Introduction

The last 10 years have seen a number of new biologic agents come to market, agents that have significantly changed the way we treat patients with rheumatoid arthritis (RA). Tumor necrosis factor (TNF) inhibitors were the first biologics to be added to the therapeutic arsenal; they have now been followed by the US Food and Drug Administration (FDA) approval of biologic agents with different modes of action. B-cell-depleting therapies, the T-cell modulator abatacept, and the interleukin (IL)-6 inhibitor tocilizumab are new agents that will likely find wider use as their unique attributes are studied. The EULAR 2008 session "B Cells and Beyond" focused on some of the latest studies related to these newer agents in the treatment of RA, with a focus on B-cell-depleting therapies.

Update on B-Cell Depletion

B-cell depletion using anti-CD20 antibodies is becoming a widely recognized therapeutic option for patients with severe RA, and currently rituximab (RTX) is FDA approved in the United States for the treatment of RA in patients who have failed methotrexate (MTX) and a TNF inhibitor. Additional B-cell therapies are also being studied and are anticipated to be on the market within the next 2-3 years.

Bokarewa and colleagues^[1] evaluated phenotype of B cells in peripheral blood and bone marrow in patients with RA before and 1 year after completing anti-CD20 treatment. Blood and bone marrow samples were obtained from 23 patients with RA admitted for treatment with anti-CD20 antibodies ( RTX). All patients had active joint disease (mean disease activity score [DAS]28: 5.82±0.74); some had tried an antiCD20 treatment before enrollment. The comparison between the 8 patients who had experienced prior anti-CD20 treatment and the 15 patients who were anti-CD20-naive revealed no difference in absolute B-cell counts in blood or bone marrow. The analysis of B-cell phenotype showed a significantly lower proportion of CD27+ cells in peripheral blood of previously treated patients compared with naive patients; this difference was most pronounced in the CD27+IgM+ population of B cells.

This study suggests that anti-CD20 treatment was associated with long-lasting changes in the phenotype of B cells both in bone marrow and in peripheral blood. These changes are characterized by a reduction of CD27 memory B cells along with an increase of early transitional and pre-germinal center population of B cells. This may have an effect on changing RA activity in a more persistent way by possibly eliminating some of the responsible B-cell populations. However, more study is needed in more patients and with disease-modifying antirheumatic drug (DMARD) controls to show that the reduction in CD27 memory B cells has long-term benefits to the RA patient.

Update on Rituximab

Some studies have suggested that up to 50% of RA patients experience a failure on anti-TNF agents ( TNF-alpha failure) and some may respond more favorably to a different class of biologic therapy, such as RTX, than to a second or third alternative TNF-alpha agent.^[2] This study analyzed the effectiveness of RTX vs alternative TNF-alphas on disease activity (DAS28) in RA patients with TNF-alpha failure and examined potential effect modification by the type of prior TNF-alpha failure or the type of TNF-alpha switch.^[2]

This was a prospective cohort including all patients with a TNF-alpha failure to at least 1 TNF-alpha agent, who received subsequently either 1 cycle of RTX or an alternative TNF-alpha. The primary outcome was the evolution of the disease activity score (DAS)28 over the first year. A total of 300 RA patients were included in the study; overall, 65% of patients had experienced a prior TNF-alpha failure due to ineffectiveness (28% primary, 72% secondary) and 35% due to adverse event (AE). At baseline, there was no significant difference between the 2 therapeutic groups in age, disease duration, function, rheumatoid factor positivity, concomitant glucocorticoid, or DMARD use, but groups differed in baseline DAS28 levels and in number of previous TNF-alpha failures. After adjustment for potential confounders, and in particular for baseline DAS28, the evolution of DAS28 was overall more favorable in the RTX group compared with the TNF-alpha group (P = .01). However, the relative benefit of RTX varied with the type of prior TNF-alpha failure (effect modification). When the motive for switching was ineffectiveness to a previous TNF-alpha, then the evolution of DAS28 was significantly better for RTX than for an alternative TNF-alpha. When the motive for switching was another cause (ie, an AE), then the evolution of DAS28 was similar for RTX and for alternative TNF-alphas. This observational study suggests that RTX may be more effective than switching to an alternative TNF-alpha in RA patients who have persistent active disease despite of TNF-alpha. However, when the motive for interrupting TNF-alpha was something other than ineffectiveness, both RTX and alternative TNF-alpha agents appear to offer similar levels of effectiveness, as shown in previous studies as well.^[3]

It has been noted that the development of anti-infliximab antibodies is associated with decreased efficiency and increased risk for adverse effects. The authors assessed the proportion of RA patients in which treatment with RTX resulted in the depletion of anti-infliximab antibodies.^[4] Consecutive RA patients with detectable anti-infliximab antibodies who were initiated on treatment with either RTX or adalimumab were included in this prospective controlled cohort study. Anti-infliximab antibody levels were measured before the first administration of RTX/adalimumab and after 16 and 24 weeks.

Of the 32 patients included, 17 were treated with RTX and 15 with adalimumab. After 24 weeks, the median serum anti-infliximab antibody levels in the RTX group and adalimumab group decreased from 29 AU/mL to 23 AU/mL and from 100 AU/mL to 44 AU/mL, respectively. The decrease in anti-infliximab antibody levels was not more pronounced in the RTX group (20% ± 38 reduction) compared with the adalimumab group (36% ± 52 reduction). In none of the patients did RTX treatment lead to seroconversion of anti-infliximab antibodies. The authors concluded that RTX neither abrogates anti-infliximab antibodies nor modulates the change of existing anti-infliximab antibody levels compared with adalimumab. This may be important in making a treatment decision, especially if patients are re-treated with infliximab after failing RTX therapy.

Update on Ocrelizumab

Ocrelizumab (OCR) is another anti-CD20 humanized monoclonal antibody. A study was done to assess OCR, administered as a single intravenous infusion, in moderate-to-severe RA patients receiving concomitant MTX after multiple DMARD failure.^[5]

Patients were randomized to receive single infusions of either OCR or matching placebo. A total of 175 patients were recruited; no peri-infusional corticosteroids (PICS) were given prior to the infusion of study drug. The primary endpoint was the proportion of patients who achieved an American College of Rheumatology (ACR) 20 response at week 24. Complete peripheral B-cell depletion was achieved in all OCR dose groups compared with placebo. The ACR20/50/70 responses at week 24 were 49%, 27%, and 14% in the combined OCR group and 34%, 9%, and 3% in the placebo group, respectively. Treatment with a single infusion of OCR in RA patients achieved B-cell depletion at all doses and was accompanied by increased ACR20/50/70 responses vs MTX alone. Single infusions were well tolerated, with only 1 withdrawal due to intolerance despite the absence of PICS. However, the use of PICS may play a role in future studies to reduce the incidence and severity of infusion-related events. The incidence and type of other AEs, including infections, were similar in the placebo and OCR groups and did not increase with longer observation and repeated exposure.

Update on TRU015

The CD20-directed drug candidate, TRU-015, is a small modular immunopharmaceutical (SMIP) protein, a new class of protein therapeutics. It has been shown to be effective as a single infusion in patients with RA. B-cell depletion has generally been dose-dependent and exposure was approximately dose-proportional. TRU-015 generally has been well tolerated. A single infusion of 5 or 15 mg/kg of TRU-015 resulted in comparable exposure and pharmacodynamic effects when compared with 2 infusions of 2.5 or 7.5 mg/kg, respectively, given 1 week apart, justifying a single infusion in future studies. This study looked at repeated infusions of TRU-015.^[6]

Fifty-four subjects were eligible for re-treatment in this protocol. A total of 102 re-treatment courses were received. No subject experienced a grade 3 or 4 AE on the day of re-treatment. Subjects have received up to 6 courses of TRU-015. B-cell profiles after each course of therapy generally have been comparable to those seen with prior infusions. ACR responses were maintained during re-treatment. In this small study, repeated administration of TRU-015 in RA subjects continued to be well tolerated in general. The safety and pharmacodynamic effects after re-treatment with TRU-015 can be said to be comparable to those seen after initial therapy. Further studies with TRU-015 are needed before any firm conclusion about its place in RA treatment can be assessed.

Update on Abatacept

Several studies have shown that early aggressive treatment of RA is associated with improved outcomes and may lead to increased remission rates. The long-term durability and safety of abatacept as a first-line biologic treatment option in patients with inadequate response to MTX was shown previously.^[7] This study looked at rates of remission and clinical outcomes after treatment with abatacept in biologic-naive RA patients with early disease (2 years or less) and an inadequate response to MTX, and then compared those rates against those of patients with long-standing RA ( more than 10 years of disease).^[7]

Data from 2 trials, a phase 2 and a phase 3 assessing the efficacy of abatacept in patients with inadequate response to MTX, were pooled for these exploratory post-hoc analyses. Outcomes assessed at Year 1 and Year 3 included ACR responses, DAS28 C-reactive protein (CRP)-defined remission, low disease activity, and improvement in physical function as measured by health assessment questionnaire (HAQ). Twenty three percent of patients (n = 108) had early remission. Of the whole cohort, 25.4% of patients at Year 1 and 35.6% of patients at Year 3 were in DAS28 remission. Patients with early disease were more likely to achieve DAS28 remission compared with patients with longer-standing disease, with 46.0% of early RA patients in remission at Year 3. Remission rates were significant at both Year 1 and Year 3. In addition, patients with early disease tended to have increased ACR responses, significant for ACR70 response at both Year 1 and 3, and significantly more patients had a meaningful improvement in their HAQ scores at Year 1.

This study showed that RA patients who have an inadequate response to MTX, early disease (2 years or less), and are treated with abatacept appear to have more significant improvement in their disease activity compared with patients with long-standing disease ( more than 10 years), with about half of the patients in DAS28 remission at 3 years. These data may support the use of abatacept in biologic-naive patients with early disease who have had inadequate response to MTX.

Update on Tocilizumab

IL-6 and TNF-alpha play major roles in the development and maintenance of RA. Tocilizumab (TCZ; an anti-IL-6 receptor monoclonal antibody) inhibits IL-6 signaling and may provide a novel therapy option for anti-TNF-refractory patients. The RADIATE study investigated the effect of TCZ plus MTX on efficacy and safety measures in patients with active RA despite prior anti-TNF treatment; ACR20 was the primary endpoint.^[8]

Notably, the proportion of patients in the 8-mg/kg group achieving remission (DAS28 < 2.6) was similar to the ACR50 response and more than double the ACR70 response. TCZ was effective irrespective of the number of or the most recently failed anti-TNF treatments. In the control, 4-mg/kg, and 8-mg/kg groups, AEs were seen in 81%, 87%, and 84%, respectively, and serious AEs were seen in 11%, 7%, and 6%. Infections occurred in 41%, 47%, and 50% and serious infections occurred in 3%, 2%, and 5%. There was no difference in safety or tolerability on the basis of prior anti-TNF treatment.

TCZ+MTX therapy showed clinical improvements in efficacy and safety in this refractory population, irrespective of the number of anti-TNF treatments or the most recently failed treatments. The dose response favored 8 mg/kg TCZ. Further studies will be needed to better define the safety profile of this agent.

Update on Denosumab

RA is characterized by periarticular bone loss and bone erosions, which are mediated by osteoclasts, whose formation, function, and survival depend on receptor activator for nuclear factor κ B ligand (RANKL).Denosumab, a fully human monoclonal antibody, inhibits RANKL and increases bone mineral density (BMD) in postmenopausal women with low bone mass. This study was conducted to evaluate the effects of denosumab on hand BMD in RA patients and assess its relationship with erosion scores of the hand.^[9] Patients with active, erosive RA who were receiving stable doses of MTX were randomized to receive subcutaneous injections of placebo or denosumab (60 or 180 mg) every 6 months. Denosumab treatment increased hand BMD at 6 months (mean percent change of 0.81% for denosumab 60 mg and 1.97% for denosumab 180 mg) compared with placebo (mean percent change of -1.17%). Denosumab-mediated increases in hand BMD were sustained at 12 months and were associated with reductions in the rate of progression of erosions. This seems to suggest that increases in hand BMD in patients with RA treated with denosumab may be associated with concomitant reductions in the rate of progression of erosions of the hand, as measured independently by MRI and radiography.

Conclusion

Several new therapies soon will be added to our recently increased number of treatment options. Different types of RA patients will require different therapies, especially those who have failed multiple agents. These new options look promising in filling the gap in our treatment of RA patients. Further studies in larger numbers of patients should help shed more light on their exact role in RA treatment.

This activity is supported by an independent educational grant from Roche.