Immunosuppression and Rheumatic Disease Flashcards
Give 4 examples of diseases that rheumatologists manage
- Inflammatory arthritis, i.e. rheumatoid arthritis
- Systemic lupud erythematosus
- Systemic vasculitis
What kind of disease is rheumatoid arthritis?
An autoimmune multi-system disease
How common is rheumatoid arthritis?
Fairly common - 1% of UK population
Where is RA initially localised to?
The synovium
What is the synovium?
The tissue covering joints and lining articular surfaces
What happens to the synovium in RA?
There is inflammatory change and proliferation of the synvoium, leading to dissolution of cartilage and bone
What causes RA?
An imbalance between pro-inflammatory and anti-inflammatory cytokines
Give 3 pro-inflammatory cytokines
- IL-1
- IL-6
- TNF-alpha
Give 2 anti-inflammatory cytokines?
- IL-4
- TGF-beta
Other than cytokines, what molecules are involved in the pathogenesis of RA?
- T cells
- B cells
- Macrophages
- Rheumatoid factor
- Metalloproteinases
- Neuropeptides
What kind of diagnosis is RA?
Clinical diagnosis
What are the diagnostic criteria for RA?
- Morning stiffness for >1 hour
- Arthritis of 3 or more joints
- Symmetrical arthritis
- Rheumatoid arthritis
- Rheumatoid arthritis
- Serum rheumatoid factor
- X-ray changes
Why are we moving away from rheumatic nodules, serum rheumatoid factor, and x-ray changes as diagnostic criteria for RA?
We want to try and treat earlier, and these are later changes
What are the treatment goals in RA?
- Symptomatic relief
- Prevention of joint destruction
What is the treatment strategy in RA?
- Early use of disease-modifying drugs
- Use of adequate doses
- Use of combinations of drugs
- Avoidance of use of long-term corticosteroids
When should disease modifying drugs be used in RA?
Start on the day of diagnosis
What is meant by ‘adequate doses’ in RA treatment?
Doses that are adequate in achieving good disease control - aim for remission
Why should you avoid the use of long-term corticosteroids in RA treatment?
Steroids have lots of side effects/complications
What systems of the body can lupus affect?
- Central and peripheral nervous system, e.g. seizures, headaches
- Heart and lungs, e.g. pericarditis, pneumonitis
- Kidneys, e.g. oedema, hypertension
- Reproductive system, e.g. miscarriages, menstrual cycle irregularities
- Blood, e.g. anaemia, thrombocytopenia
- Eyes and mucous membranes, e.g. ulcers in eyes, nose, mouth, or vagina
- Gastrointestinal, e.g. nausea, vomiting
- Musculoskeletal, e.g. extreme fatigue, myalgia
- Skin, e.g. butterfly rash, vasculitis
What organs are affected in vasculitis?
- Lungs
- Skin
What are the treatment goals in SLE and vasculitis?
- Symptomatic relief
- Reduction in mortality
- Prevention of organ damage
- Reduction in long term morbidity caused by disease and by drugs
Give 5 examples of immunosuppressant drugs
- Corticosteroids
- Azathioprine
- Ciclosporin
- Tacrolimus
- Mycophenolate mofetil
What is the mechanism of action of corticosteroids?
- Prevent interleukin 1 and 6 (IL-1 and IL-6) production by macrophages
- Inhibits all stages of T cell activation
Give 5 disease-modifying anti-rheumatic drugs (DMARD)
- Methotrexate
- Sulphasalazine
- Anti-TNF agents
- Rituixmab
- Cyclophosphamide
Broadly, what is the advantage of DMARDs over immunosuppressants?
Tend to have a more focused action
How long do DMARDs take to have an effect?
Cyclophosphamide takes about 10 days to have an effect, whereas the others take 4-6 weeks
What are the clinical uses of azathioprine?
- Used as a maintenance therapy in SLE and vasculitis
- RA, although weak evidence
- Inflammatory bowel disease
- Atopic dermatitis
- Bullous skin disease
- Many other uses as a steroid sparing drug
What is meant by a steroid sparing drug?
Allows you to drop steroids early, so you’re not exposed to the side effects of steroids
How is azathioprine metabolised?
- Azathioprine is metabolised to 6-MP
- 6-MP is converted either to;
- 6-MeMP by action of thiopurine methyltransferase (TPMT)
- TIMP
- 6-TI inactive
- TIMP is then converted to;
- 6-MeMPN by action of TPMT
- 6-TGN
What does 6-MeMPN do?
Inhibits de novo purine synthesis
What does 6-TGN do?
Incorporates into DNA
What is the clinical relevance of TPMT?
The TPMT gene is highly polymorphic, and so individuals vary markedly in TPMT activity. When there is low or absent levels of TMPT, there is a risk of myelosuppression, therefore TMPT activity must be tested before prescribing
What are the adverse effects of azathioprine?
- Bone marrow suppression
- Increased risk of malignancy
- Increased risk of infection
- Hepatitis
What should be done due to the risk of bone marrow suppression with azathioprine treatment?
Monitor FBC
Who is especially at risk of malignancy due to azathioprine treatment?
Transplant patients
What should be done due to the increased risk of hepatitis with azathioprine treatment?
Monitor LFTs
Give two examples of calcineurin inhibitors
- Ciclosporin
- Tacrolimus
Where are calcineurin inhibitors used?
- Transplantation
- Atopic dermatitis
- Psoriasis
Why are calcineurin inhibitors not often used in rheumatology?
Due to renal toxicity
What must be done due to the risk of renal toxicity with the use of calcineurin inhibitors?
Check BP and eGFR regularly
Why are multiple drug interatctions possible with calcineurin inhibitors?
Because its action involves the cytochrome P450
Give 4 examples of CYP P450 inducers
- Rifampicin
- Carbamazepine
- Phenytoin
- Omeprazole
Give 5 examples of CYP P450 inducers
- Ciprofloxacin
- Many anti-fungals
- Fluoxetine
- Paroxetine
- HIV anti-virals
What is the mechanism of action of the calcineurin inhibitors?
- They are active against helper T-cells, preventing the production of IL-2 via calcineurin inhibition
What does calcineurin normally do?
Exerts a phosphtase activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to start IL-2 transcription.
How does ciclosporin inhibit calcineurin?
It binds cyclophilin protein, and the drug/protein complexes bind calcineurin
How does tacrolimus inhibit calcineurin?
It binds tacrolimus-binding protein, and the drug/protein complex bind calcineurin
What is mycophenolate mofetil used for in clinical practice?
Primarily in transplantation, but also used in treatment of new cases of lupus
How good is mycophenolate mofetil as a treatment for lupus?
It has a good efficacy as induction and maintenance therapy for lupus nephritis
What is the active metabolite of mycophenolate mofetil?
Mycophenolic acid
Why do blood levels of mycophenolic acid need to be monitored?
There is a risk of myelosuppression
What are the adverse effects of mycophenolate mofetil?
- Nausea
- Vomiting
- Diarrhoea
- GI ulceration
- Myelosuppression
What is mycophenolate mofetil derived from?
The fungus Penicillin stoloniferum
What is the mechanism of action of mycophenolate mofetil?
- It is a prodrug, and so is metabolised to mycophenolic acid
- Mycophenolic acid inhibits inosine monophosphate dehydrogenase, which is required for guanine synthesis
- This impairs B and T cell proliferation, but spares other rapidly dividing cells
Why does mycophenolate mofetil spare other rapidly dividing cells?
Due to guanosine salvage pathways in other cells
What is the mechanism of action of cyclophosphamide?
It is an alkylating agent cross links DNA so that it cannot replicate
It is cytotoxic
WWhat are the immunological effects of cyclophosphamide?
Suppresses B and T cell activity
What are the indications for cyclophosphamide treatment?
- Lymphoma
- Leukaemia
- Solid cancers
- Lupus nephritis
- Wegener’s granulomatosis
How is cyclophosphamide metabolised?
It is converted to its active form by cytochrome P450 enzymes in the liver. It’s main active metabolite is 4-hydroxycyclophosphamide (4-HC)
What does 4-HC exist in equilibrium with?
It’s tautomer, aldophosphamide
What happens to aldophosphamide in the body?
Most of it is oxidised to make carboxyphosphamide, but a small proportion is converted into phosphoromide mustard
What is cyclophosphamide excreted by?
The kidney
What are the adverse effects of cyclophosphamide?
- Haemorrhagic cystitis
- Increased risk of bladder cancer, lymphoma, and leukaemia
- Infertility
How can cyclophosphamide cause haemorrhagic cystitis?
Acrolein (a metabolite of cyclophosphamide) is toxic to the bladder epithelium
How does haemorrhagic cystitis present?
Visible or invisible haematuria
How can haemorrhagic cystitis caused by cyclophosphamide be prevented?
The use of aggressive hydration, and/or Mesna
How does Mesna inhibit haemorrhagic cystitis?
It binds acrolein (the metabolite that causes this side effect)
What are the risks of cyclophosphamide related to?
The cumulative dose and patient age
How can infertility caused by cyclophosphamide be prevented?
- Oocyte preservation
- GnRH analogue
What should be monitored with cyclophosphamide treatment?
FBC
When should the dose of cyclophosphamide be adjusted?
In renal impairment
What is a good alternative for cyclophosphamide in lupus nephritis, and why?
It is safer, and as effective
What is the gold standard treatment for RA?
Methotrexate
Other than RA, what are the indications for the use of methotrexate?
- Malignancy
- Psoriasis
- Crohn’s disease
What is the mechanism of action of methotrexate in malignant disease?
It competitively and reversibly inhibits dihydrofolate reductase (DHFR), and therefore inhibits synthesis of DNA, RNA, and proteins
How does the affinity of methotrexate for DHFR compare to that of folate for DHFR?
The affinity of methotrexate is 1000x that of folate
What does dihydrofolate reductase do?
It catalyses the conversion of dihydrofolate to the active tetrahydrofolate, the key carrier of one-carbon units in purine and thymidine synthesis
In what stage does methotrexate act specifically?
In DNA and RNA synthesis, therefore it is cytotoxic in the S phase of the cell cycle
What is the result of methotrexate acting specifically in the S-phase of the cell cycle?
It has greater toxic effect on rapidly dividing cells, such as malignant and myeloid cells, and GI and oral mucosa), which replicate their DNA more frequently
What is the mechanism of action of methotrexate in non-malignant disease?
Not clear - not via anti-folate action, but could be;
- Inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine
- Inhibition of T cell activation
- Suppression of intercellular adhesion molecule expression by T cell
What is adenosine?
A purine nucleoside that is elaborated at injured and inflamed sites. It is a regulatory autocoid
How does adenosine act as a regulatory autocoid?
It is generated as a result of cellular injury or stress, and interacts with specific G-protein coupled receptors on inflammatory and immune cells to regulate their function
What is the mean oral bioavailability of methotrexate?
33% - ranges between 13-76%
What is the mean intramuscular bioavailability of methotrexate?
76%
How can methotrexate be administered?
PO, IM, or SC
What should be done in a patient on PO administration of methotrexate with partial response, or nausea?
Swap to SC
How often is methotrexate given?
Weekly, not daily
Why can methotrexate only be given weekly?
Because it is metabolised to polyglutamates with long half lives
What is the maximum dose of methotrexate in RA?
20-25mg/week, any more and you get increased side effects with no increase in effect
What % of methotrexate in the blood is protein bound?
50%
What can displace methotrexate from the proteins its bound to in the blood?
NSAIDs
How is methotrexate excreted?
Renally
What are the advantages of using methotrexate in practice?
- Well tolerated
- Improved QoL
- Retardation of joint damage
- Anchor drug for DMARD combinations
What is the result of methotrexate being generally well tolerated?
50% of patients continue the drug for >5 years, longer than any other DMARD
What are the adverse effects of methotrexate?
- Mucositis
- Marrow suppression
- Hepatitis
- Cirrhosis
- Pneumonitis
- Infection risk
- Highly teratogenic and abortifactient
How can the methotrexate adverse effects of mucositis and marrow suppression be treated?
Folic acid supplementation
What is sulfasalazine?
A conjugate of a salicylate (5-ASA) and a sulfapyridine molecule
What is sulfasalazine designed to do?
Relieve pain and stiffness, and fight infection
What are the immunological effects of sulfasalazine?
- Inhibition of T cell proliferation
- Possible T cell apoptosis
- Inhibition of IL-2 production
- Reduced neutrophil chemotaxis
- Reduced neutrophil degranulation
Where in the body is the main activity of sulfasalazine?
Within the intestine, as it is poorly absorbed
What is the result of the main activity of sulfasalazine being in the large bowel?
It is effective in IBD
What are the adverse effects of sulfasalazine?
- Myelosuppression
- Hepatitis
- Rash
- Nausea
- Abdominal pain and vomiting
What are the adverse effects of sulfasalazine mainly due to?
The sulfapyridine moiety
When do the adverse effects of sulfasalazine usually occur?
Within the first 2 weeks, and then are fine after
What are the advantages of suldasalazine in practice?
- Effective
- Favourable toxicity
- Long term blood monitoring not always needed
- Very few drug interactions
- No carcinogen potential
- Safe in pregnancy
How are biopharmaceuticals obtained?
Recombinant DNA technology produces substances that are nearly identical to the bodys own key signalling proteins
What kind of molecule are the majority of biopharmaceuticals?
Monoclonal antibodies
How do monoclonal antibodies work as biopharmaceuticals?
They are ‘custom-designed’ to specifically block any given substance in the body, or target any specific type
What are fusion proteins?
They are biopharmaceuticals based on a naturally occuring receptor, acting to block it
What are the effects of blocking TNF-alpha?
- Decreased inflammation
- Decreased angiogenesis
- Decreased joint destruction
