Geriatrics PDF

Geriatrics 5. Aging effects include decreased bladder elasticity and capacity, more frequent voiding, decline in bladder outlet and urethral resistance in women with loss of estrogen, and decrease in flow rate in men with prostatic enlargement. C. Types of UI Table 8. Common Types of UI and D...

Geriatrics 5. Aging effects include decreased bladder elasticity and capacity, more frequent voiding, decline in bladder outlet and urethral resistance in women with loss of estrogen, and decrease in flow rate in men with prostatic enlargement. C. Types of UI Table 8. Common Types of UI and Drug-Induced Causes Type of Incontinence Description Drug-Induced Causes Urge or overactive bladder Loss of a moderate amount of urine with an increased need to void Common in patients with AD, PD, MS, and stroke Cholinergic agents that stimulate the bladder such as bethanechol and CIs Stress incontinence Loss of small amounts of urine with increased abdominal pressure (e.g., sneezing, coughing) Stress UI is more common in postmenopausal women α-Blockers such as prazosin decrease urethral sphincter tone Overflow incontinence Loss of urine because of excessive bladder volume caused by outlet obstruction or an acontractile detrusor PVR is often high (> 300 mL), indicating incomplete emptying Anticholinergic agents, calcium channel blockers, and opioids decrease detrusor muscle contractions Functional incontinence Inability to reach the toilet because of mobility constraints Sedating drugs that cause confusion Diuretics increase voiding Mixed incontinence UI that has more than one cause, usually stress and overactive bladder AD = Alzheimer disease; CI = cholinesterase inhibitor; MS = multiple sclerosis; PD = Parkinson disease; PVR = postvoid residual; UI = urinary incontinence. D. Nonpharmacologic Interventions: First-line Therapy 1. Lifestyle modifications a. Weight loss for patients with a BMI greater than 25–30 kg/m 2 b. Limit/avoid caffeine and alcohol c. Quit smoking d. Limit fluid intake before bedtime 2. Stress incontinence a. Pelvic floor exercises (Kegel exercises) are first line for stress. b. Biofeedback may be needed to teach pelvic floor exercises. c. Pessaries (a prosthetic vaginal insertion device) or bulking agent injections also help stress incontinence. 3. Urge incontinence a. Pelvic floor exercises in combination with medication for urge or mixed UI b. Bladder training to increase time between voiding in urge incontinence c. Peripheral tibial nerve stimulation or sacral neuromodulation techniques are third line after lifestyle and pharmacologic treatments. 4. Scheduled and timed voiding may be helpful for patients with dementia. 5. Prostatectomy in men or self-catheterization for severe overflow incontinence ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-324 Geriatrics E. Pharmacologic Treatment (Table 9) Table 9. Recommended Pharmacologic Treatment by Type of Incontinence Type of Incontinence Urge or overactive bladder Drug Treatment Comments Antimuscarinic agents Magnitude of clinical efficacy is modest Oxybutynin, tolterodine, fesoterodine, trospium, solifenacin, darifenacin Strong anticholinergic effects (on Beers Criteria) β3-Agonist Long-acting formulations preferred because of modest decreased adverse effect profile Minimal anticholinergic effects Mirabegron Cost is commonly a barrier for patients Can be used in combination with antimuscarinic agents if monotherapy fails Stress OnabotulinumtoxinA Avoid in hypertension Prevents stimulation of detrusor muscle Intradetrusor or injections α-Adrenergic agonists Must be able to perform self-catheterization Efficacy evidence is limited Pseudoephedrine, phenylephrine Topical estrogens Use if other symptoms of estrogen deficiency Conjugated estrogen vaginal cream or estradiol vaginal insert or ring Serotonin-norepinephrine reuptake inhibitor Overflow Adverse effects may limit its usefulness Adverse effects vary depending on selectivity to Alfuzosin, tamsulosin, silodosin, receptors in the bladder or prostate (alfuzosin, silodosin, and tamsulosin are more specific and preferred in older doxazosin, terazosin, prazosin adults) 5-α-Reductase inhibitors To slow progression Bethanechol Phosphodiesterase type 5 inhibitors Mixed Not FDA labeled for stress UI; may reduce the severity of incontinence Duloxetine α-Adrenergic antagonists Finasteride, dutasteride Cholinomimetics Functional Vaginal estrogens may improve severity of stress incontinence Tadalafil No drug treatments Focus on predominating symptoms Reduce the size of the prostate and alter PSA values Stimulates the detrusor muscle but also has systemic cholinomimetic effects 5 mg once daily approved for BPH Consider interventions to remove any potential cause, barriers, or obstacles; provide schedules or prompted toileting; assistance may be required to transfer on and off commode Consider treatments for individual components (i.e., stress and urge) BPH = benign prostatic hyperplasia; PSA = prostate-specific antigen; UI = urinary incontinence. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-325 Geriatrics Patient Case 13. A 75-year-old woman reports urinary urgency, frequency, and loss of urine when she cannot get to the bathroom in time. She also wears a pad at night that she changes two or three times because of incontinence. Her medical history is significant for MCI (MMSE score 25/30), OA, and hypothyroidism. A urinalysis is negative for leukocyte esterase and nitrites. Physical examination is normal, and her PVR is normal (less than 100 mL). Which therapy would be best to initiate for this patient at this time? A. Mirabegron. B. Darifenacin. C. Pelvic floor exercises and solifenacin. D. Pelvic floor exercises and tolterodine immediate release. V. BENIGN PROSTATIC HYPERPLASIA A. Epidemiology 1. BPH usually develops after age 40. 2. By age 60, 50% of all men have BPH; by age 85, 90% have BPH. B. Pathophysiology and Clinical Presentation 1. Type II 5-α-reductase facilitates conversion of testosterone to dihydrotestosterone, resulting in prostate growth. 2. Lower urinary tract symptoms (LUTS) occur in 25% of men. a. Voiding (obstructive) symptoms: Decreased force, hesitancy, dribbling b. Storage (irritative) symptoms: Urinary urgency, frequency, nocturia, dysuria 3. The American Urological Association Symptom Index (AUASI) score can help determine severity and appropriate treatment. The index consists of seven questions evaluating the severity of LUTS on a 0–5 scale. Higher numbers indicate more severe symptoms. C. Evaluation 1. Medical history, digital rectal examination, BUN, SCr, and urinalysis 2. If prostate cancer is suspected, prostate-specific antigen (PSA) 3. If significant urinary retention is suspected, need to assess PVR. If PVR is greater than 50 mL, patients have an increased risk of infection. 4. Assess for medications that may exacerbate BPH symptoms. a. α-Adrenergic agonists (decongestants) can stimulate smooth muscle contraction in the prostate and urethra, obstructing urinary flow through the urethra. b. Anticholinergic drugs (urinary and GI antispasmodics, antihistamines, tricyclic antidepressants, phenothiazines) can reduce the ability of the bladder detrusor muscle to contract and empty the bladder. c. Diuretics can increase urinary frequency and volume. d. Testosterone replacement can stimulate prostate growth. 5. If the AUASI score is 0–7 (mild), use watchful waiting. 6. Patients with high AUASI scores of 20 and more (severe disease) should be assessed for prostatectomy. 7. Patients with moderate disease (scores 8–19) are candidates for medical treatment. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-326 Geriatrics D. Pharmacologic Treatment (Table 10) 1. α-Adrenergic blockers: These relieve LUTS in men with moderate or severe AUASI scores by reducing smooth muscle contractions in the urethra and surrounding tissues. a. Nonspecific α-adrenergic blockers such as doxazosin and terazosin also lower blood pressure significantly. b. Newer agents are uroselective antagonists of α1-adrenergic receptors (tamsulosin, silodosin) and selective antagonists of postsynaptic α1-adrenergic receptors (alfuzosin) in the prostate and bladder. They may have less associated hypotension. c. All α-blockers can cause hypotension. d. Compared with placebo, α-blockers lower the AUASI score by 4–6 points in patients with LUTS and BPH. e. All α-blockers are metabolized through the CYP3A4 pathway and have drug interactions with strong CYP3A4 inhibitors and inducers. f. Intraoperative floppy iris syndrome is a concern with α-blockers, especially tamsulosin. Men with LUTS being offered α-blockers should be asked about planned cataract surgery. Men with planned cataract surgery should avoid starting α-blockers until their cataract surgery is completed. If already taking an α-blocker, patients need to inform his surgeon so that precautions can be taken. 2. 5-α-Reductase inhibitors a. These agents prevent the conversion of testosterone to dihydrotestosterone, modify the disease course, and may reduce the risk of urinary retention and surgical interventions. i. Finasteride competitively inhibits type II 5-α-reductase and lowers prostatic dihydrotestosterone by 80%–90%. ii. Dutasteride is a nonselective inhibitor of both type I and II 5-α-reductase. Prostatic dihydrotestosterone production is quickly suppressed with this agent. iii. Despite these pharmacologic differences, finasteride and dutasteride did not differ in trials; both reduced prostate size. b. 5-α-Reductase inhibitors do not immediately reduce LUTS and should be reserved for use in men with a large prostate (more than 30 mL in volume or 40 g in weight). At least 6 months of therapy is usually needed for clinical benefit. Prostate size may be reduced by about 25% during this interval. c. PSA concentrations are used to monitor for prostate cancer. Because these agents lower PSA concentrations, a baseline PSA test is recommended before initiating α-reductase inhibitors. d. Long-term therapy with an α-reductase inhibitor can increase the risk of high-grade tumors of the prostate in healthy men without a history of prostate cancer. 3. Phosphodiesterase type 5 inhibitors a. Tadalafil 5 mg once daily is approved for use in BPH. b. Mechanism is thought to be caused by phosphodiesterase-induced smooth muscle relaxation in the bladder, urethra, and prostate. c. Studied as monotherapy; the FDA does not recommend use in combination with α-blockers because the combination has not been adequately studied for BPH, and there is a risk of lowering the blood pressure. May be used in practice to treat both BPH and erectile dysfunction 4. Combination therapy a. May be needed in men with LUTS, a larger prostate size, and an elevated PSA or in men with co-occurring symptoms of erectile dysfunction b. Finasteride and doxazosin are the best studied; dutasteride is FDA label approved for use with tamsulosin in symptomatic men having an enlarged prostate. c. Two large clinical trials (Medical Therapy of Prostatic Symptoms [MTOPS] and the Combination of Avodart and Tamsulosin studies [CombAT]) comparing monotherapy with combination therapy concluded that in men with LUTS and an enlarged prostate, further benefit can be achieved using the two drugs in combination. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-327 Geriatrics 5. Supplements a. Saw palmetto plant extract (Serenoa repens) i. Conflicting evidence about the efficacy of saw palmetto in relieving LUTS; 2012 systematic review suggested no benefit over placebo ii. Using this agent with 5-α-reductase inhibitors may reduce the efficacy of the reductase inhibitors. b. β-Sitosterol, Pygeum africanum show some benefit, but short-term studies 6. Management of storage (irritative) symptoms a. Anticholinergic or β3-agonist agents can be appropriate and effective alternatives in men when LUTS are predominantly storage (irritative) symptoms, regardless of PVR. 7. Surgery is preferred in men with severe symptoms and in those with moderate symptoms who lack adequate response to medical options. Table 10. Comparison of Pharmacologic Agents Used for Benign Prostatic Hyperplasia Medication Terazosin Doxazosin Dose Range 1–10 mg daily 1–8 mg daily Select Adverse Effects Orthostatic hypotension Alfuzosin ER 10 mg daily Orthostatic hypotension Tamsulosin modified release 0.4–0.8 mg daily Silodosin Finasteride Dutasteride Dutasteride/ tamsulosin Tadalafil Comments Initiate at low dose; can titrate every 2–7 days Start at bedtime No need to titrate Take after a meal Start at bedtime May cause less orthostasis Causes ejaculatory dysfunction 8 mg daily Causes ejaculatory dysfunction; Contraindicated if CrCl < 30 mL/min/1.73 m2 4 mg daily if CrCl 30–50 appears less sedating mL/min/1.73 m2 Take with food 5 mg daily Decreased libido Onset of action is usually 6 mo 0.5 mg daily Monitor PSA 0.5/0.4 mg daily Pregnancy category X 5 mg daily Orthostatic hypotension Avoid use with α-blockers No data in combination or with long-term use PSA = prostate-specific antigen. Patient Case 14. An 85-year-old man with LUTS visits his physician, who determines his AUASI score is 15. His blood pressure is 118/70 mm Hg sitting. A digital rectal examination confirms the diagnosis of BPH, and the physician schedules a further workup including a prostate ultrasound, which shows a prostate volume of 31 g. Which therapy is best at this time? A. Terazosin. B. Finasteride plus saw palmetto. C. Tamsulosin. D. Finasteride plus tamsulosin. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-328 Geriatrics VI. OSTEOARTHRITIS A. Epidemiology 1. OA is the most prevalent form of arthritis, affecting more than 46 million Americans. 2. Highly associated with aging: Large weight-bearing joints (e.g., hip and knee) are commonly affected. B. Etiology and Pathophysiology 1. Risk factors include age, female sex, obesity, genetics, sports activities, occupation, previous injury, acromegaly, and other chronic illnesses. 2. Loss of cartilage occurs in the joint as the balance of chondrocyte function shifts from formation to destruction. Secondary inflammation and production of cytokines play a role. 3. Subchondral bone and the synovium are damaged, and the joint space narrows. 4. Single injuries or repeated micro-injuries may initiate or accelerate process. 5. Symptoms of pain result from activation of nociceptive nerve endings in the damaged joint. 6. Therapy goals: Relieve pain and swelling, maintain or improve joint function, prevent loss of function, and maintain or improve quality of life C. Nonpharmacologic Treatment 1. Patient education: Lifestyle, expectations, when to seek care, and behavioral, psychosocial, and physical interventions, including self-efficacy and self-management programs to reduce pain and disability 2. Weight loss decreases the biomechanical load on large weight-bearing joints; even a small amount of weight loss helps decrease pain and disability. 3. Exercise, including yoga, tai chi, weight bearing 4. Physical and occupational therapy 5. Surgery D. Drug Therapy 1. NSAIDs are first line; topical agents are preferred, particularly for knee OA, to reduce systemic exposure and adverse effects. a. Avoid chronic use, or if necessary, use a cyclooxygenase 2 (COX-2) selective NSAID or add a proton pump inhibitor to reduce the risk of GI bleeding. This recommendation is especially important for older adults. b. If one NSAID is not effective, change to others. c. Monitor for adverse effects: Rash, abdominal pain, GI bleeding, renal impairment, hypertension, heart failure, and drug-drug interactions d. Patients taking aspirin (for cardiac disease) should be educated to take aspirin at least 30 minutes before their first daily NSAID dose in the morning to avoid any interactions or reductions in aspirin efficacy. Naproxen appears to be safest with respect to cardiac risk. e. Monitor in chronic users: CBC, BUN, SCr, and AST at least annually 2. Topical agents: Topical NSAIDs are preferred for knee OA or smaller joints near surface of skin. Limited efficacy for widespread joint pain a. Diclofenac 1% gel (or patch is FDA labeled for minor trauma): Four short-term trials showed a 50% reduction in pain in 40% of subjects (number needed to treat was 5); longer-term trials had number needed to treat of 10. Comparative trials with oral administration showed no difference in the proportion of patients who received pain relief. b. Topical capsaicin is conditionally recommended for knee OA and conditionally recommended against for hand OA; usually dosed four times daily on a scheduled basis, not as-needed; difficult to administer: Wear gloves, avoid contact with eyes, and do not skip doses. Local irritation occurs in 40% of patients. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-329 AL GRAWANY Geriatrics 3. 4. 5. 6. 7. c. Use of topical rather than oral NSAIDs for patients 75 and older who have hand or knee OA may be preferred to reduce systemic absorption and adverse effects. Intra-articular glucocorticoid injections: a. Methylprednisolone or triamcinolone 10- to 40-mg injection depending on size of joint; may be repeated every 3 months b. Primary adverse effects are risk of septic arthritis, synovitis Acetaminophen: a. Alternative to NSAIDs or when NSAID use is contraindicated; very small effect sizes in clinical trials, few of those treated experience important benefit b. Maximum dosage of 3 g daily in divided doses should be considered in older adults with frailty or those 75 and older. c. Ensure the patient knows to watch for “hidden” acetaminophen in other products. d. Monitor for hepatotoxicity in patients with an elevated risk of liver disease (previous liver problems, heavy alcohol consumption) with periodic liver function tests. May consider limiting dosage to 2 g daily Duloxetine a. Most of the evidence is in OA of knee, but conditionally recommended for patients with OA of knee, hip, or hand b. Can be used alone or in combination with NSAIDs c. Concerns about patient tolerability; use shared decision-making before initiation Dietary supplements: Glucosamine-containing supplements are commonly used for relief of OA pain. a. 2019 American College of Rheumatology (ACR) guidelines strongly recommend against use of glucosamine supplements for relief of knee, hip, and/or hand OA. b. Chondroitin sulfate or combination glucosamine/chondroitin use is recommended against for knee and/or hip OA but is conditionally recommended for hand OA. c. Evidence to support treatment is contradictory; many studies are low quality. d. The adverse effect profile of glucosamine/chondroitin is similar to that of placebo. Opioids a. Tramadol is an alternative when NSAIDs are ineffective or contraindicated; conditionally recommended for patients with knee, hand, and/or hip OA b. Non-tramadol opioids are conditionally recommended against in patients with knee, hand, and/or hip OA. However, they can be used in certain circumstances when non-opioid alternatives have been exhausted. c. Monitor and anticipate opioid adverse effects, and treat accordingly. Patient Case 15. An 85-year-old man presents with pain from OA of the knee. He has hypertension, coronary artery disease, and BPH. For OA, he has been taking acetaminophen 650 mg three times daily. He reports that acetaminophen helps but that the pain persists and limits his ability to walk. Which is the best next step for this patient? A. Change acetaminophen to celecoxib. B. Add diclofenac gel to knee. C. Change acetaminophen to ibuprofen. D. Add duloxetine. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-330 Geriatrics VII. RHEUMATOID ARTHRITIS A. Epidemiology 1. A systemic disease characterized by a bilateral inflammatory arthritis that usually affects the small joints of the hands, wrists, and feet 2. The prevalence is estimated to be 1%–2%, with women predominating until after age 60, when prevalence becomes equal. 3. RA can occur at any age but increases in prevalence up to age 70. 4. RA is an autoimmune disease with a strong genetic predisposition. B. Pathophysiology and Clinical Presentation 1. Chronic inflammation of the synovium leads to proliferation and development of a pannus. 2. The pannus invades joint cartilage and eventually causes erosion of the bone and joint destruction. 3. The cause of the initial inflammatory activation is unknown, but once activated, the immune system produces antibodies and cytokines that accelerate cartilage and joint destruction. 4. Patients present with joint pain and stiffness, fatigue, and other inflammatory symptoms. Symptoms also include warmth, redness, and swelling of the joints, usually with symmetrical distribution. 5. Laboratory tests often show a positive RF, an elevated sedimentation rate, CRP, anti–cyclic citrullinated peptide antibodies, and normochromic normocytic anemia. 6. RA can also affect other organs, causing pulmonary fibrosis, vasculitis, and dry eyes. C. Treatment 1. The treatment goal is to control the inflammatory process so that disease remission occurs. This leads to relief of pain, maintenance of function, and improved quality of life. Treatment response can be measured by: a. Reduction in the number of affected joints and in joint tenderness and swelling b. Improvement in pain c. Decreased amount of morning stiffness d. Reduction in serologic markers such as RF e. Improvement in quality-of-life scales 2. Nonpharmacologic treatment: Concurrent with pharmacologic treatment a. Rest during periods of disease exacerbation b. Occupational and physical therapy to support mobility and maintain function c. Maintenance of a normal weight (avoid overweight and obesity) to reduce biomechanical stress on joints d. Assistive devices, if needed e. Surgery for tendons or joints 3. Disease-modifying antirheumatic drugs (DMARDs) a. Initiate a DMARD within 3 months of diagnosis. b. Treatment strategies i. Treat-to-target (a) Frequent monitoring of disease activity using validated measures and modification of treatment to minimize disease activity (b) Initial goal is low disease activity, then remission (c) Based on optimization of methotrexate before adding or changing other DMARDs ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-331 Geriatrics ii. Tapering/discontinuing DMARDs (a) Continuation of all DMARDs at current doses is recommended over a dose reduction or discontinuation, regardless of remission. (b) Dose reduction or discontinuation may be considered on the basis of shared decision-making and patient preferences if the patient is at target (low disease activity or remission) for at least 6 months. Gradual dose reduction/taper is preferred to abrupt discontinuation. c. Nonbiologic DMARDs are first line. i. For DMARD-naive patients with moderate to high disease activity: (a) Methotrexate preferred first line: Oral methotrexate preferred to subcutaneous because of ease of administration and similar bioavailability at starting doses (b) Leflunomide can be considered alternative first line: Efficacy similar to methotrexate, but less long-term data and increased cost compared with methotrexate (c) Hydroxychloroquine and sulfasalazine second line ii. For DMARD-naive patients with low disease activity: (a) Hydroxychloroquine recommended first line because of low adverse effect profile (b) Sulfasalazine recommended over methotrexate and leflunomide: Sulfasalazine preferred in pregnancy iii. Some patients with poor prognostic indicators such as functional limitation, extra-articular disease, positive RF, anti–cyclic citrullinated peptide antibodies, or bony erosions on radiography may be candidates for combination DMARD therapy. d. Biologic DMARDs are used in combination with methotrexate for severe disease or as alternatives if nonbiologic DMARDs are ineffective or contraindicated. i. Tumor necrosis factor (TNF) inhibitors: Etanercept, infliximab, adalimumab, certolizumab, golimumab ii. Non-TNF biologics: Abatacept, anakinra, rituximab, tocilizumab, sarilumab iii. Biologic kinase inhibitor: Tofacitinib, baricitinib, upadacitinib iv. An FDA boxed warning was added in September 2021 for tofacitinib regarding increased risk of serious cardiac-related events such as a myocardial infarction or stroke, cancers, blood clots, and death according to the review of clinical trial safety results that compared tofacitinib with TNF inhibitors in patients with RA. Boxed warnings were also added to baricitinib and upadacitinib. Avoid in patients who currently smoke or formerly smoked, those with CV risk factors, and those with a known malignancy. v. Most often used: Etanercept, infliximab, abatacept, or rituximab 4. Glucocorticosteroid and NSAID use in RA a. Glucocorticosteroids have often been used as bridge therapy to provide anti-inflammatory effects while waiting for the DMARDs to take effect; however, this is no longer recommended because of the risk of adverse effects associated with glucocorticosteroids (osteoporosis, infection risk, CV disease [CVD]). i. Initiation/addition/changing of DMARD without glucocorticosteroids is recommended over use of concomitant glucocorticosteroids. ii. If glucocorticosteroids are required on the basis of patient-specific factors, short-term use (less than 3 months) is preferred to long-term use. b. NSAIDs do not affect disease progression in RA; their anti-inflammatory effect occurs within 1–2 weeks of daily dosing, whereas the analgesic effect begins within several hours of administration. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-332 Geriatrics D. Comorbid Conditions 1. Patients with RA are more likely to develop other chronic diseases, either from the effects of RA or from the medications used to treat RA. 2. CVD (myocarditis and heart failure) causes 40% of all deaths in patients with RA. Low-dose aspirin, omega-3 fatty acids, statins, or combination therapy should be considered. a. Follow standard guidelines to lower CV risk factors. b. In a patient with congestive heart failure, it is recommended to avoid TNF inhibitors. 3. Infection risk is elevated, particularly in pulmonary infections and sepsis. A history of tuberculosis or hepatitis B calls for extra vigilance. a. Tuberculosis and viral hepatitis screening is required for patients who are considered for therapy with biologic DMARDs. b. Immunizations are best given before initiating DMARDs or biologics. A 2-week waiting period is recommended. c. Avoid live vaccines while the patient is taking DMARDs or biologics. d. Patients with hepatitis B or C, if treated with effective antivirals, are treated the same as patients without hepatitis; however, with untreated disease, DMARDs are preferred to TNF inhibitors. Table 11. Selected DMARDs for RA Drug Customary Dose Nonbiologic DMARDs Methotrexate Initial: 15 mg weekly × 4–6 wk Comments Leflunomide (Arava) 10–20 mg/day Hydroxychloroquine (Plaquenil) 200–300 mg twice daily Sulfasalazine Biologic DMARDs TNF Inhibitors Etanercept (Enbrel)a 500–1000 mg twice daily Similar to methotrexate; an initial loading dose may give therapeutic response within the first month First line for low RA disease activity; must routinely monitor for ocular toxicity; however, this agent has a better adverse effect profile overall GI adverse effects often limit the use of this agent 50 mg SC weekly Infliximab (Remicade, biosimilar version) 3 mg/kg IV at 0, 2, and 6 wk; then every 8 wk thereafter Adalimumab (Humira)a Certolizumab pegol (Cimzia) 40 mg SC every 2 wk Golimumab (Simponi) 400 mg SC at 0, 2, and 4 wk; then 200 mg every other week 50 mg SC every month First line for moderate to high RA disease activity; monitor for myelosuppression, liver dysfunction, and pulmonary fibrosis; a teratogen Binds to TNF, inactivating this cytokine; generally well tolerated; usually used in those whose methotrexate therapy fails; monitor for infection; check baseline PPD A mouse/human chimeric antibody to TNF; used in combination with methotrexate to prevent formation of antibodies to this protein; monitor for infection; check baseline PPD Human antibody to TNF; less antigenic than other TNF antibodies; monitor for infection; check baseline PPD Monoclonal antibody against TNF; may have best response when used in combination with methotrexate Monitor for infections Monoclonal antibody against TNF Intended for use in combination with methotrexate Monitor for infections ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-333 Geriatrics Table 11. Selected DMARDs for RA (Cont’d) Drug Non-TNF Biologics Abatacept (Orencia) Customary Dose Comments Weight-based dose at 0, 2, and 4 wk; then monthly (i.e., 750 mg for those weighing 60–100 kg) Inhibit interactions between antigens and T cells; may be useful in those who do not respond to TNF inhibitors; monitor for infusion reactions Anakinra (Kineret) 100 mg SC daily IL-1 receptor antagonist; avoid combination therapy with TNF agents because of elevated risk of infection Chimeric antibody to CD20 protein on B lymphocytes; corticosteroid infusions help reduce infusion reactions; used in combination with methotrexate to improve response IL-6 receptor antagonist Rituximab (Rituxan)a Two infusions of 1000 mg given 2 wk apart Sarilumab (Kevzara) 200 mg SC once every 2 wk May use as monotherapy or in combination with nonbiologic DMARDs Should not be used in combination with biologic DMARDs Tocilizumab (Actemra) Kinase Inhibitors Baricitinib (Olumiant) 4-mg/kg IV infusion every 4 wk; can increase to 8 mg/kg depending on clinical response 2 mg daily Do not initiate if ANC < 2000/mm3, Plt < 150,000/mm3, or ALT/AST > 1.5 times the ULN Anti–human IL-6 receptor monoclonal antibody; indicated for patients who have not responded to TNF inhibitors Monitor for infections Oral Janus kinase inhibitor May be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs Not recommended for use with biologic DMARDs or potent immunosuppressants (azathioprine, cyclosporine) Tofacitinib (Xeljanz) Upadacitinib (Rinvoq) 5 mg twice daily Do not initiate therapy with absolute lymphocyte count < 500 cells/mm3, ANC < 1000 cells/mm3, or Hgb < 8 g/dL. Boxed warning (mentioned above) Oral Janus kinase inhibitor; intended as second-line therapy 15 mg daily Can be used as monotherapy or in combination with methotrexate. Boxed warning (mentioned above) Oral Janus kinase inhibitor May be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs Not recommended for use with biologic DMARDs or potent immunosuppressants Do not initiate therapy with absolute lymphocyte count < 500 cells/mm3, ANC < 1000 cells/mm3, or Hgb < 8 g/dL. Boxed warning (mentioned above) a Biosimilar available. ANC = absolute neutrophil count; DMARD = disease-modifying antirheumatic drug; IL = interleukin; IV = intravenous(ly); PPD = purified protein derivative; RA = rheumatoid arthritis; SC = subcutaneous(ly); TNF = tumor necrosis factor; ULN = upper limit of normal. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-334 Geriatrics 4. Malignancy is more common, particularly GI cancers and lymphoproliferative disorders. In addition, melanoma and lung cancer rates were elevated in one cohort study. Use DMARDs over biologics in melanoma; use rituximab over TNF inhibitors in lymphoproliferative disorders. 5. Osteoporosis is more common in patients with RA. Calcium and vitamin D are recommended. In addition, bisphosphonates should be considered for prevention if prednisone 5 mg or more daily is prescribed. Patient Case 16. A 65-year-old woman was diagnosed with RA 1 year ago. At that time, her RF titer was 1:64; she presented with joint inflammation in both hands and about 45 minutes of morning stiffness. She began therapy with oral methotrexate and currently receives methotrexate 15 mg weekly, folic acid 2 mg daily, ibuprofen 800 mg three times daily, and omeprazole 20 mg daily. At today’s clinic visit, the patient reports the recurrence of her symptoms. Radiographic evaluation of her hand joints reveals progression of joint space narrowing and bone erosion. Which is the next best step for treating this patient’s RA? A. Add etanercept. B. Change to leflunomide. C. Add prednisone bridge therapy. D. Change to hydroxychloroquine. VIII. GOUT A. Definition: A spectrum of clinical and pathologic features caused by hyperuricemia (SU concentrations more than 6.8 mg/dL) resulting in tissue deposition of monosodium urate monohydrate crystals in the extracellular fluid of joints and other sites 1. Most common form of inflammatory arthritis; prevalence estimated at 9.2 million adults (3.9%) in the United States 2. Characterized by acute intermittent episodes of synovitis presenting with joint swelling and pain, called acute gouty arthritis, acute gout attacks, or acute gout flares 3. Also known as monosodium urate crystal deposition disease B. Diagnosis 1. Typically presents as acute episodic arthritis 2. May also present as chronic arthritis of one or more joints, particularly if prolonged hyperuricemia exists 3. Tophi may be present; detected on physical examination or with imaging 4. Renal manifestations include uric acid nephrolithiasis and chronic nephropathy. 5. Features of acute gout attack include: a. Severe pain, redness, swelling; maximum severity in 12–24 hours; may continue for a few days to several weeks b. Most often affect the lower extremities in a single joint i. Most common joint: First metatarsophalangeal joint (podagra) or knee ii. May occur in many other joints, including those of upper extremities iii. May be polyarticular at first presentation (less than 20% of cases) ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-335 Geriatrics 6. Ideally, definitive diagnosis should be made by visualization of monosodium urate crystals under polarized compensated light microscopy in fluid aspirated from the affected joint during an acute gout attack. a. In the diagnosis of gout, monosodium urate crystals are negatively birefringent (needle shaped or rods). b. In pseudogout, crystals are calcium pyrophosphate dihydrate and are weakly positively birefringent (rods or rhomboidal). c. Diagnosis by joint aspiration is difficult because patients are in severe pain and often refuse joint aspiration during an acute attack. In this case, a provisional diagnosis can be made on the basis of clinical data. 7. If diagnosis by joint aspiration is not possible, a tentative diagnosis can be made by a combination of presentation or clinical picture and increased uric acid. Use of hyperuricemia as one of the criteria for diagnosing gout may be difficult during an initial acute attack because serum uric acid may be low during flares. The best time to check uric acid is 2 weeks after a flare. C. Predisposing Factors 1. Dietary: High meat and seafood consumption, fatty foods, dietary overindulgence, high intake of beer and spirits (not wine) in men, sugar-sweetened soft drinks, high-fructose foods 2. Drugs: Thiazides and loop diuretics, niacin, calcineurin inhibitors, low-dose aspirin. During initiation of therapy, xanthine oxidase inhibitors (XOIs) and uricosuric agents may increase uric acid and symptoms. 3. Medical conditions and other factors: Obesity, diabetes, hypertension, dyslipidemia, metabolic syndrome, congestive heart failure, organ transplantation, renal insufficiency, early menopause, trauma, surgery, starvation, dehydration, episodic alcohol consumption D. Classification 1. Four stages of gout: a. Asymptomatic b. Acute gouty arthritis c. Intercritical gout (intervals between attacks) d. Chronic recurrent gout 2. Severities of chronic tophaceous gouty arthropathy (CTGA) a. Mild: One joint, stable disease b. Moderate: Two to four joints, stable disease c. Severe i. CTGA of more than four joints or ii One or more unstable, complicated, severe articular tophi d. Size of joints i. Large joints (e.g., knee, ankle, wrist, elbow, hip, shoulder) ii. Medium joints (e.g., wrist, ankle, elbow) iii. Small joints (e.g., interphalangeal) E. Treatment Goals 1. The minimum SU target is less than 6 mg/dL. 2. An SU target of 5 mg/dL or less may be needed to improve gout signs and symptoms. Consider a goal of 5 mg/dL or less if tophi are present. 3. Decrease the frequency of acute gout attacks. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-336 Geriatrics F. Nonpharmacologic Therapy (Table 12) Table 12. Nonpharmacologic Therapy for Gouta Lifestyle and General Health Weight loss if obesity Healthy overall diet Exercise Smoking cessation Proper hydration Foods and Drinks to Avoid Organ meats high in purines (e.g., liver, kidney, sweetbreads) High-fructose corn syrup– sweetened sodas, beverages, and foods Alcohol overuse (> 2 per day for men, > 1 per day for women) in all patients Foods and Drinks to Limit Serving sizes of: Foods and Drinks to Encourage Low- or nonfat dairy products Beef, lamb, pork Seafood with high purine content (e.g., sardines, shellfish) Servings of naturally sweet fruit juices Vegetables Table sugar, sweetened beverages, desserts Table salt Alcohol (particularly beer, but also wine and spirits) Any alcohol use during times of frequent gout attacks or advanced gout under poor control Note: These approaches are based on a paucity of high-quality evidence on the effects of dietary and lifestyle factors for reducing the risk of recurrent gout attacks./ Adapted from: Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1. Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res 2012;64:1431-46. a G. Treatment of Acute Gout (Table 13) 1. Assess severity of gout attack (Table 14), and select treatment accordingly. 2. Initiate pharmacologic treatment within 24 hours of onset of an acute gout attack. Colchicine is appropriate only if initiated within 36 hours of attack onset. 3. Continue established urate-lowering therapy (ULT) without interruption during an acute gout attack (do not discontinue ULT). 4. Consider oral colchicine, NSAIDs, or glucocorticoids (oral, intra-articular, or intramuscular) as appropriate first-line agents for gout flares. a.  Colchicine, NSAIDs, or glucocorticoids should be chosen according to patient factors and preferences. b. When colchicine is chosen, low dose is recommended over high dose, given its similar efficacy and more favorable adverse effect profile. FDA-approved dosing should be followed: 1.2 mg immediately, followed by 0.6 mg 1 hour later with ongoing anti-inflammatory therapy until the flare resolves. c.  For patients with nothing-by-mouth status, glucocorticoids (intramuscular, intravenous, or intra-articular) are recommended over interleukin-1 (IL-1) inhibitors or ACTH (adrenocorticotropic hormone). ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-337 Geriatrics Table 13. Medication Dosing for Acute Gout Attack Drug Colchicine (Colcrys) Dose First day: 1.2 mg, then 0.6 mg 1 hr later; day 2 and thereafter: 0.6 mg twice daily until flare resolves CrCl 30–80 mL/min/1.73 m2: Monitor for adverse effects; dose adjustment not necessary CrCl < 30 mL/min/1.73 m2: Dose adjustment not necessary but may be considered; do not repeat course of treatment more often than every 2 wk Dialysis: 0.6-mg single dose; do not repeat course of treatment more often than every 2 wk NSAIDs Severe hepatic impairment: Dose reduction not necessary but may be considered; do not repeat course of treatment more often than every 2 wk Naproxen: 750 mg initially, followed by 250 mg every 8 hr Naproxen ER: 1000–1500 mg once daily, followed by 1000 mg once daily Indomethacin: 50 mg three times daily until pain is tolerable; then reduce dose until attack resolves Sulindac: 200 mg twice daily Celecoxib (Celebrex) Glucocorticoids Comments Concomitant use with P-gp inhibitors or strong CYP3A4 inhibitors is contraindicated in renal or hepatic impairment (fatal toxicity has occurred) Colchicine dose should be reduced if renal and hepatic function normal and if used concomitantly with P-gp inhibitors or moderate to strong CYP3A4 inhibitors The only FDA-approved NSAIDs are naproxen, indomethacin, and sulindac; however, other NSAIDs may be as effective Continue full dose until attack completely resolves Can taper dose if comorbidities or renal or hepatic impairment is present Use anti-inflammatory or analgesic doses of other NSAIDs, same as for treatment of acute pain or inflammation 800 mg once, followed by 400 mg on day 1, then 400 mg Only in certain patients when twice daily for 1 wk NSAIDs are contraindicated or not tolerated Intra-articular corticosteroids may Prednisone 0.5 mg/kg per day for 5–10 days or be used in combination with OCSs, Prednisone 0.5 mg/kg per day for 2–5 days, then taper NSAIDs, or colchicine for 7–10 days, then discontinue or Methylprednisolone dose pack Option for one or two large joints: Intra-articular corticosteroids Dose according to the size of the joint (e.g., triamcinolone 40 mg for large joint, 30 mg for medium joint, 10 mg for small joint or equivalent) IM triamcinolone 60 mg, followed by oral glucocorticoid (dosing as above) IM = intramuscular(ly); OCS = oral corticosteroid; P-gp = P-glycoprotein. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-338 Geriatrics Table 14. Severity, Duration, and Extent of Acute Gout Attacks Severitya Mild Moderate Severe Duration Since Onset Early Well established Late Extent One or a few small joints One or two large joints Polyarticular ≤4 5 or 6 ≥7 < 12 hr after attack onset 12–36 hr after attack onset > 36 hr after attack onset Large joints: Ankle, knee, wrist, elbow, hip, shoulder ≥ 4 joints involving > 1 region (regions: forefoot, midfoot, ankle or hindfoot, knee, hip, fingers, wrist, elbow, shoulder) Three separate large joints a Self-reported; based on a 0–10 visual analog scale. H. Management of Hyperuricemia – Chronic ULT (Table 15) 1. Consider discontinuing nonessential medications that cause hyperuricemia. 2. Recognize indications for chronic ULT: a. Strongly recommend for patients with: i. One or more subcutaneous tophi on clinical examination or imaging study ii. Two or more acute gout attacks per year iii. Radiographic damage as a result of gout b. Conditionally recommend for patients with: First gout flare AND history of stage 3 or higher chronic kidney disease (CKD), SU greater than 9 mg/dL, or urolithiasis c. Recommend against for patients with: i. First gout glare ii. Asymptomatic hyperuricemia (SU greater than 6.8 mg/dL) with no prior gout flares or subcutaneous tophi 3. Initiating ULT a. ULT initiation recommended during acute gout flare over waiting until flare resolution b. First line: XOIs i. Allopurinol is the preferred first-line agent for all patients, including those with moderate to severe stage 3 or higher CKD. Start at a low dose (100 mg/day or less) with dose titration to target SU over starting at a higher dose. (a) Allopurinol hypersensitivity syndrome is possible. (1) Highest risk during the first few months of therapy (2) Manifestations: Stevens-Johnson syndrome, toxic epidermal necrolysis, clinical constellation of symptoms (eosinophilia, rash, vasculitis, major end-organ disease) (3) Risk factors: Concomitant thiazide diuretics, renal impairment (b)  Testing for HLA-B*5801 is only recommended in patients of African American or Southeast Asian descent. ii. Change to alternative XOI (e.g., febuxostat of 40 mg/day or less) in patients intolerant of or refractory to first XOI. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-339 AL GRAWANY Geriatrics c. d. Alternative: Uricosuric agent i. A uricosuric if at least one XOI is contraindicated or not tolerated ii. Probenecid 500 mg once or twice daily with dose titration recommended over higher doses Last line: Pegloticase i. If the goal SU is still not achieved and patients continue to have frequent gout flares (2 flares/ year or more) despite XOI and uricosuric therapy, discontinue other therapies and change to pegloticase. ii. Pegloticase is not recommended for first-line therapy in any case. 4. Initiate anti-inflammatory prophylaxis for acute gout concomitantly with or just before ULT in all patients. a. There may be an early increase in acute gout attacks during ULT initiation. i. May be caused by rapid decrease in urate concentrations, resulting in remodeling of articular urate crystal deposits ii. Patient education is crucial; lack of education may increase the risk of nonadherence to ULT. b. Colchicine, NSAIDs, prednisone/prednisolone may be chosen on the basis of patient-specific factors and preferences c. Continue anti-inflammatory prophylaxis for 3–6 months, with ongoing evaluation. d. Continue anti-inflammatory prophylaxis beyond 6 months in the presence of any clinical evidence of gout disease activity (tophi, recent flare, chronic gouty arthritis). 5. Treat-to-target management a. Recommended: Treat-to-target management strategy of ULT by achieving and maintaining SU at less than 6 mg/dL rather than fixed-dose strategy b. Augmented treat-to-target protocol of ULT dose management by nonphysician providers (e.g., nurses and pharmacists) is recommended when resources are available. Table 15. Chronic ULT Drug Allopurinol (Zyloprim)a Dose Starting dose: 100 mg daily (50 mg daily in stage 4 CKD) Gradually titrate dose every 2–5 wk to appropriate maximum dose (800 mg daily with normal renal function) or until goal urate concentration reached Febuxostat (Uloric)a Maintenance dose can be > 300 mg daily, even in CKD, as long as patient is educated and regular monitoring occurs for hypersensitivity, rash, pruritus, elevated hepatic enzymes, and eosinophilia Starting dose: 40 mg once daily May increase dose to 80 mg once daily if goal SU not reached Comments XOI Low starting dose reduces early gout flares and risk of hypersensitivity syndrome Consider keeping dose lower in CKD and not increasing to maximum dose; data with dosing > 300 mg/day in CKD are limited Dose reduction algorithms in CKD have been developed but are not evidence based; the ACR guidelines do not recommend following them XOI FDA black box warning: Increased risk of CV death compared with allopurinol CrCl < 30 mL/min/1.73 m2: Use caution; insufficient data ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-340 Geriatrics Table 15. Chronic ULT (Cont’d) Drug Probenecid (generic only)a Dose Starting dose: 250 mg twice daily × 1 wk Comments Uricosuric; alternative agent after XOI May increase weekly in 500-mg/day increments to maximum dose of 1 g twice daily, if needed Pegloticase (Krystexxa)a Avoid if CrCl < 30 mL/min/1.73 m2 8 mg IV every 2 wk No dose adjustment for CKD Use only if severe gout disease burden and refractory to or intolerant of other ULT options All other antihyperuricemic agents must be discontinued before initiation of pegloticase; do not administer concomitantly Premedicate with antihistamines and corticosteroids Always initiate concomitant prophylactic therapy. CKD = chronic kidney disease; CV = cardiovascular; IM = intramuscular(ly); IV = intravenous(ly); P-gp = P-glycoprotein; PUD = peptic ulcer disease; SU = serum urate; ULT = urate-lowering therapy; XOI = xanthine oxidase inhibitor. a Table 16. Medications for Chronic Urate-Lowering Therapy and Acute Gout Attack Prophylaxis Drug Colchicine (Colcrys) Dose 0.6 mg once or twice daily (maximum 1.2 mg daily) CrCl 30–80 mL/min/1.73 m2: Monitor for adverse effects; dose adjustment not necessary CrCl < 30 mL/min/1.73 m2: Initial dose 0.3 mg/day; use caution and monitor if dose titrated further Dialysis: 0.3 mg twice weekly; monitor for adverse effects NSAIDs Oral glucocorticoids Severe hepatic impairment: Dose reduction not necessary but may be considered; do not repeat course of treatment more often than every 2 wk Lower doses than used for acute attacks (e.g., naproxen 250 mg twice daily, indomethacin 25 mg twice daily) Prednisone or prednisolone ≤ 10 mg daily Comments Concomitant use of colchicine with P-gp inhibitors or strong CYP3A4 inhibitors is contraindicated in renal or hepatic impairment (fatal toxicity has occurred) Colchicine dose should be reduced if renal and hepatic function normal and if used concomitantly with P-gp inhibitors or moderate to strong CYP3A4 inhibitors Consider concomitant proton pump inhibitor or other agent for suppression of PUD, when indicated Consider, particularly if colchicine and NSAIDs are both contraindicated, ineffective, or not tolerated P-gp = P-glycoprotein; PUD = peptic ulcer disease. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 2-341