Auto immune lecture 7-21 Flashcards

Question

Sacroiliitis a type of SpA

Answer 1

* Sacroiliitis is an inflammation of the sacroiliac joint (hip area) * Picture on the bottom right shows an individual with – sacroiliitis and Ankylosing Spondylitis. The arrows point to the inflamed and narrowed SI joints. They are white due to bony sclerosis around the joints. The joints fuse together and all the ligaments can become inflamed that connect the joints together to make it stable.

Answer 2

* Chronic disease that primarily affects the spine and may lead to stiffness of the back. The joints and ligaments that normally permit the back to move become inflamed. The joints and bones may grow (fuse) together. * The effects are inflammation and chronic pain and stiffness in the lower back that usually starts where the lower spine is joined to the pelvis or hip. * Diagnosis is made through: (a) medical history including symptoms, (b) X-rays, and possibly (c) blood tests for HLA-B27 gene

Answer 3

• Treatment options: – With early diagnosis and treatment, pain and stiffness can be controlled and may reduce fusing. In women, AS is usually mild and hard to diagnose. – Exercise – Medications: NSAIDs (phenylbutazone-rarely used because causes a lot of blood problems also pyrazoline also aspirin), sulfasalazine (dMARD) – Posture management – Self-help aids – Surgery- to straighten the back

Answer 4

* Arthritis that produces pain, swelling, redness and heat in the joints. It can affect the spine and commonly involves the joints of the spine and sacroiliac joints. It can also affect many other parts of the body such as arms and legs. Main characteristic features are inflammation of the joints, urinary tract, eyes, and ulceration of skin and mouth. * The symptoms are fever, weight loss, skin rash, inflammation, sores, and pain. * They will be seronegative you wouldn’t find any antibodies. Will look like they have RA, but don’t fit the criteria because they’re seronegative and don’t fit the criteria because they are young

Answer 5

* Reiter's often begins following inflammation of the intestinal or urinary tract. It sets off a disease process involving the joints, eyes slightly inflamed , urinary tract, and skin. Many people have periodic attacks that last from three to six months. Some people have repeated attacks, which are usually followed by symptom-free periods. * Diagnosis is made through a physical exam, skin lesions, and a test for the HLA-B27 gene

Answer 6

• For different parts of the body, different treatments are used: – Medications: NSAIDs, antibiotics, topical skin medications – Eye drops – Joint protection

Answer 7

• Causes pain and swelling in some joints and scaly skin patches on some areas of the body. • The symptoms are: – About 95% of those with psoriatic arthritis have swelling in joints outside the spine, and more than 80% of people with psoriatic arthritis have nail lesions. The course of psoriatic arthritis varies, with most doing reasonably well. Will be a seronegative so they don’t have antibodies testing for rheumatoid factor. Slower development of process – Silver or grey scaly spots on the scalp, elbows, knees and/or lower end of the spine. – Pitting of fingernails/toenails – Pain and swelling in one or more joints – Swelling of fingers/toes that gives them a "sausage" appearance.

Answer 8

``` • Diagnosis may involve X-rays, blood tests, and joint fluid tests. • Treatment options: – Skin care – Light treatment (UVB or PUVA) – Corrective cosmetics – Medications: glucocorticoids, NSAIDs, DMARDs – Exercise – Rest – Heat and cold – Splints – Surgery (rarely) ```

Answer 9

• IBD consists of two separate diseases that cause inflammation of the bowel and can cause arthritis or inflammation in joints: – Crohn's Disease involves inflammation of the colon or small intestines. – Ulcerative Colitis is characterized by ulcers and inflammation of the lining of the colon. • The amount of the bowel disease usually influences the severity of arthritis symptoms. Other areas of the body affected by inflammatory bowel disease include ankles, knees, bowel, liver, digestive tract, skin, eyes, spine, and hips. • Treatment options: – Diet – Exercise – Medication: Corticosteroids, Immunosuppressants, NSAIDs, Sulfasalazine or Alimta which dampens the immune system. – Surgery

Answer 10

* When the axial skeleton is involved, the initial symptom is morning stiffness and lower back pain * As the disease worsens, there is progressive diminution of motion of the spine * Eventually, the sacroiliac joints, lumbar, thoracic, and cervical spine become fused * At this stage, the spine is no longer painful, but the person has lost all ability to flex or rotate the spine and generally develops a hunched-over posture with fused flexion of the cervical spine and flexion contracture of the hips to compensate for the loss of the lordosis curvature in the lumbar spine

Answer 11

* Most common rheumatic disease and is characterized by progressive loss of cartilage and reactive changes at the margins of the joint and in the subchondral bone. * The disease usually begins in one’s 40s * Prevalence increases with age and the disease becomes almost universal in individuals aged 65 and older * Primarily affects weight-bearing joints such as the knees, hips, and lumbrosacral spine

Answer 12

* Cause is unclear * Considered to be a “wear and tear” arthritis * Obesity is frequently associated with it * Genetic factors play a role in the development that is sex-influenced and dominant in females, resulting in an incidence 10 times greater than in men * The final outcome is full-thickness loss of cartilage down to bone so can get bine touching bine so the connective tissue has eroded.

Answer 13

§ F > M § Increases with age § Begins often in youth § Creates cause of medical disability because joints becomes painful

Answer 14

* In early disease, pain occurs only after joint use and is relieved by rest * As the disease progresses, pain occurs with minimal motion or even at rest. This is because the joint specie decreases so the cartilage protection decreases. Bone touching bone. * Nocturnal pain is commonly associated with severe disease. Scarring occurs also which are boney outgrowth so pressure increases as the bine is eroded, the bone tries to regrow. But it cant regrow in places of high pressure, so it regrows in places of lower pressures which tends to be at the end of the joint. Start to get these bony outcrops start to appear. Looks like nodules called habitant nodes. * Start to see them growing these little lumps on the end of the bones

Answer 15

* Limited use of the involved joint * Walking and transfer activities may be impaired * Generally, ADLs will not be significantly impaired

Answer 16

* Meds- can use NSAIDs but it isn’t an inflammatory it is a degenerative disease. The problem with treating osteoarthritis with non-steroidal drugs is that they are analgesics too and they have a risk associated with them * Early PT/exercises * Heat/cold therapy * Joint protection * Surgery because joints are larger they are better patients for surgery. So joint replacement can be effective * Osteoarthritis is a slowly progressive disease * The eventual outcome is complete destruction of the joint, and ultimately surgical intervention is required

Answer 17

- common localised non articulate disorders Non joint related disorders which are located in just one single area - Good example is bursitis or tendinitis which is only limited to one part of the body. Not multiple joints its not systemic - Not inside the joints its outside the joints. - Associated joint structures that are resources that are located near to the joints that can be inflamed but they are not part of the joint themselves.

Answer 18

• A chronic musculoskeletal syndrome characterized by diffuse pain in the absence of synovitis or myositis (muscle inflammation). There is no detectable disorder in the joints to the surrounding structures

Answer 19

* 10-12% general population (2% adults) | * Strong female preponderance

Answer 20

* Normal physical examination * No significant abnormalities on joint examination * Characteristic finding is tenderness upon palpation of discrete anatomical locations termed tender points. Antibody negative normal renal function everything will appear to be okay. - These are tender points where if you press them the patient will tend to complain about those points.

Answer 21

* diffuse aching/stiffness, worse in am (may mimic RA) * fatigue/exhaustion/sleep disturbance * sensation of swelling of hands/feet (examination normal) * paresthesias (normal EMGs) * tension headaches / migraines * symptoms of irritable bowel syndrome * anxiety/depression * weight gain (++)

Answer 22

• Working model: – A disorder of pain processing – Central nervous system “sensitisation” – they perceive non painful stimuli as painful – Makes usually non-painful stimuli feel painful Local non articular disease- they will be located in one particular area. They wouldn’t be attached to joints The typical example if IDDM, but Hashimoto thyroiditis is also a good example of an organ specific (localised) not articular autoimmune disease. This is when the thyroid will self-destruct by making antibodies to those tissues that should be producing thyroxine. Another example is type 1 diabetes as the tissues will destroy that particular area.

Answer 23

* characterized by the destruction of thyroid cells by various cell- and antibody-mediated immune processes. Will become hypothyroid * Presence of typically anti-TPO (anti-thyroid peroxidase) and anti-Tg (anti-thyroglobulin) antibodies suggests Hashimoto thyroiditis however, 10-15% of patients with Hashimoto thyroiditis may be antibody negative

Answer 24

* Just like any other hypothyroid state * The treatment of choice for Hashimoto thyroiditis is thyroid hormone replacement * The drug of choice is individually tailored and titrated levothyroxine sodium administered orally, usually for life.

Answer 25

* Childhood and current low socioeconomic status are associated with increased risk of RA. * Hormonal and reproductive factors contribute to the female predominance in RA; parity, breastfeeding, and exogenous hormones.

Answer 26

* Conflicting results with some showing: * Protective link between olive oil/fish * Higher risk between red meat and protein * However neither proven in large cohort studies * Low Vit D and C and possibly copper and selenium may have a role. No studies because no money to fud the research.

Answer 27

* Statins have modest anti-inflammatory activity. Patients should be on a cardiovascular risk protection anyway. * Studies show RA risk possibly reduced by up to 40% in those taking statins * Ongoing research in progress to assess the anti-inflammatory effects

Answer 28

* These are potential associations, although epidemiological confirmation has not been possible * Epstein-Barr virus * Human Parvovirus B19

Answer 29

* The data is varied * Most recent data suggests lower education level and occupational class favours RA * A study in Sweden suggests that those without a university degree have a 40% higher risk of RA. Lifestyle of smoking triggers RA and poorer diets in people with lower socioeconomic status.

Answer 30

* Pregnancy seems to affect the onset of RA because hormone is messed up. * One study showed that the risk of RA during pregnancy is reduced, but increases in the 12 months after delivery * Some hormonal factors are in play, possibly androgen although yet unknown

Answer 31

* Higher birth weight has been shown to link to RA * Babies > 4.5kg have double the risk of developing RA * Probably a hypothalamic-pituitary axis dysfunction- hormones may have had an effect on the switching of those genes.

Answer 32

* Autoantibodies precede disease * Can be 5-10 years before symptoms * Levels rise as symptoms emerge * Rheumatoid factor (RF) * Anti-cyclic citrullinated peptide antibodies (Anti-CCP) * Not everyone is seropositive

Answer 33

- Preclinical stage you have the antibodies at a low level - All of a sudden you get this inflammation as it increases with the antibody production - You get this auto-anti autoimmune which has been triggered by something which then get these antibodies produced and then you get these symptoms which is recognised by the patient and then the joints are affected. - Yellow part can stretch out between 5-20 years

Answer 34

- There is a genetic risk and an environmental exposure - Get a switching of that genetic kind of mix to be auto immune. - Can get pre-clinical autoimmune that you can measure but there are no signs - Get clinical presentation then will get diagnosed when they’ve got auto immunity. There are all of the factors as well as all of the symptoms

Answer 35

- You have these protein antibodies increase and as a result this increases IgG response. - Building up this pool of anti-CCP and they affect the body. They will charge the immune system - They fix complements and they activate Fc receptors and can act like antigen presenting cells where there is an amplified effect in the immune response - Can tell how strong the RA is and will be an indicator how they will do in the tests and most likely they will do poorly and will need to start aggressive treatment.

Answer 36

* Currently being investigated * Aim is to ID the high risk RA autoantibodies and address the preclinical phase before it transitions * ? Role for statins * ? (Anti) Anti-CCP

Answer 37

- RF and anti-CCP antibodies and the acute reactant phase (CRP) - If you had a patient who was seropositive for all of the things so high ESR, high anti- CCP and high factor positive (RF) then you would get an idea that the prognostic value is very high. Important because it is important to start treating the patient early and very aggressively to get their disease under control because they are at a risk of deteriorating because of the indicators.

Answer 38

* Inflammatory polyarthritis many joints affected) is central * Particularly the small joints of hands and feet. People who have arthritis in larger joints tend to be more degenerative like osteoarthritis * 80% of RA patients have RF and Anti-CCP Abs. if you measure their ESR and their CEPR it will always be more raised * Inflammatory markers are raised * Joint erosion and destruction can occur and can affect every day things. It is irreversible. * Joints become swollen and tender (synovitis)- where the joint capsule becomes swollen and tender. Both presentations together

Answer 39

- On the left hand side of the diagram there are healthy joints. - On the right hand side of the diagram the joints have been affected by rheumatoid. - There are lots of mediator cells in the capsule and they are always bad because they will be acting as antigen presenting cells and they will be doing things such as fixing complements, turbocharging local immune reaction. - This will ultimately get a cytokine production which will act as a proteinase solution and will destroy the protein structures surrounding it. - The structures that are primarily attacked are the bine and the synovial membrane which will become scarred and thickened so it doesn’t work as well. The bone will go with it and it wouldn’t be able to be repaired and will lead to permanent joint damage - In early disease you will see fingers and knuckles being swollen so the mCPs and the PIPs are swollen - Difficult to see this presentation

Answer 40

- If you don’t treat the disease can develop swan neck deformity and boutonnière deformity - boutonnière deformity is where you start to get this kind of fixed flexion of the joints and the finger starts looking like this. will happen to all of the fingers in the hand. - Swan neck deformity is where the joints are fixed up in this way - Can have a severe impact on a person’s daily life. Affects quality of life

Answer 41

The joints starts to rotate and kind of collapse in on itself. Cant straighten your hands out

Answer 42

• Gradual – Most common, small joints, EMS prominent, symmetrical • Slow, monoarticular – Less common, larger joints spreading to smaller over weeks • Abrupt, acute polyarthritis – Widespread affecting small and large joints leading to incapacity

Answer 43

* Lots of inter patient variability. Typically it is a gradual onset. Can have on and off * Brief/self-limited * Palindronic * Prolonged and progressive * All of the above can range from mild to severe

Answer 44

- Count the number of joints in specific places and then look at how many of these joints are tender and hoe many of the joints are swollen - Then look at the acute phase reactants so you can do and ESR and then do a global health assessment asking ho active their RA has been and that will equate to a number between 0-100 and then put all the numbers into the DAS-28 formula. - What’s good about the das 28 is not only can it categorise disease activity in a single measurement but it can also tell you how effective that’s changed over time. If you do a das score when you initially see the patient and then after a period of time the das score will have improved. It is really helpful to give those threshold for treatment. - You have to have a das score of 5.1 to be classified as having an active disease and you can say that you can give drugs that are either very toxic or very expensive. People with higher disease activity because they are more likely to receive a benefit than those who have a low active disease. - Can also use das score to continue therapy. If you started a new drug and then after a period of time you take another das score and it comes out worse you will be able to say that that particular drug hasn’t worked so you can change it to something different - You can also measure the impact of the disease on patients quality of life by using the HAQ-DI score. Ask them a range of questions. - 0 = no disability - 3 = unable to carry out tasks Change of 0.22 is significant

Answer 45

* HAQ score at baseline is a predictor of outcome- if they score really poorly when first diagnosed then it is unlikely that they are going to make massive improvement from that. Can make significant improvements but the score will still be bad. * Radiographic changes at baseline are a poor indicator * Acute phase reactants predict damage- anti-CCP, RF can predict the amount of damage that the patient is in * Early treatment, tight control is the key

Answer 46

Fibrous growth caused by pooling of RF immune complexes- they don’t cause any medical problems jus not very nice to look at. Because they are not medically life threatening surgeons wouldn’t remove them. - The only way in which a nodule can cause a problem is that if they form at a joint or a bend because it will cause restriction in the movement of that joint. - Problem is that they often grow back again in the same place. You have removed the nodule but you have also developed scar tissue from the surgery. If the nodule grows underneath the scar tissue can make the situation worse. - Can inject nodules with a steroid to make them shrink a little bit and if the patients drug therapy is good nodules can also decrease in size

Answer 47

* Occurs frequently – often missed * Pulmonary nodules * Interstitial lung disease (ILD) happens in about 7%of RA patients, but they have a 3x increase in risk of death. * Methotrexate is an anchor drug in RA as it always used unless there is a problem with either side effects or the tolerance. Methotrexate can cause pulmonary fibrosis. Have a higher rate of interstitial lung disease and then you have also got a drug that can predispose someone to put more fibrosis. * Before you start methotrexate you should check the lungs by doing an x-ray to make sure they are okay and don’t have any sign of nodules of our lung disease before you start the patient of methotrexate

Answer 48

* RA may lead to generalised vascular disease * Pericarditits is often seen * Cardiovascular disease is common and risk of cardiac death is high. Need to do a QRISK. Make sure their blood pressure is okay * Important to treat risk i.e. antiplatelet/statin/anti-hypertensive * DMARD therapy significantly lowers risk

Answer 49

- Episcleritis – sudden onset of redness and pain | - Sicca syndrome also common- dry eyes and the patient will often ask for a lubricant eye drop for their eyes

Answer 50

- Many chronic inflammatory diseases have been shown to occur preferentially in individuals carrying certain variants of genes in the MHC (major histocompatibility complex). Part of the human leukocyte antigen and more precisely the MHC complex of human chromosome-6. If you express this gene then more likely to be susceptible of having certain types of inflammatory diseases. The contribution of genetic factors to RA • Twin and family studies show a contribution of genetic factors to RA • HLA-DRB1 is the most likely genetic link- twins c • HLA-DRB1 is modified by smoking and other environmental factors

Answer 51

- RH and anti-CPP antibodies are indicators to see how well the patient is going to do as their disease progresses

Answer 52

* Autoantibodies recognise antigens on IgG * Leads to compliment fixation (ie turbocharges the formation of immune complexes) * Detected in 50-80% of RA patients depending on stage of disease * High titre is more specific (>40IU/mL) * RF predicts disease, high titre = more severe RA, rapid progression, worse outcome

Answer 53

* RA patients have epitopes that come from citrulline, recognised by autoantibodies * Anti-cyclic citrullinated peptide antibody test is the way we check for these antibodies (Anti-CCP antibodies) * Highly specific (>95% for RA)

Answer 54

* Chronic inflammation of the synovium- layer of tissue that lines the inside of the synovial over your joints. That lining becomes infiltrated with inflammatory mediators. Cytokines are produces that causes the damage to the joints. Need to use medicines which inactivate/neutralise the cytokines. * Leads to destruction of cartilage and bone * Macrophage like synoviocytes are recruited and retained * Inflammation leads to increase in T and B cells- the inflammation mobilises from the b and t-cells and increases their numbers at the joints

Answer 55

- This Is a cascade model of the ultimate response which is the ultimate response which is the cytokine production. Can see how b and t-cells are involved - The other antigen presenting cells kind of turbocharge that cascade to the production of the cytokines. - Want to avoid TNF-alpha and some of the interleukins and a lot of the original drug targets look at trying to neutralise TNF-alpha - There are some other drugs like b-cell depleters and t-cell cause stimulation blockers. - All places in the cascade are targets for drug development so if we can disrupt the cascade in some way can stop some of the unwanted things at the end from happening.

Answer 56

- These are the cytokines that have a damaging effect on the joints - TNF-alpha, interleukin-6 is important in rheumatoid. - These are the cytokines that increase RA. - If you can neutralise them then you can reduce the damage in the joints

Answer 57

- TNF-alpha mediates a lot of things and interleukin-6 as well. They mediate the damage that happens in the bone and cartilage - TNF-alpha has an effect where it activates osteoclast and then the sites becomes active and inflamed. - This all leads to the damage of the joints of the bone and the cartilage - There is also interaction with prostaglandin activity and this is important for pain response - Prostaglandin, TNF-alpha and interleukin-6 all have this interplay with the t and b-cells and how that reacts with the osteoclasts which are the cells which are removing bone. And then the health of the cartilage by the contra sites - The TNF-alpha and interlekin-6 for rheumatoid is what is driving the process.

Answer 58

* Complete remission is the goal * Aggressive therapy is important * Erosions possible in 2 years without good Tx (treatment) * Prognostic indicators should drive most aggressive therapy * Step-up paradigm most common

Answer 59

* Use an anchor drug first (MTX)- methotrexate * Then add another * Permits graded escalation of therapy with minimum number of medicines * When traditional DMARDs ineffective as they are toxic – add a ts or bDMARD

Answer 60

- Typical treatment for RA. As long as you don’t have contra-indications to methotrexate would always use it first and then add something else in. - Glucocorticoids are very useful at dampening down any flare up for an acute presentation. - If you get a good response with methotrexate then you would continue it and then think about dose reduction if you get into a sustained remission. - Often doesn’t work on its own so you have to add something else to it - If you dint have high levels of antibodies, you would add another DMARD and if that doesn’t work you would go back to the biologic drug - You have to fail 2 DMARDs in order to have a biologic drug (a type of treatment for long term medical conditions including RA) - The JAK ace inhibitors are example of targeted synthetic drugs. - If that doesn’t work you change the DMARD biologic drug to JAK-inhibitors and if that works which is usually does, you would think about reducing the dose and see if they can have a break from the drug to see if they stay in remission

Answer 61

- Synthetic DMARDs which are known as the traditional DMARDs which are the methotrexate - Have targeted DMARDs which are not biologic drugs. They are small molecules so you can take them orally. Can consider them in the same category as biologics as they work very similar- Tofacitinib and Baricitinib those are the JAK-inhibitors - The biologic DMARDs such as adalimumab, etanercept, rituximab- targets TNF-alpha and interleukin-6 - abatacept(t-cell called stimulation blocker)

Answer 62

• About £10,000 per year per patient • NICE limits access to these medicines – Disease is severe, that is, a disease activity score (DAS28) greater than 5.1 and – Disease has not responded to intensive therapy with a combination of conventional disease modifying antirheumatic drugs (DMARDs)

Answer 63

* A team approach improves outcome * Many different professions are involved in the care of an RA patient * Pharmacists are important

Answer 64

* MSK pain significantly impacts quality of life * Opioids are often spared because of the worry of tolerance and ADRs * A proactive approach when applying the pain ladder is advocated * ADRs like constipation can be managed with good pharmaceutical care

Answer 65

* Have been abused in the past * Oxycodone one of the most widely abused prescription drugs in the US * 13,000 deaths a year from opioid OD * Correct patient selection is imperative * Right patient, right drug, right time

Answer 66

* In naïve patients use short acting agents first * Start at the lowest dose that doesn’t cause too many side effects but still relievs the patients pain * Titrate by 30-50% and assess pain * Once stable, convert total daily dose of short acting to a long acting preparation

Answer 67

- Convert everything to the aily dose of morphine and see what you are told the daily dose was - Could think about converting them to a longer acting preparation once you worked out wheat their opioid burden was for the whole day.

Answer 68

* Beware of renal impairment with morphine, easy for patients with AKI to accumulate morphine and become toxic * Role for naloxone protocols * Constipation managed proactively with softener and stimulant laxative interactions

Answer 69

• Useful as a background anti-inflammatory • There is inter patient variability between response to each NSAID • Beware of the potential side effects – consider the risk/benefit of each of – CV risk – GI risk – Renal risk

Answer 70

* Well absorbed * Highly protein bound * Metabolized by liver * Excreted by GF or TS- this may be a problem because there are some drugs which are excreted in the same way and there may be competitive interaction between excretion, which may lead to one of the drugs accumulating more than you need to be. * Peak plasma 1-4 hrs * Accumulation at site of inflammation * Short half lives- repeated dosing is needed

Answer 71

- Can explain the adverse drug reactions and the efficacy of the drugs too. - If you have a non-selective NSAID you will inhibit COX1 and COX2 and ultimately you can get ulcers, bronchoconstriction, hypertension and peripheral oedema. - Can get anti thrombotic activity - If you inhibit COX2 then there is an increase in peripheral blood pressure and fluid retention. Might get pro thrombotic activi

Answer 72

- All of the NSAIDS have different selectivity for COX-2 - On the right of the line there is a more selective and less selective on the top of the line for COX-2 - The right of the line shows progressively greater COX-2 specificity

Answer 73

* No difference in efficacy between tNSAID and COX2I * Particularly useful in acute inflammation * Choice varies between patients * If no effect in 2/52 switch to an alternative * No rationale for combo therapy

Answer 74

- Drugs which shows the side effect of having GI problems. - Ones further to the right means there is a higher risk - Naproxen has a higher GI risk than Diclofenac but it is all dose related

Answer 75

Odds ratios and 95 % confidence intervals for cardiovascular death Angiolillo DJ, Weisman SM. Clinical Pharmacology and Cardiovascular Safety of Naproxen. American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions. 2017 Apr;17(2):97-107 - Diclofenac would be the highest one then ibuprofen and then naproxen. - Naproxen is a bit strange in terms of cardiovascular risk because naproxen has a little bit of anti-platelet activity in comparison to the other traditional NSAIDs so it therefore lowers the cardiovascular risk.

Answer 76

* Various systemic effects that have an effect on disease modification * Decrease proinflammatory cytokines and enzymes just like you would see in TNF-alpha with a biologic drug * Inhibit transcription factors, decrease T cell function and Fc receptor expression * Adverse events common, short courses only

Answer 77

- Use prednisolone orally and only lasts a short period of time and triamcinolone as an injection which They are longer lasting steroids

Answer 78

* Clearance varies by time of day because of the disruption of normal cortisol production * Very early am admin results in more profound reduction of inflammation

Answer 79

- the pro inflammatory proteins: TNF-alpha and leukatirn-6 and these are the ones that ultimately we want to stop being produced. - This is because it will dampen down the inflammatory kind of response in the joints

Answer 80

* Use the lowest dose for the shortest time * Discuss risk and benefit * Use in combination with a DMARD * Offer adequate bone protection

Answer 81

• The ACR is reported as % improvement, comparing disease activity at two discrete time points (usually baseline and post-baseline comparison) • ACR20 is ≥ 20% improvement (clinically significant) • ACR50 is ≥ 50% improvement – ACR50 responders include ACR20 responders • ACR70 is ≥ 70% improvement – ACR70 responders include ACR20 & ACR50 responders

Answer 82

* Old school drugs but still very useful * Gold * Sulfasalazine * Hydroxyxchloroquine * SSZ and HCQ used in the UK gold very rarely

Answer 83

* Rapidly absorbed and highly protein bound * Very slowly eliminated via kidney * MOA unknown, probably reduces oxidative stress and affects macrophages so it cant move around so it cant act as antigen presenting cells and cytokines * IM gold as effective as oral MTX * Higher ADR rate than MTX

Answer 84

* Prodrug, metabolized by bacteria to 5ASA and sulfapyridine – only the latter is absorbed * MOA unclear, probably reduces oxidative damage * Effective as lower doses of MTX. Used as an add on with methotrexate if it fails * Generally well tolerated * Can cause oligospermia- reduction in sperm mortality

Answer 85

* Antimalarial found by chance to improve RA * T ½ is 40 days but LDs not normally used as increase in ADRs * Cpss takes 3 months ie slow acting * Often used in SLE as its ‘anchor’ drug * Inhibits Toll-like receptors affecting cytokine signalling

Answer 86

• Rank ibuprofen, naproxen, and diclofenac in terms of their relative risk of cardiovascular thrombotic events starting with the highest risk. Why is the dose of drug important and how does this affect your risk ranking

Answer 87

* Structural analogue of folic acid * Adenosine theory increasingly accepted * Can be extremely effective against RA * Must be monitored properly

Answer 88

* Can be toxic in high doses * Given WEEKLY * Use folic acid to decrease ADRs- usually stomach problems and mouth ulcers and hair falling out * Only use 2.5mg tablets- to reduce overdose. There is 10mg in practice but it is never given * Patients must have regular blood tests * Patients must be counselled on the medicine

Answer 89

inside of the cell, the methotrexate will cause an increased concentration of adenosine to be formed inside of the cell. - The adenosine will move outside of the cell through the cell membrane into the extra cellular space. - In this space the adenosine is free to circulate in the plasma. - When it does it can bind to these specialist receptors on the cell membrane: A2a and A2b receptors and doing so they will cause an increase in the intracellular cyclic AMP - It is the intracellular cyclic AMP which is having an anti-inflammatory effect at these doses - At high doses you get immunosuppression and with low doses you see an anti-inflammatory effect.

Answer 90

- If you inhibit the DHODH (an enzyme), stop the building blocks from being produced. You are reducing the amount of proliferation of these cells that were adding to the inflammatory processes.

Answer 91

* Only azathioprine used in RA usually. Doesn’t have that much side effects. * Cyclophosphamide, ciclosporin and mycophenolate more associated with severe ADRs compared to azathioprine

Answer 92

* Cleaved to 6MP when metabolised * 6MP to inactive 6-MMP catalysed by thiopurine methyltransferase (TPMT) * If low TPMT more 6MP is available to form 6-TGNs which is the inactive form so you would get greater amounts of the active form. * 89% have high TPMT 11% have moderate 0.3% have no TPMT activity * When TPMT levels are low, higher levels of 6-TGNs are produced and this is associated with a greater risk of myelosuppression. * Must measure TPMT activity before starting to ensure correct dose

Answer 93

• 6MP can be converted in the body to active 6-TGNs or inactive 6-MMP • The enzyme responsible for inactivation is TPMT • If this enzyme is low, less 6MP is inactivated and therefore more is available to be converted to active 6-TGNs 6-MP= 6-mercaptopurine 6-MMP= 6-methylmercaptopurine 6-TGNs= 6-thioguanine nucleotides TPMT=thiopurine methyltransferase

Answer 94

- 6MP Undergoes activation or inactivation . the inactivation which is driven by TMPT which is enzyme dependent. - If you don’t have much TPMT, you wouldn’t activate many of the 6MP which means that more is available to be converted to active 6-TGN - If you have lots of TPMT enzyme, you will inactivate a lot of the 6MP which means less will be converted to active 6-TGN - High enzyme, more inactive drug so you need a higher dose - Low enzyme you have more active drug so you need a lower dose. - 50mg Azathioprine with someone with inactive enzyme will be different activity levels to 50mg with someone who has a very high TPMT level because they will have much high levels of 6-TGNs

Answer 95

* T Cell activation sustains synovitis- can dampen down the number oof t-cells that are activated and therefor can attenuate the synovitis * Activation requires costimulatory signals * Abatacept blocks these costimulatory signals and prevents T cell activation

Answer 96

- Shows how antigen presenting cells and t-cells can cause stimulation - The antigen presenting cells is presented with a t -cell and then the co-stimulation begins and then the t-cell can go do something - If you can break the t-cell stimulation the antigen presenting cell will never be fully present on the t-cell

Answer 97

* Soluble human recombinant fusion protein * CTL4/FC conjugate * Prevents costimulation * IV but now available as sub cut

Answer 98

* Comparable to other biologics DMARDs * Mild infusion related reactions * Low immunogenicity

Answer 99

* B cells are required for antigen presentation * This leads to RF and Anti-CCP autoantibody production * If reactive B cells can be destroyed then antigen production can not take place

Answer 100

* Chimeric human mouse monoclonal antibody * Targets the CD20 receptor on B cells so kills b-cells * IV infusion 2 doses of 1000mg 14 days apart repeated every 6 months

Answer 101

When you bind to the b-cell, the CD20 receptor will bind to the b-cell and you get a signal for the b-cell to die. - Get rid of the b-cell by an antibody dependent cell mediated cytotoxicity

Answer 102

* Most studies show better outcome compared to MTX monotherapy * Infection rates remain low * 1 in 25,000 risk of progressive multifocal leukoencephalopathy. Life threatening adverse reaction that can occur. * No increase in malignancy. B-cells controls tumour cell growth

Answer 103

* Multifunctional cytokine important in RA * Produced by T cells B cells and many other cells * Wide range of effects including inflammation

Answer 104

* Humanised monoclonal antibody which targets IL6 * Competitively blocks IL6 from binding to its cell bound receptor * Can be given as a sub cut injection * If you bind to the receptor then IL6 cant bind to it so it is competitive so then the cell cant signal.

Answer 105

* Good efficacy | * Comparable to other biologics

Answer 106

* TNF-a has been the major target for biologic RA therapies and are first line after DMARD failure * Wide ranging attenuation of inflammatory effects cause profound disease modification * More effective when combined with MTX (methotrexate) by dampening down the immunogenic stuff

Answer 107

- There are 5 therapeutic TNF inhibitors that can bind to TNF receptors - Each TNF inhibitor has a different structure. There are 3 monoclonal antibodies - One is a fusion protein and one is a pegylated TNF inhibitor fragment. - When TNF inhibitor is attached to the TNF molecule, they prevent the TNF from binding to targeted immune cells - This reduces the pro-inflammatory potential of TNF - The immunogenicity can occur as a result of the production of the antidrug-antibody to all therapeutic proteins including TNF inhibitors - Two types of antidrug-antibodies: non-neutralising antibodies and neutralising antibodies - Neutralising antibodies are thought to bind to the TNF inhibitor and prevent it from attaching to the TNF receptor - Non-neutralising antibodies are thought to attach to the TNF inhibitor without affecting its binding to the TNF receptor - The precence of wither type of antidrug-antibody can affect the pharmacology and will have impacts on the clinical response

Answer 108

• All agents follow a similar pattern wrt ACR response

Answer 109

* Generally safe but a few things to remember * Can reactivate latent TB – must have CXR * Slight increase in infection rate but not serious * All are sub cut injections, patient must be trained to inject

Answer 110

1. Humanized 8% immunogenicity rate vs up to 50% chimeric infliximab (HACA) vs about 10% fully human adalimumab (HAHA). 2. Monovalent Does not cross-link antigens to form large supramolecular complexes. Better tissue penetration. 3. Pegylated Improves drug pharmacokinetics and bioavailability. 4. Fragment Minimizes potential Fc-mediated effects such as complement-dependent cytotoxicity (CDC) or antibody dependent cell-mediated cytotoxicity (ADCC).

Answer 111

* Offer Anti-TNFa 1st- adalimumab * Switch to different anti-TNFa or use IL6 (tocilizumab)/T-cell blocker (abatacept) * B Cell depletor (rituximab)

Answer 112

urrently, there are four known Janus kinases - JAK1, JAK2, JAK3, and TYK2. • JAK3 is restricted to the immune system and is involved in signal transduction of cytokines via signal transducers and activators of transcription.

Answer 113

cytokine binding to its cell surface receptor leads ti receptor polymerisation and autophzsphylation of associated JAKS activated JAKS phosphorylates the receptor that dock STATS activated JAKS phosphylate STATS which dimerize and move to the nucleus to activate new gene transcription

Answer 114

a oral JAK inhibitor targets immunimodulator and disease modifying therapy for RA MOA: JK1&3 specific with functional specificty over JAK2 unlike biologics which target extracellular molecules such as pro-inflamattory cytokines, Tofacitinib targets the intracellular signalling pathways that operate as hubs in the inflammatory cytokine network

Answer 115

biological product is “highly similar” to the referenced product notwithstanding minor differences in inactive components • No clinically meaningful differences between the biological product and the referenced product in terms of safety, purity and potency.

Answer 116

* The manufacturing process and environmental conditions used for a “referenced product” difficult to duplicate * “Biosimilars are highly unlikely to be identical to the “referenced product” but may not affect clinical outcome * 30% cheaper (£7,700 vs £11,000 for infliximab)

Answer 117

* Lupus is a generalised inflammatory autoimmune disease * Affects practically all organ systems * Autoantibodies are detected against DNA- anti DNA antibodies * Connective tissue/joints/kidneys/skin/brain/blood cells * End organ damage is possible

Answer 118

- These are both inflammatory conditions, with similar joint related symptoms but only one is autoimmune in origin. Driven by urea crystals in the joints and they stick in the surrounding tissues which causes inflammation.

Answer 119

* SLE is an autoimmune rheumatic disease * Unknown etiology-originates from DNA but can also have environmental triggers * Is a systemic disease involving connective tissue which is present all over the body. * Autoantibodies have intracellular targets- targets which are two parts of the cell which are involved in DNA replication. * Antinuclear antibodies (ANAs) are present in at least 95% of patients with SLE. * Anti–double-stranded DNA (dsDNA), anti-smith (anti-Sm), anti-Ro, and anti-La antibodies are examples of these ANAs * 12:1 female to male ratio

Answer 120

- Lupus development overtime looks a lot like rheumatoid - There is some sort of trigger and then there is a period of subclinical auto immunity that develops - The balance is then tipped as you get an increased formation of antibodies and antibody clusters and then you develop symptoms

Answer 121

* Autoantibodies and clinical features appear years before the diagnosis of SLE * Many patients with SLE spend time with symptoms before meeting the ACR criteria as the clinical features are so diverse they get mistaken for something else. * A wide variety of symptoms, with equally different severity between patients makes SLE difficult to diagnose. * SLE can be organ, and life threatening.

Answer 122

- These are skin presentation and can be varied | - Butterfly rash is typical presentation or inflamed rashes that looks like psoriasis

Answer 123

- Looks like an arthritis as there is some joint deformity - Slower progressive and non-invasive. These patients don’t get tested positive for RF or anti-CCP * Joint inflammation and destruction can occur * Its course is different to typical inflammatory joint disease like RA * The systemic nature can lead to the incorrect primary diagnosis

Answer 124

Renal involvement is a severe complication of SLE- because the immune compexes gets stuck in the filtration system, that is the kidneys, this can cause lots of local inflammation of the connective tissues and they can cause scarring and ultimately destruction of the tissue so it cant filter blood anymore - lupus nephritis causes scarring and destruction of renal tissue - Classified as class 1-V1 indicating the amount of damage.

Answer 125

- Renal damage as the lesions that has happened has cause the filters to become blocked - Your kidneys work in this network of filtration system and those filters (little holes) that would filter unwanted stuff and when they get blocked up by these immune complexes this leads to scarring which means that the filters don’t work anymore

Answer 126

- The immune complexes blocks little arteries in the brain of the CNS which causes lots of inflammation to occur and don’t function well - In the CNS this causes central problems to occur such as confusion states and fits that can be confused for epilepsy

Answer 127

- Can get lupus that is caused from drugs. - iatrogenic lupus is mild and doesn’t seem to be involved in as many complications as immunocompromised driven lupus’s. - auto-immune driven lupus’s tends to be more severe.

Answer 128

- This is a scoring system for measuring improvements of lupus patients to treatments - Called the systemic lupus disease activity index - Works as a scoring mechanism and then how you would classify improvements in the disease - The diagnostic criteria for lupus is large due to all the body systems that can be affected by lupus - Can see if a patient has responded to treatment in that particular domain so you can kind of work out this index based on whether the patients symptoms has improved by 50% of the score that you collected from the start.

Answer 129

* NSAIDS- need to be careful because their renal function may not be as good/damaged so it may accumulate in their kidney and not excrete it out as well. May become more toxic. * Hydroxychloroquine- more effective in lupus than in the other rheumatoid diseases. Hydroxychloroquine tends to be an add on for the other diseases, however it is considered an anchor drug in SLE because it does seem to be pretty effective. May be due to the fact that people who have lupus have skin conditions and Hydroxychloroquine is distributed in the skin layer quite well. Has a positive effect on the skin condition. * Glucocorticoids- some cases in lupus where you have to have pretty high doses of steroids even if it is for a short period of time to manage somebody’s flare

Answer 130

- Anticonvulsants and psychotropic agents , anxiolytics can dampen down the overactivity of the CNS if it causing a problem with people who are fitting or having problems with lapses of concentration - More about treating the symptoms - The underlying causes are usually handled with steroids and things like cyclophosphamide to get acute flares under control.

Answer 131

- Classification of the renal involvement: class 1-6 - shows you how much damage there is in the kidney and whether or not they function well. - Want to prevent it from developing because when you get to the more advanced stages, the kidney will not be working properly and may require a kidney transplant

Answer 132

* IV cyclophosphamide (cytotoxic drug) pulse therapy in combination with glucocorticoids is the gold standard for the treatment of severe lupus nephritis * Can quickly establish remission and prevent organ failure * Must also include a maintenance strategy. Can have an effect on fertility

Answer 133

* Have been studied as remission inducing and maintenance therapies * If used correctly can maintain remission at high rates * Seldom used for induction and IV cyclophosphamide is the standard therapy.

Answer 134

• An inflammatory arthritis caused by precipitation of uric acid crystals in the joint - Crystals don’t really show up in joints - Cant see any soft tissue

Answer 135

* Under excretion of urate- don’t pee out enough so it accumulates in your body and will crystallise out because your plasma can only hold a certain amount of urate before the solution starts to become saturated * Over production of urate- your body cant get rid of the overproduction of urate * >90% of patients with primary gout are undersecretary (their kidneys do not get rid of enough urate)

Answer 136

- Need to try to reduce the amount of urate that is circulating around - Would normally intake purine and undergo purine nucleoside metabolism which is converted to xanthine - This is converted to uric acid. And this conversion is controlled by an enzyme called xanthine oxidase - Some would go through renal excretion and some will go out through your gut and the rest will be circulating around the plasma. - If there is too much circulating around the plasma this is when the urate will come out of solution and start to crystallise at the joints - When urate is deposited at the joints you get an inflammatory reaction as a result and this inflammatory action activates neutrophils and they start neutrophils reaction which leads to inflammation and pain - If that goes on for a long time, you can get solidified urate called towfigh that builds up in the joint space - Areas of drug targets called uricosurics which helps to increase the amount of uric acid that is pushed through the renal excretion rate. - Can stop xanthine oxidase from working and that would prevent the uric acid from building up in the first place. So you can use xanthine oxidase inhibitor such as allopurinol - Can try to prevent the neutrophils from being activated and part of that activation is driven by a cytokine called interleukin-1 so you could design a drug that would block interleukin-1 and stop the neutrophil reaction. - The role of uricase and allantoin. Uricase is an enzyme which will convert excess urate in the plasma to an insoluble compound called allantoin. This enzyme is missing in humans don’t have uricase in our genome anymore. If we did have uricase there would be no gout so wouldn’t be able to express allantoin

Answer 137

- men are more affected with gout than women - Could be due to hormonal reason - Typical person who presents with gout has a poor diet, drinks too much and is overweight and doesn’t do any exercise.

Answer 138

``` • Male/post menopausal women • Metabolic syndrome • Diet – High purine intake – Alcohol – Fructose • Drugs, including: – Diuretics – Low dose aspirin – Ciclosporin • Increased cell turnover (malignant disease) • Genetic predisposition ```

Answer 139

* CAN’T LEAP * Ciclosporin * Alcohol- remember this one * Nicotinic acid * Thiazide- remember this * Loop diuretics- remember this * Ethambutol * Aspirin (LD) * Pyrazinamide

Answer 140

- 4 phases of gout you can find. - Have asymptomatic hyperuricemia- the urate concentration is raised but it is not enough for it to come out of solution and cause the crystals - Acute flares- person will get a flare and then it will go away and will happen again . they are painless segments where the body is trying to redissolve ( trying to put the excess urate back into solution) get rid of the crystals on your own. Can only do so much and as the uric levels increase your ability t0 redissolve the crystals become harder or to push the uric acid through the kidney for excretion. - The 4th stage is chronic where more than one joint is affected and get deposition of these towfigh. The urate in the joints which can cause problems

Answer 141

- Measures whether someone’s got a definite diagnosis of gout. - What does it feel like, what’s the time cause, do you have any towfigh - Measurement if urate? Can you actually see any crystals in the joints - Is there any evidence of joint damage - If you have a score of equal to or more than 8 then you are classified as having gout

Answer 142

- The rate of concentration is a measure that you use to diagnose and give guidelines of treatment choices - 4 ways you can express the concentration. Now it is micromoles per litre or millimoles per litre - Can get % or decilitre representation as well. - The range is between 180-300 micromoles or 0.18 and 0.13 millimoles per litre and then 3-5 milligrams per decilitre - Ideal range would be to below 300 micromoles per litre

Answer 143

- Xanthine oxidase inhibitors lowers the production of urate in the body eg allopurinol - Uricosuric drugs increase the excretion of uric acid in the urine and thereby reduce plasma concentration e.g. probenecid

Answer 144

- When you have an acute treatment of gout, you want to try and get the inflammation under control as quickly as possible. Do this by using NSAIDs which will quickly calm down the inflammation - Key thing about the treatment is that you can’t start urate lowering drug therapy when you are in critical periods ie an acute attack - This is because if you do tis there is a risk that you can increase the uric acid concentration - An initial response to therapy is when you start urate lowering therapy is that you see a spike in urate levels. So you have to wait for about a month or so after the acute attack before you think of initiating the drug therapy - Wouldn’t give it to someone who has a first attack, you would wait and see if there will be another attack or if it was just a one off that could be due to lifestyle that may have triggered the acute attack - If they do have continued problems with their urate then you start on the ULDs. Start of allopurinol in low doses and then titrate up to be below 0.3. start at 100mg - If you cant use allopurinol then use an alternative drug such as febuxostat or in renal insufficiency cant use allopurinol because they will accumulate and wouldn’t excrete it.

Answer 145

Serum urate must be measured regularly and urate-lowering therapy should be adjusted to attain the therapeutic target. A serum urate level <6 mg/dl (<360 micromol/l) should be targeted and maintained in all patients with gout In patients with severe gout, such as those with tophi or frequent attacks, the target should be a serum urate level <5 mg/dl (<300 micromol/l) until clinical remission is achieved Acute attacks should be treated promptly with anti-inflammatory medications, taking safety issues into consideration Prophylaxis against attacks should be initiated and continued for at least 6 months after starting urate-lowering therapy. In all patients with gout, renal function should be assessed at the time of diagnosis and then monitored regularly. Comorbidities associated with gout may influence therapy and outcomes and should be assessed regularly and managed Modifiable risk factors should be addressed primarily through patient education and support. Information about gout and its management should be made readily available to patients by their healthcare professionals.

Answer 146

``` • DO NOT EAT HIGH PURINE CONTENT – Oily fish, shellfish – Game – Offal – Marmite/yeast extract • EAT SMALL AMOUNTS OF MODERATE PURINE CONTENT – Meat/chicken – Beans/legumes/peas – Spinach/cauliflower/asparagus – Mushrooms – Wholegrains • EAT MORE LOW PURINE CONTENT – Bread/pasta – Milk (milk protein – maybe uricosuric) – Eggs – Other fruit and vegetables – Butter, cheese, ice cream, chocolate, cake (beware comorbidities…) – Cherries & Vitamin C (maybe uricosuric) • AVOID ALCOHOL ENTIRELY ```

Answer 147

* Rapid development of warmth, swelling, erythema and pain in the affected joint * Pain escalates to most intense level in 8-12 hrs * Initial attack is usually monoarticular and >50% cases involve the 1st MTP joint. * Other joints involved in early stage: midfoot, ankles, heels and knees. Less commonly wrists , fingers and elbows.

Answer 148

– Blocks microtubule assembly in neutrophils reducing phagocytosis and transport of MSU crystals so no inflammation will occur – Affects neutrophil migration into joints by reducing adhesion molecules on endothelial cells and neutrophils in response to IL-1 or TNF-a – Reduces inflammasome-driven activation by microtubule inhibition which decreases MSU delivery – Can cause diarrhoea as the dose increases.

Answer 149

* Destructive polyarticular involvement with low-grade joint inflammation, joint deformity, and tophi * Tophaceous gout develops within 5 years of onset of gout in 30% of untreated patients * Tophi are painless and rarely become infected but function and health-related QoL can be severely affected with chronic gout

Answer 150

* Build up of uric acid crystals under the skin * Often painless * Large tophi can reduce joint movement and may be surgically removed * Anti gout treatment can gradually shrink tophi

Answer 151

- Waited for the critical period so waited for 4-6 after several acute attack - Use ULDs and the first line would be allopurinol. Start low dose and then titre up. 50-100 mg daily - Want to get your target urate to less than 0.3 or less than 300 micromoles per litre - Can use prophylaxis at the same time if you want but not during an acute flare. During the critical period can give them an NSAID or some Colchicine if you can’t give them NSAIDs - If you do get a spike in urate level then you wait a bit. You don’t stop allopurinol if they do get another acute attack. Don’t start it during an acute attack but you don’t stop it if they’ve already been established on therapy so keep them on allopurinol.

Answer 152

* Start low no more than 100 mg/day * Dose reduce ALL patients with moderate to severe renal insufficiency or use alternative * Gradually up‐titrate the dose, which in some cases, can be more than 300 mg/day if needed. Max 600mg/day * Treat to Target: serum urate concentration <360 micromole/l, and <300 micromole/l if treating tophi.

Answer 153

• Careful use in patients with renal failure – Metabolites are renally cleared – hypersensitivity reactions are more common in patients with renal insufficiency – probably better options. • Purine‐associated hypersensitivity syndrome is DIFFERENT from allergic rash – Systemic and sometimes life threatening illness – Fever, hepatitis, marrow suppression, nephritis, DRESS (Drug Rash with Eosinophila and Systemic Symptoms) • The Role of HLA B5801 and allopurinol hypersensitivity is unquestioned • All patients from populations with a high allele frequency for HLA B5801 and high hazard ratio for developing hypersensitivity should be screened (Asian populations)

Answer 154

- A purine derivative which is the substrate for xanthine oxidase which is the thing we want to stop from working - Don’t want the xanthine to be converted to uric acid - Allopurinol competes the the xanthine oxidase so not able to convert xanthine into uric acid because you have used all of your xanthine oxidase up by saturating it with the allopurinol - So not as much uric acid is formed.

Answer 155

- For people who can’t use allopurinol use febuxostat for people who have mild renal impairment. - Would go to this option because the metabolites aren’t renally cleared and you can use it in patients who have mild renal impairment. - If you get to a stage where they can take the allopurinol but couldn’t get them to a good level of urate level even with a higher dose you can switch it to febuxostat - If that doesn’t work consider Uricosuric such as sulfinpyrazone or probenecid

Answer 156

- Doesn’t look like a normal substrate for xanthine oxidase but it does inhibit it - It is a selective inhibitor of xanthine oxidase s it doesn’t cause problems that allopurinol causes and the metabolites aren’t renally cleared Febuxostat use • First treatment in 40 years for chronic gout • NON‐PURINE inhibitor of xanthine oxidase • Theoretically safe to use in patients with allopurinol sensitivity reactions • Been studied in patients with mild renal insufficiency • Dosed at 40‐80mg/once daily Febuxostat benefits • More potent than 300 mg/day allopurinol • Not a purine: appropriate for patients with allopurinol hypersensitivity • Can be used safely in patients with mild renal insufficiency (unlike allopurinol)

Answer 157

- Uricosuric drugs: the uric acid come into the glomerulus and undergoes glomerulus filtration and about 90% of the uric acid is reabsorbed in the tubules so you don’t excrete that much. - Recirculate the urate back and get rid of it slowly - The idea of the Uricosuric drugs is can you stop some of the uric acid being reabsorbed and more of it excreted.

Answer 158

URAT1 (Urate 1 transporter) is a member of the OAT (organic anion transporter) family, and an anion-exchanging uptake transporter If you can stop URAT-1 transporter from working, if you block URAT-1 and you block the reabsorption of the urate back into the glomerulus, this will mean that you will be able to stop the reabsorption and more will be available for excretion. - More can be pushed out through the kidneys.

Answer 159

* Inhibits URAT-1 * Can cause GI upset * Needs to be taken with large quantities of water to prevent kidney stones * There are better alternatives

Answer 160

* Uricosuric agent blocks tubular re‐absorption of uric acid by blocking URAT-1 transporter. * Useful in patients who under‐excrete uric acid (90%) * If need be, confirm under‐excretion with 24 hr. uric acid <800 mg/24 hrs. * Do not use in: * Tophi * Renal impairment * Clear overproduction syndrome

Answer 161

* Unlicensed in the UK needs to be imported * Non competitive inhibitor of XO * Can be used in renal impairment (vs allopurinol) * Withdrawn from several markets because of hepatotoxicity- liver damage * Must have regular LFTs!

Answer 162

* Used in combination with a xanthine oxidase inhibitor where this alone doesn’t achieve target * Inhibits URAT-1 and so reduces reabsorption of uric acid in the kidneys * 200mg od with XO * NICE rejected in 2018 – ICER/QALY £62,298

Answer 163

• Nephrolithiasis (kidney stones) – Risk factors: increased uric acid excretion, reduced urine volume, and low urine pH - Chronic urate nephropathy – Urate crystals can deposit in renal medullary interstitium producing inflammatory changes and fibrosis – Clinical features are nonspecific: renal function impairment, bland urinary sediment, mild proteinuria and serum urate concentrations often higher than expected for the degree of renal impairment. – Biopsy confirms diagnosis

Answer 164

* Enzyme that converts insoluble uric acid to more soluble metabolite allantoin * Humans have lost the gene function to produce uricase * Rasburicase: a drug derived from aspergillus used to treat tumour lysis syndrome * Rasburicase is extremely immunogenic meaning that it is almost eliminated by the body, which limits its half-life and use in chronic disease. Rasburicase is a form of uricase

Answer 165

``` • Mammalian uricase • Pegylated – Increases half life – Reduces immunogenicity • Administered by IV infusion every 2 weeks ```

Answer 166

* Infusion reactions (not human, even with PEG) * Many patients develop antibodies to drug that increases its clearance * Anaphylaxis * 80% patients had gout flares despite prophylaxis * Contraindicated in G6PD deficient patients * May exacerbate heart failure

Answer 167

• Inflammatory cells can innately recognize common microbial features as danger signals – Flagella, viral RNA, etc… – Excess uric acid and associated crystals recognised in the same way • Leads to rapid inflammation • Microbial patterns bind to Toll-like receptors and lead to increase in pro IL-1

Answer 168

* Gout pathogenesis: * Super saturated serum levels of uric acid lead to crystal formation and deposits in joints * Crystals are engulfed by macrophages * Macrophages release inflammatory cytokines * Recruit more inflammatory cells and perpetuate joint inflammation

Answer 169

* Pro‐IL 1 is inactive, but capable of being rapidly metabolized to active IL‐1 * Machinery that cleaves pro IL‐1 to active IL‐1 is called the inflammasome * Uric acid is capable of activating the inflammasome IL-1 blockers (canakinumab) • IL‐1 Receptor antagonist (anakinra, commercially available for Rheumatoid Arthritis) • Anti IL‐1 antibody (canakinumab, commercially available to treat certain periodic fevers) • IL‐1 decoy receptor fusion protein (rilanocept, commercially available to treat certain periodic fevers) Several pilot studies show promising results • Single dose of Canakinumab superior to triamcinolone injection (has long half life) • Not approved as studies were only 16-weeks

Auto immune lecture 7-21 Flashcards

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