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1.
Front Immunol ; 11: 588322, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33324407

RESUMO

Background: Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal IgM gammopathy. Overactivation of the interleukin(IL)-1 system is reported, even though the exact pathophysiological pathways remain unknown. Objective: To determine ex vivo cytokine profiles of Peripheral Blood Mononuclear Cells (PBMCs) from SchS patients prior to treatment and after initiation of anti-IL-1 therapy (anakinra). The sera cytokine profile was studied in parallel. Methods: We collected blood samples from thirty-six untreated or treated SchS. PBMCs were cultured with and without LPS or anti-CD3/CD28. Cytokine levels were evaluated in serum and cell culture supernatants using Luminex technology. Results: Spontaneous TNFα, IL-6, IL-1ß, IL-1α, and IL-1RA release by PBMCs of SchS patients were higher than in controls. LPS-stimulation further induced the secretion of these cytokines. In contrast, after T-cell stimulation, TNFα, IL-10, IFNγ, IL-17A, and IL-4 production decreased in SchS patients compared to healthy controls, but less in treated patients. Whereas IL-1ß serum level was not detected in most sera, IL-6, IL-10, and TNFα serum levels were higher in patients with SchS and IFNγ and IL-4 levels were lower. Of note, IL-6 decreased after treatment in SchS (p = 0.04). Conclusion: Our data strengthen the hypothesis of myeloid inflammation in SchS, mediated in particular by IL-1ß, TNFα, and IL-6, associated with overproduction of the inhibitors IL-1RA and IL-10. In contrast, we observed a loss of Th1, Th2, and Th17 cell functionalities that tends to be reversed by anakinra.


Assuntos
Citocinas/imunologia , Síndrome de Schnitzler/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Células Cultivadas , Citocinas/sangue , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos
2.
Autoimmunity ; 52(7-8): 264-271, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31646899

RESUMO

Introduction: Schnitzler syndrome is an auto-inflammatory disease defined by chronic urticarial eruption and monoclonal gammopathy. 18F fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is often performed, but its utility in Schnitzler syndrome has not been specifically investigated. The aim of this study was to determine whether PET/CT is informative in the diagnosis and follow-up of Schnitzler syndrome relative to other imaging techniques, including bone scans.Patients and methods: Patients of this study were selected from the French cohort established by Néel et al. All patients with a diagnosis of Schnitzler syndrome (according to Strasbourg's and Lipsker's criteria) who had at least one PET/CT were included. Data were collected from medical records. PET/CT scans were all reviewed by a nuclear physician blinded to the clinical and imaging data.Results: Ten patients underwent at least one PET/CT scan and all had at least one 99mTechnetium bone scan during their follow-up. The most frequent PET/CT abnormalities were diffuse bone-marrow and/or increased femoral fluorodeoxyglucose uptake, but they did not correlate with disease activity. Conversely, bone-scan abnormalities, including mainly increased radiotracer uptake in long bones, appeared to strongly correlate with Schnitzler syndrome activity.Discussion: PET/CT does not appear to be useful for the diagnosis and follow-up of Schnitzler syndrome. However, bone scans appear to be more sensitive for diagnosis and may correlate with clinical activity. Bone scans may be well positioned to distinguish Schnitzler syndrome relapse from other aetiologies of bone, joint, or muscle pain.Conclusion: Bone scans may be favoured over PET/CT in Schnitzler syndrome.


Assuntos
Osso e Ossos/diagnóstico por imagem , Dor/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Síndrome de Schnitzler/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , Osso e Ossos/imunologia , Osso e Ossos/patologia , Estudos de Coortes , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Dor/sangue , Dor/imunologia , Dor/patologia , Compostos Radiofarmacêuticos/farmacocinética , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/imunologia , Síndrome de Schnitzler/patologia
3.
Scand J Rheumatol ; 48(3): 235-238, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30668200

RESUMO

OBJECTIVES: Schnitzler syndrome (SchS) is an autoinflammatory disorder characterized by chronic urticaria, fever, and monoclonal gammopathy. The success of interleukin-1 (IL-1) blocking therapies suggests a crucial role for IL-1 in disease induction. The aim of this study is to perform a comprehensive analysis of IL-1 family cytokines and soluble receptors in a group of SchS patients. METHOD: Three patients fulfilling the criteria for the diagnosis of SchS were recruited; 80 blood donors formed the control group. IL-1 family cytokines (IL-1α, IL-1ß, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, sIL-1R4), and antagonists [IL-1Ra, IL-18 binding protein (IL-18BP)] were measured by a multiarray enzyme-linked immunosorbent assay. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. Cytokine levels were compared by the Mann-Whitney test. RESULTS: IL-18 and free IL-18 were increased in patients compared with controls (p = 0.005 and p = 0.0082, respectively), while IL-18BP levels were not different. IL-1α, IL-1ß, and IL-33 were undetectable in both patients and controls. The soluble receptors sIL-1R1, sIL-1R2, and ST2/sIL-1R4, and the IL-1 antagonist IL-1Ra were all within normal ranges; sIL-1R3 was significantly lower in patients than in controls (p = 0.039). CONCLUSIONS: The data indicate that SchS is characterized by increased circulating levels of free IL-18, possibly leading to a higher activation of innate/inflammatory effector cells. At variance with other inflammatory diseases, the lack of increase in sIL-1R1 and sIL-1R2 and the decreased levels of sIL-R3 imply a failure in the counterbalancing mechanism aimed at inhibiting excessive IL-1ß in tissues.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-18/sangue , Interleucina-1 , Receptores de Interleucina-1 , Síndrome de Schnitzler , Feminino , Humanos , Inflamação/sangue , Interleucina-1/antagonistas & inibidores , Interleucina-1/sangue , Interleucina-1/classificação , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/sangue , Receptores de Interleucina-1/classificação , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/diagnóstico , Síndrome de Schnitzler/imunologia , Estatísticas não Paramétricas
4.
Br J Dermatol ; 180(4): 859-868, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30339714

RESUMO

BACKGROUND: Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal gammopathy, which manifest mostly in the second half of life. It involves overactivation of the interleukin (IL)-1 system, but the exact pathophysiological pathways remain largely unknown. OBJECTIVES: To identify and characterize the pathogenetic players in SchS. METHODS: Blood parameters were quantified in patients with SchS compared with healthy controls and patients with psoriasis and hidradenitis suppurativa using enzyme-linked immunosorbent assay (ELISA). CCL2 expression in cultured primary cells was analysed by quantitative reverse-transcriptase polymerase chain reaction and ELISA. RESULTS: CCL2, a chemoattractant for monocytic and further mononuclear immune cells, was found to be significantly elevated in patients with SchS. CCL2 levels showed a positive association with global disease activity, especially with bone pain, but not disease duration, gammopathy, neutrophilia or skin disease. In vitro stimulation assays demonstrated a strong CCL2 production capacity of mononuclear immune cells and fibroblasts, but not epithelial or endothelial cells. Among a range of inflammatory mediators, only IL-1ß (immune cells, fibroblasts) and tumour necrosis factor (TNF)-α (fibroblasts) were important CCL2 inducers. TNF-α, but not IL-17, strengthened the CCL2-inducing effect of IL-1ß in fibroblasts. Accordingly, CCL2 levels positively correlated with both TNF-α and IL-1ß serum levels in patients with SchS. Therapeutic IL-1ß blockade decreased CCL2 blood levels in these patients as early as 1 week after the initiation of treatment. CONCLUSIONS: CCL2 may be an important component of the pathogenetic cascade leading to bone alterations, and a suitable marker of disease activity in patients with SchS.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Quimiocina CCL2/sangue , Interleucina-1beta/antagonistas & inibidores , Dor Musculoesquelética/diagnóstico , Síndrome de Schnitzler/diagnóstico , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , Quimiocina CCL2/imunologia , Quimiocina CCL2/metabolismo , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Voluntários Saudáveis , Hidradenite Supurativa/sangue , Humanos , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Dor Musculoesquelética/sangue , Dor Musculoesquelética/tratamento farmacológico , Dor Musculoesquelética/imunologia , Cultura Primária de Células , Psoríase/sangue , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/tratamento farmacológico , Síndrome de Schnitzler/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
5.
Blood ; 131(9): 974-981, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29284595

RESUMO

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.


Assuntos
Mutação em Linhagem Germinativa , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Síndrome de Schnitzler , Adulto , Idoso , Substituição de Aminoácidos , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Feminino , Humanos , Interleucina-18/sangue , Interleucina-18/genética , Interleucina-6/sangue , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/tratamento farmacológico , Síndrome de Schnitzler/genética
6.
Yonsei Med J ; 59(1): 154-157, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29214791

RESUMO

Chronic urticaria may often be associated with interleukin (IL)-1-mediated autoinflammatory disease, which should be suspected if systemic inflammation signs are present. Here, we report a case of Schnitzler's syndrome without monoclonal gammopathy treated successfully with the IL-1 receptor antagonist anakinra. A 69-year-old man suffered from a pruritic urticarial rash for 12 years. It became aggravated episodically and was accompanied by high fever, arthralgia, leukocytosis, and an elevated C-reactive protein and erythrocyte sedimentation rate. The episodes each lasted for over one week. Neutrophilic and eosinophilic inflammation was found on skin biopsy. However, serum and urine electrophoresis showed no evidence of monoclonal gammopathy. The cutaneous lesions were unresponsive to various kinds of anti-histamines, systemic glucocorticoids, colchicine, cyclosporine, dapsone, and methotrexate, which were administered over a span of 3 years immediately preceding successful treatment. A dramatic response, however, was observed after a daily administration of anakinra. This observation suggests that the correct diagnosis of this case is Schnitzler's syndrome without monoclonal gammopathy. For an adult patient with refractory chronic urticaria and systemic inflammation, Schnitzler's syndrome could be considered as a possible differential diagnosis. Although the typical form of Schnitzler's syndrome exhibits the presence of monoclonal gammopathy as a diagnostic criterion, monoclonal gammopathy may be absent in an atypical form. In such a situation, an IL-1 antagonist should be effective for the management of chronic urticaria.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Paraproteinemias/complicações , Síndrome de Schnitzler/tratamento farmacológico , Urticária/complicações , Idoso , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Doença Crônica , Humanos , Leucócitos/metabolismo , Masculino , Síndrome de Schnitzler/sangue
7.
Yonsei Medical Journal ; : 154-157, 2018.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wpr-742490

RESUMO

Chronic urticaria may often be associated with interleukin (IL)-1-mediated autoinflammatory disease, which should be suspected if systemic inflammation signs are present. Here, we report a case of Schnitzler's syndrome without monoclonal gammopathy treated successfully with the IL-1 receptor antagonist anakinra. A 69-year-old man suffered from a pruritic urticarial rash for 12 years. It became aggravated episodically and was accompanied by high fever, arthralgia, leukocytosis, and an elevated C-reactive protein and erythrocyte sedimentation rate. The episodes each lasted for over one week. Neutrophilic and eosinophilic inflammation was found on skin biopsy. However, serum and urine electrophoresis showed no evidence of monoclonal gammopathy. The cutaneous lesions were unresponsive to various kinds of anti-histamines, systemic glucocorticoids, colchicine, cyclosporine, dapsone, and methotrexate, which were administered over a span of 3 years immediately preceding successful treatment. A dramatic response, however, was observed after a daily administration of anakinra. This observation suggests that the correct diagnosis of this case is Schnitzler's syndrome without monoclonal gammopathy. For an adult patient with refractory chronic urticaria and systemic inflammation, Schnitzler's syndrome could be considered as a possible differential diagnosis. Although the typical form of Schnitzler's syndrome exhibits the presence of monoclonal gammopathy as a diagnostic criterion, monoclonal gammopathy may be absent in an atypical form. In such a situation, an IL-1 antagonist should be effective for the management of chronic urticaria.


Assuntos
Idoso , Humanos , Masculino , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Doença Crônica , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Leucócitos/metabolismo , Paraproteinemias/complicações , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/tratamento farmacológico , Urticária/complicações
9.
Arthritis Res Ther ; 17: 187, 2015 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-26198339

RESUMO

INTRODUCTION: Schnitzler's syndrome (SchS) is a disabling autoinflammatory disorder, characterized by a chronic urticarial rash, an M-protein, arthralgia, and other signs of systemic inflammation. Anti-interleukin-1 (IL-1) beta antibodies are highly effective, but the pathophysiology is still largely unknown. Here we studied the effect of in-vivo IL-1 inhibition on serum markers of inflammation and cellular immune responses. METHODS: Eight patients with SchS received monthly subcutaneous (s.c.) injections with 150 mg canakinumab for six months. Blood was drawn for measurement of serum markers of inflammation (12 times per patient) and for functional and phenotypic analysis of both freshly isolated and toll-like receptor (TLR)-ligand-stimulated peripheral blood mononuclear cells (PBMCs) (five times per patient). All data were compared to results of healthy controls. RESULTS: IL-6 levels in serum and in lysates of freshly isolated PBMCs and serum myeloid-related protein (MRP8)/14 and S100A12 levels correlated with disease activity. In vitro, LPS stimulation resulted in higher IL-6 and IL-1 beta production in PBMCs from symptomatic SchS patients compared to healthy controls, whereas patient cells were relatively hyporesponsive to poly:IC and Pam3Cys. The mRNA microarray of PBMCs showed distinct transcriptomes for controls, symptomatic patients and anti-IL-1-treated patients. Numbers of T- and B-cell subsets as well as M-protein concentrations were not affected by IL-1 inhibition. Free light chain levels were elevated in 4 out of 8 patients. CONCLUSIONS: In conclusion, patient PBMCs are hyperresponsive to LPS, and clinical efficacy of IL-1 beta inhibition in patients with SchS is associated with in-vivo and ex-vivo suppression of inflammation. Interestingly, patient PBMCs showed divergent responses to TLR2/6, TLR3 and TLR4 ligands. Our data underscore that IL-1 beta plays a pivotal role in SchS.


Assuntos
Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/fisiologia , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/diagnóstico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Biomarcadores/sangue , Células Cultivadas , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Síndrome de Schnitzler/tratamento farmacológico
10.
Haematologica ; 98(10): 1581-5, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23812931

RESUMO

Schnitzler syndrome is considered to be a rare disorder characterized by a monoclonal IgM protein and chronic urticaria that is associated with considerable morbidity. We hypothesized that the syndrome may be under-recognized and patients may be deprived of highly effective therapy in the form of anakinra. We performed a retrospective search of the dysproteinemia database at Mayo Clinic as well as the medical records of all patients with chronic urticaria to determine the true incidence of the disease. We compared patients with the diagnosis of Schnitzler syndrome and those who met the criteria but in whom the syndrome was not recognized. Comparisons between groups were performed and survival curves determined. We identified 16 patients with diagnosed Schnitzler syndrome and an additional 46 patients who met diagnostic criteria. The monoclonal protein was IgMκ in 94% of patients. Therapy with anakinra in 4 patients led to rapid and complete resolution of symptoms. The median overall survival for this syndrome is over 12.8 years. Progression to lymphoma was only observed in 8% of patients; this is lower than previous reports. Schnitzler syndrome may be present in up to 1.5% of patients with a monoclonal IgM in their serum and likely under-recognized as a clinical syndrome.


Assuntos
Imunoglobulina M/sangue , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Síndrome de Schnitzler/mortalidade , Taxa de Sobrevida
11.
Ann Rheum Dis ; 72(10): 1634-8, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23087179

RESUMO

OBJECTIVES: 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-1ß. Canakinumab is a selective human monoclonal anti-IL-1ß 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-1ß plays a pivotal role in this disease. CLINICALTRIALS.GOV: NCT01276522.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunossupressores/uso terapêutico , Interleucina-1beta/antagonistas & inibidores , Síndrome de Schnitzler/tratamento farmacológico , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Esquema de Medicação , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Mediadores da Inflamação/metabolismo , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Síndrome de Schnitzler/sangue , Índice de Gravidade de Doença , Resultado do Tratamento
13.
Haematologica ; 97(11): 1699-703, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22689688

RESUMO

Schnitzler syndrome is a rare plasma cell disorder the pathogenesis of which is still not fully understood. We evaluated the circulating levels of four major angiogenic cytokines (VEGF, angiogenin, angiopoietin-1 and angiopoietin-2) and six bone remodeling markers (sRANKL, osteoprotegerin, dickkopf-1, CTX, osteocalcin and bone-specific alkaline phosphatase-bALP) in 13 patients with Schnitzler syndrome. At diagnosis, patients had elevated angiogenic cytokines. The mean VEGF levels were almost 3.5-fold higher in Schnitzler syndrome compared to controls, while 10 of 13 patients had higher VEGF than the upper control value. Successful treatment led to a significant reduction in VEGF. Patients with Schnitzler syndrome had increased bone formation (high bALP, osteocalcin and osteoprotegerin) which was not balanced by an increase in bone resorption (normal CTX and sRANKL). These data support a role for VEGF as a new minor criterion in the diagnosis and follow up of Schnitzler syndrome, while the uncoupling of bone remodeling in favor of bone formation justifies the presence of bone densification.


Assuntos
Proteínas Angiogênicas/sangue , Antígenos de Diferenciação/sangue , Imunoglobulina M , Neovascularização Fisiológica , Osteogênese , Síndrome de Schnitzler/sangue , Urticária/sangue , Adulto , Idoso , Reabsorção Óssea/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Schnitzler/complicações , Síndrome de Schnitzler/patologia , Urticária/complicações , Urticária/patologia
14.
Vnitr Lek ; 57(1): 97-112, 2011 Jan.
Artigo em Tcheco | MEDLINE | ID: mdl-21351669

RESUMO

Schnitzler syndrome is a rare idiopathic disease characterized by chronic urtica, presence of monoclonal IgM immunoglobuline and further, less common symptoms. This case report describes another case of this disease affecting a male adult born in 1963. The first symptoms, eruptions of non-pruritic urticarial rash, appeared in this patient at the age of 43. In addition, bone pains (mainly tibias) and joint pains (mainly knees) were present. Later on however, severe attacks of fever, chills and shaking together with bone and joint pains were added to during which new urticarial eruptions appeared. Primarily, the man was followed up without any substantial therapeutic results at a department of dermatovenerology, subsequently, due to a finding of monoclonal IgM kappa immunoglobulin (serum concentration 1.9 g/l) he was referred to our department for the reason of gammopathy being a differential diagnosis. On a CT scan hyperostosis in claviculae and pelvic bones was identified. Also on the CT, an increase in cortical thickness was described in the long bones of the lower extremities, where areas of technetium pyrophosphate accumulation were identified on a bone scintigraphy. These areas were found in the chest and sacral regions as well. From the blood exams, the proinflammatory status of the organism was apparent (CRP 35.9 mg/l, erythrocyte sedimentation rate 92 mm/h, leukocytes 12.4 x 10(9)/l). After excluding other differential diagnoses, the patient was diagnosed with Schnitzler syndrome. As regards therapy, we made initial use of the effect of corticoids which abated the symptoms, however, these were causing serious adverse reactions in the form of iatrogenous Cushing's syndrome. The therapy took a turn only after biologic therapy with anakinra (interleukin-1 receptor antagonist) had started, which minimized the Schnitzler symptoms with very good drug tolerance. In the work we measured serum levels of interleukins for disease activity monitoring. The most sensitive were interleukins IL-6 and especially IL-18 the levels of which were the highest at the time of clinical exacerbation of the disease, whereas the levels of IL-1beta and TNF-alpha (tumour necrosis factor) were during all measurements below the limit of detection. Concerning the growing numbers of the reports on successful biological therapy with anakinra and our positive experience, we propose that the therapeutic response to anakinra should be included within the diagnostic criteria of Schnitzler syndrome, which is significant above all in differential diagnosis thereof.


Assuntos
Antirreumáticos/uso terapêutico , Glucocorticoides/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Síndrome de Schnitzler/tratamento farmacológico , Citocinas/sangue , Diagnóstico Diferencial , Glucocorticoides/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/diagnóstico
17.
Eur Cytokine Netw ; 20(3): 108-11, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19825519

RESUMO

Schnitzler syndrome is a rare disease characterised by chronic urticaria and arthralgia. The recent evidence that the IL-1 receptor antagonist IL-1Ra could induce rapid and complete remission of Schnitzler symptoms has pointed to IL-1 as a major pathological factor in this disease. To examine the possibility that Schnitzler syndrome may be considered to be an autoinflammatory disease, in this study we measured the serum levels of IL-18, another cytokine of the IL-1 family that is cleaved by caspase-1, in two recently diagnosed Schnitzler patients before and after treatment with IL-1Ra. In parallel, mRNA expression of IL-1 family cytokines and caspase-1 were assessed in isolated blood monocytes. Treatment with IL-1Ra significantly inhibited IL-1beta gene expression, indicating that IL-1beta activity in Schnitzler syndrome is central to IL-1beta gene upregulation in a type of auto-amplification loop. While no IL-1beta was detected in serum, free circulating IL-18 was increased in patients with Schnitzler syndrome, despite low IL-18 gene expression in monocytes. This suggests constitutive activation of the IL-1beta/IL-18-producing inflammasome, and supports the hypothesis that Schnitzler's syndrome is a new autoinflammatory disease.


Assuntos
Inflamação/sangue , Inflamação/imunologia , Interleucina-18/sangue , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/imunologia , Idoso , Regulação da Expressão Gênica , Humanos , Inflamação/complicações , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Interleucina-18/genética , Masculino , Pessoa de Meia-Idade , Síndrome de Schnitzler/complicações
18.
Rheumatology (Oxford) ; 48(10): 1304-8, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19696060

RESUMO

OBJECTIVE: IL-1beta plays a key role in the pathogenesis of Schnitzler's syndrome (SS). We have investigated inflammasome activity in peripheral blood mononuclear cells (PBMCs) from a patient affected by a variant type of SS. METHODS: PBMCs were purified by Ficoll and examined for ability to secrete IL-1beta and -18, expression and function of the P2X(7) receptor and expression of apoptosis-associated speck-like protein containing a caspase recruitment domaine (ASC) and NOD-like receptor protein 3 (NLRP3) before and after the therapy with steroid. Furthermore, extracellular adenosine 5'-triphosphate (ATP) blood levels were determined by luciferase assay. Expression of inflammasome components was measured by real time PCR and western blotting. RESULTS: PBMCs of patient with SS showed a high, spontaneous and lipopolysaccharide-stimulated, IL-1beta release but low response to stimulation with the P2X(7) agonist benzoyl ATP. P2X(7) expression was several fold increased, whereas ASC expression was dramatically decreased compared with PBMCs from healthy controls. NLRP3 expression was unchanged. Prednisone treatment induced remission of clinical symptoms and normalized IL-1beta secretion and P2X(7) and ASC expression. CONCLUSION: These findings reveal the presence of an overall derangement of the inflammasome and IL-1beta processing and release in SS.


Assuntos
Complexos Multiproteicos/fisiologia , Síndrome de Schnitzler/sangue , Adulto , Feminino , Humanos , Mediadores da Inflamação/sangue , Interleucina-18/sangue , Interleucina-1beta/sangue , Receptores Purinérgicos P2/sangue , Receptores Purinérgicos P2X7
19.
Haematologica ; 94(9): 1297-300, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19608676

RESUMO

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.


Assuntos
Peptídeos Catiônicos Antimicrobianos/sangue , Antirreumáticos/administração & dosagem , Hemocromatose , Antígenos de Histocompatibilidade Classe I/sangue , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Interleucina-6/sangue , Ferro/sangue , Proteínas de Membrana/sangue , Mutação de Sentido Incorreto , Síndrome de Schnitzler , Peptídeos Catiônicos Antimicrobianos/genética , Hemocromatose/sangue , Hemocromatose/tratamento farmacológico , Hemocromatose/genética , Proteína da Hemocromatose , Hepcidinas , Antígenos de Histocompatibilidade Classe I/genética , Homozigoto , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/tratamento farmacológico , Síndrome de Schnitzler/genética , Fatores de Tempo
20.
Allergol Immunopathol (Madr) ; 35(2): 71-3, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17428403

RESUMO

Schnitzler's syndrome is an unusual clinical association of chronic urticaria, intermittent fever and monoclonal immunoglobulin M (IgM) gammopathy. The pathogenesis of the urticaria is unclear and treatment is problematic. We describe the case of a 61-year-old woman with a long history of chronic urticaria with severe pruritus, spiking fever and malaise. The IgM-kappa monoclonal component was detected in the patient's serum 4 years after symptom onset. After ineffective treatment with antihistamines and systemic corticosteroids, oral cyclosporine resulted in complete remission of the fever and malaise, which has persisted after an 18-month follow-up. Partial but maintained remission of the urticaria was also observed, allowing corticosteroid doses to be decreased.


Assuntos
Ciclosporina/uso terapêutico , Imunossupressores/uso terapêutico , Síndrome de Schnitzler/tratamento farmacológico , Artralgia/etiologia , Ciclosporina/administração & dosagem , Quimioterapia Combinada , Feminino , Febre/etiologia , Humanos , Imunoglobulina M/sangue , Cadeias kappa de Imunoglobulina/análise , Imunossupressores/administração & dosagem , Metilprednisolona/administração & dosagem , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Paraproteínas/análise , Recidiva , Síndrome de Schnitzler/sangue , Urticária/tratamento farmacológico , Urticária/etiologia
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