Rheumatoid Arthritis (RA)
Summary
Rheumatoid Arthritis (RA) is a chronic, systemic autoimmune disease characterized by symmetrical polyarthritis affecting primarily the small joints of the hands and feet. Unlike Osteoarthritis (wear and tear), RA is an inflammatory condition where the immune system targets the synovium, causing hypertrophy (Pannus) which erodes cartilage and bone. Left untreated, it causes progressive deformity (Ulnar deviation, Swan Neck, Boutonniere) and profound disability. It is a systemic disease with extra-articular manifestations in the Lungs (Fibrosis), Heart (Pericarditis/IHD), and Eyes (Scleritis). Early diagnosis and aggressive treatment with Disease Modifying Anti-Rheumatic Drugs (DMARDs) within the "Window of Opportunity" (first 3-6 months) is critical to induce remission and prevent irreversible joint damage. The discovery of Anti-CCP antibodies and Biologic therapies (Anti-TNF, Anti-IL6, JAKi) has revolutionised prognosis. [1,2]
Key Facts
- Target: Synovium (Synovitis).
- Distribution: Symmetrical. MCPJ, PIPJ, MTPJ, Wrists. SPARES the DIPJs.
- Epidemiology: Female > Male (3:1). Prevalence 1%.
- Key Symptom: Early Morning Stiffness (EMS) > 1 hour.
- Key Sign: "Boggy" synovitis (squishy swelling, not bony).
- Autoantibodies:
- Rheumatoid Factor (RF): Sensitive (70%) but non-specific (seen in infection/age).
- Anti-CCP (ACPA): Highly Specific (98%). Predicts erosive disease.
- Mortality: RA patients have a 50% higher risk of cardiovascular death (equivalent to Diabetes).
Clinical Pearls
"The Window of Opportunity": Joint erosion occurs early (within 2 years). Waiting "to see how it goes" is negligence. Referral to Rheumatology should happen on suspicion, not just confirmation. "Treat to Target" (remission).
"DIP Sparing": RA loves the knuckles (MCP) and middle joints (PIP). It almost never touches the DIPs. If the DIPs are involved, think Osteoarthritis (Heberden's Nodes) or Psoriatic Arthritis.
"The Cervical Trap": The neck is the only part of the spine RA affects (because C1/C2 has regular synovium). Erosion of the Transverse Ligament causes C1 to slip forward on C2 (Atlanto-axial Subluxation). This can compress the spinal cord. MANDATORY Flexion/Extension X-rays before any surgery requiring intubation.
"Septic until Proven Otherwise": If an RA patient presents with a hot, swollen single joint, do not assume it's a "flare". They are immunosuppressed. You must tap it to rule out sepsis.
Demographics
- Prevalence: 0.5-1% of global population.
- Age: Peak onset 30-50 years, but can occur at any age.
- Gender: Female > Male (3:1). Estrogen influence is debated (pregnancy often induces remission, postpartum flares common).
- Genetics: HLA-DR4 and HLA-DR1 (The "Shared Epitope").
Risk Factors
- Smoking: The biggest environmental trigger. Increases Anti-CCP production (citrullination in lungs). Smokers have more aggressive disease and respond less well to Methotrexate.
- Periodontitis: Porphyromonas gingivalis bacteria causes citrullination. Strong link between gum disease and RA.
- Microbiome: Dysbiosis of gut bacteria may play a role.
The "Pannus" Formation
- Initiation (Citrullination):
- Environmental stress (Smoking/Bacteria) causes Arginine residues in proteins to be converted to Citrulline (Citrullination).
- In genetically susceptible individuals (HLA-DR4), these citrullinated proteins are recognized as "foreign".
- ACPA (Anti-Citrullinated Protein Antibodies) are formed.
- Infiltration:
- Immune complexes deposit in the synovium.
- T-Cells (Th1, Th17) and B-Cells infiltrate the joint.
- Cytokine Storm:
- Macrophages release TNF-Alpha, IL-1, IL-6.
- These are the targets of Biologic therapy.
- Proliferation (The Pannus):
- Synoviocytes multiply uncontrollably, forming a thick, invasive, vascular tissue called Pannus.
- This pannus behaves like a local tumour.
- Destruction:
- The Pannus releases enzymes (MMPs) that degrade cartilage.
- It stimulates RANK-L, causing Osteoclasts to eat bone -> Erosions.
Articular (Joints)
Extra-Articular (Systemic)
RA is a systemic disease. "Rheumatoid Factor" is not just in joints.
Serology
- Rheumatoid Factor (RF):
- IgM antibody against the Fc portion of IgG.
- Sensitivity: 70-80%.
- Specificity: Low. Positive in infection (TB, Endocarditis), other autoimmune (Sjogren's, SLE), and 5% of healthy elderly.
- Anti-CCP (ACPA):
- Anti-Cyclic Citrullinated Peptide.
- Sensitivity: 70-80%.
- Specificity: >95%.
- Predicts erosive disease.
- ANA: Positive in 30% (confusing with Lupus).
Inflammatory Markers
- CRP / ESR: Elevated. Used to monitor disease activity (DAS28 score).
Imaging
- X-Ray:
- Early: Soft tissue swelling. Peri-articular Osteopenia (bones look "washed out" near the joint due to hyperaemia).
- Intermediate: Loss of joint space (Uniform, unlike OA which is non-uniform).
- Late: Marginal Erosions (Bites taken out of the bone edge). Subluxation. Ankylosis (fusion - rare in RA except wrist).
- Ultrasound:
- Gold standard for early synovitis.
- Detects Power Doppler signal (active inflammation) and erosions before X-ray.
- MRI:
- Most sensitive. Shows bone marrow oedema (pre-erosion).
Diagnostic Criteria (ACR/EULAR 2010)
A score of ≥ 6/10 is diagnostic of definite RA.
- Joint Involvement (0-5 points): More small joints = more points.
- Serology (0-3 points): RF or Anti-CCP positive.
- Acute Phase Reactants (0-1 point): CRP/ESR.
- Duration (0-1 point): ≥ 6 weeks.
Management Algorithm
CONFIRMED RA DIAGNOSIS
(ACR/EULAR Criteria)
↓
START DMARDs IMMEDIATELY
(Methotrexate + Steroid Bridge)
↓
REVIEW AT 3 MONTHS (DAS28)
Target: Remission/Low Activity
↓
┌───────┴───────┐
TARGET MET TARGET MISSED
↓ ↓
CONTINUE ESCALATE THERAPY
(Triple Therapy?)
- Add Sulfasalazine
- Add Hydroxychloroquine
↓
STILL HIGH DAS28?
(score > 5.1)
↓
BIOLOGICS
- Anti-TNF (Adalimumab)
- Anti-IL6 / JAK Inhibitors
1. General Measures
- Education: Smoking cessation is vital.
- Physio/OT: Splinting to prevent deformity. Joint protection.
- Vaccination: Flu/Pneumococcal (essential as patients are immunosuppressed). Live vaccines (HZV) contraindicated if on Biologics.
2. Symptomatic Relief
- NSAIDs: Ibuprofen/Naproxen (with PPI). Reduces stiffness but does NOT stop disease progression.
- Analgesia.
3. cDMARDs (Conventional Synthetic)
- Methotrexate (MTX): The "Anchor Drug".
- Mechanism: Folate antagonist. Adenosine release?
- Dose: Once weekly (Oral/Subcut) + Folic Acid 5mg (taken on a different day).
- Monitor: FBC (Marrow suppression), LFT (Hepatitis), U&E.
- Side Effects: Nausea, mucositis, Pulmonary Fibrosis (Pneumonitis).
- Teratogenic: Must stop 3 months before conception (Men and Women).
- Sulfasalazine:
- Safe in pregnancy. Good for milder disease.
- Side Effects: Orange urine, reversible male infertility, rash.
- Hydroxychloroquine:
- Mildest. Good lipid profile.
- Side Effects: Retinopathy (accumulates in retina). Annual eye checks needing OCT.
- Leflunomide:
- Pyrimidine synthesis inhibitor.
- Caveat: Very long half-life (2 years). Needs washout with Cholestyramine if toxicity occurs or pregnancy planned.
4. Steroids ("The Bridge")
- DMARDs take 3 months to work.
- Prednisolone: Oral or IM (Depo-Medrone) used at induction to suppress inflammation rapidly ("Bridging").
- We aim to taper off steroids once DMARDs kick in to avoid Cushings/Osteoporosis.
5. bDMARDs (Biologics)
Reserved for DAS28 > 5.1 despite 2 cDMARDs.
- Anti-TNF (Adalimumab, Etanercept, Infliximab, Golimumab, Certolizumab).
- Risk: Reactivation of TB. Demyelination (MS-like). Heart Failure.
- Anti-CD20 (Rituximab).
- Depletes B-Cells. Given as 2 infusions 2 weeks apart.
- Indication: Seropositive RA (works best).
- Anti-IL6 (Tocilizumab).
- CTLA-4-Ig (Abatacept): T-cell co-stimulation blocker.
6. tsDMARDs (Targeted Synthetic)
- JAK Inhibitors (Baricitinib, Tofacitinib, Upadacitinib).
- Mechanism: Blocks intracellular signaling (Janus Kinase).
- Advantage: Oral tablets (Biologics are injection/infusion).
- Risk: Slight increase in VTE and Zoster.
"Pills instead of Jabs."
- Before 2017, failing Methotrexate meant injections (Anti-TNF). Now, we have JAKi.
- Mechanism: Cytokines (IL-6 etc.) bind to receptors on the cell surface. These receptors signal to the nucleus via the JAK-STAT pathway. JAK inhibitors enter the cell and block this "phone line".
- Efficacy: Equal to or better than Adalimumab in head-to-head trials.
- Safety Warning: Recent data suggests a slightly higher risk of MACE (Major Adverse Cardiac Events) and VTE compared to anti-TNF in older patients with risk factors.
"Treat to Target."
- In the past, we treated RA until the patient said "I feel a bit better". This led to hidden progression and deformity.
- Now we use DAS28 (Disease Activity Score 28 joints).
- Calculator:
- Number of Tender Joints (out of 28).
- Number of Swollen Joints.
- ESR or CRP.
- Patient Global Assessment (0-100 VAS).
- Result:
- < 2.6: Remission (The Goal).
- > 5.1: High Disease Activity (Qualifies for Biologics).
"Salvage and Reconstruction." Surgery is now less common thanks to Biologics, but still needed for legacy disease (burnt out RA with deformity).
- Synovectomy: Removal of inflamed synovium (preventative).
- Tendon Transfer/Repair: For ruptured tendons (e.g. Vaughan-Jackson lesion - rupture of finger extensors at the wrist).
- Arthroplasty (Joint Replacement):
- MCPJ: Silastic (Silicone) spacers. Improves cosmetic appearance and ulnar drift, but grip strength may not improve much.
- Wrist: Total Wrist Replacement or Fusion (Arthrodesis). Fusion is durable and pain-free but loses movement.
- Darrach's Procedure: Excision of the ulnar head for painful DRUJ.
"The Remission and the Flare."
- Course: 70% of women improve during pregnancy (immune tolerance). 90% flare within 3 months postpartum.
- Drug Safety:
- Methotrexate: ABSOLUTELY CONTRAINDICATED. Teratogenic/Abortifacient. Stop 3-6 months before.
- Leflunomide: Teratogenic. Washout required.
- Safe Drugs: Hydroxychloroquine, Sulfasalazine, Low dose Prednisolone.
- Biologics: Anti-TNF (Certolizumab) doesn't cross the placenta and is safe throughout. Others usually stopped in Trimester 3.
Disease Complications
- Joint Destruction: Ankylosis, Flail joints.
- Cardiovascular: Accelerated atherosclerosis. 4x risk of MI. Manage lipids/BP aggressively.
- Amyloidosis (AA): Chronic inflammation leads to Amyloid A deposition in kidneys -> Nephrotic syndrome/Renal failure.
- Felty's Syndrome: Splenomegaly + Neutropenia -> Sepsis.
- Osteoporosis: Driven by cytokines + steroids + immobility.
Drug Complications
- Methotrexate Lung: Acute pneumonitis.
- Biologics: TB reactivation.
- Steroids: Diabetes, fractures, cataracts.
- Before Biologics: 50% unable to work at 10 years. Life expectancy reduced by 7 years.
- Era of Biologics: Remission is achievable in 50-60%. Work disability reduced significantly. Mortality gap closing.
- Poor Prognostic Factors:
- High Anti-CCP titre.
- Early erosions on X-ray.
- Extra-articular features (Nodules/Vasculitis).
- Smoking.
- Female sex.
Key Studies
- TICORA Study (Lancet 2004): Proved "Treat to Target" (tight control) is superior to routine care.
- BeSt Study: Compared 4 strategies. Showed starting Biologics early works, but starting Methotrexate aggressively (Triple Therapy) is often just as good and cheaper.
- ORAL Surveillance: Showed JAKi safety signal (cardiac) vs TNFi.
Guidelines
- NICE (NG100): Referral < 3 days of suspected persistent synovitis. Treat < 3 weeks.
- EULAR: Methotrexate is the first-line anchor for everyone.
What is RA?
Your immune system is confused. Instead of fighting viruses, it is attacking the lining of your joints. This makes the joints swell up ("synovitis"). If we don't stop it, the swelling releases chemicals that eat away the bone, causing permanent damage.
Is it just wear and tear?
No. That is Osteoarthritis. RA is an "inflammatory" disease. Typical signs are:
- Morning stiffness > 1 hour.
- Symmetrical swelling (both hands).
- Improving with movement.
The Drugs seem scary...
Methotrexate is a strong drug (originally for cancer), but we use tiny doses (1/100th of cancer dose). It is much safer to take the drug than to let the RA destroy your joints and heart. If Methotrexate doesn't work, we have "Biologics" - smart missiles that target the specific inflammation signals.
What can I do?
- Stop Smoking: This is the single most effective thing you can do. Smoking fuels the fire.
- Keep moving: Exercise is safe and vital.
- Aletaha D, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010.
- Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2023.
- Grigor C, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study). Lancet. 2004.
Common Exam Questions
1. Immunology:
- Q: What is the most specific antibody for RA?
- A: Anti-CCP (ACPA).
2. X-Ray Signs:
- Q: What comes first?
- A: Peri-articular osteopenia and soft tissue swelling.
- Q: What is the hallmark of late disease?
- A: Marginal Erosions.
3. Pharmacology:
- Q: What monitoring is needed for Methotrexate?
- A: FBC, LFT, U&E every 2-4 weeks initially. Folic acid given to reduce side effects.
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