Friday, April 20, 2012

Rheumatoid Arthritis

Authors: Dr Kenneth H. Fye University of California San Francisco 2008-07-28


Rheumatoid arthritis (RA) is a systemic inflammatory disease defined by its (joint) manifestations. The arthritis of RA is an inflammatory, symmetrical, progressive, destructive process that attacks primarily the small proximal joints of the upper and lower extremities, although all joints in the body, except for those of the thoracic and lumbosacral spine, can be affected. The disease afflicts about 1.5% of the North American population, meaning that approximately 4.5 million Americans have RA. Women are affected three times as often as men. The disease usually begins during the childbearing years, but because it is a chronic, incurable disorder, the peak prevalence is seen in the seventh decade of life. Although RA is often considered to be simply a painful, debilitating arthritis, it is, in fact, a systemic disorder that has a significant impact on mortality. Only 30 years ago the 5-year survival for patients with RA was the same as that for stage IV Hodgkin’s disease or triple vessel coronary artery disease (1). Fortunately, the past 3 decades have seen significant advances in the diagnosis and treatment of RA. Although the disease is not yet curable, the painful, inflammatory arthritis can almost always be controlled, and the likelihood of joint deformities has dramatically decreased, as has the incidence of internal organ involvement and non-articular tissue damage. The long-term outlook for patients with RA is now far better than it was just a few short decades ago.


Genetics play a major role in the etiology of RA (2). The incidence of the disease is different in different populations. Although RA is seen in 1.5% of Caucasians it affects over 5% of certain Native American populations, occurs in only 0.2% of the population of Japan and China, and affects less than 0.1% of rural Africans. Part of the difference in prevalence is due to differences in specific major histocompatibility (MHC) genes that determine the surface characteristics of immune and inflammatory cells throughout the body. The products of these genes, termed Human Leukocyte Antigens (HLA), affect the ability of immune cells, or immunocytes, to recognize and bind to foreign or invading substances and to communicate with other immunocytes. In Western European populations the presence of certain subsets (called alleles) of the HLA-DR4 gene imparts an increased susceptibility to RA, while in Israeli populations alleles of the HLA-DR1 gene appear to be most important. The precise role that these genetic factors play in the causation of RA is still not known.

Since most people with the genes that make them susceptible to RA do not contract the disease, non-genetic factors must also play a role in disease causation. The disparity in the sexual prevalence suggests that hormonal factors may play a role in the initiation of the disease. However, it is not just the presence of female hormones that causes the sexual disparity, because frequently women with active RA go into remission during pregnancy, when the concentrations of most female hormones are at their highest. It is now clear that smoking tobacco can both trigger the development of RA and make it worse in patients who have the disease (3). Tobacco is thought to stimulate immune reactions in the lungs that lead to the production of abnormal peptides (cyclic citrullinated peptides) that, in turn, lead to the production of antibodies that may cause disease. Lastly, experimental evidence suggests that bacterial or viral antigens (substances found in microbes that can stimulate an immune response) may play a role in RA. Certainly, several viral infections, such as Parvovirus B19 infection or hepatitis C, can cause arthritic conditions that mimic RA. To date, however, no specific infectious agent has been shown to actually cause RA.


The inflammation seen in RA is due to a complex interaction of cellular and humoral factors (circulating serum proteins or enzymes) (4). The process is felt to begin when certain cells, called macrophages, ingest an as yet unidentified antigen. The macrophage then processes and presents this antigen to special lymphocytes, called T-lymphocytes, which initiate an immune response. For unclear reasons, this response is directed at normal joint structures. The immune response is mediated by numerous types of cells, including B-lymphocytes, which produce abnormal antibodies, and both effector T-lymphocytes and macrophages, which directly invade and attack target tissues. These immune cells, or immunocytes, produce numerous humoral factors, called cytokines, that damage and even digest articular and periarticular structures. The major target tissue of the immune response is the synovium, or lining of the joint. When the synovium becomes inflamed, it can invade and destroy the cartilage (the cushioning structure of the joint). Certain types of bone cells, called osteoclasts, are activated and begin to erode the bones of the joint. Physicians and scientists are just now beginning to understand the complex interactions of the many cellular and humoral mediators of the immune reaction. Understanding these interactions has already led to the development of new therapeutic interventions that inhibit specific cytokines and decrease the inflammatory process.

Clinical Manifestations

Articular manifestations

RA usually presents as a polyarthritis (an arthritis affecting more than 3 joints) with a predilection for the wrists, the metacarpophalangeal joints (the “knuckles”), and the proximal interphalangeal joints (the finger joints closest to the knuckles) (5). Being symmetrical it tends to affect the same joints on both hands, and, because it is an inflammatory process, the joints are red, swollen, painful, and tender. One of the major components of the inflammation seen in RA is morning stiffness that lasts at least an hour. In untreated patients the stiffness may last all day. The stiffness is usually associated with the “gelling” phenomenon, which is daytime stiffness that occurs whenever a patient sits, lies down, or otherwise remains inactive for too long. With mild to moderate exercise, the pain and stiffness of RA actually improves. However, too much exercise, particularly in acutely inflamed joints, will worsen pain and may increase damage to articular and periarticular (around the joint) supporting structures. Although we define the process by involvement of the small proximal joints of the upper extremities, in fact, virtually every joint in both the upper and lower extremities, including the elbows, shoulders, hips, knees, ankles, feet, and toes, can be affected. Even the cricoarytenoid joints of the vocal cords can become arthritic. Thirty percent of patients will develop cervical spine disease, particularly at the articulation of the first and second cervical vertebrae. Inflammation of the joints of the neck may lead to laxity of the ligaments that stabilize the cervical spine, rendering RA patients susceptible to catastrophic misalignments of the spine, with damage to the spinal cord and radicular nerves. The thoracic and lumbosacral spine, as well as the sacroiliac joints, are, for unknown reasons, spared.

The damage done to the joints and periarticular supporting structures can lead to characteristic permanent deformities. The damage is caused by cellular and humoral inflammatory processes that erode cartilage and bones and digest the joint capsule and the periarticular soft tissues. Inflammation of the proximal interphalangeal joints of the fingers may result in laxity of the tendons and supporting structures resulting in hyperflexion of the proximal and hyperextension of the distal interphalangeal joints (the “boutonniere” deformity). The opposite deformity, that is, hyperextension of the proximal and hyperflexion of the distal interphalangeal joints (the “swan neck” deformity), is due to contractures of the intrinsic muscles of the hands. Ulnar deviation of the fingers and dislocation of the wrist or metacarpophalangeal joints toward the palm (called subluxation) is the result of joint capsule laxity. The combination of erosions of ulnar styloid and digestion of the extensor tendons of the hand can sometimes lead to rupture of the extensor tendons of the fourth and fifth (rarely the third) fingers, resulting in an inability to straighten the affected fingers. Long-standing arthritis of the knees is associated with a valgus deformity (“knock knees”). Involvement of the feet can lead to collapse of the midfoot and cock-up toes, resulting in “rocker bottom” feet and ulcers of the skin under the metatarsophalangeal joints. Chronic hip arthritis may result in collapse of the femoral head with secondary degenerative changes or even remodeling of the acetabulum with protrusion of the head of the femur into the pelvis (protrusio acetabuli).

Joint swelling in early rheumatoid arthritis

Deformities of long-standing rheumatoid arthritis

Deformities of the feet in chronic rheumatoid arthritis

Non-articular Manifestations

The characteristic soft tissue manifestation of RA is the rheumatoid nodule (6). It is usually a small, initially fixed but eventually moveable, nodule just under the skin. The nodule has a typical histologic appearance that allows pathologists to distinguish it from other types of nodules. Rheumatoid nodules usually develop over boney prominences, such as the elbows or finger joints, but they can occur and cause problems in tissues throughout the body, including the eyes, lungs, heart, and central nervous system. Rheumatoid inflammation of the eyes can take many forms, ranging from keratoconjunctivitis sicca (dry eyes) to episcleritis, scleritis, or scleronodular disease (inflammation of the various layers of the eye), to ulcerations of the cornea. In severe cases, blindness can result. Up to 40% of patients with RA will develop inflammation or fibrosis of the lungs or the pleura (the lining around the lungs). Inflammation of the lining around the heart (the pericardium) can be seen in a similar number of patients. Inflammation of the blood vessels (vasculitis) is one of the most devastating complications of RA. Thirty percent of RA patients will, at some time during the course of their disease, develop vasculitis that affects small arterioles or venules of the skin and digits. Ten percent will develop large ulcers of the skin over the ankles (malleolar ulcers) due to inflammation of small arteries in the skin. A rare patient will develop vasculitis of medium-sized arteries throughout the body, resulting in infarctions of target tissues that can be fatal. The nervous system can also be affected. Swelling of synovial tissue in certain areas of the skeleton can crush nearby nerves, leading to nerve pain or even paralysis of those muscles supplied by the affected nerves. The carpal tunnel syndrome (pain and weakness of the hand caused by pressure on the median nerve at the wrist) is an example of such a problem. Small vessel vasculitis can sometimes cause damage to small nerves of the hands and feet. Potentially the most severe neurologic problem faced by patients with RA occurs in those patients with arthritis of the cervical spine as noted above. In patients with laxity of the supporting structures of the first and second cervical vertebrae, even minor trauma may cause a dislocation of the cervical spine, resulting in a crush injury to the spinal cord with paralysis from the neck down. The common skin manifestations of RA include rheumatoid nodules and vascular skin lesions, as mentioned above, and livido reticularis (a reticular discoloration of the skin due to patchy blockage of small cutaneous capillaries). More unusual is a necrotic ulceration of the skin, called pyoderma gangrenosum, a lesion seen almost exclusively in patients with RA, chronic inflammatory bowel disease, or certain kinds of neoplasia. Muscle disuse caused by the painful joints often leads to muscle atrophy, and rarely a patient will develop frank inflammation of the muscle itself (myositis). About a third of patients with RA will also develop an autoimmune disease called Sjögren’s syndrome, in which the major target organs of the immune dysfunction are the exocrine glands throughout the body. These are the glands that produce secretions, such as saliva, tears, or sweat, which interface between the body and the environment. Although the major manifestation of the disorder is dryness of the mouth, eyes, skin, or vagina, the disease can affect various other organ systems, such as the kidneys, liver, or lungs. Very rarely, a patient who has had RA for many years may develop a certain kind of neoplasm, called a lymphoma. Fortunately, this is an extremely unusual complication of severe, uncontrolled disease

Laboratory and Radiologic Abnormalities.

The laboratory abnormality historically most characteristic of RA is a positive rheumatoid factor (RF). RF is an antibody directed against other antibodies, specifically antibodies composed of a specific antibody protein called IgG. Approximately 80% of patients with RA will have a positive RF at sometime during the course of their disease. Other autoantibodies (antibodies directed not at foreign invaders but at our own tissues), such as antinuclear antibodies (ANAs), antibodies against matrix metalloproteases (enzymes that cause damage to joint tissues), and anticyclic citrullinated peptide antibodies (anti-CCP antibodies), are also seen in RA (7). Anti-CCP antibodies are found almost exclusively in patients with RA and are seen almost as commonly as RF. Therefore, this test is just as valuable as the RF assay in the diagnosis of RA.

Because RA is a systemic inflammatory disorder it is not surprising that many non-specific laboratory abnormalities may be encountered. The erythrocyte sedimentation rate and C-reactive protein are non-specific measures of inflammation and are commonly elevated in patients with active disease. Chronic anemia, elevated platelet counts, hypergammaglobulinemia (occasionally monoclonal), and abnormalities of liver function are common. Unusual proteins that coagulate in the cold and are associated with vascular occlusion (cryoglobulins) may occasionally be seen. An unusual complication of long-standing disease is Felty’s syndrome (low white blood cell count, low platelet count, enlarged spleen, and, sometimes, liver inflammation). These patients are at risk for cutaneous (skin) vasculitis and for recurrent infections.

The synovial fluid characteristic of RA is also inflammatory and contains numerous white cells, high levels of proteins, low glucose levels (an usual finding that is also seen in infectious forms of arthritis), and debris from damage to the cartilaginous and boney structures of the joint (8).

RA is an erosive arthritis that destroys bone. Clinicians use x-rays and other imaging techniques to detect changes in bone that help with both the diagnosis and prognosis of RA. Although a number of x-ray changes, such as cyst formation or periarticular osteopenia (low bone mass surrounding joints), can be seen in RA, the characteristic radiographic abnormality of this disorder is a marginal erosion (an erosion of the bone just at the edge of the joint). Clinicians are just now learning how to use ultrasound machines to detect and measure inflammatory changes in the synovium before bone damage occurs. Magnetic resonance imaging (MRI) is the use of powerful magnets to detect differences in nuclear spin energy emitted by various tissues exposed to radio waves. These differences can be detected and used by computers to create images of the soft tissues being studied. Computer assisted tomography (CT scan) is a form of imaging that depends on computer analysis of serial x-rays taken of a target tissue at various focal lengths. MRI is particularly helpful in the evaluation of soft-tissue complications of RA, such as torn ligaments or tendons. Both MRI and CT scanning help with the detection of early erosive disease.

Because there are many types of inflammatory arthritis, it is not always easy to diagnose RA. In an effort to aid researchers and clinicians in their efforts to distinguish RA from other forms of destructive articular disease, the American College of Rheumatology has devised a set of seven classification criteria by which RA can be defined. Four of these criteria must be present, all other obvious diagnostic possibilities having been eliminated, before a physician can be comfortable with the diagnosis of RA. The criteria are: (1) a history of morning stiffness that lasts at least an hour; (2) findings on physical examination of an inflammatory polyarthritis (an arthritis affecting 3 or more joints); (3) arthritis that involves the wrists, metacarpophalangeal joints, or proximal interphalangeal joints of the fingers; (4) a symmetrical arthritis (involvement of the same joints on both sides of the body); (5) the presence of rheumatoid nodules; (6) a positive rheumatoid factor; (7) typical x-ray abnormalities of the hands or wrists. Even though the diagnosis can be made based on clinical criteria alone, most clinicians feel more comfortable with the diagnosis when a patient has a positive rheumatoid factor, a rheumatoid nodule, or abnormal x-rays, as well as typical clinical manifestations of RA.


Pharmacologic treatment

Over the past 30 years, it has become apparent that patients with RA do much better if treatment is started early in the course of their disease (9). The likelihood and probably the severity of joint deformities are significantly reduced and the incidence of extra-articular complications of RA is dramatically decreased when pharmacologic therapy is maximized within 6 months of the diagnosis. It is also clear that regimens using combinations of different drugs are much more effective than single drug therapy (10). Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, diclofenac, etodolac, or aspirin, just to name a few, are generally prescribed first. These drugs inhibit the production of enzymes, called prostaglandins, which mediate many of the manifestations of inflammation. Because high doses are required to achieve anti-inflammatory effects, some patients experience side effects, such as dyspepsia (“upset stomach”), gastritis (inflammation of stomach lining), peptic ulcers, fluid retention, hypertension, decreased kidney function, rash, or changes in mental function. Although helpful in decreasing the acute inflammation and pain, NSAIDs have never been shown to stop boney erosions or deformities. Therefore, all patients require one or more slow-acting, disease modifying anti-rheumatic drugs (DMARDs). The mechanisms of action of some of these agents, such as sulfasalazine or hydroxychloroquin, remain obscure. One of the most effective DMARDs is methotrexate, an antimetabolite that works in part by decreasing the formation of tetrahydrofolate (the effective form of folic acid). Other drugs, such as azathioprine, mycophenylate mofetil, or leflunomide, interfere with the production of components of nucleic acids, which are necessary for the survival or normal functioning of inflammatory cells. Minocycline and doxycycline are antibiotics that inhibit the production and release of matrix metalloproteinases, enzymes that damage articular structures. The past decade has seen the development of genetically engineered biologic agents that target specific mediators of the inflammatory process. Etanercept, infliximab, and adalimumab are antagonists of the inflammatory cytokine, tumor necrosis factor alpha (TNF alpha). These agents have proven to be particularly effective and well tolerated in patients who do not respond adequately to methotrexate. Abatacept is a biologic that is thought to work by inducing tolerance to the unknown antigen that triggers RA. Rituximab is an antibody that depletes certain lymphocytes that play a role in the chronic inflammation of RA. Kineret is a biologic that blocks the ability of the cytokine called interleukin1 to mediate many of the aspects of inflammation. The cytotoxic agents, cyclophosphamide, chlorambucil, and cyclosporine, are generally just used to treat the severe extra-articular manifestations of RA. Although gold, both oral and parenteral, and penicillamine have historically been used to treat RA, these drugs have generally been replaced by safer, more effective agents. Each of these agents has its own set of potential toxicities, some of which are significant and could be life-threatening. Most increase susceptibility to infections, many are toxic to the liver or kidneys, some suppress bone marrow function, some can cause neurologic disease, a few are associated with increased tumor formation, and all should only be used under the care of and monitored by an experienced physician.

Corticosteroids have proven to be extremely valuable in the treatment of RA. A number of preparations, such as triamcinolone, decadron, or depo-solumedrol, can be administered locally into inflamed joints or into periarticular structures, such as bursae or tendon sheaths. Sometimes rheumatoid nodules will resolve, or at least decrease in size, after local corticosteroid injection. Oral corticosteroids are particularly useful because of their rapid onset of action. Patients given prednisone generally note a decrease in pain, swelling, and stiffness, as well an increase in energy, within a few weeks of the initiation of therapy. Parenteral (intravenous or intramuscular) corticosteroids are used to treat the severe systemic complications of RA, such as vasculitis or lung disease. Although effective, corticosteroids are associated with a daunting array of side effects, including but not limited to, insomnia, weight gain, fluid retention, hypertension, thinning of the skin with easy bruisability and striae, osteoporosis, cataracts, increased infections, poor wound healing, centripetal obesity, plethoric complexion, alopecia, growth of hair on the face, and a “moon facies”. Since these potential toxicities are time and dose dependent, it is important to minimize the dose and the duration of treatment with corticosteroids. Also, many of the side effects can be controlled by changes in lifestyle, such as diet, or by the use of other protective pharmacologic agents, such as bisphosphonates to prevent osteoporosis or gastroprotective drugs to prevent gastritis or peptic ulcers. Despite the dizzying array of potential problems associated with their use, corticosteroids are so effective the majority of patients with RA will have received corticosteroid therapy at some time during the course of their disease.

Physical Therapy

Physical therapy includes temperature manipulation (11), rest, exercise (12), adaptive devices (13), and modalities. Both heat and cold have been shown to decrease pain and relax muscle spasms. Each is associated with its own set of problems. Too much cold, such as occurs when ice is applied directly to the skin for more than an hour, can lead to frostbite or chilblains. Too much heat can burn the skin. Even prolonged low heat, such as the use of a heating pad over night, may lead to atrophy and hyperpigmentation of the skin, so-called erythema ab igne. However, when used judiciously, say for 15 to 20 minutes at a time, 3 or 4 times a day, temperature manipulation can help decrease swelling, relieve muscle spasms, and decrease pain, and often, thereby, enable patients to more effectively engage in appropriate exercises.

Acutely inflamed joints have to be rested, sometimes with the use of slings or splints. Attempts to exercise inflamed and swollen joints will lead to unacceptable levels of pain and may actually amplify damage to the joint and periarticular supporting structures. Overwhelming fatigue is one of the most debilitating manifestations of RA. This fatigue is qualitatively different than the fatigue one feels after hard work or exercise. It is enervating and debilitating. Most patients with this manifestation of RA find they feel much better if they schedule a brief nap in the early afternoon, the time of day when waves of this pathologic fatigue often occur. After a brief afternoon rest, most patients find they function on a much higher plane for the rest of the evening. As inflammation begins to abate, it is important to initiate a program of exercise to maintain joint flexibility and muscle strength. There are several types of exercise that require varying levels of exertion. As joint inflammation decreases, the level of physical activity can be increased. Sometimes, a trained physical therapist is needed to guide a patient through a progressively vigorous and effective, yet safe, exercise regimen.

Adaptive devices are tools that enable patients with RA to accomplish the tasks of daily living. Splinting devices range from simple resting splints to articulated braces. Aids for ambulation include a variety of canes, crutches, walkers, and, if necessary, wheelchairs or scooters, many of which are motorized. There are a myriad of devices to help patients with severe deformities cook, eat, open doors, turn keys, dress, put on their socks and shoes, pick up objects dropped onto the floor, and accomplish all of the multitude of little tasks that confront everyone every day. If not available at your local pharmacy or medical supply house, virtually all of these tools can now be obtained online.

Modalities are mechanical techniques that allow physical therapists to modulate physiology in an effort to decrease the effects that inflammatory arthritides, such as RA, have on joints and muscles. Ultrasound machines (using frequencies and machines much different than those used to create diagnostic images) are used to apply deep heat. Electrical stimulation techniques, such as transcutaneous neurostimulation (TENS), can be used to decrease pain or to increase muscle function. Ionophoresis is a technique in which mild electric currents are used to augment the absorption of corticosteroids through the skin. Although it is difficult to find objective clinical studies that quantify the benefits of these modalities many patients do claim symptomatic relief with their use
Aids to eating for patients with severe arthritis

Surgical Therapy

Sometimes, despite the availability of appropriate medical and physical therapy, patients will develop problems that require surgical treatment. Many of the surgical procedures applicable to patients with RA are directed towards soft tissues. Patients who develop the carpal tunnel syndrome due to inflammation and swelling of the tissues of the wrist may require transection of the transverse carpal ligament to relief pressure on the median nerve. Recalcitrant synovitis of the back of the wrist occasionally requires surgical removal of the extensor tenosynovium (synovial lining around the tendons that straighten the fingers). All of the classic soft tissue deformities of the fingers can be surgically corrected, with varying degrees of success depending on the severity of the deformity. Rheumatoid nodules that interfere with normal function can be surgically removed.

Surgical arthroscopy (the introduction of a small tube into the joint) enables physicians to visualize a diseased joint and then resect inflamed synovium or repair damaged intra-articular structures. If a joint is severely damaged or deformed, surgical arthroscopy may not offer any significant therapeutic benefit. In such cases, the only way to decrease pain or increase stability and, thereby, improve function may be arthroplasty (surgical implantation of an artificial joint). Advances in surgical technique and in the construction of the various prosthetic devices have contributed significantly to the success of joint replacement. Hip and knee replacements have proven to be very reliable (14, 15). The small joints of the fingers can be replaced, but long-term success is not as predictable as that seen in hip and knee replacements. Several artificial shoulder joints have been developed, and each may be indicated in specific clinical situations. There are no really reliable wrist, elbow, or ankle prostheses. Rarely, a joint is damaged to such a degree that arthroplasty is not feasible. Sometimes there may not be a reliable prosthesis for the affected joint, as is the case when the ankle or mid-foot is involved. In such a case, the only option may be arthrodesis (joint fusion). Fusion results in the loss of motion but will impart stability to an unstable joint, will significantly decrease pain, and can be life-saving, as in RA patients with arthritis of the atlanto-axial joint (the articulation between the first and second cervical vertebrae) (16). In fact, in patients with atlanto-axial instability and signs of neurologic dysfunction the only therapy is fusion of the cervical spine.

Surgery in patients with RA is difficult (17). The medications used to treat the disease may adversely affect the quality of bone and soft tissue, thereby impeding the post-surgical healing process. Many agents are associated with an increased incidence of post-operative infections. The disease itself is so destructive it is often difficult to reconstruct normal anatomy. Despite the increased incidence of surgical complications, the dramatic improvements in the quality of life seen in RA patients who have had appropriate procedures make surgery an essential component of the therapeutic armamentarium of the physician treating rheumatoid disease.


RA is a chronic, systemic, inflammatory disorder that can be associated with a destructive arthritis and a significant decrease in life span. Fortunately, evolving diagnostic and therapeutic techniques have enabled clinicians to make early diagnoses and initiate aggressive, effective therapy before irreversible damage has been done. RA is not yet curable, but modern therapies have dramatically improved the outlook for patients with this devastating disorder.

Related Links

American College of Rheumatology:
American Association of Orthopedic Surgeons:


1. Pincus T, Callahan LF. The “side effects” of rheumatoid arthritis: joint destruction, disability and early mortality. Br J Rheumatol 1993;32(Suppl 1)28-37.

2. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987;30:1205-1213.

3. Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006;54:38-46.

4. Arend WP. Physiology of cytokine pathways in rheumatoid arthritis. Arthritis Rheum 2001;45:101-106.

5. Tehlirian CV, Bathon JM. Rheumatoid arthritis: Clinical and laboratory manifestations. In: Primer on the Rheumatic Diseases. Klippel JH, Stone JH, Crofford LJ, White PH, eds. 13th Edition. Springer/Arthritis Foundation 2008:114-121.

6. Turesson C, O’Fallon W, Crowson C, et al. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis 2003;62:722-727.

7. Nielen M, van Schaardenburg D, Reesink H, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004;50:380-386.

8. Fye KH. Arthrocentesis, synovial fluid analysis, and synovial biopsy. In: Primer on the Rheumatic Diseases. Klippel JH, Stone JH, Crofford LJ, White PH, eds. 13th Edition. Springer/Arthritis Foundation 2008:21-27.

9. Machold KP, Eberl G, Leeb BF, et al. Early arthritis therapy: rationale and current approach. J Rheumatol 1998;25(suppl 53):13-19.

10. Landewe RB, Boers M, Verhoeven AC, et al. COBA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum 2002;46:347-356.

11. Oosterveld FG, Rasker JJ. Treating arthritis with locally applied heat or cold. Semin Arthritis Rheum 1994;24:82-90.

12. Boutaugh ML. Arthritis Foundation community-based physical activity programs: effectiveness and implementation issues. Arthritis Rheum 2003;49:463-470.

13. Egan M, Brosseau L, Farmer M, et al. Splints/orthoses in the treatment of rheumatoid arthritis. Cochrane Database Syst Rev 2003:CD004018.

14. Callagham JJ, Albright JC, Goetz DD, et al. Charnley total hip arthroplasty. Minimum twenty-five year follow-up. J Bone Joint Surg Am 2000;82:487-497.

15. Rand JA, Ilstrup DM. Survivorship analysis of total knee arthroplasty. Cumulative rates of survival of 9200 total knee arthroplasties. J Bone Joint Surg Am 1991;73:397-409.

16. Boden SD, Dodge LD, Bohlman HH, et al. Rheumatoid arthritis of the cervical spine. J Bone Joint Surg Am 1993;75:1282-1297.

17. Murray RP, Bourne MH, Fitzgerald RH. Metachronous infections in patients who have had more than one total joint arthroplasty. J Bone Joint Surg Am 1991;73:1469-1474.