Just Accepted by Modern Rheumatology
Original Article
Association of anti-Ro/SSA antibody with response to biologics in patients with rheumatoid arthritis Shinya Hagiwara, Hiroto Tsuboi, Fumika Honda, Hidenori Takahashi, Izumi Kurata, Ayako Ohyama, Mizuki Yagishita, Saori Abe, Yuko Kurashima, Syunta Kaneko, Hoshimi Kawaguchi, Hiroyuki Takahashi, Hiroshi Ebe, Masahiro Yokosawa, Hiromitsu Asashima, Tomoya Hirota, Naoto Umeda, Yuya Kondo, Isao Matsumoto, Takayuki Sumida Doi: 10.3109/14397595.2016.1153567 Abstract Objective. To compare the effectiveness of three different biologics in anti-Ro/SSA antibody-positive and -negative patients with rheumatoid arthritis (RA). Methods. The study subjects were 110 biologics naïve RA patients who started treat‐ ment with biologics and examined for anti-Ro/SSA antibody between December 2003 and March 2014. For patients treated with intravenous infliximab (IFX), tocilizumab (TCZ), or abatacept (ABT), we compared the clinical characteristics and changes in composite disease activity index such as DAS28, SDAI, and CDAI for 12 months in anti-Ro/SSA antibody-positive and negative patients. Results. We examined 59 patients (9 were positive and 50 were negative for anti-Ro/SSA antibody) treated with IFX, 27 patients (5 positive and 22 negative) treated with TCZ, and 24 patients (13 positive and 11 negative) treated with ABT. For patients treated with IFX, parameters of disease activity did not change significantly from baseline in anti-Ro/SSA antibody -positive patients, whereas they improved in -negative patients. On the other hand, treatment with TCZ and ABT significantly decreased disease activity, relative to baseline, in both anti-Ro/SSA antibody-positive and -negative patients. Anti-Ro/SSA antibody-positive patients treated with IFX showed higher frequency of HACA and seroconversion of ANA, and lower serum TGF-β levels. Conclusions. Positivity to anti-Ro/SSA in RA seems to confer resistance to IFX via production of HACA and ANA, and low serum TGF-β levels, but not to TCZ and ABT.
© 2016 Taylor & Francis. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal's Just Accepted articles do not necessarily reflect those of Taylor & Francis (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
MORH-D-15-00762 Received: Dec-10-15; Accepted: Feb-09-16 Original Article
Association of anti-Ro/SSA antibody with response to biologics in patients with rheumatoid arthritis
Shinya Hagiwara, Hiroto Tsuboi, Fumika Honda, Hidenori Takahashi, Izumi Kurata, Ayako Ohyama, Mizuki Yagishita, Saori Abe, Yuko Kurashima, Syunta Kaneko, Hoshimi Kawaguchi, Hiroyuki Takahashi, Hiroshi Ebe, Masahiro Yokosawa, Hiromitsu Asashima, Tomoya Hirota, Naoto Umeda,
D
Yuya Kondo, Isao Matsumoto, and Takayuki Sumida
TE
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
EP
Correspondence to Prof. Takayuki Sumida, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-city, Ibaraki 305-8575, Japan. Tel: +81-29-853-7388,
AC C
Fax: +81-29-853-7388, E-mail: [email protected]
The number of text pages: 12, The number of tables: 4, The number of figures: 1
JU
abatacept (ABT)
ST
Key Words： rheumatoid arthritis, anti-Ro/SSA antibody, infliximab (IFX), tocilizumab (TCZ),
Abstract Objective. To compare the effectiveness of three different biologics in anti-Ro/SSA antibody-positive and -negative patients with rheumatoid arthritis (RA). Methods. The study subjects were 110 biologics naïve RA patients who started treatment with biologics and examined for anti-Ro/SSA antibody between December 2003 and March 2014. For patients treated with intravenous infliximab (IFX), tocilizumab (TCZ), or abatacept (ABT), we compared the clinical characteristics and changes in composite disease activity index such as DAS28, SDAI, and CDAI for 12 months in anti-Ro/SSA antibody-positive and -negative patients. Results. We examined 59 patients (9 were positive and 50 were negative for anti-Ro/SSA antibody) treated with IFX, 27 patients (5 positive and 22 negative) treated with TCZ, and 24 patients (13 positive
D
and 11 negative) treated with ABT. For patients treated with IFX, parameters of disease activity did not change significantly from baseline in anti-Ro/SSA antibody -positive patients, whereas they improved
TE
in -negative patients. On the other hand, treatment with TCZ and ABT significantly decreased disease activity, relative to baseline, in both anti-Ro/SSA antibody-positive and -negative patients. Anti-Ro/SSA
ANA, and lower serum TGF-β levels.
EP
antibody-positive patients treated with IFX showed higher frequency of HACA and seroconversion of
AC C
Conclusions. Positivity to anti-Ro/SSA in RA seems to confer resistance to IFX via production of
JU
ST
HACA and ANA, and low serum TGF-β levels, but not to TCZ and ABT.
Introduction New therapies for rheumatoid arthritis (RA) have become available in recent years. Several types of biologics are currently being used that can induce remission in many RA patients. However, intractable cases still exist. The American College of Rheumatology (ACR) 2012 lists the following poor prognosis factors for RA: functional limitation (e. g., health assessment questionnaire (HAQ) score or similar valid tools); extra-articular disease, positive rheumatoid factor (RF) or anti-citrullinated protein antibody (ACPA), and bone erosions by radiography (1). In particular, it is well accepted that a positive ACPA is a poor prognostic factor in patients with RA (2-4). Apart from RF and ACPA, antinuclear antibodies (ANA) and anti-double-stranded (anti-ds) DNA antibodies are occasionally detected especially in RA patients who have been treated with anti-TNF alpha biologics, and exceptionally associated with
D
clinical manifestations of lupus erythematosus (SLE) (5, 6). In fact, there is a close relationship between the clinical course of RA and autoantibodies. Moreover, anti-Ro/SSA antibodies have been
TE
used as diagnostic markers for Sjögren’s syndrome (SS), as well as occasionally for other rheumatic diseases, such as SLE and RA (7-10). Importantly, it was reported that RA patients with secondary SS
EP
had worse joint damage than RA without SS (11). Further, one report indicated that anti-Ro/SSA antibody was an independent factor associated with insufficient therapeutic response to TNF inhibitors
AC C
in patients with RA (12). In this regard, there is no information on the relationship between the response to non-TNF biologics and positivity for anti-Ro/SSA antibody. The aim of the present study was to determine the significance of anti-Ro/SSA antibodies in relation to the clinical response to three different biologics; infliximab (IFX), tocilizumab (TCZ), and
JU
ST
abatacept (ABT).
Patients and methods Study population We examined 110 Japanese patients with RA who visited the University of Tsukuba Hospital between December 2003 and March 2014, and were treated with one of the following biological disease-modifying anti-rheumatic drugs (DMARDs): IFX, TCZ, or ABT, as the first biological DMARD. All patients fulfilled the 1987 ACR criteria for RA (13) or 2010 ACR/European League Against Rheumatism (EULAR) criteria for RA (14). All patients who satisfied the 1999 Japanese Ministry of Health criteria for the diagnosis of SS (15, 16), were considered to have secondary SS. All biologics were administered intravenously. All patients were treated for anti-Ro/SSA antibody status by double immunodiffusion (DID) test. Approval for this study was obtained from the local ethics committee, and
D
signed informed consent was obtained from each patient.
TE
Clinical characteristics
The following data baseline characteristics were collected from the medical records; age, sex, RA
EP
disease duration, Steinbrocker classification, functional class, RA- and SS-related complications, tender joint count, swollen joint count, visual analog scale (VAS), C-reactive protein (CRP), erythrocyte
AC C
sedimentation rate (ESR), disease activity score in 28 joints/CRP (DAS28/CRP), disease activity score in 28 joints/ESR (DAS28/ESR), simplified disease activity index (SDAI), clinical disease activity index (CDAI), RF, ACPA, matrix metalloproteinase-3, immunoglobulin G (IgG), anti-Ro/SSA antibody, anti-La/SSB antibody, and definite diagnosis of secondary SS. We also surveyed all treatments used
ST
at the time of initiation of biologics, such as prednisolone, methotrexate, and other conventional synthetic DMARDs.
JU
Furthermore, we also compared the baseline characteristics of patients according to the type of biologics (IFX, TCZ, and ABT), and status of anti-Ro/SSA antibody.
Human anti-chimeric antibody, cytokines and autoantibody status in IFX-treated patients Additional tests were conducted in patients treated with IFX. First, we measured the trough concentration of IFX and examined human anti-chimeric antibody (HACA) in 6 out of 9 anti-Ro/SSA antibody -positive patients treated with IFX at 30 or 54 weeks after initiation of IFX; three were examined at 30 weeks, while the other three at 54 weeks. For comparison, we also measured in age
and gender matched 12 cases out of 50 -negative patients treated with IFX. Second, we measured baseline serum transforming growth factor-β1 (TGF-β1) levels by enzyme-linked immunosorbent assay (ELISA) (Quantikine Human TGF-β1 Immunoassay, R&D Systems, Inc., Minneapolis, MN), and compared those between anti-Ro/SSA antibody-positive and -negative patients. Third, we examined the seroconversion (from negative to positive status) rate for anti-nuclear antibody (ANA) and anti-double stranded DNA antibodies (anti-dsDNA antibodies) after the initiation of IFX therapy.
Changes in disease activity Disease activity was evaluated by composite measures such as DAS28/CRP, DAS28/ESR, SDAI, and CDAI at 0, 6, and 12 months after initiation of each biologic. We also compared changes in disease
D
activities over 12-month treatment period according to anti-Ro/SSA antibody status and type of
TE
biologics.
Statistical analysis
EP
Binary variables were analyzed by Fisher's exact test, while continuous variables (baseline characteristics) were analyzed by the Kruskal-Wallis test or Mann-Whitney U test. The latter test was
AC C
also used for analysis of differences in parameters between two groups, while Wilcoxon test was used for analysis of the effects of treatment at 6 and 12 months on disease activities. A p value
Original Article
Association of anti-Ro/SSA antibody with response to biologics in patients with rheumatoid arthritis Shinya Hagiwara, Hiroto Tsuboi, Fumika Honda, Hidenori Takahashi, Izumi Kurata, Ayako Ohyama, Mizuki Yagishita, Saori Abe, Yuko Kurashima, Syunta Kaneko, Hoshimi Kawaguchi, Hiroyuki Takahashi, Hiroshi Ebe, Masahiro Yokosawa, Hiromitsu Asashima, Tomoya Hirota, Naoto Umeda, Yuya Kondo, Isao Matsumoto, Takayuki Sumida Doi: 10.3109/14397595.2016.1153567 Abstract Objective. To compare the effectiveness of three different biologics in anti-Ro/SSA antibody-positive and -negative patients with rheumatoid arthritis (RA). Methods. The study subjects were 110 biologics naïve RA patients who started treat‐ ment with biologics and examined for anti-Ro/SSA antibody between December 2003 and March 2014. For patients treated with intravenous infliximab (IFX), tocilizumab (TCZ), or abatacept (ABT), we compared the clinical characteristics and changes in composite disease activity index such as DAS28, SDAI, and CDAI for 12 months in anti-Ro/SSA antibody-positive and negative patients. Results. We examined 59 patients (9 were positive and 50 were negative for anti-Ro/SSA antibody) treated with IFX, 27 patients (5 positive and 22 negative) treated with TCZ, and 24 patients (13 positive and 11 negative) treated with ABT. For patients treated with IFX, parameters of disease activity did not change significantly from baseline in anti-Ro/SSA antibody -positive patients, whereas they improved in -negative patients. On the other hand, treatment with TCZ and ABT significantly decreased disease activity, relative to baseline, in both anti-Ro/SSA antibody-positive and -negative patients. Anti-Ro/SSA antibody-positive patients treated with IFX showed higher frequency of HACA and seroconversion of ANA, and lower serum TGF-β levels. Conclusions. Positivity to anti-Ro/SSA in RA seems to confer resistance to IFX via production of HACA and ANA, and low serum TGF-β levels, but not to TCZ and ABT.
© 2016 Taylor & Francis. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal's Just Accepted articles do not necessarily reflect those of Taylor & Francis (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
MORH-D-15-00762 Received: Dec-10-15; Accepted: Feb-09-16 Original Article
Association of anti-Ro/SSA antibody with response to biologics in patients with rheumatoid arthritis
Shinya Hagiwara, Hiroto Tsuboi, Fumika Honda, Hidenori Takahashi, Izumi Kurata, Ayako Ohyama, Mizuki Yagishita, Saori Abe, Yuko Kurashima, Syunta Kaneko, Hoshimi Kawaguchi, Hiroyuki Takahashi, Hiroshi Ebe, Masahiro Yokosawa, Hiromitsu Asashima, Tomoya Hirota, Naoto Umeda,
D
Yuya Kondo, Isao Matsumoto, and Takayuki Sumida
TE
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
EP
Correspondence to Prof. Takayuki Sumida, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-city, Ibaraki 305-8575, Japan. Tel: +81-29-853-7388,
AC C
Fax: +81-29-853-7388, E-mail: [email protected]
The number of text pages: 12, The number of tables: 4, The number of figures: 1
JU
abatacept (ABT)
ST
Key Words： rheumatoid arthritis, anti-Ro/SSA antibody, infliximab (IFX), tocilizumab (TCZ),
Abstract Objective. To compare the effectiveness of three different biologics in anti-Ro/SSA antibody-positive and -negative patients with rheumatoid arthritis (RA). Methods. The study subjects were 110 biologics naïve RA patients who started treatment with biologics and examined for anti-Ro/SSA antibody between December 2003 and March 2014. For patients treated with intravenous infliximab (IFX), tocilizumab (TCZ), or abatacept (ABT), we compared the clinical characteristics and changes in composite disease activity index such as DAS28, SDAI, and CDAI for 12 months in anti-Ro/SSA antibody-positive and -negative patients. Results. We examined 59 patients (9 were positive and 50 were negative for anti-Ro/SSA antibody) treated with IFX, 27 patients (5 positive and 22 negative) treated with TCZ, and 24 patients (13 positive
D
and 11 negative) treated with ABT. For patients treated with IFX, parameters of disease activity did not change significantly from baseline in anti-Ro/SSA antibody -positive patients, whereas they improved
TE
in -negative patients. On the other hand, treatment with TCZ and ABT significantly decreased disease activity, relative to baseline, in both anti-Ro/SSA antibody-positive and -negative patients. Anti-Ro/SSA
ANA, and lower serum TGF-β levels.
EP
antibody-positive patients treated with IFX showed higher frequency of HACA and seroconversion of
AC C
Conclusions. Positivity to anti-Ro/SSA in RA seems to confer resistance to IFX via production of
JU
ST
HACA and ANA, and low serum TGF-β levels, but not to TCZ and ABT.
Introduction New therapies for rheumatoid arthritis (RA) have become available in recent years. Several types of biologics are currently being used that can induce remission in many RA patients. However, intractable cases still exist. The American College of Rheumatology (ACR) 2012 lists the following poor prognosis factors for RA: functional limitation (e. g., health assessment questionnaire (HAQ) score or similar valid tools); extra-articular disease, positive rheumatoid factor (RF) or anti-citrullinated protein antibody (ACPA), and bone erosions by radiography (1). In particular, it is well accepted that a positive ACPA is a poor prognostic factor in patients with RA (2-4). Apart from RF and ACPA, antinuclear antibodies (ANA) and anti-double-stranded (anti-ds) DNA antibodies are occasionally detected especially in RA patients who have been treated with anti-TNF alpha biologics, and exceptionally associated with
D
clinical manifestations of lupus erythematosus (SLE) (5, 6). In fact, there is a close relationship between the clinical course of RA and autoantibodies. Moreover, anti-Ro/SSA antibodies have been
TE
used as diagnostic markers for Sjögren’s syndrome (SS), as well as occasionally for other rheumatic diseases, such as SLE and RA (7-10). Importantly, it was reported that RA patients with secondary SS
EP
had worse joint damage than RA without SS (11). Further, one report indicated that anti-Ro/SSA antibody was an independent factor associated with insufficient therapeutic response to TNF inhibitors
AC C
in patients with RA (12). In this regard, there is no information on the relationship between the response to non-TNF biologics and positivity for anti-Ro/SSA antibody. The aim of the present study was to determine the significance of anti-Ro/SSA antibodies in relation to the clinical response to three different biologics; infliximab (IFX), tocilizumab (TCZ), and
JU
ST
abatacept (ABT).
Patients and methods Study population We examined 110 Japanese patients with RA who visited the University of Tsukuba Hospital between December 2003 and March 2014, and were treated with one of the following biological disease-modifying anti-rheumatic drugs (DMARDs): IFX, TCZ, or ABT, as the first biological DMARD. All patients fulfilled the 1987 ACR criteria for RA (13) or 2010 ACR/European League Against Rheumatism (EULAR) criteria for RA (14). All patients who satisfied the 1999 Japanese Ministry of Health criteria for the diagnosis of SS (15, 16), were considered to have secondary SS. All biologics were administered intravenously. All patients were treated for anti-Ro/SSA antibody status by double immunodiffusion (DID) test. Approval for this study was obtained from the local ethics committee, and
D
signed informed consent was obtained from each patient.
TE
Clinical characteristics
The following data baseline characteristics were collected from the medical records; age, sex, RA
EP
disease duration, Steinbrocker classification, functional class, RA- and SS-related complications, tender joint count, swollen joint count, visual analog scale (VAS), C-reactive protein (CRP), erythrocyte
AC C
sedimentation rate (ESR), disease activity score in 28 joints/CRP (DAS28/CRP), disease activity score in 28 joints/ESR (DAS28/ESR), simplified disease activity index (SDAI), clinical disease activity index (CDAI), RF, ACPA, matrix metalloproteinase-3, immunoglobulin G (IgG), anti-Ro/SSA antibody, anti-La/SSB antibody, and definite diagnosis of secondary SS. We also surveyed all treatments used
ST
at the time of initiation of biologics, such as prednisolone, methotrexate, and other conventional synthetic DMARDs.
JU
Furthermore, we also compared the baseline characteristics of patients according to the type of biologics (IFX, TCZ, and ABT), and status of anti-Ro/SSA antibody.
Human anti-chimeric antibody, cytokines and autoantibody status in IFX-treated patients Additional tests were conducted in patients treated with IFX. First, we measured the trough concentration of IFX and examined human anti-chimeric antibody (HACA) in 6 out of 9 anti-Ro/SSA antibody -positive patients treated with IFX at 30 or 54 weeks after initiation of IFX; three were examined at 30 weeks, while the other three at 54 weeks. For comparison, we also measured in age
and gender matched 12 cases out of 50 -negative patients treated with IFX. Second, we measured baseline serum transforming growth factor-β1 (TGF-β1) levels by enzyme-linked immunosorbent assay (ELISA) (Quantikine Human TGF-β1 Immunoassay, R&D Systems, Inc., Minneapolis, MN), and compared those between anti-Ro/SSA antibody-positive and -negative patients. Third, we examined the seroconversion (from negative to positive status) rate for anti-nuclear antibody (ANA) and anti-double stranded DNA antibodies (anti-dsDNA antibodies) after the initiation of IFX therapy.
Changes in disease activity Disease activity was evaluated by composite measures such as DAS28/CRP, DAS28/ESR, SDAI, and CDAI at 0, 6, and 12 months after initiation of each biologic. We also compared changes in disease
D
activities over 12-month treatment period according to anti-Ro/SSA antibody status and type of
TE
biologics.
Statistical analysis
EP
Binary variables were analyzed by Fisher's exact test, while continuous variables (baseline characteristics) were analyzed by the Kruskal-Wallis test or Mann-Whitney U test. The latter test was
AC C
also used for analysis of differences in parameters between two groups, while Wilcoxon test was used for analysis of the effects of treatment at 6 and 12 months on disease activities. A p value
