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K. de Vlam, R. J. U. Lories, Efficacy, effectiveness and safety of etanercept in monotherapy for refractory psoriatic arthritis: a 26-week observational study, Rheumatology, Volume 45, Issue 3, March 2006, Pages 321–324, https://doi.org/10.1093/rheumatology/kei153
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Abstract
Objectives. To investigate the efficacy, effectiveness and safety of etanercept, a soluble tumour necrosis factor-α receptor, in a prospective observational cohort of patients with refractory psoriatic arthritis and polyarticular involvement.
Methods. Twenty patients with psoriatic arthritis refractory to conventional anti-rheumatic drugs were treated with etanercept 25 mg subcutaneously twice a week for 26 weeks. Efficacy and safety were recorded at weeks 2, 6, 10, 16, 20 and 26. Effectiveness, defined as clinical remission, reduction of 50% in clinical parameters and concomitant NSAID use, was evaluated at 26 weeks.
Results. Etanercept therapy was efficacious in this cohort as 85% of the patients met the Psoriatic Arthritis Response Criterion at week 26. Effectiveness of etanercept for the individual patient was demonstrated, since at least 50% of the patients had a 90 and 85% improvement in swollen and tender joint count, respectively, and a 71% improvement in the Health Assessment Questionnaire at week 26. Four patients showed complete remission and NSAIDs were stopped in 10/15 patients. The most common adverse events were upper respiratory tract infections. Interestingly, in two patients psoriasis worsened during the study, unrelated to the course of arthritis. The administration of etanercept was interrupted in three patients for adverse events: one septic bursitis, one myocardial infarction and one tooth abscess. After resolution of the adverse events, etanercept was successfully reintroduced.
Conclusions. Etanercept in monotherapy is efficacious, effective and safe in the majority of patients with refractory psoriatic arthritis.
Current therapies for psoriatic arthritis (PsA) include anti-rheumatic drugs such as methotrexate, sulphasalazine, leflunomide and cyclosporin [1, 2]. Many patients show an insufficient response to these treatments, as measured by persistent clinical signs and disease activity [2]. The efficacy of etanercept on peripheral articular involvement in PsA was demonstrated in two randomized clinical trials (RCTs) [3, 4].
Efficacy defines the beneficial effect of a specific intervention under controlled conditions, such as an RCT, based on pharmacological effects. Effectiveness defines the effect of the intervention when used in daily clinical practice and includes patient, health system and societal characteristics [5]. Effectiveness can be considered at the level of the community as well as the individual. For the individual, the goal of therapy is remission and recovery. The value of RCTs in determining effectiveness is a matter of debate. Cohort studies and retrospective chart reviews might represent real-life situations more closely than RCTs [6]. We evaluated safety, efficacy and individual effectiveness of etanercept in 20 patients with refractory PsA in an open study.
Methods
Study protocol
The study was a single-centre, open-label, therapeutic and observational trial. The trial was approved by the local ethics committee. All patients provided written informed consent.
Patients
The study included 20 patients with refractory psoriatic arthritis (15 men, 5 women) recruited consecutively at the out-patient clinic of the rheumatology department of the University Hospitals Leuven. PsA was defined as mono-, oligo- or polyarthritis, in the presence of psoriatic skin involvement or nail changes with absence of rheumatoid nodules. Refractory was defined as persistent articular pain and swelling in three or more joints and unsatisfactory response to at least one of the following anti-rheumatic drugs: methotrexate, sulphasalazine and cyclosporin. Axial involvement was not taken into account for inclusion and follow-up. The mean (s.d.) disease duration of PsA in the entire cohort was 10.5 (6.3) yr (range 2.7–25.4) and the mean disease duration (s.d.) of psoriasis was 21.8 (13.7) yr (range 4.8–55.6). Erosive disease of hands or feet was present in 15 of the 20 patients.
Patients received etanercept (Enbrel®), a soluble TNF-α receptor (Wyeth Pharmaceuticals, Louvain-la-Neuve, Belgium) at 25 mg subcutaneously twice weekly. Eligible patients were screened for latent or active tuberculosis using purified protein derivative and chest X-ray. Patients had not received any TNF-α-blocking agent.
The mean (s.d.) number of previously used conventional anti-rheumatic drugs was 3 (1.3) (range 1–6). All patients had received methotrexate in the past. At screening, 12 patients were still on conventional anti-rheumatic drugs. After stopping the anti-rheumatic drug(s) for at least 4 weeks, 3/12 patients showed a flare, as defined by an increase in the number of swollen joints of at least 50%. At the time of entry, all anti-rheumatic drugs had been stopped for at least 4 weeks and were not allowed during the 26-week study period. At the time of inclusion, 15 patients used NSAIDs and five patients were on corticosteroid treatment. Stable dose of steroids (≤10 mg prednisolone equivalent/day) and NSAIDs were allowed during the 26-week study period. Topical treatment but not phototherapy for psoriasis was permitted if started at least 4 weeks before inclusion.
Disease activity
At baseline and weeks 2, 6, 10, 16, 20 and 26, the physician recorded swollen (76-joint count) and tender joint count, number of fingers or toes with dactylitis, the Psoriasis Area and Severity Index (PASI), physician global assessment and physician disease activity (Likert scale, range 1–5). The Health Assessment Questionnaire (HAQ) and Patient Assessment of Pain and Morning Stiffness in peripheral joints (visual analogue scale, VAS) were assessed. Response to the treatment was evaluated with the Psoriatic Arthritis Response Criterion (PsARC) [7] and the ACR response criteria. Clinical remission was defined by the physician as absence of swollen and tender joints. Laboratory measurements included erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).
Safety
At each visit, adverse events were noted and biochemical and peripheral blood analyses were performed. Serious adverse events prompted interruption of therapy at the discretion of the physician. Antinuclear antibodies were determined at baseline and week 26.
Statistical analysis
Differences between baseline, week 6 and 26 were analysed using the Wilcoxon paired sign rank test. A difference of 0.25 in HAQ was considered clinically meaningful.
Results
Efficacy
Clinical improvement was apparent from week 2, increased until week 4 and persisted. Sixteen and 17/20 patients achieved the PsARC at weeks 6 and 26, respectively (Table 1). At week 26, ACR20 and ACR50 responses were met by 16/20 and 3/20 patients respectively (Table 1). The numbers of swollen and tender joints decreased in all but two patients. Reductions in swollen and tender joints were statistically significant at weeks 6 and 26 (Table 1). Morning stiffness and joint pain were significantly reduced. Similarly, disease activity assessments significantly improved at weeks 6 and 26.
. | Start . | Week 6 . | Week 26 . | Significancea . |
---|---|---|---|---|
Activity index | ||||
ACR 20 response: number (%) | 14/20 (70) | 16/20 (80) | ||
ACR 50 response: number (%) | 7/20 (35) | 3/20 (15) | ||
ACR 70 response: number (%) | 3/20 (15) | 0/20 (0) | ||
PsARC: number (%) | 16/20 (80) | 17/20 (85) | ||
Measurements | ||||
Swollen joints | 10.2 ± 6.0 | 3.3 ± 4.2 | 2.9 ± 4.8 | P<0.001 |
Tender joints | 13.1 ± 9.3 | 4.6 ± 6.1 | 5.0 ± 7.2 | P<0.001 |
Dactylitisb | 1.2 ± 2.4 | 0.25 ± 1.1 | 0.25 ± 0.9 | P<0.05 |
Morning stiffness (min) | 52.7 ± 26.7 | 23.7 ± 26.5 | 17.0 ± 22.5 | P = 0.001 |
Patient disease activity (VAS, mm) | 55.0 ± 23.2 | 28.1 ± 25.6 | 23.2 ± 21.8 | P<0.01 |
Physician disease activity (Likert scale) | 3.7 ± 0.7 | 2.3 ± 1.0 | 1.6 ± 0.6 | P<0.001 |
Pain peripheral joints (VAS, mm) | 57.0 ± 23.4 | 24.6 ± 24.4 | 18.1 ± 21.7 | P<0.001 |
Physician global assessment (Likert scale) | 3.5 ± 0.6 | 2.2 ± 0.9 | 1.8 ± 0.7 | P<0.01 |
Patient global assessment (Likert scale) | 3.1 ± 0.7 | 2.2 ± 0.7 | 2.2 ± 0.7 | P<0.01 |
PASI | 2.7 ± 2.1 | 1.7 ± 1.4 | 1.9 ± 2.7 | P<0.05 |
CRP (mg/l) | 38.5 ± 32.1 | 19.9 ± 30.5 | 8.0 ± 7.4 | P<0.001 |
ESR (mm/h) | 41.1 ± 28.0 | 18.4 ± 20.4 | 13.2 ± 12.7 | P<0.001 |
Health Assessment Questionnaire | 1.32 ± 0.58 | 0.74 ± 0.72 | 0.61 ± 0.63 | P<0.01 |
. | Start . | Week 6 . | Week 26 . | Significancea . |
---|---|---|---|---|
Activity index | ||||
ACR 20 response: number (%) | 14/20 (70) | 16/20 (80) | ||
ACR 50 response: number (%) | 7/20 (35) | 3/20 (15) | ||
ACR 70 response: number (%) | 3/20 (15) | 0/20 (0) | ||
PsARC: number (%) | 16/20 (80) | 17/20 (85) | ||
Measurements | ||||
Swollen joints | 10.2 ± 6.0 | 3.3 ± 4.2 | 2.9 ± 4.8 | P<0.001 |
Tender joints | 13.1 ± 9.3 | 4.6 ± 6.1 | 5.0 ± 7.2 | P<0.001 |
Dactylitisb | 1.2 ± 2.4 | 0.25 ± 1.1 | 0.25 ± 0.9 | P<0.05 |
Morning stiffness (min) | 52.7 ± 26.7 | 23.7 ± 26.5 | 17.0 ± 22.5 | P = 0.001 |
Patient disease activity (VAS, mm) | 55.0 ± 23.2 | 28.1 ± 25.6 | 23.2 ± 21.8 | P<0.01 |
Physician disease activity (Likert scale) | 3.7 ± 0.7 | 2.3 ± 1.0 | 1.6 ± 0.6 | P<0.001 |
Pain peripheral joints (VAS, mm) | 57.0 ± 23.4 | 24.6 ± 24.4 | 18.1 ± 21.7 | P<0.001 |
Physician global assessment (Likert scale) | 3.5 ± 0.6 | 2.2 ± 0.9 | 1.8 ± 0.7 | P<0.01 |
Patient global assessment (Likert scale) | 3.1 ± 0.7 | 2.2 ± 0.7 | 2.2 ± 0.7 | P<0.01 |
PASI | 2.7 ± 2.1 | 1.7 ± 1.4 | 1.9 ± 2.7 | P<0.05 |
CRP (mg/l) | 38.5 ± 32.1 | 19.9 ± 30.5 | 8.0 ± 7.4 | P<0.001 |
ESR (mm/h) | 41.1 ± 28.0 | 18.4 ± 20.4 | 13.2 ± 12.7 | P<0.001 |
Health Assessment Questionnaire | 1.32 ± 0.58 | 0.74 ± 0.72 | 0.61 ± 0.63 | P<0.01 |
All data are given as mean ± s.d. aSignificance levels were calculated for week 26 compared with week 0; bmean number of fingers with dactylitis.
. | Start . | Week 6 . | Week 26 . | Significancea . |
---|---|---|---|---|
Activity index | ||||
ACR 20 response: number (%) | 14/20 (70) | 16/20 (80) | ||
ACR 50 response: number (%) | 7/20 (35) | 3/20 (15) | ||
ACR 70 response: number (%) | 3/20 (15) | 0/20 (0) | ||
PsARC: number (%) | 16/20 (80) | 17/20 (85) | ||
Measurements | ||||
Swollen joints | 10.2 ± 6.0 | 3.3 ± 4.2 | 2.9 ± 4.8 | P<0.001 |
Tender joints | 13.1 ± 9.3 | 4.6 ± 6.1 | 5.0 ± 7.2 | P<0.001 |
Dactylitisb | 1.2 ± 2.4 | 0.25 ± 1.1 | 0.25 ± 0.9 | P<0.05 |
Morning stiffness (min) | 52.7 ± 26.7 | 23.7 ± 26.5 | 17.0 ± 22.5 | P = 0.001 |
Patient disease activity (VAS, mm) | 55.0 ± 23.2 | 28.1 ± 25.6 | 23.2 ± 21.8 | P<0.01 |
Physician disease activity (Likert scale) | 3.7 ± 0.7 | 2.3 ± 1.0 | 1.6 ± 0.6 | P<0.001 |
Pain peripheral joints (VAS, mm) | 57.0 ± 23.4 | 24.6 ± 24.4 | 18.1 ± 21.7 | P<0.001 |
Physician global assessment (Likert scale) | 3.5 ± 0.6 | 2.2 ± 0.9 | 1.8 ± 0.7 | P<0.01 |
Patient global assessment (Likert scale) | 3.1 ± 0.7 | 2.2 ± 0.7 | 2.2 ± 0.7 | P<0.01 |
PASI | 2.7 ± 2.1 | 1.7 ± 1.4 | 1.9 ± 2.7 | P<0.05 |
CRP (mg/l) | 38.5 ± 32.1 | 19.9 ± 30.5 | 8.0 ± 7.4 | P<0.001 |
ESR (mm/h) | 41.1 ± 28.0 | 18.4 ± 20.4 | 13.2 ± 12.7 | P<0.001 |
Health Assessment Questionnaire | 1.32 ± 0.58 | 0.74 ± 0.72 | 0.61 ± 0.63 | P<0.01 |
. | Start . | Week 6 . | Week 26 . | Significancea . |
---|---|---|---|---|
Activity index | ||||
ACR 20 response: number (%) | 14/20 (70) | 16/20 (80) | ||
ACR 50 response: number (%) | 7/20 (35) | 3/20 (15) | ||
ACR 70 response: number (%) | 3/20 (15) | 0/20 (0) | ||
PsARC: number (%) | 16/20 (80) | 17/20 (85) | ||
Measurements | ||||
Swollen joints | 10.2 ± 6.0 | 3.3 ± 4.2 | 2.9 ± 4.8 | P<0.001 |
Tender joints | 13.1 ± 9.3 | 4.6 ± 6.1 | 5.0 ± 7.2 | P<0.001 |
Dactylitisb | 1.2 ± 2.4 | 0.25 ± 1.1 | 0.25 ± 0.9 | P<0.05 |
Morning stiffness (min) | 52.7 ± 26.7 | 23.7 ± 26.5 | 17.0 ± 22.5 | P = 0.001 |
Patient disease activity (VAS, mm) | 55.0 ± 23.2 | 28.1 ± 25.6 | 23.2 ± 21.8 | P<0.01 |
Physician disease activity (Likert scale) | 3.7 ± 0.7 | 2.3 ± 1.0 | 1.6 ± 0.6 | P<0.001 |
Pain peripheral joints (VAS, mm) | 57.0 ± 23.4 | 24.6 ± 24.4 | 18.1 ± 21.7 | P<0.001 |
Physician global assessment (Likert scale) | 3.5 ± 0.6 | 2.2 ± 0.9 | 1.8 ± 0.7 | P<0.01 |
Patient global assessment (Likert scale) | 3.1 ± 0.7 | 2.2 ± 0.7 | 2.2 ± 0.7 | P<0.01 |
PASI | 2.7 ± 2.1 | 1.7 ± 1.4 | 1.9 ± 2.7 | P<0.05 |
CRP (mg/l) | 38.5 ± 32.1 | 19.9 ± 30.5 | 8.0 ± 7.4 | P<0.001 |
ESR (mm/h) | 41.1 ± 28.0 | 18.4 ± 20.4 | 13.2 ± 12.7 | P<0.001 |
Health Assessment Questionnaire | 1.32 ± 0.58 | 0.74 ± 0.72 | 0.61 ± 0.63 | P<0.01 |
All data are given as mean ± s.d. aSignificance levels were calculated for week 26 compared with week 0; bmean number of fingers with dactylitis.
Skin disease was mild to moderate at baseline. At week 26, a small but significant reduction in PASI was found (Table 1). Two out of 20 patients reached a PASI75 response. In two patients psoriasis worsened but this was unrelated to the joint disease. Disability, measured by HAQ, improved between baseline and week 26 (Table 1). Both ESR and CRP decreased significantly (Table 1).
Effectiveness
The median change in a specific variable represents the minimal improvement obtained by at least 50% of the patients (Fig. 1). At least 50% of the patients experienced 83 and 79% reduction in morning stiffness and pain, and 85 and 90% reduction in swollen and tender joints. Patient-scored disease activity, ESR and CRP were reduced by 79, 73 and 80%, respectively, in at least half of the patients. The range of individual data points indicates that not every patient showed a clinical response. The swollen and tender joint count did not decrease in two patients. One patient developed dactylitis during the study. All patients showed a decrease in ESR and CRP.
Four patients were in remission. Dactylitis disappeared in 6/7 patients. The use of NSAIDs and analgesics was significantly reduced at week 26. NSAIDs were stopped in 10/15 patients and paracetamol was discontinued in all patients.
The degree of disability in this cohort of PsA patients, measured by the HAQ, was substantial at the time of inclusion (range 0.5–2.5). Four out of 20 patients had no significant improvement in the HAQ at week 26. Sixteen patients had a major improvement within the first 6 weeks and one patient had a worsening. In seven patients the HAQ improved further during the treatment period. In five patients there was a slight worsening of HAQ between weeks 6 and 26 but the improvement was still substantial compared with baseline. All ACR20 responders showed an improvement in HAQ of at least 0.5 at week 26. In three out of four ACR20 non-responders the HAQ worsened or remained unchanged.
Adverse events
Five patients developed at least one episode of upper respiratory infection. One patient developed severe headache, treated with paracetamol. At entry, one patient was positive for antinuclear antibodies. Three patients developed antinuclear antibodies at week 26. None of these had symptoms of induced autoimmune disease. Before the start of the study, latent tuberculosis was diagnosed in one patient. He received prophylaxis with isoniazid for 9 months. After 4 weeks, etanercept was introduced without problems. In three patients, treatment was temporarily interrupted due to a serious adverse event. These serious adverse events were seemingly unrelated to the therapy: one septic bursitis, one tooth abscess and one myocardial infarction. These conditions were treated; etanercept was interrupted for 4 weeks and reintroduced without problems.
Discussion
We confirm the efficacy of etanercept in the treatment of refractory polyarticular PsA [3, 4]. In addition, this open study evaluated effectiveness at the individual level. This is demonstrated by the number of clinical remissions, reduction of concomitant medication, side-effects, reintroduction of the therapy after temporary withdrawal and reduction of risk factors for joint damage. The absence of ACR70 responses at week 26 appears in contrast with the clinical remission in four patients. ACR response criteria were developed for RA and despite widespread use they have not been validated in PsA [3, 4, 8, 9]. ACR response criteria should be used cautiously in PsA since at least some characteristics of inflammation, disability and pain are different [10, 11]. In daily practice patients are concerned with symptoms and signs, and cure of the disease. Data from RCTs do not provide probabilities of remission or meaningful improvement. Percentages of improvement in specific features experienced by 25, 50 and 75% of the patients are illustrated by medians and quartiles.
Reduction of risk factors for disease progression is an additional relevant outcome parameter for the individual patient. Each inflamed joint represents a 4% risk of structural damage at the subsequent visit [12], with dactylitis and persistent joint swelling as negative predictors [13]. In this open study the numbers of fingers or toes with dactylitis were significantly reduced.
Side-effects are major determinants of the therapeutic index, and thus of the effectiveness of therapies. In this cohort the frequency of minor adverse events was comparable to published data from the RCTs [3, 4]. Three patients developed antinuclear antibodies without any symptoms of autoimmune disease. The appearance of these antibodies is usually considered as a minor adverse event, but long-term observational studies in SLE patients revealed that the autoantibodies may appear several years before the first clinical symptom [14]. Further observation is needed since the study was too short to assess the risk of therapy-induced autoimmunity.
Etanercept improved psoriasis in all but two patients. These two patients had a flare of the skin eruptions. Despite the flare, etanercept was continued. It is unclear whether the psoriasis in these patients was unresponsive to etanercept and must be considered as an unrelated flare or whether the use of etanercept induced or worsened skin lesions, as new-onset psoriasis after TNF blockade has been reported in SpA patients [15]. Finally, allergic skin lesions caused by etanercept have been described in RA treated with etanercept [16].
Three patients developed a serious adverse event with temporary treatment interruption. Two patients had a serious bacterial infection and needed antibiotic treatment. The infections were not caused by intracellular pathogens. Although to date it is clear that the use of TNF-α-blocking agents is associated with an increased risk of infection caused by intracellular pathogens, it is not clear whether there is an increased overall risk of infection. After resolution, etanercept was reintroduced without relapse. In RCTs, reintroduction of the treatment after a serious adverse event, regardless of any possible relationship to the drug, is not done. Our data suggest that some types of infection do not necessitate a definitive stop of treatment.
In conclusion, a beneficial response was found in patients with refractory psoriatic arthritis throughout a 26-week period in terms of both efficacy and effectiveness.
The authors wish to thank Mrs Sara Verpoest for data management and Prof. Frank Luyten and Rene Westhovens for critical reading of the manuscript. R.J.U.L. has received a post-doctoral fellowship from the Fund for Scientific Research Flanders.
K.deV. received a medical school grant from Wyeth Lederle.
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