Prevention of vascular damage in scleroderma with angiotensin-converting enzyme (ACE) inhibition
P. Maddison
North West Wales NHS Trust and School of Sport, Health and Exercise Science, University of Wales, Bangor, UK
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Abstract
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Great strides have been made in identifying and managing the organ-based complications of systemic sclerosis (SSc). There is no room for the nihilism towards treating this disease that used to be so prevalent. However, there is still relatively little hard evidence on which to base treatment decisions. Previous trials have been constrained by the low disease prevalence and the difficulty in recruiting sufficient patients especially with disease of recent onset. The results of past trials have often been confounded by the failure to recognize the marked heterogeneity of SSc and the inclusion of patient subsets with widely varying disease expression, course and outcome. It is recognized that progress will only be made in this area with coordinated multicentre studies. As a result, national and international networks of clinicians with expertise in the management of SSc have been formed. In the UK, the Systemic Sclerosis Study Group has established a national scleroderma register and, together with the Scleroderma Special Interest Group of the British Society for Rheumatology (BSR), a multicentre base for therapeutic studies. As a result of developments in our understanding of the pathogenesis of scleroderma and our ability to subset patients more effectively, a number of rather more rational approaches to treating the disease and its complications are being tested. In parallel with this, considerable progress is being made in developing universally agreed measures of disease activity and severity and in identifying surrogate laboratory markers of disease activity that are relevant to therapeutic studies. These multicentre trials need substantial funding and often do not attract support from the pharmaceutical industry. It was because of the difficulty in financing long-term, multicentre studies in uncommon conditions that the ARC/BSR Clinical Trials Programme was established. The QUINS trial, which is funded by this Programme, is described here as an example of one of several therapeutic protocols being developed by the UK Systemic Sclerosis Study Group that are currently being tested in multicentre trials. Contact details are provided in the appendix for clinicians who are interested in registering patients on the UK Scleroderma Register or participating in this or in the other therapeutic studies.
KEY WORDS: Scleroderma, ACE inhibition, Disease activity, Autoantibodies.
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Introduction
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Systemic sclerosis (scleroderma/SSc) is an autoimmune rheumatic disease of unknown aetiology characterized by microvascular injury, excessive fibrosis of the skin, distinctive visceral involvement including the lungs, heart, kidneys and gastrointestinal tract and progressive macrovascular pathology. It is an uncommon condition with an annual incidence of about 10 cases per million of the population in the UK [1]. Perhaps even more than other autoimmune rheumatic diseases, SSc poses a great therapeutic challenge. Whatever the initial presentation, serious morbidity and death, especially from respiratory and cardiovascular complications, are common outcomes [2]. Often one encounters considerable nihilism over the management of these patients. However, over the last two decades, there have been a number of important developments, which have encouraged the development of hopefully more effective strategies to treat the disease. These developments include advances in our understanding of the pathogenesis of scleroderma, our ability to recognize the disease at an early stage when Raynaud's phenomenon may be the only clinical manifestation, the ability to identify subsets at risk of particular complications, and the development of widely available techniques, such as high resolution CT scanning, to detect and monitor organ involvement.
The significant mortality and the even greater morbidity of SSc coupled with the lack of treatment guidelines makes it a very unwelcome diagnosis for the clinician let alone the patient. Treatment is largely empirical and rarely evidence based. The challenges posed by therapeutic trials in SSc have been described in a recent editorial [3]. Previous studies have been hampered by insufficient patient numbers and inadequate follow-up, the confounding effect of the marked heterogeneity of the disease and the lack of universally accepted outcome measures and surrogate markers of disease. However, the establishment of the UK Scleroderma Study Group, which already has a track record in multicentre clinical trials, and the Scleroderma Interest Group of the British Society for Rheumatology (BSR) provides a network of clinicians who are prepared to collaborate in clinical trials of this disease. In addition, a central registry of scleroderma cases has been developed by the UK Scleroderma Study Group at the Royal Free Hospital, London, which will help to identify subjects for appropriate studies. In this way, there is an opportunity to match the success of other clinical disciplines, such as oncology and haematology, in undertaking therapeutic trials that make an impact on clinical practice. Consequently, the UK Scleroderma Study Group has developed of number of therapeutic protocols some of which are now being tested in multicentre trials. This review concerns one of these trials (the QUINS trial) in which the objective is to assess the efficacy and tolerability of the angiotensin-converting enzyme (ACE) inhibitor, quinapril, in the management of peripheral vascular manifestations and in preventing progression of visceral organ involvement in patients who fall into the limited cutaneous subset of SSc.
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The heterogeneity of systemic sclerosis: clinical and serological subsets
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Scleroderma is a blanket term for a diverse range of disorders, including SSc, in which thickened indurated skin is the common clinical feature. The heterogeneity of SSc itself is increasingly being appreciated with the recognition of distinctive clinical subsets differing in disease pattern and outcomes. The most widely accepted scheme for clinical classification involves two subsets, limited and diffuse cutaneous SSc (lcSSc and dcSSc), respectively, based on the extent of cutaneous involvement that reflects to some extent the degree of visceral disease [4]. The majority of patients (over 60%) fall into the category of lcSSc. However, this is still a very heterogeneous group with patients exhibiting differing disease course and complications. Undoubtedly, this scheme of classification will evolve as pathogenesis is better understood. For example, distinctive serological subsets within the spectrum of SSc, defined by highly disease-specific autoantibodies, have been recognized, which are associated with particular patterns of disease expression [5, 6].
ANA and/or antinucleolar antibodies are an almost universal feature of SSc. Several of these antibodies are highly specific for the disease, are rarely found in other clinical settings and occur as an early feature so that their identification has an important role in early diagnosis of the disease [7, 8]. Another important observation is that there is virtually no serological overlap between subsets defined by a particular antibody profile and these subsets tend to be associated with certain patterns of clinical expression. In recent years there has been great progress in defining the molecular targets of these antibodies [9]. Table 1
lists the principle antibody specificities detected in these patients. Scleroderma-specific antibodies include anticentromere antibodies, which react with kinetochore associated proteins, and antibodies to the nucleolar antigen, ThRNP, which occur predominantly in lcSSc. In contrast, antibodies to topoisomerase 1, RNA polymerases and U3RNP are found in patients with diffuse skin disease and prominent systemic involvement. Further, prospective, studies of large patient numbers are needed to confirm these observations. Detailed serological evaluation of patients in the QUINS trial will offer an opportunity to do this.
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Limited cutaneous systemic sclerosis: a benign subset?
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Compared with dcSSc, visceral involvement in patients in the limited cutaneous subset is a late event and tends to occur 1030 yr after the onset of Raynaud's, which is usually the first clinical event. Consequently, it has been considered to be a more benign form of the disease. However, this can be misleading because progressive vascular involvement happens in most of these patients. To begin with, manifestations of microvascular disease such as Raynaud's phenomenon predominate. This is often severe and recurrent digital ischaemia, occasionally with quite extensive digital gangrene can be a major cause of morbidity. Rapidly progressive renal and pulmonary disease is less common than in the diffuse cutaneous subset but involvement of the gastrointestinal tract is prominent and about 50% develop severe GI disease, mostly oesophageal but also involving the small and large bowel [10].
Subsequently, some patients develop progressive macrovascular damage sometimes with dire consequences. Serious peripheral vascular disease has been reported in up to 60% of patients [11] and approximately 15% develop isolated pulmonary hypertension associated with intimal proliferation of the pulmonary arterioles that is almost invariably fatal [12].
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Treatment of systemic sclerosis: the role of ACE inhibition
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So far, no therapy has yet been established to alter the course of this disease. We have still a lot to learn about the pathogenesis of SSc and what processes to target for therapy [13]. However, during the past few years there have been big advances in understanding some of the cellular and molecular mechanisms involved. Major events in the disease include perivascular and tissue accumulation of mononuclear cells, dysregulation of the fibrotic response with increased deposition of extracellular matrix in the skin and internal organs and vascular injury, which many believe is the primary event and one at which to target treatment. There is compelling evidence that endothelial cell dysfunction has a pivotal role in the vascular injury. This includes up-regulated expression and increased circulating levels of endothelial adhesion molecules, altered levels of endothelial cell products and functional abnormalities such an imbalance of vasodilator and vasoconstrictor mechanisms, increased capillary permeability, impaired fibrinolysis and increased platelet aggregation [14, 15]. So far, the search for drugs to protect injured endothelial cells and to prevent platelet aggregation and subsequent release of platelet- and endothelium-derived mediators has been disappointing [16]. For example, calcium channel blockers and ketanserin, a serotonin antagonist, are effective in Raynaud's but do not influence the development of structural vascular abnormalities. Neither dipyridamole nor aspirin, although reducing platelet products, have been effective for the microvascular manifestations of SSc in controlled trials. There has been considerable interest in prostacyclins, including the stable analogue, Iloprost, which, when given intravenously, are effective for Raynaud's phenomenon with healing of ischaemic digital lesions [17]. However, studies of an oral preparation of Iloprost have not consistently demonstrated significant efficacy in the short term [18].
Inhibition of ACE has revolutionized the management of scleroderma renal crisis that previously had an almost invariably fatal outcome [19]. ACE inhibition has also been reported to be effective in treating complications due to myocardial and pulmonary artery involvement. There are anecdotal reports and open, uncontrolled studies purporting that ACE inhibitors are effective in Raynaud's phenomenon and affect digital blood flow [20, 21]. However, formal randomized controlled studies have not been reported and there are no data on long-term effects of ACE inhibition on the progression of vascular disease in SSc.
Scleroderma renal crisis occurs in up to 20% of patients with dcSSc, usually in the early phase of the disease [22]. Recent studies have suggested that the presence of antibodies to the RNA polymerases is a marker of this complication [23]. The abrupt onset of accelerated hypertension is accompanied by rapidly progressive renal failure and until successful medical management of scleroderma renal crisis was reported it was the major cause of death in SSc and one study showed that all patients with renal failure died within 1 yr [24]. Bilateral nephrectomy was thought to be the only therapy to control this emergency and permit survival [25].
Intimal thickening of the renal interlobular and arcuate arteries results in decreased renal perfusion, particularly reduced cortical blood flow. Decreased perfusion and hyperplasia of the juxtaglomerular apparatus leads to massive renin production causing the hypertension. The primary event is considered to be endothelial injury but the nature of this is still not clear. There may be an element of episodic vasospasm of the renal arterioles as demonstrated by Cannon et al. [26] (renal Raynaud's phenomenon).
Since the first report of the successful use of captopril to reverse scleroderma renal crisis [27], the early treatment with ACE inhibitors has dramatically improved the outcome of patients with this complication. However, even with this treatment some patients (up to 50% in one study [28]) have a poor outcome (death or renal dialysis). In some reports of successful treatment of the renal complication with ACE inhibition [29], improvement in skin and Raynaud's phenomenon occurred suggesting that this treatment might have long term beneficial effects on other manifestations of the disease.
Whether or not prior ACE inhibition is successful in protecting patients from developing scleroderma renal crisis is not entirely clear. Certainly patients on ACE inhibitors have developed this complication [28]. Although increased plasma renin accompanies the hypertension, hyperreninaemia is neither consistently present prior to scleroderma renal crisis nor predictive of this complication [30].
Studies have suggested that ACE inhibition is capable of producing an acute and sustained decrease in pulmonary vascular resistance in patients with pulmonary hypertension in association with SSc [31]. Pulmonary hypertension without interstitial pulmonary fibrosis more commonly complicates patients with limited cutaneous involvement than those with diffuse disease and is associated with a terrible prognosis. Typically, there is intimal proliferation and medial hypertrophy of small- to medium-sized arteries. As in the renal disease, there is evidence for recurrent episodes of pulmonary vasoconstriction which may contribute to the development of pulmonary hypertension in these patients [32].
ACE inhibition may also have a role in the primary myocardial involvement, which represents another serious complication of SSc [33, 34]. Studies have shown sustained improvement of ventricular function and thallium myocardial perfusion with ACE inhibition.
So far there has been very limited experience of ACE inhibition in Raynaud's phenomenon and no studies in progression of vascular disease. The results are rather conflicting [35]. There are case reports and uncontrolled, open studies suggesting that ACE inhibitors could benefit patients with Raynaud's phenomenon. However, these encouraging observations have not been substantiated by placebo-controlled studies. Of four placebo-controlled studies performed [3639], only one showed a trend towards clinical improvement with ACE inhibition [37] while another [38] showed objective improvement in finger blood flow. However, these studies were confined to testing captopril or enalapril, and there are no studies using newer ACE inhibitors that appear to have a relatively greater effect on the peripheral vasculature.
There is now good evidence that ACE inhibition plays a direct role in improving endothelial function in animal models of atherosclerosis [40], inhibits intimal hyperplasia after vascular injury [41], restores the normal vasodilatory response of coronary arteries in patients with coronary artery disease [42] and promotes vascular remodelling in patients with chronic hypertension [43]. This effect on endothelial function is associated with increased availability of nitric oxide [44]. Depressed nitric oxide also characterizes the endothelial dysfunction seen in SSc [45]. Amongst the ACE inhibitors, quinapril has potent binding affinity for both plasma and tissue ACE. Theoretically, this compound has the potential for more complete inhibition of ACE activity at the endothelial level, thereby inhibiting the vasospastic and mitogenic effects of angiotensin. Indeed, there is experimental evidence that quinapril is more effective than other ACE inhibitors in influencing endothelial function [46]. Furthermore, studies in patients with coronary artery disease have suggested that ACE inhibition has a beneficial effect on endothelial dysfunction and that quinapril appears to be superior in this respect to other ACE inhibitors, angiotensin II receptor antagonists and calcium channel blocking agents [46].
For this reason, quinapril has been selected for use in our study the purpose of which is to evaluate the effect of ACE inhibition on the progression of vascular disease in SSc. We hypothesize that long-term ACE inhibition will ameliorate manifestations of microvascular disease in SSc such as Raynaud's phenomenon and ischaemic digital lesions and will reduce the progression of visceral organ involvement and the occurrence of macrovascular complications including pulmonary hypertension.
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Prevention of vascular damage in scleroderma: what should be the outcome measures?
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The QUINS trial is a randomized, placebo controlled, double-blind study of quinapril in patients with lcSSc (see Appendix). The objective is to assess the efficacy and tolerability of quinapril in the management of peripheral vascular manifestations over a 3-yr treatment period and in preventing progression of visceral organ involvement of the disease. It is a multicentre study with 16 centres in the UK involved so far. Patient recruitment is at an early stage. It is funded by the ARC/BSR Clinical Trials Programme.
A challenge facing the design of studies such as this is the choice of appropriate outcome measures to assess the effect of treatment. To date, there are no universally agreed measures of disease activity or severity in SSc although progress is being made in this area. In other autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE) and primary vasculitis, it has been recognized that a combination of different aspects of the disease need to be assessed in parallel to adequately study prognosis and effects of treatment, namely disease activity, irreversible damage and quality of life [4749]. The same is true for SSc but it has proved to be very difficult to separate disease damage from disease activity. Recently, a preliminary validation of activity criteria developed by the European Scleroderma Study Group has been reported [50]. Currently, this group is collaborating with the Scleroderma Clinical Trials Consortium to develop a single instrument, which, hopefully, will be universally accepted as a measure of SSc activity.
There are widely accepted methods of quantifying involvement in individual organ systems that are likely to become the basis for measuring disease activity or severity. These include the scleroderma skin score that is a validated, semi-quantitative method of assessing the extent of skin involvement on a 03 scale at 17 different sites [51]. The rate of increase in skin score is accepted as a measure of disease activity and the size of the score correlates with patient survival. In future, ultrasound may replace clinical assessment of the skin as a more objective measure of skin thickness [52]. Similarly, high resolution CT scanning and Doppler-echocardiography have been shown to be effective ways of evaluating fibrosing alveolitis and pulmonary hypertension respectively.
Recently, as a result of another international collaboration, a disease severity score has been published [53]. Severity scales were developed for nine organ systems from 0 (no involvement) to 4 (end stage disease). No attempt was made to combine the individual scores into a global score of disease severity. The scales employed in the instrument have been validated using a large patient database. Its sensitivity to change has not yet been assessed and its usefulness in the longitudinal study of individual patients and in therapeutic trials has not been established.
To date, there is no consensus about what instruments should be used in patients with SSc to measure health status and assess the economic impact of the disease and its treatment. The Health Assessment Questionnaire, developed for rheumatoid arthritis, has been used and has been shown to correlate with loss of hand function in early diffuse SSc [54]. Recently, a scleroderma-specific questionnaire to be completed by the patient has been described which may have advantages over the HAQ [55].
Over the years, a number of laboratory markers (Table 2
) have been described to reflect important biological processes in SSc including immune reactivity, endothelial activation and vascular damage, and extracellular matrix deposition [56]. As yet their role in assessing the effects of treatment has not been established. Markers of vascular injury, of potential relevance to the QUINS study include plasma levels of von Willebrand factor antigen, which, in previous studies, correlates with the frequency, and severity of Raynaud's attacks [57]. Similarly, microalbuminuria and urine levels of renal tubular enzymes such as N-acetyl-D-glucosaminidase (NAG) have been shown in pilot studies (Dr R. Moots, personal communication) to be elevated in SSc patients compared with other forms of renal disease and normal controls. Which of these surrogate markers of SSc activity will be of value in therapeutic studies will be an important challenge for the future.
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Appendix
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QUINS Trial: Prevention of vascular damage in scleroderma with angiotensin-converting enzyme (ACE) inhibition.
Study sponsor: ARC/BSR Clinical Trials Programme (quinapril and matched placebo donated by Pfizer).
Coordinating centre: Professor P. J. Maddison, Department of Rheumatology, Ysbyty Gwynedd, Bangor, UK.
A multicentre, randomized, placebo-controlled study of quinapril (up to 80 mg/day) in patients with lcSSc for 3 yr. The objective is to assess the efficacy and tolerability of quinapril, a long-acting, tissue ACE-specific inhibitor in the management of peripheral vascular manifestations and in preventing progression of visceral organ involvement of the disease.
Patient selection criteria:
Inclusion criteria:
Patients aged 18 yr or over
and
(i) lcSSc and Raynaud's phenomenon in which scleroderma is limited to the hands, forearms, face, lower legs and feet.
or
(ii) Raynaud's phenomenon and a SSc-specific autoantibody such as anticentromere antibodies, anti-topoisomerase 1, anti-RNApolymerase antibodies, anti-ThRNP antibodies and anti-U3RNP antibodies.
Exclusion criteria include:
(i) Known allergy to or intolerance of ACE inhibitors.
(ii) Women of childbearing age not using reliable contraception [for example, abstinence, oral or implanted contraception, sexual partner had non-reversed vasectomy, or intra-uterine device (IUD)].
(iii) History of angioneurotic oedema.
(iv) Significant impairment of renal or hepatic function.
(v) Severe obstructive valvular heart disease.
(vi) Any other condition that would prevent compliance with treatment or adequate assessment.
Proposed outcome measures:
Primary:
The rate of occurrence of new ischaemic digital ulcers.
Secondary:
Frequency and severity of Raynaud's phenomenon.
Introduction of vasodilators.
Use of measures such as IV Iloprost to treat ischaemic digital lesions.
Progression of scleroderma skin score.
Progression of pulmonary and renal disease.
Occurrence of death, significant macrovascular complications such as stroke and myocardial infarction, and pulmonary hypertension.
Laboratory measures of endothelial/microvascular injury including von Willebrand factor antigen level, urinary levels of NAG and microalbuminuria.
For more information about:
the QUINS study: phone Angela Gliddon (Study Coordinator) on +44 1248 38509
the UK Scleroderma Register: phone Chris Knight on +44 207 830 2360
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Notes
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Correspondence to: P. Maddison, Department of Rheumatology, Ysbyty Gwynedd, Bangor LL572 2PW, UK. 
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Submitted 31 July 2001;
Accepted 15 March 2002