Forum Patel

Metastatic melanoma – A review of current and future treatment options

Despite advances in treatment and surveillance, melanoma continues to claim approximately 9,000 lives in the US annually (SEER 2013). The National Comprehensive Cancer Network currently recommends ipilumumab, vemurafenib, dabrafenib, and high-dose IL-2 as first line agents for Stage IV melanoma. Little data exists to guide management of cutaneous and subcutaneous metastases despite the fact that they are relatively common. Existing options include intralesional Bacillus Calmette-Guérin, isolated limb perfusion/infusion, interferon-α, topical imiquimod, cryotherapy, radiation therapy, interferon therapy, and intratumoral interleukin-2 injections. Newly emerging treatments include the anti-programmed cell death 1 receptor agents (nivolumab and pembrolizumab), anti-programmed death-ligand 1 agents, and oncolytic vaccines (talimogene laherparepevec). Available treatments for select sites include adoptive T cell therapies and dendritic cell vaccines. In addition to reviewing the above agents and their mechanisms of action, this review will also focus on combination therapy as these strategies have shown promising results in clinical trials for metastatic melanoma treatment.

Effective strategies for the management of pyoderma gangrenosum: a comprehensive review.

Pyoderma gangrenosum (PG) is an inflammatory disease characterized by painful skin ulcerations with undermined and erythematous borders. The etiology of PG is not well understood, but it is generally considered to be an aberrant immune response characterized by a dermal neutrophilc infiltrate. Given the existence of only a few PG clinical trials, treatment options are largely based upon anecdotal data and small case studies. In addition to classic immunosuppressive medications, PG has been reported to respond well to the anti-TNF agents, infliximab, etanercept, adalimumab. Newer biologics such as ustekinumab (anti-IL-23), ixekizumab (anti-IL-17) and brodalumab (anti-IL-17R) are promising given the effect of IL-17 on neutrophil migration. However, the effectiveness of these newer agents remains to be rigorously evaluated. Multi-drug regimens have not been well described in the literature but are an excellent alternative for patients with refractory disease. Herein, we provide a comprehensive review of the pathophysiology of PG and of the different treatments available for managing PG patients, including the theoretical benefit of initiating multidrug regimens. We also provide one possible treatment algorithm for patients with refractory disease and give examples of refractory PG cases successfully treated with multidrug regimens.

Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts

Importance Pyoderma gangrenosum is a rare inflammatory skin condition that is difficult to diagnose. Currently, it is a “diagnosis of exclusion,” a definition not compatible with clinical decision making or inclusion for clinical trials. Objective To propose and validate diagnostic criteria for ulcerative pyoderma gangrenosum. Evidence Review Diagnostic criteria were created following a Delphi consensus exercise using the RAND/UCLA Appropriateness Method. The criteria were validated against peer-reviewed established cases of pyoderma gangrenosum and mimickers using k-fold cross-validation with methods of multiple imputation. Findings Delphi exercise yielded 1 major criterion—biopsy of ulcer edge demonstrating neutrophilic infiltrate—and 8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history of inflammatory bowel disease or inflammatory arthritis; (4) history of papule, pustule, or vesicle ulcerating within 4 days of appearing; (5) peripheral erythema, undermining border, and tenderness at ulceration site; (6) multiple ulcerations, at least 1 on an anterior lower leg; (7) cribriform or “wrinkled paper” scar(s) at healed ulcer sites; and (8) decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Receiver operating characteristic analysis revealed that 4 of 8 minor criteria maximized discrimination, yielding sensitivity and specificity of 86% and 90%, respectively. Conclusions and Relevance This Delphi exercise produced 1 major criterion and 8 minor criteria for the diagnosis of ulcerative pyoderma gangrenosum. The criteria may serve as a guideline for clinicians, allowing for fewer misdiagnoses and improved patient selection for clinical trials.

Pathophysiology of autoimmune bullous diseases: Nature versus nurture

Pemphigus and pemphigoid are the prototypical immunobullous diseases. Although it has been well established that they are caused by deposition of autoreactive antibodies directed against adherence proteins within the skin, the specific genetic and environmental factors leading to development of these diseases continue to be an area of investigation. Herein, we discuss several of the potential environmental triggers that may induce patients to develop immunobullous diseases including medications, viral infections, UV exposure or other radiation injury and dietary factors. In addition, the potential genetic and immunologic mechanisms contributing to the pathogenesis of pemphigus and pemphigoid will be reviewed. The multifactorial nature of these diseases contributes to their complexity and highlights the importance of a detailed personal and family history when caring for these patients.

NKG2C, HLA‐E and their association with psoriasis

Natural killer (NK) cell activation is regulated by the integration of signals from inhibitory and activating cell surface receptors. Both NKG2A and NKG2C pair with CD94 to form inhibitory and activating receptors specific for the HLA‐E‐canonical peptide complex. HLA‐E is a non‐classical MHC class Ib molecule with limited polymorphism. It preferentially binds to and presents leader sequence peptides derived from classical MHC class I molecules. Wilson et al. have identified an association between NKG2C deficiency and psoriasis. They have also discovered an HLA‐C‐dependent association between HLA‐E and psoriasis. Their research highlights the importance of NK cells in the pathophysiology of psoriasis. Herein, we propose two different models to explain the association between NKG2C, HLA‐E and psoriasis. In the first model, we hypothesize that NKG2C deficiency and/or HLA‐E O1:01 can inhibit the ability of NK cells to regulate autoreactive T cells, predisposing to psoriasis. The second model proposes that HLA‐E 01:03 can disrupt the presentation of the psoriasis‐inducing self‐determinant by HLA‐C, thereby protecting against psoriasis.

Topical clobetasol for the treatment of toxic epidermal necrolysis: study protocol for a randomized controlled trial

BackgroundToxic epidermal necrolysis (TEN) is a rare systemic allergic drug eruption with high patient mortality. Currently, no established treatments have been shown to be effective for TEN beyond supportive care. Prior studies of systemic corticosteroids have yielded conflicting data, with some showing a possible benefit and others reporting in increased mortality. However, topical steroids have shown promise for treatment of ocular sequelae of TEN, such as scarring and vision loss. We have designed a randomized controlled trial to evaluate topical clobetasol for treatment of the epidermal manifestations of TEN. In addition, we propose genetic studies to characterize the TEN transcriptome and alterations in cutaneous gene expression that might occur following topical steroid treatment.Methods/DesignThis split-body randomized, double-blind, placebo-controlled Phase IIa proof-of-concept trial will evaluate the safety and efficacy of once-daily topical clobetasol applied to the skin of patients with TEN. This multicenter trial will recruit a total of 15 patients between the ages of 12 and 85 from the University of California Davis Medical Center and Shriners Hospital for Children inpatient burn units. Designated treatment areas on opposite sides of the body will be treated with blinded clobetasol 0.05 % ointment or control petrolatum ointment daily for 14 days. On day 3 of therapy, a biopsy will be taken from the treated area for genetic studies. The primary study aims will be to establish the safety of topical clobetasol treatment and determine the time to cessation of skin detachment for the control and clobetasol-treated areas. Secondary endpoints will evaluate efficacy using parameters such as time to 90 % re-epithelialization and percentage of affected skin at 0, 3, 6, 9, 12 and 15 days. Genomic DNA and RNA will be obtained from biopsy samples, to characterize the TEN transcriptome and identify changes in gene expression after topical steroid treatment.DiscussionTopical steroids have shown promise for treating ocular complications of TEN, but to date have not been evaluated for cutaneous manifestations of the disease. This trial will investigate clinical and molecular outcomes of topical clobetasol application and hopefully provide insight into the disease pathophysiology.Trial registrationClinicalTrials.gov NCT02319616. https://clinicaltrials.gov/ct2/show/NCT02351037

Classic ulcerative pyoderma gangrenosum is a T cell-mediated disease targeting follicular adnexal structures: A hypothesis based on molecular and clinicopathologic studies

Background Pyoderma gangrenosum (PG) is a debilitating ulcerative skin disease that is one of the most common associated diseases seen in patients with inflammatory bowel disease and rheumatoid arthritis. Although PG is classified as a neutrophilic dermatosis, its pathophysiology is poorly understood. Objective Use data obtained from patient-reported histories, immunohistochemistry, and gene expression analysis to formulate a hypothesis on PG pathophysiology. Methods Ten PG patients participated and answered questions about new ulcer formation. Skin biopsies of healed prior ulcers and adjacent normal skin were obtained from four patients for immunohistochemistry. Scars from healthy patients and patients with discoid lupus were used as additional controls. New onset PG papules were analyzed using immunohistochemistry and gene expression analysis via quantitative real-time PCR. Results All PG patients reported that healed sites of previous ulceration are refractory to re-ulceration. Simultaneous biopsies of healed and uninvolved skin triggered ulceration only in the latter. On immunohistochemistry, healed PG scars showed complete loss of pilosebaceous units, which were present in normal skin, and to a lesser extent in control scars, and discoid scars. Early PG papules showed perivascular and peripilosebaceous T cell infiltrates, rather than neutrophils. These early inflammatory events were dominated by increased gene expression of CXCL9, CXCL10, CXCL11, IL-8, IL-17, IFNG, and IL-36G and transcription factors consistent with Th1 phenotype. Limitations Small sample size was the main limitation. Conclusion We put forth the hypothesis that PG is a T cell response resulting in the destruction of pilosebaceous units.