Musculoskeletal Flashcards
What are the functions of bone?
• STRUCTURE
– give structure and shape to the body • MECHANICAL
– sites for muscle attachment, allowing movement
• PROTECTIVE
– vital organs and bone marrow
• METABOLIC
– reserve of calcium and other minerals
What is the composition of bone?
Inorganic (65%)
- calcium hydroxyapatite
- is storehouse for 99% of calcium in the body
- 85% of phosphorus, 65% sodium, magnesium
Organic (35%)
-bone cells and protein matrix
Collagen fibres, linking proteins
Describe bone geography.
Diagram
Epiphysis —> metaphysis —> diaphysis (shaft) —> metaphysis —> epiphysis
Describe the bone types and the classification of bone.
Anatomical bones
-flat, long (support weight, facilitate movement, allow linear growth), short/cuboid (carpels, tarsals, stabilise and facilitate movement) irregular (vertebrae, pelvis, protect specific organs), sesamoid (patella, embedded in tendon for protection)
Macroscopic structure
- trabecular/ cancellous/ spongy - criss cross through the medullary cavity
- cortical/ compact- surrounded by periosteum
Microscopic structure
- woven bone (immature) - weak, disorganised bone, developing skeleton, rapid growth, pathological high bone turnover
- lamellar bone (mature)
Classification
Cortical
-long bones
-80% of skeleton
-appendicular skeleton
-80-90% calcified -low turnover, not very active/metabolising
-mainly structural, mechanical and protective
Cancellous
- vertebrae and pelvis
- 20% of skeleton
- axial
- 15-25% calcified
- mainly metabolic
- large surface area
Describe the cortical bone micro anatomy.
Diagram
Circumferential lamellae - in periosteum
Concentric lamellae
Interstitial lamellae - in between osteoblast
Trabecular lamellae - not surrounding osteons but in layers
Each circle is an osteoblast - 0.2 mm diameter. Surround Haversian canal - contain blood vessels
Each * = osteocytes canalicular network - allows bone to signal for repair and replacing
Describe bone cells.
Osteoclasts
-mutlinuclear cells that resorb/remove bone
Osteoblasts
-produce osteoid to form new bone
Osteocytes
-mechanosensory network embedded in mature bone
Describe the bone remodelling cycle.
RANKL and M-CSF from osteoblasts cause osteoclast differentiation
Osteocytes sense damage and stress, apoptose and release RANKL, signal to osteoclast, resorb, then osteoblast recruited to produce osteoid
Why should you perform a bone biopsy?
What are the types of bone biopsy?
• Confirm the diagnosis of a bone disorder
• Find the cause of or evaluate ongoing bone pain or
tenderness
• Investigate an abnormality seen on X-ray
• For bone tumour diagnosis (benign vs malignant)
• To determine the cause of an unexplained infection
• To evaluate therapy performance
Types
-closed: needed , core biopsy (Jamshidi needle)
-open: for sclerotic/ inaccessible lesions
Osteosclerosis, can’t access with needed/ require larger bone sample
Transiliac bone biopsy - can sense all the different types of bone at this site
Describe histological staining of bone?
H and E - on decalcified samples (need to decalcify sample)
Masson - Goldner Trichrome - see amount of mineralised/ unmineralised bone (calcified)
- mineralised = green, unmineralised = orange eg. Osteoid
- useful in osteomalacia
Tetracycline/Calcein binding - measure rate of bone turnover and formation (calcified)
-lay down fluorescent line through injection, after few days another line laid down then measure amount of mineralisation within that distance (mineral acquisition rate), bone formation rate = overall bone formation .
What is metabolic bone disease?
What are the common metabolic bone diseases?
- A group of diseases that cause reduced bone mass and reduced bone strength
- Due to imbalance of various chemicals in the body (vitamins, hormones, minerals, etc)
- Cause altered bone cell activity, rate of mineralisation, or changes in bone structure
Common diseases • Osteoporosis • Osteomalacia/Rickets • Primary hyperparathyroidism • Renal osteodystrophy • Paget’s disease
Explain osteoporosis.
Defined as a bone mineral density T-score of -2.5 or lower
-standard deviations different from mean peak bone mass BMD
Primary: age, post -menopause
Secondary: drugs, systemic disease (endocrine, metabolic) - pathological
High turnover: turnover > formation. Both increase but turnover higher
Low turnover: turnover > formation. Both decrease but formation decreases more
Loss of trabecular bone, holes, thinner, thinking of corticoid bone, compression in spine .etc. = decrease in strength
Osteoclasts > osteoblasts
Decreased quantity of bone mass Microstructure normal
Fragility fractures
Deformity
Pain
Describe osteomalacia/ rickets.
Defective mineralisation of normally synthesised bone matrix
Rockets in children
2 types:
-deficiency of vitamin D - hypocalcaemia
-deficiency of PO4 - phosphate wasting syndromes
Vitamin D:
-absorption in small intestine
-reabsorption in kidneys
(Endocrinology pathway)
Sequelae
- bone pain/tenderness
- fracture
- proximal weakness
- bone deformity
Rickets
- widening of growth plates and bowing of legs
- bones try to remodel and deform
Horizontal fracture in Looser’s zone - looser zone fractures at high tensile stress areas
Decreased bone mineral
Osteopenic bone
Soft bones
Too much un-mineralised osteoid:
Looser’s zone
Compensatory: secondary hyperparathyroidism may be superimposed if
calcium stays low
Vitamin D deficiency
Biochemistry: vit d low, calc: N/low, PTH up Inadequate or delayed mineralisation
Explain hyperparathyroidism.
Excess PTH • increased Ca + PO4 excretion in urine • hypercalcaemia • hypophosphatemia • skeletal changes of osteitis fibrosa cystica = resorption of bone and replacement with fibrous tissue
4 organs are directly or indirectly affected by PTH and between them control calcium metabolism:
Parathyroid glands, bones, kidneys, proximal small intestine
Feedback mechanism lost PTH increases, calcium increases
Primary
- parathyroid adenoma (85-90%)
- chief cell hyperplasia
Secondary
- chronic renal deficiency: cannot excrete PO43-
- Vit D deficiency
Mnemonic: Stones (Ca oxalate renal stones) Bones (osteitis fibrosa cystica, bone resorption) Abdominal groans (acute pancreatitis) Psychic moans (psychosis and depression)
Tunnelling resorption: centre of trabeculae lost
Periosteum bone erosions
Brown cell tumour
Repaired with giant cell granuloma, resemble brown cell tumours
Form of osteitis fibrosa cystica
Primary (due to parathyroid adenoma)
-PTH up, calc down, phosphate down
-Bone resorption
Secondary (due to other systemic biochemical imbalance, chronic kidney disease,rickets/osteomalacia)
-PTH up, calc down, phophate normal or down
-Bone resorption AND increased density Tertiary (autonomous)
-PTH up, calc up, phosphate down
Bone resorption
- subperiosteal
- subchondral
- intracortical
- brown tumours
Describe renal osteodystrophy.
Comprises all the skeletal changes resulting from chronic renal disease:
– Increased bone resorption (osteitis fibrosa cystica)
– Osteomalacia
– Osteosclerosis
– Growth retardation
– Osteoporosis
(Failure to excrete PO42- and make Vit D so secondary hyperparathyroidism may result)
What can bone imaging do?
What are the types of imaging used.
Reveal structural failures such as fractures and ligament outs injuries
Also serves as proxy to metabolic dysfunction
- x-rays: density
- CT: density
- bone densitometry: density
- MRI: biochemical composition
- radionuclelotide bone scans - nuclear medicine bone scans: bone turnover
Define radiological sign and pathology.
What pathologies can be seen on imaging?
Pathology: a disease process that gives rise to symptoms, signs, biochemical disturbances and changes in imaging appearance
Radiological sign: a change in imaging appearance, whether structural or functional, that may point towards a pathological
Pathologies
- osteoporosis
- osteomalacia and rickets
- primary hyperparathyroidism
- secondary hyperparathyroidism (renal osteodystrophy)
- Paget’s disease
Describe the diagnosis for osteoporosis, including the radiology
Diagnosis is with bone densitometry (aka dual-energy absortiometry, DEXA)
A measure of bone mineral density (BMD)
Compares BMD to normal reference databases
and gives
▪ T-score (ref database white adult premenopausal females)
▪ Z-score (ref database age and sex matched)
T-score -1.5 to -2.5 = osteopenia; less than -2.5 = osteoporosis
Radiology
-loss of cortical bone/ thinning of cortex
-loss of trabeculae
-insufficiency fractures: stress fractures due to:
Normal stress on abnormal bones
Common sites - sacrum, underside of femoral neck, vertebral bodies, pubic rami
Insufficiency fractures seen in imaging:
X-ray
-initially normal
-can get periosteal reaction and callus
-more commonly increased sclerosis around fracture lines
MRI
-bone oedema .i.e low signal on TI, high signal on T2 and STIR
-increased osteoblastic activity i.e. increased uptake
Describe the radiology in osteomalacia/ rickets?
Radiology depends on age and closure of growth plate
Osteomalacia
- Mature skeleton
- Osteopenia
- Looser’s zones
- Codfish vertebrae
- Bending deformities
Rickets
- Before growth plate closure
- Radiological signs centred mainly to growth plates
- Changes of osteomalacia
Looser’s zones Pseudo/insufficicnecy fractures at high tensile stress areas: -Medial proximal femur -Lateral scapula -Pubic rami -Posterior proximal ulna -Ribs
Biconcave deformity of vertebrae seen in:
- Osteoporosis
- Osteomalacia
Rickets Indistinct/frayed metaphyseal margin Widened growth plate without calcification Cupping/splaying metaphyses due to weight bearing Enlargement of anterior ribs Osteopenia
Describe diagnosis of renal osteodystrophy.
Osteomalacia and osteoporosis
Secondary hyperparathyroidism
-Subperiosteal erosions, brown tumours
-Sclerosis – vertebral endplates giving a rugger jersey spine
-Soft tissue calcification (vessels, cartilages)
Explain Paget’s disease.
Disorder of bone turnover
Divided into 3 stages:
1) osteolytic - focal bone loss and bone loss in specific regions, thickened cortices
2) osteolytic-osteosclerotic - reactive stage, respond to loss, osteoclasts and active resorption
3) quiescent osetosclerotic - osteoblasts react- mosaic pattern
Onset > 40y (affects 3-8% Caucasians > 55y) M>F Rare in Asians and Africans Mono-ostotic 15% (one bone) Remainder polyostotic
Aetiology is unknown
Familial cases show autosomal pattern of inheritance with incomplete penetrance (mutations in SQSTM1 or RANK)
Parvomyxovirus type particles have been seen on EM in Pagetic bone – some doubt this is cause.
Overuse or previous bone injury.
Clinical symptoms:-
– pain
– microfractures
– nerve compression (incl. Spinal N and cord)
– skull changes may put medulla at risk
– deafness
– +/- haemodynamic changes, cardiac failure
– hypercalcaemia
– Development of sarcoma in area of involvement 1%
Disease of bone remodelling
Lytic phase
Mixed lytic/sclerotic phase
Sclerotic phase
Bone pain, deformity, spontaneous fractures May get nerve entrapment, spinal stenosis and deafness
Osteogenic sarcoma
Raised serum alk phos, urinary hydroxyproline, pyridinoline cross-links
Describe radiology in Paget’s.
Cortical thickening
Bone expansion
Coarsening of trabeculae
Osteolytic, osteoclerotic and mixed lesions Osteoporosis circumscripta
What is metabolic bone disease? What are the common metabolic bone disorders?
What are the common symptoms?
What makes a bone strong?
A group of diseases that cause a change in bone density and bone strength by:
1) increasing bone resorption
2) decreasing bone formation
3) altering bone structure
And may be associated with disturbances in mineral metabolism
Common:
- primary hyperparathyroidism
- rickets/ osteomalacia
- osteoporosis
- Paget’s disease
- renal osteodystrophy
Symptoms:
Metabolic - hypocalcaemia, hypercalcaemia, hypo/hyperphosphataemia
Specific to bone - bone pain, deformity, fractures
Mass, Material properties (matrix and mineral) - collagen crosslinking, microarchitecture -trabecular thickness, macro architecture -diameter
What are the ways in which we can access bone structure and function?
How does growth and exercise change peak bone mass?
What is meant by bone remodelling?
Bone histology
Biochemical tests
Bone mineral densitometry e.g. osteoporosis
Radiology
Growth and exercise:
Change in bone dimensions, change in bone shape, change in trabecular volumetric BMD
Bone remodelling:
Process by which areas are repaired, each osteomalacia represents a previous remodelling event
What are the biochemical investigations used in bone disease?
Explain them for each disease?
Serum
Bone profile: Calcium Corrected calcium (albumin) Phosphate Alkaline phosphatase
Renal function:
Parathyroid hormone
25-hydroxy vitamin D
Urine:
Calcium/phosphate
NTX
(Diagram)
Explain calcium balance.
Uses 3 main systems: GI tract, bone, kidney
Total calcium can be complexed, ionised (free) which then undergoes alkalosis to be protein bound
PTH
- Mg dependent
- 8 min T1/2
- PTH receptor activated also by PTHrP
PTH drives active calcium absorption in distal tubule of the kidney
PTH causes bone resorption through the RANK system
Explain primary hyperparathyroidism.
50s, female: male 3:1
Causes: parathyroid adenoma (most common), parathyroid hyperplasia, parathyroid CA
Familial syndromes - MEN 1 2%
An elevated total/ionised calcium (hypercalcaemia) with PTH levels elevated or in the upper half of normal range
Non-suppressed
Clinical features: Thirst, polyuria, tiredness, fatigue, muscle weakness “Stones, abdominal moans and psychic groans” Renal colic, nephrocalcinosis, CRF Dyspepsia, pancreatitis Constipation, nausea, anorexia Depression, impaired concentration Drowsy, coma
Patients may also suffer fractures secondary to bone resorption
High serum calcium causes a diuresis
Chronically elevated PTH increases stone risk
Chronically elevated PTH causes increased cortical bone resorption (increased bone turnover, acute/pulsed PTH: anabolic, chronic: catabolic, cortical > cancellous (light poreless bone)
Chronically elevated PTH increases fracture risk
Biochemical findings
1) increased serum calcium by absorption from bone/ gut
2) decraesed serum phosphaterenal excretion in proximal tubule
3) PTH in the upper half of the normal range or elevated
4) increased urine calcium excretion
5) Cr may be elevated
Explain metabolism and actions of vitamin D.
Vitamin D is metabolised by liver and kidney (pathway from endo)
Vit D binding protein (DBP): t1/2 3 days filtered by kidney
Activated vitamin D increases gut calcium absorption - 1,25(OH)VitD
Vit D actions
Intestine: activates Ca and P absorption in duodenum
Bone: synergies with PTH acting on osteoblasts to increase formation of osetoclasts through RANKL
Increases osteoblasts differentiation and bone formation
Kidney: facilitates PTH action to increase Ca reabsorption in distal tubule
Feedback: parathyroid directly to reduce PTH secretion and increase FGF-23 production in bone
Deficiency of Vit D effects:
Inadequate Vit D leads to defective mineralisation of the cartilaginous growth plate (before a low calcium)
Symptoms
Bone pain and tenderness (axial)
Muscle weakness (proximal)
Lack of play
Signs Age depended deformity Myopathy Hypotonia Short stature Tenderness on percussion
Explain the causes of rickets/ osteomalacia including the biochemical findings.
Vitamin D related
Dietary
Gastrointestinal: small vowel malabsorption/bypass, pancreatic insufficiency, liver/biliary disturbance, drugs -phenytoin, phenobarbitone
Renal: chronic renal failure
Rare hereditary: type I: deficient of 1a hydroxylase, II: defective VDR for calcitriol
Biochemistry Serum: Calcium N/low Phosphate N/low Alk phos High 25(OH)Vit D Low PTH High (secondarily to compensate)
Urine:
Phosphate high
Glucosuria, aminoaciduria, high pH, proteinuria
FGF-23 cause PCT phosphate loss as well as PTH
Produced by osteoblasts
Like PTH causes P loss, unlike PTH inhibits action of Vit D by 1 a OHase
Osteomalacia and phosphate
Kidney forced to lose phosphate
“Isolated” hypophosphatemia: X-lined hypophosphataemic rickets, high levels of FCF-23
Autosomal dominant hypophosphataemic rickets (ADRR) - cleavage site for FCF-23 mutated so high FGF-2
Oncogenically osteomalacia: mesenchymal tumours produce FGF-23
Therefore FGF-23 excess can cause rickets/ osteomalacia
Also:
Kidney proximal tubule damage causes phosphaturia and stops 1a hydroxylation of Vit D (normally PCT only reabsorbs P so this is problem because no reabsorption)
Fanconi syndrome: multiple myeloma, heavy metal poisoning (lead, Mercury), drugs e.g. gentamicin, congenital disease e.g. Wilsons
Explain osteoporosis including biochemical findings.
Causes:
1) High turnover - increased bone resorption greater than increased bone formation eg. Oestrogen deficiency, hyperparathyroidism, hyperthyroidism, hypogonadism
2) Low turnover - decreased bone formation more than decreased bone resorption: liver disease, heparin, age above 50
3) increased bone resorption and decreased bone formation - glucocorticoids
Oestrogen deficiency
Causes remodelling balance with increased bone resorption compared to bone formation (enhanced osteoclast survival and activity)
Trabecular perforation
Increased fracture rates
Biochemistry in osteoporosis used to exclude other causes Serum biochemistry should all be normal 1. Check for Vit D deficiency 2. Check for secondary endocrine causes Primary hyperparathyroidism PTH high Primary hyperthyroidism free T3 high, TSH suppressed Hypogonadism Testosterone low 3. Exclude multiple myeloma 4. May have high urine calcium
BMD measured in osteoporosis
DEXA measures transmissions brought the body of Xrays of two different photon energies
Enables densities of two different tissues to be inferred, i.e. bone mineral, soft tissue
T-score:
Osteoporosis = -2.5
Osteopenia = -1 to 2.5
Normal = > -1
FRAX uses hip BMD (2nd commonest fracture after vertebral)
Bone markers
Unlike BMD they are dynamic, insight into activity of bone cycle. Divided into markers of formation and resorption
Formation markers:
o P1NP – Procollagen type 1 N-terminal Propeptide.
In production of collagen (2a1, 1a2), extension polypeptides (P1NP) are cleaved.
Resorption markers:
o Serum CTX – Cross-linked C-telopeptides.
o Urine NTX – Cross-linked N-telopeptides.
3 hydroxylysine molecules condense out to form a pyridinium ring linkage on resorption of bone.
Resorption markers are used to monitor osteoporosis treatment.
o Bone reabsorption markers fall in 4-6 weeks.
o Expect a 50% drop of urine NTx by 3 months.
o Problems though:
-Hard to reproduce.
-Positive association with age anyway.
-Need to correct for creatinine.
-Diurnal variation in urine markers.
Formation markers:
o Only one formation marker is in common use – ALP.
Used in diagnosis/monitoring of:
• Paget’s disease of bone.
• Osteomalacia.
• Bony metastasis.
BSAP – Bone-Specific Alkaline Phosphatase:
• Types – tissue-specific (bone) form of ALP.
• Roles – essential for mineralisation of bone and regulates concentrations of phosphate.
• Uses – T1/2 40 hours. Increased in Paget’s, osteomalacia, bone metastasis, HPT, HT.
NOTE that ALP varies with age (younger people have more).
o P1NP is being used as a predictor of response to anabolic treatments – e.g. PTH treatment.
Explain CKD-MBD and renal dystrophy.
Chronic kidney disease mineral bone disorder
- Skeletal remodeling disorders caused by CKD contribute directly to to heterotopic calcification , especially vascular
- The disorders in mineral metabolism that accompany CKD are key factors in the excess mortality caused by CKD
- CKD impairs skeletal anabolism, decreasing osteoblast function and bone formation rates
Biochemistry
- Increasing serum phosphate
- Reduction in 1,25 Vit D (calcitriol)
SO Secondary Hyperparathyroidism develops to compensate
BUT unsuccessful and HYPOCALCAEMIA develops
LATER Parathyroids AUTONOMOUS (tertiary) causing HYPERCALCAEMIA
o Pathway – secondary hyperparathyroidism develops to compensate —> unsuccessful so hypocalcaemia —> parathyroid become autonomous (tertiary hyperparathyroidism) —> hypercalcaemia.
o There is a progressive hyperplasia of the parathyroids.
Nephron loss via CKD.
Phosphate binds calcium in serum.
o Calcium phosphate crystals are deposited causing extra-skeletal calcifications.
Acidosis causes demineralisation.
In renal osteodystrophy, you can get heterotopic calcification – bone formation at an abnormal anatomical site, usually in soft tissue.
o I.E. in MCP joints.
(Diagram)
Renal osteodystrophy is a CONSEQUENCE of CKD; the results of CKD cause the symptoms of osteodystrophy such as heterotopic calcification.
Explain systemic lupus erythematosus as a connective tissue disease.
One of the chronic overlapping autoimmune diseases
M:F 1:9, 15-40 years presentation
Increased in Afro-Caribbean, Asian and Chinese
Principally affects joints and skin
Lungs, kidneys, haematology (bone marrow)
Genetic associations
- multiple genes implicated (polygenic)
- complement deficiency e.g. C1q and C3 (these will develop lupus for sure)
- Fc receptors, IRF5, CTLA4, MHC class II HLA genes over represented
Clinical features Presentation: -malaise, fatigue, fever, weight loss -lymphadenopathy Specific features: -butterfly rash, alopecia (hair loss) -arthralgia -Raynaud’s phenomenon
Other features:
- inflammation of kidney, CNS, heart (myocarditis), lungs
- accelerated atherosclerosis
- vasculitis
4 or more of 11 criteria:
It’s a multi system chronic autoimmune inflammatory disease
- Malar rash
- Discoid rash
- Photosensitivity
- Oral ulcers
- Arthritis
- Serositis: (a) pleuritis or (b) pericarditis
- Renal disorder e.g. proteinuria > 0.5g/24h
- Neurological disorder e.g. seizures/ pyschosis
- Haematological disorder
- Immunologic disorder e.g anti-dsDNA Abs
- Antinuclear antibody in raised titre
Rash has no pus (distinguish from acne), dermis rash - loss of pigment - permanent scarring
Rash spares nasal folds ad other areas, usually on cheeks
SLE Pathogensis:
Immune complex driven type 3 hypersensitivity reaction
Irreversible tissue injury from complement
Genetic and environmental e.g. virus
SLE also related to abnormal clearance of apoptotic cells by immune system
Auto immune antibodies against abnormally cleared apoptotic cells
B cell hyper reactivity; exposure to environment antigen; generation of antibodies against apoptotic cells —> immune complexes inside organs e.g. kidneys—> inflammoraory tissue injury
B cells - antigen presentation, antibody reproduction, produce cytokines .etc.
Pathway: Abnormal clearance of apoptotic cell material —> dendritic cell uptake of autoantigens and activation of B cells —> B cell Ig class switching and affinity mutation —> IgG autoantibodies —> immune complexes —> complement activation, cytokine generation .etc.
Explain the diagnosis of SLE.
Antinuclear antibodies: ANA relatively non-specific, pattern important (find antibodies that bind to nuclei on glass slide
; indicator of autoantibodies; indirect immunofluorescence used
Pattern: homogeneous for SLE
• Homogenous - Abs to DNA
• Speckled - Abs to Ro, La, Sm, RNP
• Nucleolar - topoisomerase - scleroderma • Centromere - limited cutaneous scleroderma
Anti-dsDA and Sm (Smith antigen)
-more specific but less sensitive
Anti-Ro and/or La
-common in subacute cutaneous LE
-neonatal lupus syndrome and Sjögren’s
Other tests: • Increased complement consumption (C3 and C4 complement decrease because deposited in skin, organs and activated) • Anti-cardiolipin antibodies • Lupus anticoagulant • ß1 glycoprotein
haematology:
• Lymphopaenia, normochromic anaemia (haemolysis)
• Leukopaenia, AIHA, thrombocytopaenia (may be due to haemorrhage)
Renal:
- proteinuria, haematuria
- active urinary sediment - presence of casts = ongoing kidney inflammation
Assessing disease severity:
1. Identify pattern of organ involvement
2. Monitor function of affected organs
• Renal - BP, U & E, urine sediment + Prot:Crea ratio
• Lungs/CVS - lung function, echocardiography -myocarditis? Pulmonary hypertension?
• Skin, haematology, eyes
3. Identify pattern of autoantibodies expressed - mild? Moderate? Severe?
• Anti-dsDNA, anti-Sm - renal disease
• Anti-cardiolipin antibodies
Signs of disease activity: Try and pre-empt severe attacks Clinical Features in follow up • Wt loss, fatigue, malaise, hair loss • Alopecia • Rash
Laboratory markers
• ESR (rise)
• Increased complement consumption
• Increased anti-dsDNA
• Other Abs e.g ANA and CRP poor indicators
(Lupus one of rare active diseases where ESR increase and CRP decreases, others usually both high)
Explain the treatment of SLE.
Disease divided into three groups: -mild: joint +/- skin involvement -moderate: inflammation of other organs (pleuritic, pericarditis, mild nephritis) -severe: severe inflammation in vital organs: Severe nephritis CNS disease Pulmonary disease Cardiac involvement AIHA, thrombocytopaenia, TTP
Treatment of mild disease: Paracetamol +/- NSAID -Monitor renal fucntion Hydroxychloroquine (rash) -athropathy -cutaneous manifestations -mild disease activity Topical corticosteroids - rash not only on face
Moderate disease:
Indication - failure of hydroxychloroquine/NSAID
-organ/life threatening disease
Corticosteroids -high initial dose to suppress disease activity -iv methyprednisolone -initial oral dose for 4 weeks -reduce slowly over 2-3 months Try to control because of side effects: -osteoporosis -weight gain -diabetes -thinking of skin -acne
Severe disease: Azathioprine -moderate to severe disease -effective steroid-sparing agent -20% neutropenia -regular FBC and biochemistry monitory -safer in pregnancy and can cause liver failure
Cyclophosphamide - for more severe disease
-severe organ involvement, iv pulse or oral
-nephritis
-BM suppression, infertility, cystitis (acrolein)
And more severe side effects
Mycophenolate mofetil - teratogenic but no effect on patient’s fertility
- reversible inhibitor of inosine monophosphate dehydrogenase
- rate-limiting enzyme in de novo purine synthesis
- lymphocytes - dependent upon de novo purine synthesis
Rituximab and bilimumab
- monoclonal antibody switches off hyperreactivity
- anti CD20 mAb therapy
- leads to depletion of B cells
- effective in lupus nephritis
Belimumab is a fully human IgG1 monoclonal antibody against BLYS (also called BAFF)
Inhibits this resulting in impaired B cell survival and reduced numbers
What is the prognosis and survival in SLE?
15 year survival: no nephritis (85%), nephritis (60%)
Prognosis also worse if black, male, low sociopath-economic status
The bimodal mortality pattern of SLE
Early = active lupus - Renal failure, CNS disease
Infection
Late = myocardial infarction
Accelerated atherosclerosis
Overall SLE = automimmune mutisystem disease
Rare disease, female preponderance
Severity from mild joint pain to fulminant and life threatening
Clinical features depend on organ affected
Treatment:
Symptomatic
Immune-modulating
Immunosuppressive
What is rheumatoid arthritis and its clinical features?
What are the commonest affected joints?
What are the radiological abnormalities?
Chronic autoimmune disease characterised by pain, stiffness and symmetrical synovitis ( inflammation of the synovial membrane) of synovial (diarthrodial) joints
Can be younger, not only old
Key features:
Chronic arthritis
• Polyarthritis - swelling of the small joints of the hand and wrists is common (one joint - monoarthritis, oligoarthritis = 2-4)
• Symmetrical - left and right evenly
• Early morning stiffness in and around joints (in osteoarthritis this is for short time)
• May lead to joint damage and destruction - ‘joint erosions’ on radiographs
- Extra-articular disease can occur
- Rheumatoid nodules
- Others rare e.g. vasculitis, episcleritis
Rheumatoid ‘factor’ may be detected in blood
• IgM autoantibody against IgG - should really call this rheumatoid ‘antibody’ not ‘factor’
Important genetic component
Specific HLA-DRB gene variants mapping to amino acids 70-74 of the DRb-chains are
strongly associated with rheumatoid arthritis
• Region encodes conserved amino acid sequence in the HLA-DR antigen-binding groove
which is common to rheumatoid arthritis-associated DR alleles – termed ‘shared epitope’
• Other genes identified in genome-wide studies exert modest or weak effects
Can be seen in identical twins stronger than non-identical
Important environmental component
Smoking – contributes 25% of population-attributable risk and interacts with shared
epitope to increase risk
1% pop affected - relatively common cause of significant disability in young adults
F:M 3:1
Commonest joints:
• Metacarpophalangeal joints (MCP)
• Proximal interphalangeal joints (PIP) - swan-neck deformity affecting the ring finger - there is hyperextension at the PIP joint and hyperflexion at the DIP; boutonnière (button-like) deformity affecting little finger - there is hyperflexion at the PIP joint
Radiographs of hands show evidence of joint damage and deformity - bilateral ulnar deviation of fingers
• Wrists
• Knees
• Ankles
• Metatarsophalangeal joints (MTP) - callohys formation under heads of metatarsals due to joint deformity
Symmetrical poly arthritis
Primary site of pathology is in the synovium which includes (soft tissue swelling, osteoarthritis = bony hard swelling):
Synovial joints: proximal inter-phalangeal joint synovitis
Tenosynovium surrouding tendons: extensor tensosynovitis - note swelling is not above either the wrist or MCP joints, also incomplete extension of little and ring fingers
Bursa: olecranon bursitis - swelling of elbow joint
Sub-cutaneous nodules
-central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue
-occur in around 30% of patients
-associated with:
Severe disease, extra-articulations manifestations, rheumatoid factor
Could be on hand, e.g. fingers
Extra-articulations features:
Common
• Fever, weight loss
• Subcutaneous nodules
Uncommon
• vasculitis
• Ocular inflammation e.g. episcleritis
• Neuropathies
• Amyloidosis - AA protein build up
• Lung disease – nodules, fibrosis (methotrexate used to relate RA and can cause this as well), pleuritis
• Felty’s syndrome – triad of splenomegaly, leukopenia and rheumatoid arthritis
Radiological
- Early: juxta-articular osteopenia (thinning of bone)
- Later: joint erosions at margins of the joint
- Later still: joint deformity and destruction
Describe the role of rhematoid factor and enzymes in rheumatoid arthritis.
Rheumatoid factor
heumatoid factor
• Antibodies that recognize the Fc portion of IgG as their target antigen
• typically IgM antibodies i.e. IgM anti-IgG antibody
Aggregates of antibodies —> complement —> inflammation
Factor +ve = serum positive arthritis
• Positive in 70% at disease onset and further 10-15% become positive over the first
2 years of diagnosis
Antibodies to citrullinated protein antigens (ACPA)
• Antibodies to citrullinated peptides are highly specific for rheumatoid arthritis
Anti-cyclic citrullinated peptide antibody ‘anti-CCP antibody’
• Citrullination of peptides is mediated by enzymes termed:
Peptidyl arginine deiminases (PADs)
Why do they develop in rheumatoid arthritis?
-PADs are present in high concentrations in neutrophils and monocytes and consequently there is increased citrullination of autologous peptides in the inflammed synovium
-ACPA is strongly associated with smoking and HLA ‘shared epitope’
-The shared epitope [amino acids 70-74 of the HLA-DRb-chains associated with rheumatoid arthritis] preferentially
binds non-polar amino acids like citrulline but not positively charged amino acids like arginine – so ACPA more likely
to develop among individuals with citrulinated autoantigens who have the shared eptiope
-Smoking – increases ACPA-positive rheumatoid arthritis risk. ? Smoking enhances citrullination in lungs e.g. change in mcirobiotia, chronic infections
ARGININE —> (PADs) CITRULLINE
Is the reason that anti-CCP antibodies develop in rheumatoid because of combination of genetic factor (shared epitope) and environmental factor (inflammation resulting in citrullination)? HLA-DRbeta (class 2, MHC)
Explain the pathology behind rheumatoid arthritis.
Synovitis, bone erosion, pannus (inflammation), cartilage degrading (joint space narrowing)
Synovial joint made up of synovium (1 to 3 cell layer lining synovial joints contains macrophage like phagocytise cells, fibroblast like cells that produce hyaluronic acid, type I collagen), synovial fluid (hyaluronic acid-rich viscous fluid) and articulate cartilage (type II collagen, proteoglycan (aggrecan)
Synovial membrane is abnormal in rheumatoid arthritis:
The synovium becomes a proliferated mass of tissue (pannus) due to:
neovascularisation
lymphangiogenesis
Inflammatory cells:
• activated B and T cells
• plasma cells
• mast cells
• activated macrophages
Recruitment, activation and effector functions of these cells is controlled by a cytokine network there is an excess of pro-inflammatory vs. anti-inflammatory cytokines (‘cytokine imbalance’)
The cytokine tumour necrosis factor-alpha (TNFα) is the dominant pro-inflammatory cytokine in the rheumatoid synovium and its pleotropic actions are detrimental in this setting:
- proinflammatory cytokine release, angiogenesis, leukocyte accumulation, osteoclast activation
- Produced by activated macrophages in synovium
Explain the treatment and management of rheumatoid arthritis.
Treatment
TNFα inhibition is achieved through parenteral administration (most commonly sub-cutaneous injection) of antibodies or fusion proteins
Biological therapy
Interleukin 6 and interleukin 1 blockade (TNFa and interleukin 6 inhibition more effective than interleukin 1)
In addition to cytokine blockade, we can also deplete B cells in rheumatoid arthritis by parenteral (intravenous) administration of an antibody against a B cell surface antigen, CD20 the antibody in clinical
use is termed, rituximab
Management
Treatment goal is to prevent joint damage
This requires:
• Multidisciplinary approach e.g. physiotherapy, occupational therapy, hydrotherapy, surgery
• Medication includes:
drugs that control the disease process are termed disease- modifying anti-rheumatic drugs - ‘DMARDs’
-these are started early in the disease because joint destruction = inflammation x time
DMARDs offer safer and more effective long-term treatment than ‘steroids’ so DMARDs are often referred to as ‘steroid-sparing agents’ since they enable us to avoid long-term steroid or at least use much lower doses of
steroids than would be possible in their absence
New therapies include Janus Kinase inhibitors
• Tofacitinib (Xeljanz) • Baricitinib (Olumiant)
Important roles for glucocorticoid therapy (‘steroids’, ‘prednisolone’) but
• preference is to avoid long-term use because of side-effects
• useful as short-term treatment options in many settings e.g. to control flare of disease or control inflammation
of single joint
• Biological therapies offer potent and targeted treatment strategies
DMARD THERAPY
drugs that may induce remission (not cure) and prevent joint damage (can relapse)
achieve this by:
• reducing the amount of inflammation in the synovium
• slow or prevent structural joint damage e.g. bone erosions
• complex mechanisms of action and relatively slow onset of action i.e. weeks examples:
• methotrexate – commonly used
• sulphasalazine – commonly used
• hydroxychloroquine – commonly used
• leflunomide – uncommon
• Janus Kinase inhibitors
Tofacitinib (Xeljanz)
Baricitinib (Olumiant)
- gold (rarely used now)
- penicillamine (rarely used now)
• all have significant adverse effects and therefore require regular blood test monitoring
during therapy
BIOLOGICAL THERAPY
• Inhibition of tumour necrosis factor-alpha (‘anti-TNF’)
antibodies (infliximab, and others)
fusion proteins (etanercept)
• B cell depletion
Rituximab – antibody against the B cell antigen, CD20
• Modulation of T cell co-stimulation
Abatacept - fusion protein - extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)
linked to modified Fc (hinge, CH2, and CH3 domains) of human immunoglobulin G1
• Inhibition of interleukin-6
Tocilizumab (RoActemra) – antibody against interleukin-6 receptor.
Sarilumab (Kevzara) – antibody against interleukin-6 receptor.
Downside of using biological therpay:
Side-effects for all include increased infection risk
Some specific points of note:
• TNFα inhibition is associated with increased susceptibility to mycobacterial infection e.g. tuberculosis so need to screen all patients for tuberculosis before starting treatment and may use prophylactic antibiotics in those at
high risk
• B cell depletion therapy can be associated with hepatitis B reactivation so need to screen all patients for hepatitis B before treatment
• B cell depletion therapy can be associated with JC virus infection and progressive multifocal leukoencephalopathy (PML) - rare
Describe the key features of reactive arthritis.
Describe the musculoskeletal symptoms of reactive arthritis.
Describe the extra-articular features of reactive arthritis.
• sterile inflammation in joints following infection especially urogenital (e.g. Chlamydia trachomatis) and gastrointestinal (e.g. Salmonella, Shigella, Campylobacter infections) infections
• Important extra-articular manifestations include:
Enthesopathy -enthesitis - inflamed attachment of red one to bone e.g. plantar fascia, Achille’s tendon
Skin inflammation
Eye inflammation - uveitis - pus cells in eye
• Reactive arthritis may be first manifestation of HIV or hepatitis C infection
• Commonly young adults with genetic predisposition (e.g. HLA-B27) -MHC1, CD8 cell and environmental trigger (e.g. Salmonella infection)
• Symptoms follow 1-4 weeks after infection and this infection may be mild
• Reactive arthritis is distinct from infection in joints (septic arthritis) - this is direct infection of joint, reactive arthritis is part of immune reaction to infection
Musculoskeletal
- arthritis - asymmetrical, oligoarthritis (<5 joints), lower limbs typically affected
- enthesitis - heel pain (Achilles tendinitis), swollen fingers (dactylitis), painful feet (metatarsalgia due to plantar fasciitis)
- spondylitis - sacroiliitis (inflammation of the sacro-iliac joints), spondylitis (inflammation of the spine)
Extra-articular features:
- ocular: sterile conjunctivitis
- Genito-urinar: sterile urethritis - pain on urination
- skin: circinate balanitis; psoriasis-like rash on hands and feet
Original description of Reactive arthritis = triad of arthritis, urethritis and conjunctivitis following infectious dysentery [Reiter’s syndrome]
Compare rheumatoid arthritis to reactive arthritis.
Diagram
How is reactive arthritis diagnosed.
- Clinical diagnosis
- Investigations to exclude other causes of arthritis e.g. septic arthritis - needle take fluid, gran-drain culture, septic only affects one joint usually, reactive look more well
Examples of important investigations:
• Microbiology:
Microbial cultures – blood, throat, urine, stool, urethral, cervical
Serology e.g. HIV, hepatitis C
• Immunology
Rheumatoid factor
(HLA-B27) - not very helpful, only minority of pop
• Synovial fluid examination
Especially if only single joint affected
Describe differences between septic and reactive arthritis.
Diagram
Gonorrhoea/ gonococcal arthritis - form of septic arthritis, spread to multiple joint
Explain the treatment for reactive arthritis.
in majority of patients complete resolution occurs within 2-6 months No role for antibiotics
articular:
NSAIDs e.g. ibuprofen
intra-articular corticosteroid therapy
extra-articular:
typically self-limiting, hence symptomatic therapy
e.g. topical steroids & keratolytic agents (break down keratin deposits) in keratoderma
Refractory disease: oral glucocorticoids
steroid-sparing agents e.g. sulphasalazine
RarerL methotrexate, anti TNF
Describe osteoarthritis and its clinical features.
Chronic slowly progressive disorder due to failure of articular cartilage that typically affecting joints of the hand (especially those involved in pinch grip), spine and weight-bearing joints (hips and knees)
Not autoimmune
Wear and tear, gradual wearing, degeneration of joints
Slowly progressive disorder that typically affects the: • Joints of the hand Distal interphalangeal joints (DIP) Proximal interphalangeal joints (PIP) First carpometacarpal joint (CMC) • Spine • Weight-bearing joints of lower limbs esp. knees and hips First metatarsophalangeal joint (MTP)
Osteophytes at the DIP joints are termed Heberden’s notes
Osteophytes at the PIP joints are termed Bouchard’s nodes
Can be associated with:
• Joint pain
worse with activity, better with rest (inflammatory arthritis gets worse with inactivity)
• Joint crepitus
creaking (cartilage Ron away so bone rubbing on bone), cracking grinding sound on moving affected joint
• Joint instability - pain causing atrophy of muscles supporting joint
• Joint enlargement - boney swelling
e.g. Heberden’s nodes
• Joint stiffness after immobility (‘gelling’)
• Limitation of motion - hip
Describe the radiographic features of osteoarthritis and compare to rheumatoid arthritis.
Radiographic features of osteoarthritis: • Joint space narrowing - cartilage
• Subchondral bony sclerosis
• Osteophytes - bony spurs
• Subchondral cysts
Diagram
Spares MCPJ
Lack of space indicates loss of articulations cartilage leading to bone in contact with bone.
Describe the pathology behind osteoarthritis.
There is defective and irreversible articular cartilage and damage to underlying bone
- break down of cartilage
- atrophy of May lets
- damage to underlying bone
- bone spurs
- cartilage fragments in synovial fluid
Develops due to excessive loading on joints and/or abnormal joint components
Articulate cartilage:
Weight-bearing properties of articular cartilage depend on intact collagen scaffold and high aggrecan content
- Avascular and aneural structure (no blood supply or innervation) therefore no pain
- collagen more than 90% type II
- chondrocytes - produce cartilage
- proteoglycan monomers (aggrecan)
ECM proteoglycans
Proteoglycans - glycoproteins containing one or more sulphated glycosaminoglycan (GAG) chains
GAGs are repeating polymers of disaccharides and include:
• Chondroitin sulphate (disaccharides are: glucuronic acid and N-acetyl galactosamine) • Heparan sulphate • Keratan sulphate (disaccharides are: galactose and N-acetyl glucosamine) • Dermatan sulphate • Heparin
Examples of proteoglycans:
- intra-cellular: serglycin
- cell surface associated: betaglycan, syndecan
- secreted into ECM: aggrecan, decorin, fibromodulin, luminance, biglycan
• Aggrecan is the major proteoglycan in articular cartilage
• Hyaluronic acid is the only non-sulphated GAG and is major component of synovial fluid
where it has an important role in maintaining synovial fluid viscosity
GAGs attract water
Cartilage changes in osteoarthritis
• reduced proteoglycan
• reduced collagen
• chondrocyte changes e.g. apoptosis
Bone changes in osteoarthritis
• Changes in denuded sub-articular bone
Proliferation of superficial osteoblasts results in production of sclerotic bone e.g. subchondral sclerosis
Focal stress on sclerotic bone can result in focal superficial necrosis
• new bone formation at the joint margins (termed osteophytes) e.g. Heberden’s and Bouchard’s nodes
Describe the management and treatment of osteoarthritis.
Management:
• Education
• Physical therapy – physiotherapy, hydrotherapy
• Occupational therapy
• Weight loss where appropriate
• Exercise
• Analgesia
Paracetamol
Non-steroidal anti-inflammatory agents
Intra-articular corticosteroid injection (try not to do too much because injecting can further damage joint)
• Joint replacement - timing important - keep having to replace?
Therapeutic approaches not approved in UK
-Glucosamine and chondroitin sulphate – commonly taken
-Intra-articular injections of hyaluronic acid,
hyaluronic acid to increase lubrication
Unlike rheumatoid arthritis no disease modifying osteoarthritis drug (DMOAD)
Describe rheumatoid arthritis, ankylosing spondylitis and systemic lupus erythematosus (SLE).
Rheumatoid arthritis
• Chronic joint inflammation that can result in joint damage
• Site of inflammation is the synovium
• Associated with autoantibodies:
Rheumatoid factor and Anti-cyclic citrullinated peptide (CCP) antibodies
SYNOVITIS
Ankylosing spondylitis
• Chronic spinal inflammation that can result in spinal fusion and deformity
• Site of inflammation is the enthesis - between vertebrae
• No autoantibodies (‘seronegative’)
Arthritis but no rheumatoid factor, predilection for affecting spine
Boney fusion, spinal inflammation
Spinal deformity in ankylosing spondylitis: there is increased thoracic kyphosis and loss of the normal lumbar lordosis
ENTHESITIS
SLE
• Chronic tissue inflammation in the presence of antibodies directed against self antigens
• Multi-site inflammation but particularly the joints, skin and kidney
• Associated with autoantibodies:
Antinuclear antibodies
Anti-double stranded DNA antibodies against self
IMMUNE COMPLEXES
Explain the role of HLA molecules in rheumatology.
Major histocompatibility complex (MHC)
There is association between the MHC and disease e.g. Rheumatoid Arthritis HLA-DR4
Systemic Lupus Erythematosus HLA-DR3
Ankylosing Spondylitis HLA-B27
The genes within the MHC class I and class II regions encode cell surface proteins These were first recognised on human white cells – hence termed human leucocyte antigens (‘HLA’)
Function of MHC class I & class II molecules is to present antigen to T cells Peptide-binding site made up of walls (α-helical structures) and floor (β-pleated sheet) • Sequence in peptide-binding groove determines which antigens can bind • T cells only see antigen-bound to MHC (‘MHC restriction’)
Ankylosing Spondylitis
No arthritogenic peptide that binds HLA-B27 identified
If you express human HLA-B27 in rats (i.e. transgenic rats) you get a similar disease that develops in the absence of CD8 +ve T cells So need new hypothesis
Currently thought that the disease is due to abnormalities in both HLA-B27 and the interleukin- 23 pathway: HLA-B27 has a propensity to misfold and this causes cellular stress that triggers interleukin-23 release and triggers interleukin-17 production by
• Adaptive immune cells i.e. CD4 +ve Th17 cells
• Innate immune cells e.g. CD4 –ve, CD8 –ve (‘double-negative’) T cells
Interestingly these ‘double negative’ T cells have been detected in entheses and this may explain why enthesopathy occurs in Ankylosing Spondylitis
Explain autoantibodies in rheumatology.
Diagram
Antibody bound to antigen —> immune complexes which:
1) bind to immunoglobulin receptors - Fc —> inflammatory cascade
2) complement
SLE
Low complement levels
High serum levels of anti-ds-DNA antibodies
Apoptosis leads to translocation of nuclear antigens to membrane surface —> impaired clearance of apoptotic cells results in enhanced presentation of nuclear antigens to immune cells —> B cell autoimmunity —> tissue damage by antibody effector mechanisms .e.g. tissue damage by antibody effector mechanisms .e.g. complement activation and Fc receptor engagement
Explain cytokines in rheumatology.
Diagram
• CD4 +ve T helper cell subsets include: Th1, Th2 and Th17
• Th1 cells secrete IL-2 and γ-IFN and response is important in CD8 +ve cytotoxicity and macrophage stimulation
• Th2 cells secrete IL-4 (IgE responses), IL-5 (eosinophils), IL-6 (B cells to plasma cells) and IL-10 (inhibit macrophage
response)
• Th17 cells develop in response to IL-23 and secrete IL-17, a potent cytokine which triggers IL-6, IL-8, TNFα, matrix
metalloproteinases and RANKL in target cells. Important in mucosal immunity but also in disease including arthritis,
psoriasis, inflammatory bowel disease and multiple sclerosis
The cytokine tumour necrosis factor-alpha (TNFα) is the dominant pro-inflammatory cytokine in the rheumatoid synovium and its pleotropic actions are detrimental in this setting: (refer back to rheumatoid)
RANKL is important in bone destruction in rheumatoid arthritis
RANKL (receptor activator of nuclear factor KB (kappa beta) ligand) Produced by T cells and synovial fibroblasts in rheumatoid arthritis
Acts to stimulate osteoclast formation (osteoclastogenesis)
Upregulated by:
• Interleukin-1, TNF-a
• Interleukin-17 – potent action on osteoclastogenesis via RANKL-RANK pathway
• PTH-related peptide
Binds to ligand on osteoclast precursors (RANK)
Action antagonized by decoy receptor – osteoprotegerin (OPG)
DENOSUMAB – monoclonal antibody against RANKL - indicated for treatment of osteoporosis, bone metastases, multiple myeloma and Giant cell tumours
Describe prostaglandins in rheumatology.
lipid mediators of inflammation that act on platelets, endothelium, uterine tissue and mast cells
Synthesized from essential fatty acids: phospholipase A2 generates arachidonic acid from diacylglycerol in cell membranes. Arachidonic acid enters two pathways:
Cyclooxygenase pathway: arachidonic acid - - - - prostaglandins
• Prostaglandins mediate e.g. vasodilatation (PGI2, also termed prostacyclin, via receptor called IP), inhibit platelet aggregation (PGI2), bronchodilatation (e.g. PGE2 acting via receptor called EP2, PGI2), uterine
contraction (PGF2alpha)
Lipooxygenase pathway: arachidonic acid - - - - leukotrienes
• Leukotrienes mediate e.g. leucocyte chemotaxis (LTB4) and smooth muscle contraction, bronchoconstriction and mucus secretion (LTC4, LTD4, LTE4 via CysLT1 receptors) side note: leukotriene receptor antagonists used in asthma
Glucocorticoids inhibit phospholipase A2 Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (‘COX inhibition’)
• Benefits: analgesia, anti-pyretic, anti-inflammatory and anti-platelet (thromboxane A2)
• Unwanted effects: e.g. asthma exacerbation, gastro-intestinal ulcers, thrombosis, liver and renal problems
• Two isoforms of cyclooxygenase – COX-1 (constitutive) and COX-2 (inducible)
Used to control symptoms
What are the aims of the GALS examination.
It is a locomotor examination
Aims
1) Are any of the joints abnormal?
2) what is the nature of the joint abnormality?
Inflammation/ mechanical e.g. from football
3) what is the extent (distribution) of the joint involvement?
E.g. Symmetrical - rheumatoid
4) are any other features of diagnostic importance present?
E.g. butterfly rash - lupus
Key questions
• Have you any pain or stiffness in your muscles, joints or back?
• Can you dress yourself completely without any difficulty?
• Can you walk up and down stairs without any difficulty?
Gait
Arms
Legs
Spine
Explain how to perform a GALS examination.
GAIT
Observe patient walking, turning and walking back and look for:
-smoothness and symmetry of leg, pelvis and arm movements
-normal stride length
-ability to turn quickly
SPINE • Is paraspinal and shoulder girdle muscle bulk symmetrical? • Is the spine straight? • Are the iliac crests level? • Is the gluteal muscle bulk normal? • Are the popliteal swellings? • Are the Achilles tendons normal? • Are there signs of fibromyalgia? • Are spinal curvatures normal? • Is lumbar spine and hip flexion normal? • Is cervical spine normal?
ARMS
• Look for normal girdle muscle bulk and symmetry
• Look to see if there is full extension at the elbows
• Are shoulder joints normal?
• Examine hands palms down with fingers straight
• Observe supination, pronation, grip and finger movements
• Test for synovitis at the metacarpo-phalangeal joints (MCP joints)
(MCP squeeze test, can feel tenderness)
LEGS • Look for knee or foot deformity • Assess flexion of hip and knee • Look for knee swellings • Test for synovitis at the metatarso-phalangeal joints (MTP joints) • Inspect soles of the feet
Detailed examination of any abnormal joint(s) identified in the GALS screen
• Inspection: swelling, redness, deformity
• Palpation: warmth, crepitus, tenderness
• Movement: active, passive, against resistance
• Function: loss of function
What is the nature of the joint abnormality?
• Is there inflammation?
• Is there irreversible joint damage?
• Is there a mechanical defect?
Signs of inflammation • Swelling (tumor) • Warmth (calor) • Erythema (rubor) • Tenderness (dolor) • Loss of function (functio laesa)
Signs of irreversible joint damage
• Joint deformity
-malalignment of two articulating bones
• Crepitus
-audible and palpable sensation resulting from movement of one roughened surface on another
-classic feature of osteoarthritis e.g. patello-femoral crepitus on flexing the knee
• Loss of joint range or abnormal movement
Signs of mechanical defect
Signs of mechanical defect
• May due to inflammation, degenerative arthritis or trauma and identified by
• painful restriction of motion in absence of features of inflammation
e.g. knee ‘locking’ due to meniscal tear or bone fragment
• instability
e.g. side-to-side movement of tibia on femur due to ruptured collateral knee ligaments
Define the following:
- arthritis
- arthralgia
- dislocation
- subluxation
- varus deformity
- valgus deformity
Arthritis - refers to definite inflammation of a joint(s) i.e. swelling, tenderness and warmth of affected joints
Arthralgia - refers to pain within a joint(s) without demonstrable inflammation by physical examination
Dislocation - articulating surfaces are displaced and no longer in contact
Subluxation - partial dislocation, still some contact with articulating surfaces
Varus deformity - lower limb deformity whereby distal part is directed towards the midline e.g. varus knee with medial compartment osteoarthritis
Valgus deformity - lower limb deformity whereby distal part is directed away from the midline e.g. hallux vagus
Describe gout. (Nature)
Acute gout is a good example of arthritis
A disease in which tissue deposition of monosodium urate (MSU) crystals occurs as a result of hyperuricaemia (diet) and leads to one or more of the following:
• Gouty arthritis
• Tophi (aggregated deposits of MSU in tissue)
Gouty arthritis commonly affects the metatarsophalangeal joint of the big toe (‘1st MTP joint’) (podagra) • Abrupt onset • Extremely painful • Joint red, warm, swollen and tender • Resolves spontaneously over 3-10 days
Describe joint swelling. (Nature)
Site of injury; tissue involved; indicative of…
Articular soft tissue; joint synovium or effusion; inflammatory joint disease
Periarticular soft tissue; subcutaneous tissue; inflammatory joint disease
Non-articular synovial; bursa/tendon sheath; inflammation of structure
Boney areas; articular ends of bone; osteoarthritis
Describe enthesopathy. (Nature)
- pathology at the enthesis i.e. the site where ligament or tendon inserts into bone
- examples include:
- plantar fasciitis • Achilles tendinitis
Describe ankylosing spondylitis. (Nature)
Good example of a chronic condition in which joint deformity may occur
It is a chronic inflammatory disease affecting:
• Sacroiliac joints (sacroiliitis) and spine
• May lead to spinal fusion (ankylosis) and deformity
• Entheses resulting in chronic enthesopathy
• Non-axial joints – hips and shoulders (common), others less frequently involved
• Strong association with HLA-B27
• Rheumatoid factor is negative
It is part of a group of conditions termed ‘sero-negative spondyloarthropathies’ :
Ankylosing spondylitis
Reiter’s syndrome and reactive arthritis Arthritis associated with psoriasis (psoriatic arthritis)
Arthritis associated with gastrointestinal inflammation (enteropathic synovitis)
(Rigid fixed kyphosis)
Explain the pattern of arthritis. (Extent)
• determine number of joints involved: -polyarthritis: > 4 joints involved -oligoarthritis: 2-4 joints involved -monoarthritis: single affected joint • note if involvement is symmetrical • note the size of the involved joints • is there axial involvement?
differential diagnosis e.g.
• bilateral and symmetrical involvement of large and small joints is typical of rheumatoid
arthritis
• lower limb asymmetrical oligoarthritis and axial involvement would be typical of reactive
arthritis
• exclusive inflammation of the first metatarsophalangeal joints is highly suggestive of gout
Arthritis; joints commonly involved; joints commonly spared
-Rheumatoid arthritis; PIP, MCP, wrist, elbow, shoulder, cervical spine, hip, knee, ankle, tarsal, MTP; DIP, thoracic spine, lumbar spine
- Osteoarthritis; 1st CMC, DIP, PIP, cervical spine, thoracolumbar spine, hip, knee, 1st MTP, toe IP; MCP, wrist, elbow, shoulder, ankle, tarsal joints
- Polyarticular gout; 1st MTP, ankle, knee; axial (spine)
What are other features of diagnostic importance present in joint disease.
Rheumatoid arthritis: subcutaneous nodules (immune complexes outside joints)
Gout: tophi - subcutaneous deposits of uric acid
Systemic lupus erythematosus: malar rash
Describe synovial fluid.
Describe synovial effusions.
Viscous fluid present in joint space of synovial joints (diarthroses)
• Colourless or pale yellow transparent viscous film covering synovium and cartilage with few cells
Synthesized by synovial lining cells
• Synovium consists of lining cells 1-3 cells deep in a matrix mainly containing type I collagen and proteoglycans
• Two types of synovial lining cells: type A = macrophage-like and type B = fibroblast-like • Type B cells secrete the hyaluronic acid which results in the increased viscosity of synovial fluid
Abnormal increase in synovial fluid volume is termed ‘synovial effusion’
• Abnormal mechanical stimulation e.g. in osteoarthritis with damage to cartilage and bone
-Increase production of hyaluronic acid by synovial fibroblasts due to mechanical forces -Excess hyaluronic acid increases oncotic pressure and increases synovial volume – normal composition
• In synovitis due to inflammation the effusion is inflammatory exudate – abnormal composition: inflammatory cells and
mediators, reduced hyaluronic acid
(Chronic infections - TB, fungal infections - get biopsy)
Confirm/exclude infection
Synovial effusions
Normal; clear or pale yellow and viscous
Non-inflammatory; slightly turbid; osteoarthritis, mechanical defects
Infection; very turbid; bacterial
Describe synovial fluid examination.
When is it useful or important to examine synovial fluid?
• It is mandatory when joint infection is suspected
• It is useful to confirm diagnosis in suspected crystal arthritis
How is it performed?
• needle aspiration under aseptic conditions (termed arthrocentesis)
Relative contraindications of arthrocentesis
• Conditions / disorders that increase risk of bleeding into joint during/after procedure e.g. Anticoagulant drugs e.g. warfarin, low platelet counts, bleeding disorders like haemophilia
• Overlying skin infection because of risk of introducing infection into joint
Possible complications are all rare
• Risk of introducing infection (i.e. creating a septic arthritis)
• Bleeding into joint (haemarthrosis)
• Damage to structures within the joint e.g. cartilage
Synovial fluid samples are routinely examined for pathogens and crystals
• Rapid Gram stain followed by culture and antibiotic sensitivity assays
• Polarising light microscopy to detect crystals which can be seen in arthritis due to gout or pseudogut
Examples
- acutely painful right knee: impaired host defence, direct penetration, joint damage
- septic arthritis
- management: antibiotic therapy, joint washout for large joints (lavage)
- swelling behind elbow
- sterile olecranon bursitis due to gout
- Synovial fluid is viscous fluid rich in hyaluronic acid
- It can accumulate (synovial effusions) in joint disease
- Examination of the fluid in these circumstances is clinically very useful in crystal arthritis and mandatory when joint infection is suspected
Explain connective tissue disorders.
Key points
• Arthralgia and arthritis is typically non-erosive
• Serum autoantibodies are characteristic and…:
-May aid diagnosis
-Correlate with disease activity
-May be directly pathogenic
• Raynaud’s phenomenon is common in these conditions
• Intermittent vasospasm of digits on exposure to cold
• Typical colour changes – white to blue to red
-Vasospasm leads to blanching of digit
-Cyanosis as static venous blood deoxygenates
-Reactive hyperaemia
• Raynaud’s phenomenon is most commonly isolated and benign condition (‘Primary Raynaud’s phenomenon’)
SYSTEMIC LUPUS ERYTHEMATOSUS
Key points
• Prototypic autoimmune disease typically diagnosed in female aged between 15 – 45
years
Associated with HLA-DR3 and other genes Clinical manifestations:
• Malar rash – erythema that spares the nasolabial fold
• Photosensitive rash
• Mouth ulcers
• Hair loss
• Raynaud’s phenomenon
• Arthralgia and sometimes arthritis
• Serositis (pericarditis, pleuritis, less commonly peritonitis)
• Renal disease – glomerulonephritis (‘lupus nephritis’)
• Cerebral disease – ‘cerebral lupus’ e.g. psychosis
SJOGREN’S SYNDROME
Key points
• Autoimmune exocrinopathy
• lymphocytic infiltration of especially exocrine glands and sometimes of other organs (extra-glandular
involvement)
• Typically diagnosed in middle-aged female (F:M = 9:1)
• Exocrine gland pathology results in
-Dry eyes (xerophthalmia)
-Dry mouth (xerostomia)
-Parotid gland enlargement
• Commonest extra-glandular manifestations are non-erosive arthritis and Raynaud’s
phenomenon
-Termed ‘secondary’ Sjögren’s syndrome if occurs in context of another connective tissue disorder e.g. SLE
• Associated with autoantibodies:
-Antinuclear antibody - Anti-Ro and Anti-La antibodies
-Rheumatoid factor
INFLAMMATORY MUSCLE DISEASE
Key points
• Proximal muscle weakness due to autoimmune-mediated inflammation either with (dermatomyositis) or without (polymyositis) a rash
• Skin changes in dermatomyositis:
-Lilac-coloured (heliotrope) rash on eyelids, malar region and naso-labial folds
-Red or purple flat or raised lesions on knuckles (Gottron’s papules)
-Subcutaneous calcinosis
-Mechanic’s hands (fissuring and cracking of skin over finger pads)
• Associated with autoantibodies:
-Antinuclear antibody – Anti-tRNA synthetase antibodies (e.g. anti-Jo-1 = histidyl)
• Elevated CPK, abnormal electromyograpghy, abnormal muscle biopsy (polymyositis = CD8 T cells; dermatomyositis = CD4 T cells in addition to B cells)
• Associated with malignancy (10-15%) and pulmonary fibrosis
SYSTEMIC SCLEROSIS
Key points
• Thickened skin with Raynaud’s phenomenon
-Dermal fibrosis, cutaneous calcinosis and telangiectasia
• Skin changes may be limited or diffuse
-Diffuse systemic sclerosis:
Fibrotic skin proximal to elbows or knees (excluding face and neck)
Anti-topoisomerase-1 (anti-Scl-70) antibodies
Pulmonary fibrosis, renal (thrombotic microangiopathy) involvement
Short history of Raynaud’s phenomenon
• Limited systemic sclerosis*
-Fibrotic skin hands, forearms, feet, neck and face
-Anti-centromere antibodies
-Pulmonary hypertension
-Long history of Raynaud’s phenomenon
*CREST describes a sub-type of limited systemic sclerosis. It stands for Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia
OVERLAP SYNDROME
Key points
• When features of more than 1 connective tissue disorder are present e.g. SLE and
inflammatory muscle disease we can use the term overlap syndrome
• When incomplete features of a connective tissue disease are present we can use the
term undifferentiated connective tissue disease
• In one instance a group of patients with features of seen in SLE, scleroderma,
rheumatoid arthritis, and polymyositis were identified by the presence of an
autoantibody:
-Anti-U1-RNP antibody* - ….this condition was termed Mixed Connective Tissue Disease (‘MCTD’)
Describe effect of exercise on growth and development.
Describe eight growth plate.
Exercise when young: growth sensors on both ends affected by how much exercise you do.
Hueter-Volkmann
Compression on growth plates = stops growing
Traction on growth plates = pull on them: grow more
Eight growth plate
- the distal tibial physis can expand and grow laterally in this case
- even out, equally grow
Describe malalignment and sport. (Joint shape)
Straight leg, load is equally distributed on inside and outside of knee
Varus alignment of knees - weight mostly medial
Valgus alignment of knees - weight on lateral
People doing sport are significantly more varus constantly loading on medial
Arthritis starts either medial or lateral - loss of cartilage
Osteotomy can be used for changing bone shape; cut bone - hinge open/shut
Wolff’s law
-Bone responses to stresses you out on it
-if you out more stress, it will lay down more bone and make stronger
-if stop using, starts dissolving
Can be seen in surfer’s knuckles
Start dissolving in space, dominant arm stronger in tennis so more stronger bone
Describe developmental dysplasia of the hip (DDH).
Affects babies
Want hip bone to be in hip socket
If hip slipped out = dysplastic hip
Childbirth - oestrogen causes ligaments to become looser to push up in baby
Hip socket not formed because no hip joint
Risk of arthritis increases, wear out quickly
Describe CAM and PINCER hips.
Standard hip
-slender neck and spherical head in femur
CAM impingement
- femoral neck bone taking lots of stress
- lay down more bone
- lots of exercise
PINCER impingement
-deep socket
What are the 3 groups of people getting hip arthritis?
1) elderly - wears out, cartilage breaks down, bone nibbling
2) injury - torn structures around, hip impact on cartilage
3) young - activity when young
What is the role of the anterior cruciate ligament?
Describe the role of the meniscus.
Describe the structure of bone.
Anterior cruciate ligament
- stops knee from sliding front to back
- stability
Meniscus
- fibrous cartilage
- shock absorbers
- stability
When rupture anterior cruciform ligament, affects:
- stability - especially changing direction
- protect cartilage - loading correctly
- meniscus - back take pressure - meniscal tears
Fibrin slides forward, not lined with femur = unstable knee —> arthritis abnormalities - loading cartilage
2 treatments:
1) physiotherapist and modify activity
2) surgery - ACL reconstruction
Describe the arcade model of Benninghoff.
Describes arrangement of cartilage
1) superficial gliding zone (10-20%) - collagen fibres are flat - resistant to sliding stress from bone above
2) middle transitional zone (40-60%) - resist bit of compression and side to side
3) Deep radial zone (30%) - resist compression
4) tide mark - non-calcified cartilage —> calcified cartilage
4) calcified cartilage - stops blood from outside knee joint entering into joint e.g. infection; nutrition from synovial fluid; downside: if injury, cant repair with inflammatory factors
5) subchondral bone
6) cancellous bone
Collagen fibres from bottom to up:
Vertical —> oblique —> horizontal
What happens to bone quality as you get older.
Describe osteoporosis.
Young - trabeculae is thick
As you get older, trabeculae is thinner, holes appearing and bone more fragile
Postmenopausal, amputees
Amputees don’t load, hips becoming weak
Bisphosphates turn active osteoclast into apoptotic osteoclast
Denosumab inhibits osteoclast formation, fucntion and survival - bind to RANKL (blocking its interaction with RANK)
Describe hip fracture and osteoporosis.
Describe fractures and trauma.
Fracture of neck of femur —> mortality risk
Milk and exercise lay calcium in young age
Help osteoporosis too
Fracture healing Stage 1 – Haematoma/Inflammation – up-to 1 week. -Macrophages, leucocytes, IL-1-6, BMPs. -Granulation tissue formation. -Progenitor cell invasion.
Stage 2 – Soft callus formation – 1-4 weeks.
- Chondroblasts and fibroblasts differentiate and form —> collagen (II) and fibrous tissue.
- Proteoglycans produced (prevent mineralisation).
- Chondrocytes release calcium + degrading enzymes to break down proteoglycans (allows mineralisation).
Stage 3 – Hard callus formation – 1-4 months.
- Blood vessel invasion of soft callus.
- Chondroclasts break down calcified callus and this is replaced by osteoid (T1 collagen) from osteoblasts.
- Osteoid calcified into WOVEN bone.
Stage 4 – Remodelling – up-to several years.
- Woven to lamellar bone.
- Shapes relative to stresses, according to Wolff’s law.
- Medullary canal reforms
Fracture patterns
- soft tissue injury with underlying discontinuity in bone = fracture
- nerves and blood vessels affected too
- twisted ankle
- compression e.g. car crash
- butterfly fragment e.g. direct hit
- pulling on tension
Greenstick fractures - thick periosteum, even if one side cracks, periosteum stays intact and other side bends (in young - paediatrics)
