Características clínicas y epidemiológicas de los pacientes con esclerodermia

IntroductionScleroderma is a term used to refer to a group of fibrosing disorders affecting the skin. Two types of scleroderma can be differentiated: systemic sclerosis (SS), with visceral involvement, and localised scleroderma or morphea, confined to the skin and underlying tissues. Few studies have evaluated the characteristics of these patients. The aim of this study was to analyse demographic and clinical features of patients with a diagnosis of scleroderma.Material and methodsAn analysis was performed on the data from adult patients with a diagnosis of scleroderma and followed-up in a single speciality clinic in a tertiary hospital.ResultsThe study included 100 patients (80 with SS and 20 with morphea). The median age of onset was 45 years, and women were more frequently affected than men. Patients were classified according to the subtype of scleroderma. Prevalence of concomitant autoimmune diseases (28% patients) and lichen sclerosus (5%) were also analysed. Another classification is proposed by us for patients with morphea according to the distribution of lesions: isomorphic morphea (lesions on areas of skin friction) and non-isomorphic morphea (other locations). Patients with isomorphic morphea were more predominantly female, with a higher prevalence of overweight and obesity, and a higher association with lichen sclerosus. Patients with non-isomorphic morphea required systemic treatment less frequently.ConclusionsThe present study suggests that a classification for patients with morphea according to distribution patterns could differentiate two subtypes of patients that seem to have differences in disease course.     

Ultrasonography as an auxiliary diagnostic tool for morphea profunda: A case report

Morphea profunda is a rare subtype of localized scleroderma and it is difficult to evaluate the conditions of sclerotic changes at an early stage. Studies using ultrasonography to evaluate localized scleroderma are limited and, to date, the characteristic findings of morphea profunda assessed by ultrasonography have never been reported. Here, we present a case of morphea profunda diagnosed with the assistance of ultrasonography. A 69‐year‐old Japanese woman with a past history of morphea en plaque on her lower abdomen presented with skin indurations of her bilateral lower back and thighs. To evaluate the stiffness of the subcutis, fascia and muscle, we utilized ultrasonography and found an unexpected hyperechogenicity not only of the dermis but also in the deeper tissue. The diagnosis was revised to morphea profunda after we performed a deep skin biopsy, including the muscle tissue. From this case, we assert that ultrasonography is a useful alternative tool to assist in the differential diagnosis of morphea profunda.     

Keloid morphea and nodular scleroderma: two distinct clinical variants of scleroderma?

BACKGROUND: For nearly a century, the terms "keloid morphea" and "nodular scleroderma" have been used interchangeably without defined clinical or histologic criteria. OBJECTIVE: To define the conditions "keloid morphea" and "nodular scleroderma" by correlating the clinical and histologic features. METHODS: We retrospectively identified six patients with keloidal lesions and nodules from 70 consecutive patients with scleroderma seen in the dermatology clinic. The clinical presentation and histopathological findings were reviewed. RESULTS: Six of 70 patients with scleroderma (45 systemic and 25 morphea) exhibited keloidal or nodular lesions. All these patients had systemic sclerosis. Clinically one patient (case 1) had nodules; five (cases 2-6) had keloids. The nodular lesions had histologic findings consistent with keloid, while the keloidal plaques were variably keloids or morphea histopathologically. There was no correlation between the clinical morphology and the histologic findings, except for cases 5 and 6. These patients were African-American, with a family history of keloids and typical keloids clinically and histologically that developed from sites with normal skin. CONCLUSION: Keloid morphea and nodular scleroderma are clinical terms that describe keloidal and nodular lesions in patients most commonly with scleroderma. The clinicopathologic association is variable. Based on a review of the English literature and our series of six patients, we identified two clinical variants; (1) keloidal or nodular lesions arising from sclerodermatous skin with histologic findings of keloid or scleroderma, (2) typical keloids clinically and histologically, arising in normal skin in patients with a family history of keloids. Awareness of these entities is important for proper diagnosis of the cutaneous lesions and for recognizing that the cutaneous findings may be a sign of systemic sclerosis     

Ultraviolet A1 phototherapy for the treatment of localized scleroderma

Ultraviolet (UV)A1 phototherapy is effective for T-cell-mediated skin diseases such as atopic dermatitis and mast cell-mediated skin diseases such as mastocytoma. UVA1 phototherapy is also effective against the sclerotic lesions of systemic sclerosis and morphea. Currently, in Japan, access to UVA1 phototherapy is limited because the UVA1 phototherapy device has not yet been approved. On the basis of our experience, we report three patients with localized scleroderma who responded successfully to UVA1 phototherapy. Efficacy was assessed by histological analysis and elastography. UVA1 successfully ameliorated sclerotic lesions, including morphea, linear scleroderma and morphea lesions in a patient with limited cutaneous systemic sclerosis. No side-effects were observed during UVA1 phototherapy.     

Eosinophilic fasciitis associated with generalized morphea and IgA nephropathy

Eosinophilic fasciitis (EF) is a rare connective tissue disease characterized by increased peripheral blood eosinophils and diffuse fasciitis, generalized morphea (GM) is a subtype of localized scleroderma, and IgA nephropathy is a chronic glomerulonephritis caused by abnormal deposition of IgA in the mesangial area of the glomeruli. We describe a 49‐year‐old male patient with hard skin, cutaneous hyperpigmentation, and proteinuria. The patient had suffered from a long disease course of hard skin, while urine protein was newly detected. Finally, the clinical presentation and physical examination, limb MRI, skin biopsy, and renal biopsy confirmed the diagnosis of eosinophilic fasciitis associated with generalized morphea and IgA nephropathy. This case is the first report of EF associated with GM and IgA nephropathy.     

Giant neglected squamous cell carcinoma of the skin

Nonmelanoma skin cancers (NMSCs) are the most common type of skin tumor, representing about one‐third of all malignancies diagnosed worldwide each year. Cutaneous squamous cell carcinoma (cSCC) is the second most common form of NMSCs and the risk of cSCC invasiveness should be assessed on the basis of tumor size, anatomical location, and histological subtype. Although most cSCCs are early diagnosed and successfully treated, in a small percentage of patients with giant cSCC (maximum diameter >5 cm), metastases may occur; treatment options are limited and not really effective. We report the case of a giant metastatic cSCC that had been neglected for more than 20 years. Radiotherapy or surgery were not feasible and polichemotherapy (cisplatin, 5‐fluorouracil and paclitaxel) was not effective. Therefore, the patient was treated with palliative electrochemotherapy (ECT) achieving a partial reduction of cutaneous metastasis and pain relief but unfortunately the patient died 3 months after the second ECT treatment.     

Palindromic morphea: multiple recurrence of morphea lesions in a case of systemic sclerosis.

We report an unusual scleroderma case. A 45-year-old woman had recurrent morphea lesions over 10 times in 6 years. She had had preceding inactive systemic scleroderma. New morphea lesions developed cyclically on various portions of her body and improved within 2 years. Interestingly, new lesions have developed on once involved skin as well as uninvolved skin. No exacerbation of systemic scleroderma was induced by outbreaks of new morphea lesions. We could not find a similar case in the literature and named it "Palindromic morphea" because of its unique clinical course. D-penicillamine treatment had a limited effect. Minimal oral prednisolone (5 mg/day) completely suppressed the multiple recurrence of the morphea lesions and enhanced improvement of the sclerosis.     

Clinicopathological study of 81 cases of localized and systemic scleroderma

Background Scleroderma is a connective tissue disease that includes localized and systemic forms. Our recent encounter with a morphea case exhibiting prominent perineural inflammation microscopically prompted us to assess the features of all patients diagnosed with morphea/scleroderma at our institution. Objective/methods To describe the clinicopathological features of all patients diagnosed with morphea/scleroderma at American University of Beirut Medical Center (AUB‐MC) between 1999 and 2010, and compare our findings with those published in the literature. Results A total of 81 cases (63 women and 18 men) were identified, of which 73 were localized (morphea) and eight were systemic scleroderma. Clinically, plaque type morphea was the most common variant both in adults and children, and seven (9%) cases of morphea were associated with lichen sclerosis et atrophicus (LSA). Histopathologically, perineural inflammation was observed in 49% of cases, and may serve, in addition to other features including lichen sclerosis‐like changes (observed in exclusively nine cases of morphea), more diffuse dermal and less subcutaneous sclerosis, and intense inflammation, as clues favouring diagnosis of morphea over systemic sclerosis. Conclusion The features of morphea/scleroderma patients in this study are generally comparable to those published in the literature, with few differences. Clinically, plaque type morphea was the most common variant both in adults and children and LSA was a frequent association. Histopathologically, perineural inflammation was commonly observed and may serve in addition to lichen sclerosis‐like changes and intense inflammation as clues favouring diagnosis of morphea over systemic sclerosis.     

Epithelial–mesenchymal transition of the eccrine glands is involved in skin fibrosis in morphea

Morphea is a type of localized scleroderma. It is a skin disease involving the development of fibrosis in the dermis and subcutaneous fat tissue beneath without a visceral lesion, and the cause is still unclear. An involvement of epithelial–mesenchymal transition (EMT) has been reported as a cause of tissue fibrosis, but this was mostly observed in pulmonary and hepatic fibrosis, and the involvement of EMT in a skin disease, morphea, has not been studied . Thus, we analyzed the involvement of EMT in skin fibrosis in morphea patients using pathological techniques. Skin lesions of six morphea patients were analyzed (five female and one male patient). As a control, non‐light‐exposed skin lesions of 11 healthy females were analyzed. Concretely, tissue samples were prepared from these subjects and subjected to immunostaining of transforming growth factor (TGF)‐β1, α‐smooth muscle actin (α‐SMA) and fibronectin, which have been reported to be associated with fibrosis, and Snail1 and E‐cadherin, which are considered to be involved in EMT, and expressions of these were analyzed. In morphea patients, dermal expression of TGF‐β1, α‐SMA and fibronectin, which are involved in fibrosis, was enhanced, and, at the same time, enhanced expression of Snail1 and reduced expression of E‐cadherin, which are involved in EMT, were observed in the dermal eccrine glands. These findings suggested the progression of EMT in the dermal eccrine glands in morphea.     

Topical tacrolimus 0.1% ointment in the treatment of localized scleroderma. An open label clinical and histological study

Localized scleroderma or morphea, although a self‐limited and benign disease, may leave substantial physical and cosmetic deformity necessitating treatment but treatment remains to date unsatisfactory. The aim of our study was to evaluate the efficacy of topical tacrolimus ointment in the treatment of morphea. Thirteen patients with morphea used tacrolimus 0.1% cream b.i.d. without occlusion for 4 months. Patients were followed up for up to a year. A 4‐mm biopsy was taken before starting treatment in seven patients and 4 months after continuous use of tacrolimus 0.1% ointment, next to the previous biopsy site. Masson trichrome and elastica stains were performed to evaluate the distribution of elastic fibers as well as the streptavidin‐biotin horseradish peroxide immunohistochemical method for the detection of CD20/L‐26, CD3, CD8, CD4, CD1a, human leukocyte antigen‐DR and CD25. Four patients had a less than 25% improvement, two patients responded by 50–70% and the remaining seven by more than 70%. Patients with thick, well‐established lesions responded poorly in comparison to others with less thick and more erythematous ones. Patients with mild‐to‐moderate fibrosis histologically were more likely to improve after treatment, while the lymphocytic infiltrate decreased regardless of initial degree before treatment. It was concluded that topical tacrolimus 0.1% cream may be used in patients with morphea, particularly with early inflammatory lesions, even as a first‐line treatment.     

Treatment options for localized scleroderma

Localized scleroderma, or morphea, is a chronic disease that causes a thickening and induration of the skin. For plaque type morphea, the treatments of choice include super-potent corticosteroids and calcipotriol. For the more generalized forms, as well as the linear forms, UVA is currently the best therapeutic modality. Patients with localized scleroderma are managed by both rheumatologists and dermatologists. There is still much therapeutic uncertainty in this disease.     

Low‐dose UVA1 phototherapy for scleroderma: what benefit can we expect?

Background The first reports of the application of ultravioletA₁ (UVA₁) phototherapy for scleroderma go back only to 1995, but since then, several studies have proven its effectiveness in this disease. Objectives To evaluate the effectiveness of low‐dose (35 J/cm²) UVA₁ phototherapy in patients with scleroderma, trying to define the subgroups that benefit most from this treatment. Methods Retrospective analysis of patients diagnosed with clinical and/or histological scleroderma, undergoing low‐dose UVA₁ phototherapy between 2003 and 2010. Results We studied 21 patients (20 women and one man) aged 10–75 years (mean 50). Eighteen with morphea performed a total of 29 treatments, with an average of 33 sessions per treatment per patient, a mean dose of 31 J/cm² per session and an average cumulative dose of 1662 J/cm² (310–4270). The three patients with systemic scleroderma underwent a total of five treatments, with an average of 26 sessions per treatment per patient, a mean dose of 29.5 J/cm² per session and an average cumulative dose of 1160 J/cm² (660–1695). Using the modified Rodnan skin score, in the group of patients with morphea, a marked improvement was found in 77.8% patients and a moderate improvement was found in 11.1% patients. In the systemic scleroderma group, a patient with complete remission of the skin sclerosis is emphasized. Conclusions Our experience allows us to conclude that low‐dose UVA₁ phototherapy is a well tolerated option, with excellent results mainly in patients with morphea. This treatment is a valuable contribution to these patients, given the limited therapeutic options available.     

Connective tissue ulcers

Connective tissue disorders (CTD), which are often also termed collagen vascular diseases, include a number of related inflammatory conditions. Some of these diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (scleroderma), localized scleroderma (morphea variants localized to the skin), Sjogren's syndrome, dermatomyositis, polymyositis, and mixed connective tissue disease. In addition to the systemic manifestations of these diseases, there are a number of cutaneous features that make these conditions recognizable on physical exam. Lower extremity ulcers and digital ulcers are an infrequent but disabling complication of long-standing connective tissue disease. The exact frequency with which these ulcers occur is not known, and the cause of the ulcerations is often multifactorial. Moreover, a challenging component of CTD ulcerations is that there are still no established guidelines for their diagnosis and treatment. The morbidity associated with these ulcerations and their underlying conditions is very substantial. Indeed, these less common but intractable ulcers represent a major medical and economic problem for patients, physicians and nurses, and even well organized multidisciplinary wound healing centers.     

Rate of growth—A novel surrogate marker for high‐risk cutaneous squamous cell carcinoma? A case report and review of the literature

Cutaneous squamous cell carcinoma (cSCC) is one of the most common nonmelanoma skin cancer worldwilde, with a more invasive growth pattern and higher potential to metastatize than basal cell carcinoma. Although several risk factors have been linked to a high metastatic potential of cSCC, no widely accepted classification system for this common subtype of cancer exists. Herein we report an emblematic case of rapidly growing and metastatic cSCC and discuss the rate of growth of the tumour (ROG) as novel prognostic high risk surrogate marker.     

Identification of collagen fibrils in scleroderma skin

Skin from early and late stages of scleroderma has been shown to contain large amounts of thin (30-40 nm diameter) collagen fibrils that may be present in bundles or intermingled with large diameter fibrils (90-120 nm). The nature of these fibrils is unknown. Skin biopsies were obtained from involved areas of nine patients with progressive systemic sclerosis (PSS), one case of generalized morphea, one case of morphea, and six normal controls. Intact skin was analyzed by immunoelectron microscopy (IEM), while extracts were subjected to sodium dodecyl polyacrylamide gel electrophoresis (SDS-PAGE), Western immunoblotting, radioimmunoassay (RIA), and enzyme-linked immunosorbent assay (ELISA). Fine fibrils 20-40 nm in diameter in the mid to lower dermis of scleroderma skin were labeled with antibodies directed against the aminopropeptide (AP) of type III procollagen. Antibodies directed against the AP of type I procollagen labelled fine fibrils in the lower dermis. Larger fibrils (80-120 nm) did not label. pN alpha 1 (III) was found to be present in both normal and scleroderma skin. Extracts of scleroderma skin contained 2.5 times the amount of pN (III) collagen and 3.0 times the amount of fibronectin as did extracts of normal skin. The data indicate that the increase in thin fibrils in scleroderma skin is most likely due to an increase in type III collagen, which retains the AP at its surface.     

“Assessment of chronic sclerodermoid Graft‐versus‐Host Disease patients,using 20MHz high‐frequency ultrasonography and cutometer methods”

The development of an adverse graft‐versus‐host disease (GvHD) is a major complication of stem cell transplantations, which are widely used to cure increasing number of hematologic malignancies. Patients with chronic GvHD are at risk of joint contractures secondary to sclerodermatous skin changes. Several clinical scores or serologic markers have been used to assess skin sclerosis in scleroderma patients. Evaluation of sclerotic skin changes using biometric tools remains to be challenging. The purpose of this study was to illustrate and exemplify ultrasound measurement and measurement of skin elasticity of five chronic sclerodermoid GvHD patients. There is still a substantial lack of studies using objective and non‐invasive methods helpful in assessment of patients with skin involvement of GvHD. Although ultrasound is not the ideal method, it is worth emphasizing that it is still useful, non‐invasive, and repeatable device in monitoring patients suffering from GvHD. It should also be added, that it seems to be advisable to repeat USG examination at an interval of 3 months after the treatment. In addition, skin echogenicity may be a more sensitive parameter than skin thickness in assessment of cGvHD patients.     

Ulcers caused by bullous morphea treated with tissue-engineered skin

Bullous morphea is an uncommon form of localized scleroderma. The exact pathogenesis is unknown and treatment of the accompanying ulcers is problematic. We report a patient with bullous morphea with long-standing ulcers whom we successfully treated with the tissue-engineered skin Apligraf (Organogenesis Inc., Canton, MA). The patient experienced rapid improvement in granulation tissue and the ulcers healed 4 months after a single application. The rationale for the use of Apligraf is based on experience with patients with venous ulcers who have surrounding peri-ulcer fibrosis. This condition, termed lipodermatosclerosis, has been reported as a poor prognostic factor for healing, yet many ulcers associated with lipodermatosclerosis may respond to treatment with tissue-engineered skin. Taken in concert, these results suggest a role for tissue- engineered skin in the treatment of chronic wounds with surrounding fibrosis.     

Systematic review of the prevalence of nodal metastases and the prognostic utility of sentinel lymph node biopsy in cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and its incidence is rising. The prognosis is mostly good but patients with high‐risk cSCC have a greater risk of recurrence and death. The aim of the present study was to conduct a systematic review analyzing the prevalence, predictors and prognostic utility of sentinel lymph node (SLN) involvement in cSCC. We performed a published work search in Ovid MEDLINE and reviewed the reference lists of selected studies. Based on the 23 studies included in the systematic review, the proportion of patients with cSCC and positive SLN biopsy findings was 8% (95% confidence interval, 5.1–10.8%; I²= 44.51%). We found no studies reporting on predictors of SLN involvement in cSCC or on the prognostic utility of this finding following adjustment for confounders. The rate of positive SLN in cSCC is less than previously reported. Criteria for recommending SLN biopsy as a staging tool for cSCC vary considerably from study to study, and none of the studies were large enough to reliably identify predictors of SLN positivity. No randomized controlled trials have yet analyzed whether SLN biopsy may improve the prognosis of cSCC. More studies are required on the prognostic value of SLN positivity and the associated risk factors in cSCC.     

Lower Lip Squamous Cell Carcinoma in Disabling Pansclerotic Morphea of Childhood

Abstract:   Disabling pansclerotic morphea of childhood (DPMC) is an aggressive form of cutaneous scleroderma that involves all layers of the skin, extending through the dermis and subcutaneous tissues to involve muscle, tendon, and even bone. As DPMC is extremely rare, its association with skin squamous cell carcinoma (SCC) is rarer still. To our knowledge there are only two cases of SCC in patients with DPMC that developed within areas of chronic skin ulceration. We report the first case of lower lip squamous cell carcinoma arising in a young woman with DPMC and discuss the carcinogenic pathway that may have led to its occurrence.     

Expression of claudin‐11 by tumor cells in cutaneous squamous cell carcinoma is dependent on the activity of p38δ

The incidence of cutaneous squamous cell carcinoma (cSCC) is rapidly increasing, and the prognosis of patients with metastatic disease is poor. There is an emerging need to identify molecular markers for predicting aggressive behaviour of cSCC. Here, we have examined the role of tight junction (TJ) components in the progression of cSCC. The expression pattern of mRNAs for TJ components was determined with RNA sequencing and oligonucleotide array‐based expression analysis from cSCC cell lines (n=8) and normal human epidermal keratinocytes (NHEK, n=5). The expression of CLDN11 was specifically elevated in primary cSCC cell lines (n=5), but low or absent in metastatic cSCC cell lines (n=3) and NHEKs. Claudin‐11 was detected in cell‐cell contacts of primary cSCC cells in culture by indirect immunofluorescence analysis. Analysis of a large panel of tissue samples from sporadic UV‐induced cSCC (n=65), cSCC in situ (n=56), actinic keratoses (n=31), seborrhoeic keratoses (n=7) and normal skin (n=16) by immunohistochemistry showed specific staining for claudin‐11 in intercellular junctions of keratinizing tumor cells in well and moderately differentiated cSCCs, whereas no staining for claudin‐11 was detected in poorly differentiated tumors. The expression of claudin‐11 in cSCC cells was dependent on the activity of p38δ MAPK and knock‐down of claudin‐11 enhanced cSCC cell invasion. These findings provide evidence for the role of claudin‐11 in regulation of cSCC invasion and suggest loss of claudin‐11 expression in tumor cells as a biomarker for advanced stage of cSCC.