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To assess the prevalence of the MYD88 L265P mutation and variants within NLRP3 and evaluate the status of oligoclonal hematopoiesis in 30 patients with Schnitzler syndrome (SchS).
Thirty patients with SchS were recruited from 3 clinical centers. Six patients with known acquired cryopyrin-associated periodic syndromes (aCAPS) were included as controls. Allele-specific oligonucleotide-polymerase chain reaction was used for the detection of the MYD88 L265P variant, next-generation sequencing was applied to analyze NLRP3 and 28 genes associated with myelodysplastic syndrome, and gene scanning was performed for the detection of X chromosome inactivation.
Activating NLRP3 mutations were not present in 11 SchS patients who had not been sequenced for this gene previously. The MYD88 L265P variant was present in 9 of 30 SchS patients, and somatic mutations associated with clonal hematopoiesis were identified in 1 of 30 patients with SchS and 1 of 6 patients with aCAPS. Evidence of nonrandom X chromosome inactivation was detected in 1 female patient with SchS and 1 female patient with aCAPS.
A shared molecular mechanism accounting for the pathogenesis of inflammation in SchS remains elusive. Clonal hematopoiesis is not associated with other somatic mutations found in individuals with SchS or aCAPS.

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BACKGROUND: Schnitzler syndrome is an adult-onset autoinflammatory disease characterized by urticarial exanthema and monoclonal gammopathy accompanied by systemic symptoms such as fever, bone, and muscle pain. Up to now, approved treatment options are not available.
OBJECTIVE: We assessed effects of the anti-IL-1β mAb canakinumab on the clinical signs and symptoms of Schnitzler syndrome.
METHODS: In this phase II, randomized placebo-controlled multicenter study, 20 patients with active disease enrolled in 4 German study centers. Patients were randomly assigned to receive single subcutaneous canakinumab 150 mg or placebo injections for 7 days, followed by a 16-week open-label phase with canakinumab injections on confirmed relapse of symptoms. The primary end point was the proportion of patients with complete clinical response evaluated by physician global assessment at day 7. Key secondary end points included changes in patient-reported disease activity (Schnitzler activity score), inflammation markers (C-reactive protein and serum amyloid A), and quality-of-life assessments (Dermatology Life Quality Index and 36-item short form health survey).
RESULTS: The proportion of patients with complete clinical response at day 7 was significantly higher (P = .001) in the canakinumab-treated group (n = 5 of 7) than in the placebo group (n = 0 of 13). Levels of inflammation markers C-reactive protein and serum amyloid A and quality-of-life scores were significantly reduced in canakinumab-treated but not in placebo-treated individuals. Positive effects continued up to 16 weeks. Adverse events were manageable and included respiratory tract infections, gastrointestinal symptoms, and hypertension.
CONCLUSIONS: In this first placebo-controlled study, canakinumab was effective in patients with Schnitzler syndrome, and thus canakinumab may be further evaluated as a therapeutic option for this rare disease.

The aim of this study is to assess the long-term effectiveness and safety of IL1Ra in Schnitzler syndrome (SchS). Between 2010 and 2012, we performed a nationwide survey among French internal medicine departments to identify SchS patients. We retrospectively analyzed the long-term efficacy and safety of IL1Ra and the outcome of patients that did not receive this treatment. Forty-two patients were included in the study, 29 of whom received IL1Ra. The mean age at disease onset was 59.9years. Disease manifestations included urticaria (100%), fever (76%), bone/joint pain (86%), bone lesions (76%), anemia (67%), and weight loss (60%). The monoclonal gammopathy was overwhelmingly IgM kappa (83%). The mean follow-up was 9.5years (range: 1.6-35). Two patients developed Waldenström\'s macroglobulinemia and one developed AA amyloidosis. All of the 29 patients who received IL1Ra responded dramatically. After a median follow-up of 36months (range: 2-79), the effectiveness remained unchanged. All patients remained on anti-IL-1 therapy. Twenty-four patients (83%) went into complete remission and five (17%) into partial remission. Three patients experienced grade 3-4 neutropenia. Six patients developed severe infections. No lymphoproliferative diseases occurred while on IL1Ra. When last seen, all patients without anakinra had an active disease with variable impact on their quality of life. Their median corticosteroids dosage was 6mg/d (range: 5-25). IL1Ra is effective in SchS, with a sharp corticosteroid-sparing effect. Treatment failures should lead to reconsider the diagnosis. Long-term follow-up revealed no loss of effectiveness and a favorable tolerance profile. The long-term effects on the risk of hemopathy remain unknown.

BACKGROUND: Schnitzler syndrome is a very rare, acquired, autoinflammatory disease of mostly adult onset with characteristic combination of chronic recurrent urticaria and monoclonal immunoglobulin M or G gammopathy predisposing the patients to malignant lymphoproliferation. In this work, we analyzed the results of bio-logical therapy with anakinra on a national level aiming to supply data for effective pharmaco-economic estimates, lay the grounds of nationwide patient registry, raise awareness among professional public and optimize provided health care.
METHODS: The retrospective study (10/ 2006- 9/ 2013) included six males with definite Schnitzler syndrome verified by the new Strasbourg criteria. All patients were pretreated with antihistamines, nonsteroidal antiinflammatory drugs and glucocorticoids. Four patients underwent two or more treatment lines including intravenous bisphosphonates, 2- chlorodeoxyadenosine (cladribine), interferonα, PUVA photochemotherapy, cyclosporine A, thalidomide, bortezomib, chlorambucil, cyclophosphamide, colchicine and methotrexate. Anakinra monotherapy was initiated in standard dosing (100 mg subcutaneously daily).
RESULTS: Complete and partial remissions were achieved in five (83%) and one patients (17%), respectively. Complete remission was characterized by urticaria and pain regression (within hours), normalization of inflammatory markers (with--in days) and bone metabolism improvement assessed by the markers of osteoblastic osteoformation and osteoclastic osteoresorption in one case (within weeks). With normalized inflammatory markers (including interleukin6 and interleukin18), arthralgia and sporadic exacerbations of urticaria and fevers persist in the patient in partial remission with proven Q703K polymorphism in NLRP3 gene. The median treatment followup was 30.5 months (37.2 ± 31.2 (n = 6)). The dosing interval was prolonged in one case of complete remission to 48 hours. No serious adverse reactions occurred during anakinra application.
CONCLUSIONS: In Schnitzler syndrome, anakinra represents an effective, verified and safe medication with potentionally longterm administration not compromising its original efficacy and subjective tolerance. Anakinra, blocking autonomous inflammatory reaction of the organism via interleukin1 pathway, is a generally accepted first line treatment that should be made available in standard dosing for all Schnitzler patients.

OBJECTIVE: Schnitzler\'s 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 Schnitzler\'s syndrome.
METHODS: In an open-label, single-treatment arm trial, eight patients with Schnitzler\'s 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 Schnitzler\'s syndrome. Our data demonstrate that IL-1β plays a pivotal role in this disease. CLINICALTRIALS.GOV: NCT01276522.

BACKGROUND: Schnitzler syndrome (SchS) is a rare disease with suspected autoinflammatory background that shares several clinical symptoms, including urticarial rash, fever episodes, arthralgia, and bone and muscle pain with cryopyrin-associated periodic syndromes (CAPS). Cryopyrin-associated periodic syndromes respond to treatment with interleukin-1 antagonists, and single case reports of Schnitzler syndrome have shown improvement following treatment with the interleukin-1 blocker anakinra. This study evaluated the effects of the interleukin-1 antagonist rilonacept on the clinical signs and symptoms of SchS.
METHODS: Eight patients with SchS were included in this prospective, single-center, open-label study. After a 3-week baseline, patients received a subcutaneous loading dose of rilonacept 320 mg followed by weekly subcutaneous doses of 160 mg for up to 1 year. Efficacy was determined by patient-based daily health assessment forms, physician\'s global assessment (PGA), and measurement of inflammatory markers including C-reactive protein (CRP), serum amyloid A (SAA), and S100 calcium-binding protein A12 (S100A12).
RESULTS: Treatment with rilonacept resulted in a rapid clinical response as demonstrated by significant reductions in daily health assessment scores and PGA scores compared with baseline levels (P < 0.05). These effects, which were accompanied by reductions in CRP and SAA, continued over the treatment duration. Rilonacept treatment was well tolerated. There were no treatment-related severe adverse events and no clinically significant changes in laboratory safety parameters.
CONCLUSIONS: Rilonacept was effective and well tolerated in patients with SchS and may represent a promising potential therapeutic option.

We report a 50-year-old man who presented with a 5-year history of an intermittent widespread pruritic urticarioid rash and fever, fatigue, arthralgia and a monoclonal immunoglobulin-M paraprotein. The patient was initially treated with antihistamines and corticosteroids without the disappearance of symptoms. A skin biopsy from the urticarial rash on the thorax was performed, revealing dermal mononuclear and polymorphonuclear cell infiltrate and normal epidermis. A diagnosis of Schnitzler\'s syndrome (SS), a rare disorder in which the simultaneous occurrence of monoclonal gammopathy and chronic urticaria is usually observed, was made. After an unsuccessful trial with rituximab at a dosage of 375 mg/sqm weekly for 4 consecutive weeks, the patient was treated with anakinra, an inhibitor of interleukin-1alpha that is thought to be involved in the pathogenesis of the disease, at a dose of 100 mg daily given subcutaneously. He showed a prompt response to the drug and he is still well and symptom-free after 12 months of follow-up. On the basis of both this experience and the review of the literature we conclude that anakinra may be a promising option for the treatment of SS. However, these results need to be confirmed on a larger number of patients.

Schnitzler syndrome is a clinical entity of unknown etiopathogenesis and is an unusual cause of chronic urticaria. It is characterized by the presentation of a monoclonal band, especially IgM, as well as fever, asthenia and arthralgia. We present the case of a 48-year-old man with 5 years of recurrent urticarial lesions, slight itching, as well as lip, face and occasional pharyngeal edema. The patient had also suffered from fever and right hip and left knee arthralgia. The protein electrophoresis and the immunoelectrophoresis presented an IgG band and a slight lambda band, which is suggestive of a monoclonal gammopathy. The bone marrow examination showed a slight increase in the lymphoplasmatic cells. The marrow biopsy was negative. In order to rule out tumorous, infectious and rheumatic processes as well as collagen diseases, other complementary examinations were performed with negative results. The diagnosis of Schnitzler syndrome as a cause of chronic urticaria requires a thorough study in order to rule out other systemic processes provoking the same symptoms.