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      Anti-TNF-α treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial


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          Endometriosis is associated with an inflammatory response. Hence infliximab, an anti-TNF-α monoclonal antibody, might relieve pain.


          A randomized placebo-controlled trial was designed with 21 women with severe pain and a rectovaginal nodule of at least 1 cm. After 1 month of observation, three infusions of infliximab (5 mg/kg) or placebo were given. Surgery was performed 3 months later and follow-up continued for 6 months. The primary end-point was pain (dysmenorrhea, deep dyspareunia and non-menstrual pain) rated at each visit by the clinician and on a daily basis by the patient who in addition scored pain by visual analog pain scale and analgesia intake. Secondary end-points included the volume of the endometriotic nodule, pelvic tenderness and the visual appearance of endometriotic lesions at laparoscopy.


          Pain severity decreased during the treatment by 30% in both the placebo ( P < 0.001) and infliximab groups ( P < 0.001). However, no effect of infliximab was observed for any of the outcome measures. After surgery, pain scores decreased in both groups to less than 20% of the initial value.


          Infliximab appears not to affect pain associated with deep endometriosis. Treatment is associated with an important placebo effect. After surgery, pain decreases to less than 20%. Trials registration number ClinicalTrials.gov: NCT00604864.

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          Most cited references57

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          Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients.

          The association between lesion type, disease stage and severity of pain was studied in a large group of women with endometriosis to verify whether endometrial implants at different sites determine specific complaints and to evaluate the validity of the current classification system in women with symptomatic disease. A total of 1054 consecutive women with endometriosis undergoing first-line conservative or definitive surgery were included. Data on age at surgery, disease stage according to the revised American Fertility Society (AFS) classification, anatomical characteristics of endometriotic lesions, and type and severity of pain symptoms were collected and analysed by multiple logistic regression. Minimal endometriosis was present in 319 patients, mild in 139, moderate in 292 and severe in 304. A significant inverse relationship was demonstrated between age at surgery and moderate-to-severe dysmenorrhoea, dyspareunia and non-menstrual pain. A strong association was found between posterior cul-de-sac lesions and pain at intercourse [Wald chi (2) = 17.00, P = 0.0001; odds ratio (OR) = 2.64, 95% confidence interval (CI) = 1.68-4.24]. A correlation between endometriosis stage and severity of symptoms was observed only for dysmenorrhoea (Wald chi (2) = 5.14, P = 0.02) and non-menstrual pain (Wald chi (2) = 5.63, P = 0.018). However, the point estimates of ORs were very close to unity (respectively, 1.33, 95% CI = 1.04-1.71, and 1.01, 95% CI = 1.00-1.03). The association between endometriosis stage and severity of pelvic symptoms was marginal and inconsistent and could be demonstrated only with a major increase in study power.
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            Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain.

            In a 3-year prospective study of 643 consecutive laparoscopies for infertility, pelvic pain, or infertility and pain, the pelvic area, the depth of infiltration, and the volume of endometriotic lesions were evaluated. The incidence, area, and volume of subtle lesions decreased with age, whereas for typical lesions these parameters and the depth of infiltration increased with age. Deeply infiltrating endometriosis was strongly associated with pelvic pain, women with pain having larger and deeper lesions. Because deep endometriosis has little emphasis in the revised American Fertility Society classification and after analyzing the diagnoses made in each class, considerations for a simplifying revision with inclusion of deep lesions are suggested. In conclusion, suggestive evidence is presented to support the concept that endometriosis is a progressive disorder, and it is demonstrated that deep endometriosis is strongly associated with pelvic pain.
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              Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial.

              The objective of this prospective controlled trial was to investigate the ability of a group of serum and peritoneal fluid (PF) markers to predict, non-surgically, endometriosis. Serum and PF samples were obtained from 130 women while undergoing laparoscopy for pain, infertility, tubal ligation or sterilization reversal. Concentrations of six cytokines [interleukin (IL)-1beta, IL-6, IL-8, IL-12, IL-13 and tumour necrosis factor (TNF)-alpha] were measured in serum and PF, and reactive oxygen species (ROS) in PF, and levels were compared among women who were allocated to groups according to their post-surgical diagnosis. Fifty-six patients were diagnosed with endometriosis, eight with idiopathic infertility, 27 underwent tubal ligation or reanastomosis (control group) and 39 were excluded due to bloody PF. Only serum IL-6 and PF TNF-alpha could be used to discriminate between patients with and without endometriosis with a high degree of sensitivity and specificity (P < 0.001). A threshold of 15 pg/ml PF TNF-alpha provided 100% sensitivity and 89% specificity (positive likelihood ratio of 9.1 and negative likelihood ratio of 0). A threshold of 2 pg/ml for serum IL-6 provided a sensitivity of 90% and specificity of 67% (positive likelihood ratio of 2.7 and negative likelihood ratio of 0.14). By measuring serum IL-6 and PF TNF-alpha, it was possible to discriminate between patients with endometriosis and those without. Before these markers can be used as a non-surgical diagnostic tool, these data should be verified in a larger study.

                Author and article information

                Hum Reprod
                Human Reproduction (Oxford, England)
                Oxford University Press
                September 2008
                12 June 2008
                12 June 2008
                : 23
                : 9
                : 2017-2023
                [1 ]Department of Obstetrics and Gynaecology, UZ Gasthuisberg, Katholieke Universiteit Leuven , B3000 Leuven, Belgium
                [2 ]Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford , Oxford, UK
                [3 ]Centocor BV, Medical Affairs Europe , Leiden, The Netherlands
                Author notes
                [4 ]Correspondence address. E-mail: pkoninckx@ 123456gmail.com
                © The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

                The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed: the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given: if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative word this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

                : 18 January 2008
                : 15 March 2008
                : 11 April 2008
                Original Articles

                Human biology
                Human biology


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