An In-Depth Overview of Rheumatoid Arthritis

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.

Many different diseases cause joint pain. Differential diagnosis is the process by which the physician figues out which one is causing your problems. This is important because diseases that mimic RA 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 starting specific RA therapy. Here's a review of other disorders that can mimic RA.

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.

B. Psoriatic arthritis (PsA): About 5 to 10 percent of people with psoriasis develop a form of arthritis called PsA. While it is also a systemic disorders, it has a very different pattern from RA. PsA 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. However, because RA and psoriasis are both common disorders, a person can have both; they can co-exist and have no relation to each other.

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.

C. Osteoarthritis (OA): Everyone eventually develops X-rays changes characteristic of OA in the neck and low back. However, not all patients that develop X-ray changes have pains in those or other areas. The typical areas of OA involvement 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. Only the joints are involved. 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.

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.

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. It most commonly presents as as a highly inflamed single joint, usually 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 (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.

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.

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 the goal of our therapies is "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.

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

Modalities Employed in Rheumatoid Arthritis

The Importance of Early Treatment in Rheumatoid Arthritis

A. 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 throughout life.

B. 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.

C. 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.

D. Combinations of a non-steroidal anti-inflammatory drug (NSAID) and one or more disease-modifying anti-rheumtic drugs (DMARDs) are commonly employed. They are both effective and safe.

E. 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.

F. Physical and occupational therapy should be an important component of every regimen.

G. Patient education is mandatory for patients 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

A. The patient's function. Are you working optimally either inside or outside of the home? If working, how limited are you and is your work threatened? If you have stopped working, was it due to 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?

B. The level of joint inflammation as defined by the number of swollen and tender joints.
C. The level of fatigue using the same 0-10 scale.
D. The ESR and the level of anemia
E. The development of joint deformities or erosions
F. The presence and extent of extra-articular manifestations (i.e. nodules, lung disease, eye inflammation).

Medications in the armamentarium for RA

A. Nonsteroidal anti-inflammatory drugs (NSAIDs)

These medications suppress inflammation, pain and fever by inhibiting certain inflammation-causing chemicals in the body called 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 of PGs that have a major housekeeping, protective role. It is particularly important in shielding the stomach lining. COX-2, in contrast, does not have this protective role; it is produced in the tissues in the setting of the inflammation caused by RA.

There are two types of NSAIDs that are employed in the treatment of rheumatoid arthritis: traditional NSAIDs and COX-2 NSAIDs. They control inflammation but do not modify or change the course of RA, unlike the disease modifying drugs called DMARDs. Traditional NSAIDs and COX-2 NSAIDs share many characteristics including their equal ability to control inflammation and pain and also the potential to cause fluid and salt retention, liver and kidney effects and skin rashes. COX-2 NSAIDs are better tolerated from a gastrointestinal point of view in that they cause less stomach and duodenal irritation, a positive trait that likely disappears when a patient needs to take aspirin for some medical reason. One of the COX-2 NSAIDs named rofecoxib, or Vioxx, has recently been taken off of the market because of a higher than acceptable incidence of heart attacks in patients taking the drug when compared to traditional NSAIDs. The other two COX-2s, named 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. If you have a history of gastrointestinal intolerance for NSAIDs, your physician will need to decide whether you should continue a COX-2 + aspirin or whether you should be on a traditional NSAIDs plus a proton pump inhibitor stomach protection medication.

All NSAIDs can cause liver inflammation and kidney problems. Thus, routine tests are performed to monitor for these side effects. 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.

B. Corticosteroids

A Nobel Prize was won in 1951 for the discovery of steroids and their use in RA. While this therapy is very powerful in its ability to control inflammation, experience has shown 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. The most commonly used steroids are prednisone, prednisolone, and methylprednisolone (Medrol). 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. Steroids are used in the following fashion:

1. 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.

2. "Bridge therapy" while awaiting a response to DMARDs: In the setting of active inflammation, and while waiting the 1to 3 months for a response from NSAIDs and DMARDs, a low dose of prednisone of 5 mg/day can be helpful to allow the patient to function and control inflammation.

3. 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." 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 eye tests every six months are recommended. Dose: Less than 6.0 mg/kg/day. Usual dose is 200 mg bid (twice daily). Tablets: 200 mg each.

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 mg 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 mg bid (twice daily). Tablets: 3 mg each.

d. tetracycline (Minocycline): 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 via its anti-bacterial action. It is generally well-tolerated, except for dizziness and sun sensitivity. Dose: 100 mg bid (twice daily). Tablets: 50-100 mg each.

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

a. Methotrexate (often abbreviated MTX; Rheumatrex): This immunosuppressive medication works via its inhibition of folic acid metabolism. It 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 mg/week, orally or by subcutaneous or intramuscular injection. Tablet: 2.5 mg. Solution: 2.5 mg/0.1 cc.

b. Leflunomide (Arava): This immunosuppressive agent works via its pyrimidine inhibition. In clinical trials, it has similar effectiveness in controlling inflammation and decreasing erosion development to MTX. It is well-tolerated but can cause diarrhea, liver function test abnormalities and alopecia. However, 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. Monitoring is similar to that of MTX and includes every 6-weekly complete blood counts and liver function tests. Dose: Initially100 mg/day for three days, then 20 mg daily thereafter. Tablets: 20mg and 100mg.

c. Tumor necrosis factor (TNF) blockers: TNF is a cytokine protein chemical that plays a critical role in inflammation. 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. You should discuss multiple issues, including effectiveness, safety, how the drug is given and your likelihood of using it as prescribed, as well as costs and your insurance coverage, as the choice of a TNF blocker is being made.

i. 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 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 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 by subcutaneous injection twice weekly. (This is similar to the way people with diabetes give themselves shots for diabetes.)

ii. Infliximab (Remicade): This monoclonal molecule is composed of 3/4 human and 1/4 mouse proteins. It is an antibody to TNF itself. Thus, it binds TNF either in the blood or as it attaches to its receptor; by doing so, it stops pro-inflammatory and tissue damaging actions. Infliximab leads to both clinical improvement and a halting of erosion development and joint space narrowing. At this time, infliximab is approved only for use in combination with MTX. Rare cases of a lupus-like syndrome have been reported; 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 (a test for TB) must be performed prior to starting infliximab; if the test is positive, a chest X-ray should be done. If the chest X-ray is normal, then infliximab can be used along with a nine-month course of isoniazid and Vitamin B6 to prevent serious TB. 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.

iii. Adalimumab (Humira): Adalimumab is the first fully human anti-TNF-alpha monoclonal antibody. Therefore, it is less likely to spur your body to produce new antibodies, and it may have greater therapeutic potential than infliximab or etanercept. This is called "low immunogenicity" and it may help avoid the need for taking methotrexate at the same time - although using both drugs has been shown to yield efficacy benefits beyond those that might simply be additive. The preliminary data provided to the FDA suggest that adalimumab has an effectiveness and safety profile 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, your doctor will observe precautions for serious infections (including sepsis, tuberculosis, and fungal infections), demyelinating disease, and malignancies (including lymphoma), all of which also have been seen with adalimumab - although rarely. 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: Adalimumab offers a much more practical, patient-friendly dosing regimen than the other two TNF blockers. You will give yourself one subcutaneous injection of 40 mg every other week - again, similar to the way people with diabetes give themselves shots.

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 (protein) 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 mg/kg/day. Tablets: 50 mg.

f. Intramuscular Gold (Solganal, Myochrysine): These gold compounds can be quite safe and effective in controlling 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: 10-50mg weekly over 20 weeks, then every 2-6 weekly.

g. Cyclosporine (Neoral, Sandimmune): This immunosuppressive agent works by suppressing certain immune cell actions. It is particularly effective when used in 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, active disease, unresponsive to MTX. Dose: 2.5 mg/kg initial dose. Tablets: 50-100 mg.

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

Combination DMARD regimens 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 of the following 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 with 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 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. See your internist to make sure that your general health is good and acceptable for the planned surgery.
2. Make sure that sites of infection in the teeth, urinary tract, skin are corrected prior to surgery
3. Discuss the correct administration of all of your medications before, on the day of, and after surgery.
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 to10 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 Seek Referral to a Rheumatologist

A multidisciplinary team that includes the primary care physician, the rheumatologist, the physical therapist, and other members of the 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 in rheumatology most commonly occurs in the following situations:

• When the diagnosis is in question;
• At the start 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;
• Prior to Orthopaedic surgery.

XII. Annotated References

A. Stephen A. Paget, MD, Michael D. Lockshin, MD, and Suzanne Loebl. The Hospital for Special Surgery Rheumatoid Arthritis Handbook. John Wiley & Sons, 2001. This new handbook provides a comprehensive overview of rheumatoid arthritis that can help the patient and the family develop a deeper understanding of what causes the disease, the tests used to gauge its activity and responses to treatment, the druges and exercises prescribed, and psychological coping, as well as an in-depth discussion of joint replacement. It can be purchased at local bookstores or online from Amazon.com or BarnesandNoble.com.

B. 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, or online from Amazon.com

C. 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 demonstrated 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.

D. 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."

E. Maini RN, Breedveld FC, Kalden JR, et al. The therpeutic 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, its extraordinary ability to markedly control the disease bodes well for the future.

F. 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.

G. 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.

H. 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