EULAR 2006: 7th Annual European Congress of Rheumatology

2006年6月21－24日

荷兰阿姆斯特丹

June 21 - 24, 2006, Amsterdam, the Netherlands

Developments With Established Biologic Agents

Introduction

At the recent 2006 European League Against Rheumatism (EULAR) meeting, a number of abstracts and presentations focused on important new information concerning the efficacy and safety of established biologic agents. Many studies described the inhibitors of the central proinflammatory tumor necrosis factor (TNF).

Update on the BeSt Trial

One of the most eagerly anticipated sets of results came from the 3-year analysis of data from the initial combination therapy with methotrexate and infliximab (BeSt) study, a trial that will surely be considered one of the landmark studies in rheumatology. It addresses the optimal treatment paradigm for patients with early rheumatoid arthritis (RA). This study, initiated in The Netherlands in April 2000, involved 508 patients with early RA (defined as < 2 years of arthritis) randomized to 1 of 4 treatment arms:

• sequential monotherapy (beginning with methotrexate [MTX]);
  
  
• step-up combination therapy (also beginning with MTX);
  
  
• initial combination therapy with MTX, sulfasalazine (SSZ), and high-dose prednisone (as was used in the earlier COBRA study); and
  
  
• initial combination therapy with MTX plus a TNF inhibitor (infliximab).

In all arms, the goal was to achieve low levels of disease activity. At their 3-monthly follow-up visits, patients not achieving this goal, defined by a disease activity score (DAS) of 2.4 or less, were required to have their treatment altered according to an algorithm specific for each group. Eventually, groups 1, 2, and 3 could end up on MTX plus a TNF inhibitor. If patients did achieve low disease activity on 2 successive visits, treatment was tapered (to a minimum of MTX 10 mg/wk over the first 2 years, and off all therapy after the second year). Data from the 12-month and 2-year analyses of this pivotal study have been presented at previous scientific meetings and also have been published.^[1] In summary, patients in groups 3 and 4 achieved low disease activity and even remission quicker than did those in groups 1 and 2, although as might have been expected given the study design with its mandatory changes in therapies, clinical efficacy was comparable across all groups by 2 years. However, the progression of joint damage measured radiographically was less in groups 3 and 4 through the first 2 years of the study.

At EULAR 2006, a number of abstracts with exiting new information from the BeSt study were presented. In one analysis, investigators assessed the effect of tight control of disease activity on radiographic progression — specifically, the association between x-ray changes and known factors that have previously been shown to predict such damage, including the presence of the major histocompatibility antigen HLA-DR4, the shared epitope (SE), rheumatoid factor (RF), and antibodies to cyclic citrullinated peptides (CCP).^[2] Of note, in all groups, tight control of disease resulted in the dissociation of risk between x-ray change and the presence of HLA-DR4 or the SE. Furthermore, in groups 3 and 4, the association between x-ray progression and the presence of RF or anti-CCP antibodies was also eliminated. This suggests that treatment using such a tight control strategy, and in particular tight control with highly effective therapeutic strategies, can be the most important determinant of outcome in early RA.

In earlier analysis of the 2-year data, it was shown that 54% of the patients in group 4, who initially began treatment with MTX plus infliximab, did so well that they were able to taper off the TNF inhibitor. A presentation at EULAR 2006 provided further follow-up of this group.^[3] Remarkably, at 3 years, 66 patients, representing 55% of the 120 early RA patients beginning treatment in group 4, remained at a low level of disease activity off the TNF inhibitor. Perhaps even more notably, 14% of the 120 patients achieved remission according to DAS criteria (DAS < 1.6) while off all therapy. Thus, in early RA, the use of MTX plus a TNF inhibitor in a tight control paradigm may be effective at inducing remission and truly altering the course of RA for a subset of patients. Results from further patient follow-up are eagerly awaited, as is additional information concerning functional status and radiographic progression. Nevertheless, the idea of tapering therapy has relevant implications for safety considerations and for pharmacoeconomic analyses.

Safety Issues

Safety issues are always of concern with immunomodulatory therapies, and there were several presentations at EULAR 2006 on this topic. The use of any agent that alters immune function raises the possibility of certain adverse effects — for example, infection and malignancy. This issue is one that has been of growing concern in rheumatology, with the introduction and study of ever-increasing numbers of biologic agents that target various components of the immune system. Interesting data from the British Society for Rheumatology Biologics Registry (BSRBR) shed some light on risk factors for cancer potentially related to the use of TNF inhibitors.^[4] In this analysis, data from 9999 RA patients who received TNF inhibitors were compared with that from 1877 RA patients who received other treatments for RA, including various disease-modifying antirheumatic drugs (DMARDs), but did not receive TNF inhibitors. The authors found that when adjusted for important risk factors, including age, sex, disease severity, and smoking history, patients who received a TNF inhibitor had a comparable — or even perhaps a lower — incidence of developing cancers compared with RA patients on DMARDs alone. However, when analysis focused on patients who had already had a cancer previously, the risk for newly developing cancer was increased among patients receiving TNF inhibitors. Of note, even though the result was statistically significant, the actual numbers were small; 6 patients with a history of cancer newly developed cancer after therapy with a TNF inhibitor. While further analysis and larger numbers of patients are needed, this suggests that a history of a previous malignancy may place RA patients receiving TNF inhibitors at greater risk for newly developing cancer.

As a side point, this study shows the usefulness of registries as a way to accrue large populations of heterogeneous patients and thereby explore important clinical associations that might never be discovered in a clinical trial. Another study also took advantage of a very large dataset to address the potential association between therapy with TNF inhibitors and a particular type of cancer, lymphoma, that is known to be more common among RA patients than the general population, particularly those with severe active RA. In this study, the authors assessed data from more than 22,000 patients with RA, and also from over 6000 persons with various noninflammatory rheumatic diseases as a control.^[5] As has been noted previously, lymphoma was more common among the RA patients, with a relative risk of 1.8. The authors then assessed whether any treatment predisposed patients to a greater risk of developing lymphoma. Of note, none of the treatments assessed, including all of the TNF inhibitors individually or combined, was associated with an increased risk for lymphoma. Thus, while clinicians caring for RA patients must remain vigilant about cancers, particularly lymphoma, this study provides reassurance that treatment with TNF inhibitors does not appear to increase the risk.

Treatment Cost

In addition to safety, another issue related to TNF inhibitors that is of great interest to both doctors and patients is cost. While doctors and patients are excited about the great clinical efficacy of newer biologic agents, their acquisition costs exceed those of the DMARDs, raising the question of "value" for these newer therapies. One means to addressing this question is cost-effectiveness analyses. The cost efficacy of the TNF inhibitors in treating RA was assessed using data from the BSRBR in a presentation at EULAR 2006.^[6] The authors looked at clinical responses and other data from 7083 RA patients receiving TNF inhibitors and 870 controls also enrolled in the registry. Utilities were derived from measures of functional status and were transformed into quality-adjusted life-years (QALYs). Compared with treatment with conventional DMARDs, treatment with TNF inhibitors cost just 23,882 British pounds (approximately US$42,000) per QALY gained. Of note, in sensitivity analyses, the authors demonstrated that the cost-efficacy would increase substantially with higher rates of deterioration in functional status. This carefully performed analysis shows that treatment of RA patients with TNF inhibitors has an incremental cost-effectiveness that is within the range of generally accepted medical interventions (a commonly cited limit for "cost-effective" treatments is below US$50,000 per QALY gained). This is important information as rheumatologists advocate for their patients to receive highly effective therapies.

Treatment Nonresponders

Important information on the long-term treatment of RA patients with TNF inhibitors has come from longer-term follow-up of patients who had enrolled in earlier clinical trials and, after the completion of the trials, remained on open-label therapy for longer periods of time. For all of the TNF inhibitors, it has been shown that many patients can remain on therapy with sustained efficacy, for example as demonstrated by changes in DAS scores, for years. A question that arises when considering the data from these longer-term follow-up studies is "Why are not all patients responders?" For example, the percentage of patients achieving an ACR20 response may plateau at 70% and remain there over years of follow-up. It could be asked, then, why the 30% of patients who are "nonresponders" still in the study. This question was addressed by a poster at EULAR 2006 concerning clinical characteristics of RA patients over 6 years of open-label treatment and follow-up on adalimumab.^[7] The authors assessed patients who were nonresponders according to ACR20 response criteria, and further divided this group into:

• patients who exited the study due to lack of response;
  
  
• patients who exited the study due to adverse events or other reasons; and
  
  
• patients who remained in the study.

As might have been expected, patients exiting the study due to lack of effect experienced no meaningful response in any of the parameters measured, including tender and swollen joint counts and functional status. However, patients in the other categories did experience statistically significant improvements, in both individual parameters as well as composite indices. For example, among ACR20 nonresponders remaining in the study, the mean DAS score improved 24% from 5.6 to 4.3 (P <.0001). Thus, even patients who do not achieve ACR20 response can still experience meaningful improvement with TNF inhibitor therapy.

References

1. Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt Study). Arthritis Rheum. 2005;52:3381-3390.
2. De Vries-Bouwstra JK, Goekoop-Ruiterman YPM, Verpoort KN, et al. The Association of HLA Class II antigents and anti-CCP antibodies with progression of joint damage is affected by early and targeted treatment of rheumatoid arthritis. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0114.
3. Van der Bijl AE, Van der Kooij SM, Goekoop-Ruiterman YPM, et al. Persistent good clinical response after tapering and discontinuation of initial infliximab therapy in patients with rheumatoid arthritis: 3 year results from the BeSt trial. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0180.
4. Watson KD, Dixon WG, Hyrich KL, et al. Influence of anti-TNF therapy and previous malignancy on cancer incidence in patients with rheumatoid arthritis (RA): Results from the BSR Biologics Register. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract SAT0202.
5. Wolfe F, Michaud K. The risk of lymphoma among persons with rheumatoid arthritis in the United States: No association with anti-TNF therapy. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract SAT0204.
6. Brennan A, Nansback NJ, Nixon R, et al. The cost effectiveness of anti-TNF antagonists in rheumatoid arthritis: Results from the British Society for Rheumatology Biologics Registry. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract THU0208.
7. Weinblatt ME, Schiff MH, Furst DE, et al. Clinical characteristics of patients who continued long-term treatment in a 6-year extension study of adalimumab therapy in RA. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract THU0141.

New Therapies for Inflammatory Arthritis

Introduction

The European League Against Rheumatism (EULAR) 2006 congress, held in Amsterdam June 21-24, 2006, included topics which varied from basic science and pathogenesis to clinical observations, evaluations of available treatments, and reports on new therapies. This review will focus on the abstracts addressing therapies for rheumatoid arthritis (RA). There were no "blockbuster" reports at this meeting, but a number of reports were presented on disease-modifying antirheumatic drugs (DMARDs), tumor necrosis factor (TNF) inhibitors, and the newer biologics, broadening our understanding of their impact on patient outcomes.

DMARDs

A study from The Netherlands evaluated the impact of treatment of patients with undifferentiated arthritis with methotrexate (MTX) as determined by progression to RA and radiographic damage.^[1] The Probable Rheumatoid Arthritis Methotrexate versus Placebo Therapy (PROMPT) study enrolled 110 patients with undifferentiated arthritis who fulfilled the 1958 criteria for probable RA. Patients were randomized to treatment with MTX 15 mg/wk or placebo, and the treatment was modified every 3 months to maintain a Disease Activity Score (DAS) ≤ 2.4. At 12 months, therapy was discontinued and if the patient then fulfilled American College of Rheumatology (ACR) criteria for RA, MTX was restarted. The results showed that fewer MTX-treated patients developed RA compared with placebo (20 vs 29) and that more remissions occurred (18 vs 11) on MTX, which were statistically significant differences. Additionally, radiographic progression was less in the MTX-treated patients. A subanalysis found that fewer anticyclic citrullinated peptide (CCP)-positive undifferentiated arthritis patients receiving MTX developed RA compared with the placebo cohort (P = .0001).

A second study from the Toronto group evaluated aggressive DMARD therapy in 94 patients with early inflammatory arthritis with symptoms of less than 12 months.^[2] Sixty percent of the patients received "triple" therapy with hydroxychloroquine, sulfasalazine, and MTX, and 40% received MTX monotherapy. Patients were monitored every 3 months and the treatment goal was remission defined as a DAS 28 ≤ 2.6, Clinical Disease Activity Index (CDAI) ≤ 2.8, or Simplified Disease Activity Index (SDAI) ≤ 3.3. Fifty-nine percent of the patients who were enrolled fulfilled ACR criteria for RA. At month 12, fewer than 50% of the patients had achieved remission, and the mean swollen joint count for the cohort was 3.8. Although the study authors expressed some disappointment with the results in an early disease cohort, the observations were not unexpected. Previous remission rates in early RA trials evaluating MTX monotherapy and combination biologics plus MTX have reported remissions rates of approximately 20% with MTX monotherapy. The higher remission rate here may represent the inclusion of 41% with undifferentiated arthritis, supporting the observations from the PROMPT study.

A third study evaluating MTX in 301 early RA patients (< 1 year disease duration) over 24 months was reported.^[3] This study compared an intensive-treatment group with a group of patients receiving conventional treatment. Patients in the intensive-treatment group were seen monthly with dose modification based on predefined criteria with a clinical endpoint for disease remission. The results showed that 41% of patients in the intensive cohort achieved remission lasting at least 6 months compared with 24% in the conventional-therapy cohort. Of interest, the mean time until remission was 10 months for the intensive-treatment group and 13 months for the conventional-treatment group.

A multicenter study by a group of researchers from Germany examined the efficacy and safety of subcutaneous MTX in comparison to oral MTX.^[4] RA patients who had not previously received MTX and with active disease defined as a DAS > 4 were enrolled and followed for 24 weeks. Patients received 15 mg MTX, either oral or subcutaneous. At week 16, ACR20 nonresponders were either switched from oral to subcutaneous MTX 15 mg or escalated to 20 mg subcutaneous. A total of 384 patients were enrolled; the majority had disease duration of less than 3 months. The ACR responses at week 24 were statistically superior for the subcutaneous MTX compared with the oral MTX for ACR20 and ACR70 response but not for the ACR50. Remission, defined as a DAS < 2.6, was seen in 34% on subcutaneous MTX and 24% on oral MTX (P < .05). These data suggest a statistical superiority for subcutaneous MTX over oral MTX. This study is interesting, but the ease of oral administration will probably outweigh these findings in influencing practice behavior. As suggested by this report, a switch to subcutaneous MTX after a less than optimal response to oral MTX might be beneficial.

Several analyses from the BeSt study were presented.^[5,6] The overall results at 2 years demonstrated similar numbers of patients in remission (DAS < 1.6) for all 4 treatment groups: sequential DMARD monotherapy, step-up combination, initial combination therapy with prednisone, and infliximab/MTX. At 2 years the various treatment regimens for each group were not significantly different, and demonstrate that tight treatment control, as pursued in this trial to reduce the DAS to < 2.4, is a successful paradigm for management of signs and symptoms of patients with early-onset RA. Radiographic progression at 2 years was less for the combination therapy group with prednisone and the infliximab/MTX compared with the other 2 treatment groups. A subanalysis of the 224 patients initiating MTX in groups 1 and 2 found that 79 (32%) were still on MTX at year 2 with a DAS < 2.4.^[7] This observation is similar to other studies reported above evaluating MTX monotherapy. As also noted previously, radiographic progression as measured by Total Sharp Score (TSS) was still present in the MTX cohorts, even in those patients who demonstrated complete remission. TSS increased to 2.5 ± 5.1 in the MTX monotherapy group compared with an increase of 0.9 ± 2.3 in patients treated with combination therapy.

Cytokine Inhibitors

The impact of TNF inhibitors on cardiovascular outcomes and infections and malignancy was the subject of several oral presentations and posters. Data from the British Society of Rheumatology Register were presented evaluating the impact of TNF inhibitors on cerebrovascular accidents (CVA) and myocardial infarctions (MI).^[8] This registry follows 8076 TNF inhibitor-treated RA patients who were compared with a group of 1351 DMARD-treated patients. After adjustment the incidence rate ratios (IRRs) for the anti-TNF cohort compared with the DMARD cohort were: MI 0.72 (0.30, 1.77); CVA 0.50 (0.24, 1.05). Additionally this group reported a lower incidence of MI for TNF responders in comparison to nonresponders. These results were supported by other studies presented at the meeting which reported the reduced cardiovascular mortality with TNF inhibitors.

The British Society of Rheumatology Register also reported on the influence of TNF inhibitors and previous malignancy on the risk for development of a second malignancy.^[9] A previous preliminary report found no increased risk for subsequent cancers in patients with a past history of cancer subsequently treated with TNF inhibitors.^[10] The present study demonstrated no overall increased risk in patients treated with TNF inhibitors (adjusted IRR 0.7) compared with those treated with DMARD monotherapy. They did observe an increased risk in patients with previous cancers receiving TNF inhibitors (adjusted IRR 2.5) compared with patients receiving DMARDs with no history of cancer. Patients receiving DMARDs with a previous history of cancer had an adjusted IRR of 1.2. Although the data presented in this report are limited by the small numbers of patients with recurrent cancer, these results present important clinical issues and more investigation is necessary to allow us to properly counsel our patients.

Data from the Swedish registry monitoring TNF inhibitor utilization examined the incidence of serious infections requiring hospitalization in these patients.^[11] They compared 2465 RA patients on TNF inhibitors from 1999 to 2003 with 35,450 RA patients who had not previously been exposed to TNF inhibitors. The crude rate of infection reported was 5.6/100 patient-years, not dissimilar to that seen in clinical trials and reported in the literature. After controlling for several confounding variables, the relative risk for hospitalization for infection on TNF inhibitor was 1.39. Almost half the increase in risk was seen in patients previously hospitalized for infections prior to starting TNF inhibitors.

Results from the large Spanish database of TNF inhibitors was reported.^[12] A total of 5341 RA patients treated with TNF inhibitors between 1999 and 2005 were compared with non-TNF-treated RA patients as well as a cohort from the general population. Compared with the other RA treatment populations, the TNF inhibitor-treated cohort had a reduced standardized mortality ratio of 0.81%. There was no difference in mortality from infection between the 2 treatment cohorts.

Adalimumab

A subanalysis of the early treatment of rheumatoid arthritis with adalimumab (Humira) plus methotrexate vs adalimumab alone or methotrexate alone (PREMIER) trial was presented, examining the previously reported observation that TNF inhibitors retard radiographic progression even in patients with a less than optimal clinical response.^[13] This report divided patients on the basis of the presence or absence of radiographic progression as defined by an increase in Total Sharp Score > 0.5, and was correlated with clinical response as defined by ACR response. For patients with x-rays available at months 6 and 24, the rate of radiographic progression was 40% to 60% less for clinical nonresponders as well as ACR clinical responders receiving adalimumab/MTX compared with MTX monotherapy. The change in Total Sharp Score over 24 months was 7.5 for MTX patients achieving ACR70 and 3.9 for the combination cohort. These findings are comparable to those previously reported with infliximab^[14] and to those reported with etanercept^[15] at this meeting.

Infliximab

There were a number of presentations on the persistence of response to TNF inhibitors with varying findings. In general, approximately 20% of patients were off TNF inhibitors at 12 months, and by 3-4 years, 30% to 40% were no longer on treatment, which is still better than survival on conventional DMARD treatment. The rheumatology groups from Belgium reported their experience with infliximab.^[14] Five hundred and eleven patients entered a program to receive infliximab prior to approval in Belgium and have been followed for 4 years. At 4 years, 61.6% of patients remained on infliximab. Of interest, a high DAS score at week 14 or 22 predicted best subsequent treatment discontinuation. This confirms the previous clinical hypothesis that lack of response by week 22 is a good predictor of lack of efficacy.

Etanercept

The results of the 8-year follow-up on the safety and efficacy of etanercept in a global population of patients with RA were presented.^[16] Patients from the early RA or DMARD refractory trials were enrolled in a long-term, open-label safety database and have now been followed for up to 8 years. A total of 2054 patients have been enrolled, representing 8334 patient-years of follow-up. Fifty percent of patients are still on treatment at 7 years. The rates of serious infectious episodes ranged from 0.03/ patient-years to 0.06/ patient-years, similar to that reported in the placebo-controlled trials. The higher rates occurred in the patients with longer disease duration. One case of tuberculosis was reported. The overall number of deaths (etanercept 53, control 83) was lower than expected, and the number of malignancies (etanercept 77, control 69) was similar to that expected. Lymphomas (etanercept 13, control 3) occurred more frequently, as has been reported previously.

Tocilizumab

Tocilizumab, an interleukin(IL)-6 receptor monoclonal antibody, is currently in phase 3 trials for RA and is in development for juvenile idiopathic arthritis (JIA). Results of a 24-week RA clinical trial form Japan were reported. RA patients with active disease on MTX 8 mg/wk, the usual dose in Japan, were randomized to receive tocilizumab (TOC) 8 mg/kg every 4 weeks or placebo.^[17] A total of 125 patients were enrolled with a mean duration of 8 years disease. Compared with placebo, ACR results were statistically superior (P < .001) for TOC at week 24 (ACR20 TOC 80.3%, placebo 25%; ACR50 TOC 49.2%, placebo 10.9%; ACR70 TOC 29.5% placebo 6.3%). No difference in adverse events or serious adverse events was reported except an increase in nasopharyngitis and increase in serum lipids with TOC, as previously reported. Liver function abnormalities previously reported were not observed in this trial.

The same investigators also reported the results of 8 mg/kg TOC every 2 weeks in systemic JIA.^[18] This was an 18-week study with all patients receiving open-label TOC for 6 weeks. At week 6 the responders were randomized to a 12-week double-blind period. However, if patients subsequently relapsed despite treatment, they were withdrawn from the study, received rescue therapy, and were considered as nonresponder. Patients enrolled had a mean age of 8.3 years with 4.5 years of disease. Of the 56 eligible patients, 44 entered the open-label period. In the double-blind period, 19 of the 23 placebo patients withdrew compared with only 4 of the 20 in the actively treated cohort. The most common adverse events were upper respiratory infections and transient liver function test abnormalities. One patient had an anaphylactoid reaction. These studies demonstrate efficacy and safety similar to that seen with TNF inhibitors. It will be of interest to determine which patients will be candidates for IL-6 inhibition rather than TNF inhibitors when this drug is approved. Will TNF nonresponders respond to this cytokine inhibition? Trials to answer that question are ongoing.

IL-15 Inhibitor

IL-15 is a proinflammatory cytokine found in rheumatoid synovium and is capable of T-cell activation and augmentation of TNF alpha and IL 1 production. AMG 714 is a fully human monoclonal antibody to IL-15. This is a phase 2 dose-ranging, 24-week study that included 180 RA patients receiving background MTX but who were DMARD failures and cytokine inhibitor-naive.^[18] The primary endpoint was the ACR20 response at week 14 (ACR20 AMG 714 54%, placebo 38%) which did not achieve statistical significance, although at weeks 12 and 16 the difference was significant. Reductions in acute-phase reactants were seen with AMG 714 and no significant safety signals were seen. The author of this presentation stated that the molecule is presently being reformulated and that further trials are anticipated.

Abatacept

There were numerous abstracts on abatacept in RA documenting continued benefit for signs and symptoms of disease and health-related quality of life in the responder population enrolled in long-term, open-label trials. Genant and colleagues^[19] presented data on impact of abatacept in 2-year follow-up on radiographic progression. In a previous study, abatacept in combination with MTX had been shown at 12 months to slow radiographic progression (Genant modified Sharp Score-Aba + MTX 0.62; Pla + MTX 1.44). After year 1 all patients received open-label abatacept/MTX with 539 patients continuing into year 2. In the second year, radiographic progression was less than that in year 1 for both groups (Aba/MTX 0.21; Pla-Aba/MTX 0.25)

A preclinical study in mice using the standard protocol evaluating abatacept treatment on host resistance to Mycobacterium tuberculosis was reported.^[20] After mice were exposed to M tuberculosis, they received abatacept, anti-murine TNF, or placebo. All of the mice treated with the TNF inhibitor showed substantial increase in bacterial load with 100% dying before week 9. In contrast, the abatacept- and placebo-treated mice behaved similarly, with 100% survival at 16 weeks. Although reassuring, we await further clinical data as reactivation of tuberculosis has been reported in the transplant literature in patients receiving other T-cell modulatory therapy.

Immunogenicity of abatacept was evaluated in the RA clinical trial population.^[21] Of the patients studied, 3.0% of patients had anti-abatacept or CTLA-4 antibodies at any time during the studies as determined by an ELISA assay. Eight patients had neutralizing antibodies. Approximately 33% of patients with antibodies discontinued treatment. Antibodies were more common in patients discontinuing treatment (7.4%).

Rituximab

The 12-month radiographic outcomes were presented for rituximab from the Randomized Evaluation of Long-Term Efficacy of Rituximab in Rheumatoid Arthritis (REFLEX) trial, which evaluated efficacy in TNF-inadequate responders.^[22] At 6 months, a trend of reduction in Genant-modified Sharp score was reported that did not achieve statistical significance compared with patients on placebo plus MTX. After week 16, patients could exit the protocol for lack of response, and placebo patients could receive rituximab treatment, which the majority did. The rituximab treatment failures went on to continued treatment with standard therapies. For the radiographic analyses, patients were counted in their original treatment groups regardless of subsequent treatment. This potentially could have influenced the results, as 80 of the original 209 placebo patients actually received rituximab after week 16. At week 56, the mean change in the total Genant-modified Sharp score was 2.31 for the placebo patients and 1.00 for the rituximab cohort (P = .0043). This study is the first to demonstrate slowing of radiographic progression in TNF inhibitor-inadequate responders.

A subanalysis of this study evaluated response based on thenumber of previous TNF inhibitors failed prior to study enrollment.^[21] As previously reported with abatacept, patients failing 2 or more TNF inhibitors had a reduced (although still substantial) clinical response. The ACR responses for patients with 1 TNF inhibitor failure were ACR20 58%, ACR50 23% ACR70 13%, and for those with 2 or more TNF inhibitor failures were ACR20 42%, ACR50 19%, ACR70 10%.

A second study reported on repeat treatment with rituximab in patients with an inadequate response to MTX.^[23] The presentation focused on 99 patients with a 24-week follow-up who received a second course of treatment after loss of their initial treatment response. The median time to first re-treatment was approximately 30 weeks. The ACR responses after the second course of treatment were slightly better than after course 1 (ACR20 73%, ACR50 37%, ACR70 19%). Fourteen percent achieved remission. Safety data were presented in patients who received up to 4 courses of treatment. The frequency of serious infectious episodes did not increase over that seen in the placebo-controlled trials, and infusion reactions with subsequent treatments were less frequent. A reduction in serum IgM below the lower limits of normal was seen in 20% of patients after 3-4 courses of treatment. This drop may be partially explained by the reduction in rheumatoid factor activity but bears watching with prolonged treatment to determine whether there is any association with increased risk of infection. To date that has not been the case.

An important clinical question is how safe is anti-TNF therapy in patients who fail rituximab yet remain peripheral B-cell-depleted. A study of 78 patients with 52-57 patient-years of follow-up, who went on to TNF inhibitors in a standard-of-care cohort after failing rituximab in clinical trials, was reported.^[24] The incidence of serious infectious episodes was modestly increased (after TNF inhibitor therapy: 7.62 events/100 patient-years; before TNF inhibitor therapy: 5.23 events/100 patient-years). These preliminary findings are of interest and we await a larger experience in this population.

An unresolved question to date with rituximab is how complete is the B-cell depletion. Using standard laboratory techniques, there are no measurable peripheral B cells in the first weeks after treatment in RA patients. The group from the University of Leeds used a sensitive flow cytometry methodology to further examine this issue in 21 RA patients treated with rituximab.^[25] They observed that at weeks 2 and 14 post treatment, patients with sustained remission had undetectable B cells and pre-plasma cells by flow cytometry. In contrast, 67% of patients with an incomplete response had measurable B or pre-plasma cells. If this preliminary observation can be confirmed in a larger cohort, this would suggest that aggressive peripheral B-cell depletion is vital for a significant clinical response.

Also presented was an ongoing double-blind, randomized, placebo-controlled multicenter phase 1/2 trial of a fully human monoclonal antibody to CD20 in patients with active RA who have previously failed 1 or more DMARDs.^[26] This was a small dose-ranging study in 39 patients. Clinical efficacy was reported, and as with rituximab, a chimeric monoclonal antibody to CD20, infusion reactions were seen requiring a change in the study to allow pretreatment glucocorticoids. Other humanized or fully human B-cell depletors are under development. It remains to be seen whether they will offer any advantages to rituximab.

Summary

The improvement in RA patient outcomes is clear and was demonstrated throughout this meeting as determined by improvement in signs and symptoms, health-related quality of life, and radiographic progression. Treatment options are now available for the more TNF inhibitor-inadequate responders, and many new molecular targets are being explored in preclinical and phase 1/2 studies. This meeting also focused on long-term adherence to the TNF inhibitors and the potential safety risks of these therapies. It is clear that the benefits of current and emerging biologics and DMARDs outweigh their small but definite risks of serious infections and possibly malignancy. Proper counseling with our patients is indicated, and information from meetings such as the EULAR Congress and the American College of Rheumatology meeting continue to provide us the information necessary to allow proper informed consent.

References

1. Van Dongen H, Van Aken J, Lard LR, et al. Probable rheumatoid arthritis methotrexate versus placebo therapy (prompt)-study: indications for a window of opportunity in the treatment of patients with undifferentiated arthritis. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0001.
2. Bykerk VP, Kitamura C, Walji S, et al. Low proportion of remission with aggressive initial disease modifying anti rheumatic drug (DMARD) therapy in patients with early inflammatory arthritis (EIA) using DAS, SDAI and CDAI remission criteria. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0002.
3. Verstappen SMM, Jacobs JWG, Bijlsma JWJ. Intensive treatment with MTX of early rheumatoid arthritis patients is beneficial when compared to conventional treatment with MTX: a two year study. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0112.
4. Braun J, Kaestner P, Flaxenberg P, et al. The clinical efficacy and safety of subcutaneous (S.C.) versus oral application of methotrexate (MTX) in patients with active rheumatoid arthritis (RA) - results of a randomized, controlled, double-blind, multi-center study. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0111.
5. De Vries-Bouwstra JK, Goekoop-Ruiterman YPM, Verpoort KN, et al. The association of HLA class II antigens and anti-CCP antibodies with progression of joint damage is affected by early and targeted treatment of rheumatoid arthritis. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0114.
6. Van der Bijl AE, Van der Kooij SM, Goekoop-Ruiterman YP, et al. Persistent good clinical response after tapering and discontinuation of initial infliximab therapy in patients with early rheumatoid arthritis: 3-year results from the BeSt trial. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0180.
7. De Vries-Bouwstra JK, Goekoop-Ruiterman YPM, Van Zeben D, et al. Clinical remission and progression of joint damage with initial monotherapy or combination therapy in early rheumatoid arthritis. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract THU0229.
8. Dixon WG, Watson KD, Lunt M, et al. Rates of myocardial infarction (MI) and cerebrovascular accident (CVA) are reduced in patients with rheumatoid arthritis (RA) treated with anti-TNF therapy compared to those treated with traditional DMARDs: results from the BSR biologics register. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0181.
9. Watson KD, Dixon WG, Hyrich KL, et al. Influence of anti-TNF therapy and previous malignancy on cancer incidence in patients with rheumatoid arthritis (RA): results from the BSR biologics register. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract SAT0202.
10. Hawkins-Holt M, Hochberg MC, Cohen S, et al. Therapy with biologic agents is not associated with an increased risk of cancer recurrence in patients with rheumatoid arthritis. Arthritis Rheum. 2003;48:S339.
11. Askling J, Fored M, Brandt L, et al. TNF-antagonist treatment and risk of hospitalisation for infection. Results from the national Swedish monitoring-programme for biologics in RA (Artis). Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0182.
12. Gomez-Reino JJ, Carmona L, Pérez Pampín E, et al. Mortality rate is reduced in rheumatoid arthritis patients treated with TNF antagonists. Data from biobadaser. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract FRI0109.
13. Emery P, Genovese MC, Kavanaugh AF, et al. Adalimumab plus methotrexate results in less frequent and less severe radiographic progression than methotrexate alone at all levels of clinical response in early rheumatoid arthritis. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0113.
14. Vander Cruyssen B, Van Looy S, Wijns B, et al. Evaluation of the DAS28 at week 14 or week 22 correlates best with long term attrition to infliximab therapy in rheumatoid arthritis patients. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0197.
15. Landewe R, Van der Heijde D, Van Vollenhoven R, et al. A disconnect between inflammation and radiographic progression in patients treated with etanercept plus methotrexate and etanercept alone compared with methotrexate alone: results from the TEMPO trial. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract FRI0137.
16. Klareskog L, Moreland LW, Cohen SB, et al. Safety and efficacy of over 8 years of continuous etanercept therapy in patients with rheumatoid arthritis in North America and Europe. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract FRI0132.
17. Nishimoto N, Miyasaka N, Yamamoto K, et al. Efficacy and safety of tocilizumab in monotherapy, an anti-IL-6 receptor monoclonal antibody, in patients with active rheumatoid arthritis: results from a 24 week double-blind phase III study. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0020.
18. McInnes I, Martin R, Zimmermann-Gorska I, et al. Safety and efficacy of a human monoclonal antibody to IL-15 (amg 714) in patients with rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0022.
19. Genant HK, Peterfy C, Westhovens R, et al. Abatacept sustains inhibition of radiographic progression over 2 years in rheumatoid arthritis (RA) patients with an inadequate response to methotrexate (MTX): results from the long-term extension (LTE) of the aim trial. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0015.
20. Haggerty HG, Bigbee C, Gonchoroff DG, Flynn JL. Abatacept treatment does not impair host resistance to chronic mycobacterium tuberculosis infection in mice. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract FRI0112.
21. Haggerty HG, Abbott MA, Reilly TP, et al. Abatacept displays low levels of immunogenicity in the treatment of rheumatoid arthritis. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract FRI0113.
22. Keystone E, Emery P, Peterfy CG, et al. Prevention of joint structural damage at 1 year with rituximab in rheumatoid arthritis patients with an inadequate response to one or more TNF inhibitors (REFLEX study) Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0016.
23. Emery P, Furst DE, Ferraccioli G, et al. Long-term efficacy and safety of a repeat treatment course of rituximab in RA patients with an inadequate response to disease-modifying anti-rheumatic drugs. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0017.
24. Breedveld FC, Genovese Emery MP, et al. Safety of TNF inhibitors in rheumatoid arthritis patients previously treated with rituximab. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract THU0206.
25. Dass S, Rawstron AC, Vital EM, et al. Specific peripheral blood B-lineage cells predict response to rituximab therapy in RA: a study with high sensitivity flow cytometry. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract THU0226.
26. Østergaard M, Wiell C, Dawes PT, et al. First clinical results of humax-CD20 fully human monoclonal IgG1 antibody treatment in rheumatoid arthritis. Program and abstracts of EULAR 2006: 7th Annual European Congress of Rheumatology; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0018.