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Stage 3 - Case 3 (Musculoskeletal) > Lecture 6,7,8,9: RA: Pathophysiology, DMARDs, Case Study & Biologics > Flashcards

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
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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
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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
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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
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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
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6
Q

How do T helper cells activate B and T cells?

A
  • B- cells: autoantibodies
  • T cells: cytokines
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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)
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8
Q

What are the 2 types of autoantibodies?

A
  • Rheumatoid Fcator (RF)
  • Anti-citrullinated peptide antibodies (ACPA)
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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
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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
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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
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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
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13
Q

What are the 3 stages of RA pathogenesis?

A
  • Pre articular Phase
  • RA initiation
  • Progression
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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
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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
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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
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17
Q

What are the main types of treatment for RA?

A
  • Analgesia
  • Physio
  • Lifestyle
  • CBT
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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
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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
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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

Stage 3 - Case 3 (Musculoskeletal) (5 decks)

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