Lorenzin et al. BMC Musculoskeletal Disorders (2015) 16:166 DOI 10.1186/s12891-015-0620-4
RESEARCH ARTICLE
Open Access
Predictors of response and drug survival in ankylosing spondylitis patients treated with infliximab Mariagrazia Lorenzin, Augusta Ortolan, Paola Frallonardo, Francesca Oliviero, Leonardo Punzi and Roberta Ramonda*
Abstract Background: The advent of anti-tumor necrosis factor-α (TNFα) drugs has changed the course of ankylosing spondylitis (AS). While data are available concerning the long term effectiveness of single anti-TNF agents, little has been published about predictors of treatment response in AS. The aim of this retrospective study was to evaluate the survival, effectiveness, and safety of infliximab over a 5-year period and to identify predictors of disease outcome. Methods: Seventy AS patients attending the Rheumatology Clinic of the University of Padua who were treated with intravenous infliximab at 0, 2, 4 weeks and then every 6, 8, or up to 16 weeks were studied retrospectively. Demographic information, laboratory inflammatory and disease indices (BASDAI, BASFI, BASMI) were collected (at baseline, 3, 6, 12 months and once a year thereafter). Clinical improvement, drug tolerability, adverse events/ side effects and causes leading to discontinuation were recorded. Results: Infliximab caused a rapid, persistent improvement at all the assessment times in the BASDAI 50 (71.4 %) and ASDAS scores (97.1 % in ASAS20, 80 % in ASAS40, 80 % in ASAS5/6), and already within 6 months of beginning treatment in 50 % percent of the patients. The other 50 % withdrew because of: adverse events (12 = 34.3 %), side effects (5 = 14.3 %), drug inefficacy (12 = 34.3 %), spontaneously (4 = 11.4 %). Those who did not respond were prevalently females (34.3 % vs 17.1 %). Conclusion: Factors such as female sex, use of steroids, persistently high inflammatory levels, BASFI and BASDAI indices were found to be negative predictors of treatment response. Infliximab was found to be safe, effective and well-tolerated; it elicited satisfactory long term response and drug survival rates. Keywords: Spondyloarthritis, Ankylosing spondylitis, anti-TNFα agents, Biologic drugs, Infliximab
Background Ankylosing spondylitis (AS), a prototype of the spondyloarthritis (SpA) family, is a chronic, progressive, axial inflammatory disease mainly involving the spine and the sacroiliac joints [1], as well as other sites of the axial skeleton such as anterior chest wall joints [2]. Since the disease can lead to severe, chronic pain and discomfort [1, 3], treatment should be initiated as early as possible to prevent skeletal deformity and physical disability [4]. In the past (until’90s), few effective therapies were available and were * Correspondence: [email protected] Rheumatology Unit, Department of Medicine – DIMED, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
limited for the most part to regular physical activity and non-steroidal anti-inflammatory drugs (NSAIDs) [1, 5, 6]. Disease-modifying antirheumatic drugs (DMARDs) and corticosteroids, which are quite effective in other chronic inflammatory diseases such as rheumatoid arthritis (RA), appear to have only a limited or no effect on the course of AS [1, 6–9]. The advent of anti-Tumor Necrosis Factor-α (TNFα) agents (adalimumab, etanercept, infliximab and golimumab) has constituted a breakthrough in the management of AS patients, especially in the case of persistently active forms [1, 10–17]. Anti-TNFα agents have been found to produce clinical, functional, biological, as well as quality of
© 2015 Lorenzin et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Lorenzin et al. BMC Musculoskeletal Disorders (2015) 16:166
life improvements. Trials with infliximab and other antiTNFα agents have, in fact, demonstrated a remarkable improvement in AS patients, and their efficacy and safety have been confirmed by a number of randomised, openlabel, controlled studies [17–22]. These results need, however, to be confirmed by further studies focusing on some treatment-related aspects and patients’ real life experience. While single center studies have many limitations with respect to multicenter studies or registries, they have the advantage of studying a more homogeneous population and of thus preventing at least one confounding factor. The aim of this retrospective single center study was to evaluate the effectiveness, safety and the long-term drug survival of infliximab in AS patients over a 5-year treatment period and to identify predictors of disease outcome.
Methods Study population
Seventy AS outpatients diagnosed between 2003 and 2010 in accordance with the modified New York criteria [23] and attending the Rheumatology Clinic of the University of Padova Medical Center were enrolled in this retrospective study. This study was approved by the ethics committee of Padova University Hospital. All of the patients provide written informed consent for participation in this study. Inclusion criteria were: age >18 years and an inadequate response (no response or lack of tolerance) to previous NSAIDs. Exclusion criteria were: signs or symptoms of latent or active tuberculosis, chronic or clinically severe infection, malignancy or congestive heart failure. All the recruited patients were treated with infliximab, which was administered intravenously (3–5 mg/kg/ body weight) at 0, 2, 6 weeks and every 4 weeks thereafter for a 5-year period. Whenever drug scheduling produced an optimal treatment response, the time interval between drug infusion was prolonged to 6, 8 or to as many as 16 weeks. In addition to pharmacological therapy, all patients followed a home-based exercise program recommended by the specialized physiotherapist who collaborates with our unit. Clinimetric, laboratory tests, assessment questionnaires, and outcome measures
All the patients underwent regular clinical and clinimetric evaluations prescribed by a specialized rheumatologist. Demographic data and assessment scores at baseline (0 M), at 3 months (3 M), at 6 months (6 M), and once a year thereafter for a 5-year period were systematically collected. The instruments utilized included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) which is the most commonly used instrument to measure and evaluate the inflammatory activity of AS (values expressed from 0 to 100). Considered the gold standard to assess physical
Page 2 of 8
function in AS patients and commonly used to screen candidates for anti-TNF medication the Bath Ankylosing Spondylitis Functional Index (BASFI), is a self-reported, validated, outcome measure. Active disease was identified by the BASDAI and/or BASFI score > 4 [24, 25]. Spinal mobility was measured using the Bath Ankylosing Spondilitis Metrology Index (BASMI). Pain and global assessment were measured using the Visual Analogue Scale and patient global assessment (VAS and VASg) whose scores range from 0 to 10. Laboratory measures of inflammation, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), were regularly assessed in all the patients (normal values for our laboratory: 5 mg/day), high VASg levels at baseline, no fall in inflammatory indices, persistently high BASFI and BASDAI levels can all be considered predictors of future anti-TNFα treatment discontinuation. This study has, of course, some limitations: most importantly, the study population is small. In addition, since the patients needed to fulfill the New York criteria, only those individuals with a relatively advanced disease form were included. As a consequence, its results cannot be applied to patients with early, nonradiographic axial SpA. The study did produce one original finding: that simple clinical/laboratory markers of disease activity can already predict at baseline which AS patients are most likely to have a poor response to treatment. This information could, of course, be useful to specialists who are managing AS patients and further studies are warranted to confirm these data. Key messages The clinical impact of AS is severe and its
progression leads to disability With appropriate treatment, patients with AS can
live relatively normal, independent lives Competing interests None of the authors have any conflicts of interest to disclose regarding this manuscript. Authors’ contributions ML participated in drafting the manuscript as well as analyzing, acquiring and interpreting the data. RR and LP conceived and designed the study and participated in data processing and in drafting the manuscript. FO performed statistical analysis and participated in analyzing and interpreting the data. PF and AO participated in acquiring the data. All the authors have made substantive intellectual contributions to the study, have reviewed the article, and have given the final approval of the version being submitted.
Page 7 of 8
Acknowledgment The authors wish to thank Linda Inverso for her assistance in editing the English version. This study did not receive any financial support. Received: 10 November 2013 Accepted: 30 June 2015
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20. Arends S, Brouwer E, van der Veer E, Groen H, Leijsma MK, Houtman PM, et al. Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study. Arthritis Res Ther. 2011;13:R94. 21. Saougou I, Markatseli TE, Voulgari PV, Drosos AA. Maintained clinical response of infliximab treatment in anylosing spondylitis: A 6-year longterm study. Joint Bone Spine. 2010;77:325–29. 22. Venetsanopoulou AI, Voulgari PV, Alamanos Y, Papadopoulos CG, Markatseli TE, Drosos AA. Persistent clinical response of infliximab treatment, over a 4-year period in ankylosing spondylitis. Rheumatol Int. 2007;27:935–39. 23. Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984;27:361–68. 24. Godfrin-Valnet M, Prati C, Puyraveau M, Toussirot E, Letho-Gyselink H, Wendling D. Evaluation of spondylarthritis activity by patients and physicians: ASDAS, BASDAI, PASS, and flares in 200 patients. Joint Bone Spine. 2013;80:393–98. 25. Boonen A, van der Heijde D, Severens JL, Boendermaker A, Landewé R, Braun J, et al. Markov model into the cost-utility over five years of etanercept and infliximab compared with usual care in patients with active ankylosing spondylitis. Ann Rheum Dis. 2006;65:201–8. 26. Zochling J, van der Heijde D, Burgos-Vargas R, Collantes E, Davis Jr JC, Dijkmans B, et al. ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis. 2006;65:442–52. 27. Baraliakos X, Listing J, Fritz C, Haibel H, Alten R, Burmester GR, et al. Persistent clinical efficacy andsafety of infliximab in ankylosing spondylitis after 8 years–early clinical response predicts long term outcome. Rheumatology (Oxford). 2011;50:1690–9. 28. Spadaro A, Lubrano E, Marchesoni A, D'Angelo S, Ramonda R, Addimanda O, et al. Remission in ankylosing spondylitis treated with anti-TNF-α drugs: a national multicentre study. Rheumatology (Oxford). 2013;52:1914–19. 29. Bunchuk NV, Rumiantseva OA, Loginova EI, Bochkova AG, Storozhakov GI, Ettinger OA, et al. The efficacy and safety of infliximab in patients with ankylosing spondylitis: results of an open-labeled multicenter study. Ter Arkh. 2010;82:41–6. 30. Pavelka K, Forejtová S, Stolfa J, Chroust K, Buresová L, Mann H, et al. Anti- TNF therapy of ankylosing spondylitis in clinical practice. Results from the Czech national registry ATTRA. Clin Exp Rheumatol. 2009;27:958–63. 31. Bodur H, Ataman S, Buğdaycı DS, Rezvani A, Nas K, Uzunca K, et al. Description of the registry of patients with ankylosing spondylitis in Turkey: TRASD-IP. Rheumatol Int. 2012;32:169–76. 32. Glintborg B, Østergaard M, Krogh NS, Tarp U, Manilo N, Loft AG, et al. Clinical response, drug survival and predictors thereof in 432 ankylosing spondylitis patients after switching tumour necrosis factor α inhibitor therapy: results from the Danish nationwide DANBIO registry. Ann Rheum Dis. 2013;72:1149–55. 33. Baraliakos X, Listing J, Rudwaleit M, Haibel H, Brandt J, Sieper J, et al. Progression of radiographic damage in patients with ankylosing spondylitis: defining the central role of syndesmophytes. Ann Rheum Dis. 2007;66:910–15. 34. Masiero S, Bonaldo L, Pigatto M, Lo Nigro A, Ramonda R, Punzi L. Rehabilitation treatment in patients with ankylosing spondylitis stabilized with tumor necrosis factor inhibitor therapy: a randomized controlled trial. J Rheumatol. 2011;38:1335–42. 35. Ciprian L, Lo Nigro A, Rizzo M, Gava A, Ramonda R, Punzi L, et al. The effects of combined spa therapy and rehabilitation on patients with ankylosing spondylitis being treated with TNF inhibitors. Rheumatol Int. 2013;33:241–5. 36. Glintborg B, Ostergaard M, Krogh NS, Dreyer L, Kristensen HL, Hetland ML. Predictors of treatment response and drug continuation in 842 patients with ankylosing spondylitis treated with anti-tumour necrosis factor: results from 8 years' surveillance in the Danish nationwide DANBIO registry. Ann Rheum Dis. 2010;69:2002–8. 37. Modesti V, Ramonda R, Ortolan A, Lorenzin M, Lo Nigro A, Frallonardo P, et al. Infection relapse in spondyloarthritis treated with biological drugs: a single-centre study. Scand J Rheumatol. 2012;41:490–1.
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RESEARCH ARTICLE
Open Access
Predictors of response and drug survival in ankylosing spondylitis patients treated with infliximab Mariagrazia Lorenzin, Augusta Ortolan, Paola Frallonardo, Francesca Oliviero, Leonardo Punzi and Roberta Ramonda*
Abstract Background: The advent of anti-tumor necrosis factor-α (TNFα) drugs has changed the course of ankylosing spondylitis (AS). While data are available concerning the long term effectiveness of single anti-TNF agents, little has been published about predictors of treatment response in AS. The aim of this retrospective study was to evaluate the survival, effectiveness, and safety of infliximab over a 5-year period and to identify predictors of disease outcome. Methods: Seventy AS patients attending the Rheumatology Clinic of the University of Padua who were treated with intravenous infliximab at 0, 2, 4 weeks and then every 6, 8, or up to 16 weeks were studied retrospectively. Demographic information, laboratory inflammatory and disease indices (BASDAI, BASFI, BASMI) were collected (at baseline, 3, 6, 12 months and once a year thereafter). Clinical improvement, drug tolerability, adverse events/ side effects and causes leading to discontinuation were recorded. Results: Infliximab caused a rapid, persistent improvement at all the assessment times in the BASDAI 50 (71.4 %) and ASDAS scores (97.1 % in ASAS20, 80 % in ASAS40, 80 % in ASAS5/6), and already within 6 months of beginning treatment in 50 % percent of the patients. The other 50 % withdrew because of: adverse events (12 = 34.3 %), side effects (5 = 14.3 %), drug inefficacy (12 = 34.3 %), spontaneously (4 = 11.4 %). Those who did not respond were prevalently females (34.3 % vs 17.1 %). Conclusion: Factors such as female sex, use of steroids, persistently high inflammatory levels, BASFI and BASDAI indices were found to be negative predictors of treatment response. Infliximab was found to be safe, effective and well-tolerated; it elicited satisfactory long term response and drug survival rates. Keywords: Spondyloarthritis, Ankylosing spondylitis, anti-TNFα agents, Biologic drugs, Infliximab
Background Ankylosing spondylitis (AS), a prototype of the spondyloarthritis (SpA) family, is a chronic, progressive, axial inflammatory disease mainly involving the spine and the sacroiliac joints [1], as well as other sites of the axial skeleton such as anterior chest wall joints [2]. Since the disease can lead to severe, chronic pain and discomfort [1, 3], treatment should be initiated as early as possible to prevent skeletal deformity and physical disability [4]. In the past (until’90s), few effective therapies were available and were * Correspondence: [email protected] Rheumatology Unit, Department of Medicine – DIMED, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
limited for the most part to regular physical activity and non-steroidal anti-inflammatory drugs (NSAIDs) [1, 5, 6]. Disease-modifying antirheumatic drugs (DMARDs) and corticosteroids, which are quite effective in other chronic inflammatory diseases such as rheumatoid arthritis (RA), appear to have only a limited or no effect on the course of AS [1, 6–9]. The advent of anti-Tumor Necrosis Factor-α (TNFα) agents (adalimumab, etanercept, infliximab and golimumab) has constituted a breakthrough in the management of AS patients, especially in the case of persistently active forms [1, 10–17]. Anti-TNFα agents have been found to produce clinical, functional, biological, as well as quality of
© 2015 Lorenzin et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Lorenzin et al. BMC Musculoskeletal Disorders (2015) 16:166
life improvements. Trials with infliximab and other antiTNFα agents have, in fact, demonstrated a remarkable improvement in AS patients, and their efficacy and safety have been confirmed by a number of randomised, openlabel, controlled studies [17–22]. These results need, however, to be confirmed by further studies focusing on some treatment-related aspects and patients’ real life experience. While single center studies have many limitations with respect to multicenter studies or registries, they have the advantage of studying a more homogeneous population and of thus preventing at least one confounding factor. The aim of this retrospective single center study was to evaluate the effectiveness, safety and the long-term drug survival of infliximab in AS patients over a 5-year treatment period and to identify predictors of disease outcome.
Methods Study population
Seventy AS outpatients diagnosed between 2003 and 2010 in accordance with the modified New York criteria [23] and attending the Rheumatology Clinic of the University of Padova Medical Center were enrolled in this retrospective study. This study was approved by the ethics committee of Padova University Hospital. All of the patients provide written informed consent for participation in this study. Inclusion criteria were: age >18 years and an inadequate response (no response or lack of tolerance) to previous NSAIDs. Exclusion criteria were: signs or symptoms of latent or active tuberculosis, chronic or clinically severe infection, malignancy or congestive heart failure. All the recruited patients were treated with infliximab, which was administered intravenously (3–5 mg/kg/ body weight) at 0, 2, 6 weeks and every 4 weeks thereafter for a 5-year period. Whenever drug scheduling produced an optimal treatment response, the time interval between drug infusion was prolonged to 6, 8 or to as many as 16 weeks. In addition to pharmacological therapy, all patients followed a home-based exercise program recommended by the specialized physiotherapist who collaborates with our unit. Clinimetric, laboratory tests, assessment questionnaires, and outcome measures
All the patients underwent regular clinical and clinimetric evaluations prescribed by a specialized rheumatologist. Demographic data and assessment scores at baseline (0 M), at 3 months (3 M), at 6 months (6 M), and once a year thereafter for a 5-year period were systematically collected. The instruments utilized included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) which is the most commonly used instrument to measure and evaluate the inflammatory activity of AS (values expressed from 0 to 100). Considered the gold standard to assess physical
Page 2 of 8
function in AS patients and commonly used to screen candidates for anti-TNF medication the Bath Ankylosing Spondylitis Functional Index (BASFI), is a self-reported, validated, outcome measure. Active disease was identified by the BASDAI and/or BASFI score > 4 [24, 25]. Spinal mobility was measured using the Bath Ankylosing Spondilitis Metrology Index (BASMI). Pain and global assessment were measured using the Visual Analogue Scale and patient global assessment (VAS and VASg) whose scores range from 0 to 10. Laboratory measures of inflammation, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), were regularly assessed in all the patients (normal values for our laboratory: 5 mg/day), high VASg levels at baseline, no fall in inflammatory indices, persistently high BASFI and BASDAI levels can all be considered predictors of future anti-TNFα treatment discontinuation. This study has, of course, some limitations: most importantly, the study population is small. In addition, since the patients needed to fulfill the New York criteria, only those individuals with a relatively advanced disease form were included. As a consequence, its results cannot be applied to patients with early, nonradiographic axial SpA. The study did produce one original finding: that simple clinical/laboratory markers of disease activity can already predict at baseline which AS patients are most likely to have a poor response to treatment. This information could, of course, be useful to specialists who are managing AS patients and further studies are warranted to confirm these data. Key messages The clinical impact of AS is severe and its
progression leads to disability With appropriate treatment, patients with AS can
live relatively normal, independent lives Competing interests None of the authors have any conflicts of interest to disclose regarding this manuscript. Authors’ contributions ML participated in drafting the manuscript as well as analyzing, acquiring and interpreting the data. RR and LP conceived and designed the study and participated in data processing and in drafting the manuscript. FO performed statistical analysis and participated in analyzing and interpreting the data. PF and AO participated in acquiring the data. All the authors have made substantive intellectual contributions to the study, have reviewed the article, and have given the final approval of the version being submitted.
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Acknowledgment The authors wish to thank Linda Inverso for her assistance in editing the English version. This study did not receive any financial support. Received: 10 November 2013 Accepted: 30 June 2015
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