Rheumatoid Arthritis
Summary/Definition
Rheumatoid arthritis is a chronic inflammatory disease of the synovial joints, characterized by its symmetrical occurrence in the small joints of the hands and feet. Early symptoms include joint swelling and pain, and morning stiffness that lasts for more than an hour. It is crucial to receive specialized treatment within two years of diagnosis to achieve favorable outcomes. Recent advances, such as the discovery of Disease Modifying Anti Rheumatic Drugs (DMARDs) and the development of biological agents targeting inflammatory markers that affect the pathophysiology of the disease, aim to improve the course of the disease and achieve near-remission.
The exact cause of rheumatoid arthritis is not yet fully understood, but it is believed to result from the interaction between genetic factors and environmental triggers. For example, infections like smoking or periodontitis can influence the onset of the disease, and individuals with the HLA-DRB1 or DR4 genes have a higher risk of developing it. Evidence of the genetic factor includes the observation that if one identical twin develops rheumatoid arthritis, there is a 30-50% chance that the other twin will also develop the condition. Additionally, autoantibodies such as anti-cyclic citrullinated peptide antibodies (anti-CCP Ab) can attack the synovium, leading to arthritis.
Rheumatoid arthritis is the second most common chronic arthritis disease after osteoarthritis and is the most prevalent cause of inflammatory arthritis. It primarily affects individuals between their 40s and 70s and occurs about three times more frequently in women than in men. It is estimated to affect approximately 0.3-1.0% of the global adult population.
Symptoms
The symptoms of rheumatoid arthritis develop gradually over weeks or months, primarily manifesting as pain, stiffness, and swelling in the metacarpophalangeal joints, proximal interphalangeal joints, wrist joints, and metatarsophalangeal joints. Morning stiffness, which is the stiffness experienced upon waking or after maintaining a single position for a long time, lasts for more than an hour in rheumatoid arthritis and is characterized by the inability to clench a fist. In some patients, symptoms may appear in a single joint or a few joints sequentially and then disappear, with the possibility of recurrence after a symptom-free period lasting several months. Early extra-articular symptoms may include generalized pain, weight loss, fatigue, and depression. As the joint inflammation progresses, deformities like those illustrated in the accompanying image may develop.
Diagnostics
Laboratory Findings
Most patients with rheumatoid arthritis exhibit anemia, and levels of acute phase reactants such as Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) may remain persistently elevated. Rheumatoid factor is positive in about 80% of patients but can also be found in other autoimmune or infectious diseases. The anti-CCP antibody is useful in diagnosis with a specificity of approximately 95%, making it a strong predictor of the progression to rheumatoid arthritis. Synovial fluid analysis typically shows a yellow, cloudy appearance with a white blood cell count of 500–50,000/㎣, about two-thirds of which are neutrophils.
Radiographic Findings
Early radiographic findings include soft tissue swelling around the joints and bone demineralization. As the disease progresses, subchondral bone erosion, synovial cyst formation, lack of bone regeneration, and thinning of the cortical bone can be observed. Although MRI and ultrasound can detect early erosions and synovitis, their use is generally limited in routine practice.
Diagnosis
The 1987 American College of Rheumatology (ACR) criteria and the 2010 ACR/EULAR (European League Against Rheumatism) joint criteria are both used for diagnosing rheumatoid arthritis. The 1987 criteria alone may not be sufficient for cases where the disease initially presents with monoarthritis or oligoarthritis, or where extra-articular symptoms are more prominent than joint symptoms. Diagnosis is made by combining clinical findings from medical history, physical examination, and specific tests for rheumatoid arthritis. Laboratory findings support the diagnosis, and the pattern of joint inflammation and the distribution of affected joints are also important clues.
1987 Diagnostic Criteria for Rheumatoid Arthritis
Rheumatoid arthritis can be diagnosed if four or more of the following criteria are met. However, criteria 1. through 4. must have persisted for at least six weeks:
- Morning stiffness in and around the joints lasting at least one hour
- Arthritis of three or more joint areas
- Arthritis of hand joints
- Symmetric arthritis
- Presence of rheumatoid nodules
- Positive serum rheumatoid factor
- Radiographic changes typical of rheumatoid arthritis, involving the hand and wrist
2010 ACR/EULAR Diagnostic Criteria for Rheumatoid Arthritis
A diagnosis of rheumatoid arthritis can be made if a total score of 6 or more points is achieved from the following criteria:
- Joint Involvement
- 1 large joint (shoulder, elbow, hip, knee, ankle): 0 points
- 2-10 large joints: 1 point
- 1-3 small joints: 2 points
- 4-10 small joints: 3 points
- Serology (at least one test is required)
- Negative rheumatoid factor (RF) and anti-CCP antibody: 0 points
- Positive RF or anti-CCP antibody (less than three times the upper limit of normal): 2 points
- Positive RF or anti-CCP antibody (more than three times the upper limit of normal): 3 points
- Acute Phase Reactants (at least one test is required)
- Normal ESR and CRP: 0 points
- Elevated ESR or CRP: 1 point
- Duration of Symptoms
- Less than 6 weeks: 0 points
- 6 weeks or more: 1 point
Treatment and course of the disease
Treatment of rheumatoid arthritis requires a comprehensive approach tailored to the individual patient’s disease pattern. This approach includes medication, rest, nutrition, patient education, physical therapy, occupational therapy, and possibly surgery. The goals of treatment are to minimize pain, preserve physical function, maintain quality of life, and prevent joint inflammation and damage early on. Since bone erosion occurs in approximately 60-70% of patients within two years of onset, early treatment is crucial.
The main treatment methods include medication, surgery, and rehabilitative physical therapy. Surgery is considered when severe local deformities interfere with daily activities or when joint destruction cannot be avoided due to synovial proliferation. It is advisable to avoid surgery during periods of active disease, and surgery to increase joint range of motion should be considered before severe joint deformity occurs. For completely destroyed joints, options include joint replacement surgery (arthroplasty) or joint fusion (arthrodesis). Rehabilitative physical therapy includes joint exercises, appropriate therapeutic functional exercises, and heat therapy, with occupational rehabilitation also playing a significant role. Dietary counseling to prevent weight loss and psychological support and treatment are necessary, as depression and anxiety are common. The following are the main approaches to medication therapy:
*Medication Therapy
- Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): These drugs reduce inflammation and alleviate pain by decreasing prostaglandin production. The effectiveness and side effects vary depending on the specific drug, with COX-2 inhibitors reducing gastrointestinal side effects. Long-term use requires monitoring for renal and cardiovascular complications.
- Corticosteroids: Corticosteroids have strong anti-inflammatory effects but carry the risk of significant side effects with long-term use, so they are used at the lowest possible dose for the shortest duration. They are typically used during acute flare-ups or until disease-modifying antirheumatic drugs (DMARDs) take effect. Low doses are generally used, but higher doses may be necessary for major organ complications like vasculitis or interstitial pneumonia. Although various corticosteroids are available, shorter-acting agents like prednisone are commonly used. When one or a few joints worsen, intra-articular corticosteroid injections can help control disease progression, but it is advisable to avoid injecting the same joint more than three times a year.
- Traditional Disease-Modifying Antirheumatic Drugs (DMARDs)
- Methotrexate: Methotrexate is the most commonly used DMARD due to its relatively fast efficacy and high patient compliance. Side effects may include loss of appetite, nausea, and stomatitis. Severe liver dysfunction is a significant adverse effect. Methotrexate should not be taken by pregnant women, individuals with alcohol addiction, those with liver disease, severe lung disease, or impaired kidney function.
- Sulfasalazine: Sulfasalazine provides a relatively rapid onset of action within 1 to 3 months. Side effects can include skin rashes, nausea, abdominal pain, liver dysfunction, and bone marrow suppression. It is administered orally at a dose of 1-3g per day.
- Hydroxychloroquine: Hydroxychloroquine has a slower onset of action, typically taking 3-4 months, but it has beneficial effects on cardiovascular health. Side effects may include skin rashes, gastrointestinal disturbances, and retinal damage. Regular ophthalmologic examinations are necessary to detect retinal damage early.
- Combination Therapy: If symptom control is difficult with a single DMARD, a combination of several DMARDs, such as those mentioned above, may be used.
- Biological DMARDs
- Anti- TNF blockers: This group includes drugs like etanercept, infliximab, adalimumab, and golimumab. These medications have demonstrated superior efficacy in reducing joint pain and inhibiting bone erosion, making them suitable for use when traditional medications are ineffective.
- Non-TNF Biologics: This category includes drugs like abatacept, tocilizumab, and rituximab. These have also proven effective in reducing joint pain and inhibiting bone erosion, with long-term safety established, and are considered when traditional medications do not provide sufficient relief.
- New Oral Synthetic Small Molecule Inhibitors:
- Tofacitinib and Baricitinib: These medications are used when there is an inadequate response to existing drugs.
In the past, the approach to treatment was to start with nonsteroidal anti-inflammatory drugs (NSAIDs) and add DMARDs only if NSAIDs were ineffective. However, current recommendations suggest aggressive use of DMARDs early in the disease course. In the early stages of treatment, it is essential to educate patients about the disease and discuss the benefits and risks of the medications. Almost all patients may require a combination of NSAIDs, corticosteroids, and DMARDs. If there is insufficient response, biological agents or small molecule inhibitors may be considered. When selecting medications, factors such as the patient’s age, disease status, comorbidities, and long-term treatment safety should be taken into account.
