Drug Criteria & Outcomes - Infliximab (Remicade) for rheumatoid arthritis symptoms
By Jill Vukovich, PharmD candidate
Medical University of South Carolina
Infliximab, manufactured by Centocor in Malvern, PA, is indicated for reducing the signs and symptoms of rheumatoid arthritis (RA) when used in conjunction with methotrexate (MTX) for those patients who previously have had inadequate responses to MTX. Infliximab also is indicated for reducing the signs and symptoms of Crohn's disease in patients with moderate to severe disease who have had an inadequate response to conventional therapy and for reducing the number of draining enterocutaneous fistulae in patients with fistulizing Crohn's disease.1
Infliximab is a chimeric IgG1k monoclonal antibody composed of a murine variable and human constant regions.1-4 Infliximab binds with high affinity to tumor necrosis factor alpha (TNFa), which inhibits the binding with its receptors, thus neutralizing its activity.1 Tumor necrosis factor beta (TNFb) is not neutralized by infliximab, even though it utilizes the same receptors as TNFa.1
Biologic activities of TNFa are as follows: induction of interleukins 1 and 6 (proinflammatory cytokines); increasing endothelial permeability to facilitate leukocyte migration; enhancing expression of epithelial and leukocyte adhesion molecules; activation of functional activity of leukocytes and eosinophils; induction of liver proteins, including acute phase reactants; and induction of tissue-degrading enzymes produced by chondrocytes and/or synoviocytes.1,3 Infliximab has been shown to prevent polyarthritis in animal models and, when given after onset of disease, allows for the healing of eroded joints.1
A linear relationship between dose, maximum concentration, and area under the curve can be seen after a single dose of infliximab 1 to 20 mg/kg is administered intravenously.1 Steady state volume of distribution is 3 L and is independent of dose, which implies that infliximab primarily distributes into the vascular space. Onset of action is seen three to seven days after infusion.1,2 The terminal half-life for a 3 mg/kg dose in RA is eight to 9.5 days.1-3 Following repeated infusions at two and six weeks, predictable concentration-time profiles were seen. With continued treatment of 3 mg/kg at four- to eight-week intervals, no systemic accumulation was noted.1 Clearance and volume of distribution did not differ significantly among patients with respect to age and weight. It is unknown if gender or renal and/or liver dysfunction affects the pharmacokinetics of this agent.1
A multicenter, randomized, placebo-controlled trial was conducted over a 26-week period to determine the efficacy and safety of infliximab in conjunction with MTX for the treatment of RA.5 Patients were eligible if they had six swollen joints (from a total of 66 counted) and at least one of the following: six or more tender/painful joints (of 68 counted), morning stiffness lasting longer than 45 minutes, an erythrocyte sedimentation rate (ESR) of at least 28 mm/hour, or a C-reactive protein (CRP) concentration of at least 15 mg/dL.
Patients were excluded if they were pregnant; had severe physical incapacitation (Steinbrocker class IV); were previously exposed to chimeric monoclonal antibodies or murine proteins; had a history of chronic infection or malignancy; had a recent serious infection; hemoglobin, white blood cell, and platelet counts of less than 8.5 mg/dL, 3.5 x 109/L, and 100 x 109/L, respectively; serum creatinine concentrations over 150 micromoles/L; or serum transaminase and alkaline phosphatase concentrations of more than 1.25 to two times the upper limit of normal, respectively.
Patients stabilized on oral steroids for four weeks prior to screening were permitted to continue, as long as the dose did not exceed prednisolone 7.5 mg orally per day. All patients received MTX 7.5 mg orally once each week during the trial; however, no other disease-modifying antirheumatic drugs (DMARDs) were permitted starting four weeks prior to study initiation.5
Waiting for responses
Patients were randomized to receive one of four intravenous (IV) infusion treatment regimens: infliximab 1 mg/kg, 3 mg/kg, or 10 mg/kg or placebo (0.1% human serum albumin). Each study group consisted of 14 subjects. On day zero, prior to infusion, all baseline measurements of laboratory and clinical data were obtained. Repeated infusions were administered at two, six, 10, and 14 weeks after first infusion. Patients were assessed at weeks one and two, and then at two-week intervals up to 22 weeks with a final evaluation at week 26.5
The primary efficacy endpoint was time to exhibit a response (measured in weeks). The Paulus 20% index was used to indicate a response to therapy. Patients not completing the trial were considered "nonresponders." Secondary endpoints included frequency with which patients responded measured by the Paulus 20% index, magnitude of response measured by the Paulus 50% index, and remission. Remission was evaluated as follows: proportion of patients exhibiting more than a 50% improvement in disease as indicated by the Paulus criteria or remission of disease as defined by Pinals et al.
Those authors define remission as having no tender/swollen joints; morning stiffness lasting less than 15 minutes; no fatigue; a pain score of less than 0.5 cm on a 10 cm visual analogue scale (VAS); and an ESR of less than 30 mm/hour or 20 mm/hour for women or men, respectively. Changes from baseline were assessed for swollen joint counts (SJC), tender joint counts (TJC), physician and patient global assessments, degree of disability (measured on the modified Stanford Health Assessment Questionnaire), degree of pain (as measured on the 10 cm VAS), and human antichimeric antibody (HACA), CRP, rheumatoid factor (RF), and anti-double-stranded DNA antibody (anti-dsDNA) concentrations lasting at least eight consecutive weeks.5
At the conclusion of the trial, patients on any of the three doses had a statistically significant longer duration of response to treatment compared to placebo, for whom subjects had zero weeks of duration of response. Subjects receiving infliximab 1 mg/kg had a median duration of response to treatment of 16.5 weeks (p < 0.001). Patients receiving infliximab 3 mg/kg also had a median duration of response of 16.5 weeks. Those receiving infliximab 10 mg/kg had a median duration of response of 18.1 weeks (p < 0.001).
The secondary outcome (percentage of patients responding), as measured by the Paulus 20% index, was statistically significantly different than the placebo group for all infliximab groups measured at weeks four, eight, 12, 16, and 26 (p < 0.05) for the majority of measurements. The one exception was the infliximab 1 mg/kg group. At week 26, the percent of patients responding was not statistically significant (p = 0.51). From week eight of treatment to week 16, all patients demonstrating a response as measured by the Paulus 20% (~60% of patients in the infliximab groups) concurrently achieved a high level of clinical responses measured with the Paulus 50% index. However, the placebo group maintained an approximate 10% response as measured by the Paulus 20% index. Patients receiving infliximab 3 mg/kg and infliximab 10 mg/kg maintained a clinical response up to week 26.5
Evaluation of SJC, TJC, and CRP concentrations suggest that for those patients receiving infliximab at any of the three doses, a marked and generally sustained improvement of these parameters occurred, with a trend toward remission. The patients receiving placebo, however, did not show any substantial changes from baseline from weeks zero to six (measured until ³ 50% of patients responded). The statistical significance of these three parameters was not provided. Disease control as measured by SJC, TJC, and CRP levels exceeded 60% to 70% from baseline for the infliximab 3 mg/kg and 10 mg/kg groups, while the placebo group remained at or near baseline. No patient in the placebo group achieved the criteria to qualify for complete remission. However, complete remission lasting at least eight weeks was seen in one patient in each of the infliximab 1 mg/kg and 3 mg/kg groups and in two patients in the infliximab 10 mg/kg group.5
Discontinuation of therapy during the first 14 weeks due to lack of efficacy occurred primarily in the placebo group (eight of 14 patients), vs. one discontinuation of all 42 infliximab patients (10 mg/kg group). While adverse events occurred more frequently in patients receiving infliximab compared with those receiving placebo, those differences were not statistically significant (p = 0.186), with just one patient discontinuing therapy due to adverse events in each of the infliximab 1 mg/kg and 10 mg/kg groups.
The number of dropouts in the placebo group due to lack of efficacy may help to explain the greater number of adverse events in the infliximab groups. The adverse events considered related to therapy that were reported most often in patients receiving infliximab were headache (12%), diarrhea (9%), rash (6.9%), pharyngitis (6.9%), rhinitis (6.9%), upper respiratory tract infection (URTI) (4.6%), and urinary tract infection (4.6%). Of those patients who withdrew due to infusion-related events of infliximab, five reported infusion reactions such as urticaria, pruritis, and chills during administration; however, none of those reactions was considered serious. Also, one patient withdrew due to rash after the fourth infusion and one due to a continuing urinary tract infection with concurrent vaginitis.5
This study also included three additional groups receiving infliximab 1 mg/kg, 3 mg/kg, and 10 mg/kg, without concurrent MTX. Although not presented here, those subgroups also showed marked responses with infliximab use compared with placebo in combination with MTX. However, for completeness of safety evaluation, all patients receiving infliximab with or without MTX were included in the adverse event discussion.5
Maini and co-workers conducted a randomized, double-blind, placebo-controlled multicenter trial designed to determine the efficacy of infliximab for the treatment of RA.6 This trial consisted of 428 patients with active RA who had received MTX continuously for at least three months following four weeks of MTX therapy at a stable dose.
Eligibility requirements were diagnosis of RA according to the 1987 American College of Rheumatology Guidelines (ACR) and evidence of active disease even with treatment of MTX as defined by the following: six or more tender swollen tender or swollen joints, two with morning stiffness lasting greater than 45 minutes; ESR greater than 28 mm/hour; CRP greater than 2 mg/dL; use of MTX with dose stabilized at greater than or equal to 12.5 mg per week for at least three months with no more than a two-week break in treatment (for at least four weeks prior to screening); use of a stable folic acid dose during the same time frame as MTX use; hemoglobin, white blood cells, platelets, and serum creatinine measurements as specified in the previously discussed trial;5 and liver transaminases and alkaline phosphatase concentrations no more than two times the upper limit of normal.6
If patients were using oral corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs), doses had to be stable for four weeks prior to study; however, if no oral agents were used, NSAID use four weeks prior to the study was prohibited. Exclusion criteria consisted of the following: little or no ability for self-care; concurrent inflammatory condition(s); use of DMARDs other than MTX or steroids within four weeks of screening; use of agents toxic to TNFa or any previous use of cyclophosphamide, nitrogen mustard, chlorambucil, or any alkylating agent; past medical history of murine protein allergies; infected joint prosthesis in the past five years; serious infections (e.g., hepatitis, pyelonephritis, pneumonia) in the past three months; chronic infections of renal, chest, or airway regions; active tuberculosis in the last three years; opportunistic infections (e.g., herpes zoster) in the previous two months; any evidence of active cytomegalovirus, pneumocystis, or drug-resistant mycobacterial infections; current signs or symptoms of severe progressive organ or neurological disease; or past history of lymphoproliferative disorder or malignancy (except basal cell carcinoma within the last five years).6
All patients concurrently received MTX and were randomized to one of five groups: infliximab 3 mg/kg IV every four weeks (n = 86) or infliximab 3 mg/kg IV every eight weeks (n = 86); infliximab 10 mg/kg IV every four weeks (n = 81) or infliximab 10 mg/kg IV every eight weeks (n = 87); or placebo (0.1% human serum albumin in all sites except France, where placebo was normal saline). Patients were assessed to establish baseline measurements prior to infusion. All patients received IV infusions at weeks zero, two, and six. To maintain blinding, the placebo group and one each of the 3 and 10 mg/kg infliximab groups received infusions every four weeks, while the remaining two infliximab groups received infliximab infusions every eight weeks and placebo infusions at other specified time points. Infusions were two hours in duration. The primary endpoint was analyzed using intent-to-treat analysis and was based upon the ACR 20% improvement guidelines assessed at the 30-week timepoint.
Other measurements recorded included the need for any surgical joint procedure, addition of new drugs for RA, and increases of medication dose for RA. Secondary endpoints were defined as documented 50% to 70% improvement from baseline, reduction in measurements of disease activity, and patients' general health assessment. The study was powered at 90%. Safety endpoints were evaluated using an as-treated analysis. Patient groups were similar with respect to demographics, disease states, previous joint surgery, drug treatment, and duration of MTX use.6
All patients treated with infliximab achieved primary endpoints significantly more often than those receiving placebo (p < 0.001). Response to infliximab was seen rapidly, with 50% achieving ARC 20% at the two-week evaluation and 90% achieving it at the six-week evaluation. Total response rate remained at the 50% to 60% levels up to the 30-week endpoint. The infliximab groups also achieved more substantial responses as outlined by the ACR 50-70 criteria than the placebo. All differences from baseline in the ACR 50-70 were statistically significant, compared with placebo (p < 0.05) with the exception of the infliximab 3 mg/kg every eight weeks in pain score measurement (p = 0.075) and health assessment questionnaire (p = 0.766).6
Adverse events were assessed to monitor for safety and were seen in all groups. Two patients inadvertently received infliximab and were therefore considered as part of that group, bringing the total number of infliximab-treated patients to 342. The most commonly reported events were URTIs (placebo [16%] vs. infliximab [25%]), headache (placebo [10%] vs. infliximab [22%]), and nausea (placebo [19%] vs. infliximab [15%]). Infusion-related reactions were seen more often in the infliximab groups (19%) vs. placebo (10%); however, the result was not statistically significant (p = 0.477). Most infusion-related reactions were seen with the first infusion, and most were considered mild (headache and nausea) and of short duration. Symptoms were addressed by dosing antihistamines or slowing the infusion rate.
Two infliximab-treated patients discontinued treatment due to infusion reactions. Hypersensitivity reactions were infrequent and usually mild across groups. Serious adverse events (defined as life-threatening or requiring hospitalization) were similar across groups (17% in the placebo group vs. 11% in the infliximab groups). Although infections occurred more often in the infliximab 10 mg/kg group, those considered serious were the same between the placebo group (6%) and infliximab groups (4%).
Deaths occurred in the placebo group (3%) and infliximab groups (1%) and were attributed to disorders associated with RA. Elevated liver enzymes occurred similarly across groups without significant differences. MTX-associated toxicity was suspected in one patient in the infliximab 3 mg/kg group causing withdrawal from the study. In the placebo group, one patient withdrew due to iron-deficiency anemia, and one patient withdrew due to thrombocytopenia. No other hematologic abnormalities were noted.
The placebo group had the most patient withdrawals (36%), compared with the infliximab groups (18%). Reasons for discontinuation included lack of efficacy (22 patients in the placebo group, 44 patients in the infliximab groups); adverse events (seven patients in the placebo group, 24 in the infliximab groups); noncompliance (two patients in the placebo group); withdrawn consent (one patient in the placebo group, two in the infliximab groups); and death (three patients in the placebo group, two patients in the infliximab groups).6
All patients were determined to have negative anti-dsDNA concentrations at baseline. After completion of the trial, 54/340 (16%) of the infliximab-treated patients tested positive vs. none in the placebo group. The relevance of drug-induced lupus is not known at this time, and the one patient in the infliximab group determined to have developed this event tested anti-dsDNA negative.
Also, it was calculated that after 86 patient-years of placebo and 359 patient-years of infliximab, three patients developed a malignant disease, all in the infliximab 10 mg/kg group administered every four weeks. These observed incidences, however, were determined to be no different from the 2.8 cases expected to occur in a similar population.6
The adverse events reported most often in patients receiving infliximab include headache 157/754 (20%), nausea 111/754 (15%), and vomiting 45/754 (6%).1,2 Infusion-related reactions (16%) also are associated with infliximab and are defined as any adverse event that occurs during the actual infusion or within one to two hours afterwards.1 Acute-infusion reactions consist of nonspecific symptoms such as fever, chills, and, less commonly, pruritus or urticaria. Additional infusion-related reactions include cardiopulmonary dysfunction (hypotension, hypertension, chest pain, and/or dyspnea).1
Pregnancy and lactation:
Infliximab is rated as a Pregnancy Category C, meaning that reproduction studies in animals have shown adverse effects on the fetus, yet no well-controlled or adequate studies have been conducted in humans. The potential benefits may substantiate infliximab use during pregnancy despite the risk.1-3 Infliximab is known to react only with human or chimpanzee TNFa.1 It is unknown whether infliximab can cause harm to the fetus when administered during pregnancy or affect reproduction capabilities while present in the serum. No evidence of maternal or embryonic toxicity or teratogenicity was seen in a study conducted in mice using an antibody with similar action to infliximab against mouse TNFa. Use in pregnancy should be carefully considered and used only when clearly necessary.1
It is unknown whether infliximab is excreted into human breast milk or if it is systemically absorbed after ingestion. Many immunoglobulins are excreted into human breast milk, and because the potential for adverse events exists in nursing infants from infliximab, the decision to discontinue breast-feeding or discontinue infliximab therapy during the breast-feeding period should be carefully considered.1
Infliximab should not be used in those patients with known hypersensitivity to infliximab, murine proteins, or other components of this product.1,2
Warnings and precautions:
Serious infections have been reported in patients administered TNF-blocking agents, which include sepsis and fatal infections. Most infections occur in those patients receiving infliximab and other immunosuppressive agents that could predispose them to infection.1 Extreme caution should be used when considering infliximab use in patients with chronic infection/s or history of recurrent infection/s.1-3 Patients with clinically important, active infections should not receive infliximab.1 Patients developing a new infection during infliximab therapy should be monitored closely, and treatment should be discontinued in those patients developing serious infection or sepsis.1
Hypersensitivity reactions have been associated with infliximab infusion, including dyspnea, urticaria, and/or hypotension.1 Most reactions occur during or within two hours of infusion. Treatment of hypersensitivity reactions (e.g., antihistamines, acetaminophen, corticosteroids, epinephrine) should be readily available in case of such reactions.1
Formation of autoantibodies may result from the use of infliximab, as well as development of a lupus-like syndrome; however, those events are considered rare.1,2 In clinical trials, 23% of patients receiving infliximab developed antinuclear antibodies, compared with 6% of patients receiving placebo. In addition, 4% of patients receiving infliximab developed anti-dsDNA antibodies, compared with none in the placebo group.1,6 Two patients developing a lupus-like syndrome in trials improved with discontinuation of the drug and appropriate therapy.1
Also, development of HACA has been associated with its use. This antibody developed less in patients treated concomitantly with immunosuppressive agents such as MTX; however, repeated dosing of infliximab resulted in high serum concentrations with concomitant use of MTX.1,5 Long-term data on development of antibodies are lacking.1 Since no data exist on response to vaccinations or infection development from live vaccine usage, it is not recommended to administer live vaccines concurrently with infliximab treatment.1
Patients with long-term exposure to immunosuppressive agents or those with long duration of RA are more apt to develop lymphomas.1 It is unknown if use of infliximab may impact this finding. However, observed rates of malignancies developing during clinical trials suggest a similar rate of malignancy development in a population similar to that studied.1,2,6
Dosage and administration:
The recommended dose of infliximab for treatment of RA is 3 mg/kg administered as an intravenous infusion with additional doses of 3 mg/ kg at two and six weeks following the first infusion, and then at eight-week intervals thereafter. Treatment of RA with infliximab should be in combination with methotrexate.1-3 Infliximab is not FDA-approved for use in pediatric patients.1,3
1. Calculate the dose needed and, subsequently, the number of vials of infliximab needed (each vial contains 100 mg lyophilized infliximab). Calculate total volume of reconstituted solution required for administration.
2. Using a syringe (and ³ 21 gauge needle), reconstitute each vial of infliximab with 10 mL of Sterile Water for Injection, USP, using aseptic technique: Remove metal top and swab the vial with alcohol. Insert needle through the center of rubber stopper and inject water stream against wall of vial. Use only if a vacuum is present. Gently swirl the vial by rotating, allowing the water to dissolve the powder. Avoid vigorous or prolonged agitation. DO NOT SHAKE! Solution may foam upon reconstitution. Allow solution to rest five minutes. Appearance should be colorless to light yellow. A few translucent particles may develop. Discard if solution discolors, particles appear opaque, or any foreign particles are present.
3. Using a 250 mL bottle or bag of 0.9% Sodium Chloride for Injection, USP, aseptically withdraw amount equal to the volume of reconstituted infliximab and discard. Then, slowly add the total volume needed from the reconstituted vial(s) to the bottle or bag of sodium chloride and gently mix.
4. Administer infusion solution over a time period of at least two hours using an infusion set with an in-line, low-protein binding, nonpyrogenic, sterile filter with pore size less than or equal to 1.2 microns. DO NOT store any unused portion for later use.
5. Because no physical compatibility studies evaluating the co-administration of infliximab with any other agent have been done, no agent should be administered concurrently in the same IV line as infliximab.
6. Prior to administration, the final product should be visually inspected for any opaque particles, foreign matter, or discoloration, and the product should be discarded upon such findings.
To date, studies have not been conducted evaluating specific drug interactions with infliximab. Although other medications, such as NSAIDs, narcotics, and steroids, were used in clinical trials by patients receiving infliximab, no drug interaction data were collected.1
Dosage forms available:
Infliximab is available in single-use, 20 mL vials containing a lyophilized powder of infliximab 100 mg, sucrose 500 mg, polysorbate 80 0.5 mg, monobasic sodium phosphate 2.2 mg, and dibasic sodium phosphate 6.1 mg.1-3 No preservatives are contained in the vial.1,2
Infliximab samples should not be allowed.7
Potential for medication errors:
The potential for medication errors exists with infliximab (Remicade). Drugs with similar-sounding names include the following: abciximab (ReoPro), used for inhibition of platelet aggregation; rituximab (Rituxan), used to treat relapsed or refractory low-grade or B-cell nonHodgkin's lymphoma; daclizumab (Zenepax), and muromonab (Orthoclone), used for prevention of rejection in transplant recipients; and digoxin immune monoclonal antibody (Digibind), used in digoxin overdoses.8 The prescriber and dispensing pharmacist must be aware of the potential for confusion with those sound-alike names.
After final dilution into 0.9% Sodium Chloride for Injection, USP, infliximab is to be administered with an infusion set containing a sterile in-line, pyrogen-free, low-protein-binding filter with pore size < 1.2 microns.1
Rheumatoid arthritis is a crippling disease that afflicts more than 2 million Americans.9,10 Therapy begins with NSAIDs, such as aspirin or ibuprofen; however, most patients eventually will require stronger drugs like DMARDs and/or corticosteroids. Long-term use of those products is not without side effects, and as therapy continues, the disease may become refractory to those treatments.9,10 Infliximab, initially FDA-approved for use in refractory Crohn's disease, has recently been approved for reducing the signs and symptoms of RA when used in conjunction with MTX in patients who previously have had inadequate response to MTX therapy.1
Placebo-controlled trials involving large numbers of patients have demonstrated a decrease in disease activity, relief of symptoms, and overall improvement in quality of life for patients treated with infliximab. These trials demonstrated that infliximab therapy, in conjunction with MTX, resulted in statistically and clinically significant improvement in patients with established RA refractory to MTX treatment alone.5,6
Adverse effects seen with infliximab therapy are generally considered mild. The mechanism of development of infection associated with the use of infliximab is not completely understood. In clinical trials, severe infections occurred rarely; however, the risk of infection vs. the benefit of therapy should be recognized when therapy is considered. Furthermore, it is recommended to avoid infliximab in patients with chronic or present infections.1
Although the procurement price of infliximab may be more than other therapies for RA, infliximab is dosed less frequently than other agents used to treat RA, which helps to offset the high procurement price. In addition, the agent is indicated for refractory patients in whom alternative therapies are limited.
1. Remicade (Infliximab) package insert. Malvern, PA: Centocor Inc.; November 1999.
2. Gelman CR, Moore MB, Hutchison T, Anderson M, Shahan DR, eds. DRUGDEX System. Englewood, CO: Micromedex Inc.; August 2000.
3. Micromedex Inc. USP DI Drug Information for the Healthcare Professional Volume I. 20th ed. Englewood, CO: 2000.
4. Infliximab Monograph. Gold Standard Multimedia. World-Class Drug Information; 2000. http://www.gsm.com. (Accessed Aug. 14, 2000.)
5. Maini RN, Breedveld F, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998; 41:1,552-1,563.
6. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumor necrosis factor alpha monoclonal antibody) vs. placebo in rheumatoid arthritis patients receiving concomitant methotrexate: A randomised phase III trial. Lancet 1999; 354:1,932-1,939.
7. Centocor Inc. Verbal communication with company representative on Aug. 11, 2000. Telephone: (800) 457-6399.
8. Kizior RJ, Hodgson BB, eds. Saunders Handbook for Health Professionals. Philadelphia: WB Saunders Co.; 2000.
9. DiPiro JT, ed. Pharmacotherapy: A Pathophysiologic Approach. 4th ed. Stamford, CT: Appleton & Lange; 1999.
10. The American College of Rheumatology. Fact Sheet: Rheumatoid Arthritis. www.rheumatology.org. (Accessed Aug. 15, 2000.)