Reviews From People Who Have Been on Sulsfazine for at Least 6 Months
Ann Rheum Dis. 2009 Jul; 68(7): 1146–1152.
Extended written report
Efficacy, prophylactic and patient-reported outcomes of combination etanercept and sulfasalazine versus etanercept lone in patients with rheumatoid arthritis: a double-blind randomised 2-twelvemonth written report
B Combe
1Service d'Immuno-Rhumatologie, Hopital Lapeyronie, Montpellier, France
C Codreanu
2Centrul Metodologic de Reumatologie, Bucuresti, Romania
U Fiocco
threeCattedra due east Divisione di Reumatologia, Policlinico Universitario, Padova, Italy
M Gaubitz
4Medical Clinic B Westfalian-Wilhelms-Univ, Munster, Germany
P P Geusens
fiveBiomedical Enquiry Center, University Hasselt, Hasselt, Belgium
6Department of Internal Medicine/Rheumatology, University Maastricht, Maastricht, Holland
T K Kvien
viiDepartment of Rheumatology, Diakonhjemmets Hospital, Oslo, Norway
K Pavelka
viiiEstablish of Rheumatology, Praha, Czech Republic
P N Sambrook
9Kolling Institute, Academy of Sydney, Sydney, Commonwealth of australia
J S Smolen
102nd Department of Medicine, Krankenhaus Lainz and Department of Rheumatology, Internal Medicine III, Medical Academy of Vienna, Vienna, Republic of austria
R Khandker
11Wyeth Inquiry, Collegeville, Pennsylvania, USA
A Singh
xiWyeth Research, Collegeville, Pennsylvania, USA
J Wajdula
xiWyeth Research, Collegeville, Pennsylvania, USA
South Fatenejad
11Wyeth Research, Collegeville, Pennsylvania, USA
Abstruse
Objective:
To determine the efficacy and safe of etanercept and etanercept plus sulfasalazine versus sulfasalazine in patients with rheumatoid arthritis (RA) despite sulfasalazine therapy.
Methods:
Patients were randomly assigned to etanercept (25 mg twice weekly; sulfasalazine was discontinued at baseline), etanercept plus sulfasalazine (unchanged regimen of 2–iii g/24-hour interval) or sulfasalazine in a double-blind, randomised, 2-year study in adult patients with agile RA despite sulfasalazine therapy. Efficacy was assessed using the American Higher of Rheumatology criteria, disease activity scores (DAS) and patient-reported outcomes (PRO).
Results:
Demographic variables and baseline disease characteristics were comparable among treatment groups; mean DAS v.1, 5.2 and 5.i for etanercept (north = 103), etanercept plus sulfasalazine (northward = 101) and sulfasalazine (north = 50), respectively. Withdrawal due to lack of efficacy was highest with sulfasalazine (26 (52%) vs 6 (6%) for either etanercept group, p<0.001). Patients receiving etanercept or etanercept plus sulfasalazine had a more rapid initial response, which was sustained at 2 years, than those receiving sulfasalazine: mean DAS two.8, 2.v versus 4.5, respectively (p<0.05); ACR 20 response was accomplished past 67%, 77% versus 34% of patients, respectively (p<0.01) Overall, PRO followed a similar blueprint; a clinically meaning improvement in health assessment questionnaire was achieved past 76%, 78% versus 40% of patients, respectively (p<0.01). Commonly reported adverse events occurring in the etanercept groups were injection site reactions and pharyngitis/laryngitis (p<0.01).
Decision:
Etanercept and etanercept plus sulfasalazine are efficacious for the long-term management of patients with RA. The improver of etanercept or commutation with etanercept should exist considered as treatment options for patients not adequately responding to sulfasalazine.
Several options including disease-modifying antirheumatic drugs (DMARD), such as methotrexate and sulfasalazine and anti-neoplasm necrosis factor (TNF) agents such as etanercept, infliximab and adalimumab, are available for the treatment of patients with rheumatoid arthritis (RA). For patients with an inadequate response to DMARD therapy, ane recommended therapeutic option is anti-TNF therapy either added to or as a replacement for the existing regimen.ane two
In clinical studies, anti-TNF agents are highly effective and more often than not well tolerated when added to existing treatment regimens for patients with active RA who do not answer to a DMARD such as methotrexate3 – 8 or sulfasalazine, another ofttimes prescribed DMARD. However, in that location are very few studies assessing the benefits and risks of adding an anti-TNF agent to existing sulfasalazine therapy for patients with RA inadequately responding to sulfasalazine.nine – 12 Combe et al 10 previously reported on the 6-month acting results from the current study; the half dozen-month results showed that etanercept, in combination with or in place of sulfasalazine, resulted in substantial improvements in RA.x Both etanercept regimens were well tolerated.10
This ii-yr report provides data on the long-term therapeutic response including patient-reported outcomes (PRO) and safety of etanercept, added to or in place of sulfasalazine, versus sulfasalazine lone in patients with active RA, despite stable sulfasalazine therapy.
PATIENTS AND METHODS
Report blueprint and patients
This was a 2-year randomised, double-blind, double-dummy, multicentre study in patients with active RA who had an inadequate response to sulfasalazine.
Eligible patients were 18 years of age or older with illness duration of 20 years or less with active developed-onset RA (functional form I–III), defined as six or more swollen and 10 or more than tender joints and 1 or more than of the following: erythrocyte sedimentation rate (ESR; Westergren) ⩾28 mm at the end of the first hour; serum C-reactive protein ⩾20 mg/fifty and morning stiffness for 45 minutes or longer. Patients must accept received stable doses of sulfasalazine (2–iii yard daily) for 4 months or more before screening. Details of the exclusion/inclusion criteria take been published previously.10
This study was conducted in accord with the International Briefing on Harmonisation guidelines for skilful clinical practice in the European Community and the Announcement of Helsinki. Ethics committees of the participating centres approved the study protocol. Patients gave written informed consent before participating in the report.
Handling
Patients were randomly assigned to one of three treatment groups (in a 2 : 1 : two ratio): etanercept (etanercept 25 mg by subcutaneous injection twice weekly plus placebo); sulfasalazine (sulfasalazine 2, two.5, or 3 one thousand daily plus placebo) or combination (etanercept plus sulfasalazine) therapy. Patients in the etanercept group discontinued sulfasalazine at baseline.
Clinical assessment
Response to therapy was assessed at baseline and at weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 56, 68, 80, 92 and 104. The main efficacy endpoint, the percentage of patients achieving xx% or greater improvement, as defined by American College of Rheumatology (ACR) 20 criteria,13 at week 24, was reported previously.
Key efficacy assessments included ACR response rates (ACR 20, ACR fifty and ACR 70), disease activity score (DAS) and morning stiffness in minutes. Assessments were based on ACR criteria and DAS as previously reported.10
PRO measures included the wellness assessment questionnaire (HAQ) disability alphabetize,xiv 15 EQ-5D visual analogue calibration (VAS),16 patient global assessment of overall RA activity (PGAD) and patient general health assessment (GHVAS). The PGAD is recorded on an xi-bespeak numeric rating scale in which a score of zero ways no disease activity and a score of 10 means extreme disease activity. For the GHVAS, patients responded to the question "How do you feel concerning your arthritis?" by marking the appropriate position on a 100-mm VAS ranging from "very well" to "extremely bad." For both PGAD and GHVAS, lower scores imply better health.
To determine whether PRO closely reflected clinical improvements, the report examined the human relationship between changes in wellness status measures or disability and changes in disease action. Pearson correlation analysis was performed betwixt the iv PRO measures (HAQ, EQ-5D VAS, PGAD and GHVAS) and a measure of illness activeness, DAS.
Safety assessments
Safety assessments were based on reports of adverse events and results of routine physical examinations and laboratory determinations. An event was considered to be a treatment-emergent adverse event (TEAE) if it occurred during the written report or if the severity or frequency of a preexisting result increased during the study. A serious agin event (SAE) included any issue resulting in death, hospitalisation or cancer. An infection was a serious infection if reported as an SAE.
Testing for antinuclear, anti-double-stranded Deoxyribonucleic acid, anti-etanercept and anti-cardiolipin antibodies was performed at screening and at specified visits.
The incidence of malignancies in this study was compared with the incidence estimated from the US National Cancer Plant's (NCI) surveillance, epidemiology, and end results (SEER) database.17 The historic period and sex-specific incidence rates for cancer from the SEER database were practical to the exposure in this study.
Statistical analysis
The ACR 20, ACR 50 and ACR 70 response rates were analysed using the Mantel–Haenszel χii test, stratified by report centre. Changes from baseline in components of the ACR and PRO (HAQ disability index, EQ-5D, GHVAS and PGAD) were analysed with a two-way analysis of covariance with treatments and middle equally factors and the baseline as a covariate. Efficacy analyses were based on a modified intent-to-treat population, including patients who received any exam article and provided efficacy data at baseline and at whatever subsequent visit. The proportions of patients with clinically meaningful changes in the HAQ inability index at week 104 were compared between handling groups using χ2 analyses. Pearson correlation analyses were used to appraise correlations between DAS and PRO over 104 weeks. The terminal-ascertainment-carried-forrad (LOCF) approach was used to account for missing data points. LOCF imputation was also applied to patients who discontinued for unsatisfactory response. Adverse events were summarised and compared among treatment groups, using χ2 or Fisher's exact exam. The sample sizes, 100 for the etanercept-alone group and sulfasalazine plus etanercept group versus 50 for the sulfasalazine-lone group, gave approximately ninety% power to discover pairwise differences in the ACR 20 response of 33% versus 66% betwixt the monotherapies.
RESULTS
Efficacy
Of the 260 patients who were randomly assigned in the study, 254 patients received 1 or more examination articles (etanercept 103, sulfasalazine 50 and combination 101).ten The population was predominantly white, female, and had a hateful historic period of 51 years (consistent with the typical RA population). Every bit previously reported, there were no significant differences amid the groups in the baseline characteristics with the exception of the percentage of patients receiving previous corticosteroids and the mean number of previous DMARD.ten
A total of 96 patients discontinued the study: 38 receiving etanercept, 34 receiving sulfasalazine and 24 receiving combination therapy. Overall, a significantly greater number of the patients who continued on sulfasalazine monotherapy (68%) withdrew from the written report compared with those receiving etanercept, either as combination (24%) or replacement (37%) therapy (p<0.001); the difference between etanercept and the combination was likewise pregnant (p<0.05). The well-nigh mutual master reason for discontinuation, lack of efficacy, led to a significantly higher number of withdrawals in patients receiving sulfasalazine (52%) compared with those receiving either etanercept regimen (6% for each; p<0.001). Discontinuations because of adverse events were not significantly different among the groups (8%, nineteen% and 10%, for the sulfasalazine, etanercept and combination groups, respectively) and there was no tendency in the types of agin events that led to discontinuation in any of the groups.
Times to discontinuation were estimated using the Kaplan–Meier method (fig i); the combination group had the longest times to discontinuation. Based on the log-rank test, the differences amid the three groups were statistically significant (p<0.001 for sulfasalazine vs etanercept or combination and p = 0.06 for etanercept vs the combination).
Percentage of patients remaining in the study versus fourth dimension (in weeks). Based on the log-rank exam, the p values for the comparisons of the time to discontinuation are <0.001 (sulfasalazine versus etanercept), <0.001 (sulfasalazine versus combination), and 0.06 (etanercept versus combination).
Disease activity, as assessed by hateful DAS, was significantly lower in the groups receiving etanercept than in the group receiving sulfasalazine from calendar week ii to calendar week 104 (p<0.01, fig 2). Significantly lower mean DAS values were observed during weeks 68–104 for the combination group compared with the etanercept-solitary group (p<0.05). A significantly higher proportion of patients receiving the combination or etanercept had a low level of illness activeness (every bit assessed past DAS <2.4) compared with those receiving sulfasalazine afterward 6 months, which was maintained throughout the 2 years (p<0.01); at 2 years, 57.0% of patients receiving combination, 45.6% receiving etanercept and four.0% receiving sulfasalazine. Likewise, the proportion of patients achieving disease remission was significantly higher with the etanercept groups compared with the sulfasalazine grouping (p<0.01).
Mean affliction activeness score (DAS) over fourth dimension (in weeks; concluding-observation-carried-frontwards, modified intent-to-treat analysis). ▿ Etanercept plus sulfasalazine; • etanercept; ▪ sulfasalazine. *p<0.05 etanercept versus combination; †p<0.05 sulfasalazine versus combination; ‡p<0.05 sulfasalazine versus etanercept.
Handling response every bit assessed by ACR 20 was achieved past a significantly higher percent of patients receiving etanercept, added to or in place of sulfasalazine, compared with those receiving sulfasalazine (p<0.01; fig 3A). Similarly, these significant differences in handling response among the groups were besides seen using ACR fifty (p<0.01) and ACR 70 (p<0.01; fig 3B,C) criteria. For ACR xx responses, the differences were significant showtime at calendar week 2; for ACR l and ACR lxx, the differences were significant kickoff at weeks 8 and 12, respectively. Response rates were non significantly unlike between the two groups receiving etanercept.
Percentage of patients in each treatment group achieving an American College of Rheumatology (ACR) response (last-observation-carried-forrard). (A) ACR 20; (B) ACR l and (C) ACR 70. ▿ Etanercept plus sulfasalazine; • etanercept; ▪ sulfasalazine. *p<0.01 etanercept versus combination; †p<0.01 sulfasalazine versus combination; ‡p<0.05 sulfasalazine versus etanercept.
The early and sustained response pattern was also seen with components of the ACR response criteria. Significant differences (p<0.01) were seen for combination therapy or etanercept alone compared with sulfasalazine lonely. Comparing the etanercept groups, the combination group separated from the etanercept monotherapy group for a short menstruation (weeks 8 to 20) equally demonstrated by the lower ESR levels (p<0.05). No significant divergence between these groups was seen for other ACR components before week 68 (total swollen joints) or calendar week 92 (patient global assessment and physician global assessment), later which time the combination grouping showed amend responses (p<0.05).
Patient-reported outcomes
Mean HAQ values for the etanercept and combination groups were significantly lower than those for the sulfasalazine group from week 2 (p<0.01, sulfasalazine vs etanercept or combination) and these differences were sustained for the remainder of the 2-year study10 (p<0.01; fig four).
Mean health cess questionnaire (HAQ) scores from baseline to week 104 for patients with rheumatoid arthritis receiving sulfasalazine (SSZ), etanercept (ETN), or combination therapy with sulfasalazine and etanercept (last-observation-carried-forward analysis). ▿ Etanercept plus sulfasalazine; • etanercept; ▪ sulfasalazine. *p<0.01 sulfasalazine versus etanercept; †p<0.01 sulfasalazine versus combination.
Three health status measures using least squares means at week 104 are presented in fig v. Patients who received etanercept or combination therapy showed significantly lower GHVAS scores, indicative of improve general health, than patients who received sulfasalazine at week 104. Likewise, recipients of etanercept or combination therapy reported significantly improve health states, as indicated by lower RA activity (PGAD) and college EQ-5D scores than patients receiving sulfasalazine.
Health status at baseline and calendar week 104 for patients with rheumatoid arthritis receiving etanercept, sulfasalazine, or combination therapy every bit measured by least squares ways for EQ-5D, patient general health cess (GHVAS) and global assessment of overall rheumatoid arthritis activity (PGAD) (concluding-observation-carried-forward assay). (A) EQ-5D; (B) GHVAS; (C) PGAD.
Our analyses likewise found that a significantly college proportion of patients receiving etanercept or the combination attained the threshold of HAQ comeback ⩾0.22 by week 104 compared with those receiving sulfasalazine (p<0.01 compared with sulfasalazine alone). Similarly, a significantly higher proportion of patients receiving etanercept or the combination accomplished EQ-5D VAS scores above population norms18 at week 104 compared with those receiving sulfasalazine (p<0.01 compared with sulfasalazine alone).
Further analyses revealed that changes in disease action from baseline to 104 weeks correlated with changes in disability as measured by the HAQ disability alphabetize and with changes in health status measures. Pearson correlations between the alter from baseline in DAS and HAQ (0.57), PGAD (0.69), EQ-5D VAS (−0.61), or GHVAS (0.67) were all meaning (p<0.001).
Safety
The blueprint of adverse events reported during the ii years of the study was non different from that reported during the first 6 months of the written report.10 There were no significant differences between the combination and either monotherapy groups in the overall incidence of not-infectious adverse events (table 1). However, there were significantly more handling-emergent infections in patients receiving etanercept than in those receiving sulfasalazine (p<0.001).
Tabular array 1
Number (%) of patients with the almost mutual TEAE (⩾10% in whatever treatment grouping)
| Torso organization TEAE | Etanercept (north = 103) | Etanercept + sulfasalazine (northward = 101) | Sulfasalazine (n = 50) |
| Non-infectious adverse events | |||
| Any TEAE (excluding infection) | 90 (87.4) | 80 (79.2) | 32 (64.0)* |
| Injection site reaction | 34 (33.0) | 21 (20.8) | ii (four.0)*‡ |
| Headache | xi (10.7) | 25 (24.eight)† | 4 (8.0)‡ |
| Back hurting | 9 (8.7) | 20 (nineteen.8) | five (10.0) |
| Nausea | 7 (6.8) | 19 (xviii.8)† | five (ten.0) |
| Adventitious injury | 16 (15.5) | 17 (sixteen.eight) | 1 (2.0)*‡ |
| Asthenia | five (4.9) | xvi (fifteen.8)† | 1 (ii.0)‡ |
| Rash | fifteen (14.half-dozen) | 8 (7.9) | 3 (vi.0) |
| Dyspepsia | 14 (thirteen.6) | 12 (11.9) | 2 (4.0) |
| Abdominal pain | 14 (xiii.vi) | 12 (eleven.9) | one (two.0) |
| Injection site haemorrhage | 9 (eight.7) | 14 (thirteen.9) | 3 (half dozen.0) |
| Arthralgia | 8 (7.8) | 14 (13.nine) | 7 (14.0) |
| Rheumatoid arthritis | ten (9.7) | 12 (11.nine) | 5 (x.0) |
| Diarrhoea | 11 (ten.7) | 6 (5.9) | 0.0* |
| Coughing increased | 7 (6.8) | 12 (11.nine) | iv (8.0) |
| Parasthesia | 4 (3.nine) | 11 (x.9) | 1 (ii.0) |
| Infectious adverse events | |||
| Any TEAE infection | 76 (73.eight) | sixty (59.4)† | 21 (42.0) * |
| Upper respiratory tract infection | 29 (28.2) | 29 (28.vii) | 10 (xx.0) |
| Pharyngitis/laryngitis | 24 (23.iii) | 10 (9.ix) | 3 (6.0)*‡ |
| Bronchitis | 21 (xx.iv) | 12 (xi.9) | four (8.0) |
| Flu syndrome | eighteen (17.five) | 12 (11.ix) | 2 (iv.0) |
| Gingival/dental infection | 7 (6.8) | 12 (xi.nine) | 2 (4.0) |
| Sinusitis | 12 (eleven.seven) | 3 (three.0)† | 0.0* |
| Miscellaneous skin infections§ | 19 (18.4) | 12 (11.nine) | 0.0*‡ |
Handling-emergent infections per patient-twelvemonth were significantly higher with etanercept (1.72) than with etanercept and sulfasalazine (1.11) or with sulfasalazine (0.86; p<0.001 overall). There were meaning differences betwixt the etanercept group and both the sulfasalazine and combination groups (p<0.001). Medically important infections occurred in more patients receiving etanercept (11; 10.seven%) than in those receiving combination (v; v%, p not meaning) or sulfasalazine (0; p<0.05). Afterwards 352 days receiving combination therapy, one patient was hospitalised and withdrawn from the study and treated with antituberculous drugs following a histological conclusion of tuberculous lymphadenitis.
In that location was no clustering of SAE. In the 2 years of the study, 23 patients receiving the combination, 27 receiving etanercept and two receiving sulfasalazine had one or more SAE. Non-infectious SAE were significantly greater in patients receiving etanercept (twenty.8% for the combination and 20.4% for etanercept lone) compared with 4% for patients receiving sulfasalazine (p<0.01).
At all scheduled visits, patients receiving the combination had a significantly greater reduction in white blood cell (WBC) counts (mean change from baseline) than those receiving sulfasalazine lone (p<0.001). In contrast, in that location was no significant difference in this laboratory parameter between the etanercept and sulfasalazine groups. Across all treatment groups, no subjects developed any NCI form 3 or 4 WBC abnormalities, except for one subject who had a transient grade 4 WBC abnormality that normalised. All hateful WBC counts were inside normal limits at all visits.
Leucopenia was reported as a TEAE in 8 (7.9%) patients in the combination grouping, two (1.nine%) in the etanercept grouping and none in the sulfasalazine group (p not significant). None of the events of leucopenia were associated with NCI grade 3 or 4 levels of neutrophils or other NCI grade 3 or iv laboratory abnormalities. No patients withdrew from the study because of TEAE of leucopenia; all events were resolved during the study.
Malignancy was diagnosed in two patients receiving etanercept. One patient with a history of peel cancer developed actinic squamous cell carcinoma of the lower lip. The second patient, whose diagnosis was myelodysplastic syndrome after 12 weeks of etanercept, then adult myelocytic leukaemia and subsequently died.
The incidence of malignancy observed in this report was compared with the expected incidence based on the Us SEER programme. The observed number (ane.0) of malignancies in etanercept or combination-treated patients during the entire study was lower than the expected numbers (2.7) based on SEER, which excludes non-melanoma pare cancers.17
The 2d reported death was a patient with interstitial pneumonitis, who had a history of smoking, coronary obstructive pulmonary disease and childhood pneumonia.
No patients developed systemic lupus erythematosus or a lupus-like syndrome, glomerulonephritis, pleuritis, peritonitis, or seizure. At that place were no reports of central demyelinating diseases in this study. Occurrences of car-antibodies were not significantly dissimilar among groups at baseline and at the last visit.
Discussion
The results from this ii-twelvemonth double-blind, randomised study in patients with agile RA despite sulfasalazine therapy provide farther testify that etanercept, either solitary or when added to existing DMARD therapy, has a favourable long-term condom and efficacy contour. The improver of or switching to etanercept resulted in a rapid and sustained improvement of all clinical efficacy endpoints compared with sulfasalazine lonely. The efficacy results were similar in both etanercept groups, indicating that patients inadequately responding to sulfasalazine would do good past either the addition of etanercept to their existing (sulfasalazine) treatment or by switching from sulfasalazine to etanercept. Treatment with etanercept, sulfasalazine, or the combination did not event in whatever unexpected safety findings. The combination of etanercept and sulfasalazine was not associated with greater toxicity than either therapy lone.
Modifications to a less than adequate handling regimen, such as the addition of another agent or substitution of a "failing" drug with another agent, are a standard approach. Clinical studies in patients with RA have shown that calculation or substituting an anti-TNF agent to the existing methotrexate therapy3 4 vii 19 20 results in a significant improvement in the therapeutic response. The addition of an anti-TNF amanuensis to (or in identify of) inadequate sulfasalazine has not been extensively evaluated in clinical trials. In the just other placebo-controlled trial in RA patients non fairly treated with sulfasalazine, adalimumab was added to the existing treatment.9 12. In that study, patients receiving the combination showed a greater degree of improvement than those receiving sulfasalazine lone. Notwithstanding, modest sample sizes (sulfasalazine alone, due north = 33; sulfasalazine plus adalimumab, n = 29) brand it difficult to compare the efficacy results among the handling artillery. In a larger open-label report evaluating adalimumab solitary and in patients inadequately responding to at least ane traditional DMARD, the number of ACR 20 responders was similar for adalimumab plus sulfasalazine and adalimumab solitary.eleven
Patients who received etanercept monotherapy or etanercept plus sulfasalazine combination achieved significantly higher ACR response rates than patients in the sulfasalazine monotherapy group (p<0.01). For all three treatment groups, the core components generally followed the blueprint of the ACR composite response. Hateful ESR values in both the etanercept plus sulfasalazine combination and etanercept monotherapy groups were significantly lower than in the sulfasalazine monotherapy group from week two (p<0.01) to calendar week 104 (p<0.01). For a brusque period (calendar week 8 to week 20) the combination group had significantly lower ESR levels than the etanercept-lonely grouping (p<0.05), but the deviation was not significant from week 24 to week 104.
Concrete function scores were significantly improved in the groups receiving etanercept, either lonely or in combination with sulfasalazine, compared with sulfasalazine alone, using several previously defined thresholds.21 22 In patients with RA, a alter of 0.22 or more than units in the HAQ score has been used to estimate the number of patients with a clinically significant improvement in physical part.22 In this study, past calendar week 104, three in every four patients receiving etanercept, either solitary or every bit add-on therapy, achieved a HAQ comeback of 0.22 or more, compared with less than 1 in two patients standing on sulfasalazine therapy.
Etanercept and combination therapy resulted in significantly greater improvements in all measured PRO than the modest improvements seen with sulfasalazine therapy. Furthermore, there was a significant correlation between affliction activeness, as assessed by the DAS, and physical function, as assessed by the HAQ. Significant correlation was besides observed between disease activity and other PRO, including the EQ-5D VAS and PGAD.
The study was originally designed as a six-calendar month trial, which is not long enough to detect radiographic changes, but was subsequently extended to ii years. Even so, because both disease activity and radiographically assessed joint impairment have been shown to be major contributors to the physical functioning of the patient with RA,23 – 26 the significant improvements in disease activity and physical functioning would advise that radiographic progression was inhibited in these patients.
Treatment with etanercept, sulfasalazine, or the combination did not result in whatsoever unexpected safety findings; however, the comparison of TEAE among treatment groups in this report has bias. Generally, with whatsoever drug patients report agin events at a higher frequency during the kickoff few weeks or months after the start of treatment and patients who cannot tolerate the drug are withdrawn. As a protocol-inclusion criterion, patients in the sulfasalazine group were required to take tolerated sulfasalazine well; hence, these patients were expected to written report adverse events at a lower charge per unit than patients receiving a "new" treatment.
The use of anti-TNF agents has also been associated with the increased frequency of autoantibodies, which could result in autoimmune diseases such as systemic lupus erythematosus.27 – 29 Although the number of patients who tested positive for anti-dsDNA increased by the end of our study, there were no relevant clinical symptoms associated with the positive anti-dsDNA test results in any of the treatment groups.
Leucopenia, neutropenia, thrombocytopenia and pancytopenia have besides been reported in patients receiving anti-TNF therapies. In this study, the incidence of TEAE of leucopenia was greater in the combination group (seven.9%) than in the etanercept group (1.9%) or the sulfasalazine group (0%), but between-group differences were not statistically significant. Investigators categorised the severity of all eight events in the combination group as balmy; none of the TEAE of leucopenia were associated with NCI form 3 or 4 values of neutrophils or with other NCI grade 3 or 4 laboratory abnormalities. No patients withdrew from the study because of leucopenia. The lower WBC counts thus did non seem to exist clinically relevant. Furthermore, at that place were no reports of aplastic anaemia or pancytopenia.
This written report shows that the addition of etanercept to sulfasalazine, a DMARD other than methotrexate, can provide significant long-term comeback in efficacy. In detail, information technology shows that etanercept provides benefit when added to or switched with sulfasalazine in patients who evidence an inadequate response to sulfasalazine. The reported findings are especially relevant in view of the recent reports regarding monotherapy failures, which discourage the selection of both methotrexate plus sulfasalazine and leflunomide plus sulfasalazine combination therapy.30 31 By and large, combination handling was non associated with an increased incidence of adverse events. Etanercept either alone or added to existing sulfasalazine therapy is associated with a favourable run a risk benefit profile, thus broadening the range of options for the treatment of patients with active RA.
Acknowledgments
The authors would similar to acknowledge Ruth Pereira and J Maitland Young in the Publications and External Communications Grouping at Wyeth for their writing support and S Dominicus of Wyeth Enquiry for contributions to statistical analyses of the study.
Footnotes
Funding: Supported by Wyeth Research, Collegeville, PA, USA (study drug and grants to investigational sites).
Competing interests: Alleged. BC was a consultant and a speaker for Wyeth. CC received investigator fees for carrying out Wyeth trials. UF received reimbursement from Wyeth Italy for running educational programmes. MG was reimbursed by Wyeth for attending several conferences and was paid for giving educational talks. PPG received support for clinical studies from Wyeth Research. TKK was a consultant and a speaker for Wyeth and received funds for research. JW, RK, Every bit and SF are employees of Wyeth Research.
Ethics approving: Ethics committees of the participating centres approved the study protocol.
Patient consent: Obtained.
List of the Etanercept Report 309 Investigators in Europe and Australia (other than the authors): Professor Maxime Dougados, Hopital Cochin, Paris, France; Professor Joël Dehais, Hopital Pellegrin, Bordeaux, France; Professor Philippe Goupille, Hopital Trousseau, Tours, France; Professor Pierre Miossec, Hopital E Herriot, Lyon, France; Dr Anett Grässler, University Hospital, Dresden, Germany; Professor Umberto Ambanelli, Universita di Parma, Parma, Italy; Professor Silvano Todesco, Policlinico Universitario, Padova, Italia; Dr Hillary Capell, Glasgow Royal Infirmary, Glasgow, Uk; Dr Ian Griffiths, Freeman Hospital, Newcastle upon Tyne, UK; Dr Richard Hull, Queen Alexandra Infirmary, Portsmouth, Hants, UK; Dr George Kitas, Corbett Hospital, Stourbridge, West Midlands, Great britain; Dr Robert Moots, Fazakerley Infirmary, Liverpool, UK; Professor David GI Scott, Norfolk and Norwich Hospital, Norwich, UK; Professor David 50 Scott, Dulwich Infirmary, London, UK; Dr Peter Sheldon, Leicester Majestic Infirmary, Leicester, UK; Dr Bryan Williams, University Hospital of Wales, Cardiff, Due south Wales, Great britain; Dr Gary Wright, Musgrave Park Hospital, Belfast, UK; Dr Paresh Jobanputra, University of Birmingham, Birmingham, UK; Dr Knut Mikkelsen, Lillehammers Sanitetsforening, Lillehammer, Kingdom of norway; Dr Olav Bjorneboe, Martina Hansens Hospital, Gjetterum, Kingdom of norway; Dr Petr Vitek, Centrum Rehabilitace, Zlin, Czech Republic; Dr Ladislav Bortlik, NZZ Bormed, Ostrava, Czech republic; Dr Marie Sedlackova, Thomayer Academy Infirmary, Praha, Czech Commonwealth; Dr Sevda Augustinova, Medipont, (Jerzy Lech) Ceske Budejovice, Czech Republic; Dr Peter Nash, Sixth Avenue Specialist Centre, Maroochydore, Australia; Dr Stephen Hall, Cabrini Medical Eye, Malvern, Australia; Dr Florin Radulescu, Ambulatoriul Centrului Metodologic de Reumatologie, Bucuresti, Romania; Dr Coman Tanasescu, Institutul de Medicina Interna, Bucuresti, Romania; Dr Horatiu Bolosiu, Spitalul Clinic Judetean Cluj, Cluj-Napoca, Romania.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689524/
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