Rheumatoid arthritis Flashcards
At present, what percentage of RA sufferers are not working at 10 years?
50% due to functional impairment
Describe the pathological changes in RA, particularly noting the earliest changes.
What process seems to drive everything?
The earliest changes are in blood vessels with proliferation, high endothelial venule formation and upregulation of leucocyte adhesion molecules
The synovium is the bad business, with hyperplasia and a subsynovial infiltrate with LL and plasma cells.
The LL are usually CD4/CD45 (Th and Tmemory subsets)
Overall, this probably means T cell driven response
What is meant by the word pannus?
This is the inflammatory focus that destroys the synovium and cartilage.
The proliferative part is made up of type A and B synoviocytes. The type B also transforms and actually proliferates a lot (tumour like!)
This type B synoviocyte then invades the cartilage and releases metalloproteinases and also causes activation of osteoclasts.
The chewed-up (non-medical term) synovium is replaced by granulation tissue - this interferes with nutrient supply. Further exacerbating synovial loss
What is the major cell seen in joint fluid in RA?
The predominant cell type is PMN, which is NOT the same as pannus (which is LL predominant)
fluid contains evidence of ROS and immune complexes etc
so, whilst there are lots of signs of inflammation - AND THE FLUID IS PROBABLY RESPONSIBLE FOR THE ACUTE SIGNS OF INFLAMMATION SEEN ON EXAM - this is probably not the major player in joint destruction (see card on pannus)
Which T helper cell is traditionally thought to be responsible for RA?
Which is the newer cell that’s become implied
RA traditionally Th1 disease
New theory surrounds Th17 which has proinflammatory effects and induces osteoclastogenesis and stimulates fibroblast synoviocytes
In RA, what cytokine controls the erosive bone disease?
probably RANK-L via osteoclasts
recall:
RANK is the receptor on osteoclasts. RANK-L binds to ACTIVATE osteoclasts
OPD attaches to RANK and stops osteoclast activation. It is also known as osteoclastogenesis inhibitory factor
what is the shared epitope hypothesis of RA?
There is a shared common epitope in third hypervariable region ofhte DR B1 chain. This is the shared epitope.
Is is suggested that this area is involved in critical immune recognition events and influences susceptibility
it is associated with anti-CCP
Are there any environmental factors in RA?
Cigarette smoking increases risk of disease and seems to decrease respone to DMARDs
this is particularly true of patients with the “shared epitope”
Any special genes associated with RA in caucasians?
asians?
LOW YIELD SLIDE, I THINK
shared epitope is number one for everything
number 2 for caucasians is PTPN 22
number 2 for asians is PADI4
How does one diagnose Rheumatoid Arthritis?
We used to use the ACR criteria, but these have been superseded as we move towards earlier treatment.
It used to be about early morning stiffness of > 1 hour; soft tissue swelling of 3 or more joints; arthritis of finger IP, MCP or wrists; symmetrical arth; nodules; pos RF; radiographic erosions in hand or wrist
The new criteria is an elaborate scoring system (2010 ACR)
points for joint involvement, points for serology, points for CRP, points for duration of symptoms
To be classified as RA should be 6 or higher.
How specific is rheumatoid factor?
It is unfortunately associated with everything including being old.
It can be found in 6% - 8% of normal population!
It is an IgM against IgG’s Fc portion.
What is anti-CCP?
it seems to target everything in joints such as fibrinogen, filaggrin, collagen type II and vimentin
as sensitive, but more specific than RF for RA.
it also predicts erosive disease, extra-articular disease and cardiac risk and mortality.
What are xray findings of RA?
periarticular soft tissue swelling juxta articular osteopenia marginal erosions (where the synovium abuts the bone) joint space narrowing typically symmetric involvement
what is palindromic rheumatism?
It is RF + disease that occurs in reasonably sudden onset condition, that then remits in 3-4 days, almost like a gout attack.
What happens to the cervical spine in rheumatoid arthritis?
In about 20% of RA patients, there is involvement of the cervical spine.
It impacts the atlanto-axial with subluxation; it can cause damage to the C spine below the axial with multiple level involvement; can even lead to invagination of the basilar region
What are the lung complications of RA?
pleural disease - effusions particularly
interstitial lung disease - have a think - upper or lower zone fibrosis?
nodular lung disease (rheum nodules in the lung fields?)
BOOP
drugs can cause lung disease - MTX, leflunomide
Cardiac comp of RA?
Pericarditis is most common
can get myocarditis
can rarely get conduction defects
significant risk factor for IHD - probably through the persistent inflammatory state
Renal disease in RA?
not that common
can get a mesangial proliferation
more common to get renal disease from the drugs (particularly NSAIDs)
Eye disease in RA?
episcleritis
scleritis
sicca syndrome
drug effects - steroids and anti-malarials
neuromuscular disease in RA?
entrapment neuropathies are particularly present - carpal tunnel, but also radial palsy (look at elbow)
mononeuritis multiplex is a concern in RA
disuse muscle atrophy
What could be some reason that RA sufferer might not be able to extend fingers?
Weak finger extension is a common problem
causes: tendon subluxation tendon rupture posterior interosseous nerve entrapment entrapment of radial nerve at distal ulnar
What is Felty’s syndrome?
seropositive RA, neutropenia and splenomegaly
what happens to RA in pregnancy?
usually the disease improves in 75% of cases, usually within the 2nd trimester
we have treatment options - NSAIDs until trimester 3
sulfasalazine safe in preg and breast feeding
Azathioprine safe in preg but not breast feeding
any idea about management of MTX dosing for RA patients around surgery?
what about leflunomide?
what about biologics?
The evidence is actually that it’s prob best to continue MTX during surgery. The classical teaching was the opposite of this.
it is safe to stop though, if you have a stubborn surgeon.
leflunomide, however, seems to impair healing and increases infection risk.
Biologics don’t yet have rigorous evidence, but most recommend withholding a cycle
What is the initial treatment of a patient diagnosed with RA?
Typically NSAIDs are used for symptom control
Steroids are initially used to control disease, and have been shown to decrease erosive disease. They are typically used to control inflammation whilst waiting for biologics to start up
What is the usual first line DMARD for RA management?
Methotrexate is “best” based on evidence available.
usually given weekly, and with folic acid on other days of week
toxicity includes marrow suppression (more important with repeated dosing for RA than for high dose chemotherapy); hepatotoxicity (possible with either type of dosing); small risk of drug-induced pneumonitis and cirrhosis.
renal impairment is less common with low, repeated dosing
How does MTX work?
In cancer: MTX is an anti-folate drug. It competitively inhibits dihydrofolate reductase, leading to decreased production of Thymine (the T of ACGT used in DNA). Folate is also essential for all purine and pyrimidine biosynthesis
In RA: inhibition of DHFR is not the primary mech
it is due to direct inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine;
inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells;
increasing CD95 sensitivity of activated T cells; inhibition of methyltransferase activity, leading to (de)-activation of enzyme activity relevant to immune system function.
How does leflunomide work?
SE?
it has a similar efficacy to MTX, but more SE
it has an active metabolite that binds to dihydro-orotate dehydrogenase and then blocks T-LL prolif by inhibiting de novo pyrimidine synthesis (recall that MTX in cancer blocks thymine synth (one of the pyrimidine)
diarrhoea most common
pneumonitis is rare
infection risk is more than MTX and need to monitor closely
if given with MTX, need to monitor LFT and lungs
What are the usual responses of Anti-TNF agents?
Efficacy improvement runs as follows: 60, 40, 20
60% get an improvement of ACR 20 (not much)
40% get ACR 50 (substantial) and 20% get ACT 70 (amazing disease improvement)
Also better if taking MTX too
This 60/40/20 response also occurs with B cell depleters and Tocilizumab
Give me a list of the biologics used in RA.
firstly, the older agents are the anti-TNF
- etanercept
- infliximab
- adalimumab
Then there are the B cell depletion
- rituximab (only available on PBS with failed antiTNF)
newer agent is Tocilizumab which is anti-IL6
With anti-TNF agents, are patients able to continue with normal immunisation schedules, or are there some things you should drop?
Live vaccines should be dropped.
patients should have influenza, pneumococcus and varicella
Which malignancies are increased with anti-TNF agents?
There does not seem to be any increase with exception of non-melanomatous skin malignancies.
(there MAY be emerging evidence that melanomatous is also increased, but equivocal at present)
Are there any neurological conditions that would contraindicate anti-TNF agents?
A history of multiple sclerosis or optic neuropathy is a contraindication. this is a class effect
Is there any heart condition where anti-TNF are relatively contraindic?
In heart failure, classes III or IV - infliximab seems to increase risk of HF and death
What are the disease activity scores used in RA?
DAS 28 = disease activity score 28 - aim 3 - 3.5
SDAI = simplified disease activity index
RAPID = routine assessment of patient index data
What is the usual introduction of DMARDs?
this is an evolving area, but it seems that mostly we start with MTX monotherapy
combination therapy is used for severe disease initially, or when MTX gives poor response
usually a step up:
- MTX + sulfasalazine + plaquenil (steroids until drug starts up)
- MTX + cyclosporin
- MTX + plaquenil and steroid
Finally, anti-TNF added to MTX
If you have a patient with methotrexate related bone marrow suppression, how do you help the patient? (aside from supportive measures)
If you give the patient folic acid, and they have recently had methotrexate, then the DHFT is still inhibited, so giving folic acid won’t do anything
Instead you have to use folinic acid, which is also known as leucovorin. This is the activated stuff necessary for pyrimidine synth.
What factor is most predictive of erosions in a patient with rheumatoid arthritis?
CRP is the business!
study done some years ago showed only that CRP is predictive
What is a big dose of methotrexate?
What happens if patients aren’t responding to this?
We go as high as 30mg. So, make sure you read the question - if someone’s on a low dose and crap response, we should probs increase the dose.
At higher doses, methotrexate sometimes isn’t well absorbed. The recommendation is to trial sub/cut if oral not working
What is the joint disease most suggestive of haemochromatosis?
2nd and 3rd MCP joint osteoarthritis. (so look for bony enlargement of these joints)
However, it’s probably most common in the ankle!
In RA, which clinical feature is most strongly correlated with risk of future joint erosions?
joint swelling is the business
what is the “chemo-attractant” in rheumatoid arthritis synovial fluid?
complement C5a is apparently the thing.
this exam is bullshit
