characterization of diseases caused by the body’s immune system attacking its own tissues.
proteins that help to mediate the immune system. They are cell signaling proteins, which in the case of rheumatoid arthritis increase inflammation.
a painful joint condition caused by increased levels of uric acid.
a painful joint condition primarily found in older adult patients and characterized by decreased cartilage.
a bone condition with decreased bone density that leaves patients at increased risk for bone fractures.
Rheumatoid arthritis (RA)
a painful joint condition caused by autoimmune mechanisms that can lead to joint deformity and disability.
Systemic lupus erythematosus (SLE)
a systemic autoimmune condition that can lead to multiple organ system failure.
a natural byproduct the body produces from metabolism of purines. It has no known physiologic function.
After completing this chapter, you should be able to
Recognize the cause of gouty arthritis and list the therapies to prevent an attack.
Describe prescription and supplemental therapies for osteoporosis.
Calculate the amount of elemental calcium in a calcium supplement.
Describe prescription and supplemental therapies for osteoarthritis.
Recognize common regimens for rheumatoid arthritis and their adverse effects.
Recognize common symptoms of and organs affected by systemic lupus erythematosus.
State the brand and generic names of widely used medications for musculoskeletal conditions, along with their routes of administrations and dosage forms available.
As we learned in Chapter 12, the musculoskeletal system is a complex set of moving parts. Disorders of this system can make movement difficult and result in acute or chronic pain for the patients affected. Gout, arthritis, and osteoporosis are widespread conditions, and, while less common, autoimmune disorders such as lupus can be life threatening. In this chapter, we will discuss the causes of and treatments for several musculoskeletal disorders.
Mr. Bob is a 58-year-old male who currently is not overweight but does report joint pain in his knees and hips to his pharmacist. He does not drink alcohol on a regular basis.
High levels of uric acid are directly correlated with gouty arthritis. Uric acid is considered an unusable byproduct of degraded purines. Purines are chemicals that can come from dietary sources or be made by the body as building blocks for nucleotides. High levels of uric acid are attributed to either the overproduction or underexcretion of uric acid. When the uric acid level becomes too high, it causes uric acid crystals to form in the joints and other organs, such as the kidney, and under the skin. These crystals cause inflammation in the joints, which leads to a gouty attack (also referred to as “gout flare”).
The primary symptoms of a gouty attack include joint pain and swelling, which often presents in the great toe. Other joints that can be affected include the instep of the foot, ankles, heels, knees, wrists, fingers, and elbows. High uric acid levels may precipitate in the kidneys, causing renal stones, and under the skin, forming nodules called a tophus (plural = tophi). The incidence of gout increases with age, male gender, high blood pressure, increased body weight, and increased alcohol consumption (Figure 13-1).
Mr. Bob visits his physician for his yearly physical and receives a blood test that shows his uric acid is high. Would you expect him to need a prescription for this?
High levels of uric acid do not always lead to the occurrence of gout and should only be treated when there is an acute attack or to prevent recurrent attacks. While gouty arthritis attacks resolve spontaneously within a few weeks, medications are often used to speed the resolution. Some patients may be candidates for prophylactic medications to prevent attacks depending on certain factors, including frequency of gouty attacks or if the attacks are very severe. Medications for gout can be divided into two groups: medications used to speed the resolution of an acute attack and medications used to prevent future attacks. See Medication Table 13-1 for details on doses and dosage forms of antigout medications. (Medication Tables are located at the end of the chapter.)
Mr. Bob comes to the pharmacy to ask for the strongest pain reliever he can get without a prescription because he developed a terrible pain in his big toe 3 days ago and it has still not gone away. He mentions that his doctor had told him he had a high uric acid level. What do you expect the pharmacist might recommend?
Medications to Stop an Acute Attack
Colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or corticosteroids are appropriate therapies for an acute gouty attack. Short courses of high-dose NSAIDs are the most frequently used treatment for an acute attack of gout. Treatment is usually prescribed for 1 to 2 weeks and is usually most effective when started soon after the onset of symptoms. Gastrointestinal (GI) side effects are the most common problems encountered with NSAIDs, including serious GI bleeding, ulceration, and perforation. They should be avoided in patients with renal failure as they can worsen this condition. In patients with heart failure, salt and water retention from NSAIDs may lead to worsening of this condition. NSAIDs can also increase the risk of serious and possibly fatal cardiovascular thrombotic events.
Colchicine reduces the body’s inflammatory reaction to uric acid crystals, which decreases inflammation and pain. However, colchicine is not an analgesic. It can be very effective if initiated early after the onset of symptoms. Dose-related GI toxicity (nausea, vomiting, and diarrhea) are common. For an acute gouty attack, patients are directed to take two tablets (0.6 mg) at the first sign of a gout flare, followed by 0.6 mg 1 hour later (max 1.8 mg per total dose/course). For some patients, colchicine can also be used to prevent future acute attacks with a dose of 0.6 mg once or twice daily. Some patients may need a dose adjustment depending on renal function and/or drug-drug interactions.
Short treatment courses of corticosteroids are also useful to treat acute gout. They are preferred drugs for patients with contraindications to NSAIDs and colchicine (eg, renal failure) or when patients are unresponsive to these drugs. Dosing regimens vary, but most patients are treated initially with prednisone 20–60 mg daily and the dose is then tapered over 1 to 2 weeks. Injectable triamcinolone acetonide may also be administered directly into an inflamed joint or by intramuscular (IM) injection if the oral route is not desired or multiple joints are affected.
Mr. Bob took the pharmacist’s advice and got in touch with his physician, and returns with two prescriptions, one for enough ibuprofen 800 mg tablets to last 2 weeks and one for colchicine 0.6 mg tablets. There are no refills ordered for the ibuprofen, but for colchicine there is a 90-day supply with three refills. Why do you think the prescriptions were written this way?
Medications to Prevent Acute Attacks
Although colchicine alone may be effective for prophylaxis given chronically in low doses, it does not lower uric acid levels in the blood. Lowering uric acid is warranted in some patients, for example, patients who form renal stones or develop tophi. Many of the pharmacologic therapies to prevent attacks either work to increase the excretion or decrease the production of uric acid.
Probenecid is a uricosuric agent, meaning it prevents the kidneys from reabsorbing uric acid and thus increases its excretion. This decreases uric acid levels in the blood, which prevents the formation of uric acid crystals in joints. Probenecid is slowly titrated to a therapeutic dose (see Medication Table 13-1). Common adverse events associated with uricosuric agents include nausea, rash, occurrence of an acute gouty attack, and formation of uric acid stones. Probenecid should be avoided in patients with poor renal function and in those with a history of renal stones. Probenecid is not effective in patients who have high uric acid levels due to overproduction. Patients who are overproducers of uric acid should receive a medication to block the formation of uric acid.
Allopurinol, which decreases the blood uric acid level by preventing its formation, is used to prevent gout attacks. A very rare but serious rash can occur with allopurinol and any signs of rash should be reported to the patient’s physician as soon as possible. Allopurinol, if used alone, may actually induce an acute gout attack when therapy is initiated. That is the reason medications to minimize gout attack, such as colchicine, are usually given concurrently with the allopurinol when it is started. This helps prevent gout attacks while uric acid levels are being adjusted. Colchicine may be discontinued 3 months after patients achieve their target uric acid level in the blood if they do not have tophi. In a patient with tophi, colchicine is typically continued for 6 months after the patient achieves the target uric acid level in the blood. A lower dose of allopurinol and colchicine may be prescribed for patients with poor renal function.
Febuxostat is also used to prevent uric acid formation and decrease uric acid levels in the blood. It can be taken by some patients who develop side effects to allopurinol or those with an inadequate response to allopurinol. The recommended dose is 40–80 mg once daily. As with allopurinol, the maximum dose of febuxostat is decreased in patients with poor renal function. Febuxostat has been associated with an increased risk of cardiovascular-related deaths in patients with a history of cardiovascular disease compared with allopurinol.
Alcohol can exacerbate a gouty attack. Patients with gout should be encouraged to minimize or abstain from alcohol.
Some patients suffer from chronic gout and do not respond to any of the therapies listed above; they are said to have treatment-resistant gout. There is an injectable enzyme preparation, pegloticase, which can be used in their care. Pegloticase reduces serum uric acid by promoting a chemical reaction that changes it to allantoin, a metabolite that is excreted by the kidney. Use of pegloticase is limited by the fact that it must be administered intravenously every 2 weeks and it has been associated with severe and potentially fatal reactions, such as anaphylaxis and congestive heart failure. It has also been associated with infusion reactions and blood disorders such as hemolysis, a breakdown of red blood cells in certain patients. It is, thus, reserved for patients whose gout is severe and cannot be treated otherwise. It is not used to reduce uric acid levels in patients without symptoms.
Pegloticase is administered intravenously over at least 2 hours and only in a healthcare setting by healthcare providers who are prepared to manage severe reactions.
Pegloticase infusions are prepared by diluting the dose in 250 mL of 0.9% or 0.45% sodium chloride injection, and no other drug or solution may be added to the admixture. This infusion is stable for 4 hours and should be protected from light. Pegloticase preparations may be gently inverted, but should never be shaken.
Bones are constantly being remodeled by osteoclasts and osteoblasts. Osteoclasts are cells that resorb the bone and osteoblasts rebuild the bone. Osteoporosis is the consequence of decreased bone density that occurs when the osteoclasts are more effective than the osteoblasts; over time, more bone is removed than rebuilt. In osteoporosis bone density is declining. This leaves bones frail, brittle, and easily broken.
Osteoporosis is a health threat that puts older adult patients at a much higher risk for fractures after a fall. Fractures can be very painful and debilitating. It is not uncommon for a patient to spend time at a rehabilitation facility after a hip fracture, and many patients never regain their baseline level of function. Mortality is increased for patients who have hip fractures. Women are at risk, particularly postmenopause, but osteoporosis also occurs in males. Vitamin D deficiency, cigarette smoking, low calcium intake, low physical activity, and corticosteroid therapy all increase the risk for osteoporosis.
Osteoporosis is a silent disease as patients do not feel the decrease in their bone density unless a fracture occurs. Osteoporosis is diagnosed through a bone density test. The test used to measure bone density is a dual energy x-ray absorptiometry (DXA). It uses x-rays to take images of the thickness of the bones in specific areas, which are then interpreted as T-scores. A T-score assesses bone density, comparing a patient’s bone density to that of a young healthy sex-matched reference value. As people age, their bone density and T-scores decrease. A diagnosis of osteoporosis is usually made following a low-impact fracture or when the T-score is less than 2.5 but other circumstances in special populations may also meet the definition of osteoporosis. Treatment of osteoporosis includes nondrug and drug therapy. Lifestyle changes include a healthy diet, limiting alcohol intake, stopping smoking, weight-bearing exercise, and prevention of falls.
Mrs. Roberts is a 75-year-old woman who has never been treated for osteoporosis. She is of normal weight and has a history of smoking. She does not monitor her dairy intake and tries to walk daily for exercise when the weather is nice. She has never had her bone density measured but is wondering if she should ask her doctor about it since she has heard that women her age are at risk for osteoporosis.
Osteomalacia is another silent bone disease resulting from improper mineralization of the bones. In children this is called rickets. Osteomalacia occurs when a patient has deficiencies of calcium, phosphorus, or vitamin D. Treatment for osteomalacia varies based on the underlying cause. For some patients, vitamin D supplementation is appropriate while others may require the help of a specialist.
Proper calcium supplementation is crucial to maintaining healthy bones. Appropriate levels of calcium help to prevent osteoclasts from over-resorbing bone. Women over the age of 50 years and men over the age of 70 years are advised to take 1,200 mg of elemental calcium daily. Calcium from dietary sources is preferred but supplementation can be used if needed. When a patient asks which calcium to choose it is important to take the salt form of the calcium into account. Different forms of calcium have different percentages of elemental calcium, which is the amount available for absorption (Table 13-1). The amount of elemental calcium found in a supplement will often be included in the Supplemental Facts Panel of a product.
Percent Elemental Calcium in Various Calcium Salts
Mrs. Roberts chooses a Citracal product. How much elemental calcium is in one Citracal tablet containing 500 mg of calcium citrate?
A calcium supplement with 500 mg of calcium carbonate delivers 200 mg of elemental calcium, while one with 500 mg of calcium gluconate would deliver only 45 mg. That is why calcium supplements cannot be interchanged “milligram for milligram” unless they contain the same calcium salt.
Calcium from food should also be considered when choosing an appropriate amount of calcium supplementation. As a general rule, a serving of dairy (eg, milk, yogurt, cheese) can be considered 300 mg of elemental calcium. Calcium supplements may cause upset stomach and can be taken with food to minimize nausea. Constipation can also be a problem for some patients taking calcium supplements.
Vitamin D must also be supplemented to help calcium be absorbed. An appropriate daily dose for an adult with osteoporosis is 1,000–2,000 units of vitamin D, but some patients will need higher doses. Often patients are prescribed a daily dose. Some patients take vitamin D in a 50,000-unit capsule if their vitamin D level is deficient. Patients will start with one capsule once or twice a week until their level is normalized and then take one 50,000-unit capsule monthly. It is frequently necessary for patients to take supplemental vitamin D in addition to the vitamin D they may get from their diet and the vitamin D they produce from sunlight exposure. Clinicians can measure vitamin D levels and adjust the vitamin D dose as needed.
Bisphosphonates are a first-line medication option for the prevention and treatment of osteoporosis (see Medication Table 13-2). They work by inhibiting osteoclasts from resorbing bone. Bisphosphonates attach to bone and are taken up by the osteoclasts. They then prevent the osteoclast from functioning. Bisphosphonates can be administered on varying schedules. Some people prefer to take them daily so they will not forget a dose, but they are commonly dosed weekly or monthly. Bisphosphonates can also be given intravenously and dosed every 3 months to yearly.
There is a LOOK-ALIKE SOUND-ALIKE warning for Actonel, a commonly used bisphosphonate, and Actos, a medication to lower blood glucose in patients with diabetes.
Bisphosphonates are not interchangeable and must be administered on the dosing schedule appropriate for each medication and preparation.
Oral bisphosphonates are not absorbed very well. Patients should take them first thing in the morning on an empty stomach with a large glass of water. After taking the tablet they should refrain from eating and remain upright for an additional 30 minutes. The common adverse effects of bisphosphonates include bone pain, heartburn, and upset stomach. Irritation and ulceration of the esophagus may occur with oral bisphosphonates. Patients with a history of esophageal reflux or swallowing disorders are at increased risk. Patients should report new or worsening heartburn symptoms to a healthcare provider. A serious but rare adverse effect of bisphosphonates is osteonecrosis of the jaw (ONJ). ONJ results in exposure of jaw bone, with severe pain due to the death of bone tissue, and a high risk of infection. While still rare, it is more common in patients using intravenous (IV) bisphosphonates in an oncology setting. Patients should alert their dentists if they take bisphosphonates since ONJ is more likely to occur after dental procedures. See Medication Table 13-2 to review specific bisphosphonates and their dosing schedules.
Mrs. Roberts was told she had a T-score of -3 and had to start a prescription for weekly alendronate. She doesn’t like having to take the tablet and wait another 30 minutes until she can have her breakfast. What are possible alternatives that the pharmacist can recommend to her doctor to minimize the number of bisphosphonate tablets she takes?
Denosumab is a monoclonal antibody RANK ligand inhibitor that prevents the formation of functional osteoclasts. In addition to osteoporosis, denosumab is used in several other populations of patients at high risk for fracture, such as men with prostate cancer undergoing androgen deprivation therapy. Denosumab is administered subcutaneously (SUBQ) by a healthcare professional every 6 months using a prefilled syringe. While denosumab is generally well tolerated, the most common adverse effects include skin rashes and other dermatologic reactions unrelated to injection site reactions. Severe but rare side effects include skin infections, back and joint pain, ONJ, and severe hypocalcemia (ie, very low blood calcium). Hypocalcemia is more likely in individuals with poor kidney function.
Romosozumab is a monoclonal antibody that inhibits the formation of sclerostin. Sclerostin helps to regulate bone metabolism. This in turn increases bone formation and is associated with a small reduction in bone resorption. Romosozumab is administered by a health professional once a month for up to 1 year. Each dose is 210 mg of romosozumab SUBQ, but this requires the use of two 105-mg prefilled syringes per dose. The prefilled syringe should be stored in the refrigerator but can be at room temperature up to 30 days. The most common adverse effect is joint pain. More serious adverse effects include headache and injection site reactions. Romosozumab has a black box warning for increased risk of stroke, heart attack, and cardiovascular death. Like other medications for osteoporosis, there is a slight risk for ONJ.
Selective Estrogen Receptor Modulators
There are two approved selective estrogen receptor modulators (SERMs), raloxifene and bazedoxifene. Estrogen has a positive impact on bone. It binds to receptors on the bone and decreases the activity of osteoclasts while increasing the activity of osteoblasts. This is why bone density significantly decreases in postmenopausal women. However, the benefits do not outweigh the risk of using hormone replacement therapy in postmenopausal women for osteoporosis due to the high risk of heart attack and stroke. Raloxifene stimulates estrogen receptors at the bone but blocks estrogen in breast and uterine tissue. Raloxifene is approved both as an agent to prevent bone loss and also for breast cancer prevention. Raloxifene is only indicated for use in postmenopausal women because before menopause women create enough estrogen naturally to maintain an adequate bone density. Bazedoxifene comes in combination with conjugated equine estrogens and is also useful for women experiencing menopausal symptoms, but is not approved for breast cancer prevention.
The common side effects of SERMs include leg cramps, swelling of the extremities, joint pain, and sweating. Raloxifene can also cause hot flashes, which is reduced with bazedoxifene. SERMs also make women more likely to experience blood clots. Patients taking SERMs should be educated on the signs and symptoms of a blood clot and to take precautions, such as moving legs regularly while traveling, to help prevent clots.
Be aware of a LOOK-ALIKE SOUND-ALIKE potential for Evista (raloxifene) and Avinza. Avinza is a brand name for morphine sulfate.
Parathyroid Hormone Analogs
Parathyroid hormone (often called PTH) regulates the activity of osteoclasts and osteoblasts so that osteoblasts are more active than osteoclasts. This generates the formation of bone and a higher bone density. Teriparatide and abaloparatide are both analogs of PTH, meaning they act similarly in the body. PTH therapy is usually used if bisphosphonate therapy fails in a patient. PTH analogs are given SUBQ once daily. Both teriparatide and abaloparatide comes as a multidose, autoinjector pen. Both teriparatide and abaloparatide pens must be stored in the refrigerator before use. While abaloparatide can be stored at room temperature after the first use, the teriparatide pen must stay in the refrigerator, even between uses. There is no specific time of the day PTH analog therapy should be used; however, it is best if the patient has a consistent time to use the medication. It is currently suggested not to use these agents for longer than 2 years.
Patients are cautioned to give themselves the teriparatide injection in an environment where they can sit or lie down if they become lightheaded. PTH analogs can cause injection site reactions, leg cramps, headache, dizziness, and nausea. Lastly, as PTH analogs have increased the risk of osteomalacia in animal studies, patients are cautioned there is a potential for increased risk in humans, but this has not yet been confirmed.
The teriparatide pens contain enough medication for 28 days and should be discarded at 28 days even if there is medication remaining in the pen. The abaloparatide pen contains enough medication for 30 days and should be discarded at 30 days even if there is medication remaining in the pen.
Patients who receive teriparatide pens will also need pen needles to inject the medication.
Calcitonin also prevents further bone loss. It is not as effective as bisphosphonates and is more expensive so it is reserved for patients who cannot tolerate bisphosphonate therapy or when bisphosphonate therapy fails. Calcitonin is only approved for women 5 years postmenopause, but it is also used for men. Salmon calcitonin is used because it is more potent and works longer than human calcitonin. Most patients administer the calcitonin nasally but it can also be given SUBQ.
Some patients may need help setting up the nasal spray and having it primed for them.
Like other prescription nasal sprays, patients using the calcitonin nasal spray should be reminded to prime the device before giving themselves the first dose. The usual dose is one spray in one nostril alternating daily. Some patients may experience some irritation of the nostrils but the nasal spray is otherwise well tolerated.
There are two main forms of arthritis: osteoarthritis (OA), is localized to the joints while rheumatoid arthritis (RA) is a more systemic condition. OA is characterized by loss of joint cartilage. Cartilage is the connective tissue between joints that minimizes friction between bones. Reasons for decreased cartilage in OA is multifactorial and include joint injury (possibly from trauma or stress from obesity), decreased ability to repair joint damage, and inflammation. Over time the balance between the formation and destruction of cartilage is lost and the cushion between joints diminishes. The incidence of OA increases with age. Risk factors for OA include obesity, joint trauma, gender, and race.
OA is characterized by pain in the joints, morning stiffness lasting less than 30 minutes, crepitus (crackling sound with joint movement), and instability of weight-bearing joints. The joints most often affected are the hands, knees, and hips, but the neck and spine can also be affected. In the late stages of OA there are abnormal alignment of the joints and severe debilitation from pain. OA is diagnosed based primarily on physical exam and history; however, x-ray and specific lab tests can be used to determine the severity of OA and rule out other forms of arthritis. Patients with OA may have radiographic changes characteristic of the condition. All patients with OA should be educated about nonpharmacologic options such as exercise, weight loss, and assistive devices. See Medication Table 13-3 for medications used for OA.
Mr. Bob, first introduced in the section on gout, is found by his physician to have OA. He has been told to try an over-the-counter (OTC) acetaminophen product to help with his knee and hip pain. He also has Tylenol PM on his medication list. What should be reviewed with Mr. Bob regarding his Tylenol OTC with the suggested acetaminophen?
Acetaminophen is often the first-line pharmacologic agent for patients with OA. Acetaminophen is an analgesic. It has fewer adverse effects within the older adult population than NSAIDs and is the preferred agent for patients with kidney failure. The usual range of doses is 325–650 mg every 4–6 hours or 1 gram three to four times daily. Patients should be reminded not to exceed 4,000 mg per day of acetaminophen to prevent liver damage. In some cases, the medical provider may choose a lower maximum dose for a patient. For example, some suggest a maximum dose of 2,000 mg acetaminophen daily for older adults. Acetaminophen comes in many dosage forms, strengths, and combinations. Patients should be cautioned to verify the amount of acetaminophen they are taking to stay under the maximum amount. Patients with existing liver failure or high alcohol usage should not use acetaminophen.
Acetaminophen from all sources (prescription and OTC drugs) must be considered to ensure patients are not taking too much drug.
Nonsteroidal Anti-Inflammatory Drugs
NSAIDs are commonly used medications. NSAIDs can be first line for OA, or if acetaminophen is ineffective in a patient with OA, NSAIDs are often the next choice for pharmacotherapy. Ibuprofen and naproxen are available OTC at low doses, but all remaining NSAIDs are available by prescription only. NSAIDs work by inhibiting an enzyme called cyclooxygenase (COX). This decreases the production of prostaglandins, which reduces inflammation and relieves pain. See Medication Table 13-4.
LOOK-ALIKE/SOUND-ALIKE—Watch for a common mistake of confusing Celexa, an antidepressant, with Celebrex, a COX-2-selective NSAID.
Not all NSAIDs and products containing them are appropriate for treating arthritis. An NSAID combination NOT used for arthritis is Treximet, which contains sumatriptan, a triptan used for migraines, and naproxen.
There are two different COX enzymes: COX-1 and COX-2. COX-1 is found in the GI system, kidneys, and platelets. COX-2 is found in macrophages, epithelial cells, the central nervous system, bone, kidney, the reproductive tract, and other areas. Most NSAIDs block both COX-1 and COX-2. Celecoxib is a COX-2-selective NSAID. Since it only blocks COX-2 and does not block cyclooxygenase in the stomach, it is thought to lower the incidence of GI symptoms associated with NSAIDs. Celecoxib is not more potent than other NSAIDs but may have a lower incidence of epigastric pain in the first 3 to 6 months of use. However, following that initial use the incidence of GI adverse effects is similar to nonselect NSAIDs and there is little convincing evidence that celecoxib reduces the risk of serious GI bleeding.
Patients who have an allergy to sulfa-containing medications should refrain from using celecoxib because of a potential cross reaction.
A common adverse effect of NSAIDs is nausea. Nausea can be minimized by taking the medication with food or milk. Some patients may also notice mild dizziness or fatigue; however, these are not common effects. NSAIDs can increase blood pressure in patients and when possible should be avoided in patients who already have hypertension. Patients who have asthma are at higher risk of having sensitivity to aspirin and other NSAIDs and should contact their physician immediately with any signs of difficulty breathing after using the medications.
There can be serious adverse effects with the use of NSAIDs. They increase the risk of GI bleeding or a stomach ulcer. Approximately 20% to 30% of all serious GI bleeds that cause death or require hospitalization are attributed to NSAIDs in patients over 65 years old. For patients with other risk factors for a GI bleed or a previous GI bleed, NSAIDs should be avoided or other medications, such as a proton pump inhibitor, can be used to lower the risk of stomach ulcers. All patients who take NSAIDs should be taught the warning signs of GI bleeding. This includes dark tarry stools or vomit that looks like coffee grounds.
NSAIDs can also induce renal failure in patients and are contraindicated in patients with kidney failure. This is especially true for patients who are over 65 years old with comorbid conditions like hypertension or heart failure. NSAIDs can also increase the risk for heart attack (also known as myocardial infarction) and stroke and may worsen congestive heart failure. To reduce the risk of these toxicities, the lowest possible effective dosage should be used for the shortest time. Only a single NSAID should be taken by a patient at a time.
Diclofenac is an NSAID that can also be used topically and has similar evidence to oral NSAID use. However, topical diclofenac has decreased adverse effects and may be used in some patients with contraindications to oral NSAIDs. Topical diclofenac is especially beneficial for knee OA but can also be considered for hand OA; it is not advised for hip OA as the medication does not reach the joint. There is an increase in local adverse effects where the product is administered on the skin, including itching and rash. Different topical preparations, such as a gel or a solution, have different application instructions, which the patient needs to be educated on.
All NSAIDs are associated with increased cardiovascular risk and should be used with caution in patients with cardiovascular disease and older adults.
Women of childbearing age (who may also use NSAIDs for headaches or menstrual pain) should be warned about the increased risk of miscarriage and delayed onset of labor when NSAIDs are taken during pregnancy.
All NSAIDs carry a black box warning regarding their risk of GI bleeding, heart attack, stroke, and cardiotoxicity. Patients should receive a medication guide reviewing all of the risks of NSAIDs with each NSAID prescription dispensed.
Tramadol is approved for moderate to severe pain and can be used in patients with contraindications to NSAIDs. It can also be used in patients with poor kidney function or if other oral medications fail. Doses range from 200–300 mg in four divided doses. Tramadol is generally well tolerated, with fewer adverse effects than NSAIDs; notably there is not an increased risk for GI bleeding or cardiovascular events. Side effects are similar to opioids and include nausea, dizziness, drowsiness, and constipation. Tramadol also has the potential for withdrawal symptoms when stopped abruptly following chronic use. Additionally, tramadol does have the potential to cause seizures and caution should be used in deciding to start another medication that can lower the seizure threshold. Tramadol is a scheduled medication due to the potential for dependence and diversion.
Patients in whom first-line agents for OA fail or who have contraindications to NSAIDs may find duloxetine beneficial. Duloxetine is a serotonin/norepinephrine reuptake inhibitor (SNRI) and is thought to minimize pain by blocking pain receptors. As duloxetine is effective for central pain, it is especially useful for patients who have neuropathic pain, or nerve pain, in addition to OA. Duloxetine is taken once daily and it can take up to 4 weeks before an improvement in pain is seen. Common adverse effects include dry mouth, drowsiness, headache, nausea, vomiting, and constipation. Rare but severe adverse effects include severe rash, called Stevens-Johnson syndrome, and liver damage.
Capsaicin cream is made from the ingredient in chili peppers that makes them hot. Capsaicin can be used in combination with oral medications for knee OA and is directly applied to painful joints. Capsaicin is not recommended for use with hand OA. Capsaicin is thought to work by dulling the nerves in the immediate area where the cream is applied, minimizing the pain from OA. When the cream is applied to the skin it creates a warming feeling, which some patients are not able to tolerate. This warming sensation does diminish over time with continued use.
Capsaicin cream should be applied four times a day. However, some individuals still experience benefit using it twice a day with better adherence. The onset of action is typically several weeks to a month of using the cream until there is relief from OA.
Patients should be advised that if gloves are not used to apply capsaicin cream, the hands should be washed thoroughly to prevent capsaicin from accidentally getting into the eyes and causing a painful burning sensation. If the hands are included in the treatment area, patients should wait 30 minutes before washing them.
Intraarticular Hyaluronan Injection
There is limited evidence of efficacy, but some patients with knee OA may benefit from intraarticular hyaluronan injections. The doses used vary from 16–30 mg injected into the knee once weekly for 3–5 weeks. One product (Synvisc-One) contains 48 mg and is intended to be given as a single injection. It may take 1–2 weeks for patients to feel improvement. Given the lack of evidence supporting its effectiveness, the risk versus benefit of hyaluronan injections must be considered and it should only be offered to patients who have contraindications to other therapies or when other therapies have failed.
Patients with avian (bird) allergies should refrain from using hyaluronan. The most common adverse effects of intraarticular hyaluronan injections are injection site pain and swelling. Patients should be cautioned to avoid excessive or strenuous activity on the knee for 48 hours.
Opioids are generally not recommended for the treatment of OA, but they may be considered when patients have exhausted other options or have contraindications to recommended therapies. They should be used in the lowest possible dose for the shortest period of time possible. The risk-to-benefit ratio must be considered carefully before deciding to try an opioid for a patient with OA. All opioids can cause dizziness and drowsiness. Patients will require counseling on the increased risk of falls and may benefit from having their home evaluated to decrease their fall potential. All patients who are prescribed opioids must also be counseled on the risk for dependence, tolerance, and diversion.
Glucosamine and Chondroitin
Glucosamine and chondroitin are OTC nutritional supplements with very limited efficacy and only for OA of the hand. There is no evidence to support the use of glucosamine and chondroitin in hip or knee OA and guidelines recommend against the use of these agents in those patients. The potential mechanism of action of glucosamine and chondroitin is unclear. The usual dose is a total of 1,500 mg glucosamine and 1,200 mg chondroitin daily. Many people split this into three doses a day. Patients can take the medication with food if they experience stomach upset, but it is usually well tolerated. Patients with shellfish allergies should be cautioned not to take glucosamine as there may be cross reactions.
Patients who have a history of bleeding problems, asthma, diabetes, cancer, or liver disease should consult their primary care providers before using glucosamine.
Rheumatoid arthritis (RA) is a systemic form of arthritis that primarily affects the small joints of the hands, wrists, and feet in a symmetrical manner. RA is a progressive autoimmune disorder where the body’s immune system attacks itself. RA is characterized by prolonged joint stiffness in the morning (usually greater than 30 minutes) and inflamed joints, which are usually painful. If inadequately treated it leads to joint deformity, disability, and early mortality. The factors that stimulate the autoimmune process in RA are unknown, but in RA the immune system can no longer distinguish between a foreign substance that needs to be removed and natural joint tissues. This causes antibodies called rheumatoid factors to attack the joints, causing inflammation and degradation of cartilage and bone. B cells and T cells are also activated in RA; activated T cells produce cytokines. The cytokines contribute to joint inflammation and are directly toxic to joint tissue.
Ms. Jones is a 45-year-old woman who comes to the pharmacy wondering what she can try for her joint pain. She reports pain in her fingers and toes in the morning and feels like it takes several hours for her to “loosen up” every morning.
Nonpharmacologic measures for treating RA include physical therapy, specific exercise classes, and assistive devices to make it easier to maintain activities of daily living. Pharmacologic intervention is needed to prevent disease progression.
Is there anything the pharmacist can recommend for Ms. Jones’s pain?
Pharmacologic therapy consists of NSAIDs, corticosteroids, and disease-modifying antirheumatic drugs (DMARDs). While NSAIDs can be used to help with some of the pain associated with RA, they do not slow disease progression. Corticosteroids are not considered DMARDs, but they can help with pain and inflammation until the DMARD is efficacious. This is called bridging. Specific dosage forms and schedules of medications used in RA can be found in Medication Table 13-5.
Disease-Modifying Antirheumatic Drugs
All patients should be prescribed a DMARD within 3 months of being diagnosed with RA. Baseline evaluation of the renal and hepatic system should be conducted at diagnosis because many DMARDs have adverse effects on the kidneys and liver. DMARDs are classified as conventional and biologic. All work by decreasing different inflammatory mediators within the body to reduce RA disease activity. It is not unusual for triple therapy with conventional DMARDs to be used as first line or in the case that monotherapy or double DMARD therapy fails. Conventional DMARDs can be used in combination with a biologic DMARD; however, a biologic agent should never be used in combination with another biologic DMARD.
Conventional DMARDs are older drugs that reduce inflammation. Most conventional DMARDs are effective when taken orally.
The exact mechanism of action of hydroxychloroquine is unknown. The usual dose is 200–400 mg daily. It may take up to 6 weeks before hydroxychloroquine is efficacious; however, a course of 6 months should be tried before discontinuing the medication. Short-term adverse effects include nausea, vomiting, and diarrhea. This is often minimized by taking the medication with food. Hydroxychloroquine does not cause liver or bone marrow toxicity, which is an advantage to using the medication. Hydroxychloroquine can cause macular damage, which can lead to blurry vision, decreased peripheral vision, and night blindness. Patients who take hydroxychloroquine should report any changes in vision. An eye exam is recommended at baseline, then yearly if the patient has significant risk factors for ocular toxicity, otherwise yearly eye exams can be started after 5 years of therapy with hydroxychloroquine. Patients should also report any signs of rash while taking the medication. Hydroxychloroquine can also cause an increase in pigmentation of the skin. This is a cosmetic effect and not considered a serious adverse effect.
Ms. Jones had an appointment with her physician and was diagnosed with RA. She has a prescription for hydroxychloroquine and she is concerned about adverse effects. What might the pharmacist review with her when the prescription is dispensed?
Leflunomide decreases lymphocyte proliferation. This means lymphocytes do not divide into new cells. The lymphocytes are white blood cells responsible for protecting the body from invading cells. Decreasing the number of lymphocytes in a patient with an autoimmune disease means there are fewer cells targeting the body as foreign. Since leflunomide interferes with the immune system, live vaccinations may not work properly for patients taking it. Leflunomide has a loading dose of 100 mg three times daily for 3 days. The maintenance dose is then 10–20 mg once daily. Some clinicians do not use loading doses because of the increased side effects associated with the higher doses. The onset of action ranges from 4–12 weeks.
Common adverse effects of leflunomide include hair loss and diarrhea. Leflunomide is teratogenic (ie, can cause birth defects in the children of pregnant women taking the medication). Women on leflunomide who wish to have children should speak with their physicians. The half-life of leflunomide is long (14 days) and it takes several months after discontinuation of the medication before it is out of the patient’s system and it is safe for her to become pregnant.
Leflunomide rarely causes liver damage and liver failure. Liver function tests should be checked regularly in patients taking leflunomide. Any signs of rash should be reported to the physician as it may become life threatening. Cholestyramine may be used to eliminate leflunomide more rapidly in planned pregnancy or if severe side effects with leflunomide occur.
The mechanism of action of methotrexate is believed to be related to decreasing cytokines or other inflammatory mediators. The dose of methotrexate can vary based on response and severity but the usual dosage is 7.5–25 mg once weekly. This can be taken orally, SUBQ, or by IM injection. Using a weekly dose helps to minimize adverse effects. Onset of action may be seen as soon as 2–3 weeks but may take up to 2 months. Methotrexate may be first-line therapy for some patients if their RA is more active, but for other patients it may be second line after a different conventional DMARD fails. Methotrexate may also be used in combination with another conventional DMARD or biologic DMARD.
Use caution in processing methotrexate prescriptions. Unlike other oral DMARDs, methotrexate dosing is once weekly. Taking methotrexate daily markedly increases the risk for toxicity and is never used this way for RA treatment (although daily doses are indicated for some other conditions).
Methotrexate can cause birth defects, and if pregnancy is desired by a woman taking methotrexate she should consult her physician. Less severe adverse effects include nausea, vomiting, and diarrhea. There can also be hair loss and photosensitivity. More severe adverse effects include very low platelet count, liver damage, kidney failure, and pulmonary damage. Patients should have their blood counts and liver function tests checked periodically. They should also be educated to report any signs of rash, problems breathing, or jaundice. Patients who take methotrexate should also take a daily folic acid supplement (1 mg/day) because methotrexate can cause folate deficiency. There is an antidote available for methotrexate toxicity, glucarpidase. It can be administered IV within 48–60 hours from the start of a high-dose methotrexate infusion to prevent methotrexate toxicities. However, given that the doses of methotrexate used for RA treatment are generally oral, SUBQ, or IM and significantly lower than those used for other indications, the antidote is generally not utilized in this setting.
The exact mechanism of action of sulfasalazine in RA is unknown. It is not readily absorbed from the GI system, and bacteria in the colon cleave (divide) sulfasalazine into sulfapyridine and 5-aminosalicylic acid. The components are then absorbed systemically from the colon. The initial dose of sulfasalazine is 500 mg orally twice daily. This can be increased to 1–1.5 g twice daily if tolerated. Onset of action is seen in 1–3 months after starting sulfasalazine.
The dose-limiting toxicities of sulfasalazine include nausea, vomiting, diarrhea, and anorexia. This can be lessened by starting at a lower dose and slowly titrating up to the maintenance dose or using an enteric coated product. A rare but serious adverse effect is leukopenia, or decreased white blood cells, and patients should have their complete blood count monitored every 2–3 months. Patients should also have their liver function monitored as sulfasalazine can cause liver damage. Patients should be instructed to report any rashes to their physicians.
Patients who have an allergy to sulfa-containing medications should refrain from using sulfasalazine because of a potential cross reaction.
Other less used DMARDs include azathioprine, cyclosporine, cyclophosphamide, gold salts, d-penicillamine, and minocycline.
Biologic DMARDs are used when methotrexate or another conventional DMARD have failed to control the symptoms and disease progression or initially in patients with more severe disease. Biologic DMARDs are genetically engineered proteins that block pro-inflammatory mediators. They are all SUBQ or IV agents because, if taken orally, they are destroyed in the stomach. Their primary adverse effect is injection site reactions. Patients taking SUBQ biologics should be reminded to rotate injection sites to prevent scarring.
Biologic DMARDs require much less laboratory monitoring than conventional DMARDs; however, they put patients at risk for serious life-threatening infections. Biologic DMARDs carry a black box warning about the risk of tuberculosis and invasive fungal infections. In most cases patients will complete a tuberculosis skin test before starting, to assess their risk of latent tuberculosis, which could be reactivated while on a biologic DMARD. Hepatitis B (HBV) screening should also be completed prior to treatment with a biologic because therapy should not be initiated in acutely infected patients. In patients who are HBV carriers, there is a risk for reactivation and consideration for HBV prophylaxis may be needed.
Tumor necrosis factor-alpha (TNF-α) is a key cytokine in the inflammation cascade for patients with RA. TNF-α blockers bind to TNF-α and prevent the TNF-α from interacting with the T-lymphocytes and other cells, which decreases inflammation. TNF-α may play a role in cancer prevention in the body. It has been suggested that TNF-α blockers may increase the risk of cancer; however, long-term data is lacking. Other serious adverse effects include worsening of heart failure and, very rarely, patients experience symptoms similar to multiple sclerosis. Patients taking TNF-α blockers should avoid live vaccines due to a decreased response to the vaccine and lack of safety data for this use. Methotrexate is often given with TNF-α inhibitors as it increases the efficacy of these drugs.
All currently available TNF-α blockers are stored in the refrigerator. Patients will need a sharps container as all biologic DMARDs are injected and the autoinjector and prefilled syringes will require proper disposal.
Etanercept is a fusion TNF-α blocker. It has two TNF receptors fused onto an IgG antibody. Etanercept comes as a syringe or an autoinjector and is given by SUBQ injection either 25 mg twice weekly or 50 mg once weekly.
Approximately 2 years after starting hydroxychloroquine, Ms. Jones notes that it is no longer relieving her RA symptoms. She brings a new prescription for Humira (adalimumab) to the pharmacy and isn’t sure where to store it when she goes home. What does the package insert advise?
Infliximab is also a TNF-α blocker and is only indicated for use in RA when used in combination with methotrexate. Infliximab is a chimeric IgG antibody to TNF-α. This means the antibody is part human and part mouse. The antibody was created by injecting human TNF-α into mice. The part of the mouse antigen that binds to TNF-α is fused to a human IgG antibody. This reduces the chance that patients react to the mouse part of the antibody.
Infliximab is administered IV in a clinic and the dose is 3 mg/kg at weeks 0, 2, and 6, and then every 8 weeks. Benefits may begin within 2 weeks of administration. Since infliximab incorporates mouse proteins, patients who use it may form antibodies to the medication. These antibodies may cause infusion reactions or loss of response, requiring higher doses or less time between treatments. To prevent this, methotrexate is continued for the duration of treatment with infliximab.
Adalimumab is an IgG antibody for TNF-α. It is fully humanized, but antibodies to the medication can still form. Adalimumab comes as a pen and a prefilled syringe. The usual dose is 40 mg SUBQ every other week. There is also a citrate-free formulation available that has several benefits, including reduced injection volume and decreased pain at the injection site.
Golimumab is a TNF-α blocker requiring once-monthly administration. It is available as an autoinjector and prefilled syringe for patients to use at home. It is suggested that, when used to treat RA, golimumab should be prescribed in combination with methotrexate.
Certolizumab is a pegylated TNF-α blocker. It is given as two SUBQ injections of 200 mg for a 400 mg dose. The 400 mg dose is given every 2 weeks for a total of three doses. Then it can be given as either 200 mg every 2 weeks or 400 mg every 4 weeks. Most patients will use it as a prefilled syringe.
Interleukins are a type of cytokine that signals and stimulates other inflammatory cells to the site of inflammation. Some patients with RA produce excess interleukin-1. Anakinra is an interleukin-1-receptor antagonist (IL-1ra). It binds to the interleukin-1 receptor and prevents the interleukin from binding and interacting with the cell. This stops the activity of interleukin-1 and decreases inflammation in the joints.
Anakinra is used infrequently in RA. The recommended dose is 100 mg SUBQ daily. Anakinra is packaged in single-use, prefilled glass syringes. If a syringe has been dropped or has been left at room temperature for 24 hours, it should be discarded, even if there is no noticeable damage.
The needle cover for anakinra is made of a latex-based material and should not be handled by patients with latex sensitivities.
Abatacept is indicated for use in patients with moderate or severe RA. Abatacept inhibits T cell activity by binding to receptors responsible for cell activation. Activated T-lymphocytes have been found in the joint fluid of patients with RA and a decrease in their activity decreases inflammation and slows disease progression. Abatacept can be given as a 30-minute IV infusion by a healthcare professional and is also available in a prefilled syringe or autoinjector. For the IV formulation, dosing is based on the patient’s weight. If the patient’s weight is less than 60 kg, a 500-mg dose is used, 750 mg if a patient’s weight is 60–100 kg, and 1,000 mg if the patient’s weight is more than 100 kg. The dosing interval is week 0, 2, and 4, then every 4 weeks. For the subcutaneous route, the dose is 125 mg weekly. A patient may be started on the subcutaneous route at the initiation of therapy or may be started on the IV formulation (at weight-based dosing) and then switched to the subcutaneous route.
Patients with chronic obstructive pulmonary disease who take abatacept are more likely to experience acute exacerbations and should be monitored closely while taking the medication. Abatacept also makes patients more prone to headaches, upper respiratory infections, and urinary tract infections. There have been very rare cases of hypersensitivity or anaphylaxis while infusing the medication.
Abatacept must be reconstituted before IV administration. During the process of dissolving the powder, the vial should not be shaken but rotated gently to avoid foam. Only silicone-free syringes should be used. If a silicone-containing syringe is inadvertently used, the syringe and medication should be discarded.
B-lymphocytes are blood cells that have a role in promoting inflammation associated with RA. Rituximab binds to B-lymphocytes, causing the death of these cells. The decreased activity of B-lymphocytes causes the inflammation to lessen and slows disease progression. Rituximab is an antibody against B-lymphocytes. It should only be used in patients in whom a TNF-α blocker has failed or in patients with contraindications to TNF-α blockers. Rituximab is usually prescribed in combination with methotrexate. The initial dose is 1,000 mg IV. A second dose is given 2 weeks later. The course may be repeated every 16–24 weeks and redosing is typically based on the patient’s symptoms and disease control.
LOOK-ALIKE/SOUND-ALIKE—Use caution when processing a new prescription for rituximab or infliximab for the treatment of RA.
While receiving rituximab some patients have experienced severe infusion reactions, which rarely can result in death. To minimize the risk of infusion reaction patients are generally premedicated with a corticosteroid (such as prednisone), an antihistamine (often diphenhydramine), and acetaminophen 30 minutes prior to administration. Common adverse effects include itching, nausea, vomiting, and headache. Rare but serious adverse effects include low white blood cell counts, cardiac toxicity, and increased risk of infection. Patients should report any rashes to their physician after receiving rituximab. The risk of HBV reactivation is high in patients who are HBV carriers starting rituximab; therefore, screening prior to treatment is important.
Tocilizumab is a recombinant humanized antihuman IL-6 receptor monoclonal antibody. It binds to IL-6 receptors, a proinflammatory cytokine, and inhibits cell signaling of T cells, B cells, lymphocytes, and monocytes. This helps to decrease the inflammatory process in RA. It is available as an IV formulation, an autoinjector, or a prefilled syringe to be administered subcutaneously. The IV formulation can be dosed at 4 mg/kg every 4 weeks and the dose may be increased to 8 mg/kg every 4 weeks, with a maximum of 800 mg per dose. The SUBQ formulation is dosed at 162 mg weekly; however, if a patient’s weight is less than 100 kg, the dose should be started at 162 mg every other week and may be increased to weekly if needed. Tocilizumab can be used with or without methotrexate but should not be used in combination with another biologic DMARD. Common adverse effects of tocilizumab include headache, elevated blood pressure, increased liver enzymes, and increased cholesterol levels. Like other biologic DMARDs, the most serious adverse effect is infection, which can be life threatening. Other serious adverse reactions include GI perforation, low white blood cell count, and low platelet count.
Sarilumab is a monoclonal antibody that binds to IL-6 receptors, which reduces inflammation and alters immune response. Sarilumab can be used alone or with methotrexate or other conventional DMARDs. It is available as a pen and prefilled syringe and is given as a 200-mg dose every 2 weeks. Sarilumab has been associated with serious infections, blood disorders, liver enzyme elevations, GI perforation, and increases in cholesterol.
A biosimilar is a biologic product that is very similar in structure and function to an already-FDA-approved biologic medication. A biosimilar has no clinically meaningful differences compared to the existing biologic medication. Due to the high-cost nature of most biologic medications, there is an abbreviated approval pathway for the approval of a biosimilar medication to avoid duplication of clinical trial costs and to provide more affordable options to patients. Biosimilars are different than generics in that they are very similar but not identical to the original medication. Examples of biosimilar products that are available referencing infliximab for the treatment of RA include infliximab-abda, infliximab-dyyb.
Janus-Associated Kinase ( JAK) Inhibitors
JAK Inhibitors are labeled with warnings for increased infection risk, mortality, cardiovascular events, thrombosis, and malignancies.
Tofacitinib is an oral synthetic small molecule that inhibits janus-associated kinases (JAK) 1, 2, and 3. This mechanism of action leads to the disruption of cytokine and growth factor signaling pathways. Tofacitinib can be used alone or with methotrexate or other conventional DMARDs but should not be used with biologic DMARDs. It is available as an extended-release tablet for a dose of 11 mg daily or an immediate-release tablet for a dose of 5 mg twice daily. Tofacitinib has been associated with an increased risk of serious infections, including tuberculosis and fungal infections. It is important to screen for tuberculosis before starting this medication. Tofacitinib has also been associated with increased cancer risk; however, long-term data is lacking. Common side effects include increased cholesterol, rash, diarrhea, elevated blood pressure, liver enzyme elevations, and infections. Tofacitinib can also lead to blood disorders, including anemia, neutropenia (a decrease in the type of white blood cells called neutrophils), or lymphopenia (a decrease in the type of blood cells called lymphocytes). Tofacitinib may require dose adjustment in hepatic and renal impairment or for drug-drug interactions.
Baricitinib is a JAK inhibitor similar to tofacitinib. It is also administered by mouth and is available in a 1-mg and 2-mg tablet. It can be used alone or with methotrexate or other conventional DMARDs. Typical dosing is 2 mg daily, but lower doses (1 mg daily) may be used in patients with renal impairment and baracitinib may need to be avoided with certain degrees of renal impairment. Baricitinib also carries a risk for serious infections and cancer. It has also been associated with thrombosis. It has similar side effects as tofacitinib, including blood disorders, GI perforation, liver enzyme elevations, and cholesterol increases.
Upadacitinib is also a JAK inhibitor for the treatment of RA. It is available in an extended-release tablet dosed as 15 mg daily. It can also be used with methotrexate or other conventional DMARDs. Possible side effects are similar to baricitinib and tofacitinib and include serious infections, blood disorders, cancer, GI perforation, liver enzyme increases, thrombosis, and cholesterol increases.
Corticosteroids work by decreasing the levels and actions of inflammatory mediators such as cytokines, prostaglandins, and leukotrienes. Decreasing the mediators reduces the number and activation of inflammatory cells, diminishing inflammation. In cases of autoimmune diseases where the body is attacking itself with these inflammatory cells, corticosteroids can stop the cells from attacking the body. This decreases the inflammation and pain associated with RA. Corticosteroids have minimal disease-modifying activity and are not considered DMARDs. They are primarily used for bridging with a DMARD, because it often takes several weeks to months for the full efficacy of DMARD treatment to be established. They may also be given by injection directly into sites of inflammation in joints, tendons, or bursa. Intraarticular glucocorticoid injections are corticosteroid injections given in the joints and are used in both OA and RA.
Corticosteroid therapy is associated with many adverse effects. As with NSAIDs, practitioners try to limit the corticosteroid use to the lowest dose for the shortest period of time that is necessary. There are both long- and short-term effects to take into account. Short-term effects include upset stomach, restlessness, and trouble sleeping. Upset stomach is greatly reduced by taking the medication with food and trouble sleeping is minimized by taking steroids earlier in the day. Short courses of use under 2 weeks are generally well tolerated.
Patients may also experience an increased appetite while taking corticosteroids. This can begin with the first dose and last until the patient discontinues the medication. Long-term effects include increased risk of osteoporosis, cataracts, dermatologic changes, high blood pressure, and metabolic changes. The metabolic changes cause fat redistribution or a Cushing’s appearance (increased fat at the face and back with less fat in the extremities). Metabolic changes also include hyperglycemia, which makes it harder to control blood glucose levels in diabetes, and hyperlipidemia. The dermatologic changes include thinning of the skin, bruising, and acne.
There are also a number of adverse effects that are dose related. At doses higher than 10 mg daily patients may experience hypertension from increased sodium and fluid retention. High-dose corticosteroids may increase the risk of infection. At very high doses, even for a short period of time, some patients experience mood changes. When patients take corticosteroids for a long time, the body’s natural production of steroids is suppressed. In this case, patients need to be slowly tapered off the medication over the course of several months.
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is a chronic autoimmune condition. While many patients experience arthritis and joint pain as part of their illness, multiple other organ systems are involved. Other organ systems that can be damaged include the skin, central nervous system, lungs, heart, kidneys, and the hematologic system. A butterfly-shaped rash covering the bridge of the nose and cheekbones is a classic symptom of SLE. Fatigue can also cause quality of life concerns for many patients. The primary form of therapy consists of medications to suppress the immune system from attacking the body. Treatments chosen are dependent on disease severity and organ systems involved. Ultraviolet light from the sun can trigger flairs in SLE and patients should be cautioned to wear sunscreen and protective clothing when spending time outside.
During an SLE flair, NSAIDs are used to treat fever, joint pain, and inflammation. The same toxicities must be monitored as in other arthritic conditions. Renal toxicity especially must be monitored as decreased renal function is present in many patients with SLE. Hydroxychloroquine, described in the section on RA, is used for long-term management of SLE. It is particularly useful for skin and musculoskeletal manifestations not controlled by NSAIDs. Corticosteroids are also used, especially for SLE flares. However, the lowest dose possible for the shortest amount of time should be used to minimize toxicity. Topical corticosteroids are used to help control topical symptoms.
Belimumab is used for the treatment of SLE. It is an IgG1-lambda monoclonal antibody that prevents the survival of B-lymphocytes, thus reducing the activity of B cell–mediated immunity and the autoimmune response. It is available to be given IV or SUBQ. Initial IV dosing is 10 mg/kg every 2 weeks for three doses, then 10 mg/kg every 4 weeks. The SUBQ formulation is given as a 200-mg dose weekly. Side effects include infusion reactions with the IV formulation, GI side effects, depression and suicidality, as well as increased cancer and infection risk.
For patients with severe or refractory SLE, immunosuppressive drugs such as azathioprine (1.5–2 mg/kg every day), methotrexate (7.5–20 mg/wk with folic acid), cyclophosphamide regimens (0.5–1 g/m2 IV monthly), mycophenolate mofetil (0.5–3 g every day), and/or rituximab (1 g IV) are used. Cyclophosphamide is used in combination with corticosteroids as an immunosuppressant, especially in patients with potentially life-threatening disease complications. Cyclophosphamide therapy can decrease the likelihood that dialysis or a kidney transplant will be needed for patients with renal involvement. Cyclophosphamide can be given orally or by IV. The preferred dosing is once a month for 6 months, then every 3 months by IV. The intermittent dosing reduces adverse effects.
The adverse effects of cyclophosphamide include suppression of the immune system, which leaves patients at risk for opportunistic infections. Signs and symptoms of infection require immediate attention. The drug may suppress the bone marrow’s ability to produce blood cells and complete blood counts are needed periodically during treatment. Cyclophosphamide is teratogenic and should not be used during pregnancy. Patients with childbearing potential should use birth control measures to prevent pregnancy. The drug may cause infertility. At high doses patients are at risk from hemorrhagic cystitis, which is inflammation of the bladder that can lead to bleeding. Cyclophosphamide increases the risk of cancer. Rituximab has been found to be effective in reducing disease activity in SLE as it reduces B-lymphocytes that are responsible for the production of antibodies, which promote the inflammatory response.
Management of Other Conditions
Raynaud’s phenomenon is excess vasoconstriction resulting from the body’s overreaction to cold temperature. This lessens the blood flow to extremities and can cause tingling and pain in the hands and feet and can induce white and blue skin coloring. Raynaud’s phenomenon can occur on its own, but is more likely to be observed in patients with SLE or other autoimmune conditions. Primary prevention of Raynaud’s phenomenon involves wearing appropriate clothing in cold weather to prevent reactions. In severe cases calcium channel blockers (eg, nifedipine, amlodipine), losartan, sildenafil, or fluoxetine can be used to minimize the severity and number of reactions.
Another condition commonly seen in conjunction with SLE and autoimmune diseases is antiphospholipid syndrome. Phospholipids are part of the cell membrane, and when antibodies against them are formed this puts patients into a hypercoagulable state where they are at a higher risk for thrombosis or clots. Therapy for antiphospholipid syndrome revolves around proper anticoagulation with warfarin and aspirin.
Some musculoskeletal conditions, such as gout and osteoporosis, are related to metabolic or hormonal disorders; others, such as osteoarthritis (OA), may be related to injury and overuse. Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are autoimmune disorders in which the body’s defenses mistakenly attack its own tissues. Treatments for these conditions often require a combination of drug therapies to manage not only the diseases but also the associated pain. Because patients often use a combination of over-the-counter and prescription medications to manage their pain, patient education is important to reduce the risk of toxicities and other adverse reactions. Technicians play an important role in this education, but to do this successfully they must be able to recognize the causes and symptoms of the disease, understand the treatments, and work with the pharmacist to ensure accuracy and safety during the process.
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