Lecture 6,7,8,9: RA: Pathophysiology, DMARDs, Case Study & Biologics Flashcards
1
Q
What is Rhematoid Arthritis?
A
- Chronic, systemic, inflammatory condition
- Autoimmune disease
- Primarily affects the joints: fingers, wrists
- Progressive -> destruction of bone and cartilage
2
Q
What are the symptoms of RA?
A
- Joints are warm, swollen and painful
- Normally fatigue, abnormal sleep, morning stiffness
- Deviations of fingers & nodules
- Synovitis: press between knuckles = hot and spongy
3
Q
What is the co-morbidities of RA -> what other conditions can it affect?
A
- CVD: Due to accumulation of inflammatory mediators
- Inflammation of the lungs and heart
4
Q
What are other types of arthritis?
A
- Osteoarthritis: Wear in joints, degeneration of cartilage and bone. (Hands, knees, neck). RF: age, obesity
- Septic arthritis: Secondary to infection. Causes joint inflammation
- Post traumatic arthritis: Secondary to physical injury. Accident to joint = recruitment of cells
5
Q
What is the main natural cause of RA?
A
- Mutations in major histocompatibility complex class 2.
- Macrophages normally present foreign antigens to B and T cells
- Mutated isoforms present own antigens to immune cells (causes response). Endogenous proteins = antigens and antibodies generated against them
6
Q
How do T helper cells activate B and T cells?
A
- B- cells: autoantibodies
- T cells: cytokines
7
Q
How does this autoimmune reaction cause joint destruction?
A
- Unknown trigger sets initial focus -> attracts leukocytes to tissue (incr permeability of BVs around joint
- CD4 T cells activate macrophages -> production of proinflamm cytokines (Il-1, TNF-a)
- Cytokines induce production of MMP and RankLigand by fibroblasts ( F are already in joint)
- MMP: secrete proteases to damage tissue
- RANKL: activates osteoclasts by binding to RANK receptor (bone destruction)
8
Q
What are the 2 types of autoantibodies?
A
- Rheumatoid Fcator (RF)
- Anti-citrullinated peptide antibodies (ACPA)
9
Q
What is Rheumatoid Factor?
A
- Autoantibody used to target the Fc region of IgG antibodies
- Can be IgM (most common), IgG, IgA, IgE
- Lots binds and forms complex and precipitates and damages joint and causes inflammation
- Not specific for RA: in other autoimmune diseases and in SLE
10
Q
What are anti-citrullinated peptide antibodies (ACPAs)?
A
- Autoantibodies that target citrullinated proteins (citt fibrin and collagen) and highly specific for RA
- Causes increased inflammation
11
Q
How are citrullinated proteins produced?
A
- Conversion of amino acid arginine to citrulline by PAD enzyme (which removes amino acid to make cit which is neutral)
- Citrulline is not human and contributes to proteins in joints -> 3D structure changes -> destabilises protein and more prone to proteolysis
- In genetically susceptible: recognises as foreign leading to presentation to APCs activate macrophages and cytokines
12
Q
How does smoking affect citrullinated proteins?
A
- Smoking induces PAD expression in resp tract
- Cit proteins are produced in the resp tract
- Presented by MHC2 and activates CD4+ Tcells which activates B cells to stimulate autoantibodies
- These appear years before symptoms of RA
13
Q
What are the 3 stages of RA pathogenesis?
A
- Pre articular Phase
- RA initiation
- Progression
14
Q
What is the pre-articular phase of RA?
A
- Synovial membrane and fibrous layer form the joint capsule
- Proteins are protected in the joint and antibody cant access until injury
- The autoantibodies are just present in blood
15
Q
What is the RA initiation phase?
A
- Initiated by joint damage - joint capsule is broken
- Blood can access cit proteins, fight and more autoantibodies
- Lymphocytes, ACPA and RF enter
- Damage induces more PAD
- Activation of T cells and deposition of immune complexes
16
Q
What is the RA progression stage?
A
- CD4+ T cells differentiate into TH1 (releases IFN-y and activates macrophages) and TH17 (releases IL17 recruits neutrophils and monocytes (synoviocytes)
- Macrophages produce pro-inflamm cytokines (Il-1, Il-6, TNF, RANK
- Continual inflammation and progression over time
17
Q
What are the main types of treatment for RA?
A
- Analgesia
- Physio
- Lifestyle
- CBT
18
Q
What are some NICE guildlines on the management of RA?
A
- Treat to target: remission or low disease activity
- DAS28 scoring
- Shared decision making
- Acheiving target may involve trying multiple cDMARDs and b/tDMARDSs one after another (monotherapy)
- Dose escalation to tolerated
- Short term bridging treatment w/ glucocorticoids to provide immediate relief
- Also renally cleared - caution w/ elderly
19
Q
What is first line treatment of RA?
A
- CDMARD monotherapy using methotraxate, leflunomide or sulfalazine
- Consider Hydrochloroquine first line for mild or palindromic disease
20
Q
What are some key points for methotraxate?
A
- One dose weekly
- Upto 20mg weekly
- Dose dependent and response within 4-6 weeks
- Need to prescribe folic acid: metho is an antifolate which prevents DNA synthesis, prescribe on different day to metho as it can reverse effects
- Attacks rapidly dividing cells -> growing cells are dependent on reduced folate for replication. stomach, hairs
21
Q
What are the types of DMARDs
A
- cDMARDs: methotrexate, sulfalazine, hydroxychloriquine, azathioprine (more in IBD)
- bDMARDs: biologics: Etanercept, Adalimumab
- TsDMARDs: Stop cytokine before produced - Tofacitinib
22
Q
What is the mechanism of action of methotrexate?
A
- Stops dihydrofolate reductase - important in DNA synthesis
- Suppresses neutrophil adhesion to blood vessels - prevents entry to inflammation
- Suppresses cytokine and macrophage function
- Susceptibility to infection
23
Q
What is the DAS 28 score?
A
- Diagnostic which counts 28 tender swollen joints
- Higher score = disease more active
- Calculates: number of tender joints, serology (RF & ACPA), symptom duration, CRP and ESR levels
24
Q
Whats some general prescribing of cDMARDs
A
- Never prescribe metho and trimethoprim (anti folate too)
- Monitoring trends not single test - every WBC 2 weeks
-bMARD added if cMARD is uneffective - If on antibiotics and metho: stop metho until antibiotic finishes - illness damages the kidney and metho is excreted through teh kidney
25
Q
What are some safety considerations of metho?
A
- Drink: not binge drink
- NSAIDs - affect kidney function and metho excreted through kidney
- Contraceptive use - teratogenic
- Use subcut for less sickeness
- Report signs of infection
- Contraindicated in active infection
26
Q
What are some interactions of methotrexate? What can it affect in the body?
A
- Myelosuppression: Anemia, bone marrow suppression, Cough, sore throat. Bleed: refer
- Hepatotoxicity: Pain, jaundice, dark urine
- Nephrotoxicity: Blood tests
27
Q
What are some side effects of methotrexate?
A
- Blood disorders
- Nausea
- Ulcers
- Pulmonary (dry cough) & structural damage) and hepatic toxicity (cirrhosis)
- Stomatitis - ulceration of the mouth
- Immunosuppression
28
Q
What are the monitoring requirements for methotrexate?
A
- 1, 2 weekly then 2-4 once stabilised: U&E (kidney function), Blood count, LFTs
29
Q
How does sulfalazine work and what is it used in?
A
- Suppresses signalling pathways involved in cytokine synthesis TNF a
- Pro drug and has 2 active metabolites: 5-ASA (active in IBD) and sulfapyridine (active in RA)
- Used in RA, Psoriatic arth, UC
30
Q
What are the side effects of sulfalazine?
A
- GI disturbances
- Blood dyscrasias and disorders (affects blood count)
- Rashes
31
Q
What are some counselling points on sulfalazine?
A
- BD
- Slow loading to avoid SEs
- G6PD deficiency - susceptible developing haaemolytic anemia
- May discolour urine (orange)
32
Q
How does Leflunomide work?
A
- Inhibits pyrimidine synthesis -> important for gene expression for autoimmune lymphocytes
- reduces cytokine production and autoimmunity
- Pro drug: active form in intestinal mucosa and plasma (teriflunomide)
33
Q
What are drug interactions and drug elimination like for leflunomide?
A
- Drug elimination = slow, long t1/2
- Metabolised by CYP450 and has interactions with Clopidogrel, omeprazole, Diazepam
-Also cant be used in pregnancy
34
Q
How long does the therapeutic effect take and what are the side effects?
A
- 4-6 weeks
- GI disturbances
- Weight loss
- Transient rises in transaminases
- Hypertension - monitor BP
- Hepatotoxicity and leucopenia - monitor blood count and liver function
35
Q
What are some side effects for hydroxychloroquine?
A
- GI, skin rash, Vision disorders (retinopathy)
- No lab monitoring needed
36
Q
What do biologics work on and name some examples?
A
- Target specific components of immune signalling pathway
- For example Anti-TNF: Adalimumab and Infliximab
- Tocilizumab and Sarilumab block IL-6
37
Q
What is an antibody structure?
A
- 4 protein chains - y shaped complex
- 2 heavy and 2 light
- FC common to all antibodies
- V = High antigen specificity
38
Q
Name some pro-inflammatory and anti-inflammatory cytokines?
A
- Proinflammatory: TNFa, IL-1, IL-6 (biologics target these)
- Anti-inflammatory: IL-4, IL-13
39
Q
What are the functions of TNF - a?
A
- Macrophages: Cytokine production
- Bone Marrow: Neutrophil production
- Hypothalamus: Increase body temp
- Dentritic cells: Maturation and migration to lymph nodes
40
Q
What are the risks of Anti-TNF therapy?
A
- TNF a helps fight infection can cause reactivation of latent infection
- Pyogenic sepsis: Life threatening response to infection
- Autoimmune disease: Demyelination and frank lupus (rash, joint pain and fever)
- Cancer spread
41
Q
What is the Janus Kinase pathway for (JAK)?
A
- Crucial for transmitting signals from cytokines -> nucleus and regulating gene expression and immune responses
- Activates interleukins and interferons
42
Q
How does the JAK pathway work?
A
- Cytokine binds to receptor
- Receptor linked to Janus kinases - family of intracellular enzymes
- JAKs phosphorylate themselves and the receptor and create docking sites for STAT proteins (signal transducer and activator of transcription)
- STATs enter nucleus and bind to DNA and turn on gene: makes immune system proteins
43
Q
What are some blood tests for RA?
A
- Full blood count: RBC large (megablastic anemia) = folate deficiency, RBC small = iron deficiency
- Inflammatory markes: ESR (more stable), CRP (more rapid change)
- LFTs and U&Es
- RF & ACPA
- X rays: hands feet, chest
- For biologics: screen for Hep B, C and latent TB
44
Q
How do you manage flares in RA?
A
- In active inflammation: IM glucocorticoid or short course of oral (pred, dexamethasone, betamethasone
- Contraindicated in untreated systemic infection. Children and elderly = more likely side effects
- Escalate DMARDs and biologics (Biologics production is costly and costly
- Diclofenac (high risk of cardio and GI problems) (naproxen better)
45
Q
What are some side effects of Glucocorticoids?
A
- Weight gain, osteoporosis, risk of infection
46
Q
What are some good prescribing practices for methotrexate?
A
- Cytotoxic drug (use gloves)
- Capital letters: WEEKLY
- Methotrexate book (not used anymore)
47
Q
What are some counselling points of using NSAIDs in pain relief for RA?
A
- Lowest effective dose for shortest time
- Account for potential GI, liver, cardio and renal toxicity (risk factors age & pregnancy)
- Use PPI (omeprazole is metabolised by CYP450) lansoprazole isnt
48
Q
Should you offer paracetamol, weak opiods, strong opioids and glucosamine for pain relief?
A
- Dont offer paracetamol or weak opioids unless infrequent and short term and all other pharmacological treatments are contraindicated or ineffective
- Dont offer Strong opioids and glucosamine
