Rheumatology Flashcards
What is Rheumatology?
The medical management of musculoskeletal disease.
Made up of inflammatory (caused by autoimmune, crystal arthritis, infection) and non-inflammatory (can be degenerative or non-degenerative).
What is inflammation?
Reaction of microcirculation Movement of fluid and white blood cells into extra-vascular tissues Releases pro-inflammatory cytokines - Red, painful, hot, swollen - Stiffness - Poor mobility/function - Deformity
How can you differentiate between inflammatory and degenerative causes of musculoskeletal pain?
- Pain: will ease with use (I) or increases with use (D)
- Stiffness: significant >60mins (I) or not prolonged 30mins (D)
- Swelling: synovial +/- bony (I) or none (D)
- Inflammation: hot and red (I) or none (D)
- Demographics: Pt is young with family history (I) or Pt is older with prior occupation
- Joint distribution: hands and feet (I) or 1st CMCJ, DIPJ, knees (D)
- NSAIDs: responds (I) or doesn’t respond (D)
How can the patterns of pain indicate conditions?
Bone pain at rest and night - tumour, infection, fracture
Pain and stiffness in joints in the morning, at rest and with use - inflammatory joint pain
Pain on use, at end of day - osteoarthritis
Pain and paraesthesia in dermatomal distribution, worsened by specific activity - Root or peripheral nerve compression
Pain unaffected by local movement - referred pain
What is ESR and what can it tell us?
Erythrocyte sedimentation rate
The rate that red blood cells settle to the bottom of a test tube after centrifugation. Fibrinogen is an “acute phase protein” ie a protein made in excess level in the body in response to inflammation or infection. So a high ESR means the red cells settle to the bottom of the tube quicker, because of high levels of fibrinogen in the face of inflammation/ infection.
Can have false positives due to age, female, obesity, racial difference, hypercholesterolaemia, high immunoglobulins (inc. myeloma), anaemia.
What is CRP can what can it tell us?
C-reactive protein Acute phase protein – pentameric peptide Released in inflammation/ infection Produced by liver in response to IL-6, binds to damaged cells and activates complement - phagocytosis Rises and falls rapidly High @ 6 hrs; peak 48 hrs
What factors can be markers of rheumatoid arthritis and SLE?
Rheumatoid Arthritis - RF (Rheumatoid Factor) or CCP (cyclic citrullinated peptide)
SLE - ANA (anti nuclear antibody), binds to Antigens within cell nucleus or dsDNA (double stranded DNA)
What is Spondyloarthropathy/spondyloarthritis?
Group of over-lapping conditions which are all variously associated with the tissue type HLA B27
Includes:
Each condition variably associated = AS (up to 95%; less now with MRI diagnosis), Uveitis (50%), PsA (50-60%), ReA (60-80%)
Patients often display features of more than one individual disease from this group
What are the main conditions of Spondyloarthropathy?
Ankylosing spondylitis Enteropathic Arthritis (Crohns/ UC) Reactive Arthritis Psoriatic Arthritis Acute anterior uveitis (iritis) Undifferentiated Spondyloarthritis Juvenile Idiopathic Arthritis (enthesitis related)
What is HLA B27?
Human Leucocyte Antigen (HLA) B27
Class I surface antigen (all cells, except red blood cells)
Encoded by Major Histocompatibility Complex (MHC) on chromosome 6
Antigen presenting cell
You can either positive or negative for it
How is HLA B27 linked with Spondyloarthritis?
3 THEORIES
- Molecular mimicry: Infection → immune response → infectious agent has peptides very similar to HLA B27 molecule → auto-immune response triggered against HLA B27
- Mis-folding theory: Unfolded HLA-B27 proteins accumulate in the endoplasmic reticulum. A proinflammatory stress response called the endoplasmic reticulum unfolded protein response (ERUPR) ensues. As a result, interleukin 23 (IL-23) is released, activating a proinflammatory response via interleukin-17+ T lymphocytes.
- HLA B27 heavy chain homodimer hypothesis: B27 heavy chains can form stable dimers, which tend to dimerize and accumulate in the ER. In turn, this initiates the proinflammatory ERUPR. In addition, these heavy chains and dimers can bind to other regulatory immune receptors such as the natural killer receptors. This causes the expression and survival of more proinflammatory leukocytes and subsequent production of proinflammatory mediators.
What are the clinical features of Spondyloarthritis?
Inflammatory arthritis of the “axial skeleton” which results in new bone formation and “fusion” of the vertebrae
Enthesitis (inflammation of junction between ligament/ tendon and bone)
Acute anterior uveitis (irits) - inflammation of the anterior chamber of the eye
Peripheral arthritis
Skin psoriasis
May also have (sub-clinical) inflammatory bowel disease.
What are the major features of Spondyloarthritis?
Sausage digit (dactylitis) Psoriasis Inflammatory back pain NSAID good reponse Enthesitis (heel) Arthritis Crohn’s/ Colitis/ elevated CRP* HLA B27 Eye (uveitis)
What is Ankylosing Spondylitis or “Axial Spondyloarthritis”?
Inflammatory arthritis of the spine and rib cage – eventually leading to new bone formation and fusion of the joints
Typically starts in late teenage years/20s & was always thought to be more common in men, but with MRI diagnosis, incidence in women is increasingly recognised (although may be different phenotype – less new bone formation, more B27 (-))
Worst prognosis is male, smokers, B27 (+), syndesmophytes at presentation and high CRP
What are Syndesmophytes?
New bone formation and vertical growth from anterior vertebral corners (Romanus lesions)
What is Sacroiliitis?
One or both of the sacroiliac joints become inflamed.
May occur in Ankylosing Spondylitis
How does structural damage occur in Ankylosing Spondylitis?
“Delayed damage theory” ie once inflammation has occurred – new bone formation is inevitable, therefore once treatment started, new bone continues to form for some time after
Sets in motion a chain reaction that is difficult to stop
How is Axial Spondyloarthritis diagnosed?
Sacroilitis on imaging and one or more clinical features (inflammatory back pain, arthritis, enthesitis, uveitis, dactylitis, psoriasis, Crohn’s/UC, good response to NSAIDs, family history, HLA-B27, elevated CRP)
OR
HLA-B27 plus 2 or more features
What are the treatments available for Ankylosing Spondylitis?
Physiotherapy
Long term and high dose NSAIDs (risks of gastric ulcer, vascular disease, renal damage)
TNFi remain the only NICE approved drug: Improves symptoms almost instantly in vast majority
New group of drugs – JAK inhibitors (biologic tablets)
What are the 5 types of Psoriatic Arthritis?
Symmetrical (both sides of the body) Asymmetric and few joints Spondylitis Distal interphalangeal joints Arthritis mutilans - resorption of bones and the consequent collapse of soft tissue
How is Psoriatic Arthritis managed?
Similar to RA
Early intervention with DMARDs - MTX, leflunomide, ciclosporin, sulfasalazine
DMARDs often help skin disease
Anti TNF drugs - Etanercept, adalimumab, golimumab, certolizumab, infliximab
IL12/23 blockers - ustekinumab
What is Reactive Arthritis?
Sterile inflammation of the synovial membrane, tendons and fascia triggered by an infection at a distant site, usually gastro-intestinal or genital.
Gut associated infections: Salmonella, Shigella, Yersinia
Sexually acquired infection (NSU): Chlamydia, Ureaplasma urealyticum
What are the features of Reactive Arthritis?
CLASSIC TRIAD
Arthritis – large joint oligo/ monoarthritis, enthesitis/ dactylitis/ sacroiliitis
Conjunctivitis
Sterile urethritis
Psoriatic like skin lesions – keratoderma/ circinate balanitis
How would you investigate/diagnose Reactive Arthritis?
Exclude Septic arthritis and Gout Hot swollen joint Raised ESR/CRP Aspirate joint to exclude infection/crystals Urethral swab, stool culture Contact tracing if necessary
What is Enteropathic Arthritis?
Episodic peripheral synovitis occurs in up to 20% of patients with IBD
Asymmetric lower limb arthritis
Usually reflects the disease activity
Remission generally related to suppression of bowel disease.
AS occurs in 7% of patients with IBD.
Activity unrelated to other disease activity
50% of patients with IBD and HLA-B27 +ve develop sacroiliitis
Management similar to reactive arthritis.
What is osteoporosis?
A systemic skeletal disease characterised by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and perfectibility to fracture.
Who is at risk of osteoporosis?
Tend to be those who are older, with comorbidities.
20% of those with a hip fracture will die within a year.
30% will have permanent disability.
What is the pathophysiology contributing to a fracture?
Trauma (due to increased propensity to fall)
Bone strength:
- Bone size
- Bone mineral density (peak bone mass and rate of bone loss)
- Bone quality (dependent on bone turnover, architecture and mineralisation)
How does bone growth change through your lifetime?
Bones grow quickly in childhood - mostly your limbs
Bones grow even more quickly in adolescent - mostly your spine
What is the most important risk factor for fractures?
Age is the most important risk factor for fracture risk
More likely to break hip in old age because protective reactions (hands to the floor) are less effective, so more likely to break hip instead of wrist.
What is the bone remodelling cycle in osteoporosis?
Microcrack in the bone - resorption - formation - returned to normal
But in osteoporosis, this mechanism cannot be performed so there is a net loss of bone.
What is postmenopausal osteoporosis?
Loss of restraining effects of oestrogen on bone turnover
Preventable by oestrogen replacement
Characterised by high bone turnover, predominantly cancellous bone loss and microarchitectural disruption.
How does trabecular architecture change with ageing?
Decrease in trabecular thickness, more pronounced for non-load bearing horizontal trabeculae
Decrease in connections between horizontal trabeculae
Decrease in trabecular strength and increased susceptibility to fracture
What is bone densitometry used for?
For risk assessment and for diagnosis, the characteristic of major importance is the ability of a technique to predict fractures.
What does dual energy X ray absorptiometry do?
Measuring the sites which are most prone to fracture - good predictor of risk.
Very low radiation dose.
What is the T score?
Standard deviation score
Compared with a gender-matched young adult average
Asks how much bone have you lost since you were a young adult?
How can endocrine disease increase the risk of osteoporosis?
Thyroid hormone and parathyroid hormone increase bone turnover so hyperthyroidism and hyperparathyroidism can increase this even more.
Cortisol increases bone resorption and induces osteoblast apoptosis so cushing’s syndrome can increase even more.
Oestrogen/testosterone control bone turnover which can increase in patients with early menopause, male hypergonadism or anorexia/athletes.
How does reduced skeletal loading affect the bones?
Increases resorption in the bone
If your body weight is very low, it has a big impact on the skeletal system - it is less needed, so there is increased resorption. This occurs if you are immobile or in space travel.
What are the risk factors for osteoporosis?
Age Previous fracture Family history of osteoporosis or fracture Alcohol Smoking
What medication can cause osteoporosis?
Glucocorticoids Depo-provera Aromatase inhibitors GnRH analogues Androgen deprivation
How to treat osteoporosis?
Anti-resorptive - decrease osteoclast acitivity and bone activity: biphosphonates, HRT, denosumab
Anabolic - increase osteoblast activity and bone formation: teriparatide
What are the benefits and risks of HRT?
Benefits: - Reduces risk of fractures by 50% - Stop bone loss, bone density may increase by 10% - Prevents hot flushes and other menopausal symptoms - Reduces risk of colon cancer Risks: - Breast cancer - Stroke - Cardiovascular disease - Venous thrombo-embolic disease - Vaginal bleeding
What are biphosphonates?
Biphosphonates inhibit an enzyme in the cholesterol synthesis pathway
First line treatment for osteoporosis
Cheap, effective, many years of experience
What is Denosumab?
Monoclonal antibody to RANK ligand
Used in osteoporosis treatment
What is Teriparatide?
Reduces the risk of fractures by more than 50%
Increases bone density, improves trabecular structure
Bone density may increase up to 70%
What is vasculitis?
Rare multi-system diseases Inflammation of blood vessels Classified by vessel size and common features Heterogeneous Challenging to recognize and diagnose
How is vasculitis classified?
By vessel size
Consensus classification
What is Giant Cell Arteritis?
Commonest large vessel vasculitis
Medical emergency if present with…
Strokes
Blindness (a stroke affecting the retina and optic nerve)
Two distinct clinical patterns of disease with considerable overlap
- Cranial GCA
- Large vessel GCA (LV-GCA)
What is the pathogenesis of Giant cell arteritis?
Activation of dendritic cells in the adventitia
Recruitment and activation of T Cells
Recruitment of CD8+ cells and monocytes
Vascular damage and remodelling
What are the clinical features of giant cell arteritis?
CRANIAL
New headache (abrupt, unilateral, temporal)
Scalp tenderness (pain when brushing hair)
Jaw claudication
Visual symptoms (vision loss, diplopia)
LV-GCA
Constitutional symptoms (fever, malaise)
Polymyalgia
Limb claudication
What are the physical signs of giant cell arteritis?
Physical signs include:
Scalp tenderness
Temporal artery tenderness
Reduced/absent pulsation
What are the complications of giant cell arteritis?
Prompt treatment preventative:
Highest risk of visual loss within 4 weeks of starting steroid
Visual loss <20% (higher in ophthalmology cohorts and pre corticosteroid use)
Strokes 1.5 -7.5%
How would you investigate giant cell arteritis?
Temporal artery biopsy
Ultrasound 54% sensitivity vs. 39% Temporal artery biopsy
PET-CT scan - Helpful to identify LV-GCA
How would you treat giant cell arteritis?
Glucocorticoids (promptly!)
If failure to wean glucocorticoids:
DMARD e.g. Methotrexate, Lefunomide
Tocilizumab
Mitigating effects of treatment:
Osteoporosis prevention
Diabetes mellitus monitoring
What is ANCA-associated vasculitis?
Rare, life threatening, multisystem disease causing damage to predominantly small arteries
Anti-neutrophil cytoplasmic antibodies (ANCA) are implicated in the pathogenesis and can be measured
Two patterns of disease are observed: PR3-ANCA and MPO-ANCA.
Types:
Granulomatosis with polyangiitis (GPA)
Eosinophilic granulomatosis with poly angiitis
Microscopic polyangiitis
When to test for ANCA-associated vasculitis?
Glomerulonephritis
Pulmonary haemorrhage
Cutaneous vasculitis with systemic features
Multiple lung nodules
Chronic destructive disease of the upper airways
What are the clinical features of Granulomatosis with polyangiitis?
Variable presentation from ‘limited’ to ‘generalised’ multi-system disease
Epistaxis, crusts, stiffiness, hearing loss, hoarseness, stridor
Iritis, diplopia
Cough, dyspnoea, haemoptysis
Rash (‘vasculitic rash’)
Numbness, tingling, foot/wrist drop
Joint pain, swelling
How would you investigate Granulomatosis with polyangiitis?
- Confirm the diagnosis - history, examination, ANCA testing, tissue biopsy
- Assessment of organ involvement - CT thorax, urine protein/creatinine ratio, CT head/sinuses/neurophysiology
- Assessment of disease activity - vasculitis damage index
How would you treat Granulomatosis with polyangiitis?
Induction of remission
Cyclophosphamide or Rituximab* +
Glucocorticoids
Plasma exchange for specific complications (pulmonary haemorrhage, severe renal creatinine >500)
Maintenance of remission (3-6 months onwards)
DMARD e.g. azathioprine, mycophenolate mofetil
Rituximab (if rituximab induction)
Glucocorticoid taper
What is osteoarthritis?
Osteoarthritis is an age-related, dynamic reaction pattern of a joint in response to insult or injury
All tissues of the joint are involved
Articular cartilage is the most affected
Changes in underlying bone at the joint margins
What is the pathogenesis of osteoarthritis?
Originally considered to be an inevitable consequence of ageing and trauma, traditionally viewed as ‘degenerative’ and ‘non-inflammatory’.
No longer thought to be the case - metabolically active and dynamic process mediated by cytokines IL-1, TNF-α, Nitric oxide
Main pathological features:
Loss of cartilage
Disordered bone repair
What are the risk factors for osteoarthritis?
- Age: due to cumulative effect of low grade traumatic insult and decline in neuromuscular function
- Gender: increase prevalence in females
- Genetic predisposition: Most relevant in polyarticular disease
- Obesity: Linear relationship between BMI and risk of hip and knee OA. Thought to be due to the fact that obesity is a low grade inflammatory state. Release of IL-1
TNF, Adipokines. - Occupation: Manual labour
- Other factors: local trauma, inflammatory arthritis, abnormal bio-mechanics - joint hypermobility, congenital hip dysplasia, neuropathic conditions
What are the symptoms of osteoarthritis?
Pain
Often reason patient seeks medical advice
May not be present despite significant changes on x-ray
Functional impairment of walking and activities of daily living
What are the clinical signs of osteoarthritis?
Alteration in gait
Joint swelling: bony enlargement, effusion, synovitis (if inflammatory component)
Other joint abnormalities: limited range of movement, crepitus – cracking sound when moving the joint, tenderness, deformities
What are the radiological features of osteoarthritis?
Joint space narrowing (not specific to osteoarthritis) Osteophyte formation Subchondral sclerosis Subchondral cysts Abnormalities of bone contour
What are the features of osteoarthritis in the hands?
DIP, PIP, CMC joints
Relapsing, remitting course over a few years
‘Nodal’ form has a strong genetic component – often down the female blood line
Each involved joint often has an early ‘inflammatory’ phase
Bony swelling and cyst formation
Reduced hand function
- Heberden’s nodes at DIP joints
- Bouchard’s nodes at PIP joints
What are the features of osteoarthritis in the knee?
3 compartments
- Medial (commonest)
- Lateral
- Patellofemoral
Any may be affected in isolation or in combination
Without significant trauma, evolution very slow
Once established, often remains stable for years
What is erosive/inflammatory osteoarthritis?
Subset of OA
Strong inflammatory component
In addition to standard management, DMARD therapy (usually milder agents) often used
Very mixed results
What are loose bodies in the knee?
Associated with ‘locking’ of knee
Bone or cartilage fragment broken off and left floating around
The only indication for arthroscopy in osteoarthritis
How can osteoarthritis be treated non-medically?
Patient education Activity and exercise Weight loss – to reduce inflammation Physiotherapy – to aid with day to day tasks Occupational therapy Footwear Orthoses Walking aids: stick or frame
How can osteoarthritis be treated pharamcologically?
Topical – fairly safe, don’t always work for patients
NSAIDs and Capsaicin
Oral
Paracetamol
NSAIDs (with caution especially in old people)
Opioids
Transdermal patches – local effect
Buprenorphine
Lignocaine
Intra-articular steroid injections
Role remains unclear
DMARDs have a role in inflammatory OA
What are the alternative therapies for osteoarthritis?
Glucosamine - delay in progression of cartilage loss Chondroitin Nettle extract Turmeric Chinese herbal medicine
How can osteoarthritis be treated surgically?
Arthroscopy - only for loose bodies
Osteotomy – cut bone away
Arthroplasty
Fusion – stopping the bones grinding together to relieve pain. Usually ankle and foot, difficult to operate on.
What are the indications for arthroplasty?
Uncontrolled pain (particularly at night) Significant limitation of function
How can connective tissue disorders be classified?
Inherited
Auto-immune (inflammatory)
Give examples of inherited connective tissue disorders?
Marfan’s Syndrome - Arm span greater than their height
Long fingers, Risk of aortic dilatation and aneurysms
Ehler Danlos Syndrome - can be vascular or skeletal, skin hyperplasticity
What are the features of auto-immune connective tissue disorders?
Pathology: Inflammation leading to scarring (damage) in organs affected
Can lead to organ failure: potentially high morbidity and mortality
Early systemic involvement may not give rise to any symptoms
Any system can be affected: commonly skin, joints, kidney, lungs, blood cells and nervous system
Inflammation can be treated with immunosuppressive drugs, damage is irreversible
What are the major connective tissue disorders?
Systemic Lupus Erythematosus (SLE)
Systemic Sclerosis
Primary Sjögren’s Syndrome
Dematomyositis/ Polymyositis
What is the epidemiology of SLE?
Incidence: 4/100 000/year
90% women (14-64 years)
Genetic Association: HLA: DR2, DR3, C4 A Null Allele
What is the pathophysiology of SLE?
Inflammation: Immune complex mediated tissue damage
Thrombosis: Phospholipid antibodies
How can SLE present dermatologically?
Acute Malar “butterfly” rash Generalised erythema Bullous LE Subacute Annular Psoriasiform Chronic Discoid scarring alopecia Lupus profundus
How can SLE present?
Rashes Inflammatory arthritis - symmetrical, can be deforming, non-erosive Nephritis/Nephrosis Renal failure Pericarditis/myocarditis Acute MI Pleural effusion Pulmonary embolism Psychosis Oral ulceration Recurrent abortions Pregnancy complications Cytopenias Abnormal clotting
How can SLE present haematologically?
Anaemia (Haemolytic, Coombs positive)
Thrombocytopenia
Neutropenia
Lymphopenia
What are the auto-antibodies present in SLE?
Anti-nuclear antibody: Not specific for lupus (screening test for all connective tissue diseases) Frequently positive in healthy people.
Double stranded DNA antibody: Specific to SLE
Other antibodies: Rheumatoid factor, Cardiolipin antibodies, Anti Ro, La, Sm, RNP
How to manage SLE?
Patient education and support
UV protection – high factor sun cream
Assessment of lupus activity clinical and immunological
Screening for major organ involvement
Assessment of damage
Identify patients with phospholipid antibodies
Management of lupus in pregnancy
Good liaison with other specialists
Assessment and management of atherosclerosis risk factors
What drugs can be used in SLE?
No Treatment
Topical - Sunscreens, Steroids, Cytotoxic
NSAIDs
Antimalarial
Steroids
Cytotoxic
Anticoagulants
Biological target B cells which make the antibodies
Stem cell transplant – using the patient’s own stem cells (rare)
