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Contraceptive Recommendations for Women with Immune-Mediated Inflammatory Diseases: A Delphi Consensus
Abstract
Immune-mediated inflammatory diseases (IMID) are a group of disorders characterized by chronic inflammation caused by an altered immune regulation in targeted organs or systems. IMID itself could have an implied increased risk of venous thromboembolism (VTE) and this risk varies throughout the course of the disease as well as with some contraceptive methods and treatments. The aim of this study was to present some key considerations in relation to contraception in women with IMID.
This was an exploratory study conducted in Spain following the online modified Delphi methodology with two rounds of participation. Four questionnaires were designed for each medical specialty: gastroenterology, rheumatology, dermatology, and gynecology. Each questionnaire was divided in three domains: general recommendations about IMID, specific recommendations, and contraceptive methods for patients with IMID. A 5-point Likert scale measured agreement with each statement, with an 80% agreement threshold. Following the first round, the percentage of each response was calculated for every item. Subsequently, a second round was conducted to reach a consensus on the items for which discrepancies were observed.
A total of 52 and 50 experts participated in the first and second round, respectively. Participants agreed on the existence of a higher risk of VTE in inflammatory bowel diseases, psoriasis, and rheumatoid arthritis diseases. Regarding recommendations for contraceptive methods in patients with IMID, experts considered the hormonal intrauterine device (IUD) as a first-line contraceptive (80.0%) and low doses of progesterone-only pills if the latter is not recommended (88.0%). Most of the interviewees concurred on the importance of the patients’ contraceptive needs during the disease course (98.1%).
Raising awareness and promoting a multidisciplinary relationship among the physicians involved in the therapeutic decisions by considering all the risk factors when prescribing a contraceptive method is important to prevent VTE in women with IMID.
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Atopic dermatitis (AD) is a chronic and recurrent inflammatory skin disease that could be associated with cardiovascular diseases (CVDs). Interest in determining whether the chronic inflammation of AD is a risk factor for CVD has been growing in recent years, although there are few studies available on this topic, and the results are quite controversial. The purpose of this scoping review was to understand whether severe atopic dermatitis and its chronic systemic inflammatory process contribute, or not, as a risk factor for the development of CVD. Following the development of a study protocol, a scoping review was carried out based on the structure outlined by Arksey and O'Malley, Levac et al., the Joanna Briggs Institute and the PRISMA-ScR guidelines. PubMed, Cochrane, EMBASE, CINAHL, LILACS, Web of Science, Biblioteca Virtual em Saúde (BVS), Scopus and SciELO were the selected databases. Results: Fifty-two studies were included in this review (18 review studies, 16 cross-sectional studies, 15 cohort studies and three meta-analyses). We found that 36 studies could associate AD with CVD, while 16 studies found no relationship between AD and CVD. Conclusions: It is possible that cardiovascular risk in moderate to severe atopic disease is in confounding factors, and not necessarily because AD and CVDs share the same chronic systemic inflammatory pathway. There is no robust evidence that AD is a risk factor for CVD. To reduce CVD risk in patients with AD, we must pay attention to the risk factors commonly present in these patients and strongly recommend a healthy lifestyle.
Current medical treatment for inflammatory bowel disease (IBD) does not achieve 100% response rates, and a subset of refractory and severely ill patients have persistent active disease after being treated with all possible drug alternatives. The combination of two biological therapies (CoT) seems a reasonable alternative, and has been increasingly tested in very difficult cases. The present review suggests that CoT seems to be safe and effective for refractory and severely ill IBD patients. Ustekinumab plus vedolizumab and vedolizumab plus anti-TNF were the most used CoTs for Crohn’s disease. For ulcerative colitis, the most used CoTs were vedolizumab plus anti-TNF and vedolizumab plus tofacitinib. The aforesaid CoTs have shown good efficacy and few adverse events have been reported.
[This corrects the article DOI: 10.3389/fimmu.2021.714026.].
Many factors must be considered and discussed with women when initiating a contraceptive method and the risk of venous thromboembolism (VTE) is one of them. In this review, we discuss the numerous strategies that have been implemented to reduce the thrombotic risk associated with combined oral contraceptives (COCs) from their arrival on the market until today. Evidences suggesting that COCs were associated with an increased risk of VTE appeared rapidly after their marketing. Identified as the main contributor of this risk, the dosage of the estrogen, i.e., ethinylestradiol (EE), was significantly reduced. New progestins were also synthetized (e.g., desogestrel or gestodene) but their weak androgenic activity did not permit to counterbalance the effect of EE as did the initial progestins such as levonorgestrel. Numerous studies assessed the impact of estroprogestative combinations on hemostasis and demonstrated that women under COC suffered from resistance towards activated protein C (APC). Subsequently, the European Medicines Agency updated its guidelines on clinical investigation of steroid contraceptives in which they recommended to assess this biological marker. In 2009, estradiol-containing COCs were marketed and the use of this natural form of estrogen was found to exert a weaker effect on the synthesis of hepatic proteins compared to EE. In this year 2021, a novel COC based on a native estrogen, i.e., estetrol, will be introduced on the market. Associated with drospirenone, this preparation demonstrated minor effects on coagulation proteins as compared with other drospirenone-containing COCs. At the present time, the standard of care when starting a contraception, consists of identifying the presence of hereditary thrombophilia solely on the basis of familial history of VTE. This strategy has however been reported as poorly predictive of hereditary thrombophilia. One rationale and affordable perspective which has already been considered in the past could be the implementation of a baseline screening of the prothrombotic state to provide health care professionals with objective data to support the prescription of the more appropriate contraceptive method. While this strategy was judged too expensive due to limited laboratory solutions, the endogenous thrombin potential-based APC resistance assay could now represent an interesting alternative.
IntroductionAtopic dermatitis (AD) is a systemic inflammatory condition that may increase the risk of cardiovascular disease (CVD); however, ongoing debate exists surrounding its direct association. We aimed to elucidate whether AD contributes to a higher incidence of CVD and major adverse cardiovascular events (MACE) in adult patients with AD, independent of metabolic disorders.Methods
We retrospectively analyzed a large US-based population of patients with AD (≥ 18 years of age). Logistic regression estimated the risk of CVD and MACE in adult patients with AD, independent of metabolic disorders (including diabetes, hypertension, and obesity).ResultsThe odds ratio (OR; 95% confidence interval [CI]) for patients without metabolic disorders was 1.25 (1.13, 1.39) for CVD and 1.22 (1.01, 1.47) for MACE. The OR (95% CI) for AD patients with metabolic disorders was 1.09 (1.07, 1.12) for CVD and 1.14 (1.09, 1.18) for MACE. This trend was even more pronounced after long-term follow-up (≥ 3 years). Lifestyle and health behavioral factors of the subjects were not available in the dataset. The lack of control for these factors could potentially confound our results.Conclusions
Atopic dermatitis may contribute to the risk of developing CVD and MACE in adults, independent of metabolic disorders.
Patients with inflammatory bowel disease (IBD) are at increased risk of thrombotic events. Therapies for IBD have the potential to modulate this risk. The aims of this Evidence-Based Guideline were to summarize available evidence and to provide practical recommendations regarding epidemiological aspects, prevention and drug-related risks of venous and arterial thrombotic events in patients with IBD. A virtual meeting took place in May 2020 involving 14 international IBD experts and 3 thrombosis experts from 12 countries. Proposed statements were voted upon in an anonymous manner. Agreement was defined as at least 75% of participants voting as ‘fully agree’ or ‘mostly agree’ with each statement. For each statement, the level of evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) grading system. Consensus was reached for 19 statements. Patients with IBD harbour an increased risk of venous and arterial thrombotic events. Thromboprophylaxis is indicated during hospitalization of any cause in patients with IBD. Disease activity is a modifiable risk factor in patients with IBD, and physicians should aim to achieve deep remission to reduce the risk. Exposure to steroids should be limited. Antitumour necrosis factor agents might be associated with a reduced risk of thrombotic events.
Rheumatoid arthritis (RA) is a systemic poly-articular chronic autoimmune joint disease that mainly damages the hands and feet, which affects 0.5% to 1.0% of the population worldwide. With the sustained development of disease-modifying antirheumatic drugs (DMARDs), significant success has been achieved for preventing and relieving disease activity in RA patients. Unfortunately, some patients still show limited response to DMARDs, which puts forward new requirements for special targets and novel therapies. Understanding the pathogenetic roles of the various molecules in RA could facilitate discovery of potential therapeutic targets and approaches. In this review, both existing and emerging targets, including the proteins, small molecular metabolites, and epigenetic regulators related to RA, are discussed, with a focus on the mechanisms that result in inflammation and the development of new drugs for blocking the various modulators in RA.
Background: Patients suffering from chronic inflammatory disorders, such as inflammatory bowel disorder, are at higher risk of developing thromboembolism. The chronic inflammatory nature of inflammatory bowel disease has been identified as a predominant reason for a state of Virchow's triad (i.e., endothelial dysfunction, stasis, and general hypercoagulability), eventually leading to the onset of venous thromboembolism. Recent studies show that certain factors, such as demographics, medication history, and history of surgical intervention may increase thromboembolism risk in patients with inflammatory bowel disease. However, to date, no study has attempted to evaluate the effect of different risk factors associated with the development of venous thromboembolism in inflammatory bowel disease patients.
Objective: To evaluate the risk factors that can influence the incidence of venous thromboembolism in patients with inflammatory bowel disease.
Methods: Academic literature was systematically searched based on the PRISMA guidelines across five databases: Web of Science, EMBASE, CENTRAL, Scopus, and MEDLINE. A random-effect meta-analysis was conducted to evaluate the hazard ratio for the risk factors (i.e., aging, gender, steroid therapy, surgery, and ulcerative colitis) that can influence the incidence of venous thromboembolism in patients with inflammatory bowel disease.
Results: From a total of 963 studies, 18 eligible studies with 1,062,985 (44.59 ± 10.18 years) patients suffering from inflammatory bowel disease were included in the review. A meta-analysis revealed a higher risk of aging (Hazard's ratio: 2.19), steroids (1.87), surgery (1.48), and ulcerative colitis (2.06) on venous thromboembolism in patients with inflammatory bowel disease. We also found that the female gender (0.92) did not increase the incidence of venous thromboembolism in inflammatory bowel disease patients.
Conclusion: The study provides preliminary evidence regarding high risks associated with ulcerative colitis, steroid consumption, and aging for the development of venous thromboembolism in patients with inflammatory bowel disease. The findings from this study may contribute to developing awareness among clinicians, better risk stratification and prevention of venous thromboembolic complications in patients with inflammatory bowel disease.
Background and Aims
Although venous thromboembolism (VTE) is a well-known complication of inflammatory bowel disease (IBD) in adults, limited data exist on the risk in children. We report the incidence of VTE among children with and without IBD.
Methods
We conducted a matched cohort study within a distributed network of population-based Canadian provincial health administrative databases. Children diagnosed with IBD <16 years were identified using validated algorithms from administrative data in Alberta, Manitoba, Nova Scotia, Ontario, and Québec and compared to age- and sex-matched children without IBD. Hospitalizations for VTE within five years of IBD diagnosis were identified. Generalized linear mixed-effects models were used to pool province-specific incidence rates and incidence rate ratios (IRR) with 95% confidence intervals (CI). Hazard ratios (HR) from Cox proportional hazards models were pooled with fixed-effects meta-analysis.
Results
The five-year incidence of VTE among 3593 children with IBD was 31.2 (95%CI 23.7-41.0) per 10,000 person-years (PY) compared to 0.8 (95%CI 0.4-1.7) per 10,000 PY among 16,289 children without IBD (unadjusted IRR 38.84, 95%CI 16.59-90.83; adjusted HR 22.91, 95%CI 11.50-45.63). VTE was less common in Crohn’s disease than ulcerative colitis (unadjusted IRR 0.47, 95%CI 0.27-0.83; adjusted HR 0.52, 95%CI 0.29-0.94). Findings were similar for deep vein thrombosis (DVT) and pulmonary embolism (PE) when comparing children with and without IBD.
Conclusions
The risk of VTE is much higher in children with IBD than controls without IBD. While the absolute risk is low, we found a higher incidence rate than previously described in the pediatric literature.
Introduction:
Atopic dermatitis (AD) is associated with risk factors for venous thromboembolism (VTE). However, the risk of VTE among this population is unknown. The aim of this study was to assess the risk of VTE among adults with AD and compare the risk vs. matched non-AD controls.
Methods:
This retrospective study used claims data from the IBM Watson MarketScan® Commercial Claims and Encounters, Medicare Supplemental, and Medicaid databases to identify adults aged 18 years or older with AD. Incidence rates (IR) per 100 person-years (PY) of VTE were reported for three cohorts: overall AD, moderate-to-severe AD, and non-AD controls matched by age, sex, and calendar time to the overall cohort. Cox proportional hazards regression was used to estimate hazard ratios (HR) for VTE risk.
Results:
Overall, 198,685 patients with AD were identified. Crude VTE IRs were 0.24 for AD overall, 0.31 for moderate-to-severe AD, and 0.25 for non-AD controls. VTE risk was similar in patients with AD vs. non-AD controls (partially adjusted HR 1.00, 95% confidence interval [CI] 0.92, 1.09). VTE risk was greater in patients with moderate-to-severe AD vs. non-AD controls in partially adjusted models (HR 1.24, 95% CI 1.13, 1.36), but not after adjustment for healthcare use and VTE risk factors (HR 0.95, 95% CI 0.85, 1.07).
Conclusions:
AD was not an independent risk factor for VTE, and the risk of VTE among patients with AD was low. These findings provide valuable context for understanding VTE risk among patients with AD, which is particularly relevant as advanced therapies for the treatment of moderate to severe AD, such as janus kinase inhibitors, become available.
Estrogens and progestogens influence the bone. The major physiological effect of estrogen is the inhibition of bone resorption whereas progestogens exert activity through binding to specific progesterone receptors. New estrogen-free contraceptive and its possible implication on bone turnover are discussed in this review. Insufficient bone acquisition during development and/or accelerated bone loss after attainment of peak bone mass (PBM) are 2 processes that may predispose to fragility fractures in later life. The relative importance of bone acquisition during growth versus bone loss during adulthood for fracture risk has been explored by examining the variability of areal bone mineral density (BMD) (aBMD) values in relation to age. Bone mass acquired at the end of the growth period appears to be more important than bone loss occurring during adult life. The major physiological effect of estrogen is the inhibition of bone resorption. When estrogen transcription possesses binds to the receptors, various genes are activated, and a variety modified. Interleukin 6 (IL-6) stimulates bone resorption, and estrogen blocks osteoblast synthesis of IL-6. Estrogen may also antagonize the IL-6 receptors. Additionally, estrogen inhibits bone resorption by inducing small but cumulative changes in multiple estrogen-dependent regulatory factors including TNF-α and the OPG/RANKL/RANK system. Review on existing data including information about new estrogen-free contraceptives. All progestins exert activity through binding to specific progesterone receptors; hereby, three different groups of progestins exist: pregnanes, gonanes, and estranges. Progestins also comprise specific glucocorticoid, androgen, or mineralocorticoid receptor interactions. Anabolic action of a progestogen may be affected via androgenic, anti-androgenic, or synadrogenic activity. The C 19 nortestosterone class of progestogens is known to bind with more affinity to androgen receptors than the C21 progestins. This article reviews the effect of estrogens and progestogens on bone and presents new data of the currently approved drospirenone-only pill. The use of progestin-only contraceptives leading to an estradiol level between 30 and 50 pg/ml does not seem to lead to an accelerate bone loss.
Objectives
To assess incidence rates (IRs) of VTE in patients with rheumatoid arthritis (RA) on different DMARDs and DMARD switchers.
Methods
Adults with RA on a DMARD between 2007 and 2017 were studied in a US claims database. Conventional synthetic DMARD (csDMARD) users, first biologic/targeted synthetic DMARD (b/tsDMARD) users and b/tsDMARD switchers (from a b/tsDMARD to another b/tsDMARD) were followed for inpatient VTE (pulmonary embolism (PE)/deep vein thrombosis (DVT)). Crude and adjusted IR and 95% CIs of VTE were estimated. HRs for VTE were estimated via Cox regression. VTE risk was also evaluated by number of switches between b/tsDMARDs and in patients without a VTE history.
Results
The age and sex standardised IR (95% CI) of VTE (per 100 person-years) was 0.86 (0.70 to 1.03), 0.60 (0.52 to 0.68) and 0.58 (0.51 to 0.65) for b/tsDMARD switchers, first b/tsDMARD users and csDMARD users, respectively. After adjustment, b/tsDMARD switchers had an increased risk of VTE, compared with csDMARD users, HR adj (95% CI) being 1.36 (1.16 to 1.58), 1.36 (1.13 to 1.63) and 1.47 (1.18 to 1.83) for VTE, DVT and PE, respectively. Compared with first b/tsDMARD users, the HR adj (95% CI) for VTE was 1.35 (1.15 to 1.60) for first b/tsDMARD switchers and 1.48 (1.19 to 1.85) for second b/tsDMARD switchers.
Conclusions
In RA, b/tsDMARD switchers have a higher VTE risk compared with csDMARD users and first b/tsDMARD users. Switching b/tsDMARDs may be a proxy for higher disease severity or poorly controlled RA and an important confounder to consider in obtaining unbiased estimates of VTE risk in observational RA safety studies.
Pregnancy presents challenges for women with autoimmune diseases it is associated with significant physiological hormonal and immunomodulatory changes which are complex and vary according to the stage of pregnancy:
Pregnancy planning and counselling should be offered:
Autoimmune diseases such as rheumatoid arthritis tend to improve in pregnancy while systemic lupus erythematosus may increase in activity:
During pregnancy the chosen regimen should control or prevent underlying disease activity and minimise risk to the fetus ideally women should be on a stable regimen before conception:
Poorly controlled disease is associated with poor outcomes for both mother and fetus such as higher risks of pre-eclampsia early delivery and growth restriction of the fetus:
Postpartum there is a sudden fall in hormone concentrations and a switch to a pro-inflammatory state this increases the risk of relapse of many autoimmune diseases in particular rheumatoid arthritis crohn’s disease and autoimmune hepatitis:
Many drugs are compatible with breastfeeding but there are limited data on many of the new drugs:
Objective:
Immune-mediated inflammatory diseases (IMID) are chronic and highly disabling diseases that share inflammatory sequences and immunological dysregulations. Considered as a disease in itself, the prevalence of IMID is virtually unknown. The aim of this study was to assess the prevalence of 10 selected UDI, including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, hidradenitis suppurativa, sarcoidosis and uveitis in Spain.
Methods:
cross-sectional epidemiological study of point prevalence was made. This study was carried out through a series of computerized interviews in households chosen at random in 17 autonomous communities in Spain. A structured questionnaire was used to determine the frequency of diagnosis and the concurrence of 10 IMID in the respondents and other individuals belonging to the same family nucleus. The point prevalence estimates were used and compared with the objective of determining the frequency of IMID by age, sex and communities. The data were processed using Excel 2016 (Microsoft, Redmond, WA, USA) and the SPSS V.019 system (IBM Corp. Armonk, NY, USA) for statistical analysis using the usual statistical tests in this type of studies.
Results:
Of the 7,980 respondents, 510 were diagnosed with an IMID, representing a cross-sectional study of 6.39% (95% CI: 6.02-6.76). One, two, three or more members of the family were affected in 87.2%, 7.8% and 5% of positive relatives in IMID, respectively. The most recurrent diseases were psoriasis (2.69% [95% CI: 2.32-3.06]) and rheumatic arthritis (1.07% [95% CI: 0.70-1.44]). There were differences in prevalence due to sex (p = 0.004) and age (p = 0.000). No significant differences were identified related to geographic location (p = 0.819). Attendance of at least 2 IMID was reported in 8.9% of respondents.
Conclusions:
The overall prevalence was of the IMID studied was 6.39%, psoriasis being the most frequent with 2.69%. This study constitutes an initial step to consider IMID as an independent disease within the health system..
Immune-mediated inflammatory diseases (IMIDs) are characterised by dysregulation of the normal immune response, which leads to inflammation. Together, they account for a high disease burden in the population, given that they are usually chronic conditions with associated co-morbidities. Examples include systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease and type 1 diabetes. Since the advent of genome-wide association studies, evidence of considerable genetic overlap in the loci predisposing to a wide range of IMIDs has emerged. Understanding the genetic risk and extent of genetic overlap between IMIDs may help to determine which genes control which aspects of the different diseases; it may identify potential novel therapeutic targets for a number of these conditions, and/or it may facilitate repurposing existing therapies originally developed for different conditions. The findings show that autoantibody-mediated autoimmune diseases cluster more closely with each other than autoantibody-negative diseases such as psoriasis, psoriatic arthritis, Crohn's disease and ankylosing spondylitis, which instead form a seronegative genetic cluster. The genetic clustering largely mirrors the known response to existing biologic therapies, but apparent anomalies in treatment response are discussed. This article is protected by copyright. All rights reserved.
Objectives
To examine the independent effect of hydroxychloroquine (HCQ) treatment on cardiovascular morbidity among RA patients.
Materials and Methods
A retrospective cohort study of RA patients treated at Meir medical center between 2003-2013 was conducted. Patients were divided into two groups, those who had been treated with HCQ during the course of their disease and those who had never received it. The two groups were compared for possible confounding factors. Study endpoints included arterial and venous thrombotic events.
Results
A total of 514 suitable RA patients were identified, 241 HCQ-treated and 273 non-treated patients. Of the HCQ-treated patients, 32 (13.3%) suffered from cardiovascular events compared to 104 (38.1%) of the non-treated group. HCQ treatment had a significant protective effect for all cardiovascular events examined (HR = 0.456 CI 0.287 to 0.726) as well as arterial events alone (HR = 0.461 CI 0.274 to 0.778). A dose of 400 mg HCQ per day demonstrated a protective effect for any cardiovascular event (HR = 0.432 CI 0.243 to 0.768), while the lower dose of 200 mg per day showed no significant protective effect.
Conclusions
The use of HCQ is independently associated with decreased risk for cardiovascular morbidity among RA patients, particularly with a higher dose of 400 mg per day. This newly demonstrated effect of HCQ should be considered in the overall management of RA.
Background and aim:
Inflammatory bowel disease [IBD] is associated with 1.5- to 3-fold increased risk of venous thromboembolic events [VTE]. The aim of this study was to determine the risk of VTE in IBD as a complication of systemic corticosteroids and anti-tumor necrosis factor alpha [TNFα] therapies.
Methods:
A systematic review and meta-analysis was conducted, which conforms to the Preferred Reporting Items for Systematic Reviews and Meta-analyses [PRISMA] statement. PubMed, EMBASE, Cochrane Library, and Web of Science were searched for English-language studies published from inception inclusive 15 April 2017. The population-intervention-comparison-outcome [PICO] format and statistically the random-effects and fixed-effect models were used to compare VTE risk during steroid and anti-TNFα treatment. Quality of the included studies was assessed using the Newcastle-Ottawa scale. PROSPERO registration number is 42017070084.
Results:
We identified 817 records, of which eight observational studies, involving 58,518 IBD patients, were eligible for quantitative synthesis. In total, 3,260 thromboembolic events occurred. Systemic corticosteroids were associated with a significantly higher rate of VTE complication in IBD patients as compared to IBD patients without steroid medication [OR: 2.202; 95% CI: 1.698-2.856, p < 0.001]. In contrast, treatment with anti-TNFα agents resulted in a 5-fold decreased risk of VTE compared to steroid medication [OR: 0.267; 95% CI: 0.106-0.674, p = 0.005].
Conclusion:
VTE risk should be carefully assessed and considered when deciding between anti-TNFα and steroids in the management of severe flare-ups. Thromboprophylaxis guidelines should be followed, no matter the therapy choice.
The transdermal patch provides an effective and convenient option for hormonal contraception. The patch currently on the US market contains 150 µg norelgestromin and 35 µg ethinylestradiol (EE). The 20 cm² patch is applied once weekly for 3 weeks, followed by a patch-free week, for a 21–7 cycle. Typical failure rates are similar to that of combined oral contraceptives (COCs). Transdermal delivery results in less peaks and troughs of estrogen, but a higher total estrogen exposure compared with COCs. Though studies show mixed results, the risk of developing venous thromboembolism (VTE) is about twice as high with the patch as with COCs; however, the absolute risk of VTE remains low. The side effect profile is similar to that of COCs, with slightly higher rates of breast tenderness plus a unique adverse effect of application site reactions. Two new patches have been developed, one containing gestodene and EE in Europe and another containing levonorgestrel and EE. Overall, the patch provides an alternative to COCs for women who want autonomy and the benefit of not needing to take a pill daily, with similar efficacy and tolerability.
Background:
Persons with inflammatory bowel disease (IBD) have an increased risk of venous thromboembolism. We sought to examine whether the self-report of hormonal contraception (HC), as a proxy for exposure to estrogen-based contraception, was less common for women with multiple risk factors for venous thromboembolism.
Methods:
We examined the prevalence of personal use of hormonal birth control in a large internet-based cohort of patients with IBD. To determine whether HC was less common among patients with IBD with increased risk of thrombosis, we estimated unadjusted and adjusted prevalence ratios (PRs) for the use of HC.
Results:
Thousand four hundred ninety-nine female survey respondents answered optional fertility questions and were included in the analysis. The prevalence of HC was 33.7% (95% CI, 30.6%-36.9%) among women with Crohn's disease and was 32.6% (95% CI, 28.6%-36.8%) for women with ulcerative colitis. Women with one risk factor for thrombosis were not significantly less likely to receive HC (PR = 0.91, 95% CI: 0.76-1.08; adjusted PR = 0.94, 95% CI: 0.80-1.11) compared with women without risk factors nor were women with 2 or more risk factors (PR = 1.10, 95% CI 0.56-1.28; adjusted PR = 1.10, 95% CI: 0.83-1.45). The use of an intrauterine device was also similar between women with and without risk factors for venous thromboembolism.
Conclusions:
The prevalence of HC use in women with multiple risk factors was similar to that in women without risk factors, which represents an opportunity for prevention. Gastroenterologists should ask patients with IBD using HC about risk factors for thromboembolic disease to identify patients who may benefit from alternative contraception.
Background:
Methotrexate (MTX) has been used to treat psoriasis for over half a century. Even so, clinical data characterising its efficacy and safety are sparse.
Objective:
In order to enhance the available evidence, we conducted two meta-analyses, one for efficacy and one for safety outcomes, respectively, according to PRISMA checklist. (Data sources, study criteria, and study synthesis methods are detailed in Methods).
Results:
In terms of efficacy, only eleven studies met criteria for study design and passed a Cochrane risk of bias analysis. Based on this limited dataset, 45.2% [95% confidence interval 34.1-60.0] of patients achieve PASI75 at primary endpoint (12 or 16 weeks, respectively, n = 705 patients across all studies), compared to a calculated PASI75 of 4.4 [3.5-5.6] for placebo, yielding a relative risk of 10.2 [95% C.I. 7.1-14.7]. For safety outcomes, we extended the meta-analysis to include studies employing the same dose range of MTX for other chronic inflammatory conditions, e.g. rheumatoid arthritis, in order not to maximise capture of relevant safety data. Based on 2763 patient safety years, adverse events (AEs) were found treatment limiting in 6.9 ± 1.4% (mean ± s.e.) of patients treated for six months, with an adverse effect profile largely in line with that encountered in clinical practice. Finally, in order to facilitate prospective clinical audit and to help generate long-term treatment outcomes under real world conditions, we also developed an easy to use documentation form to be completed by patients without requirement for additional staff time.
Limitations:
Meta-analyses for efficacy and safety, respectively, employed non-identical selection criteria.
Conclusions:
These meta-analyses summarise currently available evidence on MTX in psoriasis and should be of use to gauge whether local results broadly fall within outcomes.
The close relationship between inflammation and thrombosis affects the progression and severity of inflammatory bowel disease (IBD). The prevalence of venous thromboembolism (VTE) varies between 1% and 7% among patients with IBD. The VTE risk in patients with IBD is at least 3 times higher than that in the normal general population. The absolute risk is very high during hospitalization, active disease, and surgery. The IBD-related VTE occurs at younger ages and recurs more frequently. The development of thrombosis in IBD is due to the interaction of many hereditary and acquired risk factors. Each patient diagnosed with IBD should be evaluated for a personal and family history of thrombosis and for prothrombotic drug use. Although procoagulant factors are increased during the natural course of inflammation, natural anticoagulants and fibrinolytic activity are decreased. Although IBD is accepted as a prothrombotic condition, there is no treatment that can remove this risk from daily practice. Patient training is required to control important factors, such as long-term immobilization and smoking. Oral contraceptives and hormone replacement therapy should be avoided. Inducing permanent disease remission must be the key approach for the prevention of thrombosis. Low-molecular-weight heparin (LMWH) is the basis of prophylactic treatment, which reduces the thrombosis risk by 50%. Prophylaxis with LMWH should be administered to all patients with IBD hospitalized due to disease attack or surgery. Long-term or even life-long anticoagulation therapy should be planned if there is insufficient disease control, recurrent VTE attacks, positive thrombophilia tests, or thrombosis in vital veins.
Thrombophilias are hereditary and/or acquired conditions that predispose patients to thrombosis. Testing for thrombophilia is commonly performed in patients with venous thrombosis and their relatives; however such testing usually does not provide information that impacts management and may result in harm. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance for thrombophilia testing in five clinical situations: following 1) provoked venous thromboembolism, 2) unprovoked venous thromboembolism; 3) in relatives of patients with thrombosis, 4) in female relatives of patients with thrombosis considering estrogen use; and 5) in female relatives of patients with thrombosis who are considering pregnancy. Additionally, guidance is provided regarding the timing of thrombophilia testing. The role of thrombophilia testing in arterial thrombosis and for evaluation of recurrent pregnancy loss is not addressed. Statements are based on existing guidelines and consensus expert opinion where guidelines are lacking. We recommend that thrombophilia testing not be performed in most situations. When performed, it should be used in a highly selective manner, and only in circumstances where the information obtained will influence a decision important to the patient, and outweigh the potential risks of testing. Testing should not be performed during acute thrombosis or during the initial (3-month) period of anticoagulation.
Objective:
Rheumatoid arthritis (RA) is associated with cardiovascular disease (CVD), but little is known about its association with another form of vascular disorder, venous thromboembolism (VTE).
Methods:
A retrospective cohort study was conducted using US insurance claims. RA and non-RA patients were matched on age, sex, and index date. Incidence rates (IRs) and rate ratios (RRs) of VTE, defined as the composite of deep vein thrombosis (DVT) or pulmonary embolism (PE), were calculated. Cox proportional hazards models compared VTE risks between RA and non-RA patients, adjusting for VTE risk factors such as CVD, surgery, hospitalization, medications, and acute-phase reactants.
Results:
Over the mean followup of 2 years, the IR for VTE among RA patients was 6.1 per 1,000 person-years, 2.4 times higher (95% confidence interval [95% CI] 2.1-2.8) than the rate of non-RA patients. The IRs for both DVT (RR 2.2, 95% CI 1.9-2.6) and PE (RR 2.7, 95% CI 2.2-3.5) were higher in RA patients compared with non-RA patients. After adjusting for risk factors of VTE, the VTE risk remained elevated in RA patients (hazard ratio 1.4, 95% CI 1.1-1.7) compared to non-RA patients. The result was similar after further adjustment for elevated acute-phase reactants (hazard ratio 1.5, 95% CI 0.3-6.5). One-third of patients who developed VTE had at least 1 major VTE risk factor 90 days before and after the VTE event.
Conclusion:
Our results showed an increased risk of developing VTE for RA patients compared with non-RA patients. The risk was attenuated but remained elevated even after adjusting for various risk factors for VTE.
Targeted biologic therapies have revolutionised treatment of immune-mediated inflammatory diseases (IMIDs) due to their efficacy, speed of onset and tolerability. The discovery that clinically unrelated conditions, such as rheumatoid arthritis and Crohn's disease, share similar immune dysregulation has led to a shift in the management of IMIDs from one of organ-based symptom relief to mechanism-based treatment. The fact that anticytokine therapy has been effective in treating multiple orphan inflammatory conditions confirms the IMID paradigm. In this review we examine the biologic agents currently licensed for use in the US and Europe: infliximab, etanercept, adalimumab, rituximab, abatacept, anakinra, alefacept and efalizumab. We also discuss the rationale behind the management of IMIDs using rheumatoid arthritis, Crohn's disease, psoriasis and psoriatic arthritis as examples. For the medical profession, IMID represents a breakthrough in the way pathology is classified. In this burgeoning era of biologic therapy the prospect of complete disease remission is conceivable.
Immune-mediated inflammatory diseases are common and clinically diverse. Although they are currently incurable, the therapeutic armamentarium for immune-mediated inflammatory diseases has been transformed in the past two decades. We have moved from the wide application of broad-spectrum immune modulators to the routine use of agents with exquisite specificity, arising from monoclonal and molecular biotechnology and more recently from highly targeted medicinal chemistry. Here we describe key advances and lessons that drove this remarkable progress and thereafter reflect on the next steps in this ongoing journey. In this Perspective, McInnes and Gravallese highlight the remarkable progress made over the past 20 years in treating immune-mediated inflammatory diseases. The available therapies have progressed from broad-spectrum immune modulators to highly targeted biological and small-molecule agents as our understanding of disease mechanisms has advanced.
Rheumatoid arthritis (RA) is a chronic autoimmune joint disease with persistent systemic inflammation. Patients with RA suffer from joint pain and physical disability, but have their prognosis mostly driven by cardiovascular events, including venous thromboembolism (VTE). The risk of VTE is more than double in patients with RA compared with the general population. The incidence rate in patients with RA is estimated around 4 cases per 1000 person-years. The etiology of thrombotic tendency in RA is linked to various mechanisms and causal factors (antiphsolpholid antibodies, hyperhomocyteinemia, inflammation…): vascular injury, hypercoagulation, and venous stasis, the three components of the Virchow’s triad, are activated in patients with RA. In clinical practice, situations that put patients for VTE should be identified (e.g., surgery, first year after RA diagnosis, hospitalization for acute illness…). Patients with RA are exposed to reversible risk factors, such as major surgery (knee or hip surgery) or hospitalization with immobilization. Similarly, uncontrolled RA, which is defined by the necessity to switch a biological disease-modifying anti-rheumatic drugs (DMARD), increases the incidence of VTE in observational studies. Moreover, DMARDs may impact the risk of VTE, especially in the time window after first prescription. Several biological DMARDs like tofacitinib have been associated with an increased risk of VTE. Therefore, patients with RA may require specific measures in terms of VTE diagnosis and management. In this review, we provide current insights into the pathophysiology, epidemiology, clinical considerations, and treatment strategies of VTE highlighting gaps in evidence and perspectives in patients with RA.
Fundamentos:
Aunque la práctica de actividad física (AF) tiene múltiples beneficios, el 30% de personas son inactivas. Cataluña impulsó el Día Mundial de la actividad física (DMAF) como parte de una estrategia más amplia de promoción de la AF. Este trabajo tuvo como objetivo presentar la implementación y evolución 2010-2016.
Métodos:
Estudio transversal de tendencias. Se impulsó la celebración del DMAF mediante la web www.pafes.cat, un formulario de registro y un plan de comunicación. Las variables estudiadas fueron número de entidades, tipos de eventos y participantes, el porcentaje de eventos coordinados, el número de visitas web y el coste. Se realizó un análisis descriptivo univariado y de frecuencias.
Resultados:
Se realizó la difusión a >9000 direcciones electrónicas/año. Entre 2010 y 2016 se multiplicaron por cinco las entidades organizadoras, eventos y participantes (en 2016 2,8% de la población), durante marzo y abril aumentaron las visitas a la web. Los eventos (caminatas, AF dirigida, deporte y difusión) presentaron coordinación y movilizaron de 25 a 500 personas desde diversos ámbitos. El coste estimado medio fue de 1 céntimo por participante.
Conclusiones:
El DMAF consiguió llegar a un gran volumen de población con un coste mínimo.
Inflammatory bowel disease (IBD), Crohn's Disease (CD) and Ulcerative Colitis (UC) are associated with an increased risk of arterial and venous thromboembolism. A 2 to 3 time fold increased risk of developing thromboembolic complications was reported for IBD patients compared to general population. A systematic literature search was conducted using PubMed, Medline, Scopus, Cochrane database. The key words were: "Inflammatory Bowell Disease", "Crohn's Disease and Thrombosis", "Ulcerative Colitis and Thrombosis", "Thrombosis" and "Inflammatory Bowel Diseases and Thrombosis". Full articles and abstracts were included. Studies such as case reports, letters and commentaries were excluded from the analysis if appropriate data could not be extracted. Although no randomized controlled trials (RCTs) have been established to evaluate the efficacy of thromboprophylaxis in patients with IBD due to the incidence of VTE and PE in such patients, it is highly recommended the adoption of thromboprophylactic measures. Available prophylaxis and treatment options include pharmacological anticoagulant therapy (LMWH-Low Molecular Weight Heparin, Fondaparinux and UH-Unfractionated Heparin) and mechanical prophylaxis. In case of acute VTE patient must be treated with fibrinolytic agents and in selected non-responsive cases vascular surgery. IBD patients have an increased risk of VTE complications. Prophylaxis for VTE should be recommended in all patients who do not show contraindications to treatment.
Background
Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep venous thrombosis (DVT), can be life threatening. An increased frequency of VTE has been found in inflammatory conditions. To date, evidence assessing whether this risk is also greater in patients with ankylosing spondylitis (AS) is scarce.
Methods
Using the provincial British Columbia, Canada healthcare database that encompasses all residents within the province, we conducted matched cohort analyses of incident PE, DVT and overall VTE among incident cases of AS and compared them with individuals randomly selected from the general population without AS. We calculated incidence rates (IRs) of VTE and multivariable analyses after adjusting for traditional risk factors using Cox models.
Results
Among 7190 incident cases of AS, 35 developed PE and 47 developed DVT. IRs of PE, DVT and overall VTE per 1000 person-years for patients with AS were 0.79, 1.06, 1.56 compared with 0.40, 0.50, 0.77 in the control cohort. Corresponding fully adjusted HRs (95% CI) of PE, DVT and VTE were 1.36 (0.92 to 1.99), 1.62 (1.16 to 2.26) and 1.53 (1.16 to 2.01), respectively. The risks of PE, DVT and VTE were highest in the first year of diagnosis with HR (95% CI) of 2.88 (0.87 to 9.62), 2.20 (0.80 to 6.03) and 2.10 (0.88 to 4.99), respectively.
Conclusions
These findings demonstrate an increased risk of VTE in the general AS population. This risk appears the most prominent in the first year after diagnosis.
Systemic inflammation and hypercoagulability in psoriasis are related to cardiovascular morbidity. The aim of the study was to investigate the incidence and risk of venous thromboembolism (VTE) in patients with psoriasis in Taiwan. We identified inpatients aged ≥ 18 years with a diagnosis of psoriasis and controls at a 1: 1 ratio of frequency matched by sex, age, frequency of medical visits, length of stay, and comorbidities between 2000 and 2010 in the Taiwan National Health Insurance Research Database. Each patient was traced to the date of VTE occurrence, loss to follow-up, death, or the December 31, 2011, whichever occurred first. We analysed 8945 patients with psoriasis and 8945 controls. The patients with psoriasis exhibited a greater incidence rate of VTE (19.2 vs 9.88 per 10 000 person-years) than did the controls. After adjustment for covariates, the patients with psoriasis presented a 2.02-fold risk of VTE (adjusted hazard ratio [aHR] = 2.02, 95 % confidence interval [CI] = 1.42-2.88) compared with that in the control cohort. The aHR of VTE was significantly higher in the first year of follow-up (aHR = 3.30, 95 % CI = 1.45-7.55) than after one year (aHR = 1.68, 95 % CI = 1.13-2.49).
Aims:
To determine the risk of venous thromboembolism (VTE) defined as the combined endpoint of deep venous thrombosis (DVT) and pulmonary embolism (PE) among patients with psoriatic arthritis (PsA), psoriasis and rheumatoid arthritis (RA) compared with population controls.
Methods and results:
A cohort study was conducted in a primary care medical record database in the UK with data from 1994-2014 among patients with PsA, RA, or psoriasis. Cox proportional hazards models were used to calculate the relative hazards for DVT, PE, and VTE. An interaction with disease modifying anti-rheumatic drugs (DMARD) was hypothesized a priori and was significant. Patients with PsA (n = 12 084), RA (n = 51 762), psoriasis (n = 194 288) and controls (n = 1 225 571) matched on general practice and start date were identified. Patients with RA (with and without a DMARD prescription) and patients with mild psoriasis had significantly elevated risks of VTE (HR 1.35, 1.29, and 1.07, respectively) after adjusting for traditional risk factors. Severe psoriasis and PsA prescribed a DMARD had an elevated but not statistically significant risk for VTE. Findings were similar for DVT. The age-and-sex-adjusted risk of PE was elevated in RA, severe psoriasis and PsA patients prescribed a DMARD.
Conclusion:
While systemic inflammation is a risk factor for VTE, the risk of VTE compared with controls is different among patients with three different inflammatory disorders: RA, PsA, and psoriasis.
Epidemiological studies suggested an association between atopic dermatitis (AD) and cardiovascular disease (CVD). Therefore, we investigate associations and potential underlying pathways of AD and CVD in large cohort studies: the AOK PLUS cohort (n=1.2Mio), the GINIplus/LISAplus birth cohorts (n=2286), and the KORA F4 cohort (n=2990). Additionally, metabolomics in KORA F4 and established cardiovascular risk loci in genome-wide data on 10,788 AD cases and 30,047 controls were analyzed. Longitudinal analysis of AD patients in AOK PLUS showed slightly increased risk for incident angina pectoris (AP) (adjusted risk ratio 1.17; 95%-confidence interval 1.12-1.23), hypertension (1.04 (1.02-1.06)) and peripheral arterial disease (PAD) (1.15 (1.11-1.19)) but not for myocardial infarction (MI) (1.05 (0.99-1.12) and stroke (1.02 (0.98-1.07)). In KORA F4 and GINIplus/LISAplus, AD was not associated with cardiovascular risk factors (CVRFs) and no differences in metabolite levels were detected. There was no robust evidence for shared genetic risk variants of AD and CVD. This study indicates only a marginally increased risk for AP, hypertension and PAD and no increased risk for MI or stroke in AD patients. Relevant associations of AD with CVRFs reported in US-populations could not be confirmed. Likewise, AD patients did not have increased genetic risk factors for CVD.
Thromboembolic conditions were estimated to account for 1 in 4 deaths worldwide in 2010 and are the leading cause of mortality. Thromboembolic conditions are divided into arterial and venous thrombotic conditions. Ischemic heart disease and ischemic stroke comprise the major arterial thromboses and deep-vein thrombosis and pulmonary embolism comprise venous thromboembolism. Atrial fibrillation is a major risk factor for stroke and systemic arterial thromboembolism. Estimates of the global burden of disease were obtained from Global Burden of Disease Project reports, recent systematic reviews, and searching the published literature for recent studies reporting measures of incidence, burden, and disability-adjusted life-years. Estimates per 100 000 of the global incidence rate (IR) for each condition are ischemic heart disease, IR=1518.7; myocardial infarction, IR=139.3; ischemic stroke, IR=114.3; atrial fibrillation, IR=77.5 in males and 59.5 in females; and venous thromboembolism, IR=115 to 269. Mortality rates (MRs) for each condition are ischemic heart disease, MR=105.5; ischemic stroke, MR=42.3; atrial fibrillation, MR=1.7; and venous thromboembolism, MR=9.4 to 32.3. Global public awareness is substantially lower for pulmonary embolism (54%) and deep-vein thrombosis (44%) than heart attack (88%) and stroke (85%). Over time, the incidence and MRs of these conditions have improved in developed countries, but are increasing in developing countries. Public health efforts to measure disease burden and increase awareness of symptoms and risk factors need to improve, particularly in low- and middle-income regions to address this leading cause of morbidity and mortality.
Background:
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a systemic disorder that predominantly affects the bowels but is also associated with venous thromboembolism (VTE).
Aim:
To provide a quantitative assessment of the association of IBD with venous thromboembolism risk and to explore the possible sources of heterogeneity in the current literature, a meta-analysis of case-control and cohort studies was conducted.
Methods:
Studies were identified by a literature search of the PubMed and Scopus databases (from inception inclusive 31 December 2012) for English language studies. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with fixed- and random-effects models. Several subgroup analyses were performed to explore potential study heterogeneity and bias.
Results:
Eleven studies met our inclusion criteria. The summary RR for deep venous thromboembolism (DVT) and pulmonary embolism (PE) comparing subjects both with and without IBD was 2.20 (95% CI 1.83-2.65). After adjusting for obesity and smoking, summary relative risks near 2.0 were seen for venous thromboembolism in both UC and CD patients.
Conclusion:
This meta-analysis showed that inflammatory bowel disease is associated with an approximately two-fold increase in the risk of venous thromboembolism.
Background:
Combined hormonal contraceptives (CHCs) place women at increased risk of venous thromboembolic events (VTEs) and arterial thrombotic events (ATEs), including acute myocardial infarction and ischemic stroke. There is concern that three recent CHC preparations [drospirenone-containing pills (DRSPs), the norelgestromin-containing transdermal patch (NGMN) and the etonogestrel vaginal ring (ETON)] may place women at even higher risk of thrombosis than other older low-dose CHCs with a known safety profile.
Study design:
All VTEs and all hospitalized ATEs were identified in women, ages 10-55 years, from two integrated health care programs and two state Medicaid programs during the time period covering their new use of DRSP, NGMN, ETON or one of four low-dose estrogen comparator CHCs. The relative risk of thrombotic and thromboembolic outcomes associated with the newer CHCs in relation to the comparators was assessed with Cox proportional hazards regression models adjusting for age, site and year of entry into the study.
Results:
The hazards ratio for DRSP in relation to low-dose estrogen comparators among new users was 1.77 (95% confidence interval 1.33-2.35) for VTE and 2.01 (1.06-3.81) for ATE. The increased risk of DRSP was limited to the 10-34-year age group for VTE and the 35-55-year group for ATE. Use of the NGMN patch and ETON vaginal ring was not associated with increased risk of either thromboembolic or thrombotic outcomes.
Conclusions:
In new users, DRSP was associated with higher risk of thrombotic events (VTE and ATE) relative to low-dose estrogen comparator CHCs, while the use of the NGMN patch and ETON vaginal ring was not.
Immune-mediated inflammatory diseases (IMID) present a group of common and highly disabling chronic conditions that share inflammatory pathways. Several incidence and prevalence studies of IMID during the past decades have reported a considerable variation of the disease occurrence among different populations. Overall, the estimated prevalence of IMID in Western society is 5%-7%. This article provides an overview of studies of the incidence, prevalence, natural history, and comorbidities of IMID.
Patients with inflammatory bowel disease (IBD) are at increased risk of a first venous thromboembolism (VTE), yet their risk of recurrent VTE is unknown. We performed a cohort study to determine the risk for recurrent VTE among patients with IBD compared with subjects without IBD.
We assessed 2811 patients with IBD for a history of VTE, recruited from outpatient clinics at 14 referral centers (June 2006-December 2008). Patients with VTE before a diagnosis of IBD or those not confirmed to have VTE, cancer, or a VTE other than deep vein thrombosis or pulmonary embolism, were excluded. Recurrence rates were compared with 1255 prospectively followed patients without IBD that had a first unprovoked VTE (not triggered by trauma, surgery, or pregnancy). The primary end point was symptomatic, objectively confirmed, recurrent VTE after discontinuation of anticoagulation therapy after a first VTE.
Overall, of 116 IBD patients who had a history of first VTE, 86 were unprovoked. The probability of recurrence 5 years after discontinuation of anticoagulation therapy was higher among patients with IBD than patients without IBD (33.4%; 95% confidence interval [CI]: 21.8-45.0 vs 21.7%; 95% CI: 18.8-24.6; P = .01). After adjustment for potential confounders, IBD was an independent risk factor of recurrence (hazard ratio = 2.5; 95% CI: 1.4-4.2; P = .001).
Patients with IBD are at an increased risk of recurrent VTE compared to patients without IBD.
Most pregnancies in women with rheumatologic disease will result in the delivery of a healthy baby. Pregnancy can be particularly risky in women with active disease or on teratogenic medications, making contraception an important issue for these women. All women with rheumatologic disease have contraceptive options, including barrier methods, the intra-uterine device and progesterone-only medications. Active inflammatory disease, whether in the form of lupus, systemic vasculitis or myositis, places the pregnancy at increased risk. Pre-eclampsia is a particular risk for women with lupus or antiphospholipid syndrome and may be decreased by daily low-dose aspirin. Rheumatoid arthritis typically improves and does not have a major impact on pregnancy outcomes. The expected post-partum arthritis flare may be avoided by restarting medications soon after delivery. Judicious use of medication and close observation may be the keys to successful pregnancy in women with rheumatologic disease.
Recent data indicate that users of third-generation oral contraceptives, those containing the new progestins desogestrel, gestodene, and norgestimate, have 2 to 3 times the risk of venous thromboembolism faced by users of second-generation oral contraceptives. The risk of development of deep vein thrombosis was also found to be 2 to 5 times greater with a low-estrogen, desogestrel-containing oral contraceptive than with second-generation monophasic and triphasic preparations. Investigators point to an acquired resistance to the anticoagulation effects of activated protein C, the most common cause of hereditary thrombophilia, as a possible mechanism. The American College of Obstetrics and Gynecology's Committee on Gynecologic Practice reconfirms the increased risk of venous thromboembolism associated with third-generation progestins versus other progestins. Because the third-generation oral contraceptives may have benefit for some patients, however, it defers to the individual clinician's and patient's judgment regarding the use of a desogestrel-containing formulation (the only third-generation progestin available in the United States).
Leflunomide is the first disease-modifying antirheumatic drug to be approved for rheumatoid arthritis in the past 10 years. Orally administered leflunomide is almost completely converted into its active metabolite A77 1726 (hereafter referred to as M1). M1 displays linear pharmacokinetics at the dosages of leflunomide used in clinical practice. It has a long elimination half-life (approximately 2 weeks), reaching a steady state after approximately 20 weeks. M1 is highly bound to plasma proteins. The pharmacokinetics of M1 are not affected by food intake, and dosage requirements are not influenced by age or gender. Approximately 90% of a single dose of leflunomide is eliminated, 43% in urine, primarily as leflunomide glucuronides and an oxalinic acid derivative of M1, and 48% in faeces, primarily as M1. Elimination can be dramatically increased by using charcoal or cholestyramine. In vitro studies have shown no major influence of leflunomide on the metabolism of analgesics, nonsteroidal anti-inflammatory drugs and methotrexate, drugs usually used in the treatment of rheumatoid arthritis. In clinical studies with a limited number of patients using these drugs concomitantly, no safety problems appeared. Nonspecific inducers of cytochrome P450 (CYP) and some drugs metabolised by CYP2C9 affect the metabolism of M1, and caution should be used in patients cotreated with them. Additional in vitro and in vivo pharmacokinetic studies are needed to better understand the nonenzymatic and enzymatic metabolism of leflunomide. Additional clinical trials should be performed in order to find new indications for leflunomide in other autoimmune diseases, and new combination therapeutic strategies in rheumatoid arthritis. This review is a summary of current knowledge of the pharmacokinetics of leflunomide, focusing primarily on humans and in particular on patients with rheumatoid arthritis.
Depot medroxyprogesterone acetate (DMPA) injectable contraception may decrease bone density and increase the risk for osteoporosis in later life. Prospective data are scarce, especially of the effects of DMPA discontinuation on bone.
Between 1994 and 1999, we conducted a population-based prospective cohort study among women enrollees of a Washington State health maintenance organization. We enrolled 457 nonpregnant women, ages 18-39 years (183 DMPA users and 274 non-users). Bone density was measured by dual-energy x-ray absorptiometry every 6 months for 3 years.
Bone density decreased notably among DMPA-exposed women at the spine (adjusted mean bone density was -0.0053 gm/cm for DMPA users compared with +0.0023 gm/cm for non-users for each 6-month interval) and total hip (-0.0060 compared with -0.0002 gm/cm ). This represents an annualized mean rate of change at the spine of -0.87% compared with +0.40% and, at the hip, -1.12% compared with -0.05%. Discontinuers of this method (N = 110) showed sizable increases in bone density over comparison women (for each 6-month interval, adjusted mean spine bone density was +0.0067 gm/cm compared with +0.0023 gm/cm, respectively; adjusted mean hip bone density was +0.0035 compared with -0.0002 gm/cm ). Estimated annualized mean rates of change were +1.41% compared with +0.40% [corrected] at the spine and +1.03% [corrected] compared with -0.05% at the hip. After 30 months, mean bone density for discontinuers was similar to that of non-users.
In this study, DMPA use was strongly associated with bone density loss. Substantial postdiscontinuation recovery of bone provides evidence that the effects may be largely reversible.
Autoimmune diseases are among the leading causes of death among young and middle-aged women in the United States. Incidence rates vary among the autoimmune diseases, with estimates ranging from less than one newly-diagnosed case of systemic sclerosis to more than 20 cases of adult-onset rheumatoid arthritis per 100,000 person-years. Prevalence rates range from less than 5 per 100,000 (e.g. chronic active hepatitis, uveitis) to more than 500 per 100,000 (Grave disease, rheumatoid arthritis, thyroiditis). At least 85% of thyroiditis, systemic sclerosis, systemic lupus erythematosus, and Sjögren disease patients are female. Although most diseases can occur at any age, some diseases primarily occur in childhood and adolescence (e.g. type 1 diabetes), in the mid-adult years (e.g. myasthenia gravis, multiple sclerosis), or among older adults (e.g. rheumatoid arthritis, primary systemic vasculitis). Ethnic and geographic differences in incidence of specific autoimmune diseases have been documented, but specific groups may be at higher risk for some diseases and lower risk for other diseases. The incidence of type 1 diabetes increased but the rates of rheumatoid arthritis declined over the past 40 years. Thus although there are commonalities, there are also important demographic differences between diseases. Disease-specific research, as well as studies that focus on potentially related diseases, needs to be conducted.
Disease modifying anti-rheumatic drugs (DMARD)
- O Benjamin
- A Goyal
- S L Lappin
Practice Committee of the American Society for Reproductive Medicine. Combined hormonal contraception and the risk of venous thromboembolism: a guideline
Faculty of Sexual and Reproductive Healthcare. UK medical eligibility for contraceptive use
206: use of hormonal contraception in women with coexisting medical conditions
- Acog Acog Practice Bulletin
- No
Treasure Island (FL): StatPearls; 2022
- D B Cooper
- P Patel
- H Mahdy
Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases
- Y Vinogradova
- C Coupland
- J Hippisley-Cox