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Treatment strategies and pregnancy outcomes in antiphospholipid syndrome patients with thrombosis and triple antiphospholipid positivity.
A European multicentre retrospective study Thromb Haemost. Nayer A, Ortega LM. J Nephropathol ;3 1: Guidelines on the investigation and management of antiphospholipid syndrome, Br J Haematol ; 1: Recommendation Czech Society of Rheumatology for diagnostics systemic scleroderma. Ces Revmatol ;22 2: Kidney disease other than renal crisis in patients with diffuse scleroderma.
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Clin Rheumatol ;31 3: Aschermann M, Jansa P. Drug therapy of pulmonary arterial hypertension in Vnitr Lek ;60 4: Semin Respir Crit Care Med ;35 2: Are respiratory complications common causes of death in inflammatory myopathies? Prognostic factors for myositis-associated interstitial lung disease. Long-term outcome of severe alveolar haemorrhage in ANCA-associated vasculitis: The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition. Arch Intern Med ; 4: Capizzi SA, Specks U. Does infection play a role in the pathogenesis of pulmonary vasculitis? Semin Respir Infect ;18 1: Clinical study and long-term follow-up of 96 patients.
Medicine Baltimore ;78 1: Eosinophilic granulomatosis with polyangiitis Churg-Strauss: Arthritis Rheum ;42 3: Hellmark T, Segelmark M. This definition incorporates the use of clinical expertise and external evidence, in particular from patient-centered clinical research, in order to come to optimal decisions about interventions for our patients 1.
Where there is a burden of disease, we need to know with confidence how best to improve health. It has been established that in patients with RA, CVD rates are increased as compared to those in the general population. This is manifested as an increased incidence of myocardial infarction and stroke 2 , and increased rates of death from cardiovascular causes 3. Guidelines assimilating and interpreting the expanding data are welcome: The current EULAR guidelines 5 , which were published 2 years ago, have already been cited over times, reflecting the usefulness of synthesizing the evidence into guideline form.
Critically appraising the evidence from all available sources is challenging, but vital, if we are to understand whether we have a proven, effective intervention for reducing cardiovascular risk that is worth implementing in daily practice. It can be helpful to separate the debate title into a series of sequential questions.
First, is cardiovascular disease increased? Second, by what mechanism is CVD increased?
Third, what is the evidence that intervention lowers the risk of CVD, and to what extent is it lowered? And last, is that intervention worthwhile? Typically, the evidence base weakens as we move through this series of questions. Each of these questions will be explored in turn. Cardiovascular risk in patients with RA is increased by a variety of mechanisms, including both traditional smoking, hypertension, dyslipidemia and nontraditional inflammation, medication risk factors.
This topic has been reviewed extensively elsewhere 6 , 7. Interventions can thus be targeted to many areas of potentially increased risk. However, the multiple routes from RA to increased CVD risk means that it cannot be assumed that intervening in one pathway has a predictable clinical outcome. There are many examples where pharmacologic interventions have had unpredictable, bidirectional, or even paradoxical effects, for example, increased suicidality with the use of antidepressants, atypical femoral fractures with bisphosphonates, and new-onset psoriaform lesions with anti-TNF therapy 8.
The debate must therefore focus on whether we have sufficient evidence that an intervention targeted at one of the many risk pathways truly reduces the burden of CVD. Surrogate end points are useful, but the clinical end points are the ones that matter. What, then, is the evidence that intervention lowers the incidence of CVD and to what extent is it lowered? This can be considered with respect to interventions targeted at traditional cardiovascular risk factors and nontraditional risk factors.
At present, there are no published interventional studies randomized controlled trials [RCTs] examining the efficacy of statins or antihypertensive agents on clinical cardiovascular end points exclusively in RA populations. Similarly, there are no studies of weight reduction or smoking cessation examining such end points in RA.
There are therefore no data from RCTs in this particular disease population to support the use of these primary prevention measures. This does not mean that we have no information, as we can extrapolate the results from other study designs and other populations. All rheumatologists will accept guidelines that advise smoking cessation in patients with RA, even though the research was conducted in the general population. RCTs of statins and antihypertensive agents have shown a clear reduction of cardiovascular end points in populations with existing CVD secondary prevention.
Evidence of a positive impact weakens among populations with no prevalent CVD primary prevention. Statins have been shown to have a positive effect in high-risk patients without prevalent CVD, but caution is advised in patients with low cardiovascular risk Primary prevention of CVD in the low-risk general population is not currently advocated because the background rate, and thus, the absolute risk reduction, of cardiovascular disease is low.
Many patients would need to be treated—with the associated side effects and cost implications—in order to avoid 1 case of CVD. This additional risk can move an individual across the risk, and thus the treatment, threshold. That probability is then multiplied by 1. This moves her into a risk category that requires intervention. Importantly, the advocated treatment at this point is targeted to the traditional risk factors.
But, is this increased risk conferred by RA modifiable by interventions targeted to lipids or blood pressure? Might statins work less well in RA patients than in the general population because, say, inflammation drives CVD progression in RA more than lipid metabolism does? If statins do have a positive effect, is this benefit seen at a particular stage of disease?
Might it be that, once the increased CVD is established in RA, reducing lipid levels can slow, but cannot reverse, the process? These questions remain unanswered and frame the research agenda in this area. Another option for reducing CVD in patients with RA is to treat the nontraditional risk factors, such as inflammation. There is evidence to support this. All studies, bar one, in a recent meta-analysis showed a reduced risk of cardiovascular events in patients treated with methotrexate overall relative risk 0.
The magnitude of the reduced risk is clinically meaningful.
Recommendations cite this drug as having the best evidence for risk reduction. While this may be true, we must be cautious not to infer that methotrexate leads to a greater risk reduction than sulfasalazine or leflunomide does. There have been few studies examining the cardiovascular effects of these treatments, and no comparative studies.
If we are to choose the optimal treatment that reduces disease severity and cardiovascular risk, we need to acquire this information. Predicting the cardiovascular effects of anti-TNF therapy is difficult because TNF is involved at many stages of the pathophysiologic pathway It may even have bidirectional effects, for example, by reducing inflammation but increasing lipid levels. Interestingly, observational studies of cardiovascular outcomes following anti-TNF therapy have led to discrepant, apparently conflicting, results for tabulation, see ref.
One reason for the discrepancy becomes clear as these studies are compared. Although all studies address the influence of anti-TNF therapy on CVD in patients with RA, no two studies have the same comparator group, the same definition of cardiovascular outcome, and adjust for the same confounders.
Furthermore, there are additional differences between studies in terms of the penetration of drug use, the average disease duration, and more. At present, we still do not know the effects of anti-TNF therapy on cardiovascular outcomes. Consensus in this area might be possible, but investigators need to work together to address comparable research questions The last and most important question is whether any intervention is worthwhile—ultimately, it is a balance of benefits, harms, and cost-effectiveness.
This is not always an easy balance, particularly since each outcome is measured in different units and information can be missing. Nevertheless, despite evidence gaps for a range of questions in RA populations, we can still be proactive in reducing cardiovascular risk. Lifestyle changes, such as weight reduction and smoking cessation, offer a wealth of positive benefits, and so we must continue or start!
Tight control of disease activity has already been established as the standard of care for patients with RA in order to optimize the reduction of disease progression in their joints. Cardiovascular benefits can be readily accepted as an added benefit.
However, intervening to treat traditional risk factors in patients with RA at a stage at which intervention would not be advocated in the general population does not yet have a supporting evidence base. Before committing large numbers of RA patients to such interventions, we need to have quantified the benefits and harms. Dixon begins his argument confirming that RA patients are at increased cardiovascular risk. However, we must ask ourselves whether physicians are aware of the increased cardiovascular risk conferred by RA.
A recent study suggests that there is poor cardiovascular risk management by primary care physicians as well as rheumatologists. This clearly demonstrates the need for better education to improve awareness of cardiovascular risk in RA His argument continues by highlighting the fact that cardiovascular risk in RA is attributed not only to classic risk factors, but also to nonclassic risk factors, including systemic inflammation and antirheumatic treatment.
The latter point about medications may complicate our understanding of the role of RA-specific treatment in cardiovascular risk in RA.
While we agree to some extent, this argument applies to almost all diseases and therapeutic interventions. Dixon is right, in that the extrapolation of intervention effects from non-RA patients to those with RA is not supported by the findings of RCTs. However, the same argument can be made about the use of many treatments in groups that have been underrepresented in trials, such as women and many ethnic minorities.
We should not withhold treatment of cardiovascular risk factors from these patients if knowledge of the pathobiology of CVD supports extrapolation of the findings of large intervention trials. Such extrapolations are integral to the practice of medicine, and the type of rationale to support them is part of evidence-based medicine There is no rationale for why chronic inflammation or other RA-related factors would render statins or antihypertensive agents ineffective.
This does not imply that trials should not be performed, but it does mean that RA patients should be given the benefit of the doubt. Dixon adds examples from several pharmacologic interventions in which there were potential adverse effects, for example, increased suicidality with antidepressant therapy. Does this mean that we should not treat patients who are depressed? Similarly, should we avoid statin therapy in RA patients at high risk of CVD because of its possible myopathy? We disagree with this approach.
Additionally, there are no data that would lead us to believe that statin therapy is less effective in RA, and the potential hazards of statin therapy seem to be extremely small in relation to the clear benefits in many circumstances 19 , User Account Sign in. All All Title Author Keyword. All Title Author Keyword. Recently viewed 1 Spondyloarthropathies Print Save Email Share. More Like This Show all results sharing these subjects: