An In-Depth Topic Review of Rheumatoid Arthritis

1. Definition
2. Pathogenesis
3. Clinical Presentation
4. Laboratory Findings
5. Differential Diagnosis
6. General Treatment Recommendations
7. Specific Treatment Recommendations
8. Long-term Management Issues
9. Prognosis
10. When to Refer
11. Annotated References

I.  Definition

Rheumatoid arthritis (RA) is a systemic, inflammatory disease in which joint disease is center-stage with a background of constitutional and internal manifestations.

Systemic means that many parts of the body can be involved. Inflammatory means that the patient presents with redness, warmth, swelling and functional limitation in the joints. Internally, this means that the immune and inflammatory systems of the body are activated and involving the tissues. Such involvement can lead to joint damage, a major focus of the newer therapies for RA. The inflammation also demonstrates itself by the presence of fatigue and weight loss.

We now know a great deal about what causes RA and how to control it. While we cannot cure it at present, joint damage can now be prevented. The early institution of medications is mandatory in order to avoid joint erosions and limitation in function. The rate at which new advances in care are occurring in RA is mind-boggling!

II. Pathogenesis

The actual cause of RA is unknown but it is thought to be triggered by environmental factors such as infections with viruses or bacteria. However, while some patients with RA do have a viral-type illness at the onset of the illness, most do not. To date, no specific infectious agent has been found. Some antibiotics can improve RA a bit but they appear work as anti-inflammatory drugs not via their bacteria-killing actions.

The Development of Rheumatoid Arthritis

The clinical manifestations of rheumatoid arthritis arise from an interplay between inborn genetic factors, the immune system and triggers such as infectious agents.

Genetic factors appear to play as much as a 50% role in the development of RA. It is now thought that a genetically-predisposed person comes in contact with an infectious agent and this initiates the self-perpetuating inflammation that is so characteristic of RA. While it is clear that genetics are important, if you have RA this does not at all mean that your child or grandchildren will develop it. Actually, the risk is very small.

Diet may play a role in some patients with RA. However, in most, a well-balanced diet is the correct prescription. Patients should keep a diary to determine whether the eating of one type of food is commonly associated with a flare of RA, If that is the case, a trial of avoiding that food is reasonable. Optimal weight is always appropriate, especially patients with joint inflammation in the legs.

Stress, either physical or emotional, is commonly cited by patients as being present or severe at the time of the onset of RA. This is true in other autoimmune disorders as well. Since the mind-body connection is real, most physicians appreciate the linkage between stress and disease onset or exacerbation. Because there are clear interactions between the nervous, immune and endocrine systems, the impact of various stressors on disease presentation and severity is explainable in physiologic terms. Obviously, life is stressful and thus how to employ stress reduction in a therapeutic regimen is up to the individual patient, in concert with his/her physician.

Factors involved in the Pathogenesis of Rheumatoid Arthritis and the Clinical Manifestations That They Cause

Early Disease

Immunological factor

1. Triggering of the immune system by an infectious agent
2. Activation of immunologically active cells
3. Elaboration of cytokines that are pro-inflammator

Clinical Manifestations

1. Mild limitation in function and joint range of motion
2. Fatigue, malaise, viral-type feeling
3. Joint pain, swelling, stiffness, and tenderness

More Advanced Disease

Immunological Factor

1. Enhancement of the immune response, including proliferation of immune cells
2. Activation of cartilage and synovial cells, with the elaboration of tissue-damaging enzymes
3. Cartilage, tendon and bone damage

Clinical Manifestations

1. Increase in fatigue and overall disfunction; weight loss
2. Development of joint damage such as erosions, joint space narrowing
3. Internal organ damage in the most severe disease
4. Shortened life span unless the disease is suppressed

The immune system plays a major role in development of joint inflammation and damage, as well as fatigue and the feeling that you have a chronic viral illness. The immune system is made up of body-protecting cells and antibodies.

In normal people, these help to fight off invading infectious agents. In RA, however, something goes awry and immune system appears to be directed against the person's tissues (thus it is called an autoimmune disorder). The immune cells in the body, specifically the lymphocytes and macrophages, communicate with each other via the production if chemicals called cytokines. It is cytokines like tumor necrosis factor alpha and IL-1 that eventually lead to joint inflammation, damage and flu-like symptoms. All of our therapies are directed against the many immune factors that cause this complex disorder. Our aim is to re-set the immune thermostat, so that we can avoid joint damage and dysfunction.

III. Clinical Presentation

The joint pains in RA behave in a specific manner and affect multiple joints on both sides of the body in what is called a symmetric pattern. Also, the characteristic joints include the small joints of the hand and feet, as well as the elbows, knees and ankles. Prior to 60 years of age, this disorder is three times more common in women than men. After that age, there is a more equal frequency in men and women. Of note is the fact that 30% of patients with RA develop it over the age of 60.

Characteristic Early Inflamatory Changes

This picture demonstrates the characteristic early inflammatory changes seen in patients with RA. This includes soft tissue swelling of the metacarpophalangeal (MCP or knuckle joints) and fusiform swelling of the proximal interphalangeal joints (called PIP joints). These changes would be present in the same area of both hands, consistent with the symmetrical involvement of RA.

Advanced RA with significant joint damage

This hand picture demonstrates more severe and advanced RA in which significant joint damage has occurred. Here, we can see the atrophy of the muscles of the hand, the deviation of the fingers away from the thumb (the so-called ulnar deviation) and the prominent swelling of the wrist, MCP and PIP joints. Given the newer therapies for RA, patients today can avoid the progression from the first hand picture to the second.

Uncommon Severe Joint Damage

Luckily, today, we do not commonly see the progression to this type of severe joint damage. This arthritis mutilans picture is very uncommon.

The main joint symptoms relate to inflammation and include pain, swelling, redness, warmth and limitation in range of motion of the involved joints. Patients may also have fatigue or a flu-like feeling, out of proportion to that expected from their activity schedule. All of these problems can occur suddenly, as if it were related to an infection, or slowly. The external signs of inflammation reflect a potentially-damaging disease process that can lead to injury to bone, cartilage and soft tissues such as tendons. If left untreated, this can cause deformities and limitation in function. Luckily, we have excellent treatments that can stop this inflammation and avoid further damage.

Some patients with RA develop more generalized disease in which internal organs can be inflamed and damaged. Thank goodness this is quite rare, and rarer still today with our new therapies. Some of the patients who develop this problem have little nodules under the skin of their forearms called subcutaneous nodules. Internal problems can include lung inflammation, nerve irritation called neuropathy, eye inflammation called scleritis, and dry eyes or dry mouth due to Sjogren's syndrome. Each of these problems can be treated with many of the newer medications available for RA.

IV. Laboratory Findings

The diagnosis of RA is based on clinical signs and symptoms but is supported by laboratory tests.

The following tests are performed if someone presents with a clinical pattern suggestive of RA:

1. Complete blood count: This test can demonstrate whether the RA inflammation (cytokines) has led to a low red blood cell count called an anemia. This is measured by the hemoglobin and hematocrit. Normal levels are a hemoglobin of 14 and hematocrit of 42%. In patients with RA, they may be as low as 11/33%. Patients with inflammation can also develop an elevated level of the clotting factors called platelets. This does not increase a patient's risk of clotting. A CBC is often done repeatedly over time in order to follow the course of the illness and as part of drug monitoring. When the state of inflammation is corrected to normal, the levels often return to normal.
   
   
2. Erythrocyte sedimentation rate (called an ESR): In the setting of inflammation, the body produces many proteins. These proteins can make red blood cells line up under each other. This test takes advantage of this. Here, the blood is allowed to fall in a tube. The greater the level of inflammation, the faster the red cells fall in a tube. It is measured in millimeters/hour. The normal level is less than 20 in women and less than 10 in men. In patients with active RA, the ESR level may be as high as 50mm/hour. An elevated ESR can also occur in patients with infections, trauma to tissues or tumors. Thus, it is a non-specific test. It can, however, be used in RA as a guide the amount of inflammation and response to treatment.
   
   
3. Rheumatoid factor test (RF): 80% of RA patients produce antibody proteins called rheumatoid factors. This test is also non-specific because a positive test can be found in patients who have certain infections, tumors or other autoimmune disorders such as systemic lupus. The 20% of patients with RA who do not have positive blood tests for RF often have less severe inflammation. Once this test is done, it does not have to be repeated.

   
   Potential progression of joint damage
   This series of hand X-rays demonstrates the progression of joint damage that can, but does not necessarily, occur in patients with RA. These X-rays show the PIP joint (the one in the middle of the finger). The one on the left is normal except for soft tissue swelling around the joint. The one in the center shows the early development of the major culprit in RA, a joint erosion and some minor joint space narrowing. The PIP joint on the right shows a clear erosion and significant joint space narrowing. Our primary therapeutic goal in RA is to prevent such a progression and, luckily, our newer drugs are disease-modifying, which means that they stop the erosion development shown in these pictures.

4. X-rays of the joints: Because RA can cause joint damage, often the physician will perform an X-ray of a hand or foot as a baseline study for future comparison (the most commonly involved joints in RA) or a joint that might show some deformity. Some of the characteristic X-rays findings in RA include: erosions (small punched-out areas of the bone and cartilage), joint space narrowing, thinning of the bones around the joints (called juxtarticular osteoporosis), and soft tissue swelling.

V. Differential Diagnosis

There are many disorders that must be differentiated from RA. This is important because these mimicks are often treated in a very different manner. Also, if the diagnosis of RA is delayed, joint damage may occur because of the delay in specific RA therapy.

A. Systemic lupus erythematosus (SLE) This is also a systemic disorder that occurs primarily in young women and presents with an RA-like symmetrical polyarthritis of the small joints of the hands and feet. However, patients with SLE usually have other manifestations such as fever, rash, kidney involvement, pleurisy and blood test abnormalities such as a low white, red and platelet cell counts. Also, we can find specific autoantibodies in their blood called antinuclear antibodies.

Prominent Swelling and Deformities of the distal interphalangeal joints

This hand demonstrates changes characteristic of psoriatic arthritis: prominent swelling and deformities of the distal interphalangeal joints, also called the DIP joints (those closest to the fingernail . This is very different from changes seen in RA. In psoriatic arthritis, the DIP (not the wrists, MCP/knuckes and PIP joints) are involved in an asymmetrical pattern. Similarly, joints of the knees, ankles and toes are inflamed in an asymmetrical fashion, usually involving fewer joints than that seen in RA.

Joint damage caused by psoriatic arthritis

In this hand X-ray, you can see the very different type of joint damage caused by psoriatic arthritis. First, the DIP joints are involved; second, the whittling away of the joints are characteristic of psoriatic arthritis.

B. Psoriatic arthritis (PsA) Five or ten percent of patients with psoriasis may develop arthritis called PsA. While it is also a systemic disorders, it has a very different personality than RA in that it involves large, lower extremity joints in an asymmetrical pattern. It also involves the joints at the tips of the fingers, a finding not seen in RA. Some patients with PsA also develop low back pains and stiffness. It must be noted that because RA and psoriasis are both common disorders, they can co-exist and have no relation to each other.

Characteristic findings in patients with osteoarthritis

This hand picture demonstrates the characteristic findings in patients with osteoarthritis. First, patients are usually older, in their 60's and 70's, and usually are women. Here the primary swelling and deformities are in the DIP joints and there is very little redness and no obvious psoriasis. On examination of these DIP joints, you can feel a bony spur sticking out from the top of the joint. It is this spur that causes the deformity and swelling.

Typical joint changes of osteoarthritis

This hand X-ray shows the typical joint changes of osteoarthritis: joint space narrowing and the development of bony spurs. You can see how it differs from the X-rays changes of both RA and psoriatic arthritis.

C. Osteoarthritis (OA) Everyone eventually develops the X-rays changes of OA in the neck and low back. However, not all patients that develop it have pains in those or other areas. The typical areas of OA involvement include the joints at the tips of the fingers, one knee or hip, the neck and the low back. This is not a systemic disorder such as RA, SLE or PsA. Also, joint involvement is commonly asymmetrical and gets worse as patients get older. Because OA is very common, it can co-exist with RA in certain patients. Actually, in those RA patients who need joint replacement surgery, the actual final cause of joint damage is OA that occurs secondary to the initial RA-induced damage.

Classical gouty inflamation

This picture of a foot shows the classical gouty inflammation. It differs greatly from RA, OA, and psoriatic arthritis in that it usually involves a single joint in a highly inflammatory manner. The most common joint is the metatarsophalangeal joint of the great toe, called the MTP joint. While gout can involve the finger joints, this is uncommon.

Classical gouty crystals

This slide demonstrates the classical crystals that precipitate a gout attack. These monosodium urate crystals are characteristically needle-shaped and have very specific chemical properties under the microscope. These crystals are most commonly seen in the cells that are found in an inflamed synovial fluid from a gouty joint.

D. Gout This is a disorder of men or post-menopausal women. It usually occurs in patients over the age of 50 who have a family history of gout and most commonly presents as as a highly inflamed single joint, mostly the great toe. Patients are commonly on thiazide diuretics and have an elevated serum uric acid level. The diagnosis is often confirmed by the finding of needle-shaped crystals in cells of the synovial fluid.

E. Polymyalgia rheumatica (PMR) This is a systemic inflammatory disorder that occurs primarily in women and in patients over the age of 50. These patients develop aches, pains and stiffness in the shoulders and pelvic area, as opposed to the hand and foot involvement in RA. Other characteristic findings include fatigue, fever, an elevated ESR over 50, and at times over 100mm/hour and anemia. At times, PMR is accompanied by another disorder called temporal arteritis (TA). TA is a type of vasculitis, which means that it causes inflammation and blockage of blood vessels. This vessel problem can lead to blindness if it involves the eye. Thus, visual symptoms such as flashing lights or short-lived visual loss should be brought to the attention of a physician.

VI. General Treatment Recommendations

Today, we are blessed with a deeper understanding of the pathogenesis and characteristics of RA and the availability of safe and effective medications that can alter the natural history of RA and improve function. We start with the premise that RA is eminently controllable and we aim, with our therapies, for "no evidence of disease". That means no signs of redness, warmth, swelling or tenderness and normal function. Since we would not accept uncontrolled illness in angina, chronic obstructive lung disease, hypertension or diabetes, we should similarly not accept it in RA. Luckily, today, we have the therapeutic tools to make this happen.

(Obtain a PDF version of the latest ACR guidelines for RA management)

Rheumatoid Modalities

The Importance of Early Treatment

There are some important general guidelines regarding the modern treatment of RA:

1. Early treatment with disease-modifying drugs is mandatory in order to prevent joint damage and dysfunction (i.e. within the first 2-3 months after disease onset). Treatment will continue for at least 5 years and possibly lifelong.
2. Once treatment is started, close observation of the clinical response to the initial regimen is necessary. This should include a combination of clinical, laboratory and functional assessments. Less than a 75% improvement within the first 1-2 months of therapy onset requires that the treatment protocol be re-assessed and modified.
3. The treatment regimen should be specifically crafted to be equally aggressive to that of the state of inflammation in the patient. Because the illness may change its personality and presentation, close clinical observation is important.
4. Combinations of an NSAID and one or more disease modifying drug are commonly employed and are both effective and safe.
5. Short courses of prednisone (i.e. 20 mg on day one with a taper by 5 mg/day over four days) may be used to re-set the inflammatory thermostat in patients who have significant inflammation and its attendant functional limitation. The use of chronic steroids should be avoided, if possible.
6. Physical and occupational therapy should be an important component of every regimen.
7. Patient education is mandatory for the patient and their families. The Arthritis Foundation has excellent pamphlets. For a more comprehensive approach, John Wiley & Sons, Inc. has published Hospital for Special Surgery Rheumatoid Arthritis Handbook, available in paperback.

VII. Specific Treatment Recommendations

The treatment should match the tempo, activity, aggressiveness and personality of the RA inflammation. Quantitation of the clinical outcome is mandatory! The formula that defines the type of therapy includes the following clinical information:

Treatment Modalities in Rheumatoid Arthritis

1. The patient's function. Are they working optimally either inside or outside of the house? If they are working, how limited are they and is their work threatened? If they have stopped working, was it due to their RA? Specific functional scales such as the Health Assessment Questionnaire can be followed serially as an early-warning sign to limitation in function. The patient can also measure function in the following simple manner: ten is the worst you can be, 0 is normal function. Where were you before you started the treatment regimen and where are you now?

2. The level of joint inflammation as defined by the number of swollen and tender joints.

3. The level of fatigue using the same 0-10 scale.

4. The ESR and the level of anemia

5. The development of joint deformities or erosions

6. The presence and extent of extra-articular manifestations (i.e. nodules, lung disease, eye inflammation).

Medications in the RA armamentarium

A. Nonsteroidal anti-inflammatory drugs (NSAIDs)

These medications suppress inflammation, pain and fever by inhibiting prostaglandins (PG). They do this by blocking proteins called enzymes (catalysts) that are important in the production of PG. The enzyme is called cyclooxygenase, often shortened and called COX. There are two such COX enzymes, COX-1 and COX-2. The COX-1 enzyme is found in many tissues of the body and leads to the production PGs that have a major housekeeping, protective role. It is particularly important in shielding the stomach lining. COX-2, on the other hand, does not have this protective role but is produced in the tissues in the setting of the inflammation caused by RA.

Extensive research has led to the development of NSAIDs that only block the COX-2 enzyme (the so-called COX-2 specific NSAIDs). Thus, they are much safer with regard to the stomach because they do not block the "good COX-1 enzyme". However, they are equally effective in controlling inflammation to the "traditional NSAIDs" such as Naproxen, Motrin, Feldene and aspirin. The COX-2 specific NSAIDs are employed in patients who are at high-risk for stomach irritation, including those the elderly and those with a history of NSAID-induced stomach irritation or intolerance.NSAIDs, both the traditional ones and the COX-2 specific medications, are a part of the treatment regimen in all patients with RA. While they do not appear to be able to modify the natural history of RA, they are important in controlling a significant component of the inflammatory process, decrease pain and improve function.

In general, NSAIDs are safe and well-tolerated, particularly in healthy patients. However, as a group of drugs, they do share certain side effects, particularly in the elderly and those with medical conditions such as kidney, liver or heart disease. Traditional NSAIDs can all cause stomach irritation such as gastritis or stomach ulcers. Stomach-protective medications are available and include H-2 blockers such as Zantac, acid pump inhibitors such as Prilosec and a protective PG called Cytotec (misoprostol). The COX-2 specific NSAIDs are much less irritative to the stomach. All NSAIDs can cause liver inflammation and kidney problems and thus routine tests are performed to monitor for these. The use of NSAIDs should be guided and monitored by the physician, especially in those patients who have known medical problems.The optimal NSAID is one that is taken only once or twice a day, causes minimal GI or other side effects and has a low cost.

One of the COX-2 specific NSAIDs, rofecoxib, or Vioxx, has recently been taken off of the market because of a higher than acceptable incidence of myocardial infarction and stroke in patients taking the drug when compared to traditional NSAIDs. The other two COX-2s, celecoxib (Celebrex) and valdecoxib (Bextra) continue to be scrutinized regarding this cardiac issue and have been shown to be safe. If a patient has known coronary artery disease or a predisposition to it, aspirin needs to be taken along with these two medications. Patients with rheumatoid arthritis do have an increased propensity for premature atherosclerosis because of the inflammation itself and thus treatment with a baby aspirin along with a COX-2 is appropriate. Traditional NSAIDs like naproxen can usually "stand on their own" regarding cardiac protection but, in certain situations, even with them a baby aspirin may also be needed.

B. Corticosteroids

A Nobel Prize was won in 1951 for the discovery of steroids and its use in RA. While this therapy is very powerful in its ability to control inflammation, many years of experience with it has demonstrated that chronic use is associated with many potential side effects. Thus, while steroids are used for the treatment of RA, we try to use the lowest dose for the shortest period of time in order to avoid toxicity. Side effects include: diabetes, osteoporosis, hypertension, mood changes, increased risk of infection, and bone damage called osteonecrosis. While these do not occur in everyone, the higher dose and the longer the treatment, the greater likelihood for problems. The use of steroids such as prednisone, a synthetic steroid, is employed in the following fashion:

a. In short courses for RA flares: If the setting of increased joint inflammation, fatigue and functional limitation, a short course of steroid can be helpful. A typical course would be 20 mg prednisone tapering by 5 mgm/day for a full course of four days. This often "resets" the inflammatory thermostat. b. "Bridge therapy" while we are awaiting a response to DMARDs (discussed below). In the setting of active inflammation, and while we are waiting the 1-3 months for a response from NSAIDS and DMARDs, a low dose of prednisone of 5 mgm/day can be helpful to allow the patient to function and control inflammation. c. Intra-articular steroids are injected into the joint itself to control inflammation that is localized to a single area of the body.

C. Disease-Modifying Anti-Rheumatic drugs (DMARDs)

The main goal of treatment in RA is to allow patients to live the life that they want to lead and to restore function. In infectious disorders, we accept no less than 100% effectiveness of our antibiotics. We are aiming for similar outcomes in the treatment of RA. Presently, we have very effective medications called DMARDs that can "alter the natural history of RA". That means they will stop the development of cartilage and bone damage sites called erosions, joint deformities and functional limitation. Medications in this category vary in their chemical structures, side effect profiles, routes of administration, costs and effectiveness. However, in general, they are safe and quite successful in controlling RA. Often, they are used in combination because together they may be more effective than when given alone.

1. DMARDs that are moderately effective and employed in milder disease:

a. Hydroxychloroquine (Plaquenil): This anti-malarial drug is both safe and effective for the treatment of mild RA. Its overall safety record has led to its incorporation into many combination DMARD regimens. It can rarely lead to retinal problems and thus 6-monthly ophthalmologic monitoring is indicated. Dose: Less than 6.0 mgm/kg/day. Usual dose is 200 mg po bid. Tablets: 200 mgm

b. Sulfasalazine (Azulfidine): This is a combination drug that contains both an aspirin compound and a sulfa drug. Those with sulfa allergy should avoid this. The aspirin component does not lead to stomach problems. Monitoring includes complete blood counts and liver function tests, initially weekly, then every 4-6 weeks. Dose: 2-3 grams/day in two divided doses, with meals. Tablets: Enteric-coated tablets, 500 mgm each.

c. Auranofin (Ridaura): This gold compound can be employed in mild RA. It is well-tolerated, but can cause diarrhea. Monitoring includes complete blood counts and urinalyses. Dose: 3 mgm po bid. Tablets: 3 mgm.4.

d. Minocycline (a tetracycline): This antibiotic appears to be moderately effective in controlling the inflammatory process of RA. It may be working via its inhibitory effect upon the enzymes that cause tissue damage in RA rather than its anti-bacterial action. It is generally well-tolerated, save for dizziness and sun sensitivity. Dose: 100 mg po bid. Tablets: 50-100 mgm.

2. DMARDS that are very effective and are used in moderate to severe RA:

a. Methotrexate (MTX; Rheumatrex): This immunosuppressive medication that works via its inhibition of folic acid metabolism is the best studied of all DMARDS and is both safe and effective. It is clearly disease-modifying and it is the drug against which all others are compared. Also, most DMARD combinations include MTX. While it can rarely cause liver inflammation, this side effect is quite uncommon and can be avoided by appropriate blood test monitoring and avoidance of alcohol use. Immune suppression can lead to infections, but they are rare. Bone marrow suppression is uncommon but can be monitored with serial blood counts. Dose: 7.5-25 mgm/week, orally, subcutaneously, or IM. Tablet: 2.5 mgm. Solution: 2.5 mgm/0.1 cc.

b. Leflunomide (Arava): This immunosuppressive agent works via its pyrimidine inhibition. In clinical trails, it has similar effectiveness in controlling inflammation and decreasing erosion development to MTX. Recent cases of significant and even life-threatening liver toxicity have been described, demanding close liver function test monitoring and possibly adjustment or discontinuation of the medication. Should liver function test abnormalities persist, liver biopsy should be considered. It is well-tolerated but can cause diarrhea, liver function test abnormalities and alopecia. Monitoring is similar to that of MTX and includes every 6-weekly complete blood counts and liver function tests. Dose: Initial-100 mg /day for three days, then 20 mg po qd thereafter. Tablets: 20mgm and 100mgm.

c. Tumor necrosis factor (TNF) blockers: All three of the available TNF blockers have led to quantum clinical improvement over that obtained with methotrexate alone. Infections, such as tuberculosis, and other medical problems, such as low blood counts, have recently been reported. Monitoring with blood counts and TB skin tests is appropriate and should be guided by the physician. However, despite the necessity for caution and increased monitoring, the benefits of these drugs continue to outweigh their risks. Multiple issues, including effectiveness, safety, route of administration, likelihood of compliance, and costs/insurance coverage, need to be considered before prescribing because important differences exist between these three agents.

1. Etanercept (Enbrel) This fusion protein combines two p75 TNF receptors with an Fc receptor to form an immunoglobulin-looking molecule that decoys the pro-inflammatory cytokine TNF. By doing so, it decreases the binding of TNF to its cellular receptors and thus avoids the downstream development of tissue inflammation and damage. It is both highly effective and, to date, safe. It not only leads to a clinical improvement over that obtained with MTX alone, but it has been shown to be disease-modifying. Infection risk is increased in those patients who have actively infected skin ulcers or diabetes. No increased risk of tumors or autoimmune disorders has been found. At this time, it is most commonly employed when patients have not had an excellent response to full-dose MTX. Etanercept is approved by the FDA for use with methotrexate, or may be used alone. Dose: 25 mg subcutaneously twice weekly.
2. Infliximab (Remicade) This chimeric monoclonal molecule is composed of 3/4 human and 1/4 mouse proteins and is an antibody to TNF itself. Thus, it either binds TNF in the blood or as it attaches to its receptor and, by doing so, stops its downstream pro-inflammatory and tissue damaging actions. Cells expressing transmembrane TNF bound by infliximab can be lysed in vitro by complement or effector T cells. Infliximab leads to both clinical improvement and a major trial showed a halting of erosion development and joint space narrowing. At this time, infliximab is approved only for use in combination with MTX. Two RA patients on Remicade developed clinical symptoms consistent with a lupus-like syndrome, and both patients improved following discontinuation of therapy and appropriate medical treatment. More than 80 cases of Mycobacterium tuberculosis have been reported worldwide in patients who have been treated with infliximab. The infection appears to occur soon after the institution of infliximab, and some patients have developed disseminated disease. Thus, a PPD must be performed prior to starting infliximab and, if positive, a chest X-ray. If the chest X-ray is normal, then infliximab can be used along with a nine month course of isoniazid and Vitamin B6 : To date the reported infection and tumor risk is not greater in patients treated with infliximab than in RA patients not treated with this medication. Caution in infliximab use in patients with open skin ulcerations and/or diabetes would, however, be in order. Dose: The usual starting dosing schedule is an infusion at weeks 0, 2, 6 and then every 8 weeks. While the usual starting dose is 3 mg/kg in 250 cc of saline over 2 hours, in those patients who have not responded optimally this dose, it has been increased to 5 to10 mg/kg and the frequency of infusions to monthly or every six-weeks.
   
   
3. Adalimumab (Humira) Created with phage display technology, adalimumab is the first fully human anti-TNF-alpha monoclonal antibody (IgG1). Therefore, it has low immunogenicity and may have greater therapeutic potential than infliximab or etanercept. This low immunogenicity may obviate the need for concomitant MTX, although such dual use has been shown to yield efficacy benefits beyond those that might simply be additive. The preliminary data provided to the FDA for approval purposes support a profile of clinical response that is similar to etanercept. It has been approved both for reducing signs and symptoms of RA and inhibiting the progression of structural damage in adults with moderately to severely active disease who have had insufficient response to one or more DMARDs. As with the other two TNF inhibitors, the clinician should observe precautions for serious infections (including sepsis, tuberculosis, fungal infections, and other invasive opportunistic infections), and rare cases of demyelinating disease, and malignancies (including lymphoma), all of which have been seen with each of these agents. Since rheumatoid arthritis itself has been associated with an increased risk of lymphoma, the significance of the observed lymphoma cases is as yet not determined. Dose: As the latest option, adalimumab offers a much more practical, patient-friendly dosing regimen of one subcutaneous injection of 40 mg every other week.
   
   

d. Interleukin-1 (IL-1) blocker - Anakinra (Kineret) - The FDA has approved this interleukin-1 (IL-1) receptor antagonist for the reduction of signs and symptoms of moderate to severely active RA in adult patients who have failed to achieve a significant clinical improvement from one or more DMARDs. IL-1 is an important pro-inflammatory cytokine that plays a significant role in the development and progression of RA, both with regard to inflammation and joint damage. As part of the body's attempt to maintain a balanced state, it naturally produces a blocker of IL-1, called IL-1 receptor antagonist (IL-1ra). Unfortunately, in RA, too much IL-1 is produced and too little IL-1ra is available to counter its activity. Anakinra was developed as a recombinant form of the human IL-1 receptor antagonist to re-set the inflammatory thermostat and inhibit inflammation, pain and joint damage. Both clinical markers of joint inflammation and the progression of joint damage have been significantly improved with this new biologic agent. It can be used alone or in combination with other DMARDs but not with the TNF-blocking medications etanercept or infliximab. The most common side effect was a reaction at the site of injection, usually mild and characterized by redness, swelling and pain. There was a risk of serious infection (2% in the anakinra treated patients and less than 1% in the patients treated with placebo). Thus, the drug should not be started when an active infection is present and should be stopped in the setting of an active infection. Dose and route of administration: Daily subcutaneous injections that contain 100 mgm of anakinra.

e. Azathioprine (Imuran) This antimetabolite immunosuppressive agent has been used for many years in patients with active RA unresponsive to other DMARDs. It is both safe and effective but can suppress the bone marrow and lead to infections. It has been replaced by MTX and other DMARDs because of their balance of safety and effectiveness. Dose: 2 mgm/kg/day orally. Tablets: 50 mg.

f. Intramuscular Gold (Solganal, Myochrysine) These gold compounds can be quite safe and effective in controlling the inflammation due to RA. However, they demand intramuscular (IM) injection, are associated with bone marrow and kidney toxicity and thus have been replaced by other DMARDs. Dose: Weekly IM dose of 10-50mgm over 20 weeks, then every 2-6 weekly.

g. Cyclosporine (Neoral, Sandimmune) This immu- nosuppressive agent works by suppressing certain immune cell actions. It is particularly effective when used on combination with MTX. Because of kidney and hypertension problems when used at high doses, a lower, safer dose of 2.5 mgm/kg is now employed. This medication is usually used in the setting of more severe and active disease, unresponsive to MTX. Dose: 2.5 mgm/kg initial dose. Tablets: 50-100 mgm.

3. Combination DMARD regimens that are both effective and safe:

These DMARD combinations have evolved in an attempt to maximize disease control without increasing the overall risk of side effects. While some rheumatologists begin all of the medications at the same time, most add one to another, as guided by the clinical response. Blood test monitoring usually involves serial complete blood counts, liver function tests, blood pressure and serum creatinine, as guided by the potential side effects of the components of the regimen. All are employed in the treatment of moderate to severe disease.

• Methotrexate + hydroxychloroquine
• Methotrexate + hydroxychloroquine + sulfasalazine
• Methotrexate + etanercept
• Methotrexate + infliximab
• Methotrexate + adalimumab
• Methotrexate + anakinra
• Methotrexate + leflunomide
• Methotrexate + cyclosporine

VIII. Long-term Management Issues

A. Surgery in the patient with RA: Obviously, the main thrust of therapy at this time is to avoid the need for surgery by controlling the damaging effects of RA. However, in those patients who do develop joint damage with deformity and functional limitation, surgery can have a profoundly positive impact on their ability to carry out their activities of daily living. The usual indications for surgery include pain and/or disability that are unacceptable and functionally limiting. The procedures that are most effective include:

1. Hand and wrist surgery: Carpal tunnel release can markedly improve the numbness and tingling that occurs because of flexor tenosynovitis in the wrist. In patients with significant wrist damage and threatening tendon rupture, wrist fusion, shaving of the ulnar styloid and synovectomy can be very effective. Implants into the small joints of the hands and fusion (fixation) of the thumb joints can be particularly helpful in improving the function of the small joints of the hands. Wrist replacement is sometimes needed in patients with severe wrist damage.

2. Shoulder surgery: RA-related problems of the shoulder can range from mild inflammation to rotator cuff tear, and even can lead to joint damage. Arthroscopic surgery can help the first two problems but joint replacement may be needed if the joint damage is advanced. All are effective and well-tolerated.

3. Elbow surgery: Elbow replacement is effective in improving function in patients who have severe arthritis and dysfunction.

4. Total Hip Replacement (THR): In patients with severe damage to the hip joint, the THR has been one of the more effective surgeries. Since its development 40 years ago, it has been perfected and is associated the excellent functional outcomes. With modern techniques, the potential side effects of blood clots and infections are quite uncommon.

5. Knee surgery:

1. Arthroscopic surgery: A synovectomy, which is the removal of an excessive growth of synovial tissue, can be quite helpful in improving function and decreasing inflammation in those patients who have failed to respond to local injections of steroids. Meniscal tears can also be treated via the arthroscope.
2. Total Knee Replacement (TKR): Like the THR mentioned above, the results of this procedure are excellent. In those patients with advanced knee damage due to RA, profound functional improvement is usually attained.

6. Ankle and foot surgery: Many procedures are available in order to improve the outcome of ankle and foot arthritis due to RA. These include joint replacements and the re-structuring of the bone.

7. Medical issues to consider when surgery is scheduled:

1. The patient should be checked, likely by the internist, to make sure that general health is good and acceptable for the planned surgery.
2. All sites of infection (i.e. teeth, urinary tract, skin) should be corrected prior to surgery
3. Correct administration of all medications before, on the day of, and after surgery should be discussed with the patients.
4. Be aware of potential post-operative issues such as infections, blood clots, bowel problems, and reactions to drugs such as narcotics.

IX. Prognosis

The reason why we are now quite aggressive in our approach to the treatment of RA is found in the following facts:

• If not treated quickly, as many as 80% of patients will develop erosions in their joints in the first 2 years after RA begins.
• If left untreated, over 50% of patients have to stop work within 5-10 years of the onset of RA.
• Active and persistent joint inflammation begets joint damage and functional limitation.

Today, with our new medications and a proactive approach to early therapy, equally aggressive to the disease itself, we can avoid the development of erosions, joint deformities, functional limitation and loss of work.

X. When to Refer

A multidisciplinary team that includes the primary care physician, the rheumatologist, the physical therapist and other members of health care system will bring about a coordinated treatment program that is both safe and effective. The primary care physician or internist commonly works in partnership with a rheumatologist. Referral to a specialist on rheumatology most commonly occurs in the following situations:

• When the diagnosis is in question
• At the institution of therapy in order to craft the optimal medication and physical therapy regimen
• During the course of the illness to define response to or alteration in the treatment regimen.
• In the setting of possible medication side effects
• Progressive disease despite therapy
• A single joint that is leading to significant functional limitation
• The presence of fever, marked fatigue or weight loss h. Prior to Orthopaedic surgery

XI. Annotated References

A. The 11th Edition of the Primer on the Rheumatic Diseases, an Official Publication of the Arthritis Foundation. Chapters 9 and 10 cover Epidemiology, Pathology, Pathogenesis (authors Jorg J. Goronzy, and Cornelia M. Weyand; Clinical and Laboratory Features (Ronald J. Anderson); and Treatment (Stephen A. Paget). ed. John Klippel, MD. 1997.This Primer is a must for all primary care physicians, patients, residents and medical students. In a well-written, concise format, all of the pertinent information about RA is discussed and referenced. It can be purchased from the Arthritis Foundation, 1330 West Peachtree Street, Atlanta, Georgia 30309.

B. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of Etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. New England Journal of Medicine 1999; 340: 253-259.This landmark paper demonstrates that in patients with persistent, active RA, the combination of the this new biologic agent and methotrexate was safe and well-tolerated and provided significantly greater clinical benefit than methotrexate alone. This extraordinary new, focused DMARD was able to significantly improve the status of patients with active RA despite 6 months of treatment with what was thought to be the previous "best drug on the block," methotrexate.

C. O'Dell JR. Anticytokine therapy- A new Era in the treatment of rheumatoid arthritis. New England Journal of Medicine Editorial. 1999; 340: 310-312.This excellent editorial notes that "for the first time clinicians can target a specific aspect of the pathologic process that constitutes rheumatoid arthritis". He does note that "although we are targeting a specific cytokine that affects the inflammatory response, a multitude of effects, both good and bad, may result".

D. Maini RN, Breedveld FC, Kalden JR, et al. The therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis and Rheumatism 1998; 41: 1552-1563.This landmark study evaluated the efficacy, pharmacokinetics, immunogenicity and safety of multiple infusions of one of the "breakthrough" therapies now available for the treatment of RA. While this biologic agent is the "beginning of the beginning" of such focused, effective biologic therapies, it's extraordinary ability to markedly control the disease bodes well for the future.

E. Verhoeven AC, Boers M, Tugwell P. Combination therapy in rheumatoid arthritis: updated. British Journal of Rheumatology. 1998; 37: 612-619.In this updated, complete review of combination DMARD therapies for the treatment of RA, we are guided through the various therapeutic options and given their supporting data. Combination therapies are here to stay but many of the regimens need confirmation by repeat studies.

F. Irvine S, Munro R, Porter D. Early referral, diagnosis and treatment of rheumatoid arthritis: evidence for changing medical practice. Annals of Rheumatic Diseases. 1999; 58: 510-513.This important study demonstrates that patients are being referred earlier in their disease and DMARDs are prescribed sooner in the disease course, often within six months of symptom onset. Given the power of the newer medications employed in RA, early diagnosis and treatment will clearly improve the short- and long-term outcome.

G. Madhok R, Capell HA. Outstanding issues in use of disease-modifying agents in rheumatoid arthritis. Lancet 1999; 353: 257-259.This excellent editorial stresses many important points about the modern treatment of RA:

1. Disease-modification rather than symptom control is now the desired outcome in RA, as it is in hypertension, congestive heart failure and diabetes mellitus.
2. Outcome is better with early, rather than late treatment. Treatment also needs to be continued for the effect to be sustained.
3. While many agents do demonstrate the ability to slow down radiologic progression, their longer-term impact on disability has yet to be proven.
4. Long-term assessment of outcome is important in chronic disorders like RA. Randomized trials, while paradigms as methodology for drug studies, do not tell the whole story.
5. Suppression of disease activity with single agents can be difficult to sustain