Schnitzler syndrome (SS) is a rare autoinflammatory disease that
presents with chronic urticaria and monoclonal immunoglobulin (Ig) M or G,
accompanied by fever, abnormal bone remodeling, skin biopsy with a neutrophilic
dermal infiltrate, leukocytosis, or elevated C-reactive protein. It is usually
refractory to antihistamines and immunosuppression. We present a case report
of clinical SS without monoclonal Ig with robust response to interleukin-1 inhibitor
anakinra. This suggests the possible existence of an incomplete form of
SS and underlines the risk of false negative diagnosis in individuals with such
“incomplete SS”

Gregor B.E. Jemec

Kristina S. Ibler

Mattias A.S. Henning

English

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Incomplete Schnitzler SyndromeMattias A.S. Henning1, Gregor B.E. Jemec1, Kristina S. Ibler11Department of Dermatology, Zealand University Hospital, Faculty of Health and  Medical Sciences, University of Copenhagen, DenmarkCorresponding author:Mattias A.S. Henning, MDDepartment of DermatologyZealand University HospitalSygehusvej 54000 RoskildeDenmarkmaahe@regionsjaelland.dkFinancial disclosure:Mattias A.S. Henning was provided a  research grant from Leo Foundation,  Denmark (number LF 18002).Acta Dermatovenerol Croat                                   2020;28(1):38-40                                  CASE REPORTABSTRACT Schnitzler syndrome (SS) is a rare autoinflammatory disease that presents with chronic urticaria and monoclonal immunoglobulin (Ig) M or G, accompanied by fever, abnormal bone remodeling, skin biopsy with a neutro-philic dermal infiltrate, leukocytosis, or elevated C-reactive protein. It is usually refractory to antihistamines and immunosuppression. We present a case report of clinical SS without monoclonal Ig with robust response to interleukin-1 in-hibitor anakinra. This suggests the possible existence of an incomplete form of SS and underlines the risk of false negative diagnosis in individuals with such “incomplete SS”.KEY WORDS: diagnosis, interleukin 1 receptor antagonist protein, Schnitzler syndrome, urticariaINTRODUCTIONSchnitzler Syndrome (SS) is a rare autoinflamma-tory disease defined by the Strasbourg criteria (1,2). According to the definition, chronic urticarial rash and monoclonal immunoglobulin (Ig) M or IgG are obligatory in combination with two of the follow-ing minor criteria: recurrent fever, objective findings of abnormal bone remodeling with or without bone pain, skin biopsy with a neutrophilic dermal infiltrate, and leukocytosis and/or elevated C-reactive protein (CRP) (1). Mean age of onset is 51 years, and the litera-ture describes around 300 cases (1,2). Symptoms are generally refractory to antihistamine, azathioprine, methotrexate, tumor necrosis factor inhibitors, and rituximab (1,2). However, the interleukin-1 inhibitor anakinra quickly alleviates the symptoms and most likely decreases the risk of future amyloidosis, but not Waldenström macroglobulinemia, a lymphoprolifera-tive complication (3). Discontinued anakinra usually lead to a rapid recurrence the symptoms (2). There are reports of patients with clinical SS without mono-clonal gammopathy at the time of diagnosis (4), as well as cases of delayed monoclonal gammopathy development, years after onset of symptoms (3). CASE REPORTA 51-year-old healthy man was referred to the dermatology department in 2016 after eight months of recurrent urticaria, fever, night sweats, joint and muscle pain, and minor weight loss (Figure 1). No one in his family had had similar symptoms. Labora-tory testing indicated a normocytic, normochromic anemia with hemoglobin 129 g/L, elevated CRP 46 ACTA DERMATOVENEROLOGICA CROATICA38Henning et al. Acta Dermatovenerol CroatIncomplete Schnitzler Syndrome                  2020;28(1):38-40mg/L, leukocytosis 6.7×109/L, and thrombocytosis 512×109/L. Liver, renal, and rheumatological screen-ing including anti-double stranded deoxyribonucleic acid antibodies, anti-neutrophil cytoplasmic antibod-ies, antinuclear antibodies, beta-2 microglobulin, complement factors, and extractable nuclear antigen were normal and urine and blood cultures negative. Electrophoresis showed kappa and lambda light chains of 47.2 mg/L and 28.3 mg/L, without mono-clonal gammopathy. Histopathological examination revealed subepithelial edema and discrete interstitial and perivascular neutrophilic and eosinophilic gran-ulocyte infiltration, indicative of urticaria, computer tomography (CT) showed sclerosis in the pelvic bone, and positron emission tomography (PET) -CT found increased fluorodeoxyglucose (FDG) uptake in the ax-illary and inguinal lymph nodes. A bone marrow bi-opsy indicated osteosclerosis, without evidence for malignancy. Anakinra 100 mg subcutaneously once daily was initiated for suspected SS, resulting in symp-tom mitigation within days, and the hemoglobin and acute phase reactants normalized. The symptoms reoccurred quickly during treatment pauses, and anakinra was discontinued due to a mild headache and nightly pruritus, and omalizumab 300 mg every four weeks was subcutaneously initiated for chronic urticaria. A few days later, the patient developed a productive cough, headache, and urticaria and upon hospitalization the blood samples revealed CRP 250 mg/L, leukocytosis 13.3×109/L, and hemoglobin 127 g/L. Chest X-ray, blood cultivations, and urine analy-sis were normal. Despite intravenous benzylpenicillin 1.2 million units four times daily and oral cetirizine ten mg daily, the symptoms were only reduced once he received prednisolone 50 mg daily. Shortly after anakinra was reinstated in the same dose as before, omalizumab was discontinued, and at clinical control two and eight months later the patient only had mild nightly pruritus and the laboratory values had nor-malized. DISCUSSIONThe Strasbourg criteria’s sensitivity and specific-ity are 81% and 100%, respectively (1). This particular case underlines the risk of a false negative diagnosis when SS manifests without monoclonal gammopa-thy and also emphasizes the responsiveness of such “incomplete SS” to standard therapy. The laboratory findings, including anemia, elevated CRP, leukocyto-sis, and thrombocytosis reflect an increased inflam-matory activity that together with bone marrow os-teosclerosis and bone sclerosis are characteristics of SS (2,3). Increased FDG uptake and hence metabolic activity in the axillar and inguinal lymph nodules, described in the PET-CT, is attributed to dermal in-flammation. Schnitzler syndrome has many clinical features in common with autoinflammatory cryo-pyrin-associated periodic syndrome (CAPS) (5). How-ever, age of onset for CAPS is during childhood, and family members are often affected. Moreover, genetic testing for NLRP3 mutation can sometimes distin-guish the two diseases. Other important differential diagnoses include chronic spontaneous and induc-ible urticaria, which are limited to the skin and usu-ally have normal serum markers (5). Histological neu-trophilic granulocyte infiltration is a hallmark of both SS and adult-onset Still’s disease (5). They also share some laboratory findings, including leukocytosis and elevated erythrocyte sedimentation rate. However, several clinical features distinguish them from each other. Another serious differential diagnosis and po-tential complication is Waldenström macroglobulin-emia that can be excluded with bone marrow biopsy (5). Finally, the current absence of a monoclonal gam-mopathy does not preclude future development of this diagnostic hallmark.CONCLUSIONPhysicians should consider “incomplete SS” de-spite the absence of monoclonal gammopathy if other autoinflammatory symptoms are present at Figure 1. Hives on the patient’s back.ACTA DERMATOVENEROLOGICA CROATICA 3940 ACTA DERMATOVENEROLOGICA CROATICAthe time of diagnosis (6). Early disease recognition allows for appropriate therapeutic intervention and prompt symptom control and potentially improved long-term prognosis for the affected patient. At the end of May 2020, blood samples revealed that the pa-tient had developed monoclonal IgM of 1.4 gram/L, confirming the diagnosis SS, almost four years after onset of symptoms.References:1. Gusdorf L, Asli B, Barbarot S, Neel A, Masseau A, Puechal X, et al. Schnitzler syndrome: validation and applicability of diagnostic criteria in real-life patients. Allergy. 2017;72:177-82.2. Lipsker D. The Schnitzler syndrome. Orphanet journal of rare diseases. 2010;5:38.3. Gusdorf L, Lipsker D. Schnitzler Syndrome: a Re-view. Current rheumatology reports. 2017;19:46.4. Ahn MJ, Yu JE, Jeong J, Sim DW, Koh YI. A Case of Schnitzler’s Syndrome without Monoclo-nal Gammopathy-Associated Chronic Urticaria Treated with Anakinra. Yonsei medical journal. 2018;59:154-7.5. de Koning HD. Schnitzler’s syndrome: lessons from 281 cases. Clin Transl Allergy. 2014;4:41.6. Murthy AS, Leslie K. Autoinflammatory Skin Di-sease: A Review of Concepts and Applications to General Dermatology. Dermatology (Basel, Swit-zerland). 2016;232:534-40. Henning et al. Acta Dermatovenerol CroatIncomplete Schnitzler Syndrome                  2020;28(1):38-40

Incomplete Schnitzler Syndrome

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