Arthralgia is a common extraintestinal manifesta-
tion of inflammatory bowel disease (IBD). Alterations
of the immunologic regulation in the gut may con-
tribute to the pathogenesis of arthralgia. Probiotics
(VSL#3) have proven effective in the treatment of
pouchitis in patients with ileal pouch anal anasto-
mosis after panproctocolectomy for ulcerative coli-
tis both in maintaining remission and in preventing
a flare-up without side effects. The aim of this study
was to determine the safety and efficacy of VSL#3
in patients with quiescent IBD who suffered from
arthralgia for more than two weeks. An open-label
trial was conducted using VSL#3. Pre- and post-
treatment joint pain intensity were measured on the
Ritchie Articular Index and visual analog scale.
Disease activity of the bowel was assessed by the
Truelove-Witts and the Harvey-Bradshaw scores.
Sixteen of 29 patients completed the trial; in 10 of
the 16 patients a statistically significant improve-
ment was documented by the Ritchie Articular
Index. No one of the patients had a relapse of in-
testinal disease while on probiotics. These prelimi-
nary results suggest that the probiotic mixture
VSL#3 may be an alternative treatment for arthral-
gia in patients with IBD without inducing exacerba-
PROBIOTICS (VSL#3) IN ARTHRALGIA IN PATIENTS
WITH ULCERATIVE COLITIS AND CROHN’S DISEASE:
A PILOT STUDY
Ouafae Karimi1, A. Salvador Peña1,2 and Adriaan A. van Bodegraven2
1Laboratory of Immunogenetics and 2Department of Gastroenterology,
VUmc, Amsterdam, the Netherlands
Drugs of Today 2005, 41 (7): 453-459
Copyright © 2005 PROUS SCIENCE
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
Study population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
Arthralgia scores and outcome measures . . . . . . . . . . . . . . . . . . . . . 455
Study design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458
Correspondence: A.A. van Bodegraven, VU University
Medical Center, Department of Gastroenterology, P.O.
Box 7057, 1007 MB Amsterdam, the Netherlands.
Tel.: +31 20 444 0613; FAX: +31 20 444 0554;
Available on the web at: www.prous.com/journals
tion of the disease. Because probiotics may be ef-
fective in the treatment of IBD as well, our results
suggest that patients with active disease and
arthralgia may also derive benefit from this treat-
ment. Proper randomized controlled studies are in-
dicated. © 2005 Prous Science. All rights reserved.
Spondylarthropathies (SpA) of the peripheral
and the axial joints, including arthritis and arthralgia,
are common extraintestinal manifestations in in-
flammatory bowel disease (IBD). These disorders
are reported to occur in 10–35% of patients from
various studies (1, 2). They are part of the seronega-
tive, nonerosive and nondeforming arthropathies
(3). Thomas et al. found that pouchitis and symp-
toms of the joints occurred more frequently in ul-
cerative colitis patients than in patients with famil-
ial polyposis (4).
The etiology of arthralgia in IBD is still unclear.
In many patients arthralgia is not related to disease
activity. A link with Gram-negative enterobacteria in
association with IBD was confirmed in several stu-
dies (5, 6). The involvement of Yersinia and Salmo-
nella in reactive arthritis (7, 8), as well as that of
Shigella and Campylobacter spp. has been reported.
The clinical presentation of IBD-related SpA re-
sembles reactive arthritis resulting from acute bac-
terial infection with these species. Klebsiella spe-
cies have been associated with ankylosing spon-
dylitis, based on increased serum antibody titers
Increased intestinal permeability is often ob-
served in patients with IBD and in SpA (11). The re-
sulting increased intestinal mucosal leakage may
lead to an increased bacterial translocation, which
in turn leads to bacterial mimicry depending on an
increased absorption of antigens such as in Kleb-
siella infections with activation of the immune sys-
tem (12–14). Transport of these and other antigens
from gut to joint has been hypothesized based on
their activation of lymphocytes whose lymphoid-tis-
sue trafficking and recruitment are regulated by ad-
hesins and homing molecules. The role of activat-
ed intestinal T lymphocytes as precursor of this dis-
order has been reported in several studies (15–17).
Treatment of IBD-associated SpA may be difficult;
nonsteroidal anti-inflammatory drugs (NSAIDs) are
often effective, but they can induce a flare-up of in-
testinal inflammation (18), whereas COX-2–specif-
ic inhibitors may be contraindicated due to proco-
agulative potential (19, 20).
Because the effects of probiotics in the treat-
ment of ulcerative colitis and Crohn’s disease is
being studied at present, we wanted to restrict this
preliminary study to patients with arthralgia who
are in IBD remission for the reasons described
An open-label pilot study was carried out at an
Amsterdam referral university hospital gastroen-
terology outpatient department. According to local
law and regulations, probiotics are considered to
be a nutritional supplement for which pharmaceuti-
cal ethical evaluation is not warranted. The assess-
ment of effects of this supplement as described in
this paper together with the patient information form
with consent procedure were discussed with and
approved by the president of the institutional med-
ical ethical committee.
Participants were recruited from February 2003
through February 2004. Inclusion criteria required
patients with quiescent IBD, aged 18–70 years,
providing informed consent. IBD was classified ac-
cording to the criteria of Lennard-J ones (21). Quies-
cent disease was defined as quiescent or mild dis-
ease according to the Truelove-Witts score for ul-
cerative colitis (22) in combination with a normal
C-reactive protein level, and a Harvey-Bradshaw
score for Crohn’s disease lower than 5 (23). Further-
more, two patients had an ileostomy for which an
adjusted Harvey-Bradshaw score was used. Com-
plaints of arthralgia must have been present for
more than 2 weeks with stable medical therapy.
Regarding the exclusion criteria, the following
medications were not permitted to be changed in the
indicated period: mesalamine (<2 weeks), steroids
(<last 4 weeks), azathioprine (<12 weeks), metho-
trexate (<8 weeks), initiation of first infliximab course
during the last 12 weeks. Patients with arthritis
were excluded on the presence of redness, syn-
ovial thickening, joint edema or joint dysfunction
during physical examination, and the presence of
signs of inflammation in the laboratory investiga-
tions. We also excluded patients using NSAIDs,
pregnant patients and those with expected non-
compliance. All patients were examined by the
same investigator. A total of 16 of the 29 patients
with quiescent IBD and stable medical therapy who
met the inclusion criteria completed the trial. The
patients received two VSL#3 sachets per day, each
454Probiotics (VSL#3) in arthralgia in patients with ulcerative colitis and Crohn’s disease
containing 450 billion viable lyophilized bacteria of
four strains of Lactobacillus, three strains of Bifido-
bacterium, and one strain of Streptococcus salivar-
ius subsp. Thermophilus. This probiotic mixture
was produced by VSL Pharmaceuticals Inc., Fort
Lauderdale, FL, USA, and distributed by Sigma
Tau Ethipharma, Assen, the Netherlands.
Arthralgia scores and outcome measures
The assessment of pain is known to be subjec-
tive. In order to make a quantitative objective asses-
sment of pain, we chose the Ritchie Articular Index
(RAI) as a primary outcome measure and used in-
tensity and changes in tenderness to quantify pain.
All 53 joints were assessed separately (24). How-
ever, the proximal interphalangeal and metacar-
pophalangeal joints of each hand, the metatarso-
phlangeal joints of each foot, the temporomandibu-
lar joints, the sternoclavicular joints and the
acromyoclavicular joints were calculated as a sin-
gle unit. The highest score for a single joint gave
the score for the group. The joints were graded for
tenderness on a 0–3 scale, with 3 being maximal
tenderness: 0 = patient had no tenderness; 1 = pa-
tient complained of pain on pressure; 2 = patient
complained of pain and winced; 3 = patient com-
plained of pain, winced and withdrew.
The visual analog scale (VAS) score indicated
the intensity of the patients’ subjective joint pain.
The highest VAS score meant no arthralgia. De-
creasing scores accompanied increasing joint pain
All subjects followed the treatment protocol for
3 months. Treatment with VSL#3 b.i.d. was initiat-
ed following the assessment of severity of both IBD
and arthralgia. Arthralgia was assessed by both
RAI and VAS scores, which were measured at
baseline. VAS was applied the week before as-
sessment (VAS I) and on the day of the assess-
ment (VAS II). Prior treatment for IBD, as initiated
by the clinician according to each patient’s clinical
condition, remained unchanged. At week 6, as-
sessments of complaints were conducted by tele-
phone interview and the patients were asked to
complete VAS I and VAS II as described above. At
week 12, arthralgia was reassessed by RAI and
VAS scores, as was the disease activity according
to the Harvey-Bradshaw or Truelove-Witts score in
the outpatient department. Treatment compliance
was checked by counting the remaining dosage of
VSL#3. Laboratory parameters (erythrocyte sedi-
mentation rate, C-reactive protein, hemoglobin,
hematocrite, mean corpuscular volume, platelet
count, leukocyte count, sodium, potassium, kreati-
nine, γ-GT, alkaline phosphatase and alanine trans-
ferase) were evaluated at baseline and at week 12.
Safety was reviewed by analyzing the inci-
dence of adverse events, including clinically signif-
icant laboratory abnormalities defined by the Modi-
fied World Health Organization (WHO) Common
Toxicity Grading Scale. Adverse events were de-
fined as any untoward, undesired, unplanned clini-
cal event in the form of signs, symptoms, disease,
or laboratory or physical observations occurring in a
patient during the period of treatment with VSL#3,
and 30 days afterward. Adverse events were clas-
sified according to the Modified WHO Common
Toxicity Grading Scale.
Statistical analysis was performed using Instat
3 software. The baseline and follow-up data were
compared by Wilcoxon matched-pair U-signed-
ranks test and paired Student’s t-test when appli-
cable. The significance of RAI and VAS scores was
determined by the p value of the results. The level
of statistical significance was set at p <0.05.
Of the 29 patients included in our study, 13 (10
women and 3 men, aged 30–59 years) failed to
complete the protocol. There were nine cases of
Crohn’s disease and four cases of ulcerative coli-
tis, with a period of intestinal disease varying from
5–37 years. Six patients had a surgical history.
Seven patients withdrew informed consent due to
personal reasons (three patients), spontaneous
improvement (two patients) and rhinitis, which had
been present before initiation of probiotic treatment
(one patient). One of two patients with an ileosto-
my bag had handling problems with the ileostomy
and discontinued the probiotics after three days.
The other six patients withdrew due to distaste (two
patients), nausea (one patient), mild to moderate
abdominal bloating (one patient), non–IBD-related
deterioration of general well-being (one patient) and
nonspecific gastrointestinal symptoms (one patient).
Sixteen patients (13 women and 3 men, aged
29–63 years) completed the 3-month protocol
(Table I). There were nine cases of Crohn’s dis-
ease and seven cases of ulcerative colitis, with a
period of intestinal disease varying from 1–29
O. Karimi, A.S. Peña and A.A. van Bodegraven455
years. Two patients had a surgical history. Accord-
ing to the WHO Common Toxicity Grading Scale,
none of the adverse events exceeded Grade 1.
In this group, a significant decrease of the RAI
was observed, from a median of 11 (0–28) to 5.5
(0–18) (p = 0.02) (Table II). VAS I score indicated
the patients’ subjective pain intensity score in the
week before assessment. The average VAS I
score was 57 (SD 22) at the start of the study, 72
(SD 24) at week 6 and 58 (SD 29) at the end of the
study. VAS II score indicated the patients’ subjec-
tive pain intensity score at the moment of assess-
ment. The average VAS II score was 66 (SD 24) at
the start of the study, 76 (SD 27) at week 6 and 73
(SD 28) at the end of the study. Results of both
the VAS I and VAS II scores were not significant
Five patients reported improvement of gastroin-
testinal symptoms, with concomitant increase of
general well-being. Two patients reported nausea
at the beginning, but completed the trial. Decrease
in gastrointestinal symptoms leading to improve-
ment in general well-being was reported as an un-
expected positive effect by three patients.
The results showed a difference for axial and
peripheral arthralgia. Patients with peripheral arthral-
gia reported improvement of their joint complaints
as well as improvement in their general well-being.
However, patients with axial arthralgia reported no
improvement of arthralgia.
Treatment compliance was checked by count-
ing the remaining dosage of VSL#3, and was high
for those patients participating for 3 months. All pa-
tients completed the dosage of VSL#3. We found
no changes in laboratory results between baseline
and week 12. According to the WHO Common Toxi-
city Grading Scale, none of the reported adverse
events exceeded Grade 1.
This pilot study showed a significant improve-
ment in arthralgia in patients with quiescent IBD
who used the probiotic mixture VSL#3. The improve-
ment was objectively assessed by RAI scores.
VAS scores did not change significantly and re-
mained unchanged in this group of patients, who
were in remission of IBD and had only arthralgia as
a complaint. It is interesting that only 16 patients of
the 29 who met the inclusion criteria completed the
trial successfully. This withdrawal rate has not
been observed in previous VSL#3 trials under oth-
er conditions, for example in patients with pouchi-
tis (25). No one of the total group of patients who
completed the 3-month trial had a relapse of the in-
testinal disease, and three patients reported better
To our knowledge, the exploration of the re-
sponse of peripheral joint involvement in IBD with-
in our open-label study has not been previously re-
ported. It allows an estimation to be made of the
therapeutic potential of probiotics for this indica-
tion. Therefore, a randomized placebo-controlled
456 Probiotics (VSL#3) in arthralgia in patients with ulcerative colitis and Crohn’s disease
Table I. Baseline characteristics of study participants
(n = 16).
Characteristics Number of patients*
Age, mean (SD)
Duration of IBD, mean (SD), years
*Age and duration of IBD are presented as mean (SD).
Table II. Baseline and change in Ritchie Articular Index
(n = 16).
BaselineWeek 12p value*
Ritchie Articular Index11 (0–28)5.5 (0–18)0.02
*See “Methods” section for complete description of meth-
Table III. Baseline and change in visual analog scale (VAS) scores after treatment, by weeks.
Mean (SD) VAS score (n = 16)
BaselineWeek 6 Week 12p value*
*See “Methods” section for complete description of methods used; NS = not significant.
trial is necessary to further confirm the efficacy of
VSL#3 or other probiotics in the management of
arthralgia in IBD. With the experience reported
here we believe that probiotics also should be tried
in patients with reactive arthritis or arthralgia.
In contrast to a few years ago, different prepa-
rations of probiotics are now available. Based on
several recent studies it is clear that not all probi-
otics have the same therapeutical effects for dis-
eases. The differences in therapeutical effects be-
tween single strains or mixtures of probiotics need
to be addressed. The lumen of the intestine con-
tains bacteria, bacterial products, and dietary anti-
gens capable of initiating and sustaining inflamma-
tion. The healthy intestinal epithelium provides a
relatively impermeable barrier to these luminal
The beneficial effects on human health of such
probiotics as lactic acid bacteria, based on improv-
ing the intestinal microbial balance, have already
been described for decades, though the mecha-
nisms by which they exert these beneficial effects
remain to be elucidated (27).
Cross-talk between bacteria and between bac-
teria and antigen-presenting cells of the intestine
seem to play an important role in controlling over-
growth of potentially pathogenic microorganisms
with a bacterial, viral or fungal origin. Adhesion and
colonization lead to immune modulation, which in
turn helps to enhance leukocyte phagocytic activi-
ty against enterobacteria. Survival during intestinal
transit also appears to be important for modifying
the host’s immune reactivity by regulation of the bal-
ance between pro-inflammatory and anti-inflam-
matory cytokines (26). Furthermore, there is evi-
dence for increasing intestinal permeability in exper-
imental models with ulcerative colitis and Crohn’s
disease, in which probiotics have been shown to en-
hance the intestinal barrier function (28).
VSL#3 treatment was demonstrated to reduce
colonic permeability in both IL-10 gene-deficient
mice and control mice, suggesting that the type
and quantity of bacterial species in the colon mod-
ulate intestinal permeability (29, 30). Furthermore,
VSL#3 was able to induce a significant increase in
the expression of the anti-inflammatory cytokine IL-
10 in the mucosal pouch compared to inflamed and
antibiotic-treated patients (31). Probiotic VSL#3
appears to reduce gut mucosa inflammation by
blocking NF-κB activity and increasing cytoprotec-
tion through heat-shock-protein induction, mediat-
ed by inhibition of proteasome (32).
More recently, the probiotic Lactobacillus rham-
nosus GG (LGG) was found to induce COX-2 ex-
pression in human T 84 colon epithelial cells (33).
The importance of COX-2–dependent arachidonic
acid metabolites as immunoregulatory factors in
the intestinal mucosa is supported by the observa-
tion that NSAIDs exacerbate clinical activity in hu-
man IBD (34, 35). COX-2–dependent arachidonic
acid metabolites are essential in the development
and maintenance of intestinal immune homeosta-
sis (36). LGG has been used in patients with
rheumatoid arthritis for 12 months. The mean num-
ber of tender and swollen joints decreased from 8.3
to 4.6 in the Lactobacillus group and from 5.5 to 4.8
in the placebo group. Although there were no sta-
tistically significant differences in rheumatoid arthri-
tis activity, more subjects in the LGG group report-
ed subjective well-being (37).
Interestingly, the beneficial effects of LGG both
in prevention and treatment of T-cell–dependent
experimental arthritis were demonstrated in two
animal models, thus providing experimental evi-
dence of probiotic use in arthropathies (38). In an-
other experimental model, subcutaneous adminis-
tration of L. salivarius 118 significantly attenuated
colitis in the IL-10 knockout model and suppressed
collagen-induced arthritis. This study suggested
that the oral route may not be essential for probiot-
ic anti-inflammatory effects (39). However, care
should be taken in extrapolating results obtained in
animal models to patients with IBD.
Although the safety of probiotics containing lac-
tobacilli and bifidobacteria has been evaluated crit-
ically, and although they were considered to be at
least as safe as appropriate traditional reference
food products without evidence suggesting risk of
infection (40), one has to take into consideration
that not all probiotic bacteria have similar thera-
Moreover, the many documented effects of pro-
biotics on inflammatory processes notwithstanding,
the specific therapeutic mechanism of VSL#3 that
may induce beneficial effects in IBD-associated
arthralgia is yet unclear. As recently stated by Fe-
dorak and Madsen (41), “Rigorously designed,
controlled clinical trials are vital to investigate the
unresolved issues related to efficacy, dose, dura-
tion of use, single- or multistrain formulation, and
the concomitant use of probiotics, synbiotics or an-
O. Karimi, A.S. Peña and A.A. van Bodegraven457
The authors would like to acknowledge the
support of VSL Pharmaceuticals Inc., Fort Lauder-
dale, FL, USA, for a grant to Mrs. O. Karimi; and
Sigma Tau Ethipharma, Assen, the Netherlands,
for providing the VSL#3 sachets. We would also
like to acknowledge the support of the Foundation
of Immunogenetics and the critical reading of the
manuscript by Prof. C. de Simone, from the Uni-
versity of L’Aquila, L’Aquila, Italy.
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