Characteristics of Japanese patients with eosinophilic fasciitis: A brief multicenter study.

Eosinophilic fasciitis is a relatively rare cutaneous fibrotic condition affecting the deep fascia of the extremities, with or without peripheral blood eosinophilia. To examine the characteristics of Japanese patients with eosinophilic fasciitis, we conducted a brief, multicenter, retrospective survey at seven university hospitals. In total, 31 patients were identified as having eosinophilic fasciitis, among whom 30 patients fulfilled the Japanese diagnostic criteria. The male : female ratio was 2.3:1, and the mean age was 47.7 years. Three of the patients were under 20 years old. The possible triggering factors included muscle training, sports, walking or sitting for a long time, physical work, insect bite and drug. Co-occurrence of morphea was observed in nine cases (29%), and malignancies were associated in three (two hematological malignancies and one internal malignancy). Immunological abnormalities in the serum showed positive antinuclear antibody, positive rheumatoid factor, increased aldolase levels and increased immunoglobulin G levels. The patients were treated with either monotherapy or combination therapy by oral prednisolone (20-80 mg/day), methotrexate (6-10 mg/week), cyclosporin (100-150 mg/day), mizoribine, infliximab and phototherapy. Methylprednisolone pulse therapy was performed in six cases. By contrast, spontaneous improvement due to resting only was observed in two cases, and skin hardening was improved by withdrawal of the anticancer drug in one case. This study suggests several characteristics of Japanese patients with eosinophilic fasciitis, namely male predominance, rare pediatric occurrence, immunological abnormalities and coexistence with morphea. Systemic prednisolone is the first-line therapy, but pulse therapy is occasionally required for severe cases. The triggering events of physical stress are not so frequent as have previously been reported, and various factors or even unknown factors may be associated with the induction of eosinophilic fasciitis.

Effectiveness and safety of dupilumab for the treatment of atopic dermatitis in a real-life French multicenter adult cohort.

BACKGROUND: Dupilumab is the first biologic available to treat atopic dermatitis (AD). Its effectiveness and safety were demonstrated in clinical trials. OBJECTIVE: We sought to assess the effectiveness and safety of dupilumab in adults with AD in a real-life French multicenter retrospective cohort. METHODS: We included patients treated during March 2017-April 2018. Efficacy outcomes, including Scoring Atopic Dermatitis (SCORAD) and Eczema Area and Severity Index (EASI) scores, were collected at baseline and 3 months when available. Adverse events (AEs) were recorded at follow-up. RESULTS: We included 241 patients. The median ± interquartile range (IQR) follow-up time was 3.8 ± 3.7 months. A ≥75% improvement in SCORAD was achieved in 27 of 163 (16.6%) patients, and a ≥75% improvement in EASI was achieved in 40 of 82 (48.8%) patients. The median SCORAD and EASI scores at 3 months were significantly lower than those at baseline (SCORAD ± IQR, 25 ± 21 vs 56 ± 27.4, P < 10-9 and EASI ± IQR, 4.1 ± 6.8 vs 17.9 ± 15.4, P < 10-9, respectively). Conjunctivitis was reported in 84 of 241 (38.2%) patients. The proportion with eosinophilia (>500 cells/mm3) during follow-up (57%) was higher than that at baseline (33.7%) (n = 172, P < 10-6). Dupilumab was stopped in 42 cases; 27 patients stopped because of AEs. LIMITATIONS: No control group, missing data. CONCLUSION: This real-life study demonstrated a similar dupilumab effectiveness as that seen in clinical trials, but it also revealed a higher frequency of conjunctivitis and eosinophilia.

Eosinophilic Gastrointestinal Disorders.

Eosinophilic gastrointestinal disorders (EGID) are a group of disorders characterized by pathologic eosinophilic infiltration of the esophagus, stomach, small intestine, or colon leading to organ dysfunction and clinical symptoms (J Pediatr Gastroenterol Nutr; Spergel et al., 52: 300-306, 2011). These disorders include eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), eosinophilic gastroenteritis (EGE), eosinophilic enteritis (EE), and eosinophilic colitis (EC). Symptoms are dependent not only on the location (organ) as well as extent (layer invasion of the bowel wall). Common symptoms of EoE include dysphagia and food impaction in adults and heartburn, abdominal pain, and vomiting in children. Common symptoms of the other EGIDs include abdominal pain, nausea, vomiting, early satiety, diarrhea, and weight loss. These disorders are considered immune-mediated chronic inflammatory disorders with strong links to food allergen triggers. Treatment strategies focus on either medical or dietary therapy. These options include not only controlling symptoms and bowel inflammation but also on identifying potential food triggers. This chapter will focus on the clinical presentation, pathophysiology, and treatment of these increasingly recognized disorders.

Morphea and Eosinophilic Fasciitis: An Update.

Morphea, also known as localized scleroderma, encompasses a group of idiopathic sclerotic skin diseases. The spectrum ranges from relatively mild phenotypes, which generally cause few problems besides local discomfort and visible disfigurement, to subtypes with severe complications such as joint contractures and limb length discrepancies. Eosinophilic fasciitis (EF, Shulman syndrome) is often regarded as belonging to the severe end of the morphea spectrum. The exact driving mechanisms behind morphea and EF pathogenesis remain to be elucidated. However, extensive extracellular matrix formation and autoimmune dysfunction are thought to be key pathogenic processes. Likewise, these processes are considered essential in systemic sclerosis (SSc) pathogenesis. In addition, similarities in clinical presentation between morphea and SSc have led to many theories about their relatedness. Importantly, morphea may be differentiated from SSc based on absence of sclerodactyly, Raynaud's phenomenon, and nailfold capillary changes. The diagnosis of morphea is often based on characteristic clinical findings. Histopathological evaluation of skin biopsies and laboratory tests are not necessary in the majority of morphea cases. However, full-thickness skin biopsies, containing fascia and muscle tissue, are required for the diagnosis of EF. Monitoring of disease activity and damage, especially of subcutaneous involvement, is one of the most challenging aspects of morphea care. Therefore, data harmonization is crucial for optimizing standard care and for comparability of study results. Recently, the localized scleroderma cutaneous assessment tool (LoSCAT) has been developed and validated for morphea. The LoSCAT is currently the most widely reported outcome measure for morphea. Care providers should take disease subtype, degree of activity, depth of involvement, and quality-of-life impairments into account when initiating treatment. In most patients with circumscribed superficial subtypes, treatment with topical therapies suffices. In more widespread disease, UVA1 phototherapy or systemic treatment with methotrexate (MTX), with or without a systemic corticosteroid combination, should be initiated. Disappointingly, few alternatives for MTX have been described and additional research is still needed to optimize treatment for these debilitating conditions. In this review, we present a state-of-the-art flow chart that guides care providers in the treatment of morphea and EF.

Correlation between eosinophilic oesophagitis and aeroallergens.

BACKGROUND: Aeroallergens have been implicated in the pathogenesis of eosinophilic oesophagitis. AIM: To determine whether a seasonal variation exists in the diagnoses of eosinophilic oesophagitis and whether there is a correlation with seasonal pollen count. METHODS: A retrospective review was performed from January 2006 to November 2008 to identify eosinophilic oesophagitis patients. Cases were classified by endoscopic date. Daily pollen counts for grass, trees and weeds were obtained from a certified counting station. Per cent of eosinophilic oesophagitis cases were collated seasonally and compared with mean pollen counts for grass, trees and weeds during the same time period. RESULTS: A total of 127 eosinophilic oesophagitis cases were identified (median age 41, range 19-92 years, 84% men). The highest percentage of cases (33.0%; Binomial P = 0.022) was diagnosed in the spring, while the least percentage (16%; Binomial P = 0.0.010) occurred in the winter. There was a significant association between per cent eosinophilic oesophagitis cases diagnosed seasonally and mean grass pollen count (r(s) = 1.000, P < 0.01), but not with trees (r(s) = 0.400, P = 0.600) or weeds (r(s) = 0.800, P = 0.200). CONCLUSIONS: A seasonal variation was seen in the diagnosis of eosinophilic oesophagitis which correlated with pollen counts. These findings have important implications regarding the pathogenesis of eosinophilic oesophagitis, suggesting a potential role for aeroallergens.

Microarray analysis of allergic fungal sinusitis and eosinophilic mucin rhinosinusitis.

OBJECTIVE: Our goal was to determine and compare the differential gene expression in allergic fungal sinusitis (AFS) and eosinophilic mucin rhinosinusitis (EMRS). STUDY DESIGN AND SETTING: We conducted a complementary DNA microarray analysis of prospectively gathered tissue from a tertiary rhinology practice. RESULTS: Compared to normal subjects, 38 genes or potential genes were differentially expressed in AFS patients, while 10 genes were differentially expressed in EMRS patients. Four genes differentially expressed in EMRS were not differentially expressed in AFS: cathepsin B, sialyltransferase 1, GM2 ganglioside activator protein, and S100 calcium binding protein. These genes mediate lysosomal activity and are known to have differential expression in inflammatory and neoplastic states. CONCLUSIONS: EMRS and AFS show some similarities in gene expression profiles using microarray analysis. Significant differences in gene expression in both EMRS and AFS patients compared with normal subjects provide early clues to the pathophysiology of EMRS and AFS. SIGNIFICANCE: This study demonstrates that complementary DNA microarray analysis is a feasible tool for studying different disease subclassifications and is the first to study these subclasses in chronic rhinosinusitis.

[Evolution of eosinophilia during the pollen season among the general population: a way of determining new sensitiziations]. / Evolution de l'eosinophilie au cours de la saison pollinique dans la population generale: un outil pour determiner de nouvelles sensibilisations.

The purpose of this paper was to verify the effect of pollen peaks on blood eosinophilia in an all and sundry population, including allergic as well as non-allergic subjects, so that we can open up new horizons in the understanding and prevention of pollinosis. Daily eosinophilia counts of hospital patients were measured at the time of a blood checkup (1996-1998), and divided into six classes. Those data were compared to daily pollen counts of twelve taxa, coming from the Hirst trap of Dijon (France). An eosinophilia increase occurred when hazel, hornebeam, birch, oak, grasses, ragweed and plantain were present in high concentration. In other cases, only simultaneous presence of several taxa seemed to play a part, because of cross-reactivity or polysensitization. Lastly, Cupressaceae-Taxaceae and ragweed were seen as increasing eosinophilia in seemingly non allergic people. The analysis of eosinophilia in the general population was able to reveal potential allergic patients and potential allergic diseases.

[Variation in eosinophilia and measures of pollen counts of grasses (Poaceae) and ragweed (Ambrosia) in the Rhone valley]. / Variation de l'éosinophilie et mesures des taux polliniques des graminées (Poaceae) et ambroisies (Ambrosia) dans la vallée du Rhône.

Sensitivity to ragweed pollen, along with grasses pollen, is the leading cause of pollen-induced allergy in our region. Our study focuses on the variation of eosinophilia levels in the blood taken from a sample of the general population during both ragweed and grasses pollination periods. The pollen trap located in the central Rhône River Valley region has provided weekly counts since 1995. The Etablissement Français du Sang Rhône-Alpes-Valence routinely checks hypereosinophilia in the blood through systematic analysis after a blood donation. Average cumulative pollen counts for grasses and ragweed present an interesting correlation with the levels of hypereosinophilia measured at the end of the summer.

Toxic oil syndrome: the perspective after 20 years.

Toxic oil syndrome burst upon the scene in Spain in May of 1981, draining the resources of a newly evolving political and social medicine system. The vehicle of the causative toxic agent was identified as an illicit oil that had been diverted from industrial use and refined in order to remove the aniline denaturant, and that was sold in unlabeled 5-liter containers by itinerant salesmen. Over 20,000 people were ultimately affected, and over 1,200 deaths from all causes have been recorded in the affected cohort. The epidemiologic investigation of toxic oil syndrome involved all facets of investigative and analytical work; from visits to factories and interviewing workers, to sophisticated chemical and statistical analytical techniques. This investigation serves as a further illustration that data and information of all types, and from a wide range of fields, need to be systematically collected and evaluated in order to best resolve an epidemiologic mystery. Astute clinical observation of the patients, however, led to the hypothesis that toxic oil syndrome was a result of a toxic exposure. In this and other epidemics of unknown etiology, clinical observation and the intense scrutiny of patients' histories, signs, and symptoms by treating clinicians have often led to hypotheses that could be tested epidemiologically. When there are medical unknowns, the role of the astute clinician continues to be crucial. The toxic oil syndrome epidemic is an example of how even a developed country can be affected by a massive epidemic of environmental origin if failures occur in the systems that control and regulate the food supply or other consumer products. However, such failures could occur anywhere that large commercial networks operate on the regulatory edge, and if these business lack an in depth knowledge of the consequences of alterations in manufacturing conditions. Such was the case with eosinophilia-myalgia syndrome as well, when apparently minor alterations in manufacturing conditions of L-tryptophan led to an increase in impurities in the product that were later associated with the illness. These risks are even greater in countries with few or inconsistent control systems, making the food and drug supply potential portals of entry for serious health hazards, as is further exemplified by the tragic episode of pediatric renal failure in Haiti associated with a legitimate consumer product, paracetamol elixir, that had been manufactured using a fraudulently supplied toxic ingredient, diethylene glycol (81). The potential toxicants in the adulterated rapeseed oil were present in extremely small amounts. If fatty acid anilides or related compounds are indeed the etiologic agents in toxic oil syndrome, then these compounds must be extremely toxic at the parts per million concentrations at which they were found. Further, the roles of causative agents in the development of disorders such as scleroderma, eosinophilic fasciitis, eosinophilic perimyositis, and other similar diseases are unknown, but scientists can speculate that some sort of low level environmental agent may play a role if such extremely small quantities of contaminants are indeed capable of causing disease. Although the exact identity of the etiologic agent in toxic oil syndrome remains unknown, work on toxic oil syndrome continues. Follow-up clinical studies and long-term mortality studies are under way. Investigation of the mechanisms involved in toxic oil syndrome continues. The identification of suspect chemical compounds, their characterization, and effects will hopefully one day contribute to the prevention of other similar diseases.

Sensitivity to the house dust mite and airway hyperresponsiveness in a young adult population.

BACKGROUND: The pathogenic mechanisms of airway hyperresponsiveness (AHR) in asthma are unknown and only a few studies have examined the importance of sensitivity to antigens in AHR in young adults. OBJECTIVE: We investigated the correlation between AHR and sensitivity to specific antigens, atopy, history of childhood asthma and spirometry in a young adult population. METHODS: Based on the results of interviews with 447 students at our university, 308 non-smoker students were classified into six groups. Group 1 comprised subjects with intermittent mild bronchial asthma; group 2, subjects with history of childhood asthma; group 3, subjects with atopic disease, and a RAST score for Dermatophagoides farinae (Def) of > or = 2; group 4, normal subjects with a RAST score for Def of > or = 2; group 5, subjects with cedar pollinosis; and group 6, normal subjects. We measured AHR to methacholine (MCh), spirometry, immunoglobulin E-radioimmunosorbent test (IgE-RIST), IgE-radioallergosorbent test to six common antigens, eosinophil cationic protein (ECP), and eosinophil count in peripheral blood in each subject. RESULTS: Airway hyperresponsiveness to MCh did not correlate with IgE-RIST, eosinophil count, or ECP. The highest AHR to MCh was present in groups 1 and 2 and lowest in groups 5 and 6. Multiple regression analysis showed that sensitivity to Def was the only factor that significantly influenced AHR to MCh. Airway hyperresponsiveness to MCh of groups with a RAST score for Def of 0/1 was lower than groups with a RAST score of 2 to 6. Airway hyperresponsiveness to MCh did not correlate with the degree of positivity to Def antigen among positive sensitized groups (RAST score 2 to 6). CONCLUSIONS: Sensitivity to mite antigen may be important in the pathogenesis of AHR and Def is a major contributing antigen in young adults in Japan. Once asthma occurs, AHR remains positive for a long time even after the disappearance of asthma-related symptoms.

Clinical features of eosinophilia myalgia syndrome and related disorders.

EMS, EF, and TOS are all relatively rare disorders. There are considerable data to suggest that most (if not all) of these cases may be due to toxin exposure, although the precise etiologic agent(s) has yet to be identified. It is likely that the pathogenic mechanisms responsible for disease are similar in these entities, and thus the distinctions between these illnesses may be largely semantic. Rational therapy includes the removal of an inciting agent if identified, and the application of symptom-based treatment based on the organ or tissue involved, and whether there is evidence of active inflammation is present.

Immunoglobulin E-mediated increase in vascular permeability correlates with eosinophilic inflammation.

An increase in bronchovascular permeability is thought to play an important role in the pathogenesis of allergic asthma. We sought to determine whether the increase in permeability observed 24 h after segmental antigen challenge in ragweed-allergic human volunteers was associated with the infiltration and degranulation of a specific cell type. A 20,000-fold range of antigen concentrations was used to alter the number and type of inflammatory cells recruited to the lung by challenge. Although large numbers of inflammatory cells were recruited to lung air spaces over a large range of antigen concentrations, significant numbers of eosinophils (731.3 +/- 232.9 x 10(3)/ml) were recruited only when the concentration of antigen used for segmental challenge was > or = 100-fold higher than the concentration needed to produce an 8 to 10 mm wheal 20 min after intradermal skin testing. In addition, large increases in bronchoalveolar lavage (BAL) albumin concentration (636.3 +/- 170.5 micrograms/ml) were observed only in this same group of subjects. The correlation coefficient between the logarithms of the BAL eosinophil concentration and albumin concentration was +0.82 (p < 0.001), and between eosinophil-derived neurotoxin and albumin it was +0.88 (p < 0.001). In a stepwise, multiple regression analysis, eosinophils accounted for 67% of the variance in BAL albumin concentration, whereas no other cell type was a significant predictor of albumin flux into BAL fluid. We conclude that eosinophil recruitment and degranulation are associated with large increases in bronchovascular permeability after segmental antigen challenge in humans.

Eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis with eosinophilia.

The eosinophilia-myalgia syndrome, which is associated with the ingestion of L-tryptophan that contained products, occurred as an epidemic in the United States in 1989. Eosinophilia-myalgia syndrome is similar in many ways to the toxic-oil syndrome, which occurred in Spain in 1981, and to diffuse fasciitis with eosinophilia, which has been noted since 1974 to occur sporadically. Recent studies have clarified the epidemiology, histopathology, and clinical features of eosinophilia-myalgia syndrome. These studies are reviewed, and comparisons to the related syndromes, toxic-oil syndrome and diffuse fasciitis with eosinophilia, are made.

Toxic oil syndrome: a current clinical and epidemiologic summary, including comparisons with the eosinophilia-myalgia syndrome.

In the spring and summer of 1981, an epidemic of a new illness now referred to as the toxic oil syndrome occurred in central and northwestern Spain, resulting in some 20,000 cases, 12,000 hospital admissions and greater than 300 deaths in the 1st year of the epidemic. The initial onset of illness was usually acute, and patients presented primarily with a respiratory syndrome involving cough, fever, dyspnea, hypoxemia, pulmonary infiltrates and pleural effusions. While approximately 50% of patients recovered from this acute phase of the illness without apparent sequelae, the remaining patients developed an intermediate or chronic phase, or both, of illness involving severe myalgia, eosinophilia, peripheral nerve damage, sclerodermiform skin lesions, sicca syndrome, alopecia and joint contractures, among other findings. Epidemiologic and analytic chemical studies have clearly linked the toxic oil syndrome to the ingestion of oil mixtures containing rapeseed oil denatured with aniline. However, the precise identity of the etiologic agent within this oil has never been determined. Aniline itself did not cause the illness, but the causal agent may be a reaction product of aniline with some oil component. Although many aspects of disease activity in the involved patients have lessened with time, the ultimate consequences of their disease are not clear and are the subject of ongoing study. The recently described eosinophilia-myalgia syndrome in the United States clinically resembles the toxic oil syndrome.