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Switching TNF-alpha antagonists in rheumatoid arthritis: The experience of the LORHEN registry
Autoimmunity Reviews 9 (2010) 465–469
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Switching TNF-alpha antagonists in rheumatoid arthritis: The experience of the LORHEN registry Roberto Caporali a,⁎, Piercarlo Sarzi-Puttini b, Fabiola Atzeni b, Roberto Gorla c, Matteo Filippini c, Antonio Marchesoni d, Ennio Giulio Favalli d, Francesca Bobbio-Pallavicini a, Carlomaurizio Montecucco a a
Division of Rheumatology, University of Pavia, IRCCS Policlinico S.Matteo Foundation, Pavia, Italy Rheumatology Unit, L. Sacco University Hospital, Milan, Italy Rheumatology and Immunology Unit, Spedali Civili di Brescia, Brescia, Italy d Department of Rheumatology, G. Pini Orthopaedic Institute, Milan, Italy b c
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 14 December 2009 Accepted 20 December 2009 Available online 31 December 2009
New biologic agents have changed the paradigm of rheumatoid arthritis treatment, leading to improvement in managing patients' refractory to classical DMARDs. Anti-TNF-alpha is used as first-line treatment in patients failing to respond to classical DMARDs. However, up to 50% of patients fail to respond to these drugs or develop adverse events leading to treatment discontinuation: in these cases the optimal treatment strategy is still a matter of debate even if trying with a second anti-TNF-alpha is considered a good option. We report data of patients switching from a first to a second anti-TNF-alpha from an Italian registry of patients with rheumatoid arthritis, showing that switching is valuable in patients stopping a first anti-TNFα drug. The patients with higher disease activity levels and those stopping the first anti-TNFα treatment because of a lack of efficacy are very likely to respond to the second treatment. © 2009 Elsevier B.V. All rights reserved.
Keywords: Rheumatoid arthritis Anti-TNF-alpha DMARDs Methotrexate
Contents 1.
Patients and methods . . . . 1.1. Patients . . . . . . . . 1.2. Assessments . . . . . 1.3. Statistical analysis . . 2. Results . . . . . . . . . . . . 2.1. Response rates . . . . 2.2. Predictors of treatment 3. Discussion . . . . . . . . . . Take-home messages . . . . . . . References . . . . . . . . . . . . .
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The evolution of the treatment of rheumatoid arthritis (RA) over the last ten years, with the introduction of anti-TNFα agents, has led to improvements in controlling the signs and symptoms of RA refractory to classical DMARDs, and in slowing joint destruction [1,2]. Although no head-to-head comparative trial of the three anti-TNFα agents (adalimumab, etanercept and infliximab) has been carried out, the existing data suggest that their efficacy and safety profiles are
⁎ Corresponding author. Division of Rheumatology, IRCCS S. Matteo Foundation, Piazzale Golgi 2, 27100 Pavia, Italy. Tel.: +39 0382501878; fax: +39 0382503171. E-mail address: [email protected] (R. Caporali). 1568-9972/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2009.12.010
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similar whether used alone or in combination with methotrexate (MTX) [3,4]. However, some patients do not respond (or respond suboptimally) to anti-TNFα agents, fail to maintain an initially good response over time, or develop adverse events leading to treatment discontinuation [5,6]. Adalimumab, etanercept and infliximab all block TNFα, but have different molecular structures, sites of action and dosing regimens, and also differ in the generation of autoantibodies, and the type and frequency of adverse events, which suggests that switching to a second anti-TNFα agent after the failure of a first may be beneficial and not necessarily associated with an increased adverse event rate. Although the published studies vary widely in terms of population
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sizes (most have been based on small case series), designs and outcome measures [7–26], the latest and most interesting data come from analyses of large registries of patients treated with anti-TNF agents in different countries. However, as new biological drugs have also been approved for the specific purpose of treating patients who have failed on anti-TNFα agents, clinicians may find it difficult to decide the most appropriate treatment after a first TNF failure: this is still a subject of debate and may have important clinical and economic implications in everyday practice [5]. As data from an Italian registry of RA patients treated with antiTNFα agent have recently been published [27], the aim of this paper is to describe the clinical characteristics and response rates of patients switching from a first to a second anti-TNFα agent. 1. Patients and methods 1.1. Patients Since 1999, all patients with RA diagnosed on the basis of the American College of Rheumatology (ACR) criteria [28] and treated with at least one dose of an anti-TNFα agent have been recorded in a database shared by four rheumatology centres in Lombardy (Northern Italy): the Lombardy Rheumatology Network (LORHEN) registry. The registry describes the efficacy and safety of the first three years of treatment in a large cohort of patients receiving the three currently available TNFα inhibitors – etanercept (ETA), infliximab (INF) and adalimumab (ADA) – the data of which have been recently published [3,4,6,27]. The present study considers all of the patients who switched from their first to a second anti-TNFα agent. In all cases, a standard form was used to collect demographic data, the individual components of the DAS28 [29], details of current DMARD or steroid treatment, and comorbidities at baseline (i.e. the visit before starting the second anti-TNFα agent) and six and 12 months later. 1.2. Assessments At baseline, and six and 12 months later, the treating rheumatologist recorded the number of swollen and tender joints of each patient (28-joint count), the erythrocyte sedimentation rate (ESR), rheumatoid factor level and current RA therapy (DMARDs and steroids), as well as the patient's assessment of pain and overall assessment of general health (in both cases using a 100 mm visual analogue scale, VAS). At baseline, the reason(s) for stopping the first anti-TNF treatment were recorded and classified as a lack of (primary or secondary) response, adverse events, or other reasons, which included pregnancy, patient decision, poor compliance, or unspecified causes. At each visit, all of the patients also completed the Italian version of the Disability Index of the Health Assessment Questionnaire (HAQ) [30], and their response to treatment was evaluated on the basis of the EULAR criteria and classified as good, moderate or none [29]. 1.3. Statistical analysis The differences between infliximab, adalimumab and etanercept were analysed on the basis of the data relating to all of the LORHEN patients who switched from one anti-TNFα agent to another, using the Kruskal–Wallis non-parametric test for the continuous variables (mean and standard deviation) and the Chi-squared test for the categorical variables (counts and percentages). The uni- and multivariate analyses were performed using logistic regression models. The response variable was defined as the occurrence of EULAR response criteria (yes/no) after one year of treatment. The baseline variables taken into account were age at the start of therapy, gender, the duration of the first anti-TNF treatment, the DAS28 and HAQ scores,
the concurrent use of MTX and corticosteroids, and the reasons for stopping the first anti-TNFα treatment. All of the analyses were made using SAS version 9.2 (SAS Institute, Inc; Cary, NC), and a p value of 0.05 or less was considered statistically significant. 2. Results During the three-year study period, 1114 biological agent-naïve RA patients were started on a first anti-TNFα treatment (533 on INF, 332 on ADA, and 249 on ETA), 237 of whom subsequently switched to a second anti-TNF agent and were included in the analysis. Table 1 shows their baseline characteristics, and Table 2 the type of switch. The majority of patients switched from monoclonal antibodies (INF or ADA) to ETA (65% of cases) or from ETA to monoclonal antibodies (13.5%); only 21.5% switched from one monoclonal antibody to another. 2.1. Response rates Fig. 1 shows the response rates after six and 12 months. On the basis of DAS28, EULAR good responses were achieved by 32 patients (14.9%) after six months and 36 (18.6%) after 12 months and moderate responses by respectively 80 (37.2%) and 103 patients (53.1%); and no response was observed in respectively 103 (47.9%) and 55 patients (28.3%). In general, the number of responders (those with good or moderate DAS28 responses) after six and 12 months' treatment with the first antiTNFα agent was respectively 534 (76.1%) and 668 (81.4%); the corresponding figures after treatment with the second agent were respectively 112 (52.1 %) and 139 patients (71.7 %) (p = n.s.). The patients who started treatment with a second anti-TNFα agent due to lack of response to the first were more frequently responders after six and 12 months (56.7% and 79.7%, respectively) than those who started the second treatment after stopping the first because of adverse events (44.6% and 60.3%). The percentage of non-responders to ADA and INF was higher than the percentage of non-responders to ETA at both time points. Table 1 Patient characteristics at baseline (237 patients switching to a second anti-TNF), TJC = tender joint count; SJC = swollen joint count; ESR = erythrocyte sedimentation rate; HAQ = health assessment questionnaire; DMARD = disease modifying antirheumatic drug; MTX = methotrexate. Age (yrs), mean (SD) Females, n (%) Disease duration (yrs), mean (SD) DAS-28 score, mean (SD) 28 TJC, mean (SD) 28 SJC, mean (SD) VAS global (mm), mean (SD) Physician global assessment (mm), mean (SD) ESR (mm/h), mean (SD) HAQ score, mean (SD) Previous number of DMARDsa, mean (SD) Concurrent corticosteroid use, n (%) None ≤5 mg N5 mg Weekly MTX dose (mg), mean (SD) Concurrent MTX use, n (%) Concurrent DMARDs other than MTX, n (%) MTX + other DMARDs, n (%) Reason for stopping previous anti-TNFα therapy Adverse events, n (%) Primary inefficacy, n (%) Secondary lack of response, n (%) Others, n (%) a
Includes previous biological drugs.
61.0 (13.49) 195 (82.3) 7.9 (7.93) 5.7 (1.29) 11.1 (6.85) 9.8 (5.62) 69.0 (23.86) 58.1 (24.90) 41.3 (21.96) 1.4 (0.63) 3.4 (1.34) 34 139 64 12.2 207 82 77
(14.4) (58.6) (27.0) (3.25) (87.3) (34.6) (32.5)
77 86 59 15
(32.5) (36.3) (24.9) (6.3)
R. Caporali et al. / Autoimmunity Reviews 9 (2010) 465–469 Table 2 Patients undergoing a second anti-TNFα treatment by first course of anti-TNFα treatment, and switching order. No. of patients (%) (total=237) First anti-TNFα agent Etanercept Infliximab Adalimumab
32 (13.5) 163 (68.8) 42 (17.7)
Second anti-TNFα agent Etanercept Infliximab Adalimumab
154 (65.0) 14 (5.9) 69 (29.1)
Switching order Etanercept–infliximab Etanercept–adalimumab Infliximab–etanercept Infliximab–adalimumab Adalimumab–etanercept Adalimumab–infliximab Monoclonal antibody–etanercept Etanercept–monoclonal antibody Monoclonal antibody–monoclonal antibody
8 (25.0) 24 (75.0) 118 (72.4) 45 (27.6) 36 (85.7) 6 (14.3) 154 (65.0) 32 (13.5) 51 (21.5)
2.2. Predictors of treatment response Univariate analysis (Table 3) showed that a higher DAS28 score at the beginning of the second treatment was associated with a clinical response (OR 2.15, 95% CI 1.556–2.969), as was the occurrence of an adverse event rather than lack of efficacy as the reason for stopping the first course (OR 0.388, 95% CI 0.199–0.757). At multivariate analysis, only the baseline DAS28 remained significant. The DAS 28 of the patients starting the second anti-TNFα treatment after a failure due to a lack of response was higher than that observed in the patients who experienced adverse events during the first treatment (5.954 vs 5.589). 3. Discussion The findings of this multicentre observational study of a large population of Italian RA patients confirm that the failure of a first antiTNFα agent does not preclude a response to another, although the probability of achieving a DAS28 clinical response after switching
Fig. 1. Response rates after the second anti-TNFα treatment according to reason for stopping the first course (adverse event or lack of efficacy). Responses are reported according to EULAR criteria (EULAR non-responders, moderate responders or good responders).
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from one anti-TNFα agent to another is slightly lower than that observed in patients beginning anti-TNF treatment after the failure of DMARDs. This study was based on a large cohort of more than 1000 RA patients, 237 of whom switched their anti-TNFα treatment. It has some potential limitations insofar as it was an observational study of everyday rheumatology practice in Italy, and so the treatment decisions were not randomised or strictly linked to national guidelines but left to the judgement of the treating physician. Nevertheless, the findings do reflect treatment outcomes as they occur in everyday clinical practice, and this may offer possibly important clinical insights that would not emerge from a randomised controlled trial [1]. The published guidelines of the Italian Society for Rheumatology suggest that treatment should be discontinued after six months if the DAS28 score has not improved by ≥1.2, [31] but this recommendation is not always observed in clinical practice [16]. Economic evaluations may also be an issue when deciding whether to switch to another antiTNFα agent or change treatment targets, although this was not so in our study as the Italian National Health System provides free access to the drugs. All of the available agents are potent neutralisers of TNFα, a pivotally important cytokine in the pathogenesis of RA [32]. Although they all have been found to be similarly efficacious in RA, there are some fundamental differences between them that may explain different effects. INF is a chimeric monoclonal antibody, ADA is a fully humanised monoclonal antibody, and ETA is a fusion of a recombinant soluble p75 TNF receptor and the Fc portion of human IgG. They all bind to TNFα but ETA also binds to lymphotoxin, a cytokine that has been found in the synovial tissue of RA patients and may play a role in pathogenesis [33]. The three drugs also differ in their effectiveness in other diseases: unlike the monoclonal antibodies, ETA is not effective in granulomatous diseases such as Crohn's disease; furthermore, INF and ADA are associated with an increased risk of granulomatous infections, such as mycobacterium tuberculosis, in comparison with ETA [34]. The three agents also have different half-lives, with that of ETA being the shortest (4 days) and that of ADA the longest (14 days) [35], and different dosing regimens and administration routes (INF is given every 4–8 weeks by means of an intravenous infusion, whereas ETA and ADA are administered subcutaneously). Finally, there may be differences in the induction of anti-drug antibodies, which may be associated with a loss of efficacy over time, and differences in the induced production of autoantibodies [36], both of which may provide a strong rationale for switching from one antiTNFα agent to another. A number of studies have supported this possibility, and switching to a different TNF antagonist has become common clinical practice. However, while a switch from a first to a second anti-TNFα agent is generally considered useful, a third switch does not seem to be costeffective insofar as various reports suggest that the rate of response to the third drug is significantly lower and that changing the target may be more useful [22,37]. Many of the studies of switching anti-TNFα agents are limited by their short duration, small sample sizes, and the lack of randomisation or controls; in addition, many did not include all three agents. Earlier studies mainly considered switching ETA and INF, and found that the response to the second drug was good in a large proportion of cases regardless of which was the first drug, and that there was no difference in safety between the first and second treatment [5–10]. The subsequent availability of ADA led to a number of studies exploring the possibility of switching among all three agents, and confirmed the first impression of the usefulness of a first switch, although there are some differences in terms of the rates of response to the second drug. The South Swedish Arthritis Treatment Group found that the response rate among switchers was lower than that of first-time users in a large population of RA patients (58% vs 71%) [22], whereas the results from the British Society
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Table 3 Predictors of response after 12 months of treatment (HAQ = health assessment questionnaire; DMARDs= disease modifying anti-rheumatic drugs; MTX = methotrexate). Univariate
Age (per 1 year) Male vs female Baseline DAS 28 (per unit) Baseline HAQ Concurrent corticosteroids (no vs yes) Concurrent DMARDs (no vs yes) Concurrent MTX AE vs lack of efficacy Duration of first anti-TNFα treatment
Multivariate
OR (95% CI)
p value
OR (95% CI)
p value
1.025 (0.998–1.052) 0.721 (0.311–1.671) 2.15 (1.556–2.969) 0.841 (0.457–1.547) 0.73 (0.291–1.832) 1.252 (0.433–3.62) 1.526 (0.537–4.336) 0.388 (0.199–0.757) 1.005 (0.984–1.026)
0.0670 0.4451 b 0.0001 0.5774 0.5030 0.6781 0.4273 0.0055 0.6602
1.016 (0.981–1.053)
0.3715 0.9032 0.0021 0.3783 0.75 0.6875 0.1743 0.7195 0.3783
for Rheumatology Biologics Register showed that 73% of the patients switching to a second anti-TNFα agent were still on treatment after a mean 15 months of follow-up [16], and data from the Spanish registry (BIOBADASER) indicated a similar drug survival of the first and second TNFα antagonist [14]. A recently published randomised clinical trial of the efficacy of the new anti-TNFα agent golimumab after treatment with another anti-TNFα agent found a high percentage of responses in the patients who had previously received one or more anti-TNFα agents [38]. In our study, we observed EULAR responses in 71.7% of the patients after 12 months of a second anti-TNFα treatment, in comparison with 81.4% after 12 months on the first treatment in the same setting [27], which allows us to conclude that a second anti-TNFα treatment can be useful and may lead to a large proportion of responders after switching in everyday clinical practice. Anti-TNFα agents seem to be effective regardless of the agent preceding them, and there is little published data concerning the relative merits of using them in a particular order. The vast majority of observational trials have tended to try a drug with a different mechanism of action as the second anti-TNFα agent: the receptor antagonist (ETA) after the failure of a monoclonal antibody (INF or ADA) and vice versa, and a switch between the two monoclonal antibodies is rare. The same was true in our study: the majority of patients were switched from monoclonal antibodies (INF or ADA) to ETA. However, it must be pointed that our register was begun when only INF and ETA were on the market (and INF was approved some months before ETA), and this may explain the high percentage of switching between INF and ETA and the low percentage of switching between the two monoclonal antibodies, although this approach may also be scientifically justified by the drugs' different mechanisms of action and the reported difference in the safety profiles of the monoclonal antibodies in relation to ETA [34,39]. Many studies suggest that the reason for stopping the first antiTNFα treatment may affect the rate of response to a second. It has been reported that a patient is more likely to stop taking a second anti-TNFα agent because of inefficacy if the first was also stopped because of inefficacy and, similarly, that a patient is more likely to develop an adverse event due to a second agent if the first was stopped because of an adverse event [16]. This has also been reported by some other groups [26] but not all [22]. We found that the reason for stopping the first anti-TNFα agent does not predict the response to the second. However, when analysing the factors that may predict the response to a second drug, we did find that patients stopping the first because of an adverse event were less likely to respond to the second than those who failed to respond to the first drug. This may be at least partially explained by the fact that disease activity is less in patients stopping the first drug because of an adverse event than in those stopping it because of a lack of response. It has been recently reported that the DAS28 response to anti-TNFα drugs may be less in patients with a low level of disease activity [40], and our data show that the DAS28 score at the beginning of the second anti-TNFα treatment is a significant predictor of response.
2.386 (1.372–4.147) 0.526 (0.216–1.278) 0.576 (0.169–1.966) 0.521 (0.009–28.74) 2.249 (0.043–116.652) 0.463 (0.152–1.406) 0.994 (0.964–1.025)
In conclusion, our findings confirm that switching anti-TNFα drugs is valuable in patients stopping a first anti-TNFα drug. In clinical practice, the switching usually takes place between drugs with different mechanisms of action (from monoclonal antibodies to the soluble receptor antagonist, and vice versa). The patients with higher disease activity levels and those stopping the first anti-TNFα treatment because of a lack of efficacy are very likely to respond to the second treatment. Take-home messages • Switching between different anti-TNF-alpha agents is a valuable option in patients with rheumatoid arthritis failing a first treatment course. • The patients with higher disease activity levels and those stopping the first anti-TNFα treatment because of a lack of efficacy are very likely to respond to the second treatment. References [1] Caporali R, Bobbio-Pallavicini F, Filippini M, Gorla R, Marchesoni A, Favalli EG, et al. Treatment of rheumatoid arthritis with anti-TNF-alpha agents: a reappraisal. Autoimmun Rev 2009;8:274–80. [2] Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet 2007;370:1861–74. [3] Marchesoni A, Zaccara E, Gorla R, Bazzani C, Sarzi-Puttini P, Atzeni F, et al. TNFalpha antagonist survival rate in a cohort of rheumatoid arthritis patients observed under conditions of standard clinical practice. Ann N Y Acad Sci 2009;1173:837–46. [4] Bazzani C, Filippini M, Caporali R, Bobbio-Pallavicini F, Favalli EG, Marchesoni A, et al. Anti-TNFalpha therapy in a cohort of rheumatoid arthritis patients: clinical outcomes. Autoimmun Rev 2009;8:260–5. [5] van Vollenhoven RF. Switching between anti-tumour necrosis factors: trying to get a handle on a complex issue. Ann Rheum Dis 2007;66:849–51. [6] Favalli EG, Desiati F, Atzeni F, Sarzi-Puttini P, Caporali R, Pallavicini FB, et al. Serious infections during anti-TNFalpha treatment in rheumatoid arthritis patients. Autoimmun Rev 2009;8:266–73. [7] van Vollenhoven R, Harju A, Brannemark S, Klareskog L. Treatment with infliximab (Remicade) when etanercept (Enbrel) has failed or vice versa: data from the STURE registry showing that switching tumour necrosis factor alpha blockers can make sense. Ann Rheum Dis 2003;62:1195–8. [8] Hansen KE, Hildebrand JP, Genovese MC, Cush JJ, Patel S, Cooley DA, et al. The efficacy of switching from etanercept to infliximab in patients with rheumatoid arthritis. J Rheumatol 2004;31:1098–102. [9] Haraoui B, Keystone EC, Thorne JC, Pope JE, Chen I, Asare CG, et al. Clinical outcomes of patients with rheumatoid arthritis after switching from infliximab to etanercept. J Rheumatol 2004;31:2356–9. [10] Gómez-Puerta JA, Sanmartí R, Rodríguez-Cros JR, Cañete JD. Etanercept is effective in patients with rheumatoid arthritis with no response to infliximab therapy. Ann Rheum Dis 2004;63:896. [11] Bennett AN, Peterson P, Zain A, Grumley J, Panayi G, Kirkham B. Adalimumab in clinical practice. Outcome in 70 rheumatoid arthritis patients, including comparison of patients with and without previous anti-TNF exposure. Rheumatology 2005;44:1026–31 (Oxford). [12] Wick MC, Ernestam S, Lindblad S, Bratt J, Klareskog L, van Vollenhoven RF. Adalimumab (Humira) restores clinical response in patients with secondary loss of efficacy from infliximab (Remicade) or etanercept (Enbrel): results from the STURE registry at Karolinska University Hospital. Scand J Rheumatol 2005;34:353–8. [13] Cohen G, Courvoisier N, Cohen JD, Zaltni S, Sany J, Combe B. The efficiency of switching from infliximab to etanercept and vice-versa in patients with rheumatoid arthritis. Clin Exp Rheumatol 2005;23:795–800.
R. Caporali et al. / Autoimmunity Reviews 9 (2010) 465–469 [14] Gomez-Reino JJ, Carmona L. BIOBADASER Group. Switching TNF antagonists in patients with chronic arthritis: an observational study of 488 patients over a fouryear period. Arthritis Res Ther Jan 6 2006;8(1):R29 Electronic publication. [15] Nikas SN, Voulgari PV, Alamanos Y, Papadopoulos CG, Venetsanopoulou AI, Georgiadis AN, et al. Efficacy and safety of switching from infliximab to adalimumab: a comparative controlled study. Ann Rheum Dis 2006;65:257–60. [16] Hyrich KL, Lunt M, Watson KD, Symmons DP, Silman AJ. British Society for Rheumatology Biologics Register. Outcomes after switching from one anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum 2007;56:13–20. [17] Iannone F, Trotta F, Montecucco C, Giacomelli R, Galeazzi M, Matucci-Cerinic M, et al. GISEA (Gruppo Italiano per lo Studio delle Early Arthritis). Etanercept maintains the clinical benefit achieved by infliximab in patients with rheumatoid arthritis who discontinued infliximab because of side effects. Ann Rheum Dis 2007;66:249–52. [18] Bombardieri S, Ruiz AA, Fardellone P, Geusens P, McKenna F, Unnebrink K, et al. Research in Active Rheumatoid Arthritis (ReAct) Study Group. Effectiveness of adalimumab for rheumatoid arthritis in patients with a history of TNF-antagonist therapy in clinical practice. Rheumatology 2007;46:1191–9 (Oxford). [19] Buch MH, Bingham SJ, Bejarano V, Bryer D, White J, Reece R, et al. Therapy of patients with rheumatoid arthritis: outcome of infliximab failures switched to etanercept. Arthritis Rheum 2007;57:448–53. [20] Furst DE, Gaylis N, Bray V, Olech E, Yocum D, Ritter J, et al. Open-label, pilot protocol of patients with rheumatoid arthritis who switch to infliximab after an incomplete response to etanercept: the opposite study. Ann Rheum Dis 2007;66:893–9. [21] Hjardem E, Østergaard M, Pødenphant J, Tarp U, Andersen LS, Bing J, et al. Do rheumatoid arthritis patients in clinical practice benefit from switching from infliximab to a second tumor necrosis factor alpha inhibitor? Ann Rheum Dis 2007;66:1184–9. [22] Karlsson JA, Kristensen LE, Kapetanovic MC, Gülfe A, Saxne T, Geborek P. Treatment response to a second or third TNF-inhibitor in RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatology 2008;47:507–13 (Oxford). [23] van der Bijl AE, Breedveld FC, Antoni CE, Kalden JR, Kary S, Burmester GR, et al. An open-label pilot study of the effectiveness of adalimumab in patients with rheumatoid arthritis and previous infliximab treatment: relationship to reasons for failure and anti-infliximab antibody status. Clin Rheumatol 2008;27:1021–8. [24] Laas K, Peltomaa R, Kautiainen H, Leirisalo-Repo M. Clinical impact of switching from infliximab to etanercept in patients with rheumatoid arthritis. Clin Rheumatol 2008;27:927–32. [25] Hyrich KL, Lunt M, Dixon WG, Watson KD, Symmons DP. BSR Biologics Register. Effects of switching between anti-TNF therapies on HAQ response in patients who do not respond to their first anti-TNF drug. Rheumatology 2008;47:1000–5 (Oxford). [26] Scrivo R, Conti F, Spinelli FR, Truglia S, Magrini L, Di Franco M, et al. Switching between TNFalpha antagonists in rheumatoid arthritis: personal experience and review of the literature. Reumatismo 2009;61:107–17.
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[27] Sarzi-Puttini P, Antivalle M, Marchesoni A, Favalli EG, Gorla R, Filippini M, et al. Efficacy and safety of anti-TNF agents in the Lombardy rheumatoid arthritis network (LORHEN). Reumatismo 2008;60:290–5. [28] Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24. [29] Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8. [30] Ranza R, Marchesoni A, Calori G, Bianchi G, Braga M, Canazza S, et al. The Italian version of the Functional Disability Index of the Health Assessment Questionnaire. A reliable instrument for multicenter studies on rheumatoid arthritis. Clin Exp Rheumatol 1993;11:123–8. [31] Valesini G, Montecucco C, Cutolo M. Recommendations for the use of biologic (TNF-alpha blocking) agents in the treatment of rheumatoid arthritis in Italy. Clin Exp Rheumatol 2006;24:413–23. [32] Schett G. Immune cells and mediators of inflammatory arthritis. Autoimmunity 2008;41:224–9. [33] Braun A, Takemura S, Vallejo AN, Goronzy JJ, Weyand CM. Lymphotoxin betamediated stimulation of synoviocytes in rheumatoid arthritis. Arthritis Rheum 2004;50:2140–50. [34] Aggarwal R, Manadan AM, Poliyedath A, Sequeira W, Block JA. Safety of etanercept in patients at high risk for mycobacterial tuberculosis infections. J Rheumatol 2009;36:914–7. [35] Nestorov I. Clinical pharmacokinetics of TNF antagonists: how do they differ? Semin Arthritis Rheum 2005;34(5 Suppl1):12–8. [36] Anderson PJ. Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. Semin Arthritis Rheum 2005;34(5 Suppl1):19–22. [37] Finckh A, Ciurea A, Brulhart L, Möller B, Walker UA, Courvoisier D, et al. Which subgroup of rheumatoid arthritis patients benefits from switching to rituximab versus alternative anti-TNF agents after previous failure to anti-TNF agent? Ann Rheum Dis May 15 2009. [38] Smolen JS, Kay J, Doyle MK, Landewé R, Matteson EL, Wollenhaupt J, et al. GOAFTER study investigators. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet 2009;374:210–21. [39] Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, et al. A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ Nov 2 2009:19884297 Electronic publication PubMed PMID. [40] Kristensen LE, Kapetanovic MC, Gülfe A, Söderlin M, Saxne T, Geborek P. Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients with established RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatology 2008;47:495–9 (Oxford).
Autoimmune regulator controls T cell help for pathogenetic autoantibody production in collagen-induced arthritis Autoimmune regulator (Aire) promotes the ectopic expression of tissue-restricted antigens in medullary thymic epithelial cells (mTECs), leading to negative selection of autoreactive T cells. This study, Campbell I. et al (Arthritis Rheum 2009; 60: 1683-93) was undertaken to determine whether loss of central tolerance renders Aire-deficient (Aire-/-) mice more susceptible to the induction of autoimmune arthritis. Medullary TECs were isolated from Aire-/- and wild-type C57BL/6 mice for gene expression analysis Collagen-induced arthritis (CIA) was elicited by injection of chick type II collagen (CII) were evaluated. Chimeric mice were created by reconstituting lymphocyte-deficient mice with either Aire-/- or wild type CD4 T cells and wild-type B cells. Wild-type, but not Aire-/-, mTECs expressed the CII gene Col2aI.Aire-/mice developed more rapid and severe CIA, showing elevated serum anti-CII IgG levels, with earlier switching to arthritogenic IgG subclasses. No evidence was found of enhanced T cell responsiveness to CII in Aire-/- mice; however, Aire-/- CD4 T cells were more efficient at stimulating wild-type B cells to produce anti-CII IgG following immunization of chimeric mice with CII. These findings indicate that Airedependent expression of CII occurs in mTECs, implying that there is central tolerance to self antigens found in articular cartilage. Reduced central tolerance to CII in Aire-/- mice manifests as increased CD4 T cell help to B cells for cross-reactive autoantibody production and enhanced CIA. Aire and central tolerance help prevent cross-reactive autoimmune responses to CII initiated by environmental stimuli and limit spontaneous autoimmunity.
High alpha-defensin levels in patients with systemic lupus erythematosus Innate immunity plays a role in systemic lupus erythematosus (SLE). The objective of this study was to determine the levels of defensins, which are antimicrobial and immunomodulatory polypeptides, in SLE. Sthoeger ZM. et al. (Immunology 2009; 127: 116-22). Sera from SLE patients and healthy controls were tested for pro-inflammatory human beta-defensin 2 (hBD-2) and for alpha-defensin human neutrophil peptide 1 (HNP-1).hBD-2 could not be detected by ELISA and its mRNA levels were low in SLE patients and similar to those found in controls. In contrast, the mean alpha-defensin level in the sera of all SLE patients (11.07 ± 13.92 ng/microl) was significantly higher than that of controls (0.12 ± 0.07 ng/microl). Moreover, 60% of patients, demonstrated very high serum levels (18.5 ± 13.36 ng/microl) and 50% showed elevated gene expression in polymorphonuclear cells. High alpha-defensin levels correlated with disease activity, but not with neutrophil count. Thus, activation and degranulation of neutrophils led to alpha-defensin secretion in SLE patients. Given the immunomodulatory role of alpha-defensin, it is possible that their secretion may activate the adaptive immune system leading to a systemic response.
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Switching TNF-alpha antagonists in rheumatoid arthritis: The experience of the LORHEN registry Roberto Caporali a,⁎, Piercarlo Sarzi-Puttini b, Fabiola Atzeni b, Roberto Gorla c, Matteo Filippini c, Antonio Marchesoni d, Ennio Giulio Favalli d, Francesca Bobbio-Pallavicini a, Carlomaurizio Montecucco a a
Division of Rheumatology, University of Pavia, IRCCS Policlinico S.Matteo Foundation, Pavia, Italy Rheumatology Unit, L. Sacco University Hospital, Milan, Italy Rheumatology and Immunology Unit, Spedali Civili di Brescia, Brescia, Italy d Department of Rheumatology, G. Pini Orthopaedic Institute, Milan, Italy b c
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 14 December 2009 Accepted 20 December 2009 Available online 31 December 2009
New biologic agents have changed the paradigm of rheumatoid arthritis treatment, leading to improvement in managing patients' refractory to classical DMARDs. Anti-TNF-alpha is used as first-line treatment in patients failing to respond to classical DMARDs. However, up to 50% of patients fail to respond to these drugs or develop adverse events leading to treatment discontinuation: in these cases the optimal treatment strategy is still a matter of debate even if trying with a second anti-TNF-alpha is considered a good option. We report data of patients switching from a first to a second anti-TNF-alpha from an Italian registry of patients with rheumatoid arthritis, showing that switching is valuable in patients stopping a first anti-TNFα drug. The patients with higher disease activity levels and those stopping the first anti-TNFα treatment because of a lack of efficacy are very likely to respond to the second treatment. © 2009 Elsevier B.V. All rights reserved.
Keywords: Rheumatoid arthritis Anti-TNF-alpha DMARDs Methotrexate
Contents 1.
Patients and methods . . . . 1.1. Patients . . . . . . . . 1.2. Assessments . . . . . 1.3. Statistical analysis . . 2. Results . . . . . . . . . . . . 2.1. Response rates . . . . 2.2. Predictors of treatment 3. Discussion . . . . . . . . . . Take-home messages . . . . . . . References . . . . . . . . . . . . .
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The evolution of the treatment of rheumatoid arthritis (RA) over the last ten years, with the introduction of anti-TNFα agents, has led to improvements in controlling the signs and symptoms of RA refractory to classical DMARDs, and in slowing joint destruction [1,2]. Although no head-to-head comparative trial of the three anti-TNFα agents (adalimumab, etanercept and infliximab) has been carried out, the existing data suggest that their efficacy and safety profiles are
⁎ Corresponding author. Division of Rheumatology, IRCCS S. Matteo Foundation, Piazzale Golgi 2, 27100 Pavia, Italy. Tel.: +39 0382501878; fax: +39 0382503171. E-mail address: [email protected] (R. Caporali). 1568-9972/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2009.12.010
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similar whether used alone or in combination with methotrexate (MTX) [3,4]. However, some patients do not respond (or respond suboptimally) to anti-TNFα agents, fail to maintain an initially good response over time, or develop adverse events leading to treatment discontinuation [5,6]. Adalimumab, etanercept and infliximab all block TNFα, but have different molecular structures, sites of action and dosing regimens, and also differ in the generation of autoantibodies, and the type and frequency of adverse events, which suggests that switching to a second anti-TNFα agent after the failure of a first may be beneficial and not necessarily associated with an increased adverse event rate. Although the published studies vary widely in terms of population
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sizes (most have been based on small case series), designs and outcome measures [7–26], the latest and most interesting data come from analyses of large registries of patients treated with anti-TNF agents in different countries. However, as new biological drugs have also been approved for the specific purpose of treating patients who have failed on anti-TNFα agents, clinicians may find it difficult to decide the most appropriate treatment after a first TNF failure: this is still a subject of debate and may have important clinical and economic implications in everyday practice [5]. As data from an Italian registry of RA patients treated with antiTNFα agent have recently been published [27], the aim of this paper is to describe the clinical characteristics and response rates of patients switching from a first to a second anti-TNFα agent. 1. Patients and methods 1.1. Patients Since 1999, all patients with RA diagnosed on the basis of the American College of Rheumatology (ACR) criteria [28] and treated with at least one dose of an anti-TNFα agent have been recorded in a database shared by four rheumatology centres in Lombardy (Northern Italy): the Lombardy Rheumatology Network (LORHEN) registry. The registry describes the efficacy and safety of the first three years of treatment in a large cohort of patients receiving the three currently available TNFα inhibitors – etanercept (ETA), infliximab (INF) and adalimumab (ADA) – the data of which have been recently published [3,4,6,27]. The present study considers all of the patients who switched from their first to a second anti-TNFα agent. In all cases, a standard form was used to collect demographic data, the individual components of the DAS28 [29], details of current DMARD or steroid treatment, and comorbidities at baseline (i.e. the visit before starting the second anti-TNFα agent) and six and 12 months later. 1.2. Assessments At baseline, and six and 12 months later, the treating rheumatologist recorded the number of swollen and tender joints of each patient (28-joint count), the erythrocyte sedimentation rate (ESR), rheumatoid factor level and current RA therapy (DMARDs and steroids), as well as the patient's assessment of pain and overall assessment of general health (in both cases using a 100 mm visual analogue scale, VAS). At baseline, the reason(s) for stopping the first anti-TNF treatment were recorded and classified as a lack of (primary or secondary) response, adverse events, or other reasons, which included pregnancy, patient decision, poor compliance, or unspecified causes. At each visit, all of the patients also completed the Italian version of the Disability Index of the Health Assessment Questionnaire (HAQ) [30], and their response to treatment was evaluated on the basis of the EULAR criteria and classified as good, moderate or none [29]. 1.3. Statistical analysis The differences between infliximab, adalimumab and etanercept were analysed on the basis of the data relating to all of the LORHEN patients who switched from one anti-TNFα agent to another, using the Kruskal–Wallis non-parametric test for the continuous variables (mean and standard deviation) and the Chi-squared test for the categorical variables (counts and percentages). The uni- and multivariate analyses were performed using logistic regression models. The response variable was defined as the occurrence of EULAR response criteria (yes/no) after one year of treatment. The baseline variables taken into account were age at the start of therapy, gender, the duration of the first anti-TNF treatment, the DAS28 and HAQ scores,
the concurrent use of MTX and corticosteroids, and the reasons for stopping the first anti-TNFα treatment. All of the analyses were made using SAS version 9.2 (SAS Institute, Inc; Cary, NC), and a p value of 0.05 or less was considered statistically significant. 2. Results During the three-year study period, 1114 biological agent-naïve RA patients were started on a first anti-TNFα treatment (533 on INF, 332 on ADA, and 249 on ETA), 237 of whom subsequently switched to a second anti-TNF agent and were included in the analysis. Table 1 shows their baseline characteristics, and Table 2 the type of switch. The majority of patients switched from monoclonal antibodies (INF or ADA) to ETA (65% of cases) or from ETA to monoclonal antibodies (13.5%); only 21.5% switched from one monoclonal antibody to another. 2.1. Response rates Fig. 1 shows the response rates after six and 12 months. On the basis of DAS28, EULAR good responses were achieved by 32 patients (14.9%) after six months and 36 (18.6%) after 12 months and moderate responses by respectively 80 (37.2%) and 103 patients (53.1%); and no response was observed in respectively 103 (47.9%) and 55 patients (28.3%). In general, the number of responders (those with good or moderate DAS28 responses) after six and 12 months' treatment with the first antiTNFα agent was respectively 534 (76.1%) and 668 (81.4%); the corresponding figures after treatment with the second agent were respectively 112 (52.1 %) and 139 patients (71.7 %) (p = n.s.). The patients who started treatment with a second anti-TNFα agent due to lack of response to the first were more frequently responders after six and 12 months (56.7% and 79.7%, respectively) than those who started the second treatment after stopping the first because of adverse events (44.6% and 60.3%). The percentage of non-responders to ADA and INF was higher than the percentage of non-responders to ETA at both time points. Table 1 Patient characteristics at baseline (237 patients switching to a second anti-TNF), TJC = tender joint count; SJC = swollen joint count; ESR = erythrocyte sedimentation rate; HAQ = health assessment questionnaire; DMARD = disease modifying antirheumatic drug; MTX = methotrexate. Age (yrs), mean (SD) Females, n (%) Disease duration (yrs), mean (SD) DAS-28 score, mean (SD) 28 TJC, mean (SD) 28 SJC, mean (SD) VAS global (mm), mean (SD) Physician global assessment (mm), mean (SD) ESR (mm/h), mean (SD) HAQ score, mean (SD) Previous number of DMARDsa, mean (SD) Concurrent corticosteroid use, n (%) None ≤5 mg N5 mg Weekly MTX dose (mg), mean (SD) Concurrent MTX use, n (%) Concurrent DMARDs other than MTX, n (%) MTX + other DMARDs, n (%) Reason for stopping previous anti-TNFα therapy Adverse events, n (%) Primary inefficacy, n (%) Secondary lack of response, n (%) Others, n (%) a
Includes previous biological drugs.
61.0 (13.49) 195 (82.3) 7.9 (7.93) 5.7 (1.29) 11.1 (6.85) 9.8 (5.62) 69.0 (23.86) 58.1 (24.90) 41.3 (21.96) 1.4 (0.63) 3.4 (1.34) 34 139 64 12.2 207 82 77
(14.4) (58.6) (27.0) (3.25) (87.3) (34.6) (32.5)
77 86 59 15
(32.5) (36.3) (24.9) (6.3)
R. Caporali et al. / Autoimmunity Reviews 9 (2010) 465–469 Table 2 Patients undergoing a second anti-TNFα treatment by first course of anti-TNFα treatment, and switching order. No. of patients (%) (total=237) First anti-TNFα agent Etanercept Infliximab Adalimumab
32 (13.5) 163 (68.8) 42 (17.7)
Second anti-TNFα agent Etanercept Infliximab Adalimumab
154 (65.0) 14 (5.9) 69 (29.1)
Switching order Etanercept–infliximab Etanercept–adalimumab Infliximab–etanercept Infliximab–adalimumab Adalimumab–etanercept Adalimumab–infliximab Monoclonal antibody–etanercept Etanercept–monoclonal antibody Monoclonal antibody–monoclonal antibody
8 (25.0) 24 (75.0) 118 (72.4) 45 (27.6) 36 (85.7) 6 (14.3) 154 (65.0) 32 (13.5) 51 (21.5)
2.2. Predictors of treatment response Univariate analysis (Table 3) showed that a higher DAS28 score at the beginning of the second treatment was associated with a clinical response (OR 2.15, 95% CI 1.556–2.969), as was the occurrence of an adverse event rather than lack of efficacy as the reason for stopping the first course (OR 0.388, 95% CI 0.199–0.757). At multivariate analysis, only the baseline DAS28 remained significant. The DAS 28 of the patients starting the second anti-TNFα treatment after a failure due to a lack of response was higher than that observed in the patients who experienced adverse events during the first treatment (5.954 vs 5.589). 3. Discussion The findings of this multicentre observational study of a large population of Italian RA patients confirm that the failure of a first antiTNFα agent does not preclude a response to another, although the probability of achieving a DAS28 clinical response after switching
Fig. 1. Response rates after the second anti-TNFα treatment according to reason for stopping the first course (adverse event or lack of efficacy). Responses are reported according to EULAR criteria (EULAR non-responders, moderate responders or good responders).
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from one anti-TNFα agent to another is slightly lower than that observed in patients beginning anti-TNF treatment after the failure of DMARDs. This study was based on a large cohort of more than 1000 RA patients, 237 of whom switched their anti-TNFα treatment. It has some potential limitations insofar as it was an observational study of everyday rheumatology practice in Italy, and so the treatment decisions were not randomised or strictly linked to national guidelines but left to the judgement of the treating physician. Nevertheless, the findings do reflect treatment outcomes as they occur in everyday clinical practice, and this may offer possibly important clinical insights that would not emerge from a randomised controlled trial [1]. The published guidelines of the Italian Society for Rheumatology suggest that treatment should be discontinued after six months if the DAS28 score has not improved by ≥1.2, [31] but this recommendation is not always observed in clinical practice [16]. Economic evaluations may also be an issue when deciding whether to switch to another antiTNFα agent or change treatment targets, although this was not so in our study as the Italian National Health System provides free access to the drugs. All of the available agents are potent neutralisers of TNFα, a pivotally important cytokine in the pathogenesis of RA [32]. Although they all have been found to be similarly efficacious in RA, there are some fundamental differences between them that may explain different effects. INF is a chimeric monoclonal antibody, ADA is a fully humanised monoclonal antibody, and ETA is a fusion of a recombinant soluble p75 TNF receptor and the Fc portion of human IgG. They all bind to TNFα but ETA also binds to lymphotoxin, a cytokine that has been found in the synovial tissue of RA patients and may play a role in pathogenesis [33]. The three drugs also differ in their effectiveness in other diseases: unlike the monoclonal antibodies, ETA is not effective in granulomatous diseases such as Crohn's disease; furthermore, INF and ADA are associated with an increased risk of granulomatous infections, such as mycobacterium tuberculosis, in comparison with ETA [34]. The three agents also have different half-lives, with that of ETA being the shortest (4 days) and that of ADA the longest (14 days) [35], and different dosing regimens and administration routes (INF is given every 4–8 weeks by means of an intravenous infusion, whereas ETA and ADA are administered subcutaneously). Finally, there may be differences in the induction of anti-drug antibodies, which may be associated with a loss of efficacy over time, and differences in the induced production of autoantibodies [36], both of which may provide a strong rationale for switching from one antiTNFα agent to another. A number of studies have supported this possibility, and switching to a different TNF antagonist has become common clinical practice. However, while a switch from a first to a second anti-TNFα agent is generally considered useful, a third switch does not seem to be costeffective insofar as various reports suggest that the rate of response to the third drug is significantly lower and that changing the target may be more useful [22,37]. Many of the studies of switching anti-TNFα agents are limited by their short duration, small sample sizes, and the lack of randomisation or controls; in addition, many did not include all three agents. Earlier studies mainly considered switching ETA and INF, and found that the response to the second drug was good in a large proportion of cases regardless of which was the first drug, and that there was no difference in safety between the first and second treatment [5–10]. The subsequent availability of ADA led to a number of studies exploring the possibility of switching among all three agents, and confirmed the first impression of the usefulness of a first switch, although there are some differences in terms of the rates of response to the second drug. The South Swedish Arthritis Treatment Group found that the response rate among switchers was lower than that of first-time users in a large population of RA patients (58% vs 71%) [22], whereas the results from the British Society
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Table 3 Predictors of response after 12 months of treatment (HAQ = health assessment questionnaire; DMARDs= disease modifying anti-rheumatic drugs; MTX = methotrexate). Univariate
Age (per 1 year) Male vs female Baseline DAS 28 (per unit) Baseline HAQ Concurrent corticosteroids (no vs yes) Concurrent DMARDs (no vs yes) Concurrent MTX AE vs lack of efficacy Duration of first anti-TNFα treatment
Multivariate
OR (95% CI)
p value
OR (95% CI)
p value
1.025 (0.998–1.052) 0.721 (0.311–1.671) 2.15 (1.556–2.969) 0.841 (0.457–1.547) 0.73 (0.291–1.832) 1.252 (0.433–3.62) 1.526 (0.537–4.336) 0.388 (0.199–0.757) 1.005 (0.984–1.026)
0.0670 0.4451 b 0.0001 0.5774 0.5030 0.6781 0.4273 0.0055 0.6602
1.016 (0.981–1.053)
0.3715 0.9032 0.0021 0.3783 0.75 0.6875 0.1743 0.7195 0.3783
for Rheumatology Biologics Register showed that 73% of the patients switching to a second anti-TNFα agent were still on treatment after a mean 15 months of follow-up [16], and data from the Spanish registry (BIOBADASER) indicated a similar drug survival of the first and second TNFα antagonist [14]. A recently published randomised clinical trial of the efficacy of the new anti-TNFα agent golimumab after treatment with another anti-TNFα agent found a high percentage of responses in the patients who had previously received one or more anti-TNFα agents [38]. In our study, we observed EULAR responses in 71.7% of the patients after 12 months of a second anti-TNFα treatment, in comparison with 81.4% after 12 months on the first treatment in the same setting [27], which allows us to conclude that a second anti-TNFα treatment can be useful and may lead to a large proportion of responders after switching in everyday clinical practice. Anti-TNFα agents seem to be effective regardless of the agent preceding them, and there is little published data concerning the relative merits of using them in a particular order. The vast majority of observational trials have tended to try a drug with a different mechanism of action as the second anti-TNFα agent: the receptor antagonist (ETA) after the failure of a monoclonal antibody (INF or ADA) and vice versa, and a switch between the two monoclonal antibodies is rare. The same was true in our study: the majority of patients were switched from monoclonal antibodies (INF or ADA) to ETA. However, it must be pointed that our register was begun when only INF and ETA were on the market (and INF was approved some months before ETA), and this may explain the high percentage of switching between INF and ETA and the low percentage of switching between the two monoclonal antibodies, although this approach may also be scientifically justified by the drugs' different mechanisms of action and the reported difference in the safety profiles of the monoclonal antibodies in relation to ETA [34,39]. Many studies suggest that the reason for stopping the first antiTNFα treatment may affect the rate of response to a second. It has been reported that a patient is more likely to stop taking a second anti-TNFα agent because of inefficacy if the first was also stopped because of inefficacy and, similarly, that a patient is more likely to develop an adverse event due to a second agent if the first was stopped because of an adverse event [16]. This has also been reported by some other groups [26] but not all [22]. We found that the reason for stopping the first anti-TNFα agent does not predict the response to the second. However, when analysing the factors that may predict the response to a second drug, we did find that patients stopping the first because of an adverse event were less likely to respond to the second than those who failed to respond to the first drug. This may be at least partially explained by the fact that disease activity is less in patients stopping the first drug because of an adverse event than in those stopping it because of a lack of response. It has been recently reported that the DAS28 response to anti-TNFα drugs may be less in patients with a low level of disease activity [40], and our data show that the DAS28 score at the beginning of the second anti-TNFα treatment is a significant predictor of response.
2.386 (1.372–4.147) 0.526 (0.216–1.278) 0.576 (0.169–1.966) 0.521 (0.009–28.74) 2.249 (0.043–116.652) 0.463 (0.152–1.406) 0.994 (0.964–1.025)
In conclusion, our findings confirm that switching anti-TNFα drugs is valuable in patients stopping a first anti-TNFα drug. In clinical practice, the switching usually takes place between drugs with different mechanisms of action (from monoclonal antibodies to the soluble receptor antagonist, and vice versa). The patients with higher disease activity levels and those stopping the first anti-TNFα treatment because of a lack of efficacy are very likely to respond to the second treatment. Take-home messages • Switching between different anti-TNF-alpha agents is a valuable option in patients with rheumatoid arthritis failing a first treatment course. • The patients with higher disease activity levels and those stopping the first anti-TNFα treatment because of a lack of efficacy are very likely to respond to the second treatment. References [1] Caporali R, Bobbio-Pallavicini F, Filippini M, Gorla R, Marchesoni A, Favalli EG, et al. Treatment of rheumatoid arthritis with anti-TNF-alpha agents: a reappraisal. Autoimmun Rev 2009;8:274–80. [2] Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet 2007;370:1861–74. [3] Marchesoni A, Zaccara E, Gorla R, Bazzani C, Sarzi-Puttini P, Atzeni F, et al. TNFalpha antagonist survival rate in a cohort of rheumatoid arthritis patients observed under conditions of standard clinical practice. Ann N Y Acad Sci 2009;1173:837–46. [4] Bazzani C, Filippini M, Caporali R, Bobbio-Pallavicini F, Favalli EG, Marchesoni A, et al. Anti-TNFalpha therapy in a cohort of rheumatoid arthritis patients: clinical outcomes. Autoimmun Rev 2009;8:260–5. [5] van Vollenhoven RF. Switching between anti-tumour necrosis factors: trying to get a handle on a complex issue. Ann Rheum Dis 2007;66:849–51. [6] Favalli EG, Desiati F, Atzeni F, Sarzi-Puttini P, Caporali R, Pallavicini FB, et al. Serious infections during anti-TNFalpha treatment in rheumatoid arthritis patients. Autoimmun Rev 2009;8:266–73. [7] van Vollenhoven R, Harju A, Brannemark S, Klareskog L. Treatment with infliximab (Remicade) when etanercept (Enbrel) has failed or vice versa: data from the STURE registry showing that switching tumour necrosis factor alpha blockers can make sense. Ann Rheum Dis 2003;62:1195–8. [8] Hansen KE, Hildebrand JP, Genovese MC, Cush JJ, Patel S, Cooley DA, et al. The efficacy of switching from etanercept to infliximab in patients with rheumatoid arthritis. J Rheumatol 2004;31:1098–102. [9] Haraoui B, Keystone EC, Thorne JC, Pope JE, Chen I, Asare CG, et al. Clinical outcomes of patients with rheumatoid arthritis after switching from infliximab to etanercept. J Rheumatol 2004;31:2356–9. [10] Gómez-Puerta JA, Sanmartí R, Rodríguez-Cros JR, Cañete JD. Etanercept is effective in patients with rheumatoid arthritis with no response to infliximab therapy. Ann Rheum Dis 2004;63:896. [11] Bennett AN, Peterson P, Zain A, Grumley J, Panayi G, Kirkham B. Adalimumab in clinical practice. Outcome in 70 rheumatoid arthritis patients, including comparison of patients with and without previous anti-TNF exposure. Rheumatology 2005;44:1026–31 (Oxford). [12] Wick MC, Ernestam S, Lindblad S, Bratt J, Klareskog L, van Vollenhoven RF. Adalimumab (Humira) restores clinical response in patients with secondary loss of efficacy from infliximab (Remicade) or etanercept (Enbrel): results from the STURE registry at Karolinska University Hospital. Scand J Rheumatol 2005;34:353–8. [13] Cohen G, Courvoisier N, Cohen JD, Zaltni S, Sany J, Combe B. The efficiency of switching from infliximab to etanercept and vice-versa in patients with rheumatoid arthritis. Clin Exp Rheumatol 2005;23:795–800.
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[27] Sarzi-Puttini P, Antivalle M, Marchesoni A, Favalli EG, Gorla R, Filippini M, et al. Efficacy and safety of anti-TNF agents in the Lombardy rheumatoid arthritis network (LORHEN). Reumatismo 2008;60:290–5. [28] Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24. [29] Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8. [30] Ranza R, Marchesoni A, Calori G, Bianchi G, Braga M, Canazza S, et al. The Italian version of the Functional Disability Index of the Health Assessment Questionnaire. A reliable instrument for multicenter studies on rheumatoid arthritis. Clin Exp Rheumatol 1993;11:123–8. [31] Valesini G, Montecucco C, Cutolo M. Recommendations for the use of biologic (TNF-alpha blocking) agents in the treatment of rheumatoid arthritis in Italy. Clin Exp Rheumatol 2006;24:413–23. [32] Schett G. Immune cells and mediators of inflammatory arthritis. Autoimmunity 2008;41:224–9. [33] Braun A, Takemura S, Vallejo AN, Goronzy JJ, Weyand CM. Lymphotoxin betamediated stimulation of synoviocytes in rheumatoid arthritis. Arthritis Rheum 2004;50:2140–50. [34] Aggarwal R, Manadan AM, Poliyedath A, Sequeira W, Block JA. Safety of etanercept in patients at high risk for mycobacterial tuberculosis infections. J Rheumatol 2009;36:914–7. [35] Nestorov I. Clinical pharmacokinetics of TNF antagonists: how do they differ? Semin Arthritis Rheum 2005;34(5 Suppl1):12–8. [36] Anderson PJ. Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. Semin Arthritis Rheum 2005;34(5 Suppl1):19–22. [37] Finckh A, Ciurea A, Brulhart L, Möller B, Walker UA, Courvoisier D, et al. Which subgroup of rheumatoid arthritis patients benefits from switching to rituximab versus alternative anti-TNF agents after previous failure to anti-TNF agent? Ann Rheum Dis May 15 2009. [38] Smolen JS, Kay J, Doyle MK, Landewé R, Matteson EL, Wollenhaupt J, et al. GOAFTER study investigators. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet 2009;374:210–21. [39] Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, et al. A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ Nov 2 2009:19884297 Electronic publication PubMed PMID. [40] Kristensen LE, Kapetanovic MC, Gülfe A, Söderlin M, Saxne T, Geborek P. Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients with established RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatology 2008;47:495–9 (Oxford).
Autoimmune regulator controls T cell help for pathogenetic autoantibody production in collagen-induced arthritis Autoimmune regulator (Aire) promotes the ectopic expression of tissue-restricted antigens in medullary thymic epithelial cells (mTECs), leading to negative selection of autoreactive T cells. This study, Campbell I. et al (Arthritis Rheum 2009; 60: 1683-93) was undertaken to determine whether loss of central tolerance renders Aire-deficient (Aire-/-) mice more susceptible to the induction of autoimmune arthritis. Medullary TECs were isolated from Aire-/- and wild-type C57BL/6 mice for gene expression analysis Collagen-induced arthritis (CIA) was elicited by injection of chick type II collagen (CII) were evaluated. Chimeric mice were created by reconstituting lymphocyte-deficient mice with either Aire-/- or wild type CD4 T cells and wild-type B cells. Wild-type, but not Aire-/-, mTECs expressed the CII gene Col2aI.Aire-/mice developed more rapid and severe CIA, showing elevated serum anti-CII IgG levels, with earlier switching to arthritogenic IgG subclasses. No evidence was found of enhanced T cell responsiveness to CII in Aire-/- mice; however, Aire-/- CD4 T cells were more efficient at stimulating wild-type B cells to produce anti-CII IgG following immunization of chimeric mice with CII. These findings indicate that Airedependent expression of CII occurs in mTECs, implying that there is central tolerance to self antigens found in articular cartilage. Reduced central tolerance to CII in Aire-/- mice manifests as increased CD4 T cell help to B cells for cross-reactive autoantibody production and enhanced CIA. Aire and central tolerance help prevent cross-reactive autoimmune responses to CII initiated by environmental stimuli and limit spontaneous autoimmunity.
High alpha-defensin levels in patients with systemic lupus erythematosus Innate immunity plays a role in systemic lupus erythematosus (SLE). The objective of this study was to determine the levels of defensins, which are antimicrobial and immunomodulatory polypeptides, in SLE. Sthoeger ZM. et al. (Immunology 2009; 127: 116-22). Sera from SLE patients and healthy controls were tested for pro-inflammatory human beta-defensin 2 (hBD-2) and for alpha-defensin human neutrophil peptide 1 (HNP-1).hBD-2 could not be detected by ELISA and its mRNA levels were low in SLE patients and similar to those found in controls. In contrast, the mean alpha-defensin level in the sera of all SLE patients (11.07 ± 13.92 ng/microl) was significantly higher than that of controls (0.12 ± 0.07 ng/microl). Moreover, 60% of patients, demonstrated very high serum levels (18.5 ± 13.36 ng/microl) and 50% showed elevated gene expression in polymorphonuclear cells. High alpha-defensin levels correlated with disease activity, but not with neutrophil count. Thus, activation and degranulation of neutrophils led to alpha-defensin secretion in SLE patients. Given the immunomodulatory role of alpha-defensin, it is possible that their secretion may activate the adaptive immune system leading to a systemic response.