Locally Available Biologic Agents in the Treatment - Philippine ...

Locally Available Biologic Agents in the Treatment of Psoriatic Arthritis 253
Phil. J. Internal Medicine, 47: 253-259, Nov.-Dec., 2009
LOCALLY AVAILABLE BIOLOGIC AGENTS IN THE TREATMENT
OF PSORIATIC ARTHRITIS
Sidney Erwin T. Manahan, M.D. and Bernadette Heizel D. Reyes, M.D.
ABSTRACT
Introduction: Traditional studies on psoriatic
arthritis have evaluated the response to treatment
in terms of the rheumatic condition excluding the
dermatologic condition. Treatment of the disease with
biologic agents has been demonstrated to be effective
in the control of both the arthritis and skin condition.
Objective: To systematically review the efficacy
of locally available biologic agents (etanercept
and infliximab) in the treatment of rheumatic and
dermatologic manifestations of psoriatic arthritis.
Search Strategy: A MEDLINE search (from 1966
to June 2007) was performed using the following
search terms: biologic agents, infliximab, etanercept,
psoriasis, psoriatic arthritis and randomized clinical
trials. Likewise, the Cochrane Database was also
searched for existing studies on psoriatic arthritis. This
was supplemented by citation tracking of published
bibliographies and conference proceedings.
Selection Criteria: All randomized clinical
trials evaluating the efficacy of etanercept and
infliximab in Adult patients with active Psoriatic
arthritis were included. Outcome assessments should
include evaluation of both arthritic and dermatologic
manifestations of the disease. These could be in the
form of Psoriatic Arthritis Response Criteria (PsARC),
American College of Rheumatology (ACR) Response
Criteria (20, 50, and 70) and the Psoriatic Arthritis
Severity Index (PASI) 75.
Main Results: Nine studies were identified using
the search strategy previously outlined. Of these, the
four main clinical trials involving 569 patients were
included in the quantitative analysis. Studies publishing
the results of post hoc analysis were excluded if they
did not assess for joint and dermatologic efficacy.
Reprint request to: Sidney Erwin T. Manahan, M.D., Section of
Rheumatology, Department of Medicine, UP-PGH Medical Center,
Taft Ave., Manila, Philippines
Quantitative analysis showed that patients treated
with biologic agents were more likely to experience
improvement in arthritic complaints compared to
placebo [PsARC RR 0.32 favoring treatment 95% CI
(0.25-0.40) P

254 Manahan SE T and Reyes BH D
for psoriasis. Patients who do not improve or
worsen following initial therapy are candidates for
disease modifiying anti-rheumatic drugs (DMARDs).
Available agents include gold salts, anti-malarial
agents, azathioprine, sulfasalazine and methotrexate.
Of these, methotrexate is the standard drug treatment
due to its efficacy for both articular and dermatologic
manifestations of psoriatic arthritis.
The meta-analysis by Jones, Crotty and Brooks
(Cochrane 2000) concluded that intravenous
methotrexate and sulfasalazine are effective therapies
for psoriatic arthritis and based on articular
assessments- joint counts, acute phase reactants,
pain and global assessment of disease activity, with
no reference to effects on skin psoriasis. Traditional
studies have monitored patient response in terms of
the rheumatic condition mainly clinical assessment
of joint inflammation and damage as well as
radiographic evaluations. Composite indices used to
monitor patients for treatment response, such as the
Psoriatic Arthritis Response Criteria (PsARC) and the
American College of Rheumatology Response Criteria
(ACR-N) are primarily based on joint parameters.
Responses to DMARDs are extrapolated from trials
involving patients with psoriasis, not necessarily
manifesting with joint problems.
With the entry of biologic response modifiers,
also known as biologic agents or biologics, into
the treatment of psoriatic arthritis, both skin and
joint manifestations are measured simultaneously
in clinical trials. Their use in the management of
psoriatic arthritis has been the focus of much interest
in the recent years.
OBJECTIVE
The systematic review aims to evaluate the
safety and efficacy of the locally available biologic
agents - infliximab (INF) and etanercept (ETN)
in the treatment of articular and dermatologic
manifestations of psoriatic arthritis.
Criteria for Considering Studies for this Review
Types of Studies
For inclusion in the meta-analysis, randomized
clinical trials with at least two treatment groups were
included. Concomitant therapy with methotrexate,
the standard drug used in the treatment of psoriatic
arthritis, should be permitted in the treatment
groups.
Types of Patients
Trials were included if patients enrolled were
clinically diagnosed with active psoriatic arthritis and
at least 18 years of age.
Types of Interventions
Studies comparing infliximab and etanercept
were included in the meta-analysis.
Types of Outcomes Measured
Included trials assessed outcome measures for
both psoriasis and psoriatic arthritis. Assessment of
the rheumatic condition were in the form of any of
the composite outcome measures used in previous
psoriatic arthritis studies Psoriatic Arthritis
Response Criteria (PsARC), American College of
Rheumatology Response Criteria (ACR 20, ACR 50
or ACR 70). The Psoriatic Arthritis Response Criteria
(PsARC), developed as an outcome measure for
research includes four measurements of the articular
component of the disease the swollen joint count
(SJC), the tender joint count (TJC), physician
global assessment of disease activity and patient
global assessment of disease activity. The American
College of Rheumatology Response Criteria (ACR-
N) which was originally developed for trials on
Rheumatoid Arthritis but its use has been extended
to evaluation of other inflammatory arthritides
consists of improvement in the SJC, the TJC,
pain, disability as evaluated by health assessment
questionnaires, acute phase reactants, physician
global assessment of disease activity and patient
global assessment of disease activity. Measurements
for psoriasis were in the form of the Psoriasis Area
and Severity Index (PASI 75) - which is the proportion
of patients achieving a 75 percent improvement in
psoriasis activity from baseline and assessments
of prospectively identified skin lesions (target lesion
evaluation, dermatologistÊs static global assessment
of target lesions -percent clear or almost clear).
Search Method for Identification of Studies
A MEDLINE Search was performed to identify
randomized placebo controlled clinical trials or
systematic reviews on the efficacy of infliximab and
etanercept in the treatment of psoriatic arthritis from
1966 - 2006. This was supplemented by citation
tracking in published bibliographies and conference
proceedings. The Cochrane Database of Systematic

Locally Available Biologic Agents in the Treatment of Psoriatic Arthritis 255
Reviews was likewise searched for existing studies on
biologic agents and psoriatic arthritis. The following
terms were used in the literature search: biologic
agents, etanercept, infliximab, psoriasis, psoriatic
arthritis, randomized controlled trials.
RESULTS
Nine journal articles were identified. Of these,
five were excluded: four published results of post-hoc
analysis of the main studies presenting outcomes
measures other than arthritis response criteria and
dermatologic improvement and one study by Ritchlin,
C (2006) could not be retrieved. [Table 1] The studies
included in the meta-analysis were 4 randomized
controlled clinical trials IMPACT 1, IMPACT 2,
Mease 2000 and Mease 2004 which had a total of
569 patients randomized to receive either placebo or
biologic agents.
Table I. Characteristics of Included Trials
Methods Participants Intervention Outcomes
IMPACT 1 Randomized 104 patients Infliximab 1. ACR 20, 50
Double Blind with active PsA 5mg/kg IV vs and 70 at
Placebo who had failed Placebo at week 16
Controlled at least weeks 2. PASI75 at
Trial 1 DMARD O, 2, 6, 14 week 16
3. PsARC at
week 16
4. DAS28
IMPACT 2 Randomized 200 adult Infliximab 1. ACR 20, 50
Double Blind patients with 5mg/kg IV vs and 70 at
Placebo active PsA Placebo at week 24
Controlled weeks 2. PsARC at
Trial O, 2, 6, 22 week 24
3. PASI75 at
week 24
Mease 2000 Randomized 60 adult Etanercept 1. PsARC at
Double Blind patients with 25mg sc week 12
Placebo active PsA 2x/week vs 2. ACR 20, 50
Controlled Placebo sc and 70 at
Trial for 12 weeks week 12
3. PASI75 at
week 12
Mease 2004 Randomized 205 adult Etanercept 1. ACR 20, 50
Double Blind patients with 25mg sc and 70 at
Placebo active PsA 2x/week vs week 24
Controlled Placebo sc 2. PsARC at
Trial for 24 weeks week 24
3. PASI75 at
week 24
The quality of the studies were evaluated
independently by three assessors (SETM, BHMR
and JOG) using the Quality Scale for Meta-analytic
reviews provided by the UP-PGH Department of
Medicine. IMPACT1 and IMPACT2 were evaluated to
be good-quality studies by all three assessors. While
the two trials by Mease, et al were assessed to be
studies of fair quality (Table 2).
Table II. Quality Assessment of Included Trials
Selection Performance Exclusion Detection Over-all
IMPACT 1 A A A A A
IMPACT 2 A A A A A
Mease 2000 B A A A B
Mease 2004 B A A A B
Table III. Summary of Comparisons Between Treatment and
Placebo Groups
Comparisons Studies Participants Statistical method Effect size
or outcome
01 PsARC 4 519 RR (fixed), 95% CI 3.06[2.44, 3.85]
02 PASI75 4 504 RR (fixed), 95% CI 17.69[7.88,39.70]
03 ACR 20 4 565 RR (fixed), 95% CI 4.96[3.59,6.86]
04 ACR 50 3 364 RR (fixed), 95% CI 16.78[6.62,42.49]
05 ACR 70 3 364 RR (fixed), 95% CI 17.50[4.27,71.73]
06 Serious AE 4 610 RR (fixed), 95% CI 0.84[0.43,1.65]
07 Adverse 12 1658 RR (fixed), 95% CI 1.37[1.07,1.76]
Events
All studies recruited adult patients (Aged 18-70
years) who were clinically diagnosed with Psoriatic
Arthritis and assessed to have active disease. For the
studies by Mease, disease activity was determined
by the presence of > 3 swollen and > 3 tender joints
at the time of study enrolment. While IMPACT used
a different set of criteria - at least five swollen and
five tender joints and at least one of the following
parameters: CRP > 15 mg/L, ESR > 28 mm/Hr or
morning stiffness lasting at least 45 minutes before
maximal improvement. Among the patients included
by the above criteria, only patients with at least
a baseline PASI score of 2.5 were included in the
evaluation of dermatologic response to biologic
agents.
Methotrexate was allowed as concomitant
disease modifying anti-rheumatic drug (DMARD)
in all four trials. Other DMARDs were discontinued
at least four weeks before the start of the study
in the studies by Mease. DMARDs other than
methotrexate such as leflunomide, sulfasalazine,
hydroxychloroquine, penicillamine and azathioprine

256 Manahan SE T and Reyes BH D
were allowed in IMPACT 1 and IMPACT 2. Stable
doses of corticosteroids were allowed in all four
trials. Treatments for psoriasis (oral retinoids, topical
vitamin A or D analog preparations and anthralin)
were not allowed. However, topical therapies were
permitted on the scalp, axillae and groin only as this
did not affect PASI evaluation.
Both studies by Mease involved the administration
of ETN 25 mg subcutaneously twice weekly given for
12 or 24 weeks. INF was given at a dose of 5 mg/Kg
body weight at weeks 0, 2, 6 and every 8 weeks
thereafter for 16 or 24 weeks.
Efficacy of Biologic Agents on the Rheumatic
Disease
For all outcome measures, treatment with
biologic agents was more effective than placebo in
treating psoriatic arthritis. Patients receiving biologic
agents were three times more likely to achieve the
Psoriatic Arthritis Response Criteria [RR 3.06 95% CI
(2.44, 3.85) p-value

Locally Available Biologic Agents in the Treatment of Psoriatic Arthritis 257
Fig. 2. Outcome of Treatment Measured by ACR 20
Fig. 2. Outcome of Treatment Measured by ACR 20

258 Manahan SE T and Reyes BH D
Fig. 4.
Adverse Events

Locally Available Biologic Agents in the Treatment of Psoriatic Arthritis 259
CONCLUSIONS
Locally available biologic agents are effective in
the treatment of both psoriasis and psoriatic arthritis.
Articular and cutaneous manifestations improved
similarly among patients treated with INF and ETN.
Adverse events occurred more frequently among
biologics-treated patients, mostly related to the drug
administration. The difference in the frequency of
serious adverse events between groups did not reach
statistical significance.
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