Published: May 10, 2014
By Nancy Walsh, Senior Staff Writer, MedPage Today

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Action Points

• Disease activity appears to correlate and contribute longitudinally to radiographic progression in the spine in ankylosing spondylitis.
• The effect was higher in males versus females and in patients with less years of symptom duration.

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High disease activity in ankylosing spondylitis (AS) was associated with radiographic disease progression in the spine, a longitudinal study showed.

Patients with very high disease activity — AS disease activity index (ASDAS) scores of 3.5 at baseline — had progression of 3.1 units on spine x-ray scores over 2 years, according to Sofia Ramiro, MD, of the University of Amsterdam, and colleagues.

In contrast, those with inactive disease — ASDAS scores below 1.3 at baseline — hadan average progression of only 0.71 unitsover that period of time (P=0.001), the researchers reported online in Annals of the Rheumatic Diseases.

The Role of Inflammation

Whether inflammation and disease activity correlate with the radiographic damage caused by new spinal bone formation in AS has been a matter of debate, with two main hypotheses emerging. Some have argued that the bone effects are independent of inflammation and others claim that inflammation underlies osteoblast stimulation.

This was summarized in a recent piece by Rik J.U. Lories, MD, of Catholic University Leuven in Belgium and Maxime Dougados, MD, of Universite Paris-Decartes in France.

“The first hypothesis states that inflammation, including the upregulation of TNF, triggers local damage and subsequently repair leading to new bone formation and ankylosis. The second hypothesis states that a common trigger is responsible for both inflammation and new bone formation, but that both phenomena further develop in a largely molecularly independent way,” Lories and Dougados wrote in Annals of the Rheumatic Diseases.

This holds implications for treatment, because the tumor necrosis factor (TNF) inhibitors that have been so effective in controlling disease activity have not thus far been shown to prevent spinal damage in cross-sectional studies.

OASIS Outcomes

To address these uncertainties, Ramiro and colleagues conducted the longitudinal Outcome in Ankylosing Spondylitis International Study (OASIS), which recruited 184 patients beginning in 1996.

Every 2 years during the 12-year study, the investigators obtained clinical and radiographic data from participants.

Disease activity was measured on the ASDAS and also on the patient-reported Bath AS Disease Activity Index (BASDAI). Radiographic progression was assessed on the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), which ranges from zero to 72, depending on the presence of erosions and the bony growths known as syndesmophytes.

A total of 70% of the patients were men, and mean age was 43. Mean symptom duration was 20 years, and mean time since diagnosis was 11 years.

At baseline, 48% had elevated C-reactive protein (CRP), a marker of inflammation. Mean ASDAS was 2.6 and mean BASDAI was 3.4. Almost 70% were taking nonsteroidal anti-inflammatory drugs (NSAIDs).

The mean duration of follow-up was 7.9 years.

Overall, the average radiographic progression was 1.9 units on the mSASSS over each 2-year period.

Progression according to disease activity score was similar on the BASDAI to what was seen on the ASDAS, with an increase of 1.4 units over 2 years for patients whose baseline BASDAI scores were below 4 and 2.7 units for those with BASDAI scores of 4 or higher.

Longitudinal Analyses

The researchers also performed time-lagged longitudinal analyses that can estimate progression over time. These analyses found that an increase of one unit on ASDAS could be expected to result in an 0.72-unit increase in mSASSS during the ensuing 2 years.

“We have demonstrated here for the first time that the effect of disease activity on radiographic damage is actually rather impressive,” Ramiro and colleagues wrote.

This model also suggested that, compared with patients having inactive disease, those with “very high disease activity,” or an ASDAS above 3.5, would be likely to experience a further progression of 2.3 radiographic units over that time period.

In another model, a patient whose radiographic score was 10.8 at baseline, the mean for the study cohort, could expect to have a score of 15.8 after 12 years. With very active disease, the 12-year score would be 29.8, the researchers reported.

In addition, a one-unit rise in the BASDAI would be associated with an increase in mSASSS of 0.21 units over the next 2 years, and a 10-mg/L increase in CRP could be expected to lead to an 0.2-unit increase in the radiographic score.

Further analysis revealed a significant interaction between ASDAS and male gender. Compared with women, who had a change in radiographic score of -0.06 units over 2 years with a single-unit increase on ASDAS, men could expect an increase of 0.98 units (P=0.007).

An interaction also was seen for duration of symptoms. For those whose symptom duration was less than 18 years, a one-unit increase in ASDAS was associated with an increase of 0.84 units on the radiographic score, while those with longer disease duration had an increase of only 0.16 units (P=0.011).

They suggested that the reason why progression was more pronounced in the earlier phase of disease may have been that younger patients have greater physical activity that could alter mechanical factors affecting the spine.

“One may reason that younger people with shorter disease duration will usually perform more intensive occupational physical activities with stronger forces acting on the spine,” they noted.

This may also extend to the greater progression seen in men. “Since male patients may often have physically more demanding jobs than females, this speculative explanation may extend to the demonstrated male-female disparity,” they wrote.

Questions Remain

The researchers noted that, while disease activity was associated with radiographic progression in this analysis, “we acknowledge that disease activity (inflammation) by far does not fully explain radiographic damage in AS: even without measurable disease activity there is still considerable radiographic progression.”

This was shown by the observation in the model that a patient with inactive disease for 12 years would have a 5-unit increase on the radiographic score, which is quite different from rheumatoid arthritis, where x-ray joint damage progression is almost nonexistent when patients are in remission.

“It seems as if increased bone formation in AS is partly constitutive and partly inflammation-dependent,” Ramiro’s group observed.

As to why anti-TNF therapy might not inhibit bone formation even as it controls inflammation, the researchers noted that the TNF blocking agents have effects other than the suppression of inflammation.

In fact, animal studies have suggest that these agents can encourage bone formation, “so that negative effects on unrelated bone-forming processes could counterbalance a potentially positive effect on inflammation,” they noted.

Nonetheless, they concluded that inflammation does contribute to bone changes in AS.

“We now have clear evidence that inflammation and new bone formation are related in AS,” Joachim Sieper, MD, and Denis Poddubnyy, MD, of Charite Campus Benjamin Franklin in Berlin wrote in an accompanying editorial.

“The next question will be whether lowering disease activity by drugs with various modes of action will result in less radiographic damage,” they wrote.

“As some evidence indicates that NSAIDs might be able to inhibit radiographic progression, a clinical trial investigating the effect of combination therapy of a TNF blocker with an NSAID would be of interest,” Sieper and Poddubnyy observed.

Limitations of the study included its cohort design and an inadequate sample size to examine secondary concerns such as gender differences, while strengths included the long follow-up and longitudinal data collection.