Rheumatoid arthritis

Question 1

At present, what percentage of RA sufferers are not working at 10 years?

Answer 1

50% due to functional impairment

Question 2

Describe the pathological changes in RA, particularly noting the earliest changes.

What process seems to drive everything?

Answer 2

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

Question 3

What is meant by the word pannus?

Answer 3

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

Question 4

What is the major cell seen in joint fluid in RA?

Answer 4

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)

Question 5

Which T helper cell is traditionally thought to be responsible for RA?

Which is the newer cell that’s become implied

Answer 5

RA traditionally Th1 disease

New theory surrounds Th17 which has proinflammatory effects and induces osteoclastogenesis and stimulates fibroblast synoviocytes

Question 6

In RA, what cytokine controls the erosive bone disease?

Answer 6

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

Question 7

what is the shared epitope hypothesis of RA?

Answer 7

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

Question 8

Are there any environmental factors in RA?

Answer 8

Cigarette smoking increases risk of disease and seems to decrease respone to DMARDs

this is particularly true of patients with the “shared epitope”

Question 9

Any special genes associated with RA in caucasians?

asians?

LOW YIELD SLIDE, I THINK

Answer 9

shared epitope is number one for everything

number 2 for caucasians is PTPN 22

number 2 for asians is PADI4

Question 10

How does one diagnose Rheumatoid Arthritis?

Answer 10

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.

Question 11

How specific is rheumatoid factor?

Answer 11

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.

Question 12

What is anti-CCP?

Answer 12

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.

Question 13

What are xray findings of RA?

Answer 13

periarticular soft tissue swelling
juxta articular osteopenia
marginal erosions (where the synovium abuts the bone)
joint space narrowing
typically symmetric involvement

Question 14

what is palindromic rheumatism?

Answer 14

It is RF + disease that occurs in reasonably sudden onset condition, that then remits in 3-4 days, almost like a gout attack.

Question 15

What happens to the cervical spine in rheumatoid arthritis?

Answer 15

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

Question 16

What are the lung complications of RA?

Answer 16

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

Question 17

Cardiac comp of RA?

Answer 17

Pericarditis is most common
can get myocarditis

can rarely get conduction defects

significant risk factor for IHD - probably through the persistent inflammatory state

Question 18

Renal disease in RA?

Answer 18

not that common

can get a mesangial proliferation

more common to get renal disease from the drugs (particularly NSAIDs)

Question 19

Eye disease in RA?

Answer 19

episcleritis
scleritis
sicca syndrome

drug effects - steroids and anti-malarials

Question 20

neuromuscular disease in RA?

Answer 20

entrapment neuropathies are particularly present - carpal tunnel, but also radial palsy (look at elbow)

mononeuritis multiplex is a concern in RA

disuse muscle atrophy

Question 21

What could be some reason that RA sufferer might not be able to extend fingers?

Answer 21

Weak finger extension is a common problem

causes:
tendon subluxation
tendon rupture
posterior interosseous nerve entrapment
entrapment of radial nerve at distal ulnar

Question 22

What is Felty’s syndrome?

Answer 22

seropositive RA, neutropenia and splenomegaly

Question 23

what happens to RA in pregnancy?

Answer 23

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

Question 24

any idea about management of MTX dosing for RA patients around surgery?

what about leflunomide?

what about biologics?

Answer 24

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

Question 25

What is the initial treatment of a patient diagnosed with RA?

Answer 25

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

Question 26

What is the usual first line DMARD for RA management?

Answer 26

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

Question 27

How does MTX work?

Answer 27

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.

Question 28

How does leflunomide work?

SE?

Answer 28

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

Question 29

What are the usual responses of Anti-TNF agents?

Answer 29

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

Question 30

Give me a list of the biologics used in RA.

Answer 30

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

Question 31

With anti-TNF agents, are patients able to continue with normal immunisation schedules, or are there some things you should drop?

Answer 31

Live vaccines should be dropped.

patients should have influenza, pneumococcus and varicella

Question 32

Which malignancies are increased with anti-TNF agents?

Answer 32

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)

Question 33

Are there any neurological conditions that would contraindicate anti-TNF agents?

Answer 33

A history of multiple sclerosis or optic neuropathy is a contraindication. this is a class effect

Question 34

Is there any heart condition where anti-TNF are relatively contraindic?

Answer 34

In heart failure, classes III or IV - infliximab seems to increase risk of HF and death

Question 35

What are the disease activity scores used in RA?

Answer 35

DAS 28 = disease activity score 28 - aim 3 - 3.5

SDAI = simplified disease activity index

RAPID = routine assessment of patient index data

Question 36

What is the usual introduction of DMARDs?

Answer 36

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

Question 37

If you have a patient with methotrexate related bone marrow suppression, how do you help the patient? (aside from supportive measures)

Answer 37

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.

Question 38

What factor is most predictive of erosions in a patient with rheumatoid arthritis?

Answer 38

CRP is the business!

study done some years ago showed only that CRP is predictive

Question 39

What is a big dose of methotrexate?

What happens if patients aren’t responding to this?

Answer 39

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

Question 40

What is the joint disease most suggestive of haemochromatosis?

Answer 40

2nd and 3rd MCP joint osteoarthritis. (so look for bony enlargement of these joints)

However, it’s probably most common in the ankle!

Question 41

In RA, which clinical feature is most strongly correlated with risk of future joint erosions?

Answer 41

joint swelling is the business

Question 42

what is the “chemo-attractant” in rheumatoid arthritis synovial fluid?

Answer 42

complement C5a is apparently the thing.

this exam is bullshit