Risk Factors Associated With Cervical Spine Lesions in Patients With Rheumatoid Arthritis: The Role of Biological Agents

Purpose To investigate the prevalence and risk factors of cervical lesions in patients with rheumatoid arthritis (RA) under current pharmacological treatments with biological agents. Methods One hundred and eighty-ve consecutive patients with RA who underwent both cervical plain radiography and bone mineral density (BMD) scanning were enrolled. RA cervical lesions included atlantoaxial subluxation (AAS), vertical subluxation (VS), and subaxial subluxation (SAS). We assigned patients with AAS, VS, or SAS to the cervical-lesion group, and all other patients to the non-cervical-lesion group. Radiological ndings, BMD, and clinical data on RA were collected. We used multivariate logistic regression analyses to assess the risk factors of cervical lesions in patients with RA.


Introduction
Rheumatoid arthritis (RA) is a type of autoimmune arthritis that causes chronic in ammatory synovitis.
RA lesions also invade the spine, and cervical lesions are particularly common in RA, which results in several characteristic deformities [1]. These deformities include atlantoaxial subluxation (AAS), vertical subluxation (VS), and subaxial subluxation (SAS). They possibly lead to cervical instabilities that may cause neurologic damage and induce a fatal status due to compression of the spinal cord or brain stem [2].
The treatment of RA has changed dramatically due to recent developments in biological agents. The available biological agents are the proin ammatory cytokine therapies, such as in iximab, which act by inhibition of tumor necrosis factor α (TNFα). These drugs are effective in blocking disease activities and joint degradation [3]. The incidence of cervical spine instability is 32-42%, which may be decreasing because of stable disease control due to the usage of biological agents [4,5] Unfortunately, the incidence of cervical instability in patients with RA is still greater than 30%, which represents a major health issue.
There have been several reports on RA cervical lesions [4][5][6][7][8][9]. However, few reports have described the association between RA cervical lesions and osteoporosis, especially in patients with VS that could be induced by the collapse of lateral masses in the upper cervical spine [10,1] Therefore, osteoporosis could affect the progression of VS, but the association between osteoporosis and VS development remains uncertain.
The purpose of our study was to investigate the prevalence and risk factors of cervical lesions in patients with RA under current pharmacologic treatment after the approval of biological agents. In addition, we investigated the relationship between osteoporosis and VS development.

Materials And Methods
Between 2008 and 2016, a total of 317 patients with RA who underwent cervical plain radiography were reviewed. Seventeen patients who had a history of cervical surgery were excluded. Finally, 185 patients who underwent both cervical plain radiography and bone mineral density (BMD) scans were included in this study. All patients ful lled the American Rheumatism Association RA criteria [12]. All study participants provided informed consent, and the study design was reviewed and approved by the Ethical Committee for Clinical Research at Yokohama City University Medical Center.
Radiological ndings and BMD data were collected from the electronic medical records. Clinical data on RA included age at RA onset and RA disease duration, and data on current medications including the use of prednisolone, methotrexate (MTX), and biological agents were also obtained. In addition, the Disease Activity Score based on C-reactive protein (DAS28-CRP) was reviewed. The patients were administered the following biological agents: abatacept (n=17), etanercept (n=12), in iximab (n=10), tocilizumab (n=8), certolizumab pegol (n=5), adalimumab (n=3), and golimumab (n=1).
The BMD of the lumbar spine and femoral neck was measured using Hologic Horizon A dual X-ray bone densitometry (Hologic, Marlborough, MA, USA). The BMD is described as a young adult mean score. We divided the patients into two groups based on the results of their radiographic evaluation of the cervical spine: the cervical-lesion group included patients with AAS, VS, or SAS, and the non-cervical-lesion group included patients with no cervical lesions. In the cervical-lesion group, we subdivided the patients into two subgroups: the VS group that included patients with VS, and the non-VS group that included patients with no VS.

Radiographic evaluation
Lateral cervical radiographs were obtained in neutral, extension, and exion positions. We measured the atlantodental interval, Ranawat value, and subluxation. AAS was de ned as atlantodental interval more than 3 mm [13], VS was de ned as a Ranawat value less than 13 mm [14], and SAS was de ned as vertebral translation more than 2 mm without osteophyte formation [15].

Statistical analysis
The results are expressed as mean ± standard deviation. Statistical comparisons between the groups were performed using the student's t-test, Mann-Whitney U test, chi-square test, or Fisher's exact test as appropriate. Multivariate logistic regression analysis was performed to assess the risk factors of cervical lesions. P-values of less than 0.05 were considered statistically signi cant. All statistical analyses were performed using JMP 12 (SAS Institute Inc., Cary, NC, USA).

Results
The enrolled patients included 12 males and 173 females with a mean age of 67.1 years. The mean age at RA onset was 52.9 years, and the mean RA disease duration was 14.3 years (Table 1).
There were 106 (57%) patients in the cervical-lesion group and 79 (43%) patients in the non-cervicallesion group. There were 78 patients with AAS, 42 with SAS, and 31 with VS.
In the univariate analysis comparing the cervical-lesion and non-cervical-lesion groups, the age at onset and BMD of the femoral neck in the cervical-lesion group was signi cantly lower than that in the noncervical-lesion group. RA disease duration in the cervical-lesion group was signi cantly higher than that in the non-cervical-lesion group. The usage ratios of prednisolone and biological agents in the cervicallesion group were signi cantly higher than those in the non-cervical-lesion group ( Table 2).
Multiple logistic regression analysis revealed that RA duration, use of prednisolone, use of biological agents, and BMD of the femoral neck were signi cant risk factors of cervical lesions in patients with RA (Table 3). In the univariate analysis comparing the VS and non-VS groups, the BMD of the femoral neck in the VS group was signi cantly lower than that in the non-VS group (Table 4). However, multiple logistic regression analysis for VS development did not show any signi cant differences.

Discussion
In this study, the prevalence of patients with cervical lesions was 57%. RA disease duration, use of prednisolone, biological agents, and BMD of the femoral neck were identi ed as risk factors of cervical lesions.
The cervical spine is frequently involved in patients with RA, and neural impairment is a consequent complication. Irreversible spinal cord damage, di culty with ambulation, respiratory dysfunction, and even sudden death can occur [2]. Once neurological de cits occur, neural impairment becomes progressive [16], and even surgical treatment cannot prevent neurological deterioration [17]. Therefore, RA cervical lesions are still a major health concern. Several studies have reported the risk factors of cervical lesions in RA patients [6][7][8]. However, it has not been well investigated after the use of biological agents became more popular.
The registration of biological agents has changed the standard of care for patients with rheumatoid arthritis. The available biological agents are anti-proin ammatory cytokine therapies, such as TNFα blockers and a T cell activation inhibitor [3].
Terashima et al. reported that mutilating changes at baseline, corticosteroid administration, and previous joint surgery were predictors of severe aggravation of cervical spine instabilities in RA [8]. Kaito et al. also reported that disease duration and Steinbrocker stage were identi ed as independent risk factors for the incidence of cervical lesions [5]. In this study, the multivariate analysis showed that RA disease duration, use of prednisolone, use of biological agents, and BMD of the femoral neck were risk factors of cervical lesions. Although biological agents can prevent the onset of cervical lesions, pre-existing cervical lesions cannot be reversed [9].
Several studies have shown that the prevalence of cervical lesions in RA patients ranged from 32% to 57% [4][5][6][7][8]. Fujiwara et al. prospectively examined 173 patients to clarify the development and progression of cervical spinal involvement in RA. The incidence of cervical lesions was 43% at 12.3 years of RA and 57% at 16.5 years of RA. As follow-up proceeded, more cases of cervical lesions have become apparent, indicating that cervical lesions are progressive [6]. In Japan, biological agents were approved in 2003.
This might have had an in uence on stabilizing RA cervical lesions. In fact, Takahashi et al. reported that 42% of 220 patients from 2010 to 2011 had cervical spine instability. The prevalence has decreased since the approval of biological agents. However, there were no effects of MTX and biological agents on cervical instability [4]. Kaito et al. reported that the incidence of patients with RA onset after 2000 with any cervical lesions was 31.8%. Biological agents effectively prevented the emergence of new cervical lesions but could not prevent the progression of pre-existing cervical lesions [5,9].
Our study indicated that the prevalence of patients with cervical lesions was 57%. There were 78 patients with AAS, 42 with SAS, and 31 with VS. This prevalence is higher than that in recent studies in this era of biological agents [4,5]. This might be due to the mean RA disease duration in our study, which was 14.3 years compared to the 8.5 and 11.1 years reported in previous studies. In addition, a large proportion of patients with more advanced diseases might be treated by the use of biological agents.
There have been few reports that described the association between RA cervical lesions and osteoporosis. Neva et al. reported that the severity of atlantoaxial disorders positively correlated with the grade of destruction in evaluated joints. Furthermore, patients with atlantoaxial disorders presented with decreased BMD of the femoral neck [10]. VS usually occurs after AAS. VS is considered to be a serious condition in patients with RA because it can be associated with a poor survival rate and sudden death [2]. Dokai et al. hypothesized that osteoporosis could affect the progression of VS. Their results indicated that VS could be induced by the collapse of the lateral masses in the upper cervical spine. The risk factors for VS development were age, RA symptom duration, and BMD (lumbar). However, they could not show a statistically signi cant relationship between osteoporosis and VS development [11]. In our current study, the prevalence of BMD of the femoral neck was 58.4% in the VS group, which was signi cantly lower than the 65.9% observed in the non-VS group. However, the difference in BMD of the lumbar spine did not show any statistical signi cance. This discrepancy might be due to osteophytes and endplate erosions that have been described to affect the measurement of BMD at the lumbar spine [10,18]. Nevertheless, our results indicated that the general status of osteoporosis could contribute to the development of VS. The appropriate treatment of BMD de ciency may prevent the development of VS.
Tanaka et al. reported that denosumab could prevent the progression of bone erosion in the early stage of RA and play a useful role in anti-osteoporotic therapy. However, denosumab has no effect on joint in ammation or cartilage destruction in RA [19]. The complex osteoimmunological network in patients with RA suggests that the powerful anti-in ammatory activity of biological agents beyond the control of the disease was likely to reduce osteoporosis and fracture risk [20]. Therefore, a combination of biological agents and denosumab may be effective for the prevention of VS. Further studies are required to establish these treatments.
There are several limitations to this study. First, in this cross-sectional study, we reviewed patients with varying degrees of spinal instability, and we did not consider the duration of RA treatment and the dosage of medications. This may have led to a selection bias, which may have resulted in the use of biological agents being identi ed as a risk factor of RA cervical lesions. Second, we did not access the data on clinical and neurological symptoms. Only patients with RA who complained of symptoms of cervical lesions were included in this study. It is possible that only more frail patients had a bone scan as opposed to all patients with RA to limit selection bias towards patients with lower BMD. Third, this was a crosssectional study; consequently, disease activity was only re ected over a certain period of time. A longitudinal evaluation was not performed.

Conclusions
In conclusion, the prevalence of patients with cervical lesions was 57%. The incidence of RA is still a major health issue. Age at RA onset and BMD of the femoral neck in the cervical-lesion group were signi cantly lower in the cervical-lesion group than in the non-cervical-lesion group. RA disease duration in the cervical-lesion group was signi cantly higher than that in the non-cervical-lesion group. RA disease duration, usage of prednisolone, biological agents, and BMD of the femoral neck were signi cant risk factors of cervical lesions in patients with RA. The BMD of the femoral neck was lower in the VS group than in the non-VS group. Finally, the general status of osteoporosis could contribute to the development of VS.