Development of ulcerative colitis during the course of rheumatoid arthritis: Association with selective IgA deficiency.

Abstract

A 56-year-old woman with a 29-year history of rheumatoid arthritis (RA) was admitted to the hospital, complaining of high fever, abdominal pain and severe bloody diarrhea. Colonoscopy revealed friable and edematous mucosa with spontaneous bleeding, diffuse erosions and ulcers extending from the rectum to the distal transverse colon. Histopathological findings of rectal biopsies were compatible with ulcerative colitis (UC). Being diagnosed as having severe active left-side UC, she was successfully treated with intravenous methylprednisolone followed by prednisolone and leukocytapheresis. Laboratory tests revealed low serum and saliva IgA levels, which might play a role in the development of UC. To our knowledge, this is the first case of UC occurring during the course of RA, accompanied by selective IgA deficiency.

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Yuki Asada, Hajime Isomoto, Saburo Shikuwa, Chun Yang Wen, Eiichiro Fukuda, Masaru Miyazato,
Kenta Okamoto, Takashi Nakamura, Hitoshi Nishiyama, Yohei Mizuta, Kiyoshi Migita, Masahiro Ito, Shigeru Kohno
INTRODUCTION
Recent case reports described the development of
ulcerative colitis (UC) in patients with rheumatoid arthritis
(RA)[1,2]. Although UC is commonly associated with
arthritic manifestations such as ankylosing spondylitis and
sacroilitis[3], RA complicated by UC is uncommon[4], hence
the underlying mechanisms of the association between
UC and RA remain unclear. Differentiation between UC
and colitis, primarily or secondarily related to RA or drug-
induced colitis associated with medications for RA, can be
diffi cult sometimes[5].
Selective defi ciency of immunoglobulin A (IgA) is the
most frequent hypogammaglobulinemia[6]. It is associated
with increased risk of autoimmune diseases including
RA[6,7]. One might speculate that IgA deficiency plays a
role in the mucosal immune and infl ammatory responses
of UC[6]. Herein, we describe the development of UC in a
patient with longstanding RA and selective IgA defi ciency.
To the best of our knowledge, this is the fi rst case report
on the association of RA with UC and IgA defi ciency.
CASE REPORT
A 56-year-old woman who had been diagnosed with UC
at a local clinic 5 mo earlier, was admitted to our hospital,
complaining of high fever, exacerbated lower abdominal
pain and a 4-wk duration of bloody diarrhea, despite
treatment with 30 mg/d of oral prednisolone. She had
suffered from RA for 29 years and the current stage and
class of RA, based on Steinbrocker’s classifi cation, was Ⅳ
and Ⅱ, respectively. RA had been stable for the last 5 years
under continuous treatment consisting of bucillamine (100
mg/d), prednisolone (5 mg/d) and D-penicillamine (600
mg/d). She had a history of adverse events of proteinuria
and skin eruption with itching against bucillamine
and mesalazine, respectively. She had not taken any
other medications such as antibiotics, non-steroid anti-
infl ammatory drugs (NSAIDs) or gold salts, prior to the
development of UC. She was a non-smoker, did not drink
alcohol and had not undergone pervious gastrointestinal
surgery.
On admission, physical examination revealed body
weight of 32 kg, height of 146 cm, body temperature of
37.9℃, regular pulse rate of 96/min and blood pressure
of 148/76 mmHg. Conjunctiva palpebra and bulbus were
CASE REPORT
Development of ulcerative colitis during the course of
rheumatoid arthritis: Association with selective IgA defi ciency
www.wjgnet.com
Yuki Asada, Saburo Shikuwa, Eiichiro Fukuda, Masaru
Miyazato, Kenta Okamoto, Takashi Nakamura, Kiyoshi
Migita, Department of Internal Medicine, National Nagasaki
Medical Center, 1001-1 Kubara, Omura, Japan
Chun Yang Wen, Masahiro Ito, Department of Pathology,
National Nagasaki Medical Center, 1001-1 Kubara, Omura, Japan
Hajime Isomoto, Hitoshi Nishiyama, Yohei Mizuta, Shigeru
Kohno, Second Department of Internal Medicine, Nagasaki
University School of Medicine, 1-7-1 Sakamoto, Nagasaki, Japan
Correspondence to: Hajime Isomoto, MD, Second Department of
Internal Medicine, Nagasaki University School of Medicine,1-7-1
Sakamoto, Nagasaki 852-8501,
Japan. hajimei2002@yahoo.co.jp
Telephone: +81-95-8497281 Fax: +81-95-8497285
Received: 2006-01-24 Accepted: 2006-07-20
Abstract
A 56-year-old woman with a 29-year history of
rheumatoid arthritis (RA) was admitted to the hospital,
complaining of high fever, abdominal pain and severe
bloody diarrhea. Colonoscopy revealed friable and
edematous mucosa with spontaneous bleeding, diffuse
erosions and ulcers extending from the rectum to the
distal transverse colon. Histopathological findings of
rectal biopsies were compatible with ulcerative colitis
(UC). Being diagnosed as having severe active left-
side UC, she was successfully treated with intravenous
methylprednisolone followed by prednisolone and
leukocytapheresis. Laboratory tests revealed low
serum and saliva IgA levels, which might play a role
in the development of UC. To our knowledge, this is
the fi rst case of UC occurring during the course of RA,
accompanied by selective IgA defi ciency.
© 2006 The WJG Press. All rights reserved.
Key words: Ulcerative colitis; Rheumatoid arthritis;
Selective IgA defi ciency
Asada Y, Isomoto H, Shikuwa S, Wen CY, Fukuda E, Miyazato
M, Okamoto K, Nakamura T, Nishiyama H, Mizuta Y, Migita K,
Ito M, Kohno S. Development of ulcerative colitis during the
course of rheumatoid arthritis: Association with selective IgA
defi ciency. World J Gastroenterol 2006; 12(32): 5240-5243
http://www.wjgnet.com/1007-9327/12/5240.asp
PO Box 2345, Beijing 100023, China World J Gastroenterol 2006 August 28; 12(32): 5240-5243
www.wjgnet.com World Journal of Gastroenterology ISSN 1007-9327
wjg@wjgnet.com © 2006 The WJG Press. All rights reserved.

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Asada Y et al. Ulcerative colitis, rheumatoid arthritis and IgA defi ciency 5241
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normal without pallor or jaundice. Heart sounds were
clear with regular sinus rhythm and no rales were audible
in the lung fi elds. The abdomen was tender on palpation
in the lower quadrant with weak bowel sounds, but neither
muscular guarding nor Blumberg’s sign was noted. Digital
rectal examination revealed dark red blood. There was no
edema on the face or extremities and there were no signs
of motor or sensory disturbances. Typical joint deformities
and morning stiffness of RA were noted in both hands.
Laboratory investigations showed leukocyte count,
10 900/mm3 (normal, 3500-9100); platelet, 30.6 × 104/
mm3 (normal, 13.0-36.9 × 104); hemoglobin (Hb), 132 g/L
(normal, 113-152); C-reactive protein (CRP), 6.6 g/L (nor-
mal, < 0.3); serum total protein, 53 g/L (normal, 65-82);
albumin, 23 g/L (normal, 37-52); IgG, 16.58 g/L (normal,
8.7-17); IgA, 0.2 g/L (normal, 1.1-4.1); IgM, 0.63 g/L
(normal, 0.46-2.6); rheumatoid factor, 48 000 IU/L (normal,
0-20000); passive agglutination (RAPA), 1:80 (normal, <
1:40); antinuclear antibodies < 40 (normal, < 40); CH50,
23.2 g/L, (normal, 25-48); and C3, 0.63 g/L (normal,
0.86-1.6). Saliva IgA level was low at 37.6 mg/L (normal,
51.6-931). Urinalysis was normal and no infectious agents
were identifi ed in stool specimens. Clostridium diffi cile toxin
was negative in feces.
Chest X-ray revealed no abnormalities such as
pneumonia and interstitial pneumonitis. Abdominal plain
X-ray revealed a small amount of bowel gas without
formation of air-fl uid level or free air and no toxic dilation
of the colon was seen. Hand X-rays revealed bilateral
involvement of most metacarpal phalangeal joints with
destruction and deviation, whereas systemic skeletal X-ray
study showed no abnormalities in cervical and lumbar
spine and hip joints. Barium enema showed disappearance
of haustra coli, narrowing and shortening of the affected
colon, and uneven surface with spiculation, extending from
the rectum to the distal transverse colon (Figure 1). The
terminal ileum and the ascending and proximal transverse
colon were intact. Barium study of the small intestine and
upper gastrointestinal endoscopy were normal. Contrast
computed tomography of the abdomen and pelvis showed
diffuse mural thickening of the affected colon. Initial
sigmoidoscopy performed on the next hospitalization
day revealed friable, edematous mucosa with granularity,
mucous exudates and spontaneous bleeding throughout
the rectum and sigmoid colon. Diffuse erosions and
punctate ulcers were noted with lack of normal-appearing
intervening mucosa (Figure 2A). Histopathology of
colorectal biopsies showed diffuse mucosal infi ltration of
infl ammatory cells, deformed atrophic crypts, goblet cell
depletion and crypt abscess (Figure 3). No granulomas,
inclusion bodies, vasculitic lesions or amyloid deposits
were detected under microscopic examination of
hematoxylin-eosin and Congo-red stained sections (data
not shown). Based on the clinical, radiological, endoscopic,
and histopathological fi ndings, the patient was diagnosed
as having severe active, left-sided UC.
Under total parenteral nutrition, she received a course
of intravenous methylprednisolone pulse therapy (1
g/d for 3 consecutive days), followed by large doses of
intravenous prednisolone, starting with 50 mg/d. Since
cytomegalovirus antigenemia was detected 7 d after
admission, she also received a 14-d course of intravenous
gancyclovir injection at 400 mg/d.
She also received leukocytapheresis (LCAP) therapy,
employing a commercially available leukocyte removal
column (Cellsorba, Asahi Medical, Tokyo) once a week
for 10 successive weeks. Such intensive treatment led to
dramatic improvement of clinical symptoms and signs
without any adverse reaction and to normalization of
laboratory tests. Follow-up colonoscopy 3 wk later revealed
marked improvement, and normal colonic mucosa at
discharge from the hospital three months after admission
(Figure 2B). The RA disease status was unchanged during
hospitalization and thereafter. At the last visit to the
outpatient clinic, 6 mo after discharge, the patient was still
Figure 1 Barium enema
shows loss of mucosal
pattern with speculation,
absent haustration,
narrowing and shortening
of the bowel, extending
from the rectum to the distal
transverse colon.
Figure 3 Histopathological examination of biopsied rectal mucosa showed severe
neutrophil infi ltration, goblet cell depletion and mild crypt abscess (hematoxylin
and eosin staining).
Figure 2 (A) Sigmoidoscopy revealed friable, edematous mucosa with granularity,
mucous exudates and bleeding throughout the rectum and sigmoid colon. Multiple
erosions and punctate ulcers were observed without normal-appearing intervening
mucosa. (B) Repeated colonoscopy before discharge revealed almost normal
mucosa from the distal transverse colon to the rectum.
A
B

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in complete remission of colitis under 10 mg/d of oral
prednisolone.
DISCUSSION
When colitis appears in RA patients, drug-induced colitis,
ischemic colitis due to vasculitis associated with RA and
secondary amyloidosis must be ruled out first [8-12]. It is
known that therapeutic agents for RA such as NSAIDs,
gold salts and D-penicillamine give rise to various types
of gastrointestinal complications, evidences indicate that
colitic lesions are associated with these anti-RA drugs[8-10].
Although Langer et al[9] reported a case of gold salts-
induced colitis resembling UC, our patient was not treated
with gold salts or NSAIDs. There are also reports on
D-penicillamine-induced colitis[10], with rapid recovery
after cessation of the agent. Although the patient had
used penicillamine for 6 years, colitis had never appeared.
Moreover, her colitis improved despite continuous use of
this drug. Thus, anti-RA medications are unlikely to be the
underlying cause of colitis in our patient.
Rheumatoid vasculitis (also known as malignant RA)
affects a variety of organs including kidneys, lungs and
gastrointestinal tract[13]. Previous studies indicate that
clinically apparent rheumatoid vasculitis occurs in less than
1% of RA patients and intestinal involvement is noted in
about 20% of such cases[11]. The gastrointestinal lesions
associated with rheumatoid vasculitis are characterized by
multiple sharply-defi ned ulcers, typically spared by normal-
appearing mucosa, with a predilection for the small
intestine, the sigmoid colon and cecum[8,11]. Burt et al[11]
described a patient with RA who had colonic vasculitis
presenting as pancolitis similar to UC. In that patient,
however, repeated colonoscopy following treatment with
prednisolone showed that the intervening mucosa among
superfi cial ulcers was normal, allowing differentiation of
colitis due to RA-related vasculitis from idiopathic UC.
Histopathological examination of multiple biopsies taken
from colorectal mucosa identifi ed no vasculitic lesions in
our patient, who showed no other vasculitic diseases such
as scleritis and interstitial pneumonitis[13,14].
Recent clinical studies have indicated that the incidence
of amyloidosis confirmed by biopsies in RA patients is
about 10%[12]. Kato et al[15] reported a suggestive case of
gastrointestinal amyloidosis secondary to RA manifested
as pancolitis resembling UC. In our patient, however, rectal
biopsy specimens showed diffuse infiltration of mono-
and poly-nuclear leukocytes and crypt abscess, which were
compatible with UC, but no intramucosal amyloid deposits.
In addition, neither microbiological nor histopathological
examinations showed any pathognomonic fi ndings in this
case, thus allowing differentiation between UC and other
possible infl ammatory bowel conditions.
Being diagnosed as having severe active UC extending
to the left-side colon, the patient was treated with
intravenous methylprednisolone and subsequently with
prednisolone. Given that the patient had already received
oral prednisolone even at 30 mg/d with exacerbation of
UC, she was also treated with LCAP. In previous studies,
LCAP frequently led to significant improvement of UC
that had been intractable to steroids[16,17]. A recent open-
label multicenter study demonstrated that LCAP can be
more effective than high-dose steroid treatment with fewer
adverse effects[17]. Currently, LCAP is used as a treatment
modality for active UC. Although histopathological
examination of colorectal biopsies showed no inclusion
bodies, cytomegalovirus antigenemia was detected,
allowing our patient to undergo additional treatment with
intravenous gancyclovir. We believe that the intensive
combination therapies led to complete clinical and
endoscopic remission of severe and steroid-refractory
colitis.
Arthritic manifestations represent the most common
extraintestinal manifestations of inflammatory bowel
diseases, affecting 31% and 36% of patients with UC and
Crohn’s disease, respectively[5]. Coexistence of RA and
UC is, however, rare and no more than 0.14% to 0.8%
of UC patients suffer from RA[4,18]. Larger population-
based studies are warranted to unravel the mechanisms
underlying the association between UC and RA. In this
regard, accumulation of HLA data may provide a potential
clue for this relationship[19].
In the present case, serum concentrations of IgA,
but not IgG or IgM, were constantly low ranging from
1 to 20 mg/dL and reduction of secretory IgA in saliva
was also noted during hospitalization. Systemic and local
reduction of IgA might result in weakening of the mucous
barrier against intestinal fl ora and enhance exposure of the
mucosal immune system to intestinal bacteria or the toxic
components, eventually leading to sustained infl ammation
within the colorectal mucosa[4]. However, the precritical
serum IgA level had not been estimated in our patient, and
the etiology of selective IgA defi ciency remains elusive as
to whether it occurred primarily or not. In fact, secondary
IgA deficiency may be caused by such anti-RA drugs
as D-penicillamine, steroids, both of which had been
prescribed for her RA, sulfasalazine and gold salts[7,20].
Liblau et al[6] reported that the frequency of
autoimmune diseases in IgA deficient patients ranged
from 7 to 36%, supporting the notion that selective IgA
deficiency may be a risk factor of organ-specific and
systemic autoimmune diseases. A recent study showed
that the prevalence of IgA defi ciency in RA patients was
quite low (0.3%)[6], whereas Badcock et al[7] reported that
IgA defi cient patients were more likely to have a history of
RA in the fi rst-degree relatives, suggesting inheritance of
predisposing factor(s). Of note, Snook et al[4] reported that
6.6% of UC patients had at least one autoimmune disorder
and the prevalence of a specifi ed group of autoimmune
disorders was three times greater than expected in patients
with UC.
In conclusion, we described the first case of RA,
complicated with UC and selective IgA deficiency.
Underlying immune dysfunction, possibly in addition
to genetic predisposition, might play a role in these
associations.
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