Rheumatology Anatomy Physiology Pharmacology

🦴 Rheumatology anatomy, physiology and pharmacology — the foundation page for the Rheumatology chapter. Joint and muscle diseases make much more sense when you understand how a healthy joint, tendon and bone work: why rheumatoid arthritis attacks the synovium while osteoarthritis wears the cartilage, why spondyloarthritis targets entheses, why gout flares at night in the big toe, and how each drug interrupts the disease. Clinical assessment, investigations and drug monitoring are covered on the Rheumatology Assessment, Investigations and Drugs page.
Your four questions for every musculoskeletal problem: Which tissue is the problem — synovium, cartilage, bone, enthesis, tendon, muscle or nerve? Is the process inflammatory, degenerative, crystal, infective or pain-processing? What does the anatomy predict about function and complications? Which drug targets that mechanism — and what does it risk?

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Types of Joint

• Fibrous joints — bones joined by fibrous tissue, little or no movement — skull sutures, distal tibiofibular syndesmosis, teeth in sockets.
• Cartilaginous joints — bones joined by cartilage:
  • Primary (hyaline) — growth plates, first sternocostal joint.
  • Secondary (fibrocartilage — symphyses) — intervertebral discs, pubic symphysis, manubriosternal joint — small movement; involved in spondyloarthritis.
• Synovial joints — freely moving, lined by synovium — most limb joints — the main target of inflammatory arthritis.
  • Hinge — elbow (humero-ulnar), interphalangeal joints, knee (modified).
  • Ball and socket — shoulder, hip.
  • Pivot — atlantoaxial (C1–C2 — rotation; instability in RA), proximal radioulnar.
  • Condyloid and saddle — wrist, MCP joints, first carpometacarpal (saddle — thumb opposition; common site of OA).
  • Plane — facet joints, acromioclavicular, intercarpal joints.
• Stability vs mobility — the shoulder trades stability for movement (dislocates easily); the hip has a deep socket (stable).
• Patterns of disease by joint type — RA (synovial joints, symmetrical small joints), spondyloarthritis (entheses, sacroiliac joints, spine — cartilaginous and synovial), OA (weight-bearing joints, DIPs, PIPs, first CMC — cartilage).

The Synovial Joint

• Components:
  • Articular (hyaline) cartilage covering the bone ends — smooth, low-friction surface.
  • Joint capsule — fibrous outer layer reinforced by ligaments.
  • Synovial membrane — lines the capsule (not the cartilage) — produces synovial fluid.
  • Synovial fluid — lubricates and nourishes cartilage.
  • Subchondral bone — supports cartilage; sclerosis and cysts in OA; erosions at the "bare area" in RA.
  • Accessory structures — menisci (knee), labrum (shoulder, hip), fat pads, bursae, intra-articular ligaments.
• Bare areas — where synovium meets bone at the joint margin without cartilage cover — the first site of erosions in RA (marginal erosions).
• Nerve supply — capsule and ligaments are richly innervated (pain, proprioception); cartilage has no nerves — pain in OA comes from bone, synovium, capsule and central processing, not cartilage itself.
• Hilton's law — the nerve supplying a joint also supplies the muscles moving it and the overlying skin — explains referred pain (hip disease felt in the knee — obturator nerve; shoulder pain from the diaphragm — C4).
• Proprioception — joint receptors and muscle spindles — reduced in OA, neuropathy (diabetes) and ageing; loss of protective sensation causes Charcot neuropathic joints.
• Bursae — fluid-filled sacs reducing friction — olecranon, prepatellar (housemaid's knee), trochanteric (greater trochanteric pain syndrome), subacromial; septic bursitis (Staph aureus) or crystal bursitis.

Articular Cartilage

• Structure — hyaline cartilage, 2–4 mm thick:
  • Chondrocytes — few cells (about 1–2% of volume) that make and maintain the matrix.
  • Type II collagen — tensile strength.
  • Proteoglycans (aggrecan — with negatively charged glycosaminoglycans) — attract water (about 70–80% of cartilage weight) — resist compression like a sponge.
• Avascular, aneural and alymphatic — nutrients diffuse from synovial fluid, helped by joint loading and movement (exercise is good for cartilage) — very limited capacity to repair.
• Osteoarthritis — a whole-joint disease:
  • Imbalance between matrix breakdown (matrix metalloproteinases, aggrecanases) and repair, driven by mechanical load, ageing, injury, obesity (also metabolic and inflammatory effects of fat), malalignment, genetics.
  • Changes — cartilage fibrillation and loss (joint space narrowing), subchondral sclerosis and cysts, osteophytes (attempted repair at margins), synovitis (low grade), capsular thickening, muscle weakness.
  • Pain correlates poorly with X-ray severity.
• Fibrocartilage (type I collagen) — menisci, intervertebral discs, labrum, pubic symphysis — tears with twisting or degeneration.
• Chondrocalcinosis — calcium pyrophosphate deposits in cartilage (knee menisci, wrist triangular fibrocartilage).
• Ochronosis (alkaptonuria) — dark pigment in cartilage — early OA, black urine.

Synovium and Synovial Fluid

• Synovial membrane — thin lining (1–3 cell layers) of:
  • Type A synoviocytes — macrophage-like (phagocytosis).
  • Type B synoviocytes — fibroblast-like — produce hyaluronic acid and lubricin.
• Synovial fluid — a plasma dialysate plus hyaluronic acid — viscous, clear, few cells; small volume (under 4 mL in the knee).
• In rheumatoid arthritis — the synovium becomes hyperplastic and inflamed (pannus) — infiltrated by T cells, B cells, plasma cells and macrophages; fibroblast-like synoviocytes become invasive and release enzymes (MMPs) and cytokines (TNF, IL-6, IL-1) → cartilage destruction and bone erosion (via RANKL-activated osteoclasts).
• Synovial fluid analysis:

  Type	Appearance	White cells (per mm³)	Examples
  Normal	Clear, viscous	Under 200	—
  Non-inflammatory	Clear, yellow	Under 2,000	OA, trauma
  Inflammatory	Cloudy, less viscous	2,000–50,000	RA, gout, CPPD, spondyloarthritis
  Septic	Turbid, purulent	Often over 50,000 (mainly neutrophils)	Bacterial infection — but overlap exists
  Haemorrhagic	Blood-stained	Variable	Trauma, haemophilia, anticoagulants, pigmented villonodular synovitis

• Always send fluid for Gram stain, culture and crystal microscopy — crystals and infection can coexist.
• Lipohaemarthrosis (fat in a bloody aspirate) — intra-articular fracture.

Tendons, Ligaments and Entheses

• Tendons — connect muscle to bone; mainly type I collagen; poor blood supply (slow healing); some run in synovial sheaths (hand flexors and extensors — tenosynovitis in RA, gonococcal infection, de Quervain's).
• Ligaments — connect bone to bone; stabilise joints; sprains and ruptures (ACL); laxity in hypermobility disorders.
• Entheses — where tendons, ligaments and capsules attach to bone — a fibrocartilaginous "organ" under high mechanical stress:
  • Enthesitis is the hallmark of spondyloarthritis (ankylosing spondylitis, psoriatic arthritis, reactive arthritis, IBD-associated arthritis) — Achilles tendon insertion, plantar fascia, patellar tendon, iliac crest, spinal ligament insertions.
  • Driven by mechanical stress plus IL-23/IL-17 immune pathways — explains the effect of IL-17 and IL-23 inhibitors.
  • Inflammation followed by new bone formation (syndesmophytes, ankylosis) — unlike RA, which erodes bone.
• Tendinopathy — degenerative more than inflammatory — rotator cuff, lateral epicondyle (tennis elbow), Achilles, gluteal tendons; risk factors — overuse, ageing, fluoroquinolones (tendon rupture — especially with steroids and in older people — MHRA), statins (rare).
• Dactylitis ("sausage digit") — whole-digit swelling from tenosynovitis plus joint inflammation — psoriatic arthritis, reactive arthritis, sickle cell disease, TB, sarcoid.

Skeletal Muscle

• Structure — muscle fibres (multinucleated cells) containing myofibrils of actin and myosin (sarcomeres); type I (slow, oxidative — posture) and type II (fast — power) fibres.
• Contraction — nerve impulse → acetylcholine at the neuromuscular junction → muscle action potential → calcium release from the sarcoplasmic reticulum (ryanodine receptor — RYR1 — malignant hyperthermia) → actin–myosin cross-bridging (needs ATP).
• Creatine kinase (CK) — released by damaged muscle — very high in myositis, necrotising myopathy, rhabdomyolysis, muscular dystrophies; mildly raised after exercise, IM injections, in people of Black African ancestry, hypothyroidism.
• Proximal muscle weakness (shoulder and hip girdles) — difficulty rising from a chair, climbing stairs, lifting arms:
  • Inflammatory myositis (polymyositis, dermatomyositis, inclusion body myositis — finger flexors and quadriceps in older men), necrotising myopathy (statins — anti-HMGCR).
  • Endocrine — hypothyroidism, Cushing's and steroid myopathy, osteomalacia (vitamin D deficiency), hyperparathyroidism.
  • Drugs — statins, steroids, colchicine (with renal impairment), alcohol, zidovudine.
• Pain and stiffness without weakness — polymyalgia rheumatica (shoulder and hip girdle stiffness in over-50s, raised CRP — normal CK), fibromyalgia, hypothyroidism, statin myalgia.
• Sarcopenia — age-related loss of muscle mass and strength — falls, frailty; resistance exercise and protein.

Bone Structure and Remodelling

• Bone types — cortical (compact — 80% of skeleton — long bone shafts) and trabecular (cancellous — spongy — vertebrae, ends of long bones, pelvis — high turnover — lost first in osteoporosis and steroid use — vertebral and wrist fractures).
• Composition — type I collagen (flexibility — defective in osteogenesis imperfecta) and hydroxyapatite (calcium phosphate — hardness — defective mineralisation in osteomalacia and rickets).
• Cells:
  • Osteoblasts — make bone (osteoid, then mineralise) — marker: ALP, P1NP.
  • Osteocytes — embedded osteoblasts — sense mechanical load; produce sclerostin (inhibits bone formation — target of romosozumab) and FGF23 (phosphate control).
  • Osteoclasts — multinucleated cells (monocyte lineage) that resorb bone — marker: CTX.
• Remodelling — continuous resorption and formation (about 10% of the skeleton renewed each year) — repairs microdamage and supplies calcium.
  • RANKL (from osteoblasts and activated T cells) binds RANK on osteoclast precursors → osteoclast formation; osteoprotegerin (OPG) is a decoy receptor that blocks it — denosumab mimics OPG.
  • Wnt signalling drives osteoblast bone formation (blocked by sclerostin).
• Peak bone mass — reached by about age 30; then gradual loss; rapid loss after menopause (oestrogen deficiency increases RANKL — osteoclast activity).
• Influences — oestrogen and testosterone, weight-bearing exercise, calcium and vitamin D, glucocorticoids (reduce formation, increase resorption — fracture risk rises within months), thyroid hormone excess, smoking, alcohol, low body weight, inflammation (RA).
• Disorders of remodelling — osteoporosis (low bone mass and microarchitectural damage), Paget's disease (disorganised excessive remodelling — high ALP), osteopetrosis (failed osteoclasts), osteomalacia (poor mineralisation), bone metastases (lytic or sclerotic).

Calcium, Vitamin D and Parathyroid Hormone

• Calcium — 99% in bone; plasma calcium is about half ionised (active), half protein-bound (albumin — use adjusted calcium).
• Parathyroid hormone (PTH) — released when calcium falls:
  • Bone — increases resorption (via RANKL).
  • Kidney — increases calcium reabsorption, increases phosphate excretion, activates vitamin D (1-alpha-hydroxylase).
  • Intermittent PTH (teriparatide) paradoxically builds bone.
• Vitamin D — made in the skin (UVB) or eaten → 25-hydroxyvitamin D (liver — measured to assess stores) → 1,25-dihydroxyvitamin D (calcitriol) (kidney — active) — increases gut absorption of calcium and phosphate.
  • Deficiency — osteomalacia (adults — bone pain, proximal myopathy, Looser's zones, low calcium and phosphate, high ALP and PTH) and rickets (children); risk — dark skin, covered skin, housebound, care homes, malabsorption, anticonvulsants, CKD (can't activate — use alfacalcidol or calcitriol).
  • UK advice — vitamin D 10 micrograms (400 units) daily supplements for at-risk groups and in autumn and winter.
• Calcitonin (thyroid C cells) — minor role in humans; tumour marker in medullary thyroid cancer.
• Bone profile patterns:

  Condition	Calcium	Phosphate	ALP	PTH
  Osteoporosis	Normal	Normal	Normal	Normal
  Osteomalacia	Low/normal	Low	High	High
  Paget's disease	Normal	Normal	Very high	Normal
  Primary hyperparathyroidism	High	Low/normal	Normal/high	High/inappropriately normal
  Bone metastases	High/normal	Variable	High	Low (if hypercalcaemic)
  Myeloma	High/normal	Normal	Normal (osteoblasts suppressed)	Low
  CKD–mineral bone disorder	Low/normal	High	Normal/high	High (secondary)

The Shoulder

• Joints — glenohumeral (shallow ball and socket — the most mobile and most often dislocated large joint), acromioclavicular, sternoclavicular, scapulothoracic.
• Stabilisers — glenoid labrum, capsule and ligaments, and the rotator cuff — "SITS":

  Muscle	Nerve	Action and test
  Supraspinatus	Suprascapular (C5)	Initiates abduction (first 15°) — empty can test; commonest tendon involved in impingement and tears
  Infraspinatus	Suprascapular (C5–6)	External rotation
  Teres minor	Axillary (C5)	External rotation
  Subscapularis	Subscapular nerves (C5–6)	Internal rotation — lift-off test

• Abduction — supraspinatus (0–15°), deltoid (axillary nerve — 15–90°), then scapular rotation (trapezius — accessory nerve; serratus anterior — long thoracic nerve — winged scapula).
• Common problems:
  • Subacromial pain (impingement) — painful arc 60–120°, rotator cuff tendinopathy or tear; subacromial bursitis.
  • Frozen shoulder (adhesive capsulitis) — global loss of movement, especially external rotation (passive and active) — diabetes, after immobilisation; painful, freezing and thawing phases over 1–3 years.
  • Glenohumeral OA, acromioclavicular OA (painful high arc), calcific tendinitis, dislocation (axillary nerve — regimental badge numbness).
  • Polymyalgia rheumatica — bilateral shoulder pain and stiffness with raised CRP — bursitis and synovitis on ultrasound.
• Referred shoulder pain — neck (C5), heart, diaphragm (C4 — subphrenic abscess, gallbladder, ectopic pregnancy with blood under the diaphragm), Pancoast tumour.

The Hand and Wrist

• Joints — distal interphalangeal (DIP), proximal interphalangeal (PIP), metacarpophalangeal (MCP), first carpometacarpal (CMC — base of thumb), wrist (radiocarpal, midcarpal, distal radioulnar).
• Patterns of arthritis:
  • Rheumatoid arthritis — MCPs, PIPs and wrists, symmetrical; spares DIPs; deformities — ulnar deviation, swan neck (PIP hyperextension, DIP flexion), boutonnière (PIP flexion, DIP hyperextension), Z-thumb; extensor tendon rupture (dorsal wrist synovitis rubbing on the ulnar head).
  • Osteoarthritis — DIPs (Heberden's nodes), PIPs (Bouchard's nodes), first CMC (squaring of the thumb base); spares MCPs (unless haemochromatosis — 2nd and 3rd MCPs).
  • Psoriatic arthritis — DIPs with nail changes (pitting, onycholysis), dactylitis, asymmetrical, arthritis mutilans.
  • Gout — tophi over joints and in finger pads; CPPD — wrists (triangular fibrocartilage).
• Nerves:
  • Median nerve — through the carpal tunnel (with flexor tendons) — thenar muscles (LOAF — lateral two lumbricals, opponens pollicis, abductor pollicis brevis, flexor pollicis brevis), sensation to the thumb, index, middle and half of ring finger — carpal tunnel syndrome (pregnancy, hypothyroidism, RA, diabetes, acromegaly, amyloidosis, dialysis) — night tingling, thenar wasting.
  • Ulnar nerve — behind the medial epicondyle (cubital tunnel) and through Guyon's canal — most intrinsic hand muscles, little finger sensation — claw hand.
  • Radial nerve — wrist and finger extensors — wrist drop (humeral shaft fracture, "Saturday night palsy").
• Tendons — de Quervain's tenosynovitis (abductor pollicis longus and extensor pollicis brevis — Finkelstein's test — new mothers), trigger finger (flexor tendon nodule — diabetes), Dupuytren's contracture (palmar fascia — ring and little fingers — men, family history, alcohol, diabetes, epilepsy drugs).
• Raynaud's phenomenon — digital artery vasospasm (white → blue → red) — primary (young women, benign) or secondary (systemic sclerosis, SLE — nailfold capillary changes, digital ulcers).

Hip, Knee and Foot

• Hip — deep ball and socket; capsule and strong ligaments; acetabular labrum.
  • Blood supply to the femoral head — mainly retinacular branches of the medial circumflex femoral artery — disrupted by intracapsular fractures (avascular necrosis risk) and in AVN (steroids, alcohol, sickle cell).
  • Hip pain is felt in the groin (and referred to the knee); lateral hip pain is usually greater trochanteric pain syndrome (gluteal tendinopathy and bursitis); buttock pain is often from the spine.
  • Internal rotation is lost first in hip OA.
• Knee — the largest synovial joint — tibiofemoral (medial and lateral compartments) and patellofemoral joints.
  • Menisci (fibrocartilage) — shock absorption and stability — tears with twisting (locking, effusion).
  • Cruciate ligaments (ACL, PCL) and collateral ligaments (MCL, LCL).
  • Medial compartment OA is commonest (varus — bow-legged).
  • Baker's cyst — posterior synovial cyst (OA, RA) — rupture mimics DVT.
  • Effusions — patellar tap and sweep tests; the knee is the commonest site of septic arthritis, gout (after the big toe) and CPPD (pseudogout).
• Ankle and foot:
  • First MTP joint — the classic site of gout (podagra) and hallux valgus, OA (hallux rigidus).
  • MTP joints — early RA (squeeze test — forefoot pain on walking — "walking on pebbles").
  • Achilles tendon and plantar fascia — enthesitis in spondyloarthritis; plantar fasciitis (common, mechanical).
  • Midfoot — Charcot neuroarthropathy in diabetes (hot, swollen, often painless — immobilise urgently).
  • Morton's neuroma (3rd/4th web space).

Spine and Sacroiliac Joints

• Vertebral column — 7 cervical, 12 thoracic, 5 lumbar, sacrum and coccyx; joints — intervertebral discs (fibrocartilaginous — annulus fibrosus around the gel-like nucleus pulposus) and paired facet joints (synovial — OA).
• Disc prolapse — the nucleus herniates (usually posterolaterally) and compresses the nerve root below (e.g. L4/5 disc → L5 root):

  Root	Weakness	Sensory loss	Reflex
  L3/L4	Knee extension	Anterior thigh, medial shin	Knee jerk reduced
  L5	Ankle and big toe dorsiflexion (foot drop)	Lateral shin, dorsum of foot	None reliable
  S1	Plantarflexion (tiptoe)	Lateral foot, sole	Ankle jerk reduced

• Cauda equina — the spinal cord ends at about L1–L2; below this, nerve roots form the cauda equina — a large central disc compresses many roots (saddle anaesthesia, bladder dysfunction) — emergency.
• Spinal stenosis — narrowing of the canal (facet OA, ligamentum flavum thickening, disc bulges) — neurogenic claudication (leg pain on walking relieved by sitting or bending forward — unlike vascular claudication, relieved by standing still).
• Sacroiliac joints — part synovial, part fibrous — sacroiliitis is the hallmark of axial spondyloarthritis (inflammatory back pain — age under 40, insidious onset, morning stiffness over 30 minutes, improves with exercise not rest, night pain in the second half of the night, alternating buttock pain) — MRI shows early bone marrow oedema.
• Atlantoaxial joint — RA (and Down syndrome) can cause subluxation — neck pain, myelopathy; care with intubation.
• Ankylosing spondylitis — syndesmophytes bridge vertebrae ("bamboo spine") — rigid spine prone to fractures after minor trauma.
• DISH (diffuse idiopathic skeletal hyperostosis) — flowing ossification along the right side of thoracic vertebrae — older men, diabetes, obesity; sacroiliac joints normal.

Inflammation in Joint Disease

• Features of inflammatory joint disease — early morning stiffness over 30–60 minutes, improves with activity, soft tissue swelling, warmth, raised CRP and ESR, systemic features (fatigue, fever, weight loss) — vs mechanical (worse with use, brief stiffness, bony swelling).
• Autoimmune (adaptive) inflammation:
  • Rheumatoid arthritis — genetic (HLA-DR4 "shared epitope"), smoking and gum disease (Porphyromonas gingivalis) promote citrullination of proteins → anti-CCP antibodies (years before symptoms) → T-cell and B-cell activation → synovitis driven by TNF, IL-6, IL-1, GM-CSF → cartilage and bone destruction (osteoclasts via RANKL) and systemic effects (anaemia, fatigue, cardiovascular disease, osteoporosis).
  • SLE — loss of tolerance to nuclear antigens; defective clearance of apoptotic cells; type I interferon signature; immune complexes deposit and activate complement (low C3 and C4).
  • Vasculitis — inflammation of vessel walls (large — GCA, Takayasu; medium — PAN, Kawasaki; small — ANCA vasculitis, IgA vasculitis, cryoglobulinaemia).
• Spondyloarthritis — HLA-B27, gut and skin barrier inflammation, mechanical stress at entheses → IL-23/IL-17 axis → enthesitis and new bone formation.
• Autoinflammatory (innate) inflammation — crystals (gout, CPPD) and periodic fevers activate the NLRP3 inflammasome → IL-1β → neutrophil influx — explains why colchicine and IL-1 blockers work.
• Acute phase response — IL-6 drives CRP, fibrinogen, ferritin, platelets (reactive thrombocytosis) and hepcidin (anaemia of chronic disease).
• Treat-to-target — early, aggressive suppression of inflammation in RA prevents irreversible joint damage ("window of opportunity" — first 3 months).

Urate and Crystal Biology

• Uric acid — the end product of purine breakdown (hypoxanthine → xanthine → urate, via xanthine oxidase); humans lack uricase (which other mammals use to break urate down further).
• Urate balance — about two-thirds excreted by the kidneys (filtered, mostly reabsorbed by URAT1 and others, partly secreted), one-third by the gut.
• Hyperuricaemia (over about 360 µmol/L — urate saturation point) — under-excretion in about 90% (CKD, diuretics — thiazides and loops, low-dose aspirin, ciclosporin, alcohol, lead, obesity, metabolic syndrome, genetics) or over-production (high purine diet, alcohol (beer), fructose, tumour lysis, psoriasis, haematological disease, inherited enzyme defects — Lesch–Nyhan).
• Gout — monosodium urate crystals deposit in and around joints:
  • Crystals form more easily in cooler peripheral joints (big toe), at lower pH and with dehydration — attacks often at night.
  • Triggers — alcohol, dietary excess, dehydration, illness, surgery, starting or changing urate-lowering therapy or diuretics (rapid urate shifts).
  • Crystals activate the NLRP3 inflammasome → IL-1β → intense neutrophilic inflammation.
  • Microscopy — needle-shaped, negatively birefringent crystals under polarised light.
  • Serum urate may be normal during an attack — recheck 2–4 weeks later.
• Calcium pyrophosphate deposition (CPPD) — rhomboid, weakly positively birefringent crystals — acute "pseudogout" (knee, wrist — older people, intercurrent illness, surgery), chronic arthropathy, chondrocalcinosis; associations in younger people — haemochromatosis, hyperparathyroidism, hypomagnesaemia, hypophosphatasia.
• Basic calcium phosphate (hydroxyapatite) — calcific tendinitis (shoulder), Milwaukee shoulder (destructive arthropathy in older women).

Pain Physiology and Central Sensitisation

• Nociceptive pain — tissue damage or inflammation activates nociceptors (A-delta fibres — sharp, fast; C fibres — dull, slow) → dorsal horn → spinothalamic tract → thalamus → cortex.
• Inflammatory pain — prostaglandins (made by COX), bradykinin, cytokines and nerve growth factor sensitise nociceptors (peripheral sensitisation) — explains the benefit of NSAIDs and steroids.
• Neuropathic pain — nerve damage (radiculopathy, carpal tunnel, diabetic neuropathy) — burning, shooting, numbness — amitriptyline, duloxetine, gabapentin, pregabalin (NICE CG173).
• Nociplastic pain and central sensitisation — amplified pain processing in the spinal cord and brain without tissue damage — fibromyalgia (widespread pain, fatigue, poor sleep, cognitive symptoms), chronic primary pain, and a component of many chronic conditions (OA, RA, chronic back pain).
  • Reduced descending inhibition (serotonin, noradrenaline), increased excitatory signalling; influenced by sleep, mood, stress and trauma.
  • Responds poorly to opioids and anti-inflammatories — exercise, education, psychological therapies (CBT, ACT), sleep; some benefit from antidepressants (NICE NG193 — chronic primary pain).
• Gate control theory — non-painful input (rubbing, TENS) can reduce pain transmission at the dorsal horn.
• Opioids — poor evidence for long-term benefit in chronic non-cancer musculoskeletal pain; risks — dependence, falls, constipation, hyperalgesia, hypogonadism — avoid escalating doses (NICE NG193; Opioids Aware).

Analgesics and NSAIDs — How They Work

• Paracetamol — central mechanism (weak COX inhibition in the CNS, serotonergic pathways); little anti-inflammatory effect; limited benefit in OA and back pain.
• NSAIDs — inhibit cyclo-oxygenase (COX) → reduce prostaglandins:
  • COX-1 (constitutive) — protects gastric mucosa (mucus, bicarbonate), maintains renal blood flow (afferent arteriolar dilation), platelet thromboxane A2 (aggregation).
  • COX-2 (induced in inflammation) — pain, fever, inflammation; also renal and vascular (prostacyclin) roles.
• Adverse effects follow the mechanism:
  • GI — ulcers and bleeding (COX-1) — co-prescribe a PPI in at-risk patients (over 65, previous ulcer, steroids, anticoagulants, SSRIs).
  • Kidney — reduced renal blood flow → AKI (especially with ACE inhibitors/ARBs and diuretics — the "triple whammy"), sodium and water retention (oedema, heart failure, hypertension), hyperkalaemia, interstitial nephritis.
  • Cardiovascular — increased thrombotic risk (COX-2 selective and high-dose diclofenac — contraindicated in established cardiovascular disease); naproxen and low-dose ibuprofen have lower CV risk.
  • Asthma — NSAID-exacerbated respiratory disease (shunting to leukotrienes).
  • Pregnancy — avoid after 20 weeks (oligohydramnios) and in the third trimester (premature closure of the ductus arteriosus).
• COX-2 selective (celecoxib, etoricoxib) — fewer GI effects but similar renal and CV risks.
• Topical NSAIDs — first line for knee and hand OA (NICE NG226) — low systemic absorption.
• Aspirin — irreversible COX inhibition — low dose is antiplatelet (not analgesic); raises urate at low doses.
• Practical NSAID use — lowest dose, shortest time, review regularly.

Glucocorticoids — How They Work

• Mechanism — bind the intracellular glucocorticoid receptor → enters the nucleus → switches off inflammatory genes (blocks NF-κB and AP-1 — reducing TNF, IL-1, IL-6, COX-2, adhesion molecules) and switches on anti-inflammatory genes (annexin-1, IκB) → reduce lymphocytes, eosinophils, monocytes; increase neutrophils (demargination).
• Rapid, broad and powerful — the mainstay for flares, PMR, GCA, vasculitis, SLE, myositis — bridging until DMARDs work.
• Routes — oral (prednisolone), IV methylprednisolone (pulses), IM depot (methylprednisolone acetate), intra-articular injection (triamcinolone — local effect, minimal systemic).
• Adverse effects (dose and duration dependent):
  • Metabolic — hyperglycaemia and diabetes, weight gain, central obesity, dyslipidaemia.
  • Bone — osteoporosis (reduce osteoblast function — fracture risk rises within 3–6 months — bone protection if 3 months or more expected at 7.5 mg or more, or age 65+ — NOGG), avascular necrosis.
  • Muscle — proximal myopathy.
  • Infection — and masking of infection; PCP risk with high doses plus other immunosuppressants.
  • Eyes — cataract, glaucoma.
  • CV — hypertension, fluid retention.
  • GI — peptic ulceration (especially with NSAIDs).
  • CNS — insomnia, mood change, psychosis.
  • Skin — thinning, bruising, poor healing.
  • HPA axis suppression — adrenal insufficiency if stopped suddenly after more than 3 weeks — taper; steroid emergency card; sick day rules (NHS England 2020 alert).
• Relative potencies — prednisolone 5 mg ≈ hydrocortisone 20 mg ≈ dexamethasone 0.75 mg ≈ methylprednisolone 4 mg.

Conventional DMARDs — How They Work

Drug	Mechanism	Key risks that follow
Methotrexate (weekly)	Inhibits dihydrofolate reductase and other folate enzymes → reduced purine synthesis; at low dose, increased adenosine release (anti-inflammatory)	Bone marrow suppression, hepatotoxicity, pneumonitis, mucositis, teratogenic — folic acid on a different day; once weekly only (fatal daily-dosing errors); trimethoprim/co-trimoxazole (additive antifolate) and NSAIDs reduce clearance
Hydroxychloroquine	Raises lysosomal pH → impairs antigen presentation and Toll-like receptor signalling (reduces type I interferon)	Retinopathy (annual screening after 5 years; dose 5 mg/kg/day or less), QT prolongation, rare cardiomyopathy; safe in pregnancy — the backbone of SLE treatment
Sulfasalazine	Sulfapyridine plus 5-aminosalicylic acid — reduces cytokines and leucocyte function	GI upset, rash, marrow suppression, hepatitis, orange urine and tears, reversible oligospermia; safe in pregnancy (with folic acid 5 mg)
Leflunomide	Inhibits dihydroorotate dehydrogenase → reduced pyrimidine synthesis in lymphocytes	Hepatotoxicity, hypertension, diarrhoea, marrow suppression, teratogenic with a very long half-life (washout with colestyramine)
Azathioprine	Purine analogue (6-mercaptopurine) — inhibits lymphocyte proliferation	Check TPMT; marrow suppression; allopurinol interaction; skin cancer
Mycophenolate	Inhibits IMP dehydrogenase → lymphocyte purine synthesis	Teratogenic, GI, cytopenias, infection — lupus nephritis
Ciclosporin	Calcineurin inhibitor → reduced IL-2 → reduced T-cell activation	Nephrotoxicity, hypertension, gum hyperplasia, hirsutism, interactions (CYP3A4)
Cyclophosphamide	Alkylating agent — cross-links DNA	Marrow suppression, haemorrhagic cystitis (mesna), infertility, malignancy

• DMARDs take weeks to months to work — bridge with steroids.
• Monitoring — FBC, LFTs, U&E (and others) under shared care — BSR guidance (see Rheumatology Assessment, Investigations and Drugs page).

Targeted Therapies — Which Molecule?

Target	Drugs	Rheumatology uses
TNF	Adalimumab, etanercept, infliximab, certolizumab, golimumab	RA, psoriatic arthritis, axial SpA, uveitis
IL-6 receptor	Tocilizumab, sarilumab	RA, giant cell arteritis, Still's disease
CD20 (B cells)	Rituximab	RA (seropositive), ANCA vasculitis, SLE, myositis
T-cell co-stimulation	Abatacept	RA
IL-17	Secukinumab, ixekizumab, bimekizumab	Psoriatic arthritis, axial SpA
IL-12/23, IL-23	Ustekinumab, guselkumab, risankizumab	Psoriatic arthritis (not axial disease)
IL-1	Anakinra, canakinumab	Gout flares (refractory), Still's disease, periodic fevers
BAFF / type I IFN receptor	Belimumab / anifrolumab	SLE
IL-5	Mepolizumab	EGPA
C5a receptor	Avacopan	ANCA vasculitis (steroid-sparing)
JAK (small molecules)	Tofacitinib, baricitinib, upadacitinib, filgotinib	RA, psoriatic arthritis, axial SpA — caution over 65s and smokers (MHRA)
PDE4	Apremilast	Psoriatic arthritis, Behçet's oral ulcers

• Why mechanism matters — IL-17 blockers help enthesitis and psoriasis but can worsen IBD; IL-23 blockers don't work in axial disease; anti-TNF is avoided in MS and severe heart failure; IL-6 blockers suppress CRP and fever (masking infection).
• Before starting — TB, hepatitis B and C, HIV and VZV screening; vaccines (see Immunology chapter).
• Biosimilars — prescribe by brand.

Gout Drugs

• Acute flare — treat early; continue urate-lowering therapy if already taking it:
  • NSAID (e.g. naproxen) with PPI.
  • Colchicine — inhibits microtubule polymerisation → blocks neutrophil migration and NLRP3 inflammasome activation — low dose (e.g. 500 micrograms 2–4 times daily); diarrhoea is the dose-limiting effect; toxic in overdose; reduce dose in renal impairment; interactions — clarithromycin, ciclosporin, verapamil, diltiazem (CYP3A4 and P-glycoprotein) — myopathy and toxicity.
  • Corticosteroids — oral prednisolone short course or intra-articular injection (exclude sepsis).
  • IL-1 blockade (anakinra) — refractory or when others are contraindicated (specialist).
• Urate-lowering therapy (BSR 2017; NICE NG219):
  • Offer to people with recurrent flares, tophi, joint damage, CKD stages 3–5, diuretic use, urate stones; discuss with everyone after a first flare.
  • Allopurinol — xanthine oxidase inhibitor — start low (100 mg daily, lower in CKD) and titrate monthly to a target urate under 360 µmol/L (under 300 if tophi or frequent flares); risks — rash, severe cutaneous reactions (SJS/TEN, DRESS — HLA-B*58:01 in Han Chinese, Thai and Korean ancestry); azathioprine and mercaptopurine interaction (xanthine oxidase metabolises them — toxicity).
  • Febuxostat — non-purine xanthine oxidase inhibitor — second line; caution in cardiovascular disease (MHRA — increased CV mortality in one trial).
  • Flare prophylaxis when starting — low-dose colchicine (or NSAID) for up to 6 months (starting ULT mobilises urate crystals).
  • Uricosurics (benzbromarone — specialist), pegloticase (refractory tophaceous gout — specialist).
• Lifestyle — weight loss, reduce alcohol (especially beer and spirits) and sugary drinks; review diuretics (losartan has a mild uricosuric effect).
• Rasburicase (recombinant urate oxidase) — prevents tumour lysis syndrome — contraindicated in G6PD deficiency.

Bone Drugs

Drug	Mechanism	Key points
Bisphosphonates — alendronic acid (weekly), risedronate, IV zoledronic acid (yearly)	Bind hydroxyapatite; taken up by osteoclasts → inhibit farnesyl pyrophosphate synthase → osteoclast apoptosis — anti-resorptive	Oral — take fasting with a full glass of water, sit upright 30 minutes (oesophagitis); avoid if eGFR under 35; IV — acute phase reaction; osteonecrosis of the jaw (dental check), atypical femoral fractures (thigh pain — drug holiday review after 5 years oral, 3 years IV); correct vitamin D and calcium first (hypocalcaemia)
Denosumab (6-monthly SC)	Monoclonal antibody against RANKL — blocks osteoclast formation	Usable in CKD; hypocalcaemia; never stop without follow-on therapy (rebound bone loss and multiple vertebral fractures — bisphosphonate after); ONJ; atypical fractures
Teriparatide (daily SC — PTH 1–34)	Anabolic — intermittent PTH stimulates osteoblasts	Severe osteoporosis with vertebral fractures; maximum 2 years; then anti-resorptive; avoid with Paget's, prior radiotherapy, high calcium
Romosozumab (monthly SC for 12 months)	Anti-sclerostin — increases formation and reduces resorption	Very high fracture risk in postmenopausal women; contraindicated after MI or stroke (CV signal)
HRT and raloxifene	Oestrogen (receptor) effects reduce resorption	HRT — younger postmenopausal women; raloxifene (SERM) — VTE risk, reduces breast cancer
Calcium and vitamin D	Substrate for mineralisation	Ensure adequate before and with other treatments; colecalciferol for deficiency; alfacalcidol or calcitriol in CKD and hypoparathyroidism

• Fracture risk assessment — FRAX or QFracture, then DEXA; NOGG thresholds; fracture liaison services after fragility fractures.
• Paget's disease — IV zoledronic acid for bone pain.

⚠️ Safety Pearl: Two drug-mechanism traps cause deaths every year. Methotrexate is once WEEKLY — daily dosing causes fatal marrow failure. And allopurinol blocks the enzyme that clears azathioprine and mercaptopurine — combining them without a large dose reduction causes severe myelosuppression.

Rheumatology Science at a Glance

Fact	Why it matters
Cartilage is avascular and aneural	Poor repair; OA pain comes from other tissues
Synovial bare areas	First site of RA erosions
Entheses	Hallmark of spondyloarthritis — IL-23/IL-17
RA spares DIPs; OA and PsA affect DIPs	Pattern recognition in the hands
Hip pain referred to the knee	Always examine the hip in knee pain
Supraspinatus initiates abduction	Commonest cuff tendon to tear
Frozen shoulder loses external rotation	Clinical clue; diabetes
L4/5 disc compresses L5 root	Foot drop; dermatome patterns
Cord ends at L1–2	Cauda equina below
RANKL drives osteoclasts	Denosumab target; RA erosions; menopause
Sclerostin inhibits bone formation	Romosozumab target
Urate needle-shaped, negatively birefringent	Gout; CPPD rhomboid, positive
Diuretics and low-dose aspirin raise urate	Review in gout
COX-1 protects stomach and kidney	NSAID GI bleeding and AKI
Glucocorticoids switch off NF-κB	Broad anti-inflammatory and broad side effects
Methotrexate — folate antagonist	Weekly; folic acid; avoid trimethoprim
Colchicine — microtubules	Diarrhoea; clarithromycin interaction
Allopurinol — xanthine oxidase	Titrate to urate under 360; azathioprine interaction
Denosumab	Never stop without follow-on therapy

Spot the Diagnosis

Clue	Diagnosis or mechanism
Bony swellings of the DIPs and squared thumb base in a 70-year-old	Hand osteoarthritis (Heberden's nodes, first CMC)
Symmetrical MCP and PIP swelling with morning stiffness for 2 hours	Rheumatoid arthritis
2nd and 3rd MCP arthropathy with chondrocalcinosis	Haemochromatosis
Heel pain at the Achilles insertion with psoriasis	Enthesitis — psoriatic arthritis
Whole swollen toe in a man with nail pitting	Dactylitis — psoriatic arthritis
Painful arc between 60° and 120° of abduction	Subacromial (rotator cuff) impingement
Loss of passive external rotation in a diabetic	Frozen shoulder
Night tingling of the thumb, index and middle fingers in pregnancy	Carpal tunnel syndrome
Foot drop with numb dorsum of the foot after lifting	L5 radiculopathy (L4/5 disc)
Leg pain on walking relieved by sitting and bending forward	Lumbar spinal stenosis (neurogenic claudication)
Back pain waking him at 4 am, better with exercise, age 26	Inflammatory back pain — axial SpA
Needle-shaped negatively birefringent crystals	Gout
Rhomboid weakly positively birefringent crystals in a hot knee after surgery	CPPD (pseudogout)
First gout attack 2 weeks after starting bendroflumethiazide	Diuretic-induced hyperuricaemia
Bone pain, proximal weakness, low phosphate and high ALP in a housebound woman	Osteomalacia
Isolated very high ALP with deafness and bowed tibia	Paget's disease
Multiple vertebral fractures 9 months after stopping denosumab	Rebound bone loss
Thigh pain and transverse femoral fracture after 8 years of alendronate	Atypical femoral fracture
AKI after adding ibuprofen to ramipril and furosemide	"Triple whammy"
Pancytopenia after methotrexate plus co-trimoxazole	Additive antifolate toxicity
Severe diarrhoea and myalgia after colchicine with clarithromycin	Colchicine toxicity (CYP3A4/P-gp inhibition)
Severe neutropenia after adding allopurinol to azathioprine	Xanthine oxidase interaction
Widespread pain, fatigue and poor sleep with normal bloods	Fibromyalgia (central sensitisation)

Exam-style Scenarios

1. A 58-year-old man has had three gout flares this year. Urate is 520 µmol/L. He takes bendroflumethiazide and ramipril; eGFR 52.
Answer: Recurrent gout — start urate-lowering therapy.

• Allopurinol starting low (e.g. 50–100 mg daily given CKD) and titrating monthly to urate under 360 µmol/L.
• Colchicine prophylaxis (low dose) for up to 6 months; flare plan.
• Consider switching the thiazide (e.g. to another antihypertensive; losartan lowers urate); lifestyle advice — alcohol, weight, sugary drinks.

2. A 74-year-old woman with heart failure on ramipril and furosemide is started on ibuprofen for knee OA. A week later her creatinine has doubled.
Answer: NSAID-induced AKI — "triple whammy".

• Stop ibuprofen; review ACE inhibitor and diuretic doses temporarily; assess fluid status.
• Mechanism — loss of prostaglandin-mediated afferent arteriolar dilation plus ACE-inhibitor efferent dilation and diuretic volume depletion.
• For OA — exercise, weight loss, topical NSAID, paracetamol for short-term use; avoid oral NSAIDs.

3. A 52-year-old woman with RA on methotrexate 15 mg weekly is prescribed trimethoprim for a UTI. She develops mouth ulcers and a sore throat.
Answer: Methotrexate toxicity (myelosuppression) from an antifolate interaction.

• Urgent FBC (neutropenia, thrombocytopenia), LFTs, renal function; stop methotrexate and trimethoprim.
• Folinic acid rescue; manage neutropenic sepsis if febrile; specialist advice.
• Choose antibiotics without antifolate effects (e.g. nitrofurantoin if renal function allows).

4. A 70-year-old woman has been on denosumab for osteoporosis for 4 years. She wants to stop because she dislikes injections.
Answer: Stopping denosumab causes rebound bone loss.

• Don't simply stop — risk of rebound multiple vertebral fractures within months.
• Plan follow-on therapy — usually IV zoledronic acid (or oral bisphosphonate) about 6 months after the last dose, with DEXA and bone turnover markers.
• Check calcium, vitamin D and dental health.

5. A 28-year-old man has 6 months of low back pain and stiffness, worst in the early morning and better with exercise, plus heel pain. CRP 22.
Answer: Suspected axial spondyloarthritis with enthesitis.

• MRI sacroiliac joints (bone marrow oedema), HLA-B27, X-ray pelvis; refer to rheumatology.
• NSAIDs (full dose) and physiotherapy first line.
• If inadequate — anti-TNF or IL-17 inhibitor (not IL-23 — ineffective in axial disease); screen for uveitis and IBD.

Key Points

• Synovial joints are the main target of inflammatory arthritis; RA erodes at the bare areas.
• Cartilage — chondrocytes, type II collagen, proteoglycans; avascular and aneural; OA is a whole-joint disease.
• Synovial fluid — over 2,000 WCC inflammatory; very high in sepsis; always culture and look for crystals.
• Enthesitis (Achilles, plantar fascia) and dactylitis point to spondyloarthritis.
• Proximal weakness with high CK — myositis; stiffness with normal CK and high CRP — PMR.
• Bone remodelling — RANKL drives osteoclasts; sclerostin inhibits osteoblasts.
• Osteomalacia — low phosphate, high ALP and PTH; Paget's — isolated very high ALP; myeloma — normal ALP.
• RA — MCPs, PIPs, wrists; OA — DIPs, PIPs, first CMC; PsA — DIPs and nails.
• Hip pain is felt in the groin and knee; L5 root — foot drop; cord ends at L1–2.
• Gout — needle-shaped negative crystals; CPPD — rhomboid positive; diuretics raise urate.
• Central sensitisation underlies fibromyalgia — exercise and psychological therapies, not opioids.
• NSAIDs — COX-1 (stomach, kidney, platelets), COX-2 (inflammation) — PPI and avoid triple whammy.
• Steroids switch off inflammatory genes — taper, bone protection, steroid card.
• Methotrexate weekly with folic acid; allopurinol titrate to urate under 360; colchicine — CYP3A4 interactions.
• Denosumab never stopped without follow-on; teriparatide and romosozumab build bone.

Guidelines and Further Reading

• British Society for Rheumatology: Guidelines on DMARD and biologic prescribing and monitoring; gout management (2017)
• NICE NG219: Gout — diagnosis and management (2022)
• NICE NG100: Rheumatoid arthritis in adults; NICE NG65: Spondyloarthritis
• NICE NG226: Osteoarthritis in over 16s; NICE NG193: Chronic pain
• National Osteoporosis Guideline Group (NOGG): Clinical guideline for the prevention and treatment of osteoporosis
• MHRA Drug Safety Updates: Methotrexate once-weekly; denosumab discontinuation; febuxostat; fluoroquinolone tendon damage
• BNF — for current doses