Melanoma: Learning Outcomes, Treatment, and Pathophysiology PDF

Melanoma Johnson Lee Pharmacy Guild NSW Chief Pharmacist The University of Sydney Page 1 Learning outcomes Identify the prevalence of different types of skin cancers Know the risk factors for skin cancers Recognise symptoms of BCC and SCC Know the prevention and treatments for BCC and SCC Understand the pathogenesis of cutaneous melanoma Appreciate treatments for cutaneous melanoma Compare and contrast target therapy with immunotherapy Know drug classes, names, and mode of action in cutaneous melanoma The University of Sydney Page 2 Background Approximately, two in three Australians will be diagnosed with skin cancer by the time they are 70. Skin cancers account for around 80% of all newly diagnosed cancers 1.Basal cell carcinoma (BCC) o Most common, 80% skin cancers o Low metastatic potential, but locally destructive 2.Squamous cell carcinoma (SCC) o 20% skin cancers o Can develop in sites of chronic wounds, inflammation, or scarring 3.Melanoma The University of Sydney Page 3 https://www.cancer.org/cancer/basal-and-squamous-cell-skin-cancer/about/what-is-basal-and-squamous-cell.html Risk Factors – Non- melanoma UV exposure (especially early childhood) Male> female – Melanoma UV Fair skin type Multiple atypical moles Family history of melanoma The University of Sydney Page 4 BCC and SCC Manifestations BCC SCC https://www-uptodate-com.ezproxy-so.library.usyd.edu.au/contents/images/DERM/81632/Largebasalcellcarcinear.jpg The University of Sydney Page 5 BCC / SCC Prevention and Treatments Prevention Sun protection Oral nicotinamide (Vit B3) 500mg bd (NOT nicotinic acid/niacin) Topical Fluorouracil bd 4 weeks Treatment Surgical excision Mohs surgery Curettage and electrodesiccation Photodynamic therapy (PDT) Cryosurgery Topical Fluorouracil/ Imiquimod Radiation The University of Sydney Page 6 Melanoma Manifestations Superficial spreading melanoma Nodular melanoma Lentigo maligna melanoma Acral lentiginous melanoma Mucosal melanoma https://www.aimatmelanoma.org/melanoma-risk-factors/melanoma-in-people-of-color/acral-lentiginous-melanoma-alm/ The University of Sydney http://www.pcds.org.uk/clinical-guidance/superficial-spreading-melanoma-and-melanoma-in-situ Page 7 https://www.healthline.com/health/skin-cancer/nodular-melanoma#symptoms https://www.researchgate.net/figure/Primary-oral-mucosal-melanoma-affecting-the-lower-gingival-and-lip-mucosa_fig1_319342373 Melanoma Screening and Diagnosis People at an increased risk for melanoma should be screened at regular intervals. Screening for melanoma includes a total body skin examination supported by dermoscopy or other imaging techniques. Screening is also useful for early detection of all types of skin cancer, including biopsy and histopathological diagnosis in case of suspicious lesions. People at high risk of melanoma receive regular surveillance to improve survival through early detection and to reduce unnecessary excisions. The University of Sydney Page 8 Melanoma Pathophysiology KIT Genetic level 1. Activating BRAF (B-Raf) mutation → Benign naevus formation 2. Mutations in the telomerase reverse- transcriptase (TERT) promoter → stage 0 melanoma in epidermis 3. Mutations in cell-cycle controlling genes CDKN2A → invasive potential KIT Protein level 1. Over-stimulation of MAPK pathway & NF1 deletion 2. Mutations in PTEN or tumour-protein p53 → metastasis Target therapy- BRAF/MEK inhibition The University of Sydney https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(18)31559-9.pdf Page 9 Target Therapy C-KIT - A small number of melanomas have changes in the C-KIT gene. This is more likely in melanomas that start on the palms of the hands, soles of the feet, under the nails, or in certain other places. - Clinical trials are now testing drugs such as imatinib, dasatinib, and nilotinib, which target cells with changes in C-KIT. - Most patients eventually experience disease progression. One possible reason for this drug resistance is the frequent presence of brain and central nervous system metastases in advanced melanoma as the drug penetration is limited in these areas. The University of Sydney Page 10 Target Therapy Table The University of Sydney Page 11 https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(18)31559-9.pdf Pathophysiology- Adaptive Immune Resistance Immunotherapy/checkpoint inhibition: Monoclonal antibodies against CTLA-4 CTLA4 inhibitor (ipilimumab) stops negative feedback to T cell and prolongs immune response to melanoma cells. The University of Sydney Page 12 Pathophysiology- Adaptive Immune Resistance 1. T cells release interferons and trigger JAK-STAT expression of ligand (PD-L1) on the surface of melanoma cells. 2. Binding of PD-L1 (melanoma cell) to PD-1 (T-cell)→ suppression of T-cell anti-tumour response. Immunotherapy/checkpoint inhibition: Monoclonal antibodies against PD1, PD-L1. https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(18)31559-9.pdf The University of Sydney Page 13 https://journals.lww.com/amjclinicaloncology/Fulltext/2016/02000/CTLA_4_and_PD_1_Pathways__Similarities,.17.aspx Immunotherapy Table The University of Sydney https://journals.lww.com/amjclinicaloncology/Fulltext/2016/02000/CTLA_4_and_PD_1_Pathways__Similarities,.17.aspx Page 14 Melanoma Genetic Alterations Four different genetic melanoma subtypes: 1. BRAF mutant melanomas (50%) 2. N-Ras, K-Ras, and H-Ras-mutant (25%) 3. NF1-mutant (15%) 4. Triple-wild-type (10%) Other genetic alternations: Activating TERT-promoter mutations (30-80%) Altered tumour suppressors- CDKN2A, PTEN, P53 The University of Sydney Page 15 Melanoma Treatment By Stage Treating stage 0- I melanoma (no lymph node) Surgery to remove the melanoma and a small margin of normal skin around it. The removed sample is then sent to a lab to be looked at with a microscope to assess if a wider excision is required. For melanomas in sensitive areas on the face→ Mohs surgery/ imiquimod cream if surgery might be disfiguring. Treating stage II or above melanoma surgery+ lymph node biopsy. If lymph node positive then target therapy and/ or immunotherapy. https://www.cancertodaymag.org/winter-2022-2023/setting-the-stage/ The University of Sydney Page 16 Target Therapy Considerations Rapid response within days to a few weeks. Favourable treatment outcomes when BRAF inhibitor+ MEK inhibitor, compared to monotherapy with a BRAF inhibitor. o Better disease control and reduced skin toxicity. Good safety and tolerability profile, common side effects include: nausea, diarrhoea, vomiting, arthralgia, fatigue, photosensitivity, increase in creatine kinase and liver transaminases, peripheral oedema, alopecia, hyperkeratosis. The University of Sydney Page 17 Immunotherapy Considerations CTLA4 inhibitor (ipilimumab) demonstrated superior efficacy compared with chemotherapy, but caused a range of immune- related adverse effects (irAE), e.g. gastrointestinal system, skin, liver, and endocrine organs. PD-1 blockers (nivolumab, pembrolizumab) showed superior efficacy compared with ipilimumab and chemotherapy, with lower toxicity rates. Nivolumab monotherapy, ipilimumab monotherapy, and the combination of nivolumab and ipilimumab were compared. The efficacy of the combination was superior to the monotherapies, however multiple and irreversible irAEs are more common. The University of Sydney Page 18 Management- Challenge Target therapy Multiple mechanisms of resistance against BRAF and MEK inhibitors have been identified, which eventually lead to reactivation of the MAPK signalling pathway or activation of the PI3K-AKT pathway. Immunotherapy Whilst patients show a long response duration, only around 40% of patients initially respond to these inhibitors. 20-30% initial respondents will develop acquired resistance. Lymphocyte activation gene-3 (LAG-3) normally suppresses T cells to ensure immune homeostasis, and is found to work with PD-1 to inhibit immune responses. Several studies have shown that LAG-3 blockade alleviates the patient’s tolerance to PD-1 immunotherapy. The University of Sydney Page 19 Combination Therapy Double immunotherapy PD1+PD-L1 PD1+ LAG-3 CTLA-4+ LAG-3 Triple therapy BRAF/MEK + PD1 BRAF/MEK + PD-L1 → Longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet target therapy Future ✓Whether a full combination is always needed as a first-line treatment (with all its inherent toxicity) or ✓Whether giving one drug after the other (ie, the sequencing approach) could lead to a comparable overall survival The University of Sydney Page 20 Sample exam questions Q1 Which type of skin cancer is the most common? 1. Basal cell carcinoma 2. squamous cell carcinoma 3. Melanoma 4. Merkel cell carcinoma Q2. Which one of the following is not a preventative option in BCC? 1. sun protection 2. nicotinic acid 3. nicotinamide 4. topical fluorouracil Q3. Which one of the following is not involved in cutaneous melanoma? 1. TERT promotor mutation 2. over-stimulation of MAPK pathway 3. down expression of PD-L1 4. mutation in CDKN2A Q4. Which one of the following is a CTLA-4 blocking antibody? 1. ipilimumab 2. nivolumab 3. pembrolizumab 4. atezolizumab The University of Sydney Page 21 Sample exam questions What does target therapy in melanoma inhibit, how is the target therapy response rate compared to checkpoint therapy, and what is the main challenge associated with target therapy? (3 marks) 1. BRAF inhibition and MEK inhibition 2. Target therapy has a faster response rate compared to checkpoint therapy 3. Main challenge is the development of resistance while on therapy The University of Sydney Page 22 Rheumatoid Arthritis Johnson Lee Pharmacy Guild NSW, Chief Pharmacist Acknowledgement of original content by A/Prof Kellie Charles The University of Sydney Page 1 The University of Sydney Page 2 Background – Rheumatoid arthritis (RA) symmetric polyarthritis of the hands, wrists, and feet systemic inflammation: Low-grade fevers, anaemia (fatigue) Liver- elevations of ESR/CRP Arthrosclerosis- plague formation, vascular endothelial damage, increased risk for ophthalmologic, vascular, pulmonary, cardiac, and renal disease Bone- osteoporosis Neurological- fatigue, depression – Uncontrolled synovial tissues proliferation excess fluid production destruction of cartilage, erosion of marginal bone stretching and damage of the tendons and ligaments – ~70% cases are seropositive Anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) present The University of Sydney Page 3 Symptoms – First joint symptoms Swelling and pain in metacarpophalangeal, proximal interphalangeal, and usually spares the distal interphalangeal joints Wrist pain and stiffness May be asymmetric initially, but eventually becomes symmetric Prolonged morning stiffness Pain in median nerve distribution from carpal tunnel synovial thickening Dropping or being unable to grip items owing to pain Loss of function from synovial inflammation and rupture of extensor tendon – Symptoms in larger joints Shoulder pain and stiffness (65%) Knee pain and swelling (64% of patients) Elbow pain and stiffness (38%) Hip pain and stiffness (17%) The University of Sydney Page 4 Common presentations of RA The University of Sydney Page 5 Joint changes with RA The University of Sydney Page 6 Common sites with RA RA OA PIP hyper extension OA RA The University of Sydney Page 7 https://www-clinicalkey-com-au.ezproxy1.library.usyd.edu.au/#!/content/book/3-s2.0-B9781455750177002646?scrollTo=%23hl0000525 Risk Factors The University of Sydney Page 8 Pathogenesis of RA The University of Sydney Page 9 Pathogenesis overview- New England Journal of Medicine video – https://www.youtube.com/watch?v=e_NZk8nFSPA – 3:24- 5:24 The University of Sydney Page 10 Induction of RA pathogenesis 1. Citrullination (post translational modification) 2. Macrophage presenting citrullinated protein to T cell 3. B cell proliferation and differentiation into plasma cell 4. Plasma cell produces Anti-citrullinated protein antibodies (ACPA) The University of Sydney Page 11 RA RA pathogenesis Key cells: Macrophage T cell B cell Fibroblast like synoviocyte (FLS) Key cytokines: TNF IL1 IL6 Joint basement membranes are arginine rich and therefore common sites for citrullination: fibrinogen, vimentin, collagen type II and α- enolase. The University of Sydney Page 12 Antigen presentation dysfunction in autoimmunity Antigen (sausage) MHC class 2 molecule (hotdog bun) – HLA-DRB1 variants have increased number of positive charged amino acids in binding pockets (4, 7, 9) and there is enhanced citrulline binding. – Stronger binding→ better antigen presentation→ stronger T cell activation The University of Sydney Page 13 Early B cell antigen recognition & auto- antibody production – ~60-70% early immature B cells from healthy donors are polyreactive to self antigens – They are normally removed from bone marrow (central tolerance) – In asymptomatic RA patients, autoreactive B cells are found (no central tolerance). – Other inflammatory conditions including Crohn’s, psoriasis, eczema share a similar dysfunctional central tolerance. The University of Sydney Page 14 Microbiome linkages with RA – Environmental risk factors in RA include Respiratory diseases – bronchiectasis, asthma Smoking, occupational silica exposure Periodontal disease, diet, obesity – All can change the barrier function of mucosal sites leading to tissue damage & further disease – Shared high risk of disease with HLADRB1 – Gut microbial dysbiosis is common in arthritides – Many bacteria can cause PTM incl. citrullination – Autoantibodies can be detected in sputum (ACPA-IgA and IgG) prior to RA detected clinically in high risk family members The University of Sydney Page 15 Joint erosion Inflammation starts with macrophage releasing cytokines (IL & TNF) to activate fibroblast-like synoviocyte (FLS): 1. Excessive proliferation 2. Secretion of protease which breaks down cartilage 3. Stimulate osteoclast activity (bone erosion) 4. Synovial hyperplasia with membrane rupture, so FLS can migrate to different joints causing symmetrical arthritis The University of Sydney Page 16 Joint erosion Macrophage communicates with T cells: 1. release IL to stimulate FLS 2. stimulate B cells to differentiate into plasma cells 3. plasma cells release autoantibodies (ACPA & RF) 4. ACPA triggers inflammation, while RF worsens ACPA induced inflammation. a. Presence of RF indicates more severe disease state, and lower efficacy of conventional DMARDs b. Presence of ACPA shows more relapses in disease state after drug suspension The University of Sydney Page 17 Linkages between cytokines + symptoms van Vollenhoven, R. F. (2009) Treatment of rheumatoid arthritis: state of the art 2009 Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2009.182 The University of Sydney Page 18 Management of RA The University of Sydney Page 19 Considerations – Goals of therapy Symptom relief Modify disease course Induce remission Maintain remission Prevent or treat relapse – Special circumstances Pregnancy and fertility Co-morbidities The University of Sydney Page 20 Why is treatment of early RA important? i. Damage occurs early – 70% patients have joint erosion within 2yrs – 40% patients have joint erosion at presentation – Significant Bone Mineral Density (BMD) loss in 1st year ii. Disability occurs early – Joint function is lost early iii. Spontaneous remission is rare – Large primary care based cohort study - remission < 5% The University of Sydney Page 21 How to differentiate between MSK conditions – Clinical history of presentation – Number and location of joints involved – Extent/severity of disease modification – Extra-articular symptoms (skin, eyes, git) – Blood results (particularly auto-antibodies, CRP) – Joint aspiration (crystals, blood cells, colour, pathogens) The University of Sydney Page 22 Treatment Strategy Symptomatic treatments – Non-pharmacological – weight management, exercise, OT/PT, n3-FA – analgesics – anti-inflammatory drugs non-steroidal (NSAIDs and COX-2s) Corticosteroids Disease Modifying Anti-Rheumatic Drugs (DMARDs): – Started early in combination with NSAIDs or GC – Delayed efficacy on symptoms (slow-acting) – Improve long term outcome by slowing disease progression Synthetic - Methotrexate & leflunomide (anti-metabolites), sulphasalazine, hydroxychloroquine Biological – antibodies to cellular processes or ligands The University of Sydney Page 23 Methotrexate The University of Sydney Page 24 Cellular MOA The University of Sydney Page 25 Leflunomide The University of Sydney Page 26 MOA – leflunomide (prodrug converts to teriflunomide) The University of Sydney Page 27 Sulfasalazine The University of Sydney Page 28 MOA - sulfasalazine The University of Sydney Page 29 Hydroxychloroquine The University of Sydney Page 30 MOA - hydroxychloroquine The University of Sydney https://www.nature.com/articles/s41584-020-0372-x Page 31 Efficacy comparison – Several agents can be added – Sulfasalazine – Leflunomide – Hydroxychloroquine – The choice is dependent on patient factors including comorbidity The University of Sydney Page 32 Risks & benefits of combination Rx – Increased efficacy – MTX + Hydroxychloroquine – MTX + Leflunomide – MTX + Hydroxychloroquine + Sulfasalazine – Required to qualify for biologics – sequential or together for at least 3 months – Potential for increased side effects – Infections – Abnormal liver function (esp MTX + leflunomide) The University of Sydney Page 33 Criteria for Biologics – Methotrexate for 3 months – A second DMARD for 3 months – Active disease – Erythrocyte Sedimentation Rate (ESR) >25 OR C-Reactive Protein (CRP) >15 – 20 or more joints swollen OR 4 or more large joints swollen The University of Sydney Page 34 Choice of first bDMARD for RA – Based on TGA approval regulations and guidelines – Consider patient comorbidities or characteristics – Consider patient adherence – iv, sc (at home) or oral (don’t like injections) PBS prescription & expenditure data 2018-2019 – 7 million prescriptions, 100,000 new within the year – $420 million government cost – Adalimumab – 244, 506 prescriptions ($350 million) – Etanercept – 103, 181 prescriptions ($105 million) – Infliximab – 57,023 prescriptions ($116 million) The University of Sydney Page 35 REMEMBER WHAT ARE YOU TARGETING? The University of Sydney https://www.nejm.org/doi/full/10.1056/nejmra1004965 Page 36 Structures of Monoclonal Antibodies The University of Sydney Imai and Takaoka Nature Reviews Cancer 6, 714–727 (September 2006) | doi:10.1038/nrc1913 Page 37 Immunoglobulin-FcR interactions on effector cells Target cell is destroyed by effector cell via: - anybody dependent cellular cytotoxicity (ADCC) - Complement dependent cytotoxicity (CDC) ADCC illustration The University of Sydney Antibody Ther 2018, 1 (1): b7–12, https://doi.org/10.1093/abt/tby002 Page 38 Cytokine antagonists – TNF, IL6, IL17, IL23 The University of Sydney Page 39 Non-vaccine injectables Pharmacist registration Immunisation course accredited by the Australian Pharmacy Council CPR renewed annually Medicine administration course (free for students) Appropriate knowledge on Product Information Appropriate documentation ❑ Pharmacy Connect Medicines Administration Refresher Thursday 5 Sept 9:30am-1pm The University of Sydney Page 40 MOA of TNF-a inhibitors Similar to corticosteroids – master regulator of inflammation Reduction of other cytokines, chemokines, COX, VEGF Reduced inflammation, immune cell activation + proliferation + differentiation + chemotaxis, prostaglandin synthesis, angiogenesis Etanercept MOA video https://www.pfizerpro.au/medicine/enbrel/a bout/mechanism-of-action/mechanism-of- action The University of Sydney Page 41 MOA of IL6 inhibitors and JAK inhibitors IL6 inhibitors (injectables): Tocilizumab Sarilumab The University of Sydney Page 42 Direct and indirect B-cell targeting – Similar to anti-cytokine antagonists with regards to mechanisms (B cell specific), adverse events, contraindications + practice points. – Effectiveness is long-lasting in responding patients with iv injections once every 6-12 months. Burmester, G. R. et al. (2013) Emerging cell and cytokine targets in rheumatoid arthritis Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.168 The University of Sydney Page 43 Selective co-stimulation modulator- Abatacept Once immune response is over The University of Sydney Page 44 3 main MOA for biological DMARDs The University of Sydney Page 45 Summary Pathogenesis of the RA – genetic susceptibility + environment Increased cytokine networks establish cyclic loops to mediate pathological changes in joints Treatment goals – treated symptoms to induce remission or low disease activity Start early with csDMARD – MTX alone (if no contraindications) Non-responsive – add another csDMARD for 3+ month Non-responsive to MTX + other csDMARD - need to move to bDMARD Start with TNF antagonist + MTX (although does not have to be TNF antagonist) Switch to other bDMARDS allowed, no specific preference The University of Sydney Page 46 Sample exam questions 1. Which one of the following statements is true regarding rheumatoid arthritis? a. it has extensive osteophyte formation b. it entails inhibition of proteoglycan synthesis c. it has significant subchondral scelorisis d. it is associated with Bouchard’s nodes 2. Which one of the following is a clinical feature of rheumatoid arthritis? a. monosodium urate crystal b. Bouchard nodes around PIP c. uncontrolled synovial tissues proliferation d. dactylitis 3. Which one of the following treatments is an oral formulation? a. golimumab b. adalimumab c. abatacept d. tofacitinib 4. Which one of the following statements is correct? a. new biologic DMARDs such as abatacept would not cause adverse pulmonary effects b. TNFi is preferred over conventional DMARDs in patients with heart failure c. patients with solid organ malignancy within the last five years should use conventional DMARDs over biologic agents d. newer biological agents such as tofacitinib are preferred over conventional DMARDs in patients with an active serious infection The University of Sydney Page 47 Rheumatoid Arthritis Johnson Lee Pharmacy Guild NSW, Chief Pharmacist Acknowledgement of original content by A/Prof Kellie Charles The University of Sydney Page 1 The University of Sydney Page 2 Background – Rheumatoid arthritis (RA) symmetric polyarthritis of the hands, wrists, and feet systemic inflammation: Low-grade fevers, anaemia (fatigue) Liver- elevations of ESR/CRP Arthrosclerosis- plague formation, vascular endothelial damage, increased risk for ophthalmologic, vascular, pulmonary, cardiac, and renal disease Bone- osteoporosis Neurological- fatigue, depression – Uncontrolled synovial tissues proliferation excess fluid production destruction of cartilage, erosion of marginal bone stretching and damage of the tendons and ligaments – ~70% cases are seropositive Anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) present The University of Sydney Page 3 Symptoms – First joint symptoms Swelling and pain in metacarpophalangeal, proximal interphalangeal, and usually spares the distal interphalangeal joints Wrist pain and stiffness May be asymmetric initially, but eventually becomes symmetric Prolonged morning stiffness Pain in median nerve distribution from carpal tunnel synovial thickening Dropping or being unable to grip items owing to pain Loss of function from synovial inflammation and rupture of extensor tendon – Symptoms in larger joints Shoulder pain and stiffness (65%) Knee pain and swelling (64% of patients) Elbow pain and stiffness (38%) Hip pain and stiffness (17%) The University of Sydney Page 4 Common presentations of RA The University of Sydney Page 5 Joint changes with RA The University of Sydney Page 6 Common sites with RA RA OA PIP hyper extension OA RA The University of Sydney Page 7 https://www-clinicalkey-com-au.ezproxy1.library.usyd.edu.au/#!/content/book/3-s2.0-B9781455750177002646?scrollTo=%23hl0000525 Risk Factors The University of Sydney Page 8 Pathogenesis of RA The University of Sydney Page 9 Pathogenesis overview- New England Journal of Medicine video – https://www.youtube.com/watch?v=e_NZk8nFSPA – 3:24- 5:24 The University of Sydney Page 10 Induction of RA pathogenesis 1. Citrullination (post translational modification) 2. Macrophage presenting citrullinated protein to T cell 3. B cell proliferation and differentiation into plasma cell 4. Plasma cell produces Anti-citrullinated protein antibodies (ACPA) The University of Sydney Page 11 RA RA pathogenesis Key cells: Macrophage T cell B cell Fibroblast like synoviocyte (FLS) Key cytokines: TNF IL1 IL6 Joint basement membranes are arginine rich and therefore common sites for citrullination: fibrinogen, vimentin, collagen type II and α- enolase. The University of Sydney Page 12 Antigen presentation dysfunction in autoimmunity Antigen (sausage) MHC class 2 molecule (hotdog bun) – HLA-DRB1 variants have increased number of positive charged amino acids in binding pockets (4, 7, 9) and there is enhanced citrulline binding. – Stronger binding→ better antigen presentation→ stronger T cell activation The University of Sydney Page 13 Early B cell antigen recognition & auto- antibody production – ~60-70% early immature B cells from healthy donors are polyreactive to self antigens – They are normally removed from bone marrow (central tolerance) – In asymptomatic RA patients, autoreactive B cells are found (no central tolerance). – Other inflammatory conditions including Crohn’s, psoriasis, eczema share a similar dysfunctional central tolerance. The University of Sydney Page 14 Microbiome linkages with RA – Environmental risk factors in RA include Respiratory diseases – bronchiectasis, asthma Smoking, occupational silica exposure Periodontal disease, diet, obesity – All can change the barrier function of mucosal sites leading to tissue damage & further disease – Shared high risk of disease with HLADRB1 – Gut microbial dysbiosis is common in arthritides – Many bacteria can cause PTM incl. citrullination – Autoantibodies can be detected in sputum (ACPA-IgA and IgG) prior to RA detected clinically in high risk family members The University of Sydney Page 15 Joint erosion Inflammation starts with macrophage releasing cytokines (IL & TNF) to activate fibroblast-like synoviocyte (FLS): 1. Excessive proliferation 2. Secretion of protease which breaks down cartilage 3. Stimulate osteoclast activity (bone erosion) 4. Synovial hyperplasia with membrane rupture, so FLS can migrate to different joints causing symmetrical arthritis The University of Sydney Page 16 Joint erosion Macrophage communicates with T cells: 1. release IL to stimulate FLS 2. stimulate B cells to differentiate into plasma cells 3. plasma cells release autoantibodies (ACPA & RF) 4. ACPA triggers inflammation, while RF worsens ACPA induced inflammation. a. Presence of RF indicates more severe disease state, and lower efficacy of conventional DMARDs b. Presence of ACPA shows more relapses in disease state after drug suspension The University of Sydney Page 17 Linkages between cytokines + symptoms van Vollenhoven, R. F. (2009) Treatment of rheumatoid arthritis: state of the art 2009 Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2009.182 The University of Sydney Page 18 Management of RA The University of Sydney Page 19 Considerations – Goals of therapy Symptom relief Modify disease course Induce remission Maintain remission Prevent or treat relapse – Special circumstances Pregnancy and fertility Co-morbidities The University of Sydney Page 20 Why is treatment of early RA important? i. Damage occurs early – 70% patients have joint erosion within 2yrs – 40% patients have joint erosion at presentation – Significant Bone Mineral Density (BMD) loss in 1st year ii. Disability occurs early – Joint function is lost early iii. Spontaneous remission is rare – Large primary care based cohort study - remission < 5% The University of Sydney Page 21 How to differentiate between MSK conditions – Clinical history of presentation – Number and location of joints involved – Extent/severity of disease modification – Extra-articular symptoms (skin, eyes, git) – Blood results (particularly auto-antibodies, CRP) – Joint aspiration (crystals, blood cells, colour, pathogens) The University of Sydney Page 22 Treatment Strategy Symptomatic treatments – Non-pharmacological – weight management, exercise, OT/PT, n3-FA – analgesics – anti-inflammatory drugs non-steroidal (NSAIDs and COX-2s) Corticosteroids Disease Modifying Anti-Rheumatic Drugs (DMARDs): – Started early in combination with NSAIDs or GC – Delayed efficacy on symptoms (slow-acting) – Improve long term outcome by slowing disease progression Synthetic - Methotrexate & leflunomide (anti-metabolites), sulphasalazine, hydroxychloroquine Biological – antibodies to cellular processes or ligands The University of Sydney Page 23 Methotrexate The University of Sydney Page 24 Cellular MOA The University of Sydney Page 25 Leflunomide The University of Sydney Page 26 MOA – leflunomide (prodrug converts to teriflunomide) The University of Sydney Page 27 Sulfasalazine The University of Sydney Page 28 MOA - sulfasalazine The University of Sydney Page 29 Hydroxychloroquine The University of Sydney Page 30 MOA - hydroxychloroquine The University of Sydney https://www.nature.com/articles/s41584-020-0372-x Page 31 Efficacy comparison – Several agents can be added – Sulfasalazine – Leflunomide – Hydroxychloroquine – The choice is dependent on patient factors including comorbidity The University of Sydney Page 32 Risks & benefits of combination Rx – Increased efficacy – MTX + Hydroxychloroquine – MTX + Leflunomide – MTX + Hydroxychloroquine + Sulfasalazine – Required to qualify for biologics – sequential or together for at least 3 months – Potential for increased side effects – Infections – Abnormal liver function (esp MTX + leflunomide) The University of Sydney Page 33 Criteria for Biologics – Methotrexate for 3 months – A second DMARD for 3 months – Active disease – Erythrocyte Sedimentation Rate (ESR) >25 OR C-Reactive Protein (CRP) >15 – 20 or more joints swollen OR 4 or more large joints swollen The University of Sydney Page 34 Choice of first bDMARD for RA – Based on TGA approval regulations and guidelines – Consider patient comorbidities or characteristics – Consider patient adherence – iv, sc (at home) or oral (don’t like injections) PBS prescription & expenditure data 2018-2019 – 7 million prescriptions, 100,000 new within the year – $420 million government cost – Adalimumab – 244, 506 prescriptions ($350 million) – Etanercept – 103, 181 prescriptions ($105 million) – Infliximab – 57,023 prescriptions ($116 million) The University of Sydney Page 35 REMEMBER WHAT ARE YOU TARGETING? The University of Sydney https://www.nejm.org/doi/full/10.1056/nejmra1004965 Page 36 Structures of Monoclonal Antibodies The University of Sydney Imai and Takaoka Nature Reviews Cancer 6, 714–727 (September 2006) | doi:10.1038/nrc1913 Page 37 Immunoglobulin-FcR interactions on effector cells Target cell is destroyed by effector cell via: - anybody dependent cellular cytotoxicity (ADCC) - Complement dependent cytotoxicity (CDC) ADCC illustration The University of Sydney Antibody Ther 2018, 1 (1): b7–12, https://doi.org/10.1093/abt/tby002 Page 38 Cytokine antagonists – TNF, IL6, IL17, IL23 The University of Sydney Page 39 Non-vaccine injectables Pharmacist registration Immunisation course accredited by the Australian Pharmacy Council CPR renewed annually Medicine administration course (free for students) Appropriate knowledge on Product Information Appropriate documentation ❑ Pharmacy Connect Medicines Administration Refresher Thursday 5 Sept 9:30am-1pm The University of Sydney Page 40 MOA of TNF-a inhibitors Similar to corticosteroids – master regulator of inflammation Reduction of other cytokines, chemokines, COX, VEGF Reduced inflammation, immune cell activation + proliferation + differentiation + chemotaxis, prostaglandin synthesis, angiogenesis Etanercept MOA video https://www.pfizerpro.au/medicine/enbrel/a bout/mechanism-of-action/mechanism-of- action The University of Sydney Page 41 MOA of IL6 inhibitors and JAK inhibitors IL6 inhibitors (injectables): Tocilizumab Sarilumab The University of Sydney Page 42 Direct and indirect B-cell targeting – Similar to anti-cytokine antagonists with regards to mechanisms (B cell specific), adverse events, contraindications + practice points. – Effectiveness is long-lasting in responding patients with iv injections once every 6-12 months. Burmester, G. R. et al. (2013) Emerging cell and cytokine targets in rheumatoid arthritis Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.168 The University of Sydney Page 43 Selective co-stimulation modulator- Abatacept Once immune response is over The University of Sydney Page 44 3 main MOA for biological DMARDs The University of Sydney Page 45 Summary Pathogenesis of the RA – genetic susceptibility + environment Increased cytokine networks establish cyclic loops to mediate pathological changes in joints Treatment goals – treated symptoms to induce remission or low disease activity Start early with csDMARD – MTX alone (if no contraindications) Non-responsive – add another csDMARD for 3+ month Non-responsive to MTX + other csDMARD - need to move to bDMARD Start with TNF antagonist + MTX (although does not have to be TNF antagonist) Switch to other bDMARDS allowed, no specific preference The University of Sydney Page 46 Sample exam questions 1. Which one of the following statements is true regarding rheumatoid arthritis? a. it has extensive osteophyte formation b. it entails inhibition of proteoglycan synthesis c. it has significant subchondral scelorisis d. it is associated with Bouchard’s nodes 2. Which one of the following is a clinical feature of rheumatoid arthritis? a. monosodium urate crystal b. Bouchard nodes around PIP c. uncontrolled synovial tissues proliferation d. dactylitis 3. Which one of the following treatments is an oral formulation? a. golimumab b. adalimumab c. abatacept d. tofacitinib 4. Which one of the following statements is correct? a. new biologic DMARDs such as abatacept would not cause adverse pulmonary effects b. TNFi is preferred over conventional DMARDs in patients with heart failure c. patients with solid organ malignancy within the last five years should use conventional DMARDs over biologic agents d. newer biological agents such as tofacitinib are preferred over conventional DMARDs in patients with an active serious infection The University of Sydney Page 47 Evidence-based complementary medicines for osteoarthritis pain and disability 2024 Presented by Dr Joanna Harnett, BHSc (Complementary Medicine) MHSc (Complementary Medicine) PhD (Nutritional Pharmacology) Grad Cert Educational Studies (Higher Education) The University of Sydney Page 1 Learning objectives By the end of this lecture, you should be able to: Provide evidence-based information regarding the efficacy and safety of selected CMs in the management of pain and disability associated with osteoarthritis Glucosamine, Chondroitin, Boswellia serrata extract, Curcumin, Maritime Pine bark extract, methylsulfonylmethane (MSM), Omega 3 fatty acids. Describe drug interactions that may occur between specific herbs or nutritional supplements used for osteoarthritis. Respond to requests for Complementary Medicines (CMs) for the management of osteoarthritis. The University of Sydney Page 2 APC Learning Domains Australian Pharmacy Councils Learning Domains for Degree Programs 2020 domain 2: Pharmacists have a unique role within the health care team as medicines experts and must therefore have a sound understanding of the sources, properties and actions of medicinal substances Medicines – the drug substance and drug action: ‘Evidence-based complementary and alternative therapies, and their interactions with medicines’ The University of Sydney Page 3 Introduction - Osteoarthritis (OA) OA is the most common muscular-skeletal disorder affecting Australians – projected to 3.1 million by 2030. Health care costs for OA were estimated to be over $2.1 billion in 2015; by the year 2030, these are forecast to exceed $2.9 billion ($970 for every person with the condition). (Ackerman 2018) The disabling effects of OA include substantial costs associated with healthcare and work loss due to OA‐related pain and disability (Laires 2018) There is no proven cure Goals of treatment are to: Reduce pain Improve function Prevent disability The University of Sydney Page 4 Case 2023 Mrs Bryant is a 65 year old female with pain in both her knees that impacts her mobility. She does not met the criteria for ‘knee replacement’ and is unable to continue NSAIDs due to gastritis and a history of PUD Takes no other medications Allergic to shellfish Has a preference to use CMs to manage her pain and disability Her doctor said to ask you if there is any evidence to support the efficacy of CMs commonly used to treat OA associated pain and disability? The University of Sydney Page 5 What CMs are consumers taking? (Basedow, Runciman, March, & Esterman, 2014) Objectives: To investigate complementary and alternative medicine (CAM) use amongst a cohort of osteoarthritis (OA) sufferers and to explore reasons for use. Results: Conclusion: As CAM use is a key 69% percent of respondents reported that component of the self- they had tried CAM, with little difference management strategies for a between age groups and genders. Patients who substantial proportion of had a better knowledge of their condition and Australians with OA, users need excellent self-rated health were more likely to to be more fully informed use CAM. An aversion to the side effects of about evidence of efficacy. conventional medicine, failure to engage in exercise, and a belief in the efficacy of CAM were the principal factors underlying use. The University of Sydney Page 6 What are Australians taking for osteoarthritis? Journal of Nutrition Health and Ageing 2016 Of the 10,638 women in the Australian Longitudinal Women's Health Study, 26.8% reported use of omega-3 FA and 15.9% glucosamine mainly taken for joint pain, osteoarthritis and other arthritis The University of Sydney Page 7 What you need to know – what consumers need to know What does a pharmacist need to know about CM and Osteoarthritis? Where to access reliable information on CM quickly in a Pharmacy The evidence for efficacy The evidence for safety Adverse effects Precautions and Contraindications Significant drug-nutrient-herb interactions Pregnancy and Lactation What are some of the professional considerations when communicating to people about complementary medicine product use? (refer to year 2 communications and CM lecture) The University of Sydney Page 8 8 Glucosamine – what is it? Glucosamine sulfate is a naturally occurring substance found in synovial fluid that is required for the production of proteoglycans, mucopolysaccharides and hyaluronic acid which are substances that make up joint tissue, such as articular cartilage, tendons and synovial fluid Chemical components 2-amino-2-deoxy-D-glucose Dietary sources of glucosamine are from chitin in the shells of prawns and other crustaceans. As supplements glucosamine is derived from marine exoskeletons or is produced synthetically and available in salt forms glucosamine sulfate glucosamine hydrochloride N-acetyl-glucosamine The University of Sydney Page 9 What are the ‘proposed’ actions? – The molecular mode of action is not fully understood: – Symptomatic relief and disease-modifying effects have been attributed to Glucosamine sulphate through: – Preliminary animal studies that suggest that glucosamine inhibits protein N-glycosylation and cytokine stimulated production of mediators of inflammation and cartilage degradation. (Reginster, Deroisy et al. 2001)(Bruyère, Altman, & Reginster, 2016) The University of Sydney Page 10 Is it effective in the management of osteoarthritis? Cochrane Review - updated 2009 – 25 studies with 4963 patients. – non-Rotta preparation or adequate allocation concealment failed to show benefit in pain and WOMAC function. – Rotta preparations show that glucosamine was superior to placebo in the treatment of pain and functional impairment resulting from symptomatic OA. – Glucosamine was as safe as placebo. Towheed, T. E. et al. (2005). Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev(2) (updated 2009) The University of Sydney Page 11 Glucosamine use continues to be supported by – The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm recommends chronic symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) including glucosamine sulfate (GS) and chondroitin sulfate (CS) as first-line therapy for knee osteoarthritis (OA). – Glucosamine sulphate (patented crystalline form) prescription only – Bruyère, O., Cooper, C., Pelletier, J.-P., Maheu, E., Rannou, F., Branco, J.,... Reginster, J.-Y. (2016). A consensus statement on the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis—From evidence-based medicine to the real-life setting. Seminars in Arthritis and Rheumatism, 45(4, Supplement), S3-S11. The University of Sydney Page 12 Not supported in other countries – NIH USA – “The preponderance of evidence indicates little or no meaningful effect on pain or function.” – The American College of Rheumatology (2012) (2021) – The American Academy of Orthopaedic surgeons (2010) – Arthritis Australia and Australian Rheumatology Association comment: – “This information highlights growing evidence that glucosamine does not help people with osteoarthritis and is a reminder that people with shellfish allergy should not take glucosamine (which is commonly derived from shellfish). It does not identify any new safety concerns and should not cause undue alarm in people already taking glucosamine.” https://arthritisaustralia.com.au/australian-rheumatology- association-and-arthritis-australia-statement-regarding-the-use-of- glucosamine-for-the-treatment-of-osteoarthritis/ (accessed 9th August 2022) The University of Sydney Page 13 Drug Interactions DO not combine with Warfarin (anti-thrombotic and anticoagulants) – increases risk of bleeding Avoid concurrent use with antimitotic therapy- theoretically may reduce drugs’ inhibition of topoisomerase II, an enzyme required for DNA replication Caution with anti-diabetic medications may reduce efficacy of BSL control (check IM gateway and NMD for multiple interactions with this supplement) The University of Sydney Page 14 Glucosamine safety Renally excreted – renal impairment Common mild side effects including nausea, heartburn, diarrhoea, and constipation. Rare side effects include drowsiness, skin reactions, and headache Pregnancy or breast-feeding: Insufficient evidence to recommend Asthma: Glucosamine supplements have also been implicated in worsening underlying asthma. *** Diabetics – whether it raises blood glucose levels in people with or without diabetes is unclear *** Hyperlipidaemia: Animal studies cautioned cholesterol levels may rise however this has not been found in humans **** Hypertension: monitor blood pressure*** Shellfish or sulphur allergy: Because some glucosamine sulfate products are made from the shells of shrimp, lobsters or crabs, there is concern that glucosamine products might cause allergic reactions in people who are allergic to shellfish. Surgery: Discontinue glucosamine sulfate at least 2 weeks before a scheduled surgery. *** for discussion in lecture The University of Sydney Page 15 Chondroitin (Cochrane Review 2017) Chondroitin is a complex sugar derived from the cartilage of animals; it is considered a food supplement. glycosaminoglycan produced naturally in the body. It is formed by the 1-3 linkage of D-glucuronic acid to N-acetylgalactosamine. shark and bovine cartilage, or produced synthetically 9,000 patients, majority of trials are for knee OA, for 3 months minimum. significantly reduces pain by an average of 9% to 10% compared to placebo. WOMAC scale, taking chondroitin for 6 months reduced pain scores by 20% in significantly more patients than placebo. In this analysis, 16 patients would need to be treated for one additional patient to experience a 20% reduction in pain. The typical dose of chondroitin sulfate is 200-400 mg two to three times daily or 1000-1200 mg as a single daily dose Adverse events were generally mild. – Singh JA et al. Chondroitin for osteoarthritis. Cochrane Database of Systematic Reviews 2015, Issue 1. The University of Sydney Page 16 Chondroitin - safety Chondroitin sulfate is LIKELY SAFE when taken by mouth at recommended doses. It has been used safely in research for up to 3 years. Chondroitin sulfate from animal sources ? Products from diseased animal tissue, there are no reports of chondroitin causing disease in humans, and the risk is thought to be low. It can cause some mild stomach pain and nausea. Other side effects that have been reported are diarrhoea, constipation, swollen eyelids, leg swelling, hair loss, and irregular heartbeat. Some chondroitin products contain excess amounts of manganese. Pregnancy and breast-feeding: Not enough is known about the safety of chondroitin sulfate use during pregnancy and breast-feeding. Asthma: May exacerbate asthmatic symptoms in some patients May increase bleeding in patients taking anti-coagulant medications The University of Sydney Page 17 Indian frankincense (Boswellia serrata) Indian frankincense (Boswellia serrata) is a tree. Under the bark is a gummy oleo-resin. The resin contains up to 16% of essential oil and beta-boswellic acid (BA) is the major triterpene constituent. BAs from the gum resin block the synthesis of 5-lipoxygenase products in vitro, including 5- hydroxyeicosatetraenoic acid and leukotriene B4 (pro-inflammatory) The University of Sydney Page 18 Evidence – standardised Boswellia serrata extract (BSE) – DB - RCT n=30 - improved pain, flexion, walking distance after 8 wk in the BSE group (p < 0.001) Kimmatkar, Thawani, Hingorani, & Khiyani, 2003 – Bioequivalence open label study n=66 BSE plus NSAIDs compared to NSAIDs alone were superior at 2 months, 7 months and 1 month after discontinuation Sontakke et al., 2007 – DB-RCT n=90 BSE improved pain, stiffness and functional ability scores vs placebo (p < 0.0001). Concentration of the proteolytic enzyme MMP-3 in synovial fluid pain scores were significantly lower with higher doses 250mg/d vs the low-dose 100mg/d group at day 7 Sengupta et al., 2008 – Collectively these studies support large and clinically important treatment effects for pain and disability improvement Liu 2018 – Small studies, overall low quality evidence The University of Sydney Page 19 Safety- Boswellia serrata Safety: Standardised extracts have been demonstarted to be safe and well tolerated however safety data is limited Major adverse events have not been reported in clinical trials Minor adverse events reported, include nausea, headache, abdominal pain, diarrhoea, fever and general weakness. Liu 2018 Contraindications and cautions Caution in autoimmune conditions (based on theoretical concerns) Pregnancy and Lactation Not recommended for use in pregnancy and lactation due to lack of data Interactions In vitro evidence shows that Boswellia serrata inhibits cytochrome P450 3A4,1A2, 2C19, 2C9, 2D6, 3A4. Frank 2006 There are no human studies on drug interactions with Boswellia serrata at this time. The University of Sydney Page 20 Turmeric – Curcumin (curcuma longa) Rhizome is used in curry and medicinally Turmeric rhizome contains 5% phenolic curcuminoids, which give turmeric its yellow colour. The most significant curcuminoid is curcumin Turmeric rhizome also contain polysaccharides, including acid glucans known as ukonan A, Anti-inflammatory (Chainani-Wu, 2003)(Khedr & Khedr, 2014) Curcumin inhibits 5-lipooxygenase (5LOX) and COX-2 in the arachidonic acid metabolic cycle, Anti-oxidant (Khedr & Khedr, 2014), Immuno-modulatory, wound healing, anti-proliferative (Du et al., 2013), anti- microbial activities Issues related to bioavailability of active constituents resulting in sub-optimal plasma levels to exert a biological effect Bioavailability of curcumin improved in a phosphotidylcholin phytosome complex (lecithinized delivery system) or the addition of piperine to curcumin formulation The University of Sydney Page 21 Is there any evidence for curcumin in the management of pain associated with OA of the knee? Aim: To critically appraise and evaluate the evidence for effectiveness of curcuminoids in the treatment of osteoarthritis (OA) in adults by assessing RCTs that investigated the effectiveness of orally-administered curcuminoids in OA. Results: total of 797 participants with primarily knee OA. All studies were conducted in Asia. The overall risk of bias was moderate. Improvements in WOMAC Index total scores, with signiﬁcant reductions in the use of rescue medication were also observed with curcuminoids. No serious adverse events were reported. Conclusions: Curcuminoids may have some beneﬁcial effects on knee pain and quality of life in patients with knee OA. However, they are less effective at relieving pain compared with ibuprofen. Curcuminoids appear safe on the short-term, and may reduce the need for rescue medication. Published RCTs vary in reporting quality, are characterized by small sample sizes The University of Sydney Page 22 Is there any evidence for curcumin in the management of pain associated with OA of the knee? Pain Medicine 2016 Aim: To provide the highest level of evidence on the efficacy of curcuminoids in patients with painful conditions through meta-analysis of data from randomized controlled trials (RCTs). Methods. A systematic review and meta-analysis was conducted using data reported by RCTs. The primary efficacy measure was pain intensity or algofunctional status. Results. 8 RCTs met inclusion criteria that included 606 randomized patients. Curcuminoids were found to significantly reduce pain. This pain-relieving effect was found to be independent of administered dose and duration of treatment with Conclusion: curcuminoids,Curcuminoids and was freesupplements maybias. from publication be aCurcuminoids safe and effective werestrategy safe andtowell improve tolerated pain in allseverity, by warranting evaluated RCTs. further rigorously conducted studies to define the The University of Sydney Page 23 long-term efficacy and safety. Safety – Turmeric/Curcumin (Exercise time – log into Natural Medicine Database) Contraindications and Cautions? Pregnancy and Lactation ? Toxicity - ?? Adverse reactions ?? The University of Sydney Page 24 Adverse events – hepatotoxicity Updated 2023 https://consultations.tga.gov.au/medicines-regulation-division/low-neg-risk-2023- 2024/user_uploads/tga---low-negligible-risk-annual-consultation-2023-2024---final.pdf – In July 2019, the TGA became aware of a cluster of 28 hepatotoxicity cases in Italy following consumption of C. longa/curcumin supplements. 61% (17/28) received a WHO causality assessment of probable, 36% (10/28) were assessed as possible. Of note, 33% (9/28) of cases did not involve piperine-containing medicines. – An additional 64 international AE reports of drug related hepatic disorders (reported in VigiBase1 as of 02 July 2023) of which 15 reported C. longa/curcumin as the only suspected ingredient. – Only 2 cases also involved piperine or black pepper, which were reported as ‘suspect’ along with multiple other suspected ingredients. – Of the 15 cases that reported C. longa/curcumin as the only suspected ingredient, 9 were reported as ‘serious’. The University of Sydney Page 25 Adverse events continued https://consultations.tga.gov.au/medicines-regulation-division/low-neg-risk-2023-2024/user_uploads/tga--- low-negligible-risk-annual-consultation-2023-2024---final.pdf – Between 2002 and June 2023, the TGA received 18 liver-related AE reports associated with C. longa/curcumin containing products. – Across several countries and regulatory agencies, changes to labelling and maximum doses have been implemented. – In Australia a consultation paper regarding doses and labelling of Curcuma longa and other species containing curcumin have been published – As of 22 June 2023, there were 536 oral listed medicines included in the ARTG that contained at least one Curcuma species (the majority being C. longa), 56 of which included C. longa as part of a proprietary ingredient The University of Sydney Page 26 Drug Herb Interactions (IM gateway 2020) – A study has found that curcumin causes a large increase in the blood concentrations of sulfasalazine. This may increase the risk of adverse events, and patients taking sulfasalazine should avoid taking curcumin or turmeric. IM Gateway 2020 – Based on the available details of a case report, Curcumin may have the potential to interact with warfarin resulting in elevated INR with an increased risk of bleeding. This combination should be avoided until further evidence becomes available. – Although the effect of curcumin on chemotherapy has not been studied directly in humans, the current evidence suggests that patients taking cyclophosphamide should avoid taking curcumin. The University of Sydney Page 27 Pycnogenol (bark extract of maritime pine) Pinus pinaster – a concentrate of plant polyphenols, composed of several phenolic acids, catechin, taxifolin and procyanidins Maimoona A et al 2011 – anti-inflammatory effects through the inhibition of matrix metalloproteinases. – Three studies have evaluated the effects of Pycnogenol - 50mg twice or three times daily in people living with OA (n=182) Belcaro 2008, Cisar 2008, Farid 2007 – The overall evidence indicates large and clinically meaningful effects for both pain and disability – The overall evidence is considered of moderate quality Liu 2018 – No side effects or serious adverse events were reported in the 3 clinical studies cited – While generally recognised as safe for use there is insufficient safety data for use in pregnancy and lactation The University of Sydney Page 28 Safety – theoretical drug interactions (NM database 2022) – Maritime pine bark extract inhibits platelet aggregation and therefore might increase the risk of bleeding when used with antiplatelet or anticoagulant drugs. – Clinical studies report that maritime pine bark extract decreases blood sugar in diabetic patients being treated pharmacologically – diabetic patients BSL should be monitored if they commence pine bark extract – Maritime pine bark extract may interfere with immunosuppressant therapy because of its immune stimulating activity (no animal or clinical studies to support this theoretical interaction) The University of Sydney Page 29 Methylsulfonylmethane (MSM) – What is it? – MSM is a naturally occurring organosulfur compound. – How does it work? – In vitro data indicates MSM downregulates the expression of inflammatory cytokines such as Interleukin-1and 6, and Tumour necrosis-alpha thus exerting and anti-inflammatory effect – Does it work clinically? – A 2018 review including three studies (n=148) evaluated the evidence for MSM over 12 weeks in patients with OA of the knee – Overall a modest to large treatment effects for pain relief and mobility were demonstrated (though the quality of evidence was low and very low). – No optimal dose could be established due to dose regimen variations – No major adverse events were reported in any of the three studies included. Liu X et al. 2018 Brit J Sports Med 2018;52:167 – Generally recognised as safe with no known interactions Natural Medicine Database 2020 The University of Sydney Page 30 Pharmacological plausibility - How might omega-3 fatty acids work in inflammatory conditions? Basic Biochemical Pathways of Omega-3 and Omega 6 Fatty Acids The University of Sydney Page 31 The evidence for efficacy and safety confirmed for RA but not good for OA (2017) The objective was to evaluate whether marine oil supplements reduce pain and/or improve other clinical outcomes in patients with arthritis included randomized trials of oral supplements of all marine oils compared with a control in arthritis Results:patients. Forty-two trials were included; 30 trials reported complete data on pain. A significant effect was found in patients with rheumatoid arthritis (22 trials) and other or mixed diagnoses (3 trials) but not in osteoarthritis patients (5 trials). Conclusion - The evidence for using marine oil to alleviate pain in arthritis patients was overall of low quality, but of moderate quality in rheumatoid arthritis patient The University of Sydney Page 32 Summary of omega-3 fatty acids (marine sources) for RA and OA Pain relief Evidence Rheumatoid arthritis Possibly effective in reducing morning joint modest benefits stiffness and tenderness for up to 3 months. obtained from Effects beyond three months of treatment are moderate quality unclear. evidence (Goldberg & Katz, 2007) 2.7 g/day (EPA/DHA) for 3 months possibly effective in reducing NSAID consumption by RA patients (Lee, Bae, & Song, 2012) Reductions in leukotriene B4 production (Jiang et al., 2016) 1-3 fish meals per week may lower disease activity (Senflteleber 2017) Osteoarthritis Possibly ineffective poor studies or negative outcomes for the efficacy of fish oil supplements for pain and/or functional improvements in osteoarthritis The University of Sydney Page 33 Case 2024 Mrs Bryant is a 65 year old female with pain in both her knees that impacts her mobility. She does not met the criteria for ‘knee replacement’ and is unable to continue NSAIDs due to gastritis and a history of PUD Takes no other medications Allergic to shellfish Has a preference to use CMs to manage her pain and disability Mrs Bryants doctor said to ask you if there is any evidence to support the efficacy of CMs commonly used to treat OA associated pain and disability? The University of Sydney Page 34 Recommendations for the use of supplements in OA by outcomes ASU: avocado/soybean unsaponifiables; BSE: Boswellia serrata extract; CH: collagen hydrolysate; MSM: methylsulfonylmethane; WBE: willow bark extract. Rheumatology (Oxford), Volume 57, Issue suppl_4, May 2018, Pages iv75–iv87, https://doi.org/10.1093/rheumatology/key005 The content of this slide may be subject to copyright: please see the slide notes for details. The University of Sydney Page 35 Pharmacist's role in skin care 1&2 Presented by: Daisy Cheung The University of Sydney We recognise and pay respect to the Elders and communities – past, present, and emerging – of the lands that the University of Sydney's campuses stand on. For thousands of years they have shared and exchanged knowledges across innumerable generations for the benefit of all. The University of Sydney Learning Objectives Recognise different dermatological terminology for describing skin conditions Apply history-taking skills to diagnose and differentiate dermatological conditions Examine three common types of dermatitis which present in primary care Discuss the use and role of topical corticosteroids in dermatitis Describe the general considerations of topical treatments for skincare Recognise signs and symptoms of a cutaneous drug reaction Identify when conditions need a referral List resources available for skin conditions The University of Sydney Page 3 If a patient presents in the pharmacy with a skin condition, what do you do? Physical examination: More accurate differential diagnosis Consider privacy in a consultation room Clearly explain the procedure you want to perform Gain the patient’s consent Demonstrate empathy Gain experience when recognising skin problems by seeing multiple similar cases → see http://www.dermnet.com/ for free image bank The University of Sydney Rutter, P. (2021). Community pharmacy : symptoms, diagnosis and treatment (Fifth edition ed.). Edinburgh: Elsevier. Page 4 History taking History of presenting complaint - onset, duration, periodicity - Site of onset - Spread/arrangement (discrete, coalescing, grouped) - Distribution (symmetrical/asymmetrical, unilateral, localised) - Feel of lesion (smooth/rough) - Aggravating or relieving factors Previous history and family history Buckley, D., & Pasquali, P. (2021). Textbook of primary care dermatology. Cham, Sw itzerland: Springer International Publishing. The University of Sydney Rutter, P. (2021). Community pharmacy : symptoms, diagnosis and treatment (Fifth edition ed.). Edinburgh: Elsevier. Page 5 History taking continued Medications - Oral or topical - Prescribed or OTC Medical conditions e.g. diabetes, SLE Allergies - To drugs - To food, clothing, footwear, jewellery, toiletries, or cosmetics Occupational - Past and current Buckley, D., & Pasquali, P. (2021). Textbook of primary care dermatology. Cham, Sw itzerland: Springer International Publishing. The University of Sydney Page 6 History taking continued Sports and hobbies Animal contacts - cats, dogs, birds, fish, and rodents Human contacts Foreign travel Recent stress Dietary history e.g. sugar, fats, caffeine, alcohol How patient feels about their skin problem and what they expect from treatment Buckley, D., & Pasquali, P. (2021). Textbook of primary care dermatology. Cham, Sw itzerland: Springer International Publishing. The University of Sydney Page 7 Terminology and descriptors of skin conditions The University of Sydney Page 8 Importance of understanding and using common terminology and descriptive terms Pharmacists need to take a thorough history and examine the affected area of the skin to assess the condition- this includes knowing how to describe it Assists in differentiating and diagnosing skin conditions Recording patient notes and interactions Communicating referral to a medical practitioner Reporting an adverse drug reaction The University of Sydney Page 9 Dermatology terminology: common terms Lesion = a single area of altered skin Rash = widespread eruption of lesions Dermatitis = eczema = inflammation of the skin (not a diagnosis) Tinea = name of group of diseases cause by fungus Pruritis = itchy skin Buckley, D., & Pasquali, P. (2021). Textbook of primary care dermatology. Cham, Sw itzerland: Springer International Publishing. The University of Sydney Page 10 Dermatology terminology: Colour Erythema/erythematous = redness due to dilated blood vessels that blanch when pressed Pigmentation = any shade of brown, black, grey or blue resulting from the presence of melanin at different depths in the skin Hyperpigmentation = excessive colour in the skin that causes it to be darker than the normal background skin Hypopigmentation = loss of melanin causing the skin to be paler than normal surrounding skin but not completely white Buckley, D., & Pasquali, P. (2021). Textbook of primary care dermatology. Cham, Sw itzerland: Springer International Publishing. The University of Sydney Rutter, P. (2021). Community pharmacy : symptoms, diagnosis and treatment (Fifth edition ed.). Edinburgh: Elsevier. Page 11 Dermatology terminology: texture or morphology of skin lesions and rashes Macule = a flat lesion < 1cm in diameter Patch = a flat lesion > 1cm in diameter Papule = a raised solid lesion < 1cm in diameter Nodule = a raised solid lesion > 1cm in diameter Vesicle = a clear, fluid-filled lesion, < 1 cm in diameter Bulla = a clear, fluid filled lesion, > 1cm in diameter Buckley, D., & Pasquali, P. (2021). Textbook of primary care dermatology. Cham, Sw itzerland: Springer International Publishing. The University of Sydney Rutter, P. (2021). Community pharmacy : symptoms, diagnosis and treatment (Fifth edition ed.). Edinburgh: Elsevier. Page 12 What texture/morphology are these? 3. 1. 2. 4. 5. https://www.healthline.com/health/macule https://dermnetnz.org/topics/inflammatory-lesions-in-acne https://dermnetnz.org/topics/nodulocystic-acne https://dermnetnz.org/topics/herpes-simplex-images https://www.mayoclinic.org/diseases-conditions/bullous- pemphigoid/symptoms-causes/syc-20350414 The University of Sydney Page 13 Dermatology terminology: texture or morphology of skin lesions and rashes Cyst = sac or cavity containing fluid or semi-solid material or air Pustule = < 1 cm in diameter, filled with pus (=purulent material composed of inflammatory cells i.e. neutrophils). May be yellow or white, does not always imply infection Abscess = a pus-filled cyst, usually infected, red and painful Buckley, D., & Pasquali, P. (2021). Textbook of primary care dermatology. Cham, Sw itzerland: Springer International Publishing. The University of Sydney Rutter, P. (2021). Community pharmacy : symptoms, diagnosis and treatment (Fifth edition ed.). Edinburgh: Elsevier. Page 14 What texture/morphology are these? 1. 2. 3. https://dermnetnz.org/topics/cutaneous-cysts-and-pseudocysts https://www.healthline.com/health/skin-abscess https://www.medicalnewstoday.com/articles/325342 The University of Sydney Page 15 Dermatology terminology: texture or morphology of skin lesions and rashes Scale = increased dead cells stuck together on the skin surface (also called hyperkeratosis) Plaque = a solid, raised, plateau-like (flat-topped) lesion greater than 1cm in diameter Buckley, D., & Pasquali, P. (2021). Textbook of primary care dermatology. Cham, Sw itzerland: Springer International Publishing. Rutter, P. (2021). Community pharmacy : symptoms, diagnosis and treatment (Fifth edition ed.). Edinburgh: Elsevier. The University of Sydney Page 16 What texture/morphology are these? 1. 2. https://dermnetnz.org/topics/chronic-plaque-psoriasis https://dermnetnz.org/topics/hyperkeratotic-palmar-dermatitis The University of Sydney Page 17 Dermatology terminology: secondary skin changes These are usually as result of scratching, picking or infection: Lichenification = thickening and accentuation of the skin as a result of the chronic rubbing or scratching Crusting = arises as a result of plasma exudating through an eroded epidermis. Crust is usually yellow or brown and may ooze. Epidermal crusts may contain blood, making them look red, purple or black. Excoriation = scratching which removes epidermis or localised damage to the skin which causes bleeding or oozing. They are often linear. Buckley, D., & Pasquali, P. (2021). Textbook of primary care dermatology. Cham, Sw itzerland: Springer International Publishing. The University of Sydney Rutter, P. (2021). Community pharmacy : symptoms, diagnosis and treatment (Fifth edition ed.). Edinburgh: Elsevier. Page 18 What texture/morphology are these? 1. 2. https://dermnetnz.org/images/atopic-dermatitis-images https://dermnetnz.org/topics/impetigo The University of Sydney Page 19 Dermatology terminology: shape or configuration of lesions Annular = in circle or ring Discoid/nummular = disc or coin shaped circular lesion Wheal/weal = superficial skin-coloured or pale skin swelling, usually surrounded by erythema and the skin surface is smooth Buckley, D., & Pasquali, P. (2021). Textbook of primary care dermatology. Cham, Sw itzerland: Springer International Publishing. The University of Sydney Rutter, P. (2021). Community pharmacy : symptoms, diagnosis and treatment (Fifth edition ed.). Edinburgh: Elsevier. Page 20 What shape are these? 1. 2. 3. https://dermnetnz.org/topics/tinea-corporis https://dermnetnz.org/topics/acute-urticaria https://dermnetnz.org/topics/discoid-eczema The University of Sydney Page 21 What is dermatitis? “derm” = skin, “itis” = inflammation Nonspecific inflammatory response of the skin Presentation: itchy, erythematous (red) rash, sometimes scaly Affects 1 in 5 people during their lifetime Isolated short episodes vs chronic Causes: – Endogenous e.g. atopic, seborrheic, discoid, asteatotic, venous and hand or foot, lichen simplex – Exogenous e.g. contact dermatitis – Environmental e.g. irritants, allergens, stress The University of Sydney Page 22 Principles of Managing Dermatitis 1. Avoid irritants and allergens 2. Bathe with soap-free substitutes 3. Apply emollient 4. Treat any infection 5. Apply topical corticosteroids The University of Sydney Page 23 1. Avoid irritants and allergens The University of Sydney Rutter, P. (2021). Community pharmacy : symptoms, diagnosis and treatment (Fifth edition ed.). Edinburgh: Elsevier. Page 24 Contact dermatitis Most common occupational skin condition Caused by skin contact with external agents Most cases involve hands Can have irritant or allergic cause Can result from single or repeated exposure regardless of skin type 8% of population is allergic to nickel 1-3% allergic to an ingredient in cosmetics Oakley, A. (2012). Contact dermatitis. Retrieved from https://dermnetnz.org/topics/contact-dermatitis The University of Sydney Rutter, P. (2021). Community pharmacy : symptoms, diagnosis and treatment (Fifth edition ed.). Edinburgh: Elsevier. Page 25 Therapeutic Guidelines: Dermatology. (2021). Therapeutic Guidelines: Dermatology. Retrieved from https://www-tg-org-au.ezproxy.library.sydney.edu.au Examples of allergic contact dermatitis https://dermnetnz.org/topics/contact-allergic-dermatitis-of-the-torso-images https://dermnetnz.org/topics/contact-allergic-dermatitis-of-the-hand- images The University of Sydney Page 26 Examples of irritant contact dermatitis https://dermnetnz.org/topics/irritant-contact- https://dermnetnz.org/topics/irritant-contact- dermatitis dermatitis The University of Sydney Page 27 2. Bathe in soap-free alternatives Bathe in tepid baths (no more than 30 degrees)- not hot water! The University of Sydney Page 28 3. Apply emollients - At least twice a day, and every few hours if flare or if skin is dry - Each week, for a patient who has atopic dermatitis/eczema, you should use a minimum of: - 125 g per week for babies - 250g per week for children - 500g per week for teenagers or adults Thompson, D. (2018). Atopic Eczema Management: It’s hard to get consistent information! Allergy & Anaphylaxis Australia. Retrieved from The University of Sydneyhttps://allergyfacts.org.au/images/docs/Atopic-Eczema-Management.pdf Page 29 Different formulations of emollients Consistency/viscosity Water content Absorption into skin The University of Sydney Page 30 4. Treat any infection - Atopic skin more susceptible to bacterial infection e.g. staphylococci, streptococci - Presentation: crusting, weeping, cracks, pus or increased soreness - Bleach (4.2% sodium hypochlorite) baths - 10 minutes twice weekly https://dermnetnz.org/topics/complications-of-atopic-dermatitis - 12mL bleach in 10L of water (final bleach concentration 0.005%) - Antibiotic therapy: mupirocin, dicloxacillin, flucloxacillin Therapeutic Guidelines: Dermatology. (2024). Therapeutic Guidelines: Dermatology. Retrieved from https://www-tg-org-au.ezproxy.library.sydney.edu.au The Royal Children's Hospital Melbourne. (2020). Skin infections – bleach baths. Retrieved from https://www.rch.org.au/kidsinfo/fact_sheets/skin_infections_bleach_baths/ The University of Sydney Page 31 5. Apply Topical Corticosteroids The University of Sydney Page 32 Topical Corticosteroids Topical corticosteroids are the main treatment for all age groups Australian medicines handbook online. (2023). Retrieved from https://amhonline-amh-net-au.ezproxy.library.sydney.edu.au/. from Australian Medicines Page 33 The University of Sydney Handbook Pty Ltd https://amhonline-amh-net-au.ezproxy.library.sydney.edu.au/ Topical corticosteroids Australian medicines handbook online. (2023). Retriev ed f rom https://amhonline-amh-net-au.ezproxy.library.sydney.edu.au/. from Australian Medicines Handbook Pty Ltd https://amhonline-amh-net- au.ezproxy.library.sy dney.edu.au/ The University of Sydney Page 34 Topical Corticosteroids available in Australia The University of Sydney Page 35 Potency Mild: Hydrocortisone or hydrocortisone acetate Moderate: these corticosteroids are 2-25 times as potent as hydrocortisone Potent:100-150 times as potent as hydrocortisone Very potent: 600 times as potent as hydrocortisone Oakley, A. (2016). Topical steroid. Retrieved from https://dermnetnz.org/topics/topical-steroid The University of Sydney Therapeutic Guidelines: Dermatology. (2021). Therapeutic Guidelines: Dermatology. Retrieved from https://www-tg-org- Page 36 au.ezproxy.library.sydney.edu.au Site of Application Sensitive areas of body e.g. face, axillae, groin, nappy area Limbs and trunk Thick-skinned areas e.g. palms, fingers, lichenified areas on wrist or ankles, feet, soles Australian medicines handbook online. (2023). Retrieved from https://amhonline-amh-net-au.ezproxy.library.sydney.edu.au/. from Australian Medicines Handbook Pty Ltd https://amhonline-amh-net-au.ezproxy.library.sydney.edu.au/ The University of Sydney Page 37 Therapeutic Guidelines: Dermatology. (2021). Therapeutic Guidelines: Dermatology. Retrieved from https://www-tg-org- au.ezproxy.library.sydney.edu.au Scheduling of Topical Corticosteroids HYDROCORTISONE and HYDROCORTISONE ACETATE, but CLOBETASONE (cl

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