1 Department of Rheumatology, Charité Medical School, Campus Benjamin Franklin, Berlin, 2 Rheumazentrum Ruhrgebiet, Herne, Ruhr-University Bochum and 3 German Rheumatism Research Centre, Berlin, Germany.
Correspondence to: J. Braun, Rheumazentrum Ruhrgebiet, Herne, Germany, Landgrafenstr.15, 44652 Herne, Germany. E-mail: J.Braun{at}Rheumazentrum-Ruhrgebiet.de
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Abstract |
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Methods. Twenty patients with active AS were examined by MRI at baseline, after 3 months (end of placebo-controlled-phase) and after 2 yr of continuous infliximab therapy (5 mg/kg/6 weeks). T1 pre- and post-gadolinium (T1/gadolinium-diethylenetriamine-pentaacetic acid) and short tau inversion recovery (STIR) MRI sequences were performed and read by one blinded reader using the ASspiMRI score.
Results. Spinal inflammation, detected by MRI in all patients at baseline, decreased after 3 months only in the infliximab group in both MRI sequences. Persistent improvement of spinal inflammation was seen after 2 yr by scoring STIR sequences, with a mean score of 4.6 ± 5.9 vs 15.2 ± 13.2 at baseline (P = 0.01). On an individual level, inflammatory spinal lesions decreased from 6.7 ± 5.0 per patient at baseline to 2.2 ± 1.8 after 2 yr (P = 0.003). Improvement in spinal inflammation was found in all patients by both MRI sequences. Only a minor degree but some spinal inflammation was still present after 2 yrs.
Conclusion. Spinal inflammation in MRI was persistently reduced in all patients constantly treated with infliximab, but it was not completely eradicated. Disease activity parameters did not directly correlate with MRI, but both pointed in the same direction. Both types of information may be useful for the definition of response to anti-TNF therapy.
KEY WORDS: Ankylosing spondylitis, Infliximab, Magnetic resonance imaging, Spinal inflammation
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Introduction |
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Treatment of patients with active AS with the anti-tumour necrosis factor- (TNF-
) antibody infliximab in a dosage of 5 mg/kg i.v. given every 6 weeks in a randomized controlled trial (RCT) recently performed in Germany [8] (still ongoing), showed definite improvement of disease activity and other clinical and laboratory parameters in short-term [8, 9] and long-term [10, 11] follow-up studies. No loss of efficacy was reported after 2 and 3 yr of continuous treatment with infliximab. Similar results have been reported by other groups [1217].
MRI of the spine is increasingly used to detect spinal lesions in early and active phases in AS [18]. The novel scoring system ASspiMRI was recently described to be reliable for assessment and quantification of acute (ASspiMRI-a) and chronic (ASspiMRI-c) spinal lesions of AS patients [6, 19, 20]. Importantly, it was also sufficiently sensitive to change [19].
In the present study, we evaluated MR images of the German RCT [8, 10] at different time points including those after continuous long-term treatment with infliximab. For the first time we show that spinal inflammation, although persistently reduced in all patients, is still detectable in some.
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Patients and methods |
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Of the 20 AS patients included at baseline, nine were assigned to infliximab and 11 to placebo. All patients fulfilled the modified New York criteria for AS [5], and had active disease as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI [21]) of >4. Nine female and 11 male patients, with a mean age of 40.9 yr (range 2954 yr) were examined by MRI (Table 1). The patients had received infliximab at baseline, after 2 and 6 weeks and then at 6-week intervals until week 102 of the clinical study [8, 10]. MRI examinations were performed before the first application of infliximab (baseline), after 12 weeks (end of the placebo-controlled phase of the clinical trial) and after 102 weeks (all patients treated with infliximab).
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Evaluation of the MRI examinations
The MRIs were scored by one reader (XB) who was blinded for time sequence of the images and treatment allocation (infliximab or placebo) of the patients in all three study phases. The MR images were scored by the recently evaluated ASspiMRI score [19]. Acute and chronic spinal lesions were scored on the basis of a vertebral unit (VU), which is defined as the region between two virtual horizontal lines drawn through the middle of a vertebral body [19]. Inflammatory spinal lesions were assessed by the T1/Gd-DTPA and the STIR MRI sequence and chronic spinal lesions were assessed by using the T1-weighted MRI sequence. The MRIs at baseline and at week 12 of this study had already been scored by different readers in a slightly different way in an earlier study [19].
Since MRI examinations were not mandatory for participation in the clinical study, not all patients had a complete series of MRI investigations (baseline = 20 patients, week 12 = 17 patients, week 102 = 14 patients). However, the clinical and efficacy parameters of the patients who did not undergo MRI examinations after 12 weeks and 102 weeks were similar to the patients who were included in the MRI examinations. Comparisons between time points were performed when paired samples were available for evaluation.
Statistical analysis
The paired Wilcoxon rank sum test was used to compare the readings before and after treatment and the MannWhitney U-test was used to compare the results between treatment groups at each single time point. The activity score (ASspiMRI-a) was assessed by comparing the changes detected by the MRI sequences and changes in clinical parameters, such as disease activity (BASDAI [21]), function (Bath Ankylosing Spondylitis Functional Index, BASFI [22]), mobility (Bath Ankylosing Spondylitis Metronomy Index, BASMI [23]), and laboratory parameters, such as C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR). Linear regression analysis was performed and correlation coefficients were calculated.
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Results |
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The mean ASspiMRI-a score for all patients available at baseline was not significantly different between both treatment groups with 17.1 ± 15.2 in the infliximab and 11.9 ± 8.7 in the placebo group by STIR and 13.8 ± 15.2 in the infliximab group and 10.6 ± 8.4 in the placebo group by T1/Gd-DTPA.
In the comparison of the three spinal segments, the thoracic spine (TS) had most inflammatory lesions, with 0.4 ± 0.3 and 0.3 ± 0.2 mean scoring points per VU in the STIR and the T1/Gd-DTPA sequence, respectively. In comparison, both the cervical spine (CS) and the lumbar spine (LS) had a mean of 0.2 ± 0.3 scoring points per VU in both the STIR and the T1/Gd-DTPA sequence, respectively.
The evaluation of active spinal lesions in the entire spine at baseline showed a good correlation between STIR and T1/Gd-DTPA scores with r = 0.86 (P<0.001).
Evaluation of spinal inflammation during the placebo-controlled phase of the study (3 months)
The ASspiMRI-a showed a significant reduction of mean scoring points per patient in the infliximab group, with 10.7 ± 9.4 at first follow-up vs 20.5 ± 16.6 at baseline (P = 0.04) in the STIR sequence after 12 weeks of continuous treatment. In contrast, patients in the placebo group showed only minor changes in the same time period, with 10.8 ± 6.5 mean scoring points at week 12 (baseline 11.9 ± 8.7, P = 0.4) (Fig. 1).
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The mean number of inflamed VUs per patient in the group treated initially with infliximab decreased from 10.0 ± 6.7 at baseline to 4.7 ± 3.9 at week 12 (P = 0.04) when using STIR and from 6.8 ± 5.7 to 4.5 ± 3.9 (P = 0.08) when using T1/Gd-DTPA. In the placebo group, the mean number of inflamed VUs per patient was 5.1 ± 2.9 at baseline vs 3.8 ± 2.1 at week 12 when using STIR and 4.2 ± 2.6 at baseline vs 3.4 ± 3.3 at week 12 with T1/Gd-DTPA (both P = non-significant.)
MRI evaluation of spinal inflammation after 2 yr of infliximab therapy
The patients treated initially with infliximab showed improvement of active spinal lesions at week 102 with 3.0 ± 4.6 mean scoring points per patient in comparison with baseline (18.7 ± 18.4) and week 12 (14.0 ± 11.5) in the STIR sequence, and with 5.2 ± 7.4 mean scoring points per patient at week 102 in comparison with 15.5 ± 17.7 at baseline and 13.7 ± 12.1 at week 12 in the T1/Gd-DTPA sequence, respectively (both P 0.05 between baseline and week 102).
In contrast, in the patients treated initially with placebo, inflammatory spinal lesions only decreased after switching to infliximab, with a mean score of 5.7 ± 6.7 in the STIR sequence after 102 weeks in comparison with baseline (12.9 ± 8.9) and week 12 (11.9 ± 6.3) (P = non-significant between baseline and week 102, P = 0.05 between baseline and week 102) (Fig. 2a). In the T1/Gd-DTPA sequence, the mean ASspiMRI-a score per patient after 102 weeks was 7.4 ± 7.9, in comparison with 12.6 ± 8.0 at baseline and 9.4 ± 6.7 after 12 weeks (P = 0.05 between baseline and week 102) (Fig. 2b).
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The mean number of inflamed VUs per patient decreased from 6.7 ± 5.0 at baseline to 2.2 ± 1.8 (P = 0.005) after 102 weeks when using STIR and from 5.1 ± 3.8 at baseline to 2.4 ± 2.2 (P = 0.02) after 102 weeks when using Gd-DTPA.
Overall, improvement of active inflammatory lesions at week 102 was depicted in both MRI sequences for all patients. However, after this time period at least one active spinal lesion was still present in 79% and in 84% of patients in the STIR and in the T1/Gd-DTPA sequence, respectively.
Evaluation of chronic spinal changes after 2 yr
In the evaluation of the T1-weighted MRI sequence, chronic spinal changes deteriorated during the entire study period in both groups, with a mean ASspiMRI-c of 33.9 ± 14.1 at baseline and 40.9 ± 12.2 per patient at week 102. However, this difference was not statistically significant (Fig. 1).
Overall, 83% (5/6) patients in the infliximab group and 88% (7/8) patients in the placebo group showed deterioration of chronic spinal lesions after 2 yr.
Correlation between MRI findings and clinical parameters for disease activity
There was no strong correlation between values of clinical parameters (BASDAI, BASFI, BASMI, CRP, ESR) and scoring of both MRI sequences for spinal inflammation.
In the analysis of changes between baseline and week 12, significant correlations were only found between STIR change and BASDAI change (r = 0.50, P = 0.05) and between STIR change and BASFI change (r = 0.62, P = 0.01).
Furthermore, there was also no correlation between values of clinical parameters and MRI scorings after 2 yr of follow-up and no correlation between response to the assessment of AS working group (ASAS [24]) criteria or to BASDAI improvement and improvement of the MRI results between baseline and week 102, respectively.
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Discussion |
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Improvement of spinal lesions under infliximab treatment was of the order of 4050% during the first 3 months (placebo-controlled phase) of this study. In contrast, there was only a minor change in spinal inflammation (1020%) compared with baseline in the placebo patients. After switching to infliximab, these patients also improved significantly at the 2-yr follow-up. From another point of view, the number of spinal lesions per individual patient decreased significantly after 2 yr of infliximab treatment in the range of 5070%, depending on the MRI sequence used. The overall improvement of spinal inflammation was in the range between 5070% after 2 yr of infliximab treatment. It is important to note that the patients treated with infliximab during the first 3 months of the study even showed additional improvement of active spinal lesions after 2 yr. This observation confirms the anti-inflammatory potential of infliximab and suggests an ever increasing benefit after continuous long-term therapy.
These data are consistent with short-term experiences from previous MRI studies of our group with both anti-TNF- agents, infliximab [19] and etanercept [25, 26], and also from reports of other groups [27]. This study extends those reports on the course of inflammatory spinal lesions to MRI data on long-term anti-TNF-
therapy after 2 yr. Evidence is provided on the basis of the best available imaging technique that the reduction of spinal inflammation persists in patients with active AS at baseline when treated with infliximab continuously. As already pointed out, this corresponds well to the clinical efficacy already reported [8, 10].
In this study we found a weak correlation between changes of BASDAI and BASFI only when analysing the STIR sequences after 12 weeks; this is similar to our first study [19]. However, both, clinical and imaging data point into the same direction and indicate improvement in back pain and spinal inflammation in patients treated with infliximab. As already mentioned, the number of patients examined in this study was relatively small. Thus, this question will hopefully be answered in future evaluations of larger patient cohorts such as ASSERT [17].
The issue of where the spinal inflammation predominantly takes place has recently been discussed intensively [6]. In the present study we detected inflammatory spinal lesions in 38% of the VUs in the TS, in comparison to 1726% of the VUs of both the CS and the LS. These data support our recent study in which we showed that the TS is the most frequently affected spinal segment in AS [6, 26]. Thus, all spinal segments may be affected by AS but the TS is most important. The fact that the TS is easily and usually included in MRI examinations of the spine is an advantage over conventional radiography. The performance of MRI to detect chronic spinal changes is rather good [20], but X-rays are still considered the gold standard.
As indicated in previous MRI studies on AS patients [6, 7, 19], both MRI techniques used here, the STIR and the T1/Gd-DTPA MRI sequence, are valid for evaluation of active spinal lesions in AS. In the present study, both MRI techniques performed similarly well in scoring spinal inflammation due to AS. The two different MRI sequences correlated well at the baseline (r = 0.86) and the follow-up examination (r = 0.91). While the T1/Gd-DTPA MRI sequences seemed to provide more specific results [7], the STIR scores were more sensitive to change. Thus, these MRI techniques provide rather complementary information related to the identification of active spinal lesions. However, in clinical practice STIR sequences may be preferable for practical reasons, because (i) more time is needed to perform the examination with Gd-DTPA, (ii) because of the additional risk for allergic reactions due to Gd-DTPA and (iii) because of the higher costs of this contrast agent.
In summary, the anti-inflammatory effect of infliximab on active spinal lesions of patients with AS, as detected by MRI, occurs after only 12 weeks of treatment and persists over a time period of 2 yr without loss of efficacy. However, although spinal inflammation decreased significantly in the patients treated with infliximab, some inflammatory lesions were still present in patients with AS after long-term infliximab therapy. This observation rather supports the view that continuous anti-TNF treatment is necessary. The finding that the clinical assessment of disease activity does not correlate well with MRI scores suggests that both types of information may be needed to assess response to anti-TNF therapy. The thoracic spine is the main localization of spinal inflammation in AS patients. There is as yet limited evidence that infliximab is able to decrease the progression of chronic spinal lesions in AS patients after 2 yr [28]. Larger studies are needed to provide evidence on that important issue.
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Acknowledgments |
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M. Rudwaleit declares that he served as a consultant for Schering-Plough/Essex Pharmaceuticals and received honoraria. J. Sieper and J. Braun declare that they held consultancies and received honoraria, speakers' honoraria and grants/research support from Centocor, Schering-Plough, Essex, Wyeth and Abbott. The other authors have declared no conflicts of interest.
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Notes |
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References |
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