Mahir Patel

Cutaneous manifestations of gastrointestinal disease: Part I

Cutaneous findings are not uncommonly a concomitant finding in patients afflicted with gastrointestinal (GI) diseases. The dermatologic manifestations may precede clinically evident GI disease. Part I of this 2-part CME review focuses on dermatologic findings as they relate to hereditary and nonhereditary polyposis disorders and paraneoplastic disorders. A number of hereditary GI disorders have an increased risk of colorectal carcinomas. These disorders include familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Each disease has its own cutaneous signature that aids dermatologists in the early diagnosis and detection of hereditary GI malignancy. These disease processes are associated with particular gene mutations that can be used in screening and to guide additional genetic counseling. In addition, there is a group of hamartomatous syndromes, some of which are associated with phosphatase and tensin homolog (PTEN) gene mutations, which present with concurrent skin findings. These include Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Cronkhite-Canada syndrome. Finally, paraneoplastic disorders are another subcategory of GI diseases associated with cutaneous manifestations, including malignant acanthosis nigricans, Leser-Trélat sign, tylosis, Plummer-Vinson syndrome, necrolytic migratory erythema, perianal extramammary Paget disease, carcinoid syndrome, paraneoplastic dermatomyositis, and paraneoplastic pemphigus. Each of these disease processes have been shown to be associated with an increased risk of GI malignancy. This underscores the important role of dermatologists in the diagnosis, detection, monitoring, and treatment of these disorders while consulting and interacting with their GI colleagues.

Cutaneous manifestations of gastrointestinal disease

The gastrointestinal (GI) and cutaneous organ systems are closely linked. In part I of this continuing medical education article, the intricacies of this relationship were explored as they pertained to hereditary polyposis disorders, hamartomatous disorders, and paraneoplastic disease. Part II focuses on the cutaneous systems links to inflammatory bowel disease and vascular disorders. An in-depth analysis of inflammatory bowel disease skin findings is provided to aid dermatologists in recognizing and facilitating early consultation and intervention by gastroenterologists. Cutaneous signs of inflammatory bowel disease include fissures and fistulae, erythema nodosum, pyoderma gangrenosum, pyostomatitis vegetans, oral aphthous ulcers, cutaneous polyarteritis nodosa, necrotizing vasculitis, and epidermolysis bullosa acquisita. Additional immune-mediated conditions, such as diverticulitis, bowel-associated dermatosis-arthritis syndrome, Henoch-Schönlein purpura, dermatitis herpetiformis, and Degos disease, in which the skin and GI system are mutually involved, will also be discussed. Genodermatoses common to both the GI tract and the skin include Hermansky-Pudlak syndrome, pseudoxanthoma elasticum, Ehlers-Danlos syndrome, hereditary hemorrhagic telangiectasia, and blue rubber bleb nevus syndrome. Kaposi sarcoma is a neoplastic disease with lesions involving both the skin and the gastrointestinal tract. Acrodermatitis enteropathica, a condition of zinc deficiency, likewise affects both the GI and dermatologic systems. These conditions are reviewed with updates on the genetic basis, diagnostic and screening modalities, and therapeutic options. Finally, GI complications associated with vascular disorders will also be discussed.

Current investigational drugs in psoriasis

Introduction : The advent of biologic therapies has revolutionized the treatment of psoriasis. Increased understanding of immunogenetic pathways has allowed for the development of more selective targeted biologic therapies. Multiple new treatments are currently in development for the treatment of psoriasis. Preliminary data for many of these agents, particularly with regard to agents targeting the IL-23/Th17 pathway, are promising. Proven long-term safety, however, is an absolute necessity with newly developed drugs, and should, therefore, still be considered second-line agents to current established treatments with long-term safety data. Areas covered : This review details the mechanisms of action of drugs currently in development or in clinical trials for the treatment of psoriasis, using clinical trial registries and associated publications. Readers will gain a comprehensive overview about the mechanism of action of emerging treatments targeting various immune pathways deeply involved in psoriasis. Pathogenesis, clinical efficacy and safety data for these treatments are discussed where available. Expert opinion : Psoriasis remains a heavily undertreated systemic immune-mediated disease despite increased understanding of immunopathogenesis of the disease and advent of a multitude of novel therapeutic agents with potentially improved bioavailability and safety profiles. Limitations, however, remain in the realm of topical agents for treatment of mild to moderate psoriasis, which has seen little progress over the years. A concerted effort will need to be made among researchers, clinicians and patient advocacy groups to ensure new therapeutic agents are developed and gain proper exposure.

Biological therapies for psoriasis

Introduction: Biological therapies have revolutionized moderate-to-severe psoriasis treatment. Increased understanding of disease pathogenesis has yielded multiple therapeutic targets involving the IL-23/Th17 pathway, while current therapies continue to be monitored for long-term efficacy and safety. Areas covered: This review details current understanding of psoriasis immunopathogenesis specifically related to therapeutic targets. Approved and emerging biological psoriasis therapies targeting TNF-α, IL-12/23p40, IL-17 and IL-23p19 are covered. Biological agent uses in special circumstances are reviewed together with the emerging debate on biosimilar therapies and their potential future role in psoriasis and other inflammatory diseases. Expert opinion: Psoriasis treatment has expanded and has become more effective due to increased understanding of disease pathogenesis. However, lack of efficacy in select psoriasis patients, safety concerns and limited treatment efficacy in psoriasis variants (e.g., pustular) are areas which still need improvement. As such, pharmacogenomics will be of vital importance in future for individualized psoriasis care. Further, a better understanding of the multiple psoriasis comorbidities, especially cardiovascular disease, continues to be of significant interest in the psoriasis community. Last, the emergence of biosimilar agents has the potential to change psoriasis treatment, especially as it relates to better access for the psoriasis community worldwide.

Emerging topical treatments for psoriasis.

Introduction: Psoriasis is an immune-mediated chronic inflammatory skin disease which classically presents as erythematous, scaly plaques affecting extensor surfaces of the limbs, scalp and trunk. Approximately 80% of patients have a mild-to-moderate form routinely treated with topical medications, whereas phototherapy, systemic and biological therapies are typically reserved for treatment of moderate-to-severe psoriasis. Areas covered: The major advances in psoriasis therapy in the past 15 years have been in new immunomodulatory and biological molecules, with a significant unmet need to have new, efficient and safe topical treatment options for the large percentage of patients for whom systemic therapy is not indicated. The available topical therapies (corticosteroids and vitamin D3 analogs) have remained relatively unchanged over the past several decades. This article reviews emerging topical drugs and formulations currently under evaluation in clinical trials. Expert opinion: The time is right for a revolution in our topical therapy armamentarium. It has lagged significantly behind the systemic biological evolution of new drug development. Our large psoriasis population with mild-to-moderate psoriasis certainly deserves potent but safe and innovative topical agents with a new mode of action as well as with long-lasting clinical efficacy.

Emerging therapies for the treatment of psoriasis.

Psoriasis is an immune-mediated disease that affects 1%–2% of the European and North American population. While topical agents such as corticosteroids and vitamin D derivatives are prescribed for mild disease, they are generally unable to adequately control patients with more severe disease. Over the past decade, research into the immunopathogenesis of psoriasis, including investigations into the role of tumor necrosis factor-alpha and more recently interleukins (IL) 12/23, has led to the advent of targeted biologic therapies based on the central role of a new subset of T cells, Th17. Because of their increased specificity, biologic agents have revolutionized short- to medium-term treatment outcomes and safety profiles for moderate to severe disease over previously gold standard systemic agents. The immunopathogenesis of the disease is still a focus for researchers and novel targets for future agents are being discovered and investigated in clinical trials. In particular, specifically targeting the IL-23/Th17 pathway has given rise to IL-23p19 and IL-17 antagonists, both of which have shown significant promise in clinical trials. IL-22 is involved in keratinocyte proliferation and is being studied as a treatment target for psoriasis. New small molecule oral agents, including Janus kinase and phosphodiesterase inhibitors are currently in phase 2 and 3 clinical trials.

Tumour necrosis factor-α inhibitor use in patients with psoriasis with organ transplantation.

Dear Editor, Psoriasis is an immune-mediated, genetic skin disease affecting 1–2% of the world’s population. Chronic plaque psoriasis accounts for 80–90% of all cases and can cause significant quality of life impairment. Over the past decade, biological therapies have revolutionized the treatment of psoriasis. However, clinical trials for biological agents in psoriasis exclude patients with prior organ transplantation. Therefore, there is a paucity of literature on the use of biologics in conjunction with the typical immunosuppressive regimens used in organ transplantation. We present a patient with a history of organ transplantation and psoriasis requiring biological therapy, together with a literature review. A 50-year-old man presented with a history of renal transplantation for focal segmental glomerulosclerosis and longstanding psoriasis. Renal allograft therapy included tacrolimus 2 mg twice daily, azathioprine 50 mg twice daily and prednisone 15 mg daily. Evaluation revealed psoriatic involvement of his ears, upper and lower extremities, abdomen and buttocks. His body surface area (BSA) involvement was 20 2% and his Psoriasis Area and Severity Index (PASI) was 15 5. Discussion was initiated with his nephrologist regarding the safety of biological agents in conjunction with immunosuppressive medications for organ transplantation. To date, there have been nine studies (totalling 24 patients) reporting the use of tumour necrosis factor (TNF)-a inhibitors for either severe psoriasis (Table 1) or inflammatory bowel disease (IBD) (Table 2) in the setting of liver (n = 20), renal (n = 3) or pancreas–renal (n = 1) transplantation. All patients with psoriasis were treated with etanercept, while patients with IBD were treated with infliximab (n = 13), adalimumab (n = 2), infliximab then adalimumab (n = 5) or adalimumab then infliximab (n = 1). In one series of patients with IBD, clinical response – defined as assessment of clinical improvement – was seen in seven of eight patients at 12 weeks, mucosal healing by direct visualization was observed in three of seven patients, and five out of six patients on corticosteroids for allograft-related immunosuppression were weaned after initiating anti-TNF-a therapy. There are three reports of severe, recalcitrant psoriasis in the setting of solid organ transplantation. Patient 1 is a 42-year-old man with a 20-year history of psoriasis, pancreas–kidney transplantation 8 years prior for Goodpasture syndrome, and pancreatic retransplantation 1 year prior for a nonfunctional allograft. He was on prednisone 4 mg daily, tacrolimus 8 5 mg daily and mycophenolate mofetil 1 g daily. PASI was 25 2 prior to initiation of etanercept 25 mg twice weekly. A 50% and 90% improvement in PASI (PASI 50 and PASI 90) were achieved at 4 and 12 weeks, respectively. Patient 2 is a 63-year-old man with a longstanding history of psoriasis and liver transplantation 6 years prior for cryptogenic cirrhosis; he was on tacrolimus 1 mg twice daily and sirolimus 5 mg daily. He had 50% BSA involvement and had failed low-dose methotrexate, psoralen plus long-wavelength ultraviolet A, and acitretin prior to receiving etanercept 50 mg twice weekly for 6 months followed by once weekly maintenance dosing. PASI 50 and PASI 90 were achieved at 6 weeks and 6 months, respectively. Patient 3 is a 49-year-old man with a history of psoriasis, chronic hepatitis C, alcoholic cirrhosis and hepatocellular carcinoma leading to liver transplantation. He presented with severe psoriasis (30% BSA) unresponsive to topical steroids and worsening psoriatic arthritis 1 year after transplantation. Medications included oral tacrolimus, mycophenolate mofetil, prednisone and aciclovir for herpes keratitis. Methotrexate, ciclosporin and acitretin were contraindicated due to hepatic dysfunction, and phototherapy was unfeasible. Etanercept 25 mg twice weekly was initiated with ‘marked (psoriasis) improvement’ after 6 weeks and complete clearance at

The spectrum of oculocutaneous disease: Part II. Neoplastic and drug-related causes of oculocutaneous disease

There are a multitude of diseases that commonly affect both the skin and the eye. Part II of this 2-part series reviews the oculocutaneous manifestations of neoplasms, both benign and malignant, and adverse drug reactions affecting the skin and the eye. Though rare, a number of neoplasms that primarily involve the skin, such as melanoma and basal cell carcinoma, can metastasize to the eye, leading to permanent damage if not properly treated. In addition, periocular neoplasms can irritate the conjunctiva and lid, reducing a patients ability to see clearly. Neoplastic diseases, such as xeroderma pigmentosum, Sturge-Weber syndrome, and multiple myeloma, can also lead to permanent changes in the eye if not discovered and managed promptly. Furthermore, there are a multitude of drugs, including those commonly used by dermatologists, which can result in permanent damage to the eye. With proper knowledge of the ocular manifestations and treatment recommendations described in this 2-part series, dermatologists with the assistance of their ophthalmology colleagues can help avoid the complications, including permanent blindness, associated with infectious, inflammatory, genetic, neoplastic, and drug-related conditions.

Use of tumor necrosis factor alpha (TNF α) antagonists in a patient with psoriasis and Chagas disease

There are several studies on the benefits of using TNFα antagonists in the treatment of psoriasis, but few studies addressing the interaction of these drugs with chronic infections. We report the case of a 52-year-old patient diagnosed with psoriasis refractory to traditional systemic agents, who was treated with biologic therapies. After one year of treatment with biologic agents, the patient was diagnosed with Chagas Disease.

Widespread dermal ulcerations and bullae

Bullous pemphigoid is an autoimmune disease of the skin characterized by large, tense bullae resulting in significant morbidity in affected individuals. The diagnosis of bullous pemphigoid may present challenges due to clinical similarities with various other bullous eruptions. Frequently, epidemiological features can provide clues to the diagnosis of bullous pemphigoid, with histologic analysis commonly required for definitive diagnosis. This case study illustrates the typical clinical and histologic findings seen in bullous pemphigoid patients and briefly discusses the differential diagnosis. An in-depth understanding of the intricate pathophysiology is essential in order to educate patients. After diagnosis and appropriate workup, an array of treatment approaches, including topical and systemic corticosteroids, immunosuppressive agents, antibiotics, chemotherapeutic agents, and even monoclonal antibodies, may be utilized individually or in combination to achieve an optimal therapeutic response.