A case of Schnitzler’s syndrome without monoclonal gammopathy successfully treated with canakinumab

Abstract Background Schnitzler’s syndrome (SchS) is a rare autoinflammatory syndrome with diagnostic challenge and be characterized by chronic urticaria, a monoclonal gammopath, periodic fever and bone pain. In addition to the monoclonal gammopathy, bone abnormalities are often found at the site of bone pain in patients with SchS. The remarkable efficacy of interleukin-1 (IL-1) inhibition was also demonstrated in this syndrome. Case presentation We describe a case of refractory chronic urticaria presenting with clinical manifestations consistent with SchS without monoclonal gammopathy. A 43-year-old female patient suffering from recurring of urticaria with periodic fever as well as bone pain for the past 4 years. The patient had leukocytosis and elevated levels of C-reactive protein (CRP) and serum amyloid A (SAA). PET/CT (positron emission tomography/computed tomography) and MRI (magnetic resonance imaging) examination revealed hyper-metabolism areas in both femoral bone marrow. Although bone marrow histology revealed no abnormality, urticarial skin lesions shows neutrophilic infiltrations without evidence of vasculitis. We could not exclude the possibility of SchS. The patient had been treated with antihistamines, steroids, omarizumab, colchicine and cyclosporine A, no therapeutic effect was observed. She was started on canakinumab 150 mg subcutaneous injection with 4 weeks interval. Within 48 h after the first injection, the urticarial rash disappeared, and febrile attack and bone pain had not recurred. Elevated levels of serum CRP and SAA were normalized within a week after the first injection of canakinumab. Conclusions The current case suggests an important role for IL-1 as a mediator in the pathophysiology of SchS-like refractory urticaria with bine pain. It had been presumed that monoclonal gammopathy may not always present in SchS. It is important to avoid delay in diagnosis and initiation of proper treatment in SchS or autoinflammatory conditions resembling SchS.

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FRI0480 SCHNITZLER’S SYNDROME: DESCRIPTION OF AN ITALIAN MULTICENTER COHORT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3770 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 837.1-837

Author(s):

F. Crisafulli ◽

P. Airò ◽

F. Franceschini ◽

A. Tincani ◽

M. Frassi

Keyword(s):

Monoclonal Gammopathy ◽

Interleukin 1 ◽

Diagnostic Delay ◽

Injection Site Reaction ◽

Lymphoproliferative Disease ◽

Severe Allergic Reaction ◽

Intermittent Fever ◽

Multicenter Cohort ◽

Laboratory Features ◽

Schnitzler’S Syndrome

Background:Schnitzler’s syndrome is an autoinflammatory disease characterized by monoclonal gammopathy and recurrent episodes of urticaria accompanied by clinical and laboratory signs of acute inflammation. Although the exact pathogenic mechanisms have not been fully clarified, the role of Interleukin-1 seems to be central.Objectives:To describe clinical features and therapeutic approach in patients with Schnitzler’s Syndrome.Methods:Retrospective analysis of an Italian multicenter cohort. Data are expressed as the median (IQR).Results:The clinical data of 24 patients from 9 centers (median follow-up 6 years [2-10]; median age at diagnosis 56.5 years [51.25-64.25]) were collected. The median diagnostic delay was 2 years (0-10); the diagnosis was made consensually at the onset of symptoms in 4 cases. The main clinical and laboratory features are shown in Table 1. Therapeutic response was evaluable in 20 patients: all received corticosteroids (CS; 25mg/day [25-50]); in one case, a good clinical response was observed. Eight patients were initially treated with colchicine: in 3 cases it was effective in controlling symptoms and reducing the dose of CS; other 8 patients were treated with csDMARDs (n:1 [1-2]): only 1 patient had a good response to cyclosporin.Table 1.Clinical and laboratory featuresChronic Urticarial Rash, n (%)24/24 (100)Pruritus, n (%)17/24 (71)Intermittent fever, n (%)23/24 (96)Arthralgia/Arthritis, n (%)20/24 (83)Bone pain, n (%)8/24 (33)Weight loss, n (%)9/24 (38)Angioedema, n (%)4/24 (17)Lymphoadenopathy, n (%)7/24 (29)Hepatomegaly, n (%)3/24 (12)Splenomegaly, n (%)3/24 (12)Neuropathy, n (%)4/24 (17)Raised ESR or CRP, n (%)24/24 (100)Leukocytosis, n (%)17/24 (71)Anemia, n (%)9/24 (38)Monoclonal GammopathyIgG λ, n (%)5/22 (23)IgG κ, n (%)6/22 (27)IgM λ, n (%)1/22 (5)IgM κ, n (%)12/22 (55)Bence Jones Protein, n (%)6/23 (26)A bDMARD was initiated in 15 patients. In 7 of the 14 patients initially treated with anakinra this therapy was continued with benefit whereas in the other 7 patients the treatment was discontinued for primary inefficacy (1 patient), secondary inefficacy (3 patients) and adverse events (3 patients; 2 injection site reaction, 1 severe allergic reaction). After anakinra discontinuation, 5 patients were treated with canakinumab with a good response in 3 cases and a partial response in 1 case (persistent arthritis); 1 patient died during the treatment. No response was observed in 3 patients treated with TNF inhibitors as a 2ndor 3rdline bDMARDs, as well as in 1 case initially treated with tocilizumab (in which a good response was afterwards obtained with canakinumab). bDMARDs were associated with a csDMARD in 2 patients (methotrexate and methotrexate + cyclosporine).In one case monoclonal gammopathy evolved into Multiple Myeloma and the patient died 15 years after the onset of symptoms. Idiopathic myelofibrosis and myelodysplasia were found in one and in two patients, respectively.Conclusion:In most cases csDMARDs and bDMARDs like anti-IL6 and anti-TNFα were not able to control the disease. In contrast, in some cases, a good response to colchicine was observed; refractory patients may be successfully treated with anti-IL1 agents. Patients should be supervised for possible evolution towards lymphoproliferative disease.Disclosure of Interests:None declared

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Cases of amyloidosis with diabetic encephalopathy

Vestnik of Russian military medical Academy ◽

10.17816/brmma12206 ◽

2018 ◽

Vol 20 (1) ◽

pp. 58-62

Author(s):

V I Golovkin ◽

D A Gulak ◽

T A Garan ◽

I P Magonov

Keyword(s):

Protein Metabolism ◽

Congo Red ◽

Serum Amyloid A ◽

Interleukin 1 ◽

Clinical Manifestations ◽

Serum Amyloid ◽

High Rate ◽

Diabetic Encephalopathy ◽

Biopsy Material ◽

Amyloid A

Basic clinical manifestations of diabetic encephalopathy in pre-stroke and stroke stages in the elderly are considered. Psychometrical tests (Shulte tables of and Mini Mental Score Examination scale) were used to reveal cognitive impairments, which are markers of diabetic encephalopathy progression. The case of intravital visualization of diabetic cerebral angiopathy using magnetic resonance imaging in susceptibility weighted imaging mode was described in detail. And the case of amyloidosis confirmed by kidney biopsy material coloring with Congo Red. The results of immunological examination are given, proving a high rate of Interleukin-1 production - initiator of serum amyloid A synthesis in liver (serum amyloid A). Histories of lethal cases and pathohystological analysis results of ultrathin sections, obtained by the means of cerebrum autopsy with Congo Red coloring, were investigated. Autopsy materials with positive qualitative reaction on amyloid were taken for further analyzing in polarizing light and amyloid typing. AA-amyloid was discovered in all cases. Morphologic characteristic of diabetic encephalopathy was revealed using coloring by hematoxylin, eosin and Van Gieson’s stain: angioedema, microhemorrhagia, leukoaraiosis, gliomatosis and atrophy of neurons. Case of genetic polyorganic AA- amyloidosis, not diagnosed intravital, was described in detail. It was established that impaired protein metabolism with its final conformation in toxic amyloid components of tissues is an early and fairly frequent manifestation of diabetic encephalopathy metabolic disorders. The substantiated opinion, implying the necessity of deep protein metabolism investigation in cases of diabetes complicated with encephalopathy and amyloidosis, is given. The term «diabetic amyloid encephalopathy» is offered to include in diabetic encephalopathy classification.

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Schnitzler Syndrome treated with canakinumab

Revista Argentina de Reumatología ◽

10.47196/rar.v30i3.445 ◽

2019 ◽

pp. 34-37

Author(s):

Pablo Finucci Curi

Keyword(s):

Monoclonal Gammopathy ◽

Bone Pain ◽

Interleukin 1 ◽

Rare Disorder ◽

Intermittent Fever ◽

Urticarial Rash ◽

Schnitzler Syndrome

Schnitzler syndrome is a rare disorder characterized by chronic urticarial rash and monoclonal gammopathy, accompanied by intermittent fever, arthralgia or arthritis, bone pain and lymphadenopathy, in which interleukin 1 (IL-1) has a preponderant role. The case of a 48-year-old male who meets criteria for Schnitzler syndrome and who after failing too many treatments presents a successful response to canakinumab is presented here.

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

Yonsei Medical Journal ◽

10.3349/ymj.2018.59.1.154 ◽

2018 ◽

Vol 59 (1) ◽

pp. 154 ◽

Cited By ~ 6

Author(s):

Min Joo Ahn ◽

Ji Eun Yu ◽

Jiung Jeong ◽

Da Woon Sim ◽

Young-Il Koh

Keyword(s):

Chronic Urticaria ◽

Monoclonal Gammopathy ◽

Schnitzler’S Syndrome

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Efficacy of interleukin-1 blockade in Schnitzler’s syndrome without detectable monoclonal gammopathy: a case-based review

Clinical Rheumatology ◽

10.1007/s10067-020-05501-w ◽

2020 ◽

Author(s):

Riccardo Bixio ◽

Maurizio Rossini ◽

Alessandro Giollo

Keyword(s):

Complete Remission ◽

Inflammatory Markers ◽

Monoclonal Gammopathy ◽

Interleukin 1 ◽

Autoinflammatory Disorder ◽

Urticarial Rash ◽

Schnitzler’S Syndrome ◽

Inflammatory Drugs ◽

Case Based

Abstract Schnitzler’s syndrome (SchS) is a rare autoinflammatory disorder characterized by urticarial rash and monoclonal gammopathy which is currently regarded as IL-1 mediated disease. We present the case of a 21-year-old woman presenting with urticarial rash, arthralgias, and elevated inflammatory markers. She has been suffering these symptoms for 2 years and was treated with antihistamines, omalizumab, steroids, and non-steroidal anti-inflammatory drugs (NSAIDs) without success. After an extensive diagnostic workout, we suspected SchS even without monoclonal gammopathy, and started Anakinra 100 mg daily with a dramatic response and achieving complete remission after 48 h of the beginning of the treatment, so we decided to confirm SchS diagnosis. We performed a search of the literature and found seven more cases of patients diagnosed with SchS without monoclonal gammopathy at the presentation. Five were treated with IL-1 blocking therapies and all achieved remission. We, therefore, prompt the possible role of IL-1 blockade therapy remission as support in diagnosing SchS without monoclonal gammopathy.

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Spectrum of Systemic Auto-Inflammatory Diseases in India: A Multi-Centric Experience

Frontiers in Immunology ◽

10.3389/fimmu.2021.630691 ◽

2021 ◽

Vol 12 ◽

Author(s):

Deepti Suri ◽

Amit Rawat ◽

Ankur Kumar Jindal ◽

Pandiarajan Vignesh ◽

Anju Gupta ◽

...

Keyword(s):

Health Care Professionals ◽

Periodic Fever ◽

Interleukin 1 ◽

Immunosuppressive Agents ◽

Clinical Manifestations ◽

Immune Dysregulation ◽

Mevalonate Kinase Deficiency ◽

Inherited Disorders ◽

Molecular Features ◽

Delays In Diagnosis

Background: Systemic autoinflammatory diseases (SAID) are rare inherited disorders involving genes regulating innate immune signaling and are characterized by periodic or chronic multi-systemic inflammation.Objective: To describe spectrum of clinical, immunological, molecular features, and outcomes of patients with SAID in India.Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with Inborn Errors of Immunity. Six centers provided requisite data that were compiled and analyzed.Results: Data on 107 patients with SAID were collated—of these, 29 patients were excluded due to unavailability of complete information. Twelve patients (15%) had type 1 interferonopathies, 21 (26%) had diseases affecting inflammasomes, 30 patients (41%) had non-inflammasome related conditions and 1five patients (19%) had Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA). Type1 interferonopathies identified in the cohort included patients with Deficiency of Adenosine Deaminase 2 (DADA2) (six patients; five families); STING-associated vasculopathy infantile-onset (SAVI) (three patients, one family); Spondyloenchondro-dysplasia with Immune Dysregulation (SPENCD) (two patients). Diseases affecting inflammasomes include Mevalonate Kinase Deficiency (eight patients); Cryopyrin-Associated Periodic Syndromes (CAPS) (seven patients); NLR Family, Pyrin domain-containing 12 (NLRP12) (two patients); Familial Mediterranean fever (FMF) (two patients); Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) (two patients). TNF receptor-associated periodic syndrome (TRAPS) (three patients); A20 haploinsufficiency (four patients); Deficiency of Interleukin 1 Receptor Antagonist (DIRA) (two patients) were categorized as non-inflammasome related conditions. There were significant delays in diagnosis Corticosteroids and other immunosuppressive agents were used for treatment as anti-IL-1 drugs and other biological agents were and still are not available in India. Eight (16.3%) patients had so far succumbed to their illness.Conclusions: This is the first nationwide cohort of patients with SAID from India. Clinical manifestations were diverse. Overlapping of clinical features with other relatively common rheumatological disorders often resulted in delays in diagnosis. More nationwide efforts are needed to enhance awareness of SAID among health care professionals and there is an urgent need to make targeted immunotherapies universally available.

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Schnitzler’s Syndrome: A Diagnostic Consideration in Evaluating the Constellation of Monoclonal Gammopathy and Chronic Urticaria

Journal of Hematology ◽

10.14740/jh800 ◽

2021 ◽

Vol 10 (3) ◽

pp. 143-146

Author(s):

Jyothika Mamadgi ◽

Laila Babar ◽

Rama Bhagavatula ◽

Santhosh Sadashiv ◽

Kossivi Dantey ◽

...

Keyword(s):

Chronic Urticaria ◽

Monoclonal Gammopathy ◽

Schnitzler’S Syndrome

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Bone marrow involvement by ATTR amyloid is common in cardiac amyloidosis patients and may signal advanced-stage disease

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqab191.200 ◽

2021 ◽

Vol 156 (Supplement_1) ◽

pp. S94-S94

Author(s):

S Dasari ◽

A Chiu ◽

J Theis ◽

J A Vrana ◽

P J Kurtin ◽

...

Keyword(s):

Bone Marrow ◽

Soft Tissue ◽

Monoclonal Gammopathy ◽

Cardiac Amyloidosis ◽

Patient Management ◽

Bone Marrow Involvement ◽

Reference Laboratory ◽

Advanced Stage ◽

Amyloid A ◽

Al Amyloid

Abstract Introduction/Objective Amyloidosis encompasses a heterogeneous group of disorders characterized by abnormal deposition of misfolded proteins leading to progressive organ failure. Accurate amyloid typing is essential for proper patient management, as treatment regimens vary dramatically across different types. Bone marrow (BM) biopsy, in conjunction with fat pad aspiration/biopsy, is often the first step in patients with suspected amyloidosis. Although BM involvement by AL amyloid has been previously characterized, little is known about the incidence, morphology and clinical phenotype of non-AL amyloid in BM. Methods/Case Report We retrospectively identified 1469 BM biopsies by querying our reference laboratory database of 19,298 specimens from myriad anatomic sites typed by mass spectrometry-based proteomics (LC-MS/MS). These were reviewed for frequency of amyloid types (N=1469), distribution of amyloid deposits (N=139), and clinical phenotypes (N=345), with particular emphases on cardiac involvement. Results (if a Case Study enter NA) We identified the following amyloid types: AL (N=1172; 79.8%), ATTR (transthyretin) (N=240; 16.3%), AH (immunoglobulin heavy chain) (N=38; 2.6%), AA (serum amyloid A) (N=17; 1.2%), and Aβ2M (β2-microglobulin) (N=2; 0.1%). ATTR deposits showed striking predilection for periosteal soft tissue and/or periosteal vessels, and rarely involved BM stroma and/or interstitial vessels, while AL variably involved these compartments. AA primarily involved interstitial vessels. Both AL and ATTR cases commonly had a monoclonal gammopathy (AL: 92.9%; ATTR: 62.5%) with concomitant cardiac amyloidosis (AL: 91.6%; ATTR: 100%). Compared to AL, ATTR patients had higher stage cardiac amyloidosis and lower overall survival. Conclusion ATTR is common in BM, constituting16.3% of cases in our cohort. Rarer amyloid types, such as AA, AH and AB2M can also occur in BM. ATTR was frequently identified in patients with concomitant monoclonal gammopathy, in whom AL may have been suspected. Although ATTR deposits have distinctive morphologic distribution, primarily involving periosteal soft tissue and/or periosteal vessels and rarely involving BM stroma and/or interstitial vessels, there is considerable morphologic overlap with AL. Therefore, it is imperative to type BM amyloidosis, preferably by LC-MS/MS, to ensure proper patient management. Furthermore, BM involvement by ATTR may be a marker for advanced stage of disease.

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