A retrospective cohort study of infection risk in hospitalized patients evaluated for Sweet syndrome.

Sweet syndrome (SS) is divided into malignancy-associated, classical, and drug-induced subtypes. Features associated with SS, such as fevers, neutropenia, and cancer, are also high risk for serious infection. We aimed to describe hospitalized patients with a documented concern for SS on initial dermatologic evaluation, their risk of infection, and the impact of SS subtype on treatment and outcomes. We descriptively analyzed hospitalizations at The Ohio State University evaluated for SS by dermatology and performed a retrospective cohort analysis of malignancy-associated and non-malignancy-associated SS patients. Eighty-seven patient hospitalizations were evaluated for SS from 2012 to 2019. Thirty-one hospitalizations were complicated by neutropenia. Lesions in 12.9% (n = 4/31) of neutropenic hospitalizations were infected with Fusarium species (n = 2) or methicillin-resistant staphylococcus aureus (n = 2). One patient with fungal disease died within 30 days of hospitalization. Thirty-three patients were confirmed to have a final diagnosis of SS. In the confirmed SS cohort, malignancy was associated with greater overall dapsone use (p = .021), less initial (p = .046) and overall (p = .013) corticosteroid use, and fewer SS-related readmissions within one year (p = .020) and overall (p = .004). Corticosteroid treatment delay should be considered for a short period in neutropenic patients while excluding infection. Malignancy-associated SS patients were more frequently treated with dapsone and favorable outcomes were seen in cancer patients.

Adult-onset immunodeficiency due to anti-interferon-gamma autoantibody-associated Sweet syndrome: A distinctive entity.

Sweet syndrome (SS) has been increasingly reported in patients with adult-onset immunodeficiency (AOID) due to anti-interferon-γ autoantibody who also have concomitant opportunistic infections, especially disseminated non-tuberculous mycobacterial infection (dNTMI). A retrospective study retrieving data from 2011 through 2020 was conducted. We compared clinical characteristics of SS with and without AOID and generated the prediction model and examined the interaction between AOID and dNTMI in the occurrence of SS. Lymphadenopathy, pustular lesions, and leukocytosis are the significant predictors for AOID-associated SS. Adjusted risk differences were 0.58 (95% confidence interval [CI], 0.33-0.83), 0.21 (95% CI, 0.02-0.39), and 0.24 (95% CI, 0.01-0.47), respectively. Based on the analysis of aggregated cross-sectional data, both the overall and the direct effect of AOID increased the prevalence of SS. The indirect effect of AOID on the occurrence of SS might also be mediated through dNTMI or other common opportunistic infections. In addition, there was a trend of positive additive interaction between AOID and dNTMI. Although the test of additive interaction did not reveal statistically significant results, a deviation from additivity of isolated effects might suggest potential causal interaction between AOID and dNTMI. The distinctive clinical syndrome comprising lymphadenopathy, pustular lesions, and leukocytosis in patients with SS should raise the awareness of clinicians to the potential of underlying AOID.

Neuro-Behçet Disease, Neuro-Sweet Disease, and Spectrum Disorders.

Behçet disease and its related disorder, Sweet disease, are multifactorial disorders whose susceptibility loci have been identified in the genes of various immunological factors aside from human leukocyte antigens. The neurological involvement of these diseases, including encephalitis, myelitis, and meningitis, referred to as neuro-Behçet disease (NBD) and neuro-Sweet disease (NSD) respectively, is sometimes difficult to diagnose, especially when the characteristic mucocutaneous symptoms do not precede neurological symptoms or when characteristics of both diseases are present in a single patient. NBD and NSD constitute a spectrum of diseases that are differentiated according to the combination of risk factors, including the genetic background. Encephalitis, myelitis, and meningitis similar to NBD or NSD can be diagnosed as spectrum disorders, even if the characteristic mucocutaneous symptoms fail to be detected. Understanding these conditions as a disease spectrum may help elucidate the disease pathogenesis and assist in the development of therapeutic agents.

Systematic Review: Sweet Syndrome Associated with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Sweet syndrome [SS] is a dermatological condition associated with both inflammatory bowel disease [IBD] and azathioprine use. We performed a systematic review to better delineate clinical characteristics and outcomes of SS in IBD patients. METHODS: Peer-reviewed, full-text journal publications from inception to April 2020 in English language and adult subjects with IBD were included. Skin biopsy was required as SS gold-standard diagnosis. Azathioprine-associated SS required recent azathioprine introduction or recurrence of SS after azathioprine re-challenge. RESULTS: We included 89 publications with 95 patients [mean age of SS diagnosis: 44 years; 59% female; 20 with azathioprine-associated SS and 75 without]. SS was diagnosed prior to IBD in 5.3%, at time of IBD diagnosis in 29.5% and after diagnosis in 64.2%. In total, 91% of patients with SS had known colonic involvement and the majority [76%] had active IBD at diagnosis; 22% had additional extra-intestinal manifestations. Successful therapies for SS included corticosteroids [90.5%], anti-tumour necrosis factor [TNF]-α inhibitor therapy [14.8%] and azathioprine [11.6%]. Azathioprine-associated SS was distinct, with 85% male patients, mean age of SS diagnosis of 50 years and a lower likelihood to be prescribed corticosteroids for treatment [75% vs 94.7% of non-azathioprine-associated SS, p = 0.008]. All patients with azathioprine-associated SS improved with medication cessation and developed recurrence after re-challenge. CONCLUSIONS: SS may precede or occur with IBD diagnosis in almost one-third of cases. Azathioprine and IBD-associated SS present and behave distinctly, especially with regard to gender, age at diagnosis and recurrence risk. Corticosteroids and TNF-α inhibitors have demonstrated efficacy in treating SS in IBD.

Prevalence of pyoderma gangrenosum and Sweet´s syndrome in inflammatory bowel disease at a tertiary healthcare center.

BACKGROUND AND AIM: dermatological manifestations are normally found in one third of patients with inflammatory bowel disease. In this study, the prevalence, clinical characteristics, intestinal disease activity, and treatment response of neutrophilic dermatoses (pyoderma gangrenosum and Sweet´s syndrome) were determined in patients with inflammatory bowel disease. METHODS: a retrospective, observational study was performed in patients with inflammatory bowel disease and neutrophilic dermatoses between March 2012 and March 2018. RESULTS: of 444 patients analyzed, 10 complied with the inclusion criteria. Seven had pyoderma gangrenosum and three presented Sweet's syndrome; and one patient developed both pathologies. The prevalence of neutrophilic dermatoses was 2.3 % (10/444), comprising 1.6 % with pyoderma gangrenosum and 0.7 % with Sweet's syndrome. Six out of seven patients with pyoderma gangrenosum were female and had ulcerative colitis. The most frequent clinical presentation of pyoderma gangrenosum was the ulcerative subtype. Active moderate-to-severe intestinal disease was found in 71.4 % of patients. Biological therapy was prescribed to three patients with partial response to corticosteroids and persistent intestinal disease activity. This therapy was not indicated for cutaneous manifestations only. Three patients with moderate-to-severe Crohn´s disease presented classical (n = 2) and pustular (n = 1) Sweet's syndrome. A complete response was achieved in all Sweet's syndrome cases treated with corticosteroids. Biological therapy was prescribed to control intestinal disease activity. CONCLUSIONS: pyoderma gangrenosum was the most frequent cutaneous manifestation of neutrophilic dermatoses, predominantly in females with ulcerative colitis, and highly associated with intestinal disease activity. Anti-tumor necrosis factor was effective in patients with partial cutaneous and intestinal disease response.

Sweet syndrome associated with malignancies: A retrospective analysis of 25 patients from West China hospital.

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is a rare inflammatory disorder characterized by sudden onset of variably tender brightly erythematous-to-violaceous papules, plaques, or nodules. To clarify the frequency, clinical course, therapeutic response, and outcome of Sweet syndrome with malignancy. We conducted a retrospective review of patients diagnosed with SS between 2009 and 2019 with a diagnosis of Sweet syndrome in West China hospital. Records were analyzed for variables, clinical features, etiological factors, laboratory results, and treatment outcomes. The 25 cases under study consisted of 14 (56%) females and 11 (44%) males. Mean age was 52.2 years (range: 4-76 years). Nodules were the commonest lesion presentation (48%), involving mostly the lower limbs (52%). Pain of lesion was identified as the most common symptom (88%), followed by fever (76%) and cough (44%). Among the patients, 52% exhibited the classic form, 48% showed the malignancy-associated form, and 4% exhibited the drug-induced form in the setting of malignancy. Acute myeloid leukemia was the most common malignancy, observed in 5 of 12 patients (41.6%). Anemia (P = .002) was associated with malignancy (Chi-square test).

Idiopathic, Refractory Sweet's Syndrome Associated with Common Variable Immunodeficiency: a Case Report and Literature Review.

PURPOSE OF REVIEW: Sweet's syndrome (SS) is classically considered a hypersensitivity reaction often associated with autoimmune disorders and malignancy. SS has also been increasingly reported to occur with immunodeficiencies. We present a case of treatment-refractory, systemic SS as the initial manifestation in a young child with common variable immunodeficiency (CVID). We also review current literature about SS and concurrent immunodeficiencies and autoimmunity in CVID patients. RECENT FINDINGS: Few case reports exist regarding the co-occurrence of Sweet's syndrome and primary immunodeficiencies. SS is characterized by a pro-inflammatory state with a neutrophil predominance resulting in a spectrum of clinical manifestations. CVID is a multifactorial antibody deficiency that can be associated with autoimmunity, which some studies have proposed to be secondary to altered CD21 expression. SS occurring in patients with CVID has been infrequently reported, and one case study demonstrated improvement of Sweet's associated skin lesions with immunoglobulin replacement. In our case, the patient had multi-system SS refractory to multiple immunomodulatory therapies. To our knowledge, this is the first report of the effective and safe use of intravenous tocilizumab and oral lenalidomide to treat SS in a child with CVID. Immunoglobulin replacement reduced the frequency of infections and may have contributed to the opportunity to wean the immunosuppressive therapies for Sweet's syndrome. Sweet's syndrome as an initial manifestation of co-occurring immunodeficiencies is rare, and providers need a high index of suspicion. In addition, treatment of SS associated with an immunodeficiency can be a challenge. Treatment with immunoglobulin replacement reduces the frequency of infections, and in some patients with concurrent SS may improve skin lesions and reduce the need for immunomodulator therapy. Further study is necessary to better understand the pathogenesis of CVID in patients with SS and to identify possible biomarkers that predict who with SS are at risk for developing hypogammaglobulinemia.

Allergic and Immunologic Perspectives of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammatory condition primarily involving the gastrointestinal tract. It includes Crohn's disease (CD), ulcerative colitis (UC), and a less common phenotype-indeterminate colitis. It is thought to result from a complex interplay of environmental, microbial, and host factors including genetic factors, although the exact mechanism is not known. Dietary factors have been shown to play a role in the pathogenesis of IBD and can potentially alter the intestinal microbiota as well as disrupt the immune function in the gut. CD is characterized by transmural inflammation, sometimes associated with granulomatous lesions, and involves the entire gastrointestinal tract but often spares the rectum. UC is characterized by mucosal inflammation typically confined to the colon and rectum. Although IBD is mostly seen in western world, recent data suggests that the incidence and prevalence are increasing worldwide. Enteral nutrition has been shown to be effective in inducing remission in pediatric population with CD; however, there is mixed data in adult population. Nutritional deficiencies such as vitamin D and zinc deficiency are often noted in IBD patients. Several extraintestinal manifestations are noted in patients with IBD. Some of them parallel with the disease activity and others are independent of the disease course. Assessment of IBD disease activity clinically, radiologically, if indicated, biochemically and endoscopically is important to guide therapy in IBD. To ensure comprehensive care, it is important to assess associated conditions such as nutritional and psychological well-being, as well as age appropriate health maintenance status prior to starting treatment for IBD. Several biologic agents including anti-tumor necrosis factor alpha (anti-TNF-α) drugs, anti-integrins, and antibodies to the p40 subunit of IL12/23 are approved for induction and maintenance of remission of IBD. Steroids are also often used for induction. Anti-metabolites and thiopurines are also useful either as monotherapy or in combination regimens. Potential side effects of anti-TNF-α drugs such as serious infections, malignancy, worsening of heart failure, and infusion-related reactions should be considered prior to starting these drugs. Anti-TNF-α drugs with or without immunomodulators (azathioprine, 6-mercaptopurine, methotrexate) are often used for the induction and maintenance of remission. Treating to target of endoscopic and clinical remission provides the best long-term outcomes. Our knowledge and understanding of IBD has grown significantly. However, there are several unanswered questions on pathogenesis, disease behavior, and drivers of inflammation in various patient subgroups which require further research.

Neutrophilic dermatoses: Pathogenesis, Sweet syndrome, neutrophilic eccrine hidradenitis, and Behçet disease.

Neutrophilic dermatoses are a heterogeneous group of inflammatory skin disorders that present with unique clinical features but are unified by the presence of a sterile, predominantly neutrophilic infiltrate on histopathology. The morphology of cutaneous lesions associated with these disorders is heterogeneous, which renders diagnosis challenging. Moreover, a thorough evaluation is required to exclude diseases that mimic these disorders and to diagnose potential associated infectious, inflammatory, and neoplastic processes. While some neutrophilic dermatoses may resolve spontaneously, most require treatment to achieve remission. Delays in diagnosis and treatment can lead to significant patient morbidity and even mortality. Therapeutic modalities range from systemic corticosteroids to novel biologic agents, and the treatment literature is rapidly expanding. The first article in this continuing medical education series explores the pathogenesis of neutrophilic dermatoses and reviews the epidemiology, clinical and histopathologic features, diagnosis, and management of Sweet syndrome, neutrophilic eccrine hidradenitis, and Behçet disease.

Skin Manifestations in Patients with Adult-onset Immunodeficiency due to Anti-interferon-gamma Autoantibody: A Relationship with Systemic Infections.

Adult-onset immunodeficiency due to anti-interferon-γ autoantibody is an emerging acquired immunodeficiency with frequent skin manifestations. A retrospective chart review was conducted and identified 41 patients with the syndrome. Skin involvement was detected in 33 (80%) patients, 15 (45%) with infective skin diseases and 27 (82%) with reactive skin disorders. Reactive lesions were mostly neutrophilic dermatoses, e.g. Sweet syndrome. Of note, the presence of neutrophilic dermatoses was highly associated with infections of other sites. An adjusted odds ratio for the existence of infections in patients with neutrophilic dermatoses was 14.79 (95% CI: 5.13, 42.70; p < 0.001). Moreover, neutrophilic dermatoses were significantly correlated with opportunistic infections observed in those with defects in cell-mediated immunity including non-tuberculous mycobacterium and disseminated fungal infection. The odds ratio for opportunistic infections in the presence of neutrophilic dermatoses was 12.35 (95% CI: 5.00, 30.55; p <0.001). Thus, the presence of neutrophilic dermatoses in patients with the syndrome can signal opportunistic infections that warrant physician attention.

Myelodysplastic Syndrome and Sweet's Syndrome Are Associated with a Mutation in Isocitrate Dehydrogenase 1.

BACKGROUND: Sweet's syndrome (SS) is a febrile neutrophilic dermatosis that has been clinically linked to hematological malignancies, particularly myelodysplastic syndrome (MDS), in a number of case series. Many epigenetic changes underlying MDS have been identified, such as a mutation in the isocitrate dehydrogenase 1 (IDH1) gene, which causes DNA hypermethylation and alteration of a number of genes that lead to leukemogenesis. However, the pathogenesis of malignancy-associated SS is unknown. CASE REPORT: We present two patients who were diagnosed with SS and concomitant IDH1-mutated MDS. Immunohistochemical staining of their skin lesions showed neutrophils diffusely positive for the IDH1 mutation. CONCLUSION: These cases demonstrate that IDH1 mutation may be implicated in the pathogenesis of malignancy-associated SS. Future investigation to elucidate this pathway is warranted. Establishing this molecular link can provide an earlier identification of patients with SS who are also at increased risk for developing MDS.

Sweet syndrome presenting as a febrile rash in a returning traveller.

Sweet syndrome was discovered in 1964 and is now well described in the dermatology literature. Knowledge of this unique febrile and painful dermatosis is important for the emergency physician because the syndrome can be readily identified and is extremely responsive to oral steroid therapy. Early diagnosis can greatly improve patient satisfaction and avoid days of ineffective treatment. An accurate and timely diagnosis of Sweet syndrome is also important to guide investigation into a number of associated diseases.

Disease-related and drug-induced skin manifestations in inflammatory bowel disease.

INTRODUCTION: Skin manifestations are common in patients with inflammatory bowel diseases (IBD) and can be part of a concomitant illness with a shared genetic background, an extra-intestinal manifestation of the disease, or a drug side-effect. Areas covered: We provide a practical overview of the epidemiology, pathogenesis, diagnosis, therapeutic approach and prognosis of the most frequent disease-related and drug-induced cutaneous manifestations in IBD, illustrated by cases encountered in our clinical practice. Among the most frequently encountered IBD-related lesions are erythema nodosum, pyoderma gangrenosum and Sweet's syndrome. Common skin manifestations with a strong association to TNF antagonists are local injection site reactions, psoriasiform lesions, cutaneous infections, vasculitides and lupus-like syndromes. In addition, we discuss the relation of thiopurines and TNF antagonists with the risk of skin cancer. Expert commentary: We hope this review will help caretakers involved in the management of IBD patients to recognize the lesions and to manage them in close collaboration with a dedicated dermatologist.

Histiocytoid Sweet Syndrome Is More Frequently Associated With Myelodysplastic Syndromes Than the Classical Neutrophilic Variant: A Comparative Series of 62 Patients.

Histiocytoid Sweet syndrome (H-SS) is a histological variant of Sweet syndrome (SS) differing from classical neutrophilic SS (N-SS) by a dermal infiltrate mainly composed of lymphocytes and histiocytoid myeloperoxidase-positive cells. We aimed to report a large series of H-SS and compare the frequency and type of hematological malignancies associated to H-SS and N-SS. We included 62 patients with a coding histopathologic diagnosis of SS prospectively registered between 2005 and 2014 in the database of our Department of Pathology. Overall, 22 (35.5%) and 40 (64.5%) patients had a histological diagnosis of H-SS and N-SS, respectively. Median age, sex ratio, and cutaneous lesions were similar in the 2 groups. The frequency of extra-cutaneous manifestations was similar (50% vs 37.5%, P = 0.42). Recurrent forms were significantly more frequent in H-SS than in N-SS patients (21% vs 2.5%, P = 0.01). A hematological malignancy was diagnosed in 22 patients, 12 (55.5%) with H-SS and 10 (25%) with N-SS (P = 0.019). Hematological malignancy was of myeloid origin in 8/22 (36.3%) H-SS and 5/40 (12.5%) N-SS patients (P = 0.02), and of lymphoid origin without myeloid component in 4/22 (18.1%) H-SS and 4/40 (10%) N-SS patients (P = 0.35), respectively. One N-SS patient had a hematological malignancy of mixed (myeloid and lymphoid) phenotype. A myelodysplastic syndrome (MDS) was diagnosed in 7/22 (31.8%) H-SS and 1/40 (2.5%) N-SS patients (P < 0.001). Hematological disease was diagnosed before (in 8 H-SS and 3 N-SS patients) or at the time of the occurrence of the cutaneous lesions (in 1 H-SS and 7 N-SS patients). However, in 3 H-SS patients, all with MDS, cutaneous lesions preceded the hematological disease by ≤6 months. In conclusion, H-SS was associated with MDS in one third of patients but also with lymphoid malignancies, and cutaneous lesions could precede the hematological diagnosis in patients with MDS. A complete hematological assessment is mandatory at diagnosis, and monitoring blood cell counts should be recommended for at least 6 months after the diagnosis of H-SS.

Neutrophilic Dermatoses in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A French Multicenter Study of 17 Cases and Literature Review.

A few reports suggest combination of ANCA-associated vasculitis (AAV) and neutrophilic dermatoses (ND). We aimed to describe the main characteristics of patients presenting with both AAV and ND in a French cohort and through a systematic literature review, and to discuss the possible common pathogenic process involved. We conducted a retrospective study of patients with both conditions. Patients were selected via the French Internal Medicine Society (SNFMI) and the French Vasculitis Study Group (FVSG). A literature review focusing on a combination of both conditions, concentrated only on publications with well-established diagnoses and individual detailed data. Seventeen patients diagnosed with AAV and ND were identified in this cohort. Twelve patients had granulomatosis with polyangiitis (GPA), 4 had microscopic polyangiitis (MPA) and one had eosinophilic GPA (EGPA). Eight patients, all with GPA, displayed pyoderma gangrenosum (PG). Sweet's syndrome was observed in 6 patients (4 with MPA, one with GPA and one with EGPA) and erythema elevatum diutinum in the other three (2 with GPA and 1 with MPA). The literature review identified 33 additional patients with both conditions, including 26 with GPA. Altogether, of the 50 patients (17 from our study and 33 from the literature review), 33 (66%) patients presented with PG associated with GPA in 29 cases (89%). Corticosteroids were the first-line treatment in conjunction with an immunosuppressive agent in most cases. Outcomes were good and a total of 15 patients experienced a relapse. Patients who relapsed were more likely to have ear, nose and throat manifestation than patients who did not [12/15 (80%) relapsing patients vs. 15/35 (43%) non-relapsing patients; p = 0.03)]. In our stud, the most frequent association concerned GPA and PG. ND should be considered and specifically researched within the spectrum of cutaneous manifestations observed in AAV.