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ELDERLY-ONSET RHEUMATOID ARTHRITIS
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GERIATRIC RHEUMATOLOGY
0889-857X/OO $15.00
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ELDERLY-ONSET RHEUMATOID ARTHRITIS Yusuf Yazici, MD and Stephen A. Paget, MD, FACE FACR
Rheumatoid arthritis (RA) is a systemic, inflammatory disorder affecting primarily women with a peak incidence between 30 and 50 years of age and an average age of onset of 55 years.20At this time, one third of patients acquire RA after the age of 60, and the prevalence increases with advancing age into the eighth decade. This is particularly important because of the growth of the proportion of older persons in our population and the potential implications for the care of these patients in the next century. If, as some authors have espoused, elderlyonset RA (EORA)beginning after 60 years of age is a distinctly different disorder from younger-onset RA (YORA), physicians must be aware of this and its diagnostic and therapeutic significance. The following profile of EORA, as distinct from YORA, has evolved from many clinical studies that vary in their design, control groups, and length of follow-up6f11. 14, 24. 26. 30. 1. More equal sex distribution: Whereas YORA is more common in women than in men by 3:1, in the older group, the ratio is closer to 1:l. 2. Acute onset: In YORA, an insidious onset is the most common. In EORA, there is a tendency for the onset to be acute and infectious-like. 3. More frequent involvement of large, proximal joints (i.e., shoulders): The characteristic presentation of RA is in the small joints of the hands and feet. In EORA, patients are more likely to develop proximal symptoms, more akin to polymyalgia rheumat-
From the Division of Rheumatology, Department of Medicine, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, New York
RHEUMATIC DISEASE CLINICS OF NORTH AMERICA
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VOLUME 26 * NUMBER 3 AUGUST 2000
517
518
YAZICI & PAGET
ica (PMR). This is particularly important because there is a strong consideration given to the possibility that EORA and PMR, and even remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome, may be parts of a single spectrum of inflammatory disorders of the elderly. 4. More systemic manifestations and higher ESR at onset: Fatigue, weight loss, and elevated ESR may be manifestations YORA and EORA. They appear, however, to be more prominent in EORA, a fact that might relate to some basic differences in etiology, cytokine profiles or treatment options. 5. Lower frequency of rheumatoid factor (RF) positivity: In YORA, approximately 80% of patients are seropositive. Whereas in some EORA series, this frequency is between 66% and 89%, others show levels as low as 32%. This may reflect differences in study populations or might relate to changes in the immune system that occur with aging. 6. Worse outcome: The greater functional limitation and severity of joint damage in some patients with EORA may be explained by the effect of comorbid disease in the elderly or changes in the balance between damage and repair as people age. Immunosenescence, genetics, and hormonal factors are probably important variables in the observed difference between EORA and YORA. All these factors have age-related changes that can fundamentally affect how the body responds to disease-causing or -modifying factors. IMMUNOSENESCENCE
Alterations in the immune system that occur with age are listed below. Age-related changes in the immune system
Thymic involution Changes in functional phenotypic characteristics of T cells Decline in specific antibody responses Age-related defects in apoptosis Cytokine imbalance Deficiencies in antigen processing Some or all of these might alter the response to antigens or the disease presentation in the aged. With age, the capacity to generate protective immune responses declines, whereas reactivity to autoantigens in~reases.3~ The elimination of self-reactive T cells that bind with high affinity to autoantigens present in the host’s human lymphocyte antigens (HLA) molecules and the expansion and release of T-cellsbearing receptor molecules that react only with low affinity are central in establishing self-tolerance within the immune system. This process
ELDERLY-ONSET RHEUMATOID ARTHRITIS
519
takes place in the thymus and the thymus undergoes drastic age-associated involution. This can lead to fundamental alteration in the composition of the T-cell compartment. Also, decreased T-cell proliferation and cytokine production after stimulation in vitro, increased IgG and IgA Ievels, and decreased antibody formation after vaccination accompany aging.3z Animal models of autoimmune diseases show age-related changes but are not conclusive. Some studies showed decreased incidence and severity of collagen-induced arthritis in aged DBA / 1Lac mice, whereas albumin-induced arthritis in C57B1/ 10 mice became chronic and more destructive in older female anirnal~.~, 31 Similar differences in disease manifestations with different age groups has also been shown in other inflammatory connective tissue diseases. Polymyositis starting after age 50 is associated with increased mortality, as is scleroderma. Nephropathy and central nervous system involvement in SLE are less common in older patients than in younger ones.33 Changes in the immune system with aging may be contributing to the differences between EORA and YORA. The extent of this remains to be defined clearly. GENETICS There is a well-established association between RA and certain class I1 major histocompatibility alleles, most specifically DR4. This genetic marker appears to be linked to an increased propensity for and severity of RA and has a strong association with the presence of rheumatoid factor positive RA. Some studies, but not all, have even shown such an association with seronegative disease, regardless of age. In several studies, EORA patients were HLA-typed.", 24 All confirmed the same DR4 linkage with seropositive disease that has been demonstrated in YORA. Sixty percent of patients were DR4 positive, spanning from ages 16 to 86. No such association, however, could be found in elderly seronegative RA patients. Genetic susceptibility to seropositive RA seems to remain the same at all ages. HORMONES
The possibility that sex hormones play an important role in the clinical presentation of RA is supported by the fact that the inflammatory process improves significantly during pregnancy in a large proportion of patients.I7 The development of RA is decreased in frequency in patients on oral contraceptive^.^ Exogenous estrogen administration, however, does not decrease disease activity and the differences in hormone levels between women and men do not correlate with the disease outcome.'2,26 It is of note that there is a declining incidence of RA in women
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YAZICI & PAGET
after menopause, at a time when lower estrogen and progesterone and increased androgen levels are found. This needs to be interpreted alongside the fact that decreasing androgen levels parallel an increasing incidence of RA in older man.28These apparently conflicting findings are probably a reflection of the complicated balance that exists between these three hormones and their interplay with the immune system. COMORBITIES
In the elderly, RA often coexists with other chronic medical disorders, including atherosclerosis, hypertension, diabetes, osteoarthritis, and osteoporosis. Each of these, by themselves, can alter function, change the structure of bones, joints and muscles, and demand complicated medication regimens. Soft-tissues and fat pads are atrophied and neurologic disorders may occur, leading to an increased propensity to fall and traumatize bones, tendons, ligaments, and muscles. Depression may interfere with patient compliance and disease-coping mechanisms. Polypharmacy may lead to adverse drug interactions and chronic medical disorders such as macular degeneration, kidney, or liver disease could alter the RA therapeutic options. Any treatment plan involving elderly patients should be multidisciplinary, including inputs from physical therapists, social workers, and home health agencies, and close communication between the rheumatologist and the primary care physician. CLINICAL MANIFESTATIONS
Many studies have described the clinical features of EORA (Table 1)and they can be divided into those assessing consecutive patients and others that are cross-sectional. The focus on consecutive patients and the use of a younger-onset control group, optimal methodological techniques, are employed in a few studies.16 The percentage of women in these studies is lower than the 66% to 75% generally reported for RA. One study without a comparison YORA group found that the acute onset and weight loss seem to be more
Table 1. CLINICAL PRESENTATION OF RA IN THE ELDERLY
Age of onset Number of joints involved Sites involved Arthritis onset Rheumatoid factor Sex ratio (FM)
Classic RA
EORA
30-50 Polyarticular Small joints Gradual onset Positive 2:l
>60 May be oligoarticular Large joint involvement may dominate. Abrupt onset is more common Negative 1:l
ELDERLY-ONSET RHEUMATOID ARTHRITIS
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Table 2. EORA VERSUS YORA: FOUR STUDIES, SIDE-BY-SIDE
Country Prospective Disease Duration #ON RA >proximal joint involvement PMR-like High ESR EORA RF% DR4+ % Outcome
1983
1985
1987
1991
Canada (30) poor <10 yr
Boston (9) poor
Japan (15) poor ND
Holland (14) fair <1 yr
34 I 3 4
fair poor poor 32 38
fair
791414
71I142
fair fair fair 66
fair fair fair 89 52 poor
44
ND
EORA: Elderly-onset RA; YORA: younger-onset RA; O / Y Ratio of old to young patients; ND: not discussed.
prevalent in the older patients than in historic controk6 The pattern of joint involvement suggests that large joints are more often involved at presentation primarily because of a higher frequency of shoulder involvement in the elderly patients. Studies showed the rate to be 10% to 36% more frequent in the EORA than in YORA patients9 More patients were found to have glenohumeral joint effusions and intraarticular steroid injection^.^^ Measures of disease activity, such as erythrocyte sedimentation rate and composite scores of disease activity, were higher in EORA. The patients had worse functional outcomes and greater weight loss in a Some observational cross-sectional studies had cross-sectional shown the prevalence of rheumatoid factor to be decreased in the elderly patients; van der Heijde14 and colleagues in their prospective study of EORA versus YORA have demonstrated no differences in the two age groups. Table 2 summarizes some of the findings from the four major 14, 15, 30 Even in studies with sound studies looking at EORA and YORA.9* methodologies, diagnostic heterogeneity is always a concern; it is possible that patients included in these studies may have had conditions clinically similar but pathophysiologically different from PROGNOSIS
There are not many studies addressing prognostic factors in EORA. One study shows persistent arthritis in 39% of seropositive patients versus 6% of seronegative~.'~ The former patients required more disease modifying antirheumatic drugs (DMARD). Another study showed that the seropositive patients had more swollen joints, radiological damage, and mortality than seronegative patients.26The differences in outcome between seronegative and seropositive patients were more pronounced in the EORA patients than YORA patients. These data indicate that RF positivity is an adverse prognostic factor. It should be remembered
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YAZICI & PAGET
though that the prevalence of positive RF increases steadily after age 60 to about 30% by age 90.27 DISEASE COURSE AND OUTCOME Most studies show that disease activity remains high 2 to 6 years 27 This is consistent with studies looking at RA patients after diagnosis.l4> regardless of age at onset; more radiologic damage, and functional decline were found in older-onset seropositive, but not seronegative RA patients.I4 Other factors may contribute to the worse prognosis in a cohort of EORA patients, most importantly comorbities. Most RA patients have the intercurrent illnesses and serious medical conditions that occur more frequently in this age group. They have less tolerance to systemic inflammation, joint destruction, and especially to side effects of various highly toxic drugs used in the treatment of RA.20 Life expectancy in RA is decreased: the exact degree of this decrease is a matter of dispute. Excess deaths were in most studies owing to cardiovascular causes, infections and RA itself >6 Severe disease and older age are associated independently with increased mortality. The effect of gender on mortality is not clear and studies provide conflicting results.' DIFFERENTIAL DIAGNOSIS Viral polyarthritis and seronegative spondyloarthropathies are diseases of young adulthood even though rarely can present in elderly patients. Crystal arthritis, inflammatory osteoarthritis (OA) and malignancy-associated arthritis usually occur later in life. Differential diagnosis can be rather difficult given that elderly patients may have several problems at the same time. Previously published series on EORA, especially seronegative EORA patients, most likely included patients with other diseases and this makes differentiating RA from these other disorders difficult. Crystal-induced arthritis can present with symmetrical polyarthritis of the fingers and toes.Is Up to 30% may have a positive RF and radiologic appearance of gout may resemble RA. Calcium pyrophosphate dihydrate (CPPD) crystal deposits increase with age. They are frequently associated with OA but may also present as acute or chronic synovitis. These crystals may be hard to detect depending on the stage of the disease and these patients may be incorrectly diagnosed with RA A subgroup of OA patients has recurrent inflammation of the interphalangeal and first carpometacarpal joints. Synovial fluid is noninflammatory with low-cell count and they are RF negative. They have centrally located bony erosions on radiograph and these patients are thought to have inflammatory or erosive OA.2 Synovitis in its severe form may not be easily distinguishable from that seen in RA. Some studies have suggested that inflammatory OA predisposes to RA. These
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were based on observations that during follow up, the incidence of RA was higher than expected in patients with inflammatory OA.'O In one series, 26 of 170 patients developed polyarthritis fulfilling the criteria for RA. Eight patients had subcutaneous nodules and nine had positive RF. A more recent study, however, following 24 inflammatory OA patients .~ discrepant numbers showed no RA after 3 years of f ~ l l o w - u pThese may be owing to inclusion of those patients who already had RA. When an elderly patient presents with polyarthritis or oligoarthritis, paraneoplastic arthritis should always be considered. There is a greater tendency for involvement of lower extremity joints than upper. The most frequently associated malignancies are breast and prostate cancer. An age-appropriate medical evaluation is indicated, including routine monitoring tests such as mammograms and prostate assessments. THE ASSOCIATION BETWEEN RA, PMR AND RSsPE SYNDROME
Seronegative EORA makes up 1%to 48% of the EORA patients, depending on the series.I3,14, 27 There are two syndromes that may be indistinguishable from seronegative EORA: polymyalgia rheumatica (PMR) and the syndrome of remitting seronegative symmetrical synovitis with pitting edema (RS3PEsyndrome) (Table 3). PMR and EORA may well be overlapping disease entities. Elderly patients with seronegative RA have PMR-like symptoms more often than seropositive patients.24They also can have alternating episodes of polyarthritis and PMR symptoms. Shoulder synovitis is common in PMR, as defined by arthroscopy and biopsyz1and could be contributing to the increased incidence of shoulder involvement seen in EORA. Whereas patients with PMR respond to low doses of steroids remarkably quickly, the same degree of response is not usually seen in EORA. Typical patients with RSE J' syndrome present with the sudden onset of synovitis and edema of the wrist and hands, with frequent involvement of the flexor tendon sheaths. Whereas marked morning Table 3. SUBSETS OF SERONEGATIVE ELDERLY-ONSET INFLAMMATORY DISORDERS
Proximal joints Peripheral joints Tenosynovitis Edema RF+ High ESR HLA
EORA
PMR
RS,PE
+ +++ ++ + +/+
+++ + +/+ +++
+++ +++ +++ +
CW3, DR4
DR4
B7
-
EORA: Elderly-onset RA; PMR: polymyalgia rheumatica; RS3PE remitting seronegative symmetrical synovitis with pitting edema.
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YAZICI & PAGET
stiffness is common, constitutional symptoms, such as fever and fatigue are infrequent. Rheumatoid factor is usually absent. Low dose prednisone therapy seems to be the optimal form of treatment, but regardless of therapy most patients have a remission within the first year. Some of these patients, however, go on to develop RA, systemic lupus erythematosus, or one of the vasculitides.
TREATMENT Treatment indications for rheumatoid arthritis are not different for the elderly patient, however, problems with decline in cognitive function, coexistent illness, polypharmacy, and compliance should be considered when starting treatment with potentially toxic therapeutic agents used in RA. Nonsteroidal anti-inflammatory (NSAID) medications are commonly used in EORA patients and caution is needed. Elderly are particularly susceptible to gastrointestinal, CNS, and renal side effects. The probability of NSAID continuation after one year is lower in patients with RA who are older than 65.23Whenever NSAIDs are instituted, proton-pump inhibitors (i.e., omeprazole), misoprostol, or H-2 antagonists should be considered and used as prophylactic agents. Newly available two cyclooxygenase-2 (COX-2) specific inhibitors have equal anti-inflammatory effects to traditional NSAIDs but have fewer gastrointestinal and platelet side effects. Low-dose steroids (i.e. 5-10 mg/d) are advocated by some authors as an important second-line drug in EORA because of its rapid a ~ t i o n . ~ This effect is more impressive in seronegative patients than seropositive and may reflect the clinical heterogeneity of this former group of patients. Osteoporosis remains a serious problem, especially in the elderly, who are more prone to develop osteopenia and falls and fractures. All patients taking medium to long-term steroids should receive 1500 mg of calcium and 800 IU of vitamin D, supplementation daily. Patients with low bone-mass density on DXA scans or a positive history of fracture might be candidates for antiresorptive therapy in the form of hormone replacement therapy, biphosphonates or calcitonin. The impact of age on the effectiveness and tolerance of second line (i.e. disease-modifying) antirheumatic drugs in the elderly have been * They failed to show any differences addressed in two meta-analy~es.~, between withdrawal rates in patients over and under 65 years of age. There are reports though of specific side effects that are more common in older RA patients.2z,35 These include cytopenias and nephrotic syndrome with parenteral gold, gastrointestinal symptoms with sulfasalazine, skin rash and taste changes with d-penicillamine, retinopathy with antimalarials, and liver disease as an age-related complication of lowdose methotrexate therapy. Given the recent move towards the use of multi-drug regimens in RA and the development of newer disease-
ELDERLY-ONSET RHEUMATOID ARTHRITIS
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modifying agents (e.g., TNFa antagonists), greater monitoring in elderly RA patients is needed. SUMMARY
It is appreciated that age has a modifying effect on the clinical presentations of disorders such as hyperthyroidism and systemic lupus erythematosus. Similarly in EORA, there seems to be a change in the disease phenotype when it is compared to YORA. These differences are significant not only in highlighting the importance of the aging process on the immune system but also because they have medical and therapeutic implications. Improved classification has greatly improved our understanding and treatment of systemic lupus erythematosus, juvenile chronic arthritis, and seronegative spondyloarthropathies. Similarly, appreciating the differences, and similarities, between YORA and EORA should advance the choice of therapeutic options and potentially move closer to defining pathogenesis and origin. References 1. Anderson ST: Mortality in rheumatoid arthritis: Do age and gender make a difference? Semin Arthritis Rheum 25:291, 1996 2. Belhom LR, Hess E V Erosive osteoarthritis. Semin Arthritis Rheum 22298, 1993 3. Beuningen van HM, van den Berg WB, Schalkwijk J, et al: Age- and sex-related differences in antigen-induced arthritis in C57B1/ 10 mice. Arthritis Rheum 32:789, 1989 4. Brennan P, Bankhead C, Silman A, et al: Oral contraceptives and rheumatoid arthritis: Results from a primary care-based incident case-control study. Semin Arthritis Rheum 26:817, 1997 5. Capell HA, Porter DR, Madhok R, et al: Second-line (disease-modifying) treatment in rheumatoid arthritis: Which drug for which patient? Ann Rheum Dis 52:423, 1993 6. Corrigan AB, Robinson RG, Terenty TR, et al: Benign rheumatoid arthritis of the aged. BMJ 1444, 1974 7. Cushnaghan J, Cobby M, Creamer P, et al: Erosive osteoarthritis: A longitudinal, comparative study of 24 cases. Br J Rheumatol28:102, 1989 8. Dahl SL, Samuelson CO, Williams J, et al: Second-line antirheumatic drugs in the elderly with rheumatoid arthritis: A post hoc analysis of three controlled trials. Pharmacotherapy 10:79, 1990 9. Deal CL, Meenan RF, Goldenberg DL, et al: The clinical features of elderly-onset rheumatoid arthritis. Arthritis Rheum 28:987, 1985 10. Ehrlich G: Inflammatory osteoarthritis-11:The superimposition of rheumatoid arthritis. 1 Chronic Dis 25:635, 1972 11. Hazes JMW, Dijkmans BAC, Hoevers JM, et al: DR4 prevalence related to the age at disease onset in female patients with rheumatoid arthritis. AM Rheum Dis 48:406,1989 12. Hazes JMW, Dijkmans BAC, Vandenbroucke JP, et al: Oral contraceptive treatment for rheumatoid arthritis: An open study in 10 female patients. Br J Rheumatol 28:28, 1989 13. Healey LA, Sheets PK: The relation of polymyalgia rheumatica to rheumatoid arthritis. J Rheumatol 15750, 1988 14. Heijde van der DMFM, van Riel PLCM, van Leeuwen MA, et al: Older versus younger onset rheumatoid arthritis: Results at onset and after 2 years of prospective follow-up study of early rheumatoid arthritis. J Rheumatol 18:1285, 1991
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15. Inoue K, Shichikawa K, Nishioka J, et al: Older age onset rheumatoid arthritis with or without osteoarthritis. Ann Rheum Dis 46:908, 1987 16. Kavanaugh AF: Rheumatoid arthritis in the elderly: Is it a different disease? Am J Med 103:40, 1997 17. Klippel GL, Cecere FA: Rheumatoid arthritis and pregnancy. Rheum Dis Clin North Am 15213, 1989 18. Lawry GF, Fan PT, Bluestone R Polyarticular versus monoarticular gout: A prospective, comparative analysis of clinical features. Medicine 67:335, 1988 19. Linos A, Worthington JW, OFallon WM, et al: The epidemiology of rheumatoid arthritis in Rochester, Minnesota: A study of incidence, prevalence and mortality. Am J Epidemiol 111:87, 1980 20. MacGregor AJ, Silman AJ. Rheumatoid arthritis: Classification and epidemiology. In Klippel JH, Dieppe PA (eds): Rheumatology, ed 2. London, Mosby, 1998, pp 2.1-2.6 21. Martin BA, Morris JH: Polymyalgia rheumatica: An arthroscopic study of the shoulder joint. Ann Rheum Dis 42:311, 1983 22. OCallaghan JW, Brooks PM: Disease-modifying agents and immunosuppressive drugs in the elderly. Clin Rheum Dis 12:275, 1986 23. Pincus T, Marcum SB, Callahan LF, et al: Long-term drug therapy for rheumatoid arthritis in seven rheumatology private practices: 1. Nonsteroidal anti-inflammatory drugs. J Rheumatol 19:1874, 1992 24. Salvarani C, Macchioni P, Mantovani W, et al: Polymyalgia rheumatica and seronegative rheumatoid arthritis: Some observations based on Northern Italian population. J Rheumatol 20:756, 1993 25. Schaardenburg van D, Breedveld FC: Elderly-onset rheumatoid arthritis. Semin Arthritis Rheum 23:367, 1994 26. Schaardenburg van D, Hazes JMW, de Boer A, et al: Outcome of rheumatoid arthritis in relation to age and rheumatoid factor at diagnosis. J Rheumatol 20:45, 1993 27. Schaardenburg van D, Lagaay AM, Otten HG, et al: The relation between class-specific rheumatoid factor and age in the general population. Br J Rheumatol 32:546, 1993 28. Spector TD, Perry LA, Tubb G, et al: Low free testosterone levels in rheumatoid arthritis. Ann Rheum Dis 4765, 1988 29. Symmons DPM, Barrett EM, Bankhead C, et al: The incidence of rheumatoid arthritis in the Norwich Health Authority. Arthritis Rheum 35:126, 1992 30. Terkeltaub R, Esdaile J, Decary F, et al: A clinical study of older age rheumatoid arthritis with comparison to a younger onset group. J Rheumatol 10:418, 1983 31. Vollenhoven van RF, Nagler-Anderson C, Stecher VJ, et al: Collagen-induced arthritis and aging: Influence of age on arthritis susceptibility and acute phase responses. Aging Immunol Infect Dis 1:159, 1988 32. Wade AW, Green-Johnson J, Szewczuk MR, et al: Functional changes in systemic and mucosal lymphocyte repertoires with age: An updated review. Aging Immunol Infect Dis 1:65, 1988 33. Ward MM, Polisson RP: A meta-analysis of the clinical manifestations of older-onset systemic lupus erythematosus. Arthritis Rheum 321226, 1989 34. Weyand CM, Goronzy JJ: Multisystem interactions in the pathogenesis of vasculitis. Curr Opin Rheumatol 9:511, 1997 35. Wijnands MJH, van Riel PLCM, Gribnau FWJ, et al: Risk factors of second-line antirheumatic drugs in rheumatoid arthritis. Semin Arthritis Rheum 19:337, 1990 36. Wolfe F, Mitchell DM, Sibley JT, et al: The mortality of rheumatoid arthritis. Arthritis Rheum 37481, 1994
Address reprint requests to Yusuf Yazici, MD Hospital for Special Surgery 535 East 70th Street New York, NY 10021
GERIATRIC RHEUMATOLOGY
0889-857X/OO $15.00
+ .OO
ELDERLY-ONSET RHEUMATOID ARTHRITIS Yusuf Yazici, MD and Stephen A. Paget, MD, FACE FACR
Rheumatoid arthritis (RA) is a systemic, inflammatory disorder affecting primarily women with a peak incidence between 30 and 50 years of age and an average age of onset of 55 years.20At this time, one third of patients acquire RA after the age of 60, and the prevalence increases with advancing age into the eighth decade. This is particularly important because of the growth of the proportion of older persons in our population and the potential implications for the care of these patients in the next century. If, as some authors have espoused, elderlyonset RA (EORA)beginning after 60 years of age is a distinctly different disorder from younger-onset RA (YORA), physicians must be aware of this and its diagnostic and therapeutic significance. The following profile of EORA, as distinct from YORA, has evolved from many clinical studies that vary in their design, control groups, and length of follow-up6f11. 14, 24. 26. 30. 1. More equal sex distribution: Whereas YORA is more common in women than in men by 3:1, in the older group, the ratio is closer to 1:l. 2. Acute onset: In YORA, an insidious onset is the most common. In EORA, there is a tendency for the onset to be acute and infectious-like. 3. More frequent involvement of large, proximal joints (i.e., shoulders): The characteristic presentation of RA is in the small joints of the hands and feet. In EORA, patients are more likely to develop proximal symptoms, more akin to polymyalgia rheumat-
From the Division of Rheumatology, Department of Medicine, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, New York
RHEUMATIC DISEASE CLINICS OF NORTH AMERICA
-
VOLUME 26 * NUMBER 3 AUGUST 2000
517
518
YAZICI & PAGET
ica (PMR). This is particularly important because there is a strong consideration given to the possibility that EORA and PMR, and even remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome, may be parts of a single spectrum of inflammatory disorders of the elderly. 4. More systemic manifestations and higher ESR at onset: Fatigue, weight loss, and elevated ESR may be manifestations YORA and EORA. They appear, however, to be more prominent in EORA, a fact that might relate to some basic differences in etiology, cytokine profiles or treatment options. 5. Lower frequency of rheumatoid factor (RF) positivity: In YORA, approximately 80% of patients are seropositive. Whereas in some EORA series, this frequency is between 66% and 89%, others show levels as low as 32%. This may reflect differences in study populations or might relate to changes in the immune system that occur with aging. 6. Worse outcome: The greater functional limitation and severity of joint damage in some patients with EORA may be explained by the effect of comorbid disease in the elderly or changes in the balance between damage and repair as people age. Immunosenescence, genetics, and hormonal factors are probably important variables in the observed difference between EORA and YORA. All these factors have age-related changes that can fundamentally affect how the body responds to disease-causing or -modifying factors. IMMUNOSENESCENCE
Alterations in the immune system that occur with age are listed below. Age-related changes in the immune system
Thymic involution Changes in functional phenotypic characteristics of T cells Decline in specific antibody responses Age-related defects in apoptosis Cytokine imbalance Deficiencies in antigen processing Some or all of these might alter the response to antigens or the disease presentation in the aged. With age, the capacity to generate protective immune responses declines, whereas reactivity to autoantigens in~reases.3~ The elimination of self-reactive T cells that bind with high affinity to autoantigens present in the host’s human lymphocyte antigens (HLA) molecules and the expansion and release of T-cellsbearing receptor molecules that react only with low affinity are central in establishing self-tolerance within the immune system. This process
ELDERLY-ONSET RHEUMATOID ARTHRITIS
519
takes place in the thymus and the thymus undergoes drastic age-associated involution. This can lead to fundamental alteration in the composition of the T-cell compartment. Also, decreased T-cell proliferation and cytokine production after stimulation in vitro, increased IgG and IgA Ievels, and decreased antibody formation after vaccination accompany aging.3z Animal models of autoimmune diseases show age-related changes but are not conclusive. Some studies showed decreased incidence and severity of collagen-induced arthritis in aged DBA / 1Lac mice, whereas albumin-induced arthritis in C57B1/ 10 mice became chronic and more destructive in older female anirnal~.~, 31 Similar differences in disease manifestations with different age groups has also been shown in other inflammatory connective tissue diseases. Polymyositis starting after age 50 is associated with increased mortality, as is scleroderma. Nephropathy and central nervous system involvement in SLE are less common in older patients than in younger ones.33 Changes in the immune system with aging may be contributing to the differences between EORA and YORA. The extent of this remains to be defined clearly. GENETICS There is a well-established association between RA and certain class I1 major histocompatibility alleles, most specifically DR4. This genetic marker appears to be linked to an increased propensity for and severity of RA and has a strong association with the presence of rheumatoid factor positive RA. Some studies, but not all, have even shown such an association with seronegative disease, regardless of age. In several studies, EORA patients were HLA-typed.", 24 All confirmed the same DR4 linkage with seropositive disease that has been demonstrated in YORA. Sixty percent of patients were DR4 positive, spanning from ages 16 to 86. No such association, however, could be found in elderly seronegative RA patients. Genetic susceptibility to seropositive RA seems to remain the same at all ages. HORMONES
The possibility that sex hormones play an important role in the clinical presentation of RA is supported by the fact that the inflammatory process improves significantly during pregnancy in a large proportion of patients.I7 The development of RA is decreased in frequency in patients on oral contraceptive^.^ Exogenous estrogen administration, however, does not decrease disease activity and the differences in hormone levels between women and men do not correlate with the disease outcome.'2,26 It is of note that there is a declining incidence of RA in women
520
YAZICI & PAGET
after menopause, at a time when lower estrogen and progesterone and increased androgen levels are found. This needs to be interpreted alongside the fact that decreasing androgen levels parallel an increasing incidence of RA in older man.28These apparently conflicting findings are probably a reflection of the complicated balance that exists between these three hormones and their interplay with the immune system. COMORBITIES
In the elderly, RA often coexists with other chronic medical disorders, including atherosclerosis, hypertension, diabetes, osteoarthritis, and osteoporosis. Each of these, by themselves, can alter function, change the structure of bones, joints and muscles, and demand complicated medication regimens. Soft-tissues and fat pads are atrophied and neurologic disorders may occur, leading to an increased propensity to fall and traumatize bones, tendons, ligaments, and muscles. Depression may interfere with patient compliance and disease-coping mechanisms. Polypharmacy may lead to adverse drug interactions and chronic medical disorders such as macular degeneration, kidney, or liver disease could alter the RA therapeutic options. Any treatment plan involving elderly patients should be multidisciplinary, including inputs from physical therapists, social workers, and home health agencies, and close communication between the rheumatologist and the primary care physician. CLINICAL MANIFESTATIONS
Many studies have described the clinical features of EORA (Table 1)and they can be divided into those assessing consecutive patients and others that are cross-sectional. The focus on consecutive patients and the use of a younger-onset control group, optimal methodological techniques, are employed in a few studies.16 The percentage of women in these studies is lower than the 66% to 75% generally reported for RA. One study without a comparison YORA group found that the acute onset and weight loss seem to be more
Table 1. CLINICAL PRESENTATION OF RA IN THE ELDERLY
Age of onset Number of joints involved Sites involved Arthritis onset Rheumatoid factor Sex ratio (FM)
Classic RA
EORA
30-50 Polyarticular Small joints Gradual onset Positive 2:l
>60 May be oligoarticular Large joint involvement may dominate. Abrupt onset is more common Negative 1:l
ELDERLY-ONSET RHEUMATOID ARTHRITIS
521
Table 2. EORA VERSUS YORA: FOUR STUDIES, SIDE-BY-SIDE
Country Prospective Disease Duration #ON RA >proximal joint involvement PMR-like High ESR EORA RF% DR4+ % Outcome
1983
1985
1987
1991
Canada (30) poor <10 yr
Boston (9) poor
Japan (15) poor ND
Holland (14) fair <1 yr
34 I 3 4
fair poor poor 32 38
fair
791414
71I142
fair fair fair 66
fair fair fair 89 52 poor
44
ND
EORA: Elderly-onset RA; YORA: younger-onset RA; O / Y Ratio of old to young patients; ND: not discussed.
prevalent in the older patients than in historic controk6 The pattern of joint involvement suggests that large joints are more often involved at presentation primarily because of a higher frequency of shoulder involvement in the elderly patients. Studies showed the rate to be 10% to 36% more frequent in the EORA than in YORA patients9 More patients were found to have glenohumeral joint effusions and intraarticular steroid injection^.^^ Measures of disease activity, such as erythrocyte sedimentation rate and composite scores of disease activity, were higher in EORA. The patients had worse functional outcomes and greater weight loss in a Some observational cross-sectional studies had cross-sectional shown the prevalence of rheumatoid factor to be decreased in the elderly patients; van der Heijde14 and colleagues in their prospective study of EORA versus YORA have demonstrated no differences in the two age groups. Table 2 summarizes some of the findings from the four major 14, 15, 30 Even in studies with sound studies looking at EORA and YORA.9* methodologies, diagnostic heterogeneity is always a concern; it is possible that patients included in these studies may have had conditions clinically similar but pathophysiologically different from PROGNOSIS
There are not many studies addressing prognostic factors in EORA. One study shows persistent arthritis in 39% of seropositive patients versus 6% of seronegative~.'~ The former patients required more disease modifying antirheumatic drugs (DMARD). Another study showed that the seropositive patients had more swollen joints, radiological damage, and mortality than seronegative patients.26The differences in outcome between seronegative and seropositive patients were more pronounced in the EORA patients than YORA patients. These data indicate that RF positivity is an adverse prognostic factor. It should be remembered
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though that the prevalence of positive RF increases steadily after age 60 to about 30% by age 90.27 DISEASE COURSE AND OUTCOME Most studies show that disease activity remains high 2 to 6 years 27 This is consistent with studies looking at RA patients after diagnosis.l4> regardless of age at onset; more radiologic damage, and functional decline were found in older-onset seropositive, but not seronegative RA patients.I4 Other factors may contribute to the worse prognosis in a cohort of EORA patients, most importantly comorbities. Most RA patients have the intercurrent illnesses and serious medical conditions that occur more frequently in this age group. They have less tolerance to systemic inflammation, joint destruction, and especially to side effects of various highly toxic drugs used in the treatment of RA.20 Life expectancy in RA is decreased: the exact degree of this decrease is a matter of dispute. Excess deaths were in most studies owing to cardiovascular causes, infections and RA itself >6 Severe disease and older age are associated independently with increased mortality. The effect of gender on mortality is not clear and studies provide conflicting results.' DIFFERENTIAL DIAGNOSIS Viral polyarthritis and seronegative spondyloarthropathies are diseases of young adulthood even though rarely can present in elderly patients. Crystal arthritis, inflammatory osteoarthritis (OA) and malignancy-associated arthritis usually occur later in life. Differential diagnosis can be rather difficult given that elderly patients may have several problems at the same time. Previously published series on EORA, especially seronegative EORA patients, most likely included patients with other diseases and this makes differentiating RA from these other disorders difficult. Crystal-induced arthritis can present with symmetrical polyarthritis of the fingers and toes.Is Up to 30% may have a positive RF and radiologic appearance of gout may resemble RA. Calcium pyrophosphate dihydrate (CPPD) crystal deposits increase with age. They are frequently associated with OA but may also present as acute or chronic synovitis. These crystals may be hard to detect depending on the stage of the disease and these patients may be incorrectly diagnosed with RA A subgroup of OA patients has recurrent inflammation of the interphalangeal and first carpometacarpal joints. Synovial fluid is noninflammatory with low-cell count and they are RF negative. They have centrally located bony erosions on radiograph and these patients are thought to have inflammatory or erosive OA.2 Synovitis in its severe form may not be easily distinguishable from that seen in RA. Some studies have suggested that inflammatory OA predisposes to RA. These
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were based on observations that during follow up, the incidence of RA was higher than expected in patients with inflammatory OA.'O In one series, 26 of 170 patients developed polyarthritis fulfilling the criteria for RA. Eight patients had subcutaneous nodules and nine had positive RF. A more recent study, however, following 24 inflammatory OA patients .~ discrepant numbers showed no RA after 3 years of f ~ l l o w - u pThese may be owing to inclusion of those patients who already had RA. When an elderly patient presents with polyarthritis or oligoarthritis, paraneoplastic arthritis should always be considered. There is a greater tendency for involvement of lower extremity joints than upper. The most frequently associated malignancies are breast and prostate cancer. An age-appropriate medical evaluation is indicated, including routine monitoring tests such as mammograms and prostate assessments. THE ASSOCIATION BETWEEN RA, PMR AND RSsPE SYNDROME
Seronegative EORA makes up 1%to 48% of the EORA patients, depending on the series.I3,14, 27 There are two syndromes that may be indistinguishable from seronegative EORA: polymyalgia rheumatica (PMR) and the syndrome of remitting seronegative symmetrical synovitis with pitting edema (RS3PEsyndrome) (Table 3). PMR and EORA may well be overlapping disease entities. Elderly patients with seronegative RA have PMR-like symptoms more often than seropositive patients.24They also can have alternating episodes of polyarthritis and PMR symptoms. Shoulder synovitis is common in PMR, as defined by arthroscopy and biopsyz1and could be contributing to the increased incidence of shoulder involvement seen in EORA. Whereas patients with PMR respond to low doses of steroids remarkably quickly, the same degree of response is not usually seen in EORA. Typical patients with RSE J' syndrome present with the sudden onset of synovitis and edema of the wrist and hands, with frequent involvement of the flexor tendon sheaths. Whereas marked morning Table 3. SUBSETS OF SERONEGATIVE ELDERLY-ONSET INFLAMMATORY DISORDERS
Proximal joints Peripheral joints Tenosynovitis Edema RF+ High ESR HLA
EORA
PMR
RS,PE
+ +++ ++ + +/+
+++ + +/+ +++
+++ +++ +++ +
CW3, DR4
DR4
B7
-
EORA: Elderly-onset RA; PMR: polymyalgia rheumatica; RS3PE remitting seronegative symmetrical synovitis with pitting edema.
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stiffness is common, constitutional symptoms, such as fever and fatigue are infrequent. Rheumatoid factor is usually absent. Low dose prednisone therapy seems to be the optimal form of treatment, but regardless of therapy most patients have a remission within the first year. Some of these patients, however, go on to develop RA, systemic lupus erythematosus, or one of the vasculitides.
TREATMENT Treatment indications for rheumatoid arthritis are not different for the elderly patient, however, problems with decline in cognitive function, coexistent illness, polypharmacy, and compliance should be considered when starting treatment with potentially toxic therapeutic agents used in RA. Nonsteroidal anti-inflammatory (NSAID) medications are commonly used in EORA patients and caution is needed. Elderly are particularly susceptible to gastrointestinal, CNS, and renal side effects. The probability of NSAID continuation after one year is lower in patients with RA who are older than 65.23Whenever NSAIDs are instituted, proton-pump inhibitors (i.e., omeprazole), misoprostol, or H-2 antagonists should be considered and used as prophylactic agents. Newly available two cyclooxygenase-2 (COX-2) specific inhibitors have equal anti-inflammatory effects to traditional NSAIDs but have fewer gastrointestinal and platelet side effects. Low-dose steroids (i.e. 5-10 mg/d) are advocated by some authors as an important second-line drug in EORA because of its rapid a ~ t i o n . ~ This effect is more impressive in seronegative patients than seropositive and may reflect the clinical heterogeneity of this former group of patients. Osteoporosis remains a serious problem, especially in the elderly, who are more prone to develop osteopenia and falls and fractures. All patients taking medium to long-term steroids should receive 1500 mg of calcium and 800 IU of vitamin D, supplementation daily. Patients with low bone-mass density on DXA scans or a positive history of fracture might be candidates for antiresorptive therapy in the form of hormone replacement therapy, biphosphonates or calcitonin. The impact of age on the effectiveness and tolerance of second line (i.e. disease-modifying) antirheumatic drugs in the elderly have been * They failed to show any differences addressed in two meta-analy~es.~, between withdrawal rates in patients over and under 65 years of age. There are reports though of specific side effects that are more common in older RA patients.2z,35 These include cytopenias and nephrotic syndrome with parenteral gold, gastrointestinal symptoms with sulfasalazine, skin rash and taste changes with d-penicillamine, retinopathy with antimalarials, and liver disease as an age-related complication of lowdose methotrexate therapy. Given the recent move towards the use of multi-drug regimens in RA and the development of newer disease-
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modifying agents (e.g., TNFa antagonists), greater monitoring in elderly RA patients is needed. SUMMARY
It is appreciated that age has a modifying effect on the clinical presentations of disorders such as hyperthyroidism and systemic lupus erythematosus. Similarly in EORA, there seems to be a change in the disease phenotype when it is compared to YORA. These differences are significant not only in highlighting the importance of the aging process on the immune system but also because they have medical and therapeutic implications. Improved classification has greatly improved our understanding and treatment of systemic lupus erythematosus, juvenile chronic arthritis, and seronegative spondyloarthropathies. Similarly, appreciating the differences, and similarities, between YORA and EORA should advance the choice of therapeutic options and potentially move closer to defining pathogenesis and origin. References 1. Anderson ST: Mortality in rheumatoid arthritis: Do age and gender make a difference? Semin Arthritis Rheum 25:291, 1996 2. Belhom LR, Hess E V Erosive osteoarthritis. Semin Arthritis Rheum 22298, 1993 3. Beuningen van HM, van den Berg WB, Schalkwijk J, et al: Age- and sex-related differences in antigen-induced arthritis in C57B1/ 10 mice. Arthritis Rheum 32:789, 1989 4. Brennan P, Bankhead C, Silman A, et al: Oral contraceptives and rheumatoid arthritis: Results from a primary care-based incident case-control study. Semin Arthritis Rheum 26:817, 1997 5. Capell HA, Porter DR, Madhok R, et al: Second-line (disease-modifying) treatment in rheumatoid arthritis: Which drug for which patient? Ann Rheum Dis 52:423, 1993 6. Corrigan AB, Robinson RG, Terenty TR, et al: Benign rheumatoid arthritis of the aged. BMJ 1444, 1974 7. Cushnaghan J, Cobby M, Creamer P, et al: Erosive osteoarthritis: A longitudinal, comparative study of 24 cases. Br J Rheumatol28:102, 1989 8. Dahl SL, Samuelson CO, Williams J, et al: Second-line antirheumatic drugs in the elderly with rheumatoid arthritis: A post hoc analysis of three controlled trials. Pharmacotherapy 10:79, 1990 9. Deal CL, Meenan RF, Goldenberg DL, et al: The clinical features of elderly-onset rheumatoid arthritis. Arthritis Rheum 28:987, 1985 10. Ehrlich G: Inflammatory osteoarthritis-11:The superimposition of rheumatoid arthritis. 1 Chronic Dis 25:635, 1972 11. Hazes JMW, Dijkmans BAC, Hoevers JM, et al: DR4 prevalence related to the age at disease onset in female patients with rheumatoid arthritis. AM Rheum Dis 48:406,1989 12. Hazes JMW, Dijkmans BAC, Vandenbroucke JP, et al: Oral contraceptive treatment for rheumatoid arthritis: An open study in 10 female patients. Br J Rheumatol 28:28, 1989 13. Healey LA, Sheets PK: The relation of polymyalgia rheumatica to rheumatoid arthritis. J Rheumatol 15750, 1988 14. Heijde van der DMFM, van Riel PLCM, van Leeuwen MA, et al: Older versus younger onset rheumatoid arthritis: Results at onset and after 2 years of prospective follow-up study of early rheumatoid arthritis. J Rheumatol 18:1285, 1991
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15. Inoue K, Shichikawa K, Nishioka J, et al: Older age onset rheumatoid arthritis with or without osteoarthritis. Ann Rheum Dis 46:908, 1987 16. Kavanaugh AF: Rheumatoid arthritis in the elderly: Is it a different disease? Am J Med 103:40, 1997 17. Klippel GL, Cecere FA: Rheumatoid arthritis and pregnancy. Rheum Dis Clin North Am 15213, 1989 18. Lawry GF, Fan PT, Bluestone R Polyarticular versus monoarticular gout: A prospective, comparative analysis of clinical features. Medicine 67:335, 1988 19. Linos A, Worthington JW, OFallon WM, et al: The epidemiology of rheumatoid arthritis in Rochester, Minnesota: A study of incidence, prevalence and mortality. Am J Epidemiol 111:87, 1980 20. MacGregor AJ, Silman AJ. Rheumatoid arthritis: Classification and epidemiology. In Klippel JH, Dieppe PA (eds): Rheumatology, ed 2. London, Mosby, 1998, pp 2.1-2.6 21. Martin BA, Morris JH: Polymyalgia rheumatica: An arthroscopic study of the shoulder joint. Ann Rheum Dis 42:311, 1983 22. OCallaghan JW, Brooks PM: Disease-modifying agents and immunosuppressive drugs in the elderly. Clin Rheum Dis 12:275, 1986 23. Pincus T, Marcum SB, Callahan LF, et al: Long-term drug therapy for rheumatoid arthritis in seven rheumatology private practices: 1. Nonsteroidal anti-inflammatory drugs. J Rheumatol 19:1874, 1992 24. Salvarani C, Macchioni P, Mantovani W, et al: Polymyalgia rheumatica and seronegative rheumatoid arthritis: Some observations based on Northern Italian population. J Rheumatol 20:756, 1993 25. Schaardenburg van D, Breedveld FC: Elderly-onset rheumatoid arthritis. Semin Arthritis Rheum 23:367, 1994 26. Schaardenburg van D, Hazes JMW, de Boer A, et al: Outcome of rheumatoid arthritis in relation to age and rheumatoid factor at diagnosis. J Rheumatol 20:45, 1993 27. Schaardenburg van D, Lagaay AM, Otten HG, et al: The relation between class-specific rheumatoid factor and age in the general population. Br J Rheumatol 32:546, 1993 28. Spector TD, Perry LA, Tubb G, et al: Low free testosterone levels in rheumatoid arthritis. Ann Rheum Dis 4765, 1988 29. Symmons DPM, Barrett EM, Bankhead C, et al: The incidence of rheumatoid arthritis in the Norwich Health Authority. Arthritis Rheum 35:126, 1992 30. Terkeltaub R, Esdaile J, Decary F, et al: A clinical study of older age rheumatoid arthritis with comparison to a younger onset group. J Rheumatol 10:418, 1983 31. Vollenhoven van RF, Nagler-Anderson C, Stecher VJ, et al: Collagen-induced arthritis and aging: Influence of age on arthritis susceptibility and acute phase responses. Aging Immunol Infect Dis 1:159, 1988 32. Wade AW, Green-Johnson J, Szewczuk MR, et al: Functional changes in systemic and mucosal lymphocyte repertoires with age: An updated review. Aging Immunol Infect Dis 1:65, 1988 33. Ward MM, Polisson RP: A meta-analysis of the clinical manifestations of older-onset systemic lupus erythematosus. Arthritis Rheum 321226, 1989 34. Weyand CM, Goronzy JJ: Multisystem interactions in the pathogenesis of vasculitis. Curr Opin Rheumatol 9:511, 1997 35. Wijnands MJH, van Riel PLCM, Gribnau FWJ, et al: Risk factors of second-line antirheumatic drugs in rheumatoid arthritis. Semin Arthritis Rheum 19:337, 1990 36. Wolfe F, Mitchell DM, Sibley JT, et al: The mortality of rheumatoid arthritis. Arthritis Rheum 37481, 1994
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