Ateneo School of Medicine and Public Health
EBM
Group 5
Critically Appraised Topic
Evidence-Based Medicine
Date: January 5, 2011
Theme: Therapy
Clinical Bottom Line:
Rheumatoid Arthritis (RA) is a common chronic inflammatory disorder wherein patients present with synovitis and
ultimately leads to the destruction of the bone and cartilage in joints. The disease is more common among females and can be
found worldwide making it a public health issue. Patients with RA experience a multitude of signs and symptoms such as
morning joint stiffness, arthritis, weight loss, weakness, edema/tenderness/decreased ROM of joints, etc. Tocilizumab or
Actemra is a new drug that is an IL-6 inhibitor that decreases C reactive protein and is used in the treatment of moderate to
severe RA among adult patients.
Question: Among patients diagnosed with rheumatoid arthritis with inadequate response to DMARDs, what is the ability of
Tocilizumab in preventing the progression of structural joint damage?
Search Strategies:
PubMed
Search terms: Rheumatoid arthritis, tocilizumab
Search Results = 9
Limits: english, links to free full test, humans,
clinical trial
http://www.ncbi.nlm.nih.gov/pubmed/17485422
Primary Article:
Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI) : evidence of clinical
and radiographic benefit from an x-ray reader blinded randomised controlled trial of tocilizumab. Nishimoto N, Hashimoto J,
Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Murata N, van der Heijde D, Kishimoto T. 2007 September ;66(9) :11627. Epub 2007 May 7.
Abstract
Objective
To evaluate the ability of tocilizumab (a humanised anti-IL-6 receptor antibody) monotherapy to inhibit progression of
structural joint damage in patients with RA.
Methods
In a multi-centre, x ray reader-blinded, randomised, controlled trial, 306 patients with active RA of <5 years' duration were
allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional diseasemodifying antirheumatic drugs (DMARDs) for 52 weeks. Radiographs of hands and forefeet were scored by the van der
Heijde modified Sharp method.
Results
Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total
modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the
tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the
DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p<0.01). Tocilizumab monotherapy also improved signs and symptoms. The
overall incidences of AEs were 89% and 82% (serious AEs: 18% and 13%; serious infections: 7.6% and 4.1%) in the
tocilizumab and DMARD groups, respectively.
Conclusion
Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.
Critical Appraisal:
Ateneo School of Medicine and Public Health
EBM
Group 5
Was it randomized?
Was randomization concealed?
Was the follow up sufficiently long and
complete?
Validity
Was the data analyzed on an intention to treat
basis?
Was there adequate blinding of subjects and
researchers?
Were there similar baseline characteristics in
each group?
Applicability
Clinical
Importance
Groups treated equally other than intervention?
Yes. A total of 306 patients were randomized and separated
into treatment group (Tocilizumab) and those that received
the conventional disease modifying anti-rheumatic drugs
(DMARDs). The randomization was concealed from both
the patients and the x-ray technicians that read and
interpreted the results. The randomization of patients was
performed by registering of patients at the patient
registration center with a centralized allocation method.
The study was done for a duration of 52 weeks. A total of
306 patients were enrolled, 148 in the DMARDs group and
158 in the Tocilizumab group. However 14% of patients
withdrew from the DMARDs group and 23% of patients
withdrew from the Tocilizumab group due to exacerbation
of the disease during the trial, refusal of treatment and
protocol violations.
Yes. The results that was used to determine whether or not
Tocilizumab was successful as compared to the conventional
DMARDs was based on radiographic scores taken on week
28 and week 52 of treatment. Clinical indicators included
here are the total sharp score, erosion score, and joint space
narrowing score.
It was not mentioned whether or not patients in the study
were blinded with regard to what treatment they were
receiving. However, the x-ray technicians that were tasked
to interpret the radiographic results were blinded.
Yes. Baseline characteristics of patients on both the
DMARDs and the Tocilizumab groups were matched in
terms of their demographics (age, male to female ratio),
clinical characteristics (RA duration in years, number of
tender and swollen joints, ESR, CRP) , radiographic findings
(modified TSS, erosion score, joint space narrowing score),
and all candidates had an inadequate response to at least one
DMARD in the past.
Yes. For both groups, they were not allowed to undergo
surgical treatment and the use of bisphosphonates during the
trial. Safety was also prioritized for both groups in terms of
recording adverse events, performing regular physical
examinations and doing standard laboratory tests.
What is the magnitude of treatment effect (e.g.
what is the relative risk reduction, absolute risk
reduction, NNT)?
Are any differences between patient and those
studied different enough that you would not
apply these results?
As long as the baseline characteristics of the patients used in
the study will also match the baseline characteristics of
Filipino patients diagnosed with RA, there will be no
difference. The study was also performed in Japan, another
asian country which gives us a similar racial background.
Ateneo School of Medicine and Public Health
EBM
Group 5
Is treatment feasible?
Patient preferences
Benefits vs harms
Yes. The drug is distributed in the Philippines by Zuellig and
is available at Mercury Drug store. Administration of the
drug is simple, one 8mg/kg IV infusion every 4 weeks
making compliance easy. The only possible hindrance for
Filipinos to avail of this treatment would be the high cost.
Mild to moderate AEs were experienced by 89% and 832%
in the Tocilizumab and the DMARDs group. The most
common AE was nasopharyngitis, but the incidences were
similar in both groups. Serious AEs were experienced in
18% and 135 in the Tocilizumab group and DMARDs group.
These include serious infections (pneumonia, URTI,
cellulitis, gastroenteritis, herpes zoster), and mild drug
related infusion reactions. Despite all this, Tocilizumab
monotherapy was generally well tolerated.
The study showed that despite the AEs experienced, the
Tocilizumab therapy still provided significant radiographic
benefits in patients with RA as compared to those taking
DMARDs.
Comments
Ateneo School of Medicine and Public Health
EBM
Group 5
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