IgE auto-reactivity in bullous pemphigoid: eosinophils and mast cells as major targets of pathogenic immune reactants

Abstract

Background

Bullous pemphigoid (BP) is an autoimmune disease characterised by tense blisters that are usually preceded by urticarial eruptions. Affected patients exhibit IgG and/or IgE auto-antibodies against BP180 and/or BP230. Their relative importance in disease pathogenesis has not been fully elucidated.

Objectives

The aim of this study was to better characterise circulating and tissue-resident IgE in BP patients at the serological, structural and functional level.

Methods

Sera (n=19) and skin (n=33) from BP patients were analysed via ELISA and immunofluorescence, respectively.

Results

Results obtained show that BP patients exhibit elevated IgE levels in the serum and in the skin. Within the latter, it is very rarely and only sparsely found along the basement membrane zone (BMZ), but is prominently present on mast cells and eosinophils. At least a portion of these IgE antibodies are BP-specific, as evidenced by serum ELISA and by the co-localization of BP180 and FcεRI-bound IgE on mast cells and/or eosinophils. An important role of these immune reactants can be implied by our additional finding that cross-linking of IgE, derived from BP sera, on FcεRI-expressing rat basophils with BP180 results in robust degranulation of these cells.

Conclusion

We propose the existence of a disease pathway alternative to IgG and complement that may well be responsible for some of the clinical features of this autoimmune disease.

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A 5-year randomized trial on the safety and efficacy of pimecrolimus in atopic dermatitis: a critical appraisal

Summary

Aim

The PETITE study (Sigurgeirsson et al.) aimed to compare safety and efficacy of pimecrolimus 1% cream (PIM) and low-to-medium-potency topical corticosteroids (TCS) in children with mild-to-moderate atopic dermatitis (AD).

Setting and design

Participants of this 5-year drug-company sponsored multicentre, open-label, parallel-group trial were recruited between April 2004 and October 2005. No details are reported regarding the study sites.

Study exposure

Infants aged ≥ 3 to < 12 months with mild-to-moderate AD were randomly assigned in a 1 : 1 ratio to receive either PIM or a low- or medium-potency TCS cream/ointment for 5 years. No information on specific TCS products used was provided. The topical treatment was applied twice daily 'until complete AD clearance or for as long as allowed by the label of the specific TCS', and was reinitiated at the occurrence of first signs and symptoms of AD flares. In the PIM group, exacerbations not controlled by PIM were treated with short-term TCSs.

Outcomes

Adverse events (AEs) and serious AEs (SAEs) were recorded 'during clinic visits'. In a proportion of the patients, various immunological assessments including antibody titres to common vaccine antigens, immunoglobulin levels, B and T lymphocyte cell counts, and T-cell proliferation tests were performed. The children's growth was assessed by measuring height and weight. AD severity was measured using the Investigator Global Assessment (IGA) score and the percentage of the total body surface area affected. No specific information was provided on the number and scheduling of study visits. Primary outcomes were the incidence of AEs 'of primary clinical interest' and those with a crude incidence of ≥ 5% in either treatment group. Secondary outcome was 'long-term efficacy' defined as IGA ≤ 1 at week 3 and year 5.

Results

Patients in the PIM group experienced significantly more AEs [bronchitis (P = 0·02), infected eczema (P ≤ 0·001), impetigo (P = 0·045), nasopharyngitis (P = 0·04)]. No significant differences were seen for the other AEs. The overall incidence of SAEs was slightly higher for PIM (20·5% vs. 17·3%; P = 0·046). The proportion of participants with IGA ≤ 1 at year 5 was 88·7% for PIM and 92·3% for TCS, a success rate difference of 3·6% (95% confidence interval 0·8–6·4) favouring TCS.

Conclusions

Sigurgeirsson et al. conclude that the long-term management of mild-to-moderate AD in children with both TCS and PIM is safe, and that PIM has similar efficacy to TCS. Further, they conclude that their data support the use of PIM as a first-line treatment of mild-to-moderate AD in children.

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A 17-year-old male with a Small Bowel Neuroendocrine Tumor: flushing differential diagnosis

Neuroendocrine tumors (NETs) are heterogeneous neoplasms that originate from cells with a secretory function. Small bowel NETs (SB-NETs) are related to serotonin hypersecretion which causes: flushing, diarrhea...

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Competency-based assessment in surgeon-performed head and neck ultrasonography: A validity study

Objective

Head and neck ultrasonography (HNUS) increasingly is used as a point-of-care diagnostic tool by otolaryngologists. However, ultrasonography (US) is a very operator-dependent image modality. Hence, this study aimed to explore the diagnostic accuracy of surgeon-performed HNUS and to establish validity evidence for an objective structured assessment of ultrasound skills (OSAUS) used for competency-based assessment.

Study Design

A prospective experimental study.

Methods

Six otolaryngologists and 11 US novices were included in a standardized test setup for which they had to perform focused HNUS of eight patients suspected for different head and neck lesions. Their diagnostic accuracy was calculated based on the US reports, and two blinded raters assessed the video-recorded US performance using the OSAUS scale.

Results

The otolaryngologists obtained a high diagnostic accuracy on 88% (range 63%–100%) compared to the US novices on 38% (range 0–63%); P < 0.001. The OSAUS score demonstrated good inter-case reliability (0.85) and inter-rater reliability (0.76), and significant discrimination between otolaryngologist and US novices; P < 0.001. A strong correlation between the OSAUS score and the diagnostic accuracy was found (Spearman's ρ, 0.85; P < P 0.001), and a pass/fail score was established at 2.8.

Conclusion

Strong validity evidence supported the use of the OSAUS scale to assess HNUS competence with good reliability, significant discrimination between US competence levels, and a strong correlation of assessment score to diagnostic accuracy. An OSAUS pass/fail score was established and could be used for competence-based assessment in surgeon-performed HNUS.

Level of Evidence

NA. Laryngoscope, 2017

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Prophylactic immunization with human papillomavirus vaccines induces oral immunity in mice

Objective

Although it has been shown that prophylactic vaccination can induce genital immunity, there is inadequate information on human papillomavirus (HPV) vaccine-induced oral immunity, which is of particular interest due to HPV-associated oropharyngeal malignancies and recurrent respiratory papillomatosis. Therefore, we assessed the efficacy of various HPV vaccines against oral HPV pseudovirus (PsV) infection in mice.

Study Design

Preclinical scientific investigation.

Methods

C57BL/6 mice were vaccinated three times at 2-week intervals with either Gardasil (Merck, Kenilworth, NJ) (50 µL intramuscular injection) or a candidate pan-HPV L2 vaccine with alum adjuvant (25 µg subcutaneous injection). Additional mice were immunized with passive transfer of either Gardasil (Merck) human antisera or nonimmunized sera (100 µL intraperitoneal injection). All vaccinated and naïve control mice were then challenged with HPV16 E6E7 luciferase PsV in the oral mucosa. Visualization of HPV PsV infection was monitored through in vivo luciferase imaging.

Results

Oral luciferase-expressing HPV16 PsV infection was not detected in Gardasil (Merck), L2 vaccine, and Gardasil (Merck) antisera-immunized mice, whereas robust luciferase expression was observed in all control mice. An in vitro neutralization assay from sera of Gardasil-vaccinated (Merck) mice confirmed that vaccine efficacy was due to neutralizing antibodies.

Conclusion

Oral HPV16 PsV infection in mice was completely prevented with all methods of prophylactic HPV immunization. These findings provide preliminary evidence that human vaccines induce protection against oral HPV infection, which has significant public health implications for HPV-associated oropharyngeal malignancies.

Level of Evidence

NA Laryngoscope, 2017

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Clinical characteristics of laryngeal versus nonlaryngeal amyloidosis

Objectives/Hypothesis

Amyloidosis represents a heterogeneous group of disorders marked by abnormal protein formation and deposition. Laryngeal amyloidosis is rare and classically thought to remain isolated with little risk of systemic involvement or associated malignancy. This study sought to further characterize differences in clinical characteristics between patients with laryngeal and nonlaryngeal amyloidosis.

Study Design

Retrospective case-control study.

Methods

The Stanford Translational Research Integrated Database Environment was searched to identify patients with biopsy-confirmed laryngeal amyloidosis and patients with amyloidosis without laryngeal involvement on endoscopy. Mann-Whitney U and χ² tests were used for statistical analysis.

Results

Of 865 patients treated for amyloidosis between 1996 and 2016, 22 (2.5%) patients with biopsy-proven laryngeal amyloidosis were identified. An additional 22 patients with amyloidosis of a different organ and negative laryngoscopy—and therefore without laryngeal amyloidosis—were identified as controls. Compared to these controls with nonlaryngeal amyloidosis, patients with laryngeal amyloidosis were younger (mean age 52.8 years vs. 68.4 years, P < .0006), and 18% had additional organ involvement. Immunoglobulin light-chain amyloidosis was the most common subtype in both groups of patients. Eighty-six percent of patients with laryngeal amyloidosis required surgical excision, and of these patients, over 30% required multiple excisions.

Conclusions

There is a significant rate (18%) of multiorgan involvement in patients with laryngeal amyloidosis, which contradicts conventional concepts that this is an isolated disorder. This finding could have a significant impact on the evaluation and management of patients with laryngeal amyloidosis.

Level of Evidence

3b Laryngoscope, 2017

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Kinematic evaluation of penetration and aspiration in laryngeal elevating and descending periods

Objectives

It is important to evaluate swallowing movements by dividing them into periods of laryngeal closure and release. The purpose of this study was to evaluate penetration–aspiration (PA) according to human pathophysiology and to identify the factors for predicting PA.

Study Design

Case-control study.

Methods

Eighty-one patients with complaints of dysphagia caused by various etiologies were enrolled in this study. Videofluoroscopic swallowing studies were conducted, and the spatial and temporal factors were analyzed by computer-assisted motion analysis.

Results

The initiation of laryngeal vestibule closure in the laryngeal elevating period and its duration in the laryngeal descending period were significant factors for evaluating PA.

Conclusion

A knowledge of the delay of laryngeal vestibule closure in the laryngeal elevating period and its short duration in the laryngeal descending period could make it easier to evaluate the risk of PA.

Level of Evidence

3b. Laryngoscope, 2017

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