|Year : 2016 | Volume
| Issue : 4 | Page : 207-215
Inflammatory rheumatic diseases in the elderly
Vikramraj K Jain, Vir Singh Negi
Department of Clinical Immunology, JIPMER, Puducherry, India
|Date of Web Publication||8-Nov-2016|
Dr. Vir Singh Negi
Department of Clinical Immunology, JIPMER, Puducherry - 605 006
Source of Support: None, Conflict of Interest: None
Rapid aging of world's population will translate into more elderly patients in the near future. Diagnosis of inflammatory rheumatic diseases in this age group is complicated by atypical clinical features compared to the younger onset group, nonspecific positivity of serological parameters, and confounding radiological signs. Management of these diseases also presents unique challenges in lieu of altered physiology of elderly, cognitive decline, presence of comorbidities, and altered immune system (inflammaging). Hence, this review attempts to synthesize the existing knowledge of the clinical, diagnostic, and therapeutic idiosyncrasies of inflammatory rheumatic diseases in this subgroup of population.
Keywords: Arthritis, elderly, geriatric, inflammatory, late onset
|How to cite this article:|
Jain VK, Negi VS. Inflammatory rheumatic diseases in the elderly. Indian J Rheumatol 2016;11:207-15
| Introduction|| |
The population of the world is rapidly aging. Elderly (≥60 years) presently constitute about 12.3% of global and 8.9% of the Indian population. Increase in lifespan means that more patients affected with rheumatologic disorders are likely to be elderly. Geriatric rheumatology or gerontorheumatology deals with rheumatologic disorders in the elderly. The diagnosis of rheumatologic disorders in elderly is complicated by unique and atypical clinical features, manifestations mimicking age-related changes.
Aging is associated with a state of chronic low-grade inflammation known as inflammaging. The T-cell repertoire reduces with age making the elderly more susceptible to newer infections. Autoantibodies such as rheumatoid factor (RF) and antinuclear antibody (ANA) are found with increased prevalence with age even in the general population due to immunosenescence., There are varied physiological changes associated with aging, making these patients susceptible to adverse drug effects precluding the adequate use of aggressive immunosuppressive therapy. The presence of comorbidities such as diabetes, hypertension, and atherosclerosis can make the management of these patients challenging [Figure 1].
|Figure 1: Challenges in management of inflammatory rheumatic diseases in the elderly|
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The targets of treatment may have to be lowered to focus on improving the quality of life and rehabilitation. Hence, this article aims to review the clinical manifestations, diagnosis, and management of common rheumatologic disorders in the elderly.
| Search Methodology|| |
English-language articles available on PubMed published between 2000 and 2016 were included in the review of literature. Combinations of the following search words were used: Geriatric, rheumatology, gerontorheumatology, late-onset, rheumatic, arthritis, elderly, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren's syndrome (pSS), spondyloarthritis (SpA), scleroderma, gout, and dermatomyositis (DM). Different age cutoffs and terminologies have been used in the existing literature to define elderly/late-onset subsets of various autoimmune rheumatic diseases, and the most widely used age cutoff and terminology have been utilized for the purpose of this review. The number of articles derived from the PubMed search for each of the subtopics were as follows: Geriatric and rheumatology – 14, gerontorheumatology – 2, elderly/late onset and RA – 54, late onset and SLE – 36, late onset and SpA – 16, elderly onset and pSS – 5, late onset and scleroderma – 5; elderly onset and gout – 6, and elderly onset and inflammatory myositis-1. These were then read, analyzed, and cross-referenced. Articles referring to osteoarthritis (OA), osteoporosis, and back pain were excluded since these are recognized to have an increased prevalence in the elderly. Articles on giant cell arteritis, calcium pyrophosphate disease (CPPD), and inclusion body myositis were also excluded since they are diseases almost exclusive to the elderly age group. The reference lists of selected review articles citing the above articles were studied to obtain additional original articles.
| Epidemiology|| |
The proportion of elderly population is expected to account for 20% of world's population by 2050. The major noninflammatory musculoskeletal disorders affecting the elderly are OA, osteoporosis, and back pain, whereas the predominant inflammatory arthritis includes RA, crystal arthropathy, polymyalgia rheumatica (PMR), and inflammatory forms of OA.,
| Elderly Onset Rheumatoid Arthritis|| |
RA is a chronic autoimmune disease characterized by synovial inflammation and joint destruction, whose prevalence increases with age (around 2% in elderly). RA in elderly can either be elderly onset (EORA defined as onset ≥60 years) or young onset (YORA) that persists into older age.
EORA has a lower female predominance (1.5–2:1 vs. 4–4.5:1) compared to YORA. The onset is more acute in nature with more constitutional symptoms and disabling early morning stiffness. The involvement of large joints, especially shoulder joints is a prominent feature. Rheumatoid nodules are less common.
Three patterns of disease onset are identified in EORA. The most common pattern seen in 70% of cases is similar to classical RA, with RF positivity and erosive joint disease. The next pattern, seen in 25% of patients, is that of proximal joint involvement that needs to be differentiated from PMR. Simultaneous involvement of small joints of hand and presence of anti-citrullinated peptide antigen (ACPA) helps to differentiate these patients from PMR.,, A third type with pitting edema of dorsum of hands and feet, acute onset symmetrical synovitis, and negative RF, mimicking remitting seronegative symmetrical synovitis (RS3PE) may also be seen in around 10% patients.,
EORA needs to be differentiated from OA, CPPD, gout, PMR, and carcinomatous arthritis. The diagnosis of EORA is complicated by the fact that titers of IgM RF rise with age  although this could not be confirmed in a large prospective cohort study. ACPA is highly predictive of EORA in those with a polymyalgia pattern onset., Erythrocyte sedimentation rate (ESR) elevation also occurs with increasing age and associated comorbidities such as malignancy; hence, the assessment of disease activity using disease activity score (DAS)-ESR must be done with caution. It has, however, been shown that the effect of ESR on DAS28 increased with age only in male patients with low disease activity.
RA usually spares the first carpometacarpal and distal interphalangeal joints typically involved in hand OA. Parkinsonism More Details causing Jaccoud-like arthropathy More Details may mimic hand deformities seen in RA. In the knee joint, symmetric joint space narrowing occurs in RA compared to asymmetric involvement in OA. Concomitant OA features such as marginal osteophytes and subchondral sclerosis with subchondral cysts may also be seen in elderly RA.
Ultrasound findings in RA include synovitis, tenosynovitis, and erosions. Patients with shoulder involvement may have findings of subacromial-subdeltoid bursitis, glenohumeral synovitis, and tenosynovitis of long head of biceps similar to that in PMR. However, a predominant intra-articular involvement favors RA compared to predominant periarticular involvement seen in PMR.
Management guidelines of RA need to be modified in the elderly considering comorbidities and associated polypharmacy, alterations in pharmacokinetics, and cognitive impairment in the elderly that may all predispose to increased risk of adverse events. The therapeutic goals in RA of control of pain, halting progression of disease, and improving functional status, however, remain the same in EORA. Patients with comorbidities are usually excluded from the clinical trials; consequently, elderly are not adequately represented, and hence there are no evidence-based recommendations for EORA., Data from national registries and elderly subgroup of patients in therapeutic trials form the basis of present treatment strategies.
Synthetic and biological DMARD therapy is less frequently used in EORA, for similar disease duration and activity. Methotrexate, which is the anchor drug in the management of RA, has equivalent efficacy in the elderly. However, bone marrow and central nervous system toxicity is more frequent in these patients, hence close monitoring is required, especially in patients with hepatic and renal derangement. Leflunomide is relatively well tolerated in the elderly. Sulfasalazine and hydroxychloroquine have a less toxic profile and may be preferred in patients with low disease activity and those with significant comorbidities. Monitoring of renal function and more frequent ophthalmological examination is indicated in patients on hydroxychloroquine as they are at higher risk for retinal toxicity.,
Tumor necrosis factor inhibitors (TNFi) can be used in the elderly although they have a greater frequency of contraindications, i.e., congestive heart failure and malignancy. Among the various agents etanercept has shown a slightly lower ACR20 response among the elderly, whereas infliximab and adalimumab have shown similar efficacy across all age groups., Nonsteroidal anti-inflammatory drugs (NSAIDs) therapy in elderly is associated with increased gastrointestinal and cardiovascular adverse effects. Naproxen may be preferred in patients with cardiac involvement although this is controversial. Glucocorticoids are associated with increased risk of osteoporosis, glucose intolerance, and steroid-induced hypertension in elderly. Glucocorticoid and NSAID therapy should hence be used at the lowest possible dose for least duration to minimize adverse events. Overall rates of infection in elderly are not increased with the use of DMARDs and TNFi but showed a dose-dependent increased risk with glucocorticoid therapy.
| Late-Onset Spondyloarthritis|| |
SpA usually has an onset in the second and third decade. Late-onset SpA has no standard definition, with most studies using ≥50 years as a cutoff. Most patients may in fact be late diagnosed rather than late-onset. Late-onset/late diagnosed SpA constitutes about 3%–8% of all SpA. Axial SpA, which is now classified according to the ASAS criteria, applies to patients ≤45 years of age, however, has not been evaluated in elderly patients with inflammatory low back pain.
The whole spectrum of SpA is seen even in late-onset/late-diagnosed patients. Majority, however, have undifferentiated or psoriatic subtypes. Two patterns of clinical presentation may be seen - a predominant axial disease with relatively more cervical spine involvement and lower human leukocyte antigen (HLA-B27) positivity (70% vs. 90% in younger patients) and a predominant peripheral disease with oligoarthritis of the lower limb and characteristic pitting edema of the dorsum of foot. Inflammatory markers are markedly elevated in peripheral SpA and these patients have poor response to NSAIDs.
Late-onset undifferentiated SpA is more frequent than late-onset AS  and may have PMR-like features at onset. Psoriatic arthritis is more severe in the elderly (≥60 years), with less favorable outcome. They have a male predominance (9:3 vs. 1:1.1), higher number of active joints, more peripheral arthritis (especially. symmetrical polyarthritis), erosive disease, and elevated markers of inflammation (C-reactive protein/interleukin-1β/interleukin-6). There is, however, a lesser prevalence of dactylitis and asymmetric sacroiliitis and all were HLA-B27 negative.
The differential diagnosis includes EORA, RS3PE, PMR, and diffuse idiopathic skeletal hyperostosis (DISH). Imaging evidence of sacroiliitis and syndesmophytes is difficult to interpret in the elderly due to coexistent OA and osteoporosis. There are no studies on MRI assessment of sacroiliitis and spine in late-onset/late diagnosed SpA. DISH can be differentiated from SpA with ossification of anterior and posterior longitudinal ligaments, absence of involvement of zygapophyseal joints, and lack of inflammation in synovial portion of sacroiliac joint, while RS3PE has predominant involvement of upper limb with symmetrical synovitis and good response to corticosteroids.
The treatment of late-onset/late diagnosed SpA is similar to recent recommendations in the young. NSAIDs must be used with caution in the elderly, with more intensive monitoring of renal function. Evidence regarding safety and efficacy of TNFi in the elderly is lacking. Extrapolating the use of TNFi in EORA, suggests they are safe and effective.
| Late-Onset Systemic Lupus Erythematosus|| |
SLE predominantly affects young women in the child-bearing age group. Late-onset SLE (LoSLE) is defined as SLE with diagnosis made at 50 years of age or above. They constitute 2%–20% of patients with SLE. There are contradictory views regarding the severity of LoSLE compared to early onset.
LoSLE has an insidious onset compared to early onset SLE. The clinical manifestations at onset are comparatively less with a greater duration between the onset to the diagnosis of SLE (60.13 ± 77.83 months vs. 15.40 ± 25.50 months, P = 0.005). LoSLE had lesser incidence of cutaneous, neuropsychiatric, and renal involvement, but a greater incidence of secondary Sjogren's syndrome in a retrospective case–control study. In a pooled data analysis of 714 cases of LoSLE compared to 4700 cases of young SLE, the LoSLE patients had a lower female to male ratio (4.4:1 vs. 10.6:1); lower frequency of arthritis, malar rash, cutaneous vasculitis, Raynaud's phenomenon, lymphadenopathy, renal and neuropsychiatric manifestations. These patients, however, had greater frequency of serositis, pulmonary involvement, and secondary Sjogren's syndrome.
The overall prognosis of LoSLE is poorer despite having less severe clinical manifestations. This is due to greater number of comorbidities and higher organ damage related to aging.,, These patients have greater mortality compared to younger SLE; attributable to cardiovascular involvement and malignancy, while younger SLE die more often due to disease per se.,
ANA is positive in 67%–100% of LoSLE. The prevalence of RNP, Sm, and hypocomplementemia is lower, whereas RF, anti-SSA, and anti-SSB positivity is higher compared to younger SLE.,, Anti-dsDNA antibodies have variably been reported as having equivalent or lower prevalence in LoSLE.,
Management of LoSLE depends on type and severity of clinical manifestations as in younger patients. Studies have shown that LoSLE patients received lower mean dose of prednisolone compared to younger SLE for similar manifestations, they also received lesser cumulative dose of cyclophosphamide (CYP) and had more frequent CYP-related complications such as herpes infections and bladder cancer., These patients are also at a higher risk of retinal toxicity due to hydroxychloroquine and hence frequent ophthalmological evaluations are recommended. The use of biological therapy in older patients has not been adequately addressed in clinical trials; however, increased risk of infection and malignancy has been observed.
General measures such as vaccination against influenza, pneumococcal, and hepatitis B is important, especially in the elderly to prevent infectious complications. Prevention of osteoporosis with calcium and Vitamin D supplementation, along with bisphosphonate therapy in certain cases is recommended as per standard guidelines.
| Primary Sjögren's Syndrome in the Elderly|| |
pSS is a chronic autoimmune exocrinopathy characterized by xerostomia and keratoconjunctivitis sicca, predominantly affecting middle-aged females. There prevalence of pSS in elderly is wide ranging, attributable to different classification criteria's used for diagnosis in various studies. Elderly onset Sjogren's (≥65 years) constituted 6% of a retrospective cohort of 336 patients with pSS, whereas 4.8% of elderly were found to have pSS in a Greek study.
The diagnosis of pSS in elderly is difficult, as characteristic clinical manifestations of pSS such as xerostomia, dry eyes, fatigue, and myalgias are also features of old age. Prevalence of xerostomia increases with age, affecting 17%–30% of elderly., Salivary secretion reduces with age and also varies in chemical composition. Factors such as dehydration; drugs such as tricyclic antidepressants, antihistamines, diuretics, and anticholinergics; diabetes mellitus, and radiation therapy to head and neck region all contribute to increased sicca symptoms in elderly. Neurological causes such as Parkinson's disease in elderly may cause dryness of eyes due to impaired lid function.
Comparing the demographic and clinical manifestations of elderly-onset (>65 years), adult-onset (>40 and ≤ 65 years), and young-onset (≤40 years) patients of pSS in a retrospective analysis, it was found that there was no difference between the groups regarding percentage of females, mean disease duration, and any of the clinical features.,
Abnormal Schirmer's test has been reported in 22% of healthy elderly. Similarly, lymphocytic infiltration of labial glands and SSA, SSB antibodies have been found in healthy elderly., However, a focus score >1 is adequate criterion for pSS in elderly.
The serological parameters (ANA, RF, anti-SSA, anti-SSB, complements, and γ-globulins) in the elderly onset group showed no difference compared to younger pSS, except that anti-SSA antibodies showed a decreasing trend in the elderly onset group. There was also no difference in positivity for salivary sialography, ocular tests for sicca as well as minor salivary gland biopsy.
The management of elderly onset pSS does not differ from the younger patients for similar clinical manifestations. Pilocarpine should be used with caution in elderly and is contraindicated in patients with ischemic heart disease. A low sugar diet and antimicrobial mouthwashes are useful in preventing caries. Sugar-free chewing gums can be used to stimulate salivary secretion while artificial saliva may also help decrease symptoms. Drugs with fewer xerostomic side effects should be preferred in the elderly.
| Late-Onset Scleroderma|| |
Systemic sclerosis is an acquired chronic autoimmune disease characterized by immune abnormalities, vascular damage, and tissue fibrosis. The clinical manifestations can be varied, ranging from limited skin involvement to diffuse skin tightening, complicated Raynaud's, and interstitial lung disease. Age of onset of disease influences the clinical manifestations, organ involvement, and hence the outcomes.
Late-onset scleroderma (≥65 years) constitutes 10%–20% of scleroderma patients in American and European cohorts., These patients have higher risk of pulmonary artery hypertension, muscle weakness, renal and cardiac disease compared to younger patients. However, the risk of severe Raynaud's is reduced. Similar findings were noted in the Spanish RESCLE registry. Late-onset patients were diagnosed earlier than younger patients, have lower prevalence of digital ulcers but higher pulmonary hypertension and cardiac conduction abnormalities. Cause of death did not significantly differ among the different age groups and the standardized mortality rates after correction for effects of age and sex were in fact lower in older patients. On comparing the clinical features of late (≥65 years) versus early onset scleroderma, another European cohort showed that majority of late-onset patients have limited skin disease with higher prevalence of pulmonary and cardiac involvement. These manifestations also appeared within first 6 months in these patients. Sicca syndrome is also more frequent. Esophageal involvement is, however, lower as is incidence of renal crisis. There is no significant increase in mortality due to scleroderma in these patients.
Late-onset scleroderma has a higher prevalence of anticentromere antibodies (42% vs. 27%, P = 0.001). No other significant differences in autoantibody profile have been reported. Systolic hypertension, diastolic dysfunction, and conduction abnormalities that are more prevalent in the elderly could contribute to elevated pulmonary pressure.,
Late-onset scleroderma has relatively less severe manifestations compared to young onset. The management of these patients does not differ from the younger patients for similar clinical manifestations.
| Elderly Onset Gout|| |
Gout is an inflammatory arthritis caused by crystallization of uric acid within joints associated with hyperuricemia, predominantly affecting middle-aged males and postmenopausal females. Its prevalence increases with age and it is the most common inflammatory arthritis in the elderly (≥65 years).
Prevalence of gout in elderly (≥65 years) is 4.4%–5.2% in males and 1.8%–2% in females. The prevalence in females predominates after 80 years of age. Elderly onset gout has equal distribution between men and women. A strong association with renal insufficiency and diuretics is seen, with nearly 75% of the elderly onset patients and 95%–100% of women reporting diuretic use. However, association with alcohol consumption is less strong.
Elderly onset gout has certain unique and atypical features. Nearly half of these patients have a polyarticular onset. Involvement of small joints of the hand is seen, especially in women, and these are joints usually afflicted by OA. Tophi are seen in atypical location such as the fingers more commonly than the elbow. These occur much earlier in disease and are seen more frequently in women who are on diuretics.
Elderly onset gout needs to be differentiated from EORA, OA, CPPD, and septic arthritis. The typical history of episodic arthritis and podagra may not be present, hence synovial fluid examination for crystals and synovial cultures is paramount as gout may coexist with OA or septic arthritis in the same joint. Gout needs to be considered in patients with acute pain and swelling of osteoarthritic interphalangeal joints of fingers, especially in those elderly with renal dysfunction and on chronic diuretic use.
Management of gout in elderly is influenced by associated comorbidities. NSAIDs are preferably avoided in elderly due to gastrointestinal and cardiovascular adverse events. Colchicine may be used cautiously in a lower dose, especially in patients with renal and hepatic insufficiency. Steroids are preferred during acute flares due to better short-term toxicity profile. The need for diuretic therapy and low-dose aspirin therapy needs to be reassessed and alternative medications used. Allopurinol is associated with higher adverse events in the elderly, especially in those with renal dysfunction. A lower starting dose based on the creatinine clearance reduces the risk of allopurinol hypersensitivity syndrome.,
| Elderly Onset Polymyositis and Dermatomyositis|| |
Prevalence of inflammatory myositis (excluding inclusion body myositis) peaks in childhood and mid-life. Elderly onset polymyositis (PM)/DM though rare, should prompt a search for underlying malignancy.
A retrospective study of elderly (≥65 years) versus younger onset PM/DM showed that the clinical features were similar in both groups. However, elderly onset patients tend to have a higher frequency of cancer (24% vs. 9.6%, P = 0.06), especially rectal adenocarcinoma and are diagnosed significantly later after disease onset.
Elderly patients have a normal creatinine phosphokinase more frequently compared to younger onset patients (40% vs. 5%, P = 0.02) due to decrease in muscle mass with aging. No significant difference is seen on histopathology although acute myopathic changes on electromyography are significantly less frequent in the elderly. Clinical and endoscopic rectal examination should be done in these patients apart from the routine malignancy workup.
No significant difference in treatment with respect to drugs used, duration and response to therapy as well as side effects is seen in the elderly.
A summary of clinical and serological phenotype of late versus typical onset inflammatory rheumatic diseases is presented in [Table 1].
|Table 1: Comparison of clinical and serological phenotype of late versus typical onset inflammatory rheumatic diseases|
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| Conclusion|| |
The clinical and serological phenotype of several autoimmune disorders including SLE, RA, pSS, scleroderma, and gout are modified with age. Different age cutoff by various studies has made analysis of this subgroup of patients difficult. Increasing frailty and an aging immune system combined with comorbidities make the diagnosis and management of such diseases a challenge. Exclusion of elderly patients from clinical trials due to their comorbidities has made it difficult to frame treatment recommendations for these patients.
We would like to acknowledge the help of Durga Prasanna Misra, Sonal Mehra, and Jignesh Usdadiya, for their valuable suggestions.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Goto M. Inflammaging [Inflammation+aging]: A driving force for human aging based on an evolutionarily antagonistic pleiotropy theory? Biosci Trends 2008;2:218-30.
Selmi C, Ceribelli A, Generali E, Scirè CA, Alborghetti F, Colloredo G, et al.
Serum antinuclear and extractable nuclear antigen antibody prevalence and associated morbidity and mortality in the general population over 15 years. Autoimmun Rev 2016;15:162-6.
van Schaardenburg D, Lagaay AM, Otten HG, Breedveld FC. The relation between class-specific serum rheumatoid factors and age in the general population. Br J Rheumatol 1993;32:546-9.
Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD. Writing a narrative biomedical review: Considerations for authors, peer reviewers, and editors. Rheumatol Int 2011;31:1409-17.
Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ 2003;81:646-56.
Rasch EK, Hirsch R, Paulose-Ram R, Hochberg MC. Prevalence of rheumatoid arthritis in persons 60 years of age and older in the United States: Effect of different methods of case classification. Arthritis Rheum 2003;48:917-26.
van Schaardenburg D, Breedveld FC. Elderly-onset rheumatoid arthritis. Semin Arthritis Rheum 1994;23:367-78.
Tutuncu Z, Kavanaugh A. Rheumatic disease in the elderly: Rheumatoid arthritis. Rheum Dis Clin North Am 2007;33:57-70.
Soubrier M, Mathieu S, Payet S, Dubost JJ, Ristori JM. Elderly-onset rheumatoid arthritis. Joint Bone Spine 2010;77:290-6.
Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med 2002;347:261-71.
Lopez-Hoyos M, Ruiz de Alegria C, Blanco R, Crespo J, Peña M, Rodriguez-Valverde V, et al.
Clinical utility of anti-CCP antibodies in the differential diagnosis of elderly-onset rheumatoid arthritis and polymyalgia rheumatica. Rheumatology (Oxford) 2004;43:655-7.
Ceccato F, Roverano S, Barrionuevo A, Rillo O, Paira S. The role of anticyclic citrullinated peptide antibodies in the differential diagnosis of elderly-onset rheumatoid arthritis and polymyalgia rheumatica. Clin Rheumatol 2006;25:854-7.
McCarty DJ, O'Duffy JD, Pearson L, Hunter JB. Remitting seronegative symmetrical synovitis with pitting edema. RS3PE syndrome. JAMA 1985;254:2763-7.
Nielsen SF, Bojesen SE, Schnohr P, Nordestgaard BG. Elevated rheumatoid factor and long term risk of rheumatoid arthritis: A prospective cohort study. BMJ 2012;345:e5244.
Radovits BJ, Fransen J, van Riel PL, Laan RF. Influence of age and gender on the 28-joint Disease Activity Score (DAS28) in rheumatoid arthritis. Ann Rheum Dis 2008;67:1127-31.
Santiago MB. Miscellaneous non-inflammatory musculoskeletal conditions. Jaccoud's arthropathy. Best Pract Res Clin Rheumatol 2011;25:715-25.
Caporali R, Montecucco C, Epis O, Bobbio-Pallavicini F, Maio T, Cimmino MA. Presenting features of polymyalgia rheumatica (PMR) and rheumatoid arthritis with PMR-like onset: A prospective study. Ann Rheum Dis 2001;60:1021-4.
Ruta S, Rosa J, Navarta DA, Saucedo C, Catoggio LJ, Monaco RG, et al.
Ultrasound assessment of new onset bilateral painful shoulder in patients with polymyalgia rheumatica and rheumatoid arthritis. Clin Rheumatol 2012;31:1383-7.
Villa-Blanco JI, Calvo-Alén J. Elderly onset rheumatoid arthritis: Differential diagnosis and choice of first-line and subsequent therapy. Drugs Aging 2009;26:739-50.
Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al.
Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-81.
Romão VC, Lima A, Bernardes M, Canhão H, Fonseca JE. Three decades of low-dose methotrexate in rheumatoid arthritis: Can we predict toxicity? Immunol Res 2014;60:289-310.
Bathon JM, Fleischmann RM, Van der Heijde D, Tesser JR, Peloso PM, Chon Y, et al.
Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. J Rheumatol 2006;33:234-43.
Köller MD, Aletaha D, Funovits J, Pangan A, Baker D, Smolen JS. Response of elderly patients with rheumatoid arthritis to methotrexate or TNF inhibitors compared with younger patients. Rheumatology (Oxford) 2009;48:1575-80.
Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J, Merhi A, Abramson S, Arber N, et al.
Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials. Lancet 2013;382:769-79.
Schneeweiss S, Setoguchi S, Weinblatt ME, Katz JN, Avorn J, Sax PE, et al.
Anti-tumor necrosis factor alpha therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis Rheum 2007;56:1754-64.
Toussirot E. Late-onset ankylosing spondylitis and spondylarthritis: An update on clinical manifestations, differential diagnosis and pharmacological therapies. Drugs Aging 2010;27:523-31.
Carbone LD, Cooper C, Michet CJ, Atkinson EJ, O'Fallon WM, Melton LJ 3rd
. Ankylosing spondylitis in Rochester, Minnesota, 1935-1989. Is the epidemiology changing? Arthritis Rheum 1992;35:1476-82.
Rudwaleit M, van der Heijde D, Landewé R, Listing J, Akkoc N, Brandt J, et al.
The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): Validation and final selection. Ann Rheum Dis 2009;68:777-83.
Olivieri I, Pipitone N, D' Angelo S, Padula A, Salvarani C. Late-onset rheumatoid arthritis and late-onset spondyloarthritis. Clin Exp Rheumatol 2009;27 4 Suppl 55:S139-45.
Dubost JJ, Sauvezie B. Current aspects of inflammatory rheumatic diseases in elderly patients. Rev Rhum Mal Osteoartic 1992;59(6 Pt 2):37S-42S.
Dubost JJ, Sauvezie B. Late onset peripheral spondyloarthropathy. J Rheumatol 1989;16:1214-7.
Olivieri I, Garcia-Porrua C, Padula A, Cantini F, Salvarani C, Gonzalez-Gay MA. Late onset undifferentiated spondyloarthritis presenting with polymyalgia rheumatica features: Description of seven cases. Rheumatol Int 2007;27:927-33.
López-Montilla MD, González J, Martínez FG, Fernández-Moreno JR, Collantes E. Clinical features of late onset psoriatic arthritis. Exp Gerontol 2002;37:441-3.
Padovan M, Govoni M, Castellino G, Rizzo N, Fotinidi M, Trotta F. Late onset systemic lupus erythematosus: No substantial differences using different cut-off ages. Rheumatol Int 2007;27:735-41.
Boddaert J, Huong DL, Amoura Z, Wechsler B, Godeau P, Piette JC. Late-onset systemic lupus erythematosus: A personal series of 47 patients and pooled analysis of 714 cases in the literature. Medicine (Baltimore) 2004;83:348-59.
Tomic-Lucic A, Petrovic R, Radak-Perovic M, Milovanovic D, Milovanovic J, Zivanovic S, et al.
Late-onset systemic lupus erythematosus: Clinical features, course, and prognosis. Clin Rheumatol 2013;32:1053-8.
Lalani S, Pope J, de Leon F, Peschken C; Members of CaNIOS/Faces of Lupus. Clinical features and prognosis of late-onset systemic lupus erythematosus: Results from the 1000 faces of lupus study. J Rheumatol 2010;37:38-44.
Lazaro D. Elderly-onset systemic lupus erythematosus: Prevalence, clinical course and treatment. Drugs Aging 2007;24:701-15.
Arnaud L, Mathian A, Boddaert J, Amoura Z. Late-onset systemic lupus erythematosus: Epidemiology, diagnosis and treatment. Drugs Aging 2012;29:181-9.
Marmor MF, Kellner U, Lai TY, Lyons JS, Mieler WF; American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2011;118:415-22.
Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, et al.
American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2010;62:1515-26.
Botsios C, Furlan A, Ostuni P, Sfriso P, Andretta M, Ometto F, et al.
Elderly onset of primary Sjögren's syndrome: Clinical manifestations, serological features and oral/ocular diagnostic tests. Comparison with adult and young onset of the disease in a cohort of 336 Italian patients. Joint Bone Spine 2011;78:171-4.
Drosos AA, Andonopoulos AP, Costopoulos JS, Papadimitriou CS, Moutsopoulos HM. Prevalence of primary Sjögren's syndrome in an elderly population. Br J Rheumatol 1988;27:123-7.
Moerman RV, Bootsma H, Kroese FG, Vissink A. Sjögren's syndrome in older patients: Aetiology, diagnosis and management. Drugs Aging 2013;30:137-53.
Hochberg MC, Tielsch J, Munoz B, Bandeen-Roche K, West SK, Schein OD. Prevalence of symptoms of dry mouth and their relationship to saliva production in community dwelling elderly: The SEE project. Salisbury Eye Evaluation. J Rheumatol 1998;25:486-91.
Ship JA, Pillemer SR, Baum BJ. Xerostomia and the geriatric patient. J Am Geriatr Soc 2002;50:535-43.
Ng KP, Isenberg DA. Sjögren's syndrome: Diagnosis and therapeutic challenges in the elderly. Drugs Aging 2008;25:19-33.
Haga HJ, Jonsson R. The influence of age on disease manifestations and serological characteristics in primary Sjögren's syndrome. Scand J Rheumatol 1999;28:227-32.
Radfar L, Kleiner DE, Fox PC, Pillemer SR. Prevalence and clinical significance of lymphocytic foci in minor salivary glands of healthy volunteers. Arthritis Rheum 2002;47:520-4.
Manoussakis MN, Tzioufas AG, Silis MP, Pange PJ, Goudevenos J, Moutsopoulos HM. High prevalence of anti-cardiolipin and other autoantibodies in a healthy elderly population. Clin Exp Immunol 1987;69:557-65.
Kikuchi M, Inagaki T, Ogawa K, Banno S, Matsumoto Y, Ueda R, et al.
Histopathological investigation of salivary glands in the asymptomatic elderly. Arch Gerontol Geriatr 2004;38:131-8.
Ramos-Casals M, García-Carrasco M, Brito MP, López-Soto A, Font J. Autoimmunity and geriatrics: Clinical significance of autoimmune manifestations in the elderly. Lupus 2003;12:341-55.
Manno RL, Wigley FM, Gelber AC, Hummers LK. Late-age onset systemic sclerosis. J Rheumatol 2011;38:1317-25.
Alba MA, Velasco C, Simeón CP, Fonollosa V, Trapiella L, Egurbide MV, et al.
Early- versus late-onset systemic sclerosis: Differences in clinical presentation and outcome in 1037 patients. Medicine (Baltimore) 2014;93:73-81.
Pérez-Bocanegra C, Solans-Laqué R, Simeón-Aznar CP, Campillo M, Fonollosa-Pla V, Vilardell-Tarrés M. Age-related survival and clinical features in systemic sclerosis patients older or younger than 65 at diagnosis. Rheumatology (Oxford) 2010;49:1112-7.
Mikuls TR, Farrar JT, Bilker WB, Fernandes S, Schumacher HR Jr., Saag KG. Gout epidemiology: Results from the UK General Practice Research Database, 1990-1999. Ann Rheum Dis 2005;64:267-72.
Wise CM. Crystal-associated arthritis in the elderly. Rheum Dis Clin North Am 2007;33:33-55.
Yu KH, Luo SF, Liou LB, Wu YJ, Tsai WP, Chen JY, et al.
Concomitant septic and gouty arthritis – An analysis of 30 cases. Rheumatology (Oxford) 2003;42:1062-6.
Stamp LK, Chapman PT. Urate-lowering therapy: Current options and future prospects for elderly patients with gout. Drugs Aging 2014;31:777-86.
Stamp LK, Taylor WJ, Jones PB, Dockerty JL, Drake J, Frampton C, et al.
Starting dose is a risk factor for allopurinol hypersensitivity syndrome: A proposed safe starting dose of allopurinol. Arthritis Rheum 2012;64:2529-36.
Pautas E, Chérin P, Piette JC, Pelletier S, Wechsler B, Cabane J, et al.
Features of polymyositis and dermatomyositis in the elderly: A case-control study. Clin Exp Rheumatol 2000;18:241-4.