• Abstract 1068: Methotrexate, Laboratory Testing and Risk of Serious Illness: Analyses in 20,000 Patients
• Abstract 515: Aggressive Step-up DMARD Treatment Strategy to Usual Care in Early RA
• Abstract 539: Rate of TB Among Current Infliximab Users
• Abstract 540: Cardiovascular Events in TNF-Blocker Treated RA
• Abstract 541: Granulomatous Infections and TNF Antagonist Therapies
• Abstract 543: Predictors of Lymphoma in RA
• LB Abstract 23: TNF Inhibitors are not Associated with Increased Tumor Risk in RA
• Abstract 739: 5-Year Efficacy Data with Adalimumab Patients with RA
• Abstract 204: 48-week Follow of Rituximab in RA Patients
• Abstract 1704: Anti-IL-6 Receptor Antibody (MRA) for Treatment of RA
• Abstract 1709: Alefacept for Treatment of Active RA

Abstract 1068 Methotrexate, Laboratory Testing and Risk of Serious Illness: Analyses in 20,000 Patients
Cartwright, Michaud, Wolfe

The current ACR recommendations for appropriate laboratory tests and testing intervals for monitoring methotrexate therapy in rheumatoid arthritis (RA) are stringent, reflecting fear of toxicity, most notably, liver function abnormalities, bone marrow suppression, and cirrhosis. Clinical practice suggests that these toxicities are rare. However, the actual rates of laboratory abnormalities and significant toxicities associated with methotrexate use in patients with RA are unknown. Here, Cartwright et al investigate these rates in addition to surveying self-reported compliance with current ACR recommendations for monitoring therapy among patients receiving and rheumatologists who prescribe methotrexate.

Methods: Survey of Rheumatologists - Written surveys were sent to all ACR members regarding their compliance with current ACR guidelines for methotrexate monitoring in the first year of therapy.

Patient Survey, laboratory test results, and cases of cirrhosis were obtained from the National Data Bank of Rheumatic Disease and/or the Wichita Data Bank.

Survey of Patients - Responses on the frequency of laboratory testing for methotrexate monitoring were obtained from cohort questionnaires (n=20,000).

Rates of Laboratory Abnormalities - Collected blood test results were scrutinized for non-normal laboratory parameters of complete blood count, liver function testing, albumin, and creatinine.

Cirrhosis - Collected cases were validated based on hospital record, biopsy, or death records.

Results: Survey of Rheumatologists - 3,121 rheumatologists were surveyed. Of the 1,100 responders (30%) >90% reported compliance with ACR recommendations for CBC, AST, ALT monitoring within the first 3 months of methotrexate therapy. However, after one year of methotrexate therapy, these numbers had fallen to 50% compliance with CBC, AST, and ALT on a 4 to 8 week basis.

Survey of Patients - Among the 3,928 patients receiving methotrexate who were surveyed, 60% reported 3 to 6 blood draws for laboratory tests per 6-month period.

Rates of Laboratory Abnormalities - 49,670 hematology specimens and 18,666 liver function tests were examined. Among these, approximately 50% were in patients receiving methotrexate therapy. For patients with normal baseline laboratory values, rates of laboratory abnormalities per 1000 person years were as follows:

In terms of liver function testing, mean values of AST/ALT were the same in patients with and without methotrexate therapy and were within normal limits for these tests. The average maximum ALT for RA patients receiving methotrexate was 36 U/L. Most abnormalities occurred within the first year of methotrexate therapy.

Cirrhosis 19 cases of cirrhosis were identified, 13 in patients receiving methotrexate and 6 in patients with no methotrexate exposure. Corresponding rates per 1000 patient years were as follows:

Two deaths from cirrhosis were identified, one in an elderly male never on methotrexate and one in a young female on methotrexate.

Conclusions: Patient and provider compliance with ACR recommendations for monitoring methotrexate therapy is high in the first 6 months and declines thereafter. Despite this, serious laboratory abnormalities and cirrhosis are rare.

Editorial Comments: These results support common notions as to the safety of methotrexate in the treatment of RA. Since a significant portion of the data spans years in which maximum weekly doses of 7.5 mg of methotrexate were the norm, the rates presented may not be entirely applicable in today's therapeutic climate. Relating to this shift in prescribing practice over time, maximum dosing and dates of exposure are not available in this analysis, which would also be helpful in determining the precise effect of methotrexate on risk of toxicity. Using these data to support a relaxation of monitoring recommendations is problematic, as the stringency of the current recommendations may be partially responsible for the low event rates. Nonetheless, this is the largest data set ever examined for methotrexate associated toxicities and supports the safety of this agent in liver and bone marrow functions.

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Abstract 515 A Randomised Controlled Trial of a Strategy of Tight Control of Disease Activity in Rheumatoid Arthritis - Outcome Over 18 months
Porter, Grigor, Capell et al

Using the known beneficial effects of tight control of adult-onset diabetes on disease outcomes as a hypothetical model for treatment of RA, this study compares an aggressive step-up DMARD treatment strategy to usual care in early RA.

Methods: Patients aged 18 to 75 years with active RA diagnosed within the prior 5 years were randomized to one of two groups. In group #1 (Intensive Treatment), patients were evaluated every month over the 18 month study period. All patients in the Intensive group were started on sulfasalazine monotherapy. At each visit, swollen joints could be injected with glucocorticoids or oral steroids given for active disease. At three-month intervals, DMARDs were changed in a specified, sequential regimen if disease activity persisted (defined as DAS > 2.4), as follows:

Sulfasalazine monotherapy-> Triple therapy (sulfasalazine, methotrexate, plaquenil) -> methotrexate dose increased to maximum -> sulfasalazine dose increased to 5 grams/day -> prednisone 7.5mg/day added -> sulfasalazine/plaquenil discontinued and cyclosporine added to methotrexate -> alternative DMARDs

In group #2 (Usual Care), patients were evaluated and their treatment regimens were determined solely at the discretion of their primary rheumatologist. TNF inhibitors were not allowed in either group. With the exception of evaluation of both groups by a blinded metrologist, neither patients nor prescribing rheumatologists were blinded to treatment.

The primary outcome measure was mean change in DAS. Secondary outcome measures were number achieving remission (DAS < 1.6), ACR response, change in HAQ score, and radiographic progression using the modified Sharp scoring system.

110 patients were evenly randomized into each group. Patients in the Intensive Treatment group had higher ESR/CRP at baseline. Otherwise, both groups were evenly matched. HAQ scores for both groups were approximately 2.0, and both had poor SF12 and SF36 scores, at baseline.

Results at 18 months:

No differences were detected between groups in terms of joint space narrowing. Patients in the Intensive Treatment group were more likely to be on combination therapy (76% vs. 11%). 50% of patients in the Intensive Treatment group were on triple therapy with accelerated dose methotrexate at the conclusion of the study. Only two patients in the Intensive Treatment group and one in the usual care group were taking daily, low-dose prednisone at the conclusion of the trial. As expected, more intra-articular and intra-muscular glucocorticoids were used in the Intensive Treatment group than in the Usual Care group.

Conclusions: Patients with early, active RA treated with intensive, step-up therapy demonstrate improvement in disease activity compared to usual care at 18 months. Safety of intensive treatment is comparable to usual care.

Editorial Comment: The rationale for this study - that tight control of RA disease activity will result in more favorable outcomes - is very appealing, and the results very encouraging. However, a major flaw in the study is the lack of blinding of the treating rheumatologist, which could introduce significant bias in either direction. The remarkable ACR70 response in the Intensive Treatment group, for example, could reflect such a bias. "Usual Care" is not defined in this protocol, but would appear to be less aggressive than that commonly practiced in the United States, given that the most "Intensive Therapy" encountered is triple therapy with low dose prednisone. Apparently, the study was initiated before TNF inhibitors were part of the usual practice for the treatment of RA. Nonetheless, the outcomes are compelling, but will need confirmation in larger cohorts, with blinding, and a more representative control group.

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Abstract 539 Tuberculosis Infection in Patients with Rheumatoid Arthritis and the Effect of Infliximab Therapy
Wolfe, Michaud, et al

Background: The rate of tuberculosis (TB) in rheumatoid arthritis (RA) is unknown. Post-marketing data for infliximab suggest that it is associated with a higher than background rate of TB. According to the Centers for Disease Control, the 1999 and 2000 incidence rates for TB in the US population were 6.4 and 5.8 per 100,000 persons, respectively. In 2000, infliximab began to be used widely in RA. This study was undertaken to determine the baseline rate of tuberculosis in RA prior to the introduction of infliximab and to determine the rate of TB among current infliximab users.

Methods: Patient survey followed by validation from medical records and physician reports. Study 1 consisted of 10,782 RA patients in 1998-1999 prior to infliximab use. Study 2 consisted of 15,940 RA patients, including 6,460 infliximab users, in 2000-2002.

Results: In study 1, the lifetime rate of TB was 695 per 100,000 patients (95% CI 547, 872). However, 76.8% of these cases occurred prior to the onset of RA. During the period of prospective follow-up (1998-99), only 1 case of TB developed during 16,173 patient-years of follow-up, yielding a rate of 6.2 (95% CI 1.6, 34.4) per 100,000 patients. In study 2, four (4) infliximab-treated patients developed TB, yielding an incidence rate of 52.5 (95% C.I. 14.3, 134.4) per 100,000 patient years of exposure. All 4 patients developing TB were women, and all were older than the average age of patients in the cohort (60.8 years). Only one patient was on methotrexate or prednisone. Three of the cases were extra-pulmonary. Three patients had a history of a positive PPD and one had been suspected of having TB in the past. None of these patients received prophylaxis. Three cases were extra-pulmonary. No cases of TB occurred in the 9,480 non-infliximab treated patients during the same period.

Conclusions: The rate of TB in infliximab-treated patients was 52.5 per 100,000 patient years. In contrast, the background rates of TB in the U.S. general population and in non-infliximab treated RA patients were 5.8 and 6.2, respectively. A thorough medical history regarding tuberculosis, as well as PPD testing, are essential prior to initiation of antiTNF therapy.

Editorial Comment: The concern that anti-TNF treatment might be associated with an increased risk for developing TB was based on post-licensure reports of TB primarily in infliximab treated patients. Because post-licensure reports are voluntary, the incidence of TB in treated patients cannot be assessed accurately. The current study contributes greatly by defining the background rate of TB in the modern pre-infliximab era, and clearly confirms an increased risk for TB in infliximab-treated patients. However, it is important to note that all four cases had known positive PPDs or were suspected of having TB in the past. TB is a preventable disease and careful history-taking and screening with PPDs will avert most of this risk.

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Abstract 540 540 Low Incidence of First Cardiovascular Event in Rheumatoid Arthritis Patients Treated with TNF-blockers
Jacobsson, Turesson, et al

The risk of cardiovascular (CV) disease in RA is increased. The purpose of this study was to define the impact of anti-TNF treatment on the risk of CV disease in RA patients.

METHODS Between February 1999 and December 31 2001, 412 patients with RA were registered in a data base of patients treated with etanercept or infliximab. These cases were compared with controls (N = 580) with RA from a population based register in Malm. These two registers were linked with national registers for in-patient care and cause of death up through December 31 2001. CVD was defined as the first in-patient care since 1987 or death from CVD prior to study entry during the study period. First CVD events in those treated vs. not treated with TNF blockers were estimated, using age-sex adjusted incidence density computations with anti-TNF treatment and disease severity (HAQ, patient global assessment, number of previous DMARDs, present steroid treatment) as time dependent covariates.

RESULTS: There were 14 first CVD events in the anti-TNF treated patients in 667 person-yrs at risk, while in the control group there were 123 events in 2303 person-yrs at risk. The corresponding age-sex adjusted incidence rates were 28.5 (95% CI: 11.1 45.9) and 51.1 (95% CI: 42.0 60.1) CVD events/1000 person-yrs, respectively. The age-sex adjusted rate ratio (RR) was 0.57 (95% CI: 0.33 1.00, p < 0.05 ) in anti-TNF treated vs. controls. When controlling for markers for disease severity one at a time, point estimates for RR remained significant and of similar magnitude. Point estimates were also similar when restricting the event definition by excluding congestive heart failure.

CONCLUSION: These findings suggest that the risk of developing CVD is lower in RA patients treated with TNF blockers. This is compatible with the hypotheses that inflammation contributes to the development of vascular events in subjects with RA.

Editorial Comment: These are interesting and provocative results. The CV events may be underestimated since the investigators rely on hospitalizations and deaths to diagnosis CV events. This method probably misses a significant amount of congestive heart failure and angina. Nonetheless, the scientific rationale for the study is solid, and is based on the observation that coronary artery disease is an inflammatory process that bears many similarities to the rheumatoid synovium. The investigators results will need to be confirmed, especially with respect to congestive heart failure, since clinical trials in non-RA patients with CHF suggested that anti-TNF therapy could worsen rather than improve CHF.

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Abstract 541 Granulomatous Infections and Tumor Necrosis Factor Antagonist Therapies: Update Through June 2002
Ruderman and Markenson

These investigators reviewed the FDA AERS data base in order to update the number of reported cases of granulomatous infections in patients receiving anti-TNF therapies through June 2002. At an FDA advisory meeting in March 2003, it was reported that approximately 400,000 patients had been treated with infliximab and 150,000 patients with etanercept through December 2002.

Methods: Cases of TB and other granulomatous infections associated with treatment with etanercept and infliximab and leflunomide were identified in the AERS data base using terms from the MedDRA 4.1 coding dictionary. Cases of pneumocystis carinii (PCP) were also identified.

Results: A total of 779 granulomatous infections and 64 cases of PCP were reported. Infections reported more than once are summarized below. Treatment exposure data for this specific time period is not available.

Conclusion: AERS data must be interpreted with caution, as it is limited by under-reporting, report duplication, and reports that are often incomplete. Despite such limitations, these observations suggest that there are biologically and medically important differences in the safety profiles of TNF antagonists with respect to these infections. The basis for these differences is not clear, but may relate to differences in pharmacokinetics, binding properties, complement activation, cell lysis, or effects on circulating leukocytes.

Editorial Comment: It is difficult to interpret these numbers, as in previous reports of infections from the AERS data base, because of the many limitations of this voluntary reporting system (listed above). Nonetheless, there is a clear signal for concern with infliximab. The report of Wolfe et al (Abstract 539 above) at these meetings confirm the increased risk for TB in infliximab treated patients.

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Abstract 543 Lymphoma in Rheumatoid Arthritis: the Effect of Methotrexate and AntiTNF Therapy in 18,572 Patients.
Wolfe and Michaud

Background: The risk of lymphoma is increased in patients with rheumatoid arthritis (RA). It remains unclear whether treatment with methotrexate or TNF inhibitors is associated with an increased risk for developing lymphoma in RA patients. Previous studies (prior to the anti-TNF era) have shown strong correlations between disease activity and lymphoma development. This study was undertaken to determine the rate and standardized incidence ratio (SIR) for lymphoma in RA patients, and in subsets of patients by treatment group. In addition, the investigators sought to determine predictors of lymphoma in RA.

Methods: A prospective study of 18,572 RA patients who were surveyed biannually in a long-term outcome study (1998-2002). Potential lymphoma cases received detailed follow-up. The SIR was calculated with data from the SEER cancer data resource.

Results: Twenty-nine (29) cases of lymphoma were identified, yielding a rate of 98.9 per 100,000 patient years of observation. The following SIR rates were observed/calculated:

Lymphoma was associated with increasing age (hazard ratio 1.58 per 10 year increase (95% C.I. 1.16, 2.18), male sex (HR 3.70 (1.79, 7.68)) and education (1.16 (0.99, 1.37)), but not with current or previous therapy. There was no temporal pattern for the development of lymphoma after the start of anti-TNF therapy. A wide variety of lymphoma cell types were identified. Patients receiving anti-TNF therapy had more severe RA at enrollment than did non anti-TNF patients.

Conclusion: The incidence of lymphomas is increased in RA, but confidence intervals overlap among all treatment groups. The apparent increase in lymphomas in patients treated with TNF inhibitors may be due to confounding by indication - that is, that patients with severe disease who are (historically) most likely to develop lymphomas are also the ones most likely to receive TNF inhibitors.

Editorial Comment: There has been significant concern as to whether TNF inhibitors increase an RA patients risk for developing lymphoma. Defining this risk accurately has been difficult. To date, incidence rates for lymphomas in TNF antagonist-treated patients have been compared to contemporaneous non-RA controls, or to historical RA controls, due to lack of data in contemporaneous RA controls not receiving TNF antagonists. The validity of these comparisons is questionable. Dr. Wolfe herein provides the first estimates of lymphoma rates in a prospective cohort of RA patients, some of whom received TNF antagonists and some who did not. Interestingly, the patients who were not receiving MTX or TNF antagonists did not exhibit a higher incidence of lymphomas compared to the SEER data base controls, perhaps reflecting milder disease. Likewise, the mild increase in lymphoma incidence in the TNF antagonist treated patients could be explained by more severe disease which is a known risk factor for lymphoma in RA.

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Late Breaking Abstract 23 TNF-blockers are not Associated with an Increased Overall Tumor Risk in Rheumatoid Arthritis Patients
Geborek, Bladstrom, Jacobsson

Background: TNF-alpha plays an important role in tumor surveillance, particularly lymphoma. Because of this, Using TNF-alpha blocking agents in the treatment of rheumatoid arthritis (RA) may increase the risk of developing malignancies. Clinical trials of TNF inhibitors have not identified an increase in tumor (including lymphoma) risk, but are limited by short observation intervals and small cohorts. Here, Geborek et al examine tumor risk in RA from a comprehensive population-based cohort.

Methods: All RA patients receiving TNF inhibitors (etanercept or infliximab) were identified from the South Swedish Arthritis Treatment Group (SSATG) register. This group comprises about 90% of all TNF treated patients in this region. Controls were identified from RA patients never receiving TNF inhibitors from Malmo, Sweden (A city within the SSATG region).

RA patients receiving TNF inhibitors were followed from the beginning of anti-TNF treatment until death or December 31, 2002. Matched controls were followed from July 1, 1997 until death or December 31, 2002. Over this period, incident cancers were identified from the Southern Swedish cancer registry. Deaths were identified from Swedish population census registers.

Results: 757 patients were identified as having received TNF inhibitor therapy (226 etanercept, 531 infliximab). Compared to 800 control patients, the anti-TNF treated patients tended to be younger (mean age 56 vs. 64 years), have a history of multiple previous DMARD use (an average of 3 vs. 1 previous DMARD), longer disease duration (12 vs. 11 years), and higher mean HAQ scores.

Overall Tumor Risk:

Lymphoma Risk:

Conclusion: Overall tumor risk is not increased among RA patients treated with TNF inhibitors. The increased lymphoma risk observed among RA patients treated with TNF inhibitors may be confounded by small numbers of incident lymphomas.

Editorial Comment: Large, comprehensive population based studies, such as this, are needed to accurately determine risk rates. However, as can be seen here, low incident event numbers can limit the interpretation of even the most complete analysis. Other factors have potential to increase cancer risk in this population, as well, such as disease duration and immunosuppressant use. Tumor risk, particularly lymphoma risk, with anti-TNF therapy may have a lag time of many years to decades. Thus, as more people are treated with TNF inhibitors over longer periods of time, tumor risk may become more pronounced.

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Abstract 739 Sustained 5-Year Efficacy of Adalimumab (HUMIRA^TM) Monotherapy in DMARD-Refractory Rheumatoid Arthritis (RA)
van de Putte, Rau, Burmester, Hartz, Fischkoff, Kupper, and Spencer-Green

This study examined the long-term safety and efficacy of adalimumab in patients with rheumatoid arthritis (RA) participating in open-label extension trials. Adalimumab was well tolerated and response is maintained up to 5 years. Given the long history of other DMARDs failing to provide continued therapeutic benefit over time, these findings are encouraging. (See Eular highlights for data)

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Abstract 204 Safety Data From 48 weeks Follow-Up of a Randomised Controlled Trial of Rituximab in Patients with Rheumatoid Arthritis
Szcaepanski, Szechinski, Pilipowicz-Sosnowska, Emery, Edwards, Magrini, Lehane, and Shaw

Rituximab is an anti-CD20 monoclonal antibody that depletes B cells. This study is a follow-up to a 24 week, randomized, double-blind, placebo controlled trial in patients with rheumatoid arthritis (RA). Safety and efficacy at 24 weeks were presented at Eular. Essentially, the benefits achieved by week24 in all three rituximab groups were maintained, however 4 additional serious adversee events were reported. These included arytenoiditis (RTX + CTX), viral gastroenteritis (RTX alone), goitre (RTX alone), and renal stint replacement (TRX + MTX).

Beginning at week 32, there was evidence of B cell return. Nevertheless, the median CD19 level remained only 20-40% of baseline measurements. (see Eular results)

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Abstract 1704 Efficacy of IL-6 Receptor Antagonist MRA in Rheumatoid Arthritis Patients with an Incomplete Response to Methotrexate (CHARISMA)

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