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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Objective

To study the usefulness of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum amyloid A (SAA) for response prediction and monitoring of anti–tumor necrosis factor (anti-TNF) treatment in ankylosing spondylitis (AS) patients.

Methods

Patients were included consecutively before starting etanercept or infliximab treatment. ASsessment in Ankylosing Spondylitis (ASAS) response, defined as a 50% improvement or an absolute improvement of 2 points of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; 0–10 scale), was assessed at 3 months. Inflammatory markers and the BASDAI were collected at baseline and 1 and 3 months. Longitudinal data analysis was performed to compare associations between inflammatory markers and the BASDAI over time by calculating standardized betas. Predictive values of baseline levels of inflammatory markers for ASAS response were calculated.

Results

In total, 155 patients were included, of whom, after 3 months of treatment, 70% in the etanercept cohort and 71% in the infliximab cohort responded. All markers, notably SAA, decreased significantly (P < 0.0001). Standardized betas were 0.49 for ESR, 0.43 for CRP, and 0.39 for SAA. Normal baseline levels of CRP and SAA were significantly associated with nonresponse. A combination of elevated CRP and SAA levels at baseline revealed the highest predictive value (81%) for ASAS response.

Conclusion

ESR, CRP, and SAA were significantly associated with the BASDAI over 3 months, and the association with ESR was the strongest. Elevated baseline CRP and SAA levels revealed the highest predictive value for response. Together, this study demonstrates that inflammatory markers, and notably CRP and SAA, may facilitate patient selection and monitoring of efficacy of anti-TNF treatment in AS, and could be added to response criteria.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Disease activity in ankylosing spondylitis (AS) is generally measured with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (1). Despite the fact that the BASDAI is a validated instrument used in many clinical trials as an outcome parameter for disease activity, it remains a subjective parameter that is based on a patient questionnaire. A previous study showed that the BASDAI has a high intraindividual week-to-week variability (2). Theoretically, a high BASDAI can be caused by 3 factors, including a high level of 1) ankylosis or joint destruction, 2) psychological stress, or 3) inflammation. There is an unmet need for more objective biomarkers of disease activity in AS similar to the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level in rheumatoid arthritis (RA). ESR and CRP level are sensitive markers of disease activity in RA and are a reflection of the plasma levels of proinflammatory cytokines, rendering them suitable for monitoring the effectiveness of anti–tumor necrosis factor (anti-TNF) drugs. In AS, however, the sensitivity of these inflammatory markers as biomarkers of disease activity is controversial (3). On one hand, ESR and CRP level are poorly associated with disease activity in AS, and on the other hand, they may help a clinician to predict the response on TNF blockers (4–7). Two studies reported a strong association between ESR or CRP levels at baseline and clinical response to treatment with anti-TNF after 3 months, supporting a potential distinctive exploitation of these biomarkers in identifying AS patients suitable for treatment with anti-TNF (8, 9), which is also of particular relevance in light of the costs of biologics and the side effects of these drugs. However, because changes of CRP level may be too small to be detected in AS with common methods, measurement of high-sensitivity CRP (hsCRP) might be a more appropriate marker for disease activity. Besides ESR and CRP, other inflammatory markers are known, such as serum amyloid A protein (SAA) (10). SAA is an acute-phase reactant that is mainly transported as an apolipoprotein in high-density lipoprotein and is predominantly synthesized in the liver by hepatocytes in response to proinflammatory cytokines (11). SAA was shown to correlate with disease activity in AS, and one study even suggested superiority of SAA to ESR and CRP (4, 12). However, longitudinal data and the effects of treatment with anti-TNF agents on these relationships are lacking. Therefore, we explored the usefulness of ESR, CRP, hsCRP, and SAA for monitoring inflammation in AS patients treated with anti-TNF along with the association between these inflammatory markers and the BASDAI over time. In addition, the relationship between elevated levels of these markers at baseline and ASsessment in Ankylosing Spondylitis (ASAS) response was studied in these patients after 3 months of treatment with etanercept or infliximab in order to predict efficacy of this treatment.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Patients and study protocol.

Consecutive AS patients attending the outpatient clinics of the Jan van Breemen Institute and VU University Medical Centre scheduled for treatment with etanercept were included and followed prospectively, as well as AS patients scheduled for treatment with infliximab in the VU University Medical Centre. All of the patients fulfilled the 1984 modified New York criteria (13) and started anti-TNF therapy according to the ASAS consensus statement on the initiation of TNF-blocking agents in AS (14). Patients were treated with 25 mg etanercept twice a week, 50 mg etanercept once a week, or infliximab 5 mg per kilogram of body weight every 6 weeks after a starting regimen. None of the patients was treated with adalimumab because adalimumab was not reimbursed for yet at the start of this study.

The study was approved by the medical ethical committees of both participating centers, and all of the patients gave written informed consent.

Outcome measures.

The primary outcome measure was clinical response after 3 months of treatment with etanercept or infliximab, according to the international ASAS consensus statement for the use of anti-TNF agents in patients with AS, which is equivalent to the Dutch guidelines for the continuation of TNF-blocking agents. In this consensus statement, the ASAS response was defined as a 50% improvement or as an absolute improvement of 2 points of the BASDAI (0–10 scale), and an expert opinion in favor of continuation of treatment after 3 months (15, 16).

Data and sera were collected at baseline and after 1 and 3 months of treatment. During every visit, questionnaires on disease activity (BASDAI) were obtained. ESR and CRP level were routinely determined. HsCRP and SAA were measured in a patient's sera at baseline and 1 and 3 months. Collected sera were frozen at −20°C until testing. Commercially available kits were used to measure these inflammatory markers.

Analysis of ESR, CRP, hsCRP, and SAA.

ESR was measured with the Westergren method. Values are expressed in mm/hour. An ESR <15 mm/hour was considered to be normal, according to the cutoff used at the Jan van Breemen Institute.

Serum CRP levels were determined using the Roche/Hitachi Modular P (VU University Medical Centre) or cobas c (Jan van Breemen Institute) analyzers (Roche Diagnostics, D-68298, Mannheim, Germany), based on the principle of particle-enhanced immunologic agglutination. Values are expressed in mg/liter. A CRP level <10 mg/liter was considered to be normal, according to the cutoff used at the Jan van Breemen Institute.

HsCRP levels were determined using the Roche/Hitachi cobas c systems (Roche Diagnostics), with a detection range of 0.15–20 mg/liter. The test principle consists of a particle-enhanced immunoturbidimetric assay. Human CRP agglutinates with latex particles coated with monoclonal anti-CRP antibodies.

SAA levels were assessed with an enzyme-linked immunosorbent assay, as previously described (17). A value <4 mg/liter was considered to be normal.

Statistical analysis.

Continuous variables were reported as the mean ± SD or, if skewed, as the median (interquartile range). Categorical variables were calculated as frequencies and percentages. The distribution of variables was tested for normality and transformed if necessary and possible. Because the distribution of all of the inflammatory markers was skewed, Wilcoxon's signed rank test was performed to investigate paired samples. Relative changes (percentage) of inflammatory markers were calculated. Generalized estimating equations (GEEs) were performed to investigate the longitudinal relationship between the inflammatory markers and the BASDAI over a period of 3 months by calculating standardized betas. We investigated the possible influence of demographic or clinical variables, i.e., sex, age, ethnicity, HLA–B27, presence of peripheral arthritis, and disease duration.

Logistic regression analysis was performed to investigate the association between the baseline levels of the inflammatory markers and the dichotomous outcome variable of ASAS response. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for the association between elevated baseline levels of the inflammatory markers and ASAS response. For ESR, CRP, and SAA as predictors of the ASAS response, the sensitivity and specificity were calculated and receiver operating characteristic (ROC) curves were constructed. In addition, predictive values of normal or elevated levels of CRP and/or SAA were calculated for ASAS response. Statistical analyses were performed with SPSS statistical software, version 15.0 (SPSS, Chicago, IL). The threshold for significance was set at P values less than 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

In total, 155 patients were included and monitored after starting anti-TNF treatment. The demographic and clinical features are shown in Table 1. During treatment, all pharmacologic treatment remained unchanged.

Table 1. Demographic and clinical assessments of ankylosing spondylitis patients at baseline and 1 and 3 months of treatment with etanercept or infliximab*
VariableBaseline (n = 155)1 month3 months
  • *

    Values are the median (interquartile range) unless otherwise indicated. BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; hsCRP = high-sensitivity CRP; SAA = serum amyloid A protein.

  • P < 0.0001 compared with baseline.

Male sex, no. (%)101 (65)  
Age, mean ± SD years42 ± 11  
White, no. (%)125 (81)  
HLA–B27 positive, no. (%)123 (79)  
Presence of peripheral arthritis, no. (%)88 (57)  
Disease duration, years8 (3–16)  
BASDAI (0–10 scale)6.2 (5–7.1)3.4 (1.8–5.7)2.8 (1.4–4.3)
ESR, mm/hour (normal value <15)21 (7–38)6 (2–12)5 (2–13)
CRP level, mg/liter (normal value <10)15 (5–38)3 (1–5)4 (2–6)
HsCRP level, mg/liter (normal value <10)14.3 (3.8–39.2)1.9 (0.8–4.8)1.9 (0.9–5.8)
SAA level, mg/liter (normal value <4)7.5 (1.9–26.0)0.7 (0.2–1.8)0.8 (0.2–2.0)

The etanercept cohort comprised 117 patients and the infliximab cohort comprised 38 patients. After 3 months, 70% (80 of 115, because in 2 patients the ASAS response was missing) and 71% (27 of 38) of the patients achieved an ASAS response in the etanercept and infliximab cohorts, respectively. Baseline levels of ESR, CRP, and SAA were elevated in 113 (73%), 96 (62%), and 99 (64%) patients, respectively. In 29 patients (19%), none of these markers was elevated at baseline. All of the inflammatory markers and the BASDAI decreased significantly after starting anti-TNF therapy (P < 0.0001) (Table 1 and Figure 1). Notably, the median relative decrease after 1 month was 36% for the BASDAI (Figure 1A), 67% for the ESR (Figure 1B), 75% for the CRP (Figure 1C), and 84% for the hsCRP (Figure 1D), while the SAA decreased by 90% (Figure 1E). Longitudinal linear regression analysis (GEE) showed significant association between the BASDAI and ESR, CRP, hsCRP, and SAA over time (P < 0.0001). There were no confounders influencing this association. The standardized betas were 0.49, 0.43, 0.43, and 0.39 for ESR, CRP, hsCRP, and SAA, respectively. Hereafter, only results of the associations with CRP level are shown as results because the hsCRP level did not differ from the CRP level.

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Figure 1. Change of A, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), B, erythrocyte sedimentation rate (ESR), C, C-reactive protein (CRP), D, high-sensitivity CRP (hsCRP), and E, serum amyloid A protein (SAA) after 1 and 3 months of treatment with etanercept or infliximab. IQR = interquartile range; * = P < 0.0001 compared with baseline.

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In 2 patients treated with infliximab who showed a secondary increase, particularly of CRP and SAA after initial normalization, antibodies against infliximab were detected (18) (Figure 2).

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Figure 2. A, Erythrocyte sedimentation rate (ESR), B, C-reactive protein (CRP), and C, serum amyloid A protein (SAA) levels 1 and 3 months after initiation of treatment with infliximab for ankylosing spondylitis patients without and with antibodies against infliximab (anti-infliximab, n = 2).

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Patients with an elevated baseline level of CRP (>10 mg/liter) achieved an ASAS response after 3 months of treatment significantly more often compared with patients with normal baseline CRP levels (OR 2.8, 95% CI 1.3–5.7, adjusted for sex and age). Elevated baseline SAA levels had a similar association with ASAS response at 3 months of treatment with either infliximab or etanercept (OR 2.9, 95% CI 1.4–6.1, adjusted for sex and age). Only baseline ESR levels were not significantly associated with clinical response (OR 1.4, 95% CI 0.7–3.1).

The sensitivity and specificity of CRP level for prediction of the ASAS response were 0.69 and 0.57, respectively. These figures were 0.72 and 0.54 for SAA level, respectively. ROC curves were created for ESR, CRP, and SAA as predictors of ASAS response (Figure 3). The ROC curve for ESR (Figure 3A) showed that determination of the ESR is of no additional value in predicting the ASAS response. CRP and SAA performed similarly (Figures 3B and 3C). The predictive value of the ASAS response of an elevated baseline level of CRP was 79%. This value was identical to SAA. A combination of the presence of elevated baseline levels of CRP and SAA of patients in both cohorts displayed the highest predictive value of ASAS response of 81% (Table 2). Inclusion of baseline levels of ESR had no additional value. A proportion of 48% of patients with normal values of both CRP and SAA levels at baseline were nonresponders according to the ASAS criteria.

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Figure 3. Receiver operating characteristic curves for A, erythrocyte sedimentation rate (area under the curve [AUC] 0.55), B, C-reactive protein (AUC 0.64), and C, serum amyloid A protein (AUC 0.66) as predictors of the ASsessment in Ankylosing Spondylitis response.

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Table 2. Predictive values of normal or elevated pretreatment levels of CRP and/or SAA for prediction of ASAS response/nonresponse after 3 months of treatment with etanercept or infliximab*
 ASAS nonresponse, %ASAS response, %
  • *

    CRP = C-reactive protein; SAA = serum amyloid A protein; ASAS = ASsessment in Ankylosing Spondylitis.

Normal CRP (n = 59)4456
Elevated CRP (n = 94)2179
Normal SAA (n = 55)45.554.5
Elevated SAA (n = 98)2179
Normal CRP and SAA (n = 44)4852
Elevated CRP and normal SAA (n = 11)3664
Normal CRP and elevated SAA (n = 15)3367
Elevated CRP and SAA (n = 83)1981

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

The present study demonstrated that a combination of elevated baseline levels of CRP and SAA can be a valuable instrument for the selection of those AS patients who are likely to respond to treatment with anti-TNF, unlike the BASDAI. Moreover, inflammatory markers, CRP and SAA in particular, seem useful for monitoring the level of inflammation in patients with AS who are treated with etanercept or infliximab.

Regarding monitoring therapy with anti-TNF, most of the AS patients showed a significant decrease of several inflammatory markers, most dominantly SAA. In some cases, a secondary increase of these inflammatory markers can be seen, which might be caused by a concurrent infection or inadequate therapeutic levels. The latter may be due to antibody formation, which depletes anti-TNF levels below therapeutic thresholds (18). This could be an argument to include at least one inflammatory marker next to the BASDAI in order to assess disease activity properly. Although ESR showed the strongest association with the BASDAI over time, we consider ESR the least suitable for inclusion because it has no additional value to the BASDAI, as the half-life of this inflammatory marker is too long for early detection of changes. HsCRP has been proposed to be useful as a marker to predict the risk of coronary heart disease due to inflammation in apparently healthy persons (19). In the current study, however, measurement of hsCRP level did not provide additional value because the strength of the association with disease activity of AS patients over time was not different from and not superior to that of CRP.

Although the majority of the AS patients in this study (62% to 73%) had elevated inflammatory markers before the start of anti-TNF therapy, it is known that inflammatory markers do not necessarily reflect disease activity well in AS (3). This is why inflammatory markers were not implemented for assessment of disease activity or response to treatment, which is in contrast to RA. This study shows that when inflammatory markers are raised, this is indicative of active disease. It seems useful to add the decrease of inflammatory markers to response criteria for continuation of anti-TNF treatment in AS patients who show elevated inflammatory markers at baseline.

Since anti-TNF therapy is not without risks and is also very costly, it is of great importance to identify patients likely to (non)respond to this type of drug. Although the performance of the tests was poor, the ROC curves showed that CRP and SAA are superior to ESR. In the present study, we showed that the combination of elevated CRP and SAA levels at baseline is the strongest predictor of ASAS response, providing a solid basis for a predictive assessment of the clinical response of AS patients to treatment with anti-TNF. In contrast, baseline ESR levels were not associated with clinical response. However, as demonstrated before, patients with normal baseline levels of CRP and SAA may respond to anti-TNF therapy as well (20). Therefore, at this moment, we believe inflammatory markers can be very useful as one of the predictors of a good response, but a raise of the inflammatory markers should not be mandatory for allowing AS patients to be treated with anti-TNF.

The fact that good responders do not all necessarily need to have a strong decline of CRP or SAA levels limits the use of these parameters in making the decision of whether or not this therapy should be continued. Therefore, they can be useful, but should not be considered obligatory for the decision of whether anti-TNF therapy is failing or not.

We studied SAA in relation to disease activity in AS. SAA is implicated in several chronic inflammatory diseases, such as AA amyloidosis, atherosclerosis, and RA (21). An additional advantage of monitoring SAA levels in AS patients may therefore be that SAA lowering therapy by anti-TNF could possibly prevent secondary AA amyloidosis. AA amyloidosis sometimes develops secondary to longstanding inflammation and chronically elevated levels of SAA, the plasma precursor of amyloid A deposits (10). Notably, elevated baseline levels of SAA were associated with clinical response in AS and decreased rapidly after initiation of treatment with etanercept or infliximab, which might prevent AA amyloidosis in the future.

Altogether, in this large prospective cohort of AS patients, measurement of inflammatory markers, in particular CRP and SAA, served as a powerful tool not only for monitoring the efficacy of anti-TNF therapy, but also for the selection of AS patients with a high likelihood of responding to anti-TNF treatment.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. de Vries had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. De Vries, van der Horst-Bruinsma, Peters, Nurmohamed, Dijkmans, Wolbink.

Acquisition of data. De Vries, van der Horst-Bruinsma, Peters, Hazenberg, Wolbink.

Analysis and interpretation of data. De Vries, van Eijk, van der Horst-Bruinsma, Peters, Nurmohamed, Dijkmans, Hazenberg, Wolbink.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Wyeth had no role in the study design, data collection, data analysis, and writing of the manuscript, as well as the approval of the content of the submitted manuscript. Publication of this article was not contingent on the approval of Wyeth.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

We would like to thank Professor J. W. R. Twisk for his statistical support, research nurses Mrs. P. J. Verkerke and Mrs. A. Abrahams, Mrs. M. H. M. T. de Koning for determining CRP level, Mr. J. Bijzet, BSc, for determining SAA level, and Dr. G. Jansen for reviewing the manuscript.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES
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