Rheumatoid Arthritis (RA)

Genetic Factors

• Genetic predisposition accounts for approximately 50% of RA risk.
• The HLA-DR4 cluster is strongly associated with RA. Specific alleles, such as HLA-DRB1*0401, *0404, and *0405, contain the "shared epitope," which is linked to disease susceptibility. In contrast, other HLA-DR4 alleles (e.g., *0402) lack this epitope and do not confer risk.
• Additional genetic loci associated with RA include PTPN22, TRAF5, STAT4, CTLA4, and IL2RA, many of which are related to immune regulation.
• Epigenetic modifications, such as DNA methylation and histone modifications, also play a role in altering gene expression, contributing to the autoimmune response.
  
  

Environmental Factors

• Smoking is the most significant environmental risk factor, particularly in individuals with the HLA-DRB1 shared epitope. Smoking increases the risk of RA by enhancing citrullination, a key process in autoantigen formation.
• Other exposures, such as silica, asbestos, and textile dust, have been linked to increased RA risk.
• The gut microbiome has emerged as a potential factor, with RA patients exhibiting reduced microbial diversity and increased genera such as Collinsella and Faecalibacterium.
  
  

Hormonal Factors

• RA is more prevalent in women, implicating hormonal influences.
• Pregnancy typically ameliorates RA symptoms, while the postpartum period is associated with disease flare. The use of oral contraceptives and lower levels of prolactin have been correlated with reduced RA risk.
  
  

Infectious Agents

• Infections may trigger RA in genetically predisposed individuals. Suggested pathogens include Epstein-Barr virus (EBV), rubella virus, and Porphyromonas gingivalis. These microbes may induce citrullination, leading to autoimmunity.
• Studies have demonstrated bacterial products, such as bacterial RNA, in the synovial fluid of RA patients.
  
  

Immunologic Factors

• Dysregulation of immune cells, including T and B cells, plays a central role in RA pathogenesis.
• T-helper 1 (Th1) cells and T-helper 17 (Th17) cells drive inflammation by producing proinflammatory cytokines such as IL-17, TNF-α, and IL-6.
• B cells contribute by producing autoantibodies, including rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies.
• These autoantibodies form immune complexes that exacerbate inflammation and tissue damage.
  
  

• Dietary influences, such as high intake of red meat, excessive coffee consumption, and low vitamin D levels, may increase RA risk.
• Occupations involving exposure to silica dust or high ergonomic stress are associated with a higher incidence of RA.
  
  

Initiation and Disease Progression

1. Pre-Rheumatoid Arthritis (Pre-RA):
   • RA begins with genetic and environmental factors breaking immune tolerance, often years before clinical symptoms.
   • The progression involves distinct phases:
     • Phase I: Interaction of genetic predispositions, such as the HLA-DRB1 shared epitope, with triggers like smoking and infections.
     • Phase II: Development of autoantibodies, including rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP).
     • Phase III: Emergence of arthralgia and stiffness, without clinical arthritis.
     • Phase IV: Early undifferentiated arthritis (e.g., palindromic rheumatism) or arthritis limited to a few joints.
     • Phase V: Established RA with progressive joint damage.
2. Early Pathologic Events:
   • Synovial Cell Hyperplasia: Proliferation of fibroblast-like synoviocytes (FLS), which acquire invasive properties and secrete matrix-degrading enzymes.
   • Endothelial Activation and Angiogenesis: Formation of new blood vessels to support the inflamed synovium, accompanied by leukocyte recruitment.
   • Immune Cell Infiltration: T cells, B cells, macrophages, and dendritic cells infiltrate the synovium and contribute to inflammation.
     
     

Immune Dysregulation

• T Cells: CD4+ helper T cells, including Th1 and Th17 subsets, are central to RA pathogenesis. These cells secrete proinflammatory cytokines such as IL-17, IFN-γ, and TNF-α, driving inflammation and bone erosion.
• B Cells: Produce autoantibodies like RF and anti-CCP, forming immune complexes that activate the complement system and perpetuate inflammation.
• Macrophages: Release key cytokines, including TNF-α, IL-1, and IL-6, which recruit additional immune cells and induce systemic inflammation.
• Cytokines and Chemokines:
  • Major cytokines involved include TNF-α, IL-1, IL-6, IL-17, and GM-CSF.
  • Cytokines enhance angiogenesis, leukocyte trafficking, and production of matrix metalloproteinases (MMPs), further driving tissue destruction.
    
    

Autoantibody Production

• Anti-Citrullinated Protein Antibodies (ACPAs):
  • Recognise citrullinated proteins such as vimentin, fibrinogen, and histones.
  • Generated in response to post-translational modification of proteins (citrullination) catalysed by peptidylarginine deiminase (PAD) enzymes, particularly in smokers or those with mucosal inflammation.
• Anti-Carbamylated Protein Antibodies (Anti-CarP):
  • Distinct from ACPAs but also associated with disease severity.
• Autoantibodies are detectable years before clinical RA and are markers of seropositive RA.
  
  

Chronic Inflammatory Processes

1. Pannus Formation:
   • Hyperplastic synovial tissue infiltrates cartilage and bone, producing enzymes (e.g., MMPs) that degrade the extracellular matrix.
2. Bone Erosion:
   • RANKL, expressed by FLS and activated T cells, promotes osteoclast differentiation and bone resorption.
3. Cartilage Degradation:
   • Chondrocytes activated by IL-1, TNF-α, and IL-17 produce matrix-degrading enzymes, further destroying cartilage.
     
     

Systemic Manifestations

• Chronic inflammation contributes to extra-articular features, such as cardiovascular disease, interstitial lung disease, and secondary Sjögren’s syndrome.
• Elevated levels of IL-6 and TNF-α are implicated in systemic comorbidities, including anemia of chronic disease and accelerated atherosclerosis.
  
  

Histopathology

• Early Changes:
  • Angiogenesis and infiltration of mononuclear cells, including T and B lymphocytes.
  • Synovial thickening due to fibroblast proliferation and deposition of inflammatory mediators.
• Chronic Changes:
  • Formation of pannus tissue that invades and erodes cartilage and bone.
  • Presence of rheumatoid nodules in extra-articular tissues, characterised by granulomatous inflammation with central necrosis.
    
    

Global Prevalence and Incidence

• The worldwide prevalence of RA ranges between 0.24% and 0.56%, with an estimated annual incidence of approximately 3 cases per 10,000 population.
• The disease is more common in Western and Northern Europe, North America, and populations of European descent, such as in Australia. Prevalence is lower in Central and South America, East Asia, and Africa.
• A meta-analysis (1955–2015) reported the following regional prevalence:
  • North America: 0.70% (0.57–0.86)
  • Europe: 0.54% (0.50–0.59)
  • Asia: 0.30% (0.23–0.37)
  • South America: 0.30% (0.09–0.62)
  • Africa: 0.52% (0.00–1.74)
  • Global Average: 0.46% (0.39–0.54)
    
    

Gender and Age Distribution

• Women are approximately three times more likely to develop RA compared to men, with a lifetime risk of 3.6% in women versus 1.7% in men.
• RA incidence increases with age, peaking between 35 and 50 years. However, in older populations, gender differences in prevalence decrease.
  
  

Urban-Rural and Socioeconomic Disparities

• RA prevalence is higher in urban areas (0.69%) compared to rural areas (0.54%).
• High-income countries report higher prevalence rates (0.49%) compared to low-income countries (0.35%), possibly reflecting differences in healthcare access and reporting accuracy.
  
  

Genetic and Familial Risk

• First-degree relatives of individuals with RA have a 2- to 3-fold increased risk of developing the disease. Concordance in monozygotic twins is 15–20%, highlighting a significant but not exclusive genetic component.
• The strongest genetic predisposition is associated with the HLA-DRB1 shared epitope, a key risk factor for seropositive RA.
  
  

Lifestyle and Environmental Risk Factors

• Smoking is the strongest modifiable risk factor, with a dose-dependent relationship between smoking intensity and RA risk. Individuals with the HLA-DRB1 shared epitope who smoke have a markedly higher risk.
• Obesity increases the risk of RA by 30% in individuals with a body mass index (BMI) >30 kg/m² and by 15% for those with a BMI of 25–29.9 kg/m².
• Dietary Factors:
  • Diets rich in long-chain omega-3 fatty acids are associated with a reduced risk.
  • Diets high in caloric content and low in fiber (Western diet) are linked to increased risk.
• Infections and Mucosal Health: Although no specific infectious agent has been identified, mucosal injury and dysbiosis, such as changes in the gut microbiome, are implicated.
  
  

Temporal Trends

• While some studies suggest a declining incidence of RA, evidence from global burden studies indicates an increase in prevalence by 9.75% between 1980 and 2019.
  
  

Reproductive and Hormonal Factors

• RA risk is influenced by reproductive history:
  • Women who have had one child may have a higher risk compared to those with multiple offspring.
  • The postpartum period is associated with increased disease risk, especially in women with high-risk genetic markers.
  • Conditions such as preeclampsia, hyperemesis during pregnancy, or gestational hypertension may further elevate risk.
    
    

Typical Onset and Symptoms

1. Gradual Onset:
   • Symptoms usually develop insidiously over weeks to months, initially manifesting as joint pain and stiffness before progressing to overt inflammation and swelling.
   • In some cases, RA may present with systemic symptoms, such as fatigue, malaise, and weight loss, before joint involvement becomes apparent.
2. Joint Involvement:
   • Small Joints: RA commonly affects the small joints of the hands (metacarpophalangeal [MCP] and proximal interphalangeal [PIP] joints) and feet (metatarsophalangeal [MTP] joints).
   • Symmetry: Joint involvement is typically symmetric, a hallmark feature distinguishing RA from other inflammatory arthritis.
   • Morning Stiffness: Prolonged stiffness lasting more than one hour is a cardinal symptom, indicative of inflammatory arthritis.
3. Patterns of Symptoms:
   • Palindromic Rheumatism:
     • Episodic joint inflammation that resolves without leaving permanent joint damage.
     • Often considered a precursor to RA in some patients, particularly those who test positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies.
   • Acute Onset: Although rare (10% of cases), RA can present abruptly with sudden and severe joint inflammation.
     
     

Symptom Progression

1. Localised to Generalised:
   • Early symptoms may involve only one or two joints (monoarticular or oligoarticular arthritis) before spreading to multiple joints.
   • Persistent inflammation often leads to progressive joint damage and deformities if untreated.
2. Constitutional Symptoms:
   • Patients frequently report fatigue, malaise, low-grade fever, and weight loss, which may precede or accompany joint symptoms.
3. Extra-Articular Features:
   • While RA primarily affects synovial joints, systemic manifestations can occur in advanced disease, involving the lungs (e.g., interstitial lung disease), heart (e.g., pericarditis), and eyes (e.g., scleritis).
     
     

Distinguishing Features

1. Juvenile Idiopathic Arthritis (JIA):
   • The pediatric form of RA, with different immunologic associations and clinical patterns, is typically distinct from adult-onset RA.
2. Progression Variability:
   • Some patients may experience periods of remission, while others develop persistent, progressive symptoms leading to significant disability.
     
     

Key Risk Factors and Associations

1. Demographics:
   • Most patients present between 40 and 60 years of age, with women affected approximately three times more frequently than men.
2. Genetic Predisposition:
   • Family history and the presence of the HLA-DRB1 shared epitope increase susceptibility.
3. Environmental Triggers:
   • Smoking and other environmental exposures may precipitate disease onset in genetically susceptible individuals.
     
     

Joint Involvement

1. Key Characteristics:
   • Symmetry: A hallmark feature of RA, most commonly involving the small joints of the hands and feet.
   • Inflammatory Signs:
     • Swelling: Reflects synovitis and effusion.
     • Tenderness and Pain on Movement: Indicate active inflammation.
     • Warmth: Occasional, but erythema is rare in RA.
   • Decreased Range of Motion (ROM): Results from joint inflammation or structural changes.
   • Atrophy: Early interosseous muscle atrophy is common in the hands.
2. Commonly Affected Joints:
   • Small joints: Metacarpophalangeal (MCP), proximal interphalangeal (PIP), and metatarsophalangeal (MTP).
   • Large joints: Knees, elbows, shoulders, hips.
   • Axial joints: Limited to the cervical spine, with frequent involvement at C1-C2.
     
     

Typical Deformities

1. Hand Deformities:
   • Swan Neck Deformity: Hyperextension of the PIP joint with flexion of the DIP joint.
   • Boutonnière Deformity: PIP joint flexion with DIP joint hyperextension.
   • Ulnar Deviation: Displacement of fingers toward the ulnar side, often accompanied by volar subluxation of MCP joints.
   • Zigzag Deformity: Combination of ulnar drift of fingers and radial deviation of the wrist.
   • Arthritis Mutilans: Severe joint destruction resulting in gross instability and deformity.
2. Foot Deformities:
   • Hammer Toes: Flexion deformities of the proximal interphalangeal joints.
   • Hallux Valgus: Bunion formation at the first MTP joint.
   • MTP Subluxation: Leads to pain and callus formation under the metatarsal heads.
3. Wrist and Elbow:
   • Wrist Subluxation: Includes dorsal subluxation of the ulna (caput ulnae).
   • Carpal Tunnel Syndrome: Median nerve compression due to tenosynovitis.
   • Flexion Deformities: Common in the elbows with synovial thickening.
4. Knee:
   • Large effusions and synovial thickening.
   • Genu valgus (knock knees) or varus (bowlegs) deformities in advanced disease.
     
     

Extra-Articular Manifestations

1. Rheumatoid Nodules:
   • Subcutaneous nodules over pressure points (e.g., olecranon, Achilles tendon).
2. Ocular Involvement:
   • Episcleritis, scleritis, and keratoconjunctivitis sicca in secondary Sjögren syndrome.
3. Pulmonary Manifestations:
   • Interstitial lung disease (ILD) and pleuritis.
4. Neurological Findings:
   • Atlantoaxial subluxation in cervical spine involvement, causing neck stiffness and potential neurological deficits.
     
     

Specialised Findings

1. Tenosynovitis:
   • Palpable tendon swelling, particularly in the hands.
   • Stenosing tenosynovitis ("trigger finger") with thickened tendons.
2. Periarticular and Generalized Osteoporosis:
   • Common due to chronic inflammation and corticosteroid therapy.
3. Entrapment Neuropathies:
   • Median and ulnar nerve entrapments leading to sensory loss and muscle atrophy.
     
     

Signs in Advanced Disease

• Severe Joint Destruction: Ankylosis or gross instability.
• Chronic Systemic Inflammation: May cause generalised muscle wasting and fatigue.

Primary Investigations

1. Serological Markers:
   • Rheumatoid Factor (RF):
     • Positive in 60-70% of RA patients, though not specific to RA.
     • High levels (>100 IU) are more specific but can also be seen in other conditions (e.g., hepatitis C, chronic infections).
     • RF positivity increases the likelihood of progressive disease.
   • Anti-Cyclic Citrullinated Peptide (Anti-CCP) Antibodies:
     • Present in 70-80% of RA patients, with higher specificity than RF.
     • Often positive before clinical symptoms appear, helping to predict disease onset in high-risk individuals.
     • Associated with more erosive disease.
2. Inflammatory Markers:
   • Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP):
     • Elevated in active disease and correlate with inflammation and disease activity.
     • Useful for monitoring treatment response and disease progression.
3. Synovial Fluid Analysis:
   • Typically shows a leukocyte count between 1,500 and 25,000 cells/mm³, predominantly polymorphonuclear cells.
   • Low synovial fluid complement levels (C3, C4) despite elevated serum levels.
   • High leukocyte counts (>25,000 cells/mm³) warrant evaluation for infection or crystal arthropathy.
4. Baseline Imaging:
   • Radiographs:
     • Early findings: Periarticular osteopenia and soft tissue swelling.
     • Advanced disease: Marginal erosions and joint space narrowing.
   • Ultrasound:
     • Detects synovitis, erosions, and hypervascularity even in early disease.
     • Useful for evaluating subclinical inflammation and guiding joint aspiration or injection.
   • Magnetic Resonance Imaging (MRI):
     • Identifies bone marrow edema and synovial thickening, which are predictors of erosive disease.
     • More sensitive than radiographs for early joint changes but not routinely used due to cost.
       
       

Advanced and Supporting Investigations

1. Additional Serological Studies:
   • Antinuclear Antibody (ANA):
     • Positive in up to 40% of RA patients but not specific.
   • Anti-Mutated Citrullinated Vimentin (Anti-MCV):
     • Correlates with disease activity but has lower specificity compared to anti-CCP.
2. Disease Activity Scores:
   • Tools for assessing disease severity and monitoring treatment response:
     • DAS28 (Disease Activity Score in 28 joints): Includes joint counts, patient-reported outcomes, and ESR or CRP.
     • Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI): Composite measures that include patient and clinician assessments.
     • Routine Assessment of Patient Index Data 3 (RAPID3): Patient-driven tool.
3. ACR/EULAR Classification Criteria (2010):
   • Diagnostic scoring based on:
     • Joint involvement (e.g., small vs. large joints).
     • Serology (RF and anti-CCP).
     • Acute-phase reactants (ESR, CRP).
     • Symptom duration (≥6 weeks).
       
       

Diagnostic Challenges and Considerations

1. Seronegative RA:
   • Accounts for approximately 10% of RA cases where RF and anti-CCP are negative.
   • Diagnosis relies more on clinical and imaging findings.
2. Exclusion of Other Conditions:
   • Differential diagnoses include lupus, psoriatic arthritis, gout, and chronic infections, requiring specific testing.
     
     

Imaging for Monitoring Disease Progression

1. Radiographic Changes:
   • Periarticular osteopenia and erosions typically occur at later stages.
2. MRI and Ultrasound:
   • Useful in early disease to detect subtle joint changes and monitor inflammation.
3. Spinal Imaging:
   • Evaluates cervical spine involvement, particularly atlantoaxial subluxation.
     
     

Inflammatory Conditions

1. Psoriatic Arthritis (PsA):
   • Signs/Symptoms:
     • Involves small joints, often asymmetrical; distal interphalangeal (DIP) joint involvement is more common than in RA.
     • Associated with skin and nail psoriasis in >90% of cases.
   • Investigations:
     • Typically seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies.
     • Skin biopsy may confirm psoriasis.
2. Infectious Arthritis:
   • Signs/Symptoms:
     • Acute onset, often monoarticular, with erythema, warmth, and swelling.
     • Commonly caused by bacteria, viruses (e.g., hepatitis B, Chikungunya), or fungi.
   • Investigations:
     • Synovial fluid analysis: high leukocyte count (>50,000 cells/mm³) and positive culture.
3. Systemic Lupus Erythematosus (SLE):
   • Signs/Symptoms:
     • Symmetrical polyarthritis of small joints, often non-erosive.
     • Extra-articular features: rash, nephritis, and photosensitivity.
   • Investigations:
     • Positive antinuclear antibodies (ANA), anti-double-stranded DNA, and anti-Smith antibodies.
     • Radiographs: Absence of erosions.
4. Adult-Onset Still’s Disease (AOSD):
   • Signs/Symptoms:
     • Daily spiking fevers, salmon-pink rash, and arthritis.
   • Investigations:
     • Elevated ferritin (>5x upper normal limit), leukocytosis, and elevated acute-phase reactants.
5. Reactive Arthritis:
   • Signs/Symptoms:
     • Asymmetrical arthritis often affecting large joints.
     • History of preceding infection (e.g., gastrointestinal, urogenital).
   • Investigations:
     • HLA-B27 positivity, evidence of prior infection.
6. Gout and Calcium Pyrophosphate Deposition (CPPD) Disease:
   • Signs/Symptoms:
     • Gout: Acute, monoarticular inflammation, often of the first MTP joint.
     • CPPD: Joint swelling and erythema, commonly involving the knee or wrist.
   • Investigations:
     • Synovial fluid analysis: monosodium urate crystals (gout) or calcium pyrophosphate crystals (CPPD).
7. Inflammatory Bowel Disease (IBD)-Associated Arthritis:
   • Signs/Symptoms:
     • Arthritis may precede or follow IBD diagnosis; commonly oligoarticular and asymmetrical.
   • Investigations:
     • Diagnosis supported by clinical findings of IBD and imaging of sacroiliitis.
       
       

Non-Inflammatory Conditions

1. Osteoarthritis (OA):
   • Signs/Symptoms:
     • Typically affects weight-bearing joints and DIP joints; bony swelling is common.
     • Stiffness is transient and improves with activity.
   • Investigations:
     • Radiographs: Joint space narrowing, osteophytes, and subchondral sclerosis.
2. Fibromyalgia:
   • Signs/Symptoms:
     • Widespread musculoskeletal pain and tenderness without synovitis.
     • Associated with fatigue, sleep disturbances, and cognitive dysfunction.
   • Investigations:
     • Normal acute-phase reactants and absence of joint inflammation.
3. Polymyalgia Rheumatica (PMR):
   • Signs/Symptoms:
     • Bilateral shoulder and hip pain with stiffness in individuals >50 years.
   • Investigations:
     • Elevated ESR and CRP; rapid response to low-dose corticosteroids.
4. Hypermobility Syndrome:
   • Signs/Symptoms:
     • Generalised joint hypermobility without inflammation.
   • Investigations:
     • Normal RF, anti-CCP, and inflammatory markers.
       
       

Paraneoplastic and Rare Conditions

1. Sarcoidosis:
   • Signs/Symptoms:
     • Polyarthritis with systemic features like uveitis and lymphadenopathy.
   • Investigations:
     • Elevated angiotensin-converting enzyme (ACE) levels, chest radiography for sarcoidosis.
2. Multicentric Reticulohistiocytosis:
   • Signs/Symptoms:
     • Rapidly destructive arthritis with periungual nodules.
   • Investigations:
     • Synovial biopsy showing multinucleated giant cells.
3. Paraneoplastic Syndromes:
   • Signs/Symptoms:
     • Arthritis with unexplained systemic symptoms (e.g., weight loss, night sweats).
   • Investigations:
     • Thorough cancer screening and imaging studies.

Principles of Management

1. Early Diagnosis and Aggressive Treatment:
   • Early treatment with disease-modifying anti-rheumatic drugs (DMARDs) is essential to prevent irreversible joint damage.
   • Initiation of treatment within three months of symptom onset is associated with better long-term outcomes, including lower disability rates and improved survival.
2. Treat-to-Target Strategy:
   • The goal is to achieve remission or low disease activity (LDA) through frequent disease activity assessments and treatment modifications.
   • Use validated tools such as DAS28, SDAI, or CDAI to objectively monitor disease progression.
   • Patients achieving stable target disease activity for at least six months may be considered for cautious treatment tapering.
3. Consideration of Prognostic Factors:
   • Poor prognostic factors, such as RF positivity, anti-cyclic citrullinated peptide (anti-CCP) antibodies, and early radiographic erosions, indicate the need for more aggressive therapy.
     
     

Pharmacological Management

1. Conventional Synthetic DMARDs (cDMARDs):
   • First-Line Treatment:
     • Methotrexate (MTX) is the cornerstone of RA therapy. It can be administered orally or subcutaneously.
     • Alternatives for patients intolerant to methotrexate include leflunomide, sulfasalazine, or hydroxychloroquine.
   • Combination Therapy:
     • For inadequate response to monotherapy, methotrexate may be combined with other cDMARDs or a biological DMARD.
   • Monitoring:
     • Regular monitoring of complete blood count (CBC), liver function tests (LFTs), and renal function is necessary to detect adverse effects.
2. Biological DMARDs (bDMARDs):
   • Include TNF inhibitors (e.g., adalimumab, infliximab) and non-TNF agents (e.g., tocilizumab, abatacept, rituximab).
   • Typically added to methotrexate for patients with moderate-to-severe RA or those with inadequate response to cDMARDs.
   • Safety Considerations:
     • Screen for latent tuberculosis, hepatitis B/C, and monitor for infections during therapy.
     • Avoid in patients with active infections or recent malignancy unless benefits outweigh risks.
3. Targeted Synthetic DMARDs (tsDMARDs):
   • Janus kinase (JAK) inhibitors (e.g., tofacitinib, baricitinib) are effective options for patients unresponsive to biological DMARDs.
   • Monitor for thromboembolism, cardiovascular events, and malignancy, especially in high-risk populations.
4. Corticosteroids:
   • Used as bridging therapy to control inflammation while waiting for DMARD efficacy.
   • Low-dose prednisolone (<10 mg/day) is preferred, with a goal to taper and discontinue as soon as possible.
   • Long-term use requires osteoporosis prophylaxis with calcium and vitamin D.
5. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):
   • Provide symptomatic relief for pain and stiffness but do not alter disease progression.
   • Use with proton pump inhibitors (PPIs) to minimise gastrointestinal risks.
     
     

Non-Pharmacological Management

1. Physiotherapy and Exercise:
   • Regular exercise improves joint mobility, muscle strength, and overall fitness.
   • Tailored programs, including hand exercises, are beneficial for maintaining function and reducing stiffness.
2. Occupational Therapy:
   • Provides strategies to improve daily activities and recommend assistive devices.
   • Focuses on joint protection techniques and ergonomic adjustments.
3. Podiatry:
   • Address foot deformities and pain through custom orthotics or therapeutic footwear.
   • Regular foot health assessments are essential, especially for patients with advanced disease.
4. Psychological Support:
   • Offer counseling or cognitive-behavioral therapy (CBT) to address mental health challenges such as anxiety, depression, and stress.
5. Lifestyle Modifications:
   • Smoking Cessation: Smoking impairs treatment response and worsens disease outcomes.
   • Diet: Encourage a Mediterranean diet rich in fruits, vegetables, and omega-3 fatty acids to reduce inflammation and improve cardiovascular health.
     
     

Monitoring

1. Disease Monitoring:
   • Monthly assessments during active disease, followed by less frequent visits once remission or LDA is achieved.
   • Use validated composite scores (e.g., DAS28) to evaluate treatment efficacy and adjust therapy.
2. Laboratory Tests:
   • Monitor inflammatory markers (ESR, CRP), CBC, LFTs, and renal function regularly.
3. Imaging:
   • Repeat radiographs or ultrasounds to detect early erosions or monitor disease progression.
4. Annual Reviews:
   • Assess comorbidities (e.g., cardiovascular disease, osteoporosis) and complications (e.g., cervical spine instability, interstitial lung disease).
     
     

Surgical Management

1. Indications for Surgery:
   • Persistent pain, deformity, or loss of function unresponsive to medical therapy.
   • Acute complications, such as tendon rupture or nerve compression, require prompt surgical evaluation.
2. Common Procedures:
   • Synovectomy, joint replacement, or tendon repair to restore function and relieve pain.
     
     

Pregnancy Considerations

1. Safe Medications:
   • Corticosteroids, hydroxychloroquine, and sulfasalazine are considered safe during pregnancy.
   • Biological agents, such as certolizumab, may be used in specific cases with specialist guidance.
2. Avoidance:
   • Methotrexate, leflunomide, and JAK inhibitors should be discontinued prior to conception due to teratogenic risks.
     
     

Clinical Course

1. Disease Progression:
   • RA typically follows a pattern of exacerbations and remissions, with 40% of patients becoming disabled within 10 years without treatment.
   • Periods of active inflammation lasting over a year significantly increase the risk of irreversible joint damage.
2. Treatment Impact:
   • Early and aggressive treatment within six months of symptom onset can reduce disease activity and delay joint damage.
   • However, long-term remission remains difficult to achieve for many, with disease flares common even among patients receiving treatment.
3. Variability in Outcomes:
   • Approximately one-third of patients experience mild or intermittent disease, while others have a chronic, progressive course leading to deformities and functional impairment.
     
     

Prognostic Factors

1. Poor Prognostic Indicators:
   • Genetics: HLA-DRB1 shared epitope, particularly the HLA-DRB1*04/04 genotype.
   • Serology: High titers of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies are linked to more severe disease.
   • Early Joint Damage: Radiographic evidence of erosions within the first year.
   • Extra-Articular Manifestations: Lung disease, vasculitis, and cardiovascular involvement.
   • Demographic and Clinical Features: Younger age at onset, female sex, systemic symptoms, and high initial disease activity.
2. Markers of Favorable Prognosis:
   • Rapid initiation of DMARDs.
   • Effective disease control within the first six months.
   • Sustained remission or low disease activity.
3. Biomarkers and Predictive Indicators:
   • Elevated levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) after 12 weeks of treatment predict radiographic progression.
   • Persistent anemia of chronic disease and high levels of complement components (e.g., C1q) are associated with poor outcomes.
     
     

Comorbidities and Associated Risks

1. Cardiovascular Disease:
   • RA doubles the risk of myocardial infarction and stroke due to chronic systemic inflammation and accelerated atherosclerosis.
   • Traditional and nontraditional cardiovascular risk factors, such as endothelial dysfunction and coronary vasculitis, contribute significantly.
2. Lung Disease:
   • Interstitial lung disease (ILD) is a major extra-articular manifestation, increasing morbidity and mortality.
   • Pulmonary hypertension and pleuritis are additional complications.
3. Malignancy:
   • Chronic inflammation in RA elevates the risk of lymphomas and certain solid tumors, such as lung and liver cancer.
   • Immunosuppressive therapies may further contribute to cancer risk.
4. Infections:
   • Increased susceptibility to infections due to immunosuppression and disease-related immune dysregulation.
   • Respiratory infections are particularly common.
5. Mortality:
   • Overall mortality in RA is 2-3 times higher than in the general population.
   • Leading causes of death include cardiovascular disease, infections, and respiratory complications.
     
     

Long-Term Outcomes

1. Impact of Early Treatment:
   • Early DMARD use improves functional outcomes and reduces disability rates.
   • Patients achieving sustained remission have better long-term health-related quality of life (HRQoL).
2. Functional and Occupational Impact:
   • Despite treatment advances, 50-60% of RA patients report difficulty with employment or daily activities after 10-15 years.
3. Gender-Specific Differences:
   • Postmenopausal women experience more rapid functional decline compared to premenopausal women, possibly due to hormonal changes.
     
     

Management Challenges

1. Flares and Relapses:
   • Disease flares are common, even in patients with well-controlled disease.
   • Discontinuation of biologic DMARDs often leads to increased disease activity and radiographic progression.
2. Poly-Refractory RA:
   • A small subset of patients does not respond to multiple DMARDs or biologics, posing significant treatment challenges.
     
     

Musculoskeletal Complications

1. Joint Damage and Deformity:
   • Chronic joint inflammation leads to progressive cartilage and bone destruction.
   • Common deformities include swan neck, boutonnière, and ulnar deviation.
   • Long-term untreated RA often necessitates joint replacement surgery.
2. Osteoporosis and Fractures:
   • RA patients have a 60-100% higher risk of fractures due to systemic inflammation, glucocorticoid use, and reduced mobility.
   • Risk factors include postmenopausal status, low body mass index, and advanced age.
3. Work Disability:
   • Significant loss of physical function over time results in work absenteeism and decreased productivity.

Systemic Inflammatory Complications

1. Cardiovascular Disease (CVD):
   • RA independently increases the risk of coronary artery disease (CAD) and atherosclerosis.
   • Chronic systemic inflammation accelerates the development of high-risk plaques and multi-vessel disease.
   • DMARDs, particularly methotrexate, TNF inhibitors, and abatacept, reduce cardiovascular risk.
2. Interstitial Lung Disease (ILD):
   • ILD affects 5-16% of RA patients and is associated with increased mortality.
   • Autoantibodies such as anti-CCP and genetic factors (e.g., MUC5B promoter variant) are linked to RA-ILD.
   • Methotrexate and anti-TNF therapy can also contribute to pulmonary injury in susceptible individuals.
3. Rheumatoid Vasculitis:
   • A rare but severe complication that can affect skin, nerves, and internal organs.
   • Presents as focal digital necrosis or systemic manifestations resembling polyarteritis nodosa.
4. Sjogren’s Syndrome:
   • Secondary Sjogren’s is common in RA and presents with dry eyes and mouth.
   • Affects up to 10% of RA patients.
5. Felty Syndrome:
   • A rare triad of RA, splenomegaly, and neutropenia.
   • Affects less than 1% of RA patients but increases the risk of infections and severe systemic complications.
     
     

Infections

• RA increases susceptibility to infections due to disease-related immune dysfunction and immunosuppressive therapy (e.g., DMARDs, corticosteroids).
• Opportunistic infections, including tuberculosis and fungal infections, are more common in patients on biologics or JAK inhibitors.
• DMARD therapy should be withheld during active infections.
  
  

Haematological Complications

1. Anaemia of Chronic Disease:
   • Common in active RA and correlates with systemic inflammation.
2. Lymphoma:
   • Chronic immune stimulation in RA increases the risk of non-Hodgkin lymphoma, particularly diffuse large B-cell lymphoma.
   • Active disease, rather than DMARDs or biologics, is the primary driver of lymphoma risk.
     
     

Thromboembolic Disease

• RA is associated with an increased risk of venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism.
• Higher disease activity and certain treatments (e.g., JAK inhibitors, TNF inhibitors) are linked to this risk.
  
  

Complications of Therapy

1. Corticosteroid Use:
   • Prolonged use contributes to osteoporosis, diabetes, weight gain, and increased infection risk.
   • Taper corticosteroids as soon as disease control is achieved.
2. Methotrexate Toxicity:
   • Hepatotoxicity and pulmonary toxicity (e.g., methotrexate-induced pneumonitis) require close monitoring.
3. TNF Inhibitors and JAK Inhibitors:
   • Associated with infections and potential thromboembolic events.
   • Increased malignancy risk remains a debated concern.
     
     

Psychosocial and Quality of Life Impact

• Chronic pain and functional limitations lead to increased rates of depression and anxiety.
• Fatigue and systemic inflammation further reduce quality of life.

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