Schnitzler Syndrome Research Articles

Neutrophilic Epitheliotropism is a Histopathological Clue to Neutrophilic Urticarial Dermatosis.

Neutrophilic urticarial dermatosis (NUD) comprises a particular autoinflammatory condition within the spectrum of aseptic neutrophilic dermatoses characterized by a distinct urticarial eruption clinically and a neutrophilic dermatosis histopathologically. In this study, we reviewed skin biopsies of lesional skin of patients seen in our outpatient clinic for autoimmune dermatoses and in allergy department from 1982 to 2014 that fulfilled these criteria. A total of 77 biopsies from 50 patients were analyzed histopathologically. Included were cases of Schnitzler syndrome, Still disease, systemic lupus erythematosus, Sjögren syndrome, cryopyrin-associated periodic syndrome, primary biliary cirrhosis, inflammatory bowel disease, and those that had signs of systemic inflammation not otherwise specified, that is, fever, arthritis, leukocytosis, and elevated erythrocyte sedimentation rate. A control cohort was defined as including a total of 70 biopsies from 50 patients comprising neutrophilic urticaria (pressure-induced and not pressure-induced), conventional urticaria, lupus erythematosus expressing neutrophils, and exanthematous drug reaction of macular type expressing neutrophils. Skin biopsies of NUD revealed a perivascular and interstitial neutrophilic infiltrate focally extending into the epithelia of epidermis, hair follicles, sebaceous and sweat glands, a feature which we termed neutrophilic epitheliotropism. This neutrophilic epitheliotropism proved to be of high sensitivity (83.1%) and lower specificity (74.3%). The histological findings could be substantiated by immunohistochemical markers for leukocytes (elastase and myeloperoxidase), in particular in cases where neutrophils showed uncharacteristic band-like nuclei. Neutrophilic epitheliotropism is a new sensitive and specific histopathological clue for NUD, a histopathological reaction pattern within the spectrum of neutrophilic dermatoses that needs to be differentiated from conventional urticaria.

Interleukin-1-related cytokines as potential biomarkers in autoinflammatory skin diseases

Urticarial rash is a hallmark symptom of autoinflammatory diseases such as Cryopyrin-associated periodic syndrome (CAPS) and Schnitzler's syndrome (SchS). Clinically, the urticarial rash may not be distinguished from the skin symptoms in chronic urticaria patients. As interleukin-1s (IL-1s) has been shown to play a pivotal role in the pathogenesis of CAPS and SchS we here aim at investigating IL-1s and related cytokines for their potential as diagnostic skin biomarkers in patients with urticarial autoinflammatory syndromes.

Effectiveness of canakinumab treatment in Schnitzler's syndrome: a multi-center randomized placebo-controlled study

Methods The current placebo-controlled multi-center study was designed to assess the effects of the anti-IL-1s monoclonal antibody canakinumab (CAN) on the clinical signs and symptoms of SchS. We randomly assigned 20 patients with active disease to receive CAN 150 mg or placebo s.c. injections (day 0). Following the evaluation of treatment responses on day 7 the study was continued by a 16-week open label phase with CAN injections upon confirmed relapse of clinical symptoms. Efficacy was determined by changes in the physician’s global assessment (PGA; range 0-20), a combined symptom score which includes 5 key symptoms of SchS (urticarial rash, fever, fatigue, myalgia and arthralgia/bone pain), measurement of the inflammation markers C-reactive protein (CRP) and serum amyloid A (SAA) as well as changes in quality of life assessment (DLQI, SF-36).

The case of Schnitzler syndrome in one single rheumatologic center

Background Schnitzler syndrome is characterized by chronic, nonpruritic urticaria in association with recurrent fever, bone pain, arthralgia or arthritis, and a monoclonal immunoglobulin M (IgM) gammopathy. Pathogenesis of Schnitzler syndrome is unclear. Some hypothesize that the deposition of the IgM paraprotein, leading to the formation of immune complexes and the activation of the complement cascade, is responsible for the cutaneous manifestations. Another proposed mechanism involves the uncontrolled activation of interleukin 1-alpha (IL-1 a).

Clinical symptoms and molecular investigations in 13 patients with Schnitzler syndrome identified at the single UK centre

Schnitzler syndrome (SchS) was first described in 1972 and to date 281 cases have been reported. SchS is an adult onset, apparently acquired disease, which clinically closely resembles CAPS including the response to IL-1 blockade. A hallmark of the disease is the IgM kappa paraprotein, identified in 85% of the patients; recently variant IgG have been reported in 7% of cases.

Role for mast cells in Schnitzler's syndrome: here mast cells master a rash, too.

Role for mast cells in Schnitzler's syndrome: here mast cells master a rash, too.

The role of interleukin-1 beta in the pathophysiology of Schnitzler's syndrome.

IntroductionSchnitzler’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.MethodsEight 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.ResultsIL-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.ConclusionsIn 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0696-0) contains supplementary material, which is available to authorized users.

Mast-cell interleukin-1β, neutrophil interleukin-17 and epidermal antimicrobial proteins in the neutrophilic urticarial dermatosis in Schnitzler's syndrome.

Schnitzler's syndrome (SchS) is an autoinflammatory disease characterized by a chronic urticarial rash, a monoclonal component and signs of systemic inflammation. Interleukin (IL)-1β is pivotal in the pathophysiology. Here we investigated the cellular source of proinflammatory mediators in the skin of patients with SchS. Skin biopsies of lesional and nonlesional skin from eight patients with SchS and healthy controls, and patients with cryopyrin-associated periodic syndrome (CAPS), delayed-pressure urticaria (DPU) and cold-contact urticaria (CCU) were studied. We studied invivoIL-1β, IL-17 and antimicrobial protein (AMP) expression in resident skin cells and infiltrating cells. In addition we investigated the invitro effect of IL-1β, IL-17 and polyinosinic-polycytidylic acid (poly:IC) stimulation on cultured epidermal keratinocytes. Remarkably, we found IL-1β-positive dermal mast cells in both lesional and nonlesional skin of patients with SchS, but not in healthy control skin and CCU, and fewer in CAPS. IL-17-positive neutrophils were observed only in lesional SchS and DPU skin. In lesional SchS epidermis, mRNA and protein expression levels of AMPs were strongly increased compared with nonlesional skin and that of healthy controls. When exposed to IL-1β, poly:IC or IL-17, patient and control primary human keratinocytes produced AMPs in similar amounts. Dermal mast cells of patients with SchS produce IL-1β. This presumably leads to activation of keratinocytes and neutrophil influx, and further amplification of inflammation by IL-17 (from neutrophils and mast cells) and epidermal AMP production leading to chronic histamine-independent neutrophilic urticarial dermatosis.

Schnitzler syndrome: clinical features and histopathology

Schnitzler syndrome: clinical features and histopathology David Dingli,1,2 Michael J Camilleri3 1Division of Hematology, Department of Internal Medicine, 2Department of Molecular Medicine, 3Department of Dermatology, Mayo Clinic, Rochester, MN, USA Abstract: Schnitzler syndrome is a rare and underrecognized syndrome characterized by chronic urticaria, a monoclonal protein, and a variety of other symptoms, including fever, bone pain, organomegaly, and evidence of an acute phase response. Biopsy of an involved area of the skin shows a neutrophilic infiltrate without evidence of vasculitis or hemorrhage. Although the etiology of the syndrome is unknown, current evidence suggests this is an autoinflammatory syndrome. Recognition of this syndrome is critical since it is highly responsive to anakinra. Keywords: neutrophilic urticarial dermatosis, autoinflammatory syndrome, monoclonal gammopathy, neutrophilic dermatosis, anakinra&nbsp

Schnitzler syndrome: Prompt response to treatment with anakinra

Schnitzler syndrome: Prompt response to treatment with anakinra

Role of biologics in intractable urticaria.

Chronic urticaria (CU) is a common condition faced by many clinicians. CU has been estimated to affect approximately 0.5%–1% of the population, with nearly 20% of sufferers remaining symptomatic 20 years after onset. Antihistamines are the first-line therapy for CU. Unfortunately, nearly half of these patients will fail this first-line therapy and require other medication, including immune response modifiers or biologics. Recent advances in our understanding of urticarial disorders have led to more targeted therapeutic options for CU and other urticarial diseases. The specific biologic agents most investigated for antihistamine-refractory CU are omalizumab, rituximab, and intravenous immunoglobulin (IVIG). Of these, the anti-IgE monoclonal antibody omalizumab is the best studied, and has recently been approved for the management of CU. Other agents, such as interleukin-1 inhibitors, have proved beneficial for Schnitzler syndrome and cryopyrin-associated periodic syndromes (CAPS), diseases associated with urticaria. This review summarizes the relevant data regarding the efficacy of biologics in antihistamine-refractory CU.

Lupus erythematosus and neutrophilic urticarial dermatosis: a retrospective study of 7 patients.

Neutrophilic urticarial dermatosis (NUD) resembles urticaria clinically but is a neutrophilic dermatosis histopathologically. The majority of patients with NUD have an underlying systemic condition, mainly, autoinflammatory disorders such as cryopyrin-associated periodic syndromes, Schnitzler syndrome, and adult-onset Still disease, but a few also have systemic lupus erythematosus (LE). Here, we confirm these data and we report relevant clinical and histopathological data of 7 patients with LE and NUD. We retrospectively retrieved the medical records of all patients with LE in whom skin biopsy showed NUD in registers of Strasbourg and Montpellier University hospitals since 2000. All were female and aged between 13 and 45 years. Skin lesions were typically rose or red macules or slightly elevated papules occurring in a wide distribution. Individual lesions resolved within 24 hours and were not or only slightly itchy. Every patient had associated signs, most of the time polyarthritis and/or fever. NUD was the presenting mode of LE in 2 patients. NUD was misdiagnosed as a classic lupus flare and led to therapeutic intensification with the introduction of immunosuppressive drugs in 4 patients. Histopathological findings consisted of intense neutrophilic interstitial and perivascular infiltrate with leukocytoclasia and without fibrinoid necrosis of vessel walls. Direct immunofluorescence testing showed a lupus band in 4 patients. Antinuclear antibodies were always positive, anti-dsDNA antibodies were positive in 5 patients, and anti-Ro/SSA antibodies in 6 patients. Immunosuppressive drugs such as prednisone, hydroxychloroquine, mycophenolate mofetil, and methotrexate were never effective to treat NUD. Antihistamines were effective in 1 patient and dapsone or colchicine was effective in 5 patients. NUD is not exceptional in patients with systemic LE and is easily misdiagnosed as an acute LE flare. Furthermore, we show that conventional immunosuppressive LE treatments are not efficient and we underline the major interest of dapsone and colchicine, classic neutrophil migration inhibitors, in those patients.

A rare case of monoclonal gammopathy with autoinflammatory syndrome (schnitzler syndrome): A case report

A rare case of monoclonal gammopathy with autoinflammatory syndrome (schnitzler syndrome): A case report

Myeloid lineage–restricted somatic mosaicism of NLRP3 mutations in patients with variant Schnitzler syndrome

Myeloid lineage–restricted somatic mosaicism of NLRP3 mutations in patients with variant Schnitzler syndrome

Anakinra treatment in Schnitzler syndrome - results of the first retrospective multicenter study in six patients from the Czech Republic

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. 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). 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. 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.

Imaging findings in 22 cases of Schnitzler syndrome: characteristic para-articular osteosclerosis, and the “hot knees” sign differential diagnosis

Schnitzler syndrome is characterized by chronic urticaria, monoclonal gammopathy, and a risk of developing lymphoproliferative disorders. Patients frequently present with bone pain, fever, arthralgia, and lymphadenopathy. The purpose of this study is to retrospectively review and evaluate potentially attributable imaging abnormalities in a series of patients with clinically diagnosed Schnitzler syndrome. Clinical and pathological chart review identified 22 patients meeting Strasbourg criteria for Schnitzler syndrome. Imaging of these patients was retrospectively reviewed by a musculoskeletal radiologist and a radiology fellow to determine and characterize significant "positive" findings that could potentially be attributed to their primary disease process. Evidence of abnormal bone remodeling was present in 64% (14/22) of patients with 40 bone abnormalities. Lesions were predominantly or entirely sclerotic and most commonly involved the distal femora (n = 11), proximal tibiae (nine), and innominate bones (six). Patterns of involvement were variable, but typically eccentrically intramedullary, cortical, and juxta-articular. Skeletal surveys and targeted radiographs identified only 37% (10/27) of abnormal bones subsequently "positive" by additional modalities. PET and bone scans were all positive in patients with bone sclerosis (13/13 and 17/17 bone sites, respectively). Schnitzler syndrome often presents with characteristic osteosclerosis, most commonly around the knees and in the pelvis. In patients with a suggestive clinical history, the radiologist could direct an appropriate imaging strategy or might to be the first to suggest the diagnosis. Bone scan may be the most appropriate initial screening tool in suspected cases.

Schnitzler's syndrome: lessons from 281 cases.

Schnitzler’s syndrome is an autoinflammatory disorder characterized by the association of a monoclonal IgM (or IgG) gammopathy, a chronic urticarial rash, and signs and symptoms of systemic inflammation, including fever, arthralgias and bone pain. It was first described in 1972. This review summarizes the clinical features, efficacy of therapies, and follow-up data of the 281 cases that have been reported to date. Also, the results of skin histology, bone imaging, laboratory investigations, and studies of the pathogenesis will be discussed, including the pivotal role of interleukin-1 beta in this disorder.Electronic supplementary materialThe online version of this article (doi:10.1186/2045-7022-4-41) contains supplementary material, which is available to authorized users.

Schnitzler Syndrome

A 48-year-old man with typical features of Schnitzler Syndrome is presented, followed by a discussion of the pathogenesis and clinical aspects of this rare disease. Some of the challenges we and others have faced in diagnosing and treating this disease are also discussed. Clinical pearls and pitfalls are emphasized to aid clinicians from varying specialties in recognizing this syndrome and providing appropriate therapy. Schnitzler Syndrome is associated with high morbidity and increased risk of lymphoproliferative disorders. Accurate diagnosis is vital in restoring quality of life and ensuring appropriate long-term monitoring.

Anakinra-responsive lichen planus in a woman with Erdheim-Chester disease: a therapeutic enigma

Anakinra is a recombinant form of interleukin-1 receptor antagonist. It is the drug of choice for Schnitzler syndrome and cryopyrin-associated periodic syndromes. It has also recently been demonstrated to have activity in the treatment of the non-Langerhans cell histiocytosis known as Erdheim-Chester disease. To describe the activity of anakinra in a patient with co-existing lichen planus and Erdheim-Chester disease. A 43-year-old woman with progressive Erdheim-Chester disease presented for management of her night sweats and chills, systemic skeletal bone pain, and neurologic (diabetes insipidus) manifestations. She also had widespread cutaneous lichen planus. Anakinra, 100 mg subcutaneously daily, was initiated for the treatment of her Erdheim-Chester disease. Within 2 days of starting anakinra, there was prompt resolution of her Erdheim-Chester disease-related symptoms. Subsequently, her bone pain resolved and her diabetes insipidus improved. Also, the lichen planus-associated pruritus rapidly ceased and most of the skin lesions improved. Our experience confirms the efficacy of anakinra for the treatment of Erdheim-Chester disease. The concomitant improvement of her lichen planus on anakinra suggests that this agent warrants additional study in this disorder.

Schnitzler syndrome

A 63-year-old man presented with non-pruritic urticaria for 14 months,fever of unknown origin for nearly 12 months,and arthralgias of both lower limbs for 10 months.The fever,which was unrelated to the occurrence of skin lesions,appeared once a week on average,and might be as high as 39 ℃.Physical examination revealed irregular fever and lymphadenopathy in both inguinal and axillary regions.Skin lesions,consisting of rosecolored,slightly elevated plaques and papules,affected the trunk,both upper extremities and thighs.Skin biopsy showed perivascular infiltration of neutrophils and lymphocytes in the superficial dermal layer.Laboratory examination exhibited leukocytosis,elevated erythrocyte sedimentation rate and increased C-reactive protein level.Serum protein electrophoresis revealed an IgM-κ component in the γ-globulin zone.Radiographic examination suggested slight hepatosplenomegaly and hepatic cysts.Positron emission tomography/computed tomography (PET-CT) revealed bilateral knee joint effusion,degeneration of cervical vertebrae and lumbar vertebrae,as well as lymphadenectasis in both axillary,inguinal and popliteal regions as well as around external iliac vessels.Wholebody bone scan showed abnormalities of bilateral shoulder joints,elbow joints and knee joints,which were suggestive of arthritis.A diagnosis of Schnitzler syndrome was made.The patient was given prednisone 30 mg per day,and body temperature returned to normal with the improvement of condition on the second day.Subsequently,glucoside tripterygium total 20 mg thrice daily was additionally given,and the dose of prednisone was gradually decreased to 15 mg per day,with a satisfactory control of condition,disappearance of fever,skin eruptions or other discomfort,and marked relief of ostalgia and arthralgia. Key words: Schnitzler syndrome; Urticaria; Diagnosis, differential