15. Immunosuppressants Flashcards
What diseases do rheumatologists manage?
- Inflammatory arthritis e.g. rheumatoid arthritis (RA)
- Systemic lupus erythematosus (SLE)
- Systemic vasculitis
What is rheumatoid arthritis?
- autoimmune multi-system disease
- Initially localized to synovium
- Inflammatory change and proliferation of synovium (pannus) leading to dissolution of cartilage and bone
What are the clinical criteria for diagnosis of RA? (5)
- Morning stiffness ≥ 1 hour
- Arthritis of ≥ 3 joints
- Arthritis of hand joints
- Symmetrical arthritis
- Rheumatoid nodules
What are the non-clinical criteria for diagnosis of RA?
- Serum rheumatoid factor/Anti-CCP antibodies
* X-ray changes
which pro-inflammatory cytokines are over expressed in RA?
TNF a
IL-1
IL-6
What x-ray changes are seen in RA?
- reduced joints space
- periarticular osteopenia
- juxta-articular bony erosion
- subluxation and gross deformity
What is the treatment strategy for RA?
- Early use of disease-modifying drugs
- Aim to achieve good disease control
- Use of adequate dosages
- Use of combinations of drugs
- Avoidance of long-term corticosteroids
RA treatment goals?
symptomatic relief
prevention of joint destruction
What is SLE?
Multisystem autoimmune disorder related to antibody-mediated cellular attack and deposition of antigen-antibody complexes
- arthralgia and rashes most common clinical features
- cerebral and renal disease the most serous problems
What are the treatment goals for SLE and vasculitis?
- Symptomatic relief e.g arthralgia, Raynaud’s phenomenon
- Reduction in mortality
- Prevention of organ damage
- Reduction in long term morbidity caused by disease and by drugs
Give examples of immunosuppressant (7)(some are DMARDs)
- Corticosteroids
- Methotrexate
- Azathioprine
- Ciclosporin
- Tacrolimus
- Mycophenolate mofetil
- Leflunomide
- Cyclophosphamide
Give examples of disease modifying anti-rheumatic drugs (DMARDs) non-biologics used in rheumatology.
- Hydroxychloroquine
* Sulphasalazine
Give examples of DMARDs biologics used in rheumatology.
- Anti-TNF agents
- Rituximab
- IL-6 inhibitors, JAK inhibitors
What is the mechanism of action of corticosteroids?
- bind to cytoplasmic receptor
- activated steroid-receptor complexes form dimers
- move into the nucleus
- bind to steroid response elements in the DNA
- either repress or induce particular genes
How are corticosteroids immunosuppresants?
- Prevent interleukin IL-1 and IL-6 production by macrophages
- Inhibit all stages of T-cell activation
What are some short term side effects of corticosteroid use?
- an increase in appetite,
- weight gain,
- insomnia,
- fluid retention, and
- mood changes, such as feeling irritable, or anxious
WHat are some long term side effects of corticosteroid use?
- osteoporosis (fragile bones),
- hypertension (high blood pressure),
- diabetes,
- weight gain,
- increased vulnerability to infection,
- cataracts and glaucoma (eye disorders),
- thinning of the skin,
- bruising easily, and
- muscle weakness
What is azathioprine used in?
- maintenance therapy in SLE and vasculitis (cannot induce remission)
- IBD
- severe atopic dermatitis
- bullous skin disease
- (steroid sparing drugs)
How does azathioprine work?
Inhibits purine synthesis and therefore DNA/RNA synthesis
- antimetabolite
What is the mechanism of action of azathioprine?
It is converted into 6-mercaptopurine (6-MP) (the main active metabolite) which is conjugated with ribose and incorporated into DNA halting DNA replication (also other things)
Which enzyme is important in the metabolism of 6-MP?
Thiopurine methyltransferase (TPMT)
What is important to check for in patients before giving azathioprine?
Levels of TPMT
- lower levels can result in myelosuppression
What are the adverse effects of azathioprine?
- bone marrow suppression
- increased risk of infection
- increased risk of malignancy
- hepatitis
What are 2 examples of calcineurin inhibitors?
Ciclosporin & tacrolimus
What are calcineurin inhibitors used for?
- widely used in transplantation
- atopic dermatitis and psoriasis
- (not often used in rheumatology)
What is important to regularly monitor when using calcineurin inhibitors?
Check BP and eGFR regularly
- can cause it to dip
What DDI are important with calcineurin inhibitors?
Multiple drug interactions are possible (Cytochrome P-450) - CYP450 inducers and inhibitors
which drugs are CYP450 inducers?
rifampicin
carbemazepine
phenytoin
omeprazole
which drugs are CYP450 inhibitors?
ciprofloxacin many antifungals fluoxetine paroxetine HIV antivirals e.g indinavir
What is the MOA of ciclosporin and tacrolismus?
- Active against helper T-cells, preventing production of IL-2 via calcineurin inhibition - reduce helper T cell activity
- Ciclosporin binds to cyclophilin protein
- Tacrolimus binds to tacrolimus-binding protein
- Drug/protein complexes bind calcineurin
- Calcineurin exerts phosphatase activity of activated T- cells then nuclear factor migration starts IL-2 transcription
ADRs of ciclosporin and tacrolismus?
renal toxicity
What is mycophenolate mofetil used for?
- Primarily in transplantation
- Good efficacy as induction and maintenance therapy for lupus nephritis/Vasculitis maintenance
- In transplantation medicine: Mycophenolic acid may be monitored
How does Mycophenolate Mofetil work?
Inhibits purine synthesis
- guanosine specifically
What is the MOA of mycophenolate mofetil?
- Inhibits inosine monophosphate (IMP) dehydrogenase (required for guanosine synthesis)
- impairs B- and T-cell proliferation (selectively??)
- spares other rapidly dividing cells
What are the adverse effects of mycophenolate mofetil?
- Most common include nausea, vomiting, diarrhea
- GI disease
- Most serious is myelosuppression
What is cyclophosphamide used for?
- Lymphoma, leukaemia, solid cancers
- Lupus nephritis
- Wegener’s granulomatosis (ANCA-vasculitis)
What is the MOA of cyclophosphamide?
Cytotoxic Agent : Alkylating agent -cross links DNA so that it cannot replicate Many immunological effects: – suppresses T cell activity – suppresses B cell activity
Describe the metabolism of cyclophosphamide.
- is a pro-drug
- metabolised by CYPs in liver to 4-hydroxycyclophosphamide (4HCP)
- 4HCP exists in equilibrium with its tautomer, aldophosphamide
- Most of the aldophosphamide is oxidised to make carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide mustard (main active metabolite)
what is the effect on cyclophosphamide on kidneys?
- Cyclophosphamide is excreted by the kidney
* Acrolein, another metabolite is toxic to the bladder epithelium and can lead to hemorrhagic cystitis
How is haemorrhagic cystitis prevented in use of cyclophosphamide?
through the use of aggressive hydration and/or Mesna
What ADRs are associated with cyclophosphamide?
- increased risk of bladder cancer, lymphoma and leukaemia
- Infertility: Risk relates to cumulative dose and patient age
- toxic metabolite to bladder epithelium
what is a contraindication of cyclophosphamide?
Adjust dose in renal impairment
What is usually considered instead of cyclophosphamide?
Mycophenolate mofetil
- safer and as effective in lupus nephritis
action of cyclophosphamide and Mycophenolate mofetil ?
antiproliferative - B and T cells
DDIs of cyclophosphamide?
caution with many vaccines
What is the gold standard treatment for RA?
Methotrexate
What are the indications for use of methotrexate?
- RA
- malignancy
- psoriasis
- Crohn’s disease
What is the MOA of methotrexate (neoplasms)?
Competitively and reversibly inhibits dihydrofolate reductase (DHFR)
- 1000x more affinity than folate
What does inhibition of dihydrofolate reductase result in?
- normally converts dihydrofolate to tetrahydrofolate
- key carrier of one-carbon units in purine and thymidine synthesis
- methotrexate therefore inhibits the synthesis of DNA/RNA
Why does methotrexate affect rapidly dividing cells more?
Acts during DNA and RNA synthesis hence cytotoxic during S-phase of the cell cycle. Greater toxic effect on rapidly dividing cells which replicate their DNA more frequently
What are the possible MOA in non-malignant disease?
mechanism unclear but not via anti-folate action
possible:
– Inhibition of accumulation of adenosine
- the inhibition of T cell activation activation
- suppression of intercellular adhesion molecule expression by T cells
How is methotrexate administered, what is its bioavailability?
- Mean oral bioavailability is 33% (13-76%)
- Mean intramuscular bioavailability is 76%
- Administered PO, IM or S/C
What is the dosing of methotrexate?
- WEEKLY NOT DAILY DOSING,
- metabolized to polyglutamates with long half lives
What percent of methotrexate is protein bound?
50%
- NSAIDs displace
how is methotrexate excreted?
renally
What ADRs are associated with methotrexate?
• mucositis • marrow suppression (both respond to folic acid supplementation) • hepatitis, cirrhosis • pneumonitis • infection risk - reduced fertility (reversible)
Should methotrexate be given during pregnancy?
No
- highly teratogenic, abortifacient
- need to take contraceptives whilst taking drug
What are the indications for sulfasalazine?
- IBD
- RA
What is sulfasalazine a conjugate of and what breaks it into these component parts?
- salicylate (5aminosalicylic acid, 5ASA)
- sulfapyridine (antibiotic)
Broken into these by gut bacteria
action of sulfasalazine?
• Designed to relieve pain & stiffness
(5-ASA = anti-inflammatory)
• And to 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 - reduced chemotaxis - reduced degranulation
Why is sulfasalazine effective in IBD?
Poorly absorbed -main activity is within intestine
What ADRs are associated with sulfasalazine?
• Mainly due to sulfapyridine moiety - myelosuppression - hepatitis - Rash • Milder side effects - nausea - abdo pain/vomiting
DDIs of sulfasalazine?
very few
some caution with PPIs
Is Sulfasalazine safe in pregnancy?
Yes
Give examples of biologics used in treatment of RA.
rituximab, infliximab
How does rituximab work?
Binds specifically to a unique cellsurface marker CD20, which is found on a subset of B cells but not on stem cells, pro-B cells, plasma cells or any other cell type. Causes B cell apoptosis.
causes B cell apoptosis
Effects of blocking TNF-alpha?
• reduced Inflammation Cytokine cascade Recruitment of leukocytes to joint - elaboration of adhesion molecules - production of chemokines • reduced Angiogenesis VEGF levels • reduced Joint destruction MMPs and other destructive enzymes Bone resorption and erosion Cartilage breakdown
What does anti-TNF therapy increase risk of, what should be screened before therapy?
TB reactivation
- TNFα is released by macrophages in response to M TB infection
- TNFα is essential for development + maintenance of granulomata
Screen for latent TB before treatment
DDIs of methotrexate?
NSAIDs and other drugs that reduce renal excretion or displace bound drug
DDIs of corticosteroids?
CYP inducers, bleeding risk increased with NSAIDs
