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• Response to Dr Iannone's eLetter
  Martin Neovius
  Published on: 13 February 2014
• Drug survival on TNF inhibitors: 2003-2004 data from Italian national register (GISEA Register)
  Florenzo Iannone
  Published on: 10 December 2013

• Published on: 13 February 2014

  Response to Dr Iannone's eLetter

  • Martin Neovius, MD
  • Other Contributors:
    • Johan Askling

  Dear Editor,

  We thank Dr. Iannone et al for their comment on our recent study on drug survival on etanercept, infliximab and adalimumab in patients with RA.[1] They noted similarities between our findings and their previously published data[2] on 853 Italian patients starting TNF inhibitor treatment in 2003-2004 in terms of best drug survival on etanercept, similar 4- vs 5 -year drug survival for etanercept and infl...

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  Dear Editor,

  We thank Dr. Iannone et al for their comment on our recent study on drug survival on etanercept, infliximab and adalimumab in patients with RA.[1] They noted similarities between our findings and their previously published data[2] on 853 Italian patients starting TNF inhibitor treatment in 2003-2004 in terms of best drug survival on etanercept, similar 4- vs 5 -year drug survival for etanercept and infliximab, and some shared findings regarding predictors. We agree that there are several similarities, but also differences. We also apologize for not including their study in our non-exhaustive review in the appendix, and not citing their study together with the study by Kievit et al.[3]

  Specifically, we investigated whether drug survival differed between the selected TNF inhibitors, whether these differences were modified by time on treatment, and whether discontinuation rates have changed across calendar periods. We also looked at predictors of drug discontinuation. We did this in more than 9000 prospectively followed patients who initiated their first biologic treatment between 2003 and 2011.

  We found, similar to many previous European investigators (including Iannone et al)[3-8], that etanercept had the best drug survival in overall analyses. We did, however, find that the difference was modified by time, with etanercept being superior to adalimumab only the first year. Interestingly, Iannone et al show data potentially supporting our finding of effect modification by time, although they provide no statistical test of what could be a greater difference in the first and second year (compared to later years) between etanercept and adalimumab.

  In contrast to our study, Iannone et al found similar drug survival on adalimumab and infliximab (4-year unadjusted drug survival: 36.4% vs 37.6%). In our data, the 5-year drug survival for adalimumab was 50%.

  Regarding predictors of drug discontinuation, we used Cox regression when evaluating age, sex, education level, calendar period, HAQ, concomitant DMARD use, disease duration, and two measures of general frailty. All variables but age were statistically significant predictors in the multivariable model, although the magnitude was small to moderate for most. Iannone et al investigated predictors using stepwise logistic regression, and it is unclear whether or how they took censoring into account. In contrast to our findings, they could detect few statistically significant independent predictors, although disease duration and concomitant DMARD use were statistically significant, similar to our findings.

  Considering the recognition of the importance of contextual factors (such as the number of alternative treatment options available) on the real-world effectiveness and drug survival of existing treatment options in RA, we welcome further studies of drug survival and predictors for long-lasting response to therapy.

  References

  1. Neovius M, Arkema EV, Olsson H, et al. Drug survival on TNF inhibitors in patients with rheumatoid arthritis comparison of adalimumab, etanercept and infliximab. Ann Rheum Dis. 2013.

  2. Iannone F, Gremese E, Atzeni F, et al. Longterm retention of tumor necrosis factor-alpha inhibitor therapy in a large italian cohort of patients with rheumatoid arthritis from the GISEA registry: an appraisal of predictors. J Rheumatol. 2012; 39:1179-1184.

  3. Kievit W, Adang EM, Fransen J, et al. The effectiveness and medication costs of three anti-tumour necrosis factor alpha agents in the treatment of rheumatoid arthritis from prospective clinical practice data. Ann Rheum Dis. 2008; 67:1229-1234.

  4. Du Pan SM, Dehler S, Ciurea A, et al. Comparison of drug retention rates and causes of drug discontinuation between anti-tumor necrosis factor agents in rheumatoid arthritis. Arthritis and rheumatism. 2009; 61:560-568.

  5. Marchesoni A, Zaccara E, Gorla R, et al. TNF-alpha antagonist survival rate in a cohort of rheumatoid arthritis patients observed under conditions of standard clinical practice. Annals of the New York Academy of Sciences. 2009; 1173:837-846.

  6. Kristensen LE, Saxne T, Nilsson JA, et al. Impact of concomitant DMARD therapy on adherence to treatment with etanercept and infliximab in rheumatoid arthritis. Results from a six-year observational study in southern Sweden. Arthritis Res Ther. 2006; 8:R174.

  7. Hetland ML, Christensen IJ, Tarp U, et al. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis and rheumatism. 2010; 62:22- 32.

  8. Brocq O, Roux CH, Albert C, et al. TNFalpha antagonist continuation rates in 442 patients with inflammatory joint disease. Joint, bone, spine : revue du rhumatisme. 2007; 74:148-154.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 10 December 2013

  Drug survival on TNF inhibitors: 2003-2004 data from Italian national register (GISEA Register)

  • Florenzo Iannone
  • Other Contributors:
    • Gianfranco Ferraccioli, Elisa Gremese, Giovanni Lapadula

  Dear Editor,

  We read with interest the findings of the paper by Neovius et al recently published on Annals of the Rheumatic Diseases 1 who retrospectively studied the drug survival on TNF-alpha blockers in patients with rheumatoid arthritis (RA) in real life settings. The primary endpoint of their analysis was to assess the drug discontinuation rates in RA patients starting a first ever TNF-alpha inhibitor, and to...

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  Dear Editor,

  We read with interest the findings of the paper by Neovius et al recently published on Annals of the Rheumatic Diseases 1 who retrospectively studied the drug survival on TNF-alpha blockers in patients with rheumatoid arthritis (RA) in real life settings. The primary endpoint of their analysis was to assess the drug discontinuation rates in RA patients starting a first ever TNF-alpha inhibitor, and to compare between-group survival rates for the historical anti-TNF-alpha drug, namely adalimumab, etanercept, and infliximab, during five years follow-up. Additionally, they also evaluated the discontinuation rates of each anti-TNF-alpha drug across calendar period. They selected patients starting the treatment since 2003, when all three drugs were available on the market, and claimed that it was the first study assessing adalimumab, etanercept, and infliximab retention rates from 2003 onwards, together with the article by Kievit et al2. Indeed, we have published a similar study in which the drug discontinuation of first ever adalimumab, etanercept and infliximab in RA patients starting follow-up in 2003 was compared among groups3. Our cohort was smaller because only patients beginning the treatment in 2003 through 2004 and followed up-to 4 years were analysed. Notwithstanding, our study yielded nearly identical results. After 4-year follow-up the survival rate of etanercept (51 %) was significantly greater than that of infliximab (37.6 %) or adalimumab (36.4 %; p <0.0001). Unlike the study by Neovius et al, the Kaplan-Meier life curve of adalimumab was closer to that of infliximab rather than etanercept (Figure 1). Of note, Neovius et al carried out an analysis by calendar period from 2003 to 2011 and provided evidence that discontinuation rates increased over time, maybe due to the availability of new biologics. They also showed that discontinuation rate was higher for adalimumab than etanercept during the 1st year.
  Likewise, we observed the highest discontinuation rate of adalimumab in the 1st year of follow-up, and the difference between etanercept and adalimumab was 13 % and 4 % in the 1st and 2nd year, respectively (data not shown). Furthermore, we found the same predictors of drug survival, as baseline concomitant therapy with Disease Modifying Drugs (DMARDs) and longer disease duration were associated with lower odds of drug interruption in both studies, although different statistical analysis was used. Obviously, also our study had similar weaknesses, being an analysis of a longitudinal cohort followed in standard care settings, without randomization and totally depending on own decisions of treating rheumatologist that can still influence the clinical outcome despite of the statistical adjustments. Therefore, our data are in agreement with the conclusions of the article by Neovius et al, and this is of note since the two RA cohorts become from quite far geographical areas, North and South of Europe, with racial, genetic, and cultural differences.

  Figure will be available on the Electronic Pages soon.

  Figure 1. Drug retention rate in patients with rheumatoid arthritis on TNF-? inhibitors starting from 2003 and followed-up to four (Iannone cohort) or five (Neovius cohort) years.

  References

  1 Neovius M, Arkema EV, Olsson H, et al. Drug survival on TNF inhibitors in patients with rheumatoid arthritis comparison of adalimumab, etanercept and infliximab. Ann Rheum Dis 2013;0:1 7. doi:10.1136

  2 Kievit W, Adang EM, Fransen J, et al. The effectiveness and medication costs of three anti-tumour necrosis factor alpha agents in the treatment of rheumatoid arthritis from prospective clinical practice data. Ann Rheum Dis 2008;67:1229-34.

  3 Iannone F, Gremese E, Atzeni F, et al. Longterm retention of tumor necrosis factor-? inhibitor therapy in a large italian cohort of patients with rheumatoid arthritis from the GISEA registry: an appraisal of predictors. J Rheumatol 2012;39:1179-84.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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