S8 L2 Immunosuppression and disease-modifying therapy Flashcards
What diseases does a rheumatologist manage?
Inflammatory arthritis e.g. RA
Systemic lupus erythematosus (SLE)
Systemic vasculitis
What is rheumatoid arthritis?
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
How does rheumatoid arthritis progress?
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
What is the pathology of RA?
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
How do we diagnoses RA?
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
What are the treatment goals of RA?
- Symptomatic relief
- Prevention of joint destruction → can’t reverse joint erosion, damage joints can not be restored- prevent future damage
What is the treatment strategy for RA?
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)
What is systemic lupus erythematosus?
Autoimmune disease systemic manifestation including skin rash, erosion of joints or even kidney failure
What is vasculitis?
Group of conditions characterised by the inflammation of blood vessels
What are the treatment goals in SLE and vasculitis?
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
What are immunosuppressants?
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
What are examples of immunosupresants?
- 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
What is the mechanism of action of corticosteroids?
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)
What are the other non biological DMARDs?
(disease modifiying anti-rheumatic drugs)
- Sulphasalazine → GI medicine
- Hydroxychloroquine → Immune modulatory
What are the biological DMARDs?
- 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
What is Azathioprine?
Antiproliferative immunosuppressant
Purine antametabolite - immunosuppressant
Used for maintenance therapy for SLE and vasculitis
Weak evidence of use in RA
IBD
‘steroid sparing drug’
What is the pharmacodynamics of Azathioprine?
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
What is the mechanisms of action of Azathioprine?
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
What are the adverse effects of Azathioprine?
- Bone marrow suppression → monitor FBC
- Increased risk of malignancy → esp in transplanted patients
- Increased risk of infection → benefit>risk
- Hepatitis → monitor LFT
What are calcineurin inhibitors?
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
What is the mechanism of action of ciclosporin and tacrolimus?
- 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
What is mycophenolate mofetil?
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
What is the mechanism of action of mycophenolate mofetil?
- 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)
What are the adverse effects of mycophenolate mofetil?
Common- nausea, vomiting and diarrhoea
Serious - myelosuppression
What are cyclophosphamide?
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
What are cyclophosphamides used for?
Lymphoma, leukaemia, solid cancers
Lupus nephritis
Wegener’s granulomatosis (ANCA-vasculitis)
What are the cyclophosphamide pharmacodynamics?
- 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)
What is the pharmacokinetics of cyclophosphamide?
- 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
What are the important considerations of cyclophosphamides?
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
What is methotrexate?
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
What is the mechanism of action of methotrexate?
- 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
How does methotrexate work in non-malignant disease?
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
What is the pharmacokinetics of methotrexate?
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
How is methotrexate used in practice?
- 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
What are the adverse effects of methotrexate?
- Mucositis
- Marrow suppression
Both response to folic acid supplementation - Hepatitis, cirrhosis, pneumonitis, infection risk
- Highly teratogenic, aboritifacient (gynecologically used for ectopic pregnancies)
What are sulfasalazine?
- 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)
What are the immunological effects of sulfasalazine?
T cell - Inhibition of proliferation - Possible T cell apoptosis - Inhibition of IL-2 production Neutrophil - Reduce chemotaxis - Reduce degranulation
What is the site of absorption of sulfasalazine?
Poorly absorbed
Main activity is within intestine,
Therefore effective in IBD
What are the adverse effects of sulfasalazine?
Mainly due to sulfapyridine moiety - Myelosuppression - Hepatitis - Rash Milder side effects - Nausea - Abdo pain/vomiting
How is sulfasalazine used in practice?
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)
What are biopharmaceuticals of biologicals?
- 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
What are the different biologicals?
‘-mab’ - monoclonal antibody
‘-cept’ - fusion proteins
What are the effects of blocking TNF-alpha?
- ↓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
What is anti-TNF therapy?
- 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
What is the BSR biologics register?
- Largest prospective observational register of rheumatology patients
- Contains all the patients receiving TNFalpha
What is rituximab?
- 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
What effect can drugs have in CYP P450?
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
What are examples of inducers?
Rifampicin
Carbemazepine
Phenytoin
Omeprazole
What are examples of inhibitors?
Ciprofloxacin Many antifungals Fluoxetine Paroxetine HIV antivirals e.g. indinavir
