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_Sem 4. CPT NOTES > S8 L2 Immunosuppression and disease-modifying therapy > Flashcards

S8 L2 Immunosuppression and disease-modifying therapy Flashcards

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1
Q

What diseases does a rheumatologist manage?

A

Inflammatory arthritis e.g. RA
Systemic lupus erythematosus (SLE)
Systemic vasculitis

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2
Q

What is rheumatoid arthritis?

A 
Autoimmune multisystem disease 
→ Breakdown of self tolerance
→ Produce self antigens 
→ Attack cell proteins 
Fairly common → 1% UK
Initially localised to the synovium 
Inflammatory changes and proliferation of synovium (pannus) leading to dissolution of cartilage and bone
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3
Q

How does rheumatoid arthritis progress?

A

1st → swelling of proximal interphalangeal joints
2nd→ Uncontrolled- damage due dissolution and erosion at joint
3rd→ further progression - deformity, muscle wasting due to lack of use

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4
Q

What is the pathology of RA?

A

Imbalance between pro-inflammatory and anti-inflammatory factor (IL-4, TGF-β)
Pro-inflammatory →
- IL-1 → fever, unwell
- IL-6 → ↑CRP
- TNF-α
↑metalloproteinases - responsible for erosion
T cells
Macrophages
B cells produce antibodies Rheumatoid factor and anti-CCP antibodies
Neuropeptide
Cytokines

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5
Q

How do we diagnoses RA?

A

Clinical criteria
- Morning stiffness >/= 1 hour
- Arthritis of >/= 3 joints
- Arthritis of hand joints
- Symmetrical arthritis
- Rheumatoid nodules → late finding, biopsy (late diagnosis), clinically typical joints and presentation
Non clinical criteria
- Serum rheumatoid factor/ anti-CCP antibodies
- X-rays changes- joint pain at GP, shared RA → referral
- Blood test often used for prognosis to determine outcome of disease

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6
Q

What are the treatment goals of RA?

A
  • Symptomatic relief
  • Prevention of joint destruction → can’t reverse joint erosion, damage joints can not be restored- prevent future damage
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7
Q

What is the treatment strategy for RA?

A 
Early use of disease-modifying drugs → important patient more likely to go into remission 
Aim to achieve good disease control 
Use adequate dosages 
Use of combination of drugs 
Avoidance of long-term corticosteroids

(DMARDs- supress inflammation, Biologics- B and T cell suppression, ↓cytokines e.g…, Acute flares- NSAID, glucocorticoids)

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8
Q

What is systemic lupus erythematosus?

A

Autoimmune disease systemic manifestation including skin rash, erosion of joints or even kidney failure

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9
Q

What is vasculitis?

A

Group of conditions characterised by the inflammation of blood vessels

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10
Q

What are the treatment goals in SLE and vasculitis?

A

Symptomatic relief e.g. arthralgia, Raynaud’s phenomenon
Reduction in mortality
Prevention of organ damage → preserve kidney function
Reduction in long term morbidity caused by disease and by drugs

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11
Q

What are immunosuppressants?

A

Some are DMARDs (first used for cancer treatment but now realised good for control of autoimmune conditions)
Suppress the immune system preventing inappropriate inflammatory response

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12
Q

What are examples of immunosupresants?

A
  • Corticosteroids (inhibit transcription of pro inflammatory mediators)
  • Methotrexate (differs to malignancy, indirect suppression of adhesion molecules on cells and neutrophils)
  • Azathioprine, Mycophenolate mofetil, Cyclophosphamide (antiproliferative immunosuppressant)
  • Ciclosporin, Tacrolimus (calcineurin inhibitors)
  • Leflunomide
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13
Q

What is the mechanism of action of corticosteroids?

A

Prevent interleukin IL-1 and IL-6 production by macrophages - CRP proteins
Inhibit all stages of T cell activation
→ Bind to the receptors → taken to the nucleus → transcription → prevents production of proinflammatory proteins (TNFalpha)

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14
Q

What are the other non biological DMARDs?

A

(disease modifiying anti-rheumatic drugs)

  • Sulphasalazine → GI medicine
  • Hydroxychloroquine → Immune modulatory
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15
Q

What are the biological DMARDs?

A
  • Anti-TNF agents - blockers (Infliximab, adalimumab)
  • Ab against CD-20 receptor on B cell - B cell lytic monoclonal Ab (Rituximab)
  • IL-6 inhibitors, JAK inhibitors - Multiple receptors
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16
Q

What is Azathioprine?

A

Antiproliferative immunosuppressant
Purine antametabolite - immunosuppressant
Used for maintenance therapy for SLE and vasculitis
Weak evidence of use in RA
IBD
‘steroid sparing drug’

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17
Q

What is the pharmacodynamics of Azathioprine?

A

Require TPMT (thiopurine methyltransferase) for metabolism
TPMT very polymorphic - varying amounts in each person
Patients tested for levels of this
Low/absent level ↑risk of myelosupression

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18
Q

What is the mechanisms of action of Azathioprine?

A

Azathioprine cleaved to 6-MP
Converted to inactive 6-MeMP and 6-TU and active TIMP
TIMP then converted to:
- 6-MeMPN → inhibition of de novo purine synthesis
- 6-TGN → incorporation into DNA
Decreases DNA and RNA synthesis

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19
Q

What are the adverse effects of Azathioprine?

A
  • Bone marrow suppression → monitor FBC
  • Increased risk of malignancy → esp in transplanted patients
  • Increased risk of infection → benefit>risk
  • Hepatitis → monitor LFT
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20
Q

What are calcineurin inhibitors?

A

Ciclosporin and tacrolimus → immunosuppressants
Used widely in transplantation
Also for atopic dermatitis and psoriasis
Not often used in rheumatology- renal toxicity
- Check BP and eGFR regularly
Can cause gum hypertrophy
Multiple drug interactions are possible

21
Q

What is the mechanism of action of ciclosporin and tacrolimus?

A
  • Active against helper T cells, preventing production of IL-2 via calcineurin inhibition
    → Ciclosporin binds to cyclophilin protein
    → Tacrolimus binds to tacrolimus-binding protein
    Drug protein complex binds to and inhibits calcineurin
    Complex inhibits phosphatase activity
    Inhibits Nuclear factor of activated T cells
    Inhibits mRNA synthesis for IL-2 (↓IL-2 = reduced T cell activation)
  • Normally, calcineurin exerts phosphatase activity of activated T-cells then nuclear factor migration start IL-2 transcription
22
Q

What is mycophenolate mofetil?

A

Antiproliferation immunosuppressant
Used for immunosuppression
Primarily in transplantation
Good efficacy as induction and maintenance therapy for lupus nephritis/ Vasculitis maintenance
In transplantation medicine: Mycophenolic acid (active metabolite) may be monitored
Induction of remission and then maintenance

23
Q

What is the mechanism of action of mycophenolate mofetil?

A
  • Prodrug derived from penicillium stoloniferum
  • Active metabolite mycophenolic acid
  • Inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis- require for DNA)
  • Impair B and T cell proliferation
  • Spares other rapidly dividing cells (due to guanosine salvage pathways in other cells e.g. B and T cell have to make their own)
24
Q

What are the adverse effects of mycophenolate mofetil?

A

Common- nausea, vomiting and diarrhoea

Serious - myelosuppression

25
Q

What are cyclophosphamide?

A 
Antiproliferative immunosuppressant
Cytotoxic agents 
- Alkylating agents → cross links DNA so that it cannot replicate
- Many immunological effects 
→ Supress T cells activity 
→ Supress B cell activity
26
Q

What are cyclophosphamides used for?

A

Lymphoma, leukaemia, solid cancers
Lupus nephritis
Wegener’s granulomatosis (ANCA-vasculitis)

27
Q

What are the cyclophosphamide pharmacodynamics?

A
  • Prodrug
  • Converted in liver by CYP450 into active forms
  • Main active metabolite → 4-hydroxycyclophosphamide
  • Exist in equilibrium with tautomer, aldophosphamide
  • Most of aldophosphamide oxidised to make carboxyphosphamide, small proportion converted to phosphoramide mustard (main active metabolite)
28
Q

What is the pharmacokinetics of cyclophosphamide?

A
  • Excreted by the kidneys
  • Acrolein, another metabolite is toxic to the bladder epithelium and can lead to haemorrhagic cystitis
  • Prevented through the use of aggressive hydration (2L of fluid a day and IV saline) and/or Mesna
29
Q

What are the important considerations of cyclophosphamides?

A

Significant toxicity
→ ↑risk of bladder cancer, lymphoma and leukaemia
→ Infertility: risk relates to cumulative dose and patient age (gonadotropin receptor antagonist- given to protect women as born with all eggs)
→ monitor FBC
→ Adjust dose in renal impairment
Mycophenolate mofetil safer and as effective in lupus nephritis

30
Q

What is methotrexate?

A 
Developed in 1940s 
Gold standard treatment for RA
Immunosuppressant 
Other indications
- Malignancy 
- Psoriasis 
- Crohn's disease 
Unlicensed roles: Inflammatory myopathies, vasculitis, steroid-sparing agent in asthma 
Similar structure to folic acid
31
Q

What is the mechanism of action of methotrexate?

A
  • Competitively and reversibly inhibits dihydrofolate reductase (DHFR)
  • Inhibits conversion of dihydrofolate → tetrahydrofolate
  • Inhibits purine and thymidine synthesis and therefore inhibits DNA and RNA synthesis
  • MOA for non malignant disease (RA) not clear
    → accumulation of adenosine
    → inhibition of T cell activation
    → suppression of intracellular adhesion molecule expression by T cells
  • Competitively and reversibly inhibits dihydrofolate reductase (DHFR)
  • Affinity of methotrexate for DHFR is 1000X that of folate for DHFR
  • Have to give folic acid day or so after methotrexate as it removes all the folic acid- cannot be used in pregnant women
  • DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate the key carrier of one-carbon units in purine and thymidine synthesis
  • Inhibits the synthesis of DNA, RNA and proteins
  • Cytotoxic during S-phase of cell cycle, greater toxic effect on rapidly dividing cell which replicate their DNA more frequently
32
Q

How does methotrexate work in non-malignant disease?

A

e.g. RA
mechanism unclear not via anti-folate action
Possible mechanisms include
- Inhibition of accumulation of adenosine
- Inhibition of T cell activation
- Suppression of intercellular adhesion molecule expression by T cells

33
Q

What is the pharmacokinetics of methotrexate?

A

Mean oral bioavailability is 33% (13-76%)
Mean intramuscular bioavailability is 76%
Administer PO, IM or s/c
PO → if partial response or with nausea then swap to s/c
Weekly not daily dosing → Metabolised to polyglutamates with long half lives
50% protein bound- NSAIDs displace methotrexate- toxic levels in blood
Renal excretion

34
Q

How is methotrexate used in practice?

A
  • Well tolerated
  • 50% of patients continue to use the drug for >5years,, longer than any other DMARD
  • Improved QoL
  • Retardation of joint damage
  • Anchor drug for DMARD combinations - add on therapies
35
Q

What are the adverse effects of methotrexate?

A
  • Mucositis
  • Marrow suppression
    Both response to folic acid supplementation
  • Hepatitis, cirrhosis, pneumonitis, infection risk
  • Highly teratogenic, aboritifacient (gynecologically used for ectopic pregnancies)
36
Q

What are sulfasalazine?

A
  • Conjugate of salicylate (5aminosalicyclic acid) and a sulfapyridine molecule
  • Developed in 1940s
  • RA or rheumatic polyarthritis believed to be infectious
  • Designed to relieve pain and stiffness (5-ASA = anti-inflammatory)
  • Fight infection (sulfapyridine= sulfonamide)
37
Q

What are the immunological effects of sulfasalazine?

A 
T cell 
- Inhibition of proliferation 
- Possible T cell apoptosis 
- Inhibition of IL-2 production 
Neutrophil 
- Reduce chemotaxis 
- Reduce degranulation
38
Q

What is the site of absorption of sulfasalazine?

A

Poorly absorbed
Main activity is within intestine,
Therefore effective in IBD

39
Q

What are the adverse effects of sulfasalazine?

A 
Mainly due to sulfapyridine moiety 
- Myelosuppression
- Hepatitis 
- Rash 
Milder side effects 
- Nausea
- Abdo pain/vomiting
40
Q

How is sulfasalazine used in practice?

A

Effective
Favourable toxicity - monitor up until 18 months then can stop monitoring- toxicity seen early on
Long term blood monitoring not always needed
very few drug interactions
No carcinogenic potential
Safe in pregnancy (‘s’ulfasalazine = ‘s’afe in pregnancy)

41
Q

What are biopharmaceuticals of biologicals?

A
  • Extracted from living systems e.g. whole blood + blood components, stem cell therapy
  • Recombinant DNA technology producing substances that are (nearly) identical to the body’s own key signalling proteins e.g. GH, EPO
  • Monoclonal antibodies ‘custom-designed’ made specifically to block any given substance in the body, or to target any specific cell type
  • Receptor constructs (fusion proteins), usually based on a naturally-occurring receptor, acting to block it
42
Q

What are the different biologicals?

A

‘-mab’ - monoclonal antibody

‘-cept’ - fusion proteins

43
Q

What are the effects of blocking TNF-alpha?

A
  • ↓inflammation → cytokine cascade, recruitment of leukocytes to joint → elaboration of adhesion molecules, production of chemokines
  • ↓angiogenesis, ↓VEGF levels
  • ↓joint destruction, MMPs and other destructive enzymes, bone resorption and erosion, cartilage breakdown
44
Q

What is anti-TNF therapy?

A
  • TB reactivation is a risk → if test =+ve need prophylaxis/therapy to stop Gonh focus reactivation before starting TNFalpha
  • TNFalpha is released by macrophages in response to M TB infection
  • TNFalpha is essential for development + maintenance of granulomata
45
Q

What is the BSR biologics register?

A
  • Largest prospective observational register of rheumatology patients
  • Contains all the patients receiving TNFalpha
46
Q

What is rituximab?

A
  • Bind to CD20 cell surface marker
    → Found on subset of B cells but not on stem cells
    → Pro B cells, plasma cells or any other type of cell
  • Causes B cell apoptosis
    → prevents presentation of antigen to T cells
    → prevents production of cytokines
    → prevents production of antibodies - RF and anti-CCB-
  • Effective in RA, good safety data
47
Q

What effect can drugs have in CYP P450?

A

Induce it or inhibit it

  • inducers → increase the proliferative activity of enzymes so ↓drug levels
  • inhibitors → bind to enzyme complex, drugs not broken down, can lead to toxicity
48
Q

What are examples of inducers?

A

Rifampicin
Carbemazepine
Phenytoin
Omeprazole

49
Q

What are examples of inhibitors?

A 
Ciprofloxacin 
Many antifungals 
Fluoxetine 
Paroxetine 
HIV antivirals e.g. indinavir

_Sem 4. CPT NOTES (26 decks)

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