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Keywords:

  • mizoribine;
  • systemic sclerosis;
  • ulcerative colitis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

The combinational effect of oral corticosteroid and mizoribine for ulcerative colitis is presented in a patient with systemic sclerosis (SSc). A 64-year-old woman came to our clinic complaining of a 30-year history of Raynaud’s phenomenon. She had past history of ulcerative colitis with the continued medication of mesalazine without success. She was presented with sclerodactyly and finger joint swelling. She also showed epigastric discomfort. Laboratory study showed positive anti-nuclear antibody and positive anti-centromere antibody. Histological examination showed mild perivascular mononuclear cell infiltrates in the whole dermis and increased deposition of collagen fibers in the middle and lower dermis. Chest X-ray film showed mild bibasilar pulmonary fibrosis. An upper gastrointestinal series study showed reflux esophagitis and atrophic gastritis. These findings led to the diagnosis of systemic sclerosis (limited type) complicated with ulcerative colitis. Treatment with oral corticosteroid (5 mg/day) and mizoribine (150 mg/day) in the morning was started. She showed remarkable improvement for sclerodactyly and lower intestinal bleeding stopped after 6 months. She is under the same treatment without exaggeration and adverse effect of the drug until now.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

Ulcerative colitis (UC) is a chronic inflammatory disease involving primarily the large intestine. UC involves the rectum and extends proximally in a contiguous fashion. The extent of the disease varies, ranging from proctitis to pancolitis. Whereas typical gross microscopic descriptions of UC are readily found in pathology textbooks,1 atypical features are increasingly reported of the recognition of additional, subtler forms of enteritis or colitis as well as the influence of newer powerful medications on the histology. Many kinds of diseases including pyoderma gangrenosum,2 hematological diseases3 and immunological diseases4,5 have been reported to be complicated with UC. A rare case of UC complicated with systemic sclerosis (SSc) is presented, which case was successfully treated with the combination of low-dose oral corticosteroid and mizoribine.

Case report

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

A 64-year-old woman came to our clinic complaining of a 30-year history of Raynaud’s phenomenon. She had noticed morning stiffness of her fingers for several years. She had a past history of UC, the diagnosis of which was made by a lower intestinal series study and histological finding of the biopsy specimen from the intestinal mucosa. The disease had been treated with mesalazine medication (1500 mg/day) without success for several years. She had been suffering from mild to moderate bleeding from the lower intestine. Reflux esophagitis had been treated with an oral H2 blocker. She presented with sclerodactyly and finger joint swelling (Fig. 1). She also showed epigastric discomfort. Laboratory examination showed positive anti-nuclear antibody (1280X, homogeneous pattern) and positive anti-centromere antibody. Other findings were unremarkable including rheumatoid factor, lupus erythematosus cells, anti-topoisomerase I antibody, anti-RNP antibody, anti-Sm antibody, anti-SS-A/B antibody, anti-double-strand DNA antibody, anti-single strand DNA antibody, anti-mitochondria antibody and anti-cardiolipin antibody. Histological examination from the dorsum of the left third finger showed mild perivascular mononuclear cell infiltrates in the whole dermis and increased deposition of collagen fibers in the middle and lower dermis (Fig. 2). Chest computed tomography (CT) showed mild bibasilar pulmonary fibrosis. The result of electrocardiograph was unremarkable. An upper gastrointestinal series study showed reflux esophagitis and atrophic gastritis. These findings led to the diagnosis of SSc (limited type) complicated with reflux esophagitis, atrophic gastritis and ulcerative colitis. Treatment for SSc with oral corticosteroid (10 mg/day) and mizoribine (150 mg/day) in the morning was started. The serum concentration of mizoribine after 2 weeks was 1.93 μg/mL. Two months later, the dose of oral corticosteroid was tapered to 5 mg/day. Six months after the start of the treatment, not only improvement of sclerodactyly was found, but also complete resolution of lower intestinal bleeding. No remarkable change was found on mild pulmonary fibrosis on chest CT. She is under the same treatment without exaggeration of sclerodactyly (Fig. 3) and lower intestinal bleeding. No adverse effect of the treatment has been found for 10 months after resolution of sclerodactyly and bleeding.

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Figure 1.  The patient presented with sclerodactyly and finger joint swelling.

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Figure 2.  Histological examination showed mild perivascular mononuclear cell infiltrates in the whole dermis and increased deposition of collagen fibers in the middle and lower dermis (original magnification ×100).

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Figure 3.  Sclerodactyly in the present case showed improvement.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

The present case showed a rare complication of UC and SSc, which case was successfully treated with the combination of low-dose oral corticosteroid and mizoribine. SSc has also been reported to be complicated in UC.6,7 Two white families with SSc and other connective tissue and immunological disorders, including rheumatoid arthritis, discoid lupus erythematosus, psoriasis, psoriatic arthritis, ankylosing spondylitis, UC, asthma, Sjögren’s syndrome, Raynaud’s phenomenon and thyroid disease were reported.6 In one of these families, two sisters were affected by SSc. A follow up of a patient with UC and SSc over 30 years reported in 1965 was described.7,8 The report speculated that UC is an autoimmune disorder frequently associated with other diseases with a similar underlying pathogenic mechanism.7 Crohn’s disease (CD), another inflammatory bowel disease, is also complicated with other diseases including malignant diseases,9,10 hematological diseases3,11 and immunological diseases.12,13 Accordingly, inflammatory bowel diseases are autoimmune disorders that are frequently associated with other diseases with a similar underlying pathogenic mechanism. CD may be caused by excessive inflammation, and the primary mechanism is actually that of an immunodeficiency.14 Failure of inflammatory mediator production leads to insufficient recruitment of neutrophils, resulting in inadequate removal of bacteria and other debris. Intestinal barrier function defects and genetic associations with the nucleotide-binding oligomerization domain and Toll-like receptor pathways suggest that the innate immune system has failed to protect the host against the vast array of commensal bacteria in the gut.15 This hypothesis is supported by the observation that probiotic agents exert anti-inflammatory effects in the intestine through stimulation of the mucosal innate immune system. These hypotheses led to the recent successful therapies with oral corticosteroids, immunosuppressive drugs and anti-tumor necrosis factor-α antibody. The present case showed that mizoribine, a kind of immunosuppressive drug, was effective for the treatment of lower intestinal bleeding. This result was considered to be due to the anti-inflammatory effect of mizoribine. Low-dose corticosteroid has been shown to be effective for the treatment of SSc.16 Immunosuppressive drugs including mizoribine could also be used for the treatment of SSc. Accordingly, the combination of low-dose corticosteroid and mizoribine was used for the treatment in the present case.

Mizoribine is an imidazole nucleoside and the metabolite, MZ-5-P, exerts its activity through selective inhibition of inosine monophosphate synthetase and guanosine monophosphate synthetase, resulting in the complete inhibition of guanine nucleotide synthesis without incorporation into nucleotides.17 An in vitro study suggested that mizoribine could suppress interleukin-6 release and thus may exert its efficacy on immunoglobulin A nephropathy.18 Recently, clinical advantages of imidazole for adults with rheumatoid arthritis, lupus erythematosus, lupus nephritis and other rheumatic diseases have been reported. A study indicated that mizoribine might be useful and relatively safe for patients who are poor responders to methotrexate (MTX) as an additional regimen to MTX therapy as well as for elderly patients with rheumatoid arthritis.19 High-dose mizoribine therapy showed an efficacy and safety that would warrant its application to steroid-dependent pediatric patients with lupus.20 Maintenance therapy with mizoribine administrated in combination with prednisolone was beneficial and clinically less toxic in at least a proportion of pubertal patients with lupus nephritis.21,22 The present case was treated with mizoribine pulse therapy (150 mg/day in the morning). Recently, the effect of mizoribine has been shown to depend on the peak serum level in lupus nephritis patients.23,24 Mizoribine pulse therapy was considered to be more effective than conventional t.i.d. intake. The serum concentration in the present case was sufficient for effective treatment. Mizoribine pulse therapy has been shown to be effective for steroid-dependent nephritis.25–27 In addition, mizoribine could be used for the tapering of oral corticosteroid in these patients. This method might contribute effectively to the treatment of both SSc and UC. Accordingly, combination therapy of oral corticosteroid and mizoribine may be effective for not only the sclerodactyly in SSc, but also for the lower intestinal bleeding of UC.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References
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