SYSTEMIC LUPUS ERYTHEMATOSUS IN THE ELDERLY

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GERIATRIC RHEUMATOLOGY

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SYSTEMIC LUPUS ERYTHEMATOSUS IN THE ELDERLY Gary M. Kammer, MD, and Nilamadhab Mishra, MD

Systemic lupus erythematosus (SLE) is an idiopathic autoimmune disorder that predominantly afflicts women in the childbearing years.@ SLE is acknowledged as a multigenic disease in which environmental factors are likely to modulate expression of susceptibility genes.40In addition to the environment, evidence supports the concept that the geographic origin of populations and age affect the presentation and clinical course of SLE.8, 33 Together, these factors contribute to the prevalence of SLE, which approximates 14.6 to 50.8 cases per 100,000 people in the United States. During the past two decades, epidemiologic analyses have revealed that SLE can present de novo in people in the sixth decade of life and Presentation and clinical course of the disease often differ from that observed in persons whose disease onset is in the second through fourth decades. An abnormal immune response involving both the cellular and humoral arms of the immune system has been well characterized in SLE, and continues to be the focus of intensive scrutiny.' Whether the mechanisms underlying the abnormal immune response in youngeronset SLE are similar to or different from that in older-onset lupus remains largely unexplored. This article reviews recent information about the epidemiology, This work was supported in part by grants from the National Institutes of Health ( R 0 1 AR 39501) and the Lupus Foundation of America.

From the Section on Rheumatology and Clinical Immunology, Department of Internal Medicine, The Wake Forest University School of Medicine, Winston-Salem, North Carolina

RHEUMATIC DISEASE CLINICS OF NORTH AMERICA

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VOLUME 26 * NUMBER 3 AUGUST 2000

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immune response, clinical presentation, laboratory findings, treatment, and prognosis in late-onset SLE. Because SLE has a higher incidence in younger and middle-aged adults and its clinical manifestations during these periods are more familiar, the clinical presentation and course of older and younger cohorts is compared whenever possible. Such a comparison will underscore the differences and the similarities of the clinical manifestations and will provide new insights and understanding of how age affects the clinical presentation of SLE.

EPIDEMIOLOGY OF LATE-ONSET SLE

Based on epidemiologic studies, late-onset SLE is generally defined as onset of symptoms and signs greater than or equal to 50-55 years of age. Table 1 summarizes the demographics and characteristics of lateonset SLE in 10 independent analyses published between 1979 and 1998. Several points are notable. First, female predominance is reduced from 9 to 1 in younger-onset disease to 6.9 to 1 in late-onset SLE, although the range is quite broad. Second, the mean interval between time of onset of symptoms and signs to diagnosis is about 32.5 months, a relatively long interval. Finally, analyses of Western series that indicated race, suggest that a transition from African-American to White predominance may occur with aging. In one analysis that addressed the racial distribution of SLE in different age groups, Ballou et allofound that 59% of the younger-onset subjects were black whereas 80% of late-onset subjects were white. Interestingly, 5-year survival rates for youngeronset (79%)and late-onset (72%)groups were comparable. Although the reasons for this disparity in racial composition between the age groups remain incompletely explained, it is likely that genetic factors impact on the age of presentation. It is also conceivable that nongenetic, environmental, and life-style factors may affect this distribution. Lower socioeco-

Table 1. DEMOGRAPHICS AND CHARACTERISTICS OF LATE-ONSET SLE

Authors

Age at Onset (Range in Years)

Women:Men*

Baker et a19 Ballou et allD Catoggio et a12' Cervera et a12* Costallat et aIz5 Font et a134 Ho et a145 Koh et a157 Maddison68

52-83 55-72 57-71 51-78 >50 50-78 51-86 50-73 61-85

4:l 3:l 130 5:l 1O:l 4:l 3:l 5:l 18:l

*Mean of wornexmen ratio

=

6.9:lS;tmean

I+_

Race (6lack:White)

SD duration

Time from Onset Diagnosis (Months)t

1:13 1:4 0:13 0:lO

-

Chinese Chinese

-

=

32.5 2 17 months.

36 24-36 48 24 60 14 8 40

SYSTEMIC LUPUS ERYTHEMATOSUS IN THE ELDERLY

477

nomic status and certain environmental factors may be associated with 54, 66 more severe disease activity of SLE.24, Of interest are two recently-published analyses of late-onset SLE in Chinese.45,57 As shown in Table 1, the demographics are very similar to those of Western studies. These data suggest that, at least in Asian subjects, there are essentially no differences in the demographics of lateonset SLE.

CLINICAL FEATURES OF LATE-ONSET SLE

The duration between time of symptom onset to diagnosis extends over 48 months in late-onset SLE (Table 1). During this long hiatus, symptoms and signs usually are quite variable and recredescent, often making the diagnosis problematic and difficult to establish. Interestingly, the disease may even resemble polymyalgia rhe~matica.~~, When compared with younger-onset SLE, there is a shift in the prevalence of signs in late-onset disease. Although arthritis and arthralgia and rash remain the most frequent signs in both early- and late-onset SLE, there is an increase in the frequency of interstitial pneumonitis, serositis, and 91, lo3 hematocytopenias in late-onset disease (Tables 2 and 3).9,lo, 15, Also seen in an increased prevalence during late-onset SLE are peripheral n e ~ r o p a t h y57~and ~ , a constellation of features suggestive of secondary Sjogren’s syndrome.47, By contrast, alopecia, malar rash, photosensitivity, oral and nasal ulcers, glomerulonephritis, and lymphadenopathy have a lower prevalence in late-onset compared with early-onset SLE.” 25, 34, 47, 57, Io3 Table 2 summarizes 11 studies in which an increased or decreased prevalence of particular clinical features were observed in late-onset lupus. 57, 91, lo3 As Late-onset lupus tends to be a relatively mild disorder.22, such, lupus has not usually been implicated as a principal cause of death in subjects with late-onset disease. Instead, causes of death are usually the result of infections, perforated peptic ulcers, cardiovascular disease, or undefined origins.22,25, 57 Compared with rheumatoid arthritis or progressive systemic sclerosis, there is a lower risk for all cancers except non-Hodgkin’s lymphoma in SLE,2 which may explain the absence of malignancy as a cause of death in one series.”

RADIOGRAPHIC FEATURES OF LATE-ONSET SLE

Only a single study has focused on the radiographic features of lateonset SLE.I5 The only significant finding was an increased prevalence of soft tissue swelling on hand and wrist radiographs consistent with clinical symptoms and signs of arthritis. As shown in Table 3, there is a high prevalence of arthritis in late-onset SLE. A proportion of this arthritis, however, may be osteoarthritis and chondrocalcinosis. Of par-

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Table 2. CLINICAL FEATURES OF LATE-ONSET SLE

Baker et a19

Skin rashes Alopecia Adenopathy Raynauds Neuropsychiatric Hypocomplementemia Arthritis Anti-RNP

Ballou et all0 Catoggio et a121 Cervera et

Costallat et a125 Domenech et a127 Font et aP4

Hochberg et ai47 Koh et a157 Maddison et a P Urowitz et al9I

Prevalence (Increased)

Prevalence (Decreased)

Authors

Malar rash Arthritis Photosensitivity Thrombosis Nephropathy Nephropathy Malar rash Livido reticularis Arthritis Malar rash Photosensitivity Nephropathy Alopecia Mesenteric vasculitis Nephritis Malar rash Alopecia Arthritis Raynaud's Arthritis

Pulmonary

Serositis Pulmonary Anti-IgG Anti-SSAISSB Sjogren's syndrome

Pericarditis Thrombocytopenia Sjogren's syndrome Cardiomyopathy Myositis

Neuropathy Sjogren's syndrome Anti-SSA / SSB Elevated liver enzymes Neuropathy Pancytopenia Myositis Pulmonary Sjogren's syndrome

Skin rash Arthritis Adenopathy

Table 3. THE FREQUENCY OF SYMPTOMS AND SIGNS OF SLE IN THE OLDER ADULT* Frequency Syrnptoms/Signs

("/.I

Arthritis/ arthralgia Cytopenias Glomerulonephritis (all types) Interstitial pneumonitis Neuropsychiatric Peripheral neuropathy Rash Raynaud's phenomenon Serositis

60.2 44.8 24 40.8 24.5 25 46.8 28 31.9

'Data from references 9, 10, 21, 22, 25, 27, 34, 47, 57, 68, and 91

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ticular interest was the absence of radiographic evidence of pleuropericardial disease that is observed clinically in late-onset SLE. Although the reasons for this disparity between clinical and radiographic findings remain unexplained, a more recent comparison of radiographic and computed tomographic analyses of the lung in SLE may shed some light on this issue.'l The results of this study revealed that CT of the lung is superior to chest radiography for detection of functionally relevant parenchymal and pleural disease. It is conceivable that the earlier study using chest radiography, performed before the widespread availability and use of chest CT, may have been sufficiently insensitive to identify clinically suspected pleuroparenchymal disease in late-onset SLE. CELLULAR AND HUMORAL IMMUNE RESPONSE: COMPARISON BETWEEN HEALTHY ELDERLY AND LATE-ONSET SLE To understand why some people, who have enjoyed good health throughout their middle age, develop autoimmune disorders such as SLE in late life, it is instructive to first examine what happens to immunity during the aging process. Aging is associated with a dramatic decline in immunity in healthy males and females. This altered immunity, which occurs gradually over decades, generally results from diminished cellular immunity and, ultimately, gives rise to enhanced autoantibody production. It has long been suspected that this dysregulated autoantibody generation may be the product of altered intrinsic T cell, B cell and antigen-presenting cell (APC) functions. To understand the altered immune response in healthy elderly people, recent studies have taken several tacks, including: (1)quantifying T cell-subsets; ( 2 ) quantifying cell-surface expression of receptors; (3) measuring cytokine production by T cells and APCs; and, (4) investigating signaling pathways. Importantly, these detailed analyses have revealed unanticipated, often striking alterations that may contribute to immunosenescence. Earlier analyses of T cell functions in the mid-1980s first pointed to altered cellular functions and raised the possibility of a primary immunosenescence. The results of these experiments in healthy elderly subjects revealed impaired directed mobility of CD3 in the plane of the membrane (i.e., capping), diminished T cell proliferation to anti-CD3 mAb, and markedly reduced production of B cell growth factors.loO Unexpectedly, the prevalence of these altered cellular responses was 50% to 80%, a strikingly high occurrence in this population of well elderly people. The T lymphopenia seems to be caused by a contraction in the T cell compartment and shifts in the proportions of subpopulations within the T cell compartment. This contraction affects the CD4 and CD8 subpopulations.12 Interestingly, this relative contraction in the T cell compartment is associated with a concomitant increase in the proportion of both CD4 and CD8 T cells bearing the CD45RO memory phenotype

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and a decrement bearing the CD45RA phenotype.30Of especial interest was the observation that mitogen-activated T cells express less CD154 (CD40 ligand), and that there is a concomitant reduction in CD40+ APCs, such as monocytes and B cells.62Surprisingly, there also is an increased proportion of spontaneously activated T cells expressing the IL-2a receptor, CD25.lZThe mechanism underlying this activated state remains uncertain. In centenarians, there is a significant decrement in the proportions of CD4 and CD8 T cells expressing the CD28 coreceptor, 29 At although the CD8 subset seems to be preferentially affe~ted.'~, present, a decade-by-decade analysis of CD28 expression has not been performed, so it is uncertain whether this altered CD28 expression also is a gradual, age-related manifestation that is associated with contraction of the T cell compartment. Although the molecular mechanism(s) underlying loss of CD28 expression remains to be established, it has been proposed that the absence of CD28 coreceptor expression may account for the well-known decline of T cell proliferation in response to antigens and mitogens. Taken together, these results reveal that there is marked skewing of expression of certain cell surface receptors in senescent T cells compared with young controls. Such skewing of surface receptor expression would be expected to be associated with altered cytokine responses to antigens and mitogens in vitro. In five analyses to date, either purified T cells or peripheral blood mononuclear cells were activated in vitro by various T-celldependent or-independent mitogens or antigens over various intervals.lz,19, 20, 30, Because the results were quite variable, a precise trend in the senescent T cell response cannot be ascertained with certainty. Notwithstanding, IL-1p and TNF-a were increased in two studies and IL-10 in one study. By contrast, IL-2, IFN-y, and IL-12 were reduced in other studies. Together, these data raise the possibility that there is impaired induction of the T,1 response and that certain pro-inflammatory cytokines are overproduced. Overproduction of IL-6 and IL-10 in two studiesz0,30 suggests that these cytokines might promote autoantibody formation, known to occur with higher frequency in healthy elderly people. Nonetheless, this remains a tentative and preliminary conclusion, because another study failed to document heightened production of IL-10 in vitro by activated T cells from healthy elderly subjects. Moreover, neutralization of IL-10 in vitro also did not inhibit autoantibody f ~ r m a t i o nFurther .~~ detailed assessments of cytokine gene and protein expression will be necessary to sort out these disparate findings and to better understand the mechanisms governing altered immunity in healthy elderly persons. To ascertain whether a disorder primary to the senescent T cell may account for impaired IL-2 production and diminished proliferation, Whisler and his colleagues99have examined several mechanisms underlying signal transduction in these cells. Although T cells from elderly donors have a similar cell surface epitope density of CD3 and a / p T cell receptor (TCR) subunits, coupling of 5 chains to the syk protein tyrosine kinase, zeta chain-associated protein (ZAP)-70, following crosslinking by anti-CD3 yielded less than one half the amount of tyrosyl

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phosphorylation of 5 chains in T cells from elderly subjects compared with younger Because this diminished 5 chain phosphorylation could not be accounted for on the basis of reduced 5 chain protein content, this raised the possibility that src nonreceptor protein tyrosine kinase activities may be impaired. Compared with younger controls, Whisler and his associate^^^ found that p59Fyn and p56Lck activities were markedly diminished in T cells from elderly subjects, and that these altered activities were unrelated to any decrement in enzyme protein content. No changes in protein tyrosine phosphatase activities could be identified to account for the impaired tyrosyl phosphorylation. These data suggest that, in most T cells from well, elderly donors, the protein tyrosine kinase activities of Fyn, Lck, and ZAP-70 were markedly impaired. A principal signaling pathway in human T cells is the mitogenactivated protein (MAP) kinase cascade. Based on current understanding, signals propagated from the TCR/ CD3 complex through protein kinase C isozymes activate the more distal MAP kinase pathways leading to activation of ERK1/2, JNK, and p38 k i n a ~ e s .In ~ ~turn, these kinases phosphorylate nuclear transcription factors, such as c-Myc, Elk1 and c-Jun, resulting in activation and binding of these nuclear transcription factors to their respective response elements on promoter / enhancer regions of particular genes. For example, IL-2 transcriptional regulation is controlled, in part, by the c-Jun/ c-Fos heterodimer termed activator protein-1 (AP-I) and by NF-AT and NF-KBtranscription factors. T cells from well, elderly donors often exhibited significantly reduced MEKl / MEK2 and ERKl / 2 activities following in vitro stimulation. That there was no reduction in the amount of kinase protein content suggested that the signal from the proximal segment of the pathway may be diminished. This impression was further buttressed by the demonstration that potent activators, such as phorbol esters, Ca' + ionophores or phosphatase inhibitors, did not restore MAP kinase activities in senescent T cells.1o1Moreover, further analyses of transcription factors regulating IL-2 production, such as AP-1, NF-AT, and NF-KB, demonstrated that there was a correlation between reduced IL-2 production and reduced AP-1 and NF-AT binding in electromobility shift assays in senescent T cells.97When a more detailed examination of the AP-1 transcription factor was undertaken in in vitro stimulated senescent T cells, it was learned that c-Fos, but not c-Jun, protein expression was markedly diminished. RNase protection assays, however, revealed that the amounts of transcripts of c-Fos and c-Jun were reduced compared with T cells from younger subjects.98Overall, then, these observations from carefully performed analyses point to multiple defects in the signaling apparatus in senescent T cells. Furthermore, this important information provides a window into the senescent T cell, and suggests that immunosenescence is, in part, a primary T cell disorder. Thus, immunosenescence may be the product of down-regulation of genes whose products coordinately govern T cell effector functions. Detailed analyses of signal transduction also are being carried out in younger SLE subjects, and have revealed that their T cells exhibit

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KAMMER & MISHRA

profound biochemical defects+*,52, 53, 63, @,93 Notwithstanding, it is still uncertain precisely how altered signal transduction in SLE T cells leads to T-cell dysfunctions, such as increased CD4 help and diminished CD8 cytotoxicity. One potential mechanism may be that altered signaling results in dysregulation of transcriptional regulation, yielding up-regulation and expression of certain genes and down-regulation and silencing of others. To date, these types of studies have not been performed in T cells from late-onset SLE. The changes leading to T-cell immunosenescence may create subpopulations of autoreactive T cells. Such cells may provide inappropriate help to forbidden, autoreactive B-cell clones, and, in the presence of impaired down-regulation by CD8 cells, could result in autoantibody generation. Indeed, current evidence suggests that well, elderly people produce an array of autoantibodies (Table 4).32, 48, 51, 71, 86, 87 In addition to immunoglobulin M (IgM) and immunoglobulin G (IgG) rheumatoid factors that occur in approximately 10% of people, nonpathogenic antidouble-stranded DNA autoantibodies have been found in 7.6% of well elderly by the highly specific Crithidiu ZuciZiae fluorescent assay in one analysis. Interestingly, these autoantibodies differ from those typically seen in SLE in that they are of the IgA isotype, noncomplement-fixing, and undetectable by the sensitive Farr radioirnmunoa~say.~~ Although the increased frequency of ANAs in well, elderly subjects may complicate the interpretation of the serologic findings in late-onset SLE, seven studies have demonstrated an unequivocal increase in the frequencies of other autoantibodies and hypocomplementemia in lateonset SLE (Table 5). In particular, three analyses revealed that 92% and 52% of individuals had significantly increased frequencies of autoantibodies directed against Sjogren Syndrome A (SSA)/ Ro and Sjogren Syndrome B (SSB)/ La autoantigens, respectively.21,25, 68 Nevertheless, the prevalence of anti-SSA/Ro in all studies was 2% to loo%, and 2% to 63% of anti-SSB/La. This range is unusually broad, suggesting that perhaps differences in the immunogenetic makeup of the populations studied, the extent of altered tolerance to SSA and SSB autoantigens,l6.70

Table 4. THE FREQUENCY OF AUTOANTIBODIES IN THE HEALTHY ELDERLY

Fields et aP1 Goodwin et a13’ Hooper et a148 Juby et al5I Manoussakis et a17* Ruflatti et a178 Slater et aIR6 Svec et al”

18 18 22 8 31

13 14 13 3 14 8

14

52

28 16

*ANA = antinuclear antibody; tRF = rheumatoid factor; tdsDNA = anti-double stranded DNA autoantibody; SACL = anticardiolipin autoantibody

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Table 5. PROPORTION OF PATIENTS WITH LATE-ONSET SLE EXPRESSING AUTOANTIBODIES AND/OR HYPOCOMPLEMENTEMIA (IN PERCENTAGES)* Author

ANA

Catoggio et a12* 85 Cervera et al" 97 Costallat et alZ5 88 Domenech et alZ7 67 Font et a134 97 Ho et a145 100 Koh et a157 96 MaddisonM 95

dsDNA

SSA

31 77 88 33 33 86 84 53

92 16 100 13 10 60 34 84

SSB Srn RF RNP ACL 61 6 33 13 5 8 7 63

0 5 0 0 13 24 21 0

85 21 0 32 23 63

0 5 0 7 5 20 17 0

LAC

28

13

33 63

7

JC4/C3

13 78 53

*ANA = antinuclear antibody; dsDNA = anti-double stranded DNA autoantibody; SSA = antiSSA/RO autoantibody; SSB = anti-SSB/La autoantibody; Sm = anti-Sm autoantibody; RF = IgM rheumatoid factor; RNP = anti-(U1)RNP autoantibody; ACL = anticardiolipin autoantibody; LAC = lupus anticoagulant; 1 C4/C3 = hypocomplementemia.

a reduced ratio of women to men, and environmental factors may impact on the frequency of these autoantibodies. Moreover, this work was conducted over a period during which the immunoassays were being modified and refined to enhance their sensitivities, which may account in part for the discrepant results. By contrast, about 62% of persons with late-onset SLE had anti-dsDNA autoantibodies (Table 5), a value similar to that in early-onset SLE.4I Because anti-dsDNA autoantibodies are highly specific and sensitive for SLE observed in younger and middleaged patients,46the autoantibody can be used to substantiate the diagnosis and to monitor disease activity in elderly persons with symptoms compatible with late-onset SLE.21, 25, 57 DIAGNOSIS OF LATE-ONSET SLE

A principal difficulty in making the diagnosis of SLE is a lack of awareness that the disease may affect the elderly. Vague ill health, characterized by weight loss, muscular aches and pains, and various disturbances of cognition or affect, is not infrequent in the elderly and may be the initial manifestations of lupus. In addition to the atypical clinical features, a second reason for the delay in diagnosis is that infections and endocrinopathies are far more common in this population. It often requires time and extensive testing to finally exclude these health problems before disorders, such as lupus, are considered. Yet, a third limitation is that the antinuclear antibody (ANA) is not a useful screening test for SLE in the elderly, because up to 36% of healthy older people may have nonspecific, low-titre AN AS.^^, 37, 48, 51, 71*86, 87 Titres that are less than twice the normal limit should be viewed skeptically. Because a titre of less than or equal to 1:50 in our Special Rheumatology Laboratory is within normal limits, the author regard titres of less than or equal to 1:lOO as a gray zone and recommend repeating the test in 3 to 6 months. The positive predictive value of the ANA tends to increase

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KAMMER & MISHRA

with progressively higher titres. Because autoantibodies directed against dsDNA and Sm are pathognomonic for SLE4I,82 and the frequencies of these autoantibodies in late-onset SLE are about 60% and 8% (Table 5),21, ~ 2 25, , 27, 34, 36, 57 respectively, the anti-dsDNA autoantibody may assist in the diagnosis of the disease in approximately three fifths of subjects and, therefore, should be determined. Even in the elderly, the diagnosis of SLE is apparent more when three or four typical manifestations can be identified.**More commonly, however, symptoms such as arthritis and arthralgias of the hands and wrists, rash, Raynauds phenomenon, vague central nervous system symptoms (eg., headache, memory loss, lack of concentration, irritability, anxiety), and a weakly positive ANA tend to be the rule. In that event and even in men, it is important to consider late-onset SLE and to follow the patient over time for evidence of evolving disease. TREATMENT Treatment is dictated by the disease manifestations. Because disease activity tends to be mild in late-onset SLE, the greater risks for untoward side effects associated with treatment with corticosteroids and immunosuppressive agents can often be avoided. Also, elderly persons are more likely to be taking multiple medications, and errors in medicine-taking and noncompliance are increased. Moreover, the pharmacokinetics of drugs often are altered in the elderly owing to impaired absorption, distribution, metabolism, and excretion of drugs. Arthritis and serositis are inflammatory conditions and are, therefore, optimally managed by use of a non-narcotic, anti-inflammatory analgesic. Here, a goal is to avoid the use of corticosteroids in the absence of other associated lupus disorders, such as glomerulonephritis or vasculitis. In the elderly, one can initially make use of a nonacetylated aspirin, such as choline magnesium salicylate. An alternative choice is a nonsteroidal anti-inflammatory drug (NSAID). A history of peptic ulcer disease, congestive heart failure, renal or hepatic insufficiency, or warfarin therapy, however, are relative contraindications to the use of NSAIDs. The recent availability of two cyclooxygenase-2 (COX-2)-specific inhibitors may reduce the untoward gastrointestinal complications and other adverse events of NSAID therapy,75although their safety and utility in the elderly still remains to be demonstrated. Failure of these agents to control the inflammatory response and pain may necessitate a short course of corticosteroids. Often, such a course is given in combination with an analgesic. For mild to moderate pain, acetominophen or a propoxyphene-acetominophen combination often is well tolerated and provides effective analgesia without untoward drug effects. Although experience with tramadol (Ultram) as an analgesic in the elderly is still limited, initiation of low-dose therapy and titration to symptoms may prove to be a useful alternative to acetominophen, particularly with moderately severe pain. If tramadol is selected, however, one must be mindful of potential adverse interactions with

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selective serotonin reuptake inhibitor (SSRI) antidepressants that can lead to a serotonin syndrome. This newly identified reaction, which usually occurs within a few days, results in nausea, sweating, muscle weakness or tremor, and, potentially, confusion. A useful paradigm for the treatment of chronic pain in the elderly has been proposed.79Whatever the choice of agent, round-the-clock administration of analgesics generally provides more effective control of pain. The antimalarial agents, chloroquine, hydroxychloroquine (HC), and quinacrine, traditionally have been used for the effective treatment of rashes and arthritis.58,67, 73 My anecdotal experience is that HC is well tolerated, reduces the frequency and intensity of joint and skin involvement, and diminishes the inflammatory response (as evidenced by a drop in the erythrocyte sedimentation rate and extent of polyclonal hypergammaglobulinemia).In younger onset SLE associated with severe skin eruptions, it is sometimes necessary to combine HC and quinacrine for a synergistic effect. Current evidence strongly supports its long-term use in SLE.I7,90 To date, however, there have been no prospective studies of antimalarial agents in late-onset SLE. As long as these agents are monitored appropriately, however, there would appear to be no specific contraindication to their use in the elderly?" 94 Like younger patients, elderly lupus patients also are potentially at increased risk for retinopathy, cardiomyopathy, heart block, dyskinesia, and myopathy, although the frequency of these adverse effects is low. It is recommended that patients who receive antimalarial agents have pretreatment eye assessment and regular follow-up examinations every 6 months by an ophthalmologist to avert either ectopic corneal pigment deposition or maculopathy76

Lupus pneumonitis, thrombocytopenia, and hemolytic anemia require corticosteroid therapy. As anticipated, there is a higher incidence of debilitating steroid complications in the elderly, including osteoporotic vertebral compression fractures, aseptic necrosis, and sepsis. Other problematic adverse effects that seem to be more frequent in older patients are steroid atrophy, purpura, electrolyte disturbances, fluid retention, hypertension, and glaucoma; however, psychiatric disturbances do not appear to be more frequent or severe in the elderly treated with cortico81

Several measures may reduce the troublesome and debilitating untoward effects of corticosteroid therapy. Baseline and periodic measurements of intraocular pressure permits early detection of glaucoma and, incidentally, cataract formation. Use of steroid-sparing agents, such as HC or methotrexate (MTX), may allow tapering of steroids to lower dosages over time. Of the potential MTX-related side effects identified, only hepatic toxicity may be more common in the elderly. There is no definite contraindication to the agent's use in the late-onset SLE. Although dapsone is an effective anti-inflammatory agent and also has been promoted as a steroid-sparing agent, its proclivity to induce methemoglobinemia may hamper further oxygenation in subjects with pre-existing hypoxemia caused by chronic interstitial fibrosis or chronic

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KAMMER & MISHRA

obstructive pulmonary disease. Therefore, if dapsone is selected as a steroid-sparing agent, venous methemogloblin levels must be monitored assiduously. Also, because dapsone is a sulfonamide derivative and subjects with lupus have a greater frequency of sulfonamide hypersensitivity, it is advisable to obtain a history of such sensitivities before prescribing dapsone. Although the prevalence of glomerulonephritis is reduced in lateonset compared with younger-onset lupus, it still complicates the course of disease in about one fourth to one fifth of subjects (see Table 3). To date, there are no prospective studies of lupus glomerulonephritis in the elderly, so no specific guidelines exist for this age population. Because the same concern of renal failure exists in late- as earlier-onset SLE,”7, 28, 59, 69 a similar treatment regimen of corticosteroids and intravenous pulse cyclophosphamide (CY) as that used in younger persons is generally administered. One must be mindful of the many potential untoward responses of CY. Among such adverse effects, one must be particularly concerned about protracted nausea and vomiting resulting in dehydration and hypovolemia, myelosuppression resulting cytopenias, hemorrhagic cystitis, and superinfection. Among infections, Herpes zoster may be a potentially serious, painful and debilitating complication in the elderly. In one study of unselected SLE patients, immunosuppressive therapy with CY or azathioprine (AZA) was identified as a risk factor for Herpes zoster.” Interestingly, clinical infection with Herpes zoster resulted in a benign course in that study. In fact, clinical Herpes zoster infection was a relatively common untoward effect in several recent studies of CY in lupus nephritis.23,26, 39, 72 Use of a nucleoside analogue, such as valacyclovir or famcyclovir, for Herpes zoster, often with continued use of prednisone,*02may shorten the duration of postherpetic neuralgia in Io4 Of concern, however, is that sepsis leading to shock older and death may Discontinuation of immunosuppressive therapy, however, may not be necessary,72although altering the dosage of CY may reduce the frequency and severity of these untoward events without limiting the efficacy of therapy.35 Central nervous system (CNS) manifestations of lupus are less common in late-onset than early-onset di~ease.8~ Overall, about one quarter of elderly individuals with lupus exhibit neuropsychiatric complications (see Table 3). When CNS dysfunction owing to metabolic abnormalities, occult seizures, drug toxicity, or depression are excluded, neuropsychiatric lupus must be c o n ~ i d e r e d Criteria .~~ for this diagnosis have been recently p ~ b l i s h e d . ~ Cognitive and motor deficits also may arise from stroke. In the elderly lupus patient, multiple causes of stroke may exist, including 6o Although hypertension and antiphospholipid antibody the mechanism(s) underlying stroke in the presence of antiphospholipid antibodies remains incompletely understood, a hypercoagulable state may contribute to the evolution of stroke. Careful consideration should

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then be given to use of low-dose aspirin versus warfarin anticoagulation. The selection of therapy depends upon the presence or absence of transient ischemic attacks (TIAs), documentation of multiple strokes, a history of hypertension and peptic ulcer disease, the presence of antiphospholipid autoantibodies, and thrombocytopenia. The authors recommend that this therapeutic decision be made in consultation with a neurologist and a hematologist expert in clotting disorders. Because some investigators regard neuropsychiatric lupus to be an immune-mediated disease resulting from other autoantibodies, including cross-reactive antilymphocyte antibodies, rather than an effect of chronic illness,ls~ 50* 89 recent trials of therapy have targeted the immune system by treatment with immunosuppressive and anti-inflammatory agents.'" 74, 92 Cautious interpretation of these preliminary results suggests efficacy of this therapy.

SUMMARY

Aging modifies the clinical presentation and course of autoimmune disorders, although the mechanisms by which this occurs remain to be determined. Current evidence cited above supports the general concept that there is a natural senescence of the immune system. This evidence would suggest that somehow senescence directly affects gene expression, resulting in biochemical abnormalities that culminate in T-cell immunodysfunctions. This may be a principal factor that attenuates the autoimmune response to self-antigen and, therefore, the disease course. The authors speculate that there is a disorder primary to the T cell in SLE that is expressed as abnormal immunologic responses to selfantigens, resulting in autoimmunity. Although understanding of this primary T cell disorder is still limited, clinicians now know that the T cell harbors abnormal signaling pathways that reflect defective biochemical functions and seem to be genetically reg~lated.5~ This aberrant signaling would be anticipated to affect both principal T cell subsets. It may hinder the capacity of cells, such as CD8 T cells, to effectively downregulate the response of autoreactive CD4 helper T cells to autoantigens. Loss of self-regulation would manifest itself as loss of tolerance, a fundamental component of a~toimmunity.~~ The future challenge is to understand how aberrant signaling leads to loss of tolerance. Given this underlying genetic susceptibility in an aged individual whose T cells also are undergoing natural senescence, the authors suggest that it is conceivable that a stress factor may tip the balance in the favor of clinical disease. One such factor may be unspecified environmental stimuli. Yet another consideration is an intercurrent illness, such as an infection. It remains to be determined, however, what these environmental stimuli are and how they impact on the immune system to trigger disease.

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Address reprints requests to Gary M. Kammer, MD Section on Rheumatology and Clinical Immunology The Wake Forest University School of Medicine Medical Center Boulevard Winston-Salem, NC 27157 e-mail: [email protected]