Systemic manifestations of erythema nodosum

The systemic manifestations accompanying erythema nodosum can be differentiated from those associated with the precipitating infectious process and from coincident disease processes. Erythema nodosum itself is characterized by (a) skin lesions at pressure sites, (b) malaise, fever and occasionally chills, (c) arthritis (70 per cent) and (d) over-reactivity of tissue. Tissue hypersensitivity is most pronounced at sites of trauma, at sites of specific skin testing, and in the lymphoid system draining infections in the pharynx and lung. Common infections of the respiratory tract most often antedate attacks of erythema nodosum. In New England, a beta-hemolytic streptococcus infection is a common causative factor, and tuberculosis is an unusual causative factor. In endemic areas, coccidioidomycosis is a common cause of erythema nodosum. The most important coincidental disease process is rheumatic heart disease. Rarely is it a sequel of erythema nodosum. Other "collagen diseases" may coexist with erythema nodosum. Erythema nodosum is its own most common complication. Follow-up studies indicate that over half of the patients have a subsequent attack, and a certain number have recurrent episodes for months to years. The management of erythema nodosum is expectant. In each case the cause should be found and treated. Steroid treatment is rarely justified, and should be used only after tuberculosis and other treatable entities have been ruled out.     

Vitamin A,Pregnancy, and Oral Contraceptives

It has been shown that women receiving oral contraceptives have increased levels of serum vitamin A. High vitamin A levels may constitute a teratogenic hazard and it has been suggested that women who conceive soon after discontinuing oral contraceptive therapy may be especially at risk to this hazard.We have confirmed a significant increase in vitamin A levels in women taking oral contraceptives. During early pregnancy there is no significant difference in vitamin A levels between women who have recently been taking oral contraceptives and those who have not. We have been unable to show that either taking oral contraceptives shortly before pregnancy or a high vitamin A level during the first trimester of pregnancy, comparable to that of a woman taking oral contraceptives, has any detrimental effect on the outcome of pregnancy. It seems unlikely that women who conceive soon after discontinuing oral contraception run any teratogenic risk from increased vitamin A levels.     

Effect of cyclosporine A in erythema nodosum leprosum

Erythema nodosum leprosum (ENL) is a reactional state of lepromatous leprosy in which the loss of suppressor cell function, decrease in suppressor cell numbers, and increase of interleukin 2 production are observed. We reasoned that cyclosporine A (CsA), by opposing these immune responses, could suppress the ENL reaction and restore patients to the quiescent lepromatous state. We tested this hypothesis in vitro by measuring the effect of CsA on M. leprae-triggered suppressor cells. In 24 of 25 patients with ENL, suppressor cell activity was restored by CsA. The target of CsA appeared to be macrophages. These findings are significant in that they provide the first evidence for the potential efficacy of CsA in the treatment of ENL. Preliminary clinical trials indicate a beneficial therapeutic effect associated with increased T suppressor cells in lesions.     

Platelet aggregation during oral contraception

Platelet aggregation has been found to be significantly accelerated with the coagulation-induced Chandler''s tube technique in women taking combined oestrogen-progestin oral contraceptives, though this was less than in the third trimester of pregnancy. Women taking the pure progestogen, chlormadinone acetate, have not shown this change up to the sixth month of study. In contrast the accelerated platelet aggregation resulting from conventional oral contraception became normal one month after changing to the progestogen. There was no change in the platelet aggregation response to adenosine diphosphate (A.D.P.) during oral contraception.     

Blood pressure and contraceptive use

In a survey of 461 women routinely attending family planning clinics those taking oral contraceptives had significantly higher mean systolic and diastolic blood pressures than those using non-hormonal contraception. There appeared to be a dose-response relation of blood pressure to the progestogen component of two oral contraceptives with an identical 30 μg ethinyloestradiol component. This supports the idea that the progestogen as well as the oestrogen component has an aetiological role in the rise in blood pressure. There was a significant correlation of blood pressure with duration of current use of oral contraceptive but not with total duration of use. There was also a significant negative correlation of blood pressure with time since oral contraceptives were last taken, and women who had stopped using oral contraceptives over a month previously had similar blood pressures to those who had never taken them. In women taking oral contraceptives those who had either a history of hypertension in pregnancy or a family history of hypertension had significantly higher mean blood pressures than those who did not. Both systolic and diastolic blood pressures correlated independently with weight and body mass index, but controlling for the effect of this and age did not affect the above relations. No significant differences in mean blood pressures were found between different ethnic groups, and there was no relation of blood pressure to reported marital state, social class, parity, smoking, or alcohol use.Any oral contraceptive that has a less adverse effect on blood pressure has implications for general prescribing policy; thus even small differences in the progestogen contents of low-dose oestrogen pills may be important.     

Pregnancy induced hypertension: evidence for increased cell membrane permeability to sodium.

In a cross sectional study of 137 women of childbearing age (16-40) the effects of normal pregnancy, hypertensive pregnancy, and oral contraceptives on red cell electrolyte content and sodium efflux rates were examined and the results compared with values in a control group of normotensive, non-pregnant women. Efflux rate constants were significantly increased in normotensive pregnancy and in women taking oral contraceptives. This was associated with a significant increase in sodium permeability in the contraceptive group. A much larger increase in sodium permeability and efflux rate constant was seen in the hypertensive group. The results permit a hypothesis that the hormonal changes induced by pregnancy and oral contraceptives increase membrane permeability to sodium and stimulate sodium efflux. The rise in blood pressure associated with use of oral contraceptives may have a similar aetiology to that occurring in pregnancy induced hypertension.     

Lepromatous leprosy in Saudi female from central region

Leprosy is an uncommon disease in Saudi population. Lepromatous leprosy is a most contagious form of leprosy. Erythema nodosum leprosum is an unusual complication of leprosy. We report an unusual case of leprosy from the central region of Saudi Arabia presenting as erythema nodosum leprosum.     

Oral contraceptives,pregnancy, and endogenous oestrogen in gall stone disease--a case-control study.

A case-control study of gall stone disease in women in relation to use of contraceptives, reproductive history, and concentrations of endogenous hormones was undertaken. The study population comprised 200 hospital patients with newly diagnosed gall stone disease, 182 individually matched controls selected from the community, and 234 controls who were patients in hospital. Use of oral contraceptives was associated with an increased risk of developing gall stones among young subjects but a decreased risk among older subjects. The risk of developing gall stone disease increased in association with increasing parity, particularly among younger women. The risk fell with increasing age at first pregnancy, independent of parity. Mean urinary excretion over 24 hours of oestrone, but not of pregnanediol, was significantly (p less than 0.05) greater for postmenopausal patients than controls. The age dependence of the relative risk associated with exposure to oral contraceptives and pregnancy suggests that there are subpopulations of women susceptible to early formation of gall stones after exposure to either oral contraceptives or pregnancy.     

Cytokine patterns of immunologically mediated tissue damage.

Reactional states in leprosy are produced by different immunologic mechanisms and are responsible for a major component of tissue damage of the disease. Reversal reactions exhibit increased CD4 T cell infiltration in lesions and augmented cell-mediated immune reactivity to Ag of Mycobacterium leprae that can rapidly produce nerve damage. Erythema nodosum leprosum (ENL) reactions also have CD4 T cell infiltration but appear to be associated with the formation of immune complexes that are responsible for panniculitis, arthritis, vasculitis, and nerve injury. Because these reactional states may serve as paradigms for other types of human immunologically mediated tissue damage, this study sought to characterize the dynamic changes in cytokines associated with these reactions. Expression of cytokine mRNA in lesions of leprosy reactional states were measured by PCR. In reversal reactions, IL-1 beta, TNF-alpha, IL-2, and IFN-gamma mRNA were prominent and found to increase during the reaction, concomitant with decreases in expression of mRNA for IL-4, IL-5, and IL-10. In ENL, selective increases in the expression of IL-6, IL-8, and IL-10 mRNA was observed, with persistent expression of IL-4 and IL-5 mRNA. Reversal reactions represent naturally occurring delayed-type hypersensitivity reactions that favor macrophage activation and protective immunity, but which can engender concomitant cell injury. In contrast, ENL lesions represent immediate-type hypersensitivity reactions reflecting the selective stimulation of cytokines that attract neutrophils, stimulate antibody production, and down-regulate macrophage activation. The analysis of cytokine dynamics within different inflammatory responses can provide insights into immune mechanisms of tissue damage, and provide a useful framework for developing strategies for therapeutic intervention.     

A current perspective on genetic testing for breast and ovarian cancer: the oral contraceptive decision

A clinician faces a problem in how best to counsel the woman with a family history of breast or ovarian cancer about her options for pregnancy prevention. The physician must guide her as she makes new and complex decisions. Recent data strongly support an amplified effect of the estrogens in oral contraceptives for the woman with a genetic risk for breast cancer. Nonetheless, a woman's immediate need to prevent pregnancy may be much more important to her than worrying about the long-term risk of breast cancer. Another factor is that oral contraceptives prevent ovarian cancer, so the physician may wish to prescribe them to protect her from ovarian cancer. In some genetic backgrounds, however, oral contraceptives not only do not prevent ovarian cancer, but they may raise the risk of breast cancer so significantly that they should not be taken. With other genetic backgrounds, oral contraceptives will protect the woman from ovarian cancer without much effect on her breast cancer risk. When does each of these cancer risks or benefits become significant? The clinician can provide an important benefit to a woman who must prevent pregnancy yet worries about her cancer risk. The physician can help her evaluate the evidence, with its gaps and uncertainties, in the context of her own preferences. To assist in this evaluation, this decision aid provides base-line estimates of the cancer risk that accompanies each of a woman's options. In some cases, genetic testing is likely to provide valuable information as she makes choices about contraception and the risks vs. benefits of different alternatives available to her.     

Recurrence of Venous Thromtoembolic Disease and Use of Oral Contraceptives

In 1969 this department reported on 42 women who had developed “idiopathic” venous thromboembolism while using oral contraceptives and 42 women who had developed the disease in the absence of such exposure. We have traced the subsequent history of these women to obtain information about recurrence of the disease.During the follow-up period the risk of recurrence of thromboembolism during pregnancy or the puerperium appeared to be much the same irrespective of whether or not oral contraceptives had been in use at the time of the index attack. Recurrences unassociated with childbearing however, occurred about four times more often among women who had not been using oral contraceptives at the time of the index attack than among women who had been doing so. None of these findings was influenced by the use of oral contraceptives during the follow-up period, since exposure to the preparations was negligible after the index attack.     

The Mortality Associated with Erythema Nodosum Leprosum in Ethiopia: A Retrospective Hospital-Based Study

Background

Erythema nodosum leprosum (ENL) is a debilitating multisystem disorder which complicates leprosy. It is characterised by fever, malaise and painful erythematous cutaneous nodules. ENL is often recurrent or chronic in nature and frequently severe. Patients often require prolonged treatment with high doses of oral corticosteroids. There are no data on the mortality associated with treated ENL.

Methodology

The notes of patients who were admitted, discharged, transferred to another facility or died with a diagnosis of leprosy or a leprosy-related complication for a five year period were reviewed.

Result/Discussion

414 individuals were identified from the ward database. 312 (75.4%) patient records were located and reviewed. Ninety-nine individuals had ENL and 145 had a Type 1 reaction. The median age of individuals with ENLwas 25 years. Eight patients with erythema nodosum leprosum died compared with two diagnosed with Type 1 reaction. This difference is statistically significant (p = 0.0168, Fisher''s Exact Test). There is a significant mortality and morbidity associated with ENL in this Ethiopian cohort. The adverse outcomes seen are largely attributable to the chronic administration of oral corticosteroids used to control the inflammatory and debilitating symptoms of the condition.     

Oral contraceptives and death from myocardial infarction.

We investigated 219 deaths from myocardial infarction in women under the age of 50. Their histories were compared with those of living age-matched controls selected from the same general practices. The frequency of use of oral contraceptives during the month before death was significantly greater in the group with infarction than during the corresponding month in the control group and the average duration of use was longer. No information of cigarette smoking was available but the proportion of women being treated for hypertension or diabetes was greater among those who died than among the controls. This did not alter the overall conclusion that the risk of fatal myocardial infarction was greater in the women using oral contraceptives, particularly in the older age groups.     

Effect of Oral Contraceptives on Glucuronyl Transferase

ORAL contraceptives can cause a wide spectrum of hepatic abnormalities, from mild bromsulphthalein retention to cholestatic jaundice. In the United States it has been estimated that one woman in 10,000 taking oral contraceptives becomes jaundiced¹. This jaundice is cholestatic in type and is similar to intrahepatic cholestasis of pregnancy. Most oral contraceptives are given as combinations of a synthetic oestrogen and progestogen or oestrogen given alone followed by a combination of oestrogen and progestogen. These substances can act on the liver, which plays a central part in their metabolism, to produce a variety of physiological and pathological effects.     

ENLIST 1: An International Multi-centre Cross-sectional Study of the Clinical Features of Erythema Nodosum Leprosum

Erythema nodosum leprosum (ENL) is a severe multisystem immune mediated complication of borderline lepromatous leprosy and lepromatous leprosy. ENL is associated with skin lesions, neuritis, arthritis, dactylitis, eye inflammation, osteitis, orchitis, lymphadenitis and nephritis. The treatment of ENL requires immunosuppression, which is often required for prolonged periods of time and may lead to serious adverse effects. ENL and its treatment is associated with increased mortality and economic hardship. Improved, evidence-based treatments for ENL are needed; however, defining the severity of ENL and outcome measures for treatment studies is difficult because of the multiple organ systems involved. A cross-sectional study was performed, by the members of the Erythema Nodosum Leprosum International STudy (ENLIST) Group, of patients with ENL attending seven leprosy referral centres in Brazil, Ethiopia, India, Nepal, the Philippines and the United Kingdom. We systematically documented the clinical features and type of ENL, its severity and the drugs used to treat it. Patients with chronic ENL were more likely to be assessed as having severe ENL. Pain, the most frequent symptom, assessed using a semi-quantitative scale was significantly worse in individuals with “severe” ENL. Our findings will determine the items to be included in a severity scale of ENL which we are developing and validating. The study also provides data on the clinical features of ENL, which can be incorporated into a definition of ENL and used for outcome measures in treatment studies.     

Postoperative Thromboembolism and the Use of Oral Contraceptives

We have previously reported the results of a retrospective study of the relationship between oral contraceptives and deep vein thrombosis and pulmonary embolism occurring in the absence of an evident predisposing cause. The present paper describes a similar investigation of the relationship between oral contraceptives and thromboembolism following certain surgical procedures.Of 30 patients with thromboembolism, 12 (40%) had been using oral contraceptives during the month preceding surgery, while only 9 of 60 matched controls (15%) had been doing so. From these data it is estimated that the risk of postoperative thromboembolism is increased threefold to fourfold by the use of contraceptive steroids.It is recognized that few of the episodes of deep vein thrombosis and pulmonary embolism that occur postoperatively are detectable clinically, and that not all of these are recorded in discharge summaries or diagnostic indexes. Despite these considerations, we have been unable to detect any important bias in the data which could account for the observed association between oral contraceptives and the development of postoperative thromboembolism.     

Effects of Low-dose Oral Contraceptives on Blood Coagulation

A study has been performed on the effect of Norinyl-1 and Ortho-Novin, two low-dose oral contraceptives, on blood-clotting factors. Ortho-Novin contains twice the amount of hormone as Norinyl-1. It was therefore possible to observe whether any changes detected were related to the dose of oestrogen-progestin combination. The women were tested in parallel with matched normal female controls and a group in the third trimester of pregnancy. Significant rises in factor VII and X levels were found with both low-dose preparations from the third month onwards. There was no difference between patients on Norinyl-1 and Ortho-Novin, and hence the clotting changes do not appear to be dose-dependent. The long-term effects on clotting factors of these low-dose oral contraceptive preparations remain to be investigated.     

Thalidomide in the treatment of leprosy

Leprosy is a chronic infection of the skin and nerves caused by Mycobacterium leprae. Erythema nodosum leprosum (ENL) is a reactive state in lepromatous leprosy. Thalidomide has been used to treat ENL since the 1960s. One of its mechanisms of action is anti-inflammatory through selective inhibition of the pro-inflammatory cytokine TNF-alpha produced by monocytes.     

Oral Contraceptives,Depression, and Libido

Depression, headaches, and libido were rated in 272 women before starting a contraceptive method and at intervals during the first year of use—54 were fitted with an intrauterine device (I.U.D.) and 218 used one of three oral contraceptives. Side effects caused 25% of the oral contraceptive group and 13% of the I.U.D. group to stop the method. Depression, headaches, and loss of libido were the most common reasons for stopping oral contraceptives and breakthrough bleeding was the most common reason for stopping the I.U.D.The group of women who stopped or changed their oral contraceptives during the survey were compared with the group who remained on the same oral contraceptive throughout. The former had higher mean depression and neuroticism scores at the first clinic visit and contained more women with a history of premenstrual weepiness, depression during pregnancy, outpatient psychiatric treatment, and treatment with antidepressants. Changes in the depression, headache, and libido ratings throughout the survey are presented.