H.D. de Koning

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.

Schnitzler's syndrome: diagnosis, treatment, and follow-up

Schnitzlers syndrome is characterized by recurrent urticarial rash and monoclonal gammopathy, associated with clinical and biological signs of inflammation and a long‐term risk of AA amyloidosis and overt lymphoproliferation. An extensive literature review was performed, and the following questions were addressed during an expert meeting: In whom should Schnitzlers syndrome be suspected? How should the diagnosis of Schnitzlers syndrome be established? How should a patient with Schnitzlers syndrome be treated? How should a patient with Schnitzlers syndrome be followed up?. A diagnosis of Schnitzlers syndrome is considered definite in any patient with two obligate criteria: a recurrent urticarial rash and a monoclonal IgM gammopathy, and two of the following minor criteria: recurrent fever, objective signs of abnormal bone remodeling, elevated CRP level or leukocytosis, and a neutrophilic infiltrate on skin biopsy. It is considered probable, if only 1 minor criterion is present. In patients with monoclonal IgG gammopathies, diagnosis is definite if three minor criteria are present and possible if two are present. First‐line treatment in patients with significant alteration of quality of life or persistent elevation of markers of inflammation should be anakinra. Follow‐up should include clinical evaluation, CBC and CRP every 3 months and MGUS as usually recommended.

Sustained efficacy of the monoclonal anti-interleukin-1 beta antibody canakinumab in a 9-month trial in Schnitzler's syndrome

Objectives Schnitzlers syndrome is a chronic disabling autoinflammatory disorder, characterised by chronic urticaria, paraproteinemia and systemic inflammation. The interleukin (IL) 1 receptor antagonist anakinra is a very effective treatment, but requires daily injection and blocks both IL-1α and IL-1β. Canakinumab is a selective human monoclonal anti-IL-1β antibody with a long half-life. We investigated the long-term efficacy and safety of canakinumab in Schnitzlers syndrome. Methods In an open-label, single-treatment arm trial, eight patients with Schnitzlers syndrome received monthly injections with 150 mg canakinumab subcutaneously for 6 months, followed by a 3-month observation period. Primary outcome was complete or clinical remission at day 14. Secondary outcome measures included inflammatory markers, quality of life, time to relapse, safety and tolerability. Results After stopping anakinra, patients developed moderate to severe clinical symptoms. Canakinumab induced complete or clinical remission at day 14 in all eight patients. Median C-reactive protein concentrations decreased from 169 mg/l at baseline to less than 10 mg/l on day 14 and remained low or undetectable. One patient discontinued participation on day 39 because of return of symptoms while all others remained in complete or clinical remission during the 6-month treatment period. Relapse after last canakinumab dose occurred within 3 months in four patients. For two patients, remission continued several months post-study. Five patients reported at least one adverse event, predominantly mild upper respiratory tract infections. One patient died in a traffic accident. Conclusions In this 9-month study, monthly 150 mg canakinumab injection was an effective and well-tolerated treatment for Schnitzlers syndrome. Our data demonstrate that IL-1β plays a pivotal role in this disease. ClinicalTrials.gov NCT01276522.

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.

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 Schnitzlers 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.

Erythematous nodes, urticarial rash and arthralgias in a large pedigree with NLRC4‐related autoinflammatory disease, expansion of the phenotype

DEAR EDITOR, Autoinflammatory disorders (AID) are a heterogeneous group of diseases, characterized by an unprovoked innate immune response, resulting in recurrent or ongoing systemic inflammation and fever. Inflammasomes are protein complexes with an essential role in pyroptosis and the caspase1-mediated activation of the proinflammatory cytokines interleukin (IL)-1b, IL-17 and IL-18 (reviewed in Mariathasan and Monack and Lamkanfi and Dixit). Excessive activation of inflammasomes results in systemic autoinflammatory disease. Various inflammasomes have been identified, of which the NLRP3 inflammasome is most widely studied. Gain-of-function mutations in the NLRP3 gene are associated with cryopyrinassociated periodic syndromes (CAPS), with urticarial skin rash as one of the hallmarks. Recently, gain-of-function mutations in NLRC4 (IPAF/CARD12) were found to associate with a clinically heterogeneous AID, characterized by recurrent episodes of fever, periodic urticarial rash, enterocolitis, splenomegaly and macrophage activation syndrome. Five different mutations in NLRC4 have been reported (reviewed in Vance). Gastrointestinal symptoms and haemophagocytosis distinguish the NLRC4-associated phenotype from CAPS. In this study, we describe the phenotype and skin histology of a large pedigree with 13 affected family members due to a novel mutation in NLRC4 (pedigree in Supplementary Fig. S1). Disease onset occurred in infancy in all patients. Symptoms could be triggered by changes in weather conditions, emotional stress and infection. Disease episodes were characterized by skin lesions, conjunctivitis, arthralgias and – in two patients – colitis. Skin lesions, the predominant feature, varied in severity and localization. In contrast to previous reports, we observed different skin phenotypes between the paediatric and adult patients. The adult patients had painful erythematous nodes on their lower legs and feet, either isolated or in combination with urticarial patches on arms, legs, trunk and face. In two patients, the soles were involved, which had not been reported before in AIDs. Remarkably, the paediatric cases in our cohort suffered from urticarial rash only (Fig. 1a). One patient had enterocolitis with histological signs of inflammatory bowel disease, a feature that was previously described. Histological evaluation of colon biopsies revealed active inflammation, with moderate infiltration of neutrophilic granulocytes and a submucosal mononuclear infiltrate. In contrast to the other reports where neonatal-onset enterocolitis spontaneously resolved after the age of 1 year, the onset of enterocolitis in our patient was in adulthood, with a chronic course. The low number of patients with gastrointestinal symptoms in this family is remarkable, as enterocolitis was thought to distinguish the NLRC4-associated AID from CAPS. Haemophagocytosis was not observed. Response to treatment with an IL-1 receptor antagonist (anakinra) varied (Table 1). A detailed description of the methods is given in Supplementary Methods S1. Whole exome sequencing revealed the novel heterozygous c.1333T>C (p.Ser445Pro) variant in NLRC4 in all affected family members. This variant is absent in the dbSNP or ExAC databases. Prediction software programs (Sift score 0 01, Polyphen-2 score 0 997) indicate that this mutation is probably damaging. The mutation is located next to the recently described pathogenic c.1328A>C (p.His443Pro) mutation and segregated with the disease phenotype (LOD score 3 58). Serum analysis of IL-1b, IL-6, IL-10, IL-18, tumour necrosis factor (TNF)-a and interferon-c showed extremely elevated IL-18 concentrations in eight studied patients (median 4324 pg mL , range 3097–13 984 pg mL , normal 0–34 pg mL ). Concentrations of the other cytokines were in the normal range. Skin biopsies were taken from nodes on the shins and/or calf of three adult patients. Histopathological examination in patient V5 showed a deep dermal and subcutaneous lymphocytic–histiocytic infiltrate with (para)septal and lobular panniculitis. In patient VI5, a perivascular infiltrate of lymphocytes and perivascular oedema was observed. Patient VI1 showed a perivascular and interstitial infiltrate of lymphocytes, and in the deep dermis an infiltrate of lymphocytes, histiocytes and a few mast cells (Fig. 1b). Vasculitis was absent in all samples. Skin biopsies of clinically uninvolved skin (V5 and VI1) showed no abnormalities (not shown). Skin biopsies in CAPS and in the related Schnitzler syndrome mostly show a neutrophilic dermal infiltrate without vasculitis. The absence of a neutrophilic infiltrate in the skin biopsies of our patients is remarkable. Immunofluorescence studies did not detect IL-1b in the skin biopsies, whereas it was found in mast cells in a skin biopsy from a patient with Schnitzler syndrome (data not shown). NLRC4 could not be detected in affected or unaffected skin (not shown), whereas it was present in the positive control (spleen).

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.

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

Schnitzlers syndrome (SchS) is an autoinflammatory disease characterized by a chronic urticarial rash, a monoclonal component and signs of systemic inflammation. Interleukin (IL)‐1β is pivotal in the pathophysiology.

Two types of human Th17 cells with pro- and anti-inflammatory properties and distinct roles in autoinflammation.

Th17 cells are known to be crucial mediators of autoimmune inflammation. However, two distinct types of Th17 cells have recently been described, which differed in their ability to coproduce IL-10 or IFN-g due to differential polarizations requirements for IL-1b. Whether these distinct Th17 phenotypes translate into distinct Th17 cell functions and whether this has implications for human health or disease has not been addressed yet.

PW02-035 - A role for thermo-TRP channels in innate immunity?

Exposure to cold can induce an exaggerated (local and systemic) inflammatory response in a number of rare disorders, including cryopyrin-associated periodic syndrome (CAPS), and idiopathic cold urticaria (CU). Although it is widely recognized that temperature sensing in neurons is mediated by several transient receptor potential (TRP) channels, it is not known how immune cells sense cold temperatures.