Schnitzler Syndrome: An Under-Recognised Cause of Pyrexia of Unknown Origin

Peripheral T-cell lymphoma mimicking Schnitzler syndrome.

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 (SS) is a rare disease of unknown etiology. Literature suggests that only around 300 well-diagnosed cases have only been reported worldwide and rarely from India. This syndrome has a slight male predominance with a mean age of onset of around 50 years. It is considered an autoinflammatory disease with presentation mimicking adult-onset Still's disease and systemic lupus erythematosus, and its presentation most commonly includes recurrent fever, urticarial rash, arthralgia, and bone pains. The probable pathogenesis is considered to be cytokine-mediated, mostly interleukin- 1 (IL-1), and its association with the NRLP3 gene has been mentioned in a few reports.Herein, we report a case of a 40-year-old female who presented to us with fever, jaundice, rash, and pedal edema, and detailed investigations revealed leukocytosis with low complements, normal bone marrow with an 'M band' in the immunoglobulin M (IgM) region. Skin biopsy was suggestive of leukocytoclastic vasculitis and renal biopsy was suggestive of membranoproliferative glomerulonephritis (MPGN). All autoimmune and viral markers were negative, including cryoglobulins, and by excluding all possible differentials, the diagnosis of Schnitzler syndrome was confirmed.SS is a disease of exclusion and several autoimmune, hematological infections need to be excluded, hence, this requires extensive workup. It’s the rarest of rare cases, with a variable presentation, specially pyrexia of unknown origin (PUO) with rash, hence this case will open the physician's vision of undiagnosed cases, and further research will help understand its pathogenesis.

Introduction: This review paper aims to explore the current state of knowledge regarding the underlying mechanisms of Schnitzler syndrome, its clinical manifestations, the diagnostic challenges, and to analyze current treatment approaches, along with potential complications related to the disease. Materials and Methods: A comprehensive review of the literature was conducted using the PubMed and Google Scholar databases using the following keywords: "Schnitzler syndrome", "Schnitzler-like syndrome", "NETosis", "urticaria", "fever", "monoclonal gammopathy", "neutrophilic dermatosis", "anakinra", "treatment". Summary: Schnitzler syndrome is a rare autoinflammatory disease that typically affects adults and presents with symptoms such as recurrent urticaria, fever, monoclonal gammopathy, and musculoskeletal pain. The exact cause is still not fully understood, but IL-1 antagonists have shown promising results, indicating IL-1's role in the disease's development. Despite the established diagnostic criteria, the disease still presents significant diagnostic challenges, often leading to delays in recognition or even underdiagnosis. Schnitzler syndrome, particularly if left untreated, can lead to complications such as the development of lymphoproliferative disorders, most commonly Waldenström's macroglobulinemia or, in rare cases, AA amyloidosis. Conclusions: This review emphasizes the importance of a thorough examination, as its symptoms often resemble those of other diseases, which can lead to misdiagnosis. Due to the complexity of the clinical presentation, effective collaboration among dermatologists, rheumatologists and immunologists is essential. Ongoing research is crucial to better understand the disease’s pathogenesis and to develop more effective and personalized treatment strategies. Keywords: Schnitzler syndrome, neutrophilic urticarial dermatosis, monoclonal gammopathy

Schnitzler syndrome is characterized by an urticarial rash, a monoclonal gammopathy, and clinical, histological, and biological signs of neutrophil-mediated inflammation. The aim of this study was to assess the applicability and validity of the existing diagnostic criteria in real-life patients. This multicentric study was conducted between 2009 and 2014 in 14 hospitals in which patients with Schnitzler syndrome or controls with related disorders were followed up. We compared the sensitivities and specificities and calculated the positive and negative predictive values of the Lipsker and of the Strasbourg criteria for the patients with Schnitzler syndrome and for the controls. We included 42 patients with Schnitzler syndrome, 12 with adult-onset Still's disease, 7 with cryopyrin-associated periodic disease, 9 with Waldenström disease, and 10 with chronic spontaneous urticaria. All patients with Schnitzler syndrome met the Lipsker criteria. According to the Strasbourg criteria, 34 patients had definite Schnitzler syndrome, five had probable Schnitzler syndrome, and three did not meet the criteria. One control met the Lipsker criteria and had probable Schnitzler syndrome according to the Strasbourg criteria. Sensitivity and specificity of the Lipsker criteria were 100% and 97%, respectively. For the Strasbourg criteria, sensitivity for definite and probable diagnosis was 81% and 93%, respectively, with a corresponding specificity of 100% and 97%. Diagnostic criteria currently in use to diagnose Schnitzler syndrome are reliable. More investigations must be done to attest their efficiency in patients with recent-onset manifestations.

Schnitzler syndrome associated with MYD88 L265P mutation

Schnitzler Syndrome is a rare acquired auto-inflammatory syndrome defined by an urticarial eruption and a monoclonal gammopathy, mainly of the IgM kappa isotype. It shares many clinical and biological features with other autoinflammatory disorders such as NLRP3-auto-inflammatory disorders (NLRP3-AID, formerly cryopyrin associated periodic syndromes or CAPS) or adult-onset Still disease (AOSD). Hence, recurrent fever, urticarial rash with a neutrophilic infiltrate on skin biopsy (i.e. neutrophilic urticarial dermatosis or NUD) and a significant elevation of blood inflammation markers are commonly found in Schnitzler Syndrome as well as in NLRP3-AID or AOSD. IL-1ß plays a crucial role in the pathogenesis and explains the clinical symptoms of Schnitzler Syndrome. This is emphasized by the spectacular effectiveness of IL-1 blocking therapies, especially anakinra. IL-1 blocking therapies are efficient on the inflammation-linked symptoms but not on the monoclonal component. The evolution is chronic and about 15-20% of patients may develop lymphoproliferative disease, in particular Waldenström disease, a proportion similar to patients with IgM monoclonal gammopathy of undetermined significance, and more rarely AA-amyloidosis.

Schnitzler’s syndrome is a rare clinical entity characterized by intermittent, non-pruritic urticarial rash, fevers, arthralgias, myalgias and monoclonal gammopathy, most commonly of the immunoglobulin M (IgM) subtype. Schnitzler’s syndrome should be considered in the differential diagnosis of fever of unknown origin. We report a case of a 56-year-old healthy Caucasian female, who initially presented to the primary care physician’s office with complaints of severe generalized fatigue and myalgias involving thighs and calves. Patient subsequently underwent extensive rheumatologic workup, and was treated with multiple courses of steroids with temporary resolution of symptoms. During the course of her workup she was found to have IgM kappa monoclonal gammopathy, and was referred to hematology for further evaluation. The constellation findings of fever, arthralgias, chronic intermittent non-pruritic urticaria, myalgias, and a negative rheumatologic workup in the presence of IgM monoclonal gammopathy raised the suspicion of Schnitzler’s syndrome. Following completion of additional workup, she was started on anakinra 100 mg daily with prompt resolution of her symptoms. Due to the rarity of the disease, the diagnosis of Schnitzler’s syndrome is often delayed, with an average time to diagnosis being approximately 5 years. The symptoms in most cases can be debilitating and add to significant morbidity as noted in our patient, who required bilateral hip arthroplasty at a much younger age than expected. Published reports discuss the poor quality of life associated with the delayed diagnosis and unawareness of potential end organ damage. With our case report we like to highlight the disease characteristics for an early identification to prevent further organ damage believed to be from chronic inflammation. Early diagnosis and treatment with agents such as interleukin-1 (IL-1) inhibitors can promptly provide symptomatic relief, reduce inflammation and prevent organ damage.

Schnitzler syndrome is a rare acquired autoinflammatory disease characterized by monoclonal immunoglobulin M gammopathy and urticaria. Clinical features include fever, urticarial rash, myalgia, arthralgia, hepatosplenomegaly, and enlarged lymph nodes. Schnitzler syndrome is often underdiagnosed and not usually suspected until more common autoimmune, neoplastic, and infectious etiologies are excluded. Anakinra, an interleukin-1 receptor antagonist, is the first-line treatment and has been shown to provide fast and sustained symptom relief 1-3. A 50-year-old man with presumed Castleman disease/POEMS syndrome (a multisystem syndrome combining polyneuropathy, organomegaly, endocrinopathy, M component, and skin changes) presented for evaluation of persistent hip pain and a “burning” rash of 3 years' duration. He had previously been treated with systemic corticosteroids, lenalidomide, rituximab, and bortezomib, and with an autologous stem cell transplant, resulting in initial improvement but eventual recurrence of symptoms. His physical examination revealed small, slightly edematous, pink plaques involving the back (Image 1A), trunk, and arms (Image 1B). Laboratory tests revealed elevated inflammatory markers, with an erythrocyte sedimentation rate of 75 mm/hr (reference range, 0–22 mm/hr) and C-reactive protein of 65 mg/L (reference range, 0–8 mg/L), and small monoclonal immunoglobulin M κ protein. Magnetic resonance imaging demonstrated patchy intramedullary osteosclerosis of the left iliac wing, with bone marrow edema in the left acetabulum and both knees. Whole-body fludeoxyglucose (FDG) positron emission tomography/computed tomography revealed mild increased 18F-FDG uptake and osteosclerosis in an identical anatomic distribution, as well as hepatosplenomegaly and prominent axillary and inguinal lymph nodes. The osteosclerosis was most clearly demonstrated upon review of the images from the whole-body FDG positron emission tomography/computed tomography (Image 1C). Bone marrow and lymph node biopsies were negative for hematologic abnormalities. Skin biopsy revealed primarily neutrophilic urticaria with scattered eosinophils (Image 1D). The cutaneous findings, monoclonal gammopathy, and characteristic radiological osteosclerosis led to a diagnosis of Schnitzler syndrome. Treatment was initiated with anakinra. Schnitzler Syndrome. A: Small, slightly edematous pink plaques on the back. B: Close-up of plaques on the arm. C: Axial computed tomography image of the pelvis from the whole-body FDG positron emission tomography/computed tomography. Patchy intramedullary osteosclerosis involving the left iliac wing (arrows). D: Skin histologic results showing predominant neutrophilic perivascular inflammation with scattered eosinophils (Hematoxylin–Eosin; original magnification, 20×). Since Schnitzler syndrome was first described in 1972, fewer than 250 cases have been reported 3. In addition to its severe impact on quality of life, it places patients at increased risk for lymphoproliferative malignancies that define prognosis. Lymphoma or Waldenström macroglobulinemia develops in ∼15–20% of these patients 1-3. The clinical hallmark of Schnitzler syndrome is a chronic, recurrent urticarial rash that is initially asymptomatic but can become pruritic over several years. Individual skin lesions are transient, appearing daily and completely resolving in 12 to 36 hr 1. Histologic findings reveal predominantly neutrophilic perivascular and interstitial inflammation 2. If Schnitzler syndrome is suspected, a bone scan can be a helpful screening tool. Typical findings of osteosclerosis, especially involving the knees and pelvis, can aid diagnosis 4. Given the multiple and broad features of Schnitzler syndrome, the diagnosis can be often made by a variety of specialties, including hematology, rheumatology, radiology, and dermatology. Any patient with a nonpruritic urticarial eruption, primarily with neutrophilic infiltrate and associated monoclonal gammopathy, especially immunoglobulin M κ, should be further evaluated for Schnitzler syndrome. Our case illustrates the importance of awareness and early recognition of this disease. Expedited treatment with anakinra can relieve symptoms and significantly improve quality of life 1-3. The authors thank Tania M. Gonzalez Santiago, MD, for assistance in obtaining the skin histology image.

Schnitzler syndrome is a rare chronic auto-inflammatory disease characterized by neutrophilic dermatosis and a monoclonal gammopathy of IgM type. The clinical features of this disease like fever, rash, arthralgias and lymphadenopathy often overlaps with the presenting symptoms of other diseases like Castleman’s disease, adultonset Still’s disease and lymphomas. But the line of treatment is different for each of these clinical conditions. Schnitzler syndrome is associated with over-production of IL-1 and therapies are directed against this interleukin. Here, we present a case of Schnitzler syndrome, who was initially diagnosed as multi-centric Castleman’s disease and was treated with only partial resolution of symptoms.

Schnitzler syndrome is a rare acquired autoinflammatory syndrome. It presents with an urticarial rash and a monoclonal gammopathy, usually of the IgM kappa type. In addition, patients can present with bone and/or joint pain, recurrent fever, asthenia, weight loss, myalgia, headache, lymphadenopathy, hepatomegaly, or splenomegaly. An elevation of blood inflammation markers is commonly found. Skin biopsy of the urticarial rash reveals neutrophilic infiltrate, known as neutrophilic urticarial dermatosis. To confirm the diagnosis, two sets of diagnostic criteria have been established. The syndrome shares many features with other autoinflammatory disorders, such as adult-onset Still's disease and NLRP3-auto-inflammatory disorders (NLRP3-AID, formerly known as cryopyrin-associated periodic syndromes, or CAPS). The pathogenesis of the disease is not yet fully understood; however, it is believed that interleukin (IL)-1β plays a crucial role and explains the excellent effectiveness of IL-1 blocking agents. It is a chronic disease, and some patients develop lymphoproliferative disease, and seldom AA amyloidosis.

Accessible online at: www.karger.com/journals/drm L. Schnitzler, a French dermatologist, first described the Schnitzler syndrome in 1972 [1]. It is a disabling chronic disorder defined by the presence of an urticarial eruption and a monoclonal IgM gammopathy as well as at least 2 other signs among the following: fever, bone pain, joint pain, abnormal findings on bone morphological investigations, palpable lymph nodes, spleen and/or liver enlargement, leukocytosis or an elevated erythrocyte sedimentation rate [2]. Chronic inflammation can induce severe symptomatic inflammatory anemia [3]. The diagnosis relies on this combination of clinical, biological and radiological findings as well as on exclusion of the hyperIgD syndrome, adult-onset Still disease, urticarial hypocomplementemic vasculitis, acquired C1 inhibitor deficiency and cryoglobulinemia. Although the syndrome is probably underdiagnosed, it is a rare disease and less than 60 cases have been reported. The course of the disease is long-standing, and neither spontaneous nor treatment-induced remissions have been reported. At least 15% of the patients with a Schnitzler syndrome will eventually develop a lymphoproliferative disorder, although this percentage would probably be much higher if longer follow-up periods were to be considered. The pathophysiology of the syndrome remains unclear. The clonal IgM proliferation is deposited in the skin and could play a role in the pathophysiology of the skin rash [4]. The presence of anti-IL-1 antibodies as well as elevated serum IL-6 and IL-2 receptor levels were reported with increased frequency [2, 5]. Although IL-6 is an essential plasma cell growth factor, it is also an acute-phase reactant and its increase during a systemic illness is therefore not surprising. Thus, it remains to be established if the clonal IgM proliferation is primitive in nature or the result of a continuous antigenic stimulation so that the question remains open whether the Schnitzler syndrome shoulb be considered as a ‘smoldering’ mature B cell dyscrasia. Treatment of the Schnitzler syndrome is disappointing and difficult. There is a long list of treatments (reviewed in Lipsker et al. [2]), including nonsteroidal anti-inflammatory drugs (NSAIDs), steroids at acceptable dosages, immunosuppressive drugs, antihistamines, colchicine, dapsone, antimalarials, intravenous immunoglobulins, plasmapheresis and PUVA therapy, that did not constantly prove efficient in controlling the skin rash or the other signs of the disease. Thus, the report by Schartz et al. [6] about the efficiency of interferon · to treat this disorder is noteworthy. The authors report a 51-year-old man who fulfilled the criteria for the diagnosis of the Schnitzler syndrome. The patient’s symptoms did not respond to antihistamines, NSAIDs, steroids, UVA1 full-body phototherapy and plasmapheresis. However, 5 MU of interferon ·2b administered 3 times weekly proved rapidly efficient to control the skin rash and the bone pain, although interferon did not prevent an increase in the IgM level during an 18-month treatment period. When interferon was stopped, the rash recurred, strongly suggesting that improvement was not coincidental. Two features were unusual in the observation presented by Schartz et al. [6]:

Schnitzler syndrome is a rare auto-inflammatory disease with a chronic relapsing course, characterized by recurrent urticarial lesions and monoclonal gammopathy. The manifestations of systemic inflammation are complemented by fever, bone and muscle pain, arthralgia/arthritis, lymphadenopathy, hepato- or splenomegaly, increased levels of acute inflammatory markers. A biological marker of the disease is the monoclonal gammopathy. Patients show high risk to develop AA-amyloidosis and lymphoproliferative diseases. A patient with a 5-year delay in diagnosis, who has responded well to systemic corticosteroids is presented. A comprehensive review of the new insights of disease pathogenesis and therapy is also highlighted.

IL-1 blockade in Schnitzler syndrome: Ex vivo findings correlate with clinical remission

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.