Characteristics and Treatment of Elderly-Onset Rheumatoid Arthritis: Comparison
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Elderly-onset rheumatoid arthritis (EORA) is a distinct clinical entity defined as the onset of rheumatoid arthritis (RA) in individuals aged over 60 years. EORA presents unique clinical features, including a more equitable distribution of sexes, a potential predilection for male involvement, a higher incidence of acute onset characterized by constitutional symptoms, a propensity for systemic manifestations, elevated sedimentation rates at disease onset, a reduced occurrence of rheumatoid factor positivity, increased titers of anti-citrullinated protein antibodies, a preference for involvement of large joints, elevated disease activity, the presence of bone erosions, and heightened patient disability.

  • elderly-onset rheumatoid arthritis
  • rheumatoid arthritis
  • prognosis
  • treatment

1. Introduction

Rheumatoid arthritis (RA) is a systemic, inflammatory disorder that predominantly affects women, with the peak incidence occurring between the ages of 30 and 50, and the average onset age is 55 [1]. Elderly-onset rheumatoid arthritis (EORA) is typically characterized by disease onset after the age of 60. Conversely, “young-onset rheumatoid arthritis” (YORA) describes RA with a more typical presentation at a younger age [1]. Approximately one-third of RA cases develop in individuals aged over 60, and the prevalence increases with advancing age, particularly into the eighth decade [1][2][3].
Historically, earlier studies generally concluded that EORA was a milder form of the disease with a favorable prognosis [2][4][5][6]. However, recent research has revealed a more concerning disease activity and severity, as well as poorer clinical, functional, and radiographic outcomes in EORA, compared to YORA [7]. Some authors have postulated that factors such as seropositivity [8][9], longer disease duration [10], and less intensive treatment [6] may contribute to the potentially worse prognosis of EORA. Nevertheless, the fundamental question of whether EORA and YORA genuinely represent distinct prognostic entities or variations within the broader RA spectrum remains unanswered to date. In the initial stages of EORA management, non-steroidal anti-inflammatory drugs (NSAIDs) are not typically the first-line treatment choice, because seniors are much more prone to develop side effects due to NSAIDs, and the use of NSAIDs is in reality contraindicated to the majority of seniors due to comorbidities. Disease-modifying antirheumatic drugs (DMARDs), frequently methotrexate, are introduced immediately after the diagnosis is made. In cases where elderly patients demonstrate resistance to conventional DMARD therapy, the introduction of biological or targeted synthetic DMARDs becomes a viable treatment option. In response to the evolving challenges in RA management, the burgeoning field of RA nano therapies holds significant promise. By overcoming the limitations of conventional treatments through advancements in nanotherapeutic techniques, particularly in drug delivery systems, these innovations might offer precise and targeted solutions [11].

2. Differences between EORA and YORA Diseases

EORA markedly differs from YORA in several key aspects (Table 1).

Table 1. Comparison of main characteristics of patients with EORA and YORA.
Proximal joints + +++ −
Peripheral joints +++ + +++
Tenosynovitis ++ +/− +++
Edema + + +++
RF+ +/− − −
High ESR + +++ +
Characteristics EORA YORA
Age of onset after 65 years 30–50
Prevalence 2% 0.5–1%
Female/male ratio 1/1 or more men 3/1
Onset acute and infectious-like gradual
Number of joints involved may be oligoarticular polyarticular
Sites involved large/proximal joint small joints of the hands and feet
Fatigue, weight loss more prominent less prominent
Genetic predisposition HLA-DRB1∗ 01 HLA-DRB1*04
Rheumatoid factor lower incidence higher incidence
Titer for ACPA higher lower than EORA
Subcutaneous nodules less frequent more frequent
Pauci-immune fibroid synovial pathotype less frequent more frequent
Bone erosions more frequent frequent
Elevated ESR/CRP more frequent frequent
Higher WBC, ANC more frequent frequent
Lower PLR, NLR more frequent frequent
Higher IL6, lower TNFα more frequent less frequent
Higher DAS28, CDAI, SDAI more frequent frequent
Higher ultrasound features: ST, PDS, SHC more frequent frequent
Clinical form classical RA

PMR-like form

RS3PE s/m like form		 classical RA
Comorbidity more frequent less frequent
Prognosis worse good or worse
ACPA: anti-citrullinated protein antibodies; ANC: absolute neutrophil count; CDAI: clinical disease activity index; CRP: C-reactive protein; DAS28: 28-joint disease activity score; EORA: elderly-onset rheumatoid arthritis; ESR: sedimentation rate; IL-6: interleukin 6; NLR: neutrophil-to-lymphocyte ratios; SDAI: simplified disease activity index; PDS: power Doppler synovitis; PLR: platelet-to-lymphocyte ratios; PMR: polymyalgia rheumatica; RS3PE: remitting seronegative synovitis with pitting oedema; SHC: Sharp–van der Heijde score; ST: synovial thickening; TNFα: tumor necrosis factor α; WBC: white blood cell count; YORA: young-onset rheumatoid arthritis.

3. Clinical Features and Differential Diagnosis

EORA is a heterogeneous disease characterized by three distinct clinical patterns [12]. The most common clinical form (70%) closely resembles classical RA, with positive rheumatoid factor (RF), joint erosions, and a worse prognosis than YORA. The second form (25%) resembles PMR in its presentation, with the involvement of proximal limb joints. It is typically RF-negative, exhibits an acute onset, does not result in joint erosions, and generally has a favorable prognosis. However, it is important to note that asymmetric nonerosive polyarthritis may occur in 25% of patients with PMR, making a careful differential diagnosis essential. In this context, the presence of anti-CCP positivity in EORA and bilateral subacromial bursitis in PMR can be diagnostic aids. The third EORA pattern shares the clinical and prognostic similarities of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. RS3PE syndrome, first described by McCarty et al. in 1985 [13], is characterized by an elderly onset, an acute onset, symmetrical synovitis and tenosynovitis, pitting edema of the dorsum of the hands and feet, negative RF and ACPA status, the absence of bone erosion, and an excellent prognosis, with low-dose corticosteroid therapy and spontaneous remission within 3–18 months [14][15]. Interestingly, in these subgroup cases, high HLA-B27 positivity has also been reported [12]. To distinguish RS3PE syndrome from EORA, it is essential to assess not only intra-articular but also extra-articular lesions using musculoskeletal ultrasound (MSUS).  Sometimes it is hard to differentiate EORA from PMR and RS3PE (Table 2), but it is important to note that the differential diagnosis of EORA extends beyond PMR and RS3PE syndrome. Other conditions, such as osteoarthritis, spondyloarthropathy, hypertrophic osteoarthropathy, sarcoidosis, connective tissue diseases, systemic vasculitis, paraneoplastic syndromes, crystal arthropathies (such as gout, pseudogout, or chronic pyrophosphate arthropathy), and infectious arthritis (including viral, especially hepatitis C, and bacterial infections, like septic arthritis), should also be considered and ruled out via the diagnostic process.
Table 2. Different clinical and laboratory features of EORA, PMR, and RS3PE.
Characteristics EORA PMR RS3PE
− Absent, + Occasional, ++ Frequent, +++ Very frequent; EORA: elderly-onset rheumatoid arthritis; ESR: sedimentation rate; PMR: polymyalgia rheumatica; RS3PE: remitting seronegative synovitis with pitting oedema.

4. Comorbidities

4.1. Cardiovascular Risk

Traditional cardiovascular risk factors, inflammatory pathogenesis among inflammatory arthritis and atherosclerosis, and the use of steroids and non-steroidal anti-inflammatory drugs (NSAIDs) contribute to increased cardiovascular risk in RA patients, especially the elderly [16]. Also, metabolic parameters were significantly higher in EORA patients’ body mass index (BMI), serum concentration of creatinine, and uric acid than in those of YORA patients [17].

4.2. Risk for Infections

EORA patients often have greater disease activity, leading to early disability and eventually increased immobility, which is a strong risk factor associated with infections such as respiratory and urogenital infections. In addition, the use of immunomodulatory treatment further increases the risk of infection in RA patients [16].

4.3. Risk for Developing Malignancies

The immune aging process in RA may contribute to an increased risk of developing malignancies, primarily due to the presence of chronic inflammation and impaired DNA repair mechanisms [16]. Parikh-Patel et al. [18] conducted an assessment of cancer risk among RA patients in California. Their study involved 84,475 RA patients, with a total observation period of 405,540 person-years. During this time frame, 5533 incident cancers were diagnosed among the study’s participants.

4.4. Lung Disease

Lung disease is a prevalent issue among patients with RA, and its occurrence can be attributed to a combination of factors, including the disease itself, comorbid conditions, medications used for treatment, or a combination of these elements. Chronic infections and smoking are recognized as significant contributing factors to lung-related complications in RA patients [16].

5. Treatment

The treatment approach for older patients with rheumatoid arthritis (RA) should align closely with the goals set for younger patients, which include the following issues:
-
Controlling disease activity: the primary objective is to effectively manage and control the activity of RA to minimize symptoms and inflammation;
-
Preventing structural damage: efforts should be made to prevent joint damage and deformities associated with RA;
-
Preserving functionality: maintaining or improving the patient’s ability to carry out daily activities and maintain a good quality of life is a key goal;
-
Decreasing excess mortality: RA is associated with an increased risk of mortality, and treatment should aim to reduce this excess mortality [19][20].

5.1. Non-Steroidal and Steroid Anti-Inflammatory Drugs

The use of non-steroidal anti-inflammatory drugs (NSAIDs) and corticoids (steroid anti-inflammatory drugs) as adjuncts to RA treatment is a common practice. However, existing studies on this topic are somewhat dated, and there is limited clarity regarding the long-term safety of these medications [21]. In the case of EORA, NSAIDs are often the initial choice of treatment, prescribed to approximately 60% of patients at disease onset, and they were replaced by disease-modifying antirheumatic drugs (DMARDs). The therapy with NSAID was of short duration, and no significant adverse events were associated with NSAIDs [17].

5.2. Disease-Modifying Antirheumatic Drugs

Disease-modifying antirheumatic drugs used in YORA may also be safely used in the treatment of EORA. However, drug pharmacokinetics and pharmacodynamics in the elderly population are different, while the incidence of different comorbid diseases has increased in this age group, and due to the high number of medications used, caution must be taken in terms of side-effect profile [12]. EORA patients are not always treated with sufficient doses of DMARDs. The literature data on the use of DMARDs in patients with EORA are limited and contradictory.

6. Conclusions

EORA and YORA represent distinct prognostic entities within the spectrum of rheumatoid RA. Despite advancements in science and technology, there are still ongoing controversies in the understanding and management of EORA. Real-world data have revealed that the treatment of elderly RA patients is often unsatisfactory in clinical practice. This can be attributed to several factors, including a lack of robust evidence, concerns about potential adverse events, the presence of comorbidities, polypharmacy, and cognitive dysfunction in elderly patients. As a result, physicians continually face the challenge of striking a delicate balance between the potential benefits and risks associated with treatment intensification in elderly RA patients.

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