Robert A. Harrington, MD
Were there long-term side effects that would only become evident five or 10 years from nowfi They pointed to post-traumatic stress that continues long after therapy is completed treatment emergent adverse event cheap 100mg epivir-hbv. They felt that it was important to include emotional/psychological counseling for both the patient and their loved ones symptoms gerd generic 150 mg epivir-hbv. Our search identified three single-arm trials of tisagenlecleucel for this indication medications similar to abilify buy epivir-hbv 100 mg without prescription. Caution should be taken when interpreting any comparisons across trials due to the potential for significant selection bias medicine to stop vomiting purchase discount epivir-hbv on-line. There is no accepted definition of a cure, as relapses can rarely occur more than 10 years after remission. A recent proposal is that children in remission four years after the completion of treatment could be considered cured (< 1% chance of relapse). These estimates suffer from considerable uncertainty because the trials are small, have median follow-ups of less than two years, and had different inclusion and exclusion criteria. B-cells are the target of tisagenlecleucel in order to keep the leukemia in remission. Adult Aggressive B-Cell Lymphoma There are two single-arm trials of axicabtagene ciloleucel for adult B-cell lymphoma and two singlearm trials of tisagenlecleucel for the same population. A 2014 publication proposed that event-free survival two years after the completion of treatment could be a reasonable surrogate outcome. However, the comparisons are useful as a guide to the potential magnitude of benefit for axicabtagene ciloleucel compared to other recent salvage therapies for adults with relapsed or refractory aggressive B-cell lymphoma. It was not possible to estimate a complete remission rate using an intent-to-treat analysis based on the data available from the public presentations. The risk is likely to be quite low, but is an important long-term concern for further study. The sample sizes with outcomes in the trials are less than 100 participants, and the median follow-up in the trials is less than two years. There are also theoretical concerns about complications from the viral vectors used in the manufacturing process and of secondary malignancies related to mutations in the T-cells due to the manufacturing process. There are no head to head trials of axicabtagene ciloleucel and tisagenlecleucel for patients with relapsed/refractory B-cell lymphomas. The lack of head-to-head randomized trials and the small number of patients studied render such judgements premature. Patient survival was calculated from available Kaplan-Meier survival curves which were digitized and extrapolated through five years after treatment initiation, at which point those alive and responding to treatment were considered effectively cured. For tisagenlecleucel, the payment strategy used in the base-case analysis was payment only for responders at one month, consistent with public statements from the manufacturer. Key model inputs included progressionfree survival, overall survival, occurrence of adverse events, quality of life, and health care costs. Any person alive but not responding to treatment Those alive at year five are considered long-term transitioned to death by the end of year five. All patients who transitioned to the alive and not the intervention and comparator therapies are responding to treatment health state received considered an end-of-line treatment. Full details on hospital mark-up assumptions can be found in Section 4 of the main report. Chemotherapy Base-case payment for tisagenlecleucel assumes payment only for responders at one month. Across broad ranges in influential model inputs when varied one-by-one, the incremental cost-effectiveness ratio remained within acceptable costeffectiveness thresholds. In this case, when model inputs were varied within plausible ranges one by one, cost-effectiveness estimates frequently did extend above commonly cited cost-effectiveness thresholds, highlighting the uncertainty in some of the parameter values. The incremental costeffectiveness ratio assuming no hospital mark-up for axicabtagene ciloleucel was approximately $109,000. First, we conducted a scenario analysis of different model time horizons, from one year to a lifetime time horizon. This scenario analysis is intended to provide decisionmakers with the ability to make judgements around the duration and forecasting of the cure-related benefits observed in the single-arm trials. Secondly, in the base-case analysis, we introduced a knot in the survival curve fit once the curve flattened. In a scenario analysis, we removed the knot to produce a lower bound for survival. These and other scenario analyses are discussed in further detail in the full report. The results were robust through one-way and probabilistic sensitivity analyses given the parameter uncertainty quantified. Similarly, the base-case findings from our analysis suggest that the use of axicabtagene ciloleucel in B-cell lymphoma also provides clinical benefit in terms of gains in quality-adjusted and overall survival over chemotherapy. This translated into cost-effectiveness estimates that met commonly cited cost-effectiveness thresholds in the adult relapsed/refractory B-cell lymphoma cohort under current assumptions used in the base-case analysis. Scenario analyses detailed in the main report showed, however, that the cost-effectiveness was sensitive to the time horizon and long-term benefit forecasting of the therapies. Other Benefits and Contextual Considerations Our reviews seek to provide information on other benefits offered by the intervention to the individual patient, caregivers, the delivery system, other patients, or the public that would not have been considered as part of the evidence on comparative clinical effectiveness. This intervention offers reduced complexity None that will significantly improve patient outcomes. This intervention will reduce important health None disparities across racial, ethnic, gender, socioeconomic, or regional categories. This intervention will significantly reduce None caregiver or broader family burden. This novel mechanism appears to offer significantly greater remission rates than other therapies for patients who have failed standard first and second-line therapy for these B-cell cancers. Other important benefits or disadvantages None that should have an important role in judgments of the value of this intervention. This intervention is the first to offer any None improvement for patients with this condition. There are additional contextual considerations that None should have an important role in judgments of the value of this intervention. Potential budget impact was defined as the total differential cost of using the new therapy rather than relevant existing therapy for the treated population, calculated as differential health care costs (including therapy costs) minus any offsets in these costs from averted health care events. For axicabtagene ciloleucel, we determined the size of the eligible cohort using observational study data, resulting in an annual eligible cohort size of 5,902 patients. Note: All prices are based on payment at infusion, irrespective of response to treatment. The results of these votes are presented below, and additional information on the deliberation surrounding the votes can be found in the full report. Pediatric B-cell Acute Lymphoblastic Leukemia Patient Population for questions 1-4: Patients ages 0-25 years with B-cell acute lymphoblastic leukemia that is refractory or in second or greater relapse 1) Is the evidence adequate to demonstrate a net health benefit for treatment with tisagenlecleucel versus treatment with clofarabine or comparable immunotherapy or chemotherapy. This intervention will have a significant impact on improving return to work and/or overall productivity. This intervention is intended for the care of individuals with a condition of particularly high severity in 12/13 terms of impact on length of life and/or quality of life. Compared to the clofarabine or comparable chemoor immunotherapy, there is significant uncertainty 9/13 about the magnitude or durability of the long-term benefits of this intervention. There are additional contextual considerations that should have an important role in judgments of the 4/13 value of this intervention 4) Given the available evidence on comparative effectiveness and incremental cost-effectiveness, and considering other benefits, disadvantages, and contextual considerations, what is the longterm value for money of treatment with tisagenlecleucel versus treatment with clofarabinefi
Autoimmune diseases are characterized by the inappropriate or excessive immune response against autoantigens symptoms zithromax discount epivir-hbv 100 mg line, leading to chronic inflammation medicine jobs generic 100mg epivir-hbv, tissue destruction symptoms 5 dpo epivir-hbv 100 mg without a prescription, and/or dysfunction medicine lyrics purchase genuine epivir-hbv on-line. The main measurable feature of an autoimmune disease is the production and long-lasting expression of disease-specific autoantibodies and/or autoreactive T cells. However, the classification of autoimmune disease demands additional evidence, which may be direct, indirect, or circumstantial (Rose, 1996). Much indirect evidence is shown by different kinds of animal models, such as experimental immunization, development of spontaneous autoimmunity, and animal models produced by manipulation of the immune system. The so-called classical autoimmune disease fulfils at least three criteria of direct evidence as well as almost all of those of the indirect and circumstantial evidence. Because of problems in designing and standardizing epidemiological studies and because of the fact that only limited data are available, this prevalence may be underestimated (Jacobson et al. There is epidemiological evidence of increasing prevalence of some autoimmune diseases. According to the clinical manifestation, autoimmune diseases may be classified as systemic. However, this clinically useful classification does not correspond to the underlying pathogenetic mechanisms. Despite progress in the research of autoimmune processes, the etiologies and pathological mechanisms involved in the development of autoimmune disease are incompletely understood. A multifactorial genesis, including immunological, genetic, endocrine, and environmental factors, is suggested by evidence from both human and animal studies (Shoenfeld & Isenberg, 1990). Different mechanisms, which are not mutually exclusive, may be involved in the induction and progression of pathological autoimmunity; these include genetic or acquired defects in immune tolerance or immunoregulatory pathways, molecular mimicry to viral or bacterial proteins, an impaired clearance of apoptotic cell material, the generation of autoimmunity to cryptic or modified self, adjuvant-like activity, and susceptibility of target organ(s) for the autoimmune attack (Oldstone, 1987; Wick et al. Environmental factors operating in a genetically susceptible host may directly initiate, facilitate, or exacerbate the pathological immune process, induce mutations in genes coding for immunoregulatory factors, or modify immune tolerance or regulatory and immune effector pathways. The search for such factors and the elucidation of their action are therefore of great importance for better understanding the pathogenesis of autoimmune disease as well as for improving the prophylaxis and therapy of these diseases. In evolutionary terms, the immune response of vertebrate animals represents a consolidation of two systems. The more ancient innate immune system response is shared, to some degree, by all multicellular animals. It includes a number of physical, chemical, and biological barriers that combine to prevent or control microbial invasion; together, they stand guard on an immediate and constant basis. The second, more recently evolved, system provides vertebrates with the acquired or adaptive immune response. Although it requires more time to mount, in terms of several days, adaptive immunity is aimed at a particular pathogen. Since the variety of pathogens is increasing and constantly changing, the adaptive immune response needs an extensive capacity for recognition and so has evolved a unique system of gene recombination. At the same time, the adaptive response reconfigures and reuses many of the components of the innate immune response to produce its effects. Because the adaptive immune response requires the generation of such broad diversity in recognition capabilities, it also recognizes molecules found in the body of the host itself. In an effort to avoid this harm, the body carefully shapes, regulates, and controls the adaptive immune response. The fundamental concepts of how immunity develops form the basis for an understanding of how environmental agents can interact with the immune system to trigger autoimmune disease. During the Middle Ages, it took on a derived meaning of free from disease, and the term now refers to the many strategies employed by the body to avoid or limit infectious (and perhaps malignant) disease. Initial defence is provided by the natural or innate immune response, which provides immediate, non-pathogen-specific resistance to disease. Innate immune defences are inherited and, therefore, generally present from birth. They include external chemical and physical barriers provided by the skin and mucous membranes, as well as various internal defence mechanisms, such as inflammation and phagocytosis. The skin provides a formidable physical barrier that very few, if any, microorganisms can penetrate. If, however, the skin is damaged, pathogens can invade, penetrating other parts of the body. The mucous membranes represent much less of a physical barrier, but can call upon a number of defensive devices. These include mucus itself, which entraps many microorganisms, the hair-like cilia of the respiratory passages, which propel inhaled organisms towards locations where they can be expelled by coughing or sneezing, and specific antimicrobial agents, such as the enzyme lysozyme in saliva and tears. The flow of urine retards microbial colonization of the urinary system, and the normal microbial population of the large intestine retards the overgrowth of pathogenic organisms. When pathogens penetrate the barriers of skin and mucous membranes, they encounter internal inborn defences. Inflammation is a stereotypic defensive response of the body to most forms of tissue injury, whether chemical, physical, or infectious. The cardinal signs of redness, pain, heat, and swelling serve to localize the infection and recruit cells of the innate immune response. They include the major circulating phagocytic cells, neutrophils, which leave the blood and migrate to inflamed areas. The process involves, first, adherence of the cells to the vascular endothelium of vessels near the damaged tissue site, followed by passage through the endothelial lining and chemotactic attraction to the site of damage. Tissue phagocytes, macrophages, also migrate to the site of 10 Introduction to the Immune System inflammation. A group of normally inactive proteins in the blood plasma also becomes activated by inflammatory reactions. They make up the complement system, which may directly destroy certain bacteria and may also promote the later development of adaptive immunity. Recent studies have shown that pathogens share molecular patterns that activate the innate immune response and influence the later adaptive reaction. For example, many Gram-negative bacteria express lipopolysaccharides on their outer membranes. More potent protection of the body against particular invading pathogens relies upon the subsequent development of adaptive, or acquired, immunity. In practice, any foreign material of sufficient size can act as an antigen, be it pathogenic or harmless, living or inanimate. Complete antigens usually have a molecular weight in excess of 10 000 daltons, but even smaller substances, termed haptens, can activate the adaptive immune response if they are complexed with a larger carrier molecule. Adaptive immune responses can be beneficial when they protect against invading pathogens. The two cardinal features of the adaptive immune response are specificity and memory. Specificity is exemplified by the ability of the immune response to distinguish one foreign antigen from another, as well as to distinguish autoantigens from non-autoantigens. Memory is seen when a second encounter with an antigen prompts a more rapid and vigorous immune response to the same antigen. The job of the adaptive immune response, then, is to sort out the virtually limitless array of possible antigens. The task is accomplished by expressing a large number of recognition structures on the surface of lymphocytes. These specialized white blood cells are responsible for immunological specificity and memory. In order to generate a sufficient diversity of receptors on their surface, lymphocytes employ a unique system of genetic shuffling and recombination. When they encounter an appropriately configured portion of an antigen, usually in the form of a small sequence of amino acids in a large protein molecule or a few monosaccharide units in a large carbohydrate, the lymphocyte binds the antigenic determinant. Each of the progeny bears the same specific receptor as its progenitor lymphocyte. In a few days, a large clone of lymphocytes emerges, each being the specific receptor. Some of these lymphocytes proceed to provide the specific protection against the invader. Other lymphocytes return to their normal quiescent state in which they persist for long periods of time.
The role of laparoscopy in the management of pelvic pain in women of reproductive age symptoms knee sprain proven epivir-hbv 100 mg. A randomised trial of photographic reinforcement during postoperative counselling after diagnostic laparoscopy for pelvic pain treatment 197 107 blood pressure buy generic epivir-hbv 150mg online. A randomized clinical trial to compare two different approaches in women with chronic pelvic pain treatment 4 letter word discount epivir-hbv 100mg line. Are patient symptoms predictive of the diagnostic and/or therapeutic value of hydrodistentionfi Symptoms and cystoscopic findings in patients with untreated interstitial cystitis medications available in mexico cheap epivir-hbv 150mg online. Possible mechanisms inducing glomerulations in interstitial cystitis: relationship between endoscopic findings and expression of angiogenic growth factors. Hydrodistension under local anesthesia for patients with suspected painful bladder syndrome/interstitial cystitis: safety, diagnostic potential and therapeutic efficacy. Cystoscopic findings consistent with interstitial cystitis in normal women undergoing tubal ligation. Bladder pain syndrome: do the different morphological and cystoscopic features correlatefi Radiologic findings of pelvic venous congestion in an adolescent girl with angiographic confirmation and interventional treatment. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Quality of life associated to chronic pelvic pain is independent of endometriosis diagnosis-a cross-sectional survey. Relation between pain symptoms and the anatomic location of deep infiltrating endometriosis. The usefulness of laparoscopy and hysteroscopy in the diagnostics and treatment of infertility. A randomised controlled trial comparing abdominal and vaginal prolapse surgery: effects on urogenital function. Dyspareunia and chronic pelvic pain after polypropylene mesh augmentation for transvaginal repair of anterior vaginal wall prolapse. Risk factors for exposure, pain, and dyspareunia after tension-free vaginal mesh procedure. An evidence-based position statement on the management of irritable bowel syndrome. Does evidence support physiotherapy management of adult female chronic pelvic painfi. Mensendieck somatocognitive therapy as treatment approach to chronic pelvic pain: results of a randomized controlled intervention study. Randomized multicenter feasibility trial of myofascial physical therapy for the treatment of urological chronic pelvic pain syndromes. Acupuncture and dry needling in the management of myofascial trigger point pain: a systematic review and meta-analysis of randomised controlled trials. Needling therapies in the management of myofascial trigger point pain: a systematic review. Trigger point injections for chronic non-malignant musculoskeletal pain: a systematic review. Modified Thiele massage as therapeutic intervention for female patients with interstitial cystitis and high-tone pelvic floor dysfunction. Levator ani trigger point injections: An underutilized treatment for chronic pelvic pain. Randomized multicenter clinical trial of myofascial physical therapy in women with interstitial cystitis/painful bladder syndrome and pelvic floor tenderness. What can prevalence studies tell us about female sexual difficulty and dysfunctionfi A prospective, randomized, placebo controlled, double-blind study of pelvic electromagnetic therapy for the treatment of chronic pelvic pain syndrome with 1 year of followup. Cooled transurethral microwave thermotherapy for intractable chronic prostatitis-results of a pilot study after 1 year. Is there a role for transrectal microwave hyperthermia of the prostate in the treatment of abacterial prostatitis and prostatodyniafi Extracorporeal shock wave therapy for the treatment of chronic pelvic pain syndrome in males: a randomised, double-blind, placebo-controlled study. Extracorporeal shock wave treatment for non-inflammatory chronic pelvic pain syndrome: A prospective, randomized and sham-controlled study. Efficacy of extracorporeal shock wave therapy for the treatment of chronic pelvic pain syndrome: A randomized, controlled trial. Long-term effect of extracorporeal shock wave therapy on the treatment of chronic pelvic pain syndrome due to non bacterial prostatitis. Electroacupuncture relieves pain in men with chronic prostatitis/chronic pelvic pain syndrome: three-arm randomized trial. Acupuncture relieves symptoms in chronic prostatitis/chronic pelvic pain syndrome: A randomized, sham-controlled trial. The efficacy of acupuncture in managing patients with chronic prostatitis/chronic pelvic pain syndrome: A systemic review and meta-analysis. Systematic review of acupuncture for chronic prostatitis/chronic pelvic pain syndrome. Sexual function is a determinant of poor quality of life for women with treatment refractory interstitial cystitis. Psychological therapies for the management of chronic pain (excluding headache) in adults. Psychological therapies for chronic pelvic pain: Systematic review of randomized controlled trials. Moderators of the effects of written emotional disclosure in a randomized trial among women with chronic pelvic pain. Psychotherapy With Somatosensory Stimulation for Endometriosis-Associated Pain: A Randomized Controlled Trial. A randomized controlled trial of medroxyprogesterone acetate and psychotherapy for the treatment of pelvic congestion. Randomized controlled trial of interpersonal psychotherapy versus enhanced treatment as usual for women with co-occurring depression and pelvic pain. Mindfulness-based stress reduction as a novel treatment for interstitial cystitis/ bladder pain syndrome: a randomized controlled trial. The efficacy of Web-based cognitive behavioral interventions for chronic pain: a systematic review and meta-analysis. A feasibility trial of a cognitive-behavioural symptom management program for chronic pelvic pain for men with refractory chronic prostatitis/chronic pelvic pain syndrome. Terazosin therapy for chronic prostatitis/chronic pelvic pain syndrome: a randomized, placebo controlled trial. Use of terazosine in patients with chronic pelvic pain syndrome and evaluation by prostatitis symptom score index. Alfuzosin treatment for chronic prostatitis/chronic pelvic pain syndrome: a prospective, randomized, double-blind, placebo-controlled, pilot study. Lower urinary tract symptoms, pain and quality of life assessment in chronic non-bacterial prostatitis patients treated with alpha-blocking agent doxazosin; versus placebo. Effects of a 6-month course of tamsulosin for chronic prostatitis/chronic pelvic pain syndrome: a multicenter, randomized trial. Management of chronic prostatitis/chronic pelvic pain syndrome: a systematic review and network meta-analysis. Predictors of patient response to antibiotic therapy for the chronic prostatitis/ chronic pelvic pain syndrome: a prospective multicenter clinical trial. Prostate biopsy culture findings of men with chronic pelvic pain syndrome do not differ from those of healthy controls. Purchase epivir-hbv toronto. Curing Disease Vs. Managing Symptoms. Interpretation of the tests for autoantibodies will depend on the class and titre of the antibody and the age and sex of the test subject symptoms yeast infection men effective epivir-hbv 100 mg. Autoantibodies can be found in normal symptoms 6 days after iui order epivir-hbv with visa, healthy individuals medications not to take with blood pressure meds order 100mg epivir-hbv otc, especially elderly females symptoms gout generic 100mg epivir-hbv with visa. The first step of risk assessment for any potential adverse effects, including autoimmune disease, is problem formulation. This represents a process that establishes a conceptual model for the risk assessment. During problem formulation, the adequacy of scientific data, data gaps, policy and public health issues, and factors to define the feasibility, scope, and objectives for the risk assessment are identified. This allows for early identification of important factors to be considered in developing a scientifically sound risk assessment. The key questions that the risk assessment is seeking to answer should be identified during this planning and scoping process, and a rationale for the focus of the assessment on specific toxic effects or susceptible populations should be included. Problem formulation is based upon a clear articulation and understanding of several key elements, including the objective, the overall scope, exposure considerations, and considerations of biological effects (Daston et al. Uncertainty factors are built into the risk assessment process to account for variations in individual susceptibility, extrapolation of data from studies in laboratory animals to humans. In the case of the association between exposure to chemicals and drugs and autoimmunity or autoimmune diseases, much of the information needed to evaluate risk in the context of the traditional United States National Research Council paradigm is not available. The following represents a discussion of issues in chemical-induced autoimmunity relevant to the use of existing data and data needs in risk assessment. Nevertheless, any sign of inflammation in any of the animals in a 28-day study should be regarded as an alert of hazard. A chemical that produces elevated autoantibodies in experimental animals or exacerbates autoimmune disease in autoimmune-prone animals. This is because the molecular and cellular events responsible for autoimmune disease are similar in experimental animals and humans. However, at this time, it is not possible to determine the predictive value of these models. The assumption that, for chemicalinduced autoimmunity, humans are at least as sensitive as animals is a conservative estimate of sensitivity. Because of its very complex etiology, hazard assessment of autoimmunogenic potential may require a tiered approach based on a toolbox of methods. Since sensitization is considered crucial in the induction of autoimmune disease, the potential to induce sensitization should be considered a hazard. Although frequently used in experimental settings and as a screening assay, the test is not formally validated. Supporting its potential as a first-tier assay, the popliteal lymph node assay allows screening of a set of structurally related compounds so as to select the least sensitizing, which is relevant in particular in case of drug evaluations. For instance, mercury-induced autoimmune glomerulonephritis in Brown Norway rats is transient and resolves spontaneously and cannot be induced again in the same animal. In contrast, the fact that low-dose tolerance occurs with certain chemicals suggests that a threshold exists. Chemicals affecting these known processes could be at increased potential for inducing autoimmune reactions. For example, laboratory studies have shown that thymolytic chemicals (such as cyclosporin) can induce autoimmunity when given neonatally by altering normal patterns of autoreactive T cell deletion, a process that occurs in the thymus early in life. Chemicals that form protein adducts or damage tissue in such a way as to allow expression of cryptic determinants. Common features associated with many drugs that induce autoimmune diseases include their ability to serve as myeloperoxidase substrates. The underlying biology for the latter associations is less clear but may involve formation of the specific antigenic epitopes responsible for the autoimmune response. With regard to the association with myeloperoxidase substrates, it has been suggested that many of the chemicals require metabolism in proximity to immune cells in order to be antigenic; immune cells such as monocytes contain high levels of myeloperoxidase. Also of potential concern are endocrine disruptors, as hormonal influences, particularly sex steroids, appear to play a role in many autoimmune diseases. The disposition of a chemical in an organism is dependent upon the processes of absorption, distribution, metabolism, and excretion, defined as toxicokinetic data. Qualitative and quantitative information on each of these processes would be useful in risk assessment. For autoimmune diseases, toxicokinetic data may be helpful in identifying the potential organ systems that are likely to be involved or the responsible metabolite. There are special issues in designing and standardizing epidemiological studies for general risk assessment that also apply for chemical-induced autoimmune disease. Randomized trials of environmental exposures are generally not feasible or ethical. Epidemiological studies use methodologies developed for observational research to reduce the potential role of confounding, selection bias, and misclassification of exposure and of disease that may bias the estimates of disease association, increase the imprecision or uncertainty of the estimates, or limit the ability to apply the results to the general population. Prospective studies in which exposure assessment is determined prior to disease onset avoid the potential problem of a differential misclassification of exposure based on disease status. For both prospective and retrospective designs, however, the adequacy of exposure assessment, in terms of both sensitivity and specificity, is extremely important and has been demonstrated to affect not just the precision, but the magnitude and direction of observed associations between exposures and autoimmune diseases (Parks et al. In addition, there are some unique challenges in epidemiological studies for risk assessment in chemical-induced autoimmunity. Furthermore, there are no population-based disease registries for most autoimmune diagnoses, and the diagnosis can be difficult to ascertain accurately. For example, most cases of a lupus-like illness caused by procainamide or hydralazine usually resolve when the drug is discontinued. Several forms of autoimmune disease, such as Hashimoto thyroiditis and Graves disease, may arise several weeks after delivery. Characteristically, these forms of postpartum autoimmune diseases clear spontaneously after several months and, thus, may be difficult to capture in retrospective studies. As described in detail elsewhere in this document, a variety of intrinsic factors. While there is variability in the extent of female predominance and no strong association between degree of female predominance and type of disease or age at onset, sex and/or hormonal status clearly play a role in disease susceptibility. Although a majority of autoimmune diseases are less common in children and adolescents, the relative influence of early-life exposures to environmental chemicals or infectious agents on the incidence and severity of disease later in life is largely unexplored. When insufficent evidence exists pertaining to susceptibility, the assumption of equality is generally used. Studies have shown that genetic predisposition plays an important role in susceptibility in the development of autoimmune diseases.
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