Immunosuppression Flashcards by Liam Sanders

What are the goals of RA treatment?

Symptomatic relief

Prevention of further joint destruction

How well did you know this?

Not at all

Perfectly

Describe the strategy for RA treatment.

Early use of disease modifying drugs
Good disease control
Drug combinations
Use of adequate dosage
Avoidance of long-term corticosteroids

How well did you know this?

Not at all

Perfectly

What are the treatment goals of Systemic Lupus Erythematosus and Vasculitis?

Symptom relief
Decreased mortality
Prevention of organ damage
Decreased long-term morbidity

How well did you know this?

Not at all

Perfectly

Name the 4 main types of immunosuppressant drugs

Corticosteroids
Azathioprine
Calcineurin Inhibitors
Mycophenolate Mofetil

How well did you know this?

Not at all

Perfectly

Describe the action of corticosteroids

Prevention of IL-1,6 production by macrophages

Inhibition of all stages of T cell activation

How well did you know this?

Not at all

Perfectly

Discuss the ADRs of corticosteroids

Weight gain
Fat redistribution 
Osteoporosis
Glucose intolerance
Increased infection risk
Cataracts
Glaucoma

How well did you know this?

Not at all

Perfectly

Describe the mechanism of action of azathioprine

Cleaved to 6-MP

Anti-metabolite to decrease DNA and RNA synthesis

How well did you know this?

Not at all

Perfectly

What are the uses of azothioprine?

Maintenance therapy in SLE and Vasculitis
IBD
Bullous Skin Disease
Atopic Dermatitis - steroid sparing

How well did you know this?

Not at all

Perfectly

Describe the pharmacology of Azathioprine

6-MP metabolised by TPMT enzyme
TPMT is highly polymorphic
Low TPMT levels causes myelosuppression and should be tested for before prescription is given

How well did you know this?

Not at all

Perfectly

What are the ADRs associated with Azathioprine? And how can these be monitored?

Bone marrow suppression (FBC)
👆risk of malignancy and infection
Hepatitis (LFTs)

How well did you know this?

Not at all

Perfectly

What are the common Calcineurin Inhibitors and by what mechanism do they inhibit calcineurin activity?

Ciclosporin (binds to cyclophilin protein)
Tacrolimus (binds to tacrolimus binding protein)
Both drug/protein complexes bind to calcineurin to prevent cellular activity

How well did you know this?

Not at all

Perfectly

What is the normal mechanism of calcineurin and what is the overall effect of its inhibition?

Calcineurin exerts phosphatase activity on nuclear factor of activated T-cells. This then moves to nucleus to begin IL-2 transcription.
Overall effect is 👇 in IL-2 production by helper T-cells.

How well did you know this?

Not at all

Perfectly

When are Calcineurin Inhibitors used in practise? Under what circumstances are they used to treat RA?

Transplant medicine
Atopic dermatitis
Psoriasis
Used in RA if patient is cytopenic as ciclosporin has no effect on bone marrow

How well did you know this?

Not at all

Perfectly

What are the ADRs with Calcineurin Inhibitors?

Nephrotoxicity (hyperkalaemia)
Hypertension
Hyperlipidaemia
Nausea
Hypertrichosis (gingival hypertrophy)
Hyperuricaemia
Drug interactions with those affecting CYP450.

How well did you know this?

Not at all

Perfectly

What is the mechanism of action of Mycophenolate Mofetil?

Inhibit inosine monophosphate dehydrogenase
Impair B and T cell proloferation
Spare other rapidly dividing cells

How well did you know this?

Not at all

Perfectly

What are the ADRs of mycophenolate mofetil?

Nausea
Vomiting
Diarrhoea
Myelosuppression

How well did you know this?

Not at all

Perfectly

How is mycophenolate mofetil used in practise?

Transplantation.
Induction and maintenance therapy vs lupus nephritis.
Toxicity precipitated by renal and hepatic disease.

What are the 5 main classes of DMARDs?

Disease-Modifying Anti Rheumatic Drugs

Cyclophosphamide
Methotrexate
Sulphasalazine and Mesalazine
Anti TNF-α Agents
Rituximab

Describe the mechanism of action of cyclophosphamide.

Alkylating agent -> cross links DNA to prevent replication

Suppresses B and T cell activity

What are the indications of cyclophosphamide therapy?

Lymphoma, leukaemia
Lupus nephritis
Wegener’s granulomatosis
Polyarteritis nodosum

Describe the pharmacodynamics of cyclophosphamide.

Prodrug cleaved in liver to active forms

Main metabolite is 4-hydroxycyclophosphamide

Discuss the pharmacokinetics of cyclophosphamide

Renal excretion

Metabolite (acrolein) toxic to bladder epithelium which can cause haemorrhagic cystitis

Discuss the important considerations in cyclophosphamide treatment

👆risk of bladder cancer, leukaemia and lymphoma
Infertility
Monitor FBC
Adjusted in renal impairment

What diseases can methotrexate be used for?

RA
Cancer
Psoriasis
Crohn’s

Discuss the known mechanism of action of methotrexate

Competitively and reversibly inhibits dihydrofolate reductase (DHFR). Affinity to DHFR 1000xfold that of folates Inhibition of DNA, RNA and protein synthesis Cytotoxic during S-Phase of cell cycle vs rapidly dividing cells

Discuss the more unclear MoA of Methotrexate which is most useful in non-malignancy treatment

Not via anti folate action Inhibition of enzymes in purine metabolism Inhibition of T cell activation Suppression of intercellular adhesion molecules by T cells.

Discuss the pharmacokinetics of methotrexate

33% bioavailability (76% IM) Weekly dosing as metabolites have high half-lives Renal excretion Displacement of NSAIDs

How is methotrexate used in practise?

``` Well tolerated Long continuation of drug 👆QOL Retardation of joint damage Base for DMARD combinations ```

What are the ADRs of methotrexate?

``` Mucositis Marrow suppression Hepatitis Pneumonitis Infection Teratogenic and abortifacient ```

How is methotrexate monitored?

Chest X-Ray | FBC, LFT, U and E, Creatinine (baseline and monthly)

Describe the MoA of sulfasalazine and mesalazine

Inhibition of T cell proliferation and IL-2 production. Stimulation of T cell apoptosis. 👇chemotaxis and 👇degranulation of neutrophils.

Discuss the pharmacokinetics of sulfasalazine and its implications for it use in practise

Salicylate (SASA) - largely unabsorbed, remains in enterohepatic circulation. Sulfapyridine molecule - absorbed but highly protein bound Main activity vs IBD

What are the ADRs of Sulfasalazine?

``` Myelosuppression Hepatitis Rash Nausea Abdo pain Vomiting ```

How is sulfasalazine and mesalazine used in practise?

``` Effective Low toxicity Blood monitoring not required Few drug interactions Not carcinogenic Safe in pregnancy ```

What is a major disadvantage of anti-TNFα treatment?

Expensive!

Under what circumstances are anti-TNFα agents prescribed for RA?

Only after 2 months trial of methotrexate and another DMARD. Only given with evidence of clinically active RA. Treatment withdrawn following adverse event or fails to respond after >6 months.

What are the effects of anti TNFα agents?

👇 inflammation as TNFα required for cytokine cascade and recruitment of leukocytes to joint. 👇 angiogenesis due to reduced VEGF and IL-8 levels. 👇 joint destruction due to inhibition of MMPs, bone resorption, bone erosion and cartilage breakdown.

What are the names of the common anti TNFα agents?

Etanercept Infliximab Adalimumab

What are the ADRs of TNFα agents?

👆 risk of infection of skin/soft tissue TB reactivation Similar risk of new malignancy as with DMARDs 👆 risk of malignancy recurrence

What is the MoA of Rituximab?

Binds to CD20 on B cell subset. Activation of complement mediated B cell lysis. Initiation of cell-mediated cytotoxicity via macrophages. Induction of apoptosis.

What are the risks involved in Rituximab therapy?

Hypogammaglobulinaemia Infection Hypersensitivity development Blocking of immune response

Describe the pathogenesis in RA and how this can be measured clinically.

Increase in IL-1,6 and TNF-α