TICORA

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Grigor C, et al. "Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial". '. 2004. :.
PubMed

Clinical Question

In patients with early rheumatoid arthritis, does an intensive treatment strategy, focused on the use of triple disease modifying anti-rheumatic drug therapy as required, provide sustained and tight control of disease activity compared to routine outpatient care?

Bottom Line

In patients with early rheumatoid arthritis, the study's intensive outpatient treatment strategy was associated with significantly reduced disease activity (P<0.0001), reduced radiographic disease progression, improved quality of life and improved physical function at no increased cost. This study provided evidence that the "triple DMARD" treatment strategy combining methotrexate, sulfasalazine, and hydroxycholoroquine is a potent and tolerable option that provides results comparable to biologic therapies.

Major Points

Previous trials in patients with early rheumatoid arthritis used specific drug combinations versus single components, open study designs without masked assessments, and combinations of disease-modifying antirheumatic drugs from the outset of new diagnosis. The TICORA trial aimed to ascertain an intensive, multifaceted treatment strategy that could both achieve tight disease control in patients with early rheumatoid arthritis, as well as sustain control in a large proportion of those patients long-term.

The intensive treatment strategy consisted of frequent, objective patient assessments, intra-articular steroid injections and use of a structured protocol for the escalation of disease-modifying antirheumatic therapy.

Benefits of the strategy were therefore multifactorial. More than two-thirds of patients from the intensive group required escalation of oral treatment and approximately half was on triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine. Patients in the intensive group also received higher doses of methotrexate weekly and more intra-articular steroid injections. Frequent patient review prevented medication non-compliance due to toxic effects. It was noteworthy that structured protocol offered tight control with standard disease-modifying antirheumatic drugs without use of anti-tumour necrosis factor (TNF) treatment.

Guidelines

Design

  • Multicenter, single-blind, parallel-group, randomized, controlled trial
  • N=110
    • Intensive (n=55)
    • Routine (n=55)
  • Setting: 2 National Health Service (NHS) centers in Glasgow, United Kingdom
  • Enrollment: August 1999 to April 2001
  • Mean follow-up: 18 months
  • Analysis: Intention-to-treat
  • Primary outcome: Mean fall in disease activity score (DAS), and the proportion of patients with a good response (score < 2.4 and fall in score from baseline by >1.2).
    • Disease activity score (DAS): validated composite of erythrocyte sedimentation rate, Ritchie articular index, joint swelling count, and patients’ global assessment of disease activity. Scores of 3.6, 2.4, and 1.6 represent high, moderate, and low disease activity, respectively.
  • Secondary outcome: In remission (disease activity score <1.6), ACR 20, 50, and 70 responses
    • ACR 20, 50, and 70 responses: at least 20%, 50%, and 70% improvement in joint swelling and joint tenderness counts, and three of five other variables (ie, erythrocyte sedimentation rate, health assessment questionnaire, pain score, and assessors’ and patients’ global assessments).

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 disease-modifying antirheumatic drug treatment
  • 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 treatment group:

  • 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

Interventions

  • Randomized to intensive outpatient treatment group or routine outpatient treatment group

  • Intensive treatment group followed by same rheumatologist every month where disease activity score was calculated. During the first three months the intensive group was treated with steroids only according the protocol below:
    • Any swollen joint amenable to injection was injected, up to three joints per assessment, with a maximum total dose of 120 mg triamcinolone acetonide per visit.
    • At every assessment after month 3, patients with DAS >2.4 received escalation of disease-modifying antirheumatic drug therapy. Patients initially had sulfasalazine added and titrated, followed by methotrexate and hydroxycholoroquine. If DAS remained >2.4, the DMARD doses were titrated upwards, followed by the addition of prednisone 7.5 mg PO daily, followed by the addition of ciclosporine.
    • Patients in the intensive group also continued to receive glucocorticoids in the form of triamcinolone acetonide based on the protocol mentioned above. After starting a new DMARD, if their DAS remained >2.4, they received any of the remaining 120 mg triamcinolone intramuscularaly.
  • Routine treatment group followed by two consultant rheumatologists and supervised rheumatology trainees every 3 months
    • Disease-modifying antirheumatic drug therapy given if active synovitis, with titration and addition of additional DMARDs at the discretion of the rheumatologist.
  • Every 3 months, blinded metrologist assessed patients from both groups

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

Mean fall in disease activity score
-3.5 vs. -1.9 (HR 1.6; 95% CI 1.1-2.1; P<0·0001)
Good response
82% vs. 44% (HR 5.8; 95% CI 2.4-13·9; P<0·0001)

Secondary Outcomes

In remission:
65% vs. 16% (HR 9.7; 95% CI 3.9-23.9; P<0·0001)
ACR 20
91% vs. 64% (HR 5.7; 95% CI 1.9-16.7; P<0·0001)
ACR 50
84% vs. 40% (HR 6.1; 95% CI 2.5-14.9; P<0·0001)
ACR 70
71% vs.18% (HR 11; 95% CI 4.5-27; P<0·0001)

Adverse Events

Drug-related toxic events
Gastrointestinal: 18 vs. 25
Abnormal liver function: 8 vs. 16
Dermatological: 10 vs. 15
CNS: 1 vs. 9
Infective: 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

The relative improvement in overall radiographic progression (sharp score) was statistically, but not clinically significant (a relative improvement in 5 of the sharp score is considered clinically significant).

Patients in the intensive treatment group received more intra-articular steroids than the routine group, although the difference was only 20mg of triamcinalone acetonide per month (which is equivalent to the dose of 1 large joint injection every 2 months, i.e. 40 mg per large joint injection).

Funding

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

Further Reading

CAMERA trial - Verstappen, S. M. M., Jacobs, J. W. G., van der Veen, M. J., Heurkens, A. H. M., Schenk, Y., ter Borg, E. J., … Utrecht Rheumatoid Arthritis Cohort study group, on the behalf of the U. R. A. C. study. (2007). Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Annals of the Rheumatic Diseases, 66(11), 1443–9.

TEAR trial - Moreland, L. W., O’Dell, J. R., Paulus, H. E., Curtis, J. R., Bathon, J. M., St Clair, E. W., … TEAR Investigators. (2012). A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis and Rheumatism, 64(9), 2824–35

RACAT trial - O’Dell, J. R., Mikuls, T. R., Taylor, T. H., Ahluwalia, V., Brophy, M., Warren, S. R., … CSP 551 RACAT Investigators. (2013). Therapies for active rheumatoid arthritis after methotrexate failure. The New England Journal of Medicine, 369(4), 307–18.