SPINE Volume 38, Number 26, pp 2258-2263 ©2013, Lippincott Williams & Wilkins
Spine CERVICAL SPINE
Predictors for the Progression of Cervical Lesion in Rheumatoid Arthritis Under the Treatment of Biological Agents Takashi Kaito, MD,* Shirou Ohshima, MD,t Hiroyasu Fujiwara, Takahiro Makino, MD,* and KazuoYonenobu, MD§
Study Design. Retrospective cohort analysis. Objective. To clarify the effect of biological agents (BAs) on the development and progression of cervical lesions in patients with rheumatoid arthritis (RA) and to identify biomarkers that accurately predict disease progression. Summary of Background Data. The introduction of BAs changed the paradigm of RA treatment. However, their effects on cervical lesions in patients with RA have not been studied. Methods. Ninety-one subjects who had received BAs for 2 years or more were enrolled. Mean radiographical interval was 3.9 years. Disease activity was evaluated by disease activity score-C-reactive protein levels, and matrix metalloproteinase-3 levels. Cervical lesions were defined as an atlantodental interval more than 3 mm for atlantoaxial subluxation (AAS), Ranawat value less than 13 mm for vertical subluxation (VS), and anterior or posterior listhesis more than 2 mm for subaxial subluxation. Disease progression was defined radiographically as an increase in the atlantodental interval more than 2 mm for AAS, a decrease in both Ranawat and RedlundJohnell values more than 2 mm forVS, and an increase in listhesis more than 2 mm for subaxial subluxation. We used multivariate regression techniques to assess predictors of disease progression. Results. Baseline radiographical evaluation showed no preexisting cervical lesion in 44 patients, AAS in 29, and VS in 18. Radiological progression occurred in 7% patients without baseline lesions, 79% in the AAS group, and 72% in the VS group. The From the *Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan; Departments of tRheumatology; and ^Orthopaedic Surgery, National Hospital Organization Osaka Minami Medical Center, Osaka, Japan; and §Graduate School of Health Care Sciences, Jikei Institute, Osaka, Japan. Acknowledgment date: July 31, 2013. First revision date: Septemher 5, 2013. Second revision date: September 21, 2013. Acceptance date: Septemher 25, 2013. The device(s)/drug(s) is/are FDA-approved or approved by corresponding national agency for this indication. The Japan Orthopaedics and Traumatology Foundation, Inc. No. 260 grant funds were received in support of this work. No relevant financial activities outside the submitted work. Address correspondence and reprint requests to Takashi Kaito, MD, Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; E-mail: takashikaito ©gmail.com DOi: 10.1097/BRS.0000000000000066 2258
www.spinejournal.com
incidence of progression was significantly lower in patients without lesions at baseline. Multivariate regression analysis demonstrated pre-existing cervical lesions, disease activity score-C-reactive protein levels at baseline and metalloproteinase-3 levels at final visit as good predictors of RA progression. Conclusion. BAs prevented de novo cervical lesions in patients with RA but failed to control progression in patients with preexisting cervical lesions. Disease activity score-C-reactive protein levels at baseline were related to pre-existing joint destruction, and metalloproteinase-3 levels accurately predicted ongoing bone destruction during BA treatment. Key words: biological agent, rheumatoid arthritis, cervical spine, disease activity, radiographical progression, pre-existing cervical lesion, disease activity score (DAS), matrix metalloproteinase-3 (MMP-3), predictor, multivariate regression analysis, neck pain.
Level of Evidence: 3 Spine 2013;38:2258-2263
R
heumatoid arthritis (RA) is a chronic inflammatory immune disorder that is characterized by inflammation of synovial membranes and the release of inflammatory cytokines that ultimately results in joint destruction and disability. Cervical spine involvement is a common complication of RA, occurring in 25% to 86% patients.'-- This inflammatory process can lead to progressive joint destruction and ligamentous laxity, which can result in cervical spine subluxation and instability. The most common type of anatomical cervical spine deformity is atlantoaxial subluxation (AAS), followed by vertical subluxation (VS) and subaxial subluxation (SS).' These anatomic deformities may cause spinal cord or brainstem compression, with resultant neurological deficits such as cervical myelopathy, paresis, and even death."*"** Treatment paradigms for RA have recently undergone a major shift. Standard of care now entails initiating immediate treatment using aggressive therapy with disease-modifying antirheumatic drugs or a combination of disease-modifying antirheumatic drugs plus biological agents (BAs). BAs include genetically engineered agents that target specific inflammatory cells, cellular interactions, or cytokines that cause tissue damage. After the introduction of BAs, patients with RA have experienced significant improvement in their quality of December 2013
CERVICAL SPINE
life, especially those patients with a poor response to methotrexate.'"" BAs have been reported to reduce disease activity and retard or even halt structural damage to peripheral j oints.''-'Gonsequently, there is a growing interest in determining whether this strong disease-controlling activity of BAs can also stave off or delay progression of cervical spine lesions in RA. Our preliminary report identified pre-existing cervical lesions as the sole predictor for the progression of cervical lesions." However, the limited statistical power in that study did not allow us to identify predictors for patients without cervical lesions. Therefore, the purpose of this study was to investigate the effect of BAs on the development and progression of cervical spine lesions and to identify possible predictors of lesion progression in a larger cohort.
PATIENTS AND METHODS Among the 151 subjects who received more than 2 years of continuous treatment with BAs such as infliximab, etanercept, or tocilizumab between 2003 and 2010, 91 subjects (74 females, 17 males) who had undergone cervical radiography at both baseline and at the final visit were enrolled in this study. Seventy-seven percent (70/91) of the patients were free of cervical symptoms at the time of BA introduction. All patients fulfilled the 1987 American Gollege of Rheumatism Association classification criteria for RA.'"* Patients' mean age at the start of BA treatment was 56.8 ± 9.9 (range, 33-72) years, their mean disease duration was 11.0 ± 9.0 (range, 0.5-30) months, and their mean radiographical interval was 3.9 ± 1 . 4 (range, 2.6-7.3) years. All patients were concomitantly administered both methotrexate (dose at baseline, 5.8 ± 3 . 7 mg; dose at final visit, 5.1 ± 3.7 mg) and prednisolone (dose at baseline, 6.8 ± 4.2 mg; dose at final visit, 2.6 ± 2.8 mg). According to the Steinbrocker classification,'^ 5 patients belonged to stage I, 17 to stage II, 34 to stage III, and 35 to stage IV. According to the functional classification of RA,'^' 10 patients belonged to class 1, 69 patients to class 2, and 12 patients to class 3. The clinical endpoints assessed were scores of joint tenderness and swelling at 28 sites, G-reactive protein (GRP) levels, matrix-metalloproteinase-3 (MMP-3) levels, the disease activity score (DAS)-GRP, and the Furopean League Against Rheumatism (EULAR) response criteria. Radiographical Evaluation The radiographical definitions of a cervical spine lesion were an atlantodental interval (ADI) more than 3 mm for AAS, Ranawat value'* less than 13 mm for VS, and anterior or posterior listhesis more than 2 mm for SS. Disease progression was defined radiographically as an increase in ADI more than 2 mm for AAS, a decrease in both Ranawat and RedlundJohnell values'" more than 2 mm for VS, and an increase in listhesis more than 2 mm for SS. Evaluation of Cervical Myelopathy The severity of neurological compromise was categorized according to the Ranawat classification of rheumatoid Spine
Effect of BAs on the Development of Cervical Lesions • Kaito et al
myelopathy. "" Glass 1 patients show no neurological deficit, class 2 patients exhibit subjective weakness with hyper-reflexia and dysesthesia, and class 3 patients demonstrate both objective muscle weakness and long tract signs (3A, ambulatory; 3B, bed bound or chair bound). Statistical Analyses Statistical analyses were performed using PASW Statistics version 18 software (SPSS Inc., Ghicago, IL). Values were compared using the paired t test, x^ test, and Mann-Whitney U test. To assess predictors of radiological progression, multivariate logistic regression analysis was performed using variables that had P < 0.20 on univariate analysis. P values less than 0.05 were considered significant. Intraobserver and interobserver interclass correlation coefficients (IGGs) for ADI, Ranawat and Redlund-Johnell values were calculated in 30 patients. For the analysis of intraobserver IGG, the first author measured these parameters twice at a 1-week interval. For the analysis of interobserver IGG, 2 of the authors (H.F. and T.M.) measured these parameters. RESULTS At the final visit, BAs such as infliximab were administered in 29 patients, etanercept in 17 patients, tocilizumab in 36 patients, adalimumab in 5 patients, abatacept in 2 patients, and golimumab in 2 patients (the switch-over rate was 53%). The clinical parameter measurements are shown in Table 1. BA administration significantly decreased DAS-GRP values, swollen and tender joint counts, GRP and MMP-3 levels, and the amount of steroid taken from the baseline visit to the final visit. BAs did not alter the level of methotrexate intake. Radiological Evaluation At the initiation of BA treatment, 44 patients had no cervical spine lesions (no lesion group), 29 patients had AAS alone (AAS group), and 18 patients had VS alone (VS group). At the final visit, only 3 patients (7%) in the no lesion group had developed AAS. In contrast, 23 patients (79%) in the AAS group showed progression or development of their cervical spine lesion (6 in AAS, 16 in VS, and 1 in SS), whereas 14 (72%) showed progression in the VS group (10 in VS, 1 for both VS and SS, and 3 for SS; Table 2). The incidence of progression or development of cervical spine lesions was significantly lower in the no lesion group than in the AAS and VS groups (P < 0.001, x' test). The values of the parameters measured in all the subjects were as follows: the mean ADI changed from 3.1 ± 2.4 mm to 3.6 ± 2.8 mm (P < 0.001); the mean Ranawat value decreased from 15.2 ± 3.1 mm to 13.8 ± 3.9 mm (P < 0.001); and the Redlund-Johnell value changed from 36.3 ± 5.7 mm to 34.8 ± 6.3 mm (P < 0.001, all P values assessed via paired t test). Intraobserver and interobserver IGGs were 0.997 (95% GI, 0.994-0.999) and 0.993 (95% GI, 0.9870.996) for AAS, 0.987 (95% GI, 0.974-0.994) and 0.919 (95% GI, 0.860-0.957) for the Ranawat value, and 0.997 (95% GI, 0.993-0.998) and 0.976 (95% GI, 0.957-0.988) for the Redlund-Johnell value, respectively. www.spinejournal.com
2259
Spine
CERVICAL SPINE
Effect of BAs on the Development of Cervical Lesions • Kaito et al
TABLE 1 . | w e n r
i
uemograpmcs ana i^imicai « l ^ m e t e r s at Baseline and at t h ^ a linalVisit .• ^•¿^::.i:-. ^^ ^.fl
Baseline
Patient Demographics Age
TABLE 2 patterns
56.8 ± 9.9
No. of Patients
Final Visit None
None
44
17:74
Sex (M:F)
OT Krogression OT L.ervicai No. of Patients 41
AAS
3
AAS nonprogressive
6
AAS progressive
6
Disease duration period (yr)
11.0 ± 9.0
Radiographical interval (yr)
3.9 ± 1.4
Steinbrocker stage (1:II:I11:1V)
5:17:34:35
AAS + VS
16
Functional class (1:2:3:4)
10:69:12:0
AAS + SS
1
DFXA lumbar 7 score
-1.0 ± 1.3
VS nonprogressive
5
DFXA hip 7 score
^ 1 . 6 ± 1.3
VS progressive
10
VS progressive + SS
1
VS nonprogressive + SS
3
AAS
VS
29
18
Clinical Parameters Baseline
Final Visit
P*
Prednisolone (mg/d)
6.8 ± 4.2
2.6 ± 2.8
Spine CERVICAL SPINE
Predictors for the Progression of Cervical Lesion in Rheumatoid Arthritis Under the Treatment of Biological Agents Takashi Kaito, MD,* Shirou Ohshima, MD,t Hiroyasu Fujiwara, Takahiro Makino, MD,* and KazuoYonenobu, MD§
Study Design. Retrospective cohort analysis. Objective. To clarify the effect of biological agents (BAs) on the development and progression of cervical lesions in patients with rheumatoid arthritis (RA) and to identify biomarkers that accurately predict disease progression. Summary of Background Data. The introduction of BAs changed the paradigm of RA treatment. However, their effects on cervical lesions in patients with RA have not been studied. Methods. Ninety-one subjects who had received BAs for 2 years or more were enrolled. Mean radiographical interval was 3.9 years. Disease activity was evaluated by disease activity score-C-reactive protein levels, and matrix metalloproteinase-3 levels. Cervical lesions were defined as an atlantodental interval more than 3 mm for atlantoaxial subluxation (AAS), Ranawat value less than 13 mm for vertical subluxation (VS), and anterior or posterior listhesis more than 2 mm for subaxial subluxation. Disease progression was defined radiographically as an increase in the atlantodental interval more than 2 mm for AAS, a decrease in both Ranawat and RedlundJohnell values more than 2 mm forVS, and an increase in listhesis more than 2 mm for subaxial subluxation. We used multivariate regression techniques to assess predictors of disease progression. Results. Baseline radiographical evaluation showed no preexisting cervical lesion in 44 patients, AAS in 29, and VS in 18. Radiological progression occurred in 7% patients without baseline lesions, 79% in the AAS group, and 72% in the VS group. The From the *Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan; Departments of tRheumatology; and ^Orthopaedic Surgery, National Hospital Organization Osaka Minami Medical Center, Osaka, Japan; and §Graduate School of Health Care Sciences, Jikei Institute, Osaka, Japan. Acknowledgment date: July 31, 2013. First revision date: Septemher 5, 2013. Second revision date: September 21, 2013. Acceptance date: Septemher 25, 2013. The device(s)/drug(s) is/are FDA-approved or approved by corresponding national agency for this indication. The Japan Orthopaedics and Traumatology Foundation, Inc. No. 260 grant funds were received in support of this work. No relevant financial activities outside the submitted work. Address correspondence and reprint requests to Takashi Kaito, MD, Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; E-mail: takashikaito ©gmail.com DOi: 10.1097/BRS.0000000000000066 2258
www.spinejournal.com
incidence of progression was significantly lower in patients without lesions at baseline. Multivariate regression analysis demonstrated pre-existing cervical lesions, disease activity score-C-reactive protein levels at baseline and metalloproteinase-3 levels at final visit as good predictors of RA progression. Conclusion. BAs prevented de novo cervical lesions in patients with RA but failed to control progression in patients with preexisting cervical lesions. Disease activity score-C-reactive protein levels at baseline were related to pre-existing joint destruction, and metalloproteinase-3 levels accurately predicted ongoing bone destruction during BA treatment. Key words: biological agent, rheumatoid arthritis, cervical spine, disease activity, radiographical progression, pre-existing cervical lesion, disease activity score (DAS), matrix metalloproteinase-3 (MMP-3), predictor, multivariate regression analysis, neck pain.
Level of Evidence: 3 Spine 2013;38:2258-2263
R
heumatoid arthritis (RA) is a chronic inflammatory immune disorder that is characterized by inflammation of synovial membranes and the release of inflammatory cytokines that ultimately results in joint destruction and disability. Cervical spine involvement is a common complication of RA, occurring in 25% to 86% patients.'-- This inflammatory process can lead to progressive joint destruction and ligamentous laxity, which can result in cervical spine subluxation and instability. The most common type of anatomical cervical spine deformity is atlantoaxial subluxation (AAS), followed by vertical subluxation (VS) and subaxial subluxation (SS).' These anatomic deformities may cause spinal cord or brainstem compression, with resultant neurological deficits such as cervical myelopathy, paresis, and even death."*"** Treatment paradigms for RA have recently undergone a major shift. Standard of care now entails initiating immediate treatment using aggressive therapy with disease-modifying antirheumatic drugs or a combination of disease-modifying antirheumatic drugs plus biological agents (BAs). BAs include genetically engineered agents that target specific inflammatory cells, cellular interactions, or cytokines that cause tissue damage. After the introduction of BAs, patients with RA have experienced significant improvement in their quality of December 2013
CERVICAL SPINE
life, especially those patients with a poor response to methotrexate.'"" BAs have been reported to reduce disease activity and retard or even halt structural damage to peripheral j oints.''-'Gonsequently, there is a growing interest in determining whether this strong disease-controlling activity of BAs can also stave off or delay progression of cervical spine lesions in RA. Our preliminary report identified pre-existing cervical lesions as the sole predictor for the progression of cervical lesions." However, the limited statistical power in that study did not allow us to identify predictors for patients without cervical lesions. Therefore, the purpose of this study was to investigate the effect of BAs on the development and progression of cervical spine lesions and to identify possible predictors of lesion progression in a larger cohort.
PATIENTS AND METHODS Among the 151 subjects who received more than 2 years of continuous treatment with BAs such as infliximab, etanercept, or tocilizumab between 2003 and 2010, 91 subjects (74 females, 17 males) who had undergone cervical radiography at both baseline and at the final visit were enrolled in this study. Seventy-seven percent (70/91) of the patients were free of cervical symptoms at the time of BA introduction. All patients fulfilled the 1987 American Gollege of Rheumatism Association classification criteria for RA.'"* Patients' mean age at the start of BA treatment was 56.8 ± 9.9 (range, 33-72) years, their mean disease duration was 11.0 ± 9.0 (range, 0.5-30) months, and their mean radiographical interval was 3.9 ± 1 . 4 (range, 2.6-7.3) years. All patients were concomitantly administered both methotrexate (dose at baseline, 5.8 ± 3 . 7 mg; dose at final visit, 5.1 ± 3.7 mg) and prednisolone (dose at baseline, 6.8 ± 4.2 mg; dose at final visit, 2.6 ± 2.8 mg). According to the Steinbrocker classification,'^ 5 patients belonged to stage I, 17 to stage II, 34 to stage III, and 35 to stage IV. According to the functional classification of RA,'^' 10 patients belonged to class 1, 69 patients to class 2, and 12 patients to class 3. The clinical endpoints assessed were scores of joint tenderness and swelling at 28 sites, G-reactive protein (GRP) levels, matrix-metalloproteinase-3 (MMP-3) levels, the disease activity score (DAS)-GRP, and the Furopean League Against Rheumatism (EULAR) response criteria. Radiographical Evaluation The radiographical definitions of a cervical spine lesion were an atlantodental interval (ADI) more than 3 mm for AAS, Ranawat value'* less than 13 mm for VS, and anterior or posterior listhesis more than 2 mm for SS. Disease progression was defined radiographically as an increase in ADI more than 2 mm for AAS, a decrease in both Ranawat and RedlundJohnell values'" more than 2 mm for VS, and an increase in listhesis more than 2 mm for SS. Evaluation of Cervical Myelopathy The severity of neurological compromise was categorized according to the Ranawat classification of rheumatoid Spine
Effect of BAs on the Development of Cervical Lesions • Kaito et al
myelopathy. "" Glass 1 patients show no neurological deficit, class 2 patients exhibit subjective weakness with hyper-reflexia and dysesthesia, and class 3 patients demonstrate both objective muscle weakness and long tract signs (3A, ambulatory; 3B, bed bound or chair bound). Statistical Analyses Statistical analyses were performed using PASW Statistics version 18 software (SPSS Inc., Ghicago, IL). Values were compared using the paired t test, x^ test, and Mann-Whitney U test. To assess predictors of radiological progression, multivariate logistic regression analysis was performed using variables that had P < 0.20 on univariate analysis. P values less than 0.05 were considered significant. Intraobserver and interobserver interclass correlation coefficients (IGGs) for ADI, Ranawat and Redlund-Johnell values were calculated in 30 patients. For the analysis of intraobserver IGG, the first author measured these parameters twice at a 1-week interval. For the analysis of interobserver IGG, 2 of the authors (H.F. and T.M.) measured these parameters. RESULTS At the final visit, BAs such as infliximab were administered in 29 patients, etanercept in 17 patients, tocilizumab in 36 patients, adalimumab in 5 patients, abatacept in 2 patients, and golimumab in 2 patients (the switch-over rate was 53%). The clinical parameter measurements are shown in Table 1. BA administration significantly decreased DAS-GRP values, swollen and tender joint counts, GRP and MMP-3 levels, and the amount of steroid taken from the baseline visit to the final visit. BAs did not alter the level of methotrexate intake. Radiological Evaluation At the initiation of BA treatment, 44 patients had no cervical spine lesions (no lesion group), 29 patients had AAS alone (AAS group), and 18 patients had VS alone (VS group). At the final visit, only 3 patients (7%) in the no lesion group had developed AAS. In contrast, 23 patients (79%) in the AAS group showed progression or development of their cervical spine lesion (6 in AAS, 16 in VS, and 1 in SS), whereas 14 (72%) showed progression in the VS group (10 in VS, 1 for both VS and SS, and 3 for SS; Table 2). The incidence of progression or development of cervical spine lesions was significantly lower in the no lesion group than in the AAS and VS groups (P < 0.001, x' test). The values of the parameters measured in all the subjects were as follows: the mean ADI changed from 3.1 ± 2.4 mm to 3.6 ± 2.8 mm (P < 0.001); the mean Ranawat value decreased from 15.2 ± 3.1 mm to 13.8 ± 3.9 mm (P < 0.001); and the Redlund-Johnell value changed from 36.3 ± 5.7 mm to 34.8 ± 6.3 mm (P < 0.001, all P values assessed via paired t test). Intraobserver and interobserver IGGs were 0.997 (95% GI, 0.994-0.999) and 0.993 (95% GI, 0.9870.996) for AAS, 0.987 (95% GI, 0.974-0.994) and 0.919 (95% GI, 0.860-0.957) for the Ranawat value, and 0.997 (95% GI, 0.993-0.998) and 0.976 (95% GI, 0.957-0.988) for the Redlund-Johnell value, respectively. www.spinejournal.com
2259
Spine
CERVICAL SPINE
Effect of BAs on the Development of Cervical Lesions • Kaito et al
TABLE 1 . | w e n r
i
uemograpmcs ana i^imicai « l ^ m e t e r s at Baseline and at t h ^ a linalVisit .• ^•¿^::.i:-. ^^ ^.fl
Baseline
Patient Demographics Age
TABLE 2 patterns
56.8 ± 9.9
No. of Patients
Final Visit None
None
44
17:74
Sex (M:F)
OT Krogression OT L.ervicai No. of Patients 41
AAS
3
AAS nonprogressive
6
AAS progressive
6
Disease duration period (yr)
11.0 ± 9.0
Radiographical interval (yr)
3.9 ± 1.4
Steinbrocker stage (1:II:I11:1V)
5:17:34:35
AAS + VS
16
Functional class (1:2:3:4)
10:69:12:0
AAS + SS
1
DFXA lumbar 7 score
-1.0 ± 1.3
VS nonprogressive
5
DFXA hip 7 score
^ 1 . 6 ± 1.3
VS progressive
10
VS progressive + SS
1
VS nonprogressive + SS
3
AAS
VS
29
18
Clinical Parameters Baseline
Final Visit
P*
Prednisolone (mg/d)
6.8 ± 4.2
2.6 ± 2.8
