BeSt

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Goekoop-Ruiterman YP, et al. "Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis". Arthritis & Rheumatism. 2005. 52(11):3381-3390.
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Clinical Question

In patients with early rheumatoid arthritis, which treatment strategies best prevent joint damage and functional decline?

Bottom Line

Combination DMARD plus prednisone/infliximab improves functional and radiologic outcomes when used as first-line therapy in rheumatoid arthritis.

Major Points

Initial combination therapy with DMARD plus prednisone or infliximab results in improved functional recovery and less radiographic decline at one year, as compared to sequential monotherapy or step-up combination therapy. While compelling, the BeSt study arguably did not demonstrate the best therapeutic strategies for RA, but does offer some that are better than others. A 2012 AHRQ comparative effectiveness review found no clear evidence supporting one therapy over another for RA treatment in adults.[1]

Guidelines

ACR DMARDs and biologics in RA (2012, adapted)[2]

  • For early RA (disease duration <6 months):
    • Low disease activity - DMARD monotherapy
    • Moderate disease activity without poor prognostic features - DMARD monotherapy
    • Moderate disease activity with poor prognostic features - combination DMARD (double or triple) therapy
    • High disease activity without poor prognostic features - DMARD monotherapy or hydroxychloroquine + MTX
    • High disease activity with poor prognostic features - Anti-TNF +/- MTX or combination (double or triple) therapy
  • Disease activity defined by clinician's assessment or through a validated survey tool (eg, PAS)
  • Poor prognostic features include functional limitation on HAQ or similar questionnaires, extraarticular disease, positive RF or anti-CCP, or bony erosions on radiograph
  • Combination therapy is generally MTX-based, examples given include MTX + hydroxychloroquine, MTX + leflunomide, MTX + sulfasalazine, sulfasalazine + hydroxychloroquine, and MTX + hydroxychloroquine + sulfasalazine

Design

  • Multicenter, single-blind, randomized controlled trial
  • N=508
    • Sequential monotherapy (n=126)
    • Step-up combination therapy (n=121)
    • Initial combination/prednisone (n=133)
    • Initial combination/infliximab (n=128)
  • Setting: 18 peripheral and 2 community hospitals in western Netherlands
  • Enrollment: 2000-2002
  • Follow-up: 1 year
  • Analysis: Intention-to-treat
  • Primary outcome: D-HAQ and SHS scores

Population

Inclusion Criteria

  • Patients with early RA as defined by the American College of Rheumatology
  • Disease duration ≤2 years
  • Age ≥18 years
  • Active disease with ≥6 of 66 swollen joints, ≥6 of 68 tender joints, and ESR ≥28mm/hr or global health score of ≥20mm (on 0-100mm visual analog scale, where 100 is worst)

Exclusion Criteria

  • Prior treatment with DMARDs other than antimalarials
  • Concurrent treatment with an experimental drug
  • Malignancy within last 5 years
  • Bone marrow hypoplasia
  • AST or ALT >3 times ULN
  • Creatinine >150μm/L or CrCl <75ml/min
  • Diabetes mellitus
  • Alcohol or drug abuse
  • Pregnancy, or wish to conceive during study period, or inadequate contraception

Baseline Characteristics

From the sequential DMARD group.

  • Demographics: Age 54 years, female 68%
  • Time from diagnosis to inclusion: 2 weeks (symptom duration 23 weeks)
  • Prior antimalarial therapy: 7%
  • Data:
    • IgM RF+: 67%
    • Erosions on hand or foot films: 72%
  • QOL scales:
    • DAS44 mean: 4.5
    • D-HAQ mean: 1.4
    • SHS median: 3.5
    • Erosion score median: 2.0
    • Joint space narrowing score median: 1.0

Interventions

  • Randomized to one of four treatment strategies:
    1. Sequential DMARD - Starting with MTX 15 mg/week, increased to 25-30 mg/week if DAS44 was >2.4. Poor responders were then treated with SSZ monotherapy, leflunomide monotherapy, MTX and infliximab, gold and methylprednisolone, and MTX and cyclosporine A and prednisone.
    2. Step-up combination therapy - Starting with MTX 15 mg/week, increased to 25-30 mg/week if DAS44 was >2.4, then add-on SSZ therapy, then hydroxychloroquine add-on, then prednisone add-on. Those failing to respond were treated with four drug therapy were switched to MTX and infliximab, then MTX and cyclosporine A and prednisone, then leflunomide.
    3. Initial combination with high-dose prednisone taper - Starting with MTX 7.5 mg/week, SSZ 2,000 mg/day, and prednisone 60 mg/day tapered to 7.5 mg/day over 7 weeks. If DAS44 was >2.4, MTX increased to 25-30 mg/week. Poor responders were switched to MTX and cyclosporine A and prednisone then MTX and infliximab, leflunomide monotherapy, gold and methylprednisolone, and azathioprine and prednisone. For good responders, prednisone was tapered then MTX was tapered.
    4. Initial combination therapy with TNF inhibitor infliximab - Start with MTX 25-30 mg/week with infliximab 3 mg/kg at week 0, 2, 6, then every 8 weeks. If the DAS44 was >2.4, the dose of infliximab with increased to 8 mg/kg q8 weeks. If still no response, the dose was further increased to 7.5 mg/kg and 10 mg/kg q8 weeks. If at this point the DAS44 was >2.4, then the MTX was changed to SSZ then leflunomide, then combination MTX, cyclosporine A, and prednisone. Final therapies were gold and methylprednisolone and azathioprine and prednisone. Those with good response had their infliximab dose tapered.
  • Assessments made at 3 month intervals by blinded nurse
    • Functional ability measured by Dutch Health Assessment Questionnaire (D-HAQ), where higher is worse
    • Radiographic damage measured by modified Sharp/Van deer Heijde score (SHS), ranging from 0-448
    • Treatment titrated to Disease Activity Score (DAS) in 44 joints of ≤2.4

Outcomes

Comparisons are sequential monotherapy vs. step-up combination therapy vs. initial combination/prednisone vs. initial combination/infliximab.

Primary Outcomes

Mean D-HAQ score at 3 months
Dutch Health Assessment Questionnaire.
1.0 vs. 1.0 vs. 0.6 vs. 0.6 (P<0.001)
Mean D-HAQ score at 1 year
0.7 vs. 0.7 vs. 0.5 vs. 0.5 (only sequential monotherapy vs. combination therapies reached statistical significance)
Median increases in SHS
A score for radiographically-detected damage from the disease.
2.0 vs. 2.5 vs. 1.0 vs. 0.5 (all comparisons reached statistical significance)

Secondary Outcomes

DAS44 ≤2.4 at 1 year
Disease activity score in 44 joints.
53% vs. 64% vs. 71% vs. 74% (P=0.004 for group 1 vs. 3 and P=0.001 for group 1 vs. 4; other comparisons NS)

Adverse Events

Any
43% vs. 47% vs. 37% vs. 39% (NS)
Serious
8 vs. 9 vs. 17 vs. 6 events (NS)

Criticisms

  • Unclear clinical significance of the outcomes[3][4]

Funding

Funding from Dutch College of Health Insurances, with grants from Schering-Plough BV and Centocor Inc.

Further Reading

  1. Donahue KE et al. "Drug therapy for rheumatoid arthritis in adults: An update." AHRQ Comparative Effectiveness Reviews. 2012; 12-EHC025-EF.
  2. Singh JA, et al. "2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis." Arthritis Care & Research. 2012;64(5):625-639.
  3. York M and Hunter DJ. "Initial combination therapy with prednisone or infliximab improved outcomes in early rheumatoid arthritis more than DMARDs alone." ACP Journal Club. 2006;144(3):72.
  4. Weisman MH. "Editorial: Progress toward the cure of rheumatoid arthritis? The BeSt study." Arthritis & Rheumatism. 2005;52(11):3326-3332.