How to improve morbidity and mortality in systemic lupus erythematosus

Systemic Lupus Erythematosus/Series Editors: D. Isenberg and C. Gordon SLE is a chronic multisystem disorder of presumed autoimmune origin in which cytotoxic antibodies, or circulating immune complexes, give rise to tissue damage often resulting in end organ disease and even mortality. The first large series to study mortality in this disease in 1955 revealed a survival of less than 50% at 5 yr [1]. Thus, in the past four decades much of the therapeutic initiatives in this disease have been directed at controlling the acute organ attack and inflammatory response in order to minimize tissue damage and to decrease the very high mortality rates. The therapeutic interventions have focused on the use of corticosteroids and cytotoxic agents in appropriate doses to minimize mortality on the one hand and morbidity from the disease or from the treatments on the other. This approach has in fact been quite successful and the overall mortality rates have improved dramatically over this period of time [2, 3] (Table 1). The reported 20‐yr survival of 68% [22] in the 1990s in contrast to the 50% 5‐yr survival in 1955 indicates success in controlling the acute immunological injury typical of this condition. Furthermore, we have shown that this improved survival was greater than the improvement in survival observed in the general population during the same time. The standardized mortality ratios for SLE patients improved from 10.1 in the 1970s, to 4.8 in the early 1980s, and to 3.3 in the early 1990s [27]. During this period, our prognosis studies and those of others have demonstrated distinctive mortality and morbidity patterns in these patients. Patients dying early usually succumb to active lupus and infection, while patients dying after 5 yr of disease often die of end organ dysfunction due to damage from the disease process or due to degenerative vascular disease manifested arteriosclerotic cardiovascular and cerebral vascular disease. Patients surviving into the later stages of their disease often manifest morbidity features apparently unrelated to acute immunological inflammatory mechanisms. These include: (1) accelerated atherosclerosis (angina, myocardial infarction, peripheral vascular disease and cerebral vascular disease); (2) dementia usually presenting as cognitive dysfunction; (3) bone disease presenting as osteoporosis or avascular necrosis (AVN); (4) fibromyalgia and chronic fatigue. Thus, the challenge for the treating physician is to distinguish these clinical presentations from features related to active SLE. For example, chest pain due to either ischaemic coronary artery disease, pericarditis or fibromyalgia musculoskeletal pain. Thus, an important contribution to the understanding of the clinical presentation of SLE in the past decade has been the description of the late‐stage mortality and morbidity features in this condition. Survival rates in series published from 1955 Survival rates in series published from 1955 Recent studies in our cohort revealed that at any point in time 13% of patients will have features of clinical atherosclerosis either manifested as angina, myocardial infarction or peripheral vascular disease alone or in combination. A similar prevalence of myocardial infarction and angina has been noted in other established lupus cohorts, including the Pittsburgh and the Baltimore cohorts [28–30]. Furthermore, of 124 patients who died between 1970 and 1993 in our clinic, 40 had had post‐mortem examinations [22]. Of these, 21 or 52.5% had evidence of moderate to severe atherosclerosis at the time of death either as a coexistent finding or as a primary cause of death. Furthermore, epidemiological studies have also confirmed this increase in coronary artery disease. In 1993–1994 the annual incidence of myocardial infarction in Canadian women was estimated at 0.001. This compares with incidence rates for women in our lupus cohort of 0.005. Thus, in women with lupus there was a five‐fold increase in the incidence of myocardial infarction. Moreover, the median age of myocardial infarction in Canadian women was 65–74 yr compared with 49 yr in the lupus cohort. Similar epidemiological findings have been noted in the Pittsburgh cohort where women age 35–44 yr were found to be 52.4 times more likely to have a myocardial infarction than controls [29]. Since such a significant number of patients suffered clinical atherosclerotic events, we turned our attention to detecting subclinical atherosclerotic disease that would afford us a better opportunity for intervention and hopefully prevention of these outcomes. To do this we employed a dual isotope myocardial perfusion imaging (DIMPI) technique using the two isotopes thallium‐201 (201TI) and technetium 99m‐sestamibi (99mTc sestamibi) following a dipyridamole stress. One hundred and thirty patients have been studied and 52 or 40% had perfusion abnormalities. Reversible defects consistent with ischaemia were seen in 47 (90.4%) and 14 (27%) had a fixed defect consistent with previous myocardial damage. When patients with a previous history of coronary artery disease were excluded, abnormalities were still found in 33% of these patients with lupus [28]. Another method employed to detect subclinical atherosclerosis in the general population has been the ultrasound assessment of the presence of focal plaque in the common carotid artery. Manzi et al. [31] employed B‐mode ultrasound to study the prevalence of carotid artery plaque formation in women with SLE and found that 40% of all lupus patients studied had focal plaque detected. It is thus remarkable that large studies of non‐invasive assessments such as DIMPI and carotid ultrasound have all indicated a prevalence of subclinical disease of approximately 35–40%. These studies suggest that atherosclerotic disease is prevalent and present in subclinical form for some years prior to manifesting as a clinical outcome. Since some of the classic atherosclerotic risk factors, especially cholesterol levels, have been suggested as predictors for the development of atherosclerosis in SLE, we studied an inception cohort of 134 patients seen between 1974 and 1987 with respect to cholesterol levels. The cohort was divided into three groups: a group who had normal cholesterol in each of the next 3 yr of their follow‐up; a group that had high cholesterol in each year of the next 3 yr; and a group who had variable cholesterol elevations in at least 1 or 2 of the 3 yr. The outcome evaluated was the time to a first coronary event. The results indicated that patients who had persistently elevated cholesterol had significantly more coronary events than patients who had normal cholesterol at all times. Patients with variable cholesterol levels had an intermediate number of events. Thus, persistently elevated cholesterol is a significant prognostic factor for an adverse atherosclerotic outcome [32]. In addition to dietary factors and genetic predisposition to hyperlipidaemia, therapy has also been found to have an effect on lipid levels, especially in SLE [33]. Steroid therapy has been associated with increased total cholesterol, and lipid subfractions including very low‐density lipoprotein (VLDL‐C) and LDL‐C [34]. High density lipoprotein (HDL‐C) is generally low in active untreated lupus and may actually increase towards normal in steroid‐treated patients. Higher doses of steroids will produce an adverse lipid profile and may thus act as a predisposing factor for atherosclerosis. With regards to anti‐malarial drugs, there is a growing body of evidence that these agents, in addition to their effects on disease activity, may also have beneficial effects on lipid profiles of patients with lupus. We have demonstrated that initiating anti‐malarials in patients not receiving corticosteroids lowered total cholesterol levels but only temporarily [35]. However, in patients receiving a stable dose of steroids there was a statistically significant reduction in total cholesterol over 6 months and in patients using anti‐malarials prior to initiation of corticosteroids there was also a lowering of the incidence of steroid‐induced hypercholesterolaemia [35]. Anti‐malarials were successful in lowering total cholesterol, LDL, and VLDL [36]. The effect was perhaps greatest on VLDL both in the fasting and in the non‐fasting state. Thus, we have shown that hypercholesterolaemia was a poor prognostic factor for atherosclerotic outcomes, and that anti‐malarials could minimize the steroid‐induced hypercholesterolaemia. In addition to lipid abnormalities, there is evidence that other risk factors for coronary artery disease described in the general population may be of some importance in SLE. Hypertension was found to be important in the Pittsburgh study of carotid artery plaque in these patients [31]. Hypertension may be associated with active lupus, renal disease and steroid therapy itself, and it is therefore not surprising that it is a common risk factor seen in patients with SLE [37]. Other risk factors, such as sedentary lifestyle, are common in SLE because of the fatigue associated with the disease and the possible bone and joint injury from the disease or its treatment. Finally, when patients with SLE were compared with a cohort of patients with accelerated atherosclerosis without connective tissue diseases with respect to classic risk factors for atherosclerosis, it was found that patients with lupus generally had one risk factor less than patients with accelerated atherosclerosis and no history of lupus [38]. This may suggest that SLE on its own should be listed as a risk factor for accelerated atherosclerosis similar to diabetes. It is now clearly shown that accelerated atherosclerosis is a common presentation in late‐stage SLE, and therefore patients should be regularly screened to assess the prevalence of coronary artery disease risk factors. We have shown that certain traditional factors, such as cholesterol, play an important role in the development of this disease and these potentially reversible factors should be targeted for intervention. Since patients with lupus are already starting with one risk factor, that is their disease, other risk factors should be interpreted and managed with that in mind. For patients shown to have sustained hypercholesterolaemia, an active management strategy should be undertaken to minimize the dose of steroid where possible, and consider steroid‐sparing agents, especially anti‐malarials, which have a lipid‐lowering effect. Dietary advice and lipid‐lowering drugs should be instituted early where indicated. Other factors, such as blood pressure, smoking and sedentary lifestyle, should be addressed. These facts are clear and it is also clear that rheumatologists and internists have the expertise to follow through on each risk factor investigation and treatment. Unfortunately they do not always do this. In a recent quality improvement study of the Toronto cohort, we found that there was variability in physicians' management of risk factors for coronary artery disease [39]. In general rheumatologists performed well in minimizing steroid use, controlling disease activity and managing hypertension. However, there was much inconsistency in the approach to other metabolic and lifestyle factors such as hyperlipidaemia, obesity, and smoking. While rheumatologists continue to anticipate the time when effective anti‐immunological medications will treat the acute disease process in SLE, they can contribute significantly to decreasing mortality in SLE by focusing on the early diagnosis and preventative therapy of atherosclerotic disease in late‐stage lupus. Enough is known about the investigation and treatment of this condition to effect a significant impact on morbidity and mortality from atherosclerosis in these patients in the later stages in their disease. Rheumatologists need only develop the resolve to assume the primary role in screening and co‐ordinating the management of coronary artery disease and its risk factors in these high‐risk patients. Patients with SLE complain of memory loss and loss of concentration, even in the absence of obvious neuropsychiatric manifestations. Neuropsychological testing has been increasingly used in the assessment of patients both to confirm the presence of active central nervous system (CNS) disease as well as to detect abnormalities in those without overt active cerebral disease [40–47]. This dysfunction is likely multifactorial. Early in the disease it may reflect active neuropsychiatric lupus and late in the course neurodegenerative disease secondary to previous immune damage or therapy for SLE. It has also been suggested that some of the abnormalities detected among patients with SLE may be due to depression or other psychiatric illness in these patients. Also, chronic prednisone therapy has been reported to impair memory [48]. We compared 58 patients with totally inactive SLE (SLEDAI = 0) and 47 healthy controls using a battery of standardized neuropsychological tests to evaluate neurocognitive function. This study showed that 43% of patients with inactive SLE had evidence of neurocognitive dysfunction compared with only 19% of controls. The neurocognitive dysfunction was not explained by psychiatric illness, abnormal neurophysiological studies (brain scan, electroencephalogram) or previous major organ involvement of SLE, atherosclerotic complications, or steroid therapy [49]. Two recent studies suggest that anti‐cardiolipin antibodies may play a role in the neurocognitive dysfunction documented in patients with SLE. Although these studies used different methods to define abnormalities in neurocognitive function, they both suggest an association between anti‐cardiolipin antibodies and neurocognitive dysfunction. Hanly et al. [50] studied 51 patients with SLE of whom 57% had persistently elevated anti‐cardiolipin antibodies over a 5‐yr period. They showed that persistent IgG anti‐cardiolipin antibodies were associated with a reduction in psychomotor speed, whereas IgA anti‐cardiolipin antibodies were associated with impaired conceptual reasoning and executive ability. Menon et al. [51] demonstrated that persistently elevated levels of IgG anti‐cardiolipin antibodies over a 2–3‐yr period were associated with poorer performance in cognitive function, particularly in tasks requiring speed of attention and concentration. It is not yet clear whether patients with SLE neurocognitive dysfunction and anti‐cardiolipin antibodies require anti‐coagulation or whether treating patients with anti‐cardiolipin antibody with anti‐coagulants could prevent this outcome. These questions can only be answered with prospective studies. Although the pathogenesis of neurocognitive dysfunction in patients with SLE remains unclear, it is important that when patients complain of neurocognitive impairment they be tested formally. This provides an opportunity to confirm their dysfunction and follow it. If there is evidence of active neuropsychiatric lupus, or depression, these illnesses should be treated. Patients with evidence of previous CNS clots associated with anti‐cardiolipin antibodies will already be receiving anti‐coagulation. Further study to elucidate the mechanism(s) of this early dementia are needed to develop prevention strategies for this problem. In the interim, approaches to help patients cope with this disability must be developed. Corticosteroids are a known risk factor for the development of osteoporosis. As long as steroids remain the cornerstone of therapy for SLE this complication will have to be addressed. In addition, as patients with SLE survive longer and reach menopause, the post‐menopausal state will be an added risk factor for this complication. Furthermore, patients with SLE are at risk of premature menopause both as a result of the disease or its therapy. Osteoporosis has been formally assessed in pre‐menopausal women with SLE using bone density studies [53–54]. These studies revealed that bone mineral density was lower in SLE patients compared with controls. In addition, these studies suggest a multifactorial aetiology for the osteoporosis as corticosteroids did not appear to be the only determining factor. Similar findings were documented in post‐menopausal females with SLE [55]. Furthermore, this osteoporosis is often clinically symptomatic, as in a study of 702 women with SLE 12.3% reported at least one fracture following the diagnosis of SLE [56]. Women with lupus were almost five times more likely to have a fracture than women of similar age from the US population sample. These studies all indicate that patients with SLE should be treated prophylactically for this complication, and have routine monitoring with bone density studies. Pre‐menopausal women with SLE given corticosteroids should be routinely treated with calcium and vitamin D. In those who develop frank osteopenia bisphosphonates should be prescribed to prevent complications such as vertebral collapse or peripheral fractures. Post‐menopausal women with SLE should in addition to the above treatment be offered hormone replacement. Our studies have indicated that flares in women given hormone replacement therapy are no more frequent than in SLE patients not taking these medications [57]. This pre‐emptive approach to the diagnosis and treatment of osteoporosis could lead to a significant decrease in morbidity in these patients. AVN is a common complication among patients treated with corticosteroids. It has been reported in 10–30% of unselected patients with SLE [58]. The hip is the most commonly involved joint, but most joints in the body can be affected. Up to two‐thirds of patients with AVN will have multiple sites and typically will have been on high‐dose corticosteroids at some time during the course of their illness. There is no clear association with any specific manifestation of SLE, or anti‐cardiolipin antibody [59]. The nature of the early lesion of AVN in SLE is unknown, but may be elucidated with current imaging techniques such as magnetic resonance imaging (MRI) [60]. AVN frequently results in surgical intervention, often total joint replacement. Since this complication is so prevalent and leads to significant disability in young females, measures to lessen its occurrence are important. Steroid use should be minimized using steroid‐sparing agents as appropriate. Fatigue is a very common symptom in SLE and occurs at any time in the course of the disease, even in its inactive phase [61]. Fatigue correlates with fibromyalgia [62], sleep abnormalities [63], depression [64] and poor quality of life [61–63], and is thus a major determinant of morbidity in SLE. Studies are currently underway to elucidate the mechanisms of fatigue in SLE. Until these mechanisms are fully understood, physicians should treat fibromyalgia [65, 66], depression and altered sleep physiology with standard approaches. In addition to the spectrum of features of long‐standing SLE, several other factors contribute to the morbidity among patients with this disease. These include persistent or reactivation of inflammatory disease, infections, and other damage which results from both the disease process and its therapy. Persistent inflammation and reactivation of lupus can occur late in the course of SLE [11]. It is generally believed that disease activity improves in SLE patients who develop end‐stage renal disease [67]. However, recent studies using validated measures of disease activity indicate that there is no decrease in the flare rate during dialysis or transplantation [68, 69]. While it has been suggested that patients with lupus usually flare in the same systems they presented with originally, there is evidence that new organ system involvement can occur at subsequent exacerbations of the disease [70]. At the University of Toronto Lupus Clinic we observed the onset of new disease manifestations after 5 yr of entry to the clinic in 12% of the patients. Thus, patients with SLE should be followed carefully, even when they have demonstrated clinical and laboratory remission. Infection poses a risk for both mortality and morbidity in patients with SLE throughout the course of their disease [71, 72]. There can be multiple system involvement, usually with common organisms, often bacteria, but some opportunistic organisms. Both active disease and drug therapy have been incriminated as risk factors for in a recent study of SLE patients from our the two major factors associated with in a were the use of steroids and Infection is often to in patients with SLE. as well as other and of in may be with active disease. the other the same and of may be by steroid therapy. Moreover, is more likely to occur in the of active lupus, it is often to distinguish between and active disease. Thus, the must be to the of infection, the appropriate for and therapy prior to the of the spectrum are often infections, particularly may occur in patients with SLE and require of The Systemic Lupus in with the of an to damage in patients with SLE in the course of their illness The damage damage resulting from the disease process and its therapy and seen in patients with SLE The as a of morbidity is of mortality and this is a to a population of lupus patients. As patients with SLE their disease manifestations significantly with each of the disease. of the of morbidity in patients with SLE are related to therapy. Thus, physicians should always be in the doses of steroids and use steroid‐sparing agents Until therapeutic to treat the immunological disease more the greatest impact on mortality and morbidity may be by controlling the late‐stage manifestations. D. D.