Clinical Impact of Skin Lesions in Mastocytosis: A Multicenter Study of the European Competence Network on Mastocytosis.

Mastocytosis is a rare neoplasm characterized by the expansion and accumulation of mast cells in various organ systems. Systemic mastocytosis (SM) may or may not present with cutaneous lesions. To examine the frequency and clinical impact of cutaneous involvement, data on 1,510 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis were analyzed. Cutaneous involvement was found in 1,195 of 1,510 patients (79.1%). Of these, 286 had cutaneous mastocytosis, and 721 had SM with skin involvement. Adult patients with skin involvement who did not have a bone marrow examination (n = 188) were defined as having mastocytosis in the skin. In 315 patients, SM without skin involvement was found. The percentage of cases with cutaneous involvement was higher in indolent SM (100%) and smoldering SM (87.9%) compared to aggressive SM (46.8%) or mast cell leukemia (38.5%). After a median follow-up of 5.6 years, no patient with cutaneous mastocytosis had died, but 2.6% of the patients with mastocytosis in the skin, 5.7% of the patients with SM with skin involvement, and 28.95% of the patients with SM without skin involvement had died. Overall survival was longer in patients with skin involvement (cutaneous mastocytosis and/or mastocytosis in the skin and/or SM with skin involvement) than in patients with SM without skin involvement (P < 0.0001). These data argue for a thorough examination of both the skin and bone marrow in adult patients with mastocytosis.

Scoring the Risk of Having Systemic Mastocytosis in Adult Patients with Mastocytosis in the Skin.

BACKGROUND: Mastocytosis in adults often presents with skin lesions. A bone marrow biopsy is necessary to confirm or exclude the presence of systemic mastocytosis (SM) in these cases. When a bone marrow biopsy is not performed, the provisional diagnosis is mastocytosis in the skin (MIS). No generally accepted scoring system has been established to estimate the risk of SM in these patients. OBJECTIVE: To develop a risk score to predict SM in adults with MIS. METHODS: We examined 1145 patients with MIS from the European Competence Network on Mastocytosis Registry who underwent a bone marrow biopsy. A total of 944 patients had SM and 201 patients had cutaneous mastocytosis; 63.7% were female, and 36.3% were male. Median age was 44 ± 13.3 years. The median serum tryptase level amounted to 29.3 ± 81.9 ng/mL. We established a multivariate regression model using the whole population of patients as a training and validation set (bootstrapping). A risk score was developed and validated with receiver-operating curves. RESULTS: In the multivariate model, the tryptase level (P < .001), constitutional/cardiovascular symptoms (P = .014), and bone symptoms/osteoporosis (P < .001) were independent predictors of SM (P < .001; sensitivity, 90.7%; specificity, 69.1%). A 6-point risk score was established (risk, 10.7%-98.0%) and validated. CONCLUSIONS: Using a large data set of the European Competence Network on Mastocytosis Registry, we created a risk score to predict the presence of SM in patients with MIS. Although the score will need further validation in independent cohorts, our score seems to discriminate safely between patients with SM and with pure cutaneous mastocytosis.

Prognostic impact of eosinophils in mastocytosis: analysis of 2350 patients collected in the ECNM Registry.

Systemic mastocytosis (SM) is frequently associated with eosinophilia. To examine its prevalence and clinical impact in all WHO classification-based subcategories, we analyzed eosinophil counts in 2350 mastocytosis patients using the dataset of the European Competence Network on Mastocytosis. Ninety percent of patients had normal eosinophil counts, 6.8% mild eosinophilia (0.5-1.5 × 109/l), and 3.1% hypereosinophilia (HE; >1.5 × 109/l). Eosinophilia/HE were mainly present in patients with advanced SM (17%/19%), and only rarely recorded in patients with indolent and smoldering SM (5%/1%), and some patients with cutaneous mastocytosis. The eosinophil count correlated with organomegaly, dysmyelopoiesis, and the WHO classification, but not with mediator-related symptoms or allergy. Eosinophilia at diagnosis had a strong prognostic impact (p < 0.0001) on overall survival (OS) and progression-free survival (PFS), with a 10-year OS of 19% for patients with HE, 70% for those with mild eosinophilia, and 88% for patients with normal eosinophil counts. In 89% of patients with follow-up data (n = 1430, censored at start of cytoreductive therapy), eosinophils remained stable. In those with changing eosinophil counts (increase/decrease or mixed pattern), OS and PFS were inferior compared with patients with stable eosinophil counts. In conclusion, eosinophilia and HE are more prevalent in advanced SM and are predictors of a worse outcome.

The Data Registry of the European Competence Network on Mastocytosis (ECNM): Set Up, Projects, and Perspectives.

Mastocytosis is a unique hematologic neoplasm with complex biology and pathology and a variable clinical course. The disease can essentially be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In adults, SM is diagnosed in most cases and manifests as either indolent or advanced disease. Patients with advanced SM have an unfavorable prognosis with reduced survival. However, so far, little is known about the prevalence of various categories of SM and about prognostic factors. In an attempt to learn more about the behavior and evolution of various forms of CM and SM, the European Competence Network on Mastocytosis (ECNM) initiated a mastocytosis registry in 2012. In this article, the set up and start phase of this registry are described. Until 2018, more than 3000 patients from 12 countries and 25 centers have been enrolled. In a majority of all patients, robust follow-up data and relevant clinical end points are available. Using this data set, a series of registry projects have been launched, with the aim to validate previously identified diagnostic and prognostic variables and to identify new disease-related and patient-related parameters in various forms of mastocytosis. Moreover, the core data set of the registry will be useful to establish multiparametric scoring systems through which prognostication and individualized management of patients with mastocytosis should improve in the foreseeable future.

Co-culture of human fibroblasts and Borrelia burgdorferi enhances collagen and growth factor mRNA.

Skin fibrosis has been reported in Borrelia burgdorferi infection in Europe, but has been questioned by several authors. The objective of the present study was to examine the interaction of skin fibroblasts with B. burgdorferi sensu stricto B31 (BB) and B. afzelii (BA) in vitro by electron microscopy. We also determined the expression of collagen type I, TGF-ß, FGF-1, calreticulin (CALR), decorin (DCN), and PDGF-α at the mRNA level in Borrelia/fibroblast co-cultures. Intact Borrelia attach to and transmigrate fibroblasts, and undergo cystic transformation outside the fibroblasts. Fibroblasts preserve their vitality and express a prominent granular endoplasmic reticulum, suggesting activated protein synthesis. On two different semi-quantitative real-time PCR assays, BB- and BA/fibroblast co-cultures showed a significant induction of type I collagen mRNA after 2 days compared to fibroblasts (fourfold for BA and 1.8-fold for BB; p < 0.02). In addition, there was a significant upregulation of mRNA expression of TGF-ß, CALR, PDGF-α, and DCN in BA and BB co-cultures compared to control fibroblasts in monolayer cultures after 2 days (p < 0.01). The BA/fibroblast co-culture induced a considerably greater upregulation of collagen and growth factor mRNA compared to BB/fibroblast co-culture. In contrast, a significant down-regulation of FGF-1 (20-fold for BA and 4.5-fold for BB) mRNA expression was detected in co-cultures compared to controls (p < 0.01). The results of the study support the hypothesis that BB sensu lato, and BA in particular, enhances collagen mRNA expression and can stimulate growth factors responsible for increased collagen production.

Changes in pulmonary exercise haemodynamics in scleroderma: a 4-year prospective study.

Pulmonary arterial hypertension (PAH) is a feared complication of systemic sclerosis. In this prospective cohort study, we monitored the changes in resting and exercise pulmonary haemodynamics of scleroderma patients without initial PAH over a mean follow-up period of ∼4 years.All patients underwent exercise echocardiography and cardiopulmonary exercise testing at baseline and follow-up. A subgroup underwent exercise right heart catheter (RHC) investigations. The primary end-point was the echocardiographic systolic pulmonary arterial pressure at 50 W exercise (sPAP50).We included 99 patients, of whom 58 had a complete dataset. Three out of 99 patients developed RHC-confirmed PAH (0.75 cases per 100 patient-years). sPAP50 increased (p<0.001) and peak oxygen uptake (secondary end-point) decreased significantly (p=0.001) during follow-up, but there was no significant change in resting sPAP (p=0.38). In the RHC subgroup (n=28), mean (m)PAP and pulmonary vascular resistance at 50 W increased significantly (p=0.02 and p=0.002, respectively), but resting mPAP was unchanged.Scleroderma patients without PAH develop a mild but significant deterioration of pulmonary exercise haemodynamics and exercise capacity over a 4-year follow-up period, indicating a progression of pulmonary vascular disease. The manifestation rate of RHC-confirmed PAH was 0.75 cases per 100 patient-years.

Cyclosporine Reduces Sclerosis in Morphea: A Retrospective Study in 12 Patients and a Literature Review.

BACKGROUND: The treatment of severe morphea is challenging, and treatment experience concerning the use of immunosuppressive agents for this condition is limited. OBJECTIVE: The purpose of this study is to analyze the use of cyclosporine, its tolerability, and its effect on skin sclerosis. MATERIALS AND METHODS: Patients with severe morphea who underwent treatment with cyclosporine were studied retrospectively. RESULTS: Five of 12 patients with morphea showed complete remission and 6 patients had partial remission at the end of therapy (9-46 months, median 14) under a median cyclosporine dose of 2.4 mg/kg. The mean affected body surface area fell from 50% (2-80, median 65) to 17% (0-40, median 18). Side effects were hypertension, elevated transaminases, cholesterol, and weight gain. CONCLUSION: Cyclosporine can be effective in morphea. The side effects were reversible. However, the duration of treatment with cyclosporine is limited because of its potential permanent side effects. Prospective placebo-controlled studies are needed to establish the superiority of cyclosporine over other immunosuppressive drugs in this setting.

Spiritual well-being and coping in scleroderma, lupus erythematosus, and melanoma.

BACKGROUND AND OBJECTIVES: Religious/spiritual (R-S) well-being is associated with greater vitality and lower depression scores. In this study, we investigated strategies for coping with disease and the role of religiosity/spirituality with respect to improving subjective well-being. PATIENTS AND METHODS: One hundred and forty-nine patients (107 women), 44 of whom with systemic sclerosis (SSc), 48 with lupus erythematosus (LE), and 57 with stage I or II malignant melanoma (MM) were surveyed using a self-designed questionnaire, which addressed subjective well-being and disease-related circumstances, as well as the Multidimensional Inventory for Religious/Spiritual Well-Being (MI-RSWB). RESULTS: At the time of diagnosis, disease burden is greater in LE patients than in patients with SSc and MM. Only after several years are SSc and LE patients able to accept their disease. Compared with healthy individuals, the overall score of R-S well-being is significantly lower in LE patients. In LE, photosensitivity and joint pain are inversely correlated with the ability to forgive. SSc patients with facial lesions and pulmonary involvement show greater religiosity. MM patients display significantly higher values for transcendental hope. CONCLUSION: Talks about the disease and psychological support are the most important needs of patients with SSc, LE, and MM. At present, programs aimed at improving R-S coping skills do not seem to play a significant role, but could be an important resource that should be addressed in the future.

Spirituelles Wohlbefinden und Coping bei Sklerodermie, Lupus erythematodes und malignem Melanom.

HINTERGRUND UND ZIELE: Religiös-spirituelles Wohlbefinden ist verbunden mit höherer Vitalität und verminderter Depressionsneigung. In unserer Studie untersuchten wir die Strategien zur Krankheitsbewältigung und die Rolle von Religiosität-Spiritualität (R-S) zur Verbesserung des subjektiven Wohlbefindens. PATIENTEN UND METHODIK: 149 Patienten (107 Frauen), 44 mit systemischer Sklerodermie (SKL), 48 mit Lupus erythematodes (LE) und 57 mit malignem Melanom (MM), Stadium I-II, wurden mittels eines selbstentwickelten Fragebogens zum subjektiven Wohlbefinden, zu den mit der Erkrankung einhergehenden Umständen sowie mit dem Multidimensionalen Inventar (MI-RSB) zu R-S befragt. ERGEBNISSE: LE-Patienten sind zum Zeitpunkt der Diagnosestellung stärker belastet als SKL- und MM-Patienten. SKL- und LE-Patienten können erst nach Jahren die Erkrankung akzeptieren. Der Gesamtscore des religiös-spirituellen Befindens liegt bei LE-Patienten signifikant unter dem Wert der Normalbevölkerung. Fotosensitivität und Gelenksschmerzen sind bei LE-Patienten negativ assoziiert mit der Fähigkeit Vergeben zu können. SKL-Patienten mit Gesichtsveränderungen und Lungenbeteiligung zeigen höhere allgemeine Religiosität. MM-Patienten haben höhere Werte für transzendente Hoffnung. SCHLUSSFOLGERUNGEN: Vorträge über die Krankheit und psychologische Betreuung sind die wichtigsten Bedürfnisse von Patienten mit SKL, LE und MM an ihre Betreuer. Religiös-spirituelle Angebote zur Krankheitsverarbeitung scheinen derzeit eine untergeordnete Rolle zu spielen, könnten aber eine wichtige Ressource sein, der man in Zukunft mehr Aufmerksamkeit schenken sollte.

Disease spectrum in patients with elevated serum tryptase levels.

BACKGROUND: Elevated serum tryptase levels can be a sign of mastocytosis, which is a rare disease associated with systemic and/or skin manifestations. OBJECTIVE: To investigate patients with elevated tryptase levels in regard to their underlying diseases, and to determine whether increased tryptase can be used as a diagnostic marker for underlying mastocytosis. METHODS: In a retrospective study the data of 96 patients with serum tryptase levels higher than 15 µg/L were systematically analysed. In 48 patients control investigations for baseline tryptase were performed. RESULTS: Fifty-three of the 96 patients had tryptase levels ≥20 µg/L. A mere 16% of the 96 patients suffered from mastocytosis and had the highest tryptase levels (P < 0.001). The remaining patients had anaphylaxis (36%), urticaria and angioedema (26%), local reactions to insect bites (4%), drug reactions (3%), or miscellaneous diagnoses (15%). Only 16 of these had acute symptoms at tryptase investigation. In all, 48 patients had a follow up; in 7/48 patients with acute symptoms normal tryptase levels were seen at control investigations, but 41/48 (85%) patients showed continuously elevated tryptase levels >15 µg/L and in 30 patients (62%) even values >20 µg/L; 11 of these patients had anaphylaxis, five urticaria, five other diagnoses and nine patients mastocytosis. CONCLUSION: More than 50% of patients with non-mastocytosis such as urticaria and angioedema, drug or anaphylactic reactions repeatedly had tryptase levels higher than 20 µg/L. Since baseline tryptase >20 µg/L is a minor criterion for mastocytosis, these patients should be inspected for skin lesions of mastocytosis and receive a diagnostic body work-up for systemic mastocytosis including a bone marrow biopsy.

Impaired quality of life in patients with systemic sclerosis compared to the general population and chronic dermatoses.

BACKGROUND: Systemic sclerosis (SSc) is a rare and potentially life threatening autoimmune disorder. The burden of disease compared to other dermatoses is unknown. The purpose of this study was to assess both the quality of life in patients with SSc and the variables that are associated with poor quality of life. Forty-one patients with systemic sclerosis (29 limited, 2 diffuse, 10 undifferentiated forms) were assessed with respect to their health status and compared to published data for the normal population, SSc patients from other studies, and patients with chronic skin diseases. RESULTS: For the most part, our SSc patients had better outcomes in all 8 dimensions of the SF-36 than SSc patients from other studies, and poorer scores than the healthy population and those with occupational contact dermatitis, ichthyosis, non-melanoma skin cancer, contact dermatitis, atopic eczema, chronic nail disease, vitiligo, health care workers with work-related disease, and those with other chronic skin diseases, but significantly better scores for mental health than those with nail disease, vitiligo, and health-care workers. Patients with atopic dermatitis, psoriasis and pemphigus had significantly poorer mean scores in social function and mental health than SSc patients. Patients with pemphigus were also significantly impaired in their physical and emotional roles. Patients with systemic lupus erythematosus (SLE) had the significantly poorest mean scores for QoL in all 8 domains except bodily pain and emotional role. CONCLUSION: Besides SLE, SSc is one of the most severe chronic dermatologic diseases in terms of reduced QoL. Since SSc cannot be cured, treatment strategies should include therapeutic interventions such as psychotherapy, social support, physiotherapy, and spiritual care. Their beneficial effects could be studied in future.

Guidelines and diagnostic algorithm for patients with suspected systemic mastocytosis: a proposal of the Austrian competence network (AUCNM).

Systemic mastocytosis (SM) is a hematopoietic neoplasm characterized by pathologic expansion of tissue mast cells in one or more extracutaneous organs. In most children and most adult patients, skin involvement is found. Childhood patients frequently suffer from cutaneous mastocytosis without systemic involvement, whereas most adult patients are diagnosed as suffering from SM. In a smaller subset of patients, SM without skin lesions develops which is a diagnostic challenge. In the current article, a diagnostic algorithm for patients with suspected SM is proposed. In adult patients with skin lesions and histologically confirmed mastocytosis in the skin (MIS), a bone marrow biopsy is recommended regardless of the serum tryptase level. In adult patients without skin lesions who are suffering from typical mediator-related symptoms, the basal serum tryptase level is an important diagnostic parameter. In those with slightly elevated tryptase (15-30 ng/ml), additional non-invasive investigations, including a KIT mutation analysis of peripheral blood cells and sonographic analysis, is performed. In adult patients in whom i) KIT D816V is detected or/and ii) the basal serum tryptase level is clearly elevated (> 30 ng/ml) or/and iii) other clinical or laboratory features are suggesting the presence of occult mastocytosis, a bone marrow biopsy should be performed. In the absence of KIT D816V and other indications of mastocytosis, no bone marrow investigation is required, but the patient's course and the serum tryptase levels are examined in the follow-up.

Pulmonary arterial hypertension therapy may be safe and effective in patients with systemic sclerosis and borderline pulmonary artery pressure.

OBJECTIVE: Borderline pulmonary arterial hypertension (PAH), characterized by a marked exercise-induced increase in pulmonary artery pressure (PAP) with normal resting values, may precede overt PAH in systemic sclerosis (SSc). We undertook the present study to investigate whether PAH treatment is safe in these patients and might attenuate hemodynamic progression. METHODS: SSc patients with borderline PAH underwent right heart catheterization at baseline, after a 12-month observation period, and subsequently after 6 months of bosentan therapy. Changes in mean PAP at 50W during the observation period versus during therapy were compared. RESULTS: Ten patients completed the study. Mean PAP at rest, at 50W, and during maximal exercise increased significantly during the observation period (mean ± SD increases of 2.5 ± 3.0 mm Hg [P = 0.03], 4.0 ± 2.9 mm Hg [P = 0.002], and 6.8 ± 4.1 mm Hg [P = 0.0005], respectively) and tended to decrease during the treatment period (decreases of 2.5 ± 3.9 mm Hg [P = 0.07], 1.5 ± 4.5 mm Hg [P = 0.32], and 1.8 ± 7.0 mm Hg [P = 0.43], respectively). The changes during the observation period versus the therapy period were significantly different (P = 0.03 at rest, P = 0.01 at 50W [primary end point], and P = 0.02 during maximal exercise). The changes in resting pulmonary vascular resistance were also significantly different during the observation period (increase of 8 ± 25 dynes · seconds · cm(-5) ) versus during the therapy period (decrease of 45 ± 22 dynes · seconds · cm(-5) ) (P < 0.0005). Changes in resting pulmonary arterial wedge pressure were not significantly different between the observation period and the treatment period, despite the significant increase during the observation period (2.6 ± 2.5 mm Hg [P = 0.01]). No relevant adverse effects were reported. CONCLUSION: In SSc patients with borderline abnormal pulmonary hemodynamics, resting and exercise PAP may increase significantly within 1 year of observation. Bosentan might be safe and effective to attenuate these changes. Randomized controlled trials are warranted to confirm the exploratory findings of this hypothesis-generating pilot study.

Calcinosis cutis: part I. Diagnostic pathway.

Calcinosis cutis is characterized by the deposition of insoluble calcium salts in the skin and subcutaneous tissue. The syndrome is separated into five subtypes: dystrophic calcification, metastatic calcification, idiopathic calcification, iatrogenic calcification, and calciphylaxis. Dystrophic calcification appears as a result of local tissue damage with normal calcium and phosphate levels in serum. Metastatic calcification is characterized by an abnormal calcium and/or phosphate metabolism, leading to the precipitation of calcium in cutaneous and subcutaneous tissue. Idiopathic calcification occurs without any underlying tissue damage or metabolic disorder. Skin calcification in iatrogenic calcinosis cutis is a side effect of therapy. Calciphylaxis presents with small vessel calcification mainly affecting blood vessels of the dermis or subcutaneous fat. Disturbances in calcium and phosphate metabolism and hyperparathyroidism can be observed.

Calcinosis cutis: part II. Treatment options.

Because calcinosis cutis is a rare syndrome, there is a notable lack of controlled clinical trials on its treatment. The efficacy of calcinosis treatment has only been reported in single cases or small case series. No treatment has been generally accepted as standard therapy, although various treatments have been reported to be beneficial, including warfarin, bisphosphonates, minocycline, ceftriaxone, diltiazem, aluminium hydroxide, probenecid, intralesional corticosteroids, intravenous immunoglobulin, curettage, surgical excision, carbon dioxide laser, and extracorporeal shock wave lithotripsy.

Pseudolymphomatous tumid lupus erythematosus of the oral mucosa.

Oral lesions are frequent complications of systemic lupus erythematosus, but only ulceration is included in the 1982 American College of Rheumatology revised criteria. Because the lack of a uniform classification, a range of ulcerative and keratotic lesions are typically described. In this report we describe a unique progressive irregularly cobblestoned and vegetating plaque of the oral mucosa with clinical and histological features mimicking a cutaneous lymphoma. Despite the papillomatous and extensive nature of the lesions and the dense lymphoid infiltrate with follicle formation suggesting a malignant lymphoproliferative process, the slow progression coupled with a mixed cell infiltrate and polyclonality supported a diagnosis of pseudolymphoma. Recognition of this entity is important to prevent diagnosing them as a malignant lymphoma. As well as with the other mucosal lesions in lupus erythematosus, this pseudolymphomatous variant should be added to the disease spectrum.