IL-36 as the Central Amplifier of Neutrophilic Inflammation: Lessons from Spatiotemporal Transcriptomics in Sweet Syndrome.

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is characterized by painful erythematous plaques or nodules with diffuse infiltration of mature neutrophils in the dermis. Most patients respond well to systemic corticosteroids, except for a few resistant cases. SS may be idiopathic or triggered by trauma, infection, drugs, and immune disorders. The exact pathogenesis, pathophysiology and precise treatment options beyond corticosteroids remain unclear. We applied anti-IL-36R monoclonal antibody, Spesolimab, to treat two SS patients and achieved favorable outcomes, however, the molecular mechanism is unproved. Here, we applied spatiotemporal transcriptomics at single-cell resolution and multiplex immunofluorescence on the skin lesion and blood samples from SS patients before, during, and after anti-IL-36R treatment. Releasing of neutrophil extracellular traps (NETs) was observed in the distinct NETosis neutrophil lineage infiltrating SS lesions, which secreted neutrophil elastase to splice full-length IL-36 proteins into their active forms, amplifying the inflammatory signal. From spatial view, the co-localized niches of heterogenous maturation neutrophils and IL36RN+ differentiated keratinocytes were found at the interface of the epidermis and dermis. The heterogenous maturation neutrophil activated IL-36 signaling was considered as rapid inflammatory response and was eliminated after treatment. Meanwhile, CD8+ T cells were also recruited and participated in the interferon signaling interacted with keratinocytes and neutrophils in the SS lesion, which was considered as delayed inflammatory response. Overall, a forward loop consisting of keratinocytes, heterogenous maturation neutrophils and CD8+ T cells was constructed to decipher the potential pathogenesis of SS, and IL-36 activated by neutrophil elastase released from heterogenous maturation neutrophils was one of the drivers of the loop. Moreover, IL-36 signaling was confirmed as a novel and effective treatment target for SS, which may be served as an alternative option for corticosteroid-resistant cases as well as patients with contraindications.

Sweet's syndrome (SS) is the prototypic neutrophilic dermatosis. First described in 1964, the characterization of new clinical associations, unique histopathological findings and clinical variants have stimulated much interest and discussion recently. However, the prevalence of these unusual variants and clinical associations within a single cohort of patients, has not been described. To describe and evaluate the prevalence of unusual clinical and histopathological features, as well as the clinical associations of SS seen in patients from the National Skin Centre, Singapore. This is a retrospective study of all consecutive cases of SS seen at our centre over a 5.5-year period (June 1999-December 2004). Data on associated systemic diseases was obtained from the medical records and matched with information from the National Cancer Registry, Singapore. Patients not actively followed up for more than 3 months were contacted for their updated health status. Thirty-seven patients were identified. Ten (27%) had non-idiopathic SS. These were associated with haematological disorders, connective tissue disorders, infections or a drug. Twenty-nine patients (78%) had at least one atypical clinical or histopathological feature. Atypical clinical features included bullous lesions, SS with hand involvement or neutrophilic dermatoses of the hands and the concomitant existence of subcutaneous SS with pyoderma gangrenosum. SS was the presenting feature in three patients with infections caused by atypical organisms, including Mycobacterium chelonae, Penicillium species and Salmonella type D. Unique histopathological variants included subcutaneous SS and lesions containing an admixture of mature and immature neutrophils. Subcutaneous neutrophilic inflammation seemed to be more common in patients with an underlying haematological disorder. This group of patients also had a lower mean haemoglobin level. Unusual clinical and histopathological variants of SS described in the literature are similarly encountered in our cohort of patients, with some features being more common than others. We highlight and discuss some unique clinical and histopathological observations seen in our patients with SS.

A 7-year-old-spayed female standard poodle dog presented to the Iowa State University Veterinary Teaching Hospital with an 8-day history of lethargy, left hind limb lameness, ptyalism and peripheral lymphadenomegaly. On physical examination, the dog was lethargic, febrile (40.5 degrees C) and had multifocal to coalescing erythematous papular to pustular eruptions on the skin of all four limbs, periocularly and on the ventral and lateral thorax and abdomen. Histopathological findings from skin biopsies of the papules revealed a severe diffuse neutrophilic dermatitis with sub- and intra-epithelial pustules. Four days after being admitted the dog died from cardiac and respiratory failure. At necropsy, in addition to the multifocal to coalescing erythematous papules, the skin contained scattered pustules. Additionally, the subcutaneous tissue surrounding the right stifle was diffusely oedematous, and the peripheral and visceral lymph nodes were enlarged. The predominant histologic lesion was neutrophilic inflammation, in the absence of detectable bacteria in the skin, heart, lungs, oesophagus and left tarsus. In the absence of neoplasia or bacteraemia, a syndrome similar to Sweet's Syndrome should be considered as a differential diagnosis in dogs with cutaneous and extracutaneous neutrophilic infiltrates.

Introduction/Objective Sweet syndrome is a non-vasculitic neutrophilic dermatosis characterized by acute, neutrophilic inflammation, most classically in the skin. Sweet syndrome can, however, manifest with systemic organ involvement including the lungs. Pulmonary involvement by Sweet syndrome is exceedingly rare, and its recurrence in a pulmonary allograft is understudied. Methods/Case Report A 43-year-old female with a history of Sweet syndrome with pulmonary involvement developed chronic bronchiolitis obliterans requiring bilateral lung transplantation. Seven years after transplantation, the patient began exhibiting shortness of breath requiring hospitalization. During the patient’s hospital stay, cytomegalovirus viremia and SARS-CoV-2 positivity were detected, and new oral lesions were concerning for a Sweet syndrome flare. Her respiratory status continued to decline requiring escalating ventilatory support. An autopsy limited to the chest and abdomen was performed after she expired. The pleural cavities had extensive adhesions, and both lungs were heavy. Microscopically, the lungs showed extensive, intralumenal acute inflammation of the bronchi and bronchioles with marked chronic inflammation of the submucosa, histologically similar to the patient’s explanted lung specimen. There was also focal endogenous lipoid pneumonia due to bronchiolar obstruction. In addition to the inflammatory findings, multiple infectious agents were identified in the patient’s respiratory tract including SARS-CoV-2, cytomegalovirus, Epstein-Barr virus, Candida glabrata, Klebsiella pneumoniae, and Stenotrophomonas maltophilia. No underlying malignancy was identified. (This patient’s earlier course was reported previously: PMC8411443) Results (if a Case Study enter NA) NA Conclusion Pulmonary involvement in Sweet syndrome can cause significant morbidity, and prior to this case, allograft recurrence of Sweet syndrome had not previously been reported. For transplant patients with a history of pulmonary Sweet syndrome, recurrence should be considered in cases of allograft dysfunction. This case also highlights the importance of thorough microbiological studies in autopsies of patients with systemic inflammatory diseases being treated with extensive immunosuppressive therapies.

Introduction: Extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD) are well-established. Sweet syndrome (SS), or acute febrile neutrophilic dermatosis, is a reactive mucocutaneous manifestation of IBD presenting as erythematous papules/plauqes with associated fever and arthomyalgias. There is limited evidence regarding efficacy of Ustekinumab in management of EIMs of UC, particularly SS. Case Description/Methods: The patient is a 50-year-old woman with left-sided UC (Montreal classification E2) that previously failed several therapies, including mesalamine, azathioprine, infliximab, adalimumab, vedolizumab, and a fecal microbiota transplant trial. She presented with worsening abdominal pain, diarrhea/hematochezia, and bilateral lower extremity pain. She was febrile and tachycardic with tender, violaceous, and ulcerated subcutaneous nodules on the bilateral ankles with hemorrhagic bullae (FigureA). Labs revealed negative C. diff, elevated ESR/CRP, thrombocytosis, and borderline leukocytosis with neutrophilic predominance. Lower extremity MR imaging and bone biopsy revealed multifocal sterile osteomyelitis with adjacent abscess; skin biopsy demonstrated dense granulomatous/neutrophilic infiltrate in the deep dermis/subcutis without microorganisms, consistent with subcutaneous SS (FigureB). A restaging colonoscopy demonstrated severe proctosigmoid ulcerative colitis (FigureC). Given that the patient had failed several immunomodulators and biologic therapies, she was started on prednisone and Ustekinumab. Four months later, she reported complete resolution of her cutaneous SS off steroids and improving UC symptoms (less frequent and more formed stools, minimal hematochezia). Repeat MRI demonstrated resolution of the sterile osteomyelitis and abscess. Discussion: Our case highlights the novel use of Ustekinumab in the treatment of subcutaneous SS with sterile osteomyelitis in a patient with flaring UC. SS is a neutrophilic dermatosis that is a rare EIM of IBD, classically characterized by tender cutaneous lesions. There is limited evidence supporting the use of Ustekinumab in treating EIMs of CD, and a lack of data regarding its efficacy in treating EIMs of UC. Our case fills a major gap in the literature and highlights the clinical efficacy of Ustekinumab for SS and UC especially in patients that have a contraindication to, failed previous treatment with, or otherwise cannot tolerate corticosteroids and TNF-alpha antagonists.Figure 1.: 1A. Right lateral malleolus with 2.5 cm shallow erosion with slightly violaceous borders and central bright yellow fibrinous debris. There was slight atrophy of surrounding skin with mild edema and hyperpigmentation (left image). Left medial malleolus/dorsal foot with grouped irregular shallow ulcers with surrounding mild violaceous erythema (middle and right image). 1B. Left ankle biopsies showed mixed septal and lobular panniculitis with granulomatous and neutrophilic inflammation. Histologic sections show a mildly spongiotic epidermis with dense granulomatous and neutrophilic inflammatory infiltrate in the deep dermis and subcutis (left image). The inflammatory infiltrate, which consists of prominent neutrophils, histiocytes, and scattered lymphocytes, surrounds vascular and adnexal structures, as well as adipocyte lobules. Definitive features of vasculitis are not seen. PASd (periodic acid-Schiff-diastase), GMS (Grocott’s methenamine silver), Gram, and Fite staining fail to highlight microorganisms (right image). 1C. Colonoscopy demonstrated severe (Mayo Endoscopy Score 3) proctosigmoid ulcerative colitis to 30 cm (left image). Sigmoid biopsies showed significant immune cell infiltration with crypt architectural distortion concerning for severe chronic active colitis. No evidence of granulomas, dysplasia or cytomegalovirus (right image).

From acute febrile neutrophilic dermatosis to neutrophilic disease: Forty years of clinical research

Sweet's syndrome (SS) is an inflammatory disease characterized by fever, leucocytosis and distinctive skin lesions that histologically consist of a dermal infiltrate of neutrophils with nuclear fragmentation. Aseptic neutrophilic inflammation may occur also in other organs. Central nervous system involvement in SS, Neuro-Sweet's syndrome (NSS), is rare and reported especially among Asian patients. A systematic review of the literature has been performed to find articles reporting cases of SS with neurological involvement. The search terms: "Sweet's syndrome/disease with neurological involvement, Neuro Sweet Syndrome/Disease" were used in the Pubmed Database. Sixty-nine NSS patients including 46 males and 23 females, more Asian than Caucasian, have been described from 1983 to date. The average age was 48.7year-old. The most representative neurologic symptom was the altered state of consciousness, followed by headache and memory disorders. Differently from SS with skin or other district involvement, NSS appears to be more common in Asian patients than in Caucasian ones and affects mainly the male sex in the third or fourth decade of life. A very wide range of symptoms and signs can occur, depending on which part of the nervous system is affected. Initial presentation is usually with the SS typical skin lesions followed by neurological involvement. However, also an opposite presentation or a simultaneous skin and nervous involvement may happen. Awareness of the possible neurological complications in SS is important to avoid unnecessary therapies for other forms of meningoencephalitis and lead to successful treatment with systemic corticosteroids.

INTRODUCTION: We present a unique case of Sweet Syndrome associated with primary sclerosing cholangitis. CASE DESCRIPTION/METHODS: A 39-year-old woman presented to the emergency department with diffuse necrotic skin lesions and recent uveitis. Her inflammatory markers were elevated. Serologic studies showed a positive ANA titer of 1:320 and p-ANCA titer of 1:80. A full-thickness skin biopsy revealed dense neutrophilic inflammation without evidence of vasculitis. Tissue cultures were negative. She was started on oral corticosteroids with complete resolution. She was found to have an elevated alkaline phosphatase of 677 U/L. Magnetic resonance cholangiopancreatography (MRCP) revealed intrahepatic ductal dilation in an irregular beaded pattern consistent with primary sclerosing cholangitis. She did not have any gastrointestinal symptoms and had a normal previous colonoscopy. DISCUSSION: Sweet Syndrome is an inflammatory condition characterized by the abrupt eruption of cutaneous lesions. Characteristic findings on histology include prominent edema in the dermis, a dense neutrophilic infiltrate, and endothelial swelling without vasculitis. The most common extra-cutaneous manifestation is uveitis. The pathogenesis of Sweet syndrome is unclear but has been postulated to be associated with immune and cytokine dysregulation. Sweet syndrome has been associated with multiple disorders including infections, inflammatory bowel disease (IBD), autoimmune, pregnancy, malignancies, and certain prescription medications. To our knowledge, this is the first described case of Sweet Syndrome associated with primary sclerosing cholangitis in a patient without IBD.Figure 1.: Skin Lesion.Figure 2.: Histology.Figure 3.: MRCP.

Sweet syndrome with bitter outcomes in cervical cancer: A case report

Sweet syndrome is an uncommon disorder of unknown etiology and characterized by skin and systemic inflammation. Classic Sweet syndrome is not associated with malignancy or drug exposure and typically involves elderly females. A 67-year-old female with a past medical history of multiple sclerosis and chronic kidney disease presented with worsening erythema of bilateral lower extremities, and diffuse, tender pustular lesions in her extremities, eye lids, nares, oral commissures, and tongue. A biopsy revealed marked neutrophilic inflammation suggestive of Sweet syndrome and she was started on high dose methylprednisolone which immediately improved her condition. As with most progressive inflammatory diseases, early recognition and early treatment improves the prognosis. This case is unusual because of mucosal involvement at presentation. Classic Sweet syndrome can often be diagnosed by exclusion after failed treatment for either infectious or autoimmune disorders.

The Neutrophilic Dermatoses, or the Cutaneous Expressions of Neutrophilic Inflammation

Cutis laxa presents as loose redundant skin folds and loss of dermal elastic tissue. Acquired cutis laxa (ACL) is characterized by later onset. It has been reported in association with various kinds of neutrophilic dermatoses, drugs, metabolic disorders, and autoimmune disorders. Acute generalized exanthematous pustulosis (AGEP) is usually classified as a severe cutaneous adverse reaction characterized by T cell-mediated neutrophilic inflammation. We previously reported a mild case of AGEP caused by gemcitabine in a 76-year-old man. Here, we report a case of ACL secondary to AGEP in this patient. He developed AGEP 8 days after gemcitabine administration. Four weeks after beginning chemotherapy, his skin had become atrophic, loose, and darkly pigmented in areas previously affected by AGEP. Histopathological examination revealed edema and perivascular lymphocytic infiltration but no neutrophilic infiltration in the upper dermis. Elastica van Gieson staining showed that the elastic fibers in all layers of the dermis were sparse and shortened. Electron microscopy showed elevated numbers of fibroblasts and altered elastic fibers with irregular surfaces. Finally, he was diagnosed with ACL secondary to AGEP. He was treated with topical corticosteroids and oral antihistamines. Skin atrophy decreased over 3 months. We summarize 36 cases (including our case) with ACL secondary to neutrophilic dermatosis. We discuss these clinical manifestations, causative neutrophilic disorders, treatments, and outcomes. The mean age of patients was 3.5 years. Five patients had an aortic lesion as systemic involvement. The most common causative neutrophilic disorders were Sweet syndrome (24 cases), followed by urticaria-like neutrophilic dermatosis (11 cases). There were no cases of AGEP except for our case. Although treatment for ACL secondary to neutrophilic dermatosis, such as dapsone, oral prednisolone, adalimumab, and plastic surgery were reported, ACL is generally refractory and irreversible. Our patient was considered reversibly cured due to the absence of continuous neutrophil-mediated elastolysis.

ABSTRACTIntroduction: Neutrophilic dermatoses are a heterogenous group of chronic, cutaneous inflammatory conditions characterized by the accumulation of neutrophils in the skin and by systemic inflammation. Neutrophilic dermatoses can be idiopathic or associated with other inflammatory or systemic diseases, including the group of the hereditary, autoinflammatory syndromes. Clinical management is challenging, due to limited clinical evidence and lack of clinical practice guidelines.Areas covered: This review provides an overview of current therapeutic management of the three prototypical neutrophilic dermatoses, aseptic pustulosis of the folds, Sweet syndrome and pyoderma gangrenosum. In addition, we describe innovative, pathogenesis-oriented treatment approaches, which are based on recent advances in the pathophysiology of neutrophilic dermatoses and autoinflammatory syndromes. The increasing role of the IL-1 cytokine family in initiating neutrophilic inflammation in both idiopathic and syndromic disease opened the way for the use of targeted biological treatment. Another promising treatment strategy is aimed at blocking downstream effector cytokines, such as IL12/23 and IL-17, involved in the autoinflammatory immune cascade.Expert commentary: In chronic-recurrent and syndromic cases of neutrophilic dermatoses, there is an unmet clinical need for long-term, continuous disease control. Future controlled clinical studies will optimize the use of targeted-biological agents in sequential or combination treatment strategies.

The neutrophilic dermatoses are a collection of non‐infectious dermatoses involving triggering of inflammation in the context of a reduced threshold for neutrophilic inflammation. Genetic factors have been identified in rare cases and numerous predisposing diseases play a role. They are best described as autoinflammatory conditions whereby the triggering of the inflammatory process begins with abnormal activation of the innate immune system, distinct from an autoimmune process involving T cells or antibody production. Two classical neutrophilic dermatoses exist. Pyoderma is distinguished by the tendency for ulceration and tissue destruction. Sweet syndrome is generally more time limited with full recovery expected. Multiple variants exist and the optimal treatment strategies have not been agreed.

Markers for systemic vasculitis may be useful in both assessment of disease activity and ascribing pathogenesis. Endothelial cell damage may be assessed by Factor VIII-related antigen and perhaps fibrinolysis (plasmin inhibitor/plasmin complex). Antibodies to endothelial cells potentially combine both assessment and pathogenesis. Complement fixing antibodies to endothelial cells, previously reported in systemic lupus erythematosus and Kawasaki syndrome, are also elevated in rheumatoid vasculitis. Their relationship to vascular endothelial cell antibodies, reported in a wide spectrum of systemic vasculitis, is not clear. A direct role for neutrophils in some forms of vasculitis is supported by the overlap of rheumatoid vasculitis with Sweet's syndrome, previously associated with both Behcet's and Crohn's syndrome. An indirect role of persistent neutrophil inflammation at mucosal surfaces is suggested by the vasculitis with antineutrophil cytoplasmic antibodies seen in cystic fibrosis. In other cases, vasculitis may be triggered by direct viral infection such as cytomegalovirus. Experimental models may clarify the confusion. In the MRL mouse, vasculitis appears independent of the B-cell hyperactivity. Experimental models of uveitis also support a role for T cells in the induction of vasculitis.