Sequencing Biologic Therapeutic Strategies in Rheumatoid Diseases

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - 75th Annual Meeting of the American College of Rheumatology

Chicago, Illinois / November 5-9, 2011

Chicago - By preventing tissue damage caused by inflammation, TNF inhibitors are changing the natural history of joint diseases and other autoimmune processes. At the ACR 2011 meeting, substantial data and discussion were devoted to the effort to identify a rational order of biologics in patients inadequately controlled on disease-modifying antirheumatic drugs. While TNF inhibitors are still widely considered first-line among biologics, there are important differences between agents within this class, including the mechanism by which TNF activity is blocked. In the absence of direct comparison trials, relative differences between TNF inhibitors are being explored in long-term follow-up studies, cohort analyses and other data pools with the potential of revealing relative differences in efficacy, safety and patient preference. Current studies are also continuing to explore how early to begin biologics in order to optimize long-term outcome in a variety of inflammatory joint diseases.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Across the spectrum of rheumatoid diseases, biologics have redefined the goals of treatment. Rather than just suppression of symptoms, it is now reasonable to anticipate extended periods of complete remission even in patients with severe disease. This advantage means relative protection against progressive structural damage. One key question is how early to consider TNF inhibitors or other biologics in order to reduce structural damage. At the 2011 ACR, several studies evaluated different approaches to determine reasonable treatment algorithms, particularly in rheumatoid disorders other than rheumatoid arthritis (RA), where there is already support for early biologic therapy.

Consistent Benefit of Earlier Treatment

In psoriatic arthritis (PsA), one of the most challenging of the rheumatologic disorders due to concomitant inflammation in the joints and skin, one of the strongest new pieces of evidence to support early therapy emerged from a new analysis of the PRESTA trial. In the multicentre study, 752 PsA patients were randomized to receive the TNF inhibitor etanercept 50 mg once-weekly or twice-weekly. The study’s primary results presented last year did demonstrate that the once-weekly dose was as effective for control of joint symptoms (but less so for clearing psoriasis); however, the new data demonstrate that joint outcomes were better in all patients if the biologic was initiated earlier in the course of the disease.

“In the group that received the biologic within 2 years of symptom onset, there was greater improvement from baseline in a variety of measures compared to those who started later,” reported Dr. Bruce Kirkham, Guy’s and St. Thomas’s Hospital, London, UK (Figure 1). Although both groups benefited from the TNF inhibitor, those who started later had worse baseline values in such measures as Health Assessment Questionnaire (HAQ) of Physical Function and Physician Global Assessment (PGA). Treatment did not allow the late starters to fully catch up with those started earlier.

“These findings suggest that PsA patients could achieve better outcomes if they started etanercept earlier,” confirmed Dr. Kirkham, echoing a conclusion that has been recently drawn from similar analyses conducted in RA patients. Overall, the concept is that if the inflammatory response is controlled earlier, it is easier to halt the many interrelated pathways of inflammatory signalling, providing a more profound degree of remission. It is consistent with the principle that the most sustained disease control initiated prior to joint destruction is likely to provide the greatest long-term benefit.

Figure 1.

Impact of Neutralizing Antibodies

Whether employed in PsA, RA or other inflammatory arthropathies, TNF inhibitors are widely regarded as the first-line biologic because of proven efficacy and well-defined risks. However, TNF inhibitors are not interchangeable. While all but one are monoclonal antibodies (MAbs), even these differ to the degree that they employ chimeric or humanized molecules in their structure. As a fusion protein that blocks soluble TNF receptors, etanercept is the exception.

One of the biggest differences between TNF inhibitors is their potential for generating neutralizing antibodies. Prospective comparisons have not yet been conducted, but risk of neutralizing antibodies has treatment implications in the long term.

For example, a Canadian study comparing infliximab to etanercept in 116 patients treated long-term emphasized the need for dose escalation with infliximab. In this real-world study led by Dr. Brian D. Hanna, McMaster University, Hamilton, Ontario, the baseline characteristics of 37 patients on infliximab and 79 patients on etanercept collected between June 2000 and December 2010 were similar. About 70% of patients in both groups were on concomitant methotrexate (MTX) and about 80% were positive for rheumatoid factor.

At the most recent follow-up, the proportion of patients still on their initially assigned TNF inhibitor was slightly greater in the infliximab group (59.4% vs. 53.2%), but 51.3% had required dose escalations over the course of treatment vs. none in patients receiving etanercept. Drug survival on the standard recommended doses of these agents was 58 months for etanercept and 27 months for infliximab.

The difference in the patterns in TNF inhibitor use has implications for long-term disease control. “Half of the patients treated with infliximab required dose escalation and nearly all of these patients were maintained at the higher-than-recommended dosage. The majority of these patients [73.8%] received treatment on a 6-week schedule with a median dose increase from the optimal dose of 1.22 mg/kg,” Dr. Hanna reported.

Implications of Dose Increases

The frequent need for dose escalations for infliximab, which has also been reported for other MAbs, is relevant to long-term costs of therapy. A US managed care study of patients with PsA evaluated relative costs of infliximab, adalimumab and etanercept. The one-year mean cost per patient in the group that was biologic-naive was substantially higher on infliximab ($23,329) and adalimumab ($17,614) than on etanercept ($13,447), but the differences were greater in those who had been on a TNF inhibitor and continued therapy: the one-year costs were $24,806 for infliximab, $19,098 for adalimumab and $14,476 for etanercept.

Some of the disparity in cost may have been generated by differences in mode of administration, dosing range and dosing frequency, according to the lead author Dr. Vernon F. Schabert, IMS Consulting Group, Alexandria, Virginia, but he suggested that most of the difference were produced by the development of neutralizing antibodies.

“Neutralizing antibodies can develop to adalimumab and infliximab, leading to decreased effectiveness and the need for dose escalation. In fact, their prescribing information recommends dose escalation over time as needed for inadequate response, whereas etanercept has not been associated with antibodies and dose escalation is not in the product label,” Dr. Schabert explained to delegates.

Similar results were produced by a study conducted with a US claims database in RA patients taking a biologic. This analysis was based on a cohort of biologic-naive patients who began treatment with etanercept, infliximab or adalimumab between the years 2005 and 2009 and were maintained for at least 12 months. The claims database included 1420 patients treated with etanercept, 874 treated with adalimumab and 454 treated with infliximab. The goal of the study was to calculate the percentage of patients who required a dose increase.

Dose increases were assessed by average weekly dose, average ending dispensing dose, and average dose increase over the initially assigned maintenance dose. By all 3 measures, significantly fewer patients treated with etanercept received a dose escalation, according to the lead author Dr. Amie T. Joyce, IMS Health, Watertown, Massachusetts. By the measure of the weekly dose, for example, 3.9% of patients on etanercept had a dose increase vs. 21.4% of those receiving adalimumab and 69.6% of those receiving infliximab (P<0.0001 for etanercept vs. either agent). Dr. Joyce also reported that the claims database, which captured drug costs, demonstrated lower costs for etanercept based primarily on its association with a lower likelihood of dose escalation.

Implications of a First-choice Biologic

The importance of a first-choice TNF inhibitor was also demonstrated in data provided by GISEA, an ongoing Italian multicentre registry that is collecting data from 14 tertiary treatment centres in Italy. Data from 3702 RA patients initiating a biologic between 1999 and 2010 demonstrated that patients who continued on their first biologic had better EULAR responses at 12 months than those who required a switch. When first-choice therapies were compared, patients on either etanercept or adalimumab were less likely than those on infliximab to switch. Other predictors for a switch from the first biologic were use of steroids, longer disease duration, younger age and a high rate of disease activity.

“A switch because of inadequate efficacy resulted in worse response and higher probability to fail again on the second-line agent,” reported Dr. Bernd Raffeiner, University of Padua, Italy. “As second-line agents, biologics with novel mechanisms [non-TNF inhibitors] of action presented the lowest discontinuation rates but they were not significantly lower than anakinra or etanercept when used second-line.”

A Bayesian analysis of efficacy at 24 weeks in a systematic review of randomized controlled trials supports differences between TNF inhibitors. While all of the TNF inhibitors demonstrated highly significant advantages over placebo in the 16 published trials entered into this analysis, a hierarchy emerged when TNF inhibitors were compared to each other. Of these agents, the most effective ones overall using 3 different measures of benefits were certolizumab and etanercept. Both of these agents were superior to infliximab, adalimumab and golimumab when compared for ACR20, ACR50 and HAQ. When compared to each other, etanercept was superior to certolizumab for HAQ, inferior for ACR20 and equivalent for ACR50.

As predicted by some previous efforts to compare TNF inhibitors, “Bayesian mixed-treatment comparison models suggest that there are differences in efficacy among the TNF inhibitors,” observed the principal investigator of this study, Dr. Susanne Schmitz, Trinity College, Dublin, Ireland. She acknowledged that this type of comparison is not definitive, but it does support the premise that the first-choice TNF inhibitor may make a difference in regard to efficacy.

Correlation Between DAS28 and Risk of Serious Infections

For the long-term risks of biologics, prospective observational registries are generally considered the best source for judging relative safety. One of the more interesting of the most recent analyses involved an effort to compare risk of serious infections in patients receiving DMARDs relative to a TNF inhibitor. The study, conducted with data from the British Society of Rheumatology Biologics Registry (BSRBR), defined serious infections as those that led to hospitalization, intravenous antibiotic use or death. To differentiate early and late risk of infections, the analysis was conducted at 2 time points: 6 months after initiating therapy and then at the end of observation with a mean follow-up of 4.1 years. The investigators limited the comparison of DMARDs to the TNF inhibitor etanercept.

“The interesting result was that there was a correlation between a higher DAS28 [greater disease activity] and greater risk of serious infections for both treatment groups,” reported Prof. Paul Emery, University of Leeds, UK (Figure 2). For example, the infection rate among patients with a DAS28 =5 was 27.1 per 1000 patient-years but rose to 40.5 in those with a DAS28 >6 and =7 and to 64.2 among those with a DAS28 >8. In contrast—even after adjusting for age, gender, baseline HAQ score and comorbidity index—the modest increase in the risk of serious infections in the TNF inhibitor group was not significantly greater than it was for DMARDs (HR 1.07; 95

Figure 2.


“The results of this analysis infer that the most significant factor reducing the risk of serious infections would be to reduce disease activity,” Prof. Emery told delegates. Although he cautioned that further corroboration is needed for these observational data, the findings support a hypothesis that serious infections in RA patients are not necessarily treatment-related.

Other Findings from the BSRBR

In a separate BSRBR analysis using the same data pool and an adjusted hazard ratio (aHR) to account for confounders such as comorbidities, the TNF inhibitor relative to DMARDs was associated with significant protection against cardiovascular events (aHR 0.64; 95% CI, 0.49-0.85; P=0.002). Now observed with several TNF inhibitors and attributed to a generalized modification in the inflammatory processes that drive atherosclerosis, this effect may have been responsible for the association of etanercept with a reduction in overall mortality (aHR 0.80; 95% CI, 0.62-1.04; P=0.096). Lymphoproliferative malignancy rates did not differ significantly between those on etanercept and those on a DMARD over the course of the study, although overall malignancy rates were significantly lower on the TNF inhibitor (aHR 0.74; 95% CI, 0.58-0.96; P=0.023).

The percentage of patients who remained on etanercept over the course of this analysis was relatively high. According to Prof. Emery, 71% remained on this therapy at year 1, 61% at year 2 and 54% at year 3. These rates compare favourably to other TNF inhibitors. Starting the biologic that has the greatest likelihood to provide sustained disease control is considered critically important for halting progression and the likelihood of permanent joint damage in RA.


In the full spectrum of rheumatoid arthropathies that include RA, PsA, ankylosing spondylitis and juvenile idiopathic arthritis, biologics have been credited with altering the definition of disease control by making complete remission and a reduced risk of progressive damage more achievable therapeutic goals. This is encouraging earlier use of biologics when DMARDs are inadequate. While there are limited controlled data to prove a hierarchy for selecting first- and second-line biologics, there is increasing evidence, including a series of studies presented at the 2011 ACR, that choosing an initial agent to provide sustained benefit with an acceptable safety and tolerability profile has major long-term clinical and economical implications.

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