Case report Joumal of Traditional Medicines18，122－126，2001

A case of rheumatoid arthritis complicated by bucillamine－induced nephropathy satisfactorily treated with Kampo medicines

Yutaka SHIMADA葵Toshiaki KoGuRE，Hirozo GoTo，Shinya SAKAI， Nobuyasu SEKIYA，Naoki MANTANI and Katsutoshi TERAsAwA

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Abstract

We reported a case of rheumatoid arthritis complicated by bucillamine－induced nephropathy satisfactorily treated with Kampo（Chinese／Japanese traditiona1）medicines．The patient wasa56－year－ 01d male，who suffered from polyarthralgia from December l996．In Febmary l997，he was diagnosed with RA in another hospital and treated with loxoprofen sodium，bucillamine and prednisolone．He visited ourhospital in May1997，andwebeganto tre4thimwith a combinationofmodemWestemand Kampo medicines．During his clinical course，proteinuria induced by bucillamine developed．After bucillamine was discontinued，his polyarthralgia and inflammatory parameters became worse．How－ ever，Kampo formulations，Keishi－bukuryo－gan mixed with Toki－shakuyaku－san and Dai－bofu－to， were effective for reducing the activity of RA．The clinical course of this case suggests that Kampo medicines might be useful for the treatment of RA patients，especially for those who have adverse reaction to disease－modifying antirheumatic dmgs（DMARDs）．

Key words rheumatoid arthritis，Kampo medicines，bucillamine nephropathy，Keishi－bukuryo－ gan，Toki－shakuyaku－san，Dai－bofu－to． Abbreviations RA，rheumatoid arthritis；NSAIDs，nonsteroidalantiinflammatorydmgs；DMARDs， disease modifying antirheumatic drugsl Keishi－bukuryo－gan（Gui－Zhi－Fu－Ling－Wan），（桂枝侠苓丸）； Toki－shakuyaku－san（Dang－Gui－Shao－Yao－San），（当帰筍薬散）；Dai－bofu－to（Da－Fang－Feng－Tang）， （大防風湯）；Keishi－ka－ryo－jutsu－bu－to（Gui－Zhi－Jia－Ling－Zhu－Fu－Tang），（桂枝加苓北附湯）；Ogi （Huang－Qi），（黄書），Astragali Radix，！4s！㎎召1％s窺εノn加8nα66麗s BuNGE；Keishi－ni－epPHchi－to（Gui－ Zhi－Er－YueBi－Yi－Tang），（桂枝二越女卑一湯）；Sojutsu（Cang－Zhu），（蒼オむ），Atractylodis Lanceae Rhizoma，∠4！観6砂lo46s lαn66αDE CANDoLLE；Boi（Fang－Ji），（防已），Sinomeni Caulis et Rhizoma， Sino7n6％加”6π加n REHDERetWILsoN；Yokuinin－to（Yi－Yi－Ren－Tang），（意該仁湯）lKeishi－shakuya－ ku－chimo－to（Gui－Zhi－Shao－Yao－Zhi－Mu－Tang），（桂枝葛薬知母湯）；Gosha－jinki－gan（Niu－Che－Shen－ Qi－Wan），（牛車腎気丸）；Kekkyo（Xue－Xu），（血虚），4⑳6i6nσげわloo4；Oketsu（Yu－Xue），（痂血）， 61004s嬬露l Suitai（Shui－Zhi），（水滞），s酪ゑsげ60み刀％i41Kikyo（Qi－Xu），（気虚），4⑳oi6nσげ∂吻1 6n6柳；In（Yin），（陰）；Yo（Yang），（陽）；Kyo（Xu），（虚），4⑳626nσ；Jitsu（Shi），（実），6冗06ss．

nonsteroidal antiinflammatory drugs（NSAIDs）and Introduction disease modifying antirheumatic dmgs（DMARDs）， and corticosteroid is sometimes used．In Japan，buci1－ In modem Westem medicine，essential medicinal 1amine，one of the DMARDs，is often used，but this treatment for rheumatoid arthritis（RA）is based on agent is prone to cause adverse reactions such as

＊〒930－0194 富山市杉谷2630 和漢医薬学雑誌18，122－126，2001 富山医科薬科大学医学部和漢診療学 嶋田 豊 2630Sugitani，Toyama930－0194，Japan 『｝『一r「｝

Rheumatoid arthritis treated with Kampo medicines 123

emptlon， renal dysfunction， 1nterstitial pneumo一 っヨ revealed a height of164cm and a weight of50kg．His の の ma， agranulocytosis， and so on．The renal dysfunc－ body temperature was35．70C，pulse72／min and regu－ tion induced by bucillamine is called bucillamine－in－ 1ar，and blood pressure130／78mmHg．There was no duced nephropathy and this complication is suspected edema or emption of the skin，but the bilateral by the development of proteinuria．In this paper，we metacarpophalangeal joints of the index fingers and report on a case of rheumatoid arthritis complicated the left knee joint were swollen．The conjunctivas by bucillamine nephropathy，to whom it was difficult were not anemic or icteric，and tonsils and thyroid to administer DMARDs，satisfactorily treated with were not swollen．On auscultation，heart sounds were Kampo（Chinese／Japanese traditiona1）medicines． normal and no murmur was heard．The liver，spleen and kidneys were not palpable．There Was no neuro－ Case report 10gical abnormality． His initial laboratory data in our hospital are The patient was a56－year－01d man whσhad no shown in Table I．On May l3，1997，ESR（104mm／ medical history or records of his family．In December 1hr），CRP（2．5mg／01）andrheumatoidfactor（RF：1，157 1996，he suffered from arthralgia of the bilateral 1U／m1） were elevated．Anti－nuclear antibody shoulders．In January1997，arthralgia occurred in the （ANA：×40，nucleolar type）was positive．Finger－ bilateral fingers，wrists and knees followed by mom－ bone X－ray showed mild erosion and osteoporosis． ing stiffness．In February，he consulted a doctor in There were no abnormalities in chest X－ray，electro－ another hospital and was diagnosed as having cardiogram，abdominal ultrasonography or upper rheumatoid arthritis（RA）．His C－reactive protein gastrointestinal fiberscopy．From the total of these （CRP）was4．5mg／dl and erythrocyte sedimentation findings，we diagnosed him as having RA，functiona1 ヲの rate（ESR）was87mm／1hr．He was administered stage II，anatomical class II． His joint count was loxoprofen sodium at180mg／day and bucillamine at 118and the Lansburゾs index was730n May13． 8） 200mg／day．InMarch，however，CRPincreasedto lO．3 Initial findings based on the concept of Kampo mg／d1，so he was treated with prednisolone at20mg／ medicine were as follows．Subjective symptoms：easy day for3days，15mg／day for4days，10mg／day for7 fatigability，1ack of will power，10ss of appetite，fee1－ days，then5mg／day．However，he continued to com－ ing of heaviness in the whole body，swelling and Plain about severe arthralgia． stiffness of the finger joints，swelling of the legs． He visited our hospital in May1997．He com． Pulse： pulsus superficialis， frequens and intentus． plained of arthralgia of the bilateral shoulders，wrists， Tongue：dark red，purple and livid color of the tongue fingers，knees and an：kles．Physical examination body，thick and white－yellow fur．Abdomen：slightly

Table I Initial laboratory data in our hospital（May13，1997）． WBC 7，490／μ1 TP 7．O g／d1 T－Chol 99mg／d1 RBC 421×104／μ1 alb 50．9％ TG 58mg／d1 Hb 12．8g／dl α1－91 4．0％ BUN 12mg／d1 Ht 39．7％ α2－91 12．1％ Cr 0．6mg／d1 Plt 37．7×104／μ1 β一91 14．6％ UA 4．5mg／dI γ一91 18．4％ Na l41mEq／1 ESR 104mm／hr LDH 1571U／1 K 4．2mEq／1 CRP 2．5mg／d1 AST 201U／1 CI 104mEq／1 RF 1，1571U／m1 ALT 171U／1 FBS 88mg／d1 ANA ×40（NU） γ一GTP 471U／1 Urinalysis CH50 39U／ml AIP 2181U／1 protein ± C3 103．7mg／d1 T－Bil 0．3mg／d1 oc．blood ± C4 18．6mg／dl CPK 581U／1 91ucose 124 Joumal of Traditional Medicines（Vo1．18No．32001）

decreased abdominal tension，hypertonic rectus ab． comt and Lansbury’s index were aggravated．We dominis muscle，reduced abdominal tension in the administered bucillamine again in July．From the lower abdomen． efficacy of bucillamine，we considered that the activ－ His clinical course is shown in Fig．1．We ity of RA was markedly improved． continued to administer loxoprofen at180mg／day， In December1997，proteinuria appeared again． bucilla血ne at200mg／day and prednisolone at5mg／ We considered this to be an adverse reaction of day，and added a Kampo prescription，Keishi－ka－ryo－ bucillamine，the so－called bucillamine nephropathy， jutsu－bu－to with Ogi（5g）．As this prescription was and ceased its administration．Thereafter，the activity not so effective and he complained of thirst，we chan－ of RA became aggravated，and his skin became dry ged it to Keishi－ni－eppi－ichi－to with Sojutsu（5g）and and rough，this meant Kekkyo（440i6％の・6ゾゐloo4）， Boi（59）in June．Boi administered to this patient was so we changed the Kampo prescriptioロto Yokuinin－to not！4慰olooh勿ヵ銘6h歪Wu but Sino耀ni％卿αo伽窺 and then to Keishi－shakuyaku－chimo－to with Boi（5 REHDER et WILsoN亀．Also in June，proteinuria appear－ g） and Ogi （5g），but they were not effective． ed．We considered the possibility that loxoprofen Proteinuria contimed and polyarthralgia was still might have negatively affected his kidneys，so we severe，so we changed the NSAID from diclofenac to changed to sulindac at300mg／day．Proteinuria then loxoprofen at60mg／day in March1998．At the same disappeared，but skin emption developed。We consid－ time，we changed the Kampo prescriptionfromKeishi－ ered that this emption was drug－induced，so we chan－ shakuyaku－chimo－to with Boi and Ogi to Keishi－ ged the NSAID from sulindac to25mg／day of di－ bukuryo－gan mixed with Toki－shakuyaku－san clofenac sodium，and we discontimed the administra－ because a sign of Oketsu （1うloo4 s嬬ゑs），resistance tion ofbucillamine at the same time．Hisskinemption tender on pressure of para－umbilical region，and a disappeared soon，but thereafter，ESR，CRP，joint sign of Suitai（s孟召sゑs‘ゾ60ゐ刀％iづ），swelling of the

Prednisolone 5m

Bud”amine 200m Loxoprofen sodium 180m Sulindac300mg 25m Diclofenac sodium ロ 凸 騨甜隅評utsu’ 朧轟巳鯛h謡 Keis職魏織器dwith Dai。bofu－to Keishi．shakuyaku．Chim。．t。w醜hB。iand。gi G翫寵幣n 8職f号1鳥 ロ ロめ 口 ■ Urinaツprotein±＋±一一＋柵柵斗帯＋＋＋＋±±±＋±一±一一一 J．⊂． L．1． 120 120 トerupti・n 100 100

80 80

● O 60 60 ESR⊂RP mm mg 40 40 ／1hr ！dI 100 10 20 20

80 8 0 0 J．⊂．：Joint count 60 6 Ll．：Lansbury’s index

40 4

20 2

0 0 1997 1998 1999

Fig．1 Clinical course．

￥． Rheumatoid arthritis treated with Kampo medicines 125

1egs，appeared．The loint count and Lansbury’s index bucillamine，proteimria would gradually reduce to be decreased remarkably and urinary protein also de－ eliminated within10months without specific treat－ clined．In August，we withdrew the administration of ment or without increases in the dose of corticoster一 ヨ prednisolone．In September，because he complained of oid．In our case as we11，proteinuria was eliminated arthralgia of the bilateral metatarsophalangeal joints， after the cessation of bucillamine． and swelling of legs and reduced lower abdominal In the present case，however，after stopping the tension existed，we added Gosha－jinki－gan extract at use of bucillamine，the activity of RA became exacer－ 7．5g／day．As Gosha－jinki－gan extract was not so bated．We hesitated to administer another kind of effective and he complained of fatigue and muscle DMARD because of the possibility of adverse effects， cramp，we diagnosed him as Kikyo and Kekkyo so we tried to reduce the RA activity，v》ith Kampo （4⑳oJ6nCy 601h6ゾ z／i孟‘zl6n6忽y ‘znづ1うloo4），changed medicines．From the concepts of Kampo medicine，he this to Dai－bofu－to extract at7．5g／day in March was diagnosed in the clinical course as following． 1999．This prescription was slightly effective for his Oketsu，a blood stagnation syndromel because of the arthralgia，so we administered it as a decoction and darkskinc・1・ran4．1ividlips，gingivaandt・ngue，and discontimed Keishi－bukuryo－gan mixed with Toki」 resistance tender on pressure of para－umbilical shakuyaku－san in May．Thereafter，polyarthralgia region．Kekkyo，a blood deficiency syndrome；because improved remarkably and urinary protein was of the．dry and rough skin，hypertonic rectus ab－ eliminated． dominis muscle and muscle cramp．Suitai，a body fluid stasis syndromel because of swelling and stiffness of Discussion joints and swelling of legs．Kikyo，a vital energy deficiency syndrome；because of general physica1 9） We treated this RA patient with a combination fatigue，1ack of will power and loss of appetite． therapy of modemWestem and Kampo medicines．In In this case，Keishi－bukuryo－gan mixed with this case，bucillamine，one of the DMARDs，was effec－ Toki－shakuyaku－san and Dai－bofu－to （Table II） tive for reducing the activity of RA，but proteimria were effective for improving RA after the suspension developed during its use．Bucillamine－induced mem一 of bucillamine．The former prescription is the combi－ ラヨ branous nephropathy is a known clinical entity． It nation of Keishi－bukuryo－gan and Toki－shakuyaku－ was reported that after suspending the further use of san，both of which are used for the treatment of

Table II Cmde dmgs of prescriptions mainly used in this case．

Keishi－bukuryo－gan mixed with Toki－shakuyaku－san Prescription （Gui－Zhi－Fu－Ling－Wan mixed with Dang－Gui－Shao－Yao－San）

Cinnamomi Cortex＊4．0，Hoelen＊＃5．0，Moutan Cortex＊4．0， Crude drugs （g／day） Persicae Semen＊4．0，Paeoniae Radix＊＃5．0，Alismatis Rhizoma＃6．0， Atractylodis Rhizoma＃4．0，Cnidii Rhizoma＃3．0，Angelicae Radix＃3．0

Dai－bofu－to Prescription （Da－Fang－Feng－Tang）

Angelicae Radix3．0，Paeoniae Radix3．0，Rehmamiae Radix3．0， Astragali Radix3．0，Saposhnikoviae Radix3．0，Eucommiae Cortex3．0， Crude drugs （g／day） Atractylodis Rhizoma3．0，Cnidii Rhizoma2．0，Ginseng Radix1．5， Notopterygii Rhizoma1．5，Achyranthis Radix1．5，Glycyrrhizae Radix1．5， Zizyphi Fmctus1．5，Zingiberis Siccatum Rhizoma1．0，Aconiti Tuber2．0

Keishi－bukuryo－gan mixed with Toki－shakuyaku－san was decocted in600ml of boiling water for30－40 minutes and reduced to300m1．Dai－bofu－to was decocted in800ml of boiling water for50－60minutes and reduced to300mL The decoction was taken3times a day． ＊：Crude dmgs co；nposing in Keishi－buk皿yo－gan．＃：Cmde drugs composing in Toki－shakuyaku－san。 126 Joumal of Traditional Medicines（Vol．18No．32001）

Oketsu，and the latter is also used for Kekkyo and 10）Suitai．According to the concept of Kampo Medi－ References cine，Keishi－bukuryo－gan should be administered to a patient in Yo and Jitsu state and Toki－shakuyaku－ 1）Amasaki，Y．，Sagawa，A．，Atsumi，T．，Jodo，S．，Nakabayashi，T．， Watanabe，1．，Mukai，M．，Fujisaku，A．，Nakagawa，S．and san to a patient in In and Kyo state．Therefore，these Kobayashi，H．：A case of rheumatoid arthritis developing pem－ two pr6scriptions are not commonly combined．We phigus－like skin lesion during treatment with bucillamine． dared to try to administer Keishi－bukuryo－gan mixed め吻観6hJ31，528－534，1991（in Japanese with English abstract）． with Toki－shakuyaku－san to the patient because of 2）Yoshida，A．，Morozumi，K．，Suganuma，T．，Sugito，K．，Ikeda，M．， Oikawa，T．，Fujinami，T．，Takeda，A．and Koyama，K．： his severe Oketsu state and moderate Kekkyo and Clinicopathological findings of bucillamine－induced nephrotic Suitai state．Thereafter，we administered Dai－bofu－to syndrome in patients with rheumatoid arthritis．z4別．1／Vのh名o乙 to him because of his condition of Kikyo and Kek－ 11，284－288，1991． 3）Kikuchi，M．，Saeki，T．，Ito，S．，In，H．，Saito，T．，Ueno，M．，Sato，T．， 10） kyo． There were case reports noting that Toki－ Suzuki，S．，Nakano，M．，Ozawa，T．，Nakazono，K．，Murasawa，A．， shakuyaku－san and Dai－bofu－to were effective in the Shimotori，T．and Arakawa，M．：Clinicopathological evaluation treatment of RA．11’12）It was also reported that the and treatment of bucillamine induced membranous nephropathy． Ryπ㎜6hi33，215－222，1993（in Japanese with English abstract〉． severity of Oketsu was significantly correlated with 4）Negishi，M．，Kaga，S．，Kasama，T．，Hashimoto，M．，Fukushima， the activity of RA，assessed by Lansburゾs index，and T．，Yamagata，N．，Tabata，M．，Kobayashi，K．，Ide，H．and Ta・ that these two parameters had a tendencyto change in kabayashi，T．：Lmg inlury associated with bucillamine therapy． R翅〃昭6h’32，135－139，1992（童n Japanese with English abstract）． 13） paralle1． These findings suggest the possibility that 5）Negishi，M．，Yamazaki，」．，Hosaka，M．，Iwabuchi，H．，Matsuda， the treatment for Oketsu leads to improvement of the A．，Kanemitsu，H．，Hiramatsu，K．，Kaga，S．，Hashimoto，M．， activity of RA． Kasama，T．，Kobayashi，K．and Ide，H．：A case of rheumatoid arthritis associated with agranulocゾtosis during bucillamine In conclusion，the present case report suggests treatment．R卿耀6h歪34，651－655，1994（in Japanese with English that Kampo medicines might be useful for the treat－ abstract）． 6〉Amett，F．C．，Edworthy，S．M．，Bloch，D．A．，McShane，D．J．，Fries，J． ment of RA patients，especially for those who have F．，Cooper，N．S．，Healey，L．A．，Kaplan，S．R．，Liang，M．H．，Luthar－ adverse reactions to DMARDs and must avoid them． a，H．S．，αα乙：The American Rheumatism Association1987 revised criteria for the classification of rheumatoid arthritis． ／17！h7iあs Rh6z6〃z．31，315－324，1988． 和文抄録 7）Steinbrocker，0。，Traeger，C．H．and Batterman，R．C．：Therapeu－ tic criteria in rheumatoid arthritis．μル猛140，659－662，1949． ブシラミン腎症を併発した慢性関節リウマチ（RA〉に 8）Lansbury，J．：Report of a three－year study on the systemic and 対して，漢方治療が奏功した1例を報告した。症例は56 articular index in rheumatoid arthritis．∠47！h7漉s Rh6κ窺．1，505－ 522，1958． 歳，男性。1996年12月，多関節痛出現。1997年2月，他 9）Terasawa，K．：The concepts of KI，blood，body fluids and their 院にてRAの診断のもと，ロキソプロフェン，プレドニ interrelation with various stages of disease．in“Kampo”（Ed．by ゾロン，ブシラミンにて加療を受けた。1997年5月，当 Terasawa，K．），Standard McIntyre，Tokyo，pp．15－61，1993． 10）Terasawa，K．：Kampo－prescriptions．in“Kampo”（Ed．by Teras－ 科初診以来，現代西洋医学的治療に漢方治療を併用して awa，K．），Standard McIntyre，Tokyo，pp．183－274，1993． 加療にあたった。経過中，ブシラミンによる蛋白尿が出 11〉Takahashi，K．，Kogure，T．，Shimoda，F．and Terasawa，K．：A case 現。ブシラミンを中止したところ，多関節痛と炎症反応 of rheumatoid arthritis effectively treated with Toki－shakuyaku－ san－ka－bushi． ∫ Chz61うz6 Rh6z6η2． ／1sso6． 25， 52－53， 1994 （in が悪化した。しかし，桂枝快苓丸合当帰有薬散および大 Japanese）． 防風湯が奏功し，RAの活動性が低下し蛋白尿も消失し 12）Gotoh，H．，Shintani，T．，Mitsuma，T．and Terasawa，K．：A case of た。このことから，副作用によりDMARDsが使用困難 rheumatoid arthritis with amyloidosis and renal failure success－ fully controlled with Daibofu－to．ノ伽．10万6n如1〃i6威46，459－ なRAの治療に対して，漢方治療が有効である可能性が 465，1995（in Japanese with English abstract）． 示唆された。 13）Takahashi，K．，Matsuda，H．，Shimada，Y．，Kita，T．，Itoh，T．and Terasawa，K．二Correlation between activity of rheumatoid arthri－ tis and severity of“oketsu”syndrome．／丁瓶諾〃認15，123－126， 1998．