Rheumatology & Musculoskeletal

Key Facts

OA is primarily a disease of articular cartilage failure, but it involves the entire joint including subchondral bone, synovium, ligaments, and periarticular muscles. It is a clinical diagnosis and does not require imaging for typical presentations.

Epidemiology

• Most common joint disease worldwide
• UK prevalence: ~8.75 million people with symptomatic OA
• Risk increases markedly with age (>50% of over 65s have radiographic evidence)
• F:M 2:1 (hand and knee OA); equal for hip OA
• Knee OA most common symptomatic site

Aetiology

• Primary (idiopathic): age-related, genetic predisposition
• Secondary: post-traumatic, obesity, joint instability, previous inflammatory arthritis, developmental abnormalities (DDH), metabolic (haemochromatosis, Wilson, acromegaly, CPPD)
• Risk factors: age >45, female sex, obesity (strongest modifiable risk factor), previous joint injury, occupational (kneeling, heavy lifting), family history, joint malalignment

Pathophysiology

• Not simply "wear and tear" – active biological process

• Subchondral bone: sclerosis (increased density), cyst formation
• Osteophytes: new bone formation at joint margins (attempted repair)
• Synovium: secondary low-grade synovitis (unlike RA, this is secondary to cartilage debris)
• Ligament and muscle: laxity and wasting contribute to joint instability

Typical Features

• Joint pain: worse with activity, relieved by rest (mechanical pattern)
• Morning stiffness: <30 minutes (unlike RA which is >30-60 minutes)
• Reduced range of motion: progressive
• Joint crepitus: grating sensation on movement
• Bony enlargement: Heberden nodes (DIP), Bouchard nodes (PIP)
• Joint instability: giving way, particularly knees

Distribution

• Knees: most common symptomatic joint
• Hips: groin pain, reduced internal rotation
• Hands: DIP, PIP, 1st CMC (thumb base – "squaring")
• Spine: cervical and lumbar spondylosis
• 1st MTP: can mimic gout

Red Flags (Suggest Alternative Diagnosis)

• Significant morning stiffness >60 minutes → inflammatory arthritis
• Multiple joint swelling with systemic features → RA, SLE
• Rapid onset monoarthritis → septic arthritis, gout
• Joint pain with erythema, warmth, fever → infection

Clinical Diagnosis (NICE NG226)

• No investigations required for typical presentation (age ≥45, activity-related pain, ≤30 min morning stiffness)
• Investigations only to exclude other diagnoses

If Atypical Features

• X-ray: LOSS features (Loss of joint space, Osteophytes, Subchondral sclerosis/cysts)
• FBC, ESR/CRP: normal in OA (elevated = consider inflammatory arthritis)
• RF, anti-CCP: negative in OA
• Serum urate: if gout suspected
• Ferritin/transferrin saturation: if haemochromatosis suspected (OA in unusual joints)
• Joint aspiration: if acute monoarthritis (exclude sepsis/crystal arthropathy)

Imaging

• X-ray: not needed for diagnosis but useful if atypical or pre-surgical planning
• MRI: not routine; occasionally for soft tissue assessment pre-surgery
• Poor correlation between X-ray severity and symptoms

Non-pharmacological (First-Line – Most Important)

• Exercise: strengthening, aerobic, flexibility; most effective intervention (NICE NG226)
• Weight loss: 5-10% body weight reduces pain by 25-50% in knee OA
• Patient education: self-management support, Versus Arthritis resources
• Physiotherapy: tailored exercise programme
• Walking aids: stick (opposite hand to affected hip/knee)
• Footwear advice: shock-absorbing insoles
• Occupational therapy: aids, adaptations, joint protection

Pharmacological (NICE NG226)

• Topical NSAIDs (diclofenac gel): first-line pharmacological for knee/hand OA
• Oral NSAIDs (naproxen 250-500mg BD + PPI; ibuprofen 400mg TDS + PPI): short-term, lowest effective dose
  • Consider CV risk (avoid in heart failure, IHD)
  • COX-2 selective (etoricoxib 30-60mg) if traditional NSAIDs not tolerated
• Topical capsaicin cream: 0.025-0.075% QDS; adjunct for knee/hand
• Paracetamol: NICE NG226 no longer recommends as sole analgesic for OA (limited efficacy)
• Intra-articular corticosteroid injection: for acute flares (short-term benefit)
• Duloxetine 30-60mg: emerging evidence for chronic OA pain (off-label)

NOT recommended (NICE):

• Hyaluronic acid injections
• Glucosamine/chondroitin supplements
• Acupuncture
• Opioids (avoid long-term; limited benefit, significant harm)

Surgical

• Total joint replacement (hip/knee): when non-surgical measures exhausted and significant impact on quality of life
• Refer regardless of age, BMI, or smoking status (NICE)
• >90% prosthesis survival at 10 years for knee and hip
• Alternatives: osteotomy (younger patients with malalignment), arthroscopy (very limited role)

Referral Criteria

• Failure of conservative management with significant functional limitation → orthopaedics
• Diagnostic uncertainty → rheumatology
• Night pain, rest pain, significant impact on daily activities → consider surgical referral

• Progressive condition with no disease-modifying drugs available
• Many patients manage well with lifestyle modifications and analgesia
• Knee OA: 30-50% progress to severe disease requiring arthroplasty over 10-15 years
• Hip replacement: 95% survival at 10 years; 85% at 25 years (National Joint Registry data)
• Knee replacement: 95% survival at 10 years
• Cardiovascular risk: OA-related inactivity and NSAID use increase CV risk
• Obesity: single most important modifiable risk factor for both prevention and management

OA vs RA Comparison

Heberden and Bouchard Nodes

Key Facts

Gout is the most common inflammatory arthritis in developed countries. It is curable with effective urate-lowering therapy, yet remains widely under-treated.

Epidemiology

• UK prevalence: ~3.2% (~2.5% men, ~1.4% women); increasing
• M:F 4:1 (pre-menopausal women rarely affected – oestrogen is uricosuric)
• Peak incidence: men 40-60 years; women post-menopausal
• Prevalence increasing due to obesity, metabolic syndrome, ageing, diuretic use

Aetiology

• Hyperuricaemia (serum urate >360 µmol/L) is the primary risk factor
• Under-excretion of urate (90%): CKD, diuretics (thiazide, loop), low-dose aspirin, ciclosporin
• Over-production of urate (10%): myeloproliferative disorders, tumour lysis syndrome, Lesch-Nyhan syndrome, high-purine diet
• Dietary risk factors: red meat, shellfish, alcohol (especially beer), fructose-sweetened drinks
• Protective factors: vitamin C, coffee, cherries (limited evidence)

Pathophysiology

• Hyperuricaemia → MSU crystal deposition in joints, tendons, soft tissues

• Acute gout: phagocytosis of crystals by neutrophils → intense pain and swelling
• Chronic tophaceous gout: deposition of large urate collections in soft tissues and joints
• Crystals can be present in joints for years before first clinical attack

Acute Gout

• Sudden-onset excruciating monoarthritis (often nocturnal)
• 1st MTP (podagra) in 50-70% of first attacks
• Also: ankle, knee, wrist, elbow, small hand joints
• Joint is red, hot, swollen, exquisitely tender (cannot bear weight or touch)
• Overlying skin may peel during resolution
• Self-limiting: resolves in 7-14 days without treatment

Chronic Tophaceous Gout

• Tophi: chalky deposits of MSU crystals in skin, joints, cartilage
• Common sites: pinnae of ears, olecranon, Achilles tendon, fingers
• Joint destruction and deformity
• Chronic pain and disability

Associated Conditions

• Metabolic syndrome: obesity, hypertension, diabetes, dyslipidaemia
• CKD: both cause and consequence
• Renal stones: uric acid stones (10% of gout patients)
• Cardiovascular disease: increased CV risk

Red Flags

• Monoarthritis + fever → exclude septic arthritis (MUST aspirate)
• First attack in pre-menopausal woman → unusual; consider secondary causes
• Very high urate + renal impairment → consider tumour lysis syndrome

Gold Standard

• Joint aspiration: needle-shaped, negatively birefringent crystals under compensated polarised light microscopy
• Also: WCC elevated (typically 10,000-50,000/mm³; if >50,000 consider septic arthritis)
• Send for Gram stain and culture (exclude co-infection)

Bloods

• Serum urate: may be NORMAL during acute attack (urate drops during inflammation); repeat 2-4 weeks after attack
• FBC: leucocytosis
• CRP/ESR: elevated
• U&Es: assess renal function (CKD common)
• Lipid profile, HbA1c, LFTs: metabolic syndrome screening

Imaging

• X-ray: normal in early disease; chronic: well-defined "punched-out" erosions with overhanging margins ("rat-bite" erosions), soft tissue tophi
• Dual-energy CT (DECT): identifies MSU crystal deposits; useful for diagnosis in difficult cases
• Ultrasound: "double contour sign" (MSU crystal layer on cartilage surface); hyperechoic aggregates

Acute Gout (NICE CKS / BSR Guidelines)

First-line (choose one):

• NSAID: naproxen 750mg stat then 250mg TDS (with PPI) until attack resolves
• Colchicine: 500mcg BD-TDS until attack resolves (max 6mg per course); preferred if NSAID contraindicated
• Prednisolone: 30-40mg OD for 5 days; or IM depomedrone 120mg; preferred if NSAID and colchicine contraindicated

Adjuncts:

• Rest, ice, elevate affected joint
• Intra-articular corticosteroid if single large joint

NOT recommended acutely:

• Do NOT start or stop allopurinol during acute attack
• Avoid aspirin (alters urate handling)

Urate-Lowering Therapy (Chronic Management)

Indications:

• ≥2 attacks per year
• Tophi present
• Renal stones
• CKD
• Concurrent diuretic therapy
• Consider after first attack if high urate or severe presentation

First-line:

• Allopurinol: start 100mg OD (50mg if eGFR <20); titrate by 100mg every 4 weeks to target urate <360 µmol/L (or <300 if tophi)
• Max dose: 900mg (limited by tolerability; most need 300-600mg)
• Cover initiation with colchicine 500mcg OD for 6 months to prevent flares during urate lowering

Second-line:

• Febuxostat 80mg OD (titrate to 120mg): if allopurinol intolerant/ineffective (NICE TA164)
  • CARES trial: slightly increased CV mortality vs allopurinol; use with caution in established CVD
• Uricosuric: benzbromarone (unlicensed in UK), probenecid (rarely used)

Lifestyle:

• Weight loss, reduce alcohol (especially beer), reduce purine-rich foods, increase hydration, reduce fructose intake
• Review medications: switch thiazide to alternative if possible; losartan and fenofibrate have mild uricosuric effect

Referral Criteria

• Diagnostic uncertainty (especially if septic arthritis cannot be excluded) → rheumatology
• Tophaceous gout or refractory disease → rheumatology
• Severe gout with CKD → nephrology/rheumatology

• Acute attacks are self-limiting (7-14 days) but recurrence rate is high (60% within 1 year, 78% within 2 years) without ULT
• ULT can render patients symptom-free with complete tophus resolution over months-years
• Target urate maintenance <360 µmol/L prevents crystal formation and allows dissolution
• Cardiovascular risk: gout is an independent risk factor for MI and CVD mortality
• Renal stones: 10-20% of gout patients; uric acid stones can be dissolved with urinary alkalinisation
• Gout is curable with effective ULT – yet remains under-treated in >50% of patients

Gout vs Pseudogout

Drugs Affecting Urate Levels

Key Facts

CPPD disease encompasses a spectrum from asymptomatic chondrocalcinosis to acute pseudogout to chronic arthropathy. Unlike gout, there is no effective crystal-dissolving therapy.

Epidemiology

• Prevalence increases with age: radiographic chondrocalcinosis in 10-15% of 65-75 year olds, >25% of >80 year olds
• Equal sex ratio
• Most common crystal arthropathy in the elderly

Aetiology

• Primary (idiopathic): age-related; most common
• Familial: autosomal dominant (ANKH gene mutations); younger onset
• Secondary (metabolic): hyperparathyroidism, haemochromatosis, hypomagnesaemia, hypophosphataemia, Wilson disease, hypothyroidism, gout

Pathophysiology

• Chondrocytes produce excess inorganic pyrophosphate (PPi) which combines with calcium in cartilage
• CPPD crystals deposit in hyaline and fibrocartilage → chondrocalcinosis
• Crystal shedding into joint space → acute inflammation (similar mechanism to MSU in gout)

• Chronic CPPD can cause OA-like destructive arthropathy (pyrophosphate arthropathy)

Acute Pseudogout (CPP Crystal Arthritis)

• Acute monoarthritis: knee most common, also wrist, ankle, shoulder
• Red, hot, swollen, painful joint
• Often precipitated by: surgery, illness, dehydration, blood transfusion
• Clinically indistinguishable from gout or septic arthritis
• Self-limiting over 1-3 weeks

Chronic CPPD Arthropathy

• Resembles OA but in atypical joints (wrist, MCP, elbow, shoulder)
• "Pseudo-RA": symmetrical polyarthritis with morning stiffness
• Progressive joint damage

Asymptomatic Chondrocalcinosis

• Incidental X-ray finding
• Very common in elderly; no treatment needed

Red Flags

• Acute monoarthritis + fever → exclude septic arthritis (MUST aspirate)
• CPPD in patient <55 → screen for metabolic causes
• Recurrent pseudogout → check calcium, PTH, ferritin, magnesium

Gold Standard

• Joint aspiration: rhomboid-shaped, weakly positively birefringent crystals under compensated polarised light microscopy
• WCC usually 10,000-50,000/mm³
• Gram stain and culture to exclude infection

Bloods

• Calcium and PTH: hyperparathyroidism screen
• Ferritin and transferrin saturation: haemochromatosis screen
• Magnesium: hypomagnesaemia
• TFTs: hypothyroidism
• U&Es: renal function
• ESR/CRP: elevated during acute attack

Imaging

• X-ray: chondrocalcinosis – linear calcification within cartilage
  • Knee menisci (most common site)
  • Wrist triangular fibrocartilage
  • Pubic symphysis
  • Shoulder labrum
• Ultrasound: hyperechoic deposits within cartilage (distinct from gout's double contour sign on cartilage surface)

Acute Pseudogout

• Joint aspiration: therapeutic (removes crystals and inflammatory fluid) + diagnostic
• Intra-articular corticosteroid: triamcinolone acetonide 40mg (knee) – often most effective
• NSAIDs: naproxen 500mg BD (with PPI) for 7-14 days
• Colchicine: 500mcg BD-TDS; particularly if NSAIDs contraindicated
• Oral prednisolone: 30mg for 5 days if NSAIDs and colchicine contraindicated
• Ice and rest during acute attack

Prophylaxis (Recurrent Attacks)

• Low-dose colchicine: 500mcg OD-BD (reduces frequency of attacks)
• Low-dose prednisolone: if colchicine not tolerated
• IL-1 inhibitors (anakinra): emerging evidence for refractory cases

Chronic CPPD Arthropathy

• Manage as OA: exercise, weight management, physiotherapy
• Pharmacological: paracetamol, topical/oral NSAIDs, intra-articular steroids
• Joint replacement: for severe destructive arthropathy

Treat Underlying Metabolic Cause

• Hyperparathyroidism: parathyroidectomy (may reduce attacks)
• Haemochromatosis: venesection (may not reverse chondrocalcinosis)
• Hypomagnesaemia: magnesium supplementation

Referral Criteria

• Diagnostic uncertainty → rheumatology
• Age <55 with CPPD → metabolic workup
• Recurrent/refractory attacks → rheumatology

• Acute attacks are self-limiting (1-3 weeks)
• No disease-modifying therapy available (unlike gout)
• Chronic CPPD arthropathy: progressive; similar trajectory to OA
• Chondrocalcinosis may be incidental and asymptomatic (no treatment needed)
• Metabolic causes: treating underlying condition may reduce flare frequency
• Joint replacement: effective for severe destructive CPPD arthropathy

CPPD Disease Spectrum

Metabolic Associations (Mnemonic: WHOP)

Key Facts

AxSpA represents a spectrum from non-radiographic (no X-ray sacroiliitis) to radiographic (ankylosing spondylitis). Early diagnosis and treatment prevent irreversible spinal fusion.

Epidemiology

• Prevalence: 0.1-0.5% of the UK population
• M:F 2-3:1 (being revised; women often present differently)
• Typical onset: 15-30 years; diagnosis often delayed by 8-10 years
• HLA-B27 positive in >90% of AS; only 5% of HLA-B27 carriers develop AS

Aetiology

• Strong genetic component: HLA-B27 (90%+), ERAP1, IL-23R polymorphisms
• Environmental triggers: gut microbiome, infections (reactive arthritis model)

Pathophysiology

• Enthesitis (inflammation at tendon/ligament insertions into bone) is the primary pathological process
• Sacroiliac joints and spine most affected

• TNF-α and IL-17A are key cytokines driving inflammation and new bone formation

Inflammatory Back Pain (Key Feature)

• Insidious onset, age <40 years
• Duration >3 months
• Improves with exercise, worse with rest/inactivity
• Morning stiffness >30 minutes (often >1 hour)
• Wakes patient in second half of the night
• Alternating buttock pain (sacroiliac joint inflammation)
• Good response to NSAIDs

Spinal

• Reduced spinal mobility: Schober's test (<5cm increase; normal >5cm)
• Reduced chest expansion (<2.5cm in advanced disease)

• Tragus-to-wall distance increases as cervical spine fuses

Peripheral

• Peripheral arthritis (30-40%): large joint, asymmetric (hip, knee, shoulder)
• Enthesitis: Achilles tendinitis, plantar fasciitis
• Dactylitis: sausage digit (less common than psoriatic arthritis)

Extra-Articular Manifestations

• Anterior uveitis (25-40%): acute unilateral eye pain, photophobia, red eye
• Cardiovascular: aortitis, aortic regurgitation, conduction defects
• Pulmonary: apical fibrosis (rare)
• Renal: IgA nephropathy, amyloidosis (rare)
• IBD: Crohn's or UC in 5-10%
• Osteoporosis: paradoxically common despite new bone formation; increased fracture risk

Red Flags

• Acute anterior uveitis → urgent ophthalmology
• New neurological symptoms → spinal fracture (even minor trauma in fused spine)
• Cauda equina syndrome → rare late complication

Bloods

• HLA-B27: positive in >90% of AS; but NOT diagnostic alone (5-8% of general population are HLA-B27+)
• ESR/CRP: elevated in 50-70% (poor sensitivity; normal CRP does not exclude AS)
• FBC: normocytic anaemia of chronic disease may be present

Imaging

• MRI sacroiliac joints: first-line for early axSpA; bone marrow oedema on STIR sequences indicates active sacroiliitis

• Modified New York criteria require radiographic sacroiliitis (grade ≥II bilateral or grade III-IV unilateral)

Clinical Assessment

• BASDAI (Bath AS Disease Activity Index): patient-reported; score 0-10 (≥4 = active disease)
• BASFI (Bath AS Functional Index): functional limitation
• BASMI (Bath AS Metrology Index): spinal mobility measurements
• Schober's test: mark at L5, measure 10cm above; flex forward; <5cm increase = reduced lumbar flexion
• Chest expansion: <2.5cm is abnormal

Non-pharmacological

• Regular exercise: most important intervention; supervised physiotherapy
• Hydrotherapy: warm water exercise; effective for pain and stiffness
• Posture advice: avoid prolonged flexion; firm mattress, sleep supine or prone
• NASS (National AS Society): patient education and support
• Smoking cessation: smokers have worse outcomes and poorer response to treatment

Pharmacological

First-line:

• NSAIDs (continuous): naproxen 500mg BD or etoricoxib 90mg OD
• UNIQUE in AS: regular NSAID use may slow radiographic progression (unlike other conditions)
• Try ≥2 different NSAIDs for ≥4 weeks each before declaring failure

Second-line (if NSAID failure + BASDAI ≥4):

• Anti-TNF: adalimumab 40mg SC alternate weeks, etanercept 50mg SC weekly, certolizumab, golimumab, infliximab (NICE TA383)
• IL-17A inhibitor: secukinumab 150mg SC monthly (NICE TA407), ixekizumab
• JAK inhibitors: tofacitinib, upadacitinib (emerging evidence)
• NO role for conventional DMARDs (methotrexate, sulfasalazine) for axial disease; sulfasalazine may help peripheral arthritis

Bridging:

• Local corticosteroid injection: for enthesitis, sacroiliac joint injection
• Oral prednisolone: NOT recommended for long-term use in AS (limited efficacy)

Surgical

• Hip replacement: for severe hip involvement (up to 30% require)
• Spinal osteotomy: for severe fixed kyphosis (rare, specialist centre)
• Spinal fracture fixation: fused spine is at high fracture risk (even minor trauma)

Monitoring

• BASDAI every 3-6 months
• CRP/ESR with disease activity assessments
• DEXA scan: osteoporosis screening (paradoxically common despite new bone formation)
• Cardiovascular risk: annual assessment

Referral Criteria

• Inflammatory back pain <45 years with ≥4 criteria → urgent rheumatology (NICE NG65)
• Inadequate response to ≥2 NSAIDs → biologic therapy assessment
• Acute anterior uveitis → ophthalmology (same day)

• Variable: many patients have mild disease with good functional outcomes
• Poor prognostic factors: hip involvement, high CRP, syndesmophytes at diagnosis, smoking, male sex, early onset
• Radiographic progression: ~30-50% develop significant spinal restriction; bamboo spine in ~10%
• Anti-TNF therapy: dramatically reduces disease activity and improves quality of life; may slow radiographic progression
• Life expectancy: slightly reduced (1.5-fold increased mortality, mainly cardiovascular)
• Work disability: 15-30% of patients unable to work after 20 years (improved with biologics)
• Spinal fracture risk: fused spine fractures easily (even with minor falls); often unstable → cord injury risk

Modified New York Criteria (1984)

Clinical criteria (≥1):

1. Inflammatory back pain
2. Limitation of lumbar motion (sagittal and frontal planes)
3. Reduced chest expansion (<2.5cm)

Radiological criterion:

• Sacroiliitis grade ≥II bilateral or grade III-IV unilateral

Definite AS: radiological criterion + ≥1 clinical criterion

ASAS Classification Criteria for axSpA

• Back pain ≥3 months, onset <45 years
• Imaging arm: sacroiliitis on MRI or X-ray + ≥1 SpA feature
• Clinical arm: HLA-B27 + ≥2 SpA features

SpA Features

Key Facts

PsA is a heterogeneous condition within the spondyloarthritis family. It can cause significant joint damage if untreated. Skin disease severity does not correlate with arthritis severity.

Epidemiology

• Prevalence: ~0.1-0.2% of general population; 20-30% of psoriasis patients
• Equal M:F for peripheral; M>F for axial
• Peak onset: 30-50 years (usually 5-10 years after psoriasis onset)
• Can present before psoriasis in 15-20%

Aetiology

• Genetic: HLA-B27 (axial), HLA-Cw6 (psoriasis), IL-23R, TRAF3IP2
• Environmental: trauma (Koebner phenomenon), infection, stress
• Obesity: increases risk and reduces treatment response

Pathophysiology

• IL-23/IL-17 axis is central (unlike RA which is more TNF/IL-6 driven)
• Enthesitis is a hallmark: inflammation at tendon/ligament-bone interface
• New bone formation (periostitis, enthesophytes) alongside erosion
• Synovitis with angiogenesis and pannus formation
• Nail involvement: nail matrix is anatomically continuous with DIP joint entheses

Five Clinical Patterns

1. Asymmetric oligoarthritis (40-50%): most common; few large/small joints; dactylitis
2. Symmetric polyarthritis (25-30%): mimics RA; MCP, PIP, wrist
3. DIP predominant (5-10%): classic but uncommon; strong nail association
4. Spondylitis/sacroiliitis (5-20%): inflammatory back pain; may be asymmetric sacroiliitis
5. Arthritis mutilans (<5%): severe destructive, resorptive arthropathy; telescoping digits ("opera glass" fingers)

Key Features

• Dactylitis (30-50%): diffuse swelling of entire digit ("sausage finger/toe")
• Enthesitis (30-50%): Achilles, plantar fascia, lateral epicondyle
• Nail changes (80-90% with PsA): pitting, onycholysis, subungual hyperkeratosis, oil drop sign
• Skin psoriasis: scalp, natal cleft, elbows, knees; severity does not correlate with arthritis

Extra-Articular

• Anterior uveitis: less common than AS
• IBD: associated
• Cardiovascular risk: increased (metabolic syndrome common)

Red Flags

• Rapidly progressive destructive arthritis → arthritis mutilans
• Significant functional limitation → early biologic therapy consideration
• New eye symptoms → uveitis; urgent ophthalmology

Bloods

• RF: negative in 85-90% (helps distinguish from RA)
• Anti-CCP: usually negative
• ESR/CRP: elevated in 40-50%
• Urate: may be elevated (psoriasis increases urate turnover)
• FBC: exclude other causes

Imaging

• X-ray hands/feet: erosions + periostitis (new bone formation) = characteristic; "pencil-in-cup" deformity, osteolysis, ankylosis, periosteal reaction
• X-ray pelvis: sacroiliitis (may be asymmetric, unlike AS)
• MRI SIJ: if axial disease suspected; bone marrow oedema
• Ultrasound: enthesitis, synovitis, dactylitis assessment

Classification

• CASPAR criteria: established inflammatory joint disease + ≥3 points from:
  • Current psoriasis (2 pts) or history (1 pt) or family history (1 pt)
  • Nail dystrophy (1 pt)
  • Negative RF (1 pt)
  • Dactylitis (1 pt)
  • Radiographic juxta-articular new bone formation (1 pt)

Non-pharmacological

• Exercise, physiotherapy, weight management
• Occupational therapy for hand involvement
• Dermatology co-management for skin disease

Pharmacological

Peripheral PsA:

• First-line DMARD: methotrexate 15-25mg weekly (treats both skin and joints)
• Alternatives: sulfasalazine, leflunomide (hydroxychloroquine generally avoided – can worsen psoriasis)
• Biologic DMARDs (NICE criteria: DAS28-equivalent ≥3.2 or oligoarthritis with significant impact despite csDMARDs):
  • Anti-TNF: adalimumab, etanercept, infliximab, certolizumab, golimumab
  • IL-17A inhibitor: secukinumab 150-300mg SC monthly; ixekizumab
  • IL-12/23 inhibitor: ustekinumab 45-90mg SC
  • IL-23 inhibitor: guselkumab
• Apremilast (PDE4 inhibitor) 30mg BD: oral option after DMARD failure (NICE TA433)
• JAK inhibitors: tofacitinib 5mg BD, upadacitinib 15mg OD

Axial PsA:

• NSAIDs first-line (as per axSpA)
• Anti-TNF or IL-17 inhibitor if NSAID failure
• csDMARDs NOT effective for axial disease

Enthesitis/Dactylitis:

• NSAIDs, local corticosteroid injection
• Biologics if refractory

Referral Criteria

• Suspected PsA → rheumatology
• Psoriasis patients with joint symptoms → rheumatology assessment
• Inadequate DMARD response → biologic therapy

• 20-30% develop significant erosive disease
• Arthritis mutilans in <5% – devastating but rare
• DAS28 remission achievable in 40-60% with modern therapy
• Biologics significantly reduce radiographic progression
• Cardiovascular mortality increased (HR ~1.4); aggressive CV risk management needed
• Functional outcomes: generally better than RA if treated early
• Skin and joint disease: often discordant; skin may remit while joints progress (or vice versa)

PsA vs RA

CASPAR Classification Criteria

Score ≥3 with inflammatory joint disease = PsA (98% specificity)

Key Facts

Reactive arthritis is an immune-mediated response to a distant infection. The joint itself is sterile. Identifying and treating the triggering infection (particularly Chlamydia) is important but does not alter the course of the arthritis.

Epidemiology

• Incidence: ~30-40 per 100,000 following STI; ~5-14 per 100,000 following GI infection
• Most common in young adults (20-40 years)
• Post-STI form: M>>F; Post-GI form: M=F
• 1-4% of patients with Chlamydia, Salmonella, or Shigella develop reactive arthritis

Aetiology

Genitourinary triggers:

• Chlamydia trachomatis (most common overall)
• Ureaplasma urealyticum

Gastrointestinal triggers:

• Salmonella, Shigella, Campylobacter, Yersinia enterocolitica, C. difficile

Pathophysiology

• Molecular mimicry: bacterial antigens share epitopes with self-antigens in HLA-B27+ individuals
• Bacterial components (LPS, DNA, RNA) found in synovial fluid but viable organisms are absent
• IL-23/IL-17 axis involvement (as with other spondyloarthropathies)
• Enthesitis is a primary pathological feature

Musculoskeletal

• Asymmetric oligoarthritis: typically knee and ankle (lower limb predominant)
• Onset 1-4 weeks after triggering infection
• Dactylitis: sausage digit
• Enthesitis: Achilles tendinitis, plantar fasciitis
• Sacroiliitis/spondylitis: inflammatory back pain (20-30%)

Extra-Articular

• Eyes: conjunctivitis (30-50%); anterior uveitis (less common but more serious)
• Urogenital: urethritis (even post-GI infection), prostatitis
• Skin: keratoderma blennorrhagicum (waxy papules on soles/palms – resembles pustular psoriasis), circinate balanitis (painless lesions on glans penis)
• Oral: painless oral ulcers
• Nails: nail dystrophy (resembles psoriatic nail disease)

Red Flags

• Hot, swollen joint + fever → exclude septic arthritis (aspirate urgently)
• Acute anterior uveitis → ophthalmology referral
• Cardiac conduction abnormalities (rare – aortitis)

Bloods

• ESR/CRP: elevated
• HLA-B27: positive in 50-80% (associated with severity and chronicity; NOT diagnostic)
• FBC: leucocytosis
• RF, anti-CCP: negative (excludes RA)

Infection Screen

• NAAT for Chlamydia: first-void urine or urethral/endocervical swab
• Stool culture: if GI symptoms preceded arthritis
• Blood cultures: if febrile (exclude sepsis)

Joint Aspiration

• Inflammatory fluid: elevated WCC (usually 10,000-50,000), sterile culture
• No crystals (excludes gout/pseudogout)
• Gram stain and culture to exclude septic arthritis

Imaging

• X-ray: usually normal early; periostitis and enthesophytes if chronic
• MRI SIJ: if axial symptoms
• Ultrasound: synovitis, enthesitis, dactylitis

Acute

• NSAIDs: naproxen 500mg BD or indomethacin 50mg TDS (first-line)
• Intra-articular corticosteroid: for persistent monoarthritis
• Rest and physiotherapy: maintain joint range of motion

Infection Treatment

• Chlamydia: doxycycline 100mg BD for 7 days (treat patient and partner)
• Treatment of GI infection: usually self-limiting; antibiotics do not alter arthritis course
• Prolonged antibiotics for arthritis itself: NOT recommended (no evidence of benefit)

Chronic/Refractory (>6 months)

• Sulfasalazine 500mg-1g BD: first-line DMARD for chronic reactive arthritis
• Methotrexate 15-25mg weekly: if sulfasalazine fails
• Anti-TNF: adalimumab, etanercept for severe, refractory cases
• Intra-articular steroids: ongoing for individual joint flares

Eye

• Conjunctivitis: usually self-limiting; lubricant eye drops
• Anterior uveitis: urgent ophthalmology; topical corticosteroid drops + mydriatic

Referral Criteria

• Persistent arthritis >6 weeks → rheumatology
• Acute anterior uveitis → ophthalmology
• STI confirmed → GUM clinic referral

• Self-limiting in 60-80%: resolves within 3-12 months
• Chronic or relapsing: 20-30%; more likely if HLA-B27 positive
• Progression to AS: 15-30% of HLA-B27 positive patients over 10-20 years
• Functional outcomes: majority have good functional outcome
• Recurrence: 15-50% have at least one recurrence
• Poor prognostic factors: HLA-B27, hip involvement, raised ESR, poor response to NSAIDs

Reactive Arthritis vs Gonococcal Arthritis

Spondyloarthritis Shared Features

Key Facts

Enteropathic arthritis is part of the spondyloarthritis family. Managing the arthritis requires collaboration between rheumatology and gastroenterology.

Epidemiology

• Peripheral arthritis: 10-20% of IBD patients
• Axial disease: 5-10% of IBD patients
• Sacroiliitis (asymptomatic): up to 20-30% on MRI
• More common in Crohn's (especially colonic) than UC
• Can precede IBD diagnosis in some cases

Aetiology

• Shared genetic susceptibility: IL-23R, CARD15/NOD2 (Crohn's), HLA-B27 (axial)

• Gut-joint axis: shared homing molecules on lymphocytes

Pathophysiology

• IL-23/IL-17 pathway dysregulation (common to spondyloarthropathies and IBD)
• Activated gut-derived T cells and macrophages traffic to joints
• Mucosal inflammation leads to systemic cytokine release (TNF-α, IL-6)
• Enthesitis is a feature, as with other spondyloarthropathies

Type 1 Peripheral (Pauciarticular)

• <5 joints, typically large joints (knee, ankle, hip, elbow)
• Parallels gut disease activity: flares with IBD flares
• Self-limiting: episodes last weeks to months; non-erosive
• Associated with other extra-intestinal manifestations (erythema nodosum, pyoderma gangrenosum, uveitis)

Type 2 Peripheral (Polyarticular)

• ≥5 joints, often small joints (MCP, PIP)
• Independent of gut disease activity: chronic course
• May persist despite bowel remission
• Can be erosive

Axial Disease

• Sacroiliitis and/or spondylitis
• Independent of gut disease activity
• Inflammatory back pain pattern (as per AS)
• May be symmetric or asymmetric sacroiliitis
• Similar progression to AS in some patients

Other Extra-Intestinal Manifestations

• Erythema nodosum, pyoderma gangrenosum
• Anterior uveitis
• Primary sclerosing cholangitis (UC)

Red Flags

• New arthritis symptoms in IBD patient → screen for infection (joint aspiration if monoarthritis)
• Inflammatory back pain → MRI SIJ
• Eye symptoms → urgent ophthalmology

Bloods

• ESR/CRP: elevated (may reflect bowel or joint inflammation)
• FBC: anaemia (chronic disease, iron deficiency from IBD)
• RF, anti-CCP: negative (distinguishes from RA)
• HLA-B27: positive in 50-70% with axial disease
• LFTs: baseline (PSC screening, DMARD monitoring)
• Calprotectin: faecal calprotectin if IBD not yet diagnosed

Imaging

• X-ray: usually normal in type 1; erosive changes possible in type 2
• MRI SIJ/spine: if axial symptoms; sacroiliitis, spondylitis
• Ultrasound: synovitis, enthesitis

Joint Aspiration

• If monoarthritis: exclude septic arthritis and crystal arthropathy

Endoscopy

• If IBD not yet diagnosed but enteropathic arthritis suspected → colonoscopy with biopsies

Type 1 Peripheral

• Treat underlying IBD: often resolves the arthritis
• Simple analgesia: paracetamol
• NSAIDs: use cautiously (may exacerbate IBD); short courses of COX-2 selective (etoricoxib) may be safer
• Intra-articular corticosteroid: for individual joints
• Sulfasalazine: particularly for UC + peripheral arthritis

Type 2 Peripheral

• Sulfasalazine 500mg-1g BD: first-line DMARD
• Methotrexate 15-25mg weekly: if sulfasalazine insufficient
• Anti-TNF (infliximab, adalimumab): for refractory disease; treats both IBD and arthritis

Axial Disease

• Physiotherapy: essential (as per AS management)
• NSAIDs: cautious use; COX-2 selective preferred
• Anti-TNF: first-line biologic for axial disease not responding to NSAIDs (infliximab preferred if concomitant active IBD)
• IL-17 inhibitors: effective for axial disease BUT may worsen IBD (secukinumab associated with IBD flares)

General Principles

• Avoid NSAIDs long-term in IBD: risk of disease flare; use lowest dose for shortest time
• Shared care: rheumatology + gastroenterology MDT approach
• Anti-TNF therapy is ideal as it treats both conditions simultaneously

Referral Criteria

• IBD patient with persistent joint symptoms → rheumatology
• Arthritis preceding bowel symptoms → gastroenterology (investigate for subclinical IBD)
• Axial disease or biologic therapy needed → tertiary centre

• Type 1: self-limiting; parallels IBD; good prognosis
• Type 2: chronic; may cause joint damage; independent of IBD activity
• Axial disease: similar prognosis to AS in severe cases
• Anti-TNF therapy: excellent outcomes for both gut and joint disease
• Overall: less destructive than RA in most patients; early treatment important for type 2 and axial disease

Enteropathic Arthritis Classification

Extra-Intestinal Manifestations of IBD

Key Facts

SLE is the prototypical autoimmune disease with an extraordinary range of clinical manifestations. No two patients are the same. The goal of management is to prevent damage accumulation using a treat-to-target strategy.

Epidemiology

• UK prevalence: ~1 in 1,000 (higher in Afro-Caribbean: 1 in 250)
• F:M 9:1; peak onset 15-45 years
• More severe disease in Afro-Caribbean, Asian, and Hispanic populations
• Childhood-onset SLE (<18 years): more aggressive with higher renal and neurological involvement

Aetiology

• Genetic: HLA-DR2/DR3, complement deficiency (C1q, C2, C4), TREX1, DNase1
• Environmental: UV light (major trigger), EBV infection, silica, smoking
• Hormonal: oestrogen promotes disease (explains female predominance, flares in pregnancy)
• Drugs (drug-induced lupus): hydralazine, isoniazid, procainamide, minocycline, anti-TNF agents

Pathophysiology

• Loss of self-tolerance → autoreactive B and T cells
• Defective clearance of apoptotic cells → nuclear antigen exposure
• Autoantibody production: ANA, anti-dsDNA, anti-Sm, anti-Ro/La, antiphospholipid

• Complement consumption → low C3/C4 during flares
• Type III hypersensitivity (immune complex deposition) in kidneys, skin, joints
• Type II hypersensitivity (autoantibodies) → cytopenias

Constitutional (>90%)

• Fatigue (most common symptom), fever, weight loss, malaise

Musculoskeletal (>90%)

• Arthralgia and non-erosive arthritis (unlike RA)
• Jaccoud arthropathy: reducible deformities (subluxation without erosion)
• Avascular necrosis (especially femoral head) – related to steroid use

Skin (80%)

• Malar (butterfly) rash: erythematous, spares nasolabial folds, photosensitive
• Discoid lupus: scarring, atrophic plaques; can occur without systemic disease
• Photosensitivity: rash in sun-exposed areas
• Oral/nasal ulcers (usually painless)
• Alopecia (diffuse, non-scarring in SLE; scarring in discoid)
• Raynaud phenomenon (30-50%)
• Livedo reticularis (associated with antiphospholipid)

Renal (50%)

• Lupus nephritis: proteinuria, haematuria, declining eGFR
• Class IV (diffuse proliferative) most common and severe
• Nephrotic syndrome (class V)

Neuropsychiatric (30-40%)

• Cognitive dysfunction ("lupus fog")
• Seizures, psychosis, headache
• Cerebrovascular disease (especially with antiphospholipid)
• Peripheral neuropathy, cranial neuropathy

Haematological (>50%)

• Lymphopenia (most common haematological abnormality)
• Autoimmune haemolytic anaemia (Coombs-positive)
• Thrombocytopenia (autoimmune)
• Leucopenia

Serositis

• Pleurisy (most common serositis), pericarditis
• Libman-Sacks endocarditis (sterile vegetations)

Red Flags

• New neurological symptoms → neuropsychiatric lupus or antiphospholipid-related stroke
• Pancytopenia → macrophage activation syndrome (MAS)
• Recurrent pregnancy loss → screen for antiphospholipid antibodies

Immunology

• ANA: positive in >95% (screening test; not specific)
• Anti-dsDNA: specific (>95%); titre correlates with nephritis activity
• Anti-Sm: highly specific for SLE (~30% sensitive)
• Anti-Ro (SSA): associated with photosensitivity, neonatal lupus, congenital heart block
• Anti-La (SSB): associated with Sjogren syndrome overlap
• Antiphospholipid antibodies: lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I
• C3/C4: low during flares (complement consumption)
• Anti-C1q: correlates with lupus nephritis

Bloods

• FBC: lymphopenia, anaemia, thrombocytopenia
• ESR: elevated (CRP often normal unless infection/serositis)
• U&Es, urine ACR: renal assessment
• Direct Coombs test: AIHA
• LDH, reticulocytes, haptoglobin: haemolysis screen

Urine

• Dipstick: protein, blood
• Urine ACR/PCR: quantify proteinuria
• Microscopy: red cell casts (active nephritis)

Imaging

• CXR: pleural effusion, pericardial effusion
• Echocardiogram: pericarditis, Libman-Sacks
• MRI brain: neuropsychiatric lupus
• Renal USS: kidney size

Biopsy

• Renal biopsy: essential for lupus nephritis classification (ISN/RPS classes I-VI)
• Skin biopsy: lupus band test (immunoglobulin/complement at dermo-epidermal junction)

All Patients

• Hydroxychloroquine 200-400mg daily: reduces flares by 50%, improves survival, reduces damage accumulation, lipid-lowering, antithrombotic
  • Annual ophthalmology screening after 5 years (retinal toxicity)
• Sun protection: high-factor SPF, protective clothing
• Cardiovascular risk management: statin, BP control
• Vaccination: influenza, pneumococcal (avoid live vaccines during immunosuppression)

Mild Disease (Skin, Joints)

• Topical steroids: for skin lesions
• NSAIDs: for arthralgia (short-term)
• Low-dose prednisolone: ≤7.5mg for flares
• Methotrexate: steroid-sparing for skin/joints

Moderate Disease

• Prednisolone 0.5mg/kg tapering
• Azathioprine 2mg/kg/day: maintenance immunosuppression
• Mycophenolate mofetil: alternative to azathioprine
• Belimumab (anti-BLyS): add-on therapy (NICE TA397); reduces flares

Severe Disease (Nephritis, Neuropsychiatric)

• See lupus nephritis topic for nephritis management
• IV methylprednisolone 500mg-1g × 3 days for severe flares
• Cyclophosphamide: for severe nephritis or neuropsychiatric lupus
• Rituximab: for refractory disease (off-label but widely used)
• Voclosporin + MMF: for nephritis (AURORA trial)

Pregnancy in SLE

• High-risk: flares, pre-eclampsia, fetal loss, neonatal lupus
• Continue hydroxychloroquine throughout pregnancy
• Anti-Ro positive: monitor fetal heart for congenital heart block (from 16 weeks)
• Antiphospholipid syndrome: aspirin 75mg + LMWH
• Avoid methotrexate, mycophenolate, cyclophosphamide (teratogenic)
• Safe in pregnancy: HCQ, azathioprine, tacrolimus, prednisolone (low dose)

Referral Criteria

• All suspected SLE → rheumatology
• Lupus nephritis → nephrology + rheumatology
• Neuropsychiatric lupus → neurology
• Pregnancy planning → obstetric medicine

• 10-year survival: >90% (significantly improved from 50% in the 1950s)
• Leading causes of death: infections (immunosuppression), cardiovascular disease (accelerated atherosclerosis), renal failure
• Damage accumulation: measured by SLICC/ACR Damage Index; increases over time
• Lupus nephritis: 10-year renal survival 80-90% with modern treatment
• Antiphospholipid syndrome: significantly increases morbidity
• Afro-Caribbean patients: more severe disease, higher renal involvement, worse outcomes
• Hydroxychloroquine: the single most important drug; reduces all-cause mortality

SLICC Classification Criteria (2012)

Requires ≥4 of 17 criteria (≥1 clinical + ≥1 immunological) OR biopsy-proven lupus nephritis + ANA or anti-dsDNA:

Clinical (11): acute cutaneous lupus, chronic cutaneous lupus, oral/nasal ulcers, non-scarring alopecia, arthritis, serositis, renal, neurological, haemolytic anaemia, leucopenia/lymphopenia, thrombocytopenia

Immunological (6): ANA, anti-dsDNA, anti-Sm, antiphospholipid, low complement, positive Coombs

Key Autoantibodies in SLE

Key Facts

Sjogren syndrome is one of the most common autoimmune diseases, often under-diagnosed. Systemic involvement can be significant and the lymphoma risk requires long-term monitoring.

Epidemiology

• Prevalence: 0.1-0.5% (varies by criteria used)
• F:M 9:1; peak onset 40-60 years
• Often under-diagnosed: average delay to diagnosis ~7 years
• Secondary Sjogren more common than primary

Aetiology

• Genetic: HLA-DR3, HLA-B8, IRF5, STAT4
• Environmental: viral triggers (EBV, HTLV-1)
• Hormonal: oestrogen deficiency may contribute

Pathophysiology

• Lymphocytic infiltration (CD4+ T cells, B cells) of exocrine glands
• Autoantibodies: anti-Ro, anti-La target ribonucleoprotein complexes
• Glandular destruction → reduced saliva and tear production
• B-cell hyperactivation → hypergammaglobulinaemia, RF production

• Extraglandular involvement: immune complex deposition and lymphocytic infiltration in lungs, kidneys, nerves

Sicca Symptoms

• Dry eyes (keratoconjunctivitis sicca): gritty sensation, burning, photosensitivity, recurrent conjunctivitis
• Dry mouth (xerostomia): difficulty swallowing dry foods, dental caries, oral candidiasis, voice changes
• Parotid gland enlargement: episodic or persistent bilateral swelling

Systemic Manifestations (30-40%)

• Arthralgia/arthritis: non-erosive, similar to SLE
• Fatigue: often the most debilitating symptom
• Skin: purpura (hypergammaglobulinaemic or vasculitic), Raynaud (30%)
• Lungs: ILD (NSIP most common), lymphocytic interstitial pneumonia (LIP)
• Renal: type 1 (distal) RTA, interstitial nephritis
• Neurological: peripheral neuropathy (sensory > motor), cranial neuropathy (especially trigeminal), CNS involvement (rare)
• Haematological: lymphopenia, hypergammaglobulinaemia, cryoglobulinaemia

Lymphoma Risk

• 5-10% lifetime risk of B-cell NHL (predominantly MALT lymphoma of parotid)
• Warning signs: persistent parotid swelling, falling immunoglobulins, new lymphadenopathy, splenomegaly
• Risk factors: low C4, cryoglobulinaemia, vasculitis, lymphopenia

Red Flags

• Persistent unilateral parotid swelling → exclude lymphoma
• Falling immunoglobulins in previously hypergammaglobulinaemic patient → lymphoma
• New neurological symptoms → CNS Sjogren or lymphoma
• Severe systemic disease → consider rituximab

Bloods

• Anti-Ro (SSA): positive in ~70% of primary Sjogren
• Anti-La (SSB): positive in ~40% (more specific)
• ANA: positive in 70-80%
• RF: positive in 60-70%
• Immunoglobulins: polyclonal hypergammaglobulinaemia
• C3/C4: may be low (immune complex disease)
• ESR: often elevated (high Ig levels)
• CRP: usually normal (distinguishes from infection)
• FBC: lymphopenia
• Cryoglobulins: if vasculitis suspected

Ocular Assessment

• Schirmer test: filter paper in lower fornix; <5mm wetting in 5 minutes = abnormal
• Ocular surface staining (Rose Bengal, lissamine green, fluorescein): corneal/conjunctival epithelial damage
• Tear break-up time: <10 seconds = abnormal

Salivary Assessment

• Unstimulated salivary flow rate: <0.1 mL/min is abnormal
• Salivary gland USS: inhomogeneous echotexture, hypoechoic areas
• Sialography: ductal ectasia (rarely performed now)

Biopsy

• Labial salivary gland biopsy: minor salivary glands from inner lip; focal lymphocytic sialadenitis with focus score ≥1 (≥50 lymphocytes per 4mm²) – most specific test

Screening

• Dental assessment: increased caries risk
• Pulmonary function tests: if respiratory symptoms (ILD)
• Renal function + urine pH: RTA screening

Symptomatic (Sicca)

Dry eyes:

• Artificial tears (hypromellose drops): first-line; preservative-free if used >6×/day
• Carbomer gel (Viscotears): for night-time use
• Ciclosporin 0.1% eye drops (Ikervis): for moderate-severe keratoconjunctivitis sicca
• Punctal plugs: reduce tear drainage

Dry mouth:

• Saliva substitutes (Glandosane spray, Biotene products)
• Pilocarpine 5mg TDS-QDS (muscarinic agonist): stimulates residual salivary function; side effects include sweating
• Cevimeline: alternative cholinergic agonist (not widely available in UK)
• Dental hygiene: regular dental check-ups, fluoride rinses
• Sugar-free chewing gum: stimulates saliva
• Treat oral candidiasis: nystatin or fluconazole

Systemic Disease

• Hydroxychloroquine 200-400mg daily: for arthralgia, fatigue, skin involvement
• Corticosteroids: for acute flares of systemic disease (serositis, vasculitis)
• Methotrexate/azathioprine: for arthritis, ILD
• Rituximab: for severe systemic disease (vasculitis, neuropathy, ILD); off-label but evidence from TRACTISS trial (limited efficacy for fatigue/dryness but may help systemic)
• Mycophenolate: for renal involvement

Monitoring

• Annual ophthalmology: if on hydroxychloroquine (>5 years)
• Dental review: 6-monthly
• Lymphoma surveillance: clinical monitoring; investigate persistent parotid swelling, falling Ig levels, new lymphadenopathy

Referral Criteria

• Suspected Sjogren → rheumatology
• Severe dry eyes → ophthalmology
• Suspected lymphoma → haematology urgently
• ILD → respiratory medicine

• Life expectancy: near-normal for primary Sjogren without systemic involvement
• 5-10% lifetime risk of B-cell lymphoma (most commonly MALT lymphoma of parotid gland)
• Systemic disease: occurs in 30-40%; ILD and renal involvement carry worse prognosis
• Quality of life: significantly affected by fatigue and sicca symptoms
• Dental caries: accelerated; major morbidity if inadequate prevention
• Predictors of lymphoma: low C4, cryoglobulinaemia, palpable purpura, parotid enlargement, lymphopenia

ACR/EULAR 2016 Classification Criteria

Applicable if at least 1 domain of ocular or oral dryness. Score ≥4 classifies as Sjogren syndrome:

Primary vs Secondary Sjogren

Key Facts

SSc is a devastating multisystem disease with the highest mortality of any autoimmune rheumatic disease. Early detection of organ involvement and targeted treatment are essential.

Epidemiology

• UK prevalence: ~20 per 100,000
• F:M 4:1; peak onset 30-50 years
• lcSSc more common than dcSSc (3:1)
• Higher prevalence in Afro-Caribbean populations (more severe)

Aetiology

• Genetic: HLA-DRB1, IRF5, STAT4
• Environmental: silica, vinyl chloride, organic solvents
• Triggers: possibly viral (CMV, parvovirus B19)

Pathophysiology

• Three key processes: vasculopathy (endothelial damage → Raynaud, PAH), immune activation (T cells, B cells, autoantibodies), fibrosis (TGF-β, PDGF-driven collagen deposition)

• Activated fibroblasts → excessive collagen deposition in skin and organs
• Raynaud phenomenon is often the earliest manifestation (precedes other features by years)

Raynaud Phenomenon (>95%)

• Often first manifestation, may precede other features by years
• Digital ulcers, pitting scars, gangrene in severe cases

Limited Cutaneous SSc (lcSSc/CREST)

• Skin thickening distal to elbows/knees + face
• Calcinosis cutis: subcutaneous calcium deposits
• Raynaud phenomenon
• Esophageal dysmotility: dysphagia, GORD
• Sclerodactyly: tight, shiny skin on fingers
• Telangiectasia: face, hands
• PAH: major late complication (10-15%)

Diffuse Cutaneous SSc (dcSSc)

• Skin thickening proximal to elbows/knees + trunk
• Rapid progression of skin involvement in first 3-5 years
• ILD: most common cause of death (~40%)
• Scleroderma renal crisis: 10-15%; acute hypertensive emergency
• Cardiac: myocardial fibrosis, arrhythmias, pericarditis
• GI: oesophageal dysmotility, small bowel dysmotility (pseudo-obstruction), malabsorption

Red Flags

• Scleroderma renal crisis: new severe hypertension + rising creatinine + MAHA → ACE inhibitor URGENTLY
• Breathlessness: investigate for ILD and PAH
• Digital gangrene: IV iloprost, surgical debridement

Bloods

• ANA: positive in >90%
• Anti-centromere: lcSSc (50-70%); associated with PAH
• Anti-Scl-70 (topoisomerase I): dcSSc (30-40%); associated with ILD
• Anti-RNA polymerase III: dcSSc; associated with scleroderma renal crisis and malignancy
• FBC: MAHA in renal crisis
• U&Es: renal function
• ESR/CRP: may be modestly elevated

Organ Screening

• PFTs (FVC, DLCO): annual; FVC decline indicates ILD progression; isolated DLCO decline suggests PAH
• HRCT chest: ILD assessment (NSIP most common pattern, UIP less common)
• Echocardiogram: annual; estimate PA pressure (PAH screening)
• Right heart catheterisation: if echocardiogram suggests PAH (mPAP ≥20mmHg)
• Nailfold capillaroscopy: enlarged/dropout capillaries (distinguishes SSc-related Raynaud from primary Raynaud)
• Barium swallow/manometry: oesophageal dysmotility

Special Tests

• Modified Rodnan skin score: quantify skin thickening (0-3 at 17 sites; max 51)
• 6-minute walk test: PAH and ILD functional assessment
• NT-proBNP: screening for PAH/cardiac involvement

Raynaud and Digital Ulcers

• Nifedipine 10-20mg TDS (or amlodipine): first-line vasodilator
• IV iloprost (prostacyclin analogue): for severe Raynaud, digital ulcers
• Bosentan (endothelin receptor antagonist): prevents new digital ulcers (RAPIDS-2 trial)
• Sildenafil 25-50mg TDS: PDE5 inhibitor; alternative
• Lifestyle: keep warm, avoid smoking, avoid beta-blockers

ILD

• Mycophenolate mofetil 2-3g/day: first-line (Scleroderma Lung Study II – non-inferior to CYC with fewer side effects)
• Nintedanib 150mg BD: antifibrotic; slows FVC decline (SENSCIS trial); NICE TA691
• Cyclophosphamide: alternative induction (Scleroderma Lung Study I)
• Rituximab: emerging evidence
• Autologous stem cell transplant: severe, progressive dcSSc (ASTIS, SCOT trials)

PAH

• Ambrisentan (ERA) + tadalafil (PDE5i): first-line combination (AMBITION trial)
• IV epoprostenol: for severe/refractory PAH
• Riociguat: sGC stimulator
• Managed by specialist PAH centres

Scleroderma Renal Crisis

• ACE inhibitor (captopril): IMMEDIATELY; titrate aggressively to control BP
• DO NOT use ARBs (inferior outcomes)
• Dialysis: if severe AKI; 50% may recover enough to stop dialysis within 2 years
• Avoid high-dose corticosteroids (>15mg prednisolone may precipitate renal crisis)

GI

• PPI (omeprazole 20-40mg): for GORD
• Prokinetics (domperidone, erythromycin): for gastroparesis
• Rotating antibiotics: for small bowel bacterial overgrowth (SIBO)

Referral Criteria

• All suspected SSc → rheumatology
• ILD → respiratory medicine
• PAH → specialist PAH centre
• Scleroderma renal crisis → nephrology + rheumatology
• Raynaud with nailfold changes or ANA positive → rheumatology

• lcSSc: 10-year survival ~80%; PAH is the major cause of death
• dcSSc: 10-year survival ~65%; ILD and cardiac disease are leading causes of death
• Scleroderma renal crisis: mortality 20-30%; ~50% recover renal function with ACE inhibitors
• PAH: median survival without treatment ~3 years; improved with modern therapy
• Skin disease in dcSSc may plateau and improve after 3-5 years
• Anti-RNA polymerase III: associated with concurrent malignancy screening recommended

SSc Antibody Associations

lcSSc vs dcSSc

Key Facts

Dermatomyositis is the most recognisable inflammatory myopathy due to its characteristic skin manifestations. The association with malignancy mandates thorough cancer screening in adults.

Epidemiology

• Incidence: 1-2 per 100,000/year
• F:M 2:1; bimodal peak (children 5-15, adults 40-60)
• Malignancy association predominantly in adults >40

Aetiology

• Autoimmune: humoral (complement-mediated) immune response targeting endothelial cells
• Genetic: HLA-DRB1*0301
• Environmental: UV light, drugs (statins, penicillamine), infections
• Paraneoplastic: particularly anti-TIF1γ antibodies

Pathophysiology

• Complement-mediated microangiopathy → capillary dropout in muscle and skin
• Perifascicular atrophy on biopsy (B-cell and CD4+ T-cell infiltrate, perivascular)
• Distinct from polymyositis (CD8+ T-cell-mediated direct myofibre attack)
• IFN-driven pathway increasingly recognised

Skin (Often Precedes Muscle Disease)

• Heliotrope rash: lilac/purple discolouration of upper eyelids with periorbital oedema
• Gottron papules: violaceous, flat-topped papules over MCP, PIP, DIP extensor surfaces (also knees, elbows)
• Gottron sign: erythematous/violaceous rash over extensor surfaces without papules
• Shawl sign: V-shaped erythema over upper back/chest (photosensitive)
• Mechanic's hands: rough, cracked, hyperkeratotic skin on lateral fingers
• Nail fold changes: periungual erythema, dilated capillaries, cuticular overgrowth
• Calcinosis: especially in juvenile DM; subcutaneous calcium deposits

Muscle

• Symmetric proximal muscle weakness: difficulty rising from chairs, climbing stairs, lifting arms above head
• Gradual onset over weeks to months
• Myalgia in ~50%
• Pharyngeal/oesophageal weakness: dysphagia, aspiration risk
• Respiratory muscle weakness: dyspnoea

Systemic

• ILD: 20-40%; may be subclinical; anti-Jo-1 and anti-MDA5 associated
• Arthralgia/arthritis: non-erosive
• Cardiac: myocarditis, conduction defects (rare)
• Raynaud phenomenon: 20-30%

Red Flags

• Adult >40 with DM → malignancy screening essential
• Rapidly progressive ILD (anti-MDA5) → aggressive immunosuppression + consider rituximab/tacrolimus
• Dysphagia → aspiration risk; may need NG/PEG feeding

Bloods

• CK: elevated (often 5-50× ULN); most sensitive muscle enzyme
• LDH, AST, ALT, aldolase: also elevated (muscle-derived)
• Myositis-specific antibodies: anti-Mi-2 (classic DM), anti-MDA5 (amyopathic DM, ILD), anti-TIF1γ (malignancy), anti-NXP2 (calcinosis, malignancy), anti-Jo-1 (antisynthetase syndrome)
• ANA: positive in ~60%
• ESR/CRP: may be elevated
• FBC, U&Es, LFTs: baseline

Imaging

• MRI of proximal muscles (thighs most commonly): muscle oedema on STIR sequences; guides biopsy site
• HRCT chest: ILD screening (NSIP most common pattern)
• CT chest/abdomen/pelvis: malignancy screening

Neurophysiology

• EMG: myopathic pattern (short-duration, low-amplitude polyphasic motor unit potentials, fibrillations)

Biopsy

• Muscle biopsy: perifascicular atrophy (pathognomonic), perivascular inflammation (B cells, CD4+ T cells, complement deposits)
• Skin biopsy: interface dermatitis (can be similar to SLE)

Malignancy Screening (Adults >40)

• CT CAP, mammography, pelvic USS, PSA, colonoscopy (age-appropriate)
• Repeat annually for 3 years
• Anti-TIF1γ positive: particularly high malignancy risk (~60%)

Pharmacological

First-line:

• Prednisolone 1mg/kg/day (max 60mg): taper over months as CK normalises
• Methotrexate 15-25mg weekly: steroid-sparing (preferred for skin and muscle)
• Azathioprine 2-3mg/kg/day: alternative steroid-sparing agent

Refractory:

• IV immunoglobulin (IVIg): 2g/kg over 2-5 days, then monthly maintenance; particularly effective for skin
• Rituximab: for refractory disease (RIM trial showed benefit)
• Mycophenolate mofetil: for ILD
• Ciclosporin/tacrolimus: for refractory disease, ILD

ILD:

• Mycophenolate mofetil 2-3g/day: first-line for DM-ILD
• Anti-MDA5 ILD: aggressive combination (steroids + tacrolimus + cyclophosphamide; rituximab)
• Nintedanib: if progressive fibrosis

Skin:

• Sunscreen: photosensitive rash
• Hydroxychloroquine: for skin manifestations
• Topical steroids/tacrolimus: for localised skin disease

Non-pharmacological

• Physiotherapy: graded exercise programme once CK improving
• Speech and language therapy: if dysphagia
• Malignancy screening: at diagnosis + annually for 3 years

Referral Criteria

• All suspected inflammatory myopathy → rheumatology
• ILD → respiratory medicine
• Dysphagia → gastroenterology/ENT
• Malignancy identified → oncology

• 5-year survival: ~85-90% (improved with modern immunosuppression)
• Malignancy-associated DM: prognosis depends on underlying cancer
• Anti-MDA5 with rapidly progressive ILD: mortality 40-50% without aggressive treatment
• Juvenile DM: generally good prognosis; calcinosis is major long-term morbidity
• Inclusion body myositis (if initially misdiagnosed as DM): poor response to treatment
• Most patients achieve remission or good control on combination therapy
• CK levels correlate with disease activity and guide treatment

Myositis-Specific Antibodies

DM vs PM

Key Facts

The concept of polymyositis has evolved significantly. True PM (excluding IBM and IMNM) is now thought to be uncommon. The antisynthetase syndrome is the most important subgroup.

Epidemiology

• Incidence: 2-10 per million/year (including IMNM)
• F:M 2:1; peak onset 30-60 years
• Rare in children (unlike DM)

Aetiology

• Autoimmune: CD8+ T-cell-mediated myofibre destruction
• Genetic: HLA-DRB1*0301
• Viral triggers (HIV, HTLV-1, coxsackie)
• Drug-induced: statins (IMNM with anti-HMGCR), D-penicillamine

Pathophysiology

• CD8+ cytotoxic T cells directly invade and destroy MHC class I-expressing myofibres
• Endomysial inflammation (within fascicles) – distinct from DM (perivascular/perifascicular)
• ILD driven by antisynthetase antibodies (anti-Jo-1, anti-PL-7, anti-PL-12)
• IMNM: macrophage-mediated with minimal lymphocytic infiltrate; anti-SRP or anti-HMGCR positive

Muscle

• Symmetric proximal weakness: gradual onset over weeks to months
• Hip flexors and shoulder abductors most affected
• Difficulty: rising from chairs, climbing stairs, lifting arms, combing hair
• Neck flexor weakness (head drop) in severe cases
• Myalgia in ~50%
• Dysphagia: pharyngeal/oesophageal weakness (20-30%)
• Respiratory muscle weakness: dyspnoea, reduced MIP/MEP

Antisynthetase Syndrome

• ILD: NSIP most common; may be presenting feature
• Mechanic's hands: rough, cracked, hyperkeratotic lateral finger skin
• Raynaud phenomenon: 60%
• Arthritis: symmetrical, non-erosive
• Fever: often low-grade
• Anti-Jo-1 most common antisynthetase antibody (20% of PM)

Red Flags

• Rapidly progressive weakness → consider IMNM (anti-SRP)
• Distal weakness + finger flexor/knee extensor weakness in >50 year old → consider IBM
• ILD with myositis → antisynthetase syndrome
• Failure to respond to steroids → reconsider diagnosis (IBM, IMNM)

Bloods

• CK: elevated (often 10-50× ULN)
• Myositis antibodies: anti-Jo-1, anti-PL-7, anti-PL-12 (antisynthetase); anti-SRP, anti-HMGCR (IMNM)
• ANA: positive in ~40%
• LDH, AST, ALT: elevated (muscle origin)
• ESR/CRP: may be elevated

Imaging

• MRI: muscle oedema (guides biopsy)
• HRCT chest: ILD (especially antisynthetase)
• PFTs: FVC and DLCO

EMG

• Myopathic pattern: short-duration, low-amplitude polyphasic motor units

Biopsy

• Muscle biopsy: endomysial CD8+ T-cell infiltrate, myofibre necrosis, MHC class I upregulation
• Distinguishes from DM (perifascicular) and IMNM (necrosis with minimal inflammation)

Malignancy Screening

• CT CAP at diagnosis; age-appropriate cancer screening
• Less strongly associated than DM but still elevated risk (~5-10%)

Pharmacological

• Prednisolone 1mg/kg/day: taper over months guided by CK and strength
• Methotrexate 15-25mg weekly or azathioprine 2-3mg/kg/day: steroid-sparing
• IVIg: for refractory disease (2g/kg over 2-5 days)
• Rituximab: for refractory PM (off-label; RIM trial data)
• Mycophenolate: for ILD
• Cyclophosphamide: for severe ILD

Non-pharmacological

• Physiotherapy: graduated exercise once CK improving
• SLT assessment: if dysphagia
• Pulmonary rehabilitation: if ILD

Monitoring

• CK levels every 2-4 weeks initially; guide treatment response
• PFTs 3-6 monthly if ILD
• Muscle strength assessment (MMT-8 score)

Referral Criteria

• Suspected inflammatory myopathy → rheumatology
• ILD → respiratory
• Dysphagia → gastroenterology

• 5-year survival: ~85-90% with treatment
• Antisynthetase syndrome with ILD: poorer prognosis; 5-year survival ~70-80%
• Anti-SRP IMNM: severe, often refractory; may require aggressive treatment
• Response to treatment: most patients improve significantly on prednisolone + DMARD
• IBM: important differential as it does NOT respond to immunosuppression
• CK normalisation usually precedes strength improvement by weeks-months

Inflammatory Myopathy Classification (Updated)

Antisynthetase Syndrome Features

Key Facts

MCTD remains a controversial entity – some experts consider it a transitional state rather than a distinct disease. The anti-U1 RNP antibody is the serological hallmark.

Epidemiology

• Rare; exact prevalence unknown (~0.01% estimated)
• F:M 9:1; peak onset 15-35 years

Pathophysiology

• Anti-U1 RNP antibodies target spliceosomal proteins
• Features reflect the overlap nature: vasculopathy (SSc component), immune complex disease (SLE component), muscle inflammation (PM component)
• Many patients evolve to a more defined CTD over 5-10 years

Common Features

• Raynaud phenomenon (>90%): often the first manifestation
• Puffy/swollen hands ("sausage fingers"): very characteristic early feature
• Arthritis: polyarthritis, may be deforming (Jaccoud-like)
• Myositis: proximal weakness, elevated CK
• Oesophageal dysmotility: dysphagia, GORD
• Sclerodactyly: tight skin on fingers
• Serositis: pleurisy, pericarditis
• ILD: NSIP pattern

Less Common

• Pulmonary arterial hypertension: major cause of mortality
• Trigeminal neuropathy: sensory neuropathy of CN V (relatively specific)
• Membranous nephropathy: renal involvement less common than in SLE
• Cytopenias: leucopenia, thrombocytopenia

Red Flags

• Dyspnoea → screen for PAH and ILD
• Evolving features towards a defined CTD → reassess diagnosis

Bloods

• Anti-U1 RNP: high-titre positive (defining; essential for diagnosis)
• ANA: positive (speckled pattern)
• Anti-dsDNA: usually negative (helps distinguish from SLE)
• CK: elevated if myositis component
• FBC: cytopenias possible
• ESR/CRP: often elevated

Organ Assessment

• PFTs + HRCT: ILD screening
• Echocardiogram: PAH screening
• Barium swallow/manometry: oesophageal dysmotility
• U&Es, urine ACR: renal assessment
• EMG/MRI: if myositis suspected

Treatment Guided by Predominant Feature

• Arthritis: NSAIDs, hydroxychloroquine, methotrexate
• Myositis: prednisolone + methotrexate/azathioprine
• Raynaud: nifedipine, iloprost
• ILD: mycophenolate mofetil, cyclophosphamide
• PAH: endothelin receptor antagonists, PDE5 inhibitors, prostacyclins
• Serositis: NSAIDs, corticosteroids
• Hydroxychloroquine: for all patients (as in SLE)

Monitoring

• Regular PFTs and echocardiogram (PAH/ILD screening)
• CK monitoring if myositis
• Annual organ assessment

Referral

• All suspected MCTD → rheumatology
• PAH → specialist centre
• ILD → respiratory medicine

• 10-year survival: ~80%
• PAH is the leading cause of mortality
• Evolution: many patients evolve to a defined CTD (SSc most common, then SLE)
• Renal crisis: uncommon (unlike SSc)
• Prognosis generally better than SSc or SLE in many series
• Anti-U1 RNP titres do not reliably predict disease course

MCTD Features by CTD Component

Key Facts

APS is the most common acquired thrombophilia. Early recognition prevents recurrent thrombosis and adverse pregnancy outcomes.

Epidemiology

• Antiphospholipid antibodies found in 1-5% of healthy population
• APS develops in ~30-40% of SLE patients
• Primary APS (no underlying autoimmune disease): ~50% of cases
• F:M 5:1 for secondary (SLE-associated); more equal for primary

Pathophysiology

• Antiphospholipid antibodies bind β2-glycoprotein I on endothelial cells, platelets, and trophoblasts

• Complement activation (particularly classical pathway)
• Placental thrombosis and inflammation → obstetric complications
• Lupus anticoagulant inhibits phospholipid-dependent coagulation in vitro (prolonged APTT) but is prothrombotic in vivo

Thrombotic APS

• Venous (most common): DVT, PE, cerebral venous sinus thrombosis, Budd-Chiari, renal vein thrombosis
• Arterial: stroke/TIA (especially young), MI, mesenteric ischaemia, digital gangrene
• Livedo reticularis: mottled, net-like skin pattern (common)
• Thrombocytopenia: mild (50-100 × 10⁹/L); rarely causes bleeding
• Libman-Sacks endocarditis: sterile vegetations on valve leaflets
• Sneddon syndrome: livedo reticularis + cerebrovascular disease

Obstetric APS

• ≥3 unexplained consecutive miscarriages <10 weeks
• ≥1 unexplained fetal death ≥10 weeks (morphologically normal fetus)
• ≥1 premature delivery <34 weeks due to eclampsia/pre-eclampsia/placental insufficiency

Catastrophic APS (CAPS)

• Multiorgan thrombosis developing rapidly (days-weeks)
• ≥3 organ systems involved
• Microangiopathic features (MAHA, thrombocytopenia)
• Mortality ~30-50% despite treatment

Red Flags

• Young stroke with no conventional risk factors → screen for APS
• Recurrent pregnancy loss → test antiphospholipid antibodies

Antiphospholipid Antibody Testing

• Lupus anticoagulant: DRVVT-based assay; strongest predictor of thrombosis
• Anticardiolipin antibodies (IgG/IgM): ELISA; medium-high titre significant
• Anti-β2-glycoprotein I (IgG/IgM): ELISA
• Must be positive on ≥2 occasions ≥12 weeks apart to confirm persistence

Other Bloods

• APTT: may be prolonged (LA effect); does NOT correct with mixing study (inhibitor pattern)
• FBC: thrombocytopenia (50-100 × 10⁹/L)
• Blood film: schistocytes if CAPS
• Direct Coombs test: positive in some (associated AIHA)
• Complement C3/C4: may be low if SLE-associated
• ANA, dsDNA: SLE screening

Imaging

• Guided by clinical presentation: CT head (stroke), CTPA (PE), Doppler USS (DVT)
• Echocardiogram: Libman-Sacks vegetations
• MRI brain: cerebral infarcts, white matter lesions

Thrombotic APS

• Lifelong warfarin: target INR 2-3 (first venous event); some advocate INR 3-4 for arterial events or recurrence on INR 2-3
• DOACs (rivaroxaban, apixaban): NOT recommended for triple-positive APS (TRAPS trial: increased thrombosis vs warfarin)
• DOACs may be acceptable for single/double positive venous APS (controversial; warfarin remains standard)

Obstetric APS

• Aspirin 75-150mg daily (from pre-conception) + LMWH (enoxaparin 40mg SC OD from positive pregnancy test)
• Continue LMWH throughout pregnancy + 6 weeks postpartum
• High-risk: add hydroxychloroquine (reduces complement activation)
• Refractory obstetric APS: consider IVIg, prednisolone, or higher-dose LMWH

Primary Prevention (Asymptomatic aPL Positive)

• Low-dose aspirin 75mg: for persistently positive aPL without prior thrombosis (particularly in SLE)
• Hydroxychloroquine: in SLE patients with aPL (reduces thrombotic risk)

Catastrophic APS

• Anticoagulation (heparin) + IV methylprednisolone + plasma exchange + IVIg
• Rituximab/eculizumab: for refractory CAPS

Referral Criteria

• Confirmed APS → haematology/rheumatology
• Obstetric APS → obstetric medicine/high-risk obstetrics
• CAPS → ITU, multidisciplinary

• Recurrent thrombosis without treatment: 30-50% within 5 years
• Warfarin reduces recurrence to <5% per year
• Triple-positive APS: highest risk; recurrence rate 10-15%/year even on treatment
• Obstetric APS: with aspirin + LMWH, live birth rate 70-80% (vs <20% without treatment)
• CAPS: mortality 30-50% despite treatment
• Overall mortality: primarily from thrombotic events and complications of anticoagulation

Sydney Classification Criteria (2006)

Requires ≥1 clinical + ≥1 laboratory criterion:

Clinical:

1. Vascular thrombosis (arterial, venous, or small vessel)
2. Pregnancy morbidity (as defined above)

Laboratory (positive on ≥2 occasions ≥12 weeks apart):

1. Lupus anticoagulant
2. Anticardiolipin IgG/IgM (medium-high titre)
3. Anti-β2-glycoprotein I IgG/IgM

Risk Stratification

Key Facts

GCA is an ophthalmological and rheumatological emergency. The principle of management is to treat immediately on clinical suspicion to prevent irreversible blindness.

Epidemiology

• Most common vasculitis in adults >50
• UK incidence: ~20 per 100,000 in >50s
• Peak age 70-80; almost never occurs <50
• F:M 2-3:1
• More common in Northern European/Scandinavian populations

Pathophysiology

• Granulomatous vasculitis of medium/large arteries
• CD4+ T-cell and macrophage-driven inflammation in arterial adventitia
• Multinucleated giant cells in vessel wall (not always present)

• Temporal artery: headache; ophthalmic artery: visual loss; vertebral/aortic: aortitis
• IL-6 is a key cytokine → rationale for tocilizumab

Classic Features

• New-onset headache (temporal, often unilateral; sometimes diffuse)
• Scalp tenderness (pain on brushing hair, wearing hat)
• Temporal artery abnormality: thickened, beaded, tender; reduced/absent pulse
• Jaw claudication: pain in jaw muscles on chewing (highly specific, ~50%)
• Visual symptoms (15-20%): amaurosis fugax, diplopia, sudden visual loss (AION)

Constitutional

• Fatigue, malaise, weight loss, fever, night sweats
• PMR symptoms (50%): bilateral shoulder/hip girdle pain and stiffness

Large-Vessel GCA

• Aortitis: aortic aneurysm (thoracic), aortic dissection
• Limb claudication: subclavian, axillary artery involvement
• Aortic regurgitation

Red Flags

• ANY visual symptom in suspected GCA → immediate high-dose steroids and urgent ophthalmology
• Jaw claudication → high positive predictive value for GCA
• Permanent visual loss can occur within hours of first visual symptom
• Second eye at risk within days-weeks if untreated

Bloods

• ESR: often >50 (frequently >100 mm/hr); 15-20% may be normal
• CRP: elevated (more sensitive than ESR)
• FBC: normocytic anaemia, thrombocytosis
• LFTs: raised ALP (25-30%)

Imaging

• Temporal artery USS (with expertise): halo sign (circumferential hypoechoic wall thickening); sensitivity 77%, specificity 96% (TABUL trial)
• MRI temporal arteries: mural enhancement and oedema
• CT/PET angiography: for large-vessel GCA (aortitis)

Biopsy

• Temporal artery biopsy: gold standard; ≥1cm specimen; perform within 14 days of starting steroids
• Histology: transmural granulomatous inflammation, giant cells, intimal hyperplasia, fragmentation of internal elastic lamina
• False-negative rate 15-20% due to skip lesions; contralateral biopsy if high suspicion and first negative

Ophthalmological

• Visual acuity, fundoscopy, visual fields: at presentation
• AION: pale, swollen optic disc; splinter haemorrhages

Emergency Treatment (Start BEFORE Investigations)

Without visual symptoms:

• Prednisolone 40-60mg OD (do not delay for biopsy)

With visual symptoms or jaw claudication:

• IV methylprednisolone 500mg-1g daily × 3 days, then oral prednisolone 60mg
• Urgent ophthalmology review

Steroid Tapering (BSR Guidelines)

• Taper prednisolone over 12-18 months minimum:
  • 40-60mg for 4 weeks → reduce by 10mg every 2 weeks to 20mg
  • 20mg → reduce by 2.5mg every 2-4 weeks to 10mg
  • 10mg → reduce by 1mg every 4-8 weeks
• Guide taper by symptoms and CRP/ESR (not ESR alone)
• ~50% relapse during taper

Steroid-Sparing

• Tocilizumab (IL-6 inhibitor): 162mg SC weekly or fortnightly (NICE TA518)
  • GiACTA trial: 56% sustained remission with tocilizumab vs 14% with steroids alone at 1 year
  • Allows faster steroid taper; reduces cumulative steroid dose
  • Caution: masks CRP (cannot use CRP to monitor disease activity)
• Methotrexate 10-15mg weekly: modest steroid-sparing effect; used if tocilizumab unavailable

Supportive

• Bone protection: calcium/vitamin D + bisphosphonate (prolonged steroid use)
• PPI: gastric protection during high-dose steroids
• Low-dose aspirin 75mg: consider for vascular risk reduction (limited evidence)
• Aortic screening: CT/MR angiography at diagnosis and periodically (aortic aneurysm risk)

Referral Criteria

• All suspected GCA → immediate treatment + urgent rheumatology referral
• Visual symptoms → emergency ophthalmology
• Large-vessel GCA → vascular MDT

• Visual loss prevention: if treated before permanent damage, vision can be preserved in >95%
• Permanent visual loss: occurs in 15-20% if untreated; once established, usually irreversible
• Relapse rate: ~50% during steroid taper; tocilizumab significantly reduces this
• Steroid complications: major morbidity (osteoporosis, diabetes, infections, weight gain)
• Aortic aneurysm: develops in 10-20% (particularly thoracic); lifelong surveillance recommended
• Mortality: near-normal life expectancy with treatment; increased CV risk
• Most patients can discontinue steroids by 2-3 years

BSR Steroid Taper for GCA

GCA vs PMR

Key Facts

PMR is the most common inflammatory rheumatic disease in the elderly. Its hallmark is the dramatic response to low-dose steroids. Always screen for GCA.

Epidemiology

• Incidence: ~50-80 per 100,000 in >50 age group
• Peak age: 70-80; almost never <50
• F:M 2-3:1
• More common in Northern European populations

Pathophysiology

• Synovitis and bursitis in proximal joints (shoulders, hips) and periarticular structures
• IL-6-driven inflammatory response (same pathway as GCA)
• Biopsy of synovium shows macrophage and T-cell infiltration
• Not a myopathy: CK is normal; muscle power is normal (limited by pain)

Core Features

• Bilateral shoulder pain and stiffness (most common; 70-95%)
• Bilateral hip girdle pain and stiffness (50-70%)
• Morning stiffness >45 minutes (often >1 hour)
• Difficulty: raising arms above head, getting out of bed/chair, turning in bed
• Systemic: fatigue, malaise, low-grade fever, weight loss, depression

Important Negatives

• No true muscle weakness (limited by pain, not weakness)
• CK normal (distinguishes from polymyositis)
• No joint swelling (though some peripheral oedema may occur)

Red Flags (May Indicate GCA or Alternative Diagnosis)

• New headache, jaw claudication, visual symptoms → GCA; escalate treatment
• Peripheral arthritis → consider late-onset RA
• Night sweats, weight loss → malignancy screen
• Failure to respond to 15mg prednisolone → reconsider diagnosis

Bloods

• ESR: characteristically elevated (usually >40, often >50-100)
• CRP: elevated (more responsive than ESR)
• FBC: normocytic anaemia, thrombocytosis possible
• LFTs: raised ALP (20-30%)
• CK: NORMAL (essential to exclude myositis)
• TFTs: exclude hypothyroidism
• RF, anti-CCP: negative (excludes RA)
• Myeloma screen: serum protein electrophoresis (elderly with raised ESR)
• Calcium: exclude hyperparathyroidism

Imaging

• USS shoulders: bilateral subacromial/subdeltoid bursitis, biceps tenosynovitis (supports diagnosis)
• USS hips: trochanteric bursitis, hip joint synovitis
• PET-CT: may show bursitis/synovitis; also useful for large-vessel GCA screening

Clinical Assessment

• Use BSR/BHPR guidelines or ACR/EULAR 2012 classification criteria (score ≥4/6 suggests PMR)

Pharmacological

BSR Guidelines:

• Prednisolone 15mg OD: starting dose
• Expect dramatic improvement within 24-72 hours (if not, reconsider diagnosis)

• Typical treatment duration: 1-2 years; many patients need longer (median ~2 years)
• Guided by symptoms + CRP/ESR (not CRP alone)

Relapse:

• 30-50% relapse during taper
• Increase prednisolone to last effective dose → retaper more slowly

Steroid-Sparing:

• Methotrexate 7.5-10mg weekly: consider early if high relapse risk, steroid side effects, or comorbidities (diabetes, osteoporosis)
• Limited evidence but some benefit in reducing steroid dose and relapse

Tocilizumab:

• Emerging evidence for PMR (PMR-SPARE trial); not yet standard of care

Supportive

• Bone protection: calcium/vitamin D + bisphosphonate (DEXA scan)
• PPI: if risk factors for GI complications
• Cardiovascular risk: manage diabetes, hypertension
• Exercise: maintain mobility; physiotherapy referral

Monitoring

• CRP/ESR: every 2-4 weeks initially, then 3-monthly
• Screen for GCA symptoms at every visit
• Glucose: steroid-induced diabetes screening
• DEXA scan: at baseline if starting prolonged steroids

Referral Criteria

• Typical PMR responding to steroids → GP management appropriate
• Atypical features or diagnostic uncertainty → rheumatology
• GCA symptoms → urgent/emergency treatment
• High relapse rate or steroid dependence → rheumatology for steroid-sparing therapy

• Excellent prognosis with corticosteroid treatment
• Most patients achieve remission and discontinue steroids within 1-3 years
• 15-20% require treatment for >3 years
• Relapse rate: 30-50% during taper; more common with rapid taper
• GCA development: 15-20% of PMR patients; ongoing vigilance required
• Steroid complications (osteoporosis, diabetes, cataracts, weight gain) are the main source of morbidity
• Mortality: near-normal life expectancy with appropriate treatment

ACR/EULAR 2012 PMR Classification Criteria

Score ≥4 (without USS) or ≥5 (with USS) classifies as PMR

PMR Steroid Taper (BSR)

Key Facts

GPA is the most common ANCA-associated vasculitis with distinctive upper respiratory tract involvement. PR3-ANCA is both diagnostic and prognostic.

Epidemiology

• Incidence: ~10 per million/year in the UK
• Peak age: 55-70 years; M=F
• More common in Northern European populations

Pathophysiology

• Anti-PR3 antibodies activate neutrophils → necrotising vasculitis
• Granuloma formation in respiratory tract (distinctive feature vs MPA)
• Pauci-immune crescentic GN in kidneys
• Triad: upper airway granulomatous inflammation + lung involvement + renal vasculitis

ENT (90%)

• Nasal crusting, bloody discharge, epistaxis
• Sinusitis (recurrent, destructive)
• Saddle-nose deformity: nasal septal perforation and cartilage destruction
• Subglottic stenosis: stridor, hoarseness (~15%)
• Otitis media (serous or chronic)
• Hearing loss (conductive or sensorineural)

Pulmonary (90%)

• Cavitating lung nodules: multiple, bilateral; can mimic malignancy or TB
• Pulmonary haemorrhage: dyspnoea, haemoptysis
• Cough, pleurisy

Renal (80%)

• Crescentic GN: haematuria, proteinuria, rapidly declining GFR
• May present as RPGN

Other

• Constitutional: fever, weight loss, fatigue
• Eyes: scleritis, orbital pseudotumour (proptosis)
• Skin: palpable purpura
• Nervous system: mononeuritis multiplex, cranial nerve palsies

Red Flags

• Haemoptysis + renal failure → pulmonary-renal syndrome
• Subglottic stenosis → airway compromise
• Rapidly rising creatinine → urgent treatment

Bloods

• c-ANCA (anti-PR3): positive in >90% generalised GPA
• p-ANCA (anti-MPO): positive in ~10% of GPA
• CRP/ESR: elevated
• U&Es: renal function
• FBC: anaemia, leucocytosis
• Urinalysis: haematuria, red cell casts, proteinuria

Imaging

• CT chest: cavitating nodules (bilateral), ground-glass (haemorrhage)
• CT sinuses: mucosal thickening, bony erosion
• CT neck: subglottic stenosis

Biopsy

• Renal biopsy: pauci-immune crescentic GN
• Nasal/sinus biopsy: necrotising granulomatous vasculitis (may be non-diagnostic due to superficial sampling)
• Lung biopsy: geographic necrosis with granulomata

Induction (Generalised/Organ-Threatening)

• Rituximab 375mg/m² weekly × 4 (RAVE trial) OR IV cyclophosphamide (CYCLOPS protocol) + prednisolone 1mg/kg tapering
• Avacopan 30mg BD as steroid-sparing alternative (ADVOCATE trial)
• Plasma exchange: for pulmonary haemorrhage

Maintenance (≥24 months)

• Rituximab 500mg IV every 6 months (MAINRITSAN – superior to azathioprine)
• OR azathioprine 2mg/kg/day

Limited Disease (ENT Only)

• Methotrexate 20-25mg weekly + prednisolone (NORAM trial)
• Co-trimoxazole 960mg BD: may reduce nasal/ENT relapse (Stegeman trial)

Subglottic Stenosis

• Intralesional corticosteroid injection
• Endoscopic dilation
• May persist despite systemic treatment

Supportive

• Co-trimoxazole for PCP prophylaxis
• Bone protection
• Annual influenza/pneumococcal vaccination

Referral

• All GPA → rheumatology/nephrology
• ENT involvement → ENT surgeon
• Subglottic stenosis → airway specialist

• 5-year survival: 75-80% with treatment
• Relapse rate: ~50% within 5 years; PR3 > MPO
• Renal survival: 70-80% at 5 years
• Leading causes of death: infections (immunosuppression), renal failure, cardiovascular disease
• Subglottic stenosis: may cause chronic morbidity; often refractory
• Rituximab maintenance significantly reduces relapse rate vs azathioprine

GPA vs MPA vs EGPA

Key Facts

EGPA is unique among AAV due to its association with asthma and eosinophilia. The distinction between ANCA-positive and ANCA-negative disease has important implications for organ involvement and treatment.

Epidemiology

• Incidence: ~2 per million/year
• Peak age: 40-60; M=F
• Rarest of the three AAV

Pathophysiology

• Eosinophilic tissue infiltration + granulomatous inflammation + small-vessel vasculitis
• IL-5-driven eosinophil activation and survival
• ANCA-positive: more GN and neuropathy (similar to other AAV)
• ANCA-negative: more cardiac and pulmonary infiltrates (eosinophil-driven)

Prodromal Phase

• Allergic rhinitis, nasal polyps
• Adult-onset asthma (usually severe, steroid-dependent)
• May last years before vasculitic phase

Eosinophilic Phase

• Peripheral eosinophilia (often >1.5 × 10⁹/L, sometimes >10 × 10⁹/L)
• Eosinophilic pulmonary infiltrates: migratory, transient
• Eosinophilic gastroenteritis: abdominal pain, diarrhoea

Vasculitic Phase

• Cardiac (leading cause of death): myocarditis, pericarditis, cardiomyopathy, heart failure
• Nervous system: mononeuritis multiplex (most common neuropathy; 70%), cranial neuropathy
• Skin: palpable purpura (50%), nodules
• Renal: crescentic GN (less common than GPA/MPA; ~25%)
• GI: mesenteric vasculitis, perforation
• Constitutional: fever, weight loss, fatigue

Red Flags

• Cardiac involvement → echocardiogram, troponin, cardiac MRI
• Mononeuritis multiplex → nerve conduction studies
• GI vasculitis → surgical emergency if perforation

Bloods

• FBC: eosinophilia (usually >1.5 × 10⁹/L; often >10)
• p-ANCA (anti-MPO): positive in ~40%
• IgE: elevated
• CRP/ESR: elevated
• Troponin: cardiac involvement
• U&Es: renal function

Imaging

• CT chest: patchy migratory infiltrates, ground-glass opacities
• Cardiac MRI: myocarditis, fibrosis (most sensitive for cardiac EGPA)
• Echocardiogram: pericardial effusion, LV dysfunction

Biopsy

• Tissue biopsy (skin, nerve, lung): eosinophilic infiltration, granulomata, vasculitis
• Nerve biopsy: vasculitic neuropathy

Neurophysiology

• Nerve conduction studies/EMG: mononeuritis multiplex pattern

Induction

FFS = 0 (no poor prognosis factors):

• Prednisolone 1mg/kg/day alone; taper over months

FFS ≥1 (cardiac, GI, renal, CNS):

• Prednisolone + IV cyclophosphamide (CYCLOPS protocol) OR rituximab

Maintenance

• Azathioprine 2mg/kg/day or methotrexate
• Continue low-dose prednisolone (many patients require long-term due to asthma)

Mepolizumab (Anti-IL-5)

• NICE TA845: approved for relapsing/refractory EGPA
• MIRRA trial: 300mg SC monthly; reduced relapse by 50%, reduced steroid dose
• Particularly effective for eosinophil-driven disease

Asthma Management

• Optimise asthma therapy (inhalers, biologics)
• Often severe, steroid-dependent asthma
• Mepolizumab also treats severe eosinophilic asthma

Referral

• All EGPA → rheumatology
• Cardiac involvement → cardiology (cardiac MRI)
• Neuropathy → neurology

• 5-year survival: 80-90% with treatment
• Cardiac involvement: major determinant of mortality (~50% of deaths)
• Five-Factor Score (FFS): higher score = worse prognosis
• Relapse rate: 25-35% within 5 years
• Mepolizumab: significantly reduces relapse and steroid requirements
• ANCA-positive: more renal/neurological; ANCA-negative: more cardiac

Five-Factor Score (FFS) for EGPA

FFS 0: good prognosis; FFS ≥1: poor prognosis → immunosuppression required

Key Facts

MPA is often considered the 'renal-dominant' ANCA vasculitis. It presents with severe renal disease and/or pulmonary haemorrhage.

Epidemiology

• Incidence: ~5-10 per million/year
• Peak age: 60-70; M=F or slight male predominance
• More common in Japanese populations

Pathophysiology

• Anti-MPO antibodies activate neutrophils → necrotising small-vessel vasculitis
• NO granuloma formation (distinguishing feature from GPA and EGPA)
• Pauci-immune GN: minimal immunoglobulin deposition on biopsy
• Pulmonary capillaritis → diffuse alveolar haemorrhage

Renal (>80%)

• Rapidly progressive GN: rising creatinine, haematuria, proteinuria
• May present as RPGN
• Often the predominant organ involved

Pulmonary

• Diffuse alveolar haemorrhage: haemoptysis, dyspnoea, ground-glass on CT
• Pulmonary-renal syndrome
• ILD (rarely fibrotic)

Other

• Constitutional: fever, weight loss, malaise
• Skin: palpable purpura, livedo reticularis
• Nervous system: mononeuritis multiplex (30%)
• GI: mesenteric vasculitis
• Eyes: scleritis (less common than GPA)

Red Flags

• Pulmonary haemorrhage → life-threatening; consider plasma exchange
• Rapidly rising creatinine → urgent renal biopsy and treatment

Bloods

• p-ANCA (anti-MPO): positive in ~70%
• c-ANCA (anti-PR3): positive in ~20%
• U&Es: often significantly impaired
• Urinalysis: haematuria, red cell casts
• CRP/ESR: elevated
• Anti-GBM: exclude dual positivity

Imaging

• CT chest: ground-glass (haemorrhage)
• Renal USS: normal-sized kidneys

Biopsy

• Renal biopsy: focal segmental necrotising GN with crescents; pauci-immune (no/minimal Ig on IF)
• No granulomata (distinguishes from GPA)

Induction

• Rituximab 375mg/m² × 4 or IV cyclophosphamide + prednisolone 1mg/kg tapering
• Plasma exchange: consider if severe renal disease (creatinine >500) or pulmonary haemorrhage

Maintenance

• Rituximab 500mg every 6 months (MAINRITSAN) or azathioprine for ≥24 months

Supportive

• PCP prophylaxis (co-trimoxazole)
• Bone protection
• BP control with ACEi/ARB

Referral

• All MPA → nephrology + rheumatology
• Pulmonary haemorrhage → ICU

• 5-year survival: 70-75% (slightly lower than GPA)
• Relapse rate: 20-30% (lower than GPA; MPO < PR3 for relapse)
• Renal prognosis: depends on creatinine at presentation; dialysis-dependent at presentation = 30% recover renal function
• Leading cause of death: infections (immunosuppression), renal failure
• More severe renal disease at presentation compared to GPA

MPA vs GPA

Key Facts

PAN is becoming rarer as hepatitis B prevalence decreases. It is distinguished from AAV by medium-vessel involvement without glomerulonephritis.

Epidemiology

• Incidence: ~2-9 per million/year (declining)
• Peak age: 40-60; slight male predominance
• Declining incidence due to HBV vaccination

Pathophysiology

• Necrotising inflammation of medium-sized arteries (segmental, at vessel bifurcations)
• Transmural inflammation with fibrinoid necrosis → microaneurysm formation
• Vessel occlusion → tissue ischaemia and infarction
• NO venous involvement, NO granulomata, NO small-vessel involvement

Constitutional (>90%)

• Fever, malaise, weight loss, myalgia, arthralgia

Neurological (70%)

• Mononeuritis multiplex: most common manifestation; foot drop, wrist drop
• Peripheral neuropathy (sensorimotor)

Skin (50%)

• Livedo reticularis, subcutaneous nodules
• Skin ulcers, digital gangrene
• Purpura (non-palpable, unlike small-vessel vasculitis)

GI (50%)

• Abdominal pain (mesenteric ischaemia)
• GI bleeding, perforation, cholecystitis
• Mesenteric vasculitis is the most serious visceral manifestation

Renal

• Renal artery involvement → renovascular hypertension, renal infarction
• NO glomerulonephritis (key distinction from AAV)

Cardiac

• Coronary arteritis → MI
• Pericarditis, heart failure

Testicular

• Orchitis (~20% of males): testicular pain and swelling

Red Flags

• Severe hypertension → renal artery involvement
• Testicular pain → consider PAN

Bloods

• ANCA: negative (essential for diagnosis)
• HBsAg: hepatitis B screen (positive in <10% now)
• CRP/ESR: elevated
• FBC: anaemia, leucocytosis, thrombocytosis
• U&Es: renal function (may show renovascular hypertension)

Angiography

• Mesenteric or renal angiography: microaneurysms, stenoses, occlusions at vessel bifurcations (diagnostic)
• CT angiography or MR angiography: less sensitive but non-invasive alternatives

Biopsy

• Tissue biopsy (skin, sural nerve, muscle, testis): transmural necrotising vasculitis of medium arteries, fibrinoid necrosis
• No granulomata, no venous involvement

Urinalysis

• No active sediment (no GN); may show proteinuria from renovascular disease

Idiopathic PAN

FFS = 0:

• Prednisolone 1mg/kg/day alone; taper over 12-18 months

FFS ≥1 (cardiac, GI, renal, CNS):

• Prednisolone + IV cyclophosphamide induction
• Azathioprine maintenance

HBV-Associated PAN

• Short course prednisolone (2-4 weeks only)
• Antiviral therapy: entecavir or tenofovir (aim for HBV seroconversion)
• Plasma exchange: to remove immune complexes
• Prolonged immunosuppression avoided (risk of HBV reactivation)

Supportive

• Antihypertensives for renovascular hypertension
• Neuropathic pain management
• Surgical intervention for bowel ischaemia/infarction

Referral

• All PAN → rheumatology
• Mesenteric ischaemia → surgery
• HBV-positive → hepatology

• 5-year survival: 80-90% with treatment
• Untreated: ~50% mortality at 1 year (historical)
• FFS score predicts outcome (higher = worse)
• HBV-related PAN: antiviral-induced seroconversion can lead to complete remission
• Relapse: less common than AAV (~10-20%)
• Mononeuritis multiplex: may cause permanent neuropathy despite treatment

PAN vs MPA

Five-Factor Score (FFS) for PAN

Key Facts

Behcet disease is unique among vasculitides as it can affect both arteries and veins of all sizes. The variable-vessel vasculitis classification reflects this.

Epidemiology

• Highest prevalence: Turkey (~400 per 100,000), Iran, Japan
• UK prevalence: ~1 per 100,000; higher in immigrant populations from endemic areas
• Peak onset: 20-40 years; M=F (but more severe in young males)

Pathophysiology

• Neutrophilic vasculitis affecting all vessel sizes
• Pathergy: exaggerated immune response to minor trauma (aberrant neutrophil function)
• HLA-B51 associated; likely autoinflammatory rather than autoantibody-driven
• IL-17 and TNF-α are key cytokines

Oral Ulcers (>95%)

• Recurrent (≥3 episodes/year)
• Painful, round, well-circumscribed with erythematous halo
• Affect lips, tongue, buccal mucosa, palate
• Often the first and most common manifestation

Genital Ulcers (60-80%)

• Painful; scrotum (males), vulva (females)
• May scar (unlike oral ulcers)

Eyes (50-70%)

• Posterior uveitis/panuveitis: most serious; risk of blindness
• Anterior uveitis: hypopyon (pus layer in anterior chamber) – classic but uncommon
• Retinal vasculitis: threatens vision

Skin (50-80%)

• Erythema nodosum, papulopustular lesions, pseudofolliculitis
• Pathergy positive

Vascular (25-30%)

• Venous: DVT, SVT, cerebral venous sinus thrombosis, Budd-Chiari
• Arterial: aneurysms (especially pulmonary artery – pathognomonic)

Neurological (Neuro-Behcet, 5-10%)

• Meningoencephalitis, brainstem syndrome
• Cerebral venous sinus thrombosis
• Progressive neurological disability

Other

• Arthritis: oligoarticular, non-erosive
• GI: ulceration (ileocaecal, mimics Crohn's)

Red Flags

• Posterior uveitis → urgent ophthalmology + immunosuppression

• Headache/neurological signs → neuro-Behcet or CVST

Diagnosis is Clinical (ISG Criteria)

• Recurrent oral ulceration (≥3 episodes in 12 months) PLUS ≥2 of:
  • Recurrent genital ulceration
  • Eye lesions (uveitis, retinal vasculitis)
  • Skin lesions (erythema nodosum, pseudofolliculitis)
  • Positive pathergy test

Bloods

• HLA-B51: supportive (not diagnostic)
• CRP/ESR: elevated during flares
• No specific autoantibody (ANCA negative, ANA negative)

Imaging

• CT/MR angiography: pulmonary artery aneurysms, venous thrombosis
• MRI brain: neuro-Behcet (brainstem lesions)
• MR venography: cerebral venous sinus thrombosis

Other

• Pathergy test: read at 24-48 hours; sterile pustule formation (positive)
• OCT/fluorescein angiography: retinal vasculitis assessment

Mucocutaneous (Oral/Genital Ulcers)

• Colchicine 500mcg BD: first-line for oral ulcers and arthralgia
• Topical steroids (triamcinolone oral paste)
• Azathioprine: for recurrent/severe mucocutaneous disease
• Apremilast 30mg BD: NICE approved for refractory oral ulcers

Uveitis

• Azathioprine: first-line for posterior uveitis/retinal vasculitis
• Anti-TNF (infliximab, adalimumab): for sight-threatening disease or refractory
• Ciclosporin: alternative
• Interferon-α: used in specialist centres
• Topical steroids + mydriatics: for anterior uveitis

Vascular

• Immunosuppression is primary treatment for thrombosis (NOT anticoagulation alone – risk of aneurysm rupture)
• Azathioprine, cyclophosphamide, or anti-TNF
• Anticoagulation: controversial; some use cautiously in combination with immunosuppression

Neuro-Behcet

• IV methylprednisolone + cyclophosphamide or infliximab
• Azathioprine maintenance

Pulmonary Artery Aneurysm

• Cyclophosphamide + corticosteroids: EMERGENCY
• Embolisation if life-threatening haemoptysis
• AVOID anticoagulation (aneurysm rupture risk)

Referral

• Suspected Behcet → rheumatology (specialist Behcet centre if available)
• Posterior uveitis → ophthalmology
• Neuro-Behcet → neurology + rheumatology

• Mortality: low (<5% at 10 years) with modern treatment
• Visual loss: reduced to <10% with immunosuppression (vs >25% historically)
• Pulmonary artery aneurysm: high mortality without treatment
• Neuro-Behcet: can cause significant disability; progressive form has worse prognosis
• Disease activity often diminishes with age
• Young males have the most severe disease and worst prognosis

ISG Diagnostic Criteria

Recurrent oral ulceration (≥3/year) PLUS ≥2 of:

1. Recurrent genital ulceration
2. Eye lesions
3. Skin lesions
4. Positive pathergy test

Behcet Disease UK Specialist Centres

• London (Royal London Hospital)
• Birmingham
• Liverpool
• Leeds

Key Facts

Takayasu arteritis should be considered in any young woman with unexplained hypertension, absent pulses, or limb claudication.

Epidemiology

• Incidence: 1-3 per million/year globally; higher in East Asia
• F:M 8-9:1; peak onset 15-30 years
• Very rare in Caucasian populations

Pathophysiology

• Granulomatous panarteritis of the aorta and major branches

• Medial destruction → aneurysm formation
• CD4+ T-cell and macrophage-driven inflammation
• Vasa vasorum involvement → wall ischaemia

Systemic (Early Phase)

• Fever, malaise, weight loss, arthralgia, myalgia
• Often misdiagnosed initially as infection

Vascular (Late/Occlusive Phase)

• Absent/reduced pulses in upper extremities (subclavian/axillary stenosis)
• Blood pressure discrepancy >10mmHg between arms
• Limb claudication: upper or lower limb
• Bruits: carotid, subclavian, renal, abdominal
• Renovascular hypertension: renal artery stenosis
• Aortic regurgitation: aortic root dilation
• Cerebrovascular: TIA, stroke (carotid involvement)
• Visual disturbance: retinal ischaemia

Classification (Numano)

• Type I: aortic arch branches only
• Type IIa: ascending aorta/arch
• Type IIb: ascending aorta, arch, thoracic descending
• Type III: thoracic descending, abdominal aorta, renal
• Type IV: abdominal aorta and/or renal
• Type V: entire aorta (most common overall)

Red Flags

• Young woman with unexplained hypertension → check BP in both arms
• Unrecordable BP in one arm → subclavian stenosis
• Stroke in young patient → consider Takayasu

Bloods

• ESR/CRP: elevated in active disease (may be normal in quiescent)
• FBC: anaemia of chronic disease

Imaging (Key to Diagnosis)

• CT angiography: wall thickening, stenoses, occlusions, aneurysms; excellent for anatomy
• MR angiography: avoids radiation; good for follow-up; wall oedema on T2
• PET-CT (18F-FDG): detects active vessel wall inflammation (useful for monitoring response)
• Conventional angiography: gold standard for anatomy but invasive
• USS: carotid/subclavian artery wall thickening

Clinical

• Four-limb blood pressures: discrepancy
• Pulse assessment: all peripheral pulses
• Echocardiogram: aortic regurgitation

Medical

• Prednisolone 1mg/kg/day: first-line; taper guided by symptoms and CRP/ESR/imaging
• Methotrexate 15-25mg weekly or azathioprine 2mg/kg/day or mycophenolate 2-3g/day: steroid-sparing
• Tocilizumab: effective for refractory disease (off-label but increasing evidence)
• Anti-TNF (infliximab): for refractory cases
• Cyclophosphamide: severe/life-threatening disease

Surgical/Endovascular (When Disease Quiescent)

• Bypass grafting: for critical stenoses (preferred over endovascular in many situations)
• Angioplasty/stenting: selected cases; higher restenosis rate
• Aortic valve replacement: for severe aortic regurgitation
• Timing: ideally during disease remission (surgery during active inflammation has higher complication rates)

Supportive

• Antihypertensives for renovascular hypertension
• Antiplatelet therapy: aspirin 75mg
• Exercise and rehabilitation

Referral

• All suspected Takayasu → rheumatology
• Vascular complications → vascular surgery
• Renovascular hypertension → nephrology

• 10-year survival: 80-90% with treatment
• Relapse rate: 50-70% during steroid taper
• Major morbidity: stroke, limb ischaemia, renal failure, aortic regurgitation
• Pregnancy: high-risk; risk of flare, hypertension, pre-eclampsia
• Earlier diagnosis and treatment associated with better outcomes
• Many patients require lifelong immunosuppression

Takayasu vs GCA

Key Facts

Fibromyalgia is a real condition with demonstrable neurobiological abnormalities in pain processing. It is not 'all in the mind' but requires a biopsychosocial management approach.

Epidemiology

• UK prevalence: 2-4%
• F:M 6-9:1
• Peak onset: 30-50 years
• Common in rheumatology clinics (15-20% of referrals)

Pathophysiology

• Central sensitisation: augmented pain processing in spinal cord and brain
• Reduced descending inhibitory pain modulation (serotonin, noradrenaline pathways)
• Elevated substance P in cerebrospinal fluid
• Abnormal functional MRI: increased activation of pain-processing regions
• Sleep architecture disruption: alpha-wave intrusion into stage 4 (deep) sleep
• Neuroendocrine: HPA axis dysregulation, low growth hormone
• Risk factors: genetic predisposition, physical/emotional trauma, chronic stress, other chronic pain conditions

Core Features

• Widespread pain: both sides of body, above and below waist, axial involvement; described as aching, burning, shooting
• Fatigue: often profound; not relieved by rest
• Sleep disturbance: unrefreshing sleep, difficulty falling/staying asleep
• Cognitive dysfunction ('fibro fog'): difficulty concentrating, poor memory, word-finding difficulty

Associated Symptoms

• Headaches (tension-type, migraine)
• IBS (abdominal pain, bloating, altered bowel habit)
• TMJ pain
• Paraesthesiae
• Morning stiffness (not prolonged as in inflammatory arthritis)
• Dizziness
• Depression and anxiety (>50%)
• Sensitivity to noise, light, temperature

Examination

• No objective joint swelling or inflammation
• Widespread tenderness to palpation
• Normal neurological examination
• Normal joint examination (may have some tender points)

Red Flags (Suggesting Alternative Diagnosis)

• True joint swelling → inflammatory arthritis
• Significant weight loss → malignancy, endocrine disease
• True muscle weakness → myopathy
• Abnormal blood tests → investigate further
• Progressive neurological signs → MS, neuropathy

Investigations to Exclude Other Diagnoses

• FBC: normal (exclude anaemia)
• ESR/CRP: normal (exclude inflammatory conditions)
• TFTs: normal (exclude hypothyroidism)
• CK: normal (exclude myopathy)
• Calcium, vitamin D: exclude deficiency
• HbA1c: exclude diabetes
• Coeliac screen (tTG): if GI symptoms

NOT Required

• Routine X-rays or MRI (unless specific indication)
• ANA, RF (unless clinical features of autoimmune disease)
• Repeated investigations → reinforce illness behaviour

Diagnosis

• ACR 2010/2016 criteria: WPI ≥7 + SSS ≥5 (or WPI 4-6 + SSS ≥9); symptoms present ≥3 months; no other explanation
• Clinical diagnosis: widespread pain + fatigue + sleep disturbance + cognitive symptoms + normal investigations

Non-pharmacological (Most Important)

• Graded aerobic exercise: most effective intervention; start low, increase gradually (swimming, walking, cycling)
• CBT: addresses catastrophising, pacing, coping strategies
• Patient education: understanding the condition, self-management (Versus Arthritis resources)
• Sleep hygiene: regular sleep schedule, avoid caffeine/screens before bed
• Mindfulness/relaxation: stress reduction
• Hydrotherapy: warm water exercise

Pharmacological

• Amitriptyline 10-25mg nocte: first-line; improves pain, sleep, and mood (NICE)
• Duloxetine 30-60mg OD: SNRI; for pain and comorbid depression/anxiety
• Pregabalin 150-300mg/day: for pain; α2δ ligand (gabapentinoid)
• Gabapentin: alternative to pregabalin
• Cyclobenzaprine: muscle relaxant (less used in UK)
• Tramadol: may be used cautiously for severe pain (some guidelines); avoid long-term

NOT Recommended

• Strong opioids (morphine, fentanyl): no evidence of benefit; significant harm (dependence, hyperalgesia)
• NSAIDs: minimal benefit in fibromyalgia (no peripheral inflammation)
• Corticosteroids: no role
• Benzodiazepines: avoid (dependence, worsens fatigue)

Multidisciplinary Approach

• Pain management programme: most effective model
• Physiotherapy, psychology, occupational therapy
• Self-management programmes

Referral Criteria

• Diagnostic uncertainty → rheumatology (one-off assessment)
• Severe, refractory symptoms → pain management team
• Significant psychological comorbidity → psychology/psychiatry

• Chronic condition with fluctuating symptoms
• No excess mortality associated with fibromyalgia itself
• 50-60% of patients report significant improvement with multidisciplinary management
• Exercise: most consistent evidence for sustained benefit
• Functional outcomes: variable; many patients maintain employment and function
• Factors associated with poorer outcomes: high catastrophising, low self-efficacy, comorbid mental health conditions, opioid use
• Spontaneous remission: uncommon but possible (~25% over 10 years)

ACR 2010 Fibromyalgia Criteria

Widespread Pain Index (WPI): Count of 19 body areas with pain (range 0-19) Symptom Severity Scale (SSS): Fatigue + unrefreshing sleep + cognitive symptoms (0-3 each) + headaches, abdominal pain, depression (0-3)

Fibromyalgia if: (WPI ≥7 AND SSS ≥5) OR (WPI 4-6 AND SSS ≥9); symptoms ≥3 months; no other disorder explaining pain

Pharmacological Comparison