Rheumatoid Arthritis (RA)

Rheumatoid arthritis (RA) is a systemic autoimmune disease primarily characterized by chronic inflammation of joints and associated structures, but it can also affect extra-articular organs. If symptoms persist for less than six months, the condition is referred to as early RA, whereas disease with symptoms beyond this period is called established RA.

There is no single laboratory test that can diagnose RA. Diagnosis and treatment therefore require a comprehensive approach involving clinical findings, blood tests, and imaging. Management consists of both pharmacological and non-pharmacological interventions, with early initiation of disease-modifying antirheumatic drugs (DMARDs) considered standard practice today¹.

Etiology and Pathogenesis

The cause of RA remains unknown, but the condition is believed to have a multifactorial background. It is generally accepted that genetic predisposition—particularly HLA-DRB1 alleles within HLA-DR4—together with environmental factors may trigger an autoimmune process.

The mechanism underlying RA involves:

• Activation and accumulation of CD4+ T-cells in the synovial membrane

• Production of inflammatory cytokines such as TNF-α and IL-4, stimulating synovial cells and macrophages to produce destructive enzymes like elastase and collagenase

• B-cell activation with production of autoantibodies, including rheumatoid factor (RF) and anti-CCP, forming immune complexes that further damage tissue

• Increased expression of VCAM-1 on endothelial cells, promoting accumulation of inflammatory cells in the joint

• Production of RANKL, which activates osteoclasts and leads to destruction of subchondral bone

These processes lead to the development of pannus, an inflamed, hypertrophic synovial membrane infiltrated by T- and B-cells, plasma cells, macrophages, and osteoclasts. The pannus first invades exposed areas of bone, then the articular cartilage, and may eventually cause fibrotic and later ossified ankylosis².

Epidemiology and Risk Factors

RA occurs in approximately 0.5–1% of the population and affects women two to three times more often than men. Onset most frequently occurs in adulthood, typically between the ages of 40 and 50². Juvenile idiopathic arthritis (JIA) is considered separately.

Risk factors for RA include:

• Genetic predisposition

• Female sex

• Smoking (particularly for seropositive RA)

• Overweight

• Exposure to silica dust, air pollution

• Low vitamin D intake

• Low socioeconomic status

• High intake of sodium and red meat

Protective factors may include:

• Intake of fish and omega-3 fatty acids

• Moderate alcohol consumption

• Use of oral contraceptives or hormone therapy

• Use of statins³

Clinical Presentation

RA usually develops gradually over weeks to months, but in some cases can present acutely. The most characteristic findings are:

• Symmetrical arthritis in small joints, especially in the PIP and MCP joints of the hands and the wrists

• Frequent involvement also of elbows, shoulders, hips, knees, ankles, and MTP joints

• Morning stiffness in joints lasting longer than one hour

• Pain, swelling, warmth, and reduced mobility in joints

• Reduced strength and function, including weakness and loss of fine motor skills

• Rheumatoid nodules in 20%, particularly over extensor surfaces (elbow, heel)

• In advanced disease, deformities such as:

  • Swan neck: hyperextension of PIP and flexion of DIP

  • Boutonnière deformity: flexion of PIP and extension of DIP

  • Ulnar deviation and subluxation in MCP joints

  • Trigger finger, tenosynovitis, carpal tunnel syndrome may also occur⁴

Extra-articular manifestations may include:

• Eye complications (Sjögren’s syndrome)

• Pulmonary involvement (interstitial lung disease)

• Pericarditis or pleuritis

• Hematological changes such as anemia

• Neurological symptoms from cervical instability (C1–C2)

Up to 80–90% develop cervical spine involvement, often with ligament laxity in the atlantoaxial region. This may cause headache, neurological deficits, and increased risk during manipulation⁵.

Stages of the Disease

RA is divided into four radiological stages based on progression⁶:

• Stage 1: No destructive changes on X-ray, but possible periarticular osteoporosis

• Stage 2: Osteoporosis, subchondral bone loss, no joint deformity

• Stage 3: Cartilage and bone destruction, evident joint deformity

• Stage 4: Same as stage 3, but with the addition of bony or fibrous ankylosis

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Typical Findings in Clinical Examination

• Symmetrical swelling and tenderness on palpation in small joints

• Restricted movement and functional impairment

• Reduced muscle strength, endurance, and aerobic capacity

• Positive laboratory findings: Rheumatoid factor (RF), anti-CCP, elevated CRP and ESR

• Radiological findings: joint erosions, osteopenia, and joint space narrowing⁶

Differential Diagnoses

Diagnosing rheumatoid arthritis (RA) can be challenging in the early stages, particularly as several conditions may present with similar symptoms of arthritis and systemic manifestations. The following should be considered in differential diagnosis:

• Systemic lupus erythematosus (SLE): May present with polyarthritis, butterfly rash, and organ damage

• Chronic Lyme disease: May cause persistent arthritis after a tick bite

• Osteoarthritis: Degenerative and asymmetrical, common in older adults

• Septic arthritis: Acute, painful, swollen joint, often accompanied by fever

• Psoriatic arthritis: Associated with psoriasis; may involve DIP joints and cause dactylitis

• Sjögren’s syndrome: May occur alone or in combination with RA

• Sarcoidosis: Systemic disease that may cause joint complaints and lung involvement¹

Complications

Rheumatoid arthritis is a systemic disease associated with increased morbidity and mortality. Patients with RA often have multiple comorbidities that impact quality of life, function, and prognosis. Common complications include²:

• Infections: Increased risk due to immunosuppression

• Chronic anemia: Often normochromic, normocytic anemia of chronic disease

• Cardiovascular disease: Increased risk of myocardial infarction and heart failure

• Osteoporosis: Secondary to inflammation and steroid use

• Gastrointestinal cancers: Observational studies suggest higher incidence

• Sicca syndrome: Dry eyes and mouth, often associated with RA

• Felty’s syndrome: Triad of RA, splenomegaly, and neutropenia

• Lymphoma: Higher incidence in patients with long-standing RA

• Rheumatoid lung involvement: Interstitial fibrosis and pleural effusion in some patients

• Neurological complications: For example, due to cervical instability

• Eye complications: Scleritis, episcleritis, keratoconjunctivitis sicca

• Drug-related side effects: Such as immunosuppression, liver damage, or bone marrow depression

• General deconditioning: Reduced physical capacity and increased functional decline⁷,⁸

Diagnostic Procedures

The diagnosis of RA is based on a comprehensive evaluation of clinical symptoms, laboratory tests, and imaging. No single test is diagnostic by itself.

1. Blood tests:

   • Rheumatoid factor (RF): Present in 45–75%, but not specific for RA

   • Anti-CCP (ACPA): More specific than RF, and often positive early in the disease course

   • CRP and ESR: Elevated in active disease and used as markers of inflammation

2. Imaging:

   • X-ray of hands and feet: Shows erosions and periarticular osteopenia in later stages

   • MRI and ultrasound: More sensitive for early changes such as synovitis and erosions, and can detect joint involvement before X-ray shows structural damage¹

Prognosis

RA is a chronic, progressive disease with no cure. The disease course varies, but approximately 50% of patients develop significant disability within 10 years.

The condition is associated with:

• Frequent flares and episodes of remission

• Increased prevalence of cardiovascular disease, infection, malignancy, and lung disease

• A 2–3 times higher mortality rate compared to the general population

• Reduced quality of life and work participation, especially with late diagnosis and suboptimal treatment¹

Treatment

The goal of treatment is to reduce inflammation, preserve joint function, prevent progression, and improve quality of life.

A multidisciplinary approach is recommended:

• General practitioner and rheumatologist: Overall medical follow-up and treatment adjustments

• Nurse: Patient education, symptom monitoring

• Physiotherapist: Development of exercise programs and mobility-preserving measures

• Occupational therapist: Adaptation for ADL and assistive devices

• Pharmacist: Information on medication use and side effects

Pharmacological Treatment

Treatment is divided into:

• NSAIDs: Pain relief and symptom control, not disease-modifying

• Glucocorticoids: Used short-term at initiation or during flares

• Disease-modifying antirheumatic drugs (DMARDs):

  • csDMARDs (conventional): e.g., methotrexate, leflunomide, sulfasalazine

  • bDMARDs (biological): TNF inhibitors (e.g., infliximab), abatacept, tocilizumab, rituximab

  • tsDMARDs (targeted synthetic): e.g., tofacitinib (JAK inhibitor)²

Early and aggressive treatment with DMARDs is central to slowing disease progression.

Nutrition and Lifestyle

Although evidence remains limited, studies show that dietary changes may reduce symptoms such as pain, stiffness, and joint swelling. Recommendations include:

• Avoid pro-inflammatory foods: refined sugar, trans fats, red meat, ultra-processed foods

• Increase intake of anti-inflammatory nutrients: omega-3 (e.g., fatty fish, cod liver oil), vitamin D, plant-based diets rich in antioxidants

• Consider supplementation: in consultation with a physician, some patients may benefit from vitamin D, calcium, or multivitamins⁹

Physiotherapeutic Treatment

Rheumatoid arthritis (RA) is a chronic systemic disease without a cure. The goal of treatment is therefore to reduce pain, slow disease activity, improve function, and maintain quality of life¹⁰. Physiotherapists play a central role in non-pharmacological treatment and can significantly help prevent functional decline and reduce RA-related complaints¹².

Physiotherapy measures focus on:

• Range of motion (ROM)

• Muscle strength and endurance

• Aerobic capacity

• Coordination and balance

• Prevention of deformities and falls

• Reduction of pain and stiffness

• Preservation of joint function and independence in daily activities

Guidelines in countries such as the UK recommend physiotherapy and occupational therapy as supplements to pharmacological treatment for all RA patients¹⁰.

Core Elements of Physiotherapy

Physiotherapy should be multimodal and individually tailored. Four central components in the treatment of hands and upper extremities are:

• Exercise programs: including mobility, strength, and endurance

• Joint protection and adaptation of assistive devices and orthoses

• Massage and manual techniques

• Patient education and lifestyle guidance

The goals of physiotherapy include:

• Pain relief and reduction of inflammation

• Improvement in joint mobility and function

• Prevention of contractures and deformities

• Better disease control

• Increased physical activity and social participation

• Improved quality of life, self-image, and energy levels

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Treatment Techniques

Cold and Heat Therapy:

• Cold is recommended in the acute phase to reduce inflammation

• Heat is used in the chronic phase to soften tissues before exercise¹³

TENS:

• Electrical nerve stimulation has documented effectiveness for pain relief¹⁴

Hydrotherapy and Balneotherapy:

• Weight-bearing relief and mobility training in water provide reduced joint load¹⁵

Massage Therapy:

• Relieves muscle tension, improves circulation, and provides psychological well-being¹⁶

Joint Protection:

• Involves education on how joints can be used gently and functionally in daily activities

Training Principles and Exercises

Exercise improves endurance, strength, coordination, and general physical capacity without worsening the disease¹⁰. Training should be carefully adapted to disease status and the patient’s needs.

During the acute disease phase:

• Isometric (static) exercises

• Avoid stretching and high-load movements

• Revise the program if pain lasts >2 hours after training

During the stable phase:

• Dynamic ROM exercises and strength training

• Aerobic training (walking, cycling, swimming)

• Balance and coordination exercises

• Progressive intensity: start moderately and increase gradually as tolerated

Example parameters:

• Isometric exercises: Hold for 6 seconds, 5–10 repetitions, 40% of 1RM

• Aerobic training:

  • Moderate intensity: 30 min × 5/week (55–64% of max HR)

  • High intensity: 20 min × 3/week (65–90% of max HR)

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The SARAH Program for Hand Function

The SARAH program (Strengthening and stretching for rheumatoid arthritis of the hand) combines mobility and strength exercises to improve hand and wrist function. Exercises are tailored to the patient’s self-assessed effort using a modified Borg scale.

Exercises	Frequency	Repetitions	Progression
Mobility: MCP flexion, circulation, gliding, radial walking, hand behind head and back	Daily	1×5	Gradually increase to 10 reps / 10 sec hold
Strength: eccentric extension, grip, pinch	Daily	1×8	Increase to 3×10 reps, 5–6 on Borg scale

The program contributes to improved strength, joint mobility, and dexterity⁴.

Patient Education

A key element of physiotherapy is thorough education in disease understanding, self-management, and adjustment of movement patterns. The goal is to strengthen the patient’s self-efficacy and provide tools to adapt lifestyle.

Principles:

• Formulate goals together with the patient

• Variation and motivation are essential

• Involve relatives

• Follow up regularly and adapt according to response

Management of Flare-ups

RA may cause periods of worsening—so-called flare-ups—often triggered by stress, illness, or overexertion. During a flare, the following is recommended:

• Prioritize rest and reduce activity

• Have a plan in place for flare management (backup strategy)

• Use heat/cold for pain relief and inflammation control

• Practice relaxation techniques to reduce stress and pain

• Corticosteroid injections may be necessary in some cases

Measurement Instruments in Rheumatoid Arthritis

In rheumatoid arthritis (RA), it is essential to use valid and sensitive measurement instruments to assess disease activity, patient function, and treatment effectiveness over time. Both clinicians and researchers employ a wide range of objective and subjective tools. These instruments help evaluate pain, inflammation level, joint status, general health, and functional capacity.

Simplified Disease Activity Index (SDAI) is a frequently used tool combining five components: number of tender joints, number of swollen joints, patient’s global assessment, physician’s global assessment, and the level of C-reactive protein (CRP, measured in mg/dL).

Clinical Disease Activity Index (CDAI) is similar to SDAI but does not include CRP. It assesses disease activity based on the number of tender and swollen joints, as well as patient and physician global assessments.

DAS28-ESR and DAS28-CRP (Disease Activity Score) are further standard tools that assess disease activity using a 28-joint count of tender and swollen joints, the patient’s self-assessment of health, and either erythrocyte sedimentation rate (ESR, mm/h) or CRP level (mg/dL). DAS28 values are categorized into remission, low, moderate, and high disease activity, and are often used as a basis for medication adjustments¹.

Rheumatoid Arthritis Disease Activity Index (RADAI-5) is a patient-reported questionnaire consisting of five Likert-scale questions. It maps the patient’s subjective perception of disease activity, both at present and over the past six months. This tool is simple to use in clinical practice and provides insight into the patient’s own disease understanding and symptom burden.

DASH (Disabilities of the Arm, Shoulder and Hand) is used to assess functional limitations in the upper extremity, which is often affected in RA. The questionnaire includes 30 questions measuring the patient’s ability to perform daily activities.

36-Item Short Form Survey (SF-36) is a generic health-related quality of life tool that measures physical and mental health across patient groups. It is often used in long-term conditions such as RA to assess the disease’s impact on overall quality of life.

Fatigue Severity Scale (FSS) is specialized for capturing the degree of fatigue, one of the most burdensome symptoms for RA patients. The scale measures how fatigue affects daily function and can be used to evaluate treatment effects on energy and endurance²¹.

Functional Classification

The American College of Rheumatology (ACR) has established a functional classification system for RA that is used to evaluate the patient’s ability to perform daily activities:

• Class I: Full functional capacity – the patient can perform usual activities of self-care, work, and leisure without limitations

• Class II: Limitation in leisure activities, but still able to perform occupational and self-care tasks

• Class III: Limitation in leisure and occupational activities, but still able to maintain self-care

• Class IV: Severe functional impairment affecting self-care, work, and leisure activities

This classification is often used in combination with objective disease measures to evaluate disease progression and treatment effects.

Clinical Summary

RA is a disease with a variable course. Some patients have mild symptoms with limited impact, while others develop severe disease with significant functional impairments and reduced quality of life. At least 40% of patients develop permanent disability within 10 years. The disease is characterized by a pattern of relapses and remissions, and prognosis depends on factors such as:

• Early onset (before age 30)

• High autoantibody titers

• Multiple affected joints

• Extra-articular disease

• Genetic factors (e.g., HLA-DRB1)

• Female sex

RA is also associated with increased risk of cardiovascular disease, infections, malignancy, and death. Overall mortality is approximately three times higher compared to the general population¹. Despite improved treatment methods, mortality from certain complications, such as vasculitis and infection, remains unchanged.

Refrences:

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