Neutrophilic Urticarial Dermatosis.

Neutrophilic urticarial dermatosis (NUD) is a rare form of dermatosis that is poorly understood. It was first described by Kieffer and colleagues as an urticarial eruption that is histopathologically characterized by a perivascular and interstitial neutrophilic infiltrate with intense leukocytoclasia and without vasculitis or dermal edema. NUD clinically presents as a chronic or recurrent eruption that consists of nonpruritic macules, papules, or plaques that are pink to reddish and that resolve within 24 hours without residual pigmentation. NUD is often associated with systemic diseases such as Schnitzler syndrome, lupus erythematosus, adult-onset Still's disease, and cryopyrin-associated periodic syndromes.

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 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.

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.

A patient with urticarial lesions, recurrent fever, and IgM-type monoclonal gammopathy.

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)-1ß 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.

Incomplete Schnitzler Syndrome.

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".

The First Case Report of Schnitzler Syndrome Presenting with Eye Pain.

Schnitzler syndrome is a rare, auto inflammatory condition known to manifest with bone pain, urticarial rash, fevers, relapsing arthralgia, and fatigue. In this case report, we describe a patient who was diagnosed with Schnitzler Syndrome that had initially presented with a unilateral pressure-type headache with a sensation of a 'dagger' stabbing into the back of the eye. He also had an associated ipsilateral redness of the conjunctiva, eyelid swelling, subtle optic disc elevations bilaterally and facial flushing - but with no visual acuity, pupillary, or lacrimatory changes. Anterior segment, fundoscopy, intraocular pressures and extraocular muscle movements were otherwise normal.

[Membranoproliferative glomerulonephritis with relapsing episodes of acute kidney injury in the Schnitzler syndrome].

The Schnitzler syndrome (SS) is a rare and underdiagnosed entity that associates a chronic urticarial rash, monoclonal IgM (or sometimes IgG) gammopathy and signs and symptoms of systemic inflammation. During the past 45 years the SS has evolved from an elusive, little-known disorder to the paradigm of a late-onset auto-inflammatory acquired syndrome. Though there is no definite proof of its precise pathogenesis, it should be considered as an acquired disease involving abnormal stimulation of the innate immune system, which can be reversed by the interleukin 1 (IL-1) receptor antagonist anakinra. Here we describe the case of a 56-year-old male Caucasian patient affected by SS and hospitalized several times in our unit because of relapsing episodes of acute kidney injury. He underwent an ultrasound-guided percutaneous kidney biopsy in September 2012, which showed the histologic picture of type I membranoproliferative glomerulonephritis. He has undergone conventional therapies, including nonsteroidal anti-inflammatory drugs, steroids and immunosuppressive drugs; more recently, the IL-1 receptor antagonist anakinra has been prescribed, with striking clinical improvement. Although the literature regarding kidney involvement in the SS is lacking, it can however be so severe, as in the case reported here, to lead us to recommend the systematic search of nephropathy markers in the SS.

Monoclonal Gammopathy, Arthralgias, and Recurrent Fever Syndrome: A New Autoinflammatory Syndrome?

OBJECTIVE: To describe a new autoinflammatory syndrome with recurrent fever and monoclonal gammopathy that differs from Schnitzler syndrome. METHODS: We conducted a retrospective study of patients with monoclonal gammopathy and recurrent fever of unknown origin. RESULTS: Five patients were studied; median age at onset of symptoms was 44 years. Median frequency of fever attacks was 6 episodes per year. In the absence of treatment, the median duration of fevers was 3 days. CONCLUSION: This new autoinflammatory syndrome is defined by an association among monoclonal gammopathy, arthralgias, and recurrent fever.

Neutrophilic urticarial dermatosis: A review.

Neutrophilic urticarial dermatosis (NUD) is a rare form of dermatosis. In clinical terms, it consists of a chronic or recurrent eruption comprising slightly elevated, pink to reddish plaques or macules. The elementary lesion lasts 24 to 48hours and resolves without leaving any residual pigmentation. Extra-cutaneous signs are common, particularly fever or arthralgia. At histopathology, the dermis contains dense neutrophilic interstitial infiltrate with leukocytoclasis, but without fibrinoid necrosis of vessel walls. NUD often occurs in a setting of underlying systemic disease. The most commonly associated diseases are adult-onset Still's disease, Schnitzler syndrome, lupus erythematosus and cryopyrin-associated periodic syndromes. Treatment of NUD depends on the clinical context. Dapsone and colchicine are often effective.

[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 With Delirium and Vertigo: The Utility of Neurologic Manifestations in Diagnosis.

Schnitzler syndrome (SS) is an autoinflammatory dermatosis that often goes undiagnosed for 5-6 years. Patients typically carry a diagnosis of urticaria; however, their cutaneous symptoms fail to respond to typical urticaria therapies and lack symptoms such as pruritus. Additionally, patients with SS may see multiple providers for nonspecific complaints of fever, lymphadenopathy, arthralgias, and bone pain. A correct diagnosis is paramount, as close to 20% of patients may develop a lymphoproliferative disorder and appropriate treatment may ameliorate all symptoms.1 We report 2 cases of SS misdiagnosed as urticaria for years in order to illuminate diagnostic pearls, histopathological findings, and treatment modalities. Additionally, we highlight the importance of neurologic disturbances in this rare but important differential diagnosis of urticaria.

J Drugs Dermatol. 2017;16(6):625-627.

Enfermedades autoinflamatorias en el adulto. Características clínicas e implicaciones pronósticas / Autoinflammatory diseases in adults. Clinical characteristics and prognostic implications

Las enfermedades autoinflamatorias son cuadros clínicos con manifestaciones inflamatorias que se presentan de forma periódica o persistente, producidas por alteraciones adquiridas o hereditarias de la respuesta inmune innata. En general, son más frecuentes en la edad pediátrica, pero se han descrito casos en adultos, por lo que son de interés para cualquier especialista. Existen pocas referencias de estas enfermedades en el adulto por su baja prevalencia e infradiagnóstico. El objetivo de este trabajo es revisar la literatura científica sobre estos trastornos para sistematizar sus características clínicas, pronósticas y la respuesta al tratamiento en el adulto (AU)

Autoinflammatory diseases are clinical conditions with inflammatory manifestations that present in a periodic or persistent manner and are caused by acquired or hereditary disorders of the innate immune response. In general, these diseases are more common in childhood, but cases have been reported in adults and are therefore important for all specialists. There are few references on these diseases in adults due to their low prevalence and underdiagnosis. The aim of this study is to review the scientific literature on these disorders to systematise their clinical, prognostic and treatment response characteristics in adults (AU)

Schnitzler Syndrome Without a Monoclonal Gammopathy: A Case Report.

BACKGROUND: Schnitzler syndrome (SS) is a rare autoinflammatory disorder characterized by a recurrent urticarial rash and a monoclonal immunoglobulin M gammopathy, as well as 2 of the following minor criteria: recurrent fever (>38°C), objective signs of abnormal bone remodeling, elevated C-reactive protein level or leukocytosis, and a neutrophilic infiltrate on skin biopsy. Alternatively, a monoclonal immunoglobulin G gammopathy may be present along with 3 minor criteria for diagnosis. OBJECTIVE: To report a rare case of SS without monoclonal gammopathy and inform physicians of this possible clinical presentation so that treatment is not delayed. METHODS: We report a case of a 62-year-old white man with a clinical diagnosis of SS without monoclonal gammopathy. He presented with chronic urticaria unresponsive to conventional therapy. RESULTS AND CONCLUSIONS: To our knowledge, there have only been 3 case reports of SS in the absence of monoclonal gammopathy documented in the literature. SS should be considered based on clinical presentation, even in the absence of monoclonal gammopathy, to facilitate appropriate management.

Neutrophilic Epitheliotropism is a Histopathological Clue to Neutrophilic Urticarial Dermatosis.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.