Clinical Presentation of Schnitzler's Syndrome: A Rare Autoimmune Disease.

Schnitzler's Syndrome (SS) is a rare late-onset acquired autoinflammatory disorder which consists of chronic urticaria associated with a monoclonal IgM-kappa gammopathy, arthralgias, skeletal hyperostosis, lymphadenopathy, and recurrent constitutional symptoms. The average age of diagnosis is 51 years with a slight male predominance with a male to female ratio of 1.6. Diagnosis of SS requires the presence of 2 major criteria including chronic urticaria and monoclonal IgM along with at least two of the following minor criteria: recurrent intermittent fevers, bone pain, arthralgias, elevated erythrocyte sedimentation rate (ESR), neutrophilic dermal infiltrate on skin biopsy, and leukocytosis or elevated C-reactive protein (CRP). Early diagnosis and clinical awareness are paramount in SS as it is associated with a 15-20% risk of lymphoproliferative malignancy. The median overall survival is 12.8 years. We present a case of a 39-year-old female with new onset urticaria associated with recurrent fevers and joint pain. Symptoms were refractory to steroids, and high dose antihistamines. Multi-disciplinary evaluation resulted in the ultimate diagnosis of Schnitzler's Syndrome. The patient was ultimately treated with canakinumab (Il-1 inhibitor), with near resolution of symptoms. This case demonstrates the importance of a broad differential diagnosis and maintaining a high clinical suspicion for rare diseases when presented with a complex form of an otherwise common condition.

Schnitzler syndrome.

A woman in her late 40s with a history of psoriatic arthritis presented to us with fever, migratory rash, cervical and axillary lymphadenopathy, and generalised myalgia. Her symptoms did not improve with steroids and her inflammatory markers were in the range of 200 mg/dL for C-reactive protein, erythrocyte sedimentation rate of 71 mm/hour and ferritin of 4000 ng/mL. Infectious workup was negative. Haematological malignancy and autoimmune conditions were among the top differentials, and she was eventually diagnosed with Schnitzler syndrome. A multidisciplinary team consisting of internal medicine, rheumatology, infectious disease and haematology-oncology specialists was involved in the care of this patient. We highlight the diagnostic schema that was followed for this rare and unique constellation of symptoms.

Case report: Schnitzler-like syndrome without monoclonal gammopathy.

Schnitzler syndrome is a rare autoinflammatory disorder characterized by urticarial rash, joint pain, recurrent fever, leucocytosis, elevated C-reactive protein (CRP) and serum amyloid A (SAA), and monoclonal IgM or IgG gammopathy. According to the Strasbourg criteria, both urticarial rash and gammopathy are mandatorily required for the diagnosis of Schnitzler's syndrome. However, incomplete variants lacking either skin symptoms or monoclonal gammopathy have also been described. Here, we report a case in which the diagnosis of Schnitzler-like syndrome was made despite the absence of gammopathy, based on neutrophilic dermal inflammation, episodic and excessive increase in inflammatory parameters, and prompt response to anakinra, a soluble IL1 receptor antagonist (sIL-1RA). In addition, we detected neutrophil epitheliotropism, which is highly suggestive of autoinflammatory disease. Using whole-exome sequencing, we were unable to find a causative pathogenic mutation but did find several mutations possibly related to the inflammatory processes in this patient. This and other cases highlight that the existing Strasbourg criteria are too strict to capture Schnitzler-like syndromes that may respond well and rapidly to IL1 inhibition. Recurrent episodes of disease with normalization of inflammatory symptoms in the interval, rapid response to anakinra, and neutrophilic epitheliotropism in a lesional skin biopsy may help confirm the diagnosis of Schnitzler-like syndrome.

Summary of the current status of clinically diagnosed cases of Schnitzler syndrome in Japan.

BACKGROUND: Schnitzler syndrome is a rare disorder with chronic urticaria, and there is no report summarizing the current status in Japan. METHODS: A nationwide survey of major dermatology departments in Japan was conducted in 2019. We further performed a systematic search of PubMed and Ichushi-Web, using the keywords "Schnitzler syndrome" and "Japan" then contacted the corresponding authors or physicians for further information. RESULTS: Excluding duplicates, a total of 36 clinically diagnosed cases were identified from 1994 through the spring of 2022, with a male to female ratio of 1:1. The median age of onset was 56.5 years. It took 3.3 years from the first symptom, mostly urticaria, to reach the final diagnosis. The current status of 30 cases was ascertained; two patients developed B-cell lymphoma. SchS treatment was generally effective with high doses of corticosteroids, but symptoms sometimes recurred after tapering. Colchicine was administered in 17 cases and was effective in 8, but showed no effect in the others. Tocilizumab, used in six cases, improved laboratory abnormalities and symptoms, but lost its efficacy after several years. Rituximab, used in five cases, was effective in reducing serum IgM levels or lymphoma mass, but not in inflammatory symptoms. Four cases were treated with IL-1 targeting therapy, either anakinra or canakinumab, and achieved complete remission, except one case with diffuse large B-cell lymphoma. CONCLUSIONS: Since Schnitzler syndrome is a rare disease, the continuous collection and long-term follow-up of clinical information is essential for its appropriate treatment and further understanding of its pathophysiology.

Case report: Successful treatment with tofacitinib and colchicine in a patient with Schnitzler syndrome.

We report a case of late-onset Schnitzler syndrome successfully treated with Janus-activated kinase (JAK) inhibitors and colchicine. Schnitzler syndrome should be considered for recurrent chronic urticaria when accompanied by fever, fatigue, rapid weight loss, and poor response to antihistamine treatment. Skin biopsy, bone marrow biopsy, and electrophoresis help confirm the diagnosis. Early diagnosis and treatment can lead to complete resolution of symptoms. Besides interleukin (IL)-1 and IL-6 inhibitors, JAK inhibitors and colchicine may be considered as other choices of treatment.

Schnitzler Syndrome Presenting as a Fever of Unknown Origin with Elevated Alkaline Phosphatase Levels.

Schnitzler syndrome (SchS) is a rare, acquired, autoinflammatory disease that is sometimes associated with a fever of unknown origin (FUO). Elevated alkaline phosphatase (ALP) stemming from abnormal bone remodeling is a characteristic laboratory finding of SchS and is included in the diagnostic criteria. However, its utility as a clue to the diagnosis of SchS has been under-emphasized. We herein report a case of SchS presenting with a FUO and highly elevated ALP concentration, which led to repeated, unnecessary liver biopsies.

Case Report: Therapeutic Use of Ibrutinib in a Patient With Schnitzler Syndrome.

Schnitzler syndrome is a rare adult-onset acquired autoinflammatory disorder typically characterized by chronic urticarial rash and immunoglobulin M (IgM) (rarely IgG) monoclonal gammopathy. Its clinical symptoms usually respond well to interleukin-1 blockade therapy, which, however, does not impact the underlying monoclonal gammopathy. Herein, we described a female patient who presented with urticarial rash, recurrent fevers, and fatigue for 7 years. Laboratory investigations revealed IgMκ monoclonal protein and MYD88 L265P mutation, but no lymphoplasmacytic lymphoma on bone marrow examination. She fulfilled the diagnosis of Schnitzler syndrome and was treated with the Bruton tyrosine kinase inhibitor ibrutinib in combination with prednisone. Her symptoms improved dramatically, and the level of IgMκ monoclonal protein also declined. She tolerated the treatment well. This case highlights the potential therapeutic role of Bruton tyrosine kinase inhibitors in Schnitzler syndrome.

A man in his fifties with recurrent urticaria, fever and joint pain. / En mann i 50-årene med tilbakevendende urtikaria, feber og leddsmerter.

BACKGROUND: Schnitzler's syndrome is a rare, acquired and probably underdiagnosed disorder. It is a type of autoinflammatory condition with late onset. CASE PRESENTATION: A man in his fifties had had recurrent urticaria, fever and chronic joint pain during the previous year. After an extensive investigation, no evidence of infection, autoimmune disease or malignancy was found. Blood samples showed moderately elevated SR and CRP, mild thrombocytosis and presence of monoclonal IgM in low concentration (MGUS). The combination of sterile inflammation, joint/muscle pain, urticaria and M-component was consistent with Schnitzler's syndrome. He was placed on a treatment trial with anakinra (interleukin [IL]-1 receptor antagonist) 100 mg x 1 daily, given as a subcutaneous injection. His condition was excellent until one week after the first injection. The initial treatment indicated a good clinical effect of IL-1 blockade, but due to the very unpleasant localised side effects (extensive dermatitis), treatment with anakinra was withdrawn, and canakinumab (monoclonal antibody against IL-1ß) was chosen instead. He responded very well to this treatment and experienced no adverse effects. One year after starting treatment, the patient still has an excellent treatment response. INTERPRETATION: Anakinra is the treatment of first choice for this condition, but this case history illustrates that canakinumab can be tried if anakinra is not tolerated by the patient.

Refractory serum immunoglobulin M elevation during anti-interleukin (IL)-1- or IL-6-targeted treatment in four patients with Schnitzler syndrome.

Schnitzler syndrome is characterized by chronic urticarial rash, neutrophilic dermal infiltrate, recurrent fever, bone pain, elevated C-reactive protein, and neutrophilic leukocytosis. The pathophysiology of Schnitzler syndrome is unknown, but it is considered to be an acquired form of an autoinflammatory disease because of the resemblance to clinical phenotypes of cryopyrin-associated periodic syndrome, in which a gain-of-function mutation in NLRP3 causes overexpression of interleukin (IL)-1ß. Schnitzler syndrome is generally accompanied by a monoclonal immunoglobulin (Ig)M gammopathy with a long-term risk of lymphoproliferation that is possibly associated with an MYD88 mutation. Herein, we present the following four patients with Schnitzler syndrome: a 63-year-old woman; a 65-year-old man; a 43-year-old woman; and a 63-year-old woman. Each patient fulfilled the Strasbourg diagnostic criteria, but none of the patients had any mutation in NLRP3 or MYD88 detected in their peripheral blood. Although approved treatment options for Schnitzler syndrome are lacking, our patients were treated with IL-1-targeted therapy (anakinra or canakinumab) or anti-IL-6 (tocilizumab). The acute inflammatory clinical manifestations improved completely with canakinumab and partially with anakinra and tocilizumab, but the serum IgM levels were gradually increased in all patients, even during treatment. To determine whether treatment with anti-IL-1ß or IL-6 prevents conversion to a hematopoietic disorder, further collection of cases and long-term follow-up will be needed.

Rheumatic involvement and bone scan features in Schnitzler syndrome: initial and follow-up data from a single-center cohort of 25 patients.

OBJECTIVE: To report on the characteristics and long-term course of rheumatic manifestations in Schnitzler syndrome (SchS). METHODS: A retrospective cohort study of patients with SchS followed between 2000 and 2020. Inclusion criteria included a diagnosis of SchS (Strasbourg criteria). All available bone scans were reviewed and scored according to the intensity and number of pathological sites. The scintigraphic score was compared with the clinical activity score, CRP level, and treatments. RESULTS: Twenty-five patients were included. Median age at diagnosis was 68 years. Eighty patients (72%) had SchS-related rheumatic pain. Most patients had a long-standing isolated rash before constitutional and/or rheumatic symptoms appeared. The monoclonal component level was usually very low (IgMκ in 22/25). Rheumatic pain predominated around the knees. Bone scans revealed abnormal tracer uptake in 15/18 (85%). The scintigraphic score correlated with clinical activity (r = 0.4, p < 0.02) and CRP level (r = 0.47, p < 0.01). The scintigraphic score was lower in patients receiving corticosteroids or IL1Ra (interleukin 1 receptor antagonist) than in untreated patients (median scores:2, 0, and 13, respectively; p < 0.05). Two patients developed Waldenström macroglobulinemia. Of the 22 surviving patients, median age at follow-up was 76 years. IL1Ra was used in 13 patients, with dramatic efficacy on both symptoms and bone scan features. CONCLUSIONS: Rheumatic manifestations are very prevalent in SchS. However, bone pain can be misleading and contribute to misdiagnosis. Bone scan abnormalities are very prevalent and correlate with disease activity and treatments. IL1-Ra has a dramatic and durable efficacy but may not be required in every patient early on.

Case Report: Extensive Phosphorylation of Interleukin-1 Receptor-Associated Kinase 4 in a Patient With Schnitzler Syndrome.

Schnitzler syndrome (SchS) is a rare autoinflammatory disease, characterized by urticarial rash, recurrent fever, osteo-articular pain/arthritis with bone condensation, and monoclonal gammopathy. Diagnosis may be difficult due to overlapping signs with other diseases. Here, we describe the case of a 62-year-old man with SchS, who was initially misdiagnosed with multicentric Castleman disease (MCD). As excessive release of IL-6 is characteristic of MCD, in contrast to IL-1 in SchS, we measured the phosphorylation of intracellular signaling proteins of the respective pathways by flow cytometry. We found a distinct increase of phosphorylated IRAK-4 in our patient's B cells and monocytes while phosphorylation of STAT-3 was low, suggesting predominant IL-1 signaling. In accordance with these results and the classification criteria, we established the diagnosis of SchS instead of MCD and commenced therapy with the IL-1 receptor antagonist anakinra. We observed a rapid remission of signs accompanied by a reduction of phosphorylated IRAK-4 to normal levels. In conclusion, we propose phosphorylated IRAK-4 in B cells and monocytes as a potential marker for diagnosis of SchS and for treatment response to IL-1 blockade.

The systemic autoinflammatory disorders for dermatologists. Part 2: disease examples.

The systemic autoinflammatory disorders (SAIDS) or periodic fever syndromes are disorders of innate immunity, which can be inherited or acquired. They are almost all very rare and easily overlooked; typically, patients will have seen multiple specialities prior to diagnosis, so a high level of clinical suspicion is key. It is important to note that these are 'high-value' diagnoses as the majority of these syndromes can be very effectively controlled, dramatically improving quality of life and providing protection against the development of irreversible complications such as AA amyloidosis. In Part 1 of this review, we took an overview of SAIDS and described the common features; in this article, we take a more in-depth look at the better recognized or more dermatologically relevant conditions.

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.

[Schnitzler syndrome]. / Schnitzler-Syndrom.

Schnitzler syndrome is a very rare acquired systemic disease with many similarities to hereditary autoinflammatory syndromes. The main characteristics are generalized exanthema and a monoclonal gammopathy with IgM. Other clinical features include fever, muscle, bone and/or joint pain, and lymphadenopathy. About 15-20% of patients with Schnitzler syndrome develop lymphoproliferative diseases and, in rare cases, amyloid A (AA) amyloidosis can occur if the disease is not treated. Activation of the innate immune system, especially interleukin(IL)-1ß, is central in the pathogenesis of the disease. Consequently, complete control of disease symptoms can be achieved in 80% of patients by treatment with the IL-1 receptor antagonist anakinra.

Schnitzler syndrome co-occurring with idiopathic multicentric Castleman disease that responds to anti-IL-1 therapy: A case report and clue to pathophysiology.

Patients with HHV-8-negative/idiopathic multicentric Castleman disease (iMCD) experience systemic inflammatory symptoms and polyclonal lymphoproliferation due to an unknown etiology. Schnitzler's syndrome (SS) is characterized by recurrent urticarial rash, monoclonal IgM gammopathy, and other clinical signs of inflammation. To our knowledge, we report the first case of iMCD associated with SS and the fourth case of anakinra inducing a complete response for an iMCD patient. A forty-four year old woman with a history of a recurrent urticarial rash, presented to our hospital complaining of 6 months of night sweats, fever, chronic urticaria, iliac bone pain, and generalized lymphadenopathy. An IgM Kappa monoclonal component was measured at 7.8g/L. A lymph node biopsy revealed histopathological features consistent with the plasma cell variant of iMCD. She was diagnosed with SS and iMCD. Anti-IL-1 treatment with anakinra (100mg/day) was introduced. Within 48h, we observed improvement in the fever and the urticarial rash. By one month, we considered the patient in complete remission. Two years later, the remission is persistent while the patient is still under therapy. Though this is only the fourth reported case of anakinra in iMCD, this is yet another case demonstrating the effectiveness of anti-IL-1 blockade in SS. We hypothesize that uncontrolled cytokine production is responsible for both the SS and the iMCD. The etiologies of SS and iMCD are unknown, and future research is necessary.

Schnitzler syndrome in a patient with a family history of monoclonal gammopathy.

Schnitzler syndrome is a rare disease characterized by chronic urticaria and a monoclonal gammopathy, most commonly IgM with light chains of the kappa type. There are currently no known risk factorsassociated with development of the disease. We report a case of Schnitzler syndrome in a 48-year-old man with a family history of monoclonal gammopathies. The patient's disease has been well controlled with anakinra therapy. Our case may contribute to a better understanding of the etiology of Schnitzler syndrome as his history could suggest a hereditarypredisposition for the disease. Further studies are necessary to determine whether a genetic component of Schnitzler syndrome exists, as first-degree relatives of patients with monoclonal gammopathies may be at risk for the development of the disease.