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Chapter Ten: Musculoskeletal and Joint Diseases 10.1-Drugs for rheumatoid arthritis (RA), osteoarthritis (OA), and other related disorders 1-The following medication classes are prescribed commonly for the treatment of RA: A-Non-steroidal anti-inflammatory drugs (NSAIDs). B-Glucocort...

Chapter Ten: Musculoskeletal and Joint Diseases 10.1-Drugs for rheumatoid arthritis (RA), osteoarthritis (OA), and other related disorders 1-The following medication classes are prescribed commonly for the treatment of RA: A-Non-steroidal anti-inflammatory drugs (NSAIDs). B-Glucocorticoids. C-Conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs). Commonly used agents include methotrexate (MTX), sulfasalazine, hydroxychloroquine, and leflunomide (1, 2). D-Biologic DMARDs. E- JAK inhibitors include (baricitinib, tofacitinib, and upadacitinib) (1). 2-DMARDs are the mainstay of RA treatment (3). Current RA treatment guidelines recommend initiating conventional DMARDs irrespective of disease activity once a diagnosis is established (1). 3-Because DMARDs may take 2 to 6 months to reach full effect, NSAIDs and sometimes glucocorticoids can be used in the interim to reduce pain and swelling (2). 4-Biologic DMARDs are indicated in patients who have received an adequate trial of nonbiologic DMARD monotherapy or combination therapy but have failed to achieve treatment goals (3). 5-The following medications are used for the treatment of OA (1): A-Acetaminophen B-NSAIDs C-Topical Therapies (Capsaicin, NSAIDs) E-Duloxetine and tramadol F-Glucosamine and Chondroitin G-Intraarticular (IA)Therapy (corticosteroids, hyaluronic acid derivatives). 10.1.1-Conventional synthetic DMARDs 1-Regular monitoring of DMARD therapy is essential because of the risk of liver and haematological toxicity. (e.g. liver function test to detect hepatotoxicity and complete blood count (CBC) to detect bone marrow suppression) (3). 2-The patient is warned to report immediately the onset of any feature of blood disorders (e.g. sore throat, bruising, and mouth ulcers), liver toxicity (e.g. nausea, vomiting, abdominal discomfort, and dark urine) (4). 3-Concerning Methotrexate: A-Methotrexate (MTX) is the most commonly used DMARD because of its oral, once-weekly administration, well defined safety profile (when monitored appropriately), demonstrated efficacy, and low cost (2, 3). 134  B-Other uses for MTX include: IBD, neoplastic diseases, and severe psoriasis (5). C-It is usually given once weekly (4). D- In patients who experience mucosal or gastro-intestinal side-effects with methotrexate, folic acid given every week [unlicensed indication], on a different day from the methotrexate, may help to reduce the frequency of such side-effects (4). E-Withdraw treatment if stomatitis or diarrhea develops—may be first sign of gastro-intestinal toxicity (4). F-Folinic acid following methotrexate administration helps to prevent methotrexate-induced mucositis and myelosuppression. Treatment with folinic acid (as calcium folinate) may be required in acute toxicity (4). G-Pulmonary toxicity may be a special problem in rheumatoid arthritis (warn patient to seek medical attention if dyspnoea, cough or fever develop); monitor for symptoms at each visit—discontinue if pneumonitis suspected (4). 4-Concerning hydroxychloroquine: A-Periodic ophthalmologic examinations are necessary for patients taking hydroxychloroquine for early detection of reversible retinal toxicity (1) C-To avoid excessive dosage in obese patients, the dose of hydroxychloroquine should be calculated on the basis of ideal body-weight (4). D-Hydroxychloroquine should be taken with or just after meal (4). 5-Concerning leflunomide: A-Patients should be advised not to drink alcohol for as long as they are receiving leflunomide (4). B-Washout procedure: The active metabolite persists for a long period; to aid drug elimination in case of serious adverse effect, or before starting another DMARD, or before conception, stop treatment and give either colestyramine or charcoal, activated. Procedure may be repeated as necessary (4). 6-Concerning penicillamine: A-In addition to RA, it is used also for cystinuria (therapeutic and prophylaxis), aids the elimination of copper ions in Wilson’s disease, and for autoimmune hepatitis (used rarely; after disease controlled with corticosteroids) (4). B-Patients who are hypersensitive to penicillin may react rarely to penicillamine (4). C-Proteinuria: Proteinuria occurs in up to 30% of patients—can be a sign of immune mediated nephropathy. Discontinue immediately if nephrotoxicity occurs (4). 135  D-Counselling on the symptoms of blood disorders is advised. Warn patient and carers to tell doctor immediately if sore throat, fever, infection, non-specific illness, unexplained bleeding and bruising, purpura, mouth ulcers, or rashes develop (4). DMARDs Scientific name Trade names Dosage form 1 2 3 4 5 Any extra notes: 10.1.2-Non-steroidal anti-inflammatory drugs (NSAIDs) 1-NSAIDs have analgesic, anti-inflammatory, and antipyretic properties. NSAIDs are used for the relief of mild to moderate pain, minor febrile conditions, and for acute and chronic inflammatory disorders such as osteoarthritis, and rheumatoid arthritis (5). 2-Some NSAIDs are applied topically for the relief of muscular and rheumatic pain, and some (like diclofenac) are used in ophthalmic preparations for ocular disorders (4). 3-In single doses NSAIDs have analgesic activity. In regular full dosage NSAIDs have both a lasting analgesic and an anti-inflammatory effect (4). 4-Differences in anti-inflammatory activity between NSAIDs are small, but there is considerable variation in individual response and tolerance to these drugs. About 60%of patients will respond to any NSAID; of the others, those who do not respond to one may well respond to another (4). 5-Pain relief starts soon after taking the first dose and a full analgesic effect should normally be obtained within a week, whereas an anti-inflammatory effect may not be achieved (or may not be clinically assessable) for up to 3 weeks. If appropriate responses are not obtained within these times, another NSAID should be tried (4). 136 6-The commonest adverse effects of NSAIDs are generally GI disturbances, such as GI discomfort. These are usually mild and reversible but in some patients peptic ulceration and severe GI bleeding may occur (5). 7-They vary in their selectivity for inhibiting different types of cyclo-oxygenase (COX); selective inhibitors of COX-2 (celecoxib, etoricoxib and parecoxib) are associated with less GI intolerance. This advantage may be lost in patients who require concomitant low-dose aspirin (4). Aceclofenac, diclofenac, etodolac, ibuprofen, indometacin, ketoprofen, mefenamic acid, meloxicam, naproxen, piroxicam, sulindac and tenoxicam are examples of non-selective COX-2inhibitors (4). 8-The combination of a NSAID and low-dose aspirin can increase the risk of GI side-effects; this combination should be used only if absolutely necessary (4). 9-Systemic as well as local effects of NSAIDs contribute to GI damage; taking oral formulations with milk or food, or using enteric-coated formulations, or changing the route of administration may only partially reduce symptoms such as dyspepsia (4). 10-Patients at risk of GI ulceration (including the elderly), who need NSAID treatment should receive gastroprotective treatment (4) (e.g. PPIs) (3). 11-All NSAID use (including COX-2 selective inhibitors) can, to varying degrees, be associated with a small increased risk of thrombotic events (e.g. myocardial infarction and stroke); however, the greatest risk may be in those receiving high doses long term. COX-2 selective inhibitors, diclofenac (150mg daily) are associated with an increased risk of thrombotic events. The increased risk for diclofenac (and hence aceclofenac) is similar to that of licensed doses of etoricoxib (4). 12- Naproxen (1 g daily) is associated with a lower thrombotic risk, and low doses of ibuprofen (1.2 g daily or less) have not been associated with an increased risk of myocardial infarction (4). 13-It is preferable to avoid NSAIDs in patients with active or previous gastro- intestinal ulceration or bleeding and patients with a history of hypersensitivity to aspirin or any other NSAID. Celecoxib is contra-indicated in patients with sulfonamide sensitivity (4). 14-NSAIDs should be used with caution in patients with asthma, and hypertension (it cause sodium and water retention) (5). 15-Important: Use of more than one NSAID together should be avoided because of the increased risk of adverse effects (5). 16-Indometacin use associated with a high incidence of side-effects including headache, dizziness [may affect performance of skilled tasks (e.g. driving)], and GI disturbances. Mefenamic acid has occasionally been associated with diarrhea which require discontinuation of treatment. Piroxicam has more GI side effects 137 than most other NSAIDs, and is associated with more frequent serious skin reactions. (4). 17-Accordig to its leaflet, Olfen® 50/100mg rectocaps is given before meals. NSAIDs Scientific name Trade names Dosage form 1 2 3 4 5 6 7 8 9 10 11 12 Any extra notes: 10.1.3-Glucosamine and chondroitin 1-The glucosamine sulfate and chondroitin sulfate are dietary supplements (1). Both compounds are found naturally in the body and are essential to the formation of cartilage (6). 2-The combination is believed to have a synergistic effect by stimulating cartilage production(glucosamine) and inhibiting its destruction (chondroitin) (7) but convincing evidence for this effect is lacking (2). 138 3-Indicated for symptomatic relief of mild to moderate osteoarthritis of the knee (4). 4-Glucosamine and/or chondroitin lack uniform efficacy and are not preferred treatment options (1) (any true clinical value remains to be shown)(2) (Glucosamine is not recommended for the treatment of osteoarthritis) (4). Glucosamine and chondroitin Scientific name Trade names Dosage form 2 Any extra notes: 10.1.4-Intraarticular (IA) hyaluronic acid derivatives 1-Hyaluronic acid derivatives are intended to improve elasticity and viscosity of synovial Fluid (7). 2-However, IA hyaluronic acid is not routinely recommended for knee OA pain (Limited efficacy and risks of serious events limit the routine use of these agents) (1) (are not recommended) (4). Injections do not provide clinically meaningful improvement and may be associated with serious adverse events (e.g., increased pain, joint swelling, and stiffness) (1). 3-A new hyaluronan preparation (Monovisc®) has been developed, containing 4 or 5 times the amount of hyaluronan used in the usual knee injection. It is designed to treat the symptoms of osteoarthritis with only one injection. The approach, if effective, would simplify the procedure especially for ―needle shy‖ patients (2). Hyaluronic acid derivatives Scientific name Trade names Dosage form 1 2 Any extra notes: 139 10.1.5-Biologic DMARDs 1-Five of the available biologic agents are inhibitors of TNF-α: infliximab, etanercept , adalimumab, golimumab, and certolizumab (8). Non-TNF agents are: abatacept, anakinra, tocilizumab, Sarilumab, and rituximab (1). 2-These drugs are administered parenterally (Sc or I.V) (1). 3-Treatment costs are much higher than with DMARDs and many countries have set guidelines restricting their use to patients who have active disease despite having had an adequate trial of standard therapies (9). 4-Because of immunosuppressive effects: A-Patients taking biologics should notify their providers if they are being treated for an infection or plan to undergo major surgery. Treatment may need to be held until appropriate postsurgical healing and/or resolution of infection can be confirmed (1). B-Live vaccines should not be given to patients taking biologic agents (1). C-A tuberculin skin test should be obtained before starting a biologic to detect and treat latent or active tuberculosis. Patients should also be screened for hepatitis B before starting biologic therapy because of the risk for reactivation (1). 5-TNF inhibitors should not be used in patients with moderate-to-severe heart failure (New York Heart Association [NYHA] class III/IV) because new-onset and worsening heart failure have been reported (1). 6-Secukinumab is indicated for ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis (4). 7-Ustekinumab is indicated for IBD (UC and CD), plaque psoriasis, and psoriatic arthritis (4). 8-Other indications for the biological agents are summarized in (Table 10-1) (4). 9-Biosimilars are biologic products that have been verified to have no clinically meaningful differences compared to an FDA-approved reference biologic product. These agents can increase access to RA treatment because their costs are lower than the originator products (1). Table 10-1: Other indications for biological agents (4). Drug Other indications plaque psoriasis, IBD (UC and CD), uveitis, ankylosing 1 Adalimumab spondylitis, axial spondyloarthritis, and psoriatic arthritis Certolizumab Ankylosing spondylitis, axial spondyloarthritis, psoriatic 2 pegol Arthritis, and plaque psoriasis Ankylosing spondylitis, plaque psoriasis, axial 3 Etanercept spondyloarthritis, psoriatic arthritis 141  Ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, 4 Golimumab and axial spondyloarthritis. IBD (UC and CD), ankylosing spondylitis, plaque psoriasis 5 Infliximab and psoriatic arthritis. Lymphoma (non-Hodgkin‘s), chronic lymphocytic 6 Rituximab leukaemia, granulomatosis with polyangiitis and microscopic polyangiitis, pemphigus vulgaris. Biological agents Scientific name Trade names Dosage form 1 2 3 4 Any extra notes: 10.2-Drugs for hyperuricemia and gout 10.2.1-Acute attacks of gout 1-Nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids are considered first-line monotherapy for acute attacks (3). 2-Treatment should begin as soon as possible after the onset of an attack (1). 3-Acute attacks of gout are usually treated with either colchicine or high doses of an NSAID (excluding aspirin) (4). 10.2.1.1-Colchicine 1-Colchicine is highly effective in relieving acute gout attacks but it is used infrequently today because of its low therapeutic index (1, 3). 2-Oral colchicine causes dose-dependent GI adverse effects (nausea, vomiting, and diarrhea). Non-GI adverse effects include neutropenia and neuromyopathy, which may be worsened in patients taking other myopathic drugs (e.g., statins) or with impaired kidney function. (1). 3-Use colchicine with caution in patients taking P-glycoprotein or strong CYP450 3A4 inhibitors (eg, clarithromycin) due to increased plasma colchicine levels and potential toxicity; colchicine dose reductions may be required (1). 141 4-Colchicine is also used for short-term prophylaxis during initial therapy with allopurinol and uricosuric drugs (4). 10.2.2-Long-term control of gout 1-After the first attack of acute gout, prophylactic pharmacotherapy is recommended if patients have two or more attacks per year. Other indications include presence of tophi, chronic kidney disease, or history of urolithiasis (1). 2-Urate-lowering therapy can be started during an acute attack if anti- inflammatory prophylaxis has been initiated. The guidelines recommend low-dose oral colchicine or low-dose NSAIDs as first-line prophylactic therapies (1). Continue prophylaxis until at least 1 month after hyperuricaemia corrected (usually for first 3 months) to avoid precipitating an acute attack (4). 10.2.2.1-Xanthine oxidase inhibitors (allopurinol, febuxostat) 1-Xanthine oxidase inhibitors reduce uric acid by impairing conversion of hypoxanthine to xanthine and xanthine to uric acid. They are the most widely prescribed agents for long-term prevention of recurrent gout attacks (1). 2-Allopurinol: A-Mild adverse effects of allopurinol include skin rash, GI problems, headache, and urticarial. A more severe adverse reaction known as allopurinol hypersensitivity syndrome (1). B-Allopurinol should not be taken with ampicillin owing to increased risk of rash (2). C-It also used for the prophylaxis of (hyperuricaemia associated with cancer chemotherapy, uric acid and calcium oxalate renal stones) (4). D-Take allopurinol with food to minimize GI upset (10). 3-Febuxostat : A-Febuxostat is a nonpurine xanthine oxidase inhibitor. Due to differences in chemical structure, febuxostat would not be expected to cross-react in patients with a history of allopurinol hypersensitivity syndrome (3). B-It is also used for prophylaxis and treatment of acute hyperuricaemia with initial chemotherapy for hematologic malignancies (4). 10.2.2.2-Uricosuric Drugs 1-Uricosurics (such as probenecid or sulfinpyrazone) are considered second-line treatment (2). 2-Patients with a history of urolithiasis should not receive uricosurics. Starting with low, maintaining adequate urine flow and alkalinization of the urine during the first several days of therapy may decrease likelihood of uric acid stone formation (1). 142 10.2.2.3-Pegloticase 1-Pegloticase is a recombinant form of uricase bound to polyethylene glycol that is approved for the treatment of chronic gout refractory to other therapy (3). 2-Pegloticase should be limited to patients with severe gout with tophi or nephropathy that has not responded to other agents because of significant adverse effects, including anaphylaxis (in up to 5% of patients) that mandates pretreatment with antihistamines and corticosteroids, and its high cost (3). Drugs for hyperuricemia and gout Scientific name Trade names Dosage form 1 2 3 Any extra notes: 10.3-Intra-articular corticosteroid injections 1-Corticosteroids (e.g. methylprednisolone, triamcinolone) are injected locally for an anti-inflammatory effect. They are given by intra-articular injection (4) (e.g.in case of RA, OA or gout) (1) to relieve pain, increase mobility, and reduce deformity in one or a few joints; they can also provide symptomatic relief while waiting for DMARDs to take effect (4). 2-Specific instructions are given to the patient to refrain from weight-bearing activity for 3 days, except getting up for meals and going to the bathroom (2). Local corticosteroid injections Scientific name Trade names Dosage form 1 2 Any extra notes: 10.4-Skeletal muscle relaxants: A-The skeletal muscle relaxants are used for the relief of chronic muscle spasm or spasticity associated with multiple sclerosis or other neurological damage; they are not indicated for spasm associated with minor injuries (4). 143  B-Baclofen, diazepam, pridinol and tizanidine act principally on the central nervous system. While dantrolene has a peripheral site of action; cannabis extract has both a central and a peripheral action (4). Drugs for neuromuscular disorders Scientific name Trade names Dosage form 1 2 3 4 Any extra notes: References 1-Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 11th Edition. 2021. 2-Edward T. Bope, et al, eds. Conn‘s Current Therapy. Copyright 2018. 4-Marie A. Chisholm-Burns.Pharmacotherapy Principles & Practice. 5th edition. 2019. 4-BNF-81 (2021). 5-Martindale: The Complete Drug Reference, 38th Edition. Pharmaceutical Press 2014. 6-David J Quan, Richard A Helms. Textbook of Therapeutics: Drug and Disease Management. 8th edition. 2006. 7-Leon Shargel , Alan H. Mutnick. Comprehensive pharmacy review. 8 th edition 2013. 8-Zeind, Caroline S and Carvalho, Michael G. Applied Therapeutics: The clinical use of drugs, 11th ed., 2018. 9-Stuart HR, Ian DP, Mark WJ, Richard PH. Davidson's Principles and Practice of Medicines. 23th Edition 2018. 10-Michael AM, Jason. Frequently prescribed medications. Third edition 2019. 144