Reports

Achieving Drug-free Remission in Rheumatoid Arthritis: The BeSt Strategy
MERIT Re-evaluation: Impact of an Enhanced Sensitivity Tropism Assay

Remission as a Goal of Anti-TNF Therapy for Rheumatoid Arthritis

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

72nd Annual Meeting of the American College of Rheumatology

San Francisco, California / October 24-29, 2008

The BeSt (Behandel Strategieen [Treatment Strategies in Rheumatoid Arthritis]) trial addressed three unanswered questions about rheumatoid arthritis (RA) therapy: Is combination therapy better than monotherapy? What is the appropriate position of tumour necrosis factor alpha (TNFa) inhibitors in the treatment schema? Does tight control of RA disease activity make a difference in outcomes?

The trial involved 508 patients with RA symptoms for two years or less, six or more swollen and tender joints, erythrocyte sedimentation rate (ESR) <u>></u>28 mm/hr, and no prior disease-modifying antirheumatic drug (DMARD) exposure. They were randomized to four treatment strategies: sequential monotherapy, beginning with methotrexate (MTX); step-up combination therapy after initial MTX monotherapy; initial combination therapy with MTX, sulfasalazine, and prednisone; and initial combination therapy with MTX and infliximab.

Progression of each treatment strategy was guided by the Disease Activity Scale (DAS), reported Dr. Naomi Klarenbeek, Leiden University Medical Center, The Netherlands. During the first two years of the trial, a DAS >2.4 at one level of therapy triggered progression to the next level. Patients who remained at a DAS <u><</u>2.4 for more than six months could be tapered to a maintenance dose.

Drug-free Remission

BeSt investigators defined remission as a DAS <1.6. Beginning in the third year, patients who achieved a DAS <1.6 for six months or longer had their treatment tapered to discontinuation. If the DAS returned to 1.6 or greater, treatment was restarted.

After five years of follow-up, patients who began treatment with infliximab combination had better functional ability compared with the other three groups, as reflected in a significantly lower mean Health Assessment Questionnnaire (HAQ) score (0.54 vs. 0.62 to 0.70, P<0.01 to P<0.001). Almost half (48%) of the entire study population achieved remission. The infliximab and sequential-monotherapy groups had remission rates of 51%, compared with 45% and 42% for the other two groups.

Initial treatment with infliximab or a prednisone-containing combination led to the lowest annual rate of radiologic progression (1.0 Sharp-van der Heijde Score [SHS] unit), which was significantly better than the 3.5 and 2.5 SHS-unit progression with sequential monotherapy and step-up combination therapy (P=0.04). Significantly fewer patients who began therapy with infliximab had radiologic progression of 5 SHS units or greater compared with sequential monotherapy and step-up combination therapy (P<0.02).

More patients in the infliximab group achieved drug-free remission (DAS <1.6) at five years (19%) than in the other three groups (10% to 16%). Adverse events and serious adverse events occurred in a similar proportion of patients in each group. However, the infliximab group had the lowest rate of toxicity-associated withdrawal (9% vs. 12% to 22%).

“Initial combination therapy was associated with less joint damage than initial monotherapy,” noted Dr. Klarenbeek. “Initial treatment with MTX and infliximab resulted in better HAQ scores over time.” She added, “Five years of DAS-guided treatment provided adequate suppression of radiological progression, and initial functional improvement is maintained.”

Tight Control of Disease Activity

A second report from BeSt focused on the use of a DAS-steered strategy to achieve sustained drug-free remission. The end point was defined as a DAS <1.6 for more than one year of follow-up, absence of synovitis, and no concurrent DMARD therapy, stated Dr. Diane van der Woude, Leiden University Medical Center.

Investigators compared the 508-patient BeSt cohort with 410 RA patients treated conventionally at the Leiden Early Arthritis Clinic. Patients in the two groups were similar with respect to radiologic damage (median SHS 4-5), high-sensitivity C-reactive protein (hsCRP) level (~ 20mg/dL or 190.48 nmol/L), and cyclic citrullinated peptide (CCP2) antibody positivity (~60%). However, the BeSt patients had a higher mean HAQ (1.4 vs. 1.1), more swollen joints (median 14 vs. 8), and a higher rate of positivity for rheumatoid factor (RF) 65% vs. 58%).

The two strategies led to similar rates of sustained drug-free remission: 9% of the BeSt cohort and 11% of the conventionally treated patients. Investigators examined predictors of sustained drug-free remission in a multivariate analysis of combined data from both cohorts. The presence of anti-CCP2 antibodies proved to be the strongest negative predictor, revealing less than a 10% likelihood of attaining sustained drug-free remission (OR 0.08, P<0.001). Female sex (OR 0.50, P=0.01) and higher hsCRP level (OR 0.99, P=0.04) also were negative predictors.

However, adherence to DAS-guided therapy more than doubled the likelihood of sustained drug-free remission (OR 2.44, P=0.10). Moreover, DAS-guided therapy tripled the chances of sustained remission in CCP2-positive patients (OR 2.96, P=0.07).

“These results show that DAS-guided therapy can induce sustained drug-free remission in patients with RA that has unfavourable prognostic characteristics,” confirmed Dr. van der Woude.

Cost-Effectiveness of Anti-TNF Therapy

Cost has been an issue with anti-TNFa therapy since the advent of the drug class. Virtually all of the older conventional DMARDs are available in generic formulations, making them less costly than the newer biologic DMARDs.

To add context to the cost-effectiveness discussion, Dr. Michael Ganz, Abt Bio-Pharma Solutions, Lexington, Massachusetts, analyzed two-year HAQ results from BeSt for patients who began therapy with infliximab vs. those assigned to sequential DMARD therapy. The data were incorporated into a model with a five-year timeline, supplemented by other published outcome data.

Estimated resource use and drug costs were derived from the British National Formulary and two systematic reviews of anti-TNFa therapy in RA. Outcomes included the cost per 1-point improvement in HAQ and the cost per quality-adjusted life-year (QALY). HAQ scores were translated into QALYs by use of formulas from the systematic reviews.

Over the five-year follow-up period in BeSt, cumulative costs increased from £1,155 ($2,250) to £15,875 ($31,150) for the strategy of sequential monotherapy. Cumulative costs with initial infliximab combination therapy increased from £8,131 ($15,140) to £22,155 ($43,420).

QALYs improved more with initial infliximab combination therapy (0.70 to 3.30) than with sequential monotherapy (0.62 to 2.91). The cost per QALY decreased over time with infliximab relative to sequential monotherapy. The cost per QALY began at £92,764 ($181,785) in year 1 and declined to £15,965 ($31,285) in year 5. About half of the decline occurred from year 1 to 2. Results were not sensitive to changes in drug cost, HAQ, or the conversion algorithm.

“Higher costs associated with the earlier use of infliximab are offset by this regimen’s clinical benefit over time,” Dr. Ganz and colleagues concluded. “Also, delaying the use of infliximab likely leads to costly structural damage.”

Identifying High-risk Patients

The ability to identify RA patients who are likely to progress rapidly would greatly aid physicians in clinical decision-making, particularly in the selection of a treatment regimen. The issue was examined in matrix risk models comparing initial treatment with MTX monotherapy vs. combination MTX/infliximab, reported Dr. Nathan Vastesaeger, University of Vienna, Austria.

To develop the model, he and colleagues used published data from a large clinical trial of patients with early RA. The relative risk of progression was defined as a threshold change in the modified SHS of ³5 units per year. The investigators applied Spearman’s rank analysis to identify baseline predictors of the relative risk of progression (RRP), and they used logistic regression to calculate the probability of RRP.

Using data from a published study of DMARD-naïve patients, the investigators developed a model that included a swollen 28-joint count, RF status and hsCRP value, and then tested the model with published data from a study of patients with longstanding MTX-refractory RA.

The resulting algorithm yielded a predictive model in a visual matrix comprising the baseline predictors and initial treatment strategies, arranged in order of increasing probability. Each cell of the matrix contained the predicted percentage of patients who would progress rapidly, given their baseline characteristics and intended therapy.

Dr. Vastesaeger described examples of predictive values included in a matrix. A DMARD-naïve RA patient with 18 swollen joints, a hsCRP level of 7 mg/dL (66.67 nmol/L) and RF value of 380 U/dL would have a 47% probability of progressing with MTX monotherapy and a 14% probability of rapid progression with combination therapy. A MTX-refractory patient with similar disease activity would have a 58% probability of rapid progression with MTX alone vs. 22% with MTX/infliximab.

Dr. Vestesaeger translated the data into a number needed to treat (NNT) with the combination to prevent one rapid progression with MTX alone. The calculations yielded an NNT of 3 for patients in the highest ranges of CRP values, swollen joint count and RF, and an NNT of 33 for patients in the lowest ranges for those clinical variables.

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