MSK and rheumatology Flashcards
what are types of macro bone structure?
cortical and trabecular
what are features of cortical bone?
- compact
- dense, solid
- only spaces are for cells and blood vessels
what are features of trabecular bone?
- cancellous (spongy)
- network of bony struts (trabeculae)
- looks like sponge, many holes filled with bone marrow
- cells reside in trabeculae and blood vessels in holes
what are types of micro bone structure?
woven and lamellar bone
what are features of woven bone?
- made quickly
- disorganised
- no clear structure
what are features of lamellar bone?
- made slowly
- organised
- layered structure
how does whole bone structure contribute to function?
- hollow long bone: keeps mass away from the neutral axis and minimised deformation
- trabecular bone: gives structural support while minimising mass
- wide ends: spreads load over weak, low friction surface
what is the bone composition in adults?
• 50-70% mineral:
- hydroxyapatite: crystalline form of calcium phosphate
• 20-40% organic matrix:
- type 1 collagen: 90% of all protein
- non-collagenous proteins: 10% of all protein
• 5-10% water
what is osteoarthritis?
- type of joint disease that results from breakdown of joint cartilage and underlying cartilage
• cartilage loss with accompanying periarticular bone response
• inflammation of articular and periarticular structures and alteration in cartilage structure
• non-inflammatory degenerative arthritis
what is the epidemiology of osteoarthritis?
- 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
- most common joint condition affecting the synovial joint
- the most common types of arthritis
- the most common cause of disability in the Western world in older adults
- majority is primary with no obvious factor causing it
- secondary OA occurs in joint disease or other conditions e.g. haemochromatosis, obesity and occupational
- prevalence increases with age; uncommon before the age of 50
- beyond 55 it is more common in females than males
what are risk factors for osteoarthrtitis?
- joint hypermobility
- insufficient joint repair
- diabetes
- increasing age
- more common in females
- genetic predisposition
- obesity
- occupation
- local trauma
- inflammatory arthritis e.g. RA
what is a genetic risk factor for osteoarthritis?
COL2A1 collagen type 2 gene
how can occupation act as a risk factor for osteoarthritis?
- manual labour associated with OA of the small joints of the hand
- farming is associated with OA of the hips
- football is associated with OA of the knees
what is cartilage?
cartilage is a matrix of collagen fibres, enclosing a mixture of glycosaminoglycans, proteoglycans, collagen fibres, elastin and water; it has a smooth surface and is shock-absorbing
- resilient and smooth elastic tissue, a rubber-like padding
- composed of chondrocytes that produce a large amount of collagenous extracellular matrix
what is the pathophysiology of osteoarthritis?
- progressive destruction and loss of articular cartilage with an accompanying periarticular bone response
- under normal circumstance, there is a dynamic balance between cartilage degradation and production by chondrocytes
- early in the development of OA this balance is lost and despite the increased synthesis of extracellular matrix, the cartilage becomes oedematous
- focal erosion of cartilage develops and chondrocytes die and, although repair is attempted from adjacent cartilage, the process is disordered, leading to a failure of synthesis of extracellular matrix so that the surface becomes fibrillated and fissured
- cartilage ulceration exposes the underlying bone to increased stress, producing micro-fractures and cysts
- the bone attempts repair but produces abnormal
sclerotic subchondral bone and overgrows at the joint margins which become calcified (osteophytes) - secondary inflammation
- exposed bone becomes sclerotic, with increased vascularity and cyst formation
what are osteophytes? how are they formed?
- exostoses (bony projections) that form along joint margins
- typically intraarticular
- form due to increase in a damaged joint’s surface area
- limit joint movement and typically cause pain
- bone attempts repair but produces abnormal sclerotic subchondral bone and overgrowths at the joint margins which become calcified
what are the different mechanisms for pathogenesis of osteoarthritis?
- metalloproteinases e.g. stomelysin and collagenase, secreted by chondrocytes degrade the collagen and proteoglycan
- IL-1 and TNFalpha stimulate metalloproteinase production and inhibit collagen production
- deficiency of growth factors impairs matrix repair
- gene susceptibility (35-60% influence) from multiple genes rather than a single gene defect - mutations in the gene for type II collagen have been associated with early polyarticular OA
what is the clinical presentation of osteoarthritis?
- affects many joints, typically causing mechanical pain with movement and/or loss of function
- symptoms are usually gradual in onset and progressive
- joint pain made worse by movement and relieved by rest
- joint stiffness after rest (gelling)
- in contrast to RA, there is only transient morning stiffness
- limited joint movement
- muscle wasting of surrounding muscle groups
- crepitus
- joint effusions
- Heberden’s nodes are bone swellings at the DIPJs
- Bouchard’s occur at the PIPJs
what are the joints most commonly affected by osteoarthritis?
- DIPJs (Herbeden’s nodes) and the first carpometacarpal joints of the hands
- first metatarsophalangeal joint of the foot
- weight-bearing joints: vertebra, hips and knees
what are Herbeden’s nodes?
bone swellings at the DIPJs
what are Bouchard’s nodes?
bone swellings at the PIPJs
what are differential diagnoses of osteoarthritis? how can it be differentiated from RA?
- OA is differentiated from RA by the pattern of joint
involvement and the absence of systemic features and absence of marked early morning stiffness that occurs in RA - chronic tophaceous gout and psoriatic arthritis affecting the DIPJs may mimic OA
what is used to diagnose OA?
- deformity and bony enlargement of joints
- CRP may be slightly elevated
- rheumatoid factor and antinuclear antibodies are negative
- X-rays
- MRI to see early cartilage injury and subchondral bone marrow changes
- aspiration of synovial fluid if there is a painful effusion - this shows viscous fluid with few leucocytes
what is seen on X-rays in OA?
• LOSS: - Loss of joint space - Osteophytes - Subarticular sclerosis - Subchondral cysts • abnormalities of bone contour
what is the non-medical treatment of OA?
- exercise to improve local muscle strength, improve mobility of weight bearing joints and general aerobic fitness
- lose weight if obese
- local heat or ice packs applied to affected joint
- bracing devices, joint supports, insoles for joint stability and footwear with shock-absorbing properties for lower limb OA
- acupuncture, physiotherapy and occupational therapy
what is pharmacological treatment for OA?
• paracetamol prescribed before NSAIDs
• can take weak opioids alongside paracetamol
• intra-articular corticosteroid injections produce short-term improvement when there is a painful joint effusion:
- systemic corticosteroids not used
- do not administer if joint is going to be replaced
what types of surgery can be used to treat OA?
- arthroscopy
- arthroplasty
- osteotomy
- fusion
how is arthroscopy used to treat OA?
endoscope inserted into joint through small incision to assess damage and remove loose bodies; this is the only indication for arthroscopy in osteoarthritis
how is arthroplasty used to treat OA? what are the indications for it?
- articular surface of a MSK joint is replaced, remodelled or realigned by osteotomy
- indications: uncontrolled pain and significant limitation of function
- prosthetic joint has lifespan of 10-15 years and will need replacement, in a young person it could be done up to 3 times
how is osteotomy used to treat OA?
surgical operation whereby a bone is cut to shorten or lengthen it or to change its alignment
how is fusion used to treat OA?
- usually of ankle and foot to prevent painful grinding of bones
- loss of mobility
what is rheumatoid arthritis?
- long-term, chronic systemic autoimmune disorder that primarily affects joints
- causes symmetrical deforming polyarthropathy
- disease of the synovial joints
- inflammatory autoimmune arthritis
what is the epidemiology of RA?
- it is common affecting 1% of the population worldwide with a peak prevalence between 30-50 yrs
- prevalence is increased in smokers
- not seen as much in the elderly in contrast to OA
- more common in females than males
how can genetic factors act as risk factors for RA?
HLA-DR4 and HLA-DRB1 confer susceptibility to RA and are associated with development of more severe erosive disease
how can the immune system act as a risk factor for RA?
• triggering antigen in RA is unknown but factors are produced by activated:
- T cells: interferon, IL-2 and IL-4
- macrophages: IL-1, IL-8 and TNF-alpha
- mast cells: histamine and TNF-alpha
- fibroblasts: IL-6
• these cause/contribute the ongoing synovial inflammation
• local production of rheumatoid factor (autoantibodies directed against the Fc portion of immunoglobulin) by B cells and formation of immune complexes with complement activation maintains the chronic inflammation
what are risk factors for RA?
- gender
- family history
- genetic factors
- smoking
- immune system
what is the pathophysiology of RA?
- over-production of TNF-alpha leads to synovitis
and joint destruction - the interaction of macrophages, T and B lymphocytes drives this overproduction - in RA the synovium becomes greatly thickened and becomes infiltrated by inflammatory cells
- generation of new synovial blood vessels is induced by angiogenic cytokines and activated endothelial cells produce adhesion molecules which force leucocytes into the synovium where they can trigger inflammation
- the synovium proliferates and grows out over the surface of the cartilage past the joint margins, producing a tumour-like mass called ‘pannus’
- this pannus of inflamed synovium damages the underlying cartilage by blocking its normal route for
nutrition and by direct effects of cytokines on the chondrocytes - the cartilage becomes thin and the underlying bone exposed
- the pannus destroys the articular cartilage and subchondral bone, resulting in bony erosions
what is a pannus? what is its role in RA?
- the inflamed synovium proliferates and grows out over the surface of the cartilage past the joint margins, producing a tumour-like mass called ‘pannus’
- this pannus of inflamed synovium damages the underlying cartilage by blocking its normal route for
nutrition and by direct effects of cytokines on the chondrocytes - the cartilage becomes thin and the underlying bone exposed
- the pannus destroys the articular cartilage and subchondral bone, resulting in bony erosions
what joints are usually affected by RA?
- small joints of the hand; MCP and PIP joints
- usually the DIPs are spared
- MTP joints of the feet
- wrists, elbows, shoulders, knees and ankles
- in most cases, many joints are involved
what is the clinical presentation of RA?
- slowly progressive, symmetrical swollen, painful, tender, warm and stiff joints
- symptoms worse in the morning and in the cold
- morning stiffness lasting more than 30 minutes
- symmetrical peripheral polyarthritis
- movement limitation and muscle wasting
- fatigue and disturbed sleep
- shoulder and elbows may become swollen and stiff
- feet pain in MTP joints, foot becomes broader and hammer toe deformity leading to ulcers and callouses
- synovitis and effusions in the knees
- tenosynovitis
what are hand deformities that are seen in RA?
- ulnar deviation
- swan neck/Z thumb
- Boutonniere deformity
what are extra-articular manifestations of RA in the lungs?
pleural effusions, fibrosing alveolitis, pneumoconiosis (Caplan’s syndrome, especially in miners), interstitial lung disease, bronchiectasis
what are extra-articular manifestations of RA in the eyes?
dry eyes, episcleritis (non severe mild redness of eyes), scleritis (severe pain, can’t look at bright lights)
what are extra-articular manifestations of RA in the neurological system?
- peripheral sensory neuropathies
- compression/entrapment neuropathies
- cord compression due to instability of the cervical spine; occurs in severe RA, presents with sensory loss, weakness and disturbed bladder function
what are extra-articular manifestations of RA in the kidneys?
amyloidosis, nephrotic syndrome and CKD
what are extra-articular manifestations of RA in the skin?
subcutaneous nodules
how is RA diagnosed via the blood?
- normocytic normochromic anaemia
- ESR and/or CRP raised in proportion to the activity of the inflammatory process; useful for monitoring treatment
- positive rheumatoid factor in 80%
- positive anti cyclic citrullinated peptide in 30% (indicates likelihood of progression to RA, those positive have worse prognosis)
what is seen on an X-ray in RA?
- soft tissue swelling in early disease
- joint space narrowing in late disease
- periarticular erosions
what is seen on MRI and ultrasound in RA?
erosions at joint margins and bones
what is seen on aspiration of joint in RA?
if effusion present then do an aspiration of joint; will be cloudy due to high white cells
what is general treatment of RA?
- no cure
- smoking cessation to reduce risk of CV disease
- reduce weight
- exercise
- surgery e.g. synovectomy to reduce bulk of inflamed tissue and prevent damage
what is done in pain management for RA?
- NSAIDs and COX inhibitors
- paracetamol with/without opioids
how are corticosteorids used to treat RA?
- suppress disease activity but risk of long term toxicity
- can cause osteoporosis (most common cause of secondary osteoporosis) and increase risk of fracture
- oral corticosteroids have many side effects
- IM injection of depot for those waiting for DMARDs to work
- intra-articular injection; semicrystalline steroid (rapid but short-lived effect)
what are DMARDs? how are they used to treat RA?
Disease-Modifying Anti-Rheumatic drugs
• inhibit inflammatory cytokines
• used early to reduce inflammation and slow development of joint erosions and irreversible damage
• take 6 weeks to start working
• all have serious side effects so monitoring with blood tests is required
what are examples of DMARDs?
- methotrexate (oral)
- sulfasalazine (oral)
- leflunomide (oral)
how is methotrexate used in RA? what is the mechanism and side effects?
- csDMARD
- gold standard drug used for more active disease
- purine metabolism inhibitor
- contraindicated in pregnancy
- side effects: nausea, mouth ulcers, diarrhoea, abnormal LFTs, neutropenia, thrombocytopenia, renal impairment
how is sulfasalazine used in RA? what is its mechanism and side effects?
- csDMARD
- for mild/moderate disease
- used in young people and women
- suppression of IL-1 and TNF-alpha; induces apoptosis of inflammatory cells and increases chemotactic factors
- side effects: nausea, skin rashes, mouth ulcers, neutropenia, thrombocytopenia, abnormal LFTs
how is leflunomide used in RA? what is its mechanism and side effects?
- csDMARD
- pyrimidine synthesis inhibitor
- block T cell proliferation
- side effects: diarrhoea, neutropenia, thrombocytopenia, alopecia, hypertension
what are types of biological therapy used for RA?
- very expensive
- TNF-alpha blockers
- B cell inhibitors
- interleukin blockers
- T cell activation blockers
what are TNF-alpha blockers? how are they used for RA? what is their mechanism of action?
- first line biological treatment
- slows/halts erosion formation
- given alongside methotrexate
- TNF is produced early on to initiate the immune response
- TNF levels are raised in the synovial fluid and synovium; this leads to local inflammation through signalling of synovial cells to produce metalloproteinases and collagenase
- TNF regulates other cytokines, it also stimulates osteoclast development
what are some examples of TNF-alpha blockers?
- infliximab (IV)
- etanercept (SC)
- adalimumab (SC)
what is infliximab? what is its mechanism of action and its side effects?
- chimeric monoclonal antibody biologic used in RA
- binds to TNF-alpha and prevents it from binding to its receptor
- side effects: demyelination and autoimmune syndromes
- IV
what is etanercept? what is its mechanism of action and its side effects?
- fusion protein produced by recombinant DNA
- used in RA
- fuses the TNF receptor to the constant end of the IgG1 antibody; reduces the effects of naturally present TNF
- side effects: hypersensitivity reactions, infection
- SC
what is adalimumab? what is its mechanism of action and its side effects?
- monoclonal antibody used in RA
- inactivates TNF-alpha
- side effects: hypersensitivity reactions, heart failure
- SC
what are B-cell inhibitors? how are they used in RA? what is an example?
- B cells produce rheumatoid factor (binds to Fc portion of IgG forming immune complex)
- rituximab
what is rituximab? what is its mechanism and side effects?
- monoclonal antibody used in RA
- B cell inhibitor
- destroys normal and malignant B cells that have CD20 on their surfaces
- IV
- used in patients that have failed to respond to anti-TNF agents
- side effects: hypo/hypertension, skin rash, nausea, pruritus, back pain
what are examples of interleukin blockers?
- tocilizumab
- anakinra
what is tocilizumab? what is its mechanism and side effects?
- monoclonal antibody that binds to IL-6 cytokine before it reaches target receptor; used in RA
- IL-6 and IL-1 are the most important in joint inflammation
- used alongside methotrexate
what is anakinra? what is its mechanism?
- used in RA
- a recombinant and slightly modified version of the human IL-1 receptor antagonist protein
- SC
what is an example of T cell activation blockers? what does it do?
abatacept
• blocks T cell activation which means macrophages and B cells cannot be activated, which reduces inflammation
• fusion protein composed of the Fc region of the immunoglobulin IgG1 fused to the extracellular domain of CTLA-4
• abatacept binds to the CD80 and CD86 molecule, and prevents the signal required to activated the T cell
what are the differences in pain in RA vs OA?
RA: pain eases with use
OA: pain increases with use, and there are clicks/clunks
what are the differences in stiffness in RA vs OA?
RA
- significant (>30 mins)
- early morning/at rest
OA
- not prolonged (<30 mins)
- morning/evening or after periods of activity
what are the differences in joint symptoms in RA vs OA?
RA
- synovial and/or bony swelling
- hot and red
- painful, swollen and stiff joints
OA
- joints ache and may be tender but have little or no swelling
- not clinically inflamed
what are differences in the patient demographics in RA vs OA?
RA
- young, psoriasis, family history
- can begin any time in life
- relatively rapid onset, over weeks to months
OA
- older, prior occupation/sport
- usually begins later in life
- slow onset, over years
what are differences in the joint distribution in RA vs OA?
RA
- hands and feet
- often affects small and large joints on both sides of the body (symmetrical)
OA
- 1st CMCJ, DIPJ, knees
- often begin on one side of the body and may spread to other side
- symptoms begin gradually and are often limited to one set of joints
what are differences in presence of systemic symptoms in RA vs OA?
RA
- frequent fatigue and a general feeling of being ill
- systemic symptoms
OA
- whole-body symptoms are not present
what is the definition of osteoporosis?
- asystemic skeletal disease characterised by low bone mass and a microarchitectural deterioration of bone tissue, with an increase in bone fragility and susceptibility to fracture
- defined as bone mineral density (BMD) more than 2.5 standard deviations below the young adult mean value (T score < 2.5)
what is osteopenia?
- precursor to osteoporosis characterised by low bone density
- defined as BMD between 1-2.5 standard deviations below the young adult mean value (-1 < T score < 2.5)
what is osteomalacia?
poor bone mineralisation leading to soft bone due to lack of Ca2+ (adults form of Ricket’s)
what is the T score?
- standard deviation score ascertained using a Dual Energy X-ray absorptiometry (DEXA) scan
- compared with the gender-matched young adult average (peak bone mass)
what is the epidemiology of osteoporosis?
- in those over 50 it is more common in females than males due to women losing trabeculae with age, whereas men, have stable numbers of trabeculae and reduced lifetime fracture risk
- Caucasian and Asian races at risk
- risk increases with age
what are risk factors for osteoporosis?
- old age
- women
- family history of osteoporosis or fracture
- previous bone fracture
- smoking/alcohol
what is SHATTERED in relation to osteoporosis?
risk factors
- Steroid (prednisolone) use and other drugs e.g. heparin, ciclosporin, PPIs, anticonvulsants, GnRH analogues, SSRIs, androgen deprivation
- Hyperthyroidism and Hyperparathyroidism
- Alcohol and tobacco: bad for bones
- Thin: BMI <22
- Testosterone decreased; leads to increased bone turnover
- Early menopause: oestrogen drop leading to increased bone turnover
- Renal or liver failure
- Erosive/inflammatory bone disease e.g. RA/myeloma; cytokines (TNF alpha and IL6) increase bone turnover
- Dietary calcium decrease/malabsorption, DMT1
how can hyperthryoidism and hyperparathyroidism cause osteoporosis?
- other endocrine diseases e.g. Cushing’s (high cortisol)
- thyroid hormone and parathyroid hormone increase bone turnover
- cortisol increases bone resorption via osteoclasts and induces osteoblast apoptosis
- oestrogen/testosterone control bone turnover
what is the pathophysiology of osteoporosis? what affects peak bone mass? what are genetic components?
- peak bone mass is at around 25 yrs, then you start losing bone mass
- osteoporosis results from increased bone breakdown by osteoclasts and decreased bone formation by osteoblasts, leading to loss of bone mass
- bone mass decreases with age, but will depend on the ‘peak’ mass attained in adult life and on the rate of loss in later life
- multiple genes are involved, including collagen type 1A1, vitamin D receptor and oestrogen receptor genes
- nutritional factors, sex hormone status and physical activity also affect peak bone mass
- oestrogen deficiency
- changes in trabecular architecture with ageing
how does BMD determine bone strength?
- says how much mineral is in bone
- determined by the amount gained during growth and amount lost during ageing
how does bone size determine bone strength?
- short and fat is stronger than long and thin
- distribution of cortical bone
how does bone quality determine bone strength?
- bone turnover, architecture and mineralisation affect bone strength
- if there is not enough mineralisation then bone breaks, but if too much then bones are stiff and will shatter
how does oestrogen deficiency affect osteoporosis?
- results in increased numbers of osteoclasts, premature arrest of osteoblastic synthetic activity and perforation of trabeculae with a loss of resistance to fracture
- high bone turnover
- predominantly cancellous bone loss
how do changes in trabecular architecture affect osteoporosis?
- decrease in trabecular thickness; as we age the strain is felt on bones from head to tail and in response we tend to preferentially preserve vertical trabeculae and lose horizontal trabeculae
- decreased trabecular strength and increased susceptibility to fracture
what is the clinical presentation of osteoporosis?
- fracture is the only cause of symptoms in osteoporosis
- vertebral crush fracture:
• sudden onset of severe pain in the spine, often radiating to the front
• thoracic vertebral fractures may lead to kyphosis - Colles’ fracture of the wrist follows a fall on an outstretched arm
- fractures of the proximal femur usually occur in older individuals that fall on their side or back
what is kyphosis?
- abnormally excessive convex curvature of the spine as it occurs in the thoracic and sacral regions
- occurs in osteoporosis
what is seen on X-ray in osteoporosis?
demonstrates fractures but is insensitive for osteopenia
what is seen on a DEXA scan in osteoporosis?
dual energy X-ray absorptiometry
• low radiation dose and measures important fracture sites (lumbar spine and proximal femur)
• gold standard for measuring bone density and diagnosing osteoporosis
• generates T scores
what are lifestyle measures used to treat osteoporosis?
- quit smoking and reduce alcohol consumption
- increase weight-bearing exercise
- calcium and vitamin D rich diet
- balance exercises to reduce falls
what are examples of anti-resorptive drugs used to treat osteoporosis?
- bisphosphonates (1st line treatment)
- strontium renelate
- denosunab
- HRT
- raloxifene
- testosterone (for men)
what are features of bisphosphonates given to treat osteoporosis? what is their mechanism of action and side effects?
- inhibit bone resorption through the inhibition of enzyme farnesyl pyrophosphate synthase, which is in the cholesterol pathway; this reduces osteoclast activity by removing their ruffled border
- encourage osteoclasts to undergo apoptosis
- prevent the loss of bone density
- increases bone mass at hip and spine
- reduce incidence of fracture and are cheap and effective
- e.g. oral aldendronate (most common), oral risedronate, IV zoledronate (once yearly)
- oral bisphosphonates should be taken fasting, with a large drink of water while standing or sitting upright
- associated with oesophagitis
what is the mechanism of action of strontium renelate? how is it used to treat osteoporosis?
- helps reduce fracture rates
* alternative for those who are intolerant to bisphosphonates
what is the mechanism of action of denosumab? how is it used to treat osteoporosis?
- osteoblasts produce RANKL to activate osteoclasts and thus bone resorption
- denosumab is a monoclonal antibody that inhibits RANKL signals
- reduces fracture risk
what is the mechanism of action of HRT? how is it used to treat osteoporosis?
• 2nd line for osteoporosis; used in menopausal women
• reduces fracture risk and stops bone loss
• prevents hot flushes and other menopausal symptoms, also reduces colon cancer
• side effects; breast cancer, stroke and cardiovascular
disease
what is the mechanism of action raloxifene?
- selective oestrogen receptor modulator (SERM); activates oestrogen receptor on bone whilst having no stimulatory effect on endometrium (similar to HRT)
- side effects; increased risk of thrombus formation, cramps and stroke
what is a recombinant human parathyroid peptide? what is its action and side effects? what is an example?
• increases osteoblast activity and bone formation
• reduce fracture risk
• improves bone density, improves trabecular structure
• useful in those who suffer further fractures despite treatment with other agents
• side effects; increased risk of renal malignancy and
hypercalcaemia
• e.g. teriparatide
what is the ESR? what can it indicate?
erythrocyte sedimentation rate
- rises with inflammation/infection
- the rate at which RBCs in anticoagulated whole blood descend in standardised tube over a period of one hour
- increased fibrinogen makes RBCs ‘stick together’ and thus fall faster (fall is measured in mm)
- thus if ESR rises the rate of fall is faster
- ESR rises and falls slowly (days to weeks)
- false positives i.e. falsely high: females, age, obesity, SE asians, hypercholesterolaemia, high immunoglobulins
what is CRP? what can it indicate?
C-reactive protein
- acute phase protein
- released in inflammation/infection
- produced by the liver in response to IL-6
- rises and falls rapidly:
• high at 6 hours and peaks at 48 hours
• so if patients has infection in 24 hours, the ESR won’t have risen yet since it rises slowly but CRP would have!
what are some autoimmune diseases?
- SLE
- antiphospholipid syndrome
- Sjogrens syndrome
- systemic sclerosis (scleroderma)
- CREST syndrome
- polymyositis and dermatomyositis
what is systemic lupus erythematosus?
an inflammatory, multisystem autoimmune disorder where healthy tissues in the body are attacked, with arthralgia and rashes as the most common clinical features, and cerebral and renal disease as the most serious problems
what is the epidemiology of SLE?
- more common in females than males
- peak age of onset between 20-40 yrs; typically women of childbearing age
- commoner in African-Caribbeans and Asians
what are risk factors/aetiology of SLE?
- cause unknown
- family history
- HLA genes have been linked to SLE
- pre-menopausal women are most affected
- drugs: hydralazine, isoniazid, procainamide and penicillamine
- UV light can trigger flares of SLE
- Epstein-Barr virus is a potential trigger for SLE
what is the pathophysiology of SLE?
- immune complex mediated tissue damage
- when cells die by apoptosis, the cellular remnants appear on the cell surface as small blebs that carry self antigens
- these antigens include nuclear constituents such as DNA and histones, which are normally hidden from the immune system
- in SLE, removal of these blebs by phagocytes is inefficient, so that they are transferred to the lymphoid tissues, where they can be taken up by APCs
- these self-antigens from the blebs can then be presented to T cells, which stimulate B cells to produce autoantibodies directed against the antigens
- can be years before clinical features develop
what are the consequences of SLE for the body?
the combination of availability of self antigens and failure of the immune system to inactivate the B cells and T cells that recognise these self antigens as foreign, and thus target them, leads to the following:
• development of autoantibodies that either from circulating complexes or deposit by binding directly to tissues
• activation of complement and influx of neutrophils, causing inflammation in those tissues
• abnormal cytokine production; increased IL-10 and interferon-alpha resulting in inflammation
what are effects of SLE on the body?
- SLE of the skin and kidneys is characterised by deposition of complement and IgG antibodies, and by influx of neutrophils and lymphocytes
- biopsies of other tissues show vasculitis affecting capillaries, arterioles and venules
- the synovium of joints can be oedematous and may contain immune complexes
- haematoxylin bodies (rounded, blue) are seen in inflammatory infiltrates and result form the interaction of antinuclear antibodies and cell nuclei
what is the clinical presentation of SLE?
- most patients suffer fatigue, fever, arthralgia and/or skin poblems
- joint involvement in more than 90%
- skin involvement in 85%
- lung involvement in 50%
- heart involvement in 25%
- kidney involvement in 30%
- CNS involvement in 60%
- eyes
- GI
what are features of joint involvement in SLE?
- more than 90% of cases
- symptoms similar to RA*: symmetrical small joint arthralgia
- joints are painful sometimes with soft tissue swelling
- avascular necrosis of hip and knee rarely
what are features of skin involvement in SLE?
- 85% of cases
- erythema in a butterfly distribution* on the cheeks and across the bridge of the nose
- vasculitis lesions on the fingertips and nails
- photosensitive rash*
- alopecia
- Raynaud’s phenomenon
what are features of lung involvement in SLE?
- 50% of cases
- recurrent pleural effusions and pleurisy, pneumonitis and atelctasis
- pulmonary fibrosis rarely
what are features of heart involvement in SLE?
- 25% of cases
- pericarditis and pericardial effusions
- myocarditis
- arrhythmias
- arterial and venous thromboses
- increased frequency of ischaemic heart disease and stroke
what are features of kidney involvement in SLE?
- 30% of cases
- glomerulonephritis with persistent proteinuria*
what are features of CNS involvement in SLE?
- 60% of cases
- depression
- epilepsy
- migraines
- cerebellar ataxia
- seizures* (with no causative agent)
- psychosis*
what are features of eye involvement in SLE?
- retinal vasculitis
- episcleritis
- conjunctivitis
- Sjorgren’s (15% of cases)
what are features of GI involvement in SLE?
mouth ulcers* - very common
what are differential diagnoses of SLE?
- acute pericarditis
- antiphospholipid syndrome
- B-cell lymphoma
- fibromyalgia
- scleroderma
- Sjogren’s
what are features of blood in SLE?
- raised ESR
- normal CRP
- may show leucopenia, lymphopenia and/or thrombocytopenia
- anaemia of chronic disease or autoimmune haemolytic anaemia
- urea and creatinine only raised if renal disease is advanced
- autoantibodies
- serum complements C3 and C4 are reduced due to consumption
what are features of autoantibodies in SLE?
- anti-nuclear antibodies (ANA) - 95% positive
- a raised anti-double-stranded DNA (anti-dsDNA) antibody is highly specific for SLE but only positive in 60%
- anti-Ro, anti-Sm and anti-La
- 40% are rheumatoid factor (RhF) positive
what is used to diagnose SLE?
- think SLE if ESR is raised but CRP is normal
- think infection, serositis or arthritis if CRP is raised
- blood
- histology to see deposition of IgG and complement
- MRI and CT for lesions in brain
what is the treatment of acute SLE?
IV cyclophosphamide and high dose prednisolone
what are general treatments of SLE to prevent symptoms?
- reduce sunlight exposure
- reduce CVD risk factors
- prevent rashes with high-factor sunblock
- treat BP and give statins to control CVD risk
what is treatment of symptomatic SLE?
- NSAIDs for arthralgia, fever and arthritis
* oral/IM corticosteroids for severe flares of arthritis, pleuritis and pericarditis
what is pharmacological treatment of SLE?
- topical corticosteroids for rashes
- antimalarial drugs e.g. chloroquine or hydroxychloroquine help mild skin disease, fatigue and arthralgia that cannot be controlled by NSAIDs, but watch for retinal toxicity
- corticosteroids in moderate to severe disease
- immunosuppressives e.g. oral azathioprine, oral methotrexate
what is treatment of severe SLE?
• e.g. renal or cerebral disease and severe haemolytic anaemia or thrombocytopenia
• immunosuppressives e.g. oral aziroprine, oral methotrexate
• high dose oral corticosteroid e.g. prednisolone and oral cyclophosphamide or mycophenolate mofetil (fewer side effects)
• biologicals - target B cells via CD20 on B cells:
- e.g. rituximab (anti-CD20)
what is the definition of antiphospholipid syndrome?
syndrome characterised by thrombosis (arterial or venous) and/or recurrent miscarriages with positive blood tests for antiphospholipid antibodies (aPL)
what is the epidemiology of antiphospholipid syndrome?
- associated with SLE in 20-30% of cases
- more often occurs as a primary disease
- more common in females than males
what is the pathophysiology of antiphospholipid syndrome?
- antiphospholipid antibodies (aPL) play a role in thrombosis by binding to phospholipid on the surface of cells such as endothelial cells, platelets and monocytes
- once bound, this change alters the functioning of those cells leading to thrombosis and/or miscarriage
- antiphospholipid antibodies cause CLOTs
what are CLOTs in relation to antiphospholipid syndrome?
antiphospholipid antibodies cause: • Coagulation defect • Livedo reticularis; lace-like purplish discolouration of skin • Obstetric issues i.e. miscarriage • Thrombocytopenia
what is the clinical presentation of antiphospholipid syndrome?
- thrombosis
- miscarriage
- ischaemic stroke, TIA, MI
- deep vein thrombosis, Budd-chiari syndrome
- thrombocytopenia
- valvular heart disease, migraines, epilepsy
what tests are used to diagnose antiphospholipid syndrome? what do they detect?
- anticardiolipid test: detects IgG or IgM antibodies that bind the negatively charged phospholipid cardiolipin
- lupus anticoagulation test: detects changes in the ability of the blood to clot
- anti-B2-glycoprotein I test: detects antibodies that bind B2-glycoprotein I, a molecule that interacts closely with phospholipids
what is the treatment of antiphospholipid syndrome?
- long term warfarin to minimise thrombosis
- oral aspirin and SC heparin early on in pregnancy; reduces chance of miscarriage but pre-eclampsia and poor fetal growth remain common
- prophylaxis: aspirin or clopidogrel
what is Sjogren’s syndrome?
- chronic autoimmune disease that affects the body’s moisture producing glands
- characterised by immunologically mediated destruction of epithelial exocrine glands, especially the lacrimal and salivary glands
what is the epidemiology of primary Sjogren’s syndrome?
- syndrome of dry eyes (keratoconjunctivitis sicca) in the absence of RA or any other autoimmune diseases
- more common in female than males
- associated with HLA-B8/DR3
- onset in 40s-50s; thus mainly affects middle-aged women
what is the epidemiology of secondary Sjogren’s syndrome?
associated with connective tissue disease e.g. RA, SLE and systemic sclerosis
what is the pathophysiology of Sjogren’s syndrome?
lymphocytic infiltration and fibrosis of exocrine glands, especially the lacrimal and salivary glands
what is the clinical presentation of Sjogren’s syndrome?
- dry eyes (keratoconjunctivitis sicca) due to decrease in tear production
- dry mouth due to decreased saliva production (xerostomia)
- salivary and parotid gland enlargement
- dryness of the skin and vagina
- dryness and fatigue may be the only symptoms
- systemic symptoms in a minority
what are some systemic symptoms that may be seen in Sjogren’s syndrome?
- arthralgia and occasional non-progressive polyarthritis
- Raynaud’s phenomenon
- dysphagia and abnormal oesophageal motility
- other organ specific autoimmune diseases including thyroid disease, myasthenia gravis, primary biliary cirrhosis, autoimmune hepatitis and pancreatitis
- renal tubular defects (uncommon) causing nephrogenic diabetes insipidus and renal tubular acidosis
- pulmonary diffusion defects and fibrosis
- polyneuropathy; fits and depression
- vasculitis
- increased incidence of non-Hodgkin’s B-cell lymphoma
what is used to diagnose Sjogren’s syndrome?
- Schirmer tear test
- Rose-Bengal staining
- lab tests
- salivary gland biopsy shows lymphocytic infiltration
how is Schirmer tear test used to diagnose Sjogren’s syndrome?
strip of filter paper is placed on the inside of the lower eyelid; wetting of <10 mm in 5 mins indicates defective tear production and thus Sjogrens
how is Rose Bengal staining used to diagnose Sjogren’s syndrome?
staining of the eyes shows punctate or filamentary keratitis
what are some laboratory tests used to diagnose Sjogren’s syndrome? what is seen in them?
- raised immunoglobulin levels
- rheumatoid factor is usually positive
- antinuclear antibodies (ANA) usually found in 80%
- anti-Ro (SSA) antibodies are found in 60-90%
what does salivary gland biopsy show in Sjogren’s syndrome?
lymphocytic infiltration
what is treatment of Sjogren’s syndrome?
- artificial tears and saliva replacement
- NSAIDs and hydroxychloroquine for fatigue and arthralgia
- corticosteroids are rarely needed, used to treat persistent salivary gland swelling or neuropathy
what is systemic sclerosis?
- autoimmune rheumatic disease characterised by excessive production and accumulation of collagen in the skin and internal organs
- multisystem disease with involvement of skin and Raynauds phenomenon
- distinct from localised scleroderma such as morphea, that do not involve internal organ disease and are rarely associated with vasospasm
what is the epidemiology of systemic sclerosis?
- has the highest case-specific mortality of any autoimmune rheumatic disease
- occurs worldwide
- more common in females than males
- peak incidence is between 30 and 50 years of age
- rare in children
what are risk factors and aetiology of systemic sclerosis?
- exposure to vinyl chloride, silica dust, adulterated rapeseed oil and trichloroethylene
- drugs such as bleomycin
- genetic
what is the pathophysiology of systemic sclerosis?
- widespread vascular damage involving small arteries, arterioles and capillaries is an early feature
- there is initial endothelial cell damage with release of cytokines, including endothelin-1, causing vasoconstriction
- continued vascular damage and increased vascular permeability and activation of endothelial cells
- production of cytokines and growth factors mediate the proliferation and activation of vascular and connective tissue cells
- fibroblasts activated by mediators (IL-1, -4, -6 and -8, TGF-B and PDGF synthesise) increase collagen type 1 and 2, producing fibrosis in the lower dermis of the skin and internal organs
- the end result is uncontrolled and irreversible proliferation of connective tissue and thickening of vascular walls with narrowing of the lumen
- damage to small blood vessels produces widespread obliterative arterial lesions and subsequent chronic ischaemia
what does continued vascular damage and increased vascular permeability and the activation of endothelial cells in systemic sclerosis lead to?
- upregulation of adhesion molecules - E-selectin, VCAM and intracellular adhesion molecule 1 (ICAM-1)
- cell adhesion - T and B cells, monocytes and neutrophils
- migration of cells through leaky endothelium and into the extracellular space
what is the clinical presentation of systemic sclerosis?
- Raynaud’s phenomenon is seen in almost 100% of cases and can precede the onset of the full-blown disease by many years
- limited cutaneous scleroderma (LcSSc)/crest syndrome; 70% of cases
- diffuse cutaneous scleroderma (DcSSc); 30% of cases
what is the clinical presentation of limited cutaneous scleroderma (LcSSc)?
- starts with Raynaud’s phenomenon many years (up to 15) before any skin changes
- skin involvement is limited to the hands, face, feet and forearms
- skin is tight over the fingers and often produces flexion deformities of the fingers
- face and skin involvement produces characteristic ‘beak’-like nose and a small mouth (microstomia)
- painful digital ulcers and telangiectasia
- GI tract involvement is common; oesophageal dysmotility or strictures
what is CREST in relation to limited cutaneous scleroderma (LcSSc)?
previously known as CREST syndrome:
- Calcinosis; calcium deposition in subcutaneous tissue
- Raynauds
- Eosophageal dysmotility or strictures
- Sclerodactyly - local thickening/tightness of skin on fingers/toes
- Telenagiectasia
what is diffuse cutaneous scleroderma (DcSSc)? how are other organs involved?
• skin changes develop more rapidly and are more widespread than in limited cutaneous scleroderma/CREST
• there is early involvement of other organs:
- GI involvement with dilation and atony in:
• oesophagus, resulting in heartburn and dysphagia
• small intestine, resulting in bacterial overgrowth and
malabsorption
• colon, resulting in pseudo-obstruction
- renal involvement:
• acute and chronic kidney disease
• acute hypertensive crisis is a complication of the renal
involvement
- lung disease:
• fibrosis and pulmonary vascular disease resulting in
pulmonary hypertension
- myocardial fibrosis leads to arrhythmias and conduction disturbances
how are bloods used to diagnose systemic sclerosis?
- normochromic, normocytic anaemia
- microangiopathic haemolytic anaemia is seen in some people with renal disease
- urea and creatine rise in acute kidney injury
what types of autoantibodies are seen in systemic sclerosis?
- limited cutaneous scleroderma/CREST: speckled, nucleolar or anti-centromere antibodies (ACAs) - 70% cases
- diffuse cutaneous scleroderma:
• anti-topoisomerase-1 antibodies (anti-Scl-70) - 30% of cases
• anti-RNA polymerase - 20-25% of cases - rheumatoid factor is positive in 30%
- anti-nuclear antibodies (ANA) is positive in 95%
how is imaging used to diagnose systemic sclerosis?
- CXR: to exclude other pathology, for changes in cardiac size and established lung disease
- hand X-ray: to see deposits of calcium around the fingers
- barium swallow: confirms impaired oesophageal motility
- high resolution CT: to confirm fibrotic lung involvement
what is the treatment of systemic sclerosis and its clinical presentations?
- no cure
- Raynaud’s: hand warmers, oral vasodilators (calcium channel blocker and endothelin receptor antagonists)
- oesophageal involvement (PPI)
- nutritional supplementation to treat malabsorption
- prevention of renal crisis (ACE inhibitor)
- early detection of pulmonary hypertension with annual echos and pulmonary function tests
- pulmonary fibrosis: immunosuppresant and oral prednisolone
what is polymyositis/dermatomyositis?
- type of chronic inflammation of the muscles related to dermatomyositis and inclusion body myositis
- unknown aetiology where there is inflammation and necrosis of skeletal muscle fibres
- when skin is involved it is called dermatomyositis
- lungs can be affected, resulting in interstitial lung disease
what is the epidemiology of polymyositis/dermatomyositis?
- very rare
- both affect adults and children
- more common in females than males
what are risk factors and aetiology of polymyositis/dermatomyositis?
- viruses implicated are coxsackie, rubella and influenza
- genetic predisposition; those with HLA-B8/DR3 (Sjogrens) appear to be at higher risk
what is the clinical presentation of polymyositis?
- there is symmetrical progressive muscle weakness and wasting affecting the proximal muscles of the shoulder and pelvic girdle
- patients have difficulty squatting, going upstairs, rising from a chair and raising their hands above their head
- pain and tenderness are uncommon
- involvement of pharyngeal, laryngeal and respiratory muscles can lead to dysphagia, dysphonia and respiratory failure
what is the clinical presentation of dermatomyositis?
- characteristic skin changes; heliotrope (purple) discolouration of the eyelids and scaly erythematous plaques over the knuckles (Gottron’s papules)
- arthralgia, dysphagia resulting from oesophageal muscle involvement and Raynauds phenomenon
- increased incidence of underlying malignancy
what is used to diagnose polymyositis/dermatomyositis?
- muscle biopsy
- muscle enzymes
- ESR usually not raised
- serum antibodies
- electromyography (EMG) used to detect typical muscle changes
- MRI can detect abnormally inflamed muscles
what is seen on a muscle biopsy in polymyositis/dermatomyositis?
shows fibre necrosis and inflammatory cell infiltrates; confirms diagnosis
what is seen in muscle enzymes in polymyositis/dermatomyositis?
serum creatine kinase, aminotransferases, lactate dehydrogenase (LDH) and aldolase are all raised
what serum antibodies are seen in polymyositis/dermatomyositis?
- antinuclear antibody (ANA) positive in dermatomyositis
- rheumatoid factor positive in 50%
- myositis-specific antibodies (MSAs)
what is the treatment of polymyositis/dermatomyositis?
- bed rest may be helpful but must be combined with exercise
- oral prednisolone is main treatment and is continued until at least 1 month after the myositis has become clinically and enzymatically inactive, then tapered down slowly
- hydroxychloroquine or topical tacrolimus may help with skin disease
what is done in early intervention in polymyositis/dermatomyositis?
early intervention with steroid sparing immunosuppressive therapy is useful in relapse:
• oral azathioprine
• oral methotrexate
• oral ciclosporin
what is Raynaud’s phenomenon?
- intermittent spasm in the arteries supplying the fingers and toes leading to episodes of reduced blood flow, usually precipitated by cold and relieved by heat
- if there is no underlying cause it is known as Raynaud’s disease
- if there is an underlying cause it is known as Raynaud’s phenomenon
what is the epidemiology of Raynaud’s phenomenon?
- affects 5% of the population
- more common in females than males
what is the pathophysiology of Raynaud’s phenomenon?
- peripheral digit ischaemia due to sudden vasospasm, precipitated by cold or emotion and relieved by heat
- usually bilateral and fingers are affected more commonly than toes
what is the clinical presentation of Raynaud’s phenomenon?
- vasoconstriction (causing ischaemia) causes skin pallor followed by cyanosis due to sluggish blood flow, then redness due to hyperaemia
- white, blue then red
- duration of the attacks is variable but they can sometimes last for hours
- numbness, a burning sensation and severe pain occur as the fingers warm up
- in chronic disease, infarction and digital loss can occur
- smoking can aggravate symptoms
what are conditions in which Raynaud’s phenomenon may be exhibited?
- connective tissue disorders: SLE, systemic sclerosis, rheumatoid arthritis, dermatomyositis/polymyositis
- occupational: using vibrational tools
- drugs: beta-blockers and smoking
what is the treatment of Raynaud’s phenomenon?
- avoid cold by wearing gloves and warm clothes
- stop smoking and beta-blockers
- vasodilators:
• oral nifedipine
• might be unacceptable as cerebral vasodilation causes severe headaches
what is seronegative spondyloarthropathy?
- group of diseases involving the axial skeleton and having a negative serostatus
- seronegative: diseases are negative for rheumatoid factor, indicating different pathophysiology from RA
what are the shared clinical features of conditions in seronegative spondyloarthropathy?
- axial inflammation; spine and sacroiliac joints
- asymmetrical peripheral arthritis
- absence of rheumatoid factor hence ‘seronegative’
- strong association with HLA-B27, but aetiological relevance is unclear
what are the conditions in the group of seronegative spondyloarthropathy?
- axial spondyloarthritis
- reactive arthritis
- enteropathic arthropathy or spondylitis association with IBD
- psoriatic arthritis
- isolated acute anterior uveitis
- juvenile idiopathic arthritis
- undifferentiated spondyloarthropathy
what is HLA-B27? where is it located?
- Human Leucocyte Antigen (HLA) B27
- class I surface antigen; present on all cells, except RBCs, and presents antigenic peptides (from self and non-self antigens) to T cells
- encoded by B locus of Major Histocompatibility Complex (MHC) on chromosome 6
what is PAIR in relation to HLA-B27?
diseases associatied with the HLA-B27 subtype:
- Psoriasis
- Ankylosing spondylitis
- IBD
- Reactive arthritis
why is HLA-B27 linked with disease?
main theory is ‘molecular mimicry’ whereby an infection triggers an immune response and the infectious agent has peptides very similar to the HLA-B27 molecules so there is an auto-immune response triggered against HLA-B27
what is SPINEACHE in relation to seronegative spondyloarthropathies?
think seronegative spondyloarthropathies (SpA) if SPINEACHE:
- Sausage digit (dactylitis)
- Psoriasis
- Inflammatory back pain
- NSAIDs good response
- Enthesitis (particularly in heel - planter fasciitis)
- Arthritis
- Crohn’s/Colitis/elevated CRP (can be normal in AS)
- HLA-B27
- Eye (uveitis)
what is ankylosing spondylitis?
type of arthritis in which there is a long-term inflammation of joints of the spine, ribs and sacroiliac joints
what is ankylosis?
abnormal stiffening and immobility of joint due to new bone formation
what is the epidemiology of ankylosing spondylitis?
- more common and more severe in males than females
- usually presents at 16 yrs; young adults <30yrs
- 88% are HLA-B27 positive
- women present later and are under-diagnosed
- low incidence in African and Japanese people
- native North Americans have high incidence
what are risk factors and aetiology for ankylosing spondylitis?
- HLA-B27
- environment: Klebsiella, Salmonella, Shigella
what is the pathophysiology of ankylosing spondylitis?
lymphocyte and plasma infiltration occurs with local
erosion of bone at the attachments of the intervertebral and other ligaments (enthesitis; inflammation where tendons/ligaments insert into bone), which heals with syndesmophyte formation
- normal spine
- inflammation (erosion, sclerosis and squaring)
- formation of syndesmophytes
- fusion (total bony bridge)
what is a syndesmophyte?
- bony growth originating inside a ligament, commonly seen in the ligaments of the spine, specifically the ligaments in the intervertebral joints leading to fusion of vertebrae
- new bone formation and vertical growth from anterior vertebral corners
what is the clinical presentation of ankylosing spondylitis?
- typical patient is a man <30 yrs with gradual onset of low back pain, worse at night, with spinal morning stiffness that is relieved by exercise
- episodic inflammation of the sacroiliac joints in the late teenage years or early twenties is the first manifestation; if severe then bamboo spine may be present
- pain radiates from the sacroiliac joints to hips/buttocks, and usually improves towards the end of the day
- progressive loss of spinal movement resulting in reduced thoracic expansion
- asymmetrical joint pain, normally oligoarthritis (1 or 2 joints), unlike RA which is symmetrical and affects smaller joints and more joints
- two characteristic spinal abnormalities
- enthesitis
- non-articular features
