PRACTICE POINT

18 NATURE CLINICAL PRACTICE RHEUMATOLOGY NOVEMBER 2005 VOL 1 NO 1

www.nature.com/clinicalpractice/rheum

Original article Wanders A et al. (2005) Nonsteroidal anti-inflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis. A randomized clinical trial. Arth Rheum 52: 1756–1765

SYNOPSISKEYWORDS ankylosing spondylitis, nonsteroidal anti-inflammatory drugs, radiography

BACKGROUNDTo date, ankylosing spondylitis (AS) has been treated with nonsteroidal anti-inflammatory drugs (NSAIDs), whilst maintaining a conserva -tive dose regimen because of known gastro-intestinal side effects. Since the development of gastro protective NSAIDs, it is not known how the long-term disease course of AS is affected by the prolonged continuous use of these agents.

OBJECTIVEThe objective of this study by Wanders and colleagues was to compare the efficacy of long-term, continuous treatment with NSAIDs with NSAID treatment on demand, in terms of on the radiographic progression of disease in patients with AS.

DESIGN AND INTERVENTIONThis 2-year, randomized, open-label, multi-center, controlled, comparative trial incorporated a patient population with AS that had previously taken part in a 6-week, randomized, double-blind trial comparing celecoxib, ketoprofen and placebo. Patient inclusion criteria were daily NSAID intake for 1 month before screening, an NSAID washout period for 2–14 days before baseline visit, and presentation of a disease flare at baseline. Patients were randomized into two groups; the first group received continuous daily treatment with 100 mg celecoxib for the duration of the study and the second group of patients received treatment with 100 mg celecoxib on the presentation of serious symptoms only. Patients

Nonsteroidal anti-inflammatory drugs: disease modifiers in ankylosing spondylitis?

from both groups were allowed to increase their dose of celecoxib to 200 mg or to switch to an alternative NSAID if adverse events or lack of efficacy were observed. Patients who had peripheral arthritis or active inflammatory bowel disease, along with patients who had received cortico steroid therapy or disease-modifying antirheumatic drugs before screening were excluded.

OUTCOME MEASURESThe three outcome measures were: the mean change observed in radiographic data of all participating patients at baseline compared with radiographic results at the end of study; time-averaged values of variables indicating disease progression; and the frequency of adverse events related to treatment.

RESULTSOf 215 patients participating in this trial, 111 patients were assigned continuous treat-ment with NSAIDs and 104 patients were assigned NSAID therapy on demand only. After 24 weeks, complete sets of radiographic data were obtained from 76 (68%) of the 111 continuous treatment patients and 74 (71%) of the 104 on-demand treatment patients. Analysis of results showed less radiographic progression in the continuous treatment group compared with the on-demand treatment group (0.4 ± 1.7 versus 1.5 ± 2.5, respectively, P = 0.002). Data indicating difference in signs and symptoms of disease between the two groups, along with increased adverse events in the continuous treatment group, were deemed statistically insignificant.

CONCLUSIONPatients receiving continuous treatment with NSAIDs have reduced radiographic progres-sion of AS. Adverse events are few, but are still observed.

ncprheum_2005_112.indd 18ncprheum_2005_112.indd 18 17/10/05 3:10:26 pm17/10/05 3:10:26 pm

Nature Publishing Group© 2005

PRACTICE POINT

NOVEMBER 2005 VOL 1 NO 1 NATURE CLINICAL PRACTICE RHEUMATOLOGY 19

www.nature.com/clinicalpractice/rheum

AcknowledgmentsThe synopsis was written by Jasmine Farsarakis, Associate Editor, Nature Clinical Practice.

Competing interestsThe author declared he has no competing interests.

CorrespondenceBuilding 10 CRCRoom 4-133910 Center Drive MSC 1468BethesdaMD 20892-1468USAwardm1@mail.nih.gov

Received 1 July 2005Accepted 13 September

www.nature.com/clinicalpracticedoi:10.1038/ncprheum0040

COMMENTARY

Michael M Ward

The ultimate goal of treatment of AS would be to slow or stop the progression of bony fusion and to prevent the postural changes and restric-tions of flexibility associated with long-standing AS. Identification of a ‘disease-modifying’ treat-ment for AS has been elusive. Medications that are disease modifying in rheumatoid arthritis, such as sulfasalazine and methotrexate, have limited benefit for the axial symptoms of AS.1,2 Although anti-tumor necrosis factor medi-cations can alleviate radiographic signs of inflammation, convincing evidence that these medications alter the progression of spinal fusion has yet to be provided.3

The report by Wanders and colleagues suggests that NSAIDs can slow the rate of spinal fusion, but that this effect is dependent on the dosing schedule used. Subjects in the continuous-treatment group had significantly lower rates of disease progression than those in the symptom-prompted group, despite using only slightly higher mean doses of celecoxib. The treatment effect was small, equivalent to the presence of one additional area of erosion, sclerosis or squaring in one vertebral body over 2 years. The strengths of this study include the randomized trial design, use of a validated radiographic endpoint and blinded reading of radiographs. The statistical analysis indicated that the results are unlikely to be due to chance. Although a considerable proportion of patients did not complete the study, adjustment for missing data using two different strategies did not alter the findings.

The results should also be considered in light of other aspects of the study design. Changes in the dose of celecoxib, switching to other NSAIDs and co-interventions with other medications were permitted throughout the trial. These medication changes, which were not recorded, might have altered the prognostic similarity of the groups after randomization, undermining the strength of the randomized design. The true differences in treatment between groups are unclear. Of necessity, the subjects were not blinded, but this raises questions of whether the

effects can be attributed solely to the NSAID treatment. The practice of taking medica-tion daily could have caused other behavioral changes that resulted in less radiographic progression, such as reminding subjects in the continuous treatment group to exercise more regularly. Less-severe symptoms might have also promoted more exercise in the continuous treatment group. Although statistical adjust-ment for improvements in individual symp-toms did not alter the findings, the question of whether any treatment that had the same effect on symptoms might have similar radiographic effects remains.

The mechanism by which continuous NSAID treatment achieved the reported results is un certain. A dose effect seems unlikely, given the similar mean doses in both groups. The authors suggest that periodicity of use might be impor-tant. Biologic mechanisms were not examined. It would be important to document these mecha-nisms to support an NSAID-specific effect, and to provide a biologic rationale for the need for daily NSAID use.

Progress in identifying disease-modifying medications in AS would be hastened by a greater understanding of the mechanisms involved in spinal inflammation and bony fusion, and the links between these processes. Judgment of the disease-modifying potential of NSAIDs in AS should be reserved pending evidence of its mechanism, clearer differentia-tion of treatments, and sustained improvements over time.

References1 Clegg DO et al. (1996) Comparison of sulfasalazine

and placebo in the treatment of ankylosing spondylitis. A Department of Veterans Affairs Cooperative Study. Arthritis Rheum 39: 2004–2012

2 Maksymowych WP et al. (2002) Ankylosing spondylitis and current disease-controlling agents: do they work? Best Pract Res Clin Rheumatol 16: 619–630

3 Baraliakos X et al. (2005) Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis before and after therapy with the tumor necrosis factor alpha receptor fusion protein etanercept. Arthritis Rheum 52: 1216–1223

MM Ward is an investigator at the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, USA.

PRACTICE POINTThe rationale for continuous daily NSAID treatment in patients with ankylosing spondylitis should be based on symptom control rather than on current evidence suggesting a slowing of radiographic progression

ncprheum_2005_112.indd 19ncprheum_2005_112.indd 19 17/10/05 3:10:29 pm17/10/05 3:10:29 pm

Nature Publishing Group© 2005