Mast-cell interleukin-1ß, neutrophil interleukin-17 and epidermal antimicrobial proteins in the neutrophilic urticarial dermatosis in Schnitzler's syndrome.

BACKGROUND: Schnitzler's syndrome (SchS) is an autoinflammatory disease characterized by a chronic urticarial rash, a monoclonal component and signs of systemic inflammation. Interleukin (IL)-1ß is pivotal in the pathophysiology. OBJECTIVES: Here we investigated the cellular source of proinflammatory mediators in the skin of patients with SchS. METHODS: Skin biopsies of lesional and nonlesional skin from eight patients with SchS and healthy controls, and patients with cryopyrin-associated periodic syndrome (CAPS), delayed-pressure urticaria (DPU) and cold-contact urticaria (CCU) were studied. We studied in vivoIL-1ß, IL-17 and antimicrobial protein (AMP) expression in resident skin cells and infiltrating cells. In addition we investigated the in vitro effect of IL-1ß, IL-17 and polyinosinic-polycytidylic acid (poly:IC) stimulation on cultured epidermal keratinocytes. RESULTS: Remarkably, we found IL-1ß-positive dermal mast cells in both lesional and nonlesional skin of patients with SchS, but not in healthy control skin and CCU, and fewer in CAPS. IL-17-positive neutrophils were observed only in lesional SchS and DPU skin. In lesional SchS epidermis, mRNA and protein expression levels of AMPs were strongly increased compared with nonlesional skin and that of healthy controls. When exposed to IL-1ß, poly:IC or IL-17, patient and control primary human keratinocytes produced AMPs in similar amounts. CONCLUSIONS: Dermal mast cells of patients with SchS produce IL-1ß. This presumably leads to activation of keratinocytes and neutrophil influx, and further amplification of inflammation by IL-17 (from neutrophils and mast cells) and epidermal AMP production leading to chronic histamine-independent neutrophilic urticarial dermatosis.

Unexplained recurrent fever: when is autoinflammation the explanation?

Recurrent fever can be the sole or leading manifestation of a variety of diseases including malignancies, autoimmune diseases and infections. Because the differential diagnoses are manifold, no formal guidelines for the approach of patients with recurrent fever exists. The newly recognized group of autoinflammatory diseases are often accompanied by repetitive fever attacks. As these episodes are frequently associated by a variety of divergent presentations, the differentiation of other causes for febrile illnesses can be difficult. In this article, we first review disease entities, which frequently present with the symptom of recurrent fever. In a next step, we summarize their characteristic pattern of disease presentation. Finally, we analyse key features of autoinflammatory diseases, which are helpful to distinguish this group of diseases from the other causes of recurrent fever. Recognizing these symptom patterns can provide the crucial clues and, thus, lead to the initiation of targeted specific diagnostic tests and therapies.

How not to miss autoinflammatory diseases masquerading as urticaria.

Urticarial skin reactions are one of the most frequent problems seen by allergists and clinical immunologists in daily practice. The most common reason for recurrent wheals is spontaneous urticaria. There are, however, several less common diseases that present with urticarial rash, such as urticarial vasculitis and autoinflammatory disorders. The latter include cryopyrin-associated periodic syndrome and Schnitzler's syndrome, both rare and disabling conditions mediated by increased interleukin-1 secretion. Apart from the urticarial rash, patients are suffering from a variety of systemic symptoms including recurrent fever attacks, arthralgia or arthritis and fatigue. Autoinflammatory diseases are often associated with a diagnostic delay of many years and do not respond to antihistamines and other treatments of urticaria. Also, the chronic inflammation may lead to long-term complications such as amyloidosis. It is therefore important not to miss these diseases when diagnosing and treating patients with chronic recurrent urticarial rash. Here, we present clinical clues and tips that can help to identify autoinflammatory disorders in patients presenting with chronic urticarial rash and discuss their clinical picture and management.

Expression profile of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins during skin barrier repair.

BACKGROUND: Recent studies have emphasized the importance of heritable and acquired skin barrier abnormalities in common inflammatory diseases such as psoriasis and atopic dermatitis (AD). To date, no comprehensive studies on the effect of experimental barrier disruption on cornified envelope protein expression have been performed. OBJECTIVES: To analyse the effect of experimental skin barrier disruption on the expression of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins. METHODS: We examined mRNA (day 1, 3 and 7) and protein (day 1, 2, 4 and 9) expression levels of structural proteins and regulatory molecules after sodium dodecyl sulphate (SDS) application on normal skin, and tape stripping of uninvolved epidermis of patients with psoriasis and AD and healthy controls. RESULTS: Upon tape stripping, several structural molecules were significantly downregulated (at the mRNA level as well as the protein level), including LCE5A, LCE2B, FLG, FLG2 and LOR, whereas others were upregulated: IVL, SPRR1, SPRR2, HRNR and most notably LCE3A. The epidermal crosslinking enzymes TGM1, TGM3 and TGM5 were all upregulated, whereas proteases involved in the desquamation process (CTSV, KLK5 and KLK7) were downregulated or unaffected. Most results were similar in SDS-instigated irritant contact dermatitis. There was no significant difference in response between normal epidermis and nonlesional skin of patients with psoriasis and AD. CONCLUSIONS: Skin barrier disruption induces a temporary barrier repair response composed of increased expression of several cornification-related proteins, and decreased expression of some structural and desquamation-related proteins.

Beneficial response to anakinra and thalidomide in Schnitzler's syndrome.

BACKGROUND: Schnitzler's syndrome is an inflammatory disorder characterised by chronic urticarial rash and monoclonal gammopathy, accompanied by periodic fever, arthralgia or arthritis, and bone pain. The cause and treatment are still unknown. OBJECTIVE: To assess treatment with thalidomide and an interleukin 1 receptor antagonist, anakinra, in Schnitzler's syndrome. CASE REPORTS: Three patients with Schnitzler's syndrome are described, one with IgM gammopathy, two with IgG type. In one patient, thalidomide induced complete remission, but was stopped because of polyneuropathy. Anakinra 100 mg daily in all three patients led to disappearance of fever and skin lesions within 24 hours. After a follow up of 6-18 months, all patients are free of symptoms. CONCLUSION: Anakinra proved to be effective in three patients with Schnitzler's syndrome. This treatment is preferable to thalidomide, which induced a complete remission in one of our patients, as it has fewer side effects.