Jun Ishizaki1, Ayako Takemori2, Kenta Horie3, Daisuke Hiraoka3, Koichiro Suemori3, Takuya Matsumoto3, Ken-Ei Sada4, Koichi Amano5, Masayoshi Harigai6, Yoshihiro Arimura7,8, Hirofumi Makino9, Katsuto Takenaka3, Nobuaki Takemori2, Hitoshi Hasegawa10. 1. Department of Hematology, Clinical Immunology, and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan. ishizaki@m.ehime-u.ac.jp. 2. Division of Analytical Bio-Medicine, Advanced Research Support Center, Ehime University, Toon, Ehime, Japan. 3. Department of Hematology, Clinical Immunology, and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan. 4. Department of Clinical Epidemiology, Kochi Medical School, Kochi, Japan. 5. Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University, Saitama, Japan. 6. Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan. 7. Department of Nephrology and Rheumatology, Kyorin University School of Medicine, Tokyo, Japan. 8. Department of Internal Medicine, Kichijoji Asahi Hospital, Tokyo, Japan. 9. Okayama University, Okayama, Japan. 10. Department of Hematology, Clinical Immunology, and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan. hitoshih@m.ehime-u.ac.jp.
Abstract
BACKGROUND: We previously identified tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker of disease activity that distinguished mildly or highly active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) from remission 6 months after the initiation of remission-induction therapy. In the present study, we investigated whether TIMP-1 is clinically useful as a predictor of relapse and sustained remission in AAV patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) during maintenance therapy. METHODS: The relationship between serum TIMP-1 levels and clinical outcomes in AAV patients receiving maintenance therapy was assessed using the follow-up data of a Japanese large-cohort study (the RemIT-JAV-RPGN study) and data collected from AAV patients on maintenance therapy in our hospital (the MAAV-EU study). RESULTS: In the RemIT-JAV RPGN study, serum levels of TIMP-1 were significantly higher in mildly active AAV patients with MPA and GPA 6 months after the initiation of remission-induction therapy than in patients in remission. Regarding maintenance therapy, elevated levels of TIMP-1 in patients in remission were associated with relapse and/or difficulty reducing the glucocorticoid dosage after 6 to 12 months. In the MAAV-EU study, serum levels of TIMP-1 were elevated in relapsed patients 6 months before relapse, earlier than the increase in serum levels of CRP. Analyses of both studies revealed that approximately 30% of patients in remission with a serum TIMP-1 level ≥ 150 ng/mL relapsed after 6 to 12 months, while the majority of patients with a TIMP-1 level < 150 ng/mL sustained remission for at least 12 months. CONCLUSION: We herein demonstrated that TIMP-1 is more useful as a predictive biomarker of sustained remission than as a predictor of relapse in maintenance therapy for AAV. TIMP-1 levels < 150 ng/mL are important for the long-term maintenance of remission and may be an indicator for the tapering or cessation of treatment.
BACKGROUND: We previously identified tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker of disease activity that distinguished mildly or highly active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) from remission 6 months after the initiation of remission-induction therapy. In the present study, we investigated whether TIMP-1 is clinically useful as a predictor of relapse and sustained remission in AAVpatients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) during maintenance therapy. METHODS: The relationship between serum TIMP-1 levels and clinical outcomes in AAVpatients receiving maintenance therapy was assessed using the follow-up data of a Japanese large-cohort study (the RemIT-JAV-RPGN study) and data collected from AAVpatients on maintenance therapy in our hospital (the MAAV-EU study). RESULTS: In the RemIT-JAV RPGN study, serum levels of TIMP-1 were significantly higher in mildly active AAVpatients with MPA and GPA 6 months after the initiation of remission-induction therapy than in patients in remission. Regarding maintenance therapy, elevated levels of TIMP-1 in patients in remission were associated with relapse and/or difficulty reducing the glucocorticoid dosage after 6 to 12 months. In the MAAV-EU study, serum levels of TIMP-1 were elevated in relapsed patients 6 months before relapse, earlier than the increase in serum levels of CRP. Analyses of both studies revealed that approximately 30% of patients in remission with a serum TIMP-1 level ≥ 150 ng/mL relapsed after 6 to 12 months, while the majority of patients with a TIMP-1 level < 150 ng/mL sustained remission for at least 12 months. CONCLUSION: We herein demonstrated that TIMP-1 is more useful as a predictive biomarker of sustained remission than as a predictor of relapse in maintenance therapy for AAV. TIMP-1 levels < 150 ng/mL are important for the long-term maintenance of remission and may be an indicator for the tapering or cessation of treatment.
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