Similarities and differences in autoinflammatory diseases with urticarial rash, cryopyrin-associated periodic syndrome and Schnitzler syndrome.

Cryopyrin-associated periodic syndromes (CAPS) and Schnitzler syndrome (SchS) are autoinflammatory diseases that present with urticaria-like rashes. CAPS is characterized by periodic or persistent systemic inflammation caused by the dysfunction of the NLRP3 gene. With the advent of IL-1-targeted therapies, the prognosis of CAPS has improved remarkably. SchS is considered an acquired form of autoinflammatory syndrome. Patients with SchS are adults of relatively older age. The pathogenesis of SchS remains unknown and is not associated with the NLRP3 gene. Previously, the p.L265P mutation in the MYD88 gene, which is frequently detected in Waldenström macroglobulinemia (WM) with IgM gammopathy, was identified in several cases of SchS. However, because persistent fever and fatigue are symptoms of WM that require therapeutic intervention, it is a challenge to determine whether these patients truly had SchS or whether advanced WM was misidentified as SchS. There are no established treatments for SchS. The treatment algorithm proposed with the diagnostic criteria is to use colchicine as first-line treatment, and systemic administration of steroids is not recommended due to concerns about side effects. In difficult-to-treat cases, treatment targeting IL-1 is recommended. If targeted IL-1 treatment does not improve symptoms, the diagnosis should be reconsidered. We hope that the efficacy of IL-1 therapy in clinical practice will serve as a stepping stone to elucidate the pathogenesis of SchS, focusing on its similarities and differences from CAPS.

Schnitzler syndrome and Schnitzler-like syndromes.

ABSTRACT: Schnitzler syndrome is a rare disease of adult-onset with main features including chronic urticarial rash, recurrent fever, arthralgia or arthritis, monoclonal gammopathy of undetermined significance (MGUS), and marked systemic inflammation. Schnitzler syndrome is often underdiagnosed. Patients with Schnitzler syndrome may present to dermatologists and allergists for urticaria, hematologists for MGUS, or rheumatologists for arthritis. It is important to recognize Schnitzler syndrome for its remarkable response to interleukin (IL)-1 blockade. Besides, many cases of Schnitzler-like syndromes do not meet the diagnostic criteria of classical Schnitzler syndrome but display excellent response to IL-1 inhibitors. The overly produced IL-1 is the result of a somatic mosaic gain of function mutation of NLRP3 (nucleotide-binding oligomerization domain [NOD]-like receptor [NLR] family pyrin domain containing 3) gene in some patients with Schnitzler-like syndromes. Inflammasome activation is evident in patients with classical Schnitzler syndrome although no NLRP3 gene mutation is identified. Collectively, Schnitzler syndrome and Schnitzler-like syndromes represent a spectrum of IL-1 mediated adult-onset autoinflammatory diseases.

Refractory serum immunoglobulin M elevation during anti-interleukin (IL)-1- or IL-6-targeted treatment in four patients with Schnitzler syndrome.

Schnitzler syndrome is characterized by chronic urticarial rash, neutrophilic dermal infiltrate, recurrent fever, bone pain, elevated C-reactive protein, and neutrophilic leukocytosis. The pathophysiology of Schnitzler syndrome is unknown, but it is considered to be an acquired form of an autoinflammatory disease because of the resemblance to clinical phenotypes of cryopyrin-associated periodic syndrome, in which a gain-of-function mutation in NLRP3 causes overexpression of interleukin (IL)-1ß. Schnitzler syndrome is generally accompanied by a monoclonal immunoglobulin (Ig)M gammopathy with a long-term risk of lymphoproliferation that is possibly associated with an MYD88 mutation. Herein, we present the following four patients with Schnitzler syndrome: a 63-year-old woman; a 65-year-old man; a 43-year-old woman; and a 63-year-old woman. Each patient fulfilled the Strasbourg diagnostic criteria, but none of the patients had any mutation in NLRP3 or MYD88 detected in their peripheral blood. Although approved treatment options for Schnitzler syndrome are lacking, our patients were treated with IL-1-targeted therapy (anakinra or canakinumab) or anti-IL-6 (tocilizumab). The acute inflammatory clinical manifestations improved completely with canakinumab and partially with anakinra and tocilizumab, but the serum IgM levels were gradually increased in all patients, even during treatment. To determine whether treatment with anti-IL-1ß or IL-6 prevents conversion to a hematopoietic disorder, further collection of cases and long-term follow-up will be needed.

Hereditary systemic autoinflammatory diseases and Schnitzler's syndrome.

The systemic autoinflammatory diseases are disorders of the innate immune system distinguished by severe inflammation resulting from dysregulation of the innate immune system. Hereditary fever syndromes, such as FMF, TNF receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes and mevalonate kinase deficiency, were the first group of systemic autoinflammatory diseases for which a genetic basis was established, between 1999 and 2001. Currently according to the latest report of the international union of immunological societies, 37 separate monogenic disorders were classified as autoinflammatory. In addition to the abovementioned monogenic conditions, we describe Schnitzler's syndrome, a well-defined, acquired autoinflammatory condition without a clear genetic basis. For the purposes of this review, we discuss several conditions defined by the latest consensus process as systemic autoinflammatory diseases. We focus on those disorders where recent studies have contributed to further phenotypic characterization or had an impact on clinical management.

Exploratory Study of MYD88 L265P, Rare NLRP3 Variants, and Clonal Hematopoiesis Prevalence in Patients With Schnitzler Syndrome.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Schnitzler syndrome in a patient with a family history of monoclonal gammopathy.

Schnitzler syndrome is a rare disease characterized by chronic urticaria and a monoclonal gammopathy, most commonly IgM with light chains of the kappa type. There are currently no known risk factorsassociated with development of the disease. We report a case of Schnitzler syndrome in a 48-year-old man with a family history of monoclonal gammopathies. The patient's disease has been well controlled with anakinra therapy. Our case may contribute to a better understanding of the etiology of Schnitzler syndrome as his history could suggest a hereditarypredisposition for the disease. Further studies are necessary to determine whether a genetic component of Schnitzler syndrome exists, as first-degree relatives of patients with monoclonal gammopathies may be at risk for the development of the disease.

Molecular genetic investigation, clinical features, and response to treatment in 21 patients with Schnitzler syndrome.

To date, the pathogenic mechanisms underlying Schnitzler syndrome remain obscure, in particular, the interplay between the monoclonal protein and increased interleukin-1ß (IL-1ß) production, although interest in the contribution of genetic factors has been fueled by detection of somatic NLRP3 mosaicism in 2 patients with the variant-type Schnitzler syndrome. At 2 specialist UK centers, we have identified 21 patients who fulfilled diagnostic criteria for Schnitzler syndrome with urticarial rash, fever, arthralgia, and bone pain; 47% reported weight loss, 40% fatigue, and 21% lymphadenopathy. An immunoglobulin M (IgM) κ paraprotein was detected in 86%; the remainder had IgM λ or IgG κ. Patients underwent searches for germ line and somatic mutations using next-generation sequencing technology. Moreover, we designed a panel consisting of 32 autoinflammatory genes to explore genetic susceptibility factor(s) to Schnitzler syndrome. Genetic analysis revealed neither germ line nor somatic NLRP3, TNFRSF1A, NLRC4, or NOD2 mutations, apart from 1 patient with a germ line NLRP3 p.V198M substitution. The proinflammatory cytokines and extracellular apoptosis-associated speck-like protein with caspase recruitment domain (ASC) measured in the serum of Schnitzler syndrome patients during active disease were significantly higher than healthy controls. Ninety-five percent of our cohort achieved a complete response to recombinant IL-1 receptor antagonist (anakinra). Our findings do not support a role for somatic NLRP3 mosaicism in disease pathogenesis; although elevated levels of ASC, IL-6, and IL-18 in patients' serum, and the response to anakinra, suggest that Schnitzler syndrome is associated with upregulated inflammasome activation. Despite its rarity, Schnitzler syndrome is an important diagnosis as treatment with IL-1 antagonists dramatically improves quality of life for patients.

The inflammasomes in autoinflammatory diseases with skin involvement.

During the past years, significant progress in the understanding of the complexity, regulation, and relevance of innate immune responses underlying several inflammatory conditions with neutrophilic skin involvement has been made. These diseases belong to the novel class of autoinflammatory diseases, and several are caused by mutations in genes regulating the function of innate immune complexes, termed inflammasomes, leading to enhanced secretion of the proinflammatory cytokine IL-1ß. Consequently, targeting of IL-1ß has proven successful in the treatment of these diseases, and the identification of related pathogenic mechanisms in other more common skin diseases characterized by autoinflammation and neutrophilic tissue damage also provides extended opportunities for therapy by interfering with IL-1 signaling.

[Autoinflammatory syndromes in dermatology]. / Syndromes auto-inflammatoires en dermatologie.

Hereditary periodic fever syndromes, also called autoinflammatory syndromes, are characterized by relapsing fever and additional manifestations such as skin rashes, mucosal manifestations, or arthralgias. Some of these disorders present without fever but with the associated systemic manifestations. The responsible mutated genes have been identified for most of these disorders, which lead to the induction of the uncontrolled and excessive production of interleukin-1beta (IL-1beta). The inhibition of IL-1beta through IL-1 receptor antagonist or monoclonal antibody against IL-1beta is used with success in most of these diseases. In case of TNF-receptor associated periodic syndrome (TRAPS) and paediatric granulomatous arthritis (PGA), TNF-antagonists may also be used; in familial Mediterranean fever (FMF) colchicine remains the first choice.

[Schnitzler syndrome]. / Schnitzler-Syndrom.

Schnitzler syndrome is a rare systemic inflammatory disease characterized by the presence of chronic urticarial skin rash and a monoclonal immunoglobulin M (IgM) gammopathy, combined with further, variable disease symptoms. The term refers to a young disease entity which has recently gained increasing acknowledgement and attention, also due to the availability of interleukin-1 (IL-1) blockade as an effective therapeutic option. Insights into the pathophysiology of the disease have resulted in the assumption of Schnitzler syndrome being a special form of an autoinflammatory disease with late onset or an acquired genesis. This article provides an overview on the clinical appearance, current knowledge of pathophysiology and available therapeutic options.

The Schnitzler syndrome.

The Schnitzler syndrome is a rare and underdiagnosed entity which is considered today as being a paradigm of an acquired/late onset auto-inflammatory disease. It associates a chronic urticarial skin rash, corresponding from the clinico-pathological viewpoint to a neutrophilic urticarial dermatosis, a monoclonal IgM component and at least 2 of the following signs: fever, joint and/or bone pain, enlarged lymph nodes, spleen and/or liver, increased ESR, increased neutrophil count, abnormal bone imaging findings. It is a chronic disease with only one known case of spontaneous remission. Except of the severe alteration of quality of life related mainly to the rash, fever and pain, complications include severe inflammatory anemia and AA amyloidosis. About 20% of patients will develop a lymphoproliferative disorder, mainly Waldenström disease and lymphoma, a percentage close to other patients with IgM MGUS. It was exceedingly difficult to treat patients with this syndrome until the IL-1 receptor antagonist anakinra became available. Anakinra allows a complete control of all signs within hours after the first injection, but patients need continuous treatment with daily injections.In many aspects, the Schnitzler syndrome resembles the genetically determined auto-inflammatory syndromes involving activating mutations of the NLRP3 inflammasome. This latter point and its consequences will be addressed.

Time-course analysis of serum hepcidin, iron and cytokines in a C282Y homozygous patient with Schnitzler's syndrome treated with IL-1 receptor antagonist.

It is currently unknown if the increase of the hepatic iron regulatory hormone hepcidin during inflammation in man depends on an intact HFE-protein. Here we describe the temporal relationship of serum hepcidin, serum iron and cytokines in a patient with HFE-related (C282Y homozygous) hereditary hemochromatosis who was treated for an auto-inflammatory condition, i.e. variant Schnitzler's syndrome, with the potent anti-inflammatory cytokine inter-leukin-1 receptor antagonist (IL-1ra, anakinra). The patient had bouts of fever with peaking serum IL-6 concentrations followed by peaking serum hepcidin levels, while serum iron was low. Upon treatment, these peaks disappeared and hepcidin levels became non-detectable, consistent with HFE deficiency. In conclusion, this in vivo human model: i) supports the importance of an HFE-independent IL-6-hepcidin axis in the development of hypoferremia and anemia of inflammation; and ii) suggests that chronic inflammation protects patients with HFE-related hereditary hemochromatosis from iron accumulation.

El síndrome de Schnitzler / Schnitzler's syndrome

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Respuesta de los autores: El síndrome de Schnitzler / No disponible

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