Neutrophilic dermatoses - Pathomechanistic concepts and therapeutic developments.

Neutrophilic dermatoses are a group of clinically heterogeneous diseases characterized by infiltration of neutrophils in the affected tissue. Skin symptoms comprise a spectrum of wheals, papules, plaques, pustules, nodules and ulcerations often in combination with systemic symptoms. Although the pathogenesis of these diseases has not yet been elucidated in depth, broad pathophysiological and clinical overlaps exist with autoinflammatory syndromes. Additionally, recent years have shown the relevance of the signaling pathways of TNF-α, IL-1, IL-12/23 and IL-17 in neutrophilic dermatoses. In this review, we present four selected neutrophilic dermatoses, namely pyoderma gangraenosum, Sweet syndrome, generalized pustular psoriasis and Schnitzler syndrome, discuss pathophysiological aspects and specifically address novel therapeutic options derived from the most recent pathophysiological findings.

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.

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.

Diagnostic value of 18-F fluorodeoxyglucose PET/CT and bone scan in Schnitzler syndrome.

Introduction: Schnitzler syndrome is an auto-inflammatory disease defined by chronic urticarial eruption and monoclonal gammopathy. 18F fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is often performed, but its utility in Schnitzler syndrome has not been specifically investigated. The aim of this study was to determine whether PET/CT is informative in the diagnosis and follow-up of Schnitzler syndrome relative to other imaging techniques, including bone scans.Patients and methods: Patients of this study were selected from the French cohort established by Néel et al. All patients with a diagnosis of Schnitzler syndrome (according to Strasbourg's and Lipsker's criteria) who had at least one PET/CT were included. Data were collected from medical records. PET/CT scans were all reviewed by a nuclear physician blinded to the clinical and imaging data.Results: Ten patients underwent at least one PET/CT scan and all had at least one 99mTechnetium bone scan during their follow-up. The most frequent PET/CT abnormalities were diffuse bone-marrow and/or increased femoral fluorodeoxyglucose uptake, but they did not correlate with disease activity. Conversely, bone-scan abnormalities, including mainly increased radiotracer uptake in long bones, appeared to strongly correlate with Schnitzler syndrome activity.Discussion: PET/CT does not appear to be useful for the diagnosis and follow-up of Schnitzler syndrome. However, bone scans appear to be more sensitive for diagnosis and may correlate with clinical activity. Bone scans may be well positioned to distinguish Schnitzler syndrome relapse from other aetiologies of bone, joint, or muscle pain.Conclusion: Bone scans may be favoured over PET/CT in Schnitzler syndrome.

Refractory urticaria and the importance of diagnosing Schnitzler's syndrome.

A 52-year-old man presented with chronic urticaria that was refractory to standard chronic spontaneous urticaria (CSU) treatment. Over time, he developed systemic symptoms including fatigue, weight loss, arthralgia and bone pain. His laboratory investigations also became significant for microcytic anaemia, neutrophilia and elevated C reactive protein, erythrocyte sedimentation rate and IgE levels, in addition to an IgM monoclonal protein. He achieved only partial remission with typical medications for CSU including omalizumab, cyclosporine and cetirizine. After 6 years, his worsening symptoms and abnormal investigations led to a rare diagnosis of Schnitzler's syndrome and a trial of the interleukin 1 receptor antagonist, anakinra, which caused a rapid and complete resolution of his symptoms.

Skin and Systemic Inflammation in Schnitzler's Syndrome Are Associated With Neutrophil Extracellular Trap Formation.

Schnitzler's syndrome is a rare autoinflammatory disorder characterized by interleukin-1ß-mediated and neutrophil-dominated inflammation. Neutrophil extracellular traps (NETs) are web-like structures of decondensed chromatin, histones, and antimicrobial peptides released by neutrophils. NETs were initially described in the context of pathogen defense but are also involved in autoimmune-mediated skin diseases. Here, we assessed the role of neutrophil extracellular trap formation (NETosis) in Schnitzler's syndrome. Immunofluorescence co-staining of myeloperoxidase and subnucleosomal complex was performed on lesional skin samples from patients with Schnitzler's syndrome, other neutrophilic dermatoses (cryopyrin-associated periodic syndrome, Sweet syndrome, and pyoderma gangrenosum), urticarial vasculitis and chronic spontaneous urticaria as well as healthy control skin. Blood neutrophils from patients with Schnitzler's syndrome and controls were isolated, and NETosis was induced by phorbol 12-myristate 13-acetate (PMA). Also, NETosis of control neutrophils induced by symptomatic Schnitzler's syndrome sera, cytokines and sub-threshold PMA doses was studied. Immunofluorescence co-staining revealed widespread and substantial NET formation in lesional skin of Schnitzler's syndrome patients but absence of NETs in chronic spontaneous urticaria and control skin. Neutrophils undergoing NETosis were observed in the skin of other neutrophilic diseases too. Correspondingly, blood neutrophils from Schnitzler's syndrome patients showed significantly elevated NETosis rates compared to control neutrophils following stimulation with PMA. Increased NETosis correlated well with high levels of C-reactive protein (CRP). SchS patients with the lowest NETosis rates had persistent joint and bone pain despite IL-1 blockade. Stimulation of control neutrophils and sub-threshold PMA with sera of symptomatic Schnitzler's syndrome patients disclosed enhanced NETosis as compared to control sera. Our results suggest that the induction of NET formation by neutrophils contributes to skin and systemic inflammation and may support the resolution of local inflammation in Schnitzler's syndrome.

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.

Cutaneous manifestations of multiple myeloma and other plasma cell proliferative disorders.

Plasma cell proliferative disorders cause rare but extremely varied dermatologic manifestations that may occur as an accompaniment to established diagnoses, or may be a first clue of an underlying neoplasm in the setting of clinical suspicion. In some instances skin lesions result from aggregation of misfolded monoclonal immunoglobulins or their fragments, as in light chain-related systemic amyloidosis. On other occasions the cutaneous lesions result from deposits of malignant plasma cells or monoclonal proteins. In still others, the dermatologic manifestations are related to antibody activity of monoclonal protein, as in many cases of cryoglobulinemia. This report provides insights into the well-recognized cutaneous manifestations associated with plasma cell disorders.

Clinical characterization and long-term follow-up of Schnitzler syndrome.

BACKGROUND: Schnitzler syndrome (SchS) is an acquired autoinflammatory disease characterized by chronic urticarial rash in association with monoclonal gammopathy. Patients may progress to lymphoproliferative disorders, but the associated factors and exact risk of progression are still not well defined. AIM: To characterize the clinical findings, laboratory abnormalities and histopathology of patients with SchS and their respective outcomes. METHODS: We retrospectively reviewed the clinical files and the histological specimens of patients with SchS diagnosed from 1988 to 2015. RESULTS: Nine patients (two women, seven men) were diagnosed with SchS. Mean age at diagnosis was 61.1 years (range 29-80), with a mean time to diagnosis of 3.7 years and a mean follow-up period of 10.1 years (range 3-25). Four patients displayed an association of fever and arthralgia, and all nine patients consistently showed laboratory markers of inflammation. Serum values of the monoclonal component, IgMκ in eight patients and IgGλ in one patient, progressively increased over time. During follow-up, carried out in association with the haematology department five patients progressed to lymphoproliferative disease, namely, lymphoplasmacytic lymphoma/Waldenström's macroglobulinaemia (n = 4) and diffuse large B-cell lymphoma (n = 1). CONCLUSIONS: SchS is a rare chronic inflammatory disease with a substantial impact on quality of life. Our study highlights the importance of lifelong follow-up for individuals with SchS, owing to the risk of progression to a lymphoproliferative disorder.

Hyperimmunoglobulinemia E and efficacy of elimination diet in two patients with Schnitzler syndrome.

BACKGROUND: Schnitzler syndrome (SS) is a rare clinical entity characterized by chronic recurrent urticarial rash, monoclonal IgM gammopathy, intermittent fever and other symptoms. In this report, we present the cases of two patients with SS: a male and a female aged 50 and 49 years, respectively. Both patients had hyperimmunoglobulinemia E and showed good response to elimination diet. METHODS: The patients had chronic urticaria, IgM gammopathy and an elevation of the serum levels of inflammation markers. Total IgE levels were found to be high (2000 U/ml and 540 U/ml, respectively). No underlying causes for hyperimmunoglobulinemia E (allergy, parasites, etc.) were revealed. The first patient did not respond to the treatment with antihistamines, while the second one responded only to high doses. The response to prednisolone in the second patient was incomplete. RESULTS: Following a strict elimination diet resulted in marked improvement in skin lesions in both patients. In one of our patients we observed a decrease in IgE and IgM levels after a 3 week diet. The systemic symptoms persisted and improved only after adding pefloxacin, followed by a 3-day empirical course of intravenous prednisone in the first patient and a course of plasmapheresis in the second one. CONCLUSION: The high serum levels of total IgE may be associated with chronic urticaria activity, severe disease course and a poor response to treatment with antihistamines, and may be considered a possible marker of a subset of patients with SS showing a good response to the restriction diet. In general, we can assume that elimination diet can have an influence on the skin lesions and other symptoms of SS as well as on total IgE and IgM levels, but such association, the underlying mechanisms and the reasons for excessive IgE synthesis should be investigated in further studies.

Schnitzler's syndrome: a diagnostic conundrum.

A 63-year-old man was referred to the rheumatology unit with myalgia, arthralgia and a widespread rash. He was investigated for rheumatological disease; however, this did not yield any specific findings. His symptoms were attributed to statin use and newly started antihypertensives which were promptly discontinued. There was some subsequent improvement in his symptoms so he was discharged. He re-presented 3 years later with pelvic bone pain which had responded to a course of oral steroids started by the general practitioner, who was treating a presumed diagnosis of polymyalgia rheumatica. However, MRI of the pelvis showed bone marrow oedema and the diagnosis was changed to mastocytosis. He did not tolerate or respond to initial treatment. It was not until a second opinion was sought from the dermatologists that the diagnosis of Schnitzler's syndrome was made and treatment with anakinra (an interleukin-1 receptor antagonist) was started with almost complete resolution of his symptoms.

Increased angiogenesis and enhanced bone formation in patients with IgM monoclonal gammopathy and urticarial skin rash: new insight into the biology of Schnitzler syndrome.

Schnitzler syndrome is a rare plasma cell disorder the pathogenesis of which is still not fully understood. We evaluated the circulating levels of four major angiogenic cytokines (VEGF, angiogenin, angiopoietin-1 and angiopoietin-2) and six bone remodeling markers (sRANKL, osteoprotegerin, dickkopf-1, CTX, osteocalcin and bone-specific alkaline phosphatase-bALP) in 13 patients with Schnitzler syndrome. At diagnosis, patients had elevated angiogenic cytokines. The mean VEGF levels were almost 3.5-fold higher in Schnitzler syndrome compared to controls, while 10 of 13 patients had higher VEGF than the upper control value. Successful treatment led to a significant reduction in VEGF. Patients with Schnitzler syndrome had increased bone formation (high bALP, osteocalcin and osteoprotegerin) which was not balanced by an increase in bone resorption (normal CTX and sRANKL). These data support a role for VEGF as a new minor criterion in the diagnosis and follow up of Schnitzler syndrome, while the uncoupling of bone remodeling in favor of bone formation justifies the presence of bone densification.

Clinical and histopathologic review of Schnitzler syndrome: the Mayo Clinic experience (1972-2011).

BACKGROUND: Schnitzler syndrome is a rare multisystem disorder, defined by urticaria and monoclonal gammopathy, that is associated with malignancy. Considered a neutrophilic urticarial dermatosis, previous reports have included patients with leukocytoclastic vasculitis. OBJECTIVE: We sought to better define the clinical features, histopathology, and outcomes of Schnitzler syndrome. METHODS: We retrospectively reviewed clinical records and cutaneous histopathology of all patients with Schnitzler syndrome seen at our institution from January 1, 1972, through July 31, 2011. RESULTS: Of the 20 patients identified, 80% had IgM κ monoclonal gammopathy; others had IgG λ (10%), IgG κ (5%), or IgM κ+λ (5%). Patients had fevers (85%), arthralgias (70%), leukocytosis (70%), increased erythrocyte sedimentation rate (70%), bone pain (50%), lymphadenopathy (40%), and organomegaly (5%); 45% developed a hematologic malignancy. Histopathologic examination (n = 14) showed predominantly neutrophilic perivascular and interstitial inflammation (57%) or predominantly mononuclear cell perivascular inflammation (29%), with eosinophils in 50% of cases. None showed leukocytoclastic vasculitis. LIMITATIONS: Our study was limited by its retrospective design. CONCLUSION: We added 20 patients to approximately 100 reported cases of Schnitzler syndrome. Neutrophilic urticarial dermatosis was the most common histopathologic pattern, but mononuclear cells were predominant in many cases and the infiltrates often contained eosinophils. A high index of suspicion and careful clinicopathologic correlation are needed to avoid diagnostic delays in this syndrome associated with hematologic malignancy.

Efficacy and safety of the interleukin-1 antagonist rilonacept in Schnitzler syndrome: an open-label study.

BACKGROUND: Schnitzler syndrome (SchS) is a rare disease with suspected autoinflammatory background that shares several clinical symptoms, including urticarial rash, fever episodes, arthralgia, and bone and muscle pain with cryopyrin-associated periodic syndromes (CAPS). Cryopyrin-associated periodic syndromes respond to treatment with interleukin-1 antagonists, and single case reports of Schnitzler syndrome have shown improvement following treatment with the interleukin-1 blocker anakinra. This study evaluated the effects of the interleukin-1 antagonist rilonacept on the clinical signs and symptoms of SchS. METHODS: Eight patients with SchS were included in this prospective, single-center, open-label study. After a 3-week baseline, patients received a subcutaneous loading dose of rilonacept 320 mg followed by weekly subcutaneous doses of 160 mg for up to 1 year. Efficacy was determined by patient-based daily health assessment forms, physician's global assessment (PGA), and measurement of inflammatory markers including C-reactive protein (CRP), serum amyloid A (SAA), and S100 calcium-binding protein A12 (S100A12). RESULTS: Treatment with rilonacept resulted in a rapid clinical response as demonstrated by significant reductions in daily health assessment scores and PGA scores compared with baseline levels (P < 0.05). These effects, which were accompanied by reductions in CRP and SAA, continued over the treatment duration. Rilonacept treatment was well tolerated. There were no treatment-related severe adverse events and no clinically significant changes in laboratory safety parameters. CONCLUSION: Rilonacept was effective and well tolerated in patients with SchS and may represent a promising potential therapeutic option.