Rheumatology JC082: Painful Red Joint: Monoarthropathy, Gouty Arthritis, Septic Arthritis, Haemarthrosis

Question 1

DDx of Monoarthritis

Answer 1

記: Septic, Crystal, Inflammatory (monoarthritis presentation), OA, Trauma

1. ***Septic arthritis
   - Bacterial
   - Mycobacterial
   - Lyme disease (mimic septic arthritis but it is a Borrelia infection)
2. ***Crystal arthritis
   - Gout
   - CPPD (Pseudogout: Calcium pyrophosphate deposition disease)
   - Hydroxyapatite deposition disease
   - Calcium oxalate deposition disease
3. ***Trauma
   - Fracture
   - ACL / PCL tear
   - Haemarthrosis
4. Others
   - **OA
   - Juvenile idiopathic arthritis (JIA)
   - Coagulopathy
   - Avascular necrosis of bone
   - **Monoarticular presentation of polyarticular disease (e.g. RA, SpA, PsA)

Question 2

DDx of Polyarticular diseases

Answer 2

記: Inflammatory

Occasionally present with monoarticular onset
1. RA
2. JIA
3. Viral arthritis
4. Spondyloarthritis (SpA) (inflammation in spine + joints)
- Reactive arthritis (ReA)
- Psoriatic arthritis (PsA)
- IBD-associated arthritis

Question 3

History taking of Monoarticular problem

Answer 3

1. ***Onset of Pain
   - second / min: Fracture, Internal derangement
   - over several hours / 1-2 days: Infection, Crystal arthritis
   - over days - weeks: Inflammatory arthritis syndromes, Indolent infection, OA
2. Joint overused / damaged, recently / past
   - Traumatic causes
   - OA
3. ***Previous acute attacks of self limiting arthritis
   - Crystal arthritis
   - Inflammatory arthritis syndromes
4. Treatment with immunosuppressive agents (e.g. steroid, cytotoxic agent)
   - Infection
   - ***Osteonecrosis
5. History of ***bleeding disorders / treatment with anti-coagulants
   - Haemarthrosis

Question 4

***Investigations of Monoarticular problem

Answer 4

1. ***Synovial fluid analysis
   - Appearance
   - Microscopy
   - Microbiology
2. CBC
3. ***ESR
4. Biochemistry (including Serum ***uric acid level)
5. ***PT, aPTT
6. ***Cultures of blood, urine, other possible primary sites of infection
7. ***Serological tests for ANA, RF, ACPA
8. Radiograph of joint + contralateral joint (for comparison)
9. ***Arthroscopy
10. ***Synovial biopsy
11. Other imaging studies (USG, CT, MRI)

Question 5

Synovial fluid analysis

Answer 5

USG-guided knee joint aspiration

Indications:
1. Infection
2. Crystal arthritis
3. Haemarthrosis
4. Differentiating inflammatory from non-inflammatory arthritis

Examination
1. Appearance
- Colour
- Turbidity
- Viscosity

2. Microscopy
   - **Cell stains + counts
   - Wet films
   - **Polarised light
3. Microbiology
   - Gram stain
   - Culture
   - Special techniques e.g. ZN stain, Fungal stain

Question 6

***Classification of Synovial effusions

Answer 6

1. Non-inflammatory (Normal / OA)
   - Viscosity: High
   - Colour: Straw to yellow
   - Clarity: Transparent
   - WBC: 200-2000
   - PMN leukocytes: <25%
2. Inflammatory (RA / Crystal)
   - Viscosity: ***Low
   - Colour: Yellow
   - Clarity: Translucent / Turbid
   - WBC: 2000-75000
   - PMN leukocytes: >50% often
3. Septic
   - Viscosity: Variable
   - Colour: Variable
   - Clarity: **Opaque
   - WBC: **>100000 often
   - PMN leukocytes: ***>75%
4. Haemarthrosis
   - Viscosity: ***Low
   - Colour: Bloody
   - Clarity: Blood-like
   - WBC: similar to blood level
   - PMN leukocytes: similar to blood level

Question 7

Polarised microscopy

Answer 7

Monosodium urate monohydrate (Gout): **Needle shaped, **Negative birefringence
Calcium pyrophosphate dihydrate (Pseudogout): **Rhomboid shaped, **Positive birefringence

Birefringent crystal (colour shift of crystal) altering the vector of plane polarised light —> allow it to be seen at microscope eye piece

Unpolarised light
—> Polariser
—> Light resolved into rays on a vertical axis
—> Crystal
—> Light rays twisted to a horizontal plane by crystal
—> Analyser (a red compensator to filter out background polarised light so can only see diffracted light from crystals)
—> Align crystal to axis of Analyser
—> Only rays vibrating in a horizontal axis allowed through
—> Can be seen by eye

Birefringence can be detected by a colour shift to blue (positive) or yellow (negative) when the long axis of crystal is aligned with the optical axis of a first order red compensator

Question 8

Arthroscopy

Answer 8

Allow direct visualisation of arterial surface

Diagnostic:
- Assess degree of cartilage damage
- ***Synovial biopsy for equivocal cases

Therapeutic:
- ***Debride damaged cartilage
- Remove loose bodies
- Provide a short period of pain relief

Question 9

Septic arthritis

Answer 9

• Most sinister type of monoarthritis —> ***Rheumatologic emergency
• Quick diagnosis + Aggressive treatment
• Bacterial infections esp. Gram +ve organisms can destroy joint cartilage within a few days (***very short time)
  —> need prompt + proper treatment to avoid permanent structural damage

Clinical presentation:
- **Abrupt onset
- Monoarticular involving large **weight bearing joints

Route of infection:
1. Haematogenous
2. Adjacent osteomyelitis
3. Adjacent soft tissue infection
4. Iatrogenic (e.g. diagnostic / therapeutic procedures like joint aspiration)
5. Penetrating damage by puncture / cutting

Causative agents:
1. Bacterial
2. Mycobacterial
3. Fungal
4. Viral

Risk factors:
1. **Extreme of age (<5, >65)
2. **Chronic arthritic syndromes
- RA
- Crystal arthritis
- Severe OA
- Charcot joint
- Haemarthrosis
3. **Prosthetic joints
4. **Intra-articular injection / arthrocentesis
5. **Parenteral drug user
6. **STD
- localised gonococcal disease —> disseminate to cause joint disease
7. Chronic skin infections
8. Chronic systemic illness
- DM, SLE, malignancy, immunocompromised state

Question 10

Acute bacterial arthritis

Answer 10

Children >2 years + adults
- **Streptococcus
- **Staphylococcus aureus

Special consideration
- Infant < 1month: **GBS, **Gram -ve bacilli (e.g. E. coli), Staphylococcus aureus
- Children <2 years: **Hib
- Elderly / chronically ill: **Gram -ve bacilli
- Sexually active young adults: **N. gonorrhoeae (particular of disseminated gonococcal infection, usually polyarticular)
- IVDU: Gram -ve bacilli, Pseudomonas aeruginosa, **Staphylococcus aureus
- Late prosthetic joint infection: Staphylococcus aureus
- Skin / soft tissue infection: Streptococcal
- Foul smelling / gas forming: ***Anaerobes e.g. C. difficile

Question 11

General approach to Septic arthritis

Answer 11

1. High level of suspicion
   - acute history of ***hot, swollen, tender joints with restriction of movement
2. Prompt + appropriate treatment
   - if suspicion is high, treat even in absence of fever but only after joint aspiration
   - Negative gram smear / culture does NOT exclude sepsis
3. Involve OT surgeons

Question 12

Investigations of Septic arthritis

Answer 12

1. Synovial joint aspiration + Culture (most important)
   - fluid sent fresh for relevant stains + culture
   - **prior to antibiotic therapy
   - **warfarin not CI for needle aspiration
   - if hip joint involved —> always do imaging-guided joint aspiration
2. ***Blood culture always be taken
3. CBP, ESR, CRP
4. Electrolytes, Baseline LRFT
   - detect end-organ damage
   - guide antibiotic choice
5. Plain X-ray
6. MRI (most appropriate where required)
   - also sensitive in detecting ***osteomyelitis

Question 13

Treatment of Septic arthritis

Answer 13

**Parenteral antibiotic
- mainstay of treatment
- different initial **empirical antibiotic cover for different patient groups until positive culture / sensitivity
- in doubt, consult microbiologist

Patient group:
1. No risk factors for atypical organisms
- **Flucloxacillin 2g QDS IV
- **Clindamycin 450-600mg QDS IV or 2nd / 3rd gen ***Cephalosporin IV

2. High risk of Gram -ve sepsis (elderly, frail, recurrent UTI, recent abdominal surgery)
   - 2nd / 3rd gen ***Cephalosporin IV
3. MRSA risk (known MRSA, recent inpatient, nursing home resident, leg ulcers, catheters)
   - ***Vancomycin IV + 2nd / 3rd gen Cephalosporin IV
4. Suspected gonococcus / meningococcus
   - ***Ceftriaxone IV
5. IVDU
   - Discuss with microbiologist
6. ITU patients, known colonisation of other organs (e.g. cystic fibrosis)
   - Discuss with microbiologist

Surgical management by OT surgeon
1. Confirm diagnosis by examination of joint aspirate
2. **Urgent joint irrigation / **debridement
3. Acute phase: **Arthroscopy
4. Delayed / Chronic cases: **Open arthrotomy
5. Repeated surgical debridement until infection under control
6. Be prepared for co-existing osteomyelitis

Question 14

Crystalline particles in joint disease

Answer 14

Intrinsic:
1. **Monosodium urate monohydrate (most common)
2. **Calcium pyrophosphate dihydrate (most common)
3. Calcium phosphates
- acidic: brushite, monetite, **calcium oxalate
- basic: **hydroxyapatite, octacalcium phosphate, tricalcium phosphate
4. Lipids
- cholesterol
- lipid liquid crystals
- Charcot-Leyden (phospholipase) crystals
5. Cystine
6. Xanthine, hypoxanthine
7. Protein precipitates (e.g. cryoglobulins)

Extrinsic:
1. ***Synthetic corticosteroids
2. Plant thorns (semicrystalloid cellulose), esp. blackthorn, rose, dried palm fronds
3. Sea-urchin spines (crystalline calcium carbonate)

Question 15

Clinical features of Gout

Answer 15

1. Asymptomatic hyperuricaemia
2. Acute gouty arthritis
   - M:F = 8:1
   - commonest age of onset: 30-60 yo
   - initial presentation: **monoarticular
   - 1st MTP joint affected first in 20%
   - systemic upset common during acute stage (e.g. **low grade fever)
   - pruritus + desquamation of overlying skin
   - diagnosis: **Demonstration of UA crystal in joint
   - serum UA level useful but **not diagnostic
   (- may actually ***↓ during flare up) (check urate when gout attack subside: 4-6 weeks + other tests e.g. lipid profile, RFT, FG 1 week prior to FU to check for other associated conditions (SpC FM))
3. Intercritical gout
   - entirely asymptomatic in between attacks
   - attacks getting ***more frequent
   - may become polyarticular
4. Chronic tophaceous gout
   - **tophi: hallmark
   - tophi in periarticular tissues, **helix of ears, tendon sheaths
   - rarely in larynx, tongue, heart
   - in 60% of patients after 10 years of gout

X-ray:
- 1st MTP: ***punched out erosive lesion (characteristic of gout)

Clinical associations:
1. Obesity
2. **Heavy alcohol intake
3. **Type 4 hyperlipoproteinaemia (high TG contained in VLDL)
4. Impaired glucose tolerance
5. IHD
6. HT

Question 16

Natural history of gout

Answer 16

Stage 1:
- Asymptomatic hyperuricaemia —> No arthritis

Stage 2:
- Acute gouty arthritis / Intercritical gout
- Duration: 1-2 weeks to 1 week-2 months
- Interval: 6 months-2 years to 2 weeks-4 months
- Number of joints involved: 1-2 to 4-5

Stage 3:
- Chronic gouty arthritis
—> Continuous arthritis + Superimposed acute attacks
—> Tophi

Progression from stage 1 to 2 variable: short / long

Question 17

***Causes of hyperuricaemia

Answer 17

1. Dietary excess
2. Overproduction of urate
3. Underexcretion of urate (>90%)

Balance of uric acid:
1. Dietary nucleotides, nucleoproteins (1/3)

2. Production: Cellular nucleotides, nucleoproteins breakdown (2/3)
   —> Purine (Adenine, Guanine)
   —> Purine breakdown —> Uric acid
3. Excretion
   - Gut excretion (bacterial degradation) (1/3)
   - ***Renal excretion (10% of filter load) (2/3)

Question 18

Urate in Kidney

Answer 18

1. Glomerular filtration of all serum urate
2. Proximal tubular resorption of 99% of filter load
3. Resecretion of 50% of resorbed load
4. Resorption of ~80% of resecreted urate
5. Excretion of ~10% of all filtered load

Urate secretion / reabsorption are bidirectional
- Salicylate, Thiazide, Loop diuretic —> competitive substrate for secretion by transporter ABCG2, NPT1, NPT4, MRP4
- Penicillin, Cephalosporin, Methotrexate, Thiazide —> competitive substrate for secretion by transporter OAT1, OAT3
- Fructose, Pyrazinamide, Lactic acid, Nicotinic acid —> exchange for urate —> ↑ reabsorption of urate

**Probenecid, **Losartan: antagonise urate reabsorption by blocking URAT1 —> ***uricosuric effect

Question 19

Overproduction of uric acid

Answer 19

Primary hyperuricaemia
1. **Idiopathic
2. Complete / Partial deficiency of **HGPRT (hypoxanthine-guanine phosphoribosyltransferase) —> ↑ Xanthine production
3. Superactivity of ***PRPP (phosphoribosyl pyrophosphate) synthetase —> ↑ Xanthine production

**Secondary hyperuricaemia (more common)
1. **Excessive purine consumption (e.g. heavy beer drinking)
2. **Myeloproliferative / Lymphoproliferative disorders
3. **Haemolytic diseases
4. ***Psoriasis
5. Glycogen storage diseases: type 1, 3, 5, 7

Question 20

***Underexcretion of uric acid

Answer 20

Primary hyperuricaemia
1. ***Idiopathic

**Secondary hyperuricaemia
1. **Decreased renal function
2. **Metabolic acidosis (ketoacidosis / lactic acidosis)
3. Dehydration
4. **Diuretics
5. HT
6. ***Hyperparathyroidism
7. Drugs (cyclosporine, pyrazinamide, ethambutol, low-dose aspirin)
8. Lead nephropathy

Question 21

Overproduction + Underexcretion of urate

Answer 21

1. ***Alcohol use
2. ***G6PD deficiency
3. ***Fructose-1-phosphate-aldolase deficiency

Question 22

***Management of gout

Answer 22

Objectives:
1. Rapid + safe pain relief
2. Prevent further attacks
3. Prevent formation of tophi / destructive arthritis
4. Address associated medical conditions

Drugs:
Acute attacks
1. ***Oral Indomethacin (widely used) (COX-1 selective)
- aspirin, salicylate should be avoided (↓ effect of uricosuric agents)

2. ***COX-2 selective inhibitors (recent GI bleeding / high GI risk)
   - Etoricoxib
3. **Colchicine
   - diagnostic + therapeutic value but narrow margin between therapeutic and doses
   - but **slow onset of action
4. Steroid (2nd line)
   - intra-articular / oral / parenteral (e.g. IM)
5. Anti-IL1 (2nd line)
   - Anakinra, Canakinumab (injection)

Long term management (prevent recurrent attacks)
(SpC Medicine + Blue book: Initiate when
- **>=2 attacks within 1 year
- **Tophaceous disease
- **Coexistent / Past history of renal impairment
- **Urolithiasis)
1. **Allopurinol
- **Xanthine oxidase inhibitor
- usual dose: 300mg daily
- but higher dose may be used in severe cases, smaller dose in renal insufficiency
- SE: severe skin reaction: **SJS (HLA-B5801)

2. **Probenecid / Sulphinpyrazone
   - **Uricosuric agents —> ↑ uric acid excretion
   - CI in:
   —> primary overproduction of uric acid
   —> gross hyperuricosuria
   —> evidence of urolithiasis
   —> renal insufficiency
3. Febuxostat
   - Selective Xanthine oxidase / Xanthine dehydrogenase inhibitor
   - fewer severe skin reactions but relatively CI in ***liver impairment
4. Newer urate lowering drugs
   - Pegloticase: recombinant uricase (Uricolytic agent) (changes urate to allantoin: more soluble than urate —> easier to excrete) (G6PD haemolysis)
   - Lesinurad: URAT1 inhibitor —> ↓ reabsorption of urate from proximal tubules
5. Low purine diet (CL Lai)
   - Avoid alcohol, shellfish (e.g. mussels), liver, tuna, salmon, mushrooms, strawberry
6. Avoid high fructose drink (e.g. soft drinks) (SpC FM)

Question 23

Colchicine (From MSS21)

Answer 23

Clinical applications:
- ↓ inflammation during gouty attack
- prophylaxis of gout flare with urate-lowering therapy

MOA:
**Reduce phagocytosis of urate
1. Inhibit **Tubulin polymerization into microtubules
—> inhibit leukocyte migration and phagocytosis
2. Inhibit ***Leukotriene B4 formation
—> ↓ inflammatory response

Adverse effects (**inhibit cell division in fast-growing cells: GI tract):
- **Diarrhoea
- **N+V, **abdominal pain
- Hepatic necrosis, acute renal failure, DIC
- Seizures
- Hair loss
- ***Bone marrow depression
—> IV not accepted now
—> Lower dose recommended:
Acute relief: 1.2mg followed by 0.6mg after an hour
Prophylaxis: 0.6mg OD-TDS
—> ↓ dose / less frequent in hepatic / renal disease

Question 24

Xanthine oxidase inhibitors DDI

Answer 24

Allopurinol / Febuxostat should NOT be co-prescribed with **Azathioprine
—> interfere with metabolism of Azathioprine (via **TPMT (SpC Medicine))
—> ↑ 6MP plasma level
—> potentially fatal blood ***dyscrasias

Careful monitoring of patients ***CBC if both drugs have to be prescribed

Question 25

Principles of Long-term drug treatment of gout (e.g. Xanthine oxidase inhibitor, Uricosuric agents)

Answer 25

1. NOT to be started until acute attack has completely subsided
   - may exacerbate attack (Gout flare)
2. Co-administration with **prophylactic Colchicine / NSAID during first **3 months to prevent “breakthrough” attacks
3. Serious toxic reactions may occur (although rare)
   - **Toxic epidermal necrolysis + Vasculitis (Allopurinol)
   - **Nephrotic syndrome (Probenecid)
   - Hepatitis, ***BM suppression (both)
   —> carefully monitor
4. Hypouricaemic agents considered when (Xanthine oxidase inhibitor / Uricosuric agents)
   - **Recurrent + troublesome acute attacks
   - **Evidence of tophi / chronic joint damage
   - In presence of renal disease
   - Young patient, high urate level, family history of renal / heart disease
   - Evidence of primary purine overproduction + underexcretion

Question 26

Pitfalls on gout

Answer 26

1. High serum urate + arthritis =/= Gout
2. Arthritis but low serum urate =/= Not gout
   - defined by deposition in joint
   - may not always be associated with hyperuricaemia
3. Great toe arthritis =/= gout
   - ***hallux rigidis / hallux valgus more common
4. Allopurinol not indicated in all gout cases
   - proper diet change, adequate hydration, reduction in alcohol consumption —> allopurinol may not be needed

Question 27

Calcium pyrophosphate deposition disease (CPPD)

Answer 27

Aka **Chondrocalcinosis, **Pseudogout
- present in 6% of individuals >72 yo
- M:F = 1.4:1
- incidence ↑ with age
- incidence of symptomatic disease ~50% of gout

Clinical presentation:
1. Asymptomatic (most patients)
2. May mimic gout, RA, OA, septic arthritis, rarely ankylosing spondylitis (CPPD crystals deposit in intervertebral discs)
3. ***Knees most commonly affected

(From MSS15:
2 presentations:
1. Acute synovitis (mimic gout)
- ***Pseudogout
- Superimposed on chronic arthropathy
- elderly women

2. Chronic pyrophosphate arthropathy (mimic OA)
   - unlike OA commonly affect Radiocarpal, Glenohumeral, Midtarsal joints (**Atypical joints)
   - Deposition of **rhomboidal CPP crystals (different crystal shape than urate crystal) from cartilage into joint space

(Normally:
- ATP from cells –> pyrophosphate + AMP; pyrophosphate –> inorganic phosphate by alkaline phosphatase
- under influence of growth promoting factors pyrophosphate complexes with Ca to form crystals)

X-ray:
Calcification of knee cartilage (Chondrocalcinosis) + Menisci

CPPD often **associated with OA
- OA contains replicating / damaged cells which **release ATP
- changes in cartilage matrix also interfere with growth factors (trigger Ca + pyrophosphate —> CPP crystal))

Question 28

Causes of CPPD disease

Answer 28

1. ***Hereditary
2. Sporadic (***Idiopathic)
3. Probable metabolic disease associations
   - **Hyperparathyroidism
   - Haemachromatosis
   - **Hypothyroidism
   - Gout
   - HypoMg
   - Hypophosphatasia
   - Ageing

Question 29

Treatment of CPPD disease

Answer 29

1. Asymptomatic
   - NOT require treatment
2. Acute attacks
   - **Treat as per gout (milder than gout)
   - NSAIDs, COX-2 inhibitors, Colchicine
   - Thorough **aspiration may be effective
3. NOT possible to remove CPPD crystals once deposited in cartilage
4. Treatment of underlying associated disease may NOT improve long term prognosis

Question 30

Haemarthrosis

Answer 30

Causes:
1. **Trauma
2. **Congenital Haemophilia (Factor 8 / 9 deficiency)
3. Acquired Haemophilia (AutoAb)
3. Drugs (Warfarin, Heparin)

S/S:
1. Pain
2. Swelling
3. Stiffness

Diagnosis:
- Arthrocentesis (i.e. Joint aspiration)
—> Viscosity: Low
—> Colour: Bloody
—> Clarity: Blood-like
—> WBC: similar to blood level
—> PMN leukocytes: similar to blood level

Treatment:
- Treat underlying cause

Question 31

Summary

Answer 31

Acute monoarthritis:
- Semi-emergency
- ***Septic arthritis until proven otherwise

Important investigations:
- Joint aspiration with synovial fluid analysis for **WBC, **Gram’s stain, **culture, **crystal

• Bacterial septic arthritis should be treated promptly with antibiotics according to culture sensitivity
• Surgical intervention indicated in some patients —> always get OT surgeon informed
• Acute crystal deposition arthritis: treated symptomatically with NSAIDs, Corticosteroid, Colchicine
• Implement long term prevention treatment in patients with recurrent attacks of gouty arthritis
• Definitive diagnosis of Haemarthrosis: Joint aspiration —> Treatment: treat underlying cause