International Journal of Rheumatic Diseases 2017

ORIGINAL ARTICLE

A randomized controlled trial to study the efficacy of

sulfasalazine for axial disease in ankylosing spondylitis
Shefali KHANNA SHARMA, Vikas KADIYALA, Gsrsnk NAIDU and Varun DHIR
1
Departments of Internal Medicine, Unit of Clinical Immunology and Rheumatology, Post-Graduate Institute of Medical Research
(PGIMER), Chandigarh, India

Abstract
Aim: To evaluate efficacy of sulfasalazine for axial ankylosing spondylosis.
Methods: 67 patients fulfilling the inclusion criteria were included and randomized into treatment and placebo
group.
Results: Mean age in treatment group was 31 years (range: 17–60); placebo group was 30 years (18–46). Mean
disease duration treatment group 8.4 years (range: 3–25) and placebo group was 8.3 years (3–19). Clinically sig-
nificant improvement in ASDAS (DASDAS > 1.1) seen in 15.1% of placebo and 67.7% in treatment group
(P = 0.001). The mean  SD of DASDAS in treatment group was 1.33  0.38 (range: 0.9–2.3) where as in pla-
cebo group it was 0.748  0.23 (0.4–1.3) with significant difference (P = 0.00). The mean  SD of DBASDAI
of treatment group was 3.29  0.97 (range: 1.5–5.5) placebo group was 1.47  0.99(0.5–4.5) with P = 0.00.
The mean value of DBASMI of drug group 3.29  0.97(range: 1.8–5) and of placebo group was 1.47  0.99
(0.6–3.7) with (P = 0.00). Clinical improvenent in (DASDAS > 1.1) was observed in patients of both the groups
with disease duration ≤ 4 years. However it was significantly higher in treatment group (P = 0.04). Highly sig-
nificant improvement in (DASDAS > 2) was observed in two of five patients in treatment group with disease
duration ≤ 4 years.
Conclusion: Sulfasalazine is effective in axial AS esp. in younger patients (< 25 years), disease duration
< 4 years at the time of initiation of treatment and high disease activity (BASDAI > 7, CRP > 50 mg/L). This sig-
nifies early diagnosis and treatment is very important in management and prevention of disease progression.
Key words: ankylosing spondylitis, ankylosing spondylitis, drug treatment.

INTRODUCTION during the course of the disease.2,3 Extra-articular mani-

festations include acute anterior uveitis, aortic incompe-
Axial spondyloarthritis (ax-SpA) is a chronic inflamma-
tence, cardiac conduction defects, renal involvement
tory disease of unknown etiology, characterized by
and inflammatory bowel disease.3
sacroiliac joint and axial skeletal involvement, and is
Non-steroidal anti-inflammatory drugs (NSAIDs) are
associated with human leukocyte antigen (HLA) B-27
the first line of treatment for axial disease along with
in the majority of the patients. Ax-SpA accounts for
regular exercise.4 In patients with persistently high dis-
about 5% of patients suffering from chronic low back
ease activity despite conventional treatment, anti-tumor
pain.1 Peripheral joint involvement, other than hips
necrosis factor a (anti-TNFa) therapy should be given
and shoulders, can be seen in about 30–40% of patients
according to the Assessment of Spondyloarthritis Inter-
national Society/European League Against Rheumatism
Correspondence: Dr Shefali Khanna Sharma, Department of (ASAS/EULAR) recommendations for management of
Internal Medicine, Post-Graduate Institute of Medical Research ankylosing spondylitis.4 Disease-modifying antirheu-
(PGIMER), Chandigarh, India. matic drugs (DMARDs), like sulfasalazine (SSZ) and
Email: sharmashefali@hotmail.com

© 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd
S. Sharma et al.
methotrexate are useful in peripheral arthritis but not
in axial disease.4 However, in resource-constrained set-
tings, like in India, most patients who do not obtain
improvement with NSAIDs may not be able to afford
anti-TNFa therapy. In such situations, it may perhaps
be prudent to try less expensive drugs like sulfasalazine
to attain symptomatic relief. Use of SSZ in axial disease
was studied by Dougados et al.5 who showed that the
use of SSZ decreased consumption of NASIDs and
improved functional index and patient global assess-
ment in these patients. The present trial was undertaken
to study the efficacy of sulfasalazine in relieving axial
symptoms in patients with ax-SpA.
PATIENTS AND METHODS
Patients with ax-SpA attending the Rheumatology
Clinic, Post-Graduate Institute of Medical Research
(PGIMER), Chandigarh, a tertiary care hospital in north
India, were included in the study. Inclusion criteria
were: (i) age ≥ 18 years; (ii) active disease, defined by
Bath Ankylosing Spondylitis Disease Activity Index
(BASDAI) of ≥ 4;6 and (iii) predominant axial involve-
ment. We considered patients with no peripheral joint
involvement or with involvement of ≤ 1 peripheral
joints anytime during the course of the disease as hav-
ing predominant axial involvement. Exclusion criteria
were: (i) pregnant or lactating women; (ii) patients
already taking corticosteroids or other immunosuppres-
sants; (iii) patients allergic to sulfa drugs; (iv) glucose 6-
phosphatase dehydrogenase (G6PD) deficiency; (v)
presence of active infection; and (vi) any co-morbid sys-
temic illness which hampered their participation in the
study.
Patient assessment
Detailed clinical examination of the patients was done
at baseline by the primary investigator (VK). Laboratory
investigations included hemogram, renal function tests
(RFTs, blood urea and serum creatinine), liver function
tests (LFTs, serum bilirubin, alanine transaminase,
aspartate transaminase, alkaline phosphatase, serum
albumin), erythrocyte sedimentation rate (ESR), C-reac-
tive protein (CRP) and G6PD levels. Disease activity
and functional status were assessed with BASDAI, Bath
Ankylosing Spondylitis Metrology Index (BASMI), Bath
Ankylosing Spondylitis Functional Index (BASFI) and
Ankylosing Spondylitis Disease Activity Score (ASDAS)
at baseline and at 6 months of therapy. Patients were
followed up with hemogram, RFTs, LFTs, ESR and CRP
at 3 and 6 months of therapy.
2 International Journal of Rheumatic Diseases 2017
Study design
This was a randomized, double-blind, placebo con-
trolled, single-center trial, performed between May,
2012 and April, 2013. Patients attending the Rheuma-
tology Clinic at our institute were randomized to
receive either sulfasalazine or placebo in a 1 : 1 ratio.
Randomization was done using computer-generated
random numbers and block randomization method
with variable block sizes was used. Patients and the pri-
mary investigator (VK) were blinded to treatment allo-
cation. The drugs were dispensed by a separate doctor
(SKS, for the entire duration of the study), and was not
involved in recruiting and assessing the patients into
the trial. The study protocol was reviewed and approved
by the Institute Ethics Committee. No financial incen-
tive or compensation was provided to the patients for
participation in the study. The flow chart of the
patients’ recruitment is shown in Figure 1.
Treatment
All the patients included in the trial were advised to
take etoricoxib 90 mg once a day with no extra on-
demand NSAIDs. Standard physiotherapy was advised
to all the patients and was explained to the patients in
the physiotherapy department of our institute. The
study drug group was started on SSZ 500 mg twice a
day, which was increased by 500 mg weekly to a target
dose of 2 g/day. The control group was given similar-
looking placebo. The total duration of therapy was
6 months. Both the study drug (SSZ) and placebo were
provided free of cost to the study participants, by Ipca
Laboratories Limited.
Outcomes
The primary outcome measure was the difference in
change in ASDAS from baseline to 6 months between
the treatment and control groups. Secondary outcome
measures were difference in changes in BASDAI and
BASMI from baseline to 6 months between the two
groups, difference in response to treatment based on
duration of disease as measured by changes in ASDAS
and BASDAI.
Statistical analysis
The sample size was calculated to detect a difference in
change in ASDAS of 0.7 points between the two groups,
with a power of 80%, a of 0.05 and a standard devia-
tion (SD) of 1.0. The sample size was calculated to be
68 patients, who were randomized into the two groups
in a 1 : 1 ratio. Continuous variables were reported as
 Sulfasalazine for axial disease in ankylosing spondylitis

500 patients of AS screened

433 patients were excluded

• BASDAI <4 in 210
• >1 peripheral joint involvement in 205
• G6PD deficiency in 3
• On corticosteroids in 18

67 patients were included in the study

33 patients assigned to 34 patients assigned to

SSZ group placebo group

31 patients completed 6 33 patients completed 6

months therapy months therapy
two patients lost to follow up one patient lost to follow up

Figure 1 Flowchart showing randomization and follow up of patients. AS, ankylosing spondylitis; BASDAI, Bath Ankylosing
Spondylitis Disease Activity Index; G6PD, glucose 6-phosphatase dehydrogenase; SSZ, sulfasalazine.

mean value and SD while the categorical variables were
expressed as percentages and proportions. Student’s t-
test was used for comparison of means of continuous
variables between the two groups. Wilcoxon signed rank
test was performed to compare the changes in ASDAS,
BASDAI, BASMI, BASFI and CRP from baseline to after
6 months of therapy in both SSZ and placebo groups. A
P-value of less than 0.05 was taken as significant.
RESULTS
Sixty-seven patients were randomly assigned to either
the treatment (n = 33) or placebo (n = 34) group. Two
patients in the treatment group and one patient in the
placebo group were lost to follow up and were excluded
from analysis. The age at presentation, duration of ill-
ness, disease activity scores, CRP levels at baseline were
similar between both the groups (Table 1). Most of the
patients (87.5%) had very high disease activity accord-
ing to ASDAS, with a mean value of 4.11 (SD 0.46) in
the treatment group and 4.07 (SD 0.41) in the placebo
group. Patients were stratified into three groups based
on the duration of disease onset: duration less than
4 years, between 4 and 7 years and more than 7 years.
These cutoffs were chosen arbitrarily to see if disease
duration had any effect on the efficacy of the drug. The
distribution of patients according to disease duration in
both groups is shown in Table 1.

International Journal of Rheumatic Diseases 2017 3

S. Sharma et al.

Table 1 Baseline characteristics of the study population Table 2 Results of Wilcoxon signed rank test
Characteristic SSZ group Placebo group P-value Parameter Z score Two tailed P-value
(n = 31) (n = 33)
ASDAS – treatment group 4.873 < 0.001
Age, years 31.32  10.12 30.70  8.46 0.79 ASDAS – placebo group 5.026 < 0.001
Duration of 8.40  3.94 8.36  5.01 0.92 BASDAI – treatment group 4.864 < 0.001
disease, years BASDAI – placebo group 5.019 < 0.001
CRP, mg/L 43.16  11.85 41.38  13.41 0.57 BASMI – treatment group 4.931 < 0.001
BASDAI 6.59  1.07 6.43  1.04 0.54 BASMI – placebo group 5.286 < 0.001
ASDAS 4.11  0.46 4.07  0.413 0.76 BASFI – treatment group 4.707 < 0.001
BASMI 6.32  1.077 6.21  1.053 0.68 BASFI – placebo group 5.021 < 0.001
BASFI 5.81  1.138 5.70  1.104 0.69 CRP – treatment group 4.863 < 0.001
Patients with 5 5 – CRP – placebo group 5.017 < 0.001
duration of
CRP, C-reactive protein; BASDAI, Bath Ankylosing Spondylitis Disease
disease < 4 years, Activity Index; ASDAS, Ankylosing Spondylitis Disease Activity Score;
n BASMI, Bath Ankylosing Spondylitis Metrology Index (BASMI); BASFI,
Patients with 13 10 – Bath Ankylosing Spondylitis Functional Index.
duration of
disease 4–7 years,
n disease activity. In the placebo arm, 29 patients had
Patients with 13 18 – very high disease activity at baseline and at 6 months,
duration of 15 (51.7%) patients still had very high disease and
disease > 7 years, 14 (48.3%) had high disease activity. The mean CRP
n at 6 months of therapy was 23.94 mg/L (SD 8.47) in
SSZ, sulfasalazine; CRP, C-reactive protein; BASDAI, Bath Ankylosing
the treatment group and 29.82 mg/L (SD 8) in the
Spondylitis Disease Activity Index; ASDAS, Ankylosing Spondylitis placebo group.
Disease Activity Score; BASMI, Bath Ankylosing Spondylitis Metrology The mean change in BASDAI at 6 months of follow
Index (BASMI); BASFI, Bath Ankylosing Spondylitis Functional Index.
up was 3.29 (SD 0.97) in the treatment group compared
to 1.47 (SD 0.99) in the placebo group (P < 0.01). In
Efficacy the treatment group, 61.3% (19 out of 31) of patients
The primary outcome of the study was the mean had at least 50% reduction in BASDAI at 6 months of
change of ASDAS with treatment, which was 1.33 therapy compared to just 9.1% (three out of 33) of
(SD 0.38) in the treatment group compared to 0.75 patients in the placebo group. The mean change in
(SD 0.23) in the placebo group (P < 0.001). Clini- BASMI at 6 months was significantly higher in the treat-
cally significant improvement, defined as change in ment group as compared to the placebo group
ASDAS of > 1.1 over time with treatment, was seen in (3.10  0.87 vs. 1.32  0.88, P < 0.01). All the disease
67.7% of patients in the treatment group compared activity measures noted (CRP, ASDAS, BASDAI, BASMI,
to 15.1% in the placebo group (P < 0.001). None of BASFI), decreased significantly with 6 months of treat-
the patients in either group achieved remission, as ment in both the treatment and placebo groups. Results
measured by ASDAS of < 1.3. At the end of 6 months of Wilcoxon signed rank test are shown in Table 2.
therapy, in the treatment group, three (9.7%) patients Among patients who presented early in the course of
had moderate disease activity (ASDAS of 1.3–2.1), 24 disease (disease duration less than 4 years), the mean
(77.4%) patients had high disease activity (ASDAS of change in ASDAS with SSZ was 1.96 (SD = 0.38), which
2.1–3.5) and four (12.9%) patients had very high dis- was significantly higher than that observed with placebo
ease activity (ASDAS > 3.5). In the placebo group, (1.22  0.04, P = 0.004). However, there was no signif-
none of the patients achieved moderate disease activ- icant change observed in the mean BASDAI between the
ity, while 18 (54.5%) patients had high disease activ- two groups from baseline to 6 months (4.36  0.89 vs.
ity and 15 (45.5%) patients had very high disease 3.32  1.4, P = 0.199). Among those patients who pre-
activity. Among the 27 patients in treatment arm who sented with a disease duration of 4–7 years, the mean
had very high disease activity at baseline (as measured change in ASDAS was 1.37 (SD = 0.18) in the SSZ
by ASDAS > 3.5), four (14.8%) patients still had very group compared to 0.73 (SD = 0.15) in the placebo
high disease activity at 6 months, 22 (81.5%) had group (P < 0.005). The mean change in BASDAI was
high disease activity and one (3.7%) had moderate also significantly higher with SSZ compared to placebo

4 International Journal of Rheumatic Diseases 2017

 Sulfasalazine for axial disease in ankylosing spondylitis

(3.48  0.82 vs. 1.19  0.53, P < 0.005). In the treat-
ment group, mean change in ASDAS in patients with
disease duration more than 7 years was less compared
to that among patients with disease duration less than
4 years (1.05  0.19 vs. 1.96  0.38). However, the
mean change in ASDAS in the SSZ group was signifi-
cantly higher compared to that in the placebo group
(1.05  0.19 vs. 0.67  0.17, P < 0.005). The mean
change in BASDAI was also significantly higher with
SSZ as compared to placebo (2.68  0.72 vs.
1.12  0.25, P < 0.005).
DISCUSSION
NSAIDs are the first line of pharmacological treatment
in ax-SpA patients with predominant axial symptoms.
Anti-TNF drugs are found to be effective for axial symp-
toms in patients who do not respond to NSAIDs and
physiotherapy. However, the cost of anti-TNF therapy is
much higher compared to NSAIDs or non-biological
disease-modifying drugs like SSZ. In a country like ours,
where most patients may not be able to afford anti-TNF
drugs, alternate affordable and cheaper drugs need to
be evaluated for efficacy in ax-SpA. In this study, we
tried to study the efficacy of SSZ, as measured by
changes in ASDAS, BASDAI and BASMI, in ax-SpA
patients with predominant axial involvement.
In our study, the mean changes in disease activity
scores, including ASDAS, BASDAI, BASMI were signifi-
cantly higher with SSZ compared to placebo. Clinically
significant improvement, defined by a change in ASDAS
of more than 1.1 over time, was observed in 2/3 of the
patients taking SSZ. About 80% of patients treated with
SSZ had improvement in ASDAS from very high disease
activity to high disease activity, compared to only 48%
of patients with placebo. These results indicate that SSZ
is effective in reducing axial symptoms in patients with
ax-SpA. These findings were similar to those observed

Table 3 Comparison of salient features of previous studies with present study

Study No. of Duration of Treatment Peripheral Results
patients treatment arthritis
Dougados et al.6 60 6 months SSZ 30 pts Nil SSZ decreased consumption of NSAIDS (P < 0.05) and
Placebo 30 pts improved functional index and PGA
Nissila et al.7 85 26 weeks SSZ 43 pts 66% Significant improvement in morning stiffness VAS
Placebo 42 pts (P = 0.02), chest expansion (P = 0.03) and ESR
(P = 0.02) with SSZ
Kranjc et al.8 95 24 weeks SSZ 71 pts 66% Significant improvement in duration of morning
Placebo 24pts stiffness, chest expansion, number of painful/swollen
joints and ESR with SSZ
Clegg et al.9 264 36 weeks SSZ 131 pts 29% Decline in ESR more with SSZ
Placebo 133 pts In patients with peripheral arthritis, 55.9% patients on
SSZ and 30.2% patients on placebo had peripheral
response (P = 0.023)
Corkhill et al.10 62 48 weeks SSZ 32 pts 19% No difference in spinal pain VAS, spinal stiffness VAS,
Placebo 30 pts Schober’s test, chest expansion, ESR, peripheral joint
pain VAS
Kirwan et al.11 89 3 years SSZ 44 pts 28% Episodes of peripheral arthritis less with SSZ P < 0.05)
Placebo 45 pts No difference in effect on Schober’s test, chest
expansion, lateral cervical flexion, HAQ, back pain
VAS, PGA
Schmidt et al.12 70 26 weeks SSZ 34 pts 36% No difference in back pain VAS, pain / tenderness
Placebo 36 pts score, duration of morning stiffness, spondylitis
functional index, PGA, PhGA, Schober’s test, chest
expansion, ESR, number of swollen and tender joints
Present study 67 6 months SSZ 33 pts Nil Mean change in ASDAS (P < 0.001) and BASDAI
Placebo 34 pts (P < 0.01) was more with SSZ than placebo
ASDAS change > 1.1 seen in 67.7% of patients on SSZ
and 15.1% of patients on placebo (P < 0.001)
SSZ, sulfasalazine; NSAID, non-steroidal anti-inflammatory drug; VAS, visual analogue scale; ESR, erythrocyte sedimentation rate; HAQ, Health
Assessment Questionnaire; PGA, patient global assessment; PhGA, physician global assessment; ASDAS, Ankylosing Spondylitis Disease Activity
Score; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index.

International Journal of Rheumatic Diseases 2017 5

S. Sharma et al.
by Dougados et al.,5who randomized 60 patients with
active axial symptoms to receive either SSZ (2 g/day) or
placebo. Fifteen out of 30 patients in the SSZ group had
a good to very good response with 6 months of SSZ;
daily consumption of NSAIDs also decreased signifi-
cantly and the functional index improved. Nissila et al.7
have shown that SSZ (up to 3 g/day) was effective in
decreasing duration of early morning stiffness, ESR,
CRP and improved chest expansion. However, in that
study, the majority of the patients (68%) had periph-
eral joint involvement and presented early in the course
of disease. Similar findings were noted by Krajnc et al.8
in their study of 95 patients with ankylosing spondyli-
tis, with 66% of the patients having peripheral arthritis.
The results seen in our study are contrary to various
other studies published earlier. In one of the largest
studies, Clegg et al.9 randomized 264 patients with
ankylosing spondylitis to receive either SSZ or placebo
for 36 weeks and noted their effect on physician global
assessment, patient global assessment, back pain, morn-
ing stiffness, spondylitis function score, joint swelling
score, joint tenderness score, dactylitis score, enthesopa-
thy index, chest expansion, Schober’s test, occiput to
wall test, finger to floor test, ESR and CRP. About 29%
of patients in this study had peripheral arthritis. Over
all, there was no significant difference between the two
groups in all outcomes except ESR. However, in patients
with predominant peripheral involvement, SSZ was
found to have a favorable response. In another study
involving 62 patients with ankylosing spondylitis (with
19% of patients with peripheral arthritis) by Corkill
et al.,10 no significant difference was found between
SSZ and placebo in the measured outcomes. Similar
findings were noted by Kirwan et al. and Schmidt
et al.11,12 The systematic review, including 11 trials
using SSZ in patients with ankylosing spondylitis, con-
cluded that SSZ was beneficial in reducing ESR and
improving spinal stiffness but had no benefit in physi-
cal function, pain, spinal mobility, enthesitis and
patient or physician global assessments.13 In a review
by Kiltz et al.,14SSZ was found to be ineffective in
patients with ankylosing spondylitis when compared to
TNF inhibitors, especially in patients with predominant
axial disease. Table 3 shows the comparison of salient
features of previous studies with the present study.
Recent studies have shown that dysbiosis in gut
microbiome may contribute to the pathogenesis of
SpA.15 In developing countries like India, gut infections
are much more common and may contribute to dysbio-
sis in gut microbiome and may trigger development of
SpA. SSZ acts on the adenosine receptors and has anti-
6 International Journal of Rheumatic Diseases 2017
inflammatory effects.16 SSZ may also act locally in the
gut and help in normalization of gut dysbiosis, as evi-
denced by its efficacy in patients with inflammatory
bowel disease. Dysbiosis in gut-triggering development
of SpA and the effect of SSZ on correcting this dysbiosis
may explain the better response to SSZ in our patients.
In conclusion, SSZ, at a dose of 2 g/day, was shown
to be effective in symptom control in ax-SpA patients
with predominant axial involvement. The majority of
the patients had a significant improvement in disease
activity and functional scores as measured by ASDAS,
BASDAI and BASMI. The improvement was more
marked in those patients who presented early in the
course of disease. SSZ may be used as a cheaper and
effective alternative in ax-SPA patients with persistent
axial symptoms who cannot afford anti-TNF therapy.
However, a randomized trial with larger numbers of
patients is required to confirm the findings of our
study.
FUNDING
Ipca Laboratories Limited provided the drugs free of
cost for the trial. None of the authors received any
honorarium from the company. No travel grant or any
other form of compensation was provided by Ipca Lab-
oratories Limited to any of the investigators or the insti-
tute. No financial incentive or compensation was
provided to the study participants. Ipca Laboratories
Limited was not involved in data collection or data
analysis. Trade name of the study drug was not men-
tioned to the study participants.
ETHICS APPROVAL
The study involved only human participants and the
study protocol was approved by the Institute Ethics
Committee. The procedures followed were in accor-
dance with the ethics standards of the responsible com-
mittee on human experimentation (institutional and
national) and with the Helsinki Declaration of 1975, as
revised in 2000. A written informed consent was
obtained from all subjects included in the study.
REFERENCES
1 Underwood MR, Dawes P (1995) Inflammatory back pain
in primary care. Br J Rheumatol 34, 1074.
2 Ginsburg WW, Cohen MD (1983) Peripheral arthritis in
ankylosing spondylitis. A review of 209 patients followed
up for more than 20 years. Mayo Clin Proc 58, 593–6.

3 Kim TJ, Kim TH (2010) Clinical spectrum of ankylosing
spondylitis in Korea. Joint Bone Spine 77, 235–40.
4 Braun J, van den Berg R, Baraliakos X et al. (2011) 2010
update of the ASAS/EULAR recommendations for the
management of ankylosing spondylitis. Ann Rheum Dis
70, 896–904.
5 Dougados M, Boumier P, Amor B (1986) Sulfasalazine in
ankylosing spondylitis: a double blind controlled study in
60 patients. Br Med J 293, 911–14.
6 Garrett S, Jenkinson TR, Kennedy LG, Whitelock HC, Gais-
ford P, Calin A (1994) A new approach to defining disease
status in ankylosing spondylitis. The Bath Ankylosing
Spondylitis Disease Activity Index. J Rheumatol 21, 2286–91.
7 Nissila M, Lehtinen K, Leirisalo-Repo M, Luukkainen R,
Mutru O, Yil-Kerttula U (1988) Sulfasalazine in the treat-
ment of ankylosing spondylitis. A twenty-six-week, pla-
cebo-controlled clinical trial. Arthritis Rheum 31, 1111–16.
8 Krajnc I (1990) Sulphasalazine in the treatment of anky-
losing spondylitis [Serbocroatian]. Lijec Vjesn 112, 171–4.
9 Clegg DO, Reda DJ, Weisman MH et al. (1996) Compar-
ison of sulfasalazine and placebo in the treatment of anky-
losing spondylitis. A Department of Veterans Affairs
Cooperative Study. Arthritis Rheum 39, 2004–12.
10 Corkill MM, Jobanputra P, Gibson T, Macfarlane DG
(1990) A controlled trial of sulphasalazine treatment of
International Journal of Rheumatic Diseases 2017
Sulfasalazine for axial disease in ankylosing spondylitis
chronic ankylosing spondylitis: failure to demonstrate a
clinical effect. Br J Rheumatol 29, 41–5.
11 Kirwan J, Edwards A, Huitfeldt B, Thompson P, Currey H
(1993) The course of established ankylosing spondylitis
and the effects of sulphasalazine over 3 years. Br J Rheuma-
tol 32, 729–33.
12 Schmidt WA, Wierth S, Milleck D, Droste U, Gromnica-
Ihle E (2002) Sulphasalazine in ankylosing spondylitis: a
prospective, randomized, double-blind, placebo-con-
trolled study and comparison with other controlled stud-
ies [German]. Z Rheumatol 61, 159–67.
13 Chen J, Liu C (2006) Is sulfasalazine effective in ankylos-
ing spondylitis? A systematic review of randomized con-
trolled trials. J Rheumatol 33, 722–31.
14 Kiltz U, Heldmann F, Baraliakos X, Braun J (2012) Treat-
ment of ankylosing spondylitis in patients refractory to
TNF-inhibition: are there alternatives? Curr Opin Rheuma-
tol 24, 252–60.
15 Gill T, Asquith M, Rosenbaum JT, Colbert RA (2015) The
intestinal microbiome in spondyloarthritis. Curr Opin
Rheumatol 27, 319–25.
16 Cronstein BN, Sitkovsky M (2017) Adenosine and adeno-
sine receptors in the pathogenesis and treatment of rheu-
matic diseases. Nat Rev Rheumatol 13, 41–51.
7