Atopy patch testing with aeroallergens in a large clinical population of dermatitis patients in Germany and Switzerland, 2000-2015: a retrospective multicentre study.

BACKGROUND: The diagnostic significance of the atopy patch test for the management of dermatitis possibly triggered by aeroallergens is still controversial. However, sufficiently large studies with routinely tested standardized aeroallergen patch test preparations in dermatitis patients are lacking. OBJECTIVE: To evaluate the reaction frequency and the reaction profiles of 10 until mid-2015 commercially available, standardized aeroallergen patch test preparations of the 'Stallerpatch' test series (Stallergenes, Antony Cedex, France) in a large multicentre patient cohort. METHODS: A retrospective data analysis of patients with suspected aeroallergen-dependent eczematous skin lesions was performed, who were patch tested in 15 Information Network of Departments of Dermatology-associated clinics between 2000 and 2015. Patients were stratified according to their atopic dermatitis (AD) status. RESULTS: The study group included 3676 patients (median age 41 years, 34.8% males, 54.5% AD). The most common aeroallergens causing positive patch test reactions were Dermatophagoides pteronyssinus (19.6%), Dermatophagoides farinae (16.9%), birch (6.2%), timothy grass (6.0%), cat dander (5.4%), mugwort (4.9%) and dog dander (4.6%). Reactions to other pollen allergen preparations, that is 5 grasses (3.2%), cocksfoot (2.1%) and plantain (1.6%), were less common. Positive patch test reactions to aeroallergens were consistently more frequent in patients with AD. These patients showed proportionally less dubious, follicular, irritant and weak positive reactions. Independent of AD status, a patient history of past or present allergic rhinitis was associated with an increased chance of a positive aeroallergen patch test reaction to pollen allergens. CONCLUSION: The aeroallergen patch test is a useful add-on tool in clinical routine, especially in patients with AD and/or respiratory allergy. A patch test series comprising Dermatophagoides pteronyssinus, Dermatophagoides farinae, birch, timothy grass, cat dander and mugwort seems to be suitable. Controlled studies with specific provocation and elimination procedures are required to further evaluate the diagnostic significance of the proposed screening series.

[Prurigo pigmentosa after fat-reduced diet, treated with doxycycline]. / Prurigo pigmentosa nach fettreduzierter Diät, therapiert mit Doxycyclin.

Prurigo pigmentosa is a rare inflammatory skin disease of unknown origin, mostly described in the ethnic Japanese population. Etiology and pathogenesis are not completely known. Tetracyclines or dapsone are the therapy of choice. A 17-year-old Swiss patient with Turkish parents presented with pruritic rash on the neck and trunk, which started after a diet. Under therapy with doxycycline over 5 weeks, complete healing with slight reticular hyperpigmentation was observed.

[Two faces of Janus. Coexistence of systemic lupus erythematosus and psoriasis in the same patient]. / Zwei Gesichter von Janus : Koexistenz von systemischem Lupus erythematodes und Psoriasis bei derselben Patientin.

While both lupus erythematosus and psoriasis are inflammatory dermatoses characterized by scaly erythematous plaques, they are rarely confused in clinical practice. We report a woman who alternately presented with lupus erythematosus and psoriasis over 14 years but the former condition was not recognized and adequately treated. After the complete diagnosis had been established, a combination of thalidomide and acitretin resulted in a prolonged remission of both disorders. This unusual case demonstrates that coexistence of two diseases in one patient presents a diagnostic challenge that can only be met by repeated careful correlation of all clinical and histopathologic findings. It is of particular importance if these diseases require conflicting management strategies.

[Sociomedical implications of the inability to commute in patients with cold urticaria]. / Sozialmedizinische Bedeutung der Wegefähigkeit bei der Kälteurtikaria.

One of the important functions of the dermatologist working within a social medicine framework is the determination of social security disability benefits. The primary decision deals with the question which type of work the applicant can be asked to do and to what extent. Depending on the results of the medical assessment, social security disability benefits may be approved given that other insurance criteria specific to the applicant have been met. The following case demonstrates for the first time that a significant idiopathic cold urticaria leads to a severe constraint on keeping employment due to the inability to commute. The scenario shows that the cold urticaria severely restricts social and professional interactions and that the reduced ability to commute to the place of employment must receive special consideration within the context of a sociomedical evaluation.

Treatment of severe pemphigus with protein A immunoadsorption, rituximab and intravenous immunoglobulins.

BACKGROUND: Pemphigus is a life-threatening autoimmune blistering disease usually treated with high-dose corticosteroids and other immunosuppressants. However, this regimen may prove inadequate in severe cases and cause dangerous side-effects. While protein A immunoadsorption (PAIA) induces a rapid remission in severe pemphigus, the disease usually recurs once the treatment is stopped. In contrast, anti-CD20 antibody rituximab has a delayed onset of action but may lead to a long-term remission of pemphigus. OBJECTIVE: To develop a treatment protocol combining the rapid remission induced by PAIA with the positive long-term effects of rituximab. PATIENTS AND METHODS: Five patients with pemphigus vulgaris and two patients with pemphigus foliaceus were treated with a combination of PAIA, rituximab and conventional immunosuppressants. Patients who failed to respond to this therapy subsequently received intravenous immunoglobulins (IVIg). RESULTS: All seven patients showed a sharp decline of circulating autoantibody levels and rapid improvement of cutaneous and mucosal lesions within 4 weeks of therapy. Long-term remission was induced in three patients and one further patient showed a partial improvement of his disease. The three remaining patients who could not be weaned off PAIA and remained resistant to rituximab treatment showed a good response to IVIg therapy. CONCLUSION: The combination of PAIA and rituximab induces a rapid and durable remission in a subset of patients with severe pemphigus. IVIg therapy appears to be a good treatment option for rituximab nonresponders.

An unusual case of systemic mastocytosis associated with chronic lymphocytic leukaemia (SM-CLL).

AIMS: Whereas focal accumulations of reactive lymphocytes around mast cell (MC) infiltrates are often seen in indolent systemic mastocytosis (ISM) involving the bone marrow, an association of systemic mastocytosis (SM) with malignant lymphoma/lymphatic leukaemia is very rare. This report contributes to the differential diagnosis of ISM by demonstrating that such lymphocytic aggregates may be neoplastic. METHODS: Biopsy specimens (bone marrow and gastrointestinal mucosa) of a 69 year old woman with mild blood lymphocytosis and a history of urticaria pigmentosa-like skin lesions that had disappeared a few years earlier, were investigated immunohistochemically using antibodies against CD3, CD5, CD20, CD23, CD25, CD34, CD117, chymase, and tryptase. Rearrangements of the IgH and TCRy genes were studied by seminested PCR. Mutation analysis of c-kit was performed by melting point analysis of nested PCR using amplified DNA from pooled microdissected single cells (MC and B cells) of both sites. RESULTS: The histomorphological features of the bone marrow corresponded to that of ISM with multifocal accumulations of MC surrounded by clusters of lymphocytes of mature appearance. However, these lymphocytes revealed an aberrant immunophenotype with coexpression of CD5, CD20, and CD23, thus enabling the final diagnosis of SM with an associated clonal haematological non-MC lineage disease, in particular SM with associated B cell chronic lymphocytic leukaemia (SM-CLL). Monoclonality for both ISM and B-CLL could be confirmed by demonstrating the typical activating c-kit point mutation D816V in bone marrow MC, and a monoclonal IgH rearrangement in bone marrow B cells. CONCLUSIONS: Usually, focal accumulations of lymphocytes around MC infiltrates in the bone marrow of patients with SM are reactive in nature (lymphocytosis). However, a low grade malignant lymphoma should also be included in the differential diagnosis. We describe here the first case, to our knowledge, with synchronous diagnosis of SM and associated B-CLL. This diagnosis could only be established by application of appropriate immunohistochemical and molecular techniques, as the bone marrow histology on first investigation resembled that of typical ISM.

[Unclear intraoperative cardiorespiratory decompensation. Anaphylactic reaction?]. / Unklare intraoperative kardiorespiratorische Dekompensation. Ist es eine Anaphylaxie?

During anaesthesia a patient is exposed to a variety of substances, all of which could lead to anaphylactic reactions. In addition, other drugs may exert clinical side-effects by non-immunological mechanisms, e.g. by direct stimulation of the release of histamine by mast cells. Initially, the observed symptoms, such as hypotension or tachycardia, may be misunderstood by the anaesthetist, leading to a possible delay in diagnosis and subsequent treatment of the anaphylactic event. Cardiac ischemia and lung embolisms are important differential diagnoses that often cannot be definitely ruled out during the acute situation and that have to be followed up once the patient has been stabilised. We report a case of anaphylactic reaction after the administration of ampicillin which required treatment and ventilation in the intensive care unit. Despite an accurate determination of serum tryptase levels, the diagnosis of an anaphylactic reaction to ampicillin was eventually confirmed by skin testing. During anaesthesia, anaesthetists should consider anaphylaxis when unforeseen symptoms such as bronchospasm, haemodynamical instability and/or flush arise. In cases of unexpected reactions, patients should undergo allergological follow-up to prevent fatal re-exposure.

[Physical urticaria]. / Physikalische Urtikaria.

The different types of physical urticaria are triggered by mechanical and thermal stimuli, as well as electromagnetic waves. Localized forms restricted to the skin and mucous membranes are most common, but generalized urticaria with variable extracutaneous manifestations can also occur. Physical urticaria is usually sporadic but may rarely have a familial form; it is often associated with chronic urticaria. In most instances, the short time interval between the physical stimulus and reaction points to a causal relationship, but in delayed types the exact diagnosis may be missed without provocation tests. The clinical implication of physical urticaria is demonstrated by investigations showing a greater degree of disability in affected patients as compared to other types of urticaria. There is still an incomplete understanding of the crucial pathophysiological aspects; most likely inflammatory reactions involving leukocytes, endothelial cells and nerves stimulated by various mediators play an important role in this form of urticaria.

Calcineurin antagonists differentially affect mediator secretion, p38 mitogen-activated protein kinase and extracellular signal-regulated kinases from immunologically activated human basophils.

BACKGROUND: Basophils participate in allergic diseases by invading affected tissues and secreting histamine, leukotriene (LT)C4, IL-4 and IL-13 following FcepsilonRI cross-linking. A reduction of basophil mediator production is therefore of considerable therapeutical interest. Macrolactam derivatives, which inhibit calcineurin activation, may be candidates for antiallergic therapy as they reduce both symptoms of inflammatory skin disease in animal models and mast cell degranulation. OBJECTIVE: To investigate the effects of the calcineurin antagonists ascomycin and cyclosporin A on IgE-dependent mediator release from human basophils. METHODS: Basophils were purified by Ficoll density centrifugation, elutriation and negative selection. Histamine release was measured spectrofluorometrically; LTC4, IL-4 and IL-13 secretions were assayed by enzyme-linked immunosorbent assay (ELISA). Lysed cells were subjected to Western blotting using specific antibodies to phospho-p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK)-1 and -2. RESULTS: Ascomycin (0.01 nm to 1 micro m) and cyclosporin A (0.1 nm to 10 micro m) strikingly inhibited (maximally 100%) anti-IgE-induced histamine and cytokine release from basophils, and these actions were unaffected by IL-3 priming. Ascomycin, however, was less potent at blocking LTC4 secretion, whereas cyclosporin A was unable to block production of this mediator. In immunoblotting studies, ascomycin and cyclosporin A reduced IgE-dependent p38 MAPK activation but were less potent at reducing ERK phosphorylation in basophils. CONCLUSION: Calcineurin antagonists like ascomycin and cyclosporin A block IgE-dependent basophil degranulation and cytokine synthesis. Calcineurin may target p38 MAPK activation, but seems to have less activity on ERK phosphorylation. This is paralleled by a reduced or even absent effect of calcineurin antagonists on eicosanoid production.

Effect of granulocyte macrophage colony-stimulating factor in a patient with benign systemic mastocytosis.

We report the in vitro and in vivo effects of granulocyte macrophage colony stimulating factor (GM-CSF), a known inhibitor of in vitro mast cell differentiation, in a patient with benign, adult-onset systemic mastocytosis. In vitro effects of GM-CSF on bone marrow cultures before the start of treatment showed a marked inhibition of mast cell marker expression [tryptase, Kit, and high-affinity IgE receptor (FcepsilonRIalpha)] at both protein and mRNA levels. Therefore, the patient was treated with daily injections of GM-CSF for 10 weeks. After an initial improvement, increasing worsening of clinical symptoms was noted, and the patient refused further treatment. Lesional skin biopsies showed an increase of toluidine blue-positive mast cells, compared with uninvolved skin, with further significant increase after treatment. Similar results were obtained on staining for mast cell-specific tryptase and Kit, as well as for CD1a and FcepsilonRIalpha. These findings show that GM-CSF inhibits human bone marrow mast cell differentiation in vitro, and also in mastocytosis. However, GM-CSF apparently enhances recruitment of mast cell as well as dendritic cell precursors into the tissue during systemic treatment. These findings and the observed adverse clinical effects in the present patient make it unlikely that GM-CSF monotherapy will be beneficial for the treatment of mastocytosis.

Human skin mast cells rapidly release preformed and newly generated TNF-alpha and IL-8 following stimulation with anti-IgE and other secretagogues.

Several groups have previously reported that rodent or human leukemic mast cells produce inflammatory cytokines such as TNF-alpha and IL-8 as well as the pro-allergic cytokines IL-4, IL-5 and IL-13. Comparatively little is known, however, regarding the ability of normal human skin mast cells to secrete these factors following either IgE-dependent or IgE-independent modes of activation. We therefore investigated whether normal human skin mast cells produce these cytokines following stimulation by a variety of secretagogues. Enriched isolated skin mast cells released both TNF-alpha and IL-8 following activation with either anti-IgE, SCF, substance P, compound 48/80 or A23187. This release was dose- and time-dependent, with maximal levels being reached within 4 h of stimulation involving, in part, the secretion of preformed stores of both cytokines. In accordance with this, using lysates of highly purified (>90%) skin mast cells, we could demonstrate that both TNF-alpha and IL-8 mRNA and protein were present in both unstimulated as well as stimulated mast cells. In stark contrast to these results, no significant levels of either IL-4, IL-5 or IL-13 were detected, regardless of the secretagogue used or the period of stimulation. These results show that human skin mast cells are capable of rapidly secreting pro-inflammatory cytokines like TNF-alpha and IL-8 following IgE-dependent activation and stimulation by the neuropeptide substance P, SCF and the basic polypeptide analogue compound 48/80. In contrast to other types of human mast cells however, human skin mast cells were incapable of secreting IL-4, IL-5 or IL-13 in these settings.

Mercuric chloride enhances immunoglobulin E-dependent mediator release from human basophils.

Mercuric chloride (HgCl2) is an industrial agent known to cause autoimmune disorders and induce IgE synthesis, which plays a crucial role in the manifestation of allergic diseases. In rodents, the immunomodulatory effects of HgCl2 have been shown to involve the enhancement of mast cell-derived IL-4 secretion, which facilitates both Th2-lymphocyte development and IgE production. In humans, rapid allergen-dependent release of IL-4 and the related cytokine IL-13 from histamine-containing cells occurs primarily in basophils, along with other proinflammatory mediators such as histamine and LTC4. In this study, we therefore investigated the effects of HgCl2 on the release of the above basophil mediators, either due to the compound alone or in conjunction with IgE-dependent stimulation. HgCl2 (10(-9) to 10(-6) M) did not induce mediator secretion alone but significantly enhanced the release of histamine, LTC4, IL-4, and IL-13 caused by anti-IgE. Higher concentrations of HgCl2 (10(-5) to 10(-3) M) strikingly reduced cell viability; however, toxicity varied depending on cell density and incubation time. Removal of HgCl2 following a short incubation with basophils did not reverse the potentiating effects on basophil mediator secretion to anti-IgE and the concentration of free mercury in the supernatants significantly diminished by up to 20% after incubation with the cells, indicating irreversible Hg binding to cells. By upregulating IgE-dependent human basophil mediator release, our results clearly indicate that HgCl2 potentially exacerbates allergic disorders and promotes a Th2-cytokine profile.

GM-CSF downmodulates c-kit, Fc(epsilon)RI(alpha) and GM-CSF receptor expression as well as histamine and tryptase levels in cultured human mast cells.

GM-CSF is known primarily as a hematopoietic growth factor, but it has also been shown to inhibit mast cell differentiation in vitro. In order elucidate the mechanisms involved, we investigated the effects of GM-CSF in vitro on the differentiation of human leukemic mast cells (HMC-1 cells) and normal cord blood-derived mast cells (CBMC) under the influence of SCF, NGF, and fibroblast supernatant (FS). Under all culture conditions, GM-CSF induced a dose- and time-dependent reduction in intracellular histamine levels, tryptase activity, and numbers of cells immunoreactive for c-Kit and FcepsilonRIalpha. This effect leveled off between 10-100 ng/ml and after 4 days of culture. There was an associated decrease in mRNA expression for c-kit, FcepsilonRIalpha and tryptase. In contrast, no significant changes in the expression of the NGF receptor TrkA were noted under the same conditions. The GM-CSF receptor was found in HMC-1 cells and CBMC at both the mRNA and protein levels, but its expression decreased during culture with FS, and even more markedly during culture with GM-CSF. GM-CSF thus selectively inhibits in vitro induction and/or upregulation of all major mast cell characteristics in HMC-1 cells and CBMC irrespective of the growth factors present, and a concomitant downregulation of GM-CSF receptors can counteract these effects. GM-CSF may therefore function as a regulatory factor in mast cell growth and differentiation under normal and pathological conditions.

Pathomechanisms in physical urticaria.

Various exogenous stimuli, e.g., rubbing, pressure, cold, heat, or electromagnetic waves, have been described to elicit whealing reactions, the so-called physical urticarias. They may occur as isolated diseases or in association with other types of urticaria. In many cases, the respective physical factors can be defined exactly, e.g., the degree of temperature changes or the range of eliciting ultraviolet wavelengths. In contrast, the underlying pathomechanisms are mostly still obscure. In the past, often contradictory results have been reported regarding the role of IgE, complement factors, histamine, or even mast cells. Recently, many investigations have been performed on solar urticaria where subgroups of patients with different clinical and pathophysiologic features could be defined and mechanisms of tolerance induction have been studied that also offered an efficient treatment modality. Therefore this review will mainly focus on this type of disease as a paradigm of the pathomechanisms of physical urticaria.