Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by symmetric inflammatory polyarthritis with progressive destruction of joints due to synovial inflammation and pannus formation.

Rheumatoid Arthritis (RA)

2. Epidemiology

Parameter	Detail
Global prevalence	~0.5–1% worldwide
Hong Kong prevalence	~0.3–0.4% ^[1]^[2]^[4]
UK/US prevalence	0.5–1.5% ^[4]
Racial variation	Found in all races; 1–2% in Caucasians, 0.3–0.4% in Chinese, rare in Black Africans ^[2]

RA is the commonest cause of autoimmune inflammatory polyarthritis worldwide ^[2].

Parameter	Detail
Sex ratio	Female : Male = 3:1 ^[1]^[2]^[3]^[4]
Lifetime risk	~1 in 28 for females, ~1 in 59 for males ^[2]
Age of onset	Can occur at any age; peak age of onset 4th–5th decades (35–55 years) ^[2]^[3]^[4]
Peak (Felix Lai)	50–75 years old ^[3]

"Female to male 3:1, age of presentation 4th to 5th decades" ^[4].

Why the female predominance? Oestrogen has immunomodulatory effects — it tends to enhance B-cell function and antibody production while modulating T-cell responses. This is why many autoimmune diseases (RA, SLE, Sjögren's) are more common in women. Interestingly, RA often remits during the 3rd trimester of pregnancy (when oestrogen is very high — but also progesterone and cortisol, which are immunosuppressive), then commonly flares postpartum ^[2].

3. Risk Factors

"Genetic factors — HLA-DR4 & DR1, first degree relative had 3× risk" ^[4].

Factor	Detail
MHC Class II	HLA-DR4 is the major susceptibility haplotype (also HLA-DR1) ^[1]^[2]^[4]
Shared epitope hypothesis	HLA-DR4 and DR1 share a common amino acid sequence in the third hypervariable region of the DRβ1 chain → this "shared epitope" binds citrullinated peptides with high affinity → presents them to T cells → initiates/perpetuates autoimmune response
Concordance	Monozygotic twins: 12–15%; Dizygotic twins: ~3% ^[2]
Family history	First-degree relatives have ~3× the risk ^[4]
Other genes	PTPN22 (phosphatase involved in T-cell signalling), CD40L, CTLA4, STAT4, TRAF1/C5 ^[2]

Why HLA-DR4? Think of it this way: MHC Class II molecules present antigens to CD4+ T-helper cells. If you have an HLA-DR4 allele, the "groove" of your MHC II molecule happens to bind citrullinated peptides particularly well. Citrullinated proteins are generated in inflamed tissue (e.g., in smokers' lungs, in gum disease). So HLA-DR4 essentially acts as a "matchmaker" between citrullinated self-antigens and T cells, kick-starting the autoimmune cascade.

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.

High Yield

RA spares DIP joints — because DIP joints have very little synovial lining ^[1]. If you see DIP involvement, think osteoarthritis (Heberden's nodes), psoriatic arthritis, or erosive OA.

5. Aetiology and Pathophysiology

5.2 Detailed Pathophysiology — Step by Step

Autoantibody	Target	Sensitivity	Specificity	Notes
Rheumatoid Factor (RF)	Fc portion of IgG	~70–80%	~80%	Not specific — present in other AI diseases, chronic infections, 5–10% of healthy elderly
Anti-CCP (ACPA)	Citrullinated proteins (e.g., citrullinated vimentin, fibrinogen, α-enolase)	~70%	> 95%	Highly specific; can precede symptoms by years; predicts erosive disease

High Yield — RF vs Anti-CCP

RF = sensitive but not specific (present in many conditions: SLE, Sjögren's, chronic infections, sarcoidosis, healthy elderly).
Anti-CCP = similarly sensitive but much more specific for RA. A positive anti-CCP in a patient with early inflammatory arthritis is very strong evidence for RA.
Both positive = very high predictive value for RA and for erosive disease.

6. Classification

	Seropositive RA	Seronegative RA
RF and/or Anti-CCP	Positive	Negative
Prevalence	~70–80% of RA	~20–30% of RA
Prognosis	Generally worse — more erosive, more extra-articular manifestations	Generally milder — but can still be destructive
Genetic association	Strong HLA-DR4 association	Weaker genetic association

Stage	Description
I	Early — no destructive changes on X-ray
II	Moderate — radiographic evidence of osteoporosis ± slight cartilage/subchondral bone destruction, no deformity
III	Severe — cartilage and bone destruction, deformity (deviation, subluxation, ulnar drift)
IV	Terminal — fibrous or bony ankylosis

This is a high-yield GC lecture concept ^[7]:

Feature	RA	Spondyloarthritis (SpA)	Osteoarthritis (OA)
Inflammation	Yes — synovitis	Yes — enthesitis + synovitis	Minimal/secondary
Symmetry	Symmetric	Asymmetric	Often symmetric
Joints	MCP, PIP, wrist, MTP	DIP, large joints (LL > UL), axial (SIJ, spine)	DIP, PIP, 1st CMC, knee, hip, spine
DIP involvement	Spared	Common (PsA)	Common (Heberden's nodes)
Axial involvement	Usually spared (except C1/2)	Common (sacroiliitis, spondylitis)	Facet joints
Morning stiffness	> 1 hour	> 30 min	< 30 min
RF / Anti-CCP	Positive (70–80%)	Negative	Negative
HLA association	HLA-DR4	HLA-B27	None specific
Extra-articular	Nodules, lung, eye, vasculitis	Uveitis, psoriasis, IBD, enthesitis	None

7. Clinical Features

7.2 Articular (Joint) Features

Symptom	Pathophysiological Basis
Morning stiffness > 1 hour ^[1]^[3]	Overnight, synovial fluid accumulates in inflamed joints + interstitial oedema → stiffness. During the day, movement "pumps" fluid away → improvement. The duration of morning stiffness correlates with disease activity. In OA, stiffness is brief (< 30 min) because there is less inflammation.
Symmetrical polyarthralgia	Autoimmune process is systemic → affects same joints bilaterally. The immune complexes deposit in synovium of multiple joints simultaneously.
Joint swelling (soft, "boggy" swelling)	Synovial inflammation → synovial hypertrophy + effusion (excess synovial fluid production due to inflamed synovium)
Exacerbated with rest, relieved with use ^[1]	Inflammatory mediators accumulate during rest; gentle movement promotes venous/lymphatic drainage and disperses inflammatory mediators
Joints typically affected first: MCP, PIP, wrist, MTP	These joints have abundant synovium — more "target" for autoimmune attack.
DIP joints and axial joints (except C1/2) spared ^[1]	DIP joints have minimal synovial lining. Axial joints (except atlantoaxial) are amphiarthrodial (cartilaginous), not synovial. C1/2 is a synovial joint, hence it can be involved.

High Yield Pattern

RA = MCP + PIP + wrist + MTP (bilateral, symmetric, > 6 weeks, morning stiffness > 1 hour). This is the classic "board-style" presentation. If DIP is involved → think PsA or OA. If asymmetric large joints → think SpA.

Sign	Description	Pathophysiological Basis
Boggy synovial thickening	Palpable soft, "doughy" swelling over joints (especially MCP, PIP, wrist)	Synovial hypertrophy — the synovium thickens from normally 1–3 cell layers to many cell layers due to inflammatory infiltration and FLS proliferation
Joint effusion	Fluctuant swelling, positive "bulge test" (knee)	Excess synovial fluid production by inflamed synovium
Warmth	Joints feel warm to touch	Increased blood flow to inflamed synovium (vasodilation from inflammatory mediators: prostaglandins, nitric oxide)
Tenderness	Pain on palpation, especially at joint line	Sensitisation of nociceptors by prostaglandins, bradykinin, and other inflammatory mediators in the synovium
Reduced range of movement (ROM)	Pain-limited ROM initially, later structural limitation	Early: pain and effusion limit movement. Late: cartilage/bone destruction and fibrosis restrict movement mechanically
Squeeze test (MCP/MTP)	Lateral compression of MCPs or MTPs causes pain	Synovitis of these small joints — compression compresses inflamed synovium → pain

C. Late Disease — Deformities

These deformities develop over months to years of uncontrolled disease as the pannus destroys cartilage, bone, tendons, and ligaments.

Deformity	Description	Mechanism
Boutonnière deformity (buttonhole)	Flexed PIP, hyperextended DIP ^[1]	Rupture/stretching of the central slip of the extensor tendon at PIP → PIP drops into flexion. The lateral bands slip volar to the PIP axis → pull on DIP → DIP hyperextension. The PIP "pokes through" the torn tendon like a button through a buttonhole.
Swan neck deformity	Hyperextended PIP, flexed DIP ^[1]	Contracture of intrinsic muscles (interossei, lumbricals) or laxity of the volar plate at PIP → PIP hyperextends. Secondary tightening of lateral bands → pulls DIP into flexion. Opposite of Boutonnière.
Z deformity of thumb	Flexed MCP, hyperextended IP ^[1]	Synovitis at MCP → stretching of MCP joint capsule → MCP fixed flexion. Compensatory hyperextension at IP joint. The thumb looks like a "Z" from the side.
Ulnar deviation of fingers	Fingers deviate towards the ulnar side at MCP joints ^[1]	Synovitis weakens the radial collateral ligaments and the radial sagittal bands → extensor tendons sublux ulnarly → pull fingers towards ulnar side
Volar (palmar) subluxation of MCP	MCP joints sublux palmarly ^[1]	Synovitis stretches the dorsal capsule and collateral ligaments → proximal phalanx slides palmarly relative to metacarpal head
Radial deviation at wrist	Wrist deviates radially ^[1]	Destruction of ulnar carpal ligaments by synovitis → the carpus shifts radially. Often occurs together with ulnar deviation at MCPs (the "zigzag" deformity).
Piano key sign (ulnar styloid)	The ulnar styloid is subluxed dorsally and can be depressed like a piano key ^[1]	Synovitis at the distal radioulnar joint (DRUJ) → ligamentous laxity → dorsal subluxation of the ulnar head. Press it down → it springs back up.
Trigger finger	Finger locks in flexion, then "snaps" straight	Tenosynovitis of flexor tendons → thickening of tendon sheath → tendon catches on the A1 pulley

"Late joint damage & deformities: Boutonnière deformity, Z deformity of thumb, Swan neck deformity, Ulnar deviation & volar subluxation of MCPJ, Radial deviation at wrist, piano key movement of ulnar styloid" ^[1].

Deformity	Mechanism
Hallux valgus	Synovitis at 1st MTP → medial collateral ligament laxity → great toe deviates laterally
Hammer toe	Hyperextension at MTP, flexion at PIP, extension at DIP — due to intrinsic muscle weakness and extensor tendon imbalance
Claw toe	Hyperextension at MTP, flexion at PIP and DIP
"Cock-up" deformity ^[1]	Dorsal subluxation of MTP joints → metatarsal heads become weight-bearing (painful callosities on sole of foot)
Broadened forefoot	Spreading of metatarsal heads due to loss of transverse arch support

Feature	Detail
Atlantoaxial subluxation (C1/2)	Synovitis of the atlantoaxial joint → erosion/laxity of the transverse ligament of the atlas (which normally holds the odontoid peg of C2 against the anterior arch of C1) → C1 slides forward on C2
Symptoms	Neck pain radiating to occiput, slowly progressive myelopathy (UMN signs in limbs), vertebrobasilar insufficiency (dizziness, drop attacks), sudden death (rare — cord compression)
Investigation	Lateral cervical spine X-ray in flexion: anterior atlantodental interval (AADI) > 3 mm is abnormal
Clinical relevance	Always assess before intubation/general anaesthesia — forced neck extension could cause fatal cord compression

Danger — Cervical Spine in RA

Any RA patient requiring intubation for surgery MUST have a lateral cervical spine X-ray in flexion to exclude atlantoaxial instability. This is a classic exam and clinical pearl.

This is a commonly tested distinction ^[8]:

Feature	RA	SLE
Arthritis	Common, destructive	Common, NON-erosive
Deforming	Yes (irreversible)	Rare (Jaccoud's arthropathy — reducible deformities)
Swan neck	Common (fixed, not reducible)	Rare (reducible)
Ulnar deviation	Common (not reducible)	Rare (reducible)
Synovial hypertrophy	Common	Rare
Erosions on X-ray	Common	Rare
Morning stiffness	Hours	Minutes
Subcutaneous nodules	Common	Rare

7.3 Extra-Articular Manifestations (EAMs)

Extra-articular manifestations occur in ~40% of RA patients, more common in seropositive RA (RF+ and/or anti-CCP+), long-standing disease, and severe/poorly controlled disease. They are a marker of systemic disease.

Feature	Pathophysiology
Fatigue	Circulating pro-inflammatory cytokines (TNF-α, IL-6) act on the CNS → "sickness behaviour." Also contributed to by anaemia, poor sleep from pain, and depression.
Low-grade fever	IL-1, IL-6, TNF-α → act on hypothalamic thermoregulatory centre → raise set point
Weight loss	Catabolic state driven by TNF-α (hence its old name "cachectin") → muscle wasting, appetite suppression
Malaise	Generalised inflammatory cytokine-mediated symptom

Feature	Detail
Prevalence	~20–30% of RA patients; almost exclusively seropositive
Location	Pressure points — olecranon (elbow), dorsal forearm, Achilles tendon, sacrum, occiput; also found in lungs, sclera, heart valves
Pathology	Central fibrinoid necrosis surrounded by a palisade of macrophages (epithelioid histiocytes), then an outer zone of chronic inflammatory cells and fibrosis
Clinical significance	Marker of severe, seropositive disease. Can occur in lungs (Caplan's syndrome when combined with pneumoconiosis)

RA affects the lungs in ~10% of patients; most commonly UIP and NSIP patterns ^[9].

Manifestation	Pathophysiology
Interstitial lung disease (ILD)	Most common: UIP (usual interstitial pneumonia) and NSIP (non-specific interstitial pneumonia). Autoimmune-mediated inflammation → fibrosis of lung parenchyma.
Pleural effusion	Rheumatoid pleuritis → exudative effusion (characteristically low glucose, high LDH, high protein, low complement). More common in men.
Rheumatoid nodules (lung)	Can mimic malignancy on CXR. Caplan's syndrome = rheumatoid nodules + pneumoconiosis (coal dust exposure).
Ruptured rheumatoid nodule in the lung → lung collapse ^[10]	Nodule cavitates and ruptures → pneumothorax or bronchopleural fistula
Bronchiolitis obliterans	Rare but serious — small airway disease, obstructive pattern
Bronchiectasis	Increased susceptibility to recurrent infections
Methotrexate pneumonitis ^[10]	Drug-induced hypersensitivity reaction — acute onset dyspnoea, dry cough, fever while on MTX
Pulmonary fibrosis ^[10]	Chronic inflammatory process → progressive fibrosis → restrictive lung disease

Manifestation	Pathophysiology
Accelerated atherosclerosis	Chronic systemic inflammation → endothelial dysfunction → premature coronary artery disease. RA patients have 1.5–2× increased CV mortality.
Pericarditis	Autoimmune pericardial inflammation — often subclinical
Myocarditis	Rare — inflammatory infiltration of myocardium
Valvular disease	Rheumatoid nodules on heart valves → regurgitation
Cardiac amyloidosis ^[10]	Long-standing RA → chronic inflammation → AA amyloidosis → amyloid deposition in heart → restrictive cardiomyopathy

Manifestation	Pathophysiology
Anaemia of chronic disease (ACD)	Most common haematological finding. IL-6 → liver produces hepcidin → hepcidin degrades ferroportin → iron is "trapped" in macrophages → cannot be used for erythropoiesis. Low serum iron, low TIBC (cf. IDA where TIBC is high), low transferrin saturation, but normal/elevated ferritin.
Iron deficiency anaemia (IDA)	From chronic NSAID use → GI bleeding (peptic ulcer, gastritis). Low serum iron, HIGH TIBC, low ferritin.
Combined ACD + IDA	Very common in RA patients on NSAIDs — mixed picture ^[10]
Felty syndrome	RA + splenomegaly + neutropaenia. Mechanism: increased white pulp function (immune-mediated destruction of neutrophils) + splenic sequestration. Associated with severe, long-standing, seropositive RA. Risk of recurrent infections. ^[11]
Thrombocytosis	Reactive thrombocytosis due to IL-6 driving thrombopoiesis — marker of active inflammation
Large granular lymphocyte (LGL) syndrome	Clonal expansion of LGLs → neutropaenia (overlaps with Felty syndrome)

Haematology Interactive Tutorial Case

A 58-year-old woman with RA presents with malaise and SOB. Hb 7.5, MCV 70, WCC 3.5, Plt 410, CRP 8, ESR 70. Serum iron 3, TIBC 75, Transferrin sat 4% ^[10].

This picture shows microcytic anaemia with very low serum iron, high TIBC, and very low transferrin saturation → classic iron deficiency anaemia (IDA). But she also has elevated CRP/ESR (active inflammation). So the cause is likely NSAID-induced GI blood loss (→ IDA) superimposed on anaemia of chronic disease.

Key DDx to consider:

IDA from NSAID-related GI bleeding
Anaemia of chronic disease
Methotrexate-induced bone marrow suppression (would show pancytopaenia)
Felty syndrome (RA + splenomegaly + neutropaenia)

"RA: secondary Sjögren's syndrome, PUK, episcleritis, scleritis, uveitis" ^[12].

Manifestation	Pathophysiology
Secondary Sjögren's syndrome (keratoconjunctivitis sicca)	Most common ocular manifestation of RA. Lymphocytic infiltration of lacrimal glands → reduced tear production → dry eyes (gritty, sandy sensation).
Episcleritis	Inflammation of the episclera — typically mild, self-limiting, bright red eye without pain
Scleritis	Deeper inflammation of the sclera — painful (deep, boring pain), can lead to scleral thinning (scleromalacia perforans). More serious than episcleritis.
Peripheral ulcerative keratitis (PUK) ^[12]	Autoimmune-mediated peripheral corneal thinning → crescent-shaped corneal ulcer ("Mooren's ulcer" if isolated). Immune complex deposition → complement activation → MMP production by keratocytes → corneal breakdown. Can lead to perforation.

Manifestation	Pathophysiology
Carpal tunnel syndrome	Most common neurological manifestation. Synovial hypertrophy at the wrist → compression of the median nerve in the carpal tunnel.
Cervical myelopathy	Atlantoaxial subluxation → spinal cord compression (see above)
Peripheral neuropathy	Vasculitis of vasa nervorum → nerve ischaemia → sensorimotor polyneuropathy or mononeuritis multiplex ^[13]
Entrapment neuropathy	Synovial thickening compresses nerves at various sites

Manifestation	Cause
AA amyloidosis	Long-standing, poorly controlled RA → chronic elevation of serum amyloid A (SAA) protein → deposition as AA amyloid in kidneys → nephrotic syndrome, progressive renal failure
Drug-related nephrotoxicity	NSAIDs (interstitial nephritis, papillary necrosis), gold (membranous nephropathy), D-penicillamine (membranous nephropathy), cyclosporine (nephrotoxicity)
Membranous nephropathy	Can occur as part of RA itself or drug-related (gold, penicillamine)

Manifestation	Detail
Rheumatoid nodules	See above
Vasculitic skin lesions	Nail fold infarcts, digital gangrene, purpura, leg ulcers — indicate systemic vasculitis (rheumatoid vasculitis)
Pyoderma gangrenosum	Rare association
Palmar erythema	Non-specific
Skin fragility/easy bruising	Often iatrogenic — chronic steroid use

Feature	Detail
Osteoporosis	Multifactorial: chronic inflammation (cytokines promote osteoclast activity), immobility (disuse), corticosteroid use
Muscle wasting	Disuse atrophy, TNF-α-mediated catabolism, steroid myopathy
Rheumatoid vasculitis	Severe complication — necrotising vasculitis of small/medium vessels. Manifests as digital ischaemia, skin ulcers, neuropathy, visceral infarction. Almost exclusively in severe, seropositive, nodular RA.
Depression	Chronic pain, disability, fatigue → high prevalence of depression in RA
Increased infection risk	Disease-related immune dysregulation + immunosuppressive therapy

Felty syndrome = RA + splenomegaly + neutropaenia ^[11].

Feature	Detail
Epidemiology	< 1% of RA; almost always seropositive, long-standing, deforming RA
Mechanism	Splenomegaly → increased destruction and sequestration of neutrophils. Also anti-neutrophil antibodies. The spleen's "white pulp" function is increased (immune-mediated neutrophil destruction) ^[11].
Clinical significance	Neutropaenia → recurrent bacterial infections (especially skin and respiratory)
Treatment	Treat the underlying RA aggressively (DMARDs). Splenectomy considered if recurrent severe infections. G-CSF for severe neutropaenia.

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].

Investigation	What It Shows in RA
X-ray	Early: soft tissue swelling, periarticular osteopaenia. Late: marginal erosions, joint space narrowing, subluxation, deformity
Ultrasound (USG)	Can detect subclinical synovitis and tenosynovitis — allows earlier, more aggressive treatment. Also guides joint aspiration. Power Doppler shows increased vascularity = active inflammation.
MRI	Gold standard for early erosions and bone marrow oedema (pre-erosive). Also detects synovitis, tenosynovitis, effusion. More sensitive than X-ray for early disease.

Work-Up for Inflammatory Arthritis — Don't Forget Septic Arthritis!

"Work up ALL inflammatory arthritis as septic arthritis until proven otherwise, even without fever/leukocytosis/CRP or ESR elevation — i.e., you need a synovial fluid analysis" ^[15].

If a patient presents with an acute hot, swollen joint → always aspirate and send synovial fluid for analysis (cell count, crystals, Gram stain, culture) before attributing it to RA flare. A septic joint can destroy cartilage in days. The only exception: if you are very confident of RA (e.g., EULAR classification score ≥ 6 with classic polyarticular pattern) ^[15].

High Yield Summary

Definition: RA = chronic, systemic, autoimmune inflammatory disease → symmetric erosive polyarthritis of peripheral joints → pannus formation → cartilage/bone destruction → deformity.

Epidemiology: 0.3–0.4% in HK; F:M = 3:1; peak 4th–5th decade; commonest AI inflammatory polyarthritis.

Risk Factors: HLA-DR4 (major), smoking (strongest modifiable — interacts with HLA-DR4 via citrullination), P. gingivalis, EBV, nulliparity, family history (3× risk in 1st degree relatives).

Pathogenesis: Gene-environment interaction → citrullination → anti-CCP/RF → immune complex deposition → synovitis → pannus → erosion → deformity. TNF-α is the master cytokine.

Joint Pattern: Symmetric, MCP/PIP/wrist/MTP, spares DIP, spares axial (except C1/2), morning stiffness > 1 hour, additive pattern.

Key Deformities: Boutonnière (flexed PIP/hyperextended DIP), Swan neck (hyperextended PIP/flexed DIP), Z-thumb, ulnar deviation, volar subluxation, cock-up toe, atlantoaxial subluxation.

Extra-Articular: Rheumatoid nodules, ILD (UIP/NSIP), Felty syndrome (RA + splenomegaly + neutropaenia), 2° Sjögren's, scleritis/PUK, carpal tunnel, vasculitis, AA amyloidosis, anaemia (ACD ± IDA from NSAIDs), accelerated atherosclerosis.

Autoantibodies: RF (sensitive, not specific) and anti-CCP (sensitive AND highly specific, > 95%). Both positive = high predictive value for RA and erosive disease.

Anti-TNF and TB: Screen for latent TB (IGRA/TST) before starting anti-TNF biologics; isoniazid prophylaxis × 3 months if latent TB.

Active Recall - Rheumatoid Arthritis (Definition, Epidemiology, Risk Factors, Pathophysiology, Clinical Features)

Differential Diagnosis of Rheumatoid Arthritis

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

Differential	Key Discerning Features from RA	Why It Can Mimic RA	How to Distinguish
Osteoarthritis (OA)	Non-inflammatory; DIP/PIP/1st CMC/weight-bearing; hard bony swelling; < 30 min stiffness; worsens with use	Can be symmetric polyarticular (generalised OA); PIP involvement overlaps	DIP involved (Heberden's nodes), hard bony enlargement (not boggy), evening stiffness, RF/anti-CCP negative, XR shows osteophytes not erosions ^[3]^[17]
Psoriatic arthritis (PsA)	Usually asymmetric oligo/polyarthritis; DIP involvement; dactylitis; enthesitis; nail changes	Can present as symmetric polyarthritis mimicking RA (one of 5 PsA patterns)	Psoriasis skin/nail changes, DIP involvement, dactylitis ("sausage digits"), seronegative (RF/anti-CCP usually negative), pencil-in-cup erosions on XR ^[3]^[17]^[18]
SLE-associated arthritis	Non-erosive, non-deforming (or Jaccoud's = reducible); migratory; morning stiffness minutes not hours	Symmetric small joint polyarthritis	Reducible deformities, no erosions on XR, synovial fluid = transudate, ANA/anti-dsDNA positive, multi-system involvement (malar rash, nephritis, serositis) ^[3]^[8]^[19]
Viral polyarthritis	Self-limiting ( < 6 weeks); symmetric small joints; preceded by viral prodrome	Pattern can look exactly like early RA	Duration < 6 weeks (RA by definition ≥ 6 weeks), viral serology positive (HBV, HCV, parvovirus B19, EBV, rubella, Dengue, HIV), resolves spontaneously ^[3]^[16]
Gout / Pseudogout	Acute monoarthritis typically (1st MTP for gout); can become chronic polyarticular	Chronic polyarticular gout or pseudogout (CPPD) can mimic RA	Crystals on synovial fluid microscopy (MSU = needle-shaped, negatively birefringent; CPPD = rhomboid, weakly positively birefringent), tophi, punched-out erosions ^[3]^[16]^[20]
Reactive arthritis	Asymmetric large joint oligoarthritis (LL > UL); post-infectious	Can present with polyarthritis	History of preceding GI or GU infection, "can't see, can't pee, can't climb a tree" triad (conjunctivitis, urethritis, arthritis), keratoderma blennorrhagica, HLA-B27+ ^[16]^[21]
Ankylosing spondylitis (AS)	Predominantly axial (sacroiliitis, spondylitis); young male	Can have peripheral arthritis	Inflammatory back pain, sacroiliitis on imaging, HLA-B27+, bamboo spine, enthesitis ^[17]
IBD-associated arthritis	Asymmetric large joint LL arthritis; tracks with bowel flares (Type 1)	Polyarthritis can occur	GI symptoms (bloody diarrhoea, abdominal pain), endoscopy confirms IBD ^[16]^[21]
Septic arthritis	Usually acute monoarthritis; high fever; very hot/swollen joint	Polyarticular in ~20% (especially in immunocompromised or pre-existing RA)	Joint aspiration is mandatory: WBC > 50,000, > 90% neutrophils, positive Gram stain/culture. Hot swollen joint = septic until proven otherwise ^[15]^[22]
Systemic sclerosis (SSc)	Raynaud's, skin thickening, GERD, ILD	Polyarthralgia/arthritis can occur	Raynaud's + GERD = think SSc, sclerodactyly, anti-Scl-70 or anti-centromere antibodies ^[8]^[19]
Sjögren's syndrome	Dry eyes + dry mouth; can have polyarthritis	Symmetric polyarthritis	Keratoconjunctivitis sicca + xerostomia, anti-Ro/SSA and anti-La/SSB, Schirmer test ^[8]^[19]
Dermatomyositis/Polymyositis	Proximal muscle weakness predominates	Arthralgia/arthritis present in ~30%	Proximal weakness, elevated CK, Gottron's papules, heliotrope rash, anti-Jo1/anti-MDA5 ^[8]^[19]
Polymyalgia rheumatica (PMR)	Bilateral shoulder + pelvic girdle pain/stiffness; no true synovitis	Symmetrical stiffness in elderly; very high ESR	Age > 50, dramatic response to low-dose prednisolone (15–20 mg), exclude GCA (temporal artery tenderness), no small joint synovitis ^[16]^[23]
Adult-onset Still's disease (AOSD)	Quotidian spiking fever, evanescent salmon-pink rash, serositis, lymphadenopathy	Can have polyarthritis	Ferritin markedly elevated, leucocytosis, liver dysfunction, RF/ANA usually negative, diagnosis of exclusion ^[16]
Rheumatic fever	Migratory polyarthritis; preceded by Strep pharyngitis	Acute polyarthritis in young	Jones criteria, evidence of preceding GAS infection (ASO titre), carditis, erythema marginatum ^[16]
Bacterial endocarditis	Polyarthralgia/arthritis; fever; new murmur	Immune complex-mediated arthritis	Blood cultures positive, vegetations on echocardiogram, Osler's nodes, Janeway lesions ^[16]
Malignancy	Paraneoplastic polyarthritis, hypertrophic pulmonary osteoarthropathy (HPOA)	Can mimic RA	Clubbing + periostitis (HPOA), rapid onset, doesn't respond to DMARDs, search for underlying malignancy ^[16]

9.3 The "Big Five" DDx to Know Cold

For exams, these five conditions represent the most commonly tested differential diagnoses of RA:

Why it mimics RA: OA can be polyarticular and symmetric (generalised nodal OA), involving PIPs just like RA.

Why it's NOT RA:

Feature	OA	RA
Primary joints	DIP (Heberden's) + PIP (Bouchard's)	PIP + MCP
Joint characteristics	Hard and bony	Soft, warm, tender (boggy)
Stiffness	Evening stiffness; worsens after effort	Early morning stiffness; worsens after resting
Heberden's nodes	Present	Absent
RF / Anti-CCP	Negative	Positive
ESR / CRP	Normal	Elevated
Radiological findings	Joint space narrowing + osteophytes	Erosions of bone and cartilage

^[3]^[17]

Pathophysiological explanation: OA is primarily a disease of cartilage degradation (mechanical wear + imbalanced remodelling), not immune-mediated synovial inflammation. The bony enlargements (osteophytes) are the body's attempt to stabilise an unstable joint by increasing surface area — fundamentally different from the erosive destruction of RA.

Why it mimics RA: SLE causes symmetric small joint polyarthritis — looks like RA on first glance.

Why it's NOT RA: The table below is extremely high-yield ^[3]^[8]^[19]:

Feature	SLE	RA
Myalgia	Common	Myositis rare
Symmetry	Yes	Yes
Joints involved	PIP > MCP > Wrist > Knee	MCP > Wrist > Knee
Morning stiffness	Minutes	Hours
Synovial membrane	Minimal abnormality	Proliferative
Synovial fluid	Transudate	Exudate
Synovial hypertrophy	Rare	Common
Subcutaneous nodules	Rare	Common
Erosions	Rare	Common
Deforming arthritis	Rare	Common
Swan neck deformities	Rare (reducible)	Common (not reducible)
Ulnar deviation	Rare (reducible)	Common (not reducible)
Osteoporosis	Variable	Common
Avascular necrosis	Common	Rare

Key pathophysiological distinction: In SLE, the arthritis is mediated by immune complex deposition in the joint but does not produce destructive pannus. Hence it is characteristically non-erosive. When deformities do occur in SLE (Jaccoud's arthropathy), they are reducible (passively correctable) because the tendons and capsule are lax, not destroyed — think of it as ligamentous laxity rather than structural erosion.

Overlap syndrome ("Rhupus"): Some patients have features of BOTH RA and SLE — erosive deforming polyarthritis with anti-CCP positive, subsequently developing lupus nephritis ^[14]. This is a distinct entity from MCTD.

Condition	Key Distinguishing Feature
Polymyalgia rheumatica (PMR)	Age > 50, bilateral shoulder + hip girdle pain/stiffness, dramatically elevated ESR ( > 40), dramatic response to 15–20 mg prednisolone. No true small joint synovitis — if MCPs/PIPs are inflamed, reconsider RA. Always consider co-existing GCA (headache, jaw claudication, visual symptoms). ^[23]
Adult-onset Still's disease (AOSD)	Systemic onset JIA equivalent in adults: quotidian spiking fever (spikes to ≥ 39°C daily, returns to normal), evanescent salmon-pink macular rash, polyarthritis, lymphadenopathy, serositis, markedly elevated ferritin ( > 1000), leucocytosis. RF/ANA usually negative. Diagnosis of exclusion — infection and leukaemia are major differential diagnoses ^[24].
Rheumatic fever	Post-streptococcal (GAS pharyngitis), migratory polyarthritis (not additive like RA), Jones criteria, carditis. Usually in children/young adults.
Bacterial endocarditis	Immune complex-mediated polyarthralgia/arthritis + fever + new murmur + embolic phenomena. Blood cultures essential.
Haemochromatosis	2nd–3rd MCP arthropathy ("iron fist" sign) — can mimic RA. Look for hepatomegaly, bronze skin, diabetes. Raised ferritin, transferrin sat > 45%.
Sarcoidosis	Acute polyarthritis (Löfgren's syndrome: bilateral hilar lymphadenopathy + erythema nodosum + polyarthritis + fever). Usually self-limiting.
Hypertrophic pulmonary osteoarthropathy (HPOA)	Clubbing + painful wrists/ankles + periostitis on XR. Paraneoplastic — look for lung malignancy.
Palindromic rheumatism	Recurrent self-limiting attacks of acute monoarthritis/polyarthritis (hours to days) with complete resolution between attacks. ~50% progress to RA. Anti-CCP+ predicts conversion to RA.

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

Parameter	Normal	Non-inflammatory	Inflammatory	Septic
Clarity	Transparent	Transparent	Translucent	Opaque
WBC/mL	< 200	< 2,000	2,000–100,000	50,000–300,000
% Neutrophils	< 25%	< 25%	25–75%	> 90%
Crystal microscopy	None	None	Possible (gout, CPPD)	None (unless coexists)
Gram stain/Culture	Negative	Negative	Negative	Positive

^[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.

High Yield — Septic Arthritis in RA Patients

RA patients are at increased risk of septic arthritis (damaged joints, immunosuppressive therapy). A sudden flare of a single joint in RA must be aspirated and sent for Gram stain/culture — do not assume it is just a flare ^[15]^[22].

Condition	RF	Anti-CCP	ANA	HLA Association	Other Antibodies
RA	+ (70–80%)	+ (70%, > 95% specific)	± (low titre in ~30%)	HLA-DR4	—
SLE	± (~20%)	Rare	+ (≥ 95%)	HLA-DR2/DR3	Anti-dsDNA, anti-Sm
PsA	Usually –	Usually –	–	HLA-B27 (~20%)	—
AS	–	–	–	HLA-B27 (~90%)	—
Sjögren's	+ (~75%)	Rare	+ (~80%)	—	Anti-Ro/SSA, Anti-La/SSB
SSc	±	Rare	+	—	Anti-Scl-70, anti-centromere
DM/PM	–	–	±	—	Anti-Jo1, anti-MDA5
Reactive arthritis	–	–	–	HLA-B27 (~60–80%)	—

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]:

Feature	Seropositive	Seronegative (SpA)
Demographics	F > M	M > F
Peripheral arthritis	Symmetrical, peripheral small joints (PIP, MCP)	Asymmetrical, peripheral + axial joints
Extra-articular	Raynaud's phenomenon	Acute anterior uveitis, GI symptoms (IBD), GU symptoms (reactive arthritis), psoriasis (PsA)
RF	Positive	Negative
HLA-B27	Negative	Positive

^[16]

High Yield Summary — Differential Diagnosis of RA

Common DDx of chronic symmetric polyarthritis: RA, SLE, viral polyarthritis, OA, PsA (symmetric pattern).

Key distinctions:

OA: DIP, hard bony, evening stiffness, XR shows osteophytes, seronegative
PsA: DIP involved, dactylitis, nail changes, asymmetric (usually), seronegative
SLE: Non-erosive, reducible deformities, morning stiffness minutes, transudate SFA, ANA+
Viral: Self-limiting < 6 weeks, preceded by viral prodrome, positive viral serology
Crystal: Crystals on SFA microscopy; gout = needle, negatively birefringent; CPPD = rhomboid, weakly positive
Septic: WBC > 50k, > 90% PMN, positive Gram stain/culture — always rule out in any acute hot joint
Seropositive vs Seronegative (SpA): Symmetric/F > M/RF+ vs Asymmetric/M > F/HLA-B27+
PMR: Age > 50, shoulder+hip girdle, no small joint synovitis, dramatic steroid response
AOSD: Quotidian fever, salmon rash, markedly elevated ferritin, diagnosis of exclusion

The 6-week rule: The 2010 ACR/EULAR criteria require ≥ 6 weeks of symptoms — this critical threshold excludes most viral polyarthritis.

Always aspirate an acutely inflamed joint to exclude septic arthritis and crystal disease — even in a known RA patient.

Active Recall - Differential Diagnosis of RA

References

^[3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (RA differential diagnosis section, p.1677–1679; OA section p.1667) ^[8] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (SLE vs RA comparison table, p.712) ^[14] Senior notes: Block A - Syncope and irregular heartbeat_ Cardiac arrhythmia; Heart blocks, Bradycardia.pdf (p.30 — overlap syndrome / Rhupus) ^[15] Senior notes: Block A - Painful red joint_ monoarthropathy, gouty arthritis, septic arthritis, haemarthrosis.pdf (p.7) ^[16] Senior notes: Ryan Ho Rheumatology.pdf (Approach to Polyarthritis, p.30–31; DDx table); Ryan Ho Fundamentals.pdf (p.408–409) ^[17] Lecture slides: GC 074. Multiple joint pain.pdf (p.4 — Clinical features of different arthritis; p.18 — Features of RA) ^[18] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Psoriatic arthritis DDx, p.1708–1710) ^[19] Senior notes: Block A - Fingers turn white and blue_ Scleroderma and MCTD, Raynaud's disease, other rheumatic diseases.pdf (p.1) ^[20] Senior notes: Ryan Ho Rheumatology.pdf (Crystal microscopy and synovial fluid, p.30) ^[21] Senior notes: Maksim Medicine Notes.pdf (Reactive arthritis, p.328; IBD-associated arthritis, p.328) ^[22] Senior notes: Adrian Lui Pediatrics Notes.pdf (Septic arthritis, p.453) ^[23] Senior notes: Block A - Rheumatology Interactive Tutorial.pdf (PMR/GCA case, p.2) ^[24] Lecture slides: GC 053. Fingers turn white and blue.pdf (p.65 — Systemic onset JIA)

Diagnostic Criteria, Diagnostic Algorithm, and Investigations for Rheumatoid Arthritis

"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].

#	Feature	Description
1	Morning stiffness	Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement ^[3]^[4]
2	Arthritis of ≥ 3 joint areas	≥ 3 of 14 possible joint areas simultaneously have soft tissue swelling or fluid (not bony outgrowth alone). The 14 areas: R or L PIP, MCP, wrist, elbow, knee, ankle, MTP ^[3]
3	Arthritis of hand joints	At least 1 area swollen in a wrist, MCP, or PIP joint ^[3]
4	Symmetric arthritis	Simultaneous involvement of same joint areas on both sides of body ^[3]
5	Rheumatoid nodules	Subcutaneous nodules over bony prominences or extensor surfaces or in juxta-articular regions ^[3]^[4]
6	Serum rheumatoid factor	Abnormal amount of serum rheumatoid factor (IgM) ^[3]^[4]
7	Radiographic changes	Radiographic changes typical of RA on PA hand or wrist radiograph — must include erosions or unequivocal bony decalcification localised in or most marked adjacent to involved joints (OA changes alone do not qualify) ^[3]

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:

Domain	Category	Points
A. Joint involvement	1 large joint	0
	2–10 large joints	1
	1–3 small joints (± large joints)	2
	4–10 small joints (± large joints)	3
	> 10 joints with at least 1 small joint	5
B. Serology	RF− AND ACPA−	0
	Low-positive RF OR low-positive ACPA	2
	High-positive RF OR high-positive ACPA	3
C. Acute phase reactants	Normal CRP AND normal ESR	0
	Abnormal CRP OR abnormal ESR	1
D. Duration of symptoms	< 6 weeks	0
	≥ 6 weeks	1

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].

High Yield — Understanding the 2010 Criteria Point System

Why small joints score more than large joints: RA has a predilection for small joints (MCP, PIP, MTP). Large joint involvement alone could be many things (OA, septic, reactive), but polyarticular small joint involvement is much more specific for RA.

Why high-positive serology scores 3 instead of 2: Higher titres of RF/anti-CCP have stronger predictive value for RA. A weakly positive RF in an elderly person may be a false positive; a strongly positive anti-CCP is very convincing.

Why ≥ 6 weeks is required: This criterion exists specifically to exclude viral polyarthritis, which typically resolves within 6 weeks.

Joint definitions:

Large joints: shoulders, elbows, hips, knees, ankles
Small joints: MCP, PIP, 2nd–5th MTP, thumb IP, wrists
Excluded from scoring: DIP, 1st CMC, 1st MTP (because these are typical OA joints)

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.

Feature	1987 ACR	2010 ACR/EULAR
Purpose	Classify established RA	Classify early RA
Threshold	≥ 4 of 7 features	≥ 6 of 10 points
Duration requirement	Criteria 1–4 must be present > 6 weeks	≥ 6 weeks scores 1 extra point
Anti-CCP included?	No (discovered after 1987)	Yes (key component)
Erosions required?	Required for criterion 7	Not required (but sufficient alone)
Rheumatoid nodules?	Included as criterion 5	Not included
Sensitivity	Lower for early RA	Higher for early RA (82%)
Specificity	Higher for established RA	Lower (61%) — trade-off for early detection

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:

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

DAS28-ESR Score	Interpretation
< 2.6	Remission
2.6–3.2	Low disease activity
3.2–5.1	Moderate disease activity
> 5.1	High disease activity

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

10.7 Investigations — Complete Workup

"Bloods: Baseline: CBC, LRFT, HBsAg, anti-HCV, G6PD" ^[1].

Investigation	What to Look For	Why
CBC	Normocytic anaemia (ACD); microcytic anaemia (IDA from NSAIDs); thrombocytosis (reactive); leucopaenia (Felty's)	Anaemia is very common in RA. Thrombocytosis = active inflammation (IL-6 drives thrombopoiesis). Leucopaenia → think Felty's syndrome or drug toxicity.
LFT	Baseline before starting hepatotoxic drugs (MTX, leflunomide)	Methotrexate is hepatotoxic — need baseline and regular monitoring
RFT	Baseline renal function	NSAIDs are nephrotoxic; some DMARDs need dose adjustment in renal impairment
HBsAg, anti-HCV	Screen for hepatitis B and C	Before starting immunosuppression — risk of viral reactivation (especially HBV on rituximab, MTX, steroids). Extremely important in Hong Kong where HBV prevalence is ~7–8%.
G6PD	Screen for G6PD deficiency	Before starting sulfasalazine or dapsone — these drugs cause oxidative haemolysis in G6PD-deficient patients. Relevant in HK where G6PD deficiency prevalence is ~4–5% in males.

High Yield — Pre-Treatment Screening

HBsAg, anti-HCV, and G6PD are mandatory baseline investigations before starting DMARDs ^[1]. This is commonly tested in SAQs. Missing HBsAg screening before starting immunosuppression could lead to fatal HBV reactivation.

"Acute phase reactants: CRP, ESR" ^[1]^[17].

Marker	Interpretation in RA
CRP (C-reactive protein)	Direct marker of acute inflammation, produced by the liver in response to IL-6. Rises quickly (hours) and falls quickly with treatment. Better for monitoring disease activity.
ESR (erythrocyte sedimentation rate)	Indirect marker — elevated by fibrinogen, immunoglobulins. Rises slowly and falls slowly. Also elevated by anaemia, age, obesity (less specific than CRP). Used in DAS28-ESR.
Interpretation	Both are elevated in active RA. Abnormal CRP or ESR scores 1 point in the 2010 ACR/EULAR criteria. Normal inflammatory markers do NOT exclude RA (some patients have "seronegative, CRP-normal" RA).

"Serology: RF (70%), Anti-CCP (50–75%)" ^[1].

Test	Target	Sensitivity	Specificity	Clinical Significance
Rheumatoid Factor (RF)	IgM autoantibody against the Fc fragment of IgG	~70–80%	~80%	Present in ~70% of RA. False positives: normal population (~4%, up to 25% in elderly), other CTD (SLE, Sjögren's, cryoglobulinaemia), SBE, TB ^[1]. Not for monitoring — titre does not correlate with activity.
Anti-CCP (ACPA)	Anti-citrullinated protein antibodies	~50–75%	~96%	Similar sensitivity but much more specific (96%) ^[1]. Predicts erosive disease and more aggressive course. Can be positive years before symptoms.

"Role of serology in RA: Diagnostic and prognostic value (seropositive = more aggressive joint disease, increased extra-articular manifestations, increased radiographic progression). NOT for disease monitoring (titre does not correlate with activity)" ^[1].

High Yield — Interpreting Serology

RF	Anti-CCP	Interpretation
+	+	Very high probability of RA; predicts erosive disease
+	−	May be RA, but consider false positive RF (elderly, chronic infection, other CTD)
−	+	Strongly supports RA diagnosis (anti-CCP is very specific)
−	−	Seronegative RA (~20–30%) — still possible but consider DDx more carefully (PsA, SpA)

Test	Purpose
ANA	Screen for SLE, Sjögren's, other CTD. Low-titre ANA can be positive in ~30% of RA (non-specific).
Anti-dsDNA, C3/C4	If SLE suspected
HLA-B27	If spondyloarthritis suspected
Serum urate	If gout suspected (check 2 weeks after acute flare resolution)
Viral serology	HBV, HCV, parvovirus B19, EBV — if acute polyarthritis < 6 weeks

"Also take RF and anti-CCP → just to show that it's negative, diagnosis by exclusion" ^[23] — this was stated in the Rheumatology Interactive Tutorial for PMR, emphasising that RF/anti-CCP are sent even when RA is NOT the suspected diagnosis, to definitively exclude it.

"Joint fluid analysis: MOST IMPORTANT TEST" (for monoarthritis) ^[16].

Parameter	RA Finding	Significance
Appearance	Cloudy/translucent, yellow	Inflammatory exudate
Viscosity	Low	Hyaluronidase in inflammatory fluid degrades hyaluronic acid → loses viscosity (cf. normal/OA where viscosity is high)
WBC count	2,000–50,000/mm³	Inflammatory range
Neutrophils	50–70%	Neutrophil-predominant (but less so than septic, where > 90%)
Crystals	Absent	Rules out gout/pseudogout
Gram stain/culture	Negative	Rules out septic arthritis

When to aspirate: Any time there is diagnostic uncertainty, especially in acute monoarthritis or an acute flare in a single joint in a known RA patient (to exclude superimposed septic arthritis or crystal disease) ^[15].

RA pleural effusion has characteristic features: low glucose ( < 0.5× serum or ≤ 3.33 mmol/L), low pH ( < 7.30), high LDH ( > 1000 IU/L) ^[26].

F. Imaging

"Disease damages: X-rays, CT. Disease activities: Ultrasound assessment, MRI assessment" ^[17].

Radiological features in chronological order of development ^[20]:

Stage	X-ray Finding	Pathophysiological Basis
1 (Earliest)	Soft tissue swelling and widened joint space	Synovial inflammation → effusion → distension of joint capsule
2	Juxta-articular (periarticular) osteopaenia	Hyperaemia and disuse → increased osteoclast activity in bone adjacent to inflamed joint ^[20]
3	Joint space narrowing	Cartilage destruction by pannus — loss of articular cartilage = loss of joint space ^[20]
4	Periarticular (marginal) erosions	Pannus destruction of unprotected bone at insertion of joint capsule — the "bare area" where synovium meets bone without cartilage covering ^[20]
5 (Late)	Subluxation, deformity, ankylosis	End-stage joint destruction with secondary OA changes

Standard views: PA X-ray of both hands and wrists; PA X-ray of both feet. Lateral cervical spine in flexion (if C-spine disease suspected).

"Radiographic changes typical of RA on posteroanterior hand or wrist radiograph — must include erosions or unequivocal bony decalcification localised in or most marked adjacent to the involved joints (OA changes alone do not qualify)" ^[3]^[4].

Key X-ray Distinction: RA vs OA vs PsA

Feature	RA	OA	PsA
Joint space	Uniform narrowing	Non-uniform narrowing	Variable
Erosions	Marginal, periarticular	Absent (subchondral cysts instead)	Marginal + "pencil-in-cup"
Osteophytes	Absent	Present (hallmark)	Absent/rare
Periarticular osteopaenia	Present	Absent (subchondral sclerosis instead)	May be present
New bone formation	Absent	Osteophytes	Periostitis, ankylosis
Distribution	MCP/PIP/wrist (symmetric)	DIP/PIP/1st CMC/knee (may be symmetric)	DIP/asymmetric

"USG: for detection of synovitis (when unsure diagnosis), diagnosis of Baker's cyst" ^[20].

Feature	Detail
Synovitis	Grey-scale shows thickened hypoechoic synovium; Power Doppler shows increased vascularity = active inflammation
Tenosynovitis	Fluid/thickening around tendons within tendon sheaths
Erosions	Can detect small erosions earlier than X-ray — cortical breaks visible on ultrasound before they become apparent on plain film
Effusion	Anechoic/hypoechoic fluid within joint
Subclinical disease	Can detect subclinical inflammation — allows more aggressive early treatment even when physical exam is equivocal
Baker's cyst	Posterior knee cyst (popliteal cyst) — common in RA, can rupture and mimic DVT
Guided aspiration	Real-time guidance for joint aspiration/injection

Advantages over X-ray: No radiation, real-time, detects soft tissue changes (synovitis, tenosynovitis) not visible on X-ray, more sensitive for early erosions. Limitation: operator-dependent, cannot assess deep structures as well as MRI.

"MRI: for detection of synovitis and cervical spine compression in AA joint disease" ^[20].

Feature	Detail
Synovitis	Post-gadolinium enhancement of thickened synovium (most sensitive imaging modality for synovitis)
Bone marrow oedema (BMO)	Pre-erosive change — predicts future erosion development. T2/STIR hyperintensity in subchondral bone. If you see BMO, erosions are likely coming.
Erosions	Earlier detection than X-ray — MRI can show cortical breaks before they are visible on plain film
Tenosynovitis	Fluid/enhancement within tendon sheaths
Atlantoaxial subluxation	Assessment of C1/C2 instability and spinal cord compression — mandatory before GA/intubation
Cervical myelopathy	Signal change in spinal cord (T2 hyperintensity)

When is MRI indicated?

Diagnostic uncertainty (early undifferentiated arthritis)
Assessment of atlantoaxial disease before surgery
Monitoring treatment response in clinical trials
Suspicion of complications (cervical myelopathy, tendon rupture)

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

Category	Investigations
Baseline bloods	CBC, LRFT, HBsAg, anti-HCV, G6PD ^[1]
Inflammatory markers	CRP, ESR
Serology	RF, anti-CCP
Additional serologies (if DDx)	ANA, anti-dsDNA, C3/C4, HLA-B27, serum urate, viral serology
Urinalysis	Proteinuria (amyloidosis, drug toxicity)
Imaging	XR hands/feet (PA), ± MSUS, ± MRI
Synovial fluid analysis (if indicated)	Cell count, crystals, Gram stain, C/ST, AFB smear/culture
Additional (for complications)	HRCT chest (ILD), CXR (nodules, effusion), echocardiography, lateral C-spine in flexion
Pre-biologic screening	Latent TB (IGRA/TST), HBsAg/anti-HBs/anti-HBc, anti-HCV, CXR

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:

Hb 7.5, MCV 70 → microcytic anaemia
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.
CRP 8, ESR 70 → active systemic inflammation
Platelet 410 (high) → reactive thrombocytosis (IL-6 driven)
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.

High Yield Summary — Diagnosis of RA

Two sets of criteria:

1987 ACR: ≥ 4 of 7 features, criteria 1–4 present > 6 weeks. Includes nodules and erosions (late features). Mnemonic: RAS.
2010 ACR/EULAR: ≥ 6 of 10 points. Domains: Joint involvement (0–5), Serology (0–3), Acute phase reactants (0–1), Duration (0–1). Designed for early RA. Entry: ≥ 1 joint with clinical synovitis not explained by another disease. Typical erosions = automatic classification.

Key investigations:

Baseline: CBC, LRFT, HBsAg, anti-HCV, G6PD (SAQ favourite)
Inflammatory markers: CRP, ESR (for scoring and monitoring)
Serology: RF + anti-CCP (diagnostic and prognostic, NOT for monitoring)
Imaging: X-ray hands/feet (soft tissue swelling → periarticular osteopaenia → joint space narrowing → marginal erosions → subluxation/deformity)
MSUS: detects subclinical synovitis and early erosions; Power Doppler = active inflammation
MRI: bone marrow oedema (pre-erosive), C-spine assessment
Synovial fluid: inflammatory exudate, no crystals, no organisms

Disease activity: DAS28 (tender + swollen joints, ESR/CRP, patient global assessment). Remission < 2.6.

Active Recall - Diagnostic Criteria, Algorithm and Investigations for RA

References

^[1] Senior notes: Maksim Medicine Notes.pdf (Section 13.4 Rheumatoid arthritis, p.312) ^[3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (RA diagnosis section, p.1678–1680; septic arthritis SFA table p.1689) ^[4] Lecture slides: Upper Limb Painful Conditions_Dr. Margaret Woon Man FOK_3. Inflammatory conditions.pdf (p.6 — 1987 ARA criteria) ^[10] Senior notes: Block A - Hematology Interactive Tutorial.pdf (RA anaemia case, p.2) ^[15] Senior notes: Block A - Painful red joint_ monoarthropathy, gouty arthritis, septic arthritis, haemarthrosis.pdf (p.7) ^[16] Senior notes: Ryan Ho Fundamentals.pdf (p.407–410 — approach to monoarthritis and polyarthritis, investigations, synovial fluid) ^[17] Lecture slides: GC 074. Multiple joint pain.pdf (p.4 — clinical features; p.18 — features of RA; p.21 — 2010 ACR/EULAR criteria) ^[20] Senior notes: Ryan Ho Rheumatology.pdf (p.51 — 1987 ACR criteria, 2010 ACR/EULAR criteria, radiological features, DAS28) ^[23] Senior notes: Block A - Rheumatology Interactive Tutorial.pdf (p.2 — sending RF/anti-CCP to exclude RA) ^[25] Lecture slides: Upper Limb Painful Conditions_Dr. Margaret Woon Man FOK_3. Inflammatory conditions.pdf (p.6) ^[26] Senior notes: Ryan Ho Respiratory.pdf (p.25 — pleural effusion in RA: low glucose, low pH, high LDH) ^[27] Lecture slides: GC_Interactive tutorial (Haem case 1) student copy.pdf (p.2)

Management of Rheumatoid Arthritis

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

Modality	Detail	Rationale
Patient education and counselling	Disease nature, drug compliance, pregnancy planning, fertility issues, expectations	Poor compliance is a major risk factor for poor prognosis ^[20]. Patients must understand that DMARDs take weeks to work and that stopping them leads to flare.
Exercise and physiotherapy	ROM exercises, strengthening, aerobic conditioning	Maintain joint mobility, prevent contractures, reduce muscle wasting. Must be gentle during flares.
Occupational therapy	Joint protection techniques, splinting, assistive devices, workplace modifications	Reduce stress on inflamed joints. Resting splints can reduce pain and prevent deformity.
Podiatry	Orthotics, cushioned footwear	Offload pressure from MTP joints (cock-up toes, metatarsal head callosities)
Smoking cessation	Strongest modifiable risk factor	Smoking worsens disease activity, accelerates erosions, reduces DMARD efficacy ^[20]
Cardiovascular risk optimisation	Lipid management, BP control, diabetes screening	RA is an independent CV risk factor (1.5–2× increased CV mortality from accelerated atherosclerosis)
Immunisation	Influenza (annual), pneumococcal, COVID-19, shingles vaccine (recombinant)	Immunosuppression from DMARDs/biologics increases infection risk. Live vaccines contraindicated on immunosuppression (e.g., live shingles, BCG, oral polio).
Occupation modification	Ergonomic adjustments	Reduce repetitive joint stress

Overview of Drug Categories

Category	Examples	Key Feature
Symptomatic relief	Analgesics, NSAIDs	Pain control only — do NOT modify disease course
Glucocorticoids	Prednisolone, methylprednisolone	Rapid anti-inflammatory — bridging while DMARDs take effect
Conventional synthetic DMARDs (csDMARDs)	Methotrexate (anchor), hydroxychloroquine, sulfasalazine, leflunomide	Modify disease course — slow or halt progression
Biological DMARDs (bDMARDs)	Anti-TNF, anti-IL-6, anti-CTLA4, anti-CD20	Target specific cytokines/cells — for refractory disease
Targeted synthetic DMARDs (tsDMARDs)	JAK inhibitors (tofacitinib, baricitinib, upadacitinib)	Small molecule inhibitors — oral alternative to biologics

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

Drug	Mechanism	Role in RA	Cautions
Paracetamol	Central COX inhibition + serotonergic pathways (exact MOA debated)	Simple analgesia, first-line for pain	Hepatotoxicity in overdose; limited efficacy in inflammatory pain
NSAIDs (non-selective) e.g., naproxen, ibuprofen, diclofenac	Inhibit COX-1 and COX-2 → reduce prostaglandin synthesis → anti-inflammatory + analgesic + antipyretic	Initial treatment to curb joint inflammation while awaiting action of DMARDs ^[20]	GI bleeding (COX-1 inhibition reduces gastric PG → mucosal damage), renal vasoconstriction, CV risk
COX-2 selective inhibitors e.g., celecoxib, etoricoxib	Selectively inhibit COX-2 (the inducible isoform at sites of inflammation) → preserve COX-1 (constitutive gastroprotective PG)	Preferred if GI risk factors; similar efficacy to non-selective NSAIDs	Still have CV risk (COX-2 in vascular endothelium produces prostacyclin → selective inhibition tips balance towards thromboxane → prothrombotic)

STOPP Criteria — Inappropriate Prescribing

The STOPP/START criteria (Screening Tool of Older Persons' Prescriptions) explicitly flag ^[29]:

"NSAID with concurrent corticosteroids for treatment of arthritis/rheumatism of any kind — increased risk of peptic ulcer disease"
"Long-term corticosteroids (> 3 months) as monotherapy for RA — risk of systemic corticosteroid side effects"

These are prescribing pitfalls to avoid — never use long-term steroids alone as the sole therapy for RA, and never combine NSAIDs with systemic steroids without gastroprotection.

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].

Aspect	Detail
Rationale	DMARDs (especially MTX) take ~6–12 weeks to reach full effect. Steroids provide rapid symptom relief during this "lag" period.
Dosing	Low-dose oral prednisolone (≤ 7.5–10 mg/day); taper rapidly once DMARD effect sets in
Flare management	Short courses ( < 1 month) very effective; IM injection can be used for systemic flares ^[20]
Intra-articular steroids	Useful for mono/oligoarticular flares — e.g., triamcinolone injection into a single inflamed knee ^[20]
Long-term use	Should be avoided ^[20]. S/E at > 10 mg/d: osteoporosis, DM, Cushingoid features, infections, cataracts, adrenal suppression, growth restriction (children)
IA steroid risks	Tendon rupture, osteonecrosis, acute synovitis (crystal flare from suspension), septic arthritis, systemic effects ^[20]

"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].

11.8 Conventional Synthetic DMARDs (csDMARDs) — Individual Agents

"Methotrexate: anchor drug for rheumatoid arthritis" ^[28].

Aspect	Detail
Full name	Methotrexate — "metho" (methyl), "trex" (related to pteridine/folic acid), "-ate" = folate antagonist
Mechanism	Inhibits dihydrofolate reductase (DHFR) → blocks purine and pyrimidine synthesis → inhibits rapidly dividing immune cells (T and B cells). At the low doses used in RA, the primary mechanism is actually adenosine-mediated anti-inflammatory effect — MTX increases extracellular adenosine, which suppresses inflammation via A2A receptors.
Dosing	Common dose 7.5–15 mg/week ^[28] (can go up to 25 mg/week). Given once weekly — NOT daily (daily dosing is a potentially fatal error causing pancytopaenia). Oral, SC, or IM.
Onset of action	~4–8 weeks
Efficacy	~70% effective; most patients achieve significant improvement ^[22]
Folic acid supplementation	5 mg folic acid on the day AFTER MTX (or on non-MTX days) to reduce S/E (stomatitis, nausea, myelosuppression) without reducing efficacy
Contraindications	Pregnancy (Category X — teratogenic), chronic kidney disease ^[28], significant liver disease, active infection, pre-existing bone marrow suppression, significant ILD
Side effects	Nausea, stomatitis (mouth ulcers), hepatotoxicity (fibrosis/cirrhosis with chronic use), myelosuppression (pancytopaenia), methotrexate pneumonitis (hypersensitivity lung reaction — acute onset dyspnoea + fever + dry cough), infections, teratogenicity
Monitoring	CBC, LFT, RFT — at baseline, then every 2–4 weeks for 3 months, then every 3 months
Drug interactions	Trimethoprim (also a DHFR inhibitor → additive myelosuppression — potentially fatal combination), NSAIDs (reduce renal clearance of MTX → toxicity)

High Yield — Methotrexate Safety

Three critical safety points about MTX:

Weekly dosing only — daily dosing causes fatal pancytopaenia
Always co-prescribe folic acid — reduces toxicity
Absolutely contraindicated in pregnancy — teratogenic (neural tube defects, limb defects). Women must use reliable contraception. Discontinue MTX at least 3 months before planned conception (some guidelines say 1–3 months for women, 3 months for men).

Pre-treatment screening: CBC, LFT, RFT, HBsAg, anti-HCV, G6PD, CXR ^[1].

"Methotrexate lung → hypersensitivity reaction from the csDMARD" ^[10] — this is an important cause of acute dyspnoea in an RA patient on MTX. It presents like acute pneumonitis (fever, dry cough, dyspnoea, bilateral infiltrates on CXR) and requires immediate MTX cessation and steroid treatment.

Aspect	Detail
Name	Hydroxy-chloro-quine — a hydroxylated derivative of chloroquine (the antimalarial)
Mechanism	Inhibits antigen processing/presentation in lysosomes (raises lysosomal pH → impairs MHC class II peptide loading), inhibits Toll-like receptors (TLR7/9), modulates cytokine production. NOT immunosuppressive ^[3] — hence safer than other DMARDs.
Indication	Mild RA (often in combination with MTX); also used in SLE (all patients unless C/I)
Side effects	GI disturbance (most common S/E requiring discontinuation ^[3]), skin hyperpigmentation, myopathy, neuropathy, corneal deposits (reversible), retinopathy (Bull's eye maculopathy — irreversible) ^[3]^[20]
Monitoring	Baseline ophthalmological examination required; annual screening after 5 years of use ^[3]^[20]
Advantages	Safe in pregnancy (one of few DMARDs safe in pregnancy), no myelosuppression, no hepatotoxicity

Aspect	Detail
Name	Sulfa-sala-zine → compound of sulfapyridine + 5-aminosalicylic acid (5-ASA)
Mechanism	Not fully understood; the sulfapyridine moiety is thought to be the active component in RA. Suppresses T-cell proliferation, reduces immunoglobulin production, inhibits folate-dependent enzymes.
Indication	RA (as part of combination csDMARD regimen); also used in IBD ^[30]
Side effects	Skin rash, haemolysis, neutropaenia, male infertility (oligospermia — reversible on discontinuation), pancreatitis ^[30], GI upset, hepatotoxicity
Critical screening	G6PD test before starting — sulfapyridine causes oxidative haemolysis in G6PD-deficient patients ^[1]
Monitoring	CBC, LFT every 2–4 weeks initially, then every 3 months

Aspect	Detail
Name	Le-FLU-nomide — mnemonic: "flu" → interferes with pyrimidine synthesis
Mechanism	Inhibits dihydroorotate dehydrogenase (DHODH) → blocks de novo pyrimidine synthesis → inhibits rapidly proliferating lymphocytes (which are uniquely dependent on de novo pyrimidine synthesis, unlike most cells which can use the salvage pathway)
Indication	Alternative to MTX or used in combination (MTX + LEF)
Side effects	Hepatotoxicity (can be severe — monitor LFT closely), diarrhoea, hypertension, peripheral neuropathy, myelosuppression, teratogenicity
Special feature	Very long half-life (~14–18 days) due to enterohepatic recirculation. Requires cholestyramine washout for rapid elimination (e.g., before pregnancy or in toxicity)
Contraindications	Pregnancy (Category X), significant liver disease, immunodeficiency

Agent	Notes
Azathioprine	Purine analogue → inhibits DNA synthesis; used more commonly in SLE than RA. Check TPMT (thiopurine methyltransferase) before starting — deficiency causes severe myelosuppression.
Cyclosporin A	Calcineurin inhibitor → blocks T-cell activation (inhibits IL-2 production). S/E: nephrotoxicity, hypertension, gingival hyperplasia, hirsutism.
IM Gold	Rarely used today. Historically effective but replaced by MTX/biologics. S/E: membranous nephropathy, myelosuppression, dermatitis.

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

Strategy	Description
Step 1: MTX monotherapy	Start MTX as anchor drug, titrate to optimal dose
If persistent activity despite MTX monotherapy	Add second csDMARD ^[28]
Common combinations	Methotrexate + Leflunomide ^[28]
	Methotrexate + Sulfasalazine + Hydroxychloroquine ("triple therapy") ^[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.

11.10 Biological DMARDs (bDMARDs) — For Refractory Disease

"Biological DMARDs — Indications: Persistent activity despite methotrexate monotherapy with poor prognostic factors for joint damage; persistent activity despite combination csDMARDs" ^[28].

"Anti-TNF / Anti-IL6 / Anti-CTLA4 / Anti-CD20" ^[28].

"There are three TNF inhibitors approved for use in RA. Infliximab and adalimumab are anti-TNF-α antibodies whereas etanercept is a recombinant soluble p75 TNF receptor:Fc fusion protein." ^[5]

Agent	Type	Route	Frequency	Mechanism
Infliximab	Chimeric anti-TNF monoclonal antibody	IV	Every 6–8 weeks	Binds and neutralises soluble and membrane-bound TNF-α
Adalimumab	Fully human anti-TNF monoclonal antibody	SC	Every 2 weeks	Same as above
Etanercept	Recombinant soluble p75 TNF receptor:Fc fusion protein	SC	Weekly	Acts as a "decoy receptor" — mops up circulating TNF-α before it can bind cell-surface receptors
Certolizumab pegol	PEGylated Fab' fragment of anti-TNF	SC	Every 2 weeks	Binds TNF-α; lacks Fc portion so does not cross placenta — safest anti-TNF in pregnancy
Golimumab	Fully human anti-TNF monoclonal antibody	SC or IV	Monthly	Same as infliximab/adalimumab

Common side effects of anti-TNF agents:

Increased infection risk (especially TB reactivation, opportunistic infections)
Injection site reactions (SC) or infusion reactions (IV)
Rare: demyelinating disease, heart failure exacerbation, lupus-like syndrome, lymphoma (controversial — RA itself increases lymphoma risk)

Anti-TNF and TB — The Classic Scenario

"Anti-TNF-alpha is the classical example that can increase risk of developing TB, given the importance of TNF-α in confining TB to the tuberculoma" ^[6].

Pre-biologic screening is mandatory:

IGRA (QuantiFERON or T-SPOT) or tuberculin skin test
CXR
If latent TB detected → isoniazid chemoprophylaxis for 3 months before starting anti-TNF ^[6]

The paradoxical reaction scenario ^[6]: Patient on anti-TNF → develops TB → stops anti-TNF + starts anti-TB → TNF-α returns → exaggerated immune response to TB → paradoxical worsening (enlarging lymph nodes, worsening radiology) → eventually resolves.

Contraindications to anti-TNF ^[20]:

Active infection (including active TB)
Latent TB (unless chemoprophylaxis given)
Demyelinating disease (multiple sclerosis)
Heart failure (NYHA III–IV)
Malignancy (current or recent)

Aspect	Detail
Name	Tocilizumab — "-cizumab" = humanised monoclonal antibody
Mechanism	Blocks IL-6 receptor → inhibits IL-6 signalling → reduces acute-phase response, B-cell differentiation, Th17 differentiation
Route	IV (every 4 weeks) or SC (weekly)
Key advantage	Can be used as monotherapy (without MTX) — unlike most other biologics which work best combined with MTX
Key side effect	Suppresses CRP/ESR (because IL-6 drives CRP production) → cannot rely on CRP/ESR to monitor disease activity or detect infections while on tocilizumab. Also: hyperlipidaemia, transaminitis, neutropaenia, GI perforation (rare).

Aspect	Detail
Name	Abatacept — "ab" = antibody-like; CTLA4-Ig fusion protein
Mechanism	CTLA4-Ig fusion protein → binds CD80/CD86 on APCs → blocks the "second signal" (co-stimulation) needed for T-cell activation. Without co-stimulation, T cells become anergic (functionally inactive).
Route	IV (every 4 weeks) or SC (weekly)
Key advantage	May be preferred in patients with latent TB (lower TB reactivation risk than anti-TNF), ILD
Side effects	Infections, infusion reactions

Aspect	Detail
Name	Rituximab — "-ximab" = chimeric monoclonal antibody
Mechanism	Binds CD20 on B cells → depletes B cells via antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptosis. Reduces RF/anti-CCP producing B cells and B cell antigen presentation.
Route	IV — two infusions of 1g, 2 weeks apart; repeat every 6 months
Key indication	Usually reserved for RF+/anti-CCP+ RA that has failed anti-TNF
Key side effects	Infusion reactions (pre-medicate with steroids + antihistamines), hypogammaglobulinaemia (long-term B-cell depletion), HBV reactivation (screen HBsAg/anti-HBc before use), progressive multifocal leukoencephalopathy (PML — very rare)

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

Agent	Target	Route
Tofacitinib	JAK1/JAK3	Oral, BD
Baricitinib	JAK1/JAK2	Oral, OD
Upadacitinib	JAK1 (selective)	Oral, OD

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]:

Factor	Category
High disease activity at onset (high DAS28 score)	Clinical
High baseline joint damage (erosive disease)	Clinical
Presence of rheumatoid nodules	Clinical
Extra-articular manifestations	Clinical
Persistently high CRP level	Serological
High rheumatoid factor or anti-CCP titre	Serological
Positive family history of RA	Family history

"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].

Step	Treatment	Indication
1	MTX monotherapy (7.5–15 mg/week, uptitrate) ± low-dose steroid bridge	All newly diagnosed RA
2	MTX + 2nd csDMARD (LEF, or SSZ + HCQ)	Persistent activity despite optimised MTX monotherapy
3a	bDMARD (anti-TNF, anti-IL-6R, CTLA4-Ig, anti-CD20) ± MTX	Persistent activity despite combination csDMARDs OR persistent activity despite MTX monotherapy with poor prognostic factors ^[28]
3b	tsDMARD (JAK inhibitor) ± MTX	Alternative to bDMARD, especially if parenteral route not tolerated. Caution in elderly with CV risk factors ^[28].
4	Switch to different mechanism bDMARD or tsDMARD	Failure of first bDMARD/tsDMARD

11.14 Role of Surgery

"Role of surgery in management of RA" ^[20]:

Aspect	Detail
Aim	Achieve a joint that is (1) pain-free, (2) stable, (3) mobile ^[20]

Procedure	Description	Indication
Synovectomy	Removal of inflamed synovium	Early disease, to prevent tendon rupture. Rarely done nowadays with multiple DMARDs available ^[20].
Arthrodesis (fusion)	Artificial induction of joint ossification	C1/2 subluxation, ankle joint — gives pain-free, stable but NOT mobile joint ^[20]
Re-alignment osteotomy	Removal of bone parts to restore alignment	Young patients with OA knee + genu varum → delays arthroplasty
Joint replacement (arthroplasty)	Prosthetic joint	Most reliable method for a pain-free, stable AND mobile joint ^[20]. Used for OA knee, RA knee, AVN hip. Limited lifespan ( > 15 years typically) due to aseptic loosening.

Comorbidity / Concern	Management
Osteoporosis	Screen with DEXA. Calcium + vitamin D supplementation. Bisphosphonates if indicated. Steroid use accelerates bone loss.
Cardiovascular risk	RA is independent CV risk factor. Aggressive lipid management, BP control, smoking cessation.
Infection risk	Immunisation (avoid live vaccines on immunosuppression). Pneumococcal, influenza, COVID-19, recombinant shingles vaccine. Screen for latent TB before biologics.
HBV monitoring	If HBsAg+, monitor HBV DNA regularly. Consider antiviral prophylaxis before immunosuppression.
Drug toxicity monitoring	CBC + LFT + RFT every 2–4 weeks initially for MTX, then every 3 months. Ophthalmology review for HCQ.
Pregnancy planning	Stop MTX/LEF ≥ 3 months before conception. HCQ and SSZ generally safe. Certolizumab safest anti-TNF (no Fc → does not cross placenta).

Drug	Class	MOA	Key S/E	Key C/I	Monitoring
Methotrexate	csDMARD	DHFR inhibition / adenosine	Hepatotoxicity, myelosuppression, MTX pneumonitis, teratogenicity	Pregnancy, CKD, liver disease	CBC/LFT/RFT Q2–4w → Q3m
HCQ	csDMARD	↑ lysosomal pH, TLR inhibition	Bull's eye maculopathy, GI	Retinal disease	Ophthalmology baseline + Q1y after 5y
SSZ	csDMARD	Folate-dependent enzyme inhibition	Haemolysis, neutropaenia, male infertility	G6PD deficiency, sulfa allergy	CBC/LFT, G6PD before starting
LEF	csDMARD	DHODH inhibition	Hepatotoxicity, hypertension, diarrhoea	Pregnancy, liver disease	LFT closely
Infliximab	bDMARD (anti-TNF)	Chimeric anti-TNF mAb	Infections (TB!), infusion reactions	Active/latent TB (without prophylaxis), HF, MS	Latent TB screen, HBsAg
Adalimumab	bDMARD (anti-TNF)	Human anti-TNF mAb	As above	As above	As above
Etanercept	bDMARD (anti-TNF)	Soluble TNF receptor decoy	As above	As above	As above
Tocilizumab	bDMARD (anti-IL-6R)	Blocks IL-6 receptor	Suppresses CRP, hyperlipidaemia, GI perforation	Diverticulitis, active infection	Cannot rely on CRP for monitoring
Abatacept	bDMARD (anti-CTLA4)	Blocks T-cell co-stimulation	Infections	Active infection	—
Rituximab	bDMARD (anti-CD20)	Depletes B cells	Infusion reactions, hypogammaglobulinaemia, HBV reactivation	Active HBV, active infection	Ig levels, HBV monitoring
Tofacitinib	tsDMARD (JAK inh)	JAK1/3 inhibition	Herpes zoster, VTE, MACE, malignancy	Significant CV risk (relative)	CBC, LFT, lipids

High Yield Summary — Management of RA

Principles: Treat early (window of opportunity ≤ 3–6 months), treat to target (DAS28 < 2.6 = remission), switch at 3 months if < 50% improvement, switch at 6 months if target not reached.

Non-pharmacological: MDT (PT/OT/podiatry), patient education, smoking cessation, CV risk optimisation, immunisation.

Step-up algorithm:

MTX monotherapy (anchor drug, 7.5–15 mg/week) + steroid bridge
Combination csDMARDs (MTX + LEF, or MTX + SSZ + HCQ)
bDMARD (anti-TNF / anti-IL-6R / CTLA4-Ig / anti-CD20) or tsDMARD (JAK inhibitor) — for refractory disease or those with poor prognostic factors

Key pre-treatment screening: HBsAg, anti-HCV, G6PD, CXR, CBC, LFT, RFT, latent TB (IGRA) before biologics

Steroids: Bridge only (< 3–6 months), NOT monotherapy. Long-term steroids = STOPP criterion.

Surgery: Emergency indications (septic arthritis, C1/2 instability, tendon rupture). Elective: synovectomy, arthrodesis, joint replacement. Arthroplasty = most reliable for pain-free, stable, mobile joint.

Poor prognostic factors: High DAS28, erosive disease, nodules, EAMs, high CRP, high RF/anti-CCP, family history.

Active Recall - Management of Rheumatoid Arthritis

References

^[1] Senior notes: Maksim Medicine Notes.pdf (Section 13.4 Rheumatoid arthritis — Management, Investigations, p.312–313) ^[3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (HCQ section p.1732; RA management) ^[5] Senior notes: Block A - Treatments for skin diseases (eczema, psoriasis and urticaria).pdf (p.34 — TNF inhibitors in RA) ^[6] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (p.37 — Anti-TNF and TB) ^[10] Senior notes: Block A - Hematology Interactive Tutorial.pdf (p.2 — MTX lung, NSAID GI bleeding) ^[20] Senior notes: Ryan Ho Rheumatology.pdf (p.52–56 — Treatment principles, DMARDs, biologics, surgery) ^[22] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.456 — JIA management, MTX efficacy) ^[28] Lecture slides: Handbook of Internal Medicine 2024.pdf (p.433 — Treatment section) ^[29] Lecture slides: GC 079 (supp-2)STOPP-START-V3.pdf (p.8, p.11 — STOPP/START criteria) ^[30] Senior notes: Block A - Upper abdominal pain_ peptic ulcer; pancreatitis and gallstone.pdf (p.25 — NSAID gastroprotection); Block A - Chronic diarrhoea_ irritable bowel syndrome and inflammatory bowel disease.pdf (p.44 — Sulfasalazine)

Complications of Rheumatoid Arthritis

Complications of RA arise from three distinct sources: (1) the disease process itself (joint destruction + extra-articular inflammation), (2) treatment-related adverse effects (DMARDs, steroids, NSAIDs), and (3) comorbidities accelerated by chronic systemic inflammation. Understanding which bucket a complication falls into is essential for clinical reasoning — and for exam answers.

These are the direct consequences of unchecked synovitis → pannus → structural destruction.

"Proliferative synovium (Pannus) erodes into surrounding structures, including articular cartilage, bone, ligament, and tendon" ^[4].

Complication	Pathophysiology	Clinical Significance
Joint deformities ^[3]	Progressive pannus erosion of cartilage and bone + tendon/ligament laxity → Boutonnière, swan neck, Z-thumb, ulnar deviation, volar subluxation, cock-up toes (covered in clinical features)	Irreversible once established. Functional disability — inability to grip, walk, dress. This is exactly why early DMARD therapy is imperative.
Tendon rupture ^[3]	Tenosynovitis (inflammation of the tendon sheath) weakens tendons. Also: bony spicules from eroded joints can abrade tendons. Classic site: extensor tendons of fingers (especially extensor digitorum over the dorsal wrist)	Sudden inability to extend a finger. Rupture of extensor pollicis longus → loss of thumb extension. Considered an indication for early/emergency surgery ^[20].
Septic arthritis ^[3]^[15]	Damaged joints + immunosuppressive therapy → predisposition to bacterial seeding (haematogenous spread or direct inoculation during joint injection). Most common organism: S. aureus.	Rheumatological emergency. Sudden flare of a single joint in RA must be aspirated — never assume it's just a disease flare. Delayed treatment destroys cartilage within days.
Secondary osteoarthritis	After years of joint destruction, the damaged joint surfaces undergo degenerative changes indistinguishable from primary OA	End-stage RA joints often show mixed inflammatory + degenerative features
Atlantoaxial (C1/C2) subluxation	Synovitis at the atlantoaxial joint erodes the transverse ligament → C1 slides forward on C2	Cervical myelopathy (UMN signs in limbs), vertebrobasilar insufficiency, risk of sudden death from cord compression. Must screen before intubation.
Osteoporosis ^[1]^[3]	Multifactorial: (1) Pro-inflammatory cytokines (TNF-α, IL-6, IL-1) upregulate RANKL → increased osteoclast activity → generalised bone loss. (2) Disuse/immobility. (3) Corticosteroid use.	Increased fragility fracture risk. Screen with DEXA. Co-prescribe calcium + vitamin D. Bisphosphonates if indicated.
Muscle weakness ^[1]	Due to: (1) disuse atrophy from painful joints, (2) myositis (inflammatory infiltration of muscle), (3) drug-induced — steroid myopathy, hydroxychloroquine myopathy, statin myopathy ^[1]	Contributes to functional disability and falls risk. Distinguish from inflammatory myositis (check CK).

Tendon Rupture — Surgical Emergency

Tendon rupture or pending rupture is one of the indications for emergency or early surgery in RA ^[20]. The extensor tendons over the dorsal wrist are at highest risk due to tenosynovitis + bony spicules from the eroded distal ulna ("Vaughan-Jackson lesion" = sequential rupture of the extensor tendons from little to index finger). Prophylactic synovectomy and Darrach procedure (distal ulna excision) can be performed to prevent this.

The lungs are one of the most commonly affected extra-articular organs in RA.

"Rheumatoid-related causes: pleural effusion, ruptured rheumatoid nodule in the lung → lung collapse, pulmonary fibrosis" ^[10].

Complication	Pathophysiology	Key Features
Interstitial lung disease (ILD) ^[1]^[9]^[31]	Autoimmune-mediated inflammation of lung parenchyma → fibrosis. Most commonly UIP (usual interstitial pneumonia) and NSIP (non-specific interstitial pneumonia) ^[9]^[31].	Progressive dyspnoea, dry cough, bilateral fine inspiratory crackles. HRCT: ground-glass opacity (NSIP), honeycombing (UIP). Restrictive PFTs. Most common pulmonary cause of death in RA.
Pleural effusion ^[1]^[31]	Rheumatoid pleuritis → exudative effusion	Typically small, unilateral, exudative with characteristically low glucose and pH ^[31]. Also high LDH, high protein, low complement. More common in seropositive men.
Rheumatoid pulmonary nodules ^[1]^[31]	Same histology as subcutaneous nodules (central necrosis + palisading macrophages) but in lung parenchyma	Generally asymptomatic but may rupture → pleural effusion, pneumothorax, infection ^[31]. Can mimic lung malignancy on CXR (need biopsy/PET to distinguish). Caplan syndrome = rheumatoid nodules + pneumoconiosis (coal workers).
Bronchiolitis obliterans ^[1]	Small airway inflammation and fibrosis → obstructive pattern	Rare but serious. Can also be a complication of gold or penicillamine therapy.
Bronchiectasis ^[31]	Chronic inflammation of airways → structural damage → dilatation and recurrent infections	More common than in general population. Productive cough, recurrent infections.
Methotrexate pneumonitis ^[10]	Drug-induced hypersensitivity reaction — NOT dose-dependent. Acute interstitial pneumonitis.	Acute onset dyspnoea, fever, dry cough, bilateral infiltrates on CXR. Can occur at any time on MTX. Management: stop MTX immediately, systemic corticosteroids. Distinguished from RA-ILD by acuity and temporal relationship to MTX.

Complication	Pathophysiology	Key Features
Accelerated atherosclerosis	Chronic systemic inflammation → endothelial dysfunction, oxidised LDL, plaque instability. RA is an independent cardiovascular risk factor ^[1].	RA patients have 1.5–2× increased CV mortality. CAD, PAD, stroke. Treat aggressively with lipid management, BP control, smoking cessation.
Pericarditis ^[1]^[3]	Autoimmune pericardial inflammation — often subclinical (found incidentally on echocardiogram or autopsy)	May present as chest pain, pericardial rub. Usually mild and self-limiting. Rarely → pericardial effusion → tamponade.
Myocarditis ^[1]	Inflammatory infiltration of myocardium (rare)	Can contribute to heart failure
Cardiac amyloidosis ^[10]	Long-standing RA → chronic inflammation → sustained elevation of serum amyloid A (SAA) protein → SAA misfolds into AA amyloid fibrils → deposits in myocardium → restrictive cardiomyopathy	Late complication of poorly controlled, long-standing RA. Also deposits in kidneys (nephrotic syndrome), GI tract (diarrhoea, malabsorption).
Valvular disease	Rheumatoid nodules on heart valves → regurgitation	Uncommon
Atrial fibrillation / Heart failure ^[3]	Chronic inflammation + amyloidosis + valvular disease	Increased risk in long-standing RA

Complication	Pathophysiology	Key Features
Anaemia of chronic disease (ACD) ^[1]	IL-6 → hepcidin production by liver → hepcidin degrades ferroportin on macrophages → iron is "trapped" → functional iron deficiency	Most common haematological abnormality. Normocytic normochromic. Low serum iron, low TIBC, normal/high ferritin.
Iron deficiency anaemia (IDA) ^[10]	NSAID-induced GI bleeding (peptic ulcer, gastritis)	Microcytic hypochromic. Low serum iron, HIGH TIBC, low ferritin. Often coexists with ACD in RA patients on NSAIDs.
Felty syndrome ^[1]^[3]^[11]	RA + splenomegaly + neutropaenia. Spleen's increased white pulp function → immune-mediated destruction of neutrophils + splenic sequestration ^[11].	Almost exclusively in severe, long-standing, seropositive RA. Recurrent bacterial infections (skin, respiratory). Treat underlying RA aggressively. May require G-CSF or splenectomy.
Reactive thrombocytosis	IL-6 drives thrombopoiesis	Platelet count rises with active inflammation — a marker of disease activity, not a "complication" per se
Increased risk of lymphoma ^[1]	Chronic immune stimulation → lymphoproliferative disease. Also: immunosuppressive therapy may contribute.	Mainly non-Hodgkin's lymphoma. Risk is 2–4× general population.
Secondary (AA) amyloidosis ^[1]	Chronic inflammation → SAA deposition	Nephrotic syndrome (proteinuria → hypoalbuminaemia → oedema), renal failure, hepatomegaly. Now much rarer with effective DMARD therapy.
Large granular lymphocyte (LGL) leukaemia ^[20]	Clonal expansion of LGL cells → neutropaenia	Overlaps clinically with Felty syndrome. Distinguished by flow cytometry showing clonal LGL expansion.
MTX-induced myelosuppression	Folate antagonism → suppressed haematopoiesis	Pancytopaenia. Risk increased by renal impairment, folate deficiency, concomitant trimethoprim.
SSZ-induced haemolytic anaemia ^[1]	Oxidative stress on RBCs	Especially in G6PD-deficient patients → screen G6PD before starting SSZ

The RA Anaemia Case — Commonly Examined

The Interactive Tutorial (Haem case 1) ^[10] presents a classic scenario: RA patient with Hb 7.5, MCV 70, low iron, high TIBC → IDA from NSAID-induced GI bleeding on top of ACD. Always ask about drug history. Always consider combined ACD + IDA. The key differentiator: TIBC is high in IDA (body trying to scavenge iron) but low/normal in ACD (iron is "trapped" — no need to make more carrier).

Complication	Pathophysiology	Key Features
Carpal tunnel syndrome ^[1]^[20]	Tenosynovitis at the wrist → compression of median nerve in the carpal tunnel	Most common neurological complication. Paraesthesiae in thumb, index, middle finger + radial half of ring finger. Worse at night. Tinel's sign, Phalen's test. Can be an early presenting feature of RA.
Cervical myelopathy ^[1]^[20]	Atlantoaxial subluxation → spinal cord compression	Gradual-onset UMN signs in limbs (hyperreflexia, spasticity, Babinski+), bladder dysfunction. Can be catastrophic if acute.
Mononeuritis multiplex (vasculitic) ^[1]^[20]	Rheumatoid vasculitis of vasa nervorum → nerve ischaemia → infarction of individual nerve trunks	Combined motor + sensory deficit in distribution of specific nerves (e.g., wrist drop + foot drop). Indicates systemic vasculitis → aggressive immunosuppression required.
Peripheral entrapment neuropathies ^[20]	Hypertrophied synovium or subluxed joints compress nerves at specific anatomical sites	Carpal tunnel (median nerve), ulnar neuropathy at elbow, peroneal nerve palsy at fibular head, tarsal tunnel syndrome (posterior tibial nerve) ^[20]
Distal symmetric sensory neuropathy ^[20]	NOT due to ischaemic vasculitis — mechanism unclear, possibly drug-related or chronic inflammation	Stocking-glove sensory loss, paraesthesiae

"Rheumatoid arthritis: 2° Sjögren's syndrome, PUK, episcleritis, scleritis, uveitis" ^[12].

Complication	Pathophysiology	Key Features
Secondary Sjögren's syndrome (keratoconjunctivitis sicca)	Lymphocytic infiltration of lacrimal glands → reduced tear production	Most common ocular manifestation. Dry, gritty eyes. Schirmer test < 5 mm in 5 minutes.
Episcleritis	Inflammation of episclera (superficial)	Mild, self-limiting, bright red eye, minimal pain
Scleritis	Deeper scleral inflammation — immune complex-mediated	Severe, deep boring pain; can lead to scleromalacia perforans (necrosis and perforation of the sclera — sight-threatening). More serious than episcleritis.
Peripheral ulcerative keratitis (PUK) ^[12]	Immune complex deposition → complement activation → MMP production by keratocytes → corneal breakdown ^[12]	Crescent-shaped corneal ulcer, thinning, can perforate. RA accounts for 34–42% of PUK cases ^[12]. Requires systemic immunosuppression.

Complication	Cause
AA amyloidosis	Chronic RA → SAA deposition in kidneys → nephrotic syndrome → CKD. Now much rarer with modern DMARD therapy.
NSAID nephrotoxicity	Chronic NSAID use → inhibition of renal prostaglandins → afferent arteriolar vasoconstriction → reduced GFR; also interstitial nephritis, papillary necrosis
Gold/penicillamine nephropathy	Membranous nephropathy (historical — these drugs are rarely used now)
MTX nephrotoxicity	Direct tubular toxicity; precipitation in renal tubules (high-dose); exacerbated by dehydration and renal impairment ^[30]

Feature	Detail
Who	Severe, long-standing, seropositive (usually high-titre RF+), nodular RA. Fortunately now rare with effective DMARD/biologic therapy.
Pathology	Necrotising vasculitis of small and medium-sized arteries (similar to polyarteritis nodosa)
Manifestations	Nail fold infarcts (earliest sign), digital gangrene, skin ulcers (especially legs), mononeuritis multiplex, visceral infarction (mesenteric, coronary), scleritis/PUK
Significance	Indicates severe systemic disease. High mortality if untreated. Requires aggressive immunosuppression (high-dose steroids + cyclophosphamide or rituximab).

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].

Drug / Class	Key Complications	Mechanism
NSAIDs	Upper GI bleeding (peptic ulcer, gastritis) ^[10]^[30]; renal impairment; CV risk (especially COX-2 selective)	COX-1 inhibition → reduced gastric mucosal prostaglandins → mucosal damage. Renal PG inhibition → afferent vasoconstriction → ↓GFR.
Corticosteroids (chronic) ^[3]	Osteoporosis, AVN of hip, Cushingoid features, DM, hypertension, cataracts, infections, adrenal suppression, gastric ulcer, myopathy, psychiatric effects	Multifactorial: catabolic effects on bone/muscle, immunosuppression, metabolic effects
Methotrexate	Hepatotoxicity (fibrosis/cirrhosis), myelosuppression (pancytopaenia) ^[1], MTX pneumonitis ^[10], stomatitis, infections, teratogenicity, folate deficiency ^[1]	Direct folate antagonism; hypersensitivity (pneumonitis); cumulative hepatotoxicity
Sulfasalazine	Haemolytic anaemia (especially in G6PD deficiency) ^[1], neutropaenia, male infertility (oligospermia), skin rash, pancreatitis	Sulfapyridine moiety causes oxidative haemolysis
Leflunomide	Hepatotoxicity, hypertension, diarrhoea, peripheral neuropathy	DHODH inhibition
Hydroxychloroquine	Bull's eye maculopathy (retinal toxicity — irreversible) ^[1], GI upset, myopathy, neuropathy	Accumulation in retinal pigment epithelium → photoreceptor toxicity
Anti-TNF agents	TB reactivation ^[6], serious infections, infusion/injection reactions, demyelinating disease (rare), HF exacerbation (rare), lupus-like syndrome, lymphoma (debated)	TNF-α is critical for granuloma maintenance (TB), general immune defence
Rituximab	Infusion reactions, hypogammaglobulinaemia, HBV reactivation, progressive multifocal leukoencephalopathy (PML — rare)	Sustained B-cell depletion → reduced immunoglobulin production
JAK inhibitors	Herpes zoster reactivation, VTE, MACE and malignancy (FDA warning) ^[28], hyperlipidaemia	Broad intracellular cytokine signalling inhibition including IFN-γ (needed for viral control)

Complication	Mechanism	Management
Accelerated cardiovascular disease	Chronic inflammation → endothelial dysfunction, plaque instability	Aggressive CV risk management (lipids, BP, smoking). Consider RA itself as an additional CV risk factor in risk calculators.
Depression and psychological impact	Chronic pain + disability + fatigue + body image changes (deformity, steroid side effects)	Screen for depression. MDT support. Pharmacotherapy if needed.
Infection	Both disease-related (immune dysregulation) and treatment-related (immunosuppression)	Immunisation, infection surveillance, patient education (report fevers early), reduce immunosuppression if serious infection occurs

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

System	Complications
MSS	Tendon rupture, joint deformities, septic arthritis
Neurological	Mononeuritis (vasculitic), entrapment neuropathy
Lung	Pleural effusion, fibrosing alveolitis (ILD)
Others	Pericarditis, lymphadenopathy, splenomegaly, anaemia, Raynaud's phenomenon, keratoconjunctivitis
Immunosuppressant use	Infection, blood dyscrasia
Steroid use	Cushingoid features, immunosuppression, gastric ulcer, osteoporosis, AVN of hip

"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].

High Yield Summary — Complications of RA

Disease-related joint complications: Deformities (irreversible), tendon rupture (emergency surgery), septic arthritis (always aspirate), atlantoaxial subluxation (screen before intubation), secondary OA, osteoporosis.

Pulmonary: ILD (UIP/NSIP — most common cause of pulmonary death), pleural effusion (low glucose, low pH), rheumatoid nodules (may rupture → pneumothorax), Caplan syndrome, bronchiolitis obliterans, MTX pneumonitis.

Cardiovascular: Accelerated atherosclerosis (1.5–2× CV mortality — leading cause of death), pericarditis, cardiac amyloidosis.

Haematological: ACD (most common), IDA (NSAID GI bleeding), Felty syndrome (RA + splenomegaly + neutropaenia), lymphoma (2–4× risk), AA amyloidosis, MTX myelosuppression, SSZ haemolysis.

Neurological: Carpal tunnel (most common neuro complication), cervical myelopathy (C1/2), mononeuritis multiplex (vasculitis), entrapment neuropathies.

Ocular: 2° Sjögren's (most common), episcleritis, scleritis (→ scleromalacia perforans), PUK.

Treatment-related: NSAIDs → GI bleed/renal; Steroids → osteoporosis/AVN/Cushing's/DM; MTX → liver/marrow/lung; Anti-TNF → TB/infections; HCQ → retinopathy; SSZ → haemolysis (G6PD); JAK inhibitors → MACE/malignancy/herpes zoster.

Leading cause of death in RA: Cardiovascular disease (accelerated atherosclerosis).

Active Recall - Complications of Rheumatoid Arthritis

References

^[1] Senior notes: Maksim Medicine Notes.pdf (Section 13.4 Rheumatoid arthritis — Extra-articular manifestations, p.312) ^[3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Complications Q3 p.1684; Complications Q5 p.1685; Prognostic factors p.1682) ^[4] Lecture slides: Upper Limb Painful Conditions_Dr. Margaret Woon Man FOK_3. Inflammatory conditions.pdf (p.3 — Pannus erosion) ^[6] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (p.37 — Anti-TNF and TB) ^[9] Senior notes: Ryan Ho Respiratory.pdf (p.121 — ILD in CTD; p.128 — Respiratory manifestations of RA) ^[10] Senior notes: Block A - Hematology Interactive Tutorial.pdf (p.2 — RA anaemia case, NSAID GI bleeding, MTX lung) ^[11] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (p.7 — Felty syndrome) ^[12] Senior notes: Ryan Ho Opthalmology.pdf (p.131 — Ocular manifestations of RA, PUK) ^[15] Senior notes: Block A - Painful red joint_ monoarthropathy, gouty arthritis, septic arthritis, haemarthrosis.pdf (p.7) ^[17] Lecture slides: GC 074. Multiple joint pain.pdf (p.22 — RF and prognosis) ^[20] Senior notes: Ryan Ho Rheumatology.pdf (p.50 — Neurological and haematological involvement; p.56 — Surgical indications) ^[28] Lecture slides: Handbook of Internal Medicine 2024.pdf (p.433 — JAK inhibitor warning) ^[30] Senior notes: Block A - Upper abdominal pain_ peptic ulcer; pancreatitis and gallstone.pdf (p.25 — NSAID gastroprotection); Block A - Drugs and the Kidney.pdf (p.9 — MTX nephrotoxicity) ^[31] Senior notes: Ryan Ho Respiratory.pdf (p.127–128 — Respiratory manifestations of RA)

High Yield Summary

Definition: RA = chronic, systemic, autoimmune inflammatory disease → symmetric erosive polyarthritis of peripheral joints → pannus formation → cartilage/bone destruction → deformity.

Epidemiology: 0.3–0.4% in HK; F:M = 3:1; peak 4th–5th decade; commonest AI inflammatory polyarthritis.

Pathogenesis: Gene-environment interaction → citrullination → anti-CCP/RF → immune complex deposition → synovitis → pannus → erosion → deformity. TNF-α is the master cytokine.

Joint Pattern: Symmetric, MCP/PIP/wrist/MTP, spares DIP, spares axial (except C1/2), morning stiffness > 1 hour, additive pattern.

Key Deformities: Boutonnière (flexed PIP/hyperextended DIP), Swan neck (hyperextended PIP/flexed DIP), Z-thumb, ulnar deviation, volar subluxation, cock-up toe, atlantoaxial subluxation.

Autoantibodies: RF (sensitive, not specific) and anti-CCP (sensitive AND highly specific, > 95%). Both positive = high predictive value for RA and erosive disease.

Anti-TNF and TB: Screen for latent TB (IGRA/TST) before starting anti-TNF biologics; isoniazid prophylaxis × 3 months if latent TB.

High Yield Summary — Differential Diagnosis of RA

Common DDx of chronic symmetric polyarthritis: RA, SLE, viral polyarthritis, OA, PsA (symmetric pattern).

Key distinctions:

OA: DIP, hard bony, evening stiffness, XR shows osteophytes, seronegative
PsA: DIP involved, dactylitis, nail changes, asymmetric (usually), seronegative
SLE: Non-erosive, reducible deformities, morning stiffness minutes, transudate SFA, ANA+
Viral: Self-limiting < 6 weeks, preceded by viral prodrome, positive viral serology
Crystal: Crystals on SFA microscopy; gout = needle, negatively birefringent; CPPD = rhomboid, weakly positive
Septic: WBC > 50k, > 90% PMN, positive Gram stain/culture — always rule out in any acute hot joint
Seropositive vs Seronegative (SpA): Symmetric/F > M/RF+ vs Asymmetric/M > F/HLA-B27+
PMR: Age > 50, shoulder+hip girdle, no small joint synovitis, dramatic steroid response
AOSD: Quotidian fever, salmon rash, markedly elevated ferritin, diagnosis of exclusion

The 6-week rule: The 2010 ACR/EULAR criteria require ≥ 6 weeks of symptoms — this critical threshold excludes most viral polyarthritis.

Always aspirate an acutely inflamed joint to exclude septic arthritis and crystal disease — even in a known RA patient.

High Yield Summary — Diagnosis of RA

Two sets of criteria:

1987 ACR: ≥ 4 of 7 features, criteria 1–4 present > 6 weeks. Includes nodules and erosions (late features). Mnemonic: RAS.
2010 ACR/EULAR: ≥ 6 of 10 points. Domains: Joint involvement (0–5), Serology (0–3), Acute phase reactants (0–1), Duration (0–1). Designed for early RA. Entry: ≥ 1 joint with clinical synovitis not explained by another disease. Typical erosions = automatic classification.

Key investigations:

Baseline: CBC, LRFT, HBsAg, anti-HCV, G6PD (SAQ favourite)
Inflammatory markers: CRP, ESR (for scoring and monitoring)
Serology: RF + anti-CCP (diagnostic and prognostic, NOT for monitoring)
Imaging: X-ray hands/feet (soft tissue swelling → periarticular osteopaenia → joint space narrowing → marginal erosions → subluxation/deformity)
MSUS: detects subclinical synovitis and early erosions; Power Doppler = active inflammation
MRI: bone marrow oedema (pre-erosive), C-spine assessment
Synovial fluid: inflammatory exudate, no crystals, no organisms

Disease activity: DAS28 (tender + swollen joints, ESR/CRP, patient global assessment). Remission < 2.6.

High Yield Summary — Management of RA

Principles: Treat early (window of opportunity ≤ 3–6 months), treat to target (DAS28 < 2.6 = remission), switch at 3 months if < 50% improvement, switch at 6 months if target not reached.

Non-pharmacological: MDT (PT/OT/podiatry), patient education, smoking cessation, CV risk optimisation, immunisation.

Step-up algorithm:

MTX monotherapy (anchor drug, 7.5–15 mg/week) + steroid bridge
Combination csDMARDs (MTX + LEF, or MTX + SSZ + HCQ)
bDMARD (anti-TNF / anti-IL-6R / CTLA4-Ig / anti-CD20) or tsDMARD (JAK inhibitor) — for refractory disease or those with poor prognostic factors

Key pre-treatment screening: HBsAg, anti-HCV, G6PD, CXR, CBC, LFT, RFT, latent TB (IGRA) before biologics

Steroids: Bridge only (< 3–6 months), NOT monotherapy. Long-term steroids = STOPP criterion.

Poor prognostic factors: High DAS28, erosive disease, nodules, EAMs, high CRP, high RF/anti-CCP, family history.

High Yield Summary — Complications of RA

Cardiovascular: Accelerated atherosclerosis (1.5–2× CV mortality — leading cause of death), pericarditis, cardiac amyloidosis.

Haematological: ACD (most common), IDA (NSAID GI bleeding), Felty syndrome (RA + splenomegaly + neutropaenia), lymphoma (2–4× risk), AA amyloidosis, MTX myelosuppression, SSZ haemolysis.

Neurological: Carpal tunnel (most common neuro complication), cervical myelopathy (C1/2), mononeuritis multiplex (vasculitis), entrapment neuropathies.

Ocular: 2° Sjögren's (most common), episcleritis, scleritis (→ scleromalacia perforans), PUK.

Leading cause of death in RA: Cardiovascular disease (accelerated atherosclerosis).

Rheumatoid Arthritis

Rheumatoid Arthritis (RA)

2. Epidemiology

3. Risk Factors

4.1 Structure of a Normal Synovial Joint

5. Aetiology and Pathophysiology

5.2 Detailed Pathophysiology — Step by Step

6. Classification

7. Clinical Features

7.2 Articular (Joint) Features

C. Late Disease — Deformities

7.3 Extra-Articular Manifestations (EAMs)

Active Recall - Rheumatoid Arthritis (Definition, Epidemiology, Risk Factors, Pathophysiology, Clinical Features)

Differential Diagnosis of Rheumatoid Arthritis

9.3 The "Big Five" DDx to Know Cold

Active Recall - Differential Diagnosis of RA

References

Diagnostic Criteria, Diagnostic Algorithm, and Investigations for Rheumatoid Arthritis

10.7 Investigations — Complete Workup

F. Imaging

Active Recall - Diagnostic Criteria, Algorithm and Investigations for RA

References

Management of Rheumatoid Arthritis

Overview of Drug Categories

The Concept

11.8 Conventional Synthetic DMARDs (csDMARDs) — Individual Agents

11.10 Biological DMARDs (bDMARDs) — For Refractory Disease

11.14 Role of Surgery

Active Recall - Management of Rheumatoid Arthritis

References

Complications of Rheumatoid Arthritis

Active Recall - Complications of Rheumatoid Arthritis

References

On this page

Rheumatoid Arthritis

1. Definition

2. Epidemiology

2.1 Prevalence and Burden

2.2 Demographics

3. Risk Factors

3.1 Genetic Factors

3.2 Smoking

3.3 Infection (Possible Inciting Factor)

3.4 Pregnancy-Related Factors

3.5 Other Factors

4. Anatomy and Function of the Synovial Joint

5. Aetiology and Pathophysiology

5.1 Overview of Pathogenesis

5.2 Detailed Pathophysiology — Step by Step

Step 1: Pre-clinical Phase (Loss of Tolerance)

Step 2: Initiation of Synovitis

Step 3: Pannus Formation

Step 4: Bone Erosion

Step 5: Joint Destruction and Deformity

5.3 Immunological Targets — Key Autoantibodies

5.4 TNF-α — The Master Cytokine in RA

6. Classification

6.1 Seropositive vs Seronegative RA

6.2 By Disease Activity

6.3 By Stage (Steinbrocker Functional Classification)

6.4 Important Distinction: RA vs Spondyloarthritis vs Osteoarthritis

7. Clinical Features

7.1 Approach to Joint Pain — The Framework

7.2 Articular (Joint) Features

A. Early Disease — Symptoms

B. Early Disease — Signs

C. Late Disease — Deformities

Hand and Wrist Deformities

Foot Deformities

Cervical Spine — The Critical One

D. Comparison with SLE Joint Features

7.3 Extra-Articular Manifestations (EAMs)

A. Constitutional Symptoms

B. Rheumatoid Nodules

C. Pulmonary Manifestations

D. Cardiovascular Manifestations

E. Haematological Manifestations

F. Ocular Manifestations

G. Neurological Manifestations

H. Renal Manifestations

I. Skin Manifestations

J. Other Manifestations

7.4 Felty Syndrome — Special Mention

7.5 Summary of Joint Distribution

8. Investigations Overview (Bridging to Diagnosis)

Active Recall - Rheumatoid Arthritis (Definition, Epidemiology, Risk Factors, Pathophysiology, Clinical Features)

References

9.1 Framework: How to Think About the DDx

9.2 Differential Diagnosis of Polyarthritis — Master Table

9.3 The "Big Five" DDx to Know Cold

1. Osteoarthritis (OA) — The Non-Inflammatory Mimic

2. Psoriatic Arthritis (PsA) — The Seronegative Mimic

3. SLE-Associated Arthritis — The Non-Erosive Mimic

4. Viral Polyarthritis — The Acute Mimic

5. Crystal Arthropathy (Gout and Pseudogout) — The Acute Flare Mimic

9.4 The "Don't Forget" DDx — Less Common but Testable

9.5 Approach to Differential Diagnosis — Decision Flowchart

9.6 Synovial Fluid Analysis — The Great Discriminator

9.7 Key Serological Distinctions

9.8 Seropositive vs Seronegative Arthritis — The Fundamental Divide

Active Recall - Differential Diagnosis of RA

10.1 Overview — Why Classification Criteria Exist

10.2 The 1987 ACR Classification Criteria (Established RA)

10.3 The 2010 ACR/EULAR Classification Criteria (Early RA)

10.4 Comparison of 1987 vs 2010 Criteria

10.5 Disease Activity Assessment — DAS28

10.6 Diagnostic Algorithm — Integrated Approach

10.7 Investigations — Complete Workup

A. Baseline Blood Tests

B. Inflammatory Markers

C. Serology — The Key Tests

D. Additional Serological Tests (to Exclude DDx)

E. Synovial Fluid Analysis

F. Imaging