Alan Cooper

Psychiatric morbidity in psoriasis: A review

SUMMARY Psoriasis is a common condition, affecting 1.5–2% of the population of industrialized countries. It is important for clinicians to be aware that psoriasis can have a substantial emotional impact on an individual, which is not necessarily related to the extent of skin disease. This review examines current literature addressing the psychological and emotional aspects of psoriasis. A literature search of the MEDLINE (1966–2002) and PsycINFO (1984–2002) computer databases and bibliographies was carried out. Papers selected for the review included English language reviews and all original research relevant to the topic, in the form of randomized controlled trials, cohort studies, case–control studies, cross‐over and uncontrolled clinical trials, patient surveys, quality‐of‐life studies, case series and case reports. Despite significant shortcomings, the available prevalence studies showed uniformly high rates of psychopathology among psoriasis sufferers. The few intervention studies available are summarized and critically discussed. Psoriasis is associated with a variety of psychological problems, including poor self esteem, sexual dysfunction, anxiety, depression and suicidal ideation. The clinical severity of the psoriasis may not reflect the degree of emotional impact of the disease. A number of psychological interventions have shown promise in recent trials. It is important that clinicians consider the psychosocial aspects of this illness.

Activated protein C prevents inflammation yet stimulates angiogenesis to promote cutaneous wound healing

Activated protein C (APC) is a serine protease that plays a central role in physiological anticoagulation, and has more recently been shown to be a potent anti‐inflammatory mediator. Using cultured human cells, we show here that APC up‐regulates the angiogenic promoters matrix metalloproteinase‐2 in skin fibroblasts and umbilical vein endothelial cells, vascular endothelial growth factor in keratinocytes and fibroblasts, and monocyte chemoattractant protein‐1 in fibroblasts. In the chick embryo chorioallantoic membrane assay, APC promoted the granulation/remodeling phases of wound healing by markedly stimulating angiogenesis as well as promoting reepithelialization. In a full‐thickness rat skin‐healing model, a single topical application of APC enhanced wound healing compared to saline control. APC‐treated wounds had markedly more blood vessels on day 7 and a significantly lower infiltration of neutrophils at days 4 and 7. The broad spectrum matrix metallo‐proteinas, GM6001, prevented the ability of APC to promote wound healing. In summary, our results show that APC promotes cutaneous wound healing via a complex mechanism involving stimulation of angiogenesis and inhibition of inflammation. These unique properties of APC make it an attractive therapeutic agent to promote the healing of chronic wounds.

The endothelium in psoriasis.

Summary This article is a review of the role of the endothelium in psoriasis, with emphasis on angiogenesis and lymphocyte—endothelial interactions.

Treatment of Chronic Leg Ulcers With Topical Activated Protein C

BACKGROUND The treatment of skin ulcers frequently presents a management challenge. Nonhealing wounds with poor response to conventional wound management therapy represent a significant cause of disability, affecting approximately 1% of the global population. Activated protein C is a serine protease with anticoagulant, angiogenic, and anti-inflammatory properties that has shown efficacy in patients for the treatment of severe sepsis. We report 4 cases of nonhealing lower limb skin ulcers that were treated with activated protein C. OBSERVATIONS The study included 4 patients whose wounds were not improving despite standard wound treatment for 4 months or more. Activated protein C was applied topically to their wounds once weekly for 4 weeks. All 4 patients showed a rapid positive response to treatment that was maintained during a 4-month follow-up period. The treatment was well tolerated, with no remarkable adverse effects or complications. CONCLUSIONS Activated protein C can stimulate wound healing in patients with skin ulcers that are refractory to conventional wound-healing therapies. The likely mechanism of action is its recognized ability to stimulate angiogenesis and reepithelialization and to inhibit inflammation. Activated protein C has potential as a therapeutic option for patients with chronic skin ulcers.

Thalidomide in dermatology.

Thalidomide is an effective agent to treat over 25 seemingly unrelated dermatological conditions that have an inflammatory or autoimmune basis. The main side‐effects of teratogenesis and peripheral neuropathy limit its use. Currently, in Australia no assurance is given as to the quality, safety and efficacy of thalidomide. The use of thalidomide for toxic epidermal necrolysis can lead to an increase in mortality, and its use as a prophylactic agent for the prevention of chronic graft‐versus‐host disease following bone marrow transplantation has raised more speculations as to the safety of this notorious drug. A review of the therapeutic indications for thalidomide in dermatology as well as the mechanisms of action and side‐effects of this drug are presented. The current suggested guidelines for its use in clinical practice in Australia are discussed.

Atopic dermatitis: Review of immunopathogenesis and advances in immunosuppressive therapy

This paper reviews the theories of the pathogenesis of atopic dermatitis (AD), with a particular emphasis on its immunopathogenesis. The contribution of predisposing factors, immunopathogenic factors and provoking factors in the pathogenesis of AD are considered. Predisposing factors explored in this article include genetics and the disturbance of skin function. Immunopathogenic factors reviewed include T cell dysfunction, biphasic cytokine expression and the role of immunoglobulin E. Provoking factors considered include microbial factors, psychosomatic interactions, contact allergens and irritants, inhalant allergens, food and climate. Immunosuppressive treatments reviewed include cyclosporin, azathioprine, methotrexate, tacrolimus, interferon‐γ, phosphodiesterase inhibitors and pimecrolimus (SDZ ASM 981).

Combining etanercept with traditional agents in the treatment of psoriasis: a review of the clinical evidence

Psoriasis is a chronic, systemic inflammatory disorder manifesting primarily in skin and potentially in joints, frequently necessitating treatment with conventional systemic therapies, phototherapy or biological agents. Patients with moderate to severe disease suffer a diminished quality of life, experience significant comorbidities and have a higher mortality. Although traditional treatments are effective in the short‐term, their use is often limited by concerns over long‐term toxicity, including end‐organ damage and risk of malignancy. Combination therapy is a commonly used approach and is often more effective than any single agent. Lower doses of two treatments in combination can also minimize potential side effects from a single agent at higher doses. Etanercept is a recombinant human tumour necrosis factor (TNF)α receptor (p75) protein fused with the Fc portion of IgG1 that binds to TNFα. This article reviews the evidence on the efficacy and safety of etanercept in combination with methotrexate, acitretin, narrowband UVB and cyclosporin. The largest body of evidence assesses the combination with methotrexate, although evidence is available for the other combinations. Data suggest that although highly effective as monotherapy, etanercept in combination with a conventional systemic agent can enhance efficacy and allow drug sparing. Potentially, the combination may also result in faster treatment responses and permit safe transitioning from one systemic agent to another. Evidence to date suggests that these benefits can be achieved without significant additional toxicity, although long‐term data on the efficacy and safety of the combination in psoriatic populations is limited and further evaluation is warranted.

Sulfasalazine and dermatitis herpetiformis

Dermatitis herpetiformis that is unable to be controlled using dapsone and a gluten‐free diet presents a therapeutic challenge. Three cases that responded well to sulfasalazine are presented. Two cases, who were unable to tolerate dapsone, had a rapid response to sulfasalazine, without apparent side‐effects. The third case with dapsone‐responsive blistering dermatoses, presumed to be dermatitis herpetiformis on the basis of serology, showed an excellent clinical response to sulfasalazine, but after 6 weeks of therapy had to cease it because of side‐effects. Sulfasalazine is metabolized variably to sulfapyridine, a sulphonamide known to be an effective therapy for dermatitis herpetiformis but no longer available. Sulfasalazine should be considered as a management option for dermatitis herpetiformis.

PUVA treatment of alopecia areata totalis and universalis: A retrospective study

The results of PUVA treatment of alopecia areata (AA) totalis and universalis were reviewed in 26 adult patients. Eight of 15 patients with AA totalis and six of 11 patients with AA universalis achieved a complete response (>90% hair regrowth). Patients with AA totalis had a greater incidence of treatment failure (<25% hair regrowth) than those with AA universalis. Patients with a family history of AA were significantly less likely to have a positive response to PUVA than those with no family history. Sex, age at diagnosis and treatment, interval between diagnosis and treatment, and background of atopy were not significant determinants of outcome. Although unable to show significance for clinical response to treatment, this study demonstrates complete hair regrowth in patients with both AA totalis (53%) and universalis (55%) while reporting a low relapse rate among these patients (21%) within a long period of follow up (mean 5.2 years).

Immunopathogenesis of psoriasis

This paper reviews the pathogenesis of psoriasis, in particular, the immunological cascade in psoriasis. Psoriasis is an immune‐mediated skin disease where the T cell plays a pivotal role in the pathogenesis of the disease. The critical steps involved in the pathogenesis include Langerhans cell activation and maturation by antigens in the skin, activation of the T cell by mature Langerhans cells, differentiation and expansion of T cells within the lymph nodes, trafficking of activated T cells from the lymph node to the skin and the subsequent release of cytokines. These cytokines are responsible for epidermal and vascular hyperproliferation and pro‐inflammatory effects. Each of these steps provides an opportunity for biological agents designed to block the psoriatic immunological cascade. This paper reviews the immunopathogenesis of psoriasis. Biologic agents in psoriasis, to be published separately, reviews the new biologic therapies that aim to selectively block the immunological steps implicated in the pathogenesis of psoriasis outlined in this paper.