Arthritis

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CHAPTER 21 Arthritis

I. Osteoarthritis

1. Osteoarthritis (OA), also called degenerative joint disease, is marked by the breakdown of cartilage that lines the ends of most limb bones. This type of cartilage is known as articular cartilage, and it serves to cushion the bones and allow painless joint movement. Because OA affects the articular cartilage, patients with OA experience pain and reduced mobility in their joints. OA may affect any joint in the body, but it occurs most often in fingers, spine, and weight-bearing joints. Individuals with OA often experience inflammation around the affected joint, which is caused by bits of cartilage that break off and aggravate the synovial tissue lining the joints.

2. Besides cartilage loss, OA is characterized by irregular thickening and remodeling of bone. The synovial tissue may bulge out of joints to form cysts (commonly known as Baker cysts), or become hardened with fibrous tissue overgrowth (a condition known as sclerosis). Bony protrusions, called bone spurs or osteophytes, may also form. These pathological changes result in increased blood flow and joint inflammation.

C. Signs and symptoms

1. OA may affect any joint in the body; however, because it develops slowly, many patients do not experience symptoms right away. The pain and inflammation in OA is typically less severe and more localized than that of rheumatoid arthritis (RA), another form of arthritis that is more systemic.

2. Common symptoms of OA

a. Joint pain (arthralgia)

b. Swelling and/or stiffness in a joint (especially after not moving for a while); stiffness in morning lasts < 30 minutes.

c. Joint discomfort before or during a change in the weather (such as conditions of low pressure and high humidity)

d. Bony lumps on the fingers

e. Loss of joint flexibility

3. When individuals have OA, the cells that form cartilage (called chondrocytes) cannot efficiently repair the damaged cartilage. Thus, OA represents a failure of the chondrocyte to maintain proper balance between cartilage formation and destruction. Instead, new bone grows alongside the existing bone, causing small lumps to form. Although these lumps cause minimal pain, they may be disfiguring and limit the joint’s mobility.

2. Pharmacologic

a. Acetaminophen (Tylenol): The American College of Rheumatology has recommended acetaminophen as first-line therapy for osteoarthritis of the hip or knee.

(1) Dose, maximum 4 g/day

(2) Adverse effects: Hepatotoxicity may occur.

b. Nonsteroidal anti-inflammatory drugs (NSAID)

(1) Mechanism of action

(a) Decrease production of prostaglandins

(i) Nonselective inhibitors of cyclooxygenase (COX)-1 and COX-2

(b) Increase vascular permeability and sensitivity to the release of bradykinins

(c) Inhibits formation of prostacyclin and thromboxane, resulting in reduced platelet aggregation

(2) May be used if patients fail to respond to acetaminophen

(3) Adverse effects

(a) Abdominal pain

(b) Gastrointestinal (GI) bleeding

(d) Hypersensitivity reactions

(e) Renal or hepatic impairment

(f) Impaired bone marrow function

(g) Platelet aggregation

(4) Primarily metabolized in liver by cytochrome P-450 (CYP) 2C9 and excreted in urine

(a) Indomethacin, sulindac, and piroxicam undergo enterohepatic circulation resulting in a prolonged half-life (avoid in the elderly)

(5) Contraindications

(a) Active peptic ulcer disease

(b) Renal disease

(c) Heart failure

(6) NSAID examples

(a) Salicylates (aspirin)

(b) Propionic acids (ibuprofen [Motrin], naproxen [Aleve, Naprosyn], oxaprozin [Daypro], ketoprofen [Orudis])

(c) Acetic acids (diclofenac [Voltaren], etodolac [Lodine], indomethacin [Indocin])

(i) Diclofenac is available for topical use.

(d) Oxicams (piroxicam [Feldene])

(e) COX-2 inhibitors (celecoxib [Celebrex])

(i) Mechanism of action: inhibits COX-2, thereby impairing the transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes

(ii) Rofecoxib (Vioxx) and valdecoxib (Bextra) were removed from marketing due to safety concerns.

(iii) Adverse effects: similar adverse event profile to other NSAID; linked to an increased risk of serious heart-related side effects, including heart attack and stroke. Selective COX-2 inhibitors have also been shown to increase the risk of stomach bleeding, fluid retention, kidney problems, and liver damage.

c. Glucocorticoids

(1) Systemic glucocorticoids are not used for osteoarthritis

(2) Intraarticular injections may be used in patients who do not respond to NSAID or for whom NSAID are contraindicated.

(a) Examples: triamcinolone acetonide, triamcinolone hexacetonide, methylprednisolone

d. Hyaluronic acids

(1) Used for osteoarthritis of the knee in patients who do not respond to NSAID therapy or who have a history of gastric ulcer disease

(2) Examples: sodium hyaluronate (Hyalgan, Supartz, Nuflexxa), hylan G-F 20 (Synvisc)

e. Other analgesics

(1) Tramadol (Ultram): 50–100 mg can be administered as needed for pain relief every 4–6 hours, not to exceed 400 mg/day (immediate release)

(a) Mechanism of action: centrally acting synthetic analgesic

(b) Adverse effects: risk of seizure

(2) Opioids, such as codeine, oxycodone, or propoxyphene may be used short term in patients with acute pain exacerbations.

f. Topical pain relievers

Used for localized pain control at a specific joint. Topical NSAID generally considered more effective than topical capsaicin.

(1) Capsaicin 0.025% cream

(2) Trolamine salicylate (e.g., Aspercreme, Sportscreme, Icy Hot, Ben-Gay)

(3) Methylsalicylate (e.g., Exocaine and Gordogesic)

(4) Topical NSAID: e.g., diclofenac (Voltaren Gel)

g. Alternative therapies

(1) Glucosamine/chondroitin combination is most studied, particularly in patients with OA of the knee; may help with pain relief.

(a) Patients should be taking at least 1.5 g of glucosamine daily. Significant pain benefit may not occur in all patients. Does not appear to limit progression of OA in the joint.

II. Rheumatoid Arthritis

1. Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects the peripheral joints in a symmetrical pattern. Although the exact cause is currently unknown, RA is thought to be due to autoimmune phenomena. These are characterized by abnormal immune responses against healthy host tissue. In RA, autoimmune reactions can cause joint inflammation and eventual degeneration.

2. Because RA is a type of autoimmune disorder, most patients have antibodies called rheumatoid factors. The presence of these antibodies in the blood confirms a diagnosis of RA, but it does not necessarily indicate the severity. Proinflammatory factors (such as tumor necrosis factor, interleukin, T cells, prostaglandins, and histamine) may also be elevated. Blocking these proinflammatory substances is the major target of most therapies for RA. The presence of chronic inflammation in the joints eventually leads to breakdown of synovial tissue, cartilage, and bone.

B. Risk factors

1. Sex (women more likely than men)

2. Age (most commonly between 20 and 50 years old)

3. Family history

C. Signs and symptoms

1. RA is marked by pain and swelling in the joints. Unlike OA, which affects only bones, cartilage, and synovial tissue, RA is an autoimmune disorder that may also cause swelling in other areas of the body, including the tear ducts, salivary glands, lining of the heart, lungs, and occasionally, the blood vessels. Furthermore, although osteoarthritis tends to be localized to a few joints, RA often affects many joints at the same time. The severity of symptoms varies among patients. Early nonspecific symptoms include fatigue, weakness, low-grade fever, loss of appetite, and joint pain.

1. Treatment initially begins with NSAID, salicylates, or COX-2 inhibitors for relief of pain and inflammation, allowing for improvement in joint function while baseline assessments of joint damage, disease activity, and laboratory testing are completed.

2. Glucocorticoids may be used in dosages equivalent to or less than 10 mg of oral prednisone daily. Intraarticular injections may be effective for selected joints (Table 21-1).

3. Disease-modifying antirheumatic drugs (DMARD)

Table 21-1 Oral Corticosteroid Equivalencies

Corticosteroid Agent	Equivalent Oral Dose (mg)
Cortisone	25
Hydrocortisone	20
Prednisone	5
Prednisolone	5
Triamcinolone	4
Methylprednisolone	4
Dexamethasone	0.75
Betamethasone	0.6

DMARD drugs are usually initiated within 3 months of RA diagnosis. DMARDs may reduce or prevent joint damage, preserve joint function, and may help financially to reduce care costs and preserve work status. The DMARDs most commonly used for RA include hydroxychloroquine, sulfasalazine, methotrexate (MTX), leflunomide, etanercept, infliximab, and anakinra (Table 21-2).

a. Non-biologic DMARD: methotrexate (Rheumatrex), hydroxychloroquine (Plaquenil), sulfasalazine (Azulfidine)

b. Biologic DMARD: infliximab (Remicade), etanercept (Enbrel), Anakinra (Kineret), abatacept (Orencia), rituximab (Rituxan)

(1) Typically used only if insufficient response with nonbiologic DMARD; many agents added to existing MTX treatment.

c. Immunosuppressants: leflunomide (Arava), azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan)

1. Gout is an intensely painful form of arthritis that causes the joints to become red, swollen, and stiff. Symptoms are most likely to develop in the big toe. It occurs when there is too much uric acid, a waste product that forms when the body breaks down purines found in red meat, poultry, and fish in the blood (hyperuricemia). Uric acid is carried through the bloodstream to the kidneys. If the body produces too much uric acid or if the kidneys do not eliminate adequate amounts, uric acid will build up in the blood. This condition is called hyperuricemia.

B. Signs and symptoms

1. Attacks occur suddenly, especially at night.

2. Joints become red, swollen, and stiff.

3. The big toe is most commonly affected; the symptom is often called podagra.

4. Other commonly affected joints include the ankles, heels, knees, wrists, hands, fingers, and elbows.

5. The pain may be so severe that a bed sheet touching the affected skin is unbearable.

6. Symptoms generally subside after 1–2 weeks.

1. Nonpharmacologic therapy

a) Limit foods high in purines (e.g., red meat)

b) Maintain ideal body weight

c) Limit alcohol and drink appropriate amounts of fluids/water

2. Pharmacologic therapy

a. Colchicine (Colcrys)

(1) Mechanism of action: blocks microtubule polymerization

(2) Usual adult dose for acute attacks: 1.2 mg PO followed by 0.6 mg PO in 1 hour (total 1.8 mg)

(a) May be given 0.6 mg once or twice daily as maintenance regimen to prevent gout attack; may be combined with probenecid for maintenance treatment

(3) Adverse effects: abdominal cramps, diarrhea, nausea, and vomiting. Gastric intolerance may indicate toxicity (decrease the dose or discontinue the drug). Other adverse reactions indicating toxicity include numbness or tingling in the extremities, unusual bleeding or bruising, feeling weak or tired, increased infections, and pale or gray color of the lips, tongue, or palms.

(4) Be aware that concomitant use of P-glycoprotein (e.g., grapefruit juice) and strong CYP 3A4 inhibitors (e.g., erythromycin, clarithromycin) may cause severe drug interactions with colchicine, including death.

b. Allopurinol (Zyloprim)

(1) Mechanism of action: xanthine oxidase inhibitor

(2) Usual adult dose: 200 to 300 mg/day PO for mild gout and 400 to 600 mg/day for those with moderate to severe tophaceous gout. If daily dose is >300 mg, administer in divided doses twice daily.

c. Febuxostat (uloric)

(1) MOA: Same as allopurinol

(2) Usual adult dose: 40 to 80 mg PO once daily

d. Sulfinpyrazone: uricosuric agent

e. Probenecid: uricosuric agent

f. NSAID (ibuprofen, naproxen, indomethacin, sulindac)

g. Corticosteroids

Table 21-2 Common Medications Used in DMARD Therapy of RA

Drug	Typical adult maintenance dosage used in RA
Methotrexate	7.5–20 mg PO once weekly.
Hydroxychloroquine	200 mg PO twice daily
Sulfasalazine	1000 mg PO 2-3 times per day
Leflunomide	20 mg PO once daily if tolerated; otherwise, 10 mg/day
Etanercept	25 mg SC twice per week
Infliximab	3-10 mg/kg IV infusion given every 8 weeks
Anakinra	100 mg SC once daily
Adalimumab	40 mg SC every other week

PATIENT PROFILE

Patient Initials: JN

Height: 6′ 1″

Weight: 81.8 kg

Allergies: No known drug allergies (NKDA)

Patient Consultation: JN is a 60-year-old white man in overall good health who has just received a consultation with an orthopedic physician at the request of his family physician. He has increasing pain in his right knee with noted “creaking” feelings. The discomfort and stiffness are worse in the morning upon arising, and symptoms improve quickly as the patient gets up and “moves around.” He sometimes has difficulty with going down large flights of stairs, such as at the football stadium. Most daily activities are not limited by the condition at this time. He self-treated for several months with glucosamine/chondroitin but states “it did not help all that much.”

Current Health Conditions:

Familial hypercholesterolemia

Gastroesophageal reflux disease (GERD); now on maintenance therapy

Recent Laboratories:

Cholesterol: 180 mg/dL

LDL cholesterol: 120 mg/dL

Serum creatinine: 0.9 mg/dL

Rheumatoid factor: negative

Notes from recent doctor visit:

Joint findings local to the right knee only; + crepitus, slight reduction in range of motion (ROM). Radiologic exam at orthopedic office noted narrowing of the joint space and some apparent calcification. No effusions or erosions are present.

Social History: Tobacco use: None

Alcohol use: Occasional beer or wine when out to eat

Exercise: Avid runner in past; used to compete in marathons; still jogs for short distances a few times per week, but knee sometimes “gives way” and he has curtailed his running program in the past 6 months

Pharmacy Medication Profile:

Lipitor 20 mg PO once daily

Glucosamine/chondroitin supplement 500 mg PO three times per day

Prevacid 15 mg PO once daily in the morning

New Prescriptions:

Celebrex 100 mg PO twice daily

Physical therapy twice weekly for 2 weeks to learn quadriceps strengthening exercises; physician recommended moderate low-impact aerobic exercise (e.g., an aquatics program) in place of jogging to reduce impact on joints.

PATIENT PROFILE QUESTIONS

1. What symptoms does JN have that are consistent with a diagnosis of osteoarthritis (OA) versus rheumatoid arthritis?

I. Unilateral joint involvement of a large joint

II. Limited periods of morning stiffness (e.g., 30 minutes or less)

IV. Radiologic evidence

c. I, II, and IV

d. I, II, III, and IV

Answer: d. All of the above. Patients with osteoarthritis usually complain of symptoms in larger joints, and it is common that a unilateral joint is affected. Morning stiffness usually improves quickly upon arising as the patient moves about. Crepitus is a crackling sound of the joint that feels like a vibration on movement of the joint, which indicates wear and tear. Radiographic evidence of OA includes joint narrowing with osteophyte formation and sometimes tissue calcification. There are no laboratory alterations specifically associated with OA. JN has relatively mild to moderate OA at this time, given the lack of usual interference with normal activities of daily living, such as bathing. The presentation of OA differs significantly from that of rheumatoid arthritis (RA). RA involves four of the following seven findings: 1) morning stiffness usually lasting >1 hour, 2) symptoms in three or more joints, 3) involvement of the joints in the hands, 4) symptoms in symmetric joints, 5) rheumatoid nodules on physical exam, 6) positive serum rheumatoid factor, and 7) radiographic evidence of joint erosions and bony deformities. JN does not have symptoms consistent with RA.

2. JN will receive added benefit by continuing to take the glucosamine/chondroitin supplement with his new prescriptions.

Answer: b. False. JN has stated he has received no apparent benefit from the use of the supplement and continued therapy is not recommended. There is no evidence to state that continuing this supplement with Celebrex will confer additional benefit. Many organizations recommend that such supplements be discontinued if no apparent benefit is noted after 6 months of supplementation.

3. Which of the following is true regarding Celebrex therapy for JN?

I. The Prevacid prescription is likely to reduce his risk for an NSAID-induced ulcer.

II. If JN had listed an allergy to sulfa, Celebrex would be contraindicated.

III. The initial drug of choice for treating osteoarthritis pain is a NSAID.

IV. The Celebrex dose for JN is incorrect and should be 200 mg PO once daily.

e. II, III, and IV

Answer: b. Prevacid is one medication that can help prevent NSAID-induced gastrointestinal ulcers. Although JN does not have apparent risk factors for GI ulceration, it is an additional benefit conferred by his existing prescriptions. Celebrex contains a sulfa moiety in its chemical structure and is contraindicated in patients with a sulfa allergy. The initial medication recommended for treating the pain and symptoms of mild to moderate OA is usually acetaminophen; acetaminophen has been shown to be as effective as ibuprofen (NSAID) and poses less risk for side effects when taken within appropriate adult limits (e.g., no more than 1 gram four times per day). Patients with moderate to severe symptoms typically respond better to prescription therapies. The dose of Celebrex for OA is either 200 mg PO once daily or 100 mg PO twice daily; the current prescribed dose is correct.

REVIEW QUESTIONS

(Answers and Rationales on page 377.)

1. The drug(s) of choice for controlling hyperuricemia include:

III. Nizatidine

e. I, II, and III

2. Which of the following is a sign of colchicine toxicity?

a. Abdominal pain

b. Constipation

c. Photosensitivity

3. Which of the following is an oral gold compound?

b. Corticosteroids

d. Penicillamine

4. Which of the following medications must be given on an empty stomach?

a. Corticosteroids

e. Penicillamine

5. Which of the following should NOT be combined with allopurinol?

a. Methotrexate

b. Mercaptopurine

c. Cyclophosphamide

e. L-Asparaginase

6. Which of the following are considered uricosuric drugs?

III. Sulfinpyrazone

e. I, II, and III

7. Which of the following is/are drug(s) of choice for treating acute gout attacks?

I. Indomethacin

III. Allopurinol

e. I, II, and III

8. All of the following are true about rheumatoid arthritis EXCEPT:

a. More common in men than in women

b. Onset occurs commonly between the ages of 40 and 60

c. Smoking increases risk

d. There may be a genetic component

e. It is a chronic disease and there is no cure

9. True or False: Colchicine is not an analgesic or uricosuric agent.

10. Osteoarthritis involves which of the following tissues?

II. Articular cartilage

c. I and II only

d. II and III only

e. I, II, and III

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