Cervical Spine Involvement in Rheumatoid Arthritis Over Time
Cervical Spine Involvement in Rheumatoid Arthritis Over Time
Cervical spine involvement in RA has long been recognized. Varying degrees of prevalence have been reported as reflected in our literature search. This can be explained by numerous factors, such as differences in sample size, disease duration, follow-up period, medications used, and radiological criteria. There may also be reporting bias in which once something is well described, fewer publications follow over time. To the best of our knowledge, this is the first study to systematically evaluate the prevalence and progression of cervical subluxations and cervical myelopathy in patients with RA.
The earliest form of cervical instability in patients with RA has been shown to be a reducible AAS. AAS is the most common cervical subluxation in RA. (AAS is twice as common as VS or SAS, and other types are very uncommon.) No regional differences in aAAS were found between Asia, Europe, and North America. However, a significant temporal reduction in the prevalence of aAAS exists, decreasing by one third from the 1960s and 1970s to 2000. The could reflect the changes in RA management (earlier introduction of DMARDs with higher doses and more combinations), or changing epidemiology of RA with fewer complications compared to years ago, and or reporting bias where the complications that are well described are less likely to be published over time so the contemporary rates may not be fully reported (publication bias).
The effects of DMARDs were addressed specifically in a number of studies. For example, Neva and colleagues recruited 198 early RA patients who were randomly assigned to either combination DMARDs (sulfasalazine, methotrexate, and hydroxychloroquine) or a single DMARD with or without prednisone. After 2 years of follow-up, aAAS was found in 3% of the patients. None of the patients who were receiving combination therapies had aAAS. Lending further support to the role of DMARDs in preventing cervical involvement, biological agents were examined in two studies. A cohort of 38 early RA patients who received more than 2 years of continuous infliximab treatment in addition to methotrexate and prednisone was followed for 4 years. Only one of the patients developed de novo AAS. In another study, a group of 91 patients who were on infliximab, etanercept, or tocilizumab was followed for 4 years and three developed AAS.
Whereas the prevalence of aAAS seemed to be on the decline with the introduction of DMARDs, that of SAS and VS did not. This could be related to the natural progression of cervical subluxations. Our results demonstrated that, once formed, 4 out of 100 aAAS lesions would have an increase in atlanto-dental interval per year. After a certain point, AAS can have the appearance of stabilization or even improvement in the atlanto-dental interval on x-ray, signaling the beginning of VS. For example, Rana followed 41 AAS patients over a period of 10 years. Ten percent of the patients had less AAS secondary to new development of VS and upward translocation of odontoid process. Smith and colleagues reported a similar phenomenon in 13% of their cases. SAS generally develops at a later stage and is often seen after development of VS. The lack of temporal reduction in the prevalence of VS and SAS may therefore be because DMARDs are less effective in preventing progression of existing lesions or due to a very low prevalence resulting in insufficient power to detect a change. When biologics were used, if there was C-spine subluxation, 79% to 80% progressed further. We suspect that, eventually, the prevalence of VS and SAS will decrease as fewer de novo AASs are being formed.
Although cervical subluxations are common as illustrated above, their clinical presentation is often asymptomatic or associated with neck pain. Neurological complications are less frequent and tend to occur later in the disease course. In our study, we reported a 5% prevalence rate for observed neurological deficits in patients with RA on the basis of the Ranawat grading system. Class I patients have pain but no neural deficits and therefore were not counted for our study. Class II patients have subjective weakness with hyperreflexia and dyssthesias. Class III patients have objective weakness and long tract signs. Class IIIA patients are ambulatory whereas IIIB patients are non-ambulatory. Serious complications were rare, however. Paraplegia was reported in 0.2% of patients with RA, and symptoms of possible brainstem involvement, such as vertigo and drop attacks, were found in another 0.2%. We did not observe a decrease in the already-rare prevalence or progression of cervical myelopathy over time.
This study has limitations. Non-English studies were excluded. Although some asymmetries existed in our funnel plots, we do not believe that this represented major publication bias. Our data had significant heterogeneity. Age, disease duration, RA activity and severity, and treatments such as DMARDs and corticosteroids were not assessed. Estimates were generated at a population level. Inclusion criteria for some case series were not described in detail, and so the generalizability of the findings is unknown. We did not present the overall meta-analysis results, because heterogeneity (as measured by the I with respect to between-study variation) was high, but we could explore trial-level differences contributing to the heterogeneity (such as year of publication) by using meta-regression, which quantifies the effect of a study characteristic (publication year) on the overall effect of heterogeneity in the rate of C-spine subluxations. The review may be limited by variation in study quality, especially with the earlier publications having lower STROBE scores (as is often seen when comparing older with more recent studies due to different standards). Lastly, another factor to consider when interpreting the study is that cervical complications tend to develop over time. Even though our review included data from recent studies, the long-term effects of modern DMARDs (type and how we use them) on development and progression of cervical instabilities have yet to be adequately studied, and it could take years before differences in complications can be identified as C-spine complications could take years to develop or be prevented.
Discussion
Cervical spine involvement in RA has long been recognized. Varying degrees of prevalence have been reported as reflected in our literature search. This can be explained by numerous factors, such as differences in sample size, disease duration, follow-up period, medications used, and radiological criteria. There may also be reporting bias in which once something is well described, fewer publications follow over time. To the best of our knowledge, this is the first study to systematically evaluate the prevalence and progression of cervical subluxations and cervical myelopathy in patients with RA.
The earliest form of cervical instability in patients with RA has been shown to be a reducible AAS. AAS is the most common cervical subluxation in RA. (AAS is twice as common as VS or SAS, and other types are very uncommon.) No regional differences in aAAS were found between Asia, Europe, and North America. However, a significant temporal reduction in the prevalence of aAAS exists, decreasing by one third from the 1960s and 1970s to 2000. The could reflect the changes in RA management (earlier introduction of DMARDs with higher doses and more combinations), or changing epidemiology of RA with fewer complications compared to years ago, and or reporting bias where the complications that are well described are less likely to be published over time so the contemporary rates may not be fully reported (publication bias).
The effects of DMARDs were addressed specifically in a number of studies. For example, Neva and colleagues recruited 198 early RA patients who were randomly assigned to either combination DMARDs (sulfasalazine, methotrexate, and hydroxychloroquine) or a single DMARD with or without prednisone. After 2 years of follow-up, aAAS was found in 3% of the patients. None of the patients who were receiving combination therapies had aAAS. Lending further support to the role of DMARDs in preventing cervical involvement, biological agents were examined in two studies. A cohort of 38 early RA patients who received more than 2 years of continuous infliximab treatment in addition to methotrexate and prednisone was followed for 4 years. Only one of the patients developed de novo AAS. In another study, a group of 91 patients who were on infliximab, etanercept, or tocilizumab was followed for 4 years and three developed AAS.
Whereas the prevalence of aAAS seemed to be on the decline with the introduction of DMARDs, that of SAS and VS did not. This could be related to the natural progression of cervical subluxations. Our results demonstrated that, once formed, 4 out of 100 aAAS lesions would have an increase in atlanto-dental interval per year. After a certain point, AAS can have the appearance of stabilization or even improvement in the atlanto-dental interval on x-ray, signaling the beginning of VS. For example, Rana followed 41 AAS patients over a period of 10 years. Ten percent of the patients had less AAS secondary to new development of VS and upward translocation of odontoid process. Smith and colleagues reported a similar phenomenon in 13% of their cases. SAS generally develops at a later stage and is often seen after development of VS. The lack of temporal reduction in the prevalence of VS and SAS may therefore be because DMARDs are less effective in preventing progression of existing lesions or due to a very low prevalence resulting in insufficient power to detect a change. When biologics were used, if there was C-spine subluxation, 79% to 80% progressed further. We suspect that, eventually, the prevalence of VS and SAS will decrease as fewer de novo AASs are being formed.
Although cervical subluxations are common as illustrated above, their clinical presentation is often asymptomatic or associated with neck pain. Neurological complications are less frequent and tend to occur later in the disease course. In our study, we reported a 5% prevalence rate for observed neurological deficits in patients with RA on the basis of the Ranawat grading system. Class I patients have pain but no neural deficits and therefore were not counted for our study. Class II patients have subjective weakness with hyperreflexia and dyssthesias. Class III patients have objective weakness and long tract signs. Class IIIA patients are ambulatory whereas IIIB patients are non-ambulatory. Serious complications were rare, however. Paraplegia was reported in 0.2% of patients with RA, and symptoms of possible brainstem involvement, such as vertigo and drop attacks, were found in another 0.2%. We did not observe a decrease in the already-rare prevalence or progression of cervical myelopathy over time.
This study has limitations. Non-English studies were excluded. Although some asymmetries existed in our funnel plots, we do not believe that this represented major publication bias. Our data had significant heterogeneity. Age, disease duration, RA activity and severity, and treatments such as DMARDs and corticosteroids were not assessed. Estimates were generated at a population level. Inclusion criteria for some case series were not described in detail, and so the generalizability of the findings is unknown. We did not present the overall meta-analysis results, because heterogeneity (as measured by the I with respect to between-study variation) was high, but we could explore trial-level differences contributing to the heterogeneity (such as year of publication) by using meta-regression, which quantifies the effect of a study characteristic (publication year) on the overall effect of heterogeneity in the rate of C-spine subluxations. The review may be limited by variation in study quality, especially with the earlier publications having lower STROBE scores (as is often seen when comparing older with more recent studies due to different standards). Lastly, another factor to consider when interpreting the study is that cervical complications tend to develop over time. Even though our review included data from recent studies, the long-term effects of modern DMARDs (type and how we use them) on development and progression of cervical instabilities have yet to be adequately studied, and it could take years before differences in complications can be identified as C-spine complications could take years to develop or be prevented.
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