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Recent Clinical Applications of Japanese Oriental (Kampo) Medicine for Rheumatoid Arthritis: Search for Kampo Responder
Toshiaki Kogure, MD, PhD
ABSTRACT Rheumatoid arthritis (RA) is a heterogeneous disease. In rheumatology, researchers have not identified useful clinical markers to predict the effects of biological agents or of nonbiological, antirheumatic drugs before administration. Since the advent of biological agents, therapeutic strategies for RA have focused on early detection and early intensive treatment. Although responders to Japanese Oriental (Kampo) medicine exist, physicians first have had to diagnose RA using the practices of conventional medicine. They could identify those patients who would benefit from administration of Kampo medicine only by
administering the treatment. Only the presence of a positive response could confirm the benefits for a particular individual. In this article, the author discusses the clinical importance of Kampo medicine within the context of the present RA classification criteria and therapeutic treatment and discusses the use of the basal value of anti-CCP antibody (aCCP) titer as a prognostic factor for use of Kampo medicine for RA. The author then defines a methodology for determining who should receive the treatment. (Altern Ther Health Med. 2013;19(6):50-52.)
Toshiaki Kogure, MD, PhD, is head of the Department of Japanese Oriental Medicine at Gunma Central and General Hospital in Maebashi, Japan. Corresponding author: Toshiaki Kogure, MD, PhD E-mail address: firstname.lastname@example.org
heumatoid arthritis (RA) is one of the diseases for which medical practitioners have used Japanese Oriental (Kampo) medicine clinically for a long period.1,2,3 Practitioners have administered various Kampo prescriptions, such as boiogito, keishikajutsubuto, and yokuininto, to patients with RA, and the medicine has played a role in therapeutic strategies for RA in Japan.4,5,6 Over time, therapeutic strategies for RA have changed markedly. Physicians began to apply methotrexate (MTX) clinically for RA in the 1960s. Researchers confirmed its effectiveness against RA by large-scale, controlled trials in the 1980s.7 Since the end of the 1990s, medical practitioners have used biological agents clinically (eg, infliximab in Japan since 2003). At present, regulatory scientific societies recom50 ALTERNATIVE THERAPIES, NOV/DEC 2013, VOL. 19, 6
mend strict control of biological agents. To achieve this control, the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) established classification criteria in 2010.8 The induction rate of clinical remission using biological agents is 40% to 50%, and the induction of clinical remission still remains a difficult problem. Compared with results using conventional diseasemodifying antirheumatic drugs (DMARDs), however, those using biological agents are excellent. Given this background, this article discusses the role of Kampo medicine in RA treatment. As the core of this article, the author elaborates on the belief that some markers exist that can predict the therapeutic effect of Kampo for RA patients, and using these markers, physicians can assess patients and try to find those individuals who will respond to Kampo therapy before its administration. RESEARCH ON KAMPO MEDICINES As of the 1990s, some case reports did exist that showed the effects of various Kampo medicines on RA. The major medicines used included keishikaryojutsubuto, boiogito, and eppikajutsuto (or their combinations) as well as yokuininto, juzentaihoto, and daibofuto. In addition, researchers also have reported the effects of makyoyokukanto and
Kogure—Clinical Applications of Kampo
15 Based on that recommendation.9. which the clinic treated12 as indicated using keishinieppiittokaryojutsubu (KER). In terms of recent therapeutic strategies for RA. Responders to Kampo medicines.97 Mo 7 Time 3.09 Mo 9 2.30 2. To share or copy this article. Mo 1 in the time scale is September 2009. use of the methodology called objectification of SHO in RA) may be a promising method of determining which patients should receive Kampo medicines (Figure 2).2. 19. it has encountered some patients who have shown favorable responses and clinical remission. physicians should use the following method to decide if they should employ Kampo medicines in clinical practice: (1) Exclude patients with high activity based on DAS28 and (2) Administer Kampo medicines clinically only to patients with mild-moderate activity. the author’s clinic has administered multicomponent drugs (decoctions) to 80% to 90% of its patients with RA. the team has examined the correlation between traditional features—such as thirst. please visit copyright. the researchers had evaluated changes in symptoms.30 Mo 12 2. x Kogure—Clinical Applications of Kampo PROTOCOL FOR KAMPO MEDICINES As described above. showed high activity (DAS28-CRP = 5. such as salazosulfapyridine (SASP) and bucillamine (BUC). a Kampo medicine. As reported in an article in 2003.com. clarification of the subtypes of RA that respond to Kampo medicine (ie. these practices were not a problem since the Japan College of Rheumatology (JCR) used the same parameters. Since the latter half of the 1980s.37). erythrocyte sedimentation rate (ESR). Until the 1990s. VOL. The team observed a favorable response in terms of DAS28-CRP. Therefore. Use ISSN#1078-6791. however.14 However. hochuekkito. do exist among RA patients showing extremely high activity. C-reactive protein (CRP).com Figure 1. Due to resistance to MTX (6 mg). She was a responder to the Kampo medicine. the clinical team administered KER. Clinical Course—57-year-old Female Treatment PSL 10 mg/d MTX 8 mg/d 5 mg 5 mg KER 8 First visit to our hospital aCCPab 4 mg 3 mg Figure 2. visit alternative-therapies. which is similar to the use of DMARDs.13 Even when the team has used a current evaluation method. NOV/DEC 2013. The author can only speculate whether reports on Kampo medicine prior to 2000 fulfilled the new diagnostic and evaluative criteria. Abbreviation: KER = keishinieppiittokaryojutsubu. however. the ACR regarded the “window of opportunity” (period suitable for treatment) to initiate treatment before significant damage to the joint occurs as 6 months. sweating. ALTERNATIVE THERAPIES. In 2008. responders to Kampo medicines do exist among RA patients. Objectification of Kampo Diagnosis of SHO Syndrome in RA Kampo Formula 80 (U/mL) CRP (mg/dL) 6 4 60 200 RF 2 40 0 RA Responder to Kampo in RA (IU/L) 100 20 0 0 DAS28 Mo 1 5. In the past. and weight loss—and immunological status.46 Mo 15 Note: Represents clarification of the subtypes (closed space) of RA that respond to Kampo medicines using the parameters of Western medicine but not using traditional methodology. the diagnosis and evaluation of RA have become more objective. and they used Lansbury’s activity index for comprehensive evaluation. After 2000. swollen joints.10. To subscribe. Given this trend. or rheumatoid factor (IgM-RF). the JCR also recommended considering biological agents even 3 months after onset in the presence of the progression of bone erosion or of a disease activity score of DAS28-ESR > 3. the author’s research team has reported on the effectiveness of KER.This article is protected by copyright. 6 51 . it may be difficult to administer Kampo prescriptions for some months or even some years while observing their effects as physicians did in the 1990s. within 1 y after onset. as a 2009 article discusses (Figure 1). and aCCPab also gradually decreased. The ACR recommended use of a TNF inhibitor in combination with MTX within 3 months of onset for RA patients who show high disease activity and who have no problems regarding the payment of medical costs. the findings concerning the correlation between conventional symptoms and the serum levels of anti-CCP antibody (aCCP) titer have not yet been demonstrated.37 Mo 2 Mo 3 4. however. with the advent of potent drugs. Note: The woman was an RA patient whom.11 In many case reports showing the effects of these Kampo medicines on RA. These patients often exhibited pathological conditions (a syndrome called SHO in Japanese Oriental Medicine).
RA is a heterogeneous disease. Ogihara Y.63(1):3742. 52 ALTERNATIVE THERAPIES. van der Linden MP. Fujinaga H. 2011. even if positive. To subscribe. 2010. In this article. 2008. on collagen-induced arthritis. Tatsumi T. 2004. 12. Kogure T. Terasawa K. NOV/DEC 2013. those showing a decrease in this titer within 3-6 mo of treatment were often responders. 16. Ono Y.27(6):857-862. to clarify more detailed patterns. et al. Terasawa K. Niizawa A. Sato H. Fujinaga H. Clinical and immunomodulatory effect of Fun-boi. physicians currently must first diagnose RA using the practices of conventional medicine. KAMPO-Prescription. 7. Li J. does identify responders to treatment with KER. the author discussed the possibility of providing Kampo treatment using the present RA classification criteria and therapeutic treatment. including Kampo. 2004. visit alternative-therapies. Methods of deriving EULAR/ACR recommendations on reporting disease activity in clinical trials of patients with rheumatoid arthritis. Rheum Dis Clin North Am. Tatsumi T. In brief. See See Kogure T for details. Niizawa A. No research exists. J Tradit Med. A case of rheumatoid arthritis with a decrease in the serum concentration of soluble CD23 by traditional herbal medicine. If the research team is able to demonstrate the subtypes of RA that respond to Kampo. Traditional Chinese medicine in the treatment of rheumatoid arthritis: a general review. Inoue M. et al. Serum levels of anti-cyclic citrullinated peptide antibodies in patients with Sjögren Syndrome accompanied by rheumatoid arthritis. Clin Exp Rheumatol. the research team is working on a comprehensive analysis of autoantibody expression patterns. Kogure T.29(12):1441-1447. 2011. Venkatesha SH. Kishi D. van der Helm-van Mil AH. Clin Med Insights Arthritis Musculoskelet Disord. 10. At present. that demonstrates the characteristics of responders for each formula available in Kampo medicine.127(3):547-550. Tatsumi T. Kishi D. 9. Serum aCCP Titers Before Treatment With a Kampo Medicine 1000 aCCP Titer (IU/mL) 800 600 400 200 0 Responder Nonresponder Note: The figure shows serum aCCP titers in responders and nonresponders. it decreases by 3 months after treatment with KER. Ernst E.67(10):1365-1373. J Tradit Med.This article is protected by copyright. Qin L. Insights From Clinical Cases. 2011.20(1):16-21. a specific formula of Kampo medicine. In its research. et al. 5. Rheumatol Int . the use of herbal medicine. J Clin Rheumatol. the author’s research team defines a Kampo responder as a patient successfully treated with KER. two findings identified KER responders: (1) The aCCP titer is not high even if positive. Japan: KK Standard McIntyre. VOL. which is similar to the use of DMARDs. Suppressive effect of Dai-bofu-to on collagen-induced arthritis.37(1):95-102. Rheumatol Int. in rheumatoid arthritis. Kogure T. Shimada Y. Niizawa A. The topic of this review was presented during the 28th Annual Meeting of Medical and Pharmaceutical Society Symposium in Japan. 2007. a Kampo medicine. Tokyo.30(6):713718. Ann Rheum Dis.2:19-22.6(5):244-249. The author’s prior research did find. The characteristic is based on the basal value of aCCP antibody titer (Figure 3). 11. Suppressive effect of hochu-ekki-to on collagen induced arthritis in DBA1J mice. Conclusion Currently in rheumatology. et al. Tahara E.com MARKERS FOR EFFECTIVENESS OF KAMPO MEDICINE As a result of previous studies by the author’s collaborators. by RA patients will be becoming increasingly popular in several developed countries. Moudgil KD. Increases in use of methotrexate since the 1980s. Hai le X. Biol Pharm Bull. 1993:183-274. Although responders to Kampo medicine exist. Arthritis Rheum. Huizinga TW. 2009. Fjinaga H. however. Berman BM. Sokka T. Terasawa K.27(9):1406-1413. Karonitsch T. 2010. such as the United States. Knevel R. Shimada Y. Kogure T. Boers M. only the first characteristic is helpful in identifying responders prior to treatment. 6. In: KAMPO Japanese-oriental Medicine. Ono Y. Yakugaku Zasshi. that an aCCP titer that is not high. Niizawa A. the author believes that markers do exist that can identify responders to Kampo medicines and that researchers can evaluate them employing the evaluation methods of 2011.2011:986797. June 2009. The author believes that Kampo medicine will continue to play an important clinical role in various aspects of RA treatment in the future. Population of CD40L-expressing cells was slightly but not significantly decreased in lymphoid tissues of collagen-induced arthritic mice treated with Hochu-Ekki-To. Evid Based Complement Alternat Med. an herbal medicine. Inoue M. and KER is the representative formula for RA. To share or copy this article. Yu XW. 8. ACKNOWLEDGEMENTS A Grant-in-Aid for Scientific Research from the Japan Society for the Ministry of Health and from the Uehara Memorial Foundation supported this study. Serum levels of anti-cyclic citrullinated peptide antibodies are associated with a beneficial response to traditional herbal medicine (Kampo) in rheumatoid arthritis. 14. 2003. 2. Kogure T. Takahashi K. such as SASP and BUC. Use ISSN#1078-6791. Biol Pharm Bull . a specific formula of Kampo medicine. 19. Immunomodulation of autoimmune arthritis by herbal CAM.29(8):1601-1608. Zhang P. 1999. Mantani N. Ito T. 4. no useful clinical markers exist to predict the effects of biological agents and nonbiological antirheumatic drugs before administration. The author recommends that physicians should employ Kampo medicines in clinical practice in the following manner: (1) Exclude patients with high activity based on DAS28 and (2) administer Kampo medicines clinically only to patients with mild-moderate activity. Rajaiah R. The titer was low in many responders.28(5)(suppl 61):S13-S20. please visit copyright. The research team previously reported a characteristic of some RA patients who provide a positive prognosis for treatment with KER.com.16 REFERENCES 1. 2002. Classification of rheumatoid arthritis: comparison of the 1987 American College of Rheumatology criteria and the 2010 American College of Rheumatology/ European League Against Rheumatism criteria. 13. 6 Kogure—Clinical Applications of Kampo . Herbal medicine in the treatment of rheumatic diseases.16 Obviously. Immunological analysis into KI-disorder based on traditional Japanese Oriental diagnostic system. Ito T. Han Y. Mizukami H. Figure 3. Kogure T. 15. and (2) even if the aCCP titer is high. 2000. J Rheumatol. Among patients with a high titer. however. Researchers also have not yet clarified the subtypes of RA that respond to a Kampo formula. 3. Kogure T. Mizukami H. and Kampo medicine is personalized. Suppressive effect of Kanzo-bushi-to.16(5-6):190-195. Aletaha D.
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