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Module 13. Bone and Joint Diseases
The following common bone diseases are discussed within this module:
- Osteoporosis
- Rheumatoid arthritis
- Osteoarthritis
- Gout
OSTEOPOROSIS
Overview
Epidemiologic studies have estimated that 8 million women and 2 million men in the United States have osteoporosis, making it the most common bone disorder in this country.1,2 Osteoporosis is defined as a reduction in bone strength that leads to increased fracture risk. Considered a “silent disease,” patients with osteoporosis are often asymptomatic until a fracture occurs.3 If signs and symptoms do occur, they are often fracture-related and may include pain, lack of mobility, depressed mood due to physical limitations, decreased height (defined as > 1.5-inch loss), and rounding of the spine.4
Osteoporosis results from an imbalance in bone remodeling; osteoclast activity (bone resorption) exceeds osteoblast activity (bone formation) causing decreased bone mineral density (BMD).2,5 This imbalance in bone remodeling is a normal age-related process that begins around age 30 and, for women, this imbalance becomes more apparent after menopause.2 Physical activity and adequate vitamin D and calcium intake are important for developing and maintaining adequate BMD. Other factors that can contribute to low BMD or osteoporotic fractures include low body weight, premature menopause, chronic disease, smoking, alcohol use (3 or more drinks/d), and medications (eg, corticosteroids).4
Clinically, osteoporosis can be diagnosed by the presence of a fracture without major trauma (also known as a fragility fracture).3,4 Osteoporosis may also be diagnosed based on BMD with a dual-energy x-ray absorptiometry (DXA) scan, which measures bone density at the hip and spine. The DXA report includes the actual bone density, a T-score, and a Z-score.4 The T-score is used for diagnosis and compares the patient’s bone density to the peak bone density of a healthy 20- to 29-year-old adult. The T-score is the number of standard deviations from the mean reference population. On the other hand, a Z-score compares the patient’s bone density to that of an individual of the same age, sex, and ethnic background. Z-scores help diagnose osteoporosis in men younger than 50 years old, children, or premenopausal women.
The World Health Organization (WHO) has defined bone density levels which are summarized in Table 1.3,6 Additionally, the Fracture Risk Assessment Tool (FRAX), developed by the WHO, calculates the estimated risk of fracture based on BMD and individual patient factors.3,7
Table 1. World Health Organization Definitions Based on Bone Density Levels3,6 |
Level |
Definition |
Normal |
BMD is within 1 SD (T-score +1 or -1) of the young adult mean |
Low bone mass (osteopenia) |
BMD is between 1 and 2.5 SD below the young adult mean (T-score -1 to -2.5 SD) |
Osteoporosis |
Bone density is ≥ 2.5 SD below the young adult mean (T-score -2.5 or lower) |
Osteoporosis (severe, established) |
Bone density is ≥ 2.5 SD below the young adult mean and ≥ 1 fractures |
Abbreviations: BMD, bone mineral density; SD, standard deviation. |
The incidence of osteoporosis can be reduced by optimizing skeletal development and peak bone mass early in life.4 Prevention of age-related and secondary causes of bone loss is also important. Once osteoporosis develops, the goal is to prevent fractures, stabilize the skeletal system, and improve strength and bone mass.
Treatment Recommendations
The American Academy of Clinical Endocrinologists (AACE), the American College of Rheumatology (ACR), and the National Osteoporosis Foundation (NOF) provide recommendations for the prevention and management of osteoporosis using both lifestyle modifications and pharmacologic therapies.3,8,9 Additional guidelines from the Endocrine Society, the American Society for Bone and Mineral Research, (ASBMR) and the American College of Physicians (ACP) focus on the pharmacologic treatment of osteoporosis.10-12 Maintenance of a bone-healthy lifestyle can reduce the risk of fractures. Specific lifestyle modifications are summarized in Table 2.
Table 2. Osteoporosis Lifestyle Modifications3,4,9 |
|
Recommendations |
Nutrition |
Consume a well-balanced diet limited in excess salt, caffeine, and protein |
Ensure adequate intake of calcium and vitamin D |
Total daily elemental calcium*
- Women 19-50 years – 1000 mg
- Men 51-70 years – 1000 mg
- Women > 50 years and men > 70 years – 1200 mg
- Maximum daily dose: 2000-2500 mg (depending on age)
|
Total daily vitamin D
- Adults < 50 years – 400-800 IU
- Adults ≥ 50 years – 800-1000 IU
- Up to 4000 IU daily is considered safe
|
Regular weight-bearing exercises |
Walking, jogging, stair climbing, weight machines, free weights, or elastic bands |
Avoid tobacco use |
Smoking cessation |
Limit alcohol consumption |
Increased risk with ≥ 3 drinks/d |
Limit caffeine |
≤ 2 servings/d |
Fall precautions |
Checking/correcting visual or hearing problems; monitor for low blood pressure or heart rate; use proper footwear; replace high-risk medications for falls with safer alternatives; home safety assessment |
Hip protectors |
For patients with high risk of falls or previous fracture |
* Dosages expressed as elemental calcium; calcium carbonate is 40% elemental calcium; calcium citrate is approximately 21% elemental calcium.
Abbreviation: IU, international units. |
Adequate calcium intake is essential for the development of bone mass during childhood and for maintenance of bone mass throughout life.3 The primary source of calcium should be obtained through a patient’s diet. Supplementation with calcium is recommended when dietary intake is inadequate. Calcium intake recommendations are based on the amount of elemental calcium in each product. For example, calcium carbonate is 40% elemental calcium. Therefore, 1250 mg calcium carbonate contains 500 mg of elemental calcium. Since the dosage of elemental calcium varies between products, it is important to consult the product labeling.
Pharmacologic treatment is recommended for postmenopausal women or men who are at least 50 years of age with T-scores less than 2.5 in the femoral neck, total hip, or lumbar spine; those with a hip or vertebral fracture; or those with a T-score between -1 and -2.5 and a 10-year fracture probability of at least 20% for major osteoporotic fracture or at least 3% for hip fracture based on the FRAX tool.4,10,13
The choice of pharmacologic therapy is based on antifracture benefits demonstrated in clinical studies.3,9,10 The various agents approved by the US Food and Drug Administration (FDA) for the prevention and treatment of osteoporosis are summarized in Table 3.
First-line agents recommended by the AACE include alendronate, risedronate, zoledronic acid, or denosumab.3 They recommend use of oral agents for patients at low or moderate risk of fractures. Injectable medications are preferred as initial therapy in those with a very high fracture risk, those with gastrointestinal (GI) concerns, and those who have difficulty remembering or adhering to a medication schedule. The 2019 guidelines from the Endocrine Society recommend bisphosphonates as first-line therapy in postmenopausal women at high risk of fractures.10 They do note that ibandronate is not recommended to reduce nonvertebral or hip fractures. Denosumab is recommended as an alternative initial treatment, and the parathyroid hormone analogs (teriparatide and abaloparatide) are reserved for postmenopausal women at very high risk of fracture. The selective estrogen receptor modulators (raloxifene and bazedoxifene) reduce the risk of vertebral fractures and can be used in patients who have a low risk of thromboembolism when bisphosphonates or denosumab are inappropriate. Calcitonin is the last-line agent recommended only in patients who do not tolerate any other therapy. The role of romosozumab has not yet been addressed in clinical practice guidelines.3,10
Osteoporosis is one of the most significant adverse effects of glucocorticoid therapy. The ACR published guidelines in 2017 for the prevention and treatment of osteoporosis in patients who are treated with glucocorticoids.8 They recommend all patients practice a bone-healthy lifestyle and optimize calcium and vitamin D intake. Specific pharmacologic agents are recommended based on age and risk factors. An oral bisphosphonate is recommended for patients who are at least 40 years of age with a moderate or high risk of fracture.
Table 3. Agents Used for the Treatment/Prevention of Postmenopausal Osteoporosis3,4,8,10,14,15 |
Drug |
FDA-approved indication in osteoporosis |
Dosage |
Comments/dosing adjustments |
Bisphosphonates (oral)* |
Alendronate
(Fosamax, Fosamax-D, Binosto, generic) |
Treatment |
10 mg daily or 70 mg weekly |
· 70 mg dose is also available as an effervescent tablet or combination tablet with 2800 or 5600 units of vitamin D
· Also available in a 70 mg/75 mL liquid formulation
· Not recommended in patients with CrCl < 35 mL/min |
Prevention |
5 mg orally or 35 mg weekly |
Ibandronate
(Boniva, generic) |
Treatment, prevention |
150 mg monthly |
· Not recommended in patients with CrCl < 30 mL/min |
Risedronate
(Actonel, Atelvia delayed-release, generic) |
Treatment, prevention |
5 mg daily, 35 mg weekly, 150 mg monthly |
· 35 mg dose is also available as a delayed-release tablet for treatment
· Not recommended in patients with CrCl < 30 mL/min |
Bisphosphonates (IV) |
Ibandronate
(Boniva) |
Treatment |
3 mg IV once every 3 mo |
· Not recommended in patients with CrCl < 30 mL/min |
Zoledronic acid
(Reclast) |
Treatment |
5 mg IV once yearly |
· May premedicate with acetaminophen or NSAIDs to decrease infusion reactions
· Contraindicated in patients with CrCl < 35 mL/min
· Also marketed under the brand name Zometa with different dosing for the treatment of hypercalcemia of malignancy, multiple myeloma, and bone metastases in patients with solid tumors |
Prevention |
5 mg IV once every 2 y |
Selective estrogen receptor modulator |
Raloxifene
(Evista, generic) |
Treatment, prevention |
60 mg daily |
· Not recommended in hepatic impairment
· Use with caution in patients with moderate-to-severe renal impairment |
Conjugated estrogens and selective estrogen receptor modulator |
Conjugated estrogens and bazedoxifene
(Duavee) |
Prevention |
0.45 mg/20 mg (1 tablet) daily |
· Not recommended for women older than 75 years
· Not recommended in patients with renal impairment
· Contraindicated in patients with hepatic impairment |
Anti-RANK ligand antibody |
Denosumab
(Prolia) |
Treatment |
60 mg SC every 6 mo |
· Administered by a health care professional
· Concomitant calcium (1000 mg daily) and vitamin D (400 IU) are recommended
· Prior to administration, correct hypocalcemia
· Also marketed under the brand name Xgeva for the prevention of skeletal-related events from bone metastases from solid tumors |
Calcitonin |
Calcitonin
(Miacalcin nasal sprays, generic) |
Treatment |
200 units (1 spray) daily |
· Administer in 1 nostril daily, alternating nostrils each day
· Refrigerate until opened for daily use, then store at room temperature
· Prime with first use |
Calcitonin
(Miacalcin injection) |
Treatment |
100 units SC or IM daily, every other day, or 3 times weekly |
· Administer as IM route for injection volumes over 2 mL, otherwise administer as SC route |
Parathyroid hormone |
Abaloparatide
(Tymlos) |
Treatment |
80 mcg SC daily |
· Available as a prefilled pen
· Refrigerate until first use then may be stored at room temperature |
Teriparatide
(Forteo) |
Treatment |
20 mcg SC daily |
· Available as a prefilled pen
· Refrigeration required |
Sclerostin inhibitor |
Romosozumab
(Evenity) |
Treatment |
210 mg SC monthly for 12 mo |
· Must be administered by a health care provider |
* Oral bisphosphonates should be administered first thing in the morning on an empty stomach with 6-8 oz of plain (not mineral) water. After administration, the patient may not eat or drink (except water) and remain upright for at least 30 min (60 min with ibandronate).
Abbreviations: CrCl, creatinine clearance; FDA, US Food and Drug Administration; IM, intramuscular; IU, international units; IV, intravenous; NSAIDs, nonsteroidal anti-inflammatory drugs; SC, subcutaneous. |
Safety and Monitoring Parameters
Table 4 provides a summary of both common and severe adverse effects, as well as monitoring parameters for the agents used for the treatment or prevention of osteoporosis.4,14,15 An important consideration with bisphosphonate therapy is the duration of therapy to maximize benefits while minimizing adverse events. Recent guidelines from the Endocrine Society and ASBMR have focused on appropriate duration of these agents.10,12 Generally, patients at high risk of fracture are recommended to continue oral therapy for up to 10 years or up to 6 years with IV therapy. However, those at lower risk may consider a drug holiday for 2 or 3 years after an initial 3 to 5 years of therapy.
Table 4. Monitoring Medications Used in the Treatment/Prevention of Osteoporosis4,14,15 |
Drug |
Adverse drug reactions |
Monitoring parameters |
Comments |
Bisphosphonates |
Alendronate, Ibandronate, Risedronate, Zoledronic acid |
· Common: heartburn, esophageal irritation, esophagitis, abdominal pain, nausea, vomiting, diarrhea, transient musculoskeletal pain, headache
· Rare: GI perforation, ulceration and/or bleeding; osteonecrosis of the jaw; severe bone, joint, and muscle pain; ocular inflammation; hypocalcemia; atypical femur fractures; renal failure (injection only); infusion reactions (injection only) |
· Serum calcium and vitamin D levels
· Fractures |
|
Selective estrogen receptor modulator |
Raloxifene |
· Common: hot flashes, leg pain, spasms, cramps, peripheral edema
· Rare: thromboembolism |
· Fractures
· Hot flashes
· Leg cramps
· Blood clots |
· Boxed warning: increased risk for VTE and death from stroke |
Conjugated estrogens and selective estrogen receptor modulator |
Conjugated estrogens/ bazedoxifene |
· Common: muscle spasm, diarrhea, nausea, dyspepsia, abdominal pain, oropharyngeal pain
· Rare: thromboembolism, dementia |
· Fractures
· Leg cramps
· Blood clots |
· Boxed warning: increased risk for: VTE and death from stroke; endometrial cancer; dementia |
Anti-RANK ligand antibody |
Denosumab |
· Common: rash, eczema, dermatitis, arthralgias, back pain, infection
· Rare: osteonecrosis of the jaw, atypical femur fractures, severe hypocalcemia |
· Serum calcium, creatinine/BUN, magnesium, and phosphate
· Fractures |
· REMS: medication guide and monitoring due to the risk of serious infections, dermatologic adverse effects, and suppression of bone turnover |
Calcitonin |
Nasal spray |
· Common: rhinitis, sinusitis, occasional epistaxis
· Rare: severe allergic reactions |
· Fractures
· Serum calcium, vitamin D, and alkaline phosphatase |
· Many experts recommend avoiding calcitonin due to potential serious allergic reactions and increased risk of malignancy |
Injectable |
· Common: nausea and flushing, injection site reactions
· Rare: severe allergic reactions |
Parathyroid hormone |
Abaloparatide |
· Common: orthostasis, hypercalcemia, hypercalciuria, nausea
· Rare: increase in uric acid, anaphylaxis |
· Fractures
· Serum calcium and uric acid |
· Boxed warning: potential risk for osteosarcoma
· Not to be used longer than 2 years |
Teriparatide |
· Common: orthostasis, hypercalcemia, hypercalciuria, leg cramps, nausea
· Rare: increase in uric acid, anaphylaxis |
· Fractures
· Serum calcium, creatinine/BUN, magnesium, and uric acid |
· Boxed warning: potential risk for osteosarcoma
· Not to be used longer than 2 years |
Sclerostin inhibitor |
Romosozumab (Evenity) |
· Common: arthralgia, headache, peripheral edema
· Rare: allergic reactions, hypocalcemia, osteonecrosis of the jaw, atypical femur fractures, cardiac events |
· Fractures
· Serum calcium |
· Boxed warning: may increase the risk of MI, stroke, or CV death |
Abbreviations: BMD, bone mineral density; BUN, blood urea nitrogen; CV, cardiovascular; GI, gastrointestinal; MI, myocardial infarction; REMS, Risk Evaluation Mitigation Strategy; VTE, venous thromboembolism. |
Oral bisphosphonates should not be administered at the same time as food or other medications.4,14,15 Dosing instructions state that bisphosphonates should be administered first thing in the morning on an empty stomach with 6 to 8 oz of plain (not mineral) water. After administration, the patient may not eat or drink (except water) and remain upright for at least 30 minutes (60 minutes with ibandronate). Coadministration with aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of GI effects. Raloxifene is highly protein-bound; therefore, caution should be taken when coadministered with other highly protein-bound agents. Raloxifene can decrease prothrombin time by 10%; therefore, close monitoring is recommended when used with warfarin. Denosumab has minimal drug interactions. The agent may enhance the adverse effects of immunosuppressant agents, specifically the risk of infections. The risk of hypercalcemia due to teriparatide may cause toxicity in patients taking digoxin. There are no known drug interactions with abaloparatide or romosozumab.15
Patient Case #1:
Chief Complaint
“I am worried I am going to get osteoporosis.”
MB is a 53-year-old female who presents to her gynecologist to discuss preventive measures for osteoporosis. She started having irregular periods about 6 months ago with mild hot flashes at night.
Personal medical history:
None
Family history:
Strong history of breast cancer
Social history:
Former cigarette smoker (until age 30); drinks 1 to 2 glasses of wine per month
Allergies:
None
Medications:
Calcium carbonate 1000 mg daily
Acetaminophen – as needed for headaches
Physical examination is normal.
Vital signs: BP 112/70, P 80, RR 14, T 37; Wt 108 pounds, Ht 5′2″
All labs WNL
DXA scan of spine: T-score is –2
What preventive measures would help decrease MB’s risk for developing osteoporosis?
- Starting an aerobic and weight-bearing exercise program
- Ensuring an adequate intake of calcium and vitamin D (recommendation is 1200 mg elemental calcium and 800-1000 IU vitamin D daily)
What are the goals of pharmacotherapy for MB?
- Prevent additional loss of BMD
- Prevent fractures
What recommendations should be made regarding therapy for MB?
- Initiate preventative therapy with alendronate 35 mg weekly
- Counsel to administer first thing in the morning on an empty stomach with 6 to 8 oz of plain (not mineral) water. After administration, she may not eat or drink (except water) and remain upright for at least 30 minutes.
RHEUMATOID ARTHRITIS
Overview
Rheumatoid arthritis (RA) is a common chronic inflammatory disorder.16-18 The prevalence is estimated to be 0.5% to 1% worldwide. The disease is more common in women. Rheumatoid arthritis has the highest incidence in patients between 25 and 55 years of age, and incidence declines after 75 years of age.18 The cause of RA is complex and multifactorial.16-18 Genetic predisposition, environmental factors (eg, cigarette smoking), older age, and immunologic dynamics are thought to be linked to the disease. Factors that initiate the inflammatory process are unknown. Chronic inflammation of the synovial tissue leads to joint deformity and destruction of cartilage, bone, tendons, ligaments, and joints.17,19 Antibodies that may indicate a poorer prognosis with RA include rheumatoid factors and anticitrullinated protein antibody (ACPA).17
Individuals with RA initially present with pain, stiffness, and swelling of multiple joints for > 6 weeks.17,19,20 Patients may also present with fatigue, low-grade fever, and loss of appetite. The small joints including the fingers, thumbs, and wrists, as well as the joints of the toes, are affected first. Patients may also experience pain in large joints, including the elbows, shoulders, ankles, and knees. A predominant feature of RA is morning stiffness, defined as: “slowness or difficulty moving the joints when getting out of bed or after staying in one position too long, which involves both sides of the body and gets better with movement.”19,21
The diagnosis of RA cannot be made by 1 physical finding or laboratory result.20,22 The ACR/European League Against Rheumatism (EULAR) provides specific criteria for the diagnosis of RA.20,22,23 Patients that present with synovitis in at least 1 joint, and the swelling of the joint is not the result of another disease, should be tested for RA. Patients that score ≥ 6 (out of a possible 10) on the ACR/EULAR classification criteria are diagnosed as having RA (Table 5).
Table 5. ACR/EULAR Classification Criteria for RA*22 |
Classification criteria |
Score |
- Joint involvement
- 1 large joint
- 2-10 large joints
- 1-3 small jointsa
- 4-10 small jointsa
- > 10 joints (with ≥ 1 small joint)
|
0
1
2
3
5
|
- Serologyb
- Negative RF and negative ACPA
- Low-positive RF or low-positive ACPA
- High-positive RF or high-positive ACPA
|
0
2
3
|
- Acute-phase reactantsb
- Normal CPR and normal ESR
- Abnormal CPR or abnormal ESR
|
0
1
|
- Duration of symptoms (patient self-report)
|
0
1
|
*Add scores of categories A to D; a score of ≥ 6/10 is needed for classification of definite RA.
a With or without involvement of large joints.
b At least 1 test result is needed for classification.
Abbreviations: ACPA, anticitrullinated protein antibody; ACR, American College of Rheumatology; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; RF, rheumatoid factor. |
The primary goal in the treatment of RA is to improve quality of life by reducing pain and maintaining or improving functional abilities.17 Ideally, the goal of therapy is disease remission or low disease activity.21,24 Additional goals include slowing destructive joint damage and delaying disability.17 Treatment of RA includes both nonpharmacologic and pharmacologic therapies. An emphasis is placed on aggressive treatment in early RA.17,24,25
Treatment Recommendations
A nonpharmacologic treatment plan includes rest, occupational or physical therapy, weight loss, and/or surgery.17 Engaging in these lifestyle modifications will aid in relieving stress on inflamed joints, decrease pain, and increase or maintain mobility. Surgery, which includes tendon repair or joint replacement, is reserved for patients with severe disease.
The primary medication classes used in the treatment of RA include: NSAIDs, corticosteroids, synthetic disease-modifying anti-rheumatic drugs (DMARDs), Janus kinase (JAK) inhibitors and biologic DMARDs, which include tumor necrosis factor (TNF)-α inhibitors, interleukin-6 inhibitors and other non-TNF agents.17,24-26 Table 6 provides a summary of agents used in the treatment of RA, with a focus on synthetic and biologic DMARDs.17,18,24 Corticosteroids and NSAIDs are used for symptomatic relief but have no effect on disease progression.17 The ACR guidelines provide pharmacologic recommendations based on disease activity, stage of RA (early vs established), and degrees of prognosis.24,25 Generally, in patients with early RA (< 6 mo), with low or high disease activity and without features of poor prognosis, DMARD monotherapy is the standard of care. Combination therapy (double or triple) is recommended for patients with any degree of disease activity and the presence of poor prognostic factors. Initially, DMARD monotherapy is the treatment of choice in patients with established RA (≥ 6 mo). However, as a result of disease progression or adverse effects, patients will often require a change in therapy from 1 DMARD to another or to a biologic agent or addition of agents. The ACR provides specific recommendations for switching drug regimens. It is also recommended that all patients are vaccinated against influenza, pneumococcal, hepatitis B, human papilloma, and herpes zoster; however, live-attenuated vaccinations are contraindicated in patients receiving biologics such as TNF inhibitors and non-TNF agents for RA (see Interactions section below).26
Table 6. Common Agents Used for the Treatment of RA14,15,17,26 |
Drug |
Usual dosage |
Comments/dosing adjustments |
DMARDS |
Methotrexate, oral (Trexall, Xatmep, generic) |
7.5-25 mg orally once weekly |
- Use with caution and dose adjust in patients with moderate renal dysfunction
- Not recommended in patients with severe renal dysfunction (CrCl < 10 mL/min)
- May be given with folic acid 1-5 mg weekly to reduce adverse reactions
|
Methotrexate, injectable (Otrexup, Rasuvo, generic) |
7.5-25 mg IM or SC once weekly |
Hydroxychloroquine (Plaquenil) |
200-400 mg orally daily |
- Use with caution in renal and hepatic impairment
|
Sulfasalazine
(Azulfidine, Azulfidine EN-tabs, generic) |
2 g orally in divided doses |
- Use extreme caution for patients with renal or hepatic impairment
|
Leflunomide
(Arava, generic) |
10-20 mg orally daily |
- Loading dose of 100 mg daily for 3 days is recommended to reduce GI effects
- Not recommended in liver disease (ALT > 2 x ULN)
|
Biologic agents – TNF-α inhibitors |
Adalimumab
(Humira) |
40 mg SC every 1-2 wks |
- Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red, or hard
- No information regarding dosing in renal or hepatic impairment
|
Certolizumab pegol
(Cimzia) |
400 mg SC at 0, 2, and 4 wks; then 200 mg every other wk or 400 mg every 4 wks |
- The 400 mg dose is given as 2 SC injections of 200 mg
- Data are lacking to provide dosing recommendations in patients with moderate and severe renal impairment
|
Etanercept
(Enbrel) |
25 mg SC twice weekly or 50 mg SC once weekly |
- Use caution in patients with moderate-to-severe alcoholic hepatitis
|
Golimumab
(Simponi, Simponi Aria) |
50 mg SC once monthly
2 mg/kg IV at 0 and 4 wks; then every 8 wks |
- No information regarding dosing in renal or hepatic impairment
|
Infliximab, infliximab-dyyb, infliximab-abda
(Remicade, Inflectra [biosimilar], Renflexis [biosimilar]) |
3 mg/kg IV at 0, 2, and 6 wks; then every 8 wks |
- Only approved for use in combination with methotrexate
- Antihistamines, acetaminophen and/or corticosteroids may be administered as premedications to manage infusion-related reactions
|
Biologic agents – Non-TNF inhibitors |
Abatacept
(Orencia) |
500, 750, or 1000 mg IV at 0, 2, and 4 wks; then every 4 wks IV |
- IV dose is dependent upon weight:
- < 60 kg = 500 mg
- 60-100 kg = 750 mg
- > 100 kg = 1000 mg
|
125 mg once weekly SC |
- SC dose may be initiated with or without an IV loading dose (see above for dosing)
- If initiating with an IV loading dose, administer 125 mg SC within 24 h of the IV infusion, followed by 125 mg SC once weekly thereafter
|
Anakinra
(Kineret) |
100 mg SC once daily |
- Consider administering the dose every other day for patients who have severe renal insufficiency or end-stage renal disease (CrCl < 30 mL/min)
|
Rituximab
(Rituxan) |
1000 mg IV followed by a second 1000 mg IV dose 2 wks later
Subsequent doses to be given no sooner than 16 wks |
- Only approved for use in combination with methotrexate in patients with an inadequate response to at least 1 TNF-α antagonist
- Methylprednisolone 50-100 mg IV infused over 30 min is recommended before administration to reduce the incidence and severity of infusion reactions
|
Interleukin-6 inhibitors |
Sarilumab
(Kevzara) |
200 mg SC every 2 wks |
- Not recommended in patients with active hepatic disease or hepatic impairment
- Dose adjustment or discontinuation is recommended for elevated LFTs, neutropenia, and thrombocytopenia
|
Tocilizumab
(Actemra) |
4-8 mg/kg IV every 4 wks |
- Reduction of dose from 8 to 4 mg/kg, dose interruption, or discontinuation is recommended in the settings of elevated LFTs, neutropenia, and thrombocytopenia
- Not recommended in patients with active hepatic disease or hepatic impairment
|
162 mcg SC every wk or every other wk |
- Administer every other wk or every wk depending on clinical response in patients weighing less than 100 kg; administer every wk in patients weighing 100 kg or more
- Administration modification necessary with elevated LFTs, neutropenia, and thrombocytopenia
- Not recommended in patients with active hepatic disease or hepatic impairment
|
JAK inhibitors |
Baricitinib (Olumiant) |
2 mg orally once daily |
- Not recommended in patients with severe hepatic impairment or estimated GFR < 60 mL/min/1.73 m2
- Determine hemoglobin, ANC, and ALC prior to initiating therapy
- Dose interruption recommended in patients who develop anemia, lymphopenia, neutropenia, or infection
|
Tofacitinib (Xeljanz, Xeljanz XR) |
5 mg orally twice daily (immediate release)
11 mg orally once daily (extended release) |
- Dose reduction of immediate-release product in patients with moderate-to-severe renal impairment or moderate hepatic impairment (avoid use of extended-release product)
- Avoid use in patients with severe hepatic impairment
- Dose interruption or discontinuation recommended in patients who develop anemia, lymphopenia, neutropenia, or infection
- Use of higher dose (10 mg twice daily) for RA has been associated with increased risk of PE and death
|
Abbreviations: ALC, absolute lymphocyte count; ALT, alanine aminotransferase; ANC, absolute neutrophil count; CrCl, creatinine clearance; CYP, cytochrome P450; DMARDs, disease-modifying anti-rheumatic drugs; EN, enteric-coated; GFR, glomerular filtration rate; GI, gastrointestinal; IM, intramuscular; IV, intravenous; JAK, Janus kinase; LFTs, liver function tests; PE, pulmonary embolism; RA, rheumatoid arthritis; SC, subcutaneous; TNF, tumor necrosis factor; ULN, upper limit of normal. |
Monitoring Parameters
Table 7 provides a summary of both common and serious adverse effects, as well as monitoring parameters for the agents used in the treatment of RA.14,15,17,26 Of the medications used in the treatment of RA, methotrexate is associated with the most drug interactions.14,15 Drugs that interfere with folate metabolism, such as trimethoprim/sulfamethoxazole, may increase bone marrow suppression caused by methotrexate.15 A decrease in the renal clearance of methotrexate, which may increase toxicity, is the result of concomitant therapy with probenecid and NSAIDs; however, clinically methotrexate and NSAIDs have been used together without adverse effects. A 20% reduction in digoxin concentration may occur with concurrent administration of sulfasalazine and digoxin. Dual therapy with 2 TNF-α inhibitors should be avoided due to an increased risk of serious infections. Iron supplements may reduce the absorption of sulfasalazine.17 Additionally, sulfasalazine may potentiate the effect of warfarin or cause warfarin resistance.14,15,17 Drug-herbal interactions have been reported for some of the agents. Echinacea increases the therapeutic effects of immunosuppressants and the combination should be avoided.14 Tocilizumab and sarilumab may reduce concentrations of cytochrome (CYP) 3A4 substrates (eg, combined oral hormonal contraceptives).14,15,17 Additionally, monitor patients taking tocilizumab and sarilumab with drugs with a narrow therapeutic index (eg,warfarin).
Although it is recommended that patients should be administered needed immunizations after starting therapy with a DMARD or a biologic agent, live vaccinations should be avoided after starting biologic agents.17 Such vaccines include herpes zoster (Zostavax), MMR (measles, mumps, rubella), varicella, and intranasal influenza.27 If live-attenuated vaccines are necessary in patients with RA, it is recommended that they are given at least 3 months after immunosuppressants.14
Table 7. Monitoring Parameters for Common Medications Used in the Treatment of RA14,15,17,26 |
Drug |
Adverse drug reactions |
Monitoring parameters |
Comments |
DMARDs |
Methotrexate |
- Common: nausea, diarrhea, vomiting, stomatitis/mouth ulcers, alopecia, fatigue, photosensitivity
- Serious: hepatotoxicity, myelosuppression, infection, interstitial pneumonitis
|
- Initial: CBC, LFTs, viral hepatitis panel, chest x-ray, pregnancy testing
- Routine: CBC, creatinine/BUN, LFTs
|
- Boxed warning:
- Deaths have occurred with the use of methotrexate in malignancy, psoriasis, and RA
- Bone marrow suppression may occur and result in anemia, leukopenia, or thrombocytopenia
- Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis after prolonged use
- Methotrexate-induced lung disease is a potentially dangerous lesion that may acutely occur at any time
- Caution if using methotrexate in patients with impaired renal function
- Diarrhea and ulcerative stomatitis require interruption of therapy
- Hemorrhagic enteritis and death may occur from intestinal perforation
- Use only preservative-free formulations and diluents for intrathecal use
- Severe and fatal skin reactions have occurred with methotrexate
- Potentially fatal opportunistic infections have occurred
- Methotrexate has reportedly caused fetal death and congenital anomalies
- Malignant lymphomas have occurred with low-dose methotrexate and may regress after stopping methotrexate
|
Hydroxychloroquine |
- Common: nausea, diarrhea, headache, rash
- Serious: irreversible retinal damage, cardiotoxicity, blood dyscrasia
|
- Initial: eye examination, CBC
- Routine: CBC and ocular screening
|
|
Sulfasalazine |
- Common: nausea, diarrhea, vomiting, anorexia, headache, rash, oligospermia
- Serious: granulocytopenia, hemolytic anemia (with G6PD deficiency)
|
- Initial: CBC, LFT, serum creatinine/BUN, G6PD level
- Routine: CBC, LFT, serum creatinine/BUN
|
|
Leflunomide |
- Common: alopecia, diarrhea, nausea, headache, rash
- Serious: hepatotoxicity, myelosuppression, infection
|
- Initial: pregnancy test, CBC, LFTs, viral hepatitis panel*
- Routine: CBC, creatinine, LFTs
|
- Boxed warning:
- Severe liver injury, including fatal liver failure, has been reported
- Contraindicated in pregnancy due to potential for fetal harm.
|
Biologic agents |
TNF-α inhibitors |
Adalimumab |
- Common: injection site reactions, upper RTI
- Serious: increase risk of bacterial/fungal infections, reactivation of latent TB, increase risk of lymphoma, drug-induced lupus-like syndrome, demyelinating conditions
|
- Initial: PPD skin test, viral hepatitis panel*
- Routine: injection site reactions
|
- Boxed warning:
- Patients are at increased risk of developing serious infections that may lead to hospitalization or death
- Lymphoma and other malignancies, some fatal, have been reported in children and adolescents treated with TNF-α blockers
|
Certolizumab pegol |
Etanercept |
Golimumab |
Infliximab |
- Common: infusion reactions, increased LFTs, nausea, diarrhea, headache, abdominal pain, upper RTI
- Serious: increase risk of bacterial/fungal infections, reactivation of latent TB, increase risk of lymphoma, drug-induced lupus-like syndrome, demyelinating conditions
|
- Initial: PPD skin test, viral hepatitis panel*
- Routine: LFTs, CBC
|
Non-TNF inhibitors |
Abatacept |
- Common: headache, upper RTI, nausea
- Serious: increase risk of bacterial/viral infections
|
- Initial: PPD skin test, viral hepatitis panel*
- Routine: infusion reactions
|
|
Anakinra |
- Common: headache, injection site reaction, vomiting, fever
- Serious: increase risk of bacterial/viral infections, reactivation of latent TB, neutropenia
|
- Initial: PPD skin test, CBC with differential
- Routine: CBC
|
Rituximab |
- Common: rash, fever
- Serious: increase risk of bacterial/viral infections, infusion reactions, cytopenia, hepatitis B reactivation
|
- Initial: CBC, viral hepatitis panel*
- Routine: CBC, creatinine/BUN
|
- Boxed warning:
- Administration can result in serious, or fatal, infusion reactions
- Severe, including fatal, mucocutaneous reactions can occur
- HBV reactivation can occur in patients treated with rituximab, in some cases resulting in fulminant hepatitis, hepatic failure, and death
- John Cunningham virus infection can cause progressive multifocal leukoencephalopathy and death
|
Interleukin (IL-6) inhibitors |
Sarilumab |
- Common: elevated ALT and AST
- Serious: risk of infection, neutropenia, infusion reactions, dyslipidemia
|
- Initial: PPD skin test, viral hepatitis panel*
- Routine: CBC, lipids, and LFTs
|
- Boxed warning: patients are at an increased risk for developing serious infections that may lead to hospitalization or death
|
Tocilizumab |
- Common: elevated serum cholesterol (in combination therapy), elevated ALT, AST, injection site reaction
- Serious: risk of infection, infusion reactions, LFT elevation, dyslipidemia, cytopenias
|
- Initial: PPD skin test, viral hepatitis panel*
- Routine: CBC, LFTs, lipids
|
- Boxed warning: patients are at an increased risk for developing serious infections that may lead to hospitalization or death
|
JAK inhibitors |
Baricitinib |
- Common: URT infections and nausea
- Serious: risk of infection, thromboembolic events, GI perforations, cytopenias, dyslipidemia, and elevated LFTs
|
- Initial: PPD skin test, CBC, LFTs, viral hepatitis panel*
- Routine: CBC, LFTs, lipids, creatinine/BUN, skin cancer screening
|
- Boxed warning:
- Patients are at increased risk of developing serious infections that may lead to hospitalization or death
- Lymphoma and other malignancies have been reported in patients taking baricitinib
- Thrombosis, including DVT, PE, and arterial thrombosis has been observed with baricitinib
|
Tofacitinib |
- Common: respiratory infections, nasopharyngitis, diarrhea, headache
- Serious: risk of infection, GI perforations, LFT elevation, dyslipidemia, cytopenias
|
- Initial: PPD skin test, LFTs, CBC, viral hepatitis panel*
- Routine: CBC, LFTs, creatinine/BUN, skin cancer screening, and lipids
|
- Boxed warning:
- Patients are at increased risk of developing serious infections that may lead to hospitalization or death
- Lymphoma and other malignancies, some fatal, have been reported in patients taking tofacitinib
|
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; DMARDs, disease-modifying anti-rheumatic drugs; DVT, deep vein thrombosis; G6PD, glucose-6-phosphate dehydrogenase; GI, gastrointestinal; HBV, hepatitis B virus; JAK, Janus kinase; LFT(s), liver function test(s); PE, pulmonary embolism; PPD, purified peptide derivative; RA, rheumatoid arthritis; RTI, respiratory tract infection; TB, tuberculosis; TNF, tissue necrosis factor. |
Patient Case #2:
Chief complaint:
“I ache all over, I feel exhausted, and I am having a hard time getting going in the morning.”
SP is a 33-year-old female who presents to her rheumatologist with generalized arthralgias, fatigue, and morning stiffness. She presented with similar symptoms 3 months ago, at which time she was started on a regimen of methotrexate and prednisone. She reports slight improvement in her symptoms relative to her visit 3 months ago.
Personal medical history:
Rheumatoid arthritis x 3 months
Family history:
Father is alive and is being treated for hypertension and hypercholesterolemia. Mother is alive and suffers with severe RA and osteoporosis. Two siblings with no health issues.
Social history:
Executive secretary. Married for 3 years; wants to start a family within the next year. Denies tobacco use. Drinks 1 to 2 glasses of wine per week.
Allergies:
None
Medications:
Prednisone 5 mg orally daily
Methotrexate 15 mg orally once weekly (2.5 mg x 6 tablets)
Folic acid 1 mg orally daily
Review of systems:
Eighteen tender joints and 16 swollen joints bilaterally; decreased range of motion, in hands and wrists; morning stiffness every day for about 2 hours; fatigue experienced daily during afternoon hours; swelling in hands, knees, and feet; denies HA, chest pain, SOB, bleeding episodes, or syncopal attacks; denies nausea, vomiting, diarrhea, loss of appetite, or weight loss.
Physical examination:
Caucasian woman in moderate distress because of pain, swelling, and fatigue related to arthritis
VS: BP 118/76, P 82, RR 14, T 37; Wt 65 kg, Ht 5′6″
Na 135 mEq/L |
Glu 103 mg/dL |
AST 15 u/L |
Fasting lipid profile |
K 4.2 mEq/L |
Hbg 10.8 g/dL |
ALT 12 u/L |
TC 186 mg/dL |
Cl 101 mEq/L |
Hct 31% |
Alk phos 56 u/L |
LDL 106 mg/dL |
CO2 22 mEq/L |
WBC 13x103/mm3 |
T. billi 0.8 mg/dL |
HDL 50 mg/dL |
BUN 12 mg/dL |
Plt 356x103/mm3 |
ESR 55 mm/h |
TG 150 mg/dL |
SCr 0.8 mg/dL |
Ca 9.1 mg/dL |
RF(+1) 1:1280 |
|
Assessment:
A 33-year-old woman in moderate distress with RA not adequately controlled with current therapy. Disease Activity Score exhibits high disease activity although patient reports slight improvement in symptoms over 3 months ago. Patient is adherent with current medication regimen. Patient expresses desire to start a family within the next year.
List SP’s drug therapy problems.
- Prednisone is not helping to treat SP’s symptoms
- The dose of methotrexate may be increased up to 25 mg weekly
- Methotrexate is contraindicated in pregnancy and should not be used in women of child bearing age
- Methotrexate may be contributing to SP’s fatigue
What are the goals of pharmacotherapy for SP?
The goals of therapy for SP are:
- Reduce pain
- Maintain or improve functional abilities
- Improve quality of life
- Lower disease activity and induce disease remission
What nonpharmacologic modalities may be beneficial for SP?
- SP may benefit from physical/occupational therapy
What recommendations should be made regarding therapy for SP?
- SP has a poor response to therapy with methotrexate. Additionally, this is not an appropriate agent, as it is contraindicated in pregnancy. Prednisone is not helping to relieve the pain.
The following should be recommended:
- Discontinue prednisone and methotrexate
- Initiate sulfasalazine 0.5 to 1 gram daily; increase the dose weekly to a maintenance dose of 1 gram twice daily
- Initiate a TNF-α inhibitor (adalimumab, certolizumab, etanercept, or golimumab). Choice of agent should be based on cost
- Discontinue folic acid and initiate a prenatal vitamin once daily
- Ensure adequate intake of elemental calcium and vitamin D
OSTEOARTHRITIS
Overview
Osteoarthritis (OA) is the most common type of arthritis in the United States and a leading cause of disability in the elderly.28-30
OA is estimated to affect over 30 million people in the United States.31 The incidence is on the rise due to increasing rates of obesity and longer life expectancy.30 The prevalence of OA increases with age (> 60 years), is higher in females, and prevalence varies by race and ethnicity.28-31 The causes of OA are complex and multifactorial.28 Age, gender, joint trauma, previous joint injury or surgery, occupation, obesity, genetic predisposition, and muscle weakness are common risk factors.28,30 An improper balance between cartilage formation and destruction leads to loss of cartilage in the joint(s) and damage to the underlying bone. The knees are most commonly affected, as well as the hands (thumb and fingers) and hips.
Frequently, patients with OA present with pain in the affected joint.30 Patients may also experience stiffness that is prevalent in the morning and after periods of rest. Additional symptoms of pain are described as:28
- Deep and aching
- Joint pain increases with activity (eg, walking up and down stairs)
- Resolves with motion or occurs at rest
- Duration < 30 minutes
- Related to the weather
- Limited joint motion
- Joint instability (joints “giving way”)
- Difficulty with previous daily activities (eg, holding, gripping, or writing with a pen)
The diagnosis of OA is primarily based on symptoms and physical examination, but may also include laboratory blood tests and screening autoantibodies (to rule out other arthritis causes), and radiographic imaging.29,30 The ACR has established criteria for classification of OA of the hand, knee, and hip (Table 8).28,32
Table 8. Criteria for Diagnosis of OA of Primary Joints28,32 |
Hand |
Knee |
Hip |
Hand pain, aching, or stiffness |
Knee pain |
Hip pain |
AND |
AND |
AND |
Hard tissue enlargement of ≥ 2 joints |
Radiographic osteophytes |
≥ 2 of the following:
- ESR < 20 mm/h
- Radiographic femoral or acetabular osteophytes
- Radiographic joint space narrowing
|
AND |
AND |
|
< 3 swollen MCP joints |
≥ 1 of the following:
- age ≥ 50 years
- morning stiffness < 30 minutes
- crackling/popping sounds on motion
|
|
AND |
|
|
≥ 2 DIP joints with hard tissue enlargement |
|
|
OR |
|
|
Deformity in ≥ 2 select joints (DIP, PIP, and first CMC) |
|
|
Abbreviations: CMC, carpometacarpal; DIP, distal interphalangeal; ESR, erythrocyte sedimentation rate; MCP, metacarpophalangeal; PIP, proximal interphalangeal. |
As previously mentioned, OA is a leading cause of disability in the elderly.28 The prognosis of OA depends on the joint(s) affected; it is the leading cause of hip and knee replacements in the United States.28,33 Goals of therapy are to: decrease pain and stiffness, improve or maintain joint function, reduce disability, and increase quality of life.28,30,33
Treatment Recommendations
The treatment of OA relies heavily on nonpharmacologic therapy as it is simple and effective.28-30,33 It is the only treatment that delays disease progression and improves joint function.28 It is recommended that patients avoid painful activities.29,30 Additional interventions are summarized in Table 9.
Table 9. Nonpharmacologic Interventions for the Treatment of OA28,29,32,33 |
Conventional interventions |
Unconventional interventions |
- Exercise (aerobic and/or weight lifting)
- Weight loss (if overweight)
- Patient education
- Use of assistive devices (eg, cane or walker)
- Use of shoe insoles/orthotics (help align knees)
- Cold or hot packs
- Use of fitted knee braces
|
- Transcutaneous electrical nerve stimulation
- Pulsed electromagnetic fields
- Static magnets
- Acupuncture
- Spa therapy
- Yoga
|
Pharmacologic therapy is used in conjunction with nonpharmacologic therapy as an aid to pain and symptom relief.28-30 Agents for OA may be administered by the oral, topical, or intra-articular route. The ACR recommendations for drug therapy depend on the affected joint(s), prior success/failure with analgesics, and comorbid conditions.28,34 In general, the drug of choice for the initial treatment of OA is acetaminophen.28-30,35 However, acetaminophen often is not adequate for complete symptom control and so most patients require additional agents. NSAIDs are alternative first-line agents, specifically in patients in which acetaminophen is contraindicated or not effective. Topical NSAIDs (knee) or oral NSAIDs taken “as needed” are recommended to decrease adverse effects. GI effects are most common; approximately 30% to 40% of patients experience GI toxicity.29,35 If a patient is at high-risk for GI effects, a GI protective agent, such as a proton pump inhibitor, should be added.28-30,35 Patients may also benefit from a cyclooxygenase-2 (COX-2) inhibitor in place of an NSAID; however, COX-2 inhibitors should be prescribed with caution in patients at risk for cardiovascular events. Topical rather than oral NSAIDs are recommended in patients ≥ 75 years of age.28,34 Intra-articular corticosteroids, alone or in combination with NSAIDs or tramadol, may be used in patients unresponsive to NSAIDs alone. Alternative agents include opioid analgesics as needed, duloxetine, or intra-articular hyaluronates.28,29,35 Surgery is reserved for patients with functional disability and/or severe pain. A summary of NSAIDs, and other agents used in the management of OA, is provided in Tables 10 and 11,
Table 10. Some NSAIDs Used in the Treatment of OA14,28 |
Drug |
Usual dosage |
Comments/dosing adjustments |
Aspirin – plain, buffered, or EC (Bayer, Ecotrin, Bufferin) |
325-650 mg 4 times daily |
Doses of 3600 mg daily are needed for anti-inflammatory effects |
Celecoxib (Celebrex) |
100 mg twice daily or 200 mg daily |
COX-2 inhibitor |
Diclofenac IR (Cataflam) |
50 mg twice or 3 times daily |
|
Diclofenac XR (Voltaren-XR) |
100 mg daily |
|
Diflunisal (Dolobid) |
500-750 mg twice daily |
|
Etodolac (Lodine) |
400-500 mg twice daily |
|
Fenoprofen (Nalfon) |
400-600 mg 3-4 times daily |
|
Flurbiprofen (Ansaid) |
200-300 mg daily in 2-4 divided doses |
|
Ibuprofen (Motrin, Advil) |
1200-3200 mg daily in 3-4 divided doses |
Available as prescription and OTC |
Indomethacin (Indocin) |
Initiate 25 mg 2-3 times daily; titrate dose by 25-50 mg daily until pain controlled |
Maximum dose is 50 mg 3 times daily |
Indomethacin SR (Indocin SR) |
Initiate 75 mg daily; titrate to 75 mg twice daily if needed |
|
Ketoprofen (Orudis) |
50-75 mg 3-4 times daily |
|
Meclofenamate (Meclomen) |
50-100 mg 3-4 times daily |
|
Mefenamic acid (Ponstel) |
250 mg 4 times daily |
FDA-approved for 1 wk of therapy |
Meloxicam (Mobic) |
15 mg daily |
|
Nabumetone (Relafen) |
500-1000 mg 1-2 times daily |
|
Naproxen (Naprosyn) |
500 mg twice daily |
Available as prescription and OTC |
Naproxen sodium (Anaprox, Aleve) |
220-550 mg twice daily |
Naproxen sodium XR (Naprelan) |
375-750 mg twice daily |
|
Oxaprozin (Daypro) |
600-1200 mg daily |
|
Piroxicam (Feldene) |
20 mg daily |
|
Salsalate (Disalcid) |
500-1000 mg 2-3 times daily |
|
Abbreviations: COX, cyclooxygenase; EC, enteric-coated; FDA, US Food and Drug Administration; IR, immediate-release; NSAIDs, nonsteroidal anti-inflammatory drugs; OTC, over-the-counter; SR, sustained-release; XR, extended-release. |
Table 11. Commonly Used Agents for the Treatment of OA14,28 |
Drug |
Usual dosage |
Comments/dosing adjustments |
Oral analgesics |
Acetaminophen (Tylenol) |
325-650 mg every 4-6 h or 1 g 3-4 times daily |
- Avoid in patients with chronic alcohol intake or significant hepatic disease
- Contained in many OTC combination products
- Maximum daily dose is 4 g
|
Tramadol (Ultram) |
50-100 mg 3 times daily* |
- Maximum dose in patients with CrCl < 30 mL/min is 200 mg/d
|
Tramadol ER (Ultram ER) |
Titrate to 200-300 mg daily* |
- Avoid in patients with CrCl < 30 mL/min
|
Opiates (various) |
Usual dose varies by opiate prescribed |
- Titrate dose slowly in elderly patients
- For combination products, the maximum dose is limited by the total daily dose of acetaminophen
|
Topical analgesics |
Capsaicin (Capzasin-HP) |
Apply to affected joint 3-4 times daily |
|
Diclofenac 1% gel (Voltaren) |
Apply 2 or 4 g per site as prescribed, 4 times daily |
Diclofenac 1.3% patch (Flector) |
Apply 1 patch twice daily to the affected joint |
Diclofenac 1.5% solution |
Apply 40 drops to the affected knee; apply by rubbing in 10 drops at 1 time and repeat for a total of 4 times |
Diclofenac 2% solution (Pennsaid) |
Apply 40 mg (2 pump actuations) twice daily |
Intra-articular injections |
Corticosteroids |
Methylprednisolone acetate (Depo-Medrol) |
20-80 mg per large joint (knee, hip, shoulder) |
- 10-40 mg for medium joints (elbows, wrists)
|
Triamcinolone (Kenalog) |
10-40 mg per large joint (knee, hip, shoulder) |
- The maximum dose given at 1 visit (administered into 1 joint or separated among multiple joints) is 80 mg
- Often administered concomitantly with a local anesthetic
|
Triamcinolone (Zilretta) |
32 mg per joint |
- FDA-approved for OA of the knee only
|
Hyaluronic acid derivatives |
Durolane |
60 mg as a single injection |
|
Euflexxa |
20 mg once weekly for 3 wks |
|
Gel-One |
30 mg as a single injection |
- May inject a local anesthetic prior to administration
|
Gelsyn-3 |
16.8 mg once weekly for 3 wks |
|
GenVisc 850 |
25 mg once weekly for 5 wks |
- Some patients benefit with 3 injections given at weekly intervals
- May inject a local anesthetic prior to administration
|
Hyalgan |
20 mg once weekly for 5 wks |
- Some patients benefit with 3 injections given at weekly intervals
- May inject a local anesthetic prior to administration
|
Hymovis |
24 mg once weekly for 2 wks |
|
Monovisc |
88 mg as a single injection |
|
Orthovisc |
30 mg once weekly for 3-4 wks |
- Repeat courses may be administered if symptoms return
|
Supartz |
25 mg once weekly for 5 wks |
- Some patients benefit with 3 injections given at weekly intervals
- May inject a local anesthetic prior to administration
|
Synvisc |
16 mg once weekly for 3 wks |
|
Synvisc-One |
48 mg as a single injection |
|
Trivisc |
25 mg once weekly for 3 wks |
- May inject a local anesthetic prior to administration
|
Visco-3 |
25 mg once weekly for 3 wks |
|
*taper dose upon discontinuation to prevent withdrawal symptoms.
Abbreviations: CrCl, creatinine clearance; ER, extended-release; FDA, US Food and Drug Administration; OA, osteoarthritis; OTC, over-the-counter. |
Monitoring Parameters
Table 12 provides a summary of the adverse effects and monitoring parameters for the agents used in the treatment of OA.14,28 Clinically meaningful drug interactions are minimal with acetaminophen; however, some patients require close monitoring. The risk of hepatotoxicity is increased with the concurrent administration of isoniazid. Chronic administration of maximum acetaminophen doses (4 g daily) may intensify the anticoagulant effect in patients taking warfarin. Acetaminophen should be avoided in the setting of chronic alcoholic intake. Potentially serious drug interactions may occur when NSAIDs are administered with lithium, warfarin, or other agents that increase bleeding risk. The antihypertensive effects of angiotensin-converting enzyme inhibitors (ACE-I) and beta-blockers may be decreased when administered with NSAIDs. An increased risk of nephrotoxicity can occur when NSAIDs are coadministered with ACE-I or tacrolimus. Celecoxib is metabolized by CYP2C9. Therefore, use caution when administered with CYP2C9 enzyme inducers or inhibitors. Tramadol must be used cautiously with medications that lower the seizure threshold, such as tricyclic antidepressants, first-generation antipsychotics, and cyclobenzaprine. Concurrent administration of tramadol with serotonergic agents increases the risk of serotonin syndrome. Drug interactions with topical NSAIDs (diclofenac) are similar to that of systemic agents; however, the incidence is likely decreased due to the limited systemic absorption of topical NSAIDs. Additive central nervous system depression is potentiated when opioids are used concurrently with other central nervous system depressants.
Table 12. Monitoring Parameters for Common Medications Used in the Treatment of OA14,28 |
Drug |
Adverse drug reactions |
Monitoring parameters |
Comments |
Oral analgesics |
Acetaminophen |
Hepatotoxicity |
Total daily dose limits (4 g daily) |
|
Tramadol |
Nausea, vomiting, constipation, somnolence |
No routine labs recommended |
- Boxed warning:
- Risk of addiction, abuse, and misuse
- Serious, life-threatening, or fatal respiratory depression may occur
- Accidental ingestion may result in fatal overdose
- Prolonged use during pregnancy may result in neonatal opioid withdrawal syndrome
- Concomitant use of benzodiazepines and other CNS depressants may result in sedation, respiratory depression, coma, and death
- Cytochrome P450 interactions (select opioids)
- Ultrarapid metabolism and other risk factors for life-threatening respiratory depression in children (select opioids)
- Scheduled controlled substances
|
Opioids |
Sedation, constipation, nausea, vomiting, dry mouth, falls, and respiratory depression |
NSAIDs |
Dyspepsia, CV events, GI bleeding, renal impairment |
BUN/creatinine, Hgb/Hct, blood pressure |
- Boxed warning:
- May cause an increased risk of serious CV thrombotic events, myocardial infarction, and stroke, which can be fatal
- May cause an increased risk of serious GI events, including bleeding, ulceration, and perforation, which can be fatal
- Risks of adverse effects increase over 60 years of age
|
Topical analgesics |
Capsaicin |
Skin irritation, erythema, and burning |
Inspect all areas of application |
- Wash hands thoroughly after application
|
NSAIDs |
Skin itching, rash, irritation, dyspepsia, CV events, GI bleeding, renal impairment |
Inspect all areas of application as needed: BUN/creatinine, Hgb/Hct, blood pressure |
|
Intra-articular injections |
Corticosteroids |
Hypertension, hyperglycemia |
Glucose, blood pressure |
- Monitor HPA axis suppression if used too frequently
|
Hyaluronates |
Local joint swelling, stiffness, pain |
No routine labs recommended |
- Less effective than intra-articular corticosteroids
- Expensive
|
Abbreviations: BUN, blood urea nitrogen; CNS, central nervous system; CV, cardiovascular; GI, gastrointestinal; Hgb, hemoglobin; Hct, hematocrit; HPA, hypothalamic-pituitary-adrenal; NSAIDs, nonsteroidal anti-inflammatory drugs; OTC, over-the-counter. |
GOUT
Overview
Gout is an inflammatory arthritis caused by monosodium urate crystal deposits in the bone and joints as a result of excess uric acid in the blood.36,37 It is the most common inflammatory arthritis among men.38 The incidence and prevalence of gout are increasing. It is estimated that 8.3 million people suffer from gout in the United States.36
Uric acid in the body results from purine metabolism.36,39 Excess uric acid or hyperuricemia is the result of urate overproduction, urate underexcretion, or both. Some causes of uric acid overproduction include alcohol, purine-rich diet, or obesity while decreased uric acid excretion can occur with hypertension, renal insufficiency, or drugs such as salicylates, diuretics, or alcohol.37,40 The majority of patients with hyperuricemia will be asymptomatic, but patients with gout typically present with an acute episode of arthritis resulting from the formation of crystal salt deposits in the joints and soft tissues. There is a direct correlation between serum urate levels and gout; however, hyperuricemia does not have to be present during an acute gouty attack.
The diagnosis of gout is based on symptoms.36,39 Clinically, gout presents as a rapid onset of joint pain, erythema, and swelling. The majority of patients typically complain of symptoms in the first metatarsophalangeal joint at the base of the big toe; however, any lower extremity joint can be affected. Monosodium urate crystals will be present in synovial fluid or a tophus. The goals in the treatment of gout are to treat the acute attack, prevent future attacks, and lower serum urate levels (< 6 mg/dL), thereby preventing complications of chronic crystal deposits.36,39,41,42
Treatment Recommendations
Both the ACR and ACP have developed guidelines for the nonpharmacologic and pharmacologic management of hyperuricemia and the prevention and treatment of acute gouty attacks.37,41,42 Lifestyle recommendations outlined by the ACR are designed to promote health and minimize comorbidities (eg, type 2 diabetes, hypertension), which in turn will lower serum urate levels and decrease the risk of acute gouty attacks.41 The recommendations are summarized in Table 13.
Table 13. Nonpharmacologic Recommendations for Patients with Gout41 |
Intervention |
- Weight loss for obese patients
- Exercise
- Smoking cessation
- Stay well hydrated
- Avoid:
- Organ meats high in purine content (eg, liver, kidney)
- High fructose corn syrup sweetened sodas, beverages, or foods
- Alcohol overuse (> 2 daily servings for men and > 1 daily serving for women)
- Any alcohol use during periods of attack or advanced gout under poor control
- Limit:
- Servings sizes of beef, pork, lamb, and seafood with high purine content (eg, sardines, shellfish)
- Servings of naturally sweet fruit juices
- Table sugar and sweetened beverages and desserts
- Table salt
- Alcohol in all patients (particularly beer, but also wines and spirits)
- Encourage:
- Low-fat or non-fat dairy products
- Vegetables
|
Acute attacks can be successfully treated with anti-inflammatory agents, specifically, NSAIDs, colchicine, or corticosteroids.37,42 There is no evidence suggesting that 1 NSAID is preferred over another.37 Combination therapy of these agents may be necessary in patients with severe pain, multiple joints affected, or those unresponsive to monotherapy.36,42 Acute treatment should begin within 24 hours of the attack and continue for the duration of the attack. Although not FDA-approved for gout, the interleukin-1 inhibitors, canakinumab and anakinra, may be used in patients unable to take NSAIDs, colchicine, or corticosteroids.42
Once the pain associated with an acute attack has resolved, the focus of therapy shifts to the prevention of flares.36,39 Pharmacologic therapy, in addition to lifestyle modifications, is recommended for patients who experience ≥ 2 gout attacks per year.36,41,42 All patients with ≥ 1 tophus, chronic kidney disease (stage 2 or worse), and a history of urolithiasis should receive pharmacologic therapy as well. The ACR guidelines provide a step-wise approach for the treatment of gout.41 Xanthine oxidase inhibitors (allopurinol or febuxostat) are recommended first-line agents; probenecid is considered an alternative agent if at least 1 xanthine oxidase inhibitor is contraindicated or not tolerated. In refractory cases, combination therapy of a xanthine oxidase inhibitor and an agent that increases the renal clearance of uric acid (eg, probenecid, losartan, fenofibrate) can be tried. Pegloticase, an intravenous pegylated urate oxidase enzyme, is considered a third-line agent for highly symptomatic patients that have not responded to combination therapy as stated above. Prophylaxis with colchicine or an NSAID may be used to prevent an acute gout attack during the initiation of urate-lowering therapy. Table 14 provides a summary of select agents used in the treatment of gout.
Table 14. Selected Agents Used in the Treatment of Gout14,15,36 |
Drug |
Usual dosage |
Comments/dosing adjustments |
Anti-inflammatory drugs |
Colchicine
(Colcrys, generic) |
Acute: 1.2 mg orally, then 0.6 mg orally 1 h later
Prophylaxis*: 0.6 mg orally once or twice daily for 6 mo |
Adjust dose in patients with CrCl < 30 mL/min or in patients receiving dialysis |
NSAIDs
(various) |
Dosing based on specific agent |
|
Interleukin-1 inhibitors* |
Anakinra
(Kineret) |
100 mg SC daily for 3 days |
|
Canakinumab
(Ilaris) |
150 mg SC for 1 dose |
|
Urate-lowering drugs |
Xanthine oxidase inhibitors |
Allopurinol
(Zyloprim, generic) |
100-800 mg daily to achieve serum urate ≤ 6 mg/dL |
Initiate dose at 50 mg daily for patients with mild-to-moderate renal impairment; titrate to a maintenance dose > 300 mg daily |
Febuxostat
(Uloric) |
40-80 mg once daily |
No dosage adjustment in mild to moderate renal impairment; do not exceed 40 mg daily in several renal impairment (CrCl < 30 mL/min) |
Uricosurics |
Probenecid
(Probalan, generic) |
500-2000 mg daily with dosage adjusted to maintain normal serum urate levels |
Not recommended if CrCl ≤ 50 mL/min |
Other |
Pegloticase
(Krystexxa) |
8 mg IV every 2 wks |
Optimal treatment duration has not been established |
*not FDA-approved.
Abbreviations: CrCl, creatinine clearance; FDA, US Food and Drug Administration; IV, intravenous; SC, subcutaneous. |
Monitoring Parameters
Table 15 provides a summary of the adverse effects as well as monitoring parameters for select agents used in the treatment of gout.14,15,36 Refer to Table 12 for information regarding NSAIDs. Of the medications used in the management of gout, colchicine is associated with the most drug interactions. Table 16 summarizes clinically significant drug interactions. The combination of allopurinol with thiazide diuretics or ACE-I may increase the risk of hypersensitivity reactions. Concurrent use of allopurinol or febuxostat with didanosine is contraindicated due to the increased systemic exposure of didanosine. Salicylates are contraindicated in patients on probenecid because it antagonizes the uricosuric action of probenecid. Do not use pegloticase with other medications for gout due to enhanced toxic effects of pegloticase.
Table 15. Monitoring Parameters for Common Medications Used in the Treatment of Gout14,15,36 |
Drug |
Adverse drug reactions |
Monitoring parameters |
Comments |
Anti-inflammatory drugs |
Colchicine |
Dose-dependent GI effects (diarrhea, nausea, vomiting), rare myelosuppression, reversible neuromyopathy |
Therapeutic: resolution of pain, frequency of gout attacks (prophylaxis)
Toxic: GI symptoms, complete blood count |
|
Interleukin-1 inhibitors |
Anakinra, canakinumab |
Injection site reactions, neutropenia, immune hypersensitivity reaction, infections, malignancy |
Therapeutic: resolution of pain, frequency of gout attacks (prophylaxis)
Toxic: neutrophil count (prior to initiation, monthly for the first 3 mo, then after 6, 9, and 12 mo of therapy), signs and symptoms of infection |
|
Urate-lowering drugs |
Xanthine oxidase inhibitors |
Allopurinol |
Rash, serious hypersensitivity reactions |
Therapeutic: serum urate level, frequency of gout attacks
Toxic: rash, renal function |
|
Febuxostat |
Liver enzyme elevation, nausea, arthralgias, rash |
Therapeutic: serum urate level, reduced frequency of gout attacks
Toxic: LFTs, renal function |
· Boxed warning: increased risk of CV death in patients with established CV disease |
Uricosurics |
Probenecid |
Urolithiasis |
Therapeutic: serum urate level, frequency of gout attacks
Toxic: renal function |
- Useful in urate underexcretion
- Avoid in patients with a history of urolithiasis
|
Other |
Pegloticase |
Acute gout attack during treatment initiation, anaphylaxis, GI symptoms (constipation, nausea, vomiting), chest pain, nasopharyngitis |
Therapeutic: serum urate level, frequency of gout attacks
Toxic: signs/symptoms of anaphylaxis following infusion |
- Boxed warning: anaphylaxis and infusion reactions have been reported to occur during and after administration
- G6PD deficiency-associated hemolysis and methemoglobinemia
- Reserved for patients with gout refractory to conventional therapies
- Can be used in both urate overproduction and underexcretion
|
Abbreviations: CV, cardiovascular; G6PD, glucose-6-phosphate dehydrogenase; GI, gastrointestinal; LFT(s), liver function test(s). |
Table 16. Colchicine Drug interactions and Recommended Dosing Adjustments36 |
Drug |
Treatment of acute gout flares |
Prophylaxis of gout flares |
Strong CYP3A4 inhibitors:
- Atazanavir
- Clarithromycin
- Darunavir/ritonavir
- Indinavir
- Itraconazole
- Ketoconazole
- Lopinavir/ritonavir
- Nefazodone
- Nelfinavir
- Ritonavir
- Saquinavir
- Telithromycin
- Tipranavir/ritonavir
|
Single 0.6 mg oral dose followed by 0.3 mg orally 1 h later; dose to be repeated no earlier than 3 d |
0.3 mg orally once every other d to 0.3 mg once daily |
Moderate CYP3A4 inhibitors:
- Amprenavir
- Aprepitant
- Diltiazem
- Erythromycin
- Fluconazole
- Fosamprenavir
- Grapefruit juice
- Verapamil
|
Single 1.2 mg oral dose; dose to be repeated no earlier than 3 d |
0.3-0.6 mg orally daily (0.6 mg dose may be given as 0.3 mg twice daily) |
P-glycoprotein inhibitors:
|
Single 0.6 mg oral dose; dose to be repeated no earlier than 3 d |
0.3 mg orally once every other d to 0.3 mg orally once daily |
Abbreviation: CYP, cytochrome P450. |
Focus points for Medication Therapy Management (MTM) in Bone Disorders
Osteoporosis
- Goals of treatment are to prevent loss of BMD and prevent fractures
- All patients should maintain a bone-healthy lifestyle, including an adequate intake of calcium and vitamin D
- Calcium should be administered preferably with food, 2 hours before or after other medications
- Patients with low BMD will not experience symptoms of osteoporosis; therefore, they must be counseled on the importance of medication adherence
- First-line agents recommended by the AACE include alendronate, risedronate, zoledronic acid, or denosumab. The Endocrine Society guidelines recommend bisphosphonates as first-line therapy
- Due to the risk of GI effects, oral bisphosphonates should not be administered with food or medications. Dosing instructions state that bisphosphonates should be administered first thing in the morning on an empty stomach with 6 to 8 oz of plain (not mineral) water. After administration, the patient may not eat or drink (except water) and remain upright for at least 30 minutes (60 min with ibandronate)
- The optimal duration of therapy for osteoporosis agents has not been established
Rheumatoid Arthritis
- The initial goal of therapy is to reduce pain and improve quality of life; ideally treatment should prevent disease progression
- Lifestyle modifications, including rest, occupational/physical therapy, and weight loss can help to alleviate joint pain
- Corticosteroids and NSAIDs are used only for symptomatic relief
- Combination therapy with DMARDs and biologic agents may be warranted early in the disease
- Patients taking biologic therapies are at increased risk for developing serious infections; practice good hand hygiene to prevent infections
- All patients should be vaccinated against influenza, pneumococcal, hepatitis B, and herpes zoster
Osteoarthritis
- Goals of therapy are to decrease pain and stiffness, improve or maintain joint function, reduce disability, and increase quality of life
- Lifestyle modifications are crucial to delay disease progression and improve joint function
- The agent of choice for OA is acetaminophen
- Patients should be counseled that acetaminophen is found in many OTC combination products; the maximum dose is 4 g daily
- Patients taking NSAIDs should be counseled on GI toxicities. The addition of an acid suppression agent may be necessary in some patients
Gout
- Goals of therapy are to treat the pain of an acute attack, prevent future attacks, and lower serum urate levels
- Lifestyle and diet modifications to prevent comorbidities will decrease the risk of acute gouty attacks
- Anti-inflammatory agents, specifically, NSAIDs, colchicine, or corticosteroids, are the recommended agents for the treatment of an acute gouty attack
- Preventative pharmacologic therapy is indicated in patients that experience ≥ 2 acute gouty attacks per year
- Xanthine oxidase inhibitors (allopurinol or febuxostat) are recommended first-line agents for the prevention of acute gouty attacks
- Patients with hyperuricemia do not require treatment to lower serum urate levels, as the majority of patients will never experience a gout attack
- Colchicine is associated with numerous drug-drug interactions
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