Rheumatoid Arthritis - TNF Antagonists
Three agents that inhibit TNF are currently approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: etanercept (Enbrel®), adalimumab (Humira ®), and infliximab (Remicade®). Two new TNF antagonists are being evaluated in rheumatoid arthritis and other rheumatic disease indications. At last year’s ACR meeting information regarding certolizumab pegol (Cimzia®) was presented and discussed and subsequently published (1,2).
At this year’s meeting, new clinical trials of golimumab and etanercept in RA were reported.
- Abstract 1211: Golimumab Administered Subcutaneously Every 4 Weeks in Patients with Active Rheumatoid Arthritis Despite Methotrexate: Week 24 Results of the Randomized, Double-Blind, Placebo-Controlled, GO-FORWARD Study
- Abstract 1208: Clinical Remission, Radiographic Non-progression, and Normalized Function With the Combination of Etanercept and Methotrexate in the Treatment of Early Active Rheumatoid Arthritis: 1-year Results of the COMET Trial
Abstract 1211: Golimumab Administered Subcutaneously Every 4 Weeks in Patients with Active Rheumatoid Arthritis Despite Methotrexate: Week 24 Results of the Randomized, Double-Blind, Placebo-Controlled, GO-FORWARD Study
Authors:
E. Keystone, M. C. Genovese, L. Klareskog, E. C. Hsia, J. Livingston, M. Wiekowski, S. T. Hall, P. Miranda, J. Pazdur, S. C. Bae, W. Palmer, Z. Wu, M. U. Rahman.
Background:
Golimumab is a fully human monoclonal antibody that binds to TNF with high affinity. Phase II results have recently been published with this compound (3). Other studies were presented at ACR 2008: GO-AFTER for RA patients failing other TNF antagonists, GO-RAISE for ankylosing spondylitis, and GO-REVEAL for psoriatic arthritis.
Purpose:
To assess the efficacy and safety of golimumab (GLM) in patients with active RA despite methotrexate (MTX).
Methods:
Multicenter randomized, DB, placebo (PBO)-controlled study of adult pts with active RA despite MTX. Randomized (3:3:2:2 ratio) to PBO injections + MTX, GLM 100 mg + PBO capsules, GLM 50 mg + MTX, or GLM 100 mg + MTX. Injections were administered every 4 weeks. Co-primary endpoints were the proportion of patients achieving ACR 20 at week 14 and improvement from baseline in HAQ at week 24.
Results:
444 patients were enrolled. GLM + MTX was significantly better than PBO + MTX in improving signs and symptoms of RA, as well as in improving physical function. The 2 GLM doses + MTX were comparable in efficacy. While the GLM alone group had numerically better efficacy parameters than MTX alone, they generally did not reach statistical significance. GLM was generally well-tolerated. Through week 16, the proportions of patients who had >1 adverse event was 60.9%, 63.2%, 68.5%, and 69.7% in the PBO + MTX, GLM 100 mg + PBO, GLM 50 mg + MTX, and GLM 100 mg + MTX, respectively. Serious adverse events occurred in 2.3%, 3.8%, 5.6%, and 9.0% of patients, respectively. Serious infections occurred in 0.8%, 2.3%, 2.2%, and 5.6% of patients, respectively. Injection site reactions occurred in 0.0%, 5.3%, 3.4%, and 4.5% of patients, respectively. One patient in the GLM 100 mg alone group died due to diarrhea, colitis, and sepsis. Three pts had malignancies: 1 breast cancer (GLM 100mg + MTX), 1 Bowen’s disease and squamous cell skin cancer (GLM 100 mg + PBO), and 1 basal cell carcinoma (PBO + MTX). There were no reports of tuberculosis or opportunistic infections.
Assessment |
PBO + MTX | Golimumab 100 mg + PBO |
Golimumab 50 mg + MTX | Golimumab 100 mg + MTX |
| n | 133 | 133 | 89 | 89 |
| ACR 20 Week 14 | 44 (33.1%) | 59 (44.4%) | 49 (55.1%)** | 50 (56.2%)* |
| ACR 50 Week 14 |
13 (9.8%) | 27 (20.3%)† | 31 (34.8%)* | 26 (29.2%)* |
| ACR 70 Week 14 |
5 (3.8%) | 10 (7.5%) | 12 (13.5%)** | 8 (9.0%) |
| Median improvement from baseline in HAQ a | 0.13 (-0.13, 0.38) |
0.25 (-0.13, 0.63) |
0.38 (0.12, 0.75)* |
0.38 (0.13, 0.63)* |
| ACR 20 Week 24 | 37 (27.8%) | 47 (35.3%) | 53 (59.6%)* | 53 (59.6%)* |
| ACR 50 Week 24 | 18 (13.5%) | 26 (19.5%) | 33 (37.1%)* | 29 (32.6%)* |
| ACR 70 Week 24 | 7 (5.3%) | 15 (11.3%) | 18 (20.2%)* | 13 (14.6%)† |
| *p < 0.001, **p < 0.01, †p < 0.05. a: HAQ = Health Assessment Questionnaire | ||||
Conclusion:
In patients with active RA despite MTX, the addition of GLM 50 mg or 100 mg SC injections every 4 weeks to MTX significantly reduced the signs and symptoms of RA and improved physical function.
Editorial Comment:
These data presented for golimumab are similar to the results seen with other TNF antagonists. In this study, as with other agents, the combination of a TNF antagonist with methotrexate was superior to MTX or the TNF antagonist alone. There have been no studies to date however to study TNF antagonists head to head. The side effects reported for these additional TNF antagonists are similar to other agents are seen including infections. Monitoring for malignancies will need to continue through large safety registries. The monthly administration schedule for this particular agent may provide some additional convenience to patients.
Editor: Clifton Bingham, III, M.D.
Abstract 1208:
Clinical Remission, Radiographic Non-progression, and Normalized Function With the Combination of Etanercept and Methotrexate in the Treatment of Early Active Rheumatoid Arthritis: 1-year Results of the COMET Trial
Authors:
P. Emery, F. C. Breedveld, S. Hall, P. Durez, D. J. Chang, R. Pedersen, A. S. Koenig, D. Robertson, B. Freundlich
Background:
COMET (Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis) was a study to evaluate etanercept in combination with MTX in comparison to MTX alone in patients with early RA. This study was also recently published (Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, Singh A, Pedersen RD, Koenig AS, Freundlich B. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet. 2008 Aug 2;372(9636):375-82.)
Methods:
Double-blind, randomized study of RA pts with disease duration <=2 years, MTX-naïve, and active RA (DAS28 >=3.2) with either elevated ESR (>=28 mm/hr) or CRP levels (>=20 mg/L). MTX was titrated from week 4 to a maximum of 20 mg/wk at week 8. Efficacy endpoints were DAS28 remission (<2.6), modified Total Sharp Score (mTSS), low disease activity (DAS28 <=3.2), radiographic non-progression (mTSS <=0.5), and HAQ score within the norm (<=0.5). Missing values were imputed using last-observation-carried-forward for clinical analyses and linear extrapolation for radiographic analyses.
Results:
Of 542 pts enrolled, 528 pts were evaluable for clinical efficacy (n=265, ETN+MTX; n=263, MTX) and 476 pts for radiographic efficacy (n=246, ETN+MTX; n=230, MTX). Only 21% had prior DMARD use; 92% had severe disease (DAS28 >5.1). At week 52, 50% (132/265) in the ETN+MTX group achieved DAS28 remission vs 28% (73/263) in the MTX group (p<0.001). A significantly greater proportion in the combination therapy group (64%) also achieved low disease activity than in the MTX alone group (41%; p<0.001). Combination therapy resulted in significantly lower radiographic progression than MTX monotherapy, with mean mTSS changes from baseline of 0.27 (ETN+MTX) and 2.44 (MTX; p<0.001) at wk 52. Radiographic non-progression was achieved by 80% (196/246) of pts receiving ETN+MTX and 59% (135/230) receiving MTX (p<0.001). The proportion of pts achieving HAQ scores within the norm (<=0.5) was significantly greater with ETN+MTX (55% [140/256]) than with MTX (39% [93/241]; p<0.001). Serious AEs were reported by 33 pts (12%) in the ETN+MTX group and 34 (13%) pts in the MTX group. There were no differences in rates of serious infections or malignancies and no cases of tuberculosis or demyelinating disease.
Conclusion:
These results show that the combination of etanercept with MTX in early RA was superior to MTX alone in terms of clinical endpoints, including DAS28 remission, radiographic non-progression, and normalized physical function.
Editorial Comment:
The results of this study are not surprising and are in line with what has been shown for other TNF antagonists in similar study designs. The TEMPO study has been often cited showing the benefits of combination therapy, but enrolled many patients who had established disease. The COMET study recruited early RA patients, similar to those seen in ASPIRE with infliximab (4) and PREMIER with adalimumab (5). While on a group level we have seen several studies that suggest that combination therapy with a biological agent with MTX is superior to MTX alone in early disease, at the individual level many patients have excellent results with MTX alone aggressively dosed as monotherapy. What is still lacking is the ability to risk stratify patients at disease onset for those needing the more aggressive approach. Additional studies of that evaluate initial combination biological vs nonbiological DMARDS + MTX therapy vs MTX step up therapy to biological or nonbiological agents for inadequate responders in early disease are needed.
Editor: Clifton Bingham, III, M.D.
- Abstract 1263: Drug-Specific Risk of Tuberculosis in Patients with Rheumatoid Arthritis Treated with Anti-TNF Therapy: Results from the BSRBR
- Abstract 1264: The Influence of Anti-TNF Therapy upon Cancer Incidence in Patients with Rheumatoid Arthritis who have had a Prior Malignancy: Results from BSRBR
Abstract 1263: Drug-Specific Risk of Tuberculosis in Patients with Rheumatoid Arthritis Treated with Anti-TNF Therapy: Results from the BSRBR
Authors:
Dixon, Hyrich, Watson, Lunt, Symmons; Manchester, United Kingdom
Background:
TNF is required to maintain tuberculosis (TB) latency within granulomas and cases of TB, presumably due to reactivation of latent disease, have been reported with the use of TNF inhibitors. Consequently, screening for latent TB is recommended prior to the initiation of TNF inhibitor therapy in most areas. Because of their high affinity for TNF, treatment with monoclonal anti-TNF antibodies may be more highly associated with TB than with decoy TNF receptors, although drug-specific effects have not been studied. Dixon and colleagues reported an investigation comparing TB rates among users of the three commercially available TNF inhibitors in the United Kingdom.
Methods:
The BSR Biologics Register was used to compare rates of TB among users of etanercept, infliximab, and adalimumab against rates in non-biologic DMARD users. TB cases were confirmed and classified as definite or probable. Events were attributed to the most recent drug prior to TB incidence.
Results:
The registry contained 10,408 patients enrolled at the time of beginning a TNF inhibitor (5,471 etanercept, 3,714 infliximab, and 4,471 adalimumab), and 3,106 at the time of beginning a non-biologic DMARD. TNF inhibitor treated patient were slightly younger than non-biologic treated patients (mean age 56 vs. 60 years, respectively), and were slightly more likely to be female (76 vs. 72%, respectively), had a longer disease duration (11 vs. 6.5 years, respectively) and a higher DAS28 score (6.6 vs. 5.0, respectively).
During follow-up, 35 cases of TB were reported (20 definite; 15 probable). All cases were in TNF inhibitor treated patients with no cases noted in non-biologic treated patients, resulting in an unadjusted incidence rate ratio (IRR) for TB associated with TNF inhibitors of 8.7 (95% CI 1.0 – 73.8) if a hypothetical case were included in the non-biologic group. Among TNF inhibitor treated patients, the rate of TB was lowest for etanercept treated patients (50/100,000 patients years) compared to infliximab (131/100,000 patient years) and adalimumab (196/100,000 patients years). Thus, compared to etanercept, the IRR for TB after adjusting for age, gender, and year of enrollment was 2.8 times higher for infliximab users and 3.8 times higher for adalimumab users. Very early cases, likely representing reactivation, were seen primarily in infliximab treated patients and disseminated disease was observed only with use of monoclonal antibody TNF inhibitors.
Conclusions:
Although rates of TB were low overall, TNF inhibitor exposure, in particular use of monoclonal antibodies against TNF, was associated with significantly higher rates than in patients using other non-biologic DMARDs.
Editorial Comment:
Large registry studies such as this are required to uncover risks related to rare outcomes, such as TB. Despite its rarity, any case of TB associated with a drug is important and these data do, for the first time, make a convincing quantitative argument that TB occurring with monoclonal antibody TNF inhibitors may be both more frequent and severe than that occurring with decoy receptors. Still, the risk of TB with etanercept was higher than with other DMARDs, suggesting that there is no TNF inhibitor free from all risk. The authors did not evaluate the impact of TB screening on risk, or the role of treating for latent tuberculosis prior to TNF inhibitor therapy. Thus, there still may be ways to reduce the already low rates observed here. Finally, it should be noted that the differences observed in this study may be more pronounced in geographic locations with a higher prevalence of latent tuberculosis.
Editor: Jon Giles, M.D.
Abstract 1264: The Influence of Anti-TNF Therapy upon Cancer Incidence in Patients with Rheumatoid Arthritis who have had a Prior Malignancy: Results from BSRBR
Authors:
Dixon, Watson, Lunt, Hyrich, Symmons; Manchester, United Kingdom.
Background:
Although TNF inhibitor use has not been consistently linked to an increased risk for new solid or hematologic malignancies, their use has been discouraged in patients with prior malignancies. Thus, there is no evidence that use increases the risk of recurrent or new incident malignancies. Dixon and colleagues presented an investigation exploring TNF inhibitor use in patients with prior malignancies.
Methods:
Patients enrolled in the BSR Biologics Register were identified using links to a national cancer registry with prior diagnoses of any malignancy (excepting carcinoma in situ and non-melanomatous skin cancers) occurring before the initiation of TNF inhibitor therapy or enrollment into the cohort for non-biologic treated patients. Patients were then followed for the development of new primary malignancies, local recurrence, and metastatic disease and the incidence rates compared between TNF inhibitor treated and untreated patients. Non-confirmed cases were excluded.
Results:
Among the 10,735 enrolled subjects using TNF inhibitors, 177 (1.6%) had a prior included malignancy compared to 118 (3.6%) of the 3,236 non-biologic DMARD treated patients. Among subjects with prior malignancies, TNF inhibitor treated subjects were slightly younger than DMARD treated subjects (62 vs. 66 years at enrollment, respectively), more likely to be female (81% vs. 74%, respectively), and have a longer disease duration (11 vs. 9 years, respectively), higher DAS28 at initiation of therapy (6.7 vs. 5.0, respectively), and higher HAQ score (2.2 vs. 1.6, respectively). Prior malignancies occurring greater than 10 years prior to enrollment were seen in 58% of the TNF inhibitor treated patients and 40% of the DMARD treated patients. Prior solid tumors were noted in 83% of the TNF inhibitor treated patients and 82% of the DMARD treated patients.
Among TNF inhibitor treated patients, 13 incident cancers were observed in 11 patients over a median follow-up time of 3 years, resulting in an incidence rate of 25 per 1000 patient years. Among DMARD treated patients, 9 incident cancers were observed in 9 patients, resulting in an incidence rate of 38 per 1000 patient years. The resulting incidence rate ratio for new cancers was 0.68 for TNF inhibitor treatment compared to non-treatment, a ratio that was not statistically different from 1.0. Adjusting for age and gender did not alter the significance of the association.
Among the 17 TNF inhibitor treated patients with melanoma, 4 incident cancers were observed in 3 patients compared to no incident cancers in the 10 DMARD treated patients with prior melanoma.
Conclusions:
As currently prescribed, TNF inhibitor use is not associated with an increased risk of incident new or recurrent cancer in RA patients with prior malignancy.
Editorial Comment:
These findings are reassuring for RA patients with prior malignancies in whom elevated RA disease activity would benefit from TNF inhibitor therapy. However, as the authors were careful to point out in their discussion, these results only support no added risk when current guidelines for limiting use in patients with prior malignancies are followed. More liberal use in RA patients with prior malignancy could be associated with greater risk, although it is difficult to assess from these data. Thus, caution should still be observed in patients with prior cancers. Although the numbers are low and follow-up relatively short, an increased signal for recurrent melanoma with TNF inhibitor use may be indicated, suggesting that TNF inhibitors should be carefully used in patients with prior melanoma.
Editor: Jon Giles, M.D.
References
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