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Successful treatment of rectal ulcers in a patient with systemic lupus erythematosus usingcorticosteroids and tacrolimus

Authors: Shinjiro Kaieda · Teppei Kobayasi · Mariko Moroki · Seiyo Honda · Kentaro Yuge · HiroshiKawano · Keiichi Mitsuyama · Michio Sata · Hiroaki Ida · Tomoaki Hoshino · Takaaki Fukuda

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ArticleTitle Successful treatment of rectal ulcers in a patient with systemic lupus erythematosus using corticosteroids andtacrolimus

Article Sub-Title

Article CopyRight Japan College of Rheumatology(This will be the copyright line in the final PDF)

Journal Name Modern Rheumatology

Corresponding Author Family Name KaiedaParticle

Given Name ShinjiroSuffix

Division Division of Respirology, Neurology and Rheumatology, Department ofMedicine

Organization Kurume University School of Medicine

Address 67 Asahi-machi, Kurume, 830-0011, Japan

Email [email protected]

Author Family Name KobayasiParticle

Given Name TeppeiSuffix

Division Division of Gastroenterology, Department of Medicine


Address Kurume, Japan

Email

Author Family Name MorokiParticle

Given Name MarikoSuffix




Email

Author Family Name HondaParticle

Given Name SeiyoSuffix




Email

Author Family Name YugeParticle

Given Name KentaroSuffix

Division Department of Internal Medicine

Organization Saiseikai Omuta Hospital

Address Omuta, Japan

Email

Author Family Name KawanoParticle

Given Name HiroshiSuffix




Email

Author Family Name MitsuyamaParticle

Given Name KeiichiSuffix




Email

Author Family Name SataParticle

Given Name MichioSuffix




Email

Author Family Name IdaParticle

Given Name HiroakiSuffix




Email

Author Family Name HoshinoParticle

Given Name TomoakiSuffix




Email

Author Family Name FukudaParticle

Given Name TakaakiSuffix

Division Center for Rheumatic Diseases

Organization Kurume University Medical Center


Email

Schedule

Received 20 June 2012

Revised

Accepted 19 September 2012

Abstract Systemic lupus erythematosus (SLE) is frequently accompanied by gastrointestinal symptoms. Although allparts of the gastrointestinal tract may be affected, colonic involvement is quite rare. Colonic ulceration,particularly in the rectum, is associated with a high mortality rate in patients with SLE, despiteimmunosuppressive therapy. While a standard regimen for treating rectal ulcers complicated with SLE hasnot been established, combination therapy with steroids and immunosuppressive agents is necessary becauseof the associated high mortality rate. In this report, we describe a patient with SLE whose condition wascomplicated with ulcerative lesions in the rectum and sigmoid colon; the lesions were successfully treatedwith a combination of corticosteroids and tacrolimus therapy. Tacrolimus could be a useful additional oralternative modality for treating rectal involvement in SLE.

Keywords (separated by '-') Rectal ulcer - Systemic lupus erythematosus - TacrolimusFootnote Information

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Journal: 10165

Article: 775

UNCORRECTEDPROOF

CASE REPORT1

2 Successful treatment of rectal ulcers in a patient with systemic

3 lupus erythematosus using corticosteroids and tacrolimus

4 Shinjiro Kaieda • Teppei Kobayasi • Mariko Moroki • Seiyo Honda •

5 Kentaro Yuge • Hiroshi Kawano • Keiichi Mitsuyama • Michio Sata •

6 Hiroaki Ida • Tomoaki Hoshino • Takaaki Fukuda

7 Received: 20 June 2012 / Accepted: 19 September 20128 � Japan College of Rheumatology 2012

9 Abstract Systemic lupus erythematosus (SLE) is fre-

10 quently accompanied by gastrointestinal symptoms.

11 Although all parts of the gastrointestinal tract may be

12 affected, colonic involvement is quite rare. Colonic ulcera-

13 tion, particularly in the rectum, is associated with a high

14 mortality rate in patients with SLE, despite immunosup-

15 pressive therapy.While a standard regimen for treating rectal

16 ulcers complicated with SLE has not been established,

17 combination therapy with steroids and immunosuppressive

18 agents is necessary because of the associated high mortality

19 rate. In this report, we describe a patient with SLE whose

20 condition was complicated with ulcerative lesions in the

21 rectum and sigmoid colon; the lesions were successfully

22 treated with a combination of corticosteroids and tacrolimus

23 therapy. Tacrolimus could be a useful additional or alterna-

24 tive modality for treating rectal involvement in SLE.

25

26 Keywords Rectal ulcer � Systemic lupus erythematosus �

27 Tacrolimus

28Introduction

29Systemic lupus erythematosus (SLE), a complex autoim-

30mune disease that affects various organs, is frequently

31accompanied by gastrointestinal symptoms, and lupus

32enteritis has been reported to be the most common cause of

33acute abdominal pain in SLE, accounting for up to 45 % of

34cases [1, 2]. Gastrointestinal vasculitis is one of the most

35serious complications of SLE, even though the occurrence

36of colonic lesions is quite rare (0.2 %) [1, 3]. Vasculitis of

37the bowel may lead to ulceration, hemorrhage, perforation,

38or infarction, and colonic ulceration, particularly in rectal

39lesions, has been associated with high mortality rates [4, 5].

40Despite immunosuppressive treatment, severe complica-

41tions, such as perforations of the intestinal tract, may occur,

42thus leading to an unfavorable prognosis.

43Tacrolimus, a T-cell-specific calcineurin inhibitor with

44cyclosporine A-like immunosuppressive effects, sup-

45presses T cell activation, thereby inhibiting inflammatory

46cytokine production [6]. In vivo and in vitro studies have

47shown that tacrolimus is 10 to 100 times more potent than

48cyclosporine A in inhibiting these processes [7]. Tacroli-

49mus has been approved for use worldwide in organ trans-

50plantation and for treating autoimmune diseases, including

51inflammatory bowel disease (IBD), lupus nephritis, and

52rheumatoid arthritis [8–14]. Furthermore, several reports

53have demonstrated the efficacy of tacrolimus in the treat-

54ment of various conditions not associated with nephritis,

55including arthritis, skin eruption, alopecia, cystitis, and

56hemophagocytic syndrome, in patients with SLE [15–18];

57however, its efficacy for the treatment of colonic lesions

58complicated with SLE has not been reported.

59To date, no standard therapeutic strategies for colonic

60ulcers in SLE have been established. While corticosteroids

61are routinely used as a first-line therapy, many cases have

A1 S. Kaieda (&) � M. Moroki � S. Honda � H. Ida � T. Hoshino

A2 Division of Respirology, Neurology and Rheumatology,

A3 Department of Medicine, Kurume University School of

A4 Medicine, 67 Asahi-machi, Kurume 830-0011, Japan

A5 e-mail: [email protected]

A6 T. Kobayasi � H. Kawano � K. Mitsuyama � M. Sata

A7 Division of Gastroenterology, Department of Medicine, Kurume

A8 University School of Medicine, Kurume, Japan

A9 K. Yuge

A10 Department of Internal Medicine, Saiseikai Omuta Hospital,

A11 Omuta, Japan

A12 T. Fukuda

A13 Center for Rheumatic Diseases, Kurume University Medical

A14 Center, Kurume, Japan

123Journal : Large 10165 Dispatch : 27-9-2012 Pages : 5

Article No. : 775h LE h TYPESET

MS Code : MORH-D-12-00268 h CP h DISK4 4

Mod Rheumatol

DOI 10.1007/s10165-012-0775-x

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62 been reported to be steroid resistant, and perforations of the

63 intestinal tract may occur after the induction of steroid

64 therapy [3–5]. These findings suggest that combination

65 therapy with steroids and an immunosuppressant is nec-

66 essary. However, guidelines for the use of potent immu-

67 nosuppressive agents have not yet been established, and

68 low-dose oral tacrolimus may represent an alternative

69 therapy for the treatment of colonic ulcers in SLE. In the

70 current report, we describe a case of SLE complicated with

71 ulcerative lesions of the rectum and sigmoid colon in which

72 combination therapy with steroids and tacrolimus contrib-

73 uted to the remission of rectal ulcers and had steroid-

74 sparing effects for 12-month follow-up.

75 Case report

76 A 51-year-old man, who had been diagnosed with SLE and

77 lupus nephritis at 36 years of age, remained in a stable

78 condition while receiving 5 mg prednisolone (PSL) and

79 150 mg mizoribine daily. Nonsteroidal anti-inflammatory

80 drugs and antibiotics were not prescribed. Before admis-

81 sion to our department, he developed gastrointestinal

82 symptoms and experienced more than 10 episodes of

83 diarrhea associated with abdominal cramps. He presented

84 with an elevated body temperature (37.6 �C); other vital

85 signs were normal. A physical examination revealed mild

86 tenderness of the middle lower abdomen without muscular

87 defense. The palpebral conjunctiva was anemic. No skin

88 rash was evident on either the face or extremities.

89 Laboratory evaluations revealed mild anemia (Hb 9.8 g/

90 dL) and leukopenia (WBC 2500 9 102/lL). Routine blood

91 chemistry and coagulofibrinolytic tests were normal. The

92 erythrocyte sedimentation rate was elevated (93.0 mm/h),

93 but C-reactive protein (CRP) was undetectable. Urinalysis

94 findings were positive for urinary protein (1.18 g/day);

95 however, no casts were observed in the urinary sediment.

96 Serum albumin levels were mildly decreased. The results of

97 routine kidney function tests were normal, and creatinine

98 clearance was 94.4 mL/min. An immunological test

99 revealed the patient to be positive for anti-nuclear antibodies,

100 with a titer of 1:160 (a speckled pattern), and anti-dsDNA

101 antibody levels were elevated (81.2 IU/mL). Serum com-

102 plement levels were normal, and anti-Sm antibodies, anti-U1

103 RNP antibodies, anti-SS-A antibodies, and rheumatoid fac-

104 tor were positive. Anti-cardiolipin antibodies and lupus

105 anticoagulant were negative. Laboratory data revealed leu-

106 kocytopenia, proteinuria, and an increase in the anti-dsDNA

107 antibody titers, suggesting elevated disease activity.

108 An endoscopic examination revealed girdle ulcerative

109 lesions in the rectum (Rs to Ra; Fig. 1a). The fundus of the

110 ulcer and surrounding mucosa were erythrogenic and prone

111 to bleeding. A histopathological examination of biopsy

112specimens taken from the ulcer showed nonspecific gran-

113ulation and proctitis, but no evidence of vasculitis. Gast-

114rografin enema radiography detected a stenosis of the

115sigmoid colon due to an intestinal tract edema (Fig. 1b,

116arrow). An abdominal enhanced computed tomography

117(CT) image revealed bowel wall thickening of the rectum

118(Fig. 1c). The patient’s stool samples were positive for

119occult blood, and fecal cultures were positive for a small

120number of Enterobacteriaceae species, but no other

121pathogens, including Clostridium antigen and acid-fast

122bacillus. Cytomegalovirus (CMV) infection was excluded

123because intranuclear inclusions were not observed histo-

124logically, and CMV antigen-positive leukocytes were not

125detected in the patient’s peripheral blood.

126The absence of any positive evidence for infective

127agents and the presence of colonic ulcers were thought to

128be consistent with a gastrointestinal manifestation of SLE.

129IBD, such as Crohn’s disease and ulcerative colitis, was

130considered as a differential diagnosis. Although IBD is

131rarely associated with SLE, SLE is rarely active at the time

132of IBD manifestation [19]. Furthermore, neither colonos-

133copy nor pathological study revealed specific findings that

134were sufficient to change the diagnosis of IBD.

135Treatment with 500 mg intravenous methylprednisolone

136for 3 days, followed by 50 mg/day oral PSL and 2 mg/day

137tacrolimus was initiated. As shown in Fig. 2, the gastroin-

138testinal symptoms improved after the start of treatment.

139Furthermore, treatment with systemic steroids and oral ta-

140crolimus healed the ulcer endoscopically 5 weeks after ini-

141tiation of therapy (Fig. 2, CF�), and a reduction in PSL dose

142was possible. The patient was discharged from the hospital in

143an improved condition and has been monitored on an out-

144patient basis. Follow-up colonoscopies, which were con-

145ducted at 3 and 5 months after the initiation of treatment,

146demonstrated a reduction in the ulcerated area and regener-

147ation of epithelium covering the surface (Fig. 2, CF` and

148´).WBC counts normalized and anti-dsDNA antibody titers

149and proteinuria were decreased during the subsequent out-

150patient course (Fig. 2), indicating that the patient’s SLE was

151under control. Anti-DNA antibodies were examined by

152radioimmunoassay approximately 12 months after patient

153discharge and were confirmed to be within normal limits

154(5.8 IU/mL, normal range\6 IU/mL). Currently, the patient

155occasionally complains of abdominal pain without diarrhea,

156and oral tacrolimus has been increased to 3 mg/day. The

157patient has remained well for 12 months, and PSL has been

158reduced to 15 mg/day.

159Discussion

160Gastrointestinal manifestations are a frequent complication

161associated with SLE [1, 2]. Although colonic lesions are

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162 quite rare, ulcerative lesions in the large intestine have

163 been demonstrated in several studies [3–5, 20]. Of the 25

164 cases that have been reported in Japan, complications, such

165 as perforations and fistulas, were observed in 9 patients, 4

166 of whom died [5]. In another study, perforation was

167 observed in 5 out of 6 cases involving rectal ulceration, and

168 4 of these patients died, indicating a poor prognosis for

169 such cases [4]. Colonic ulceration, particularly rectal

170 lesions, is associated with a high mortality rate. However,

171 despite this high mortality, ulcerative lesions in the rectum

172 and sigmoid colon were improved by appropriate medical

173 treatment in the present case. We emphasize that early

174 administration of immunosuppressants, such as tacrolimus

175 with high-dose steroid therapy, may contribute to an

176 improvement in its poor prognosis.

177 Intestinal vasculitis was diagnosed in 45–60 % of SLE

178 patients presenting with acute abdominal pain [1, 21, 22].

179 In our patient, findings of vasculitis were not obtained from

180 the tissue biopsy specimen. Rectal and sigmoid colon

181 ulcers were presumably caused by vasculitis based on the

182 following facts: (1) a typical vasculitis pattern is difficult to

183 prove on the basis of endoscopic biopsy [4, 5, 20]; (2) the

184 bowel wall thickness detected in abdominal CT (Fig. 1c)

185 was suggestive of bowel ischemia [23]; (3) a drop in the

186 WBC count at the time of acute abdominal pain correlates

187 with the occurrence of intestinal vasculitis, as observed in

188 the present case [1]; and (4) the rectal ulcer responded to

189immunosuppressive therapy, indicating impressive

190improvement. Thrombosis of the mesenteric vessels asso-

191ciated with antiphospholipid syndrome (APS) may give

192rise to mesenteric ischemia [24]; however, APS was

193excluded because these antibodies were not detected in the

194present case.

195High-dose corticosteroid therapy is considered the

196treatment of choice for gastrointestinal complications

197associated with SLE; however, not all patients respond

198sufficiently, and some may relapse when steroids are

199tapered. Prior studies demonstrated sustained remission

200after the use of oral mesalazine and pulse cyclophospha-

201mide when steroid therapy alone was not effective [3, 5]. It

202should be noted that the outcomes in patients with perfo-

203rations are extremely poor, and therefore immunosup-

204pressants are clearly necessary for the treatment of colonic

205ulcers, particularly when rectal lesions are involved.

206Tacrolimus, a potent T cell inhibitor, has been suc-

207cessfully administered for the treatment of inflammatory

208bowel disease, lupus nephritis, and rheumatoid arthritis [9–

20914]. While various immune response abnormalities have

210been identified in patients with SLE, aberrant and persistent

211T cell abnormalities involving signal transduction defects

212have been recognized as important factors in disease

213development in the last decade [25]. On the basis of these

214findings, T cell blockade is thought to be a potential ther-

215apeutic target for SLE and its manifestations. Recently,

(A)

(C)

(B)Fig. 1 a Endoscopic

examination of the rectum

showing girdle ulcerative

lesions. b Barium enema

examination showing narrowing

of the sigmoid colon (arrow).

c Abdominal enhanced

computed tomography showing

bowel wall thickening of the

rectum (arrow)

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216 tacrolimus has been successfully applied in the treatment of

217 various manifestations without nephritis in SLE [15–18].

218 Furthermore, tacrolimus, a drug that has been shown to be

219 well absorbed, even in patients with severe colitis, serves

220 as a rational therapeutic option for inflammatory bowel

221 disease that is refractory to conventional therapy [26].

222 Thus, this immunosuppressive agent was administered to

223 our current patient. Tacrolimus does not act quickly, and its

224 onset of action usually requires 2–4 weeks; thus, we

225 simultaneously initiated high-dose steroid therapy and

226 tacrolimus [27]. Although an improvement in gastrointes-

227 tinal symptoms may result from high-dose corticosteroid

228 treatment, low-dose oral tacrolimus has also been shown to

229 help maintain the remission of rectal lesions while exerting

230 a steroid-sparing effect. Therefore, tacrolimus could be an

231 additional or alternative modality for treating rectal

232 involvement in SLE.

233 In conclusion, colonic lesions, particularly those

234 occurring in the rectum, are quite rare in patients with SLE,

235 but are associated with a high mortality rate. The present

236 case demonstrated that combination therapy with steroids

237and tacrolimus is an effective therapeutic option for treat-

238ing rectal involvement in patients with SLE.

239Conflict of interest None.

240References

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Mizoribine 150mg

Tacro limus 2mg

CF

3mg

Steroidtherapy

Diarrhea

Abdominalpain

2010

CF

PSL10mg

mPSL

500mg

Oct. Nov.

DischargeCF2011

PSL50 45 40 35 25 20

Admission

Dec. Jan. Feb. Mar.

17.5

CF CF

CF

35 30

May

WBC 2500 2000 12200 6200 4100 5100 5400 5700

abs 81.2 99.9 30.8 <25

Protein Urea 1.18 0.5 +/- +/- +/-

g/day g/day

Anti-dsDNA

Fig. 2 Clinical course of the patient. Anti-dsDNA antibodies were quantified by enzyme-linked immunosorbent assay (normal range\25 IU/

mL). mPSLmethylprednisolone, PSL prednisolone, CF colon fiber,WBC white blood cell, Anti-dsDNA abs anti-double-stranded DNA antibodies

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