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| Joan Bathon, M.D. and Clifton Bingham, M.D.
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Abstracts 1917 Rituximab in Rheumatoid Arthritis (RA): A Double-Blind, Placebo-Controlled, Dose-Ranging Trial (the DANCER study) Abstracts 1922 Safety and Tolerability of Rituximab in Patients with Moderate to Severe Rheumatoid Arthritis: Results from the Dose-Ranging Assessment International Clinical Evaluation of Rituximab in Rheumatoid Arthritis (DANCER) Study Background: Rituximab (Rituxan; RTX) is an anti-CD20 B cell depleting monoclonal antibody that has been shown in phase II trials in RA to be efficacious and safe in combination with methotrexate (MTX). However, in previous trials, RTX was administered concomitantly with high doses of glucocorticoids (GC). Whether GCs are necessary for the efficacy of rituximab, and whether they contribute any additional toxicity or enhance safety, is unknown. The purpose of this study was to examine the efficacy and safety of RTX with or without GC in patients with active RA despite MTX. Methods: Patients aged 18 to 80 y.o. with RA with inadequate response to MTX were recruited. Patients continued to receive MTX and were randomized to one of 9 treatment arms:
Randomization was stratified by region (US/non-US) and RF status. Inclusion criteria included swollen joint count (SJC) >8; tender joint count (TJC) >8; elevated CRP or ESR. RF negative patients were enrolled only in the 1000 mg RTX and PLR/PLC arms. The primary outcome was ACR20 at week 24. ACR50/70, DAS28, ESR and EULAR responses were also measured. Results: 465 patients were enrolled. RF+ pts (n=367) comprised the primary intention to treat (ITT) efficacy population. Baseline characteristics of the various treatment groups did not differ significantly from one another [mean SJC=21, TJC=33, and DAS28=6.8]. The mean MTX dose was 15.5 mg/wk. The average duration of disease was 10.4 y. 32% of the participants had previously received one or more biologic therapies. ACR responses are shown below. ACR responses in RTX treated patients were superior to placebo, although no dose response was observed. GC use did not contribute to the efficacy of RTX (p=0.17). However, patients treated with GC had fewer RTX-associated infusion reactions. Efficacy results were not significantly altered when RF- pts were added to the main effect model (p=0.452 for RF+/-).
RTX was generally well tolerated. Infusion reactions were the most commonly reported adverse event (AE) and occurred primarily with the first infusion: 18% with placebo, 31% with RTX 500 mg, and 38% with RTX 1000 mg. Infusion reactions decreased with the Day 15 infusion, occurring in 11% with placebo, 7% with RTX 500 mg, and 10% with RTX 1000 mg. Two serious infusion reactions with the first infusion in the RTX group receiving no GCs. Infectious AEs were largely due to upper respiratory infections (28% of placebo and 35% of RTX pts). There were 6 serious infections (SIs): 2 in placebo pts (2 pneumonias), and 4 in the RTX 1000 mg group (epiglottitis, bronchitis, 2 pyelonephritis). No opportunistic infections or TB reactivations were reported. Serious AEs were seen in 7% of RTX pts and in 3% of control pts. One fatality due to a stroke occurred in the RTX 500 mg group. HACA rates at Week 24 were higher in the RTX groups (0.7% in placebo, 4.9% in RTX 500 mg, and 2.7% RTX 1000 mg). Mean immunoglobulin levels in pts receiving RTX decreased slightly from baseline to Week 24, but remained within normal limits. Conclusions: These results confirm the efficacy of a single course of RTX for the treatment of RA and efficacy was not dependent upon concomitant GC use. Both doses were tolerated. GC use reduced infusion reactions. Editorial Comment: Prior studies of RTX in RA utilized the 1000 mg dose of RTX but the present study suggests that 500 mg is enough. One would hope that this will translate to a lower cost for RA patients. The data presented at the ACR meetings did not show breakdown by GC use (even though this was a primary goal of the study), although we were told that there was no difference in efficacy. We will look forward to seeing the data at the time of publication. While it is comforting that these high doses of GC are not necessary for the efficacy of RTX, they were beneficial in suppressing infusion related reactions. Thus, it is likely that we will want to continue to use steroids in conjunction with RTX, at least for the first infusion (as the frequency of infusion reactions decreases with RTX after the first infusion). But what amount is needed remains to be discerned. Abstract 1830 Efficacy and Safety of Rituximab in Active R A Patients who Experienced an Inadequate Response to one or More Anti-TNFa Therapies (REFLEX Study) Background: While data have previously been presented showing the efficacy of Rituximab (RTX), a selective B-cell depleting CD20 targeted monoclonal antibody, in patients with RA who have had inadequate responses to methotrexate (MTX), the efficacy of the drug in RA patients who have not responded to TNF antagonist therapy has not been well studied. This was a study to specifically evaluate the efficacy and safety of plus MTX in patients with rheumatoid arthritis who experienced an inadequate response to one or more TNF antagonists and had active disease despite ongoing treatment with MTX and a TNF inhibitor. Methods: 520 patients on a background regimen of MTX (10-25 mg/week) with stable doses at least 4 weeks, were randomized to a single course of either RTX 1000 mg or placebo (PBO), given by IV infusion on Days 1 and 15. All patients received parenteral methylprednisolone (100 mg) immediately prior to each infusion, and a brief course of oral glucocorticoids between the two RTX infusions (Prednisone 60 mg days 2-7, 30 mg days 8-14). Patients were withdrawn from DMARDs other than MTX at least 4 weeks prior to randomization (8 weeks for infliximab, leflunomide and adalimumab). Inadequate response to TNF antagonist therapy was defined as Etanercept for > 3 months at 25 mg BIW, or Infliximab for > 4 infusions at > 3 mg/kg, or Adalimumab for > 3 months at 40 mg QOW with toxicity or inadequate efficacy. Clinical assessments were conducted every 4 weeks between Weeks 4 and 24. Patients who failed to respond to treatment during the study (i.e., achieved < 20% improvement in both swollen and tender joint counts) could receive rescue therapy from weeks 16 to 24 with standard of care or RTX. Key inclusion criteria were: swollen joint count (SJC) and tender joint count (TJC) each > 8; elevated C-reactive protein (> 1.5 mg/dL) and/or erythrocyte sedimentation rate (>28 mm/h). Patients also had to demonstrate radiographic evidence of at least one joint with definite erosion attributable to RA in the hands wrists, or feet. The primary endpoint was the proportion of patients in each group that achieved an ACR20 response at Week 24. Secondary endpoints included ACR50 and ACR70 responses, changes in Disease Activity Score (DAS28), and EULAR response. A nonresponder imputation was used for missing data of ACR and EULAR responses for the primary analysis and by LOCF for continuous variables. Results: 499 patients (298 RTX, 201 PBO) comprised the primary intent to treat efficacy population, which included both rheumatoid factor (RF) positive and negative pts (81% RF+, 79% in the presentation). Mean baseline data were: SJC/TJC, 23/34; RA duration, 12 years; DAS28, 6.9; number of prior TNF antagonists, 1.5; mean MTX dose, 16.5 mg/week; HAQ 1.9. Pts were well matched at baseline in each group. 90-91% in each group were TNF inadequate responders due to efficacy. Completers for the 24 weeks included 82% of pts in the RTX group and 54% in the PBO group. Withdrawals due to a lack of efficacy to RTX or PBO were 12% and 40%, and withdrawals due to adverse events (AEs) were low, 3% and <1%, respectively.
Data that were presented in the oral presentation but not in the abstract included an exploratory radiographic analysis at 24 weeks was conducted. While a reduction in Genant-modified total Sharp score was decreased in the Rituximab treated patients compared to placebo (0.6 vs 1.2), the change was not statistically significantly different (p=0.1693). Although changes in erosion scores were also reduced in rituximab vs placebo (0.4 vs 0.8, p=0.2358) only reductions in joint narrowing scores were statistically significant (0.2 vs 0.5, p=0.0156). The most common adverse events were infusion-related, and were more frequent in the RTX groups. Slightly more serious adverse events were observed in PBO group (10%) than in RTX (7%). The incidence of serious infections was low in both groups (2% in RTX vs <1% PBO). Conclusions: These results show that 1000 mg RTX, given as 2 infusions with MTX is effective in decreasing signs and symptoms of active RA in patients who have experienced an inadequate response to TNF antagonists. Editorial Comment: This is an important study demonstrating the efficacy of Rituximab in combination with methotrexate for patients with RA who have had inadequate responses to TNF antagonists. This study used a 1000 mg dose given as 2 infusions, and all patients received both preinfusion IV steroids as well as a course of oral corticosteroids before the infusions. Most of the patients enrolled in REFLEX had inadequate responses defined as insufficient efficacy, though a smaller proportion (10%) were enrolled having experienced toxicity from these agents. Whether there are differences in responses between these two groups of "TNF inadequate responders" and whether there are other predictors such as baseline RF status are additional needed analyses. The clinical responses seen are similar but slightly lower than those reported for studies of Rituximab in patients who were required to fail MTX only, as may have been expected given a potentially refractory group of patients with longer disease duration (~12 yr for REFLEX vs ~10 yr for DANCER). While in other studies of Rituximab presented at ACR 2005 (DANCER) a substantial proportion of patients (26-33%) had previously received TNF antagonists, we have not seen any subset analysis from these studies to demonstrate whether corticosteroids and dose of Rituximab affect responses in TNF inadequate responders, questions that remain unanswered. Interpretation of the exploratory radiographic data presented in the oral presentation is difficult as most prior clinical trials have evaluated progression in TNF-naïve patients and the time point of assessment in this study was over 6 months. It is hoped that additional data will be forthcoming from other Rituximab clinical trials that help to better clarify the "disease modification" properties of this agent. Abstract 1918 Safety and Patient-Reported Outcomes Associated with Abatacept in the Treatment of Rheumatoid Arthritis Patients Receiving Background DMARDs: The ASSURE Trial Background: Abatacept is a biologic agent that inhibits T cell co-stimulation and is efficacious for the treatment of RA. Prior studies have evaluated the efficacy and safety of abatacept as monotherapy and in combination with methotrexate (MTX). The current study, the ASSURE trial (Abatacept Study of Safety in Use with other Rheumatoid Arthritis thErapies) was designed to evaluate the safety of abatacept in combination with one or more DMARDs in patients with active rheumatoid arthritis (RA). This scenario was meant to mimic what might happen in clinical practice. Methods: Patients with active RA were randomized to treatment with abatacept (~10 mg/kg by monthly infusion) or placebo for 1 year. All patients had active disease despite background DMARDs. The primary endpoint was safety. However, patient related outcomes (PROs) were also assessed quarterly. These included patient physical function (via the Health Assessment Questionnaire [HAQ]) and patient global assessments of disease activity and pain (using a visual analog scale [VAS]). Results: 1441 patients were enrolled. Most were receiving combination therapy with non-bio DMARDs; a much smaller group received background bio DMARDs (see below). The frequency of total AEs, serious AEs, infections, serious infections, and neoplasms were all higher in the abatacept/bio DMARD group compared to the other 3 treatment groups. In contrast, patients treated with abatacept in combination with non-bio DMARDs had AE frequencies similar to that of the two placebo/non-bio DMARD group. As for the PROs, abatacept treatment was associated with better responses than placebo treatment. These effects were 2- to 3-fold higher than placebo in the non-bio group, but less than 2-fold higher than placebo in the bio group. At 1 year, 47.3% of all patients treated with abatacept achieved a clinically meaningful HAQ response (improvement of at least 0.3 HAQ units from baseline) vs 34.6% of patients receiving placebo (p<0.001). Safety data, n(%)
PRO: mean % improvement from baseline at 1 year (SE), n(%)
Conclusions: These data indicate that abatacept is safe in patients receiving background non-biologic DMARDs, but not in patients receiving background biological DMARDs. Furthermore, patients on background biologic DMARDs did not experience much benefit from abatacept (in comparison to placebo). Editorial Comment: In a prior study in which biologics were combined (etanercept [anti-TNF] plus anakinra [anti-IL-1]), a higher incidence of infection was observed in the combination group compared to monotherapy. Now in this study we see a similar trend, in that abatacept (the first successful anti-T cell therapy for RA) in combination with anti-TNF or anti-IL1 therapies also causes more serious AEs. However, in this case it is not just an increase in infections but also in malignancies. Keeping in mind, however, that only a small number of patients on these combinations were studied, it will be hard to know for sure whether this association with malignancy is real. It is interesting to keep in mind, however, the etanercept study in Wegeners granulomatosis in which etanercept was added to cycylosphamide, a another T cell inhibitor but which is non-biologic and less specific than abatacept. In this study, the patients receiving etanercept + cyclophosphamide had a higher rate of malignancies compared to those receiving placebo + cyclophosphamide. The general themes that seem to be emerging are: 1) danger of infections when combining two biologic therapies with different mechanisms; and 2) potential danger of malignancies when combining anti-T cell therapies with anti-TNF therapy. We should confine our use of abatacept to patients on non-biologic DMARDs. Abstract 1919 Use of Anti-TNF Alpha Drugs and Incidence of Hematologic and Solid Cancers in Patients with Rheumatoid Arthritis Background: Lymphomas have been reported in RA patients treated with anti-TNF therapy. However, RA itself is a risk factor for development of lymphoma and it has been difficult to disentangle the effect of the disease from the effect of the treatment on this adverse outcome. The goal of this study was to estimate the association between biologic DMARDs (BIO) and the risk of hematologic and solid cancers. Methods: Healthcare utilization databases from two U.S. states (1994-2002, age >65) and one Canadian Province (1996-2003, age >18) were accessed. A cohort of subjects with a diagnosis of RA and prescription for any antirheumatic drug during the study period were identified. Subjects with > 1 prescription of BIO were identified as BIO users regardless of other antirheumatic drugs use, and subjects with > 1 prescription of MTX but no BIO use were identified as MTX users. MTX users served as the comparison group. Potential confounders that were assessed included demographic variables, known risk factors for cancers, variables associated with severity of RA, health care utilization, and major comorbid conditions. Covariates were collapsed into a propensity score (probability of receiving BIO vs MTX). The primary endpoint was occurrence of hematologic cancers and common solid cancers. Stratified Cox proportional hazards regression was used to estimate the unadjusted, age-sex adjusted and propensity score adjusted effects of BIO on cancer incidence. Results: The pooled cohort consisted of 43,178 potential patients. Of these 1591 BIO users and 11934 MTX users were identified for further analysis. The cancer incidence rates in BIO and MTX users were comparable to US standardized rates (see below). No significant increase was observed in the risk of cancers in BIO users compared with MTX users. Number of cases, person-years and rate ratio of cancer risk in BIO and MTX users
Conclusion: A large increase in the risk of hematologic and/or solid cancers in BIO users compared to MTX users can be ruled out, but a small increase or decrease in the risk cannot be excluded. Despite combining very large datasets, it remains a challenge to study the effect of a rare exposure (BIO) on rare diseases. Editorial Comment: Only in large administrative data sets like these can reasonable attempts to assess the rate of rare side effects with drugs be made. Some of the limitations of these types of data sets, however, include the accuracy/validation of the diagnosis of RA, and lack of information on how long the patients were treated (in this study patients were assigned to the BIO or MTX group on the definite basis of only one prescription). It seems rather unlikely that the potential relationship of TNF inhibitors to lymphoma will ever be definitively resolved. Abstract 1920 Efficacy and Safety of Belimumab (BmAb), a Fully Human Monoclonal Antibody to B-Lymphocyte Stimulator (BLyS), for the Treatment of Rheumatoid Arthritis (RA) Background: BLyS is a growth and survival factor for B cells. BmAb is a monoclonal Ab directed against BLys that inhibits its biological activity. This study was undertaken to evaluate the safety and efficacy of BmAb in RA patients who had active disease despite current treatment with nonbiologic and/or biologic DMARDs. Methods: 283 patients with active RA [> 6 swollen joints (SJ) and > 8 tender joints (TJ)] despite prior treatment with non-biologic and/or biologic DMARDs were enrolled. Biologic DMARDs had to be washed out before enrollment, but nonbiologic DMARDs were continued. Patients were randomized to receive intravenous (IV) BmAb (1, 4 or 10 mg/kg) or placebo on Days 0, 14 and 28, then every 28 days through 24 wks. The primary outcome was ACR20 response at 24 weeks. Results: Mean baseline characteristics were similar among the 4 groups: age 50 yrs, 80% women, RA duration 11 yrs, 84% RF+, 20 SJ, 29 TJ. On average, patients had failed 2.2 DMARDs (38% > 1 TNFa-inhibitor). The ACR20 response at Wk 24 in the combined BmAb groups was 29% compared to 16% in the placebo group (p=0.02). No dose response was observed. BmAb treatment was association with a 30% reduction in levels of rheumatoid factor (RF) (p<0.001) and a significant reduction in CD20+ cells (p< 0.001) compared to placebo. There were no significant differences in the incidence of severe, serious or infection adverse events (AEs), Sinusitis (9%, 4 mg/kg) and pruritis (11%, 1 mg/kg) were the only AEs with significantly higher incidence in a single active dose group vs. PB. Conclusions: BmAb was well tolerated but only weakly effective in patients with moderate to severe RA. Editorial Comment: These are curious results. In contrast to rituximab (a mAb that depletes B cells and is very effective in the treatment of RA), this antibody that is a functional inhibitor of B cells was not effective. It is hard to reconcile these seemingly contradictory results. One potential explanation is that the dose of BmAb was too low. Alternatively, one might argue that the effectiveness of rituximab is not related to its effects on B cells, since treatment with BmAb did not reproduce the effects of rituximab. If true, then this would suggest that B cell mediated pathways are not critical to the pathogenesis and/or propagation of RA. Continued studies with BmAb might be useful from a research perspective in order to better understand the role of B cells and autoantibodies in RA. Additional large clinical trials to further study efficacy do not seem warranted, however. Abstract 1921 Subcutaneous Injection of CNTO 148 Compared with Placebo in Patients with Active Rheumatoid Arthritis Despite Treatment with Methotrexate: A Randomized, Double-Blind, Dose-Ranging Trial Background: The manufacturers of infliximab have developed a new human anti-TNFamonoclonal antibody (CNTO 148) that is more potent than infliximab in preclinical studies and, given subcutaneously, has a long half-life. This phase II dose-ranging study was undertaken to assess the efficacy and safety of subcutaneous (SC) injections of CNTO 148 in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy. Methods: Patients with RA with active disease despite MTX were enrolled and randomized to one of 5 treatment groups: placebo q 2 wks; CNTO 148 50 mg q2 or 4 wks; CNTO 148 100 mg q 2 or q 4 wks. Patients received stable doses of MTX (> 10 mg/wk). The primary endpoint was the ACR 20 response at wk 16.Results: 172 patients were enrolled. All doses of CNTO 148 were associated with significantly higher ACR50 and ACR70 responses compared to placebo treatment. For the ACR20 response, two doses of CNTO 148 were associated with statistically significantly better responses than placebo, although they were rather modest (placebo response was quite high in this study). Serious adverse events (SAEs) occurred in 8% of patients in the combined CNTO 148 vs 5.9% in the placebo group. The most common SAEs in CNTO 148 treated patients were pneumonia (2 patients), lung cancer (1 patient), cardiac tamponade (1 patient), and heart failure (1 patient). There were no deaths or cases of TB or lymphoma. Efficacy results at Wk 16
Conclusion: CNTO 148 was effective, compared to placebo, in relieving signs and symptoms of RA. No unexpected adverse events were observed in this relatively short trial. Editorial Comment: It is not clear that we need another TNF inhibitor. Presumably the manufacturer is developing this one in order to compete with the other subcutaneously administered TNF inhibitors, adalimumab and etanercept. The ACR20 responses in this study are rather modest when one takes into account the quite high placebo responses. Abstract L27 Blocking Interleukin-6 (IL-6) By Tocilizumab (A Humanized Anti-Interleukin-6 Receptor Monoclonal Antibody) Monotherapy Reduces Joint Damage In Active Rheumatoid Arthritis (RA): Evidence From A X-Ray Reader -Blinded Randomised Controlled Trial Background: IL-6 has been implicated as an important cytokine in the pathogenesis of RA. The cytokine is a potent inducer of acute phase reactants and is a multifunctional cytokine with affects on many other immunological and inflammatory cells including T cells, B cells, and osteoclasts. Previous studies (Arthritis Rheum 2004; 50(6): 1761) have reported the efficacy of a monoclonal antibody, tocilizumab, (also called MRA) directed against the IL6-receptor in patients with RA (see study summary), though these studies have not evaluated a radiographic endpoint. This study was designed to assess the ability of tocilizumab monotherapy to inhibit progression of structural joint damage, clinical efficacy and tolerability, in patients with active RA. Methods: 306 patients with active early RA of <5 years duration were randomly allocated to receive either tocilizumab at 8 mg/kg IV every 4 weeks or conventional DMARDs for 52 weeks. In the control group, the dose, type and combination of DMARDs could be varied according to disease activity, but anti-TNF agents and leflunomide were not permitted. The efficacy endpoints included change from baseline to week 52 in van der Heijde modified Sharp score, evaluated by 2 readers blinded for treatment and order of films, and ACR response rates. Adverse events (AEs) and laboratory values were monitored for safety. Results: A total of 302 patients (157 on tocilizumab and 145 on DMARDs) received study drugs. MTX was the most common treatment (80%) in the DMARDs group at study start. All baseline characteristics were similar in the two groups. Patients had a mean disease duration of 2.3 years, DAS28 score of 6.9 and CRP of 4.8 mg/dL at baseline, indicating very active disease. Mean Total Sharp Score (TSS) at baseline was 30.0, which was very high despite relatively short disease duration. At week 52, patients in the tocilizumab group showed statistically significantly less radiographic progression, as measured by change in TSS, than those receiving DMARDs (2.3 + 5.6 versus 6.1 + 11.4; p=0.001). Tocilizumab was superior to DMARDs in preventing both erosion and joint space narrowing (p<0.001 and p=0.018 respectively). The percentages of patients who achieved ACR20, 50 and 70 were 89%, 70% and 47% in the tocilizumab group and 35%, 14% and 6% in the DMARDs group (LOCF data; p<0.001, p<0.001, p<0.001 respectively). The overall incidences of AEs including laboratory abnormalities were 96% and 87% (serious AEs: 19% and 13%) in the tocilizumab and DMARDs groups, respectively. Nasopharyngitis, and mild, transient increases in LFTs were frequently observed in both groups. Lipid increases were predominantly reported in the tocilizumab group but the mean cholesterol level became stable (217 + 39.3 mg/dL) at around the normal upper limit. No tuberculosis was observed. Conclusion: This study demonstrates an apparent slowing of radiographic progression with tocilizumab blocking IL6 compared to ad libitum administration of traditional DMARD therapy. Editorial Comment: While the study suggests an effect of tocilzumab on slowing radiographic progression, the results of this study, concerning drug efficacy on signs and symptoms and X-ray endpoints, are to be interpreted with caution. This was not a traditional double-blind placebo-controlled study, but rather was open label in allocation with an unclear randomization strategy. The treatment in the traditional DMARD group was not standardized but could be varied or changed according to disease activity. This confounds interpretation of any treatment response on signs and symptoms. The baseline characteristics of the study population were notable for extremely high acute phase reactants and relatively early disease. The low efficacy responses noted in the DMARD group (far less than has been seen in other studies of effectively dosed MTX in other studies of early RA) and the lack of detail provided concerning drug dosages and details in the DMARD group make interpretation of differences between tocilizumab and a comparator group difficult to assess as the differences may reflect underdosing or less than aggressive clinical care in the comparator group. As in prior clinical trials, an effect of IL6 inhibition with tocilizumab has been an elevation in cholesterol measurements and LFTs. The clinical significance of these changes with long term administration needs to be determined. Additional studies are needed that use traditional randomized double-blind placebo-controlled study designs to better understand the efficacy of tocilizumab alone and in combination with other DMARDS on clinical and radiographic endpoints. Abstract 289 A 2-Year Double-Blind Comparison of Etanercept (enbrel) and Sulfasalazine, Alone and Combined in Patients with Active Rhuematoid Arthritis Purpose: While etanercept has been studied in combination with MTX in the treatment of RA, the combination with other nonbiological DMARDS has not been well studied. This study was designed to compare the efficacy and safety of etanercept (E), sulfasalazine (SSZ), alone and in combination in patients with rheumatoid arthritis (RA). Methods: In a double-blind, randomized, 2-year study, adult RA patients who had been previously treated with SSZ (2-3 g/day) with persistent active disease were randomized in a 2:2:1 ratio: E 25 mg twice weekly SC, (with SSZ discontinued at trial baseline), E 25 mg twice weekly SC plus SSZ tablets (E+SSZ), or SSZ tablets only (unchanged regimen). ACR20, ACR50, ACR70 responders, DAS, and HAQ scores were analyzed with intention to treat (last observation carried forward to replace missing values). Results: The treatment groups (E: 103; E+SSZ: 101; SSZ: 50 patients) were comparable at baseline for demographic variables and disease activity; the mean number of tender and swollen joints ranged from 30-31 and 19-19, respectively. The mean baseline DAS was 5.1 (E), 5.2 (E+SSZ), 5.1 (SSZ). Ninety-six (96) patients discontinued: 38 taking E; 24 taking E+SSZ; and 34 taking SSZ (p< 0.001). A significantly higher number of patients discontinued due to lack of efficacy in the SSZ group (52%) compared to E monotherapy (6%) and in combination (6%). A significantly higher percentage of patients receiving E either as monotherapy (67%) or in combination (77%) achieved an ACR 20 response at 2 years, compared to SSZ alone (34%). ACR 50 and ACR 70 responses were also significantly more frequent for patients in either E group. Mean DAS scores at 2 years were 2.8, 2.5, 4.5 for E; E+SSZ; SSZ, respectively; both E treatment groups were superior to SSZ. Patients receiving E monotherapy or in combination treatment had a greater improvement in HAQ scores (E: 34%; E+SSZ: 40%) compared to the SSZ (5%) group. In general the adverse events were similar in E and E+SSZ treatment groups. The most frequent infections were skin, upper respiratory (URI), bronchitis, flu syndrome, and pharyngitis/laryngitis with no significant difference among the treatment groups except for pharyngitis/laryngitis, which occurred higher, in the E monotherapy group. Conclusion: In patients who had an inadequate response to SSZ, etanercept either alone or in combination provided sustained superior efficacy compared with SSZ alone for 2 years. Efficacy of Etanercept alone was comparable to the combination group throughout the study. All treatments were well tolerated and the safety of etanercept monotherapy was consistent with that observed in other RA studies of etanercept. Editorial Comment: This study demonstrates that etanercept can provide efficacy to patients with active RA in spite of treatment with SSZ, either alone or in combination with SSZ. There was little apparent synergy as there was no significant additive benefit for etanercept in combination with SSZ compared to etanercept alone. A radiographic endpoint was not included but would be important for future studies of TNF antagonists with other DMARDS. Based on other clinical trial data with MTX in combination with TNF antagonists, there are clearly patients, in spite of similar clinical responses, who have synergy in terms of combinations on radiographic outcomes. Nonetheless, this study does not demonstrate any safety signal with the combination. Whether in patients with Early RA, aggressively dosed SSZ in combination with Etanercept would be superior to monotherapy is also unknown. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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