The patient had worked as a domestic for 20 years but was now having difficulty performing her job. She had tried over-the-counter ibuprofen and acetaminophen; neither provided significant relief.  She denied fever, aphthous ulcers, serositis, neurologic disorder, renal disease, or photosensitivity. She had no significant personal or family history of disease. 

 

Examination of the hands revealed significant warmth and swelling in both wrists and a noticeable reduction in both flexion and extension. There was mild swelling of the PIP and MCP joints in a bilateral and symmetric distribution. Palpation of the forefoot produced notable tenderness.

 

Laboratory studies showed a white blood count of 6,500/mm3, with a differential of 59% polymorphonuclear leukocytes and 31% lymphocytes; hematocrit, 38.3%; platelet count, 275,000/mm3; blood urea nitrogen (BUN), 11 mg/dL; serum creatinine, 0.7 mg/dL; aspartate aminotransferase (AST), 22 U/L; alanine aminotransferase (ALT), 16 U/L. Assays for antinuclear antibody (ANA) and rheumatoid factor (RF) were negative. The erythrocyte sedimentation rate (ESR) was 39 mm/hr. A urinalysis was normal.

 

This patient has rheumatoid arthritis. Her presentation is fairly typical. Rheumatoid arthritis affects women more often than men, with the peak incidence between ages 40 and 60, although the disease can appear at any time of life. Onset is often gradual and insidious, occurring over a period of days or weeks. Usually it begins in the small joints of the hands or the feet. A woman may notice that her shoes do not fit quite as well as they used to or experience pain while wearing high heels. Her hands appear mildly swollen to her but not to others; she may have difficulty taking rings on and off.

 

Many patients with early rheumatoid arthritis take over-the-counter medications, such as acetaminophen or ibuprofen, for a period of time before seeking medical attention. Since the clinical picture at this stage may still be vague, the primary care physician may simply prescribe a nonsteroidal anti-inflammatory drug and recommend continued follow-up.

 

The arthritis may be asymmetric at first (i.e., limited to one side of the body) but over a period of weeks to months tends to become symmetric. As in this case, patients may experience stiffness--a hallmark of the disease--and complain of diminished energy and fatigue. Eventually they will begin to manifest more overt features of synovitis or swelling and tenderness in the involved joints.

 

With time, disease manifestations will become objective and more obvious to those around the patient. Examination typically shows involvement of the small joints of the hands, feet, or both. In the hands, there is characteristically involvement of PIP or MCP joints, but sparing of the distal interphalangeal (DIP) joints. X-rays at this stage may or may not show features of the disease.

 

 Some patients will have normal radiographs while others demonstrate erosions and sometimes joint space narrowing within six months to a year after onset.

 

Laboratory studies initially may not contribute to the diagnosis. The rheumatoid factor assay is initially negative in many patients--and in up to 30%, the assay is never positive. The ESR may or may not be elevated at presentation; the elevation may not occur for weeks or even months.

 

The other diagnostic possibility that the physician should consider is systemic lupus erythematosus (SLE). In this patient, the lack of findings consistent with SLE (e.g., photosensitivity, cutaneous disease, internal organ involvement) made that diagnosis unlikely.  It is also important to make sure that a patient such as this does not have parvovirus B19 or hepatitis B or C infection.

 

Formal diagnosis of rheumatoid arthritis requires that the case meet at least four of seven criteria: 1) Morning stiffness lasting at least one hour. In fact, even stiffness for more than 30 minutes strongly suggests inflammatory disease. 2) Alleviation of morning stiffness with activity is a hallmark of inflammatory arthritis. Later in the day, continued activity will aggravate the problem and exacerbate the pain. 3)Swelling in three or more joints simultaneously.  Swelling in the hand joints (PIP, MCP, or wrist). 4)Symmetric arthritis. Initially, joints on only one side may be involved, but the arthritis tends to spread to the other side of the body. 5)Erosions or decalcifications on x-ray of the hand. 6))Subcutaneous rheumatoid nodules. 7)A positive serum rheumatoid factor assay.

 

Even this early in her disease, this patient had all of the first four criteria. Since she had sufficient clinical criteria, were the x-rays needed? Yes, they serve several purposes. First, x-rays provide a baseline. After one or two years, the physician can obtain another x-ray to see whether the disease has continued to progress radiographically. 

 

This can occur independently of clinical manifestations; even patients whose symptoms have responded well to therapy may continue to show radiographic progression. Second, if erosions or joint space narrowing had already been present, it would have helped to predict the disease course and to determine the therapeutic strategy.

 

Even if a patient does not meet four criteria, the primary care physician still should entertain the possibility of rheumatoid arthritis. Patients whose disease has features characteristic of rheumatoid arthritis may merit referral to a rheumatologist. During the past few years, there has been a much greater emphasis on early diagnosis. Underlying that emphasis is the realization that some patients experience early functional and radiographic decline that ultimately produces significant impairment in their ability to function.  The sooner the diagnosis is made and disease-modifying therapy initiated, the better off the patient is likely to be, over both the short and long term. 

 

The patient was treated with oral methotrexate, 7.5 mg once a week, and this dosage was titrated to 20 mg during the next three months. Her liver function tests remained normal, and she reported no significant side effects. However, she experienced only mild amelioration of symptoms.

 

The rheumatologist considered adding one of the newer antirheumatic agents (leflunomide, etanercept, or infliximab), but the patient's insurance company refused to pay for treatment with these agents until therapy with at least two of the established disease-modifying drugs had failed. Consequently, hydroxychloroquine and sulfasalazine were added to her regimen. Within three months, she showed substantial improvement.

 

Two decades ago, patients such as this were usually kept on nonsteroidal therapy until they showed evidence of joint damage or increased disease activity. During the last 10 to 15 years, however, rheumatologists have become more aggressive about starting disease-modifying antirheumatic drugs much earlier in the course of the disease.

 

 The principal agents used are hydroxychloroquine, sulfasalazine, and methotrexate. Gold salts, while still available, are not often utilized, especially in their oral form. D-penicillamine has fallen out of favor, predominantly because of its side effects. Other medications, such as cyclosporine, are generally reserved for combination therapy or refractory disease.

 

During the last two years, our therapeutic options have increased significantly. The introduction of leflunomide, a pyrimidine synthesis inhibitor, has provided an alternative for early therapy. Etanercept, a fusion protein that interrupts the inflammatory cascade by binding to tumor necrosis factor (TNF)-alpha, can also be used in early disease. Another TNF-alpha inhibitor, infliximab, would probably work very well in early disease, but currently its use is limited to refractory cases, in which it is given in combination with traditional medications such as methotrexate.

 

Both leflunomide and etanercept improve function, and there is good evidence that they slow radiographic progression of rheumatoid arthritis. This would argue for their use early in the disease, especially in patients who seem likely to have an aggressive or a destructive course. Traditional disease-modifying agents can also slow radiographic progression, however, and they are much less expensive than the newer agents. Consequently, some third-party payers impose restrictions on the use of the new agents. They may stipulate that patients must first be unresponsive to as many as three traditional agents before they will pay for treatment with a TNF-alpha inhibitor.

 

These restrictions are being relaxed somewhat as evidence of the new agents' efficacy accumulates. The case for etanercept, for example, has been bolstered by data from the Early Rheumatoid Arthritis study showing that it is effective in early disease. A U. S. Food and Drug Administration advisory board has approved its early use.

 

For physicians whose choice of initial therapy is limited to traditional agents, the first question is whether to start with a single agent or combination therapy. Possible combinations include hydroxychloroquine with sulfasalazine or methotrexate, sulfasalazine with methotrexate, or all three together.

 

The choice of initial therapy can be a difficult one. Rheumatologists do not want to administer more medication than is necessary, yet they want to be aggressive enough to improve function and prevent the development of radiographic destruction, thereby ultimately minimizing functional impairment and keeping down the long-term cost of care.

 

At present, the most common strategy is to start with methotrexate alone. However, to minimize the risk of hepatotoxicity, the patient must agree not to consume alcohol (or to do so only very modestly).

 

Most rheumatologists choose not to start treatment with hydroxychloroquine monotherapy, except perhaps in patients with mild disease. They generally may use hydroxychloroquine in combination with methotrexate or sulfasalazine. Another alternative would be to start with sulfasalazine alone, but that approach is less common in the United States than in Europe.

 

In the past, this patient's methotrexate dosage (7.5 mg orally once a week) would have been titrated up slowly over six months or even a year. Now rheumatologists tend to move much faster, starting with up to 10 mg per week and taking the dose to as high as 20 mg or even 25 mg a week within the first two to three months.

 

Faster dose escalation requires more frequent follow-up. Rheumatologists look for abnormalities on liver function tests, mouth sores or ulcerations, significant fatigue, nausea, or discomfort during the first 24 hours after taking the drug.

 

Patients are asked to return two weeks after first taking the drug, at which point the dose may be increased to 12.5 mg. They then usually return within four weeks. If they have not had a substantial response, the dose might be increased to 15 to 17.5 mg. Four weeks after that, if patients still have not responded, the dose is increased to 20 to 25 mg.

 

Clinical trials suggest that about 50% of patients respond to methotrexate monotherapy. Unfortunately, the average degree of improvement tends to be about 25%. For example, the number of tender or swollen joints may decrease from 20 to 16.

 

A few years ago, monotherapy was usually continued for six months to a year, and patients who had not responded might be switched to another drug. Today, if patients do not respond sufficiently to an adequate dose of medication, physicians add other medications--hydroxychloroquine, sulfasalazine, or (if possible) etanercept, infliximab, or leflunomide. They might consider switching to one of the newer agents, but if the patient has shown some improvement and has not been troubled by side effects, most rheumatologists will add rather than switch.

 

Hydroxychloroquine can be added at a dosage of 400 mg once a day or 200 mg twice a day. Sulfasalazine is usually added at a dosage of 500 mg once or twice a day, escalating to a total dose of 1 gm twice a day. The escalation schedule traditionally recommended is for the patient to take one tablet a day for the first week, one tablet twice a day for the second week, one in the morning and two in the evening during the third week, and two tablets twice a day during the fourth week and thereafter.

 

For patients on combination therapy, physicians generally follow the same schedule for toxicity monitoring as with methotrexate. They obtain a complete blood count and liver function tests and look for myelosuppression. The other medications do not need to be monitored as frequently as methotrexate, but since the patient is in the office anyway, all the monitoring can be done at the same time.

 

This patient responded well to triple therapy. If combination therapy does not produce substantial improvement within three months, the physician has a good clinical basis to move to anticytokine therapy, and there should be little difficulty convincing a third-party payer of the necessity of using these agents.

 

If a patient responds well to disease-modifying treatment, the physician should eventually think about reducing dosages or withdrawing the agents one by one. The goal is to provide just enough therapy to keep the disease under control. In this patient, that might involve the reduction or removal of sulfasalazine or hydroxychloroquine at some point in the future.

 

At the initial referral, the rheumatologist should educate patients about the nature of their condition. They need to know that rheumatoid arthritis usually is a lifelong disease. Current treatment can provide significant improvement, but complete relief is unlikely.

 

Patients need to learn the importance of avoiding trauma or stress in involved joints and of physical or occupational therapy to improve structures around the joints to decrease pain and improve function. Education about medication is also vital. Patients need to know the potential complications and toxicities of the drugs they are taking. They also need to understand that the benefits of disease-modifying antirheumatic drugs are slow to appear.

 

Physicians should reassure patients that during the interval (weeks to months) between initiation of therapy and the appearance of therapeutic effects, they will provide other medications as a bridge. Virtually all rheumatoid arthritis patients initially receive nonsteroidal anti-inflammatory drugs (NSAIDs), since their analgesic and anti-inflammatory effects can provide short-term improvements. Patients often receive low-doses glucocorticoid therapy (e.g., up to 7.5 mg of prednisone a day).

 

Many rheumatoid arthritis patients are at risk of gastrointestinal complications from standard non-steroidal drugs. These patients tend to be older, have comorbidities, and take glucocorticoids; they may or may not have a history of coronary artery disease. The cyclooxygenase (COX)-2 inhibitors are a welcome innovation for such patients, since they appear to have a lower risk of gastrointestinal toxicity.

 

The improved safety of these drugs should not be assumed to imply improved efficacy, however. No nonsteroidal medication can alter the course of rheumatoid arthritis; they do not change radiographic progression or slow joint destruction. For that reason, they should be used as adjuncts, never as monotherapy.

 

Physicians still encounter patients with rheumatoid arthritis who take 10 aspirin a day for symptomatic relief. Usually their disease is of long duration (10-20 years), and they began to take aspirin on the advice of their physician. They have continued it on their own because they found that it worked better than any of the other nonsteroidal medications they had tried.

 

Most patients do not take aspirin. Some have tried it but did not take enough to experience its anti-inflammatory benefits; others took sufficiently high doses but experienced complications. When most rheumatologists prescribe chronic treatment with aspirin or an NSAID, they often add a gastroprotective agent (e.g., misoprostol or a proton pump inhibitor).

 

2nd Case: A 71-year-old woman was referred to a rheumatologist for evaluation. She had a six-year history of bilateral pain in her knees and wrists. Rheumatoid arthritis had been diagnosed four years earlier, and three years of treatment with low doses of prednisone (5 mg/day) and hydroxychloroquine had provided subjective improvement. She used no other medications. The patient complained of morning stiffness that lasted 45 minutes but felt that her ability to function had not been significantly impaired.

 

However, during her most recent visit to her primary care physician, it had become apparent that she had occasional warmth, tenderness, and swelling in her second and third MCP joints bilaterally as well as in her wrists and knees, and that she occasionally used a wrist splint for pain relief. The physician realized that she might not be doing as well as she thought and referred her for a possible adjustment in therapy.

 

Examination by the rheumatologist showed mild soft-tissue swelling and synovitis in both wrists. Their range of motion had decreased to 45° of flexion and 30° of extension. There was mild tenderness and swelling of the MCP and PIP joints bilaterally and evidence of mild effusions in the knees.

 

Laboratory studies showed a white blood count of 6,400/mm3; hematocrit, 39.1%; platelet count, 288,000/mm3; BUN, 13 mg/dL; serum creatinine, 1.6 mg/dL; ALT, 21 U/L; RF, negative; ESR, 25 mm/hr.

 

X-rays showed extensive bony erosions in MCP joints as well as erosive disease involving carpal bones of the right wrist, distal ulna, and radius. In the left arm, there was foreshortening of the radius and significant erosion of the ulnar styloid.

 

The patient said that she was allergic to sulfa antibiotics.

 

This case illustrates why rheumatologists have become more rigorous in the follow-up of patients with rheumatoid arthritis. The patient thought that treatment had brought significant improvement, and her primary care physician, and possibly a previous rheumatologist, had agreed. Because no one realized that her treatment was inadequate, significant joint destruction had occurred.

 

The current evaluation provides clear-cut evidence that the patient's disease is still quite active, showing tender, swollen joints, overt reduction in range of motion, joint space narrowing, and erosion. The radiographic changes are fairly significant; they warn of potential future complications. Although the test for rheumatoid factor was negative, that is not always a predictor of long-term outcome. The ESR is still within the normal range, but that may be misleading; it is possible that the prednisone and hydroxychloroquine have been able to decrease the ESR without suppressing the disease. In short, the addition of another medication should be considered.

 

Sulfasalazine is out of the question because of the patient's sulfa allergy. The elevated serum creatinine level obviates methotrexate (moost physicians shy away from using methotrexate, at least in high doses, in patients with renal impairment). That limits the options to leflunomide or etanercept..

 

Generally,they use infliximab only in combination with methotrexate, or sometimes another disease-modifying drug.

 

The patient was started on leflunomide, at a loading dose of 100 mg a day for three days, and then a maintenance dose of 20 mg a day. She experienced mild diarrhea with the loading dose and was instructed to take loperamide (1-3 mg) after each loose bowel movement. The diarrhea resolved over the next 10 days, and she had no further complications. Disease signs and symptoms improved during the next three months

 

One possible strategy in this case would have been to replace hydroxy chloroquine with leflunomide. Since the patient appears to have had some benefit from hydroxychloroquine and has been tolerating it well,some physicians would prefer to add leflunomide,(many other rheumatologists prefer methotrexate).

 

Serious complications are rare with leflunomide (also MTX). The physicians should be on the alert for rash, diarrhea or loose stools, and liver inflammation.

 

The rashes tend to be reversible with either dose reduction or discontinuation of the medication. To monitor for liver inflammation, physicians usually ask patients to return in two weeks for liver function tests, and then every six to eight weeks thereafter. They often obtain intermittent complete blood counts to make sure that there have been no decreases, although they are quite rare.

 

Diarrhea is among the most common complications of leflunomide; altered bowel function occurs in up 33% of patients. Diarrhea can develop at any point, but patients often experience it with the loading dose. It tends to be mild and self-limited and can be treated symptomatically with loperamide.

 

One of the attractive aspects of leflunomide is that dose escalation often is not required; the patient can simply be started at 20 mg a day. However, when leflunomide is given in combination with other drugs, physicians often prefer to give 100 mg daily for two days as a loading dose, followed by 10 mg a day or 20 mg every other day. The dose can be increased later if necessary. Should toxicity develop, the medication can be withdrawn or the dosage cut in half. Cholestyramine can be given to bind the leflunomide in the bowel and remove it from the body.

 

The benefits of leflunomide often begin to appear within four weeks, and most patients who are going to benefit will see it within 12 weeks. The drug is expected to improve function and impede radiographic progression
 
Case 3: Presentation: A 55-year-old man was referred by his primary care physician for evaluation of refractory rheumatoid arthritis. The patient complained of persistent pain and swelling in the joints of his hands and feet despite treatment with methotrexate.

 

Symptoms had begun three years earlier with swelling, significant pain, warmth, and erythema of the second PIP joint of the left hand. Not long afterward, the patient noted similar involvement of the right second PIP. Subsequently, progressive involvement of the PIP, MCP, and MTP joints occurred. Chronic pain and swelling of those joints was accompanied by 30 to 60 minutes of morning stiffness.

 

The patient's primary care physician had initially prescribed NSAIDs, with only modest benefit. A year later, he was referred to a rheumatologist who prescribed methotrexate, initially at low doses and then rapid escalation to 20 mg a week. The morning stiffness, joint tenderness, and swelling decreased, but he continued to experience active arthritis.

 

When the methotrexate dosage was increased to more than 20 mg a week, the patient experienced nausea, fatigue, and lack of energy for the next two to three days. The rheumatologist switched from oral to subcutaneous methotrexate and added folic and folinic acid, but the patient remained unable to tolerate the higher dosages.

 

Examination by the rheumatologist revealed marked bilateral synovitis and swelling of the PIP joints in a virtually symmetric pattern. The second and third PIP joints showed the greatest involvement, with both swelling and mild deformity. There was also notable enlargement of the MCP joints, with mild ulnar deviation. Examination of the feet revealed mild tenderness and swelling of the MTP joints.

 

Laboratory studies showed a white blood count of 4,900/mm3; hematocrit, 34%; platelet count, 197,000/mm3; BUN, 21 mg/dL; serum creatinine, 0.8 mg/dL; AST, 27 U/L.; RF, positive; ESR, 35 mm/hr.

 

X-rays of the hands showed juxta-articular osteopenia and small erosions of the second and fourth PIP joint on the left and of the third MCP joints bilaterally.

 

This case represents a situation that rheumatologists unfortunately see all too often--a patient who has received a timely diagnosis and been given appropriate treatment but who nevertheless continues to have active disease.

 

 Although his disease showed some response to methotrexate, the limit of its usefulness clearly had been reached. Fatigue and nausea are not uncommon with high doses of methotrexate. Switching from oral to subcutaneous administration often reduces the side effects, but that tactic had not been effective.

 

Hence, this patient is an ideal candidate for anticytokine therapy. Cytokines are involved in the inflammatory cascade of all autoimmune inflammatory conditions. Those considered most important in mediating the swelling, pain, stiffness, and radiographic destruction are TNF-alpha and interleukin (IL)-1.

 

The two TNF-alpha inhibitors currently available, etanercept and infliximab, have different structures, but both bind to TNF-alpha, preventing it from binding to cell surface receptors. Drugs recently approved include a receptor antagonist that will bind to the IL-1 receptor (Anakinra) and additional monoclonal antibodies targeted against TNF-alpha and possibly other cytokines (Humira). 

 

Both etanercept and infliximab often dramatically reduce disease symptoms and signs after the first few injections. Dramatic reductions in joint tenderness, swelling, and stiffness and improvements in function can occur during the first four weeks of therapy, and retardation of radiographic progression can occur within a year.

 

Since etanercept is injected subcutaneously, and this patient was already giving himself subcutaneous injections of methotrexate, etanercept is the logical choice for him. He still has to come into the office for an educational session, however, during which a nurse shows him how to draw up the medication in a syringe, how to select and rotate injection sites, and how to give the injection. Potential complications are explained. He also watches an educational video produced by the drug manufacturer.

 

For patients who cannot or refuse to self-inject, infliximab is a more acceptable choice. The drug is given intravenously, so patients initially come to the hospital every two weeks, then every eight weeks for the infusion.

 

The patient was started on etanercept, 25 mg subcutaneously twice a week. He experienced mild erythema, itching, and swelling at the injection sites, but continued with treatment and within four weeks began to experience notable clinical improvement. Over time, injection site reactions became less frequent, then ceased entirely. Follow-up x-rays one year later showed stabilization of his disease.

 

Etanercept injection site reactions tend to be mild and self-limiting. Patients who continue the injections generally find that they have fewer reactions and eventually none at all.  Another potential side effect of etanercept is impaired eradication of infection. Patients taking etanercept do not appear to have an increased risk of infection, but if a significant infection does develop, etanercept therapy should be stopped until it has healed.

 

There have been some patients--typically those who are older or have comorbidities--who have had difficulty clearing an infection if they remain on etanercept.

 

Since this patient is still taking methotrexate, he requires regular liver function studies, and occasionally a complete blood count. Etanercept therapy does not require additional monitoring.

 

If a patient such as this shows a substantial response to therapy after six to nine months, one might consider reducing the methotrexate dosage from 20 mg to 15 mg a week or less, or even stopping it entirely. Withdrawal should be done slowly and carefully, over a period of about six months, because in some patients, reduction of the methotrexate dosage results in disease exacerbation.

Most rheumatologists and primary care physicians now appreciate the often rapid devastation caused by the disease and the consequent need to treat the patient earlier with disease-modifying drugs.

 

The availability of at least five  new relatively safe drugs that can halt disease progression in many patients previously refractory to treatment has fundamentally changed the approach to management. Indeed,in many cases, the major stumbling block is not medical but financial--obtaining insurance company approval to administer these expensive newer drugs.

 

The first patient, a 44-year-old woman, posed a bit of a diagnostic dilemma for her rheumatologist. In spite of her clinical history and findings on examination, her serum was negative for both rheumatoid factor and antinuclear antibody, and it is not clear whether there were any abnormalities on x-ray. The decision to start methotrexate at the first visit was a judgment call;  Other rheumatologists might have tried another (prescription) NSAID at full dosage, added a few milligrams of prednisone each morning, and checked films of the hands and wrists for at least evidence of some tell-tale juxta-articular osteoporosis.

 

If the films were normal, a few weeks of a full-dose NSAID or low-dose steroid, or both, would probably have been satisfactory. With minimal changes on x-ray (i.e., mild osteoporosis) still, another rheumatologist,might have started with hydroxychloroquine because of its great safety (eye examinations are really all that is needed for sound follow-up) and paucity of side effects. If the films showed any evidence of erosion, most physicians would have started with methotrexate, with rapid escalation of dosage as needed.

 

Had hydroxychloroquine been started and found inadequate, methotrexate could have been added at any time--as could sulfasalazine, but methotrexate appears to be more effective.  Many rheumatologists prescribe folic acid whenever treatment with methotrexate is begun. It appears to improve safety with little or no loss of methotrexate efficacy. Also, the importance of educating the patient cannot be overemphasized. This requires time on the part of the physician and staff but is essential.

 

The role of COX-2 inhibitors or other medications to protect the stomach is important. COX-2 inhibitors are not more effective than nonselective NSAIDs, but they do much less damage to the gastric mucosa.

 

One other interim strategy to keep in mind when one or two joints remain troublesome is to inject them with corticosteroids. These injections--which may be given once or twice--can provide excellent relief for many weeks or months. The main concern is to be sure that there is no infection in the joint.

 

The second case illustrates the problems that can occur if periodic x-rays are not obtained. In patients with any evidence of ongoing disease activity, a plain film of the most severely affected joints can be very helpful. Had that been done, documentation of progressive joint destruction would have permitted far earlier intervention with aggressive therapy.

 

Usually, the patients who are most prone to joint destruction are rheumatoid-factor positive; this patient was not. Her hematocrit of 39.1% is remarkably good for a patient with smoldering arthritis, but she may have been a smoker. Acute phase reactants (white blood cell count, platelets, ESR, and C-reactive protein) may not be elevated in patients with active arthritis, especially in an elderly patient. A sometimes-useful strategy is to obtain and analyze synovial fluid, which should show features of disease activity.

 

The third case illustrates the special problems associated with methotrexate therapy. A trial of subcutaneous methotrexate can be valuable, because it often eliminates the gastrointestinal side effects seen with the oral route and, amazingly, is less expensive. (the patient probably should have taking folic acid from the start of methotrexate therapy.)

 

This patient is a fine candidate for etanercept; infliximab would be equally satisfactory. The safety record for both medications remains excellent, although there have been recent reports of reactivation of mycobacterial infections and, possibly, significant cytopenia. Neuropathies may also be an issue. Just how long etanercept should be continued is not known, but it appears clear that if the drug is withdrawn, the arthritis will flare.

 

The most formidable hurdle to management of arthritis in the world is cost. Insurance companies are, of necessity, wary of unlimited authorization of the newer medications. However, as it becomes ever more clear that they can stop joint destruction more effectively than any other available medications, it is also becoming more clear that they are cost-effective--the follow-up expenses for a patient with improved function and no pain are significantly less.

 

Furthermore, it is expected that with new technologies, production costs of these and other agents under investigation will be reduced.  Ongoing studies of a host of biological inhibitors, which may be used alone or in combination with currently available medications, appear extremely promising.

 

As with gout, rheumatologists should now be able to subdue rheumatoid arthritis in the vast majority of patients. In addition to these therapeutic advances, genetic profiling of patients at the time of diagnosis (although also costly) may well become the future gold standard for establishing an optimal regimen from the outset.