Quality of life outcomes in women with endometriosis are highly influenced by recruitment strategies.

STUDY QUESTION: To what extent are outcome measures in endometriosis-related quality of life studies influenced by the setting in which patient recruitment is performed? SUMMARY ANSWER: Quality of life outcomes in women with endometriosis are highly influenced by recruitment strategies. WHAT IS KNOWN ALREADY: Most studies on quality of life in women with endometriosis are conducted in tertiary care centres or patient associations. It is conceivable that the setting in which patient recruitment is performed influences the quality of life results. This has not been investigated before. STUDY DESIGN, SIZE, DURATION: Retrospective questionnaire based cohort study (part of the World Endometriosis Research Foundation (WERF) EndoCost study). The investigated women were recruited in three settings: a tertiary care centre for endometriosis (n = 135); five secondary care centres (n = 63); an endometriosis patient association (n = 291). PARTICIPANTS/MATERIALS, SETTING, METHODS: The secondary and tertiary care population included women with a laparoscopic and/or histological diagnosis of endometriosis. The patient association population consisted of women with a self-reported diagnosis of surgically confirmed endometriosis. MAIN RESULTS AND THE ROLE OF CHANCE: The populations did not differ in terms of age, co-morbidities and education level. Delay of diagnosis was the longest in the patient association (median 7 years) (tertiary care 2 years; secondary care 1.5 years) (P < 0.001). The tertiary care population reported more laparotomies (64%) than the other populations (secondary care 43%; patient association 47%) (P = 0.002). Affected job was least prevalent in the secondary care setting (35%) (patient association 64%; tertiary care 56%) (P < 0.001). Affected relationships were most prevalent in the patient association setting (52%) (tertiary care 38%; secondary care 22%) (P < 0.001). Chronic pain was least prevalent in patients in secondary care (44%) (tertiary care 65%; patient association 61%) (P = 0.009). Substantial differences in quality of life were detected between secondary care (median physical component 50.4, mental component 49.6); tertiary care (physical component 46.2, mental component 46.2) and the patient association (physical component 45.0, mental component 44.6) (P < 0.001, P = 0.018). LIMITATIONS, REASONS FOR CAUTION: The response rate was relatively low (35%). Analysis of the hospital populations revealed that non-responders and responders did not differ with respect to age or revised American Fertility Society classification, indicating that the non-responder bias is limited. However, other factors, such as social and marital status or symptomatology, might be different for non-responders. Missing values were analysed as if the symptom was not present. Missing values never exceeded 10%, except for one value. Therefore, it can be expected that the effect of missing data on the outcome is negligible. Twenty-five patients belonged to more than one category. A sensitivity analysis showed that the influence of assigning patients to another category was limited. WIDER IMPLICATIONS OF THE FINDINGS: Outcomes regarding quality of life are highly influenced by recruitment strategy. None of the groups appeared to be a representative selection of the total population of women with endometriosis. An alternative strategy for creating a representative population for cost and quality of life studies is probably to recruit women who live in a specific geographic area rather than women that visit a specific hospital or are a member of a patient association. STUDY FUNDING/COMPETING INTERESTS: The WERF EndoCost study was funded by the World Endometriosis Research Foundation. The sponsors did not have a role in the design and conduct of this study: collection, management, analysis, interpretation of the data; preparation, review, approval of the manuscript. L.H. is the chief executive and T.M.D. was a board member of WERF at the time of funding. T.M.D holds the Merck-Serono Chair and the Ferring Chair in Reproductive Medicine in Leuven, Belgium and has served as consultant for Merck-Serono, Schering-Plough, Astellas, and Arresto. TRIAL REGISTRATION NUMBER: Not applicable.

The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey.

STUDY QUESTION: To what extent do the management of endometriosis and the symptoms that remain after treatment affect the quality of life in women with the disease? SUMMARY ANSWER: Many women with endometriosis had impaired quality of life and continued to suffer from endometriosis-associated symptoms even though their endometriosis has been managed in tertiary care centres. WHAT IS KNOWN ALREADY: The existing literature indicates that quality of life and work productivity is reduced in women with endometriosis. However, most studies have small sample sizes, are treatment related or examine newly diagnosed patients only. STUDY DESIGN, SIZE, DURATION: A cross-sectional questionnaire-based survey among 931 women with endometriosis treated in 12 tertiary care centres in 10 countries. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women diagnosed with endometriosis who had at least one contact related to endometriosis-associated symptoms during 2008 with a participating centre were enrolled into the study. The study investigated the effect of endometriosis on education, work and social wellbeing, endometriosis-associated symptoms and health-related quality of life, by using questions obtained from the World Endometriosis Research Foundation (WERF) GSWH instrument (designed and validated for the WERF Global Study on Women's Health) and the Short Form 36 version 2 (SF-36v2). MAIN RESULTS AND THE ROLE OF CHANCE: Of 3216 women invited to participate in the study, 1450 (45%) provided informed consent and out of these, 931 (931/3216 = 29%) returned the questionnaires. Endometriosis had affected work in 51% of the women and affected relationships in 50% of the women at some time during their life. Dysmenorrhoea was reported by 59%, dyspareunia by 56% and chronic pelvic pain by 60% of women. Quality of life was decreased in all eight dimensions of the SF-36v2 compared with norm-based scores from a general US population (all P < 0.01). Multivariate regression analysis showed that number of co-morbidities, chronic pain and dyspareunia had an independent negative effect on both the physical and mental component of the SF-36v2. LIMITATIONS, REASONS FOR CAUTION: The fact that women were enrolled in tertiary care centres could lead to a possible over-representation of women with moderate-to-severe endometriosis, because the participating centres typically treat more complex and referred cases of endometriosis. The response rate was relatively low. Since there was no Institute Review Board approval to do a non-responder investigation on basic characteristics, some uncertainty remains regarding the representativeness of the investigated population. WIDER IMPLICATIONS OF THE FINDINGS: This international multicentre survey represents a large group of women with endometriosis, in all phases of the disease, which increases the generalizability of the data. Women still suffer from frequent symptoms, despite tertiary care management, in particular chronic pain and dyspareunia. As a result their quality of life is significantly decreased. A patient-centred approach with extensive collaboration across disciplines, such as pain specialists, psychologists, sexologists and social workers, may be a valuable strategy to improve the long-term care of women with endometriosis. STUDY FUNDING/COMPETING INTEREST(S): The WERF EndoCost study is funded by the World Endometriosis Research Foundation (WERF) through grants received from Bayer Schering Pharma AG, Takeda Italia Farmaceutici SpA, Pfizer Ltd and the European Society of Human Reproduction and Embryology. The sponsors did not have a role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript. L.H. is the chief executive and T.D. was a board member of WERF at the time of funding. T.D. holds the Merck-Serono Chair in Reproductive Medicine and Surgery, and the Ferring Chair in Reproductive Medicine at the Katholieke Universiteit Leuven in Belgium and has served as consultant/research collaborator for Merck-Serono, Schering-Plough, Astellas and Arresto.

Increased serum ß2-microglobulin is associated with clinical and immunological markers of disease activity in systemic lupus erythematosus patients.

The objective of this study was to explore the relationship between serum levels of ß2-microglobulin (ß2MG), which some studies suggest reflect disease activity in systemic lupus erythematosus (SLE), and various clinical and immunological markers of disease activity in SLE. Twenty-six SLE patients and 10 healthy controls were included. Disease activity was assessed by: SLEDAI, 24 hr-proteinuria, circulating levels of complement C3, anti-double-stranded DNA (anti-dsDNA), ß2MG and various pro-inflammatory and anti-inflammatory cytokines (IL-6, IL-8, IL-10, IL-18) measured with a multiplex assay, IFN-α assessed with a reporter gene assay, and a combined expression score of 12 IFN-α inducible genes in peripheral blood mononuclear cells. Median serum levels of ß2MG were significantly higher in SLE patients vs controls (2.8 mg/L, range: 1.1-21.6 and 1.2 mg/L, range: 0.9-1.7, respectively, p < 0.001). ß2MG was correlated with SLEDAI score (R = 0.68, p < 0.001), 24 hr-proteinuria (R = 0.64, p < 0.001), and complement C3 (R = -0.52, p = 0.007). The cytokines were significantly correlated with ß2MG: IL-6 (R = 0.45, p = 0.02), IL-8 (R = 0.75, p < 0.001), IL-10 (R = 0.67, p < 0.001) and IL-18 (R = 0.71, p < 0.001) as were serum IFN-α (R = 0.45, p = 0.02) and the IFN-α inducible gene-score (R = 0.51, p = 0.01). The results support that ß2MG may serve as a marker of disease activity in SLE. The correlations with the measured cytokines indicate that increased ß2MG in SLE reflects immunological activity.

Endometriosis: cost estimates and methodological perspective.

This article aims to provide a systematic review of estimates and methodology of studies quantifying the costs of endometriosis. Included studies were cost-of-illness analyses quantifying the economic impact of endometriosis and cost analyses calculating diagnostic and treatment costs of endometriosis. Annual healthcare costs and costs of productivity loss associated with endometriosis have been estimated at $2801 and $1023 per patient, respectively. Extrapolating these findings to the US population, this study calculated that annual costs of endometriosis attained $22 billion in 2002 assuming a 10% prevalence rate among women of reproductive age. These costs are considerably higher than those related to Crohn's disease or to migraine. To date, it is not possible to determine whether a medical approach is less expensive than a surgical approach to treating endometriosis in patients presenting with chronic pelvic pain. Evidence of endometriosis costs in infertile patients is largely lacking. Cost estimates were biased due to the absence of a control group of patients without endometriosis, inadequate consideration of endometriosis recurrence and restricted scope of costs. There is a need for more and better-designed studies that carry out longitudinal analyses of patients until the cessation of their symptoms or that model the chronic nature of endometriosis.

Lack of immunogenicity of ice structuring protein type III HPLC12 preparation administered by the oral route to human volunteers.

Before a novel protein can be used in foods, its potential allergenicity must be assessed. In this study, healthy volunteers consumed ice structuring protein (ISP) Type III preparation or a control material 5 days a week for a total of 8 weeks. General measures of health were recorded during the study, and the immunogenicity of the protein was assessed by monitoring the levels of IgG and IgE antibodies specific for ISP Type III. The participants remained in good health throughout the study and during the 4 week follow-up period. No IgG or IgE antibodies specific for ISP Type III were detected in the blood of the participants. Investigations of immunogenicity in man have not been previously applied in the context of safety evaluation and they do not form part of the regimens proposed for the evaluation of protein allergenicity. Consequently no standardised protocols exist for such studies, nor any background against which to interpret the results. Nevertheless, the absence of an immune response using a protocol which could have been expected to result in a response with a strongly immunogenic protein, confirms the conclusions of earlier published work, and attests to the lack of allergenicity of ISP Type III preparation.

Multi-disciplinary centres/networks of excellence for endometriosis management and research: a proposal.

Centres/networks of excellence are the only way forward to ensure that women with endometriosis receive consistent, evidence-based care, ensuring excellence, continuity of care, multi-disciplinarity, research, training and cost-effectiveness. Clinical excellence should be achieved by proper training, adherence to evidence-based guidelines, quality management and continuous measurement of patient outcome as a central focus. To ensure continuity of care, the first step is to assign to each patient a central gynaecologist who must have continuously updated knowledge regarding all diagnostic and management options for endometriosis and who must set priorities and realistic expectations together with the woman using a long-term multi-disciplinary treatment plan. Scientific research within and scientific collaboration between centres/networks of excellence will create the critical mass of patients and tissue samples that is needed to make progress. Centres/networks of excellence should be accredited as training centres by professional bodies. They should aim at improving the cost-effectiveness of the management of endometriosis by a reduction in the time to diagnosis, a reduction in the time before individualized specialist care is invoked, a reduction of expensive hit-and-miss treatments and a reduction in expensive fertility treatments, if the disease is under control before fertility is impaired.

The role of the interleukin-10 subfamily members in immunoglobulin production by human B cells.

Interleukin (IL)-10 has been shown to have various effects on B cells, including positively affecting the production of immunoglobulin A (IgA) and IgG. Several human IL-10-related molecules have been identified. These include IL-19, IL-20, IL-22, IL-24, IL-26, IL-28 and IL-29. To determine the effects of the IL-10 analogues on the class switch recombination in B cells, we analysed Ig production from naïve B cells stimulated with these cytokines in the presence of anti-CD40. None of the cytokines were found to induce Ig production by themselves in the presence of anti-CD40 Ab. However, all cytokines inhibited the production of IgA and IgG induced by anti-CD40 Ab alone. In combination with anti-CD40 Ab and IL-4, IgG4 were inhibited in cultures stimulated with IL-20, IL-22, IL-26, IL-28 and IL-29 compared with IL-4 and anti-CD40 Ab alone, whereas all IL-10 analogues increased the production of total IgG. All analogues reduced anti-CD40 Ab + transforming growth factor (TGF)-beta-induced IgA production compared with cultures stimulated with anti-CD40 Ab and TGF-beta alone. Together, these data show that the IL-10-related cytokines in combination with anti-CD40 Ab are not by themselves directly involved in the Ig regulation in B cells. However, some of the analogues might have regulatory effects on CSR induced by CD40-ligation in combination with IL-4 or TGF-beta.

Class switch recombination in selective IgA-deficient subjects.

Selective IgA deficiency is a common immunodeficiency in Caucasians, but the molecular basis of the disorder remains elusive. To address this issue we examined the molecular events leading to IgA production. Naive IgD positive B cells were purified from four donors with IgA deficiency and four control donors, all Caucasians. Stimulation of B cells from IgA-deficient donors with the cytokines transforming growth factor (TGF)-beta, interferon (IFN)-gamma or interleukin (IL)-10 in the presence of anti-CD40 antibodies showed reduced expression of both activation-induced cytidine deaminase (AID) and alpha germline transcripts (GLT) compared to controls. It was possible, however, to induce AID and alpha GLT when stimulating the cells with anti-CD40 antibody and TGF-beta in the combination with IL-10. Moreover, in anti-CD40 antibody-stimulated cultures, addition of IL-10 or IL-10 + TGF-beta in combination, induced IgA production, albeit lower than found in B cells from controls. The B cells from the IgA-deficient subjects were less effective in differentiating into CD138(+) X-box binding protein 1 (XBP-1)(+) plasma cells when stimulated with TGF-beta, IFN-gamma or IL-10. Interestingly, when adding IL-4 to TGF-beta alone or in combination with IL-10, the immunoglobulin production in B cells from IgA-deficient donors was comparable with those of normal controls. These data show that in healthy subjects in vitro IgA production can be up-regulated by addition of IL-10 to CD40-stimulated B cells, whereas a similar B cell differentiation does not occur in IgA-deficient subjects. Addition of IL-4, however, reverts this abnormality.

Are basophil histamine release and high affinity IgE receptor expression involved in asymptomatic skin sensitization?

BACKGROUND: Immunoglobulin (Ig)E-sensitized persons with positive skin prick test, but no allergy symptoms, are classified as being asymptomatic skin sensitized (AS). The allergic type 1 disease is dependant on IgE binding to the high affinity IgE-receptor (FcepsilonRI) expressed on basophils and mast cells. However, a relationship between the AS status and FcepsilonRI has not been investigated. We aimed to characterize basophils from AS by looking at histamine release (HR) (sensitivity and reactivity) and the FcepsilonRI molecule, and compare it with nonatopic (NA) or allergic (A) persons. METHODS: Blood was obtained from NA (n = 14), grass and/or birch A persons (n = 17) and mono-sensitized grass or birch pollen AS (n = 12). The basophil sensitivity and reactivity were examined by anti-IgE triggered HR. Surface expression of FcepsilonRI and IgE were measured by flow cytometry, FcepsilonRIalpha protein was identified using a radioimmunoassay and Western blot. mRNA coding for the classic FcepsilonRIbeta-chain and the truncated form (FcepsilonRIbetaT) were determined by real-time PCR. RESULTS: The AS group was less reactive than NA or A persons when triggered by anti-IgE and had a significant higher number of nonresponders. However, there was no difference in sensitivity among the three groups and furthermore; the groups did not vary in FcepsilonRI- and IgE-surface expression, FcepsilonRIalpha-protein level or beta/betaT ratio. CONCLUSION: Basophils from AS persons are less reactive and include more nonresponders than basophils from NA and A persons, but do not differ regarding the FcepsilonRI molecule.

Is immunotherapy-induced birch-pollen-specific IgG4 a marker for decreased allergen-specific sensitivity?

BACKGROUND: The role of IgG4 during allergen-specific immunotherapy (SIT) is still controversial. The available studies present paramount differences in in vitro techniques, allergens, and clinical outcome parameters. By implementing a sensitive method, and pivotal clinical outcome parameters, we wanted to ascertain the utility of IgG4 as a clinical marker of decreased allergen-specific sensitivity to a common aeroallergen. METHODS: Sera were drawn from 23 birch-pollen-allergic patients during a placebo-controlled clinical trial on birch pollen SIT. Seventeen patients received active treatment. Blood samples were drawn at 0, 2, 4, 7, and 30 treatment weeks, and 36 months. The binding activity of autologous IgG, IgG4, IgE, and IgE- and/or IgG-depleted serum to (125)I-labelled recombinant Bet v 1 was assessed in a fluid-phase radioimmunoassay. Disease severity was assessed subjectively on a visual analogue scale (VAS), and objectively by intradermal late-phase reaction diameters. RESULTS: Before SIT IgG4 fraction of IgG-allergen binding varied from 4 to 74%, with a median of 36%, increasing to 71% after 36 months. Changes in IgG4 or IgG4/IgG fraction were not correlated to clinical outcome parameters. Changes in IgG allergen binding and VAS were significantly correlated (sigma = 0.72; p < 0.05). SIT increased the serum-blocking activity of IgE allergen binding from 25% before SIT to 80% after SIT. No changes were observed in the placebo group. CONCLUSION: The data suggest that IgG4 per se is a poor marker of decreased allergen-specific sensitivity to birch pollen, both as a single measurement and as delta values.