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Rheumatology - Coggle Diagram

- - - - overporduction of urate through the purine degradation pathway
        
        high purine diet (red meat, beer, seafood, fructose)
        
        alcohol
        
        high cell turnover (malignancy)
        
        tumour lysis syndrome
        
        Genetic (LeschNyhan syndrome)
      - Underexcretion of urate
        
        medications: thiazide + loop diuretics, aspirin, ACEi + ARB except losartan,
        
        CKD
  - - - goal is to reduce inflammation and resolve symptoms
      - first line: NSAIDs(Naproxen)
        
        MOA: COX1+2 inhibition
        
        Side effects: Acute tubular necrosis, gastric ulcers, agioedema
      - Second line: Colchicine
        
        MOA: binds tubulin, decreases neutrophil adhesion to regulate cell proliferation
        
        Side effects: Diarrhoea, bone marrow suppression( cytopenias)
        
        substrate for CYP3A4 and P-glycoprotein, toxicity occurs if used with 3A4 inhibitors(ciclosporin and clarithromycin
      - third line: Corticosteroids
        
        short course, 3-5 days
        
        prednisolone
    - - indication
        
        indicated for those with recurrent gout flares, tophi, CKD or kidney stones
      - 1st line: XANTHINE OXIDASE INHIBITORS
        
        ALLOPURINOL
        
        moa: Inhibits uric acid synthesis via xanthine oxidase inhibition.
        
        side effects: hypersensitivity, precipitates gout flares, blood dyscrasias
        
        can cause steven johnson syndrome and toxic epidermal necrolisis in HLA-B 5801 subtye (common in thai and chinese populations)
        
        don't initiate during acute attack - can precipitate gout, flare ups can be caused by sudden changes in uric acid
        
        interactions: Azathioprine is metabolised to 6-mercaptopurine, which is
        converted to inactive products by xanthine oxidase. Resulting toxicities.
        
        FEXOBUSTAT
        
        Advantage: Metabolised liver – less issues with renal impairment
        
        similar side effects and interactions
      - 2nd line: URICOSURICS
        
        PROBENECID
        
        MOA: prevents reabsorption of uric acid in the kidney tubules, competitive inhibiter of OAT1+3
        
        side effects: GI irritation, nephrotic syndrome aplastic anaemia,
        uric acid stones- need to maintain large volume of urine
        
        interactions: inhibits renal excretion of cephalosporin
        
        Probenecid is used concomitantly with certain βlactam antibacterial (e.g., penicillin G to decrease clearance and increase plasma concentrations of the antibacterial
        
        LESINURAD
        
        oral selective inhibitor of the URAT1 and OAT4 uric
        acid (UA) transporters of the kidney
        
        not cost effective
      - 3rd line: Recombinant uricase
        
        RASBURICASE
        
        • MOA: Uricase converts uric acid to allantoin. Humans do not have the uricase enzyme
        
        used in treatment and prophylaxis of acute hyperuricaemia, in order to prevent acute renal failure in pts with haematological malignancy with a high tumour burden and at risk of a rapid tumour lysis or shrinkage at initiation of chemotherapy.
        
        Side effects: anaphylaxis, can cause haemolysis in G6PD deficiency
      - aim
        
        uric lowering therapy aims for target urate of <360mmol/l
        
        Goal is to reduce urate concentration that achieves dissolution of monosodium urate crystals
      - risks
        
        starting treatment puts patient at risk of acute flare so colchicine + antibiotics given prophylactically for first few weeks
- - - - only for short term use to control symptoms
  - - - synthetic (sDMARD)
        
        conventional synthetic DMARD
        
        Methotrexate
        
        First line therapy - low dose once weekly methotrexate
        
        MOA: DiHydroFolate Reductase (DHFR) inhibitor
        • Inhibits the folic acid‐dependent synthesis of purines and pyrimidines
        
        Side effects: Bone marrow suppression, pneumonitis, cytopenia, infections, liver damage, mucocutaneous toxicity, teratogenic
        
        NSAID induced inhibition of prostaglandin synthesis leads to reduced renal perfusion, which reduces the renal excretion of methotrexate which is an issue for high dose MTX.
        
        signs of toxiccity = neutropenia, blood disorders, liver toxicity, respiratory effects
        
        fevers, chills, rigor, tachycardia, hypotension, malaise
        
        given with folate tablet to reduce side effects
        
        Leflunomide
        
        MOA: inhibitng mitochondrial enzyme dihydroorotate dehydrogenase which plays a key role in de novo synthesis of pyrimidines --> activated lymhocytes can't move from G1 to S and undergo apoptosis
        
        Prodrug
        
        side effects = diarrhoea, raised LFTs, rash, Reversible alopecia, weight gain, hypertension, also teratogenic
        
        Hydroxychloroquinine
        
        Moa: Suppression of T lymphocyte response to mitogens
        
        Side effects: ocular toxicity, dyspepsia
        
        clinical use: SLE, not very effective in RA
        
        Sulfasalazine
        
        Moa: metabolised to sulfasapyridine + 5-aminosalicylic acid, suppresses T cell response
        
        Used in RA, JIA(juvenile idiopathic arthrits), IBD
        
        side effects: N+V, headache haemolytic anaemia, agranulocytosis, skin rash, nephrotoxicity
        
        ADR more common in poor acetylators
        
        targeted synthetic DMARD
        
        used when csDMARDs have failed and at least one biological/rituximab
        
        Tofacitinib
        
        Moa: JAK1+3 inhibitor - JAKs are enzymes important in the signalling pathways of cytokines such as interleukins, interferons and growth factors involved in immune responses
        
        contraindicated in patients with HRT/combined hormone contraceptives, heart failure, previous VTE/PE, coagulation disorders, malignancy, major surgery
        
        Baracitinib
        
        JAK1+2 inhibitor
        
        JAK inhibitors increased risk of MACE(major adverse cardiovascular events) and cancers compared to TNFa inhibitors so not used very commonly
      - biological (bDMARD)
        
        biological (boDMARDs)
        
        Anti-TNF agents
        
        MOA: Bind to transmembrane or soluble TNFa therefore blocking the interaction between TNFa and TNFR1/2
        
        examples: Etanercept, Adalimumab,
        Infliximab, Golimumab, Certolizumab
        
        Side effects: Infections, injection site reactions(subcut) or acute infusion reactions(IV). must screen for latent infections before starting
        
        TB screening - CXR, Mantu test, quantiferon(Igra)
        
        CTLA4-GgG Fusion Protein ABATACEPT
        
        MOA: CTLA4-Ig (Abatacept) binds to CD80/86 (on
        Antigen Presenting Cells). This prevents T cells interacting with APCs thus preventing activation
        
        co-stimulation blocker
        
        side effects: headache, upper respiratory tract
        infection, nasopharyngitis, and nausea. Also infections and decreased resistance to malignancy
        
        Anti-CD20: Rituximab
        
        • MOA: humanized chimeric anti-CD20 monoclonal antibody which induces killing of CD20+ cells via multiple mechanisms
        
        Indications: severe active rheumatoid arthritis who have had an inadequate response or intolerance to other DMARDs and a TNF inhibitor
        
        Side effects: infusion reactions, must ensure no active malignancies, rare - progressive multifocal leukoencephalopathy
        
        Anti-IL1: Anakinra
        
        MOA: Recombinant human IL-1 receptor antagonist
        
        Well tolerated, most frequent adverse event is mild injection site reaction
        
        Not used, mainly IL6
        
        Anti-IL6: Tocolizumab
        
        IL-6 is a key cytokine in the pro-inflammatory state of RA
        
        Increased incidence of gastrointestinal perforation
        
        biosimilar (bsDMARD)
        
        A biosimilar medicine (biosimilar) is a biologicalmedicine that is developed
        to be highly similarto an approved(reference) biological medicine