European dermatology forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxedema, scleredema and nephrogenic systemic fibrosis.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this guideline provides clinicians with an overview of the diagnosis and treatment of scleromyxedema, scleredema (of Buschke) and nephrogenic systemic sclerosis (nephrogenic fibrosing dermopathy).

European Dermatology Forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: localized scleroderma, systemic sclerosis and overlap syndromes.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this guideline provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes of systemic sclerosis with diseases of the rheumatological spectrum.

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.

Systemic sclerosis with multiple nodules: characterization of the extracellular matrix.

Systemic sclerosis (SSc) is still an enigmatic disease of unknown etiology, although the pathophysiology is thought to be based on vascular alterations as well as immunological and fibrotic processes. Here we present the case of a female patient with diffuse SSc (dSSc), who developed multiple subcutaneous nodules. Histologic evaluation confirmed the diagnosis of nodular scleroderma, a very rare condition. Histological analysis of biopsies was combined with ultrastructural analysis by transmission electron microscopy and immunohistochemistry/immunofluorescence, using antibodies against different collagens and non-collagenous ECM proteins. Collagen fibrils were deposited at very high density in nodules as well as in adjacent extra nodular skin. Within nodules, a large fraction of immature collagen fibrils was detected with smaller and highly variable diameter. Activated fibroblasts were present, however no myofibroblasts were identified. Cartilage Oligomeric Matrix Protein (COMP), collagen XII and fibrillin-1 were all deposited at increased amounts within nodules and their distribution differed markedly from that in healthy skin. The excessive deposition of COMP within nodules closely resembled the distribution of COMP in keloids. Nodules-like keloids-were characterized by lack of myofibroblasts. By virtue of its structural properties and the capacity to avidly bind collagen I and XII, COMP is thought to reorganize and compact the collagen network, leading to a tissue with locally increased biomechanical tension acting on fibroblasts. In addition, COMP may present active TGFß to fibroblasts. Both mechanisms in concert can activate fibroblast proliferation and production of extracellular matrix, resulting in a sustained activation loop.

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.