Definition

Rheumatoid arthritis is an autoimmune disease of unknown origin characterized by symmetric inflammation of joints, especially of the hands, feet, and knees. The severity of the disease varies widely from patient to patient and fluctuates over time within the same patient. Disease onset usually occurs between ages 35 and 50 years. RA is more prevalent in women than in men by a 3 : 1 ratio.

Epidemiology

Prevalence is somewhat difficult to determine because of lack of well-defined markers of the disease; however, estimates range from 1% to 2% of the U.S. population.

Etiology

The cause of RA is unknown; however, evidence seems to implicate an interrelationship of infectious agents, genetics, and autoimmunity. One theory suggests that a viral agent alters the immune system in a genetically predisposed person, leading to destruction of synovial tissues. Although the disease can occur within families, suggesting a genetic component, specific associated genes have not been identified. Nevertheless, many people who develop RA have a genetic predisposition that occurs in the form of a tissue marker called HLA-DR4; however, not everyone with this tissue type develops the disease.

Pathophysiology and Complications

The fundamental abnormality of RA involves microvascular endothelial cell activation and injury. Primary changes occur within the synovium, which is the inner lining of the joint capsule ( Fig. 20.1 ). Edema of the synovium occurs followed by thickening and folding. This excessive tissue, composed of proliferative and invasive granulation tissue, is referred to as pannus. In addition, marked infiltration of lymphocytes and plasma cells into the capsule occurs. Eventually, granulation tissue covers the articular surfaces and destroys the cartilage and subchondral bone through enzymatic activity ( Fig. 20.2 ). This process also extends to the capsule and ligaments, causing distention and rupture. New bone or fibrous tissue then is deposited, resulting in loss of mobility.

The joint surface (top) has lost its cartilage and consists of granulation tissue with scar tissue. Subchondral bone shows degenerative changes and areas of necrosis.

(Courtesy of A. Golden, Lexington, KY.)

A micrograph of a pannus resulting from severe synovitis in rheumatoid arthritis. The pannus is eroding articular cartilage and bone (arrow) .

(Courtesy of Richard Estensen, MD, Minneapolis, MN.)

The sequence of pathologic events begins with a synovitis that stimulates immunoglobulin G (IgG) antibodies. These antibodies form antigenic aggregates in the joint space, leading to the production of rheumatoid factor (RF; autoantibodies). RF then complexes with IgG complement, a process that produces an inflammatory reaction that injures the joint space. The key drivers of RA include proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6).

An associated finding in 20% of patients with RA is the presence of subcutaneous nodules, which are commonly found around the elbow and finger joints. These nodules are thought to arise from the same antigen–antibody complex that is found in the joint. Antigen-mediated vasculitis confined to small- and medium-sized vessels also may occur.

Rheumatoid arthritis is a pleomorphic disease with variable expression. The most progressive period of the disease occurs during the earlier years; thereafter, it slows. Onset is gradual in more than 50% of patients, and as many as 20% follow a limited course that abates within 2 years. Approximately 10% of patients with RA who do not receive adequate treatment experience relentless crippling that leads to nearly complete disability. The remainder follows a polycyclic or progressive course. The long-term prognosis for individuals with abrupt onset of disease is similar to that for those with gradual disease onset. The course and severity of RA are unpredictable, but the disorder is characterized by remissions and exacerbations. For most patients, however, the disease is a sustained, lifelong problem that can be managed to allow a normal or nearly normal life.

The life expectancy of persons with severe RA is shortened by 10 to 15 years. This increased mortality rate usually is attributed to infection, pulmonary and renal disease, and gastrointestinal bleeding.

Many complications may accompany RA, including skin ulcers, muscle atrophy, keratoconjunctivitis sicca (SS), digital gangrene, temporomandibular joint (TMJ) involvement, pulmonary interstitial fibrosis, pericarditis, amyloidosis, anemia, thrombocytopenia, neutropenia, and splenomegaly (Felty syndrome).

Clinical Presentation

The usual onset of RA is gradual and subtle ( Table 20.2 ), and the disorder is commonly preceded by a prodromal phase of general fatigue and weakness with joint and muscle aches. Characteristically, these symptoms come and go over varying periods. Then, painful joint swelling, especially of the hands and feet, occurs in several joints and progresses to other joints in a symmetric fashion ( Fig. 20.3 ). Joint involvement persists and gradually progresses to immobility, contractures, subluxation, deviation, and other deformities. Characteristic features include pain in the affected joints aggravated by movement, generalized joint stiffness after inactivity, and morning stiffness that lasts longer than 1 hour. The joints most commonly affected are fingers, wrists, feet, ankles, knees, and elbows. Multiple joint changes noted in the hands include a symmetric spindle-shaped swelling of the proximal interphalangeal (PIP) joints, with dorsal swelling and characteristic volar subluxation of the metacarpophalangeal (MCP) joint (see Fig. 20.3 ). TMJ involvement occurs in up to 75% of RA patients. Because of the variable rate of progression and pain intensity, the median period between onset of symptoms of RA and its diagnosis is 36 weeks.

Hands of a patient with advanced rheumatoid arthritis.

(From Damjanov I: Pathology for the health professions, ed 4, St. Louis, 2012, Saunders.)

Extraarticular manifestations include rheumatoid nodules, vasculitis, skin ulcers, SS, interstitial lung disease, pericarditis, cervical spine instability, entrapment neuropathies, and ischemic neuropathies. The American Rheumatism Association has developed revised criteria for the diagnosis and classification of RA to be used in clinical trials and epidemiologic studies ( Box 20.1 ). These criteria have high specificity (89%) and sensitivity (91%–94%) compared with control participants when used to classify patients with RA. For the diagnosis of RA to be made, four of seven criteria must be met.

Laboratory and Diagnostic Findings

Laboratory tests are not pathognomonic or diagnostic of RA, although they are used in conjunction with clinical findings to confirm the diagnosis. Laboratory findings most commonly seen in RA include an increased erythrocyte sedimentation rate (ESR), the presence of C-reactive protein (CRP), a positive RF (in 85% of affected patients), and a hypochromic microcytic anemia. In patients with Felty syndrome (RA with splenomegaly), a marked neutropenia may be present.

Autoantibodies to cyclic citrullinated proteins (CCPs) are helpful in the diagnosis of RA. Anti-CCP antibodies are highly associated with RA. They occur in 70% to 80% of patients with RA as well as in some other forms of inflammatory arthritis. These antibodies may appear before any signs or symptoms of RA and therefore may prove beneficial as early screening markers for earlier diagnosis and intervention of RA.

The American College of Rheumatology (ACR) has established criteria for the diagnosis of RA (see Box 20.1 ), the classification of severity by radiography, functional classes, and the definition of remission. Although they were not designed for managing individual patients, these criteria are useful as a frame of reference and for describing clinical phenomena.

By definition, the diagnosis of RA cannot be made until the disease has been present for at least several weeks. Many extraarticular features of RA, the characteristic symmetry of inflammation, and the typical serologic findings may not be evident during the first few months after disease onset. Therefore, the diagnosis of RA usually is presumptive early in its course.

Although extraarticular manifestations may dominate in some patients, documentation of an inflammatory synovitis is essential for a diagnosis. Inflammatory synovitis can be documented by demonstration of synovial fluid leukocytosis, defined as white blood cell (WBC) counts greater than 2000/µL, histologic evidence of synovitis, or radiographic evidence of characteristic erosions.

Medical Management

Treatment of RA focuses on use of antiinflammatory drugs and disease-modifying antirheumatic drugs (DMARDs), which are helpful in controlling disease and limiting joint damage. The treatment approach to RA is, by necessity, mostly palliative because no cure yet exists for the disease. The ultimate aims of management are to achieve disease remission and maintain or regain functional activity.

Clinical tools for monitoring the patient’s well-being and the efficacy of therapy include self-assessment of the duration of morning stiffness and severity of fatigue, as well as functional, social, emotional, and pain status, as measured by a health assessment questionnaire. A patient-derived global assessment based on a visual analogue scale is a simple and effective means of recording patient well-being. The number of tender and swollen joints is a useful measure of disease activity, as is the presence of anemia, thrombocytosis, and elevated ESR or CRP. Serial radiographs of target joints, including the hands, are useful in assessing disease progression.

Patient education is essential early in the disease course and on an ongoing basis. Patients are best served by a multidisciplinary approach with early referral to a rheumatologist and other specially trained medical personnel, including nurses, counselors, and occupational and physical therapists who are skilled and knowledgeable about RA. Appropriate medical care of patients with RA encompasses attention to smoking cessation, immunizations, prompt treatment of infections, and management of comorbid conditions such as diabetes, hypertension, and osteoporosis. Remission is elusive, however, so more practical treatment goals are to reduce joint inflammation and swelling, relieve pain and stiffness, and facilitate and encourage normal function. These goals are accomplished through a basic treatment program that consists of patient education, rest, exercise, physical therapy, and various nonsteroidal antiinflammatory drugs (NSAIDs) and DMARDs.

The major goals of therapy are to reduce joint damage; relieve pain, swelling, and fatigue; improve joint function; and prevent disability and disease-related morbidity. These goals are constant throughout the disease course, although emphasis may shift to address specific patient needs.

Drugs for the management of RA have been traditionally, but imperfectly, divided into two groups: those used primarily for the control of joint pain and swelling and those intended to limit joint damage and improve long-term outcome ( Table 20.3 ). Symptoms of pain and swelling in RA are mediated, at least in part, by intense cytokine activity. NSAIDs inhibit proinflammatory prostaglandins and are effective treatments for pain, swelling, and stiffness, but they have no effect on the disease course or on risk of joint damage. On the other hand, antiinflammatory properties have been noted for several DMARDs, which are used principally to control disease and to limit joint damage. These drugs include methotrexate and biologic response modifiers with actions targeted against specific cytokines, such as TNF-α. Corticosteroids are powerful, nonspecific inhibitors of cytokines and have been demonstrated to effectively delay joint erosion.

Many different drugs are used in the treatment of patients with RA. Some are used primarily to ease the symptoms of RA; others are used to slow or stop the course of the disease and to inhibit structural damage. Most of these drugs fall into one of the following categories.

NSAIDs

These drugs effectively reduce arthritis pain and inflammation. NSAIDs, including aspirin, constitute the cornerstone of treatment. A common approach is to start a patient on three 5-grain tablets four times a day and then to adjust the dosage on the basis of patient response. The most common sign of aspirin toxicity is tinnitus. If this occurs, dosage is decreased. In addition to aspirin, many NSAIDs are available for use (see Table 20.3 ). Some of the more common NSAIDs include cyclooxygenase (COX)-2 inhibitors, namely, celecoxib (Celebrex), ibuprofen (Motrin, Advil, Rufen, Nuprin), naproxen (Naprosyn, Aleve), sulindac (Clinoril), tolmetin (Tolectin), fenoprofen (Nalfon), piroxicam (Feldene), diclofenac (Voltaren), flurbiprofen (Ansaid), diflunisal (Dolobid), etodolac (Lodine), and nabumetone (Relafen). All NSAIDs can cause a qualitative platelet defect that may result in prolonged bleeding, especially when given in high doses. The effects of aspirin are irreversible for the life of the platelet (10–12 days); thus, this effect continues until new platelets have replaced the old. The effect of the other NSAIDs on platelets is reversible and lasts only as long as the drug is present in the plasma (see Chapter 24 ). Celecoxib (Celebrex), a COX-2 inhibitor, is designed to be safer for the stomach. In addition to NSAIDs, a variety of other drugs can be used to treat patients with RA (see Table 20.3 ).

Corticosteroids

Corticosteroids, including prednisone, prednisolone, and methylprednisolone, are potent and quick-acting antiinflammatory medications. These medications provide immediate control of inflammation while waiting for NSAIDs and DMARDs take effect. Because of the risk of side effects with corticosteroids, they are prescribed for as short a time as possible and in doses as low as possible.

DMARDs

Disease-modifying antirheumatic drugs, through various mechanisms, actually modify the course of the disease. The most commonly used DMARD for RA is methotrexate. Other frequently used DMARDs include hydroxychloroquine (Plaquenil), sulfasalazine (Azulfidine, Azulfidine EN-Tabs), leflunomide (Arava), and azathioprine (Imuran).

An individual diagnosed with RA is likely to be prescribed a DMARD fairly early in the course of the disease because studies have demonstrated that starting these drugs early can help prevent irreparable joint damage.

Biologic Agents

Biologic agents are highly targeted DMARDs that in many ways have revolutionized the management of RA. Biologics have been shown to help slow progression of RA when all other treatments have failed to do so. Aggressive RA treatment is known to help prevent long-term disability from RA.

A list of biologic drugs can be seen in Table 20.4 . There are currently nine such agents approved for RA: abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab pegol (Cimzia), etanercept (Enbrel), infliximab (Remicade), golimumab (Simponi), and rituximab (Rituxan). Each of the biologics targets a specific molecular mediator in the inflammation cascade. Cimzia, Enbrel, Humira, Remicade, and Simponi block a cytokine called TNF-α and are referred to as TNF inhibitors or blockers. Kineret targets a cytokine called IL-1. Orencia inhibits the activation of T cells. Rituxan targets CD20 thereby inactivating B cells. Actemra blocks a cytokine called IL-6. IL-6 is a proinflammatory cytokine that is usually increased in most rheumatologic disorders. The biologic agents etanercept and infliximab (and other TNF-α inhibitors) have been shown to be highly effective in the treatment of patients with early RA relative to the “gold standard” agent, methotrexate. Although costly and difficult to administer (requiring an injectable route), etanercept (e.g., Enbrel, Immunex) has been shown to significantly reduce symptoms of RA and to more effectively slow joint damage when compared with methotrexate. Likewise, infliximab (Remicade), which also is costly and requires administration by the intravenous (IV) route, when used with methotrexate significantly reduced RA symptoms and slowed joint damage to a greater extent than that achieved with methotrexate therapy alone.

These agents are administered by injection or IV infusion and usually have side effects. The most common side effect seen with biologics is pain and rash at the injection site. This occurs in fewer than 30% of patients. Because biologics given by infusion (in the vein) have the potential to cause an allergic infusion reaction, patients are monitored during infusions. Symptoms of infusion reactions include flulike illness, fever, chills, nausea, and headache. Biologics have also been implicated in increased infections in patients using them. In fact, one study found that patients taking high-dose biologics were nearly 2.5 times more likely to have a serious infection than control participants.

As with any drugs that suppress the immune system, biologic therapy poses some increased to infections and other diseases. People taking biologics should seek immediate medical attention if they develop persistent fever or unexplained symptoms. Vaccinations that prevent infections should be considered before taking biologics. While taking biologic medications, people should not receive live vaccines.

Janus-Associated Kinase Inhibitors

Tofacitinib (Xeljanz) is a janus-associated kinase inhibitor that disrupts cytokine and growth factor signaling pathways, thereby effectively reducing inflammation.

Prosthetic Joints

A potential long-term complication of chronic RA (also OA and other types, including fractures that do not heal and avascular necrosis) is the ultimate destruction of particular joint structures to the degree that the joint must be replaced with synthetic materials.

Patients who have recently received a prosthetic joint (particularly the knee) are at increased risk (up to nine times more likely) to have a thromboembolic event (including a possible myocardial infarction) within 1 month of the implant, and they are also more likely to have a pulmonary embolism for several years after their implant. Patients with prosthetic joints (most commonly, hip and knee replacement, followed by shoulder, elbow, wrist, and ankle) often are encountered in dental practice; when this occurs, a question concerning the need for antibiotic prophylaxis to prevent infection of the prosthesis can arise.

Dental Management

Depending on which joints are involved, patients may not be comfortable in a supine position in the dental chair. Consideration should be given to providing a more upright chair position, using neck, back, and leg supports, and scheduling short appointments ( Box 20.2 ).