RA Therapy PDF - Integrated Pharmacology and Therapeutics 3

Integrated Pharmacology and Therapeutics 3 Module 1.1.2 Pharmacotherapeutic Management of Rheumatoid Arthritis Faculty of Health Sciences | School of Pharmacy and Biomedical Sci...

Integrated Pharmacology and Therapeutics 3 Module 1.1.2 Pharmacotherapeutic Management of Rheumatoid Arthritis Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  COMMONWEALTH OF AUSTRALIA Copyright Regulation 1969 WARNING This material has been copied and communicated to you by or on behalf of Curtin University of Technology pursuant to Part VB of the Copyright Act 1968 (the Act) The material in this communication may be subject to copyright under the Act. Any further copying or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Learning Outcomes To identify the signs, symptoms and diagnostic laboratory test for rheumatoid arthritis (RA) To identify the goal of treatment in RA To understand the management of RA To be aware of monitoring associated with disease progression and adverse effect from treatments for RA Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Diagnosis and Clinical Findings Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Diagnosis and Clinical Findings Symptoms begin gradually and progress Symptoms include: malaise, fatigue (+/- diffuse musculoskeletal pain) symmetrical pattern of joint pain, stiffness, swelling and redness involvement of metacarpophalangeal (MCP), proximal interphalangeal (PIP) joints and metatarsophalangeal joints (MTP) rare involvement of DIP joints morning stiffness weight loss, fever, depression and other extra articular symptoms Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Know your joints! Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Diagnosis and Clinical Findings: Joint Involvement Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Laboratory Findings ↑ ESR ↑ C-reactive protein (CRP) Presence of RF HLA typing Antinuclear antibodies (ANA), antibody to cyclic citrullinated peptide (CCP) Normocytic/microcytic, normochromic anaemia low serum iron, normal-to-low TIBC, normal-to-high ferritin Changes in joint radiographs Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Summary Features of RA Source: eTG: Rheumatology 2017 Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Prognosis Most patients experience temporary or permanent disability (↓ QoL) Mortality rates 2-3X higher in the presence of extra- articular manifestations Infection, cardiovascular disease Risk factors include those with high disease activity Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Treatment Goal Main objective = REMISSION symptomatic relief + normalisation of inflammatory markers + absence of joint swelling Maintain joint and muscle function Minimise side effects of treatment Return to desirable and productive life Reduce onset of co-morbidities e.g. depression Prevent complications to heart, lungs, and other organs Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Non Drug Intervention Physiotherapy, exercise Diet OT- appliances and devices Smoking cessation Immunisation Omega-3 fatty acid supplement i.e. fish oil (2.7g daily) Gamma-linolenic acid (GLA) i.e. evening primrose oil (up to 2.8 g GLA daily) Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Role of Fish Oil in RA Studies suggest about 2-3g/day of isolated DHA/EPA to reduce inflammation associated with RA (i.e. more than 2- 3 capsules daily) Benefits include reduction in joint pain duration of morning stiffness fatigue time number of tender of swollen joints use of painkillers Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Drug Treatment Four main drug classes: 1. Analgesics: NSAIDs, paracetamol 2. Corticosteroids: systemic and intra- articular 3. Synthetic Disease Modifying Anti- Rheumatic Drugs (sDMARDs) 4. Biological DMARDs (bDMARDs) Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  1. NSAIDs Treat acute synovitis in all stages of RA Reduce inflammation, joint swelling and stiffness COX-2 selective vs non-selective COX inhibitors Choice depends on risk vs benefit, age, renal function, co- morbidity Side effects: GI, renal, CVD adverse effects Efficacy equivalent for equivalent doses Variable response between individuals No rationale for using >1 NSAID concomitantly Lowest effective dose for shortest time period Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  1. NSAIDs cont’d… Can be used concomitantly with paracetamol. Avoid combining with anticoagulant and corticosteroid PPI prophylaxis recommended for RA patients aged > 65 and those with a past history of peptic ulcer disease Source: RACGP Clinical guideline for the diagnosis and management of early rheumatoid arthritis August 2009 Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  1. NSAIDs cont’d… Source: eTG Rheumatology 2017 Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  1. NSAIDs cont’d… Source: eTG Rheumatology 2017 Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  2. Corticosteroids Indicated for (i) Symptoms control while waiting for synthetic DMARDs to be effective –”Bridge therapy” OR (ii) Patients with disease “flare” IM, IV corticosteroid Intraarticular injections with methylprednisolone acetate 120 mg: prolonged effect up to 8 weeks not repeated in same joint > 4x/year injection followed by 24-48hrs splint and bed rest risks: infection, osteonecrosis, tendon rupture Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  2. Corticosteroids cont’d… Orally e.g. prednisolone 5 to 15 mg daily Used at the lowest possible dose and for the shortest possible duration Taper dose slowly when ceasing therapy if doses is >7.5mg daily or tx duration of >3 weeks Advantages: Dramatically reduce pain and swelling Decrease disease progression Increase patient well-being Disadvantages: Efficacy reduce with dose reduction Undesirable side effects with long term use Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  3. Synthetic DMARDs Reduce synovial inflammation and prevent joint damage Slow, variable onset of action Variable: 6 to 12 weeks Response to monotherapy often suboptimal; combination therapy preferred Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  3. Synthetic DMARDs cont’d… Introduced at time of diagnosis Aim: quick eradication of inflammation Efficacy greatest early in the disease course Significant joint destruction in first 2 years Source: Roberts LJ et al. Early combination disease modifying antirheumatic drug treatment for rheumatoid arthritis Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  3. Synthetic DMARDs cont’d… Sulfasalazine 1st line in mild disease Dose: 500mg daily increasing up to 1.5g bd 4-12 weeks for onset Exclude G6PD deficiency or sulfonamide allergy GI adverse effects (minimised by EC tablet), blood dyscrasias Monitor FBP, CrCl, LFTs Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  3. Synthetic DMARDs cont’d… Hydroxychloroquine 1stline in mild disease (less effective but least toxic) Primarily used in combination with other DMARDs Dose: 200 to 400 mg daily Onset: 2-6 months Exclude G6PD deficiency Risk of retinopathy and worsening psoriasis Monitor FBP, CrCl, LFT Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  3. Synthetic DMARDs cont’d… Methotrexate (MTX) Current ‘gold standard’ sDMARDs for moderate to severe RA proven to slow radiographic progression of disease Drug of choice for most patent with RA Relatively quick onset of action (4-6 weeks) Used alone or in combination Backbone of combination regimen MTX+ hydroxychloroquine or sulfasalazine or leflunomide MTX+ biological DMARDs Dose: 10 to 25mg WEEKLY (oral) Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  3. Synthetic DMARDs cont’d… Methotrexate cont’ A/Es: Myelosuppression, GI toxicity, pulmonary toxicity, hepatotoxicity, rash, photosensitivity Co administration of folic acid 5 to10mg weekly as single dose on a different day to when methotrexate is taken – at least 24 hours after methotrexate dose Adverse effects can be limited by administering the methotrexate dose at night OR splitting the weekly dose over 2 consecutive days Monitor FBP, CrCl, LFTs, CXR Beware of drug Interactions: Interaction between NSAIDs and MTX is only clinically significant with high dose methotrexate Appropriate patient counselling (refer to AMH for counselling points) Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  3. DMARDs cont’d… Leflunomide Reserved for patient where methotrexate is not suitable Onset usually approx. 4 weeks Dose: 10 to 20 mg daily Transient elevation of ALT and AST A/Es: GI, alopecia, dyspnoea, pneumonia, hypertension, blood dyscrasias, skin reaction Monitor FBP, CrCl, LFTs, BP Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  3. DMARDs cont’d… Others: Gold salts Penicillamine Azathioprine Cyclosporin Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  4. Biological DMARDs Reserved for patients who failed to response to sDMARDs Often used in combination with methotrexate Avoid using > 1 biological DMARDs Risk of infection and malignancy Includes TNF-α Inhibitors, Rituximab, Abatacept, Anakinra, Tocilizumab, Tofacitinib Monitor for opportunistic infection including reactivation of hepatitis B and TB in susceptible individual Pneumococcal, influenza, hepatitis A and B, and human papilloma virus vaccination Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  4. Biological DMARDs TNF-α Inhibitors - 1st line biological agent Adalimumab (Humira®, SC) Certolizumab (Cimzia®, SC) Etanercept (Enbrel®, SC) Golimumab (Simponi®, SC) Infliximab (Remicade®, IV) Source: McColl G. Tumour necrosis factor alpha inhibitors for the treatment of adult rheumatoid arthritis. Aust Prescr 2004; 27:43–6. Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  4. Biological DMARDs TNF-α Inhibitors cont’d… Rapid onset of action Contraindicated in patients with TB, hepatitis B and C, grade III/IV heart failure Review immunisation status and history of malignancy before tx A/Es: infusion/injection site reactions, URTIs and other infections, thrombocytopenia, malignancies Monitor FBP, CrCl, LFT Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  4. Biological DMARDs Rituximab Severe RA not responding to TNF-α inhibitor Onset: 4 months Administered as IV infusion A/Es: infusion related reactions, infections, muscle pain, weakness, Monitoring: FBP, LFT and CrCl Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  4. Biological DMARDs Abatacept Reserved for RA not responding to TNF-α inhibitor Onset: 14 days Administered by IV infusion A/Es: Infusion related reactions, infections, hypertension, increased liver enzymes, blood dyscrasias, hypersensitivity Monitoring: FBP, LFT and CrCl Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  4. Biological DMARDs Anakinra Slower onset (2 weeks) and less effective than TNF-α inhibitors Administered by SC inj A/Es: injection site reactions, neutropenia, serious infections, raised TC Monitoring: FBP and lipid profile Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  4. Biological DMARDs Tocilizumab Onset: 2-4 weeks Administered by IV infusion A/Es: infusion site reactions, neutropenia, thrombocytopenia, hyperlipidaemia, infections, GI ulceration Monitoring: FBP, LFT, lipids Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  4. Biological DMARDs Tofacitinib Moderate to severe RA failing to response to methotrexate and TNF alpha antagonist Can be used as monotherapy or in combination with other DMARDs (except cyclosporine, azathioprine) Contraindicated in patients with TB, hepatitis B and C A/Es: Infections, elevated LFT, diarrhoea, nausea, rash, headache, dyslipidaemia, blood dyscrasias, GI perforation Monitoring: FBC, Hb, lipid, LFT Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  4. Biological DMARDs Baricitinib Used in combination with MTX Contraindicated in patients with TB, hepatitis B and C A/Es: Nausea, abdominal pain, infections, elevated CK and LFT, dyslipidaemia, blood dyscrasia Monitoring: FBC, Hb, lipid, LFT Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Treatment Algorithm Factors affecting choice of treatment Disease severity Prognosis Patient factors Age Childbearing status Comorbidities Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Treatment Algorithm Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Treatment Algorithm Source: RACGP Clinical guideline for the diagnosis and management of early rheumatoid arthritis August 2009 Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Monitoring of RA Progression Efficacy of treatment Number of tender and swollen joints Duration of morning stiffness ESR and CRP Functional status Monitor development of extra-articular manifestations Adverse effects of treatment Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  Summary RA is a chronic, progressive, immune mediated inflammatory disease of the joints RA affects the joints in a symmetrical pattern and normally affect the MCP and PIP joints Aim of treatment is symptomatic relief with analgesics, induce and maintain remission and joint and muscle function Treatment option include non opioid analgesic, synthetic and biological DMARDs and systemic or intra-articular corticosteroids for acute flare/ bridging therapy Combination therapy with two or more DMARD(s) is more effective than monotherapy. Methotrexate is the preferred sDMARD in moderate to severe RA. Folic acid supplementation is required to reduce anti-folate side effects associated with methotrexate Biological DMARDs are reserved for patients who failed to respond to sDMARD(s). Avoid using more than one biological DMARD together due to risk of adverse effects Monitor for adverse effects while being treated with DMARDs Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J  References Wilsdon TD, Hill CL. Managing the drug treatment of rheumatoid arthritis. Australian Prescriber 2017; 40: 51– 58. The Royal Australian College of General Practitioners. Clinical guideline for the diagnosis and management of early rheumatoid arthritis 2009. Available from: https://www.racgp.org.au/FSDEDEV/media/documents/Clinical%20Reso urces/Guidelines/Joint%20replacement/Clinical-guideline-for-the- diagnosis-and-management-of-early-rheumatoid-arthritis.pdf E Therapeutic Guidelines: Rheumatology 2017. Roberts LJ et al. Early combination disease modifying antirheumatic drug treatment for rheumatoid arthritis. MJA 2006; 184: 122–125. Walker R, Whittlesea C (eds). Clinical Pharmacy & Therapeutics. 5th ed. United Kingdom: Elsevier Churchill Livingstone 2012. Australian Medicines Handbook 2019. Faculty of Health Sciences | School of Pharmacy and Biomedical Sciences CRICOS Provider Code 00301J