Skin resident memory CD8+ T cells are phenotypically and functionally distinct from circulating populations and lack immediate cytotoxic function.

The in-depth understanding of skin resident memory CD8+ T lymphocytes (TRM ) may help to uncover strategies for their manipulation during disease. We investigated isolated TRM from healthy human skin, which expressed the residence marker CD69, and compared them to circulating CD8+ T cell populations from the same donors. There were significantly increased proportions of CD8+ CD45RA- CD27- T cells in the skin that expressed low levels of killer cell lectin-like receptor G1 (KLRG1), CD57, perforin and granzyme B. The CD8+ TRM in skin were therefore phenotypically distinct from circulating CD8+ CD45RA- CD27- T cells that expressed high levels of all these molecules. Nevertheless, the activation of CD8+ TRM with T cell receptor (TCR)/CD28 or interleukin (IL)-2 or IL-15 in vitro induced the expression of granzyme B. Blocking signalling through the inhibitory receptor programmed cell death 1 (PD)-1 further boosted granzyme B expression. A unique feature of some CD8+ TRM cells was their ability to secrete high levels of tumour necrosis factor (TNF)-α and IL-2, a cytokine combination that was not seen frequently in circulating CD8+ T cells. The cutaneous CD8+ TRM are therefore diverse, and appear to be phenotypically and functionally distinct from circulating cells. Indeed, the surface receptors used to distinguish differentiation stages of blood T cells cannot be applied to T cells in the skin. Furthermore, the function of cutaneous TRM appears to be stringently controlled by environmental signals in situ.

Sustained improvement in urticaria pigmentosa and pruritus in a case of indolent systemic mastocytosis treated with cladribine.

Systemic mastocytosis (SM) is a myeloproliferative disorder, characterized by a clonal proliferation of abnormal mast cells accumulating in internal organs and sometimes in the skin, leading to cutaneous and systemic symptoms. Mutations within the gene KIT, which encodes the receptor tyrosine kinase (KIT) on mast cells, is found in most patients with SM. We report a case of a 62-year-old woman presenting with a pruritic rash on her limbs and trunk. Several years later she developed gastrointestinal symptoms, associated with raised serum tryptase. Skin and bone marrow biopsies confirmed a diagnosis of SM, initially presenting with urticaria pigmentosa. Responses to multiple therapies, including potent topical steroids, oral antihistamines, phototherapy and the tyrosine kinase inhibitor, nilotinib, were inadequate. Treatment with cladribine (2-chlorodeoxyadenosine) produced a marked and sustained reduction in her symptoms and serum tryptase level.

Late-onset pretibial recessive dystrophic epidermolysis bullosa.

Pretibial epidermolysis bullosa (EB) is a rare form of localized dystrophic EB, characterized by recurrent blistering and scarring plaques occurring predominantly in the pretibial area. In most cases, nail dystrophy, especially of the toenails, is also present. Often there are no clinical abnormalities at birth, and the disorder may only appear after several years. We report a patient who developed symptoms in his fifth decade. Genetic testing identified compound heterozygosity for two pathogenic mutations in the COL7A1 gene. This case highlights a rare variant of mechanobullous disease, and stresses the importance of molecular screening in establishing a correct diagnosis. Precisely why the disorder specifically localizes to the shins or why it may only become apparent in later life is not known.

Investigation of the cutaneous response to recall antigen in humans in vivo.

In this paper we provide a detailed description of an experimental method for investigating the induction and resolution of recall immune response to antigen in humans in vivo. This involves the injection of tuberculin purified protein derivative (PPD) into the skin, followed by inducing suction blisters at the site of injection, from which leucocytes and cytokines that are involved in the response can be isolated and characterized. Using this technique we found that although the majority of CD4(+) T cells in the skin that are present early in the response express cutaneous lymphocyte antigen (CLA), the expression of this marker is reduced significantly in later phases. This may enable these cells to leave the skin during immune resolution. Furthermore, interleukin (IL)-2 production can be detected both in CD4(+) T cells and also in the blister fluid at the peak of the response at day 7, indicating that mediators found in the blister fluid are representative of the cytokine microenvironment in vivo. Finally, we found that older humans have defective ability to respond to cutaneous PPD challenge, but this does not reflect a global immune deficit as they have similar numbers of circulating functional PPD-specific CD4(+) T cells as young subjects. The use of the blister technology enables further characterization of the skin specific defect in older humans and also general mechanisms that govern immune regulation in vivo.

Long-term safety of biologics in the treatment of moderate-to-severe plaque psoriasis: review of current data.

Conventional non-biologic systemic agents are regarded as second-line therapy for the treatment of moderate-to-severe plaque psoriasis after topical treatments. However, long-term data have highlighted a number of safety concerns associated with their prolonged use. Biologic agents targeting specific immune mediators have emerged as an alternative treatment option for patients with moderate-to-severe plaque psoriasis who are unresponsive to, or intolerant of, non-biologic systemic agents. Although several biologics have demonstrated good efficacy and tolerability in short-term trials, treatment guidelines recommend them as third-line therapies due to a relative lack of long-term safety data. Here, we have reviewed the long-term (≥ 1 year) safety data from randomized controlled trials, open-label extension studies and meta-analyses of etanercept, infliximab, efalizumab, adalimumab, alefacept and ustekinumab in the treatment of adults with moderate-to-severe plaque psoriasis. With the exception of efalizumab, which has been withdrawn from both the European and U.S. markets due to long-term safety concerns, these biologics are generally well tolerated in long-term studies, and offer a viable alternative to conventional non-biologic agents in patients with moderate-to-severe plaque psoriasis.

A follow-up of four cases of nephrogenic systemic fibrosis: is gadolinium the specific trigger?

We originally reported four patients with nephrogenic systemic fibrosis (NSF) in the British Journal of Dermatology in 2003, and now present an update of their outcome. All four patients (three females and one male) presented within a six month period at our institution, and had received gadolinium contrast agents prior to disease onset. Two patients with functioning renal transplants had limited cutaneous disease, two patients maintained on haemodialysis had more severe disease and died one year after disease onset. Gadolinium deposition was demonstrated in lesional skin of one patient using electron microscopy and energy dispersive spectroscopy.

The safety of tacrolimus ointment for the treatment of atopic dermatitis: a review.

Tacrolimus ointment is a topical calcineurin inhibitor (TCI) that was developed specifically for the treatment of atopic dermatitis (AD). It is one of the most extensively tested dermatological products, with more than 19 000 patients (including approximately 7600 children) having participated in the tacrolimus ointment clinical development programme. Recent regulatory reviews have focused on the potential risk of malignancy with TCIs, based on their mode of action and the effects of systemic tacrolimus when given to transplant recipients. Studies have shown, however, that the systemic absorption of tacrolimus when applied topically is very low, with blood concentrations being below the level of quantification in most patients. Moreover, TCIs are not associated with a decrease in immunocompetence in the skin and there is no increase in the incidence of infections with long-term treatment. More than 5.4 million prescriptions for tacrolimus ointment have been issued worldwide, with no evidence of an increased risk of malignancy in adults or children compared with the general population. Similarly, epidemiological studies have failed to demonstrate an increased incidence of skin cancer in patients using TCIs. The most common adverse events (AEs) that occur with tacrolimus ointment treatment are transient application-site reactions, such as burning or pruritus. These complications are related to disease severity, and decrease in frequency over time as AD improves. The incidence of nonapplication-site AEs does not increase with long-term treatment, and most such events occurring in clinical trials were considered to be unrelated to therapy. Although it is important that clinicians are aware of the recent changes in product labelling, extensive clinical trials continue to show that tacrolimus ointment is well tolerated, and is generally an effective therapy for suitable patients with AD.

Application of topical mitomycin C to the base of shave-removed keloid scars to prevent their recurrence.

BACKGROUND: Keloid scars are formed by over-activity of fibroblasts producing collagen and they cause significant morbidity both from their appearance and from their symptoms. Existing treatments are often unsatisfactory. Topical mitomycin C is known to inhibit fibroblast proliferation. OBJECTIVES: To determine whether application of mitomycin C to the base of shave-removed keloids would prevent their recurrence. METHODS: Ten patients had all or part of their keloid shave-removed. After haemostasis topical mitomycin C 1 mg mL(-1) was applied for 3 min. This application was repeated after 3 weeks. The keloids were photographed before treatment and the patients were reviewed every 2 months for a total of 6 months when a final photograph of the keloid site was taken. The patients and the Clinical Trials Unit staff scored the outcome on a linear analogue scale of 0-10, where 0 = disappointed and 10 = delighted. The pretreatment and 6-month post-treatment photographs were also assessed by two dermatologists who were not involved in the clinical trial. RESULTS: Four of the 10 patients were delighted with the outcome of treatment and only one was disappointed. On average there was an 80% satisfied outcome. CONCLUSIONS: This new treatment of keloids has been shown to be effective in the majority of patients but further studies are required to confirm this benefit.

Relative impact of CD4+CD25+ regulatory T cells and tacrolimus on inhibition of T-cell proliferation in patients with atopic dermatitis.

BACKGROUND: It has been established recently that CD4+CD25+ regulatory T cells (Tregs) play an important role in controlling various immune responses. Immunosuppressive drugs are often used to treat immune dysregulation but are frequently associated with undesirable side-effects. OBJECTIVES: We examined the suppressive capacity of circulating Tregs in patients with atopic dermatitis (AD). Combined effects of Tregs and tacrolimus on the inhibition of T-cell proliferation in vitro were also assessed. METHODS: CD4+CD25+ and CD4+CD25- T cells were isolated from peripheral blood mononuclear cells using immunomagnetic beads. CD4+CD25- T cells were stimulated with purified protein derivative (PPD) or house dust mite allergen (Der p1) for 6 or 7 days, respectively. A dose range of tacrolimus and CD4+CD25+ T cells were added separately, or together. Proliferation was measured by (3)H-thymidine incorporation. RESULTS: CD4+CD25+ T cells from normal controls and patients with AD are anergic and inhibit the proliferation of CD4+CD25- T cells in response to PPD and Der p1 in vitro in a dose-dependent manner. Addition of tacrolimus and Tregs together showed significantly stronger inhibition of proliferation than either on their own. This was true for both antigens and both in normal controls and in patients with AD. CONCLUSIONS: CD4+CD25+ T cells in patients with AD have normal suppressive activity compared with healthy controls. Tregs and tacrolimus have additive effects on the inhibition of proliferation in response to PPD and Der p1.

Dementia associated with scleromyxoedema reversed by high-dose intravenous immunoglobulin.

Scleromyxoedema is a rare skin disease, characterized by deposition of acid mucopolysaccharides in the dermis. Although the disease primarily affects the skin, cardiovascular, renal and rheumatological manifestations have been described. In addition to these noncutaneous manifestations, about 15% of patients have central neurological symptoms such as psychosis, convulsions and encephalopathy. Successful therapy is difficult but high-dose intravenous immunoglobulin (IVIg) has been reported to be a successful treatment. We describe a patient with scleromyxoedema who presented with novel central nervous system manifestations of chronic cognitive impairment and dementia (Folstein Mini Mental State test score 8/30), which improved within a week after treatment with high-dose IVIg, with full restoration (Folstein Mini Mental State test score 27/30) at 2 months.

The immunomodulatory effects of regulatory T cells: implications for immune regulation in the skin.

Regulatory T cells are thought to have a critical role in the suppression of immune responses. In addition to the prevention of the development of autoimmunity, they are also thought to have a role in the prevention of allergic responses to environmental allergens, immune responses to tumours and the development of memory responses to chronic infections. They have been isolated within the skin and have been shown to express surface markers that enable skin-specific migration, suggesting that regulatory T cells have a functional role in the skin. There is accumulating evidence to suggest that regulatory T cells may be involved in numerous skin disorders and may also be modified by various therapeutic agents used to treat these disorders. We review the evidence for the presence of this T-cell subset in humans, the suppressive effects of regulatory T cells, and their role in the skin.

Pyoderma gangrenosum outside the context of inflammatory bowel disease treated successfully with infliximab.

A 63-year-old man with chronic lymphocytic leukaemia developed pyoderma gangrenosum following minor trauma to the leg. He required intensive inpatient management with a multitude of treatments including larval therapy, surgical debridement, ciclosporin, methotrexate, thalidomide, pulsed intravenous methylprednisolone and high-dose intravenous immunoglobulin, clofazamine and high dose oral corticosteroids, none of which were helpful. Treatment complications included steroid-induced diabetes, Cushing's syndrome and perforated peptic ulcer. The pyoderma remained refractory to treatment and continued to extend until he received intravenous infliximab 5 mg/kg at weeks 0, 2 and 6.

Localized granulomatous reaction to a semi-permanent hyaluronic acid and acrylic hydrogel cosmetic filler.

Dermalive, an injectable skin filler composed of a combination of synthetic hyaluronic acid and acrylic hydrogel particles was recently developed for soft tissue augmentation. Dermalive produces longer term results than temporary injectable fillers and is associated with a reportedly low incidence of adverse reactions. We describe a marked local reaction to the injection of Dermalive in the nasolabial fold developing within 4 months with histological confirmation of a granulomatous response. To our knowledge there has been only one previous report of a local granulomatous reaction to Dermalive.

Etanercept-induced systemic lupus erythematosus.

Tumour necrosis factor (TNF) is a pro-inflammatory cytokine with a role in the pathogenesis of a number of conditions including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. Etanercept (Enbrel; Immunex Corp., Seattle, WA, USA) is a recombinant soluble fusion protein of TNF-alpha type II receptor and IgG which acts by blocking the action of TNF-alpha. It is licensed for use in rheumatoid arthritis and juvenile chronic arthritis. A number of studies report the development of antinuclear and anti-double-stranded DNA antibodies in patients treated with TNF antagonists for rheumatoid arthritis. There are few reports of the development of clinical features of discoid, subacute or systemic lupus erythematosus. We present one of the first reported cases of etenercept-induced systemic lupus erythematosus and review the literature of lupus and TNF antagonists.