Chapter 24 - Arthritis - Osteoarthritis, Gout, &amp Amp Rheumatoid Arthritis

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Chapter 24: Arthritis: Osteoarthritis, Gout, & Rheumatoid Arthritis
Bruce E. Johnson
INTRODUCTION
Arthritis is a complaint and a disease afflicting many patients and accounting for >10% of appointments to a generalist practice. Arthritis is
multifaceted and can be categorized in several different fashions. For simplicity, this chapter focuses on conditions affecting the anatomic joint
composed of cartilage, synovium, and bone. Other discussions would include localized disorders of the periarticular region (eg, tendonitis and
bursitis) and systemic disorders that have arthritic manifestations (eg, vasculitides, polymyalgia rheumatica, and fibromyalgia). The chapter discusses
three prototypical types of arthritis: osteoarthritis, as an example of a cartilage disorder; gout, as an example of both a crystal-induced arthritis and an
acute arthritis; and rheumatoid arthritis, as an example of an immune-mediated, systemic disease and a chronic deforming arthritis.
OSTEOARTHRITIS
ESSENTIALS OF DIAGNOSIS
Degenerative changes in the knee, hip, shoulder, spine, or virtually any other joint.
Pain with movement that improves with rest.
Joint deformity and mechanical alteration.
Sclerosis, thickening, spur formation, warmth, and effusion in the joints.
General Considerations
Arthritis is among the oldest identified conditions in humans. Anthropologists examining skeletal remains from antiquity deduce levels of physical
activity and work by searching for the presence of the degenerative changes of osteoarthritis (OA). OA is more prevalent among people in occupations
characterized by steady, physically demanding activity such as farming, construction, certain sports, and production-line work. Obesity is a significant
risk factor for OA, especially of the knee. Heredity and gender play a role in a person’s likelihood of developing OA, regardless of work or recreational
activity.
Pathogenesis
It is increasingly accepted that most OA results, at least in part, from altered mechanics within the joint. Certain metabolic conditions such as
hemochromatosis and Gaucher disease involve a genetic defect in collagen/cartilage. Altered mechanics may occur from minor gait abnormalities or
major traumas that, over a lifetime, result in repeated stress and damage to cartilage. Repeated trauma may result in microfracture of cartilage, with
incomplete healing due to continuation of the altered mechanics. Disruption of the otherwise smooth cartilage surface allows differential pressure on
remaining cartilage, as well as stress on the underlying bone. Debris from fractured cartilage acts as a foreign body, causing low-level inflammation
within the synovial fluid. Indeed, increasing evidence suggests that inflammation, from damaged cartilage or even as a primary activity, is involved in
most OA, and actions taken to reduce inflammation are increasingly used to alter the path to joint damage. These multiple influences combine to alter
intrinsic efforts at cartilage repair, leading to progressive cartilage destruction and bony joint change. Current thinking suggests that the process is not
immutable, but any intervention would have to be made while the joint is still asymptomatic—an unlikely occurrence.
Prevention
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Chapter 24: Arthritis: Osteoarthritis, Gout, &amp; Rheumatoid Arthritis, Bruce E. Johnson Page 1 / 23
It is difficult to advise patients on measures to prevent OA. Obese persons should lose weight, but few occupational or recreational precautions can be
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expected to alter the natural history of OA. Altered mechanics may be an important precipitating cause of arthritis, but recognizing minor changes,
especially within the currently accepted range of normal, makes diagnosis and preventive steps unrealistic.
within the synovial fluid. Indeed, increasing evidence suggests that inflammation, from damaged cartilage or even as a primary activity, is involved in
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most OA, and actions taken to reduce inflammation are increasingly used to alter the path to joint damage. These multiple influences combine to alter
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intrinsic efforts at cartilage repair, leading to progressive cartilage destruction and bony joint change. Current thinking suggests that the process is not
immutable, but any intervention would have to be made while the joint is still asymptomatic—an unlikely occurrence.
Prevention
It is difficult to advise patients on measures to prevent OA. Obese persons should lose weight, but few occupational or recreational precautions can be
expected to alter the natural history of OA. Altered mechanics may be an important precipitating cause of arthritis, but recognizing minor changes,
especially within the currently accepted range of normal, makes diagnosis and preventive steps unrealistic.
Berenbaum F, Wallace IJ, Lieberman DE, et al. Modern-day environmental factors in the pathogenesis of osteoarthritis. Nat Rev Rheumatol .
2018;14(11):674–681.
[PubMed: 30209413]
Brandt KD, Dieppe P, Radin E. Etiopathogenesis of osteoarthritis. Med Clin North Am . 2009;93:1–24.
[PubMed: 19059018]
Clinical Findings
A. Symptoms and Signs
Symptomatic OA represents the culmination of damage to cartilage, usually over many years. OA typically progresses from symptomatic pain to
physical findings to loss of function, but actually any of these can be first to present. OA can occur at any joint, but the most commonly involved joints
are the knee, hip, thumb (carpometacarpal), ankle, foot, and spine. The strongly inherited (primarily females) spur formations at the distal
interphalangeal joins (Heberden nodes) and proximal interphalangeal joints (Bouchard nodes) are often mistakenly referred to as OA. In fact, the
swelling and deformity are more an abnormality of bone itself rather than the joint. Indeed, pain or disability is actually rather uncommon in what
otherwise appear to be significantly altered joints (Figure 24–1).
Figure 24–1.
Heberden nodes (distal interphalangeal joint) noted on all fingers and Bouchard nodes (proximal interphalangeal joint) noted on most fingers.
Cartilage has no pain fibers, so the pain of OA arises from other tissues, most significantly bone itself. Osteoarthritic pain is typically associated with
movement, meaning that at rest the patient may be relatively asymptomatic. Patient’s awareness that at rest the joint is less painful can be maladaptive,
especially at weight-bearing joints such as knees, hips, and ankles. A protective role played by surrounding muscle of both a normal and arthritic joint
is that of a shock absorber. Well-maintained muscle can actually reduce mechanical stress on cartilage and bone. However, if a patient learns to favor
the involved joint, disuse of supporting muscle groups may result in relative muscle weakness. Such weakness may decrease the shock-absorber
effect, hastening joint damage. This mechanism also may lead to the complaint that a joint “gives way,” resulting in dropped items (if at the wrist) or
falls (if at the knee). In joints with mild OA, pain and instability may counterintuitively improve with exercise or activity.
Advanced OA is characterized by bony destruction and alteration of joint architecture. Secondary spur formation with deformity, instability,Page
or 2 / 23
Chapter 24: Arthritis: Osteoarthritis, Gout, &amp; Rheumatoid Arthritis, Bruce E. Johnson
restricted motion is a common finding. Fingers, wrists, knees, and ankles appear abnormal and
©2021 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibilityasymmetric. Warmth and effusion are seen in joints
with advanced OA. At this stage, pain may be exacerbated by any movement, weight-bearing, or otherwise.
especially at weight-bearing joints such as knees, hips, and ankles. A protective role played by surrounding muscle of both a normal and arthritic joint
is that of a shock absorber. Well-maintained muscle can actually reduce mechanical stress on cartilage and bone. However, ifUniversitas Islam Bandung
a patient learns to favor
the involved joint, disuse of supporting muscle groups may result in relative muscle weakness. Such weakness may decreaseAccess Provided by:
the shock-absorber
effect, hastening joint damage. This mechanism also may lead to the complaint that a joint “gives way,” resulting in dropped items (if at the wrist) or
falls (if at the knee). In joints with mild OA, pain and instability may counterintuitively improve with exercise or activity.
Advanced OA is characterized by bony destruction and alteration of joint architecture. Secondary spur formation with deformity, instability, or
restricted motion is a common finding. Fingers, wrists, knees, and ankles appear abnormal and asymmetric. Warmth and effusion are seen in joints
with advanced OA. At this stage, pain may be exacerbated by any movement, weight-bearing, or otherwise.
B. Laboratory Findings
There are few laboratory studies of relevance to the diagnosis of OA. Rarely, the erythrocyte sedimentation rate (ESR) will be raised, but only if an
inflammatory effusion is present (and even then, an elevated ESR or C-reactive protein is more likely to be misleading than helpful). If an effusion is
present, arthrocentesis can be helpful in ruling out other conditions (see discussion of laboratory findings in gout, later).
Osteoarthritis can be secondary to other conditions, and these diseases have their own laboratory evaluation. Examples include OA secondary to
hemochromatosis (elevated iron and ferritin, liver enzyme abnormalities), Wilson disease (elevated copper), acromegaly (elevated growth hormone),
and Paget disease (elevated alkaline phosphatase).
C. Imaging Studies
Radiographs are seldom helpful in early stages of OA because changes in cartilage are difficult to see in plain film radiographs. Plain films of joints
afflicted with advanced OA show changes of sclerosis, thickening, spur formation (enlargement of some aspects of bone), loss of cartilage with
narrowing of the joint space, and malalignment (Figure 24–2). Such radiographic changes typically occur late in the disease process. Patients may
complain of significant pain despite a relatively normal appearance of the joint on plain films. Conversely, considerable radiographic damage may be
seen with only modest symptoms. In addition, plain-film radiography does not provide useful information about cartilage, tendons, ligaments, or any
soft tissue. Such findings may be crucial to explaining a patient complaint, especially if there is loss of function.
Figure 24–2.
Osteoarthritis of the knees showing loss of joint space with marked reactive sclerosis and probable malalignment.
To see cartilage, ligaments, and tendons, magnetic resonance imaging (MRI) is important and, in many instances, essential. MRI can detect
abnormalities of the meniscus or ligaments of the knee; cartilage or femoral head deterioration at the hip; misalignment at the elbow; rupture of
muscle and fascia at the shoulder; and a host of other abnormalities. Any of these findings may be incorrectly diagnosed as OA before MRI scanning.
Computed tomography (CT) and ultrasonography have lesser, more specialized uses. CT, especially with contrast, can detect structural abnormalities
of large joints such as the knee or shoulder. Ultrasonography is an inexpensive means of detecting joint or periarticular fluid or unusual collections of
fluid such as a popliteal (Baker) cyst at the knee.
Differential Diagnosis
In practice, it should not be difficult to differentiate among the three prototypical arthritides discussed in this chapter. Table 24–1 suggests some key
differential findings. Page 3 / 23
Table 24–1.
Essentials of diagnosis.
Computed tomography (CT) and ultrasonography have lesser, more specialized uses. CT, especially with contrast, can detect structural abnormalities
of large joints such as the knee or shoulder. Ultrasonography is an inexpensive means of detecting joint or periarticular fluidUniversitas Islam Bandung
or unusual collections of
fluid such as a popliteal (Baker) cyst at the knee. Access Provided by:
In practice, it should not be difficult to differentiate among the three prototypical arthritides discussed in this chapter. Table 24–1 suggests some key
differential findings.
Table 24–1.
Essentials of diagnosis.
Osteoarthritis Gout Rheumatoid Arthritis
Key Pauciarticular; pain with movement, Monoarticular; abrupt onset; pain at rest Polyarticular; gradual, symmetric involvement;
presenting improving with rest; site of old injury and movement; precipitating event morning stiffness; hands and feet initially involved
symptoms (sport, trauma); obesity; occupation (meal, physical stress); family history more than large joints; fatigue, poorly restorative
sleep
Key Infrequent warmth, effusion; crepitus; Podagra; swelling, warmth; exquisite Symmetric swelling, tenderness; MCP, MTP, wrist,
physical enlargement/spur formation; pain with movement; single joint ankle usually before larger, proximal joints;
findings malalignment (exceptions: plantar fascia, lumbar rheumatoid nodules
spine); tophi
Key Few characteristic (early); loss of joint Synovial fluid with uric acid crystals; Elevated ESR/CRP; rheumatoid factor; anemia of
laboratory, space, spur formation, malalignment elevated serum uric acid; 24-hour urine chronic disease; early erosions on x-ray, osteopenia at
x-ray (late) uric acid involved joints
findings
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MCP, metacarpophalangeal; MTP, metatarsophalangeal.
A common source of confusion and misdiagnosis occurs when a bursitis-tendinitis syndrome mimics the pain of OA. A common example is anserine
bursitis. This bursitis, located medially at the tibial plateau, presents in a fashion similar to OA of the knee, but can be differentiated by a few simple
questions and directed physical findings.
Treatment
Typically, the early development of OA is silent. When pain occurs, and pain is almost always the presenting complaint, the osteoarthritic process has
already likely progressed to joint damage. Cartilage is damaged, bone reaction occurs, and debris mixes with synovial fluid. Consequently, when a
diagnosis of OA is established, goals of therapy become control of pain, restoration of function, and reduction of disease progression. Although
control of the patient’s complaints is possible, and long periods of few or no symptoms may ensue, the patient permanently carries a diagnosis of OA.
Treatment of OA involves multiple modalities and is inadequate if only a prescription for anti-inflammatory drugs is written. Patient education,
assessment for physical therapy and devices, and consideration of intra-articular injections are additional measures in the total management of the
patient.
Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and
pharmacologic therapies for osteoarthritis of the hand, hip and knee. Arthritis Care Res . 2012;64(4):465–474.
[PubMed: 22563589]
A. Patient Education
Patient education is a crucial step. Patients must be made aware of the role they play in successful therapy. Many resources are available to assist the
provider in patient education. Patient education pamphlets are widely available from government organizations, physician organizations (eg,
American College of Rheumatology, American Academy of Family Physicians), insurance companies, pharmaceutical companies, or patient advocacy
groups (eg, the Arthritis Foundation). Many communities have self-help or support groups that are rich sources of information, advice, and
encouragement.
Page 4 / 23
One of the most effective long-term measures to both improve symptoms and slow progression of disease is weight loss. Less weight carried by the
hip, knee, ankle, or foot reduces stress on the involved arthritic joint, decreases the destructive processes, and probably slows progression of disease.
A. Patient Education
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Patient education is a crucial step. Patients must be made aware of the role they play in successful therapy. Many resources are available to assist the
provider in patient education. Patient education pamphlets are widely available from government organizations, physician organizations (eg,
American College of Rheumatology, American Academy of Family Physicians), insurance companies, pharmaceutical companies, or patient advocacy
groups (eg, the Arthritis Foundation). Many communities have self-help or support groups that are rich sources of information, advice, and
encouragement.
One of the most effective long-term measures to both improve symptoms and slow progression of disease is weight loss. Less weight carried by the
hip, knee, ankle, or foot reduces stress on the involved arthritic joint, decreases the destructive processes, and probably slows progression of disease.
Unfortunately, because of the pain and occasional limited mobility of OA, exercise—an almost required component of weight loss regimens—is less
likely to be utilized. On the other hand, exercise is a crucial modality that should not be overlooked. Evaluation for appropriate exercise focuses on two
issues: overall fitness and correction of any joint-specific disuse atrophy. One must be flexible in the choice of exercise. Swimming is an excellent
exercise that limits stress on the lower extremities. Many older persons are reluctant to learn to swim anew, yet they may be amenable to water aerobic
exercises. These exercises encourage calorie expenditure, flexibility, and both upper and lower muscle strengthening in a supportive atmosphere.
Stationary bicycle exercise is also accessible to most people, is easy to learn, and may be acceptable to those with arthritis of the hip, ankle, or foot.
Advice from an occupational or recreational therapist can be most helpful.
Connelly AE, Tucker AJ, Kott LS, et al. Modifiable lifestyle factors are associated with lower pain levels in adults with knee osteoarthritis. Pain Res
Manag . 2015;20(5):241–248.
[PubMed: 26125195]
B. Physical Therapy and Assistive Devices
The pain of OA can result in muscular disuse. The best example is quadriceps weakness resulting from OA of the knee. The patient who favors the
involved joint loses quadriceps strength. This has two repercussions—both cushioning (shock absorption) and stabilization are lost. The latter is
usually the cause of the knee “giving way.” Sudden buckling at the knee, often when descending stairs, is rarely due to the destruction of cartilage or
bone but rather to inadequate strength in the quadriceps to handle the load required at the joint. Physical therapy with quadriceps strengthening is
highly efficacious, resulting in improved mobility, increased patient confidence, and reduction in pain.
The physical therapist or physiatrist should also be consulted for advice regarding assistive devices. Advanced OA of lower extremity joints may cause
instability and fear of falls that can be addressed by canes of various types. Altered posture or joint malalignment can be corrected by orthotics, which
has the advantage, when used early, of slowing progression of OA. Braces can protect the truly unstable joint and permit continued ambulation.
Fransen M, McConnell S. Land-based exercise for osteoarthritis of the knee: a metaanalysis of randomized controlled trials. J Rheumatol .
2009;36:1109–1117.
[PubMed: 19447940]
C. Pharmacotherapy
The patient wants relief from pain. Despite the widespread promotion of nonsteroidal anti-inflammatory drugs (NSAIDs) for OA, there is no evidence
that NSAIDs alter the course of the disease. Nevertheless, NSAIDs are used for their analgesic, rather than disease-modifying effects. Although effective
as analgesics, NSAIDs have significant side effects and are not necessarily first-line drugs.
Begin with adequate doses of acetaminophen. Acetaminophen should be prescribed in large doses, 3–4 g/d, and continued at this level until pain
control is attained. Once pain is controlled, dosage can be reduced if possible. Maintenance of adequate blood levels is essential, and because
acetaminophen has a relatively short half-life, frequent dosing is necessary (3 or 4 times a day). High doses of acetaminophen are generally well
tolerated, although caution is important in patients with liver disease or in whom alcohol ingestion is heavy.
Some patients find relief with medications delievered as gels or creams. There are a couple NSAIDs and capsaicin products that are formulated this
way, although compounding pharmacies may assist in delivering other products. Gels or creams tend to be more effective in small joints (fingers, wrist,
ankle) than larger joints, although it is occasionally surprising how benefit can be seen even in large, deeper joints such as the hip or shoulder. One
distinct advantage to gels or creams is relatively consistent lack of gastrointestinal upset. Unfortunately, this treatment rarely gives long-lasting relief.
Two main classes of NSAIDs are available, differentiated largely by half-life. NSAIDs with shorter half-lives (eg, diclofenac, ibuprofen) need more
frequent dosing than longer-acting agents (eg, naproxen, meloxicam). Several NSAIDs are available in generic or over-the-counter (OTC) form, which
reduces cost. Despite differing pharmacology, there is little difference in efficacy, so a choice of medication should be based on individual patient
issues such as dosing intervals, tolerance, toxicity, and cost. As with acetaminophen, adequate doses must be used for maximal effectiveness. For
tolerated, although caution is important in patients with liver disease or in whom alcohol ingestion is heavy.
Some patients find relief with medications delievered as gels or creams. There are a couple NSAIDs and capsaicin products that are formulated this
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way, although compounding pharmacies may assist in delivering other products. Gels or creams tend to be more effective in small joints (fingers, wrist,
ankle) than larger joints, although it is occasionally surprising how benefit can be seen even in large, deeper joints such as the hip or shoulder. One
distinct advantage to gels or creams is relatively consistent lack of gastrointestinal upset. Unfortunately, this treatment rarely gives long-lasting relief.
Two main classes of NSAIDs are available, differentiated largely by half-life. NSAIDs with shorter half-lives (eg, diclofenac, ibuprofen) need more
frequent dosing than longer-acting agents (eg, naproxen, meloxicam). Several NSAIDs are available in generic or over-the-counter (OTC) form, which
reduces cost. Despite differing pharmacology, there is little difference in efficacy, so a choice of medication should be based on individual patient
issues such as dosing intervals, tolerance, toxicity, and cost. As with acetaminophen, adequate doses must be used for maximal effectiveness. For
example, ibuprofen at doses of ≤800 mg 3 or 4 times a day should be maintained (if tolerated) before concluding that a different agent is necessary.
Examples of NSAID dosing are given in Table 24–2.
Table 24–2.
Selected nonsteroidal anti-inflammatory drugs with usual and maximal doses.
Drug Frequency of Administration Usual Daily Dose (mg/d) Maximal Dose (mg/d)
Oxaprozin (eg, Daypro) Every day 1200 1800
Piroxicam (eg, Feldene) Every day 10–20 20
Nabumetone (eg, Relafen) 1–2 times a day 1000–2000 2000
Sulindac (eg, Clinoril) Twice a day 300–400 400
Naproxen (eg, Naprosyn) Twice a day 500–1000 1500
Diclofenac (eg, Voltaren) 2–4 times a day 100–150 200
Ibuprofen (eg, Motrin) 3–4 times a day 600–1800 2400
Etodolac (eg, Lodine) 3–4 times a day 600–1200 1200
Ketoprofen (eg, Orudis) 3–4 times a day 150–300 300
Occasionally patients find help with pain management by use of medications originally developed for psychiatric conditions. The more common
medications used in this manner include duloxetine (Cymbaltra), escitalopram (Lexapro), and citalopram (Celexa). It is unclear how these medications
help with arthritic pain management since patients are infrequently diagnosed with depression, anxiety, or bipolar disorders. However, the use of such
agents should at least be considered before proceeding to some other medications or more invasive treatments.
Because such a major thrust of OA management is pain control, one must acknowledge the role played by narcotics. Narcotics should be confined to
the patient with severe disease incompletely controlled by nonpharmacologic and nonnarcotic analgesics and in whom joint replacement is not
indicated. The narcotic medication should be additive to all other measures; for instance, full-dose acetaminophen or NSAIDs should be continued.
The patient must be reminded of the fluctuating nature of OA symptoms and not expect complete elimination of pain. Once narcotics are started (in
any patient for any cause), most generalist practices institute monitoring measures such as a “drug contract” or referral to a specialist pain
management clinic.
Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee arthritis, Part II: OARSI evidence-based, expert
consensus guidelines. Osteoarthr Cartilage . 2008;16:137–162.
[PubMed: 18279766]
D. Intra-articular Injections
Hyaluronic acid (hyaluronan) is a constituent of both cartilage and synovial fluid. Injection of hyaluronic acid, usually in a series of several weekly
Chapter 24: Arthritis: Osteoarthritis, Gout, &amp; Rheumatoid Arthritis, Bruce E. Johnson Page 6intra-
/ 23
articular insertions, is purported to provide improvement in symptomatic OA for ≤6 months. It is unknown why hyaluronic acid helps; there is no
evidence that hyaluronic acid is incorporated into cartilage, and it apparently does not slow the progression of OA. It is expensive, and the injection
process is painful. Use of these agents (Synvisc, Artzal) is limited to patients who have failed other forms of OA therapy.
consensus guidelines. Osteoarthr Cartilage . 2008;16:137–162.
[PubMed: 18279766] Universitas Islam Bandung
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D. Intra-articular Injections
Hyaluronic acid (hyaluronan) is a constituent of both cartilage and synovial fluid. Injection of hyaluronic acid, usually in a series of several weekly intra-
articular insertions, is purported to provide improvement in symptomatic OA for ≤6 months. It is unknown why hyaluronic acid helps; there is no
evidence that hyaluronic acid is incorporated into cartilage, and it apparently does not slow the progression of OA. It is expensive, and the injection
process is painful. Use of these agents (Synvisc, Artzal) is limited to patients who have failed other forms of OA therapy.
Intra-articular injection of corticosteroids has been both under- and overutilized in the past. There is little question that steroid injection rapidly
reduces inflammation and eases symptoms. The best use is one in which the patient has an exacerbation of pain accompanied by signs of
inflammation (warmth, effusion). The knee is most commonly implicated and is most easily approached. Most authorities recommend no more than
two injections during one episode and limiting injections to no more than two or three episodes per year. Benefits of injection are often shorter in
duration than similar injection for tendinitis or bursitis, but the symptomatic improvement buys time to reestablish therapy with oral agents, physical
exercise, and assistive devices.
New therapeutic investigation and translational studies hold some promise for actual cartilage modification of damaged joints. Therapies involving
strontium ranelate, platelet-rich plasma injections, and mesenchymal stem cells are currently in stages of development and may truly alter the
otherwise somewhat relentless progression of this disease.
Reginster JY, Badurski J, Bellamy N, et al. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind,
randomized placebo-controlled trial. Ann Rheum Dis . 2013;72:179–186.
[PubMed: 23117245]
Two new intra-articular injections for knee osteoarthritis. JAMA . 2018;320(21):2262–2263.

[PubMed: 30512097]
E. Surgery
At one time, orthopedic surgeons performed arthroscopic surgery on osteoarthritic knees in an effort to remove accumulated debris and to polish or
débride frayed cartilage. However, a clinical trial using a sham-procedure methodology demonstrated that benefit from this practice could be
explained by the placebo effect. Numbers of these procedures have reduced rather significantly, although there still remain some indications for
performing this operation.
Joint replacement is a well-established option for treatment of OA, especially of the knee and hip. Pain is reduced or eliminated altogether. Mobility is
improved, although infrequently to premorbid levels. Expenditures for total joint replacement have been increasing dramatically as the Baby Boomer
generation reaches the age at which OA of large joints is more common. Indications for joint replacement (which also apply to other joints, including
shoulder, elbow, and fingers) include pain poorly controlled with maximal therapy, malalignment, and decreased mobility. Improvement in pain relief
and quality of life should be realized in approximately 90% of patients undergoing the procedure. Because complications of both the surgery and
rehabilitation are increased by obesity, few orthopedic surgeons will consider hip or knee replacement without at least an attempt by the obese patient
to lose weight. Patients need to be in adequate medical condition to undergo the operation and even more so to endure the often lengthy
rehabilitation process. Some surgeons refer patients for “prehabilitation” or physical training prior to the operation. Counseling of patients should
include the fact that there often is a 4- to 6-month recovery period involving intensive rehabilitation.
Kirkley A, Birmingham TB, Litchfield RB, et al. A randomized trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med .
2008:359(11):1097–1107.
[PubMed: 18784099]
Moseley JB, O’Malley K, Petersen NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med . 2002;347:81.
[PubMed: 12110735]
F. Complementary and Alternative Therapies

Chapter 24: Arthritis: Osteoarthritis, Gout, &amp; Rheumatoid Arthritis, Bruce E. Johnson Page 7 /and
Glucosamine, capsaicin, bee venom, acupuncture, and a host of other products have been promoted as alternative therapies for OA. Glucosamine 23
chondroitin sulfate are components of glycosaminoglycans, which make up cartilage; although some advocates might suggest otherwise, there is no
evidence that orally ingested glucosamine or chondroitin sulfate is actually incorporated into cartilage. Studies suggest these agents are superior to
Moseley JB, O’Malley K, Petersen NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Universitas Islam Bandung
Med . 2002;347:81.
[PubMed: 12110735] Access Provided by:
F. Complementary and Alternative Therapies
Glucosamine, capsaicin, bee venom, acupuncture, and a host of other products have been promoted as alternative therapies for OA. Glucosamine and
chondroitin sulfate are components of glycosaminoglycans, which make up cartilage; although some advocates might suggest otherwise, there is no
evidence that orally ingested glucosamine or chondroitin sulfate is actually incorporated into cartilage. Studies suggest these agents are superior to
placebo in symptomatic relief of mild OA. The onset of action is delayed, sometimes by weeks, but the effect may be prolonged after treatment is
stopped. Glucosamine–chondroitin sulfate combinations are available over the counter and are generally well tolerated by patients.
Capsaicin, a topically applied extract of the chili pepper, relieves pain by depletion of substance P, a neuropeptide involved in pain sensation.
Capsaicin is suggested for tendinitis or bursitis but may be tried for OA of superficial joints such as the fingers. The cream should be applied 3 or 4
times a day for ≥2 weeks before reaching any conclusion regarding benefit.
Bee venom is promoted in complementary medicine circles. A mechanism for action in OA is unclear. Although anecdotal reports are available,
comparison studies to other established treatments are difficult to find. Various vitamins (D, K) and minerals have been recommended for treatment of
OA but are supported, if at all, by only poorly controlled studies.
Acupuncture can be useful in managing pain and improving function. There are more comparisons between acupuncture and conventional treatment
for OA of the back and knee than for other joints. Generally, acupuncture is equivalent to oral treatments for mild symptoms at these two sites.
Prognosis
Investigations into restoring and rebuilding damaged cartilage continue, but consistent positive results are elusive. Prevention, or at least delay of
development, of OA is the major impact physicians can have on the population. However, these efforts involve activities that are themselves
challenging to accomplish, such as weight control or avoidance of joint stress from jobs and recreational activities. Much of the current, and
anticipated, management of OA will continue to be pain control, appropriate exercise for joint protection, orthotics and braces/devices, and surgery.
GOUT
Podagra (intense inflammation of the first metatarsophalangeal joint).
Inflammation of the overlying skin.
Pain at rest and intense pain with movement.
Swelling, warmth, redness, and effusion.
Tophi (in long-established disease).
Elevated serum uric acid level.
Gout, first described by Hippocrates in the fourth century BCE, has a colorful history, characterized as a disease of excesses, primarily gluttony. An
association with diet is germane, as gout has a lower incidence in countries in which obesity is uncommon and the diet is relatively devoid of alcohol
and reliance on meat and abdominal organs (liver, spleen). Gout is strongly hereditary as well, affecting as many as 25% of the men in some families.
Prevention
Despite the previously noted associations, it is difficult with any assurance to advise patients on measures to prevent gout. Even thin vegetarians
develop gout, although at a markedly lower rate than obese, alcohol-drinking men. Gout has multiple etiologies, and no consistent preventive steps
are available to patients.
Clinical Findings

Prevention
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Despite the previously noted associations, it is difficult with any assurance to advise patients on measures to prevent gout. Even thin vegetarians
develop gout, although at a markedly lower rate than obese, alcohol-drinking men. Gout has multiple etiologies, and no consistent preventive steps
are available to patients.
Clinical Findings
Gout classically presents as an acute monoarthritis, perhaps best described by Thomas Sydenham in the seventeenth century. Podagra—abrupt,
intense inflammation of the first metatarsophalangeal joint—remains the most common presentation (Figure 24–3). The first attack often occurs
overnight, with intense pain awakening the patient. Any pressure, even a bed sheet on the toe, increases the agony. Walking is difficult. The overlying
skin can be intensely inflamed. On questioning, an exacerbating event may be elicited. Common stories include an excess of alcohol, a heavy meal of
abdominal organs, or a recent physiologic stress such as surgery or serious medical disease. Alcohol alters renal excretion of uric acid, allowing rapid
buildup of serum uric acid levels. Foods such as liver, sweetbread, anchovies, sardines, asparagus, salmon, and legumes contain relatively large
quantities of purines that, when broken down, become uric acid.
Figure 24–3.
Classic podagra involving the first metatarsophalangeal joint. In this photo, the ankle is also involved and the intense erythema could be mistaken for
cellulitis.
Acute gout is not limited to the great toe; any joint may be affected, although lower extremity joints are more common.
The typical abrupt, single-joint presentation may be overlooked (Table 24–3). Hence, given any acute monoarthritis, one should certainly search for
both inflammatory and noninflammatory clues that would be suggestive of a diagnosis other than gout.
Table 24–3.
Inflammatory and noninflammatory causes of monoarthritis.
Inflammatory Noninflammatory
Crystal-induced gout Fracture or meniscal tear or other

Pseudogout (calcium pyrophosphate deposition disease) trauma
Apatite (and others) Osteoarthritis
Infectious Tumors
Bacteria Osteochondroma
Fungi Osteoid osteoma
Lyme disease or other spirochetes Pigmented villonodular synovitis
Tuberculosis and other mycobacteria Precancerous growths
Viruses (eg, HIV, hepatitis B) Osteonecrosis
Chapter 24: Arthritis: Osteoarthritis, Gout, &amp; Rheumatoid Arthritis, Bruce E. Johnson Hemarthrosis Page 9 / 23
Systemic diseases
Cancers
Psoriatic or other spondyloarthropathies
Reactive (eg, inflammatory bowel, Reiter syndrome)
Acute gout is not limited to the great toe; any joint may be affected, although lower extremity joints are more common. Universitas Islam Bandung
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The typical abrupt, single-joint presentation may be overlooked (Table 24–3). Hence, given any acute monoarthritis, one should certainly search for
both inflammatory and noninflammatory clues that would be suggestive of a diagnosis other than gout.
Table 24–3.
Inflammatory and noninflammatory causes of monoarthritis.
Inflammatory Noninflammatory
Crystal-induced gout Fracture or meniscal tear or other

Pseudogout (calcium pyrophosphate deposition disease) trauma
Apatite (and others) Osteoarthritis
Infectious Tumors
Bacteria Osteochondroma
Fungi Osteoid osteoma
Lyme disease or other spirochetes Pigmented villonodular synovitis
Tuberculosis and other mycobacteria Precancerous growths
Viruses (eg, HIV, hepatitis B) Osteonecrosis
Hemarthrosis
Systemic diseases
Cancers
Psoriatic or other spondyloarthropathies
Reactive (eg, inflammatory bowel, Reiter syndrome)
Systemic lupus erythematosus
Reproduced with permission from Klipper JH: Primer on the Rheumatic Diseases, 11th ed. Atlanta, GA: Arthritis Foundation; 1997.
Gout in joints other than the great toe is actually not uncommon in older women and in men who have already had several previous attacks of podagra
(gout of the great toe). A not uncommon presentation of gout in an older woman may initially be mistaken for plantar fasciitis. Gout of the ankle with
inflammation and even a positive Homans sign can be mistaken for phlebitis.
Untreated, attacks of gout spontaneously resolve, with the involved joint becoming progressively less symptomatic over 8–10 days. Longstanding,
untreated gout with consistent elevated uric acid can result in the development of extra-articular manifestations. Tophi are deposits of urate crystals
and are classically found as nodules in the ear helix or elsewhere; atypically placed tophi (eg, Heberden nodes, heart valves) serve as the source of
colorful medical anecdotes. Chronic, untreated gout is a contributor to renal insufficiency (especially in association with heavy metal lead exposure).
Physiologic stress is a common precipitating factor for an acute attack. Monoarthritis within days of a surgical procedure raises concern of infection
(which it should!) but is just as likely due to crystal-induced gout or pseudogout. In some circumstances, prophylaxis in a person with known gout can
prevent these attacks.
Approximately 10% of kidney stones include uric acid. A person with nephrolithiasis due to uric acid stones need not have attacks of gout, but patients
with gout are at increased risk of developing uric acid stones. A prior history of nephrolithiasis is an important factor in choosing therapy in the patient
with gout.
Gout is largely a disease of men, with a male-to-female ratio of 9:1. The first attack of podagra typically occurs in men in their 30s or 40s. One attack
need not necessarily predict future attacks. In fact, some 20% of men who have a first attack of gout never have a second episode. In addition, even
after a second attack of gout, about 5% do not progress to recurrent attacks. Hence, although a correct diagnosis should be made, it may not be
necessary to institute long-term therapy after a first of second episode of acute monarthritis due to gout.
Premenopausal women rarely have gout; indeed, confirmed gout in a young woman might raise the question of an inborn error of metabolism.
Diagnosis of gout in postmenopausal women is infrequent, less so because it does not occur than because it is unsuspected. Gout is also more likely to
have an atypical presentation in joints other than the great toe in women. A high index of suspicion must be practiced.
The fundamental abnormality in gout is excess uric acid. In most first attacks of gout, serum uric acid is elevated. In longstanding disease, the uric acid
value may be within the normal range, yet symptoms still occur. It is important to note, however, that mild hyperuricemia has a rather highPageprevalence
Chapter 24: Arthritis: Osteoarthritis, Gout, &amp; Rheumatoid Arthritis, Bruce E. Johnson 10 / 23
in the general population. Indeed, fewer than 25% of persons with elevated uric acid will ever
©2021 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility have gout.
During acute attacks of gout, the white blood cell count may be slightly elevated and ESR increased, reflecting acute inflammation. Gout is not
Diagnosis of gout in postmenopausal women is infrequent, less so because it does not occur than because it is unsuspected. Gout is also more likely to
have an atypical presentation in joints other than the great toe in women. A high index of suspicion must be practiced.
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The fundamental abnormality in gout is excess uric acid. In most first attacks of gout, serum uric acid is elevated. In longstanding disease, the uric acid
value may be within the normal range, yet symptoms still occur. It is important to note, however, that mild hyperuricemia has a rather high prevalence
in the general population. Indeed, fewer than 25% of persons with elevated uric acid will ever have gout.
During acute attacks of gout, the white blood cell count may be slightly elevated and ESR increased, reflecting acute inflammation. Gout is not
uncommon in chronic kidney disease, and measurement of blood urea nitrogen and creatinine is recommended following a first gout attack.
Gout usually results from either inappropriately low renal excretion of uric acid (implicated in 90% of patients) or abnormally high endogenous
production of uric acid. Collecting a 24-hour urine sample for the evaluation of uric acid and creatinine clearance can be useful in therapy (discussed
as follows).
A strong recommendation must be made to attempt arthrocentesis of the joint in suspected acute gout. First episodes of gout present as an acute
monoarthritis, for which the differential diagnosis is noted in Table 24–3. It is extremely important to rule out infectious arthritis because this
condition could lead to sepsis as well as possible permanent damage to the joint. Synovial fluid analysis should distinguish between infection and the
crystal conditions, gout and pseudogout. This may be somewhat difficult on the basis of clinical presentation alone. However, excess white blood cells
(plus bacteria if seen on stain) or crystals should lead to a diagnosis. The presence of negatively birefringent needle-shaped crystals is diagnostic of
gout and confirms the correct diagnosis. Features of synovial fluid in selected disease settings are highlighted in Table 24–4.
Table 24–4.
Synovial fluid analysis in selected rheumatic diseases.
Disease Fluid WBC Count (in Fluid) Differential Glucose Crystals
Gout Clear/cloudy 10–100,000 >50% PMNs Normal Needle-shaped, negative birefringence
Pseudogout Clear/cloudy 10–100,000 >50% PMNs Normal Rhomboid-shaped, positive birefringence
Infectious Cloudy >50,000 Often >95% PMNs Decreased Nonea
Osteoarthritis Clear 2–10,000 <50% PMNs Normal Nonea
Rheumatoid Clear 10–50,000 >50% PMNs Normal or decreased Nonea

arthritis
aDebris in synovial fluid may be misleading on plain microscopy, but only crystals respond to polarizing light.
PMNs, polymorphonuclear leukocytes; WBC, white blood cells.
C. Imaging Studies
Radiographs are not needed for the diagnosis of gout. Other means of diagnosing gout (eg, arthrocentesis) are more useful. Characteristic erosions
occur with longstanding gout but are rarely seen in first attacks.
The first attack of gout must be distinguished from an acute monoarthritis. A review of Tables 24–1 and 24–3 is relevant.
Treatment
The inflammation of acute gout is effectively managed with anti-inflammatory medications. Once recognized, most cases of gout can be controlled
within days, occasionally within hours. Remaining as a challenge is the decision regarding long-term treatment.
Standard therapy for acute gout is a short course of NSAIDs at adequate levels. As one of the first NSAIDs developed, indomethacin (50 mgPage
Chapter 24: Arthritis: Osteoarthritis, Gout, &amp; Rheumatoid Arthritis, Bruce E. Johnson 3 or 411times
/ 23
a day) is occasionally assumed to be somehow unique in the treatment of gout. In fact, all NSAIDs are probably equally effective, although many
practitioners feel that response is faster with short-acting agents such as naproxen (375–500 mg 3 times a day) or ibuprofen (800 mg 3 or 4 times a day).
Pain often decreases on the first day, with treatment indicated for not much more than 3–5 days.
The first attack of gout must be distinguished from an acute monoarthritis. A review of Tables 24–1 and 24–3 is relevant.
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Treatment
The inflammation of acute gout is effectively managed with anti-inflammatory medications. Once recognized, most cases of gout can be controlled
within days, occasionally within hours. Remaining as a challenge is the decision regarding long-term treatment.
Standard therapy for acute gout is a short course of NSAIDs at adequate levels. As one of the first NSAIDs developed, indomethacin (50 mg 3 or 4 times
a day) is occasionally assumed to be somehow unique in the treatment of gout. In fact, all NSAIDs are probably equally effective, although many
practitioners feel that response is faster with short-acting agents such as naproxen (375–500 mg 3 times a day) or ibuprofen (800 mg 3 or 4 times a day).
Pain often decreases on the first day, with treatment indicated for not much more than 3–5 days.
A classic medication for acute gout is colchicine. Typically given orally, the instructions to the patient can sound bizarre. The drug is prescribed every
1–2 hours “until relief of pain or uncontrollable diarrhea.” Most attacks actually respond to the first two or three pills, with a maximum of six pills in 24
hours as a prudent upper limit. Most patients develop diarrhea well before the sixth pill. Colchicine is then dosed 3 times daily and, as with NSAIDs, is
seldom needed after 3–5 days. Around 2009, using a feature in US Food and Drug Administration (FDA) law, colchicine actually received new
medication status and was allowed to be patented. This permitted the pharmaceutical company to charge prices as much as 50 times the previous cost.
By 2016, the FDA persuaded the company to allow a generic version of colchicine to be marketed, resulting (once again) in more affordable medication
for an acute episode of gout.
On occasion, corticosteroids are used in acute gout. Oral prednisone (eg, ≥60 mg), methylprednisolone or triamcinolone (eg, 40–80 mg)
intramuscularly, or intra-articular agents can be used. Indications include intense overlying skin involvement (mimicking cellulitis), polyarticular
presentation of gout, and contraindication to NSAID or colchicine therapy. Intra-articular steroid use may be considered for ankle or knee gout, if
infection is ruled out.
Decisions regarding long-term treatment of gout must factor in the individual’s history of attacks. The first attack, especially in young men with a clear
precipitating event (eg, an alcohol binge), may not be followed by a second attack for years, even decades. As stated earlier, as many as 20% of men will
never have a second gouty attack. Data from the Framingham longitudinal study suggest that intervals of ≤12 years are common between first and
second attacks. This is not always the case for young women with gout (who tend to have a uric acid metabolic abnormality) or for either men or
women who have polyarticular gout. But for many young men, a reasonable recommendation after a first episode is to watch expectantly but not
necessarily to treat with uric acid–lowering drugs.
The physician and patient may even decide to withhold prophylactic medication after a second attack, but when episodes of gout become more
frequent than one or two a year, both physician and patient are usually ready to consider long-term medication. The primary medications used at this
point are probenecid and the xanthine oxidase inhibitors allopurinol and febuxostat. Probenecid is a uric acid tubular reuptake inhibitor that results in
increased excretion of uric acid in the urine. Allopurinol and febuxostat inhibit the uric acid synthesis pathway, blocking the step at which xanthine is
converted to uric acid. Xanthine is much more soluble than uric acid and is not implicated in acute arthritis, nephrolithiasis, or renal insufficiency.
Until recently, guidelines recommended obtaining 24-hour uric acid excretion levels. The patient found to have low excretion of uric acid (<600 mg/d)
and normal renal function was often prescribed probenecid. Probenecid loses effectiveness when the creatinine clearance falls below 50 mL/min, so
alternative therapy was necessary in patients with chronic kidney disease. If the patient had uric acid nephrolithiasis, probenecid was contraindicated
to avoid increased delivery of uric acid to the stone-forming region.
Recent guidelines from the American College of Rheumatology have modified this approach. These guidelines now suggest that initial therapy can
begin with a xanthine oxidase inhibitor, obviating the need to measure 24-hour uric acid excretion. The guidelines recommend treating to a serum uric
acid level of ≤6 g/dL. If this goal cannot be reached with xanthine oxidase inhibitors alone (an infrequent occurrence), probenecid might then be
added. This newer modification recognizes that both allopurinol and febuxostat are well tolerated with infrequent toxic side effects. An important
difference, though, is that allopurinol is usually dosed lower in chronic kidney disease because of the potential for adverse effects, whereas febuxostat
does not seem to have such dosing requirements. Interestingly, a relatively recent (2016) American College of Physicians guideline on treatment of
gout reinforced the treat-to-symptoms approach more typically used by physicians—that is, to treat several attacks of gout with anti-inflammatory
agents such as NSAIDs or colchicine with no chronic medication until there have been several attacks, which then warrant long-term treatment with
either a uric acid excretion agent or a xanthine oxidase inhibitor.
Recently, the FDA has issued a “black box” warning for both allopurinol and febuxostat. The warning is regarding possible cardiovascular adverse
events with the use of either agent. The likelihood of any adverse event is felt to be low but is an issue that should be considered when choosing one of
these agents for long-term therapy.
White WB, Saag KG, Becker MA, et al. Cardiovascular safety of febuxostat and allopurinol in patients with gout. N Engl J Med . 2018;378(13):1200–
1210.
[PubMed: 29527974]
Recently, the FDA has issued a “black box” warning for both allopurinol and febuxostat. The warning is regarding possible cardiovascular adverse
events with the use of either agent. The likelihood of any adverse event is felt to be low but is an issue that should be considered when choosing one of
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these agents for long-term therapy.
White WB, Saag KG, Becker MA, et al. Cardiovascular safety of febuxostat and allopurinol in patients with gout. N Engl J Med . 2018;378(13):1200–
1210.
[PubMed: 29527974]
Xanthine oxidase inhibitors are especially indicated for treatment of tophaceous gout and for uric acid nephrolithiasis. These agents also are drugs of
choice for those with uric acid metabolic abnormalities (often young women) and polyarticular gout. Caution must be used, however, when starting
any uric acid–lowering drug for the first time. Rapid lowering of the serum uric acid causes instability of uric acid crystals within the synovial fluid and
can actually precipitate an attack of gout. Consequently, prior establishment of either NSAID or colchicine therapy is recommended to obviate this
complication.
Patients are occasionally seen who have been prescribed long-term therapy with colchicine. There is some conceptual attraction to this choice.
Between attacks of gout (the “intercritical period”), examination of synovial fluid continues to show uric acid crystals. Using colchicine to prevent the
spiral to inflammation seems to make sense. But this choice is deceptive. Colchicine does nothing to lower uric acid levels. Long-term use allows
deposition of uric acid into destructive tophi or contributes to renal disease and kidney stones. Colchicine can be an effective prophylactic agent,
however, if started prior to a surgical procedure in a patient with known gout who is not using allopurinol or probenecid. However, use of this drug as a
solo agent can result in significant complications.
Prognosis
Gouty attacks can be both effectively treated and prevented. A clear diagnosis is important, and arthrocentesis is essential. Management is relatively
straightforward, and no patient should have to endure tophi or repeated acute attacks.
Kanna D, Fitzgerald JD, Khanna PP, et al. American College of Rheumatology guidelines for management of gout. Part 1: systemic nonpharmacologic
and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res . 2012;64:1431–1446.
[PubMed: 23024028]
Kanna D, Khanna PP, Fitzgerald JD, et al. American College of Rheumatology guidelines for management of gout. Part 2: therapy and anti-
inflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res . 2012;64:1447–1461.
[PubMed: 23024029]
Qaseem A, Harris RP, Forciea MA, et al. Management of acute and recurrent gout: A clinical practice guideline from the American College of
Physicians. Ann Intern Med . 2017;166(1):58–68.
[PubMed: 27802508]
RHEUMATOID ARTHRITIS
Arthritis of three or more joint areas.
Arthritis in hands, feet, or both (bilateral joint involvement).
Morning stiffness.
Fatigue.
Swelling, tenderness, warmth, and loss of function.
Rheumatoid nodules.
Elevated ESR and C-reactive protein.

Positive test for rheumatoid factor. Page 13 / 23
[PubMed: 27802508]
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RHEUMATOID ARTHRITIS
Arthritis of three or more joint areas.
Arthritis in hands, feet, or both (bilateral joint involvement).
Morning stiffness.
Fatigue.
Swelling, tenderness, warmth, and loss of function.
Rheumatoid nodules.
Elevated ESR and C-reactive protein.
Positive test for rheumatoid factor.
Bony changes consistent with rheumatoid arthritis (RA) have been found in the body of a Native American who lived 3000 years ago. Differentiation of
RA from other types of arthritis is more recent, delineated only in the late nineteenth century. RA is more frequently seen in women, with the ratio of
premenopausal women to age-matched men approximately 4:1; after the age of menopause, the ratio of incident RA is closer to 1:1.
Pathogenesis
Although the etiology of RA is not known, the pathophysiology has been elucidated to a remarkable degree in recent decades. Important knowledge of
all inflammatory processes has come from studies in RA. Early in the disease process, the synovium of joints is targeted by T cells (this is the feature
that leads to the “autoimmune” moniker). Release of interleukins, lymphokines, cytokines, tissue necrosis factor, and other messengers attracts
additional inflammatory cells to the synovium. Intense inflammation ensues, experienced by the patient as pain, warmth, swelling, and loss of
function. Reactive cells move to the inflammatory synovium, attempting to repair damaged tissue. Without treatment, this intense reaction develops
into the pathologic tissue called pannus, an exuberant growth of tissue engulfing the joint space and causing destruction itself. Cartilage becomes
swept into the pathologic process, resulting in breakdown, deterioration, and eventual destruction. Periarticular bone responds to inflammation with
resorption, seen as erosions on radiographs. All these changes clearly are maladaptive and responsible for deformity and disability.
Prevention
Because the etiology of RA is not fully elucidated, it is difficult to counsel patients on measures that might prevent the arthritis. Besides, because it is
not even clear that there is a hereditary component to the disease, there rarely are occasions when the physician would be approached about steps
that might be taken to prevent it. There is some suggestion that RA may be more common in smokers, but clearly there are stronger reasons to advise
patients to stop smoking than bringing up the somewhat remote possibility of developing RA.
Clinical Findings
RA is a systemic disease always involving joints but with inflammatory responses that include fatigue, rash, nodules, and even clinical depression as
joints become increasingly stiff and inflamed. Most, but by no means all, of the initial symptoms are in the joints. There is inflammation, so the
presence of swelling, warmth, and loss of function is imperative to the diagnosis. Joints of the hands (Figure 24–4) and feet are typically affected first,
although larger joints can be involved at any time. The disease is classically symmetric with symptoms present bilaterally in hands, feet, or both. This
mirroring is almost unique to RA; systemic lupus erythematosus, which is often confused with RA in its early stages, is not so consistently symmetric.
Figure 24–4.
Swelling of the proximal interphalangeal joints of the second and third fingers in rheumatoid arthritis. Symmetric swelling might be expected on the
other hand.
joints become increasingly stiff and inflamed. Most, but by no means all, of the initial symptoms are in the joints. There is inflammation, so the
presence of swelling, warmth, and loss of function is imperative to the diagnosis. Joints of the hands (Figure 24–4) and feet areUniversitas Islam Bandung
typically affected first,
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although larger joints can be involved at any time. The disease is classically symmetric with symptoms present bilaterally in hands, feet, or both. This
mirroring is almost unique to RA; systemic lupus erythematosus, which is often confused with RA in its early stages, is not so consistently symmetric.
Figure 24–4.
Swelling of the proximal interphalangeal joints of the second and third fingers in rheumatoid arthritis. Symmetric swelling might be expected on the
other hand.
Fingers and wrists are stiff and sore in the mornings, requiring heat, rubbing, and movement to be functional (“morning stiffness”). Stiffness after
prolonged lack of movement (“gelling”) is seen in many joint disorders, but the morning stiffness of RA is prolonged and characteristic enough that
queries regarding this symptom are quite helpful as one works toward a diagnosis.
The patient often reports fatigue out of proportion to lack of sleep. Daytime naps are almost unavoidable, yet are not fully restorative. Anorexia, weight
loss, or even low-grade fever can be present. Along with musculoskeletal complaints, these somatic concerns may lead to mistaken diagnoses of
fibromyalgia or even depression.
RA can eventually involve almost any joint in the body. Selected important manifestations of RA in specific joints are listed in Table 24–5. Because the
hand and wrist are so commonly affected by RA, the complications listed for these sites are so likely seen in long-standing disease as to be almost
pathognomonic. The cause of any one manifestation may be unique to a particular joint and the surrounding periarticular structure. Common features
include inflammation-induced stretching of tendons and ligaments resulting in joint laxity, subconscious restriction of movement resulting in “frozen”
joints, and consequences of inflammatory synovitis with cartilage destruction and periarticular bone erosion. An objective sign of destruction includes
the high-pitched, “crunchy” sound of crepitus.
Table 24–5.
Manifestations of rheumatoid arthritis in specific joints.
Joint Complication
Hand Ulnar deviation (hand points toward ulnar side), swan neck deformity (extension of PIP joint), Boutonniere deformity (flexion at DIP)
pathognomonic. The cause of any one manifestation may be unique to a particular joint and the surrounding periarticular structure. Common features
include inflammation-induced stretching of tendons and ligaments resulting in joint laxity, subconscious restriction of movement resulting in “frozen”
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joints, and consequences of inflammatory synovitis with cartilage destruction and periarticular bone erosion. An objective sign of destruction includes
the high-pitched, “crunchy” sound of crepitus.
Table 24–5.
Manifestations of rheumatoid arthritis in specific joints.
Joint Complication
Hand Ulnar deviation (hand points toward ulnar side), swan neck deformity (extension of PIP joint), Boutonniere deformity (flexion at DIP)
Wrist Swelling causing carpal tunnel syndrome
Elbow Swelling causing compressive neuropathy

Deformity preventing complete extension, loss of power
Shoulder “Frozen shoulder” (loss of abduction, nighttime pain)
Neck Subluxation of C1-C2 joint with danger of dislocation and spinal cord compression (“hangman’s injury”)
Foot “Cockup” deformity and/or subluxation at MTP
Knee Effusion leading to Baker cyst (evagination of synovial lining and fluid into popliteal space)
DIP, distal interphalangeal; MTP, metatarsophalangeal; PIP, proximal interphalangeal.
Extra-articular manifestations of RA can be seen at any stage of disease. Most common are rheumatoid nodules, found at some point in ≤50% of all
patients with RA. These occur almost anywhere in the body, especially along pressure points (the typical olecranon site), along tendons, or in bursae.
Vasculitis is an uncommon initial presentation of RA. Dry eyes and mouth are seen in the RA-associated sicca syndrome. Dyspnea, cough, or even chest
pain may signal respiratory interstitial disease. Cardiac, gastrointestinal, and renal involvement in RA is not common. Peripheral nervous system
symptoms are seen as compression neuropathies (eg, carpal or tarsal tunnel syndrome) and reflect not so much direct attack on nerves, but rather
primarily as consequences of squeezing compression as nerves are forced into passages narrowed by nearby inflammation.
In contrast to OA, the laboratory findings in RA can be significant and helpful. A normocytic anemia is common in active RA. This anemia is almost
always the so-called anemia of chronic disease. The white blood cell count is normal or even slightly elevated; an exception is the rare Felty syndrome
(leukopenia and splenomegaly in a patient with known RA).
RA does not typically affect electrolytes and renal function. There is no pathophysiologic reason why transaminases, bilirubin, alkaline phosphatase,
or other liver, pancreatic, or bone enzymes should be altered. Similarly, calcium, magnesium, and phosphate values should be unchanged. Most
hormone measurements are normal, particularly thyroid and the adrenal axis. Any chronic inflammatory disease may alter the menstrual cycle, but
measurement of luteinizing hormone and follicle-stimulating hormone is of little help.
An elevated ESR is almost ubiquitous in RA; this is not surprising since RA is clearly a strong, chronic inflammatory state. However, there are more than
a few conditions in which the measured ESR might be altered because of other physiologic states. For instance, the ESR, even in a patient with active
RA, might be inappropriately “normal” if there also are red blood cell changes such as sickle cell or microcytosis, or blood protein abnormalities such
as hyperviscosity or polycythemia. For these reasons, rheumatologists often also measure the C-reactive protein (CRP), another measure of
inflammation. The CRP is not affected by many of the conditions that can interfere with measurement of the ESR. An elevated CRP, just as the ESR, is
indicative of an inflammatory state (though is not specific for RA).
The test most associated with RA is the rheumatoid factor (RF) blood test. RF is actually a family of antibodies, the most common of which is an
immunoglobulin M (IgM) antibody directed against the Fc (fragment, crystallizable) portion of immunoglobulin G (IgG). There is no question this
antibody is frequently present in RA, with RF-negative RA accounting for only approximately 5% of all patients with RA. The problem lies with the low
specificity of the test. Surveys demonstrate that in a young population, 3–5% of “normal” individuals have a high RF titer (positive test), whereas in an
older cohort, the prevalence of positive RF reaches 25%. With the national prevalence of RA only 1%, it is clear that many people with an elevated RF
titer do not have RA. In fact, a false-positive RF titer is a common reason for incorrect referral of patients to rheumatologists. Some of the conditions
that are associated with a positive RF test are listed in Table 24–6.
Table 24–6.
indicative of an inflammatory state (though is not specific for RA).
The test most associated with RA is the rheumatoid factor (RF) blood test. RF is actually a family of antibodies, the most common of which is an
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immunoglobulin M (IgM) antibody directed against the Fc (fragment, crystallizable) portion of immunoglobulin G (IgG). There is no question this
antibody is frequently present in RA, with RF-negative RA accounting for only approximately 5% of all patients with RA. The problem lies with the low
specificity of the test. Surveys demonstrate that in a young population, 3–5% of “normal” individuals have a high RF titer (positive test), whereas in an
older cohort, the prevalence of positive RF reaches 25%. With the national prevalence of RA only 1%, it is clear that many people with an elevated RF
titer do not have RA. In fact, a false-positive RF titer is a common reason for incorrect referral of patients to rheumatologists. Some of the conditions
that are associated with a positive RF test are listed in Table 24–6.
Table 24–6.
Conditions associated with a positive rheumatoid factor test.
Normal aging
Chronic bacterial infections
Subacute bacterial endocarditis
Tuberculosis
Lyme disease
Others
Viral disease
Cytomegalovirus
Epstein-Barr virus
Hepatitis B
Chronic inflammatory diseases

Sarcoidosis
Periodontal disease
Chronic liver disease (especially viral)
Sjögren syndrome
Systemic lupus erythematosus
Mixed cryoglobulinemia
Another frequent test useful for diagnosis of RA in the early stages is the anticyclic citrullinated peptide (anti-CCP; also called anticitrullinated
protein/peptide antibody [ACPA]). This test is positive in most patients with RA and may precede the onset of clinically diagnosed RA by months or even
years. When combined with the RF test, this test will confirm the diagnosis even in confusing settings.
Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for
rheumatoid arthritis. Ann Intern Med . 2007;146:797–808.
[PubMed: 17548411]
Suarez-Almazor ME, Gonzalez-Lopez L, Gamez-Nava JI, et al. Utilization and predictive value of laboratory tests in patients referred to
rheumatologists by primary care physicians. J Rheumatol . 1998;25:1980–1985.
[PubMed: 9779854]
C. Imaging Studies
Radiographs are no longer needed for the initial diagnosis of RA. Other means of diagnosing RA are more useful. Nonetheless, RA is a disease of
synovial tissue, and, because the synovium lies on and attaches to bone, inflammation can cause changes on plain film radiography. Small erosions, or
lucencies, on the lateral portions of phalanges are early indications of significant inflammation and should prompt immediate suppressive treatment.
Computed tomography and/or MRI have limited but useful supporting roles. An undesired complication of treatment of RA, aseptic necrosis (eg, of the
femoral head), has a characteristic appearance on MRI. Although MRI can be used to differentiate the synovitis of RA from infection (eg, septic arthritis,
osteomyelitis), positive cultures are much more important to eventual diagnosis and treatment.
In practice, it should not be difficult to differentiate among the three prototypical arthritides discussed in this chapter (see Table 24–1). Relatively new
synovial tissue, and, because the synovium lies on and attaches to bone, inflammation can cause changes on plain film radiography. Small erosions, or
lucencies, on the lateral portions of phalanges are early indications of significant inflammation and should prompt immediate suppressive treatment.
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Computed tomography and/or MRI have limited but useful supporting roles. An undesired complication of treatment of RA, aseptic necrosis (eg, of the
femoral head), has a characteristic appearance on MRI. Although MRI can be used to differentiate the synovitis of RA from infection (eg, septic arthritis,
osteomyelitis), positive cultures are much more important to eventual diagnosis and treatment.
In practice, it should not be difficult to differentiate among the three prototypical arthritides discussed in this chapter (see Table 24–1). Relatively new
(2010) criteria developed by subspecialty organizations give valuable guidelines to making an accurate diagnosis of RA (Table 24–7). Because treatment
started early is generally successful, rheumatologists promote early referral—treating a new diagnosis of RA almost as a “medical emergency.”
Table 24–7.
1987 American College of Rheumatology diagnostic criteria for rheumatoid arthritis.
The diagnosis of rheumatoid arthritis is confirmed if the patient has had at least four of the seven following criteria, with criteria 1–6
present for ≥6 weeks:
1. Morning stiffness (≥1 hour)
2. Arthritis of three or more joint areas (areas are right or left of proximal interphalangeal joints, metacarpophalangeal, wrist, elbow, knee, ankle, and
metatarsophalangeal)
3. Arthritis of hand joints (proximal interphalangeal joints or metacarpophalangeal joints)
4. Symmetric arthritis, by area
5. Subcutaneous rheumatoid nodules
6. Positive test for rheumatoid factor
7. Radiographic changes (hand and wrist radiography showing erosion of joints or unequivocal demineralization around joints)
Adapted with permission from Arnett FC, Edworthy SM, Bloch DA, et al: The American Rheumatism Association 1987 revised criteria for the classification of
rheumatoid arthritis. Arthritis Rheum 1988; Mar;31(3):315–324.
Moreland LW, Bridges SL Jr. Early rheumatoid arthritis: a medical emergency? Am J Med . 2001;111:498.
[PubMed: 11690579]
Neil VP, Machold KP, Eberl G, et al. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with
early rheumatoid arthritis. Rheumatology . 2004;43:906–914.
[PubMed: 15113999]
Complications
Serious extra-articular manifestations of RA are not infrequent. Some of these are life-threatening and require sophisticated management by
physicians experienced in dealing with these crises. The responsibility often remains with the primary care physician to recognize these conditions and
refer the patient appropriately. Table 24–8 lists several of these complications with a brief description of the clinical presentation.
Table 24–8.
Extra-articular manifestations of rheumatoid arthritis (RA).
Complication Brief Comments
Rheumatoid Found over pressure points, classically olecranon; typically fade with disease-modifying antirheumatic drug (DMARD) therapy; also
nodules may be found in internal organs; if causing disability, may attempt intralesional steroids, or surgery
Popliteal cyst Usually asymptomatic unless ruptures, then mimics calf thrombophlebitis; ultrasonography (and high index of suspicion) useful
Anemia Usually “chronic disease” and, despite low measured iron, does not respond to oral iron therapy; improves with control of
inflammatory disease
Scleritis/episcleritis Inflammatory lesion of conjunctiva; more prolonged, intense, and uncomfortable than “simple” conjunctivitis; requires
Complications
Serious extra-articular manifestations of RA are not infrequent. Some of these are life-threatening and require sophisticated management by
Access Provided by:
physicians experienced in dealing with these crises. The responsibility often remains with the primary care physician to recognize these conditions and
refer the patient appropriately. Table 24–8 lists several of these complications with a brief description of the clinical presentation.
Table 24–8.
Extra-articular manifestations of rheumatoid arthritis (RA).
Complication Brief Comments
Rheumatoid Found over pressure points, classically olecranon; typically fade with disease-modifying antirheumatic drug (DMARD) therapy; also
nodules may be found in internal organs; if causing disability, may attempt intralesional steroids, or surgery
Popliteal cyst Usually asymptomatic unless ruptures, then mimics calf thrombophlebitis; ultrasonography (and high index of suspicion) useful
Anemia Usually “chronic disease” and, despite low measured iron, does not respond to oral iron therapy; improves with control of
inflammatory disease
Scleritis/episcleritis Inflammatory lesion of conjunctiva; more prolonged, intense, and uncomfortable than “simple” conjunctivitis; requires
ophthalmologic management
Pulmonary disease Ranges from simple pleuritis and pleural effusion (noted for low glucose) to severe bronchiolitis, interstitial fibrosis, nodulosis, and
pulmonary vasculitis; may require high-dose steroid therapy once diagnosis established by bronchoscopy or even open-lung biopsy
Sjögren syndrome Often occurring with RA, includes sicca syndrome with thickened respiratory secretions, dysphagia, vaginal atrophy,
hyperglobulinemia, and distal renal tubule defects; treatment of sicca syndrome possible with muscarinic receptor agonists; other
manifestations more difficult
Felty syndrome Constellation of RA, leukopenia, splenomegaly, and often anemia, thrombocytopenia; control underlying RA with DMARDs; may
need granulocyte colony-stimulating factor, especially if infectious complications are frequent
Rheumatoid Spectrum from digital arteritis (with hemorrhage) to cutaneous ulceration to mononeuritis multiplex to severe, life-threatening
vasculitis multisystem arteritis involving heart, gastrointestinal tract, and other organs; resembles polyarteritis nodosum
Treatment
Therapy of RA has changed from managing inflammation to specific measures directed against the fundamental sources of the inflammation. In more
recent decades, treatment of RA has undergone perhaps the most wholesale shift of any of the rheumatologic conditions. Therapy is now directed at
fundamental processes and begins with aggressive, potentially toxic disease-modifying drugs. The outlook can be hopeful, with preservation of joints,
activity, and lifestyle a realistic goal. RA need no longer be the “deforming arthritis” by which it was known just a short time ago.
Kremers HM, Nicola P, Crowson CS, et al. Therapeutic strategies in rheumatoid arthritis over a 40-year period. J Rheumatol . 2004;31:2366–2373.
[PubMed: 15570636]
A. Assessment of Prognostic Factors
One of the early steps in treating RA is to assess prognostic factors in the individual patient. Poor prognosis leads to the decision to start aggressive
treatment earlier. Some prognostic features are demographic, such as female sex, age >50 years, low socioeconomic status, and a first-degree relative
with RA. Clinical features associated with poor prognosis include a large number of affected joints, especially involvement of the flexor tendons of the
wrist, with persistence of swelling at the fingers; rheumatoid nodules; high ESR or C-reactive protein and high titers of RF; presence of erosions on
radiographs; and evidence of functional disability. Formal functional testing and disease activity questionnaires are frequently employed, not only in
establishing stage of disease but also at interval visits. In practice, though, most rheumatologists urge their generalist colleagues to refer patients
identified with new-onset RA early. Despite certain prognostic factors noted earlier, most patients are indicated for, and respond to, early therapeutic
intervention.
Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use
in clinical practice. Arthritis Care Res . 2012;64:640–647.
treatment earlier. Some prognostic features are demographic, such as female sex, age >50 years, low socioeconomic status, and a first-degree relative
with RA. Clinical features associated with poor prognosis include a large number of affected joints, especially involvement ofUniversitas Islam Bandung
the flexor tendons of the
wrist, with persistence of swelling at the fingers; rheumatoid nodules; high ESR or C-reactive protein and high titers of RF; presence of erosions on
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radiographs; and evidence of functional disability. Formal functional testing and disease activity questionnaires are frequently employed, not only in
establishing stage of disease but also at interval visits. In practice, though, most rheumatologists urge their generalist colleagues to refer patients
identified with new-onset RA early. Despite certain prognostic factors noted earlier, most patients are indicated for, and respond to, early therapeutic
intervention.
Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use
in clinical practice. Arthritis Care Res . 2012;64:640–647.
[PubMed: 22473918]
B. Patient Education
Therapy begins with patient education, and again, there are multiple sources of information from support and advocacy groups, professional
organizations, government sources, and pharmaceutical companies. Patients should learn about the natural history of RA and the therapies available
to interrupt the course. They should learn about joint protection and the likelihood that at least some activities need to be modified or discontinued.
RA, especially before disease modification is established, is a fatiguing disorder. Patients should realize that rest is as important as appropriate types
of activity. Of vital importance is the patient’s acknowledgment that drug regimens about to be started are complex but that compliance is critical to
successful outcomes. The patient should frankly be told that the drugs are toxic and may have adverse effects.
C. Pharmacotherapy
1. Pain relief
Pain in RA is caused by inflammation, and establishment of effective anti-inflammatory drugs is the first goal of RA intervention. This is a step often
expected of generalist physicians if there is likely to be delay in referral of the newly diagnosed RA patient to the rheumatologist. NSAIDs, at doses
recommended earlier (see Table 24–2), give the patient early relief. NSAIDs continue to be used throughout the course of treatment; it is not
uncommon to switch from one to another as effectiveness falters. It should be noted, though, that NSAIDs will not alter the course of the disease, and
the patient should not be deluded into thinking that early pain relief substitutes for comprehensive treatment.
However, the effective management of RA should limit uncontrolled pain. Indeed, the goal of RA management is to find treatments that will alter the
otherwise progressive course of disease and that will also alter and control joint pain. Indeed, the goal of any RA management is to find therapies that
will limit pain. Consequently, both generalist and specialist physicians to the patient with RA should continuously seek treatment modifications rather
than settle for a degree of uncontrolled pain that might prompt use of narcotics.
2. Complementary and alternative medicine
If the patient is reluctant to start drugs, fish oil supplementation may provide symptomatic relief. But the same caution mentioned earlier for pain relief
applies to complementary and alternative therapies—these products do not alter the natural history of RA. Even with some degree of pain relief and
anti-inflammatory efficacy, these products are no substitute for effective treatment.
Nevertheless, physicians regularly are asked for recommendations of alternative treatments. Both omega-3 and omega-6 fatty acids in fish oil
modulate synthesis of highly inflammatory prostaglandin E2 and leukotriene E4. The fish oil chosen must contain high concentrations of the relevant
fatty acids. A large number of capsules need to be taken, and palatability, diarrhea, and halitosis are frequent adverse effects. γ-Linolenic acid
interrupts the pathway of arachidonic acid, another component of the inflammatory cascades. Extracted from the oils of plant seeds such as linseed,
sunflower seed, and flaxseed, γ-linolenic acid demonstrates some efficacy in short-term studies using large doses of the extract.
3. Anti-inflammatory medications
RA is an inflammatory disease, and all treatments are directed, in one way or another, to the reduction or elimination of the inflammatory process.
Patients with RA will be taking one form of anti-inflammatory medication throughout the course of the disease.
As noted earlier, NSAIDs are almost continuously recommended, even with other effective treatments established. It is common to switch from one
drug to another as efficacy wanes. It is important to modify use of NSAIDs if well-identified effects are noted. Gastrointestinal upset, even
gastrointestinal bleeding, is common; this may be ameliorated as well by use of H2-blockers such as ranitidine or proton pump inhibitors such as
omeprazole. NSAID use should be modified, if not discontinued, in advancing stages of chronic kidney disease.
Steroids are widely used in RA. Relatively high-dose oral or parenteral use of steroids can reduce inflammation in the early stages of RA or at times of
RA flare. Certain manifestations of RA, such as vasculitis or pulmonary involvement, will require steroids for more prolonged periods of time. The use
of steroids for intra-articular injection into symptomatic joints can enhance systemic anti-inflammatory medications. The well-known complications of
RA is an inflammatory disease, and all treatments are directed, in one way or another, to the reduction or elimination of the inflammatory process.
Patients with RA will be taking one form of anti-inflammatory medication throughout the course of the disease.
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As noted earlier, NSAIDs are almost continuously recommended, even with other effective treatments established. It is common to switch from one
drug to another as efficacy wanes. It is important to modify use of NSAIDs if well-identified effects are noted. Gastrointestinal upset, even
gastrointestinal bleeding, is common; this may be ameliorated as well by use of H2-blockers such as ranitidine or proton pump inhibitors such as
omeprazole. NSAID use should be modified, if not discontinued, in advancing stages of chronic kidney disease.
Steroids are widely used in RA. Relatively high-dose oral or parenteral use of steroids can reduce inflammation in the early stages of RA or at times of
RA flare. Certain manifestations of RA, such as vasculitis or pulmonary involvement, will require steroids for more prolonged periods of time. The use
of steroids for intra-articular injection into symptomatic joints can enhance systemic anti-inflammatory medications. The well-known complications of
high-dose steroids require that these be used only for short periods of time if at all possible
Sulfasalazine has been noted to have some efficacy as an anti-inflammatory in RA; initially, this was found when patients with RA were also being
treated for another inflammatory condition (eg, inflammatory bowel disease). Another antibiotic, minocycline, may have similar anti-inflammatory
effects. It is evident that the mechanism is not through some bacterial/viral effect but likely through inhibition of metalloproteinase metabolism.
4. Disease-modifying antirheumatic drugs (DMARDs)
These agents are almost always the first line of intensive therapy for patients newly diagnosed with RA. Fortunately, a large number of patients can be
maintained in disease remission with use of medications in this category. Depending on the classification used to describe RA therapy, there may be a
limited number of DMARD agents available, or some of these may be used in combination with agents described under anti-inflammatories earlier.
Nonetheless, almost all patients with RA will be prescribed agents in this class at some time during their therapy.
The prototypical DMARD agent is methotrexate. Methotrexate is effective at decreasing inflammation, lowering ESR, slowing bony erosions, and
reducing destructive pannus. Methotrexate is generally given in weekly doses with beneficial results seen as early as 4–6 weeks. Treatment can be
continued for years. Toxicity includes liver and hematologic changes, and regular monitoring is essential. Other adverse effects are not infrequent and
may require modification of dose. For most patients, there will be regular modification of the dose in an attempt to find the lowest effective dose.
Azathioprine and cyclosporine are occasionally used as DMARDs, although rarely concurrently with methotrexate. Complications from these drugs are
well recognized, and patient counseling should be extensive before use. One use for these agents appears to be during therapy for complications such
as vasculitis. Another antibiotic, the antimalarial drug hydroxychloroquine, is often given in conjunction with methotrexate. There is a rare, but
unfortunate, adverse effect to the retina seen with use of hydroxychloroquine that requires periodic ophthalmologic visits. Leflunomide blocks protein
synthesis by lymphocytes and has been shown to be almost as effective as methotrexate. However, its half-life is almost 2 weeks, and liver toxicity is not
infrequent. In addition, leflunomide has been associated with birth defects, making effective contraception mandatory when used in women of
reproductive age.
5. Tissue necrosis factor (TNF) inhibitors
TNF is a messenger that attracts other inflammatory cells to a site. TNF is also involved in production of interferon and interleukins. Blockade of these
TNF effects diminishes the inflammatory response, both decreasing patient symptoms and slowing disease progression. Etanercept, infliximab, and
adalimumab are examples of frequently used TNF inhibitors in treatment of RA. Other TNF inhibitors are available and occasionally used in very
specific circumstances. These drugs require subcutaneous or intravenous injection, as often as every other week. Yet, they are relatively well tolerated,
and any hematologic toxicity responds to discontinuation. Although TNF inhibitors carry FDA indication for moderate to severe RA, they are often given
with methotrexate or even as single agents.
A serious consideration relates to the role of TNF inhibitors in host defenses. In particular, patients on TNF inhibitors who have tuberculosis often have
rapid extrapulmonary spread and poor response to treatment. Consequently, assurance of the absence of tuberculosis, either by the purified protein
derivative test or even the blood-based test QuantiFERON, is indicated.
6. Interleukin (IL) inhibitors
IL inhibitors have found increasing use in RA, typically in conjunction with other modalities. IL-6 inhibitor (tocilizumab) and IL-1 inhibitor (anakinra)
block different steps in both immune response and acute-phase response. Both inhibitors can be used with methotrexate for added disease-modifying
activity. Side effects are not uncommon, ranging from local injection inflammation to leukopenia, liver enzyme abnormalities, and even alterations in
lipids. In addition, interleukin inhibitors should not be used with TNF inhibitors because infectious complications are increased.
7. T-cell blockade
Continuing the effort to block parts of the immune and/or inflammatory response, the T-cell blocker abatacept functions by arresting activation of
naïve T cells. When used in conjunction with other DMARDs, there can be a moderate improvement in response criteria in a significant number of
patients. This agent does carry an increased risk of infection. In addition, perhaps because of suppressed immune surveillance, there is concern for
IL inhibitors have found increasing use in RA, typically in conjunction with other modalities. IL-6 inhibitor (tocilizumab) and IL-1 inhibitor (anakinra)
block different steps in both immune response and acute-phase response. Both inhibitors can be used with methotrexate for added disease-modifying
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activity. Side effects are not uncommon, ranging from local injection inflammation to leukopenia, liver enzyme abnormalities, and even alterations in
lipids. In addition, interleukin inhibitors should not be used with TNF inhibitors because infectious complications are increased.
7. T-cell blockade
Continuing the effort to block parts of the immune and/or inflammatory response, the T-cell blocker abatacept functions by arresting activation of
naïve T cells. When used in conjunction with other DMARDs, there can be a moderate improvement in response criteria in a significant number of
patients. This agent does carry an increased risk of infection. In addition, perhaps because of suppressed immune surveillance, there is concern for
increased risk of neoplasia.
8. B-cell depletion
The biologic agent rituximab is widely used in treatment of B-cell lymphoma and has also been demonstrated to have efficacy in RA similar to that of
abatacept. Rituximab works by blocking a signaling molecule from mature B cells, resulting in the depletion of B cells. Reduction of B cells reduces the
inflammatory response in the synovium of the patient with RA. This agent, along with abatacept, may be used in patients with a poor response to TNF
inhibitors. Other “biologics” are being developed or introduced for therapy of RA. The choice of one agent over another is very often related as much
to the rheumatologist preference and experience as to medical studies showing increased efficacy.
9. Drug administration and precautions
Although many of the anti-inflammatory and DMARD medications can be taken orally, most of the TNF inhibitors, the IL inhibitors, and the T- and B-cell
blockers must be given either by injection (subcutaneous) or intravenous infusion. Since the frequency of administration, even once stabilized, ranges
from weekly to monthly, it is clear that the patient will have frequent office visits to the rheumatologist. Unfortunately, local or systemic reaction to
these agents is frequent and may require coadministration of other drugs (often steroids) to ameliorate the reactions.
As noted earlier, a frequent concern in use of biologics is increased infection. Patients are routinely tested for subclinical tuberculosis infection and
are strongly advised to remain up to date with immunizations. Specific immunizations to be considered should include pneumococcal (both 23 and 13
strains), human papillomavirus, hepatitis B, and herpes zoster. The yearly influenza vaccine should be strongly considered. Most vaccines can be given
even while the patient is receiving DMARDS; current evidence suggests that even the herpes zoster vaccine is effective if given to a patient receiving
biologic agents. A concern also alluded to earlier is the possibility of increased occurrence of neoplasm. Since the purpose of most of these products is
to suppress the immune/inflammatory response, the very real concern is that neoplasia surveillance mechanisms are also suppressed. To date,
although tumors have been reported during use of these agents, there does not seem to be a significant increase in incidence.
Singh JA, Furst DE, Bharat A, et al. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying
antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res . 2012;64:625–639.
[PubMed: 22473917]
Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care
Res . 2016;68:1–25.
[PubMed: 26545825]
Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-
modifying antirheumatic drugs. Ann Rheum Dis . 2010;69:964–977.
[PubMed: 28264816]
D. Surgery
Joint instability and resultant disability are often due to a combination of joint destruction, a primary effect of synovial inflammation, and tendon or
ligament laxity, a secondary effect or “innocent bystander.” The innocent bystander effect notes that these connective tissues are stretched,
weakened, or malaligned as a result of inflammation of the joints over which they cross, but not the result of a direct attack on the tendon or ligament
itself. Nonetheless, at some point, joint destruction and connective tissue laxity combine to produce useless, and frequently painful, joints. At this
point, the surgeon has much to offer. Joint stabilization, connective tissue reinsertion, and joint replacement of both small (interphalangeal) and large
(hip, knee) joints provide return of function and reduction of pain. The timing of surgery is still an art and is most effective when close collaboration
exists between the treating physician and surgeon.
Prognosis
Morbidity and mortality are increased in patients with RA over age-matched persons without RA. Correlated with active disease, there is a well-
ligament laxity, a secondary effect or “innocent bystander.” The innocent bystander effect notes that these connective tissues are stretched,
weakened, or malaligned as a result of inflammation of the joints over which they cross, but not the result of a direct attack on Universitas Islam Bandung
the tendon or ligament
itself. Nonetheless, at some point, joint destruction and connective tissue laxity combine to produce useless, and frequentlyAccess Provided by:
painful, joints. At this
point, the surgeon has much to offer. Joint stabilization, connective tissue reinsertion, and joint replacement of both small (interphalangeal) and large
(hip, knee) joints provide return of function and reduction of pain. The timing of surgery is still an art and is most effective when close collaboration
exists between the treating physician and surgeon.
Prognosis
Morbidity and mortality are increased in patients with RA over age-matched persons without RA. Correlated with active disease, there is a well-
described increase in stroke and myocardial infarction. These manifestations may be due to a hypercoagulable state induced by the autoimmune
process and circulating antibodies. There are suggestions that the increased rate of stroke and myocardial infarction may be reduced by effective
DMARD therapy. Even so, it is recommended that appropriate cardiovascular interventions be considered (eg, aspirin, lipid management). Even under
conscientious treatment, complications from infection, pulmonary and renal disease, and gastrointestinal bleeding occur at rates higher than those in
the general population. Many of the latter complications are related as much to the drugs used to control the disease as to the disease itself.
Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis. JAMA . 2018;320(13);1360–1372.
[PubMed: 30285183]
Myasoedova E, Gabriel SE. Cardiovascular disease in rheumatoid arthritis: a step forward. Curr Opin Rheumatol . 2010;22:342–347.
[PubMed: 20164773]
Websites
American Academy of Family Physicians (Family doctor–designed for patient information more than the academy website). www.familydoctor.org
American College of Physicians (for physicians; little of relevance for patients—nothing on OA, gout, or RA readily found—and much that requires sign-
in by members). www.acponline.org
American College of Rheumatology (a section for patients, “Patient Resources,” with appropriately written information is available without sign-in).
www.rheumatology.org
Arthritis Foundation (user-friendly information for patients, written without medical jargon, somewhat superficial, strong community support).
www.arthritis.org
National Center for Complementary and Alternative Medicine (National Institutes of Health [NIH]) (for physicians and patients; easy to use;
comprehensive; balanced information on conventional and alternative treatments). www.nccam.nih.gov
National Guideline Clearinghouse (for physicians; functions as a search engine for guidelines on subject desired; links to publications, some of which
require sign-in; comprehensive and international). www.guideline.gov
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH) (for physicians and sophisticated patients; relatively easy to use;
comprehensive, though technical, information). www.niams.nih.gov

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CURRENT Diagnosis & Treatment: Family Medicine, 5e

Chapter 24: Arthritis: Osteoarthritis, Gout, & Rheumatoid Arthritis

Pain with movement that improves with rest.

Joint deformity and mechanical alteration.

Sclerosis, thickening, spur formation, warmth, and effusion in the joints.

A. Symptoms and Signs

Osteoarthritis Gout Rheumatoid Arthritis

B. Physical Therapy and Assistive Devices

Oxaprozin (eg, Daypro) Every day 1200 1800

Piroxicam (eg, Feldene) Every day 10–20 20

Nabumetone (eg, Relafen) 1–2 times a day 1000–2000 2000

Sulindac (eg, Clinoril) Twice a day 300–400 400

Naproxen (eg, Naprosyn) Twice a day 500–1000 1500

Diclofenac (eg, Voltaren) 2–4 times a day 100–150 200

Ibuprofen (eg, Motrin) 3–4 times a day 600–1800 2400

Etodolac (eg, Lodine) 3–4 times a day 600–1200 1200

Ketoprofen (eg, Orudis) 3–4 times a day 150–300 300

Two new intra-articular injections for knee osteoarthritis. JAMA . 2018;320(21):2262–2263.

F. Complementary and Alternative Therapies

F. Complementary and Alternative Therapies

Podagra (intense inflammation of the first metatarsophalangeal joint).

Inflammation of the overlying skin.

Pain at rest and intense pain with movement.

Swelling, warmth, redness, and effusion.

Tophi (in long-established disease).

Elevated serum uric acid level.

A. Symptoms and Signs

A. Symptoms and Signs

Crystal-induced gout Fracture or meniscal tear or other

Crystal-induced gout Fracture or meniscal tear or other

Systemic lupus erythematosus

Disease Fluid WBC Count (in Fluid) Differential Glucose Crystals

Gout Clear/cloudy 10–100,000 >50% PMNs Normal Needle-shaped, negative birefringence

Pseudogout Clear/cloudy 10–100,000 >50% PMNs Normal Rhomboid-shaped, positive birefringence

Infectious Cloudy >50,000 Often >95% PMNs Decreased Nonea

Osteoarthritis Clear 2–10,000 <50% PMNs Normal Nonea

Rheumatoid Clear 10–50,000 >50% PMNs Normal or decreased Nonea

PMNs, polymorphonuclear leukocytes; WBC, white blood cells.

these agents for long-term therapy.

Arthritis of three or more joint areas.

Arthritis in hands, feet, or both (bilateral joint involvement).

Swelling, tenderness, warmth, and loss of function.

Elevated ESR and C-reactive protein.

Arthritis of three or more joint areas.

Arthritis in hands, feet, or both (bilateral joint involvement).

Swelling, tenderness, warmth, and loss of function.

Elevated ESR and C-reactive protein.

Positive test for rheumatoid factor.

A. Symptoms and Signs

Wrist Swelling causing carpal tunnel syndrome

Elbow Swelling causing compressive neuropathy

Shoulder “Frozen shoulder” (loss of abduction, nighttime pain)

Foot “Cockup” deformity and/or subluxation at MTP

DIP, distal interphalangeal; MTP, metatarsophalangeal; PIP, proximal interphalangeal.

Chronic inflammatory diseases

Complication Brief Comments

Complication Brief Comments

A. Assessment of Prognostic Factors