Association of CCL2 with systemic inflammation in Schnitzler syndrome.

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.

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.

A Case of Schnitzler's Syndrome without Monoclonal Gammopathy-Associated Chronic Urticaria Treated with Anakinra.

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.

Schnitzler syndrome: an under-diagnosed clinical entity.

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.

Increased angiogenesis and enhanced bone formation in patients with IgM monoclonal gammopathy and urticarial skin rash: new insight into the biology of Schnitzler syndrome.

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.

[Schnitzler syndrome: case report, the experience with glucocorticoid and anakinra (Kineret) therapies and monitoring of systemic cytokine response]. / Schnitzler-syndrom: popis prípadu, zkusenosti s lécbou glukokortikoidy a preparátem anakinra (Kineret) a sledování cytokinové odpovedi organizmu.

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.

Dysfunctional inflammasome in Schnitzler's syndrome.

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.

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.

[Schnitzler syndrome: a rare cause of systemic urticaria]. / Syndrome de Schnitzler: une cause rare d'urticaire systémique.

INTRODUCTION: The Schnitzler's syndrome first described in 1972, associates urticaria, bone pain, and monoclonal IgM gammapathy. EXEGESIS: A 50-year-old man presented symptoms of urticaria restricted to the trunk and lower members, with episodes of fever accompanied by inflammatory pain in the knees and legs. Slight deterioration of his general condition was also observed. Biological findings showed the existence of an inflammatory syndrome. Electrophoresis and immunoelectrophoresis provided evidence for the existence of underlying IgM gammapathy. Bone X-ray demonstrated the presence of tibial and peroneal metaphysis thickening, with hyperfixation on bone scintigraphy. The patient's condition improved after cortisone and colchicine treatment, allowing decrease in coricosteroid doses. Two years later, except for urticaria, clinical features have disappeared and no hematological disorder has been observed.

Schnitzler's syndrome presenting as fever of unknown origin (FUO). The role of cytokines in its systemic features.

A patient with Schnitzler's syndrome is described presenting with fever of unknown origin. Although he had all characteristic features of the syndrome (urticarial vasculitis, hyperostosis, lymphadenopathy, fever and serum IgM monoclonal component), it was recognized very late in the diagnostic process. Cytokines were measured to get more insight into the role of cytokines in this syndrome, but only interleukin-6 was elevated. It is important for internists and rheumatologist to recognize this entity in order to prevent unnecessary diagnostic procedures.