The molecular pathogenesis of morphoea: from genetics to future treatment targets.

A number of immunoinflammatory and profibrotic mechanisms are recognized in the pathogenesis of broad sclerotic skin processes and, more specifically, morphoea. However, the precise aetiopathogenesis is complex and remains unclear. Morphoea is clinically heterogeneous, with variable anatomical patterning, depth of tissue involvement and sclerotic, inflammatory, atrophic and dyspigmented morphology. Underlying mechanisms determining these reproducible clinical subsets are poorly understood but of great clinical and therapeutic relevance. Regional susceptibility mechanisms (e.g. environmental triggers, mosaicism and positional identity) together with distinct pathogenic determinants (including innate, adaptive and imbalanced pro- and antifibrotic signalling pathways) are likely implicated. In the age of genetic profiling and personalized medicine, improved characterization of the environmental, systemic, local, genetic and immunopathological factors underpinning morphoea pathogenesis may open the door to novel targeted therapeutic approaches.

Severe recalcitrant cutaneous manifestations in systemic lupus erythematosus successfully treated with fumaric acid esters.

Fumaric acid esters (FAEs) have proven efficacy in the treatment of psoriasis and have been in use for decades. More recently, as their mechanism of action and abundant immunomodulatory effects become clearer, the potential benefits of treating other inflammatory skin conditions using FAEs are increasingly being recognized. The use of FAEs as combination systemic therapy has not been well studied and data are lacking regarding the safety and efficacy of this type of therapy. In this case report, three patients with severe, extensive and recalcitrant cutaneous manifestations of systemic lupus erythematosus (SLE) (one case of disseminated discoid lesions and two with severe chilblain lesions) were treated with Fumaderm® (containing the FAE dimethylfumarate and monoethylhydrogen fumarate salts), after failing to respond to a multitude of other monotherapies and combination therapies. All patients showed a substantial clinical response when FAEs were added to their treatment, with concurrent improvements in quality-of-life instrument scores. The treatment was well tolerated in the context of systemic organ involvement and as combination therapy with other agents, such as hydroxychloroquine and mycophenolate mofetil. These cases of SLE illustrate the potential use of FAEs in severe, disfiguring and otherwise therapy-resistant skin lesions, including, to our knowledge, the first two reported cases of FAE-treated chilblain lupus erythematosus.

Pseudoacromegalic facial features in Fabry disease.

Although Fabry disease (FD) is an X-linked lysosomal storage disorder, there is a high prevalence of affected heterozygous females who show symptoms and have an increased mortality associated with the disease. FD usually progresses slowly, and death can result from stroke, heart disease or renal failure. Diagnosis can be delayed in female patients who often present with more subtle features. The classic cutaneous phenotype of 'angiokeratoma corporis diffusum' is less common in female patients. We report the case of a woman with a family history of FD, who showed some of the less well-recognized features of FD, including the typical 'pseudo-acromegalic' facial appearance. She had a deletion at exon 1 of the α-galactosidase (GLA) gene, confirming the diagnosis of FD. As is the case in 30% of women with FD, her plasma and leucocyte α-galactosidase levels were at the lower end of the normal range. At presentation, she already had symptoms and signs of end-organ damage.

Angiokeratoma: decision-making aid for the diagnosis of Fabry disease.

Isolated angiokeratomas are common benign cutaneous lesions, generally deemed unworthy of further investigation. In contrast, diffuse angiokeratomas should alert the physician to a possible diagnosis of Fabry disease, a rare X-linked lysosomal storage disorder, characterized by α-galactosidase deficiency. Glycosphingolipids accumulate in cells throughout the body resulting in progressive multi-organ failure. Difficulties are encountered when trying to interpret the significance of angiokeratomas because they may also occur in other lysosomal storage disorders and rarely in an isolated manner in Fabry disease. We present an algorithm for the classification of angiokeratomas which might prove useful for the diagnosis and management of Fabry disease. Assessment of the clinical features and location of the lesions, personal and family history, skin biopsy, dermoscopy and electron microscopy imaging are sequential steps in the diagnostic process. Assessing the deficiency of α-galactosidase enzyme activity is essential to confirm the diagnosis in males, while mutation analysis is always needed in females. Potentially this algorithm can change the current approach to patients when Fabry disease is suspected, thus improving the diagnostic strategy and management of this disorder. It remains to be decided whether the use of an algorithm might reduce the number of genetic consultations. As evidence has shown the efficacy of enzyme replacement therapy in halting progression of the disease before the onset of irreversible organ damage, it is advisable to aim at an early diagnosis in order to achieve timely initiation of effective treatment with benefits for patients and appropriate use of medical resources.

Late-onset Fabry disease associated with angiokeratoma of Fordyce and multiple cherry angiomas.

Fabry disease (FD) is a lysosomal storage disorder. The prevalence and clinical spectrum is higher than previously thought. The average time between onset of symptoms and diagnosis is 10 years. Early identification of patients is essential to institute enzyme therapy and reduce morbidity. We report the case of a 76-year-old man, who presented with loss of consciousness following exertional chest pain. He was found to have tortuous corneal vessels, > 100 cherry angiomas on his trunk, and angiokeratomas on his scrotum. The latter were indistinguishable from angiokeratoma of Fordyce, a diagnosis reported in 15% of men over the age of 50 years, and generally ignored by them. The patient's α-galactosidase levels were low, and a mutation in exon 5 of the GLA gene was identified on DNA analysis, confirming the diagnosis of FD. This case highlights the importance of considering a diagnosis of FD in all male patients with angiokeratoma. It also raises the question of whether the presence of multiple cherry angiomas in patients with cardiac disease should raise the possible diagnosis of FD.

Fabry disease and the skin: data from FOS, the Fabry outcome survey.

BACKGROUND: Fabry disease (also known as Anderson-Fabry disease) is a rare, X-linked lysosomal storage disorder that is characterized by accumulation of globotriaosylceramide throughout a range of tissues in the body. OBJECTIVES: To ascertain the prevalence and nature of cutaneous manifestations in patients with Fabry disease and to relate these to the severity of systemic manifestations of the disease. METHODS: We have documented the dermatological features of this disease with reference to data from 714 patients (345 males, 369 females) registered on the Fabry Outcome Survey (FOS), a multicentre European database. RESULTS: We confirm that the commonest disease manifestation is angiokeratoma. Overall, 78% of males and 50% of females had one or more dermatological abnormality, the commonest being angiokeratoma (66% males, 36% females), hypohidrosis (53% males, 28% females), telangiectasia (23% males, 9% females) and lymphoedema (16% males, 6% females). We demonstrate for the first time that the presence of cutaneous vascular lesions correlates with the severity of the systemic manifestations of the disease (pain, renal failure, cardiac disease, premature cerebrovascular disease) as assessed by a severity scoring system. Although the condition is X linked, there is a surprisingly high prevalence of abnormalities in females. CONCLUSIONS: The FOS database is a useful epidemiological tool in establishing the variety and relevance of cutaneous manifestations in Fabry disease. The present study confirms that the presence of dermatological manifestations appears to be a marker of greater severity of systemic disease, which emphasizes the importance of the dermatological assessment of these patients.

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.

Recalcitrant erosive flexural lichen planus: successful treatment with a combination of thalidomide and 0.1% tacrolimus ointment.

A 79-year-old woman has had chronically eroded and ulcerated flexural lichen planus for 12 years, resistant to many forms of treatment. She was successfully treated initially with a combination of topical 0.1% tacrolimus ointment and oral thalidomide and then with topical tacrolimus alone. She has remained free of exacerbations for 12 months and treatment has been well tolerated. Erosive lichen planus involving flexures alone is rare. All reports on treatment of this condition address erosive oral or mucosal lichen planus and both thalidomide and topical tacrolimus have been reported individually to be beneficial.

Systemic lupus erythematosus presenting with oral mucosal lesions: easily missed?

Two caucasian patients are described in whom oral mucosal lesions were the first manifestation of systemic lupus erythematosus. In both cases the diagnosis was delayed despite histological examination of oral lesions. Treatment with antimalarials and azathioprine was of significant benefit. In the absence of cutaneous or systemic features, distinguishing oral lupus erythematosus from lichen planus and epidermal dysplasia can be difficult, both clinically and on histology, and requires a high index of suspicion.

The pathophysiology of photosensitivity in lupus erythematosus.

The strong association between photosensitivity and lupus erythematosus has led to the suggestion that abnormal photoreactivity participates in the pathogenesis of cutaneous lesions. In this review we discuss the evidence for abnormal cutaneous reactivity to sunlight in lupus and speculate on the cellular, molecular and genetic factors that may underlie this abnormality.

Cytomegalovirus-associated gastric ulcer in an immunosuppressed patient with pemphigus vulgaris.

A 79-year-old female with pemphigus vulgaris developed a cytomegalovirus (CMV)-associated gastric ulcer whilst on standard immunosupression with azathioprine and prednisolone. Following treatment with ganciclovir and ranitidine the ulcer healed. CMV infection frequently involves the gastrointestinal tract of immunocompromised patients causing inflammation, ulceration and haemorrhage. Although it has also been described in patients treated with immunosuppressive therapy for malignancy and other autoimmune disease, we are not aware of previous reports in patients treated for autoimmune bullous disease.

The inhibition of cutaneous T cell apoptosis may prevent resolution of inflammation in atopic eczema.

Atopic eczema (AE) is characterized by the persistence of infiltrating T lymphocytes in the dermis. To test the hypothesis that dysregulation of normal T cell apoptosis may contribute to the pathogenesis and chronicity of AE we compared patients with a normal resolving immune response (Mantoux reaction (MR)) induced in healthy volunteers by cutaneous PPD injection. Significantly less T cell apoptosis was observed in lesional skin of AE patients compared with either the peak or the resolution phase of the MR (P < 0.0001). The low incidence of T cell apoptosis in AE was associated with significantly increased levels of Bcl-2 relative to Bax (P < 0.0001) and significantly decreased CD95-L expression (P < 0.002) compared with the resolving MR. The cytokines IL-15 and interferon-beta (IFN-beta), which prevent activated T cell apoptosis, were expressed maximally on day 7 and day 14 of the MR, respectively. In contrast, AE patients expressed high levels of both IL-15 and IFN-beta in cutaneous lesions at the same time. This suggests that the co-expression of two anti-apoptotic cytokines, which are not found together during resolving cutaneous responses, may contribute to excessive T cell survival which leads to the persistence of inflammation in patients with AE.

Interferon-beta mediates stromal cell rescue of T cells from apoptosis.

The resolution of immune responses is characterized by extensive apoptosis of activated T cells. However, to generate and maintain immunological memory, some antigen-specific T cells must survive and revert to a resting G0/G1 state. Cytokines that bind to the common gamma chain of the IL-2 receptor promote the survival of T cell blasts, but also induce proliferation. In contrast, soluble factors secreted by stromal cells induce Tcell survival in a resting G0/G1 state. We now report that interferon-beta is the principal mediator of stromal cell-mediated Tcell rescue from apoptosis. Interferon-alpha and -beta promote the reversion of blast Tcells to a resting G0/G1 configuration with all the characteristic features of stromal cell rescue; such as high Bcl-XL expression and low Bcl-2. Type I interferons and stromal cells stimulate apparently identical signaling pathways, leading to STAT-1 activation. We also show that this mechanism may play a fundamental role in the persistence of T cells at sites of chronic inflammation; suggesting that chronic inflammation is an aberrant consequence of immunological memory.

The role of apoptosis in the resolution of T cell-mediated cutaneous inflammation.

We have investigated cutaneous purified protein derivative-induced delayed-type hypersensitivity (DTH) responses in healthy volunteers to determine features associated with both the generation and resolution of the reaction. The clinical peak of the response occurred at day 3; however, T cell numbers were maximal on day 7. There was a preferential increase of CD4+ CD45RO+ T cells on day 7, which was largely due to proliferation, since a mean of 19% was in cycle. The proliferation of this subset was associated with the presence of IL-15, which was expressed as early as 12 h, and IL-2, which showed peak expression at 7 days. By day 14, there was a significant decrease in both the mean T cell number/unit area and IL-2 and IL-15 expression in perivascular infiltrates. Maximal CD95 (Fas/Apo-1) ligand and TNF-alpha expression were observed at 7 days and were associated with the presence of 1.83% (range 0.81-2.48%) apoptotic T cells. At 14 days, CD95 ligand and TNF-alpha expression were reduced significantly, and the presence of 2.5% (range 1.5-3.75%) of apoptotic T cells at this time was probably due to cytokine deprivation, associated with decreased Bcl-2 relative to Bax expression. The induction and resolution of the Mantoux reaction may depend on the expression of cytokines, such as IL-2 and IL-15, which regulate both proliferation and apoptosis in T cells. Failure to control either of these phases of the Mantoux reaction may contribute to the chronicity of inflammatory responses in certain cutaneous diseases.

CD44 variant expression in cutaneous T-cell lymphoma.

Expression of the lymphocyte homing receptor CD44 and its splice variants have been linked to tumour dissemination and poor prognosis in non-Hodgkin's lymphoma. Specifically, the in vitro expression of variant exon V6 confers metastatic potential in rat pancreatic carcinoma cell lines. In this study, we investigated the expression of CD44 splice variants in cutaneous T-cell lymphomas, including patients with mycosis fungoides (MF), Sezary syndrome (SS), large-cell anaplastic lymphoma (LCAL) and HTLV1-associated cutaneous lymphoma. In addition, 4 involved lymph nodes from 2 patients with MF and 1 patient with SS were examined. Inflammatory dermatoses, lichen planus and psoriasis, and normal skin were also studied. Immunohistochemistry was performed using a panel of monoclonal antibodies, including those with specificity for CD44H (standard isoform) and variant exons V3, V6 and V8-9. Normal epidermal keratinocytes were consistently CD44H and CD44 V3, V6 and V8-9 positive. In all the different clinicopathological subtypes and stages of cutaneous T-cell lymphomas, including involved lymph nodes, tumour cells consistently expressed CD44H, but were CD44 V3 and V6 negative. CD44 V8-9 was expressed on a majority of tumour cells in 2/5 LCAL and on occasional tumour cells in 2/5 LCAL. Occasional V8-9 positive tumour cells were also identified in 6/13 MF, 1/4 SS and 3/4 HTLV1. In 2/3 lymph node samples from 2 patients with tumour-stage MF, CD44 V8-9 expression was found on a small percentage of atypical mononuclear cells. Scattered V8-9 positive dermal mononuclear cells were present in sections of lichen planus and psoriasis. We have found no evidence to suggest that the metastasis-associated CD44 variant exon (V6) is expressed in cutaneous T-cell lymphoma, or that CD44H expression is associated with an adverse prognostic group. It is not clear whether the strong expression of CD44 V8-9 in 2 patients with CD30 positive LCAL reflects activation status or metastatic potential.