Schnitzler's syndrome - a novel hypothesis of a shared pathophysiologic mechanism with Waldenström's disease.

Schnitzler's syndrome is an auto-inflammatory disorder which is characterized by two mandatory features: an urticarial rash and a monoclonal gammopathy. Although the pathophysiology of this syndrome is not yet fully understood, a role for interleukin-1 seems apparent. While this presumed link between interleukin-1 and the monoclonal gammopathy is not yet elucidated, a mutual factor in pathophysiology however seems likely. Here we present a novel hypothesis of a shared pathophysiologic mechanism between Schitzler's syndrome and monoclonal gammopathy.

Síndrome de Schnitzler: descripción de 3 casos / Schnitzler syndrome: report of 3 cases

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Dysregulation of proinflammatory versus anti-inflammatory human TH17 cell functionalities in the autoinflammatory Schnitzler syndrome.

BACKGROUND: TH17 cells have so far been considered to be crucial mediators of autoimmune inflammation. Two distinct types of TH17 cells have been described recently, which differed in their polarization requirement for IL-1ß and in their cytokine repertoire. Whether these distinct TH17 phenotypes translate into distinct TH17 cell functions with implications for human health or disease has not been addressed yet. OBJECTIVE: We hypothesized the existence of proinflammatory and anti-inflammatory human TH17 cell functions based on the differential expression of IL-10, which is regulated by IL-1ß. Considering the crucial role of IL-1ß in the pathogenesis of autoinflammatory syndromes, we hypothesized that IL-1ß mediates the loss of anti-inflammatory TH17 cell functionalities in patients with Schnitzler syndrome, an autoinflammatory disease. METHODS: To assess proinflammatory versus anti-inflammatory TH17 cell functions, we performed suppression assays and tested the effects of IL-1ß dependent and independent TH17 subsets on modulating proinflammatory cytokine secretion by monocytes. Patients with Schnitzler syndrome were analyzed for changes in TH17 cell functions before and during therapy with IL-1ß-blocking drugs. RESULTS: Both TH17 cell subsets differ in their ability to suppress T-cell proliferation and their ability to modulate proinflammatory cytokine production by antigen-presenting cells because of their differential IL-10 expression properties. In patients with Schnitzler syndrome, systemic overproduction of IL-1ß translates into a profound loss of anti-inflammatory TH17 cell functionalities, which can be reversed by anti-IL-1ß treatment. CONCLUSION: IL-1ß signaling determines the differential expression pattern of IL-10, which is necessary and sufficient to induce proinflammatory versus anti-inflammatory TH17 cell functions. Our data introduce TH17 cell subsets as novel players in autoinflammation and thus novel therapeutic targets in autoinflammatory syndromes including other IL-1ß mediated diseases. This demonstrates for the first time alterations in the adaptive immune system in patients with autoinflammatory syndromes.

[Schnitzler's syndrome]. / Le syndrome de Schnitzler.

Schnitzler syndrome (SS) is a rare clinical entity, which belongs to the spectrum of monoclonal gammapathy-associated systemic disorders. Its pathophysiology remains elusive, even if it is tempting to consider it as a late onset and probably acquired auto-inflammatory syndrome. SS mainly occurs in the fifth and sixth decade, and present with an urticariform rash with periodic fever and/or osteoarticular pain. Systemic inflammation and monoclonal gammapathy (overwhelmingly IgM kappa) are constant features. SS is a chronic disease, which can severely impair quality of life of the affected individuals. Many drugs have been used and proved disappointing. In the last few years, accumulating reports provided evidence for the dramatic efficacy of anakinra, which has revolutionized the management of most severe cases. The main long-term threat to these patients is to develop a lymphoproliferative disorder (mainly Waldenström's macroglobulinemia). The mechanisms underlying the different facets of the disease remain to be elucidated.

Schnitzler syndrome, an autoimmune-autoinflammatory syndrome: report of two new cases and review of the literature.

Schnitzler syndrome is a rare disorder characterized clinically by chronic urticarial rash accompanied by fever, arthralgia or arthritis, bone pain and lymphoadenopathy and biochemically by monoclonal gammopathy and elevation of inflammatory indices. The disorder is very likely under-recognized and its origin remains obscure although it may be included among the immune mediated inflammatory diseases with features of autoinflammation and autoimmunity. We describe here two patients affected by Schnitzler syndrome, both refractory to corticosteroids and immunosuppressive therapy, successfully treated with the interleukin-1 receptor antagonist Anakinra. Unfortunately after two weeks, one patient experienced an important local adverse reaction to the biological drug. We decided to discontinue Anakinra with flare of the disease after 24 h. We therefore switched to Rituximab obtaining a complete remission in two months. We searched MEDLINE in order to analyze the frequency of the disease, its pathogenesis and outcome. The electronic search was conducted using the following key words "Schnitzler syndrome" and "Treatment of Schnitzler syndrome". All the selected papers, except the clinical reviews, described at least one case of Schnitzler syndrome. The review of the literature highlighted that Schnitzler syndrome remains an enigmatic disorder hard to categorize and to treat.

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.

Schnitzler's syndrome: increased levels of bone formation and angiogenesis factors are reduced after successful pefloxacin treatment.

Schnitzler's syndrome is characterized by chronic urticaria and monoclonal immunoglobulin (Ig) M gammopathy, with other features including intermittent fever, joint and/or bone pain with radiologic evidence of osteosclerosis, lymphadenopathy, enlarged liver and/or spleen, leukocytosis, and elevated erythrocyte sedimentation rate. The etiology of the syndrome remains obscure, although involvement of various cytokines has been proposed. Bone metabolism and angiogenesis markers are deregulated in Waldenström macroglobulinemia and IgM monoclonal gammopathy of unknown significance, but these markers have not been assessed in Schnitzler's syndrome. Herein, we report a patient with Schnitzler's syndrome who was treated with oral pefloxacin. Serum levels of osteoclast regulators, markers of bone remodeling and angiogenesis cytokines, were measured before treatment and serially after the initiation of treatment. High bone turnover and strikingly elevated levels of angiogenic cytokines were observed at diagnosis. Treatment with pefloxacin resulted in a normalization of the bone remodeling process and a significant reduction of angiogenic cytokines, with rapid and sustained improvement of symptoms, suggesting that these factors might be implicated in the pathophysiology of this syndrome. Furthermore, pefloxacin was proven to be an effective treatment for patients with Schnitzler's syndrome.

Schnitzler syndrome.

Schnitzler syndrome is characterized by monoclonal IgM gammopathy, urticaria, recurrent fever, evidence of inflammation, bone pain, and arthralgia, occasionally in combination with lymphadenopathy and/or hepatosplenomegaly. Only about 80 cases have been reported to date. Development of a hematological malignancy is the main complication. Recent reports of remissions induced by IL-1 receptor antagonist therapy shed new light on the pathophysiology of the disease.

Schnitzler syndrome: heterogeneous immunopathological findings involving IgM-skin interactions.

The Schnitzler syndrome is the association of chronic urticaria, intermittent fever, osteosclerotic bone lesions and a monoclonal IgM gammopathy. It is not yet firmly established whether the monoclonal immunoglobulin component plays a part in the pathophysiology of the urticarial lesions. Immunoblotting on epidermal and dermal human skin extracts as well as immunoelectron microscopic (IEM) studies on Lowicryl K4M-embedded skin sections were performed in three patients with the Schnitzler syndrome. Western blotting on epidermal extracts showed the presence of IgM-kappa antiskin autoantibodies in two patients. These antibodies displayed the same isotype as the monoclonal components and recognized a 280-290-kDa antigen in one patient and a 200-kDa antigen in the other patient. IEM studies showed sparse IgM deposits in the epidermis, around the keratinocytes, near the desmosomes in one patient and dense deposits below the lamina densa, in the region of the anchoring fibrils, in another patient. Antiskin IgM autoantibodies of the same isotype as their monoclonal gammopathies can be present in the serum of some patients with the Schnitzler syndrome. These IgM antibodies seem to deposit in vivo in the epidermis and at the dermal-epidermal junction, in the region of the anchoring fibrils. These findings suggest that the monoclonal gammopathy plays a part in the pathophysiology of the skin rash. They also suggest patient heterogeneity both in the skin antigens that are recognized as well as in their localization.

Schnitzler syndrome: a case study.

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.