunction, and decreased salivation. Oral candidiasis may be asymptomatic. More frequently, however, it is physically uncomfortable, and the patient may complain of burning mouth, dysgeusia, dysphagia, anorexia, and weight loss, leading to nutritional deficiency and impaired quality of life. A plethora of antifungal treatments are available. The overall prognosis of oral candidiasis is good, and rarely is the condition life threatening with invasive or recalcitrant disease.

Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats

Mesenchymal stem cells (MSCs) are a promising therapy for immune‐mediated and inflammatory disorders, because of their potent immunomodulatory properties. In this study, we investigated the use of fresh, autologous, adipose‐derived MSCs (ASCs) for feline chronic gingivostomatitis (FCGS), a chronic, debilitating, idiopathic, oral mucosal inflammatory disease. Nine cats with refractory FCGS were enrolled in this pilot study. Each cat received 2 intravenous injections of 20 million autologous ASCs, 1 month apart. Oral biopsies were taken before and at 6 months after the first ASC injection. Blood immune cell subsets, serum protein, and cytokine levels were measured at 0, 1, 3, and 6 months after treatment to assess immunomodulatory effects. Seven of the 9 cats completed the study. Five cats responded to treatment by either complete clinical remission (n = 3) or substantial clinical improvement (n = 2). Two cats were nonresponders. Cats that responded to treatment also exhibited systemic immunomodulation demonstrated by decreased numbers of circulating CD8+ T cells, a normalization of the CD4/CD8 ratio, decreased neutrophil counts, and interferon‐γ and interleukin (IL)‐1β concentration, and a temporary increase in serum IL‐6 and tumor necrosis factor‐α concentration. No clinical recurrence has occurred following complete clinical remission (follow‐up of 6–24 months). In this study, cats with <15% cytotoxic CD8 T cells with low expression of CD8 (CD8lo) cells were 100% responsive to ASC therapy, whereas cats with >15% CD8lo cells were nonresponders. The relative absence of CD8lo cells may be a biomarker to predict response to ASC therapy, and may shed light on pathogenesis of FCGS and mechanisms by which ASCs decrease oral inflammation and affect T‐cell phenotype.

Adrenergic Signaling in Human Oral Keratinocytes and Wound Repair

Catecholamines are present in saliva, but their influence on oral epithelium is not understood. Because psychological stress increases salivary catecholamines and impairs oral mucosal wound healing, we sought to determine if epithelial adrenergic signaling could link these two findings. We found that cultured human oral keratinocytes (HOK) express the α2B- and β2-adrenergic receptors (ARs). Exposure of HOK to either epinephrine or the β-AR agonist, isoproterenol, reduced migratory speed and decreased in vitro scratch wound healing. Incubation with the β-AR antagonist timolol reversed the catecholamine-induced effects, indicating that the observed response is mediated by β-AR. Epinephrine treatment decreased phosphorylation of the mitogen-activated protein kinases (MAPK) ERK1/2 and p38; these decreases were also reversed with timolol. Cultured HOK express enzymes of the epinephrine synthetic pathway, and generate epinephrine. These findings demonstrate that stress-induced elevations of salivary catecholamines signal through MAPK pathways, and result in impaired oral keratinocyte migration required for healing.

Mucosal Lichen Planus: An Evidence-Based Treatment Update

BackgroundMucosal lichen planus (MLP) is a chronic mucosal disorder that often poses a therapeutic challenge to dermatologists, dentists, and gynecologists. To relieve patients’ pain and discomfort, improve their quality of life, and achieve clinical improvement, various therapeutic approaches can be considered for this disease. Based on the current literature it is difficult to define any particular treatment as the main therapeutic modality.ObjectiveWe aimed to systematically review the current literature for the effectiveness of available treatment modalities for MLP.MethodsAll of the randomized controlled trials and systematic reviews of MLP were collected by searching Pubmed, EMBASE, the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, and China National Knowledge Infrastructure. Meta-analysis was performed, if possible.ResultsTopical betamethasone valerate, clobetasol-17-propionate, and fluocinonide are effective in the treatment of oral lichen planus (OLP) when compared with placebo. Calcineurin inhibitors and topical retinoids are also beneficial treatment options.LimitationsThe review does not include therapies with a lower level of evidence.ConclusionTopical corticosteroids are the mainstay of therapy for OLP. High-quality evidence is lacking for the treatment of lichen planus.

Patient-centered, direct-access online care for management of atopic dermatitis: a randomized clinical trial.

IMPORTANCE New models of health care delivery for dermatological care have the potential to increase access and improve patient-centered outcomes. OBJECTIVE To compare effectiveness of a direct-access, online model for follow-up dermatologic care in pediatric and adult patients with atopic dermatitis with that of in-person office visits. DESIGN, SETTING, AND PARTICIPANTS This was a 1-year, randomized controlled equivalency clinical trial in medically underserved areas, outpatient clinics, and the general community. Participants included children and adults with atopic dermatitis with access to the Internet, computers, and digital cameras. INTERVENTIONS After an initial in-person visit, patients were randomized 1:1 to direct-access online or usual in-person care for follow-up management of atopic dermatitis. In the direct-access online group, patients captured and transmitted clinical images and history asynchronously to dermatologists online; dermatologists evaluated the clinical information, provided recommendations and education, and prescribed medications online asynchronously. In the in-person group, patients visited dermatologists in their offices for follow-up care. MAIN OUTCOMES AND MEASURES Atopic dermatitis disease severity as assessed by patient-oriented eczema measure (POEM) and investigator global assessment (IGA). RESULTS A total of 156 children and adults were randomized. Between baseline and 12 months, the mean (SD) within-group difference in POEM score in patients in the direct-access online group was -5.1 (5.48) (95% CI, -6.32 to -3.88); in the in-person group, the within-group difference was -4.86 (4.87) (95% CI, -6.27 to -3.46). The difference in the change in POEM scores between the 2 groups was 0.24 (6.59) (90% CI, -1.70 to 1.23), which was contained within the predetermined 2.5 equivalence margin. The percentage of patients achieving clearance or near-clearance of their disease (IGA score of 0 or 1) was 38.4% (95% CI, 27.7% to 49.3%) in the direct-access online group and 43.6% (95% CI, 32.6%-54.6%) in the in-person group. The difference in the percent of patients achieving clearance or near-clearance between the 2 groups was 5.1% (90% CI, 1.7%-8.6%), which was contained within the predetermined 10% equivalence margin. CONCLUSIONS AND RELEVANCE The direct-access online model results in equivalent improvements in atopic dermatitis clinical outcomes as in-person care. Direct-access online care may represent an innovative model of delivering dermatological services to patients with chronic skin diseases. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00985894.

Cutaneous lichen planus: A systematic review of treatments

Abstract Various treatment modalities are available for cutaneous lichen planus. Pubmed, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database were searched for all the systematic reviews and randomized controlled trials related to cutaneous lichen planus. Two systematic reviews and nine relevant randomized controlled trials were identified. Acitretin, griseofulvin, hydroxychloroquine and narrow band ultraviolet B are demonstrated to be effective in the treatment of cutaneous lichen planus. Sulfasalazine is effective, but has an unfavorable safety profile. KH1060, a vitamin D analogue, is not beneficial in the management of cutaneous lichen planus. Evidence from large scale randomized trials demonstrating the safety and efficacy for many other treatment modalities used to treat cutaneous lichen planus is simply not available.

Ustekinumab for the treatment of psoriatic arthritis: an update

Psoriatic arthritis occurs in 30% of psoriasis patients, and the treatment can be challenging in some patients. Recently, the US Food and Drug Administration approved ustekinumab, a fully human monoclonal antibody, for the management of psoriatic arthritis. In this article, we review large-scale randomized clinical trials addressing the efficacy and safety profile of ustekinumab for the treatment of psoriatic arthritis.

Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis

Mesenchymal stem cells (MSCs) have potent immunomodulatory functions and are a promising therapy for immune‐mediated inflammatory disorders. We previously demonstrated the efficacy of fresh, autologous, adipose‐derived MSCs (ASCs) to treat feline chronic gingivostomatitis (FCGS), a chronic oral mucosal inflammatory disease similar to human oral lichen planus. Here, we investigate the use of fresh allogeneic ASCs for treatment of FCGS in seven cats. Radiolabeled ASCs were also tracked systemically. Each cat received two intravenous injections of 20 million ASCs, 1 month apart. Oral inflammation, blood lymphocyte subsets, anti‐fetal bovine serum antibody levels, ASC crossmatching and serum proteins and cytokine concentrations were determined. Four of the 7 cats (57%) responded to treatment [complete clinical remission (n = 2) or substantial clinical improvement (n = 2)]. Three cats were nonresponders. Prior to therapy, most cats had increased circulating CD8+ T cells, decreased CD8lo cells, and a decreased CD4/CD8 ratio, however clinical resolution was not associated with normalization of these parameters. Nonresponders showed more severe systemic inflammation (neutrophilia, hyperglobulinemia and increased interferon gamma and tumor necrosis factor alpha concentration) prior to ASC therapy. Clinical remission took up to 20 months and no clinical relapse has occurred. A higher fraction of radiolabeled ASCs were identified in the oral cavity of FCGS affected cats than the control cat. The administration of fresh, allogenic ASCs appeared to have lower clinical efficacy with a delayed response as compared to the fresh, autologous ASCs. In addition, the mechanism(s) of action for autologous and allogenic ASCs may differ in this model of oral inflammation. Stem Cells Translational Medicine 2017;6:1710–1722

Human and feline adipose-derived mesenchymal stem cells have comparable phenotype, immunomodulatory functions, and transcriptome

BackgroundAdipose-derived mesenchymal stem cells (ASCs) are a promising cell therapy to treat inflammatory and immune-mediated diseases. Development of appropriate pre-clinical animal models is critical to determine safety and attain early efficacy data for the most promising therapeutic candidates. Naturally occurring diseases in cats already serve as valuable models to inform human clinical trials in oncologic, cardiovascular, and genetic diseases. The objective of this study was to complete a comprehensive side-by-side comparison of human and feline ASCs, with an emphasis on their immunomodulatory capacity and transcriptome.MethodsHuman and feline ASCs were evaluated for phenotype, immunomodulatory profile, and transcriptome. Additionally, transwells were used to determine the role of cell-cell contact in ASC-mediated inhibition of lymphocyte proliferation in both humans and cats.ResultsSimilar to human ASCs, feline ASCs were highly proliferative at low passages and fit the minimal criteria of multipotent stem cells including a compatible surface protein phenotype, osteogenic capacity, and normal karyotype. Like ASCs from all species, feline ASCs inhibited mitogen-activated lymphocyte proliferation in vitro, with or without direct ASC-lymphocyte contact. Feline ASCs mimic human ASCs in their mediator secretion pattern, including prostaglandin E2, indoleamine 2,3 dioxygenase, transforming growth factor beta, and interleukin-6, all augmented by interferon gamma secretion by lymphocytes. The transcriptome of three unactivated feline ASC lines were highly similar. Functional analysis of the most highly expressed genes highlighted processes including: 1) the regulation of apoptosis; 2) cell adhesion; 3) response to oxidative stress; and 4) regulation of cell differentiation. Finally, feline ASCs had a similar gene expression profile to noninduced human ASCs.ConclusionsFindings suggest that feline ASCs modulate lymphocyte proliferation using soluble mediators that mirror the human ASC secretion pattern. Uninduced feline ASCs have similar gene expression profiles to uninduced human ASCs, as revealed by transcriptome analysis. These data will help inform clinical trials using cats with naturally occurring diseases as surrogate models for human clinical trials in the regenerative medicine arena.