Rheumatoid Arthritis (RA) is a chronic, systemic, autoimmune inflammatory disease of unknown definitive aetiology that primarily targets the synovial membrane of peripheral joints, leading to a symmetric, erosive polyarthritis ^[1][2][3]. If untreated, the persistent synovial inflammation (synovitis) produces a destructive granulation tissue called pannus, which progressively erodes articular cartilage and juxta-articular bone, culminating in irreversible joint deformity and locomotor disability ^[2][3].

Let's break the name down:

• Rheuma (Greek) = "flowing/flux" — historically referred to the notion that disease substances "flowed" to the joints.
• -oid = "resembling."
• Arthritis = "arthro" (joint) + "-itis" (inflammation).

So "rheumatoid arthritis" literally means "joint inflammation resembling rheumatic flux" — distinguishing it from other forms of arthritis (e.g., osteoarthritis, which is primarily degenerative).

"Inflammatory + Symmetrical + Polyarthritis" — this is the classic triad to remember ^[3].

To understand RA, you need to understand the target — the synovial joint.

4.1 Structure of a Normal Synovial Joint

┌─────────────────────────────────┐
│         Joint Capsule           │
│  ┌───────────────────────────┐  │
│  │    Synovial Membrane      │  │
│  │  (lines inner capsule)    │  │
│  │  ┌─────────────────────┐  │  │
│  │  │   Synovial Fluid    │  │  │
│  │  │  (lubricant/nutrient)│  │  │
│  │  └─────────────────────┘  │  │
│  └───────────────────────────┘  │
│                                 │
│   Articular Cartilage          │
│   (covers bone ends)           │
│                                 │
│   Subchondral Bone             │
└─────────────────────────────────┘

• Synovial membrane (synovium): a thin (1–3 cell layers thick) vascular connective tissue lining the inner surface of the joint capsule. It does NOT cover articular cartilage.
  • Type A synoviocytes (macrophage-like): phagocytic, remove debris from joint space.
  • Type B synoviocytes (fibroblast-like): produce hyaluronic acid and lubricin → synovial fluid.
• Synovial fluid: viscous, clear fluid that lubricates and nourishes avascular articular cartilage.
• Articular cartilage: hyaline cartilage covering bone ends — avascular, aneural. Depends on synovial fluid for nutrients.
• Joint capsule: fibrous outer layer providing structural support.

Why does RA target synovial joints? Because the synovial membrane is the primary site of the autoimmune inflammatory attack. Joints with abundant synovium (MCP, PIP, wrist, MTP) are preferentially affected, while joints with minimal synovial lining (e.g., DIP) are spared.

While the full diagnostic criteria, algorithm, and management will be covered in the next section (as requested), here is a brief overview of the investigative modalities to assess joints that were mentioned in the lectures:

"Investigative modalities to assess joints: X-ray, USG (can detect subclinical inflammation in the joints, allow for more aggressive treatment), MRI" ^[14].

^[1] Senior notes: Maksim Medicine Notes.pdf (Section 13.4 Rheumatoid arthritis, p.312) ^[2] Senior notes: Ryan Ho Rheumatology.pdf (Section 2.6, p.44; Approach Section B, p.409 in Ryan Ho Fundamentals.pdf) ^[3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Rheumatoid arthritis section, p.1672–1674) ^[4] Lecture slides: Upper Limb Painful Conditions_Dr. Margaret Woon Man FOK_3. Inflammatory conditions.pdf (p.2, p.4) ^[5] Senior notes: Block A - Treatments for skin diseases (eczema, psoriasis and urticaria).pdf (p.34 — TNF-α cascade in RA) ^[6] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (p.37 — Anti-TNF and TB) ^[7] Senior notes: Ryan Ho Fundamentals.pdf (Approach to joint pain, p.409) ^[8] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (SLE vs RA comparison table, p.712) ^[9] Senior notes: Ryan Ho Respiratory.pdf (ILD with known causes table, p.121) ^[10] Senior notes: Block A - Hematology Interactive Tutorial.pdf (RA anaemia case, p.2) ^[11] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (Felty syndrome, p.7) ^[12] Senior notes: Ryan Ho Opthalmology.pdf (Rheumatological Disease and the Eye, p.131) ^[13] Senior notes: Ryan Ho Neurology.pdf (Mononeuritis multiplex and polyneuropathy, p.180) ^[14] Senior notes: Block A - Syncope and irregular heartbeat_ Cardiac arrhythmia; Heart blocks, Bradycardia.pdf (p.30 — investigative modalities for joints) ^[15] Senior notes: Block A - Painful red joint_ monoarthropathy, gouty arthritis, septic arthritis, haemarthrosis.pdf (p.7)

When a patient presents with polyarthritis (or any joint complaint), the key clinical reasoning task is to distinguish RA from the many other conditions that can mimic it. The approach follows the systematic framework established in the previous section:

1. Is it inflammatory or non-inflammatory (degenerative)? — morning stiffness duration, rest vs use, swelling
2. How many joints? — mono / oligo / poly
3. Which joints? — small vs large, symmetric vs asymmetric, axial vs peripheral, DIP spared vs involved
4. Duration? — acute ( < 6 weeks) vs chronic ( > 6 weeks)
5. Extra-articular clues? — rash, eye disease, GI symptoms, urethritis, psoriasis
6. Serology? — RF, anti-CCP, ANA, HLA-B27

The differential diagnosis can be broadly divided by temporal pattern and number of joints ^[1][16].

This table integrates points from GC lecture slides, senior notes, and standard references. The conditions most likely to mimic RA are listed first.

Clinical features of different arthritis — history ^[17]:

• RA: Younger age, insidious onset, polyarthritis, small hand joints, sparing DIP joints, early morning stiffness ≥ 30 mins
• Spondyloarthritis: Younger age, insidious onset, mono or polyarthritis, any joint could be involved, psoriasis, IBD, STD/dysentery, uveitis, back pain, family history
• Osteoarthritis: Insidious onset, DIP joints or weight-bearing joints, older age
• Gout: Acute onset, first metatarsophalangeal joint involvement, usually self-limiting, sometimes fever

Synovial fluid analysis is mandatory in any acute inflammatory monoarthritis/oligoarthritis to rule out septic arthritis and crystal arthropathy ^[15][16].

^[16]

In RA: synovial fluid is inflammatory (cloudy/translucent, WBC 2,000–50,000, 50–70% neutrophils) but Gram stain and culture are negative, and no crystals are seen.

Important point: RF is NOT specific for RA — it is positive in many conditions (SLE ~20%, Sjögren's ~75%, chronic infections, sarcoidosis, 5–10% healthy elderly). Anti-CCP is the key specific test — specificity > 95% for RA. A patient who is RF+ but anti-CCP– needs careful consideration of the alternatives.

This is a critical conceptual framework emphasised in the GC lectures ^[16][17]:

^[16]

A critical concept to understand upfront: there is no single "gold standard" diagnostic test for RA. Unlike, say, septic arthritis (where you culture the bug) or gout (where you see crystals), RA is diagnosed by pattern recognition — a combination of clinical features, serology, inflammatory markers, and imaging findings. Classification criteria exist to standardise this pattern recognition for clinical trials and epidemiological studies, but they are also the practical framework by which clinicians make the diagnosis.

There are two main sets of classification criteria you need to know:

1. 1987 ACR (American College of Rheumatology) criteria — designed for established/classified RA
2. 2010 ACR/EULAR criteria — designed for early RA (to catch the disease before irreversible damage)

The evolution from 1987 → 2010 reflects a paradigm shift: treat early, treat aggressively ("window of opportunity"). The old criteria required features like erosions and nodules that only appear in advanced disease — by then, irreversible damage has already occurred. The new criteria were designed to capture RA at its earliest stage when DMARDs can change the disease trajectory.

"Criteria of RA (1987 ARA) — At least 4/7 and criteria 1–4 must be present for > 6 weeks" ^[4][25].

"1987 ACR classification criteria: ≥ 4 out of 7 with clinical symptoms lasting ≥ 6 weeks" ^[20].

Mnemonic: "RAS = at least Six weeks of ≥ 4 out of 7" ^[20]:

• Rheumatoid nodules, Rheumatoid factor ≥ 95th percentile, Radiographic changes
• Arthritis of ≥ 3 joints, AM stiffness ≥ 1h
• Small hand joint arthritis, Symmetrical arthritis

Limitations of the 1987 criteria (why we needed the 2010 criteria):

• Criteria 5 (nodules) and 7 (erosions) are late features — present only in established disease
• By the time erosions are visible on plain X-ray, significant irreversible joint damage has already occurred
• Poor sensitivity for early RA — misses patients in the "window of opportunity" for treatment
• Does not include anti-CCP, which was discovered after 1987 and is more specific than RF

The 2010 ACR/EULAR classification criteria for rheumatoid arthritis ^[17][20].

This is the current standard and is designed to classify patients with early, undifferentiated inflammatory arthritis as having "definite RA" so that treatment can be initiated promptly.

Entry requirement (must be met before scoring):

• Patient must have at least 1 joint with definite clinical synovitis (swelling) that is not better explained by another disease (e.g., SLE, PsA, gout)

Then score the following 4 domains:

Total score ≥ 6 out of 10 = classified as definite RA ^{[1][3][17][20]}.

"2010 ACR/EULAR classification criteria: ≥ 6 out of 10 points classified as definite RA. Sensitivity 82%, Specificity 61%" ^[1].

Important additional rule ^[1]:

"In case of erosiveness (chronic RA deformity), no other points needed" — if a patient already has typical RA erosions on X-ray, they can be classified as RA regardless of the point score. This recognises that some patients present late with established disease.

"Must exclude DDx (e.g., PsA, SSc)" ^[1] — the criteria only apply after other diagnoses have been reasonably excluded.

Once RA is diagnosed, disease activity must be monitored to guide treatment decisions (treat-to-target strategy). The DAS28 (Disease Activity Score in 28 joints) is the most widely used composite score ^[17][20].

"Disease activities: Pain, Swelling, Stiffness (morning), Functional limitation" ^[17].

"DAS28 score for assessing disease activity, response to treatment, and need for biologics" ^[20].

Components of DAS28:

1. Tender joint count (out of 28 joints)
2. Swollen joint count (out of 28 joints)
3. ESR or CRP (depending on DAS28-ESR vs DAS28-CRP)
4. Patient global assessment (VAS 0–100)

The 28 joints assessed: bilateral shoulders, elbows, wrists, MCPs (1–5), PIPs (1–5), knees. Note: feet/ankles are NOT included in DAS28 (a known limitation — MTP involvement can be missed).

Parameters for clinical assessment ^[3]:

• Degree of joint pain
• Duration of morning stiffness
• Number of tender and swollen joints
• Functional status (by Health Assessment Questionnaire, HAQ)
• Patient's and physician's global assessment
• ESR or CRP
• Radiographic progression

"Investigations (SAQ!)" ^[1] — this is explicitly marked as an SAQ-likely topic in the senior notes.

Interactive Tutorial Case (Haem Case 1) ^[10][27]: A 58-year-old woman with RA. Hb 7.5 g/dL, MCV 70 fL, MCH 25 pg, WCC 3.5 × 10⁹/L, Plt 410 × 10⁹/L. CRP 8 mg/dL, ESR 70 mm/hr. Serum iron 3, TIBC 75, Transferrin Sat 4%.

Step-by-step interpretation:

1. Hb 7.5, MCV 70 → microcytic anaemia
2. Serum iron 3 (low), TIBC 75 (high), Transferrin sat 4% (low) → pattern of iron deficiency anaemia (IDA)
   • Why? In IDA, the body is iron-depleted → liver produces more transferrin (iron-carrier) to scavenge whatever iron is available → TIBC rises. Transferrin saturation falls because there's very little iron loading the transferrin.
3. CRP 8, ESR 70 → active systemic inflammation
4. Platelet 410 (high) → reactive thrombocytosis (IL-6 driven)
5. WCC 3.5 (low) → could be drug-related (MTX myelosuppression) or Felty syndrome

Most likely diagnosis: IDA from NSAID-related GI bleeding in the context of active RA. The drug history is critical — non-selective NSAIDs can cause GI bleeding ^[10].

Why not just ACD? In ACD, TIBC would be low/normal (not high) and ferritin would be normal/elevated (not low). The high TIBC here clinches IDA. However, a component of ACD likely coexists given the elevated inflammatory markers.

The management of RA has been revolutionised over the past two decades. The old paradigm of "wait and see" has been replaced by the "treat early, treat aggressively, treat-to-target" strategy. Understanding the principles is essential before memorising individual drugs.

Treatment principles ^[1][28][20]:

1. Early initiation of DMARDs — the earlier you start, the better the long-term outcome ^[28]
2. Treat-to-target: aim for low disease activity or clinical remission ^[1][20][28]
3. Aim to prevent joint damage and preserve daily function ^[28]
4. Best outcome if controlled within 2 years of onset ^[1][20]

"Early aggressive treatment (initiate within window of opportunity: ≤ 3–6 months of symptom onset)" ^[1]. "Maintain lowest possible disease activity (DAS28 < 2.6) — follow-up every 3 months" ^[1].

Why the "window of opportunity"? ^[20]:

• > 70% of RA patients with active polyarticular disease and RF+ develop joint damage or erosions within 2 years of onset
• 90% of joint erosions occur within the first 2 years, and sensitive modalities like MRI can detect erosions as early as 4 months
• Rate of bone mineral density loss is highest in early RA
• Once erosions and deformity develop, they are irreversible — no drug can rebuild destroyed cartilage or eroded bone

"Switch therapy if < 50% activity improvement at 3 months, or target not reached at 6 months" ^[1].

"Management: multidisciplinary approach (PT, OT, podiatrist, dietitian)" ^[1][20].

Overview of Drug Categories

"Symptomatic relief: analgesics / NSAIDs" ^[1].

Minimising NSAID GI risk ^[30]:

• Review indications — is the NSAID truly necessary?
• Switch to COX-2 selective inhibitor if GI risk
• Co-prescribe PPI (first-line gastroprotection)
• Check and eradicate H. pylori if present
• Avoid combining NSAID + corticosteroid

"Low-dose + short-term (< 3–6 months) steroids: bridging when switching DMARDs" ^[1].

"Consider short course of corticosteroids during the initial phase of treatment while waiting for methotrexate to take effect" ^[28].

"Long-term corticosteroids (> 3 months) as monotherapy for RA — risk of systemic corticosteroid side-effects" — this is explicitly listed as a STOPP criterion in elderly prescribing ^[29].

The Concept

DMARDs are the cornerstone of RA management. Unlike analgesics and NSAIDs (which only treat symptoms), DMARDs are proven to alter the disease course — they slow or halt the underlying inflammatory process, prevent joint damage, and preserve function ^[1][20].

The word itself tells you the concept:

• Disease — targets the disease process itself
• Modifying — changes the natural history (not just symptomatic relief)
• Anti-Rheumatic — specifically for rheumatic diseases
• Drugs — pharmacological agents

"Effect: slow onset of action, suppresses underlying rheumatoid process but does not reverse" ^[20]. Key point — DMARDs cannot reverse existing damage. They prevent new damage. This is why early initiation is critical.

"All take time to act (~6 weeks)!" ^[1] — hence the need for steroid bridging.

"Conventional synthetic DMARDs (csDMARDs) combinations" ^[28]:

The concept of combination csDMARDs is analogous to treating TB with multiple drugs — you hit the disease from multiple angles to achieve better control.

"Target synthetic DMARDs: JAK inhibitors" ^[28].

Mechanism: JAK (Janus kinase) enzymes are intracellular tyrosine kinases that sit downstream of cytokine receptors. When a cytokine (IL-6, IL-12, IL-23, IFN-γ, etc.) binds its receptor, it activates JAK → JAK phosphorylates STAT transcription factors → STAT translocates to nucleus → gene transcription. By inhibiting JAK, you block multiple cytokine signalling pathways simultaneously — a "broad-spectrum" intracellular approach.

Advantages: Oral (convenient), rapid onset, effective as monotherapy

"FDA warning: Cancer and cardiovascular risk" ^[28] — post-marketing data (ORAL Surveillance trial) showed increased risk of major adverse cardiovascular events (MACE) and malignancy (especially lung cancer and lymphoma) with tofacitinib compared to anti-TNF in patients ≥ 50 years with ≥ 1 CV risk factor. Current guidelines recommend JAK inhibitors only after failure of a bDMARD in patients with these risk factors, or in patients without these risk factors where bDMARDs are inappropriate.

Other side effects: Herpes zoster reactivation (consider recombinant shingles vaccine), venous thromboembolism, hyperlipidaemia, transaminitis, myelosuppression.

"Poor prognostic factors predicting joint damage" ^[28][20]:

"3 clinical factors, 2 serological factors, 1 family history" ^[20] — a useful framework for remembering the poor prognostic indicators. Patients with these factors should have early aggressive use of DMARDs and lower threshold for escalation to biologics ^[20].

These complications arise from the drugs used to treat RA. A well-examined topic because it tests whether students understand drug side effects.

Complications of chronic immunosuppressant usage: infection, blood dyscrasia ^[3]. Complications of chronic steroid usage: Cushingoid features (acne, hirsutism, buffalo hump, central obesity), immunosuppression, gastric ulcer, osteoporosis, avascular necrosis of hip ^[3].

"Q3: What are the complications of long-standing rheumatoid arthritis?" ^[3]:

"Poor prognostic factors indicating early aggressive use of DMARDs" ^[3]:

• High disease activity at onset (≥ 18 joints)
• High baseline joint damage (erosive disease)
• Persistently high CRP level
• Positive IgM RF or anti-CCP
• Positive family history of RA
• Nodular disease
• Extra-articular manifestations

Overall prognosis:

• RA is a chronic disease with no cure. However, with modern treatment (early DMARDs, biologics, treat-to-target), many patients achieve sustained remission or low disease activity.
• Life expectancy is reduced by ~5–10 years compared to the general population, primarily due to cardiovascular disease (the leading cause of death in RA) and infections.
• Seropositive RA (especially high-titre anti-CCP+) carries a worse prognosis with more erosive disease and more extra-articular manifestations.
• The shift to early aggressive treatment and the availability of biologics have dramatically improved outcomes compared to 20–30 years ago.

"Rheumatoid factor: high levels in rheumatoid arthritis → poor prognosis" ^[17].