Multiple neurological manifestations in a patient with systemic lupus erythematosus and anti-NXP2-positive myositis: A case report.

RATIONALE: Systemic lupus erythematosus (SLE) is a complex autoimmune inflammatory disease that frequently affects various organs. Neuropsychiatric manifestations in SLE patients, known as neuropsychiatric SLE, are clinically common. However, the principal manifestation of cranial neuropathy in patients with SLE and comorbidities is relatively rare. PATIENT CONCERNS: In this report, we describe a 51-year-old Chinese woman who was admitted with a chief complaint of chronic-onset facial paresthesia, dysphagia, and choking cough when drinking water, accompanied by slurred speech, salivation, and limb weakness. The blood autoantibody test results showed that many SLE-associated antibodies were positive. Meanwhile, anti-nuclear matrix protein 2 (NXP2) antibody was strongly positive in the idiopathic inflammatory myopathy (IIM) spectrum test from the serum. Muscle biopsy indicated inflammatory infiltration of the muscle fiber stroma. DIAGNOSES: Taking into account the clinical manifestations and laboratory tests of the present case, the diagnosis of SLE and probable IIM was established. INTERVENTIONS: Corticosteroids and additional gamma globulin were administered and the clinical symptoms were relieved during the treatment process. OUTCOMES: Unfortunately, the patient experienced sudden cardiac and respiratory arrest. Multiple system dysfunctions exacerbated disease progression, but in the present case, we speculated that myocardial damage resulting from SLE could explain why she suddenly died. LESSONS: To our knowledge, multiple neurological manifestations in patients with SLE and anti-NXP2-positive myositis are rare. Note that SLE is still a life-threatening disease that causes multiple system dysfunctions, which requires increasing attention.

Factors Associated with Lymph Node Count in Mucosal Squamous Cell Carcinoma Neck Dissection.

OBJECTIVE/HYPOTHESIS: Decreased lymph node count (LNC) from neck dissection (ND) for mucosal head and neck squamous cell carcinoma (HNSCC) patients is correlated with decreased survival. Advanced age and low BMI due to undernutrition from dysphagia from advanced T-stage tumors are common in patients with HNSCC. We studied the relationship between these two well-described causes for immune dysfunction and LNC in patients undergoing neck dissection. STUDY DESIGN: We conducted a retrospective review at a single tertiary care institution of patients with HNSCC that underwent neck dissection from 2006 to 2017. METHODS: Stepwise linear and logistic regression analyses were performed on 247 subjects to identify independent significant factors associated with 1) the LNC per neck level dissected; 2) advanced T-stage. One-way ANOVA was utilized to demonstrate differences between the p16 positive and negative subgroups. RESULTS: Low BMI (<23 vs. ≥23) (P = .03), extra nodal extension (ENE) (P = .0178), and advanced age (P = .005) were associated with decreased LNC per neck level dissected on multivariable analysis. Higher T-stage (P = .0005) was correlated with low BMI (<23) after controlling for the effects of tobacco, smoking, sex, ECE, and p16 status. p16+ patients, on average had higher BMI, were younger and produced a higher nodal yield (P < .0001, .007, and .035). CONCLUSIONS: Patient intrinsic factors known to correlate with decreased immune function and worse outcomes, including p16 negative status, advanced age, and low BMI from undernutrition and ENE are associated with low nodal yield in neck dissections. LNC may be a metric for anti-tumor immune function that correlates with prognosis and T-stage. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:1516-1521, 2021.

Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE. METHODS: We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety. RESULTS: The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P = .0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P < .0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P < .0001 vs placebo), and the endoscopic reference score by 1.6 (P = .0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P < .0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group). CONCLUSIONS: In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052.

Esophageal IgE, IgG4, and mucosal eosinophilia in individuals with dysphagia.

BACKGROUND: Eosinophilic esophagitis (EoE) is an inflammatory disease of the esophagus, producing failure to thrive in infants and dysphagia with food impaction in older children and adults. Although most people with EoE manifest atopic/allergic disease, the specific allergens to which immunoglobulin E (IgE) is directed, if any, have not yet been characterized. METHODS: Mucosal brush biopsy (MBB) and solid tissue biopsy (STB) specimens were prospectively obtained from 25 individuals with dysphagia and suspicion of EoE. Specific IgE (sIgE) against 112 epitopes from airborne and food proteins, antigens known to cause a polyclonal IgE response and IgG4 to food allergens, were measured. RESULTS: There was no difference in total IgE harvested between the 2 biopsy methods (p > 0.05) or between the EoE-positive (N = 12) and EoE-negative (N = 13) groups (p > 0.05). None of the samples in either group contained measurable serum IgE to any of the airborne or food proteins tested, but low levels of IgE specific to Candida and Staphylococcus enterotoxins were detected. Low levels of IgG4 specific to wheat, soy, peanut, and egg were also detected. CONCLUSIONS: Both MBB and STB are able to harvest measureable levels of IgE and IgG4 from the esophageal mucosa. Low levels of serum-specific IgE suggest that other inflammatory mechanisms, besides type I, IgE-mediated, allergen-specific hypersensitivity, may act as the primary catalyst for mucosal eosinophilia. Clarifying the role of both IgE-mediated and non-IgE-mediated inflammatory mechanisms will help identify more targeted diagnostic and treatment strategies for individuals who present with dysphagia and esophageal eosinophilia.

Variations in the Clinical Course of Patients with Herpes Simplex Virus Esophagitis Based on Immunocompetence and Presence of Underlying Esophageal Disease.

BACKGROUND AND AIMS: Herpes simplex esophagitis (HSE) is the second most common cause of infectious esophagitis and occurs in both immunocompetent and immunocompromised patients. The aim of this study was to reappraise the clinical course of HSE in different patient populations based on degree of immunocompetence and the presence or absence of underlying esophageal disease. METHODS: Patients with histopathologically confirmed HSE identified from the Mayo Clinic pathology database from 2006 to 2016 were included in this study. Relevant demographic, clinical, and endoscopic data were retrospectively reviewed and compared between two cohorts: (a) immunocompromised and immunocompetent patients and (b) patients with and without underlying esophageal disorders. RESULTS: Forty-six patients were included in the study. The most common presenting symptoms were odynophagia (34.8%) and dysphagia (30.4%). Thirty-three (71.7%) patients were immunocompromised, and these patients who experienced longer duration of symptoms (25.5 ± 23.4 days vs. 7.0 ± 5.5 days, p = 0.04) were more likely to require an extension of treatment course (38.1% vs. 8.3%, p = 0.05) compared to their immunocompetent counterparts. Seventeen (37%) patients had underlying esophageal disease, and these patients were more likely to have concomitant esophageal candidiasis (41.2% vs. 10.3%, respectively; p = 0.01). CONCLUSION: Herpes simplex virus causes esophagitis in both immunocompetent and immunocompromised patients. While the disease course appears to be self-limited for all patient populations, clinical and endoscopic differences in the disease presentation and clinical course based on immune status and the presence or absence of underlying esophageal disease exist.

[Myasthenia gravis should be considered in cases of Parkinson's disease and progressive dysphagia]. / Bei Morbus Parkinson und progredienter Dysphagie an Myasthenia gravis denken.

We report on four consecutive patients with Parkinson's disease, in whom anti-acetylcholine receptor (AChR) antibody positive bulbar myasthenia gravis (MG) turned out to be responsible for progressive dysphagia.

Cutaneous and Systemic Findings Associated With Nuclear Matrix Protein 2 Antibodies in Adult Dermatomyositis Patients.

OBJECTIVE: To characterize the cutaneous and systemic clinical phenotype of dermatomyositis patients with antinuclear matrix protein 2 (anti-NXP-2) antibodies. METHODS: We conducted a retrospective cohort analysis of 178 dermatomyositis patients seen at the Stanford University Clinic. An electronic chart review employing a keyword search strategy was performed to collect clinical and laboratory data. Anti-NXP-2 antibodies were assayed by immunoprecipitation using NXP-2 produced by in vitro transcription/translation. RESULTS: Antibodies to NXP-2 were detected in 20 of the 178 patients (11%). Anti-NXP-2 antibodies were associated with male sex (50% versus 25%; P = 0.02), dysphagia (74% versus 39%; P = 0.006), myalgia (89% versus 52%; P = 0.002), peripheral edema (35% versus 11%; P = 0.016), and calcinosis (37% versus 11%; P = 0.007). These patients were less likely to be clinically amyopathic (5% versus 23%; P = 0.08). Five of the 20 patients with anti-NXP-2 antibodies (25%) had an associated internal malignancy. No other cutaneous characteristics were associated with anti-NXP-2 antibodies, except a decreased frequency of Gottron's sign (44% versus 75%; P = 0.012) and a greater likelihood of having mild skin disease. CONCLUSION: Dermatomyositis patients with anti-NXP-2 antibodies have a distinct and often severe systemic phenotype that includes myalgia, peripheral edema, and significant dysphagia, despite having milder inflammatory skin disease.

Associations between micronutrient intakes and gut microbiota in a group of adults with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) involves chronic inflammation and oxidative stress affecting mainly the respiratory and digestive systems. Survival rates for CF have improved with advances in treatment including nutritional interventions such as micronutrient supplementation. Diet can modulate gut microbiota in the general population with consequences on local and systemic immunity, and inflammation. The gut microbiota appears disrupted and may associate with pulmonary status in CF. This study investigated associations between micronutrient intakes and gut microbiota variations in a group of adults with CF. METHODS: Faecal microbiota of sixteen free-living adults with CF was profiled by 16ss rDNA sequencing on the GS-FLX platform. Associations were tested between UniFrac distances of faecal microbiota and time-corresponding micronutrient intakes. Associations between relative abundances of bacterial taxa and micronutrient intakes (those showing significant associations with UniFrac distances) were examined by Spearman correlation. RESULTS: Unweighted UniFrac distances were associated with intakes of potassium and antioxidant vitamins C, E and beta-carotene equivalents, whereas weighted UniFrac distances were associated with antioxidant vitamins riboflavin, niacin equivalents, beta-carotene equivalents and vitamin A equivalents. Intakes of beta-carotene equivalents, vitamin C, vitamin E, niacin equivalents and riboflavin correlated negatively with Bacteroides and/or its corresponding higher level taxa. Intakes of beta-carotene equivalents and vitamin E also positively correlated with Firmicutes and specific taxa belonging to Firmicutes. CONCLUSION: Some micronutrients, particularly antioxidant vitamins, correlated with gut microbiota variations in the studied cohort. Further research is required to clarify whether antioxidant vitamin intakes can influence CF gut microbiota and potential clinical/therapeutic implications in CF.

Stroke-induced immunodepression and dysphagia independently predict stroke-associated pneumonia - The PREDICT study.

Stroke-associated pneumonia is a frequent complication after stroke associated with poor outcome. Dysphagia is a known risk factor for stroke-associated pneumonia but accumulating evidence suggests that stroke induces an immunodepressive state increasing susceptibility for stroke-associated pneumonia. We aimed to confirm that stroke-induced immunodepression syndrome is associated with stroke-associated pneumonia independently from dysphagia by investigating the predictive properties of monocytic HLA-DR expression as a marker of immunodepression as well as biomarkers for inflammation (interleukin-6) and infection (lipopolysaccharide-binding protein). This was a prospective, multicenter study with 11 study sites in Germany and Spain, including 486 patients with acute ischemic stroke. Daily screening for stroke-associated pneumonia, dysphagia and biomarkers was performed. Frequency of stroke-associated pneumonia was 5.2%. Dysphagia and decreased monocytic HLA-DR were independent predictors for stroke-associated pneumonia in multivariable regression analysis. Proportion of pneumonia ranged between 0.9% in the higher monocytic HLA-DR quartile (≥21,876 mAb/cell) and 8.5% in the lower quartile (≤12,369 mAb/cell). In the presence of dysphagia, proportion of pneumonia increased to 5.9% and 18.8%, respectively. Patients without dysphagia and normal monocytic HLA-DR expression had no stroke-associated pneumonia risk. We demonstrate that dysphagia and stroke-induced immunodepression syndrome are independent risk factors for stroke-associated pneumonia. Screening for immunodepression and dysphagia might be useful for identifying patients at high risk for stroke-associated pneumonia.

[Unusual dysphagia in IgG4-related disease]. / Ungewöhnliche Schluckbeschwerden bei IgG4­assoziierter Erkrankung.

This article presents the case of an IgG4-related disease in a patient with clinical signs of a malignant tumor of the oral cavity. After excluding the suspicion of a malignant lesion, vasculitis and various infectious diseases were ruled out. Finally, due to further immunohistochemical studies, IgG4-related disease was diagnosed.

The Endoscopic Reference Score shows modest accuracy to predict either clinical or histological activity in adult patients with eosinophilic oesophagitis.

BACKGROUND: Conflicting results have been recently reported for the accuracy of the Endoscopic Reference Score (EREFS), an standardised endoscopic classification, to predict the histological activity of eosinophilic oesophagitis (EoE). AIM: To evaluate the accuracy of the EREFS to predict either histological or clinical activity of EoE. METHODS: Prospective multicentre study conducted in eight Spanish centres evaluating adult EoE patients, either naïve or after treatment. Symptoms were evaluated before upper endoscopy through the Dysphagia Symptom Score, whereas researchers scored the EREFS immediately after the endoscopic procedure, unaware of the histological outcome. RESULTS: One hundred and forty-five EoE patients undergoing 240 consecutive endoscopic procedures were included. Exudates (P = 0.03), furrows (P = 0.03) and a composite score of inflammatory signs (exudates, furrows and oedema) (P < 0.001) accurately predicted histological activity. Exudates were the only endoscopic sign showing a good correlation with histological outcome after therapy. Furrows and oedema persisted in 50% and 70% of patients despite histological remission. No endoscopic feature exceeded 70% accuracy to predict histological activity. Likewise, no endoscopic finding could adequately predict dysphagia severity. Crepe paper mucosa, diffuse exudates and severe rings correlated with higher symptom scores. CONCLUSIONS: Endoscopic findings assessed by the Endoscopic Reference Score did not correlate with histological or clinical disease activity in adult EoE patients. Only exudates correlated with peak eosinophil count and histological outcome, whereas furrows and oedema persisted in over half of patients despite histological remission.

Oropharyngeal Dysphagia in Dermatomyositis: Associations with Clinical and Laboratory Features Including Autoantibodies.

OBJECTIVE: Dysphagia develops with low frequency in patients with dermatomyositis. Our objective was to determine the clinical and laboratory features that can estimate the development of dysphagia in dermatomyositis. METHODS: This study included 92 Japanese patients with adult-onset dermatomyositis. The associations between dysphagia and clinical and laboratory features including disease-specific autoantibodies determined by immunoprecipitation assays were analyzed. RESULTS: Videofluoroscopy swallow study (VFSS) was performed for all patients with clinical dysphagia (n = 13, 14.1%) but not for patients without clinical dysphagia. Typical findings of dysphagia (pharyngeal pooling, n = 11 and/or nasal regurgitation, n = 4) was detected by VFSS in all patients with clinical dysphagia. Eleven patients with dysphagia (84.6%) had anti-transcription intermediary factor 1γ (TIF-1γ) antibody. By univariate analysis, the average age and the male to female ratio, internal malignancy, and anti-TIF-1γ antibody were significantly higher and the frequency of interstitial lung diseases and manual muscle testing (MMT) scores of sternomastoid and dertoid muscles were significantly lower in patients with dysphagia than in patients without dysphagia. Among patients with anti-TIF-1γ antibody, the mean age, the ratios of male to female and internal malignancy were significantly higher and mean MMT scores of sternomastoid muscle were significantly lower in patients with dysphagia compared with patients without dysphagia. By multivariable analysis, the risk of dysphagia was strongly associated with the existence of internal malignancy and ant-TIF-1γ antibody and was also associated with reduced scores of manual muscle test of sternomastoid muscle. Dysphagia was markedly improved after the treatment against myositis in all 13 patients. CONCLUSION: These findings indicate that dysphagia can develop frequently in patients with internal malignancy, anti-TIF-1γ antibody, or severe muscle weakness of sternomastoid muscle.

Rare cause of odynophagia: Giant esophageal ulcer.

Gastrointestinal complications are a frequent cause of morbidity after transplantation and may affect up to 40% of kidney transplant recipients. Here we report a rare case of idiopathic giant esophageal ulcer in a kidney transplant recipient. A 37-year-old female presented with a one-week history of odynophagia and weight loss. Upon admission, the patient presented cold sores, and a quantitative cytomegalovirus polymerase chain reaction was positive (10(5) copies/mL). An upper endoscopy demonstrated the presence of a giant ulcer. Serological test and tissue biopsies were unable to demonstrate an infectious origin of the ulcer. Immunosuppression was reduced and everolimus was introduced. An empirical i.v. therapy with acyclovir was started, resulting in a dramatic improvement in symptoms and complete healing of the ulcer. Only two cases of idiopathic giant esophageal ulcer in kidney transplant recipients have been reported in the literature; in both cases, steroid therapy was successful without recurrence of symptoms or endoscopic findings. However, this report suggests that correction of immune imbalance is mandatory to treat such a rare complication.

High rate of galactose-alpha-1,3-galactose sensitization in both eosinophilic esophagitis and patients undergoing upper endoscopy.

Eosinophilic esophagitis (EoE) is an antigen/allergy-mediated chronic inflammatory condition. The rapid rise in the number of cases of EoE suggests an as-yet undiscovered environmental trigger. This study tested the hypothesis that immunoglobulin E (IgE) to galactose-alpha-1,3-galactose (alpha-gal), a newly recognized sensitization induced by a tick bite that causes mammalian meat allergy, is a risk factor for EoE. We conducted a case-control study using prospectively collected and stored samples in the University of North Carolina EoE Patient Registry and Biobank. Serum from 50 subjects with a new diagnosis of EoE and 50 non-EoE subjects (either with gastroesophageal reflux disease or dysphagia from non-EoE etiologies) was tested for alpha-gal-specific IgE using an ImmunoCAP-based method. Specific IgE > 0.35 kUA /L was considered a positive result. Subjects with EoE were a mean of 35 years old, 68% were male, and 94% were white. Non-EoE controls were a mean of 42 years, 50% were male, and 78% were white. A total of 22 (22%) subjects overall had alpha-gal-specific IgE > 0.35 kUA /L. Of the EoE cases, 12 (24%) were positive, and of the non-EoE controls, 10 (20%) were positive (p=0.63). Neither the proportion sensitized nor the absolute values differed between EoE and non-EoE subjects. We found a similar but high rate of alpha-gal sensitization in patients with EoE as found in non-EoE controls who were undergoing endoscopy. While our data do not support alpha-gal sensitization as a risk factor for EoE, the high rates of sensitization observed in patients undergoing upper endoscopy for symptoms of esophageal dysfunction is a new finding.

Eosinophilic oesophagitis: investigations and management.

Eosinophilic oesophagitis (EO) is an immune/antigen mediated, chronic, relapsing disease characterised by dysphagia, food bolus impaction and a dense oesophageal eosinophilic infiltrate. Characteristic endoscopic features include corrugated rings, linear furrows and white exudates, but none are diagnostic. Despite its increasing prevalence, EO remains underdiagnosed. There is a strong association with other atopic conditions. Symptoms, histology and endoscopic findings can overlap with gastro-oesophageal reflux disease. Currently endoscopy and oesophageal biopsies are the investigation of choice. Oesophageal physiology studies, endoscopic ultrasound, impedance planimetry and serology may have a role in the diagnosis and monitoring of response to therapy. Acid reducing medication is advocated as first line or adjuvant therapy. Dietary therapy is comprised of elimination diets or can be guided by allergen assessment. In adults, topical corticosteroids are the mainstay of therapy. Endoscopic dilatation is safe and effective for the treatment of non-responsive strictures. Other therapeutic options (immunomodulators, biological agents, leukotriene receptor antagonists) are under investigation.

T-helper 2 cytokines, transforming growth factor ß1, and eosinophil products induce fibrogenesis and alter muscle motility in patients with eosinophilic esophagitis.

BACKGROUND & AIMS: Patients with eosinophilic esophagitis (EoE) often become dysphagic from the combination of organ fibrosis and motor abnormalities. We investigated mechanisms of dysphagia, assessing the response of human esophageal fibroblasts (HEFs), human esophageal muscle cells (HEMCs), and esophageal muscle strips to eosinophil-derived products. METHODS: Biopsy specimens were collected via endoscopy from the upper, middle, and lower thirds of the esophagus of 18 patients with EoE and 21 individuals undergoing endoscopy for other reasons (controls). Primary cultures of esophageal fibroblasts and muscle cells were derived from 12 freshly resected human esophagectomy specimens. Eosinophil distribution was investigated by histologic analyses of full-thickness esophageal tissue. Active secretion of EoE-related mediators was assessed from medium underlying mucosal biopsy cultures. We quantified production of fibronectin and collagen I by HEF and HEMC in response to eosinophil products. We also measured the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 by, and adhesion of human eosinophils to, HEFs and HEMCs. Eosinophil products were tested in an esophageal muscle contraction assay. RESULTS: Activated eosinophils were present in all esophageal layers. Significantly higher concentrations of eosinophil-related mediators were secreted spontaneously in mucosal biopsy specimens from patients with EoE than controls. Exposure of HEFs and HEMCs to increasing concentrations of eosinophil products or co-culture with eosinophils caused HEFs and HEMCs to increase secretion of fibronectin and collagen I; this was inhibited by blocking transforming growth factor ß1 and p38 mitogen-activated protein kinase signaling. Eosinophil binding to HEFs and HEMCs increased after incubation of mesenchymal cells with eosinophil-derived products, and decreased after blockade of transforming growth factor ß1 and p38 mitogen-activated protein kinase blockade. Eosinophil products reduced electrical field-induced contraction of esophageal muscle strips, but not acetylcholine-induced contraction. CONCLUSIONS: In an analysis of tissues samples from patients with EoE, we linked the presence and activation state of eosinophils in EoE with altered fibrogenesis and motility of esophageal fibroblasts and muscle cells. This process might contribute to the development of dysphagia.