TICORA

Published

Grigor C, et al. "Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial". The Lancet. 2004. 364(9430):263-269.
PubMed • Full text

Clinical Question

In patients with early rheumatoid arthritis, does an intensive medical strategy that emphasizes a structured, advancing regimen driven by objective disease activity criteria, lead to improved disease control at 18 months when compared to standard therapy?

Bottom Line

Among patients with early rheumatoid arthritis, an intensive medical strategy emphasizing structured, advancing regimen driven by objective disease activity criteria improves disease control at 18 months when compared to standard therapy.

Major Points

In the late 1990s and early 2000s, it was recognized duration of RA-associated inflammation was related to degree of disease-related joint destruction, and earlier disease control might improve long-term outcomes in RA. As early control of RA often requires multiple agents used in tandem, and such medications are associated with adverse events, there was a need for high-quality evidence of benefit to support multi-agent regimens for early RA control rather than monotherapy.

Published in 2004, the Tight Control of Rheumatoid Arthritis (TICORA) trial randomized 111 patients with RA with moderate or worse activity and disease for <5 years to intensive vs. standard care in a single-blinded fashion. Those in the intensive arm were more likely to receive ≥2 medications (67% vs. 11%). At 18 months, the group assigned to intensive care had greater reduction in disease severity and had a higher proportion who achieved a "good" response. The intensive arm had less progression of joint destruction as assessed by the Sharp score (P=0.02).

Since TICORA began recruiting in the UK prior to approval of etanercept or any other anti-TNF-alpha DMARD (recruitment began in 1999, the European Medicines Agency approved Enbrel/etanercept in 2000), the TICORA protocol did not include these agents. The authors note that radiographic progression in the intensive therapy arm was "less impressive" than in a 2000 trial describing the use of the anti-TNF-alpha medication, etanercept, in early RA. Regardless, TICORA provided evidence that an intensive, stepwise approach to early RA management improves RA-related outcomes, including progression of joint destruction.

Guidelines

ACR RA Treatment (2021, adapted)

• A guiding principle of these recommendations is that RA requires early management, in addition to early evaluation and diagnosis.

Design

• Multicenter, examiner-blinded (i.e., single-blinded), randomized controlled trial
• N=110
  • Intensive (n=55)
  • Standard (n=55)
• Setting: 2 centers in the UK
• Enrollment: 1999-2001
• Follow-up: 18 months
• Analysis: Intention-to-treat
• Primary outcomes:
  • Mean fall in disease activity score (DAS)
  • Proportion of patients with a good response

Population

Inclusion Criteria

• Age 18 to 75 years
• Rheumatoid arthritis <5 years
• Active disease (disease activity score >2.4)

Exclusion Criteria

• Previous treatment with combination DMARD therapy
• Liver disease ((aspartate aminotransferase >80 IU/L, alkaline phosphatase >700 IU/L)
• Renal disease (creatinine >200 umol/L)
• Hematological disease (white blood cell count <4.0x10^9/L, platelet count <150x10^9/L)

Baseline Characteristics

For the intensive arm

• Mean age: 51 years
• Mean disease duration: 19 months
• Disease activity score: 4.9
• Swollen joint score (0-44): 12
• Ritchie articular index: 23
• Pain score (0-100): 62
• Patient global assessment (0-100): 69
• Physician global assessment (0-100): 70
• C-reactive protein: 44 mg/L
• Erythrocyte sedimentation rate: 43 mm/h
• Health assessment questionnaire score: 2
• SF-12 details: Physical summary 28, mental health 39
• Total sharp score: Median 21.5

Interventions

• Randomized to a group:
  • Intensive - Monthly rheumatology visits.
    • Participants received monthly triamcinolone injections in up to 3 joints, with maximum total dose of 120 mg triamcinolone.
    • After month 3, those with DAS >2.4 were treated with escalating therapy outlined in Figure 1 of the manuscript. In brief, it involved initial addition and titration of sulfasalazine, then MTX and HCQ therapy, with titration of these agents for DAS >2.4. Further treatment included prednisone 7.5 mg PO daily, followed by the addition of cyclosporine, then change to leflunomide or sodium aurothiomalate.
  • Standard - Routine follow-up in rheumatology clinic, presumably with q3mo follow-up. Objective scoring (i.e., DAS) was not used in decision making.
    • DMARD monotherapy was given for active synovitis. The attending rheumatologist was allowed to change to alternative monotherapy or add additional medications to monotherapy for persistent symptoms or adverse effects.
    • Triamcinolone injections were given in the same fashion as the intensive arm.
• Every 3 months, a blinded examiner assessed each patient

Outcomes

Comparisons are intensive vs. standard therapy.

Primary Outcomes

Mean change in disease activity score (DAS) from baseline to 18 months

DAS includes ESR, Ritchie articular index, joint swelling count, and self-reported global assessment of disease activity. Disease activity is qualified as "high" at 3.6, "moderate" at 2.4, and "low" at 1.6.

-3.5 vs. -1.9 (difference 1.6; 95% CI 1.1-2.1; P<0.0001)

Good response at 18 months

Defined as DAS <2.4 and >1.2 fall in score since baseline

82% vs. 44% (OR 5.8; 95% CI 2.4-13.9; P<0.0001)

WJC ed note: Since the prevalence of this and other outcomes are >10%, the odds ratio (OR) does not approximate a risk ratio (RR). If the authors used modified Poisson regression or negative binomial regression instead, they would report a RR around 1.86 for this outcome. Interested readers can convert ORs to RRs using an online calculator.

Secondary Outcomes

In remission

65% vs. 16% (OR 9.7; 95% CI 3.9-23.9; P<0.0001)

ACR 20

≥20% improvement in joint swelling count, joint tenderness count, and 3 of 5 of the following: ESR, health assessment questionnaire, pain score, and assessors and self-reported global assessment

91% vs. 64% (OR 5.7; 95% CI 1.9-16.7; P<0.0001)

ACR 50

84% vs. 40% (OR 6.1; 95% CI 2.5-14.9; P<0.0001)

ACR 70

71% vs.18% (OR 11; 95% CI 4.5-27; P<0.0001)

Additional Outcomes

Treatment received

Group sizes were 53 and 51 for this comparison. The authors are rather unclear about the breakdown of these groups, and the WJC editors attempted to abstract this from the prose but might have made errors given the poor reporting quality by the authors.

Sulfasalazine, MTX, sodium aurothiomalate, or penicillamine monotherapy: 18 vs. 45

MTX, sulfasalazine, & HCQ triple therapy: 27 vs. 2

MTX and cyclosporine or other DMARD combination: 7 vs. 4

Change in other disease parameters from baseline to 18 months (mean except where specified)

Joint swelling count: -11 vs. -8 (difference 3; 95% CI 1 to 5; P=0.0028)

Joint tenderness count: -20 vs. -12 (difference 8; 95% CI 4 to 12; P=0.0003)

Patient global assessment: -51 vs. -21 (difference 30; 95% CI 17 to 42; P<0.0001)

Assessor global assessment: -58 vs. -34 (difference 24; 95% CI 14 to 34; P<0.0001)

Pain score: -45 vs. -20 (difference 25; 95% CI 14 to 36; P<0.0001)

Erythrocyte sedimentation rate: -30 vs. -12 (difference 18; 95% CI 8 to 28; P=0.0007)

C-reactive protein: -30 vs. -14 (difference 16; 95% CI -3 to 34; P=0.09)

Health assessment questionnaire: -0.97 vs. -0.47 (difference 0.5; 95% CI 0.2 to 0.8; P=0.0025)

Short form-12 physical summary score: 9.3 vs. 4 (difference 5.3; 95% CI 0.8 to 9.8; P=0.021)

Short form-12 mental health summary score: 10.9 vs. 6 (difference 5.0; 95% CI -1.6 to 11.6; P=0.138)

Erosion score (median): 0.5 vs. 3 (P=0.002)

Radiographic joint space narrowing (median): 3.25 vs. 4.5 (P=0.331)

Radiographic total Sharp score (median): 4.5 vs. 8.5 (P=0.02)

Adverse Events

Adverse events related to the medications

Gastrointestinal: 18 vs. 25

Abnormal liver function: 8 vs. 16

Dermatological: 10 vs. 15

CNS: 1 vs. 9

Infective therapy: 5 vs. 7

Hematological: 2 vs. 6

Others: 2 vs. 7

Total: 46 events in 32/55 patients vs. 85 events in 42/55 patients

Hospitalizations

25 admissions in 20 patients vs. 30 admissions in 20 patients

Deaths

1 vs. 3

Criticisms

• Did not include TNF-alpha antagonists, which were available partway through enrollment.
• Not double-blinded

Funding

Chief Scientist’s Office Scottish Executive. No conflicts of interest.