Rheumatoid Arthritis in the Older Patient

A Case of Rheumatoid Arthritis in an Older Patient

RC is a 75-year-old woman who gives a history of a healthy adult life until she began to experience pain in many joints, but predominately in both hands. At first, primary generalized osteoarthritis (OA) was suspected as the cause, a diagnosis influenced by her age. However, the pain worsened over the next several months, particularly in the morning, and was associated with severe stiffness. She then developed swelling in both wrists and knees and became unable to dress herself because of difficulty with buttons and shoelaces. Over the next month, she lost approximately 5 lb unintentionally and sustained several falls. RC’s functional status continued to decline, and she presented to her primary care physician.

On examination, she has findings of Heberden’s and Bouchard’s nodes, but also subtle swelling of the metacarpophalangeal (MCP) joints and bilateral knee effusions. A knee arthrocentesis produces clear synovial fluid, with a white blood cell count of 5000/mm³ and no crystals. Laboratory studies reveal an elevated erythrocyte sedimentation rate (ESR), an increased C-reactive protein (CRP) level, and the presence of anti-citrullinated peptide antibodies (ACPAs). Radiographs of the hands show periarticular osteoporosis.

A diagnosis of rheumatoid arthritis (RA) is appropriately made. Treatment with methotrexate, prednisone, and, eventually, a biologic agent, is initiated, in conjunction with physical therapy to strengthen her muscles.

Introduction

RA is a systemic autoimmune inflammatory disease characterized primarily by joint swelling and pain with resultant joint destruction and disability. The incidence of RA increases significantly with age, and late-age onset disease is not unusual. The importance of RA in the older population has been long recognized and is even included in one of the earliest descriptions of RA from France during the 1800s when Dr. Jacob Landré-Beauvais described a severe illness with involvement of the joints, a female predominance, a chronic course, and a precipitous decline in general health among several patients over the age of 70 years.¹

The past 20 years have brought great advances in our understanding of the complex pathophysiology of RA, including the identification of important genetic markers of susceptibility (eg, the HLA-DR4 shared epitope),²the important influence of environmental factors such as smoking on the development of disease and disease severity,³ and the role of antibodies to citrullinated peptides as disease-specific markers.⁴ Further, treatment of RA has been revolutionized with the advent of early, aggressive treatment strategies with disease-modifying antirheumatic drugs (DMARDs) such as biologic immunotherapies that target specific molecules in the pathogenic pathways of RA. The care of older adults with RA, many of whom have multiple comorbidities, polypharmacy, and high healthcare costs, introduces additional considerations in disease management and requires shared monitoring between primary care providers and rheumatologists. 

In this article, we review features of RA in the elderly, the differential diagnosis of common symptoms and signs of the disease, and special considerations for providing comprehensive care to older patients with RA in the era of biologic therapies, including vaccinations and comorbid conditions.

Epidemiology of Rheumatoid Arthritis Among Older Individuals

The incidence rate of RA is approximately 0.40 per 1000 person-years for women and 0.26 per 1000 person-years for men in the United States.^5,6 Recent data suggest that the incidence of RA among women has increased significantly between 1995 and 2007.7 Studies have demonstrated a positive correlation between the incidence of RA and age in both sexes, with the number of cases peaking between 60 and 80 years of age.^6,8 Interestingly, some reports suggest that the incidence of RA consistently increases even up to 85 years of age.⁸

Estimates of the prevalence of RA range from approximately 0.8% to 0.9% for North American and European populations.^5,9,10Among persons 60 years of age and older in the United States, the prevalence of RA is approximately 2% and is highest among women and individuals over the age of 70 years.¹¹ It is projected there will be more than 29 million individuals age 70 years or older living in the United States by 2012,¹² which translates to more than half a million adults in this age demographic living with RA and requiring care.

Clinical Features of Rheumatoid Arthritis in Older Patients

The hallmark clinical feature of RA is a symmetric inflammatory polyarthritis that involves the small joints of the hands, wrists, and feet. Patients typically also recount a history of morning stiffness, joint swelling, and associated systemic constitutional symptoms. The onset of RA may occur with an indolent course over several months or may occur suddenly, mimicking an acute crystalline arthritis. Further clinical evidence of systemic inflammation may also be present, such as severe fatigue, unintentional weight loss, low-grade fevers, and asthenia. Extra-articular manifestations of RA such as nodules, pulmonary disease (usually asymptomatic), and vasculitis may occur in conjunction with articular disease or may precede joint symptoms and can be detected by careful history taking and physical examination. The incidence and severity of extra-articular manifestations of RA are decreasing with the advent of more effective therapies.

Early epidemiologic studies suggest that the subset of patients with late-age onset RA may represent a unique phenotype with a more equal sex distribution, more frequent involvement of large joints, and lower frequency of autoantibodies.^13,14 Although the literature contains conflicting reports on the clinical manifestations of RA in the elderly, RA indisputably demonstrates wide heterogeneity among this demographic.^15,16 Further, RA as a disease can be equally as severe in the old as in the young, with erosions, joint destruction, and profound disability potentially occurring within only 3 years of diagnosis.¹⁷

As expected, geriatric syndromes such as cognitive impairment, depression, falls, urinary incontinence, and malnutrition are more prevalent in older patients with RA than in younger patients with RA.¹⁸ Risk factors for the development of geriatric syndromes among elderly patients with RA include higher RA disease activity, longer disease duration, and functional impairment, as measured by the Health Assessment Questionnaire (HAQ).¹⁸ Functional impairment as measured by the HAQ increases with age among the general population¹⁹ and is highest among female patients with RA who are over age 70 years.²⁰ For patients with arthritis, in general, older age, depression, and cognitive impairment are strong predictors of functional decline.²¹ Lack of regular vigorous physical activity is also a significant risk factor for functional decline in older adults with arthritis (adjusted odds ratio [OR], 1.9; 95% confidence interval [CI], 1.5-2.4).²¹

Diagnosing Rheumatoid Arthritis in Older Patients

Diagnosing RA in older patients can be challenging, as signs and symptoms of RA may be subtle and difficult to distinguish from other conditions common in the elderly (see the “Differential Diagnosis for Rheumatoid Arthritis in Older Patients” section). The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) recently collaborated to establish a new classification system for RA.²² The goal of the new ACR/EULAR classification criteria for RA (Table), which include a combination of clinical features (synovitis) and laboratory values (autoantibodies, acute-phase reactants), is to identify patients in the early stages of disease, before they experience damage (ie, erosions, joint deformity, disability) and before the disease affects a large number of joints or demonstrates symmetrical involvement.²² These new RA classification criteria are in contrast to the 1987 ACR criteria for RA, which were developed based on the characteristics of long-standing disease.²³

The clinical examination in RA is marked by synovial proliferation and synovitis. As noted in the new ACR/EULAR criteria, the small joints of the hands (MCP, proximal interphalangeal [PIP]), feet (metatorsophalangeal), and wrists are almost always involved.²² This does not exclude the additional involvement of large joints, such as the shoulders and knees, but it is unusual for RA to affect large joints only. Tenosynovitis may occur in combination with synovitis and palpable nodules. The axial spine is not involved in RA, except for the atlantoaxial joint (C1-C2), where tenosynovitis can lead to joint instability and subluxation.

Although autoantibodies (notably rheumatoid factor [RF] and ACPA) and acute-phase reactants (ESR and CRP) are included as important aspects of the ACR/EULAR classification criteria for RA, caution should be employed when interpreting these laboratory studies in the elderly. RF is an antibody that recognizes the Fc portion of the immunoglobin G (IgG) molecule (usually IgM isotype is measured). It is one of the most commonly recognized autoantibodies that occur in the healthy elderly population (those without RA). Estimates of the prevalence of RF in the general older population (≥60 years) range from 10% to 48% among elderly persons in North America and Europe as compared with less than 5% in the younger populations.^24-27 RF positivity can occur in many nonrheumatic conditions, such as infections (notably hepatitis C), hematologic malignancies, and paraproteinemias; hence, it lacks specificity for RA, particularly among the elderly.

ACPAs, which include anti-cyclic citrullinated peptide antibodies (anti-CCP), are much more specific for RA compared with RF (>95%), and therefore may be more useful in diagnosing RA in older patients.^4,28 However, it is important to note that RF and ACPA/anti-CCP are not required to make a diagnosis of RA (Table), and up to 15% to 20% of patients with established RA are without either of these antibodies.²⁹

ESR and CRP are nonspecific markers of systemic inflammation that can be helpful in diagnosing RA and in assessing response to treatment. However, it should be emphasized that these measures are nonspecific and can be elevated to very high levels in a multitude of conditions commonly seen in elderly patients, including infection, malignancy (particularly elevated ESR with paraproteinemias), and other systemic inflammatory rheumatic diseases, such as giant cell arteritis.

Rheumatoid Arthritis-Associated Comorbidities in Older Patients

Many chronic conditions that are common in older individuals also have an increased prevalence in elderly patients with RA. Individuals with RA have a significantly increased risk of cardiovascular disease,³⁰ malignancy (especially lymphoproliferative disorders),³¹ anemia,³² and infections.³³ Carefully monitoring elderly patients for these frequent complications of RA and potential complications of RA treatments requires a multidisciplinary approach that incorporates appropriate screening measures and interventions.

Differential Diagnosis for Rheumatoid Arthritis in Older Patients

Joint pain and swelling in an elderly patient should elicit a thoughtful and extensive differential diagnosis beyond RA. Elderly patients are at increased risk for other types of inflammatory and noninflammatory arthropathies (eg, gout, OA) whose incidence and prevalence increase significantly with age.^34,35 Other systemic rheumatic diseases also frequently present with arthritis in the elderly (eg, polymyalgia rheumatica [PMR], dermatomyositis) and may mimic RA, particularly early in the disease course. Malignancy can also masquerade as RA, generating a multitude of similar joint and cutaneous manifestations that mimic RA.³¹

Crystalline Arthropathies
Gout, caused by uric acid crystals, is a robustly inflammatory arthropathy that disproportionately affects the older population.³⁴ Although classically described as an acute monoarthritis or oligoarthritis (involving <3 joints), chronic gouty arthritis can progress to a destructive, erosive disease with chronic synovitis and deformity of multiple joints that closely resembles RA. Age is the strongest risk factor for the development of pseudogout, caused by calcium pyrophosphate dihydrate (CPPD) crystals, which, similarly, can cause an inflammatory arthritis primarily of the knees, shoulders, and wrists.³⁶

The key to distinguishing crystalline arthropathies from RA is the identification of crystal deposition. Crystals can be identified in the subcutaneous tissue (uric acid tophi), in the form of chondrocalcinosis (calcium salt deposition seen on radiographs), or—most definitively—in synovial fluid (negatively birefringent needle-shaped uric acid crystals or positively birefringent rhomboid CPPD crystals).

Osteoarthritis
OA is the most common form of arthritis in the United States³⁵ and, similar to RA, may affect the small joints of the hands. Involvement of the MCP joints is not seen in OA, and involvement of the distal interphalangeal (DIP) joints alone cannot be attributed to RA. OA is typically characterized by pain with activity, whereas RA may improve over the course of the day. Joint stiffness can be seen both in OA and RA, but typically lasts less than 30 minutes in OA and is more persistent in RA. 

Firm, bony Heberden’s and Bouchard’s nodes may be found on examination of the DIP and PIP joints, respectively, but usually lack synovitis in OA. OA at the base of the thumb or carpometacorpal joint is also common in the aging population and can sometimes be confused with rheumatoid involvement of the first MCP joint or wrist. Osteophytes and new bone formation are seen in OA radiographs (typically without erosions), in contrast to joint erosions without new bone growth, which are seen in RA radiographs. When joints are aspirated in OA, a noninflammatory synovial fluid (white blood cell count of <1000/mm³) is seen.

OA and RA can coexist in a single patient and frequently do in the elderly. Hence, a careful comprehensive evaluation with detailed history, joint assessment for synovitis, serologic profiling (RF, ACPA/anti-CCP), and radiographs are necessary to distinguish OA from RA.

Polymyalgia Rheumatica
The prevalence of PMR increases dramatically with age and is estimated to be 739 per 100,000 (95% CI, 674-808) among individuals 50 years of age and older, but more than doubles to 2737 per 100,000 among individuals 80 to 85 years of age.^35,37 Peripheral inflammatory arthritis is present in up to 38% of patients with PMR, making it difficult to distinguish PMR from RA, particularly early in the disease course.^38,39 One study that examined 142 patients with late-age onset RA (defined as ≥60 years) or PMR found that arthritis of the PIP joints, MCP joints, and wrist, and the combination of arthritis of the wrist plus MCP and PIP joints was highly suggestive of RA (instead of PMR).⁴⁰ ACPA/anti-CCP antibodies, which are highly specific for RA, are not seen in patients with PMR, and testing for these may be useful in distinguishing between PMR and RA.⁴¹ The absence of ACPA/anti-CCP antibodies, however, does not rule out RA.

Remitting Seronegative Symmetrical Synovitis With Pitting Edema Syndrome
Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome occurs almost exclusively in individuals over 60 years of age and is characterized by pitting edema primarily of the hands and feet and symmetric polyarthritis.⁴² When RS3PE was first described in the 1980s, it was thought to represent a subclassification of RA among the elderly.⁴³ However, RS3PE lacks several key features of RA, including joint erosions and autoantibodies (RF, ACPA/anti-CCP). The absence of these features combined with the unique finding of pitting edema in RS3PE indicates that this is a distinct entity. From an arthritis perspective, the prognosis is excellent; patients respond quite well to therapy and are not at risk for developing joint-deforming sequelae. Clinicians should be cognizant of the association between RS3PE and malignancy, and appropriate evaluation for cancer should be pursued.^42,44

Other Connective Tissue Disorders
Many systemic inflammatory diseases can present with inflammatory arthritis that resembles RA. The presence of arthritis plus additional symptoms such as muscle weakness, late-age onset Raynaud phenomenon, skin thickening, rashes, parotid enlargement, or sicca (eg, oral and ocular dryness) should prompt consideration of other rheumatic diseases known to occur in the elderly, such as dermatomyositis, scleroderma, and Sjögren’s syndrome. A careful physical examination and laboratory investigation, as appropriate, should be pursued when evaluating patients for these conditions. 

Malignancy
Particularly in older individuals, the new onset of inflammatory arthritis should generate concern for a paraneoplastic process. Arthritis as a paraneoplastic syndrome presents most frequently as a symmetric polyarthritis of the hands and wrists without any unique distinguishing features from RA.⁴⁵ In patients with solid tumors, the arthritis may improve significantly with resection of the malignancy and treatment.⁴⁵ Multicentric reticulohistiocytosis is a mimic of RA that presents with a severe inflammatory arthritis, frequently arthritis mutilans, and characteristic cutaneous periungual and facial papules.⁴⁶ It is very closely associated with malignancy, and an aggressive workup for such should be pursued. Similarly, palmar fasciitis (thickening of the palmar skin of the hands leading to contractures resembling a deforming arthritis) is highly associated with malignancies, particularly ovarian and breast cancers.^47,48 Amyloid arthropathy can be the presenting symptom of multiple myeloma and is associated with a spectrum of clinical features, including shoulder hypertrophic arthropathy, RA-like polyarthritis, and carpal tunnel syndrome.⁴⁹ Although rare, amyloid arthropathy should be considered when an elderly patient develops a new, inflammatory arthritis. Screening with serum and urine immunoelectrophoresis is appropriate.

Treatment of Rheumatoid Arthritis in Older Patients

The treatment of RA has been revolutionized over the past 10 years. Advancement in pharmacotherapy, coupled with a better understanding of important prognostic features (ACPA/anti-CCP, erosions, extra-articular manifestations), has allowed for the early identification of patients at high risk for serious long-term sequelae and disability from RA and has led to evidence-based recommendations for the initiation of early aggressive treatment.^50,51

Disease-Modifying Antirheumatic Drugs
Synthetic DMARDs such as methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine are oral agents commonly used to treat RA. It is now well established that, unless contraindicated, methotrexate should be the cornerstone of treatment for RA, as it has repeatedly demonstrated efficacy in all populations studied.^52,53 Combination therapy with synthetic DMARDs has also demonstrated significant efficacy, particularly with the triplet regimen of methotrexate, sulfasalazine, and hydroxychloroquine.⁵⁴ Therapy with hydroxychloroquine alone, however, does not appear to have significant effects on preventing joint destruction in patients with RA.

Biologic DMARDs constitute a newer class of disease-modifying agents for the treatment of RA and target specific components of the immunological and inflammatory pathways integrally involved in propagating the inflammatory and destructive cycle of RA. These medications currently include, but are not limited to, inhibitors of the proinflammatory cytokine tumor necrosis factor (TNF; infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol); B-cell–depleting agents (rituximab), inhibitors of T-cell co-stimulation (abatacept); and drugs that target the cytokines interleukin-6 (tocilizumab) and interleukin-1 (anakinra). Biologic DMARDs appear to be most effective at decreasing RA disease activity and preventing radiographic progression when combined with synthetic DMARDs. Many biologic DMARDs have also demonstrated significant efficacy as monotherapies.

Safe Disease-Modifying Antirheumatic Drug Use in Older Patients. A 2007 analysis of healthcare claims data for a subset of Medicare beneficiaries with RA demonstrated that the use of DMARDs has increased steadily over time (DMARDs prescribed for 24% of patients with RA in 1996 compared with 43% of patients in 2003 [P for trend <0.001]).⁵⁵ Despite these gains, older patients are significantly less likely to receive DMARDs than their younger counterparts, even with data supporting comparable disease severity, activity, and duration.⁵⁶ Similar findings were reported among a cohort of elderly Japanese patients with RA.⁵⁷ Age has been identified as an independent predictor for decreased use of biologic DMARDs (10-year OR, 0.74; 95% CI, 0.66-0.82).⁵⁸ 

The reason for the decreased use of DMARDs in the elderly is likely multifactorial. Methotrexate, lefluonomide, and, less commonly, sulfasalazine can lead to hepatotoxicity, which may be worsened by concomitant medications or fatty infiltration of the liver, issues that are not uncommon among the elderly. Regular assessment of transaminases is required in all patients taking these medications. These agents may also cause cytopenias, necessitating regular laboratory monitoring.⁵⁰ Methotrexate is renally excreted; hence, dose adjustment is required and its use may be limited in patients with renal impairment. All patients taking methotrexate require folic acid repletion at a dose of at least 1 mg daily, which exceeds the amount of folic acid contained in most multivitamins. Within the first year of treatment with methotrexate, between 20% and 70% of patients experience gastrointestinal adverse events such as nausea, anorexia, and dyspepsia.⁵⁹ These adverse effects are usually managed easily with leucovorin (folinic acid) and/or by changing the route of administration from oral to subcutaneous. Infrequently, methotrexate can induce central nervous system side effects such as headache, altered mood, or memory impairment.⁶⁰ This has been observed primarily among patients with RA who are over age 60 years, and older patients should be closely monitored for these adverse events.⁶⁰

Patients taking hydroxychloroquine require routine monitoring (every 6 months) for retinal toxicity, and it should not be used in patients with maculopathy, a condition that is more common in the elderly. Although rare, long-term use of hydroxychloroquine can lead to an infiltrative myopathy.

Patients with RA intrinsically have an increased risk of infection that is significantly increased by the use of corticosteroids.^61,62 However, most DMARDs (synthetic or biologic) also have the potential to increase the risk of infection. The comparison of this risk between synthetic DMARDs, TNF inhibitors, and other biologic agents is somewhat controversial. A study with a large cohort of Medicare beneficiaries with RA age 65 years and older (mean age, 76.5 years) found no significant difference in the rate of serious bacterial infections between patients taking TNF antagonists and those taking methotrexate.⁶³ However, in another study of patients with RA enrolled in the British Society for Rheumatology Biologics Register, TNF inhibitors were associated with a 20% higher risk of serious infection compared with synthetic DMARD therapy (adjusted hazard ratio, 1.2; 95% CI, 1.1-1.5).⁶⁴ The risk of infection increased with age at a comparable rate between the synthetic DMARD group and the TNF antagonist arm.⁶⁴

Vigilant surveillance for infection among elderly patients taking synthetic or biologic DMARDs is critical. Patients should be educated with a plan to contact their physician and discuss temporary discontinuation of biologic medications in the context of infections. Healthcare providers should have a low threshold for rapid clinical assessment and initiation of antibiotics for patients on biologic DMARDs with fever (temperature ≥100.4°F or 38°C). Atypical infections, notably histoplasmosis, coccidiomycosis, and tuberculosis, should be considered pathogens in the immunocompromised RA patient.

Corticosteroids
The use of corticosteroids for the management of RA has largely been replaced by synthetic and biologic DMARDs; however, in patients who are acutely flaring or with newly diagnosed disease, steroids still maintain an important role for quick, efficient, short-term symptomatic control of RA. With long-term use, corticosteroids can lead to many complications including hyperglycemia, hypertension, and premature cataract formation. Elderly patients taking corticosteroids may be particularly susceptible to alterations in mood and delirium. The treatment and prevention of glucocorticoid-induced osteoporosis is critical among older patients with RA and should be anticipated and proactively managed. Recently published ACR guidelines on the prevention and treatment of glucocorticoid-induced osteoporosis include the combined assessment of fracture risk, anticipated steroid dose, and steroid treatment duration to determine therapeutic and preventive interventions.⁶⁵ All patients on steroids for 3 months or longer should be counseled on lifestyle modification (smoking cessation, vitamin D assessment, fall risk assessment, etc), and older patients (≥50 years) should also be considered for pharmacologic therapy (based on fracture risk and steroid dose).⁶⁵

Nonpharmacologic Rheumatoid Arthritis Therapies
Pharmacologic RA therapies should always be used in conjunction with nonpharmacologic RA therapies in the care of elderly patients with RA. Physical therapy and exercise are safe and efficacious in patients with RA.^66,67 This is of particular importance among elderly patients who are at risk for sarcopenia, falls, and malnutrition due to competing comorbidities, medications, and functional limitations. Smoking cessation should be a part of all RA treatment plans as well. In addition to cigarette smoking being detrimental to overall health, it may influence RA severity. All patients should be strongly advised by their healthcare providers to quit smoking and should be made aware of smoking cessation resources.

Special Considerations for the Older Patient With Rheumatoid Arthritis

There are several aspects of the care of elderly patients with RA that deserve special attention. Elderly patients with RA are at risk for infection due to immune dysregulation attributable to inflammatory disease, age, and immunomodulatory treatments. The safe administration of vaccinations to provide optimal protection against infection is critical for these patients. The preoperative management and postoperative care of elderly patients with RA require careful medication management and specific preoperative screening. Finally, when treating pain in older patients with RA, safety concerns for analgesic agents should be carefully considered for each individual patient.

Vaccinations
Vaccines are important tools for preventing serious infections, and they are a critical resource for immunosuppressed patients. The safety and efficacy of vaccinations against common pathogens such as influenza and pneumococcus are well established for patients with rheumatic diseases,^68,69 but their use in practice is still suboptimal.^70,71 Previous studies have suggested lack of physician initiative and patient concerns regarding adverse effects as reasons for mediocre vaccination rates.⁷² Although inactivated and recombinant vaccines are generally considered safe for patients on immunosuppressive drugs, the use of live vaccines for this population has historically been avoided per guidelines put forth by the Centers for Disease Control and Prevention (CDC).⁷³

In 2006, a new live vaccine for herpes zoster emerged. It was initially approved for use in immunocompetent adults. Herpes zoster infections have a high prevalence in patients with RA and in patients on immunomodulatory drugs, which led to great interest in the use of this live vaccine in these populations.⁷⁴ However, as the herpes zoster vaccine is a live vaccine, initially it was not considered appropriate for use in patients on immunosuppressive therapy, and many patients being treated for rheumatic disease were not candidates for its use. In June 2008, the CDC officially changed its guidelines regarding this particular live vaccine and extended the recommendation of its use for patients on low-dose prednisone (<20 mg, <2 weeks), low-dose methotrexate (≤0.4 mg/kg/week [the dose used to treat RA]), azathioprine (≤3.0 mg/kg/day), or 6-mercaptopurine (≤1.5 mg/kg/day).75 It is important to note that it is still not appropriate to administer any live vaccines (including the zoster vaccine) to patients taking TNF antagonists or other biologic agents. If a live vaccine has been administered and treatment with a biologic agent is being considered, it is recommend that a period of at least 2 to 3 weeks elapse after the immunization and before starting biologic therapy.

The use of B-cell–depleting agents (rituximab) in the treatment of RA has led to important investigations regarding the immune response in patients with RA following the administration of this drug. A recent, randomized controlled trial examining the immune response in patients with RA treated with rituximab demonstrated decreased immune responses to neoantigens and polysaccharides.⁷⁶ Therefore, to maximize the response to vaccinations, immunizations should ideally be administered prior to rituximab.⁷⁶

The need for boosters in patients treated with biologic DMARDs is still unknown and is an area of active investigation.

Surgery/Preoperative Evaluation
Disease activity, use of DMARDs, and exposure to corticosteroids should be carefully taken into consideration during the preoperative evaluation of an elderly patient with RA. For elective surgery, the patient should ideally be clinically in a low disease activity state with few tender or swollen joints. It is recommended that TNF antagonists be discontinued prior to surgery, although the optimal time period is unclear and may need to be extended for drugs with longer half-lives.⁵⁰ There are no consistent data regarding recommendations for synthetic DMARDs in the pre- and postoperative periods.⁵⁰

Perioperative stress-dose steroids are recommended for patients exposed to corticosteroids. C1-2 subluxation should be assessed preoperatively using cervical spine films (flexion and extension), particularly in patients with long-standing RA.

Pain Management
Patients with RA may require analgesics for joint pain, either while DMARD therapy is being initiated (which may take several months to become effective) or to relieve pain from irreversible joint damage due to RA and secondary OA. The most commonly used analgesics for pain relief in patients with RA are nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, and opioids. Note that none of the drugs in these classes are considered DMARDs for the treatment of RA and will not prevent progression of destructive arthritis or treat systemic or extra-articular manifestations of the disease.

Safety concerns for NSAIDs, COX-2 inhibitors, and opioids are relatively well established. There is a clear association between NSAIDs and serious upper gastrointestinal complications.⁷⁷ In addition, patients’ cardiovascular risks should be taken under consideration when prescribing either NSAIDs or COX-2 inhibitors.^78,79 Sedation, delirium, and constipation are potential worrisome side effects to weigh when prescribing opioids for elderly patients. A recent study investigated the comparative safety of the five opioid agents most commonly prescribed to treat nonmalignant pain in older adults (codeine phosphate, hydrocodone bitartrate, oxycodone hydrochloride, propoxyphene hydrochloride, and tramadol hydrochloride).⁸⁰ Many of these drugs are also used for managing pain in patients with RA. Solomon et al⁸⁰ demonstrated that the rate of safety events (cardiovascular, fracture risk, all-cause mortality) among different opioids varied considerably by agent and duration of use.

Several studies have compared the safety of various NSAIDs to specific COX-2 inhibitors. Recently, important data were published on the comparative safety of analgesics in elderly patients with RA or OA. Solomon et al⁸¹ evaluated the incidence rates of various safety events in 12,840 Medicare patients with RA or OA who used NSAIDs, COX-2 inhibitors, or opioids. They found high incidences of several safety events (cardiovascular, falls, all-cause mortality, hospitalized adverse event) among all three analgesic groups. However, rates of many serious adverse events, including cardiovascular events; fractures of the hip, humerus, pelvis, and radius; hospitalized adverse events; and all-cause mortality, were highest among opioid users.⁸¹ Given the increased use of opioids for nonmalignant pain, clinicians must carefully weigh the benefits and risks of these medications, especially when using them in older adults with comorbidities.

Conclusion

RA can be challenging to diagnose and manage in older patients. Although RA is now a treatable and manageable chronic disease, significant gaps remain in our knowledge regarding the optimal management of elderly patients with RA. It is important to include this population in future randomized controlled trials of RA therapies. This will facilitate the development of treatment strategies that specifically address the unique needs of older individuals. Providing comprehensive care to older patients with RA requires a multidisciplinary approach with open communication between all members of the patient’s care team to optimize treatment, prevent complications, and minimize disability.

Dr. Manno is supported by NIH T32 AR048522.

Dr. Bingham is a consultant for Amgen Inc, Abbott Laboratories, Centocor Ortho Biotech Inc., Bristol-Myers Squibb, UCB, Pfizer Inc, Flexion Therapeutics, Celgene Corporation, Roche, and Genentech, Inc. He has also received research grants from Roche, Bristol-Myers Squibb, Amgen Inc, and UCB. From the Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD. 

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