An open, multicentre, randomized clinical study in patients with bullous pemphigoid comparing methylprednisolone and azathioprine with methylprednisolone and dapsone.

BACKGROUND: Current treatment of bullous pemphigoid (BP) is based on the long-term use of topical and/or systemic corticosteroids, which are associated with a high rate of adverse events and increased mortality. OBJECTIVES: To study the corticosteroid-sparing potential of azathioprine and dapsone. METHODS: This was a prospective, multicentre, randomized, nonblinded clinical trial that compared the efficacy and safety of two parallel groups of patients with BP treated with oral methylprednisolone 0·5 mg kg-1 per day in combination with either azathioprine 1·5-2·5 mg kg-1 per day or dapsone 1·5 mg kg-1 per day. Nine German and Austrian departments of dermatology included 54 patients based on clinical lesions, positive direct immunofluorescence (IF) microscopy and detection of serum autoantibodies by indirect IF microscopy, immunoblotting or enzyme-linked immunosorbent assay. The primary end point was the time until complete tapering of methylprednisolone, and the most important secondary end point was the cumulative corticosteroid dose. RESULTS: In eight patients (five azathioprine, three dapsone), methylprednisolone could be discontinued after a median time of 251 days in the azathioprine group and 81 days in the dapsone group. The median cumulative corticosteroid dose was 2·65 g for azathioprine compared with 1·92 g for dapsone (P = 0·06). The median numbers of days when corticosteroids were applied were 148 and 51, respectively (P = 0·24). No significant difference in the number of adverse events was seen between the treatment arms. Four patients (8%) died within the observation period of 12 months. CONCLUSIONS: Due to the lower than intended number of patients, the results of the primary and secondary end points were not or only barely significant. Dapsone appeared to have a moderately higher corticosteroid-sparing potential than azathioprine. The combination regimen of either drug with oral methylprednisolone is associated with a relatively low 1-year mortality in this vulnerable patient population.

S2k guideline for treatment of cutaneous lupus erythematosus - guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV).

Cutaneous lupus erythematosus (CLE) is a rare inflammatory autoimmune disease with heterogeneous clinical manifestations. To date, no therapeutic agents have been licensed specifically for patients with this disease entity, and topical and systemic drugs are mostly used 'off-label'. The aim of the present guideline was to achieve a broad consensus on treatment strategies for patients with CLE by a European subcommittee, guided by the European Dermatology Forum (EDF) and supported by the European Academy of Dermatology and Venereology (EADV). In total, 16 European participants were included in this project and agreed on all recommendations. Topical corticosteroids remain the mainstay of treatment for localized CLE, and further topical agents, such as calcineurin inhibitors, are listed as alternative first-line or second-line topical therapeutic option. Antimalarials are recommended as first-line and long-term systemic treatment in all CLE patients with severe and/or widespread skin lesions, particularly in patients with a high risk of scarring and/or the development of systemic disease. In addition to antimalarials, systemic corticosteroids are recommended as first-line treatment in highly active and/or severe CLE. Second- and third-line systemic treatments include methotrexate, retinoids, dapsone and mycophenolate mofetil or mycophenolate acid, respectively. Thalidomide should only be used in selected therapy-refractory CLE patients, preferably in addition to antimalarials. Several new therapeutic options, such as B-cell- or interferon α-targeted agents, need to be further evaluated in clinical trials to assess their efficacy and safety in the treatment of patients with CLE.

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.

Anaphylaxis with clonal mast cells in normal looking skin - a new entity?

BACKGROUND: Patients with elevated basal tryptase (sBT) >15 µg/l and anaphylaxis may have an underlying mastocytosis. A monoclonal mast cell activation syndrome with aberrant mast cells (MC) at extracutaneous sites has been described in patients with severe hypotension or anaphylaxis. METHODS: As MC in patients with elevated sBT might be altered in the skin as well, we studied MC in normal neck skin in anaphylaxis and urticaria patients with elevated sBT. RESULTS: A mean of 93.1 (SD 19.1) MC/mm² was counted in normal neck skin in 14 patients with anaphylaxis, 84.0 (SD 13.6) in seven patients with urticaria, 142.0 (SD 24.0) in two patients with eczema, 124.4 (SD 43.2) in five patients with systemic mastocytosis (SM) in comparison with autopsy skin (39.1 MC/mm², SD 12.4). In five of 14 (35.7%) of the anaphylaxis and three of five (60%) SM patients more than 25% of MC were spindle shaped and expressed CD25 antigen. CONCLUSIONS: We could show for the first time that the normal skin can harbour clonal MC in anaphylaxis patients. Analogous to the criteria for mastocytosis, we suggest a skin score criteria including an elevated number of MC, spindle shape, CD25 expression, c-Kit mutation and sBT values >20 µg/l. In patients with anaphylaxis and elevated sBT, skin should be biopsied and, as with the approach for mastocytosis diagnosis in the bone marrow, MC should be analysed for their number, clonality and c-Kit mutation. This approach should be confirmed in further studies. Patients with aberrant skin MC should be handled as mastocytosis patients.

Clonal mast cell proliferation in pruriginous skin in hypereosinophilic syndrome.

BACKGROUND: Hypereosinophilic syndrome (HES) is defined as a high eosinophilic granulocyte count in peripheral blood and other tissues. It can be associated with clonal and non-clonal haematological neoplastic diseases. METHODS: Here we present a patient with a 27-year history of pruritus, urticarial lesions, recurrent diarrhoea, depression and a monoclonal gammopathy in the setting of HES. RESULTS: The patient presented with erythemas, disseminated plaques, papules and scaling. Eosinophils continuously increased from 14% in 2002 to 65% in 2011. Tryptase levels were >20 µg/l. Skin biopsies were unspecific. In the bone marrow biopsy 30% of eosinophilic differentiated precursors and 10% plasma cells were noticed. Skin and bone marrow initially not indicative for mast cell proliferation were investigated for clonal mast cell proliferation. By immunostaining, single tryptase-, CD117c- and CD25-positive mast cells were detected not only in bone marrow, but also in the skin. Molecular investigations revealed a D816V exon 17 mutation of the c-KIT gene in bone marrow and skin biopsies. CONCLUSION: In this patient HES was associated with high tryptase levels with 2 underlying clonal cell populations - IgGκ-positive plasma cells and single clonal mast cells with a high percentage of eosinophils in the bone marrow with symptoms of a clonal mast cell activation syndrome. Because of 3 minor criteria the patient finally fulfilled the criteria for systemic mastocytosis (according to the WHO). Patients with high tryptase levels and symptoms of mast cell activation syndrome should be investigated for clonal mast cell disease even in the absence of increased mast cells in the skin and bone marrow.

CXCL13 chemokine in pediatric and adult neuroborreliosis.

OBJECTIVES: Diagnosis of Lyme neuroborreliosis (NB) depends on the proof of intrathecal antibody production against Borrelia burgdorferi. CXCL13 has been seen to be elevated early in NB, before antibody production has started. In this study, we determined the diagnostic role of the CXCL13 chemokine in cerebrospinal fluid (CSF) and serum for the first time in pediatric NB patients as well as in adults, compared to controls and blood donors (BD). MATERIAL AND METHODS: CXCL13 levels were measured in CSF and serum of 33 children and 42 adult patients. Serum CXCL13 was measured in 300 BD. RESULTS: CSF CXCL13 levels were significantly elevated in definite and probable acute NB in children and adults compared to seropositive and seronegative neurological controls (P < 0.001). Serum CXCL13 levels showed great fluctuations and were not significantly elevated in NB patients. CONCLUSIONS: Our study suggests that CSF CXCL13 can be used as a diagnostic marker for NB in children as well. In contrast, CXCL13 serum levels show great variance even in the healthy population and are not indicative of active NB.

Epidemiologic, socioeconomic and psychosocial aspects in lupus erythematosus.

Epidemiologic, socioeconomic, and psychosocial factors play an important role in health care and handling of patients with the various clinical forms of lupus erythematosus (LE). Patients with LE are mostly young women; adolescents and some ethnic groups are especially prone to a severe course of disease. The unpredictable and fluctuating flares of disease, the need for longterm treatment, and the side effects and damage caused by the disease itself severely reduce quality of life. Problems arise, involving family members, adherence to medical advice and therapy, communication and self management. Socioeconomically, patients are often unable to take regular employment and to pay for health insurance. Stress factors that arise have a negative impact on the course of disease, increasing both fatigue and the basic burden of illness. Healthcare professionals must pay careful attention to all these items, as they attempt to treat flares, minimize drug side effects, provide pain relief, arrange communication and exercise programs along with behavioral and psychosocial interventions in multidisciplinary cooperation, and also involve and support family members.

[Lupus erythematosus. Wide range of symptoms through clinical variation, associated diseases and imitators]. / Lupus erythematodes. Symptomenvielfalt durch klinische Variabilitäten, Koexistenzen und Imitatoren.

The typical clinical forms of cutaneous lupus erythematosus (LE) are the butterfly rash, acute, subacute and chronic cutaneous lupus, intermediate lupus (lupus tumidus), chilblain- and bullous lupus, lupus profundus, and ulcerating lesions on the mucous membrane. Besides the typical lupus forms, nonspecific skin lesions are also observed such as dermal mucinosis, acneiform skin lesions, different variants of livedo, necrotizing vasculitis with ulcers, purpura, urticaria vasculitis, neutrophilic dermatosis, hyperpigmentation, hair and nail changes as well as overlap syndromes with erythema multiforme, scleroderma, Sjögren syndrome, Raynaud phenomenon, lichen planus, bullous pemphigoid und psoriasis. There are lupus imitators which create differential diagnostic challenges, such as infections with atypical mycobacteria or subcutaneous T-cell lymphoma both of which are similar to lupus profundus. All these skin lesions can present as maximal pathological findings seen in lupus or be caused by a variety of pathological laboratory findings such as the anti-phospholipid antibodies or a deficiency of complement factors. In the latter situation severe lupus often with complications can be expected.

Large Variability of Frequency and Type of Physical Therapy in Patients in the German Network for Systemic Sclerosis.

OBJECTIVE: To determine the type and frequency of physical therapy (PT) prescribed by physicians for patients in the registry of the German Network for Systemic Sclerosis. METHODS: The data for 4,252 patients were analyzed using descriptive statistics, chi-square tests, and odds ratios (ORs). RESULTS: Overall, 37.4% of patients (1,590 of 4,252) received PT at the end of a yearly follow-up. The most frequently used type of PT was lymphatic drainage (n = 1,061, 36.8%), followed by exercise therapy (n = 1,047, 36.3%) and heat therapy (n = 689, 23.9%). More than three-fourths of treated patients (82%) received 1 or 2 different forms of PT simultaneously. The prescription of PT was associated with the extent of skin fibrosis as measured by the modified Rodnan skin thickness score (<10 [41.8% of patients], 11-20 [55.8% of patients], and >21 [63.9% of patients]; P < 0.001). Patients with musculoskeletal involvement (e.g., arthritis, muscle weakness, joint contractures, tendon friction rubs) had a higher chance of receiving PT than patients without these symptoms, with corresponding ORs ranging from 1.96 (95% confidence interval [95% CI] 1.69-2.28) for joint contractures to 3.83 (95% CI 2.89-5.08) for arthritis. When comparing the type of PT prescription across the initial and all follow-up visits from 2003 to 2017, significant alterations with a decreasing frequency of patients receiving PT could be observed (P = 0.001). CONCLUSION: To our knowledge, this is the first study reporting the use of PT in patients with systemic sclerosis (SSc) in a large cohort. Although SSc is characterized by considerable disability and restriction of motion, <40% of patients received PT.

The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement.

OBJECTIVE: Systemic sclerosis (SSc) is a rare, heterogeneous disease, which affects different organs and therefore requires interdisciplinary diagnostic and therapeutic management. To improve the detection and follow-up of patients presenting with different disease manifestations, an interdisciplinary registry was founded with contributions from different subspecialties involved in the care of patients with SSc. METHODS: A questionnaire was developed to collect a core set of clinical data to determine the current disease status. Patients were grouped into five descriptive disease subsets, i.e. lcSSc, dcSSc, SSc sine scleroderma, overlap-syndrome and UCTD with scleroderma features. RESULTS: Of the 1483 patients, 45.5% of patients had lcSSc and 32.7% dcSSc. Overlap syndrome was diagnosed in 10.9% of patients, while 8.8% had an undifferentiated form. SSc sine scleroderma was present in 1.5% of patients. Organ involvement was markedly different between subsets; pulmonary fibrosis for instance was significantly more frequent in dcSSc (56.1%) than in overlap syndrome (30.6%) or lcSSc (20.8%). Pulmonary hypertension was more common in dcSSc (18.5%) compared with lcSSc (14.9%), overlap syndrome (8.2%) and undifferentiated disease (4.1%). Musculoskeletal involvement was typical for overlap syndromes (67.6%). A family history of rheumatic disease was reported in 17.2% of patients and was associated with early disease onset (P < 0.005). CONCLUSION: In this nationwide register, a descriptive classification of patients with disease manifestations characteristic of SSc in five groups allows to include a broader spectrum of patients with features of SSc.

[Cryotherapy in discoid lupus erythematosus (DLE)]. / Kryotherapie bei diskoidem Lupus erythematodes.

Discoid lupus erythematosus (DLE) is a chronic, scarring, photosensitive autoimmune dermatosis that usually occurs in sun-exposed areas. While the face, chest, and extremities are often affected, involvement of the eyelid is rare. In cases of DLE lesions that are resistant to local or systemic recommended therapies, contact cryotherapy should be considered as an alternative treatment option.

Spirituality and mood pathology in severe skin conditions: a prospective observational study.

Although the association between spirituality and parameters of psychological health and disease has been investigated extensively, little evidence is available for its potential role in dermatology. In a single-centre observational prospective study, 149 outpatients (107 women) with systemic sclerosis (SSc; n = 44), lupus erythematosus (LE; n = 48), or early stage malignant melanoma (MM; n = 57) were investigated using the multidimensional inventory for religious/spiritual well-being together with the Brief Symptom Inventory for psychiatric symptoms (BSI-18). SSc patients reported the highest amount of Somatization in comparison with LE and MM patients (p < 0.05). Furthermore, in line with the previous research, spiritual dimensions, such as Hope for a better future (p < 0.01) or Hope for a better afterlife (p < 0.01), proved to be especially negatively predictive for the global amount of psychiatric symptom burden in these dermatological patient groups. Our findings suggest that greater attention should be given to spiritual issues, such as encouraging patients, imbuing them with optimism, and offering interventions that address spiritual well-being.

Aging and diabetes increase the aggregating potency of rat skin collagen towards normal platelets.

Acid-soluble collagen samples were prepared from individual skins of 24 month old rats (n = 8), 2 month old young controls (n = 8) and from 6 month old streptozotocin-diabetic rats (n = 5) and their age-matched controls (n = 10). Less collagen was obtained by acid extraction and salt precipitations from skins of diabetic and aged rats than from those of their respective controls. The collagen preparations from diabetic and aged rats showed an increased ratio of beta/alpha components. The rate of "in vitro" fibrillogenesis was less for collagen from diabetic rats than from controls. It was not modified for collagens from aged rats. The aggregating potency towards normal human platelets was markedly increased for collagens from aged and diabetic rats: reduced latency time (p less than 0.01) and increased velocity (p less than 0.01) were observed for collagens from aged rats when compared with young rats (16.5 micrograms/ml). Increased velocity (p less than 0.01) was also observed for collagens from diabetic rats (8.25, 11 and 16.5 micrograms/ml), without modification of latency time.