Rheumatoid Arthritis (RA)
1. Definition and Basic Concept
Rheumatoid arthritis is a chronic systemic autoimmune inflammatory disease that mainly affects synovial joints in a
symmetrical pattern and progressively leads to cartilage destruction, bone erosion and deformity. Although joints are
the major target, RA is actually a systemic disease and may involve the skin, eyes, lungs, heart, blood vessels and
nervous system.
The disease usually affects women more than men and commonly begins between 30–50 years of age. The classic
patient is a middle-aged woman complaining of symmetrical pain and swelling of the small joints of the hands
associated with prolonged morning stiffness.
RA is an inflammatory arthritis, unlike osteoarthritis which is mainly degenerative. Because inflammation is the main
problem, patients develop warm swollen joints and morning stiffness lasting more than one hour that improves with
movement. The earliest pathology occurs in the synovium, where persistent inflammation eventually forms pannus,
the destructive inflammatory tissue characteristic of RA.
The disease most commonly involves:
- MCP joints
- PIP joints
- wrists
- MTP joints
DIP joints are usually spared, which is an important exam clue.
The long-term danger of RA is not only pain but progressive structural damage. Chronic inflammation destroys
cartilage, weakens tendons and ligaments and produces deformities such as ulnar deviation, swan-neck deformity
and boutonnière deformity.
The major ideas to remember are:
- autoimmune disease
- inflammatory synovitis
- symmetrical small-joint polyarthritis
- morning stiffness
- pannus formation
- progressive deformity
- extra-articular manifestations
2. Pathophysiology
RA develops when genetic susceptibility interacts with environmental triggers. The strongest genetic associations are
HLA-DR4 and HLA-DRB1. Among environmental factors, smoking is the most important because it increases both the
risk and severity of disease.
In susceptible individuals, proteins undergo citrullination, meaning they become abnormally modified. The immune
system then recognizes these proteins as foreign. Antigen-presenting cells activate CD4+ T cells, which become
central drivers of inflammation.
Activated T cells stimulate macrophages and B cells. B cells produce autoantibodies, especially rheumatoid factor
(RF) and anti-CCP antibodies. Anti-CCP is highly specific for RA and is strongly associated with erosive disease.
Macrophages release inflammatory cytokines, mainly TNF-α, IL-1 and IL-6. These cytokines maintain synovial
inflammation and explain many clinical features of RA. TNF-α is particularly important because it amplifies
inflammation, stimulates osteoclasts and drives joint destruction. This is why anti-TNF drugs are highly effective
treatments.
The synovium becomes thickened and infiltrated by inflammatory cells, producing chronic synovitis. Synovial
fibroblasts release destructive enzymes such as matrix metalloproteinases that damage cartilage. At the same time,
osteoclast activation causes bone erosion.
Eventually the inflamed synovium transforms into pannus, a vascular granulation tissue that spreads across cartilage
and bone. Pannus is the hallmark destructive lesion of RA and is responsible for erosions, tendon damage and
deformities.
Systemic cytokine release also explains fatigue, fever, weight loss, anemia and raised ESR/CRP. Morning stiffness
occurs because inflammatory fluid accumulates during rest and improves after movement disperses it.
3. Clinical Features
The onset is usually gradual. Patients initially complain of fatigue, malaise and vague musculoskeletal pain before
clear arthritis develops. The hallmark presentation is symmetrical inflammatory polyarthritis affecting the small joints.
Pain, swelling and stiffness are usually worst in the morning and improve with activity. Patients often describe difficulty
opening jars, making a fist or getting out of bed because of prolonged stiffness.
The hands are most commonly affected. MCP and PIP joints become swollen and tender, while DIP joints are usually
spared. Wrists are very commonly involved and loss of grip strength is frequent. MTP involvement causes pain while
walking and patients may complain of walking on “pebbles.”
With progression, chronic inflammation damages tendons and ligaments, producing characteristic deformities. Ulnar
deviation occurs because tendon and ligament imbalance pulls the fingers toward the ulnar side. Swan-neck deformity
consists of hyperextension of the PIP joint with flexion of the DIP joint, whereas boutonnière deformity produces
flexion of the PIP with hyperextension of the DIP.
The disease is not confined to joints. Constitutional symptoms include fatigue, low-grade fever, anorexia and weight
loss. Rheumatoid nodules may appear on extensor surfaces, especially in RF-positive patients.
Eye involvement includes keratoconjunctivitis sicca, episcleritis and scleritis. Pulmonary manifestations include pleural
effusion, pulmonary fibrosis and rheumatoid nodules in the lung. Cardiac involvement may produce pericarditis and
increases cardiovascular risk.
Neurological problems include carpal tunnel syndrome, peripheral neuropathy and cervical cord compression due to
atlanto-axial subluxation. Cervical spine disease is particularly important because ligament destruction around the
atlanto-axial joint may compress the spinal cord and produce occipital headache, weakness or neurological deficits.
Felty syndrome is an important exam topic and consists of:
- rheumatoid arthritis
- splenomegaly
- neutropenia
4. Investigations
The investigations in RA aim to confirm inflammation, detect autoantibodies, assess joint damage and monitor
treatment toxicity.
Inflammatory markers such as ESR and CRP are usually elevated and reflect disease activity. Full blood count may
show anemia of chronic disease and thrombocytosis due to inflammation.
Rheumatoid factor is positive in about 70% of patients but is not specific because it may occur in other autoimmune
and chronic inflammatory conditions. Anti-CCP antibodies are much more specific and strongly support the diagnosis
of RA, especially early disease.
X-rays are important both diagnostically and for monitoring progression. Early findings include soft tissue swelling and
periarticular osteopenia. Later, the disease produces joint-space narrowing, marginal erosions and deformities.
Marginal erosions are highly characteristic because pannus attacks bone at the joint margins.
Ultrasound and MRI are more sensitive than plain X-ray and can detect early synovitis and erosions before
radiographic changes become obvious.
Patients receiving DMARD therapy require regular monitoring with:
- CBC
- liver function tests
- renal function tests
- ESR/CRP
because many treatments may cause bone marrow, liver or kidney toxicity.
5. Diagnostic Criteria
The current classification system is the 2010 ACR/EULAR criteria. A score of 6 or more confirms definite RA.
The criteria evaluate four major areas:
- joint involvement
- serology
- duration of symptoms
- acute phase reactants
Small-joint involvement carries higher scores because it is typical of RA. Positive RF or anti-CCP increases the score,
especially when antibody levels are high. Symptoms lasting more than six weeks support chronic inflammatory
disease rather than transient arthritis. Elevated ESR or CRP provides evidence of active inflammation.
Clinically, the diagnosis is strongly suggested by symmetrical inflammatory polyarthritis affecting MCP and PIP joints
together with prolonged morning stiffness and positive anti-CCP antibodies.
6. Management
The goals of treatment are to suppress inflammation, prevent irreversible joint damage, preserve function and improve
quality of life. Modern management emphasizes early aggressive treatment because structural damage begins early
in the disease.
Non-pharmacological management includes patient education, physiotherapy, occupational therapy and smoking
cessation. Physiotherapy helps preserve mobility and muscle strength, while occupational therapy helps patients
adapt daily activities and protect joints.
NSAIDs improve pain and stiffness but do not prevent disease progression. Corticosteroids are useful for rapid
symptom control and are often used as bridging therapy while DMARDs begin to work.
DMARDs are the cornerstone of treatment because they slow disease progression and prevent erosions.
Methotrexate is the first-line drug in most patients and is usually combined with folic acid to reduce toxicity. Other
conventional DMARDs include sulfasalazine, hydroxychloroquine and leflunomide.
When disease remains active despite conventional therapy, biologic agents are used. Anti-TNF drugs such as
infliximab, etanercept and adalimumab target the major inflammatory cytokine driving RA. Other biologics include
rituximab, abatacept and tocilizumab.
Disease activity is commonly monitored using the DAS28 score, which combines tender joints, swollen joints,
inflammatory markers and patient assessment.
Surgery may be necessary in advanced disease for tendon repair, synovectomy or joint replacement.
Pregnancy requires special attention because methotrexate and leflunomide are contraindicated. Interestingly,
disease activity often improves during pregnancy.
The major complications of RA include:
- deformity
- tendon rupture
- cervical spinal cord compression
- vasculitis
- infection
- cardiovascular disease
- amyloidosis
Final Integrated Picture
RA begins as autoimmune synovitis in genetically susceptible individuals exposed to environmental triggers.
Persistent cytokine-driven inflammation produces pannus, which destroys cartilage and bone, leading to symmetrical
inflammatory polyarthritis, deformity and systemic manifestations. Early recognition and aggressive DMARD therapy
are essential to prevent irreversible disability.