Immunosuppressants and DMARDs

Question 1

Pathogenesis of RA

Answer 1

Proliferation of synovium into a PANNUS. This then leads to gross deformation of bone and cartilage. RA is effectively an imbalance between pro inflammatory factors (such as IL1, IL6 and TNF-alpha) and inflammatory factors (such as IL4 and TGF-Beta).

Question 2

RA Diagnostic Criteria

Answer 2

Clinical: Morning stiffness lasting for >1hr? Signs in >3 joints? Small joints preferentially attacked? Rheumatoid nodules? Symmetry (same joint affected on both sides of body)? Raised RF or Anti-CCP? X-Ray changes should never be seen in 21st Century!

Question 3

Goals of RA Treatment

Answer 3

• Relieving symptoms.

- Preventing progression to joint destruction, deformity and the resulting disability.

Question 4

Why should DMARDs be used in RA?

Answer 4

Early use is the best way to prevent progression.

They have steroid sparing properties, meaning we can avoid systemic steroids and all of their adverse effects.

Question 5

Why should DMARDs be used in Lupus/Vasculitis?

Answer 5

Reducing mortality by preventing organ damage. Relieving symptoms.

Question 6

MOA of Steroids

Answer 6

• Prevent IL-1 and IL-6 production by macrophages.

- Prevent T-cell activation at all stages.

Question 7

Adverse effects of steroids…

Answer 7

We an think of them as accelerated processes of ageing.

• Hyperglycaemia
• Trunkal obesity
• Glaucoma
• Hypertension
• Irregular menstrual cycle
• Impaired healing.
• Growth limitation in children.

Question 8

Indications for Azathioprine?

Answer 8

Maintenance in SLE and Vasculitis.

Inflammatory Bowel Disease.

Question 9

How is Azathioprine metabolised?

Answer 9

1) It is cleaved to 6-MP.
2) This goes on to become one of three molecules, one of these TIMP itself has metabolites that decrease DNA and RNA synthesis. This inhibits the rapid multiplication in immune cells that is seen in cases of autoimmunity.

Question 10

In Azathioprine therapy, polymorphisms in what gene must be checked for and how does hypofunction here put a patient at risk?

Answer 10

6-MP is metabolised by TPMT (Thiopurine Methyltransferase). Low levels of this enzyme mean that active 6-MP can build up causing MYELOSUPRESSION.

Question 11

How can we detect myelosuppression?

Answer 11

FBC to monitor white cells. Investigate signs of infections thoroughly as pts on immunosuppressants are at a greater risk than the general population.

Question 12

Give two other adverse effects of Azathioprine…

Answer 12

• Hepatitis - monitor LFT’s for this.

- Increased risk of malignancy.

Question 13

Name the two common Calcineurin Inhibitors

Answer 13

• Ciclosporin

- Tacrolimus

Question 14

Some common uses of Calcineurin inhibitors…

Answer 14

• Atopic Dermatitis.
• Psoriasis
• Solid organ transplant recipients.

Question 15

What are some adverse effects of the Calcineurin inhibitors?

Answer 15

• They are nephrotoxic so we need to assess kidney function regularly.
• They are CYP inhibitors so they have effects on other drug levels. Inhibit CYP 3A4.

Question 16

What part of the immune system do calcineurin inhibitors act on?

Answer 16

Inhibit the calcineurin pathway in T-helper cells preventing IL-2 production. This acts to suppress T cell reactions. These cell mediated reactions are central to transplant rejection.

Question 17

Name some uses of Mycophenolate Mofetil

Answer 17

• Preventing organ rejection in transplant.
• Induction and maintenance therapy in Lupus Nephritis.
• Maintenance therapy in Vasculitis.

Question 18

In transplantation medicine, which parameter (relating to Mycophenolate) may be monitored.

Answer 18

Mycophenolic Acid - Mycophenolate Mofetil is the pro-drug to this.

Question 19

How does Mycophenolate work?

Answer 19

It inhibits an enzyme required for guanosine synthesis, impairing B and T cell proliferation. The effect of this is more controlled than steroids as other (non pathological) rapidly dividing cells have guanosine salvage mechanisms.

Question 20

Adverse effects of Mycophenolate…

Answer 20

N, V and D. Myelosuppression and mouth ulcers.

Question 21

MOA of Cyclophosphamide…

Answer 21

It is an alkylating agent so it forms cross links both within and between DNA strands so they cannot replicate, suppressing T and B call activity.

Question 22

Uses of Cyclophosphamide…

Answer 22

A classical induction therapy. Used to treat lupus nephritis, and ANCA Vasculitis. Remember, this is a chemotherapy agent so has its uses in haem-onc.

Question 23

Metabolism of cyclophosphamide…

Answer 23

Prodrug, metabolised in the liver into active 4-hydroxycyclophosphamide. It goes through several metabolites before forming its main active metabolite, PHOSPHORAMIDE MUSTARD.

Question 24

Main risk of Cyclophosphamide.

Answer 24

It is excreted by the kidney. One of its metabolites (Acrolein) is toxic to bladder epithelium –> haemorrhagic cystitis. This can be prevented by combining agressive hydration and MESNA which mops up the acrolein.

Question 25

Long term risks of Cyclophosphamide…

Answer 25

Increases the risk of bladder cancer, leukaemia and lymphoma.
Can cause infertility with increasing cumulative dose and patient age.
Can, of course, myelosuppress.

Question 26

Mycophenolate vs Cyclophosphamide in Lupus Nephritis

Answer 26

Mycophenolate safer, no less effective.

Question 27

Methotrexate

Answer 27

Developed as an anti-cancer agent. Now the treatment of choice in RA. Some use in Crohn’s and psoriasis.

Question 28

MOA of Methotrexate

Answer 28

Commonly known as a dihydrofolate reductase inhibitor which is how it exerts its anti-cancer effects but its DMARD effects are via a different pathway, the AICAR pathway, PREVENTING THE ACCUMULATION OF ADENOSINE.

Question 29

Dosing of Methotrexate.

Answer 29

Given weekly not daily. Oral bioavaliability of c. 1/3. It is higher if given s/c or i/m. Convert to s/c injection if patient experiencing nausea or has only limited response to oral drug.

Question 30

DDI’s with Methotrexate

Answer 30

It is 50% protein bound so NSAID’s displace it. It is excreted by the kidneys.

Question 31

Bridging treatment in RA while Methotrexate starts to work…

Answer 31

Steroids. These can be tapered when methotrexate starts to work, can be used in primary care to manage an acute flare up.

Question 32

Adverse effects of Methotrexate

Answer 32

Mucositis and myelosuppression can be both managed by giving folinic acid.
Can also cause hepatitis, cirrhosis and pneumonitis.
Highly teratogenic and ABORTIFACIENT; this explains how it can be used to medically manage ectopic pregnancy.

Question 33

Sulfasalazine / 5-Aminosalicylic acid effects on B and T cells.

Answer 33

T cells: inhibits proliferation and IL2 production as well as (possibly) stimulating T cell apoptosis.
Neutrophils: it reduces chemotaxis and degranulation.

Question 34

Absorption characteristics of Sulfasalazine and how this influences its uses.

Answer 34

Poorly absorbed but is primarily active in the intestines, making it useful in managing inflammatory bowel diseases.

Question 35

Sulfasalazine adverse effects

Answer 35

• Myelosupression
• Hepatitis
• Rash

Milder side effects include abdominal pain, N+V.

Question 36

Advantages of Sulfasalazine

Answer 36

Few interactions
Long term blood monitoring often not needed.
Safe in pregnancy
No carcinogenic potential.

Question 37

Biologics of choice in RA

Answer 37

TNF - alpha blockers. ADALIMUMAB AND INFLIXIMAB.

Question 38

How does TNF-alpha blockade help in RA?

Answer 38

Decreases inflammation and thus the recruitment of leukocytes to a joint.
Angiogenesis and VEGF levels are decreased.
Lower levels of matrix metalloproteases and other destructive enzymes.

Question 39

Main infective risk of TNF-alpha blockade?

Answer 39

Reactivation of Latent TB infection as TNF plays a large role in walling TB mycobacteria off in granulomas. IGRA testing is needed before starting a patient on adalimumab or infliximab.

Question 40

Rituximab

Answer 40

An Anti-CD2- mAb used a lot in B cell lymphomas. Also has a use in RA as B cells produce cytokines, antibodies and present antigens to T cells.