Wk11 - MSK Flashcards
Function and structure of a tendon
Tendon – Transmits force from muscle to achieve movement
Parallel collagen fibrils with tenocytes
Surrounded by paratenon / sheath
Largely avascular, nutrition via paratenon
As avascular - slow to heal
How does tendinopathy occur
Chronic Tendon Injury of over use – repetitive loading
- -> Degeneration, disorganisation of collagen fibres
- -> Increased cellularity
- -> Little inflammation
Loss of balance between micro damage from overuse and reparative mechanisms
Risk factors for tendinopathy
Age - more middle age (elderly tend to less activity)
Chronic Disease
Diabetes, Rheumatoid Arthritis
Adverse Biomechanics
Repetitive Exercise
Recent increase in activity
Quinolone 9e.g. ciprofloxacin Antibiotics
Pathology of tendinopathy - what happens
Probably not inflamation – tendinosis not tendinitis
Deranged collagen fibres / Degeneration with a scarcity of inflammatory cells (Astrom and Rausing 1995)
Increased vascularity around the tendon
Failed healing response to micro tears
Inflammatory mediators released IL-1, NO, PG’s – cause apoptosis, pain and provoke degeneration through release of matrix metalloproteinases
Common sites of tendinopathies
Achilles Tendinopathy Rotator cuff tendonitis Tennis Elbow (Lateral epicondylitis) Golfers Elbow (Medial epicondylitis) Patella Tendinopathy Hamstring tendonitis Adductor tendonitis Plantar fasciitis
Clinical features of tendinopathy
Pain
Swelling
Thickening
Tenderness
Provocative tests - Contract that msucle group against resistance
Diagnosis of tendinopathy
X-ray? - Excludes bone pathology
Ultrasound
MRI – Tendinopathy best seen on T1.
Non-operative Tx of tendinopathy
NSAID’s
Activity modification
Physiotherapy – stretching , eccentric exercises
GTN patches
PRP injection - To bring extra growth factors into area –> promote healing
Prolotherapy – irritant injection, dextrose (The dextrose will stimulate inflammation to try get tendon to begin healing)
Extracorporeal Shockwave Therapy
Topaz – radiofrequency coblation
Steroid injection – controversial, avoid intrasubstance, ?avoid suppressing inflammatory and healing response (Steroid injection is avoided most of the time - risk of tearing the tendon)
Etc etc
FEatures of physiotherapy for tx of tendinopathy
Eccentric loading
Contraction of the musculotendinous unit whilst it elongates
Beneficial in approx 80%
GTN patches for Tx of tendinopathy
¼ patch 125 mcg
Vasodilator - Increases local perfusion
Takes up to 12 weeks to see effects (compliance is often a problem)
Side effects - headaches
Extra corporeal shockwave therapy for tx of tendiopathy
3 weekly treatments
Approx 75% improve
Breaks down calcification and stimulates healing of underlying problem
Operative treatment of tendinopathy
Debridement
Excision of diseased tissue
Possible to debride 50% of tendon without loss of function
(Tendon transfers)
Definition of compartment syndrome
- Common sites
Elevated interstitial pressure within a closed fascial compartment resulting in microvascular compromise
Common sites - leg, forearm, thigh
Orthopaedic emergency - loss of function, limb or life
Causes of compartment syndrome
Internal Pressure Trauma – fractures, entrapment Bleeding Muscle oedema / myositis Intracompartmental administation of fluids / drugs Re-perfusion – vascular surgery
External compression Impaired consciousness / protective reflexes Drug / alcohol misuse Iatrogenic Positioning in theatre - lithotomy Bandaging / casts Full thickness burns
Combination
Pathophysiology of compartment syndrome
Pressure within the compartment exceeds pressure within the capillaries
Muscles become ischemic and develop oedema through increased endothelial permeability
Necrosis begins in the ischaemic muscles after 4 hours
Ischaemic nerves become neuropraxic. This may recover if relieved early, permanent damage may result after as little as 4 hours
Compromise of the arterial supply – late
Increased pressure Increased venous pressure Decreased perfusion Muscle ischaemia Muscle swelling Increased permeability – fluid leaks into interstitial space Increased pressure Autoregulatory mechanisms overwhelmed Muscle necrosis and myoglobin release Loss of function , extremity or loss of life.
Effects of ischaemia of limbs at different time zones
1 hour
Nerve conduction normal, Muscle viable
4 hours
Neuropraxia in nerves - reversible
Reversible Muscle ischaemia
8 hours
Nerve axonotmesis and irreversible change
Irreversible muscle ischaemia and necrosis
End stage compartment syndrome
Stiff fibrotic muscle compartments
Impaired nerve function
Clawing of limbs
Loss of function
Diagnosis of compartment syndrome
Clinical Diagnosis
History
Examination
Pulses present (until late stages) unless associated vascular injury
Parasthesia and paralysis – usually later. Deep nerves affected first
1st Dorsal webspace
Impaired conscious level
Compartment pressure measurement
Normal pressure 0-4 mmHg, 10mmHg with exercise
DBP-CP <30mmHG = diagnostic
CP>30mmHG = diagnostic
Clinical features of compartment syndrome
Pain – out of proportion to that expected from the injury
Pain on passive stretching of the compartment (E.g. moving the tones or bending the fingers)
Pallor
Parathesia
Paralysis
Pulselessness (late sign)
Urgent treatemtn of compartment syndrome
Open any constricting dressings / bandages
Reassess
Surgical release
Later wound closure
Skin grafting / Plastic surgery input
If urgent treatment nor enough…
Surgical Release:
Full length decompression of all compartments
Excise any dead muscle
Leave wounds open
Repeat debridement until pressure down and all dead muscle excised
Wound closing/skin grafting
Compartments of the forearm
Flexor
Extensor
Mobile Wad of three
Compartment of the leg
Anterior
Lateral
Deep posterior
Superiffical posterior
Compartments of thigh
Anterior
Abbductor
Posterior
Peri-operative management of compartment syndrome
Adequate hydration Fluid loss Monitor and regulate electrolytes (K+) Correct acidosis Myoglobinuria Renal function
Late presentation/ diagnosis of compartment syndrome
Irreversible damage already present
Fasciotomy will predispose to infection
Consider non-operative treatment
Splint in position of function
FEatures of septic arthritis
pain, fever, swollen joint, loss of function
Causative organisms of septic arthritis
Staphylococcus aureus (Staph auereus - most common (60-75%) - MRSA emerging problem), Neisseria gonorrhoea, Haemophilus influenzae (children)
Increased risk if steroids, rheumatoid arthritis
Suspected septic arthritis is a medical emergency
What are the 3 main classficiation of bone tumours
secondary tumours in bone : very common
myeloma : common, commonest primary bone tumour
primary bone tumours : rare
What type of cancers commonly metasasise to bone
metastatic carcinoma
bronchus, breast, prostate, kidney, thyroid (follicular)
childhood
neuroblastoma, rhabdomyosarcoma
Typically goes to bones with a good blood supply - long bones (femur and humorus), vertebrae
Presentation of metastases to bone
often asymptomatic bone pain bone destruction long bones : pathological fracture spinal metastases: vertebral collapse, spinal cord compression, nerve root compression, back pain. hypercalcaemia
What type of imaging is useful for picking up metasasis on bone
PET CT
2 types of bone metastasis
Lytic V sclerotic bone mets
Majority are lytic
Sites from which sclerotic metastasis to the bone occurs
prostatic carcinoma breast carcinoma carcinoid tumour (neuroendocrien tumour) sclerotic on x-ray reactive new bone formation, induced by tumour cells
2 tumours that produce solitary bone metastases
Renal and thyroid carcinomas
- often longer survival
- surgical removal often valuable
Features of myeloma
Commonest malignant primary bone tumour
Neoplasmic monoclonal proliferation of plasma cells
solitary (plasmacytoma) or multiple myeloma
orthopaedic consequences
“medical” consequences (as can get in bone marrow)
Clinical effects of myeloma
- Osteolytic bone lesions (lytic ‘punched out’ lesions) - backaches, pathological fractures and vertebral collapse
- Hypercalcaemia
- Anaemia, neutropenia or thrombocytopenia
- Recurrent bacterial infections
- Renal impairment
Immunoglobulin excess
- ESR > 100 (can be diagnostic)
- serum electrophoresis : monoclonal band (diagnostic)
- urine : immunoglobulin light chains (Bence Jones protein) (diagnostic)
2 types of light chains in plasma - Kappa and Lambda
If have myeloma - only have one type - either Kappa or Lambda - as monoclonal proliferation
Light chains present in plasma and yeloma
2 types of light chains in plasma - Kappa and Lambda
If have myeloma - only have one type - either Kappa nad Lambda - as monoclonal proliferation
Marrow replacement (due to myeloma) results in
Renal impairment with myeloma
pancytopenia
anaemia
leucopenia: infections
thrombocytopenia: haemorrhage
Myeloma kidney: precipitated light chains in renal tubules
Hypercalcaemia
Amyloidosis
The types of primary bone tumours
Benign
- Osteoid osteoma
- Chondroma
- Giant cell tumour
Malignant
- Oesteosarcoma
- Chondrosarcoma
- Ewing’s tumour
Features of osteoid osteoma
A small, benign osteoblastic proliferation
Common, any age especially adolescents, M:F 2:1
Any bone, especially long bones, spine
Pain, worse at night, relieved by aspirin, scoliosis
juxta-articular tumours : sympathetic synovitis
Tx - radio-frequency ablation
Features of osteosarcoma
- definition
- epidemiology
A malignant tumour whose cells form osteoid or bone
Age : peak 10 -25
Site : metaphysis of long bones, 50% around knee
Sex : male preponderance, 3:2
Incidence : 2-3 / million / year (not very common)
Classic presentation - pain, swelling (shoulder), inability to move a limb
highly malignant
early lung metastases
5 year survival : 15-20% pre-chemotherapy
modern survival : 50-60%
Tumour can often produce a new cortex of bone –> forming a codman’s triangle
Image guided biopsy - by ultrasound or CT
8 weeks of chemotherapy, surgery to remove tumour, often have another 8 weeks of chemotherapy if responded well
Worse prognosis of osteosarcoma - a variant
Paget’s
multifocal
post-irradiation
Pagets disease:
Common in elderly, Anglo-saxon origin
Disorder of excessive bone turnover
Increased osteoclasis, increased bone formation, structurally weak bone
Disorganized bone architecture (often in vertebrae, pelvis, skull, femur)
Usually lytic
- bone pain
OA, deafness, spinal cord compression, high cardiac output - cardiac failure, pagets sarcoma (aggressive form of osteocarcinoma)
Name the common cartilaginous tumours
Benign: Enchondroma, Osteocartilaginous exostosis
Malignant: Chrondrosarcoma
Features of enchondroma
Lobulated mass of cartilage within medulla
Common, any age.
>50% hands and feet, long bones.
Often asymptomatic in long bones.
Hands - swelling, pathological fracture.
Low cellularity, often surrounded by plates of lamellar bone
Features of osteocartilaginous exostosis
Benign outgrowth of cartilage with endo-chondral ossification,
Probably derived from growth plate
Very common, usually in adolescence
Uncommonly multiple-diaphyseal aclasis, autosomal dominant
Metaphysis of long bones, not cranio-facial
Features of chondrosarcoma
de novo (primary) or from a pre-existing enchondroma or exostosis (secondary)
Central,within the medullary canal or peripheral on bone surface
10% of malignant primary bone tumours
predominantly middle aged and elderly
Males: females; 2:1
axial skeleton, pelvis, ribs, shoulder girdle proximal femur and humerus. Hands and feet rare
Main difference between chondrosarcoma and osteosarcome
-
Features of Ewins
Malignant primary bone tumour seen in children - peak 5-15 years
long bones (diaphysis or metaphysis)
flat bones of limb girdles
early metastases to lung, bone marrow and bone
Historical 5 year survival of 5%
Modern 5 year survival 50-60%
Often tibia, fibia or pelvis
Responds well to radio and chemotherapy
Diagnosisng ewins
Stain it for C99 (/) - also do molecular geentics - has a specfic translocation (11 to 22)
Differentials of an acute hot joint
Septic arthritis
Crystal arthropathy
Trauma/haemarthrosis
Early presentation of polyarthropathy (RA, PsA)
Routes by which bacteria can reach the joint (–> septic arthritis)
- The hematogenous route
- Dissemination from osteomyelitis
- Spread from an adjacent soft tissue infection
- Diagnostic or therapeutic measures.
- Penetrating damage by puncture or trauma
Investigations for septic arthritis
Joint aspirate - microbiology for gram stain and culture
Blood culture
FBC - leucocytosis
X-ray - of no value
With septic arthritis the synovium is inflamed with…
fibrin exudation and numerous neutrophil polymorphs
Other specific types of septic arthritis
Lyme disease - borrelia burgdoferi
Brucellosis
Syphilitic arthritis - congenital and acquired
Features of crystal arthropathy
Gout and Pseudogout
Excess levels of uric acid
Leads to deposition of urate crystal in joints or soft tissue (tophi)
Acute gout - precipitation in joint stimulated acute inflammatory process
Chronic gout - tophi formation
How is gout diagnosed?
Feature of primary and secondary gout
Hisotry - rapid onset pain, swelling, tenderness, max intensity within 6-12 hours
Diagnsoed by aspirate - negatively birefringent needel shaped cyrstals in polarized microscopy
Serum urate levels and U&Es
Definitive diagnosis = MSU crystals
Primary - hyperuricaemia due to genetic predisposition e.g. Lesch-Nyhan syndrome
Secondary - high uric acid due to myeloproliferative disorder (PCRV), leukaemia treated by chemo, thiazides, chronic renal disease
Where is the most common site affected by gout?
1st metatarsal (big toe) Podagra - inflammation of 1st metatarsal joint - classical presentation of gout
Management of gout (both acute and chronic)
Acute:
NSAIDs - high doses rapipdly reduce pain and swelling
Cochicine - works best when initiated within 24 hours of attack; works in several ways e.g. IL-1 interference, microtubule interference; Need to stop statins with cochicine treatmen
Corticosteroids
Long term:
Aim SUA <300 using ULT (urate lowering therapy)
Emphasise lifestyle alterations
Allopurinol - excrteed renally; ; Xanthine oxidase inhibitor; Risks include DRESS syndrome - occurs wihtin first few months usually, particulalry HLA mutations at risk
FEbuxostat - XO inhibitor, hepatic metabolism, very expensive (20x allopurinol)
Uricosuric agent (probenecid) - increases secretion of uric acid into urine
Rasburicase - given via IV - progressive risk of anaphylaxis, recombinate urate oxidase
Management of pseudogout
Aspiration helps reduce the pain and swelling
NSAIDs
Colchicine
Features of reactive arthritis
Sterile synovitis which occurs following an infection
Trigger organisms - salmonella, shigella, yersinia, chlamydia thrachomatis
Preceding illness usually a urethritis or diarrhoral
Association with HLA B27 (75%)
Clinical features of reactive arthritis
Acute, asymmetrical lower limb arthritis
More common in men
Days - weeks post infection
Asymetry oligoarthritis, larger jiont of lower limbs, daylitis, enthesitis (e.g. plantar fasciitis), bursitis, onjuctivits/uveitis, circinate balanitis, mouth ulcers, conjuctivities, keratoderma blenorrhagica (dark rash on base of foot)
Management of reactive arthritis
Little evidence that treating the triggering infection alters the course of the disease
Pain control - NSAIDs, intra-articular steroids
Prognosis of reactive arthritis
Usually self limited, lasts up to 6 months
May be chronic
Very occassionally there may be cardiac complications e.g. aortic regurgitation, aortitis, and amyloidosis
Features of enteropathic arthritis
Form of reactive synovitis seen in association with UC and Crohn’s disease
An asymmetrical lower limb arthritis
Treatment of the bowel disease and NSAIDs
Define OA
Features of osteoarthritis
Definition: Degenerative joint disease involving loss of articular cartilage, influenced by mechanical and biological factors.
Degenerative joint disease Commonest form of arthritis Middle aged/elderly Weightbearing joints - hip, knee Pathology - disorder of articular cartilage
Primary generalized - multiple joints, hands
Secondary - fracture, previous sepsis, RA, osteonecrosis, CDH, steroids, chronic overuse, gout, haemochromotosis, ochronosis, peripheral neuropathy
Signs and symptoms of osteoarthritis
Differential diagnosis of OA
Ix/Tx of OA
Pain and stiffness - worse at end of day
Cerpitations
Reduced ROM
Loss of articular cartilage, exposure of underlying bone, subchondral cysts and slcerosis, osteophytes
Synovium becomes hyperplastic, mild inflammation, bony detritus
Differential diagnosis:
bursitis, gout/pseudogout, RA, PA, AVN, meniscal tear
X-ray - LOSS Bloods Exercise Physio/OT NSAIDs + paracetamol Steroid injection Arthroplasty
Function of bone
Structural - support, protection, movement
Mineral storage - calcium and phsophate
Structure of bone
Cortical bone: Compact or tubular bone 80% of the skeleton Slow turnover rate/ metabolic activity Higher Young's modulus and resistance to torsion and bending
Cancellous bone:
Spongy or trabecular bone
Higher turnover rate and undergoes greater remodelling
Lower YOung’s modulus, and is correspondingly more elastic
Composition - Matrix & Cells
Matrix:
Organic - collagen, non-cllagenous proteins, mucopolysaccharides
Inorganic - calcium, phosphorus
Cells: Osteoprogenitor, osteocyte,, osteoblast, osteoclast
Diaphysis (shaft)
Epiphysis (end)
Metaphysis (transitional flared area between diaphysis and epiphysis)
Features of physis of bone
Unique feature of children’s bone
Responsible for skeletal growth
Allows remodelling of angular deformity after fracture
If physeal blood supply damaged, will lead to growth arrest (either partial or complete)
Stages of indirect fracture healing
- Fracture haematoma and inflammation:
Blood from broken vessels forms a clot.
6-8 hours after injury
Swelling and inflammation to dead bone cells at fracture site. - Fibrocartialge (SOFT) callus:
(lasts about 3 weeks)
New capillaries organise fracture haematoma into granulation tissue - ‘procallua’
Fibroblasts and osteogenic cells invade procallus.
Make collagen fibres which connect ends together
Chondrocytes begin to produce fibrocartilage - Bony (HARD) callus
(after 3 weeks and lasts about 3-4 months)
Osteoblasts make woven bone - Bone remodelling
Osteoclasts remodel woven bone into compact bone and trabecular bone
- Often no trace of fracture line on X-rays
Stages of direct fracture healing
Unique ‘artifical’ surgical situation
Direct formation of bone (via osteoclastic absorption and osteoblastic formation), without the process of callus formation, to restore skeletal continuity.
Relies upon compression of the bone ends
No callus
Cutting cones cross fracture site
Lay down new osteones
Blood supply to bones
Endosteal - inner 2/3rds
Periosteal - outer 1/3rd
Injured by a fracture
Further damaged by surgery
Certain fractures are prone to problems with union or necrosis because of potential problems with blood supply… e.g.
Proximal pole of scaphoid fractures
Talar neck fractures
Intracapsular hip fractures
Surgical neck of humerus fractures
What patient factors can inhibit fracture healing?
Increasing age Diabets Anaemia Malnutrition PVD Hypothyroidism Smoking Alcohol
What medications can inhibit fracture healing
NSAIDs (COX 2 NSAIDs inhibit fracture healing more than non-specific NSAIDs)
Steroids
Bisphosphonates (Inhibit osteoclastic activity; Delay fracture healing as a result; Long half-life
Epidemiology of RA
FEmales:males 3:1
Clusters in families
If 1st degree relative affected, 2-10 times greater risk
Aetiology of RA
HLA-DR4 and other genetic factors
Smoking - definite, multiple studies, ACPA
Infection (EBV< TB, prophyromonas gingivalis)
Hormonal (pregnancy, female prepond)
(Rheumatoid can go into remission with pregnancy and then flares again after pregnancy)
Risk factors for RA
Genetic risk factors (60% of risk0
- Susceptibility genes (e.g. HLA-DRB1)
- Epigenetic modifications
Non-genetic risk factors (40% of risk)
- Smoking
- Microbiota
- Female sex
- Western diet
- Ethnic factors
Pathophysiology of RA
Synovitis = immune cells invading a normally relatively cellular synovium in the form of a pannus Pannus = hyperplastic, invasive tissue leading to cartilage breakdown, erosions and consequent reduced function
What is the first area where erosions occur in rheumatoid?
The synovial lining = the bare area
And moves in from the margins
Clinical features of RA
Synovitis - any synovial joint
Symmetrical
Small jts hands and feet early on; shoulder/hip at onset rare
MCPs/PIPs/wrists
Inflammatory - pain, erythema, swelling, EMS
Tenosynovitis, bursitis, CTS
Constitutional sx: fatigue, weakness, low grade fever, weight loss, anorexia
Joint features - late signs of RA
Boutonniere Swan neck Z-thumn (Boutonniere of thumb) Volar subluxation of wrist Ulnar deviation of digits Radial deviation wrist Paino key ulnar head
Extra-articular features of RA
Respiratory - e.g. pulmonary fibrosis
Cardiac - e.g. pericarditis
Dermatological - Rheumatoid nodules, thinning, ulceration
Ophthalmic - scleritis, keratoconjunctivitis
Neurological - carpal tunnel syndrome, peripheral neuropathy
Haematological - anaemia, thrombocytosis
RA investigations
Bloods: FBC, U&Es, LFTs, ESR/CRP, RF, ACPA
Rheumatoid factor
Imaging - Xray, MRI
Rheumatoid factor
Autoantibody against Fc portion of IgG
Usually IgM against IgG, though can be any isotype
60% sens, 80% spec
other conditions that also show +ve RF = SLE, SBE, TB, EBV etc.
Part of assesment but is not diagnostic
Anti-CCP/ACPA
Newer antibody than RF
Sens 60%, spec 80-90%
Picks up those who may be RF -ve.
Predictor of worse prognosis, more erosions, resistant disease
Linked with smoking (increases citrullination)
Imaging for RA
X-rays: Soft tissue swellign, joint spcae narrowing, erosions, periarticular OP
USS: more sensitive for synovitis and erosions
MRI: bone marrow oedema
Differentials of RA
OA, SLE, PMR, psoriatic arthropathy, reactive arthritis, sarcoid, Lyme’s
Treatment of RA
Non-pharmacological:
OT/PTc(mobility help, walking aids etc.), Podiatrists (specialty foot assessment, footwear adjustments). Dieticians
Pharmacological: Symptomatic - NSAIDs, Analgesia etc. DMARDs: - Glucocorticoids (oral, IA, IM) - Biologics (anti-TNF, anti-CD20, anti-IL6 etc)
How does Methotrexate (a DMARD) work in the Tx of RA
- Side effects
MTX is a systemic immunosuppressant (1 mark). MTX stops the actionof the enzyme dihydrofolate (1 mark) needed for production of DNA Is a Dihydrofolate reductase inhibitor 7.5mg-25mg per week orally Common side effects - GI, hair, skin, rashes Serious side effects: lungs, liver, BM Concomitant folic acid Pregnancy - total contraindication Withhold during infection and if on abx (Can't give with trimethoprim)
How does Sulfasalazine (a DMARD) work in Tx of RA?
MOA Salazyopyrin and mesalazine (5-ASA) RA, IBD etc. 500mg-4g OD orally Common side effects: GI, rashes Serious side effects: BM Safe in pregnancy Fine in infection unless cytopenic (cf guidelines)
Name the biologics used to treat RA
Anti-TNF:
Etanercept, infliximab, adalimumab, golimumab, certolizumab
TB, infection risk, MS, CHF
Anti-CD20 (depletes T cell, reduces immunoglobulin levels)
Rituximab
Infection, PML, Hypogammaglobulinaemia
Anti-IL6:
Tocilizumab
Minimal CRP, infections, high lipids
CTLA4-Ig:
Abatcept
Infections
JAK inhibitors:
Tofacitinib and others e.g. Baricitinib
High lipids, infections esp VZV, reduced CRP
SLE epidemiology
Commoner in Afro-Caribbean, South Asian, Mexican populations
Female preponderance
Symptom onset commonly during reproductive years
Diagnosed 40-50 years
Premature death - average 25 years earlier - infection, cardiovascular disease, ESRF
Diagnosing SLE
ACR classification criteria
- Malar rash
- Discoid rash
- Photosensitivity
- Oral ulcers
- Non-erosive arthritis
- Pleurisy or pericarditis
- Renal
- Neurological
- Haematological
- Immunological
- Positive ANA
At least 4 criteria needed for the classification of SLE (don’t need to have them at the same time)
SLICC classification:
Need at least 1 clinical and 1 serological manifestation (need 4 in total)
Diagnosis possible with just biopsy proven LN and positive immunology
Less specific
Problems with ACR criteria (used for diagnosing SLE)
Classification rather than diagnositc criteria
Subset of the clinical manifestations - seizure and psychosis only induced for NPSLE; Proteinuria and casts only renal criteria (renal biopsy not included)
Clinical presentation of SLE
Variable Mild to severe disease Common features: - Constitutional symptoms (fatigue) - Cutaneous manifestations - Arthralgia and arthritis
Musculoskeletal manifestations with SLE
Inflammatory arthritis
Jaccoud’s arthropathy (ligaments are loose but no erosive properties)
AVN - seen out with steroid use
Fibromyalgia
Osteoporosis
Renal involvement with SLE
20% will develop ESRF in 10 years
Typically presents within first year or two
Urinalysis, U&E, BP monitored at clinic
ds-DNA - if have level more likely to have renal involvement
Renal biopsy helpful for diagnosis, prognosis and determining treatment
Pulmonary effects from SLE
Pleurisy Pleural effusions Acute pneumonitis Diffuse alveolar haemorrhage Pulmonary hypertension Shrinking lung syndrome
Cardiovascular effects from SLE
Pericarditis +/- effusion Myocarditis Vavular abnormalities Cornoary heart disease - high risk of morbidity and mortality long-term Risk of MI 50x
Neuropsychiatric effects from SLE
Headache (constant) Anxiety and mood disorder Seizure Demyelination GBS Mononeuritis
Requires tailored investigation EEG MRI LP Psychiatric evaluation
Anti-ribosomal P
Associated with mood disorders
Gastrointestinal involvement with SLE
Rare Dysphagia Reduced peristalsis Peritonitis Pancreatitis Lupus hepatitis
Haematological involvement with SLE
Anaemia of chronic disease
Autoimmune haemolytic anaemia
Thrombotic thrombocytopenic purpura (TTP) – MAHA, low plts, fever, neuro/renal involvement - check aPLS antibodies
Leukopenia
Can have associated lymphadenopathy and splenomegaly
Thrombocytopenia
- Mild or ITP
ANA
Present in 95-98% of patients
SLE results due to activation of innate and adaptive immunity
Interaction of self antigens on or released by apoptotic cells
Sensitive but not specific
5% healthy population have positive ANA – need clinical context
ENA
If ANA positive, helpful to know which antigens affected
Ro/La – SLE, Sjogrens Ds-DNA – SLE Sm - SLE RNP – mixed CTD Centromere – limited SScl Scl-70 – diffuse SScl Histone - drug induced lupus
Compliment involvement with SLE
Complement consumption in active disease C3 more specific C4 can be chronically low Trends more important than absolute numbers > 90% negative predictive value
Investigation for suspected SLE
3 medications for SLE
- FBC - leukopenia
- U&Es - looking for renal manifestations
- Urinalysis - for renal manifestations
- ESR/CRP
- Activated PTT
- ANA
○ Best diagnostic test and is positive in virtually all patients with SLE
○ Clinically relevant ANAs are IgG antibodies
○ Can also be positive in other connective tissue disease e.g. RA, systemic sclerosis, Sjogren’s syndrome, thyroid disease - CXR - if has cardiopulmonary symptoms - looking for pleural effusion etc.
- ECG - if has cardiopulmonary symptoms
In the UK 3 medications are licensed:
- Steroids
- Hydroxychloroquine
- Belimumab
Treatment of mild disease of SLE
Cutaneous disease – topical therapies, UVA/UVB sunblock
MSK – NSAIDS, IA/IM steroid, low dose oral prednisolone, HCQ +/- MTX
Serositis – NSAIDS, MTX
Treatment of moderate disease of SLE
Treatment as per mild disease plus:
Oral prednisolone (0.5mg/kg)
MTX, Aza, MMF, Ciclosporin, Tacrolimus
Belimumab
Refractory disease – Rituximab
Treatment of severe disease of SLE
Treatment as per mild and moderate disease activity plus:
High dose steroid
DMARDs
B cell therapy
Cyclophosphamide
IVIG – Refractory cytopenias, TTP, Catastrophic APLS
Plasmapheresis – TTP, Catastrophic APLS, Diffuse alveolar haemorrhage, Refractory NPSLE or LN
Adjunctive therapy for SLE
Topical lubricants for sicca symptoms
Fatigue management groups
Calcium channel blockers for Raynauds
Treatment of co-existent Fibromyalgia
CVS risk
Osteoporosis risk
Co-existent APLS: Anticoagulation in confirmed thromboembolic disease. Use of antiplatelets debatable
What is vasculitis?
Inflammation of blood vessels
Skin, kidneys, lungs, joints, nerves, ENT
It is an autoimmune reaction
What are the different types of vasculitis?
Large vessel vasculitis
Medium vessel vasculitis
ANCA-Associated Small Vessel Vasculitis
Immune complex Small Vessel Vadculitis
Subtypes of Large Vessel Vasculitis
Takayasu Arteritis
Giant Cell Arteritis
Features of giant cell arteritis
Systemic vasculitis that affects the aorta and its major branches
Prevalence increases with advancing age - Peak incidence between 70-79 years
Female:Male ratio 2-3:1
Clinical presentation of giant cell arteritis
Headache - temporal headache with tenderness, subacute onset, constant, little relief with analgesics Visual symptoms Jaw claudication Polymyalgia rheumatica symptoms Constitutional upset
Complications of GCA
1) Visual loss
- Acute ischaemic optic neuropathy
- Sudden painless loss of vision, occassionally preceded by amaurosis fugax
2) Large vessel vasculitis
- Vascular stenoses nad aneurysms
3) CVA
- Obstruction or occlusion of internal carotid artery or vertebral arteries
Diagnosing GCA
Clinical presentation - typical headache, appropriate age, associated clinical features - jaw claudication , constitutional symptoms, PMR
Clinical examination findings - temporal artery asymmetry, thickening, loss of pulsatility
Acute phase response - ESR/CRP
Further investigations
Investigations for GCA
Temporal artery biopsy - Gold standard: Interruption of internal elastic laminae with mononuclear inflammatory cell infiltrate within vessel wall. Multinucleated giant cells are typical (40-60%) but their absence does not exclude a diagnosis.
Temporal Artery USS
MRI
PET CT
Treatment of GCA
1mg/kg/day prednisolone (max 60mg) for 1 month
Taper to 15mg by 12 weeks
IV methylprednisolone if visual symptoms
Aim to discontinue corticosteroids by 12-18 months
Aspirin 75mg daily - reduces ischaemic complications
Differential diagnosis for cutaneous (small vessel) vasculitits
Idiopathic
Drugs
Infection: HCV, HBV, gonococcus, meningococcus, staph.
Secondary RA/CTD/PBC/UC
Malignancy
Manifestation of small/medium vessel ANCA associated vasculitis
FEatures of Henoch-Schonlein Purpura (HSP)
Small vessel vasculitis More common in children, 2-11y Observed in adults, mean age 43y Male > Females FRequently self limiting illness, 4-16 weeks Good overall prognosis Mortality 1-2%
Clinical features of Henoch Schonlein Purpura (HSP)
Classic purpuric rash: buttocks, thighs>lower legs
Urticarial rash, confluent petechiae, ecchymoses, ulcers
Arthralgia/arthritis (lower limb) in 75%
Complications of HSP
Gastrointestinal: pain, bleeding, diarrhoea, rarely intussuseption. More common in children
Renal: IgA nepphropathy, more common in adults
urological: orchitis
CNS: very rare
HSP management and prognosis
Often no treatment required
Corticosteroids for certain complciations; testicular torsion, GI disease, occasionally arthritis
Steroids in renal disease: evidence limited. Steroids do not prevent development or progression of renal disease.
Clinical presentation of ANCA associated small vessel vasculitis
2 month history of: weight loss, fatigue, joint pain, headaches/facial pain
Investigations for ANCA associated vasculitis
FBC
CRP
U&Es
Urine dipstick: +++ protein, + blood
Urine portin: Creatinine ratio (PCR): 30
Initial treatment for ANCA associated vasculitis
Intravenous antibiotics
Intravenous fluids for presumed respiratory tract infection with dehydration
Immunology of ANCA associated vasculitis
cANCA stongly positive
PR3 130 IU
Diagnosing ANCA associated vasculitis
GRanulomatosis with polyangitis (GPA):
Characterised by granulomatous necrotising inflammatory lesions of the upper and lower respiratory tract and often a pauci-immune glomerulonephritis
GPA: the classic triad of disease
Upper airway/ENT: - rhinitis, chronic sinusitis, chronic ottits media, nasal septal perforation, saddle nose deformity
Lower respiratory: Parenchymal nodules + cavitation, Alveolar haemorrhage
Renal: (rapidly progressive) pauci-immune glomerulonephritis
Constitutional symptoms: Fatigue, weight loss, fever/sweats, myalgia/arthralgia, failure to thrive in elderly
Immunological diagnosis of ANCA
Autoantibodies directed against cytoplasmic constituents of neutrophils and monocytes
2 means of testing:
- Indirect immunofluorescence
- ELISA for PR3/MPO
Looking for cANCA and pANCA
cANCA with PR3 suggesstive of…
GPA
pANCA with strong MPO suggestive of…
MPA (or EGPA)
2 broad reasons for using immunosuppressant drugs
Abnormal inflammation:
- Inflammatory arthropathies
- Ulcerative colitis/Crohns
- Psoriasis
Unwanted normal inflammation
- Solid organ transplants
- Bone marrow grafts
Steroids (e.g. prednisolone) being used for immunnospuressants
& adverse effects
Steroids are excellent immunosuppressants:
Rapid onset (within hours)
Easy to administer
Able to treat wide variety of inflammatory conditions
Limited by intolerable adverse effects, especially at high dose
Weight gain and fluid retention Glaucoma Osteoporosis Infection Hypertension and hypokalaemia Peptic ulceration and GI bleed Psychological/psychiatric symptoms
MOA of corticosteroids
Modulators of transcription factors
Cortciosteroids enter the cell and bind to a glycocorticoid receptor (either in cytoplasm or nucleus) –> will upregulate transcription factors which will promote anti-inflammatory products
Examples of non-steroid immunosuppressive drugs
Inhibitors of DNA synthesis:
Methotrexate
Azathioprine
Mycophenolate
Lymphocyte signalling inhibitors: Cyclosporin Tacrolimus Sirolimus Leflunomide
What are the 2 roles that methotrexate has?
When given as a high does - is a cytotoxic chemotherapeutic agent
Low dose - immunosuppressant
MOA of methotrexate
Methotrexate inhibits the folate cycle (has very similar structure to folic acid) and pentose-phosphate pathway –> prevents the development of nucleotides that go into DNA synthesis; therefore preventing DNA synthesis
From 50 drugs database:
Stops the action of the enzyme dihydrofolate needed for production of DNA
Methotrexate: effect on cells
Causes cell cycle arrest due to inhibition of DNA synthesis
Different cellular functions of methotrexate
Folate Antagonism Inhibiton of adenosine signalling Inhibits Methyl donors Eicosanoids and MMPs Cytokines Adhesion molecules
Adverse effects of methotrexate
GI: nausea, vomitting, diarrhoea, hepatitis, stomatitis, hepatotoxicity
Haematological: leukopenia (predisposition to infection, nausea and vomiting)
Kidney failure
Abdominal pain
Birth defects
Others: frequent infections, pulmonary fibrosis
What medication is often given alongside methotrexate
Folic acid 5mg usually given 4 days after MTX
“Methotrexate on Mondays; Folic acid on Fridays”
Indications for methotrexate in practice
Most commonly used for rheumatological disease: RA, psoriasis and psoriatic arthropathy
Steroid sparing agent in giant cell arteritis
Describe common indications for immunosuppressant drugs and biologic therapies
Autoimmune conditions - IBD, Grave’s disease, RA etc.
Post-transplant immunosuppression
Renal vasculitis
Paediatric leukaemia (methotrexate)
Mechanism of action of Azathioprine
Blocks purine synthesis, mainly in lymphocytes, disrupting DNA synthesis and therefore blocking continued immune response
Side effects of Azathioprine
Birth defects Nausea and vomiting Hepatitis Cholestasis Dizziness/fatigue Diarrhoea Leukopenia Thrombocytopenia Skin rashes Anaemia - bone marrow suppression
Azathioprine metabolsim
TPMT enzyme vital in reducing active drug in cells
A small percentage of people lack this enzyme
Without TPMT there is an accumulation of the most active metabolites of azathioprine within cells and development of severe toxicity
Checking TPMT activity prior to treatment with azathioprine prevents this problem.
Indications for Azathioprine in practice
Most commonly used for IBD
Used in other autoimmune disorders: Myaesthenia Gravis & Eczema
Clinical use of Azathioprine in practice
Given orally on a daily basis
Effects take several weeks to become evident
Need to monitor bloods on a monthly basis
MOA of cyclosporine
This lowers the activity of T cells by binding to cyclosporin, a protein which facilitates protein binding and regulates activity of other proteins. Inhibition of this inhibits phosphatase activity which is required for activation of transcription factors which up-regulate expression of inflammatory cytokines
Side effects of cyclosporin
Nephrotoxicity Hypertension Hepatotoxicity Anorexia and lethargy Hisituism Gum enlargement Peptic ulcers Fever Vomiting and diarrhoea Confusion HYpercholesterolaemia
When used in post-renal transplantation, is associated with development of gout
What is the drug Tacrolimus?
Different class of drug to cyclosporin but similar MOA.
More potent activity.
Very similar use to cyclosporin but may be a little tolerated
Indications for Tacrolimus use in practice
Usually given for organ transplantation - liver, kidney, heart/lung
Disadvantages of immunosupressants
Immunosuppressants often insufficient to control inflammatory disease with subsequent progression.
Usually have a slow rate of onset limiting usefulness in acute severe disease
Even at low doses they have significant toxicities
Class effects include: Bone marrow suppression, infections.
What route are biologic therapies usually delivered by?
Parenteral
Know the features of mechanical back pain
This is non-specific low back pain, accounting for 97% of back pain
Onset at any age and generally worsens with movement or prolonged standing - early morning stiffness for less than 30 minutes
Causes of mechanical back pain (non-specific lower back pain)
Lumbar strain/sprain is most common cause
Degenerative discs/facet joints - Degenerative disc disease is spondylosis (asymptomatic/pain increases with flexion, sitting and sneezing); Degenerative facet disease (more localised pain, increased with extension)
Disc prolapse/spinal stenosis
Compression fractures - common in elderly patients
What are the 3 broad differentials of back pain
- Mechanical (97%)
- Systemic - infection, malignancy, inflammatory
- Referred (i.e. no pathology in the back)
Non-specific LBP management
Education, promote self-management –> advise to stay active
Exercise programme and physiotherapy
Analgesics as appropriate (avoid opiates)
Also acupuncture
Mechanical back pain - radiculopathy
Disc prolapse: Herniated nucleus pulposus:
May be acute, increase cough
Typicaly leg> back pain; sciatica is the most common nerve affected
Leg pain = dermatomal distribution
Straight leg raising test +ve
Reduced reflexes
Most resolve spontaneously within 12 weeks
Wait 12 weeks before doing MRI scan
Mechanical back pain - spinal stenosis
Anatomical narrowing of spinal canal:
Congenital and/or degenerative
Often presents with ‘claudication’ in legs/calves - worse walking, rest in flexed position
Natural history variable
Investigations = xray, MRI
Only operate on those whose symptoms are getting worse and worse
Neuropathic agents used e.g. gabapentin
Features of cauda equina syndrome
Spinal cord ends at L1/2 (need to do lumbar puncture below this)
Neuropathic symptoms - bilateral sciatics, saddle anaesthesia
Bladder or bowel dysfunction - reduced anal tone (need to test perianal sensation and anal tone)
usually a large prolapsed disc
Urgent neurosurgical review
Mechanical back pain - spondylolisthesis
'Slip' of one vertebra on the one below: Pain may radiate to posterior thigh Increased pain with extension Born with defect (?) Often found incidentally on imaging Often asymptomatic Rarely needs surgery (only if severe)
Mechanical back pain - compression fracture
Elderly patient
Often sudden onset, severe
Radiates in ‘belt’ around chest/abdomen
most pain settles in 3/12; chronic mechanical and kyphosis
Associated osteoporosis - risk of recurrence high
Investigations - x-ray, DEXA scan
Treatment:
Conservative (analgesia)
Vertebroplasty (cement) or kyphoplasty (balloon)
Referred pain in back
Retroperitoneal structures:
Aortic aneurysm - CVS features (BP, inc. HR), collapse
Acute pancreatitis - epigastric pain, relief lean forwards, unwell
Peptic ulcer disease (duodenal) - epigastric pain (meals), history PUD, vomit, blood/malaena
Acute pyelonephritis/Renal colic - history UTI/stones, unwell, radiation, haematuria, frequency
Endometriosis/gynae
Systemic causes of back pain
Infection - discitis, osetomyelitis, epidural abscess
Malignany
Inflammatory
Features of infective discitis
High index of suspicion
Fever (may be PUO), weight loss
Constant back pain - rest, night pain
Immunnosppuressed, diabetes, IV drug use
Bloods: FBC, ESR, CRP, blood cultures Imaging xray, MRI Radiology-guided aspiration Most common Staph aureus IV antibiotics +/- surgical ddebridement Look for source
Malignancy causing back pain
History of malignancy: “LP Thomas Knows Best” - Lung, prostate, thyroid, kidney, breast
Onset age >50 years
Constant pain, often worse at night
Systemic symptoms, primary tumour signs and symptoms
X-ray (lytic/destructive), MRI, bone scan
Look for primary site
Inflammatory back pain (IBP)
Onset <45 years (often teens)
Early morning stiffness >30 mins
Back stif after rest and improves with movement
May wake 2nd half of night, buttock pain
Approach to investigating back pain
History (red flags)
Examination - back, neurology, abdomen
Most = non-specific LBP = No further investigation
Keep diagnosis under review - investigate if unusual/new features
Imaging - x-ray, MRI
Bloods - if suspect infective/inflammatory, myeloma screen
Red flags for back pain
Symptoms: New onset <16 or >50 Following significant trauma Previous malignancy Systemic = fevers/rigors, general malaise, weight loss Previous steroid use IV drug abuse, HIV or immunosuppressed Recent significant infection Urinary retention Non-mechanical pain (worse at rest "night pain") Thoracic spine pain
Signs: Saddle anaesthesia Reduced anal tone Hip or knee weakness Generalised neurological deficit Progressive spinal deformity
Yellow flags for back pain
Bio-psycho-social model = patients likely to develop chronicity: ABCDEFW Attitudes Beliefs Compensation Diagnosis Emotions Family Work relationship
Mechanical vs Inflammatory back pain
Age of onset - Any age (M); Usually <40 yrs (I)
Onset - Variable, may be acute (M); Insidious (I)
Morning stiffness - <30 mins (M); >30 mins (I)
Exercise: May worsen pain (M); Improves pain (stiffness) (I)
Rest - Often improves (M); No improvement (I)
Night - May imporve (M); May wake during second half of night (I)
Features of ankylosing Spondylitis
A type of inflammatory back pain.
Low back pain and stiffness for more than 3 months which improves with exercise, but is not relieved by rest.
Limitation of movement of the lumbar spine in both the sagital and frontal planes.
Limitation of chest expansion relative to normal values correlated for age and sex.
Radiological criterion: Sacrolitis grade>=2 bilaterally or grade 3-4 unilaterally
Features of Axial Spondyloarthritis (axSpA)
Type of inflammatory back pain. Enthesitis and dactylitis Axial involvement New bone formation/Ankylosis Extra-articular manifestations *Heterogeneity*
ASAS classification criteria for axial SpA
In patients with >= 3 months back pain and age at onset <45 years
Sacroilitis on imaging (active (acute inflam on MRI) plus >=1 SpA feature - e.g. inflam back pain, arthritis, enthesis, uveitis, datylitis, psoarsis, IBD, family histoy, elevated CRP
OR
HLA-B27 plus >=2 other SpA features
Who gets axSpA and AS?
Onset <45 years
Many in late teens-early childhood 15-35 years
AS = mainly male
axSpA = approaching 1:1 gender split
Sympotms in axSpA
Inflammatory back pain Fatigue Arthritis in other joints e.g. hip, knee Enthesitis: Achilles tendon, plantar fasciitis Inflam outside joints = extra-articular: - Eye: Uveitis - Skin: Psoiasis - Bowel - Crohns/UC - Other: heart, lungs, osteoporosis Family history of above
Recommended imaging for axSpA
x-rays = pelvis AP films
Lumbar spin films
MRI allows earlier identification of sacro-ilitits
Diagnosis of AS and axSpA
Remains a clinical diagnosis
- suggestive symptoms (inc IBP)
- Imaging
- Associated features e.g. family history, psoriasis, colitis, uveitis
Other investigations:
HLA-B27 status
CRP/ESR (usually normal)
Treatment options for axSpA
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Clinical presentation of OA
Joint pain and stiffness
Joint swelling and decreased range of movement
Bouchards nodes - middle finger joint
Heberdens nodes - DCP joints
Causes of OA
Previous injury
Abnormal anatomy
Obesity
Jobs with high stress on joint/sports
Pathophysiology of OA
Proteolytic breakdown of the cartilage matrix from an increased production of enzymes, e.g. metalloproteinases.
The proteoglycan and collagen fragments released into the synovial fluid as the disease progresses, Erosion to the cartilage roughens the surface and fibrillation which narrows the joint space.
There is increased production of synovial metalloproteinases, cytokines and TNF that can diffuse back into the cartilage to destroy the soft tissue around the knee.
Diagnosis of OA
- General examination
- Imaging
General examination - include gait Systemic examination Specific joint examination Look/feel/move/special tests Neurovascular status distally Leg length measurement
Imaging - x-ray will show loss of joint space
Blood
Urine
Aspirate
Kellgren Lawrence Stages of OA on radiographs
Stage 0 - no radiographic evidence of OA is present
Stage 1 - doubtful JSN and possible osteophytic lipping
Stage 2 - definite osteophytes and possible JSN on anteroposterior weight-bearing radiograph
Stage 3 - multiple osteophytes, definite JSN, sclerosis, possible bone deformity
Stage 4 - large osteophytes, marked JSN, severe sclerosis and definite joint deformity
Management of OA at different stages
Stage 1: Lifestyle - e.g. regular exercise, weight loss
Stage 2: Physiotherapy, strict regimen of exercise and strength training for inc joint stability and weight loss, analgesia as required
Stage 3: NSAIDs, paracetamol or stronger pain-reliefs e.g. codeine, oxycodone; acupuncture, head/cold therapy, massage, local anti-inflam gels; Intra-articular injections of steroid/hyaluronic acid into the joint.
Stage 4: If do not respond to analgesia, physical therapy, weight loss, use of NSAIDs, brace, acupuncture, heat/cold therapy the surgery may be required:
Realignment
Replacement - most common
Excision
Fusion
Joint replacement
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Features of juvenile idiopathic arthritis
This is a disease of childhood onset, characterised primarily by arthritis persisting for at least weeks and currently having no known cause
Chronic inflammatory arthropathy, commonest rheumatic disease in childhood
Diagnosis of JIA
Clinical diagnosis but following tests should be considered: Acute phase response Anaemia ANA RF X-rays
Differential diagnosis of swollen joint in a child
Trauma
Inflammation - infection or autoimmune
Malignancy - leukaemia, bone tumours
Know similarities and difference between types of chronic inflammatory arthritis in children compared to adults
-
Recognise the key clinical presentations of arthritis in children and how these differ from adults
Clinical signs which occur in children over adults include:
Oligoarthritis
Uveitis
Systemic dises occurs in systemic JIA - fever, rash
Micrognathia occurs in polyarthritis
Understand the differences between seropositive and seronegative arthritis
Seropositive:
Symmetrical
Affects small and large joints, often widespread
Commonly affects wrists and MCPS
Seronegative:
Asymmetrical
AS/ERA/Reactive/IBD after lower limb weight-bearing joints
Psoriatic affects large and small joints
