Nicolas Hunzelmann

Improvement of cold urticaria by treatment with the leukotriene receptor antagonist montelukast

A 29-year-old woman had suffered from cold urticaria for 2.5 years. Diagnosis was based on history and a cold challenge test. Urticarial lesions developed predominantly on her face after exposure to cold wind or changes in environmental temperature from warm to cold. The patient reported that the urticaria had never been accompanied by systemic symptoms. She denied any familial cold urticaria. Testing with plastic tubes ®lled with water at different temperatures demonstrated that hives could be provoked upon exposure to 03C for 5 min at the forearm and were still present after 20 min. Cold urticaria secondary to other diseases in our patient was excluded by extensive laboratory work-up. The routine laboratory tests, including erythrocyte sedimentations rate, total blood cell count, urine analysis, blood sugar level, antinuclear antibodies, antistreptolysin titer, liver function tests and serum electrolytes did not reveal any abnormalities. Cold agglutinins and cryoglobulins were negative. Gamma-globulins were slightly elevated with unremarkable immun®xation. Based on these results, we diagnosed an acquired, immediate cold urticaria. Various antihistamines, such as cyproheptadine (4 mg daily) and cetirizine (30 mg daily) as well as doxycyclin (200 mg daily for 3 weeks), were administered. However, they provided only minimal or no relief. Eventually, treatment with montelukast (Singulair), a leukotriene receptor antagonist, signi®cantly improved the urticaria after only 4 days of oral administration at a daily dose of 10 mg. Thus, using a visual analogue scale (VAS) with a range of 1 ± 10 for recording severity of self-assessed symptoms, the patient ranked the wealing and itching from initially 10 to 2, where 1 indicated no wealing and 10 extensive wealing, under treatment with montelukast. Administration of montelukast was continued for 5 weeks with signi®cant and stable improvement of symptoms. Re-challenge under montelukast treatment revealed a substantial suppression of hives to 5% of initial wealing.

Management of localized scleroderma.

Localized scleroderma denotes a spectrum of conditions characterized by circumscribed fibrotic areas involving different levels of the dermis, subcutis, and sometimes underlying soft tissue and bone. Although the clinical course of the disease is often benign, widespread lesions and disabling joint contractures may lead to significant complications. The pathogenesis of the different types of localized scleroderma is still unknown. Numerous therapeutic agents have been reported to be effective in this disease spectrum, but controlled studies are rare. The purpose of this review is to summarize previous experience and to discuss recent advances in the management of localized scleroderma.

Successful Sulfasalazine Treatment of Severe Chronic Idiopathic Urticaria Associated with Pressure Urticaria

Sir, Chronic urticaria is a common cutaneous disease, but its pathogenesis is still poorly understood. We report on a patient with corticosteroid-dependent chronic idiopathic urticaria associated with pressure urticaria who failed to respond to treatment with antihistamines, a leukotriene receptor antagonist, and PUVA, but showed stable improvement after administration of sulfasalazine. CASE REPORT A 31-year-old male patient suffered for 5 years from recurrent episodes of hives and swellings often associated with shortness of breath. Weals occurred spontaneously and after pressure application. The patient repeatedly suffered from pronounced weals that developed after working in his profession as a moving packer, or from plantar swellings after long-distance walks. Whereas pressure testing with an 8-kg weight placed on the patient’s thigh for 20 min failed to induce wealing over an observation period of 24 h, repeated strong grasping of an object for 10 min evoked prominent palmar hives. Routine laboratory tests, including serum electrolytes, total blood cell count, erythrocyte sedimentation rate, blood sugar level, antinuclear antibodies, anti-streptolysin titer, and urine analysis, failed to reveal any abnormalities, besides a mildly elevated gammatransaminase level that was attributed to the regular alcohol consumption of the patient. Intracutaneous injection of autologous serum did not induce wealing (1) and food-associated urticaria was ruled out by food allergy testing and an elimination diet for 10 days. Based on these results, we diagnosed chronic idiopathic urticaria and pressure urticaria associated with shortness of breath. Variousantihistamines,such asloratidine,cetirizine,terfenadine,and ranitidine as well as systemic PUVA treatment failed to improve the symptoms. To control repeated episodes of shortness of breath and severeswellings,intravenouscorticosteroidswereneededatleast3times monthly. As a consequence, the patient started to develop signs of Cushing’s syndrome, with a signi® cant increase in body weight. The leukotrienereceptorantagonistmontelukastwasthenadministered, but failed to be effective. Subsequently, we started treatment with sulfasalazine at a dosage of 500 mg/day, which was slowly increased to a maximum of 3 g/day over a period of 3 months. After only a few days of treatment, the patient experienced a substantial improvement. At a dosage of 3 g/day he achieved complete resolution of the urticaria symptoms. Repeated testingdemonstrated that wealingcould nolonger beinduced even bystrong grasping.Usingavisual analoguescalewitha range of 1± 10, where 1 indicated no wealing and 10 extensive wealing, the patient ranked the wealing as being initially 9 and improving to 1 after beginning treatment with sulfasalazine. Furthermore, he denied any occurrence of wealing associated with walking. During6 months of treatment with sulfasalazine, no adverse reactions were observed and regular laboratory follow-ups were unremarkable. After 6 months of successfulsulfasalazinetreatment,wetriedtoreducethedosageto2 g/day, which resulted in an increase in pressure-related symptoms. Therefore, the patient subsequently received 3 g of sulfasalazine per day, leading again to an improvement in clinical symptoms. After 1 year of treatment, the patient is free of weals with 3 g/day of sulfasalazine.

German guidelines for the diagnosis and therapy of localized scleroderma.

Localized scleroderma designates a heterogeneous group of sclerotic skin disorders. Depending on the subtype, severity, and site affected, adjacent structures such as adipose tissue, muscles, joints, and bones may be involved. This is an update of the existing German AWMF (Association of the Scientific Medical Societies in Germany) guidelines (classification: S2k). These guidelines provide an overview of the definition, epidemiology, classification, pathogenesis, laboratory workup, histopathology, clinical scoring systems, as well as imaging and device‐based workup of localized scleroderma. Moreover, consensus‐based recommendations are given on the management of localized scleroderma depending on its clinical subtype. Treatment recommendations are presented in a therapeutic algorithm. No financial support was given by any pharmaceutical company. The guidelines are valid until July 2019.

Cytokines alter mRNA steady state levels for basement membrane proteins in human skin fibroblasts

Keratinocytes and fibroblasts synthesize basement membrane proteins and even contribute to the formation of basement membrane structures following injury or tissue damage. Under these conditions many cellular functions are regulated by mediators e.g. transforming growth factor-beta, tumor necrosis factor alpha, interferon-gamma or interleukin-1 alpha. We therefore describe here their influence on synthesis of basement membrane proteins in human skin fibroblasts. A comparative analysis of mRNA steady levels coding for BM-40, nidogen, laminin B1 and B2 chains and collagen IV in fibroblasts, in primary human keratinocytes and a epidermal cell line grown in monolayer culture demonstrated that the highest amounts were present in human fibroblasts. Interferon-gamma reduces all mRNA steady state levels dose dependently in comparison to the control, while transforming growth factor-beta simultaneously induces BM-40, alpha 1 and alpha 2 (IV) collagen mRNAs. TGF-beta, however, has no effect on nidogen and laminin mRNA levels. Interleukin-1 alpha and tumor necrosis factor alpha do not affect the mRNA levels of most basement membrane proteins. However, the alpha 1 (IV) collagen mRNA is upregulated by both cytokines to 300%. These data demonstrate a specific control of the expression of several basement membrane proteins by cytokines and indicate that fibroblasts could contribute to basement membrane formation during wound healing and tissue repair.

Pharmacology and rationale for imatinib in the treatment of scleroderma.

Systemic sclerosis (scleroderma) is a chronic, multisystem, fibrotic disease. Although the pathogenesis is not completely understood, early vascular damage leads to an inflammatory reaction and a severe fibrotic response. Therapy of systemic sclerosis is still not convincing and is mainly restricted to the management of organ complications. A wide choice of immunosuppressive and antifibrotic drugs has been used to try to modify the course of the disease, but significant breakthroughs are still lacking. Imatinib is a tyrosine kinase inhibitor known to regulate growth, proliferation, and differentiation as well as apoptosis of cells and is already widely used for several malignancies, eg, chronic myeloid leukemia and gastrointestinal stromal tumors. It has been used in preclinical as well as clinical studies to modulate the fibrotic process in patients with systemic sclerosis. This is based on its activity to interfere selectively with both the transforming growth factor-β and platelet-derived growth factor signaling pathway. Preclinical studies in mouse models of scleroderma showed significant anti-inflammatory and antifibrotic effects; however, several clinical, proof-of-concept trials have not yet confirmed these initially promising results.

Allergic drug eruption secondary to intravenous acyclovir.

A 62-year-old woman presented at our department 10 days after returning from a trip to Alaska. Over the previous 7 days she had developed headache, elevated temperature and disseminated erythematous vesicles. The only medication she was taking at this time was L-thyroxine 75 mg once daily for treatment of hypothyroidism. Her skin showed widespread vesicles on an erythematous base without palmar and plantar affection. There was no mucous membrane involvement. The patient was otherwise healthy. A diagnosis of disseminated herpes zoster infection was made subsequently, indicating the need for systemic antiviral treatment. A polymerase chain reaction (PCR) was performed and confirmed varicella zoster infection. According to the patient, she had formerly developed eczema to external acyclovir and external betamethasone. Otherwise, her personal and family history was negative for skin diseases. Due to this medical history of a potential acyclovir sensitization a prick-test was performed, whose results were negative. Given the negative prick results, a test dose of 70 mg acyclovir (1 mg/kg bodyweight), equivalent to 10% of the regular dose, was given intravenously. After 8 h, the patient developed a plain macular erythema with slight infiltration of the popliteal fossae and the trunk (Fig. 1). There was no other medication given at that point. The rash was topically treated with corticosteroids (betamethasone), leading to a complete remission of the exanthema within 2 days. The zoster infection also regressed with out any further treatment or any complications. There was no evidence for neurological involvement at any point. For further diagnostic work-up, we presented the patient to our allergy department, where prick-testing and epicutaneous testing for acyclovir (tablets), valacyclovir (tablets) and a topical preparation (acyclovir, propylene glycol, natrium lauryl) were performed. Patch tests showed a pronounced eczematous reaction (++) at 48, 72 and 96 h for each of the 3 substances. Prick-testing remained negative, as did epicutaneous and prick-testing of corticosteroid series (Fig. 2).

The effect of interferon‐gamma on the invasiveness of HT‐180 cells

It has been shown that tumour necrosis factor‐α (TNF‐α) induces the gene expression of collagenase and enhances the invasiveness of many cell types. However, we have previously demonstrated that interferon‐γ (IFN‐γ) induces the chemotactic response of cells and we have studied the in vitro effects of both cytokines on invasive migration using a human fibrosarcoma cell line (HT‐1080). Invasive migration occurred with HT‐1800 cells through a basement membrane equivalent (matrigel) and collagen type I gel. Pre‐incubation of cells with increasing concentration of IFN‐γ resulted in a dose‐dependent reduction of this invasive migration. TNF‐α considerably enhanced the invasiveness of HT‐1080 cells and of fibroblasts. This effect could be significantly diminished by the pre‐incubation of cells with IFN‐γ. Inhibition of invasiveness did not appear to be due to an altered binding to the barriers or altered collagenolytic activity of these cells, as shown by attachment and collagenase assays. These data support the concept that IFN‐γ can reduce the invasiveness of transformed cells which contributes to its in vivo anti‐neoplastic effect.

AWMF‐Leitlinie Nr. 013/066 Diagnostik und Therapie der zirkumskripten Sklerodermie

Localized scleroderma is a rare autoimmune disease with primary affection of the skin, and occasional involvement of the fat tissue, muscle, fascia, and bone. Depending on the clinical subtype, the spectrum of skin lesions ranges from singular plaque lesions to severe generalized or linear subtypes which may lead to movement restrictions and permanent disability. This German S1‐guideline proposes a classification of localized scleroderma that, considering the extent and depth of fibrosis, distinguishes limited, generalized, linear, and deep forms of localized scleroderma, together with its associated subtypes. The guideline includes a description of the pathogenesis, of differential diagnoses, and particular aspects of juvenile localized scleroderma, as well as recommendations for histopathologic, serologic, and biometric diagnostic procedures. Based on studies of topical and systemic treatments as well as phototherapy for localized scleroderma published in international literature, a treatment algorithm was developed which takes account of the different subtypes and the extent of disease.

Deutsche Leitlinie zur Diagnostik und Therapie der zirkumskripten Sklerodermie

Bei der zirkumskripten Sklerodermie handelt es sich um eine heterogene Gruppe von sklerotischen Erkrankungen der Haut mit je nach Subtyp, Schweregrad und Lokalisation möglicher Beteiligung von hautnahen Strukturen wie Fettgewebe, Muskulatur, Gelenke und Knochen. Dies ist eine Aktualisierung der bereits bestehenden deutschen Leitlinie der AWMF (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Wissenschaften) mit dem Klassifizierungsgrad S2k. Die Leitlinie gibt einen Überblick zur Definition, Epidemiologie, Klassifikation, Pathogenese, Labordiagnostik, Histopathologie sowie klinischen Scores und apparativen Diagnostik der zirkumskripten Sklerodermie. Des Weiteren erfolgen konsensbasierte Empfehlungen zum Management der zirkumskripten Sklerodermie in Abhängigkeit vom klinischen Subtyp. Die Behandlungsempfehlungen sind in einem Therapiealgorithmus dargestellt. Eine finanzielle Unterstützung zur Erstellung der Leitlinie durch die pharmazeutische Industrie erfolgte nicht. Die Leitlinie ist bis Juli 2019 gültig.