Introduction This study aimed to evaluate whether a long-term increase in serum matrix metalloproteinase-3 (MMP-3) levels leads to joint destruction in rheumatoid arthritis (RA) patients with negative serum C-reactive protein (CRP) values after methotrexate (MTX) therapy.

Methods Patients with RA (n = 182) whose CRP values became negative due to MTX therapy were divided into two groups based on their MMP-3 positivity at the end of the observation period, and the 1-year progression of joint destruction was retrospectively compared. Radiological joint destruction was assessed using the modified van der Heijde total sharp score (mTSS).

Results Among 109 (MMP-3(−), n = 63; MMP-3(+), n = 46) patients who achieved low disease activity or clinical remission (28 joint disease activity score erythrocyte sedimentation rate < 2.6), joint destruction (ΔmTSS ≥ 0.5) progressed in 24.6% and 48.9% of the MMP-3(−) and MMP-3(+) groups (p < 0.01), respectively. Prednisolone-induced increases in serum MMP-3 levels also resulted in joint destruction.

Conclusion To prevent progressive joint destruction, the target MMP-3 value is 49.7 ng/mL in female patients, which is below the current MMP-3 cutoff value of 59.7 ng/mL. Residual MMP-3 activity may lead to the progression of joint destruction in patients with RA, even after CRP normalization by successful treatment with MTX.

The Department of Advanced Medicine for Rheumatic Diseases in Kyoto University is supported by Nagahama City, Shiga, Japan, Toyooka City, Hyogo, Japan, and five pharmaceutical companies (Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co. Ltd, UCB Japan Co. Ltd, AYUMI Pharmaceutical Co., and Asahi Kasei Pharma Corp.). It is also supported by a grant from Daiichi Sankyo Co. Ltd. The above-mentioned pharmaceutical companies were not involved in the study design, data collection and analysis, manuscript writing, or manuscript submission. KMurakami received speaker fees and/or consulting fees from Eisai Co. Ltd., Chugai Pharmaceutical Co. Ltd., Pfizer Inc., Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Corporation, UCB Japan Co. Ltd., Daiichi Sankyo Co. Ltd., and Astellas Pharma Inc. HO received research grants and/or speaker fees from AbbVie, Asahi Kasei, Astellas Pharma Inc., Eisai Co. Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and Daiichi Sankyo Co. Ltd. AO received research grants and/or speaker fees from Pfizer Inc., Bristol-Myers Squibb., Advantest, Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K. K., Ono Pharmaceutical Co., UCB Japan Co., Mitsubishi Tanabe Pharma Co., Eisai Co. Ltd., AbbVie Inc., Takeda Pharmaceutical Co. Ltd., and Daiichi Sankyo Co. Ltd. TF received speaker fees from AbbVie, Asahi Kasei, Jansen, Tanabe Mitsubishi, and Eisai. KMurata received speaker and/or consulting fees from AbbVie G.K., Eisai Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Bristol-Myers Squibb, Daiichi Sankyo Co. Ltd., and Asahi Kasei Pharma Corp. MT received research grants and speaker fees from AbbVie G.K., Asahi Kasei Pharma Corporation, Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly and Company, Pfizer Inc., UCB Japan Co., Ltd., Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Taisho Pharma Co., Ltd., and Teijin Pharma, Ltd. AM received honorarium from AbbVie G.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Eisai Co. Ltd., Pfizer Inc., Bristol-Myers Squibb., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., and Gilead Sciences Japan. AM received research grants from AbbVie G.K., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., and Eisai Co. Ltd. for work outside the scope of this study. HK, MM, MN, and MK declare no conflicts of interest.

The author(s) received no specific funding for this work.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Ethics Committee of Hyogo Medical University gave ethical approval for this work (Protocol No. 3923).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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Email:

Hiroe Konishi Email hiroe-khyo-med.ac.jp

Mai Morimoto Email mai-mhyo-med.ac.jp

Masayoshi Nakano Email ms-nakanohyo-med.ac.jp

Masahiro Koshiba Email mkoshibahyo-med.ac.jp

Kosaku Murakami Email kosakukuhp.kyoto-u.ac.jp

Hideo Onizawa Email honizawakuhp.kyoto-u.ac.jp

Akira Onishi Email aonishikuhp.kyoto-u.ac.jp

Takayuki Fujii Email fujiitkuhp.kyoto-u.ac.jp

Koichi Murata Email kchmkuhp.kyoto-u.ac.jp

Masao Tanaka Email masatanakuhp.kyoto-u.ac.jp

Akio Morinobu Email morinobukuhp.kyoto-u.ac.jp

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Competing Interests

The Department of Advanced Medicine for Rheumatic Diseases in Kyoto University is supported by Nagahama City, Shiga, Japan, Toyooka City, Hyogo, Japan, and five pharmaceutical companies (Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co. Ltd, UCB Japan Co. Ltd, AYUMI Pharmaceutical Co., and Asahi Kasei Pharma Corp.). It is also supported by a grant from Daiichi Sankyo Co. Ltd. The above-mentioned pharmaceutical companies were not involved in the study design, data collection and analysis, manuscript writing, or manuscript submission.

KMurakami received speaker fees and/or consulting fees from Eisai Co. Ltd., Chugai Pharmaceutical Co. Ltd., Pfizer Inc., Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Corporation, UCB Japan Co. Ltd., Daiichi Sankyo Co. Ltd., and Astellas Pharma Inc.

HO received research grants and/or speaker fees from AbbVie, Asahi Kasei, Astellas Pharma Inc., Eisai Co. Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and Daiichi Sankyo Co. Ltd.

AO received research grants and/or speaker fees from Pfizer Inc., Bristol-Myers Squibb., Advantest, Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K. K., Ono Pharmaceutical Co., UCB Japan Co., Mitsubishi Tanabe Pharma Co., Eisai Co. Ltd., AbbVie Inc., Takeda Pharmaceutical Co. Ltd., and Daiichi Sankyo Co. Ltd.

TF received speaker fees from AbbVie, Asahi Kasei, Jansen, Tanabe Mitsubishi, and Eisai.

KMurata received speaker and/or consulting fees from AbbVie G.K., Eisai Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Bristol-Myers Squibb, Daiichi Sankyo Co. Ltd., and Asahi Kasei Pharma Corp.

MT received research grants and speaker fees from AbbVie G.K., Asahi Kasei Pharma Corporation, Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly and Company, Pfizer Inc., UCB Japan Co., Ltd., Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Taisho Pharma Co., Ltd., and Teijin Pharma, Ltd.

AM received honorarium from AbbVie G.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Eisai Co. Ltd., Pfizer Inc., Bristol-Myers Squibb., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., and Gilead Sciences Japan.

AM received research grants from AbbVie G.K., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., and Eisai Co. Ltd. for work outside the scope of this study.

HK, MM, MN, and MK declare no conflicts of interest.

Funding Open access funding provided by the Hyogo Medical University.

All relevant data are within the manuscript and its Supporting Information files.