**1. Introduction**

264 Rheumatoid Arthritis – Etiology, Consequences and Co-Morbidities

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America Emerging Infections Network. (2008). Mycobacterial and other serious infections in patients receiving anti-tumor necrosis factor and other newly approved biologic therapies: case finding through the Emerging Infections Patients in Norway with rheumatoid arthritis (RA) and involvement of the cervical column with subluxations during the years 1974-1999 were routinely referred to the Rheumasurgical Department of Oslo Sanitetsforening's Rheumatism Hospital in Oslo (OSR) for critical evaluation, treatment and follow-up. The patients were recruited from a large and widely dispersed area of the country.

The primary aim of the current study was to assess the mortality rate of operated patients with cervical neurological symptoms or signs in this cohort and compare the results with RA patients operated during the same period for cervical involvement without relevant neurology. Secondarily we wanted to disclose important factors affecting the mortality rate in operated RA patients with neurology. The results for the total RA population with cervical subluxations (n=532) treated during the same 25 year period (217 operated and 315 non-operated) have been published previously (Paus et al., 2008).

#### **2. Material and methods**

#### **2.1 Patients**

All patients referred with RA and neurological symptoms or signs related to involvement of the cervical column, were consecutively included from 1974 in the present prospective cohort study. Patients with other differential diagnoses, e.g. spondyl-arthritis, were excluded. After the end-point on December 31st 1999, all medical journals of included patients were revisited.

During this period 75 patients with RA and cervical spine subluxations with cervical radiculopathy, myelopathy or paresthesia were operated on in our department. There were 54 females (72%) and 21 males (28%) with a mean age at the first visit of 60 (SD, 11.9) years.

Increased Mortality Rate in Rheumatoid Arthritis Patients with Neurological Symptoms

Numbers (percentages)

**2.3 Statistical analysis** 

operation' was included in the final model.

System (SAS version 9.1.3; Cary, North Carolina, USA).

magnetic resonance imaging (MRI).

**2.2 Radiology** 

or Signs Secondary to Cervical Spine Subluxations – Reduced Mortality if Postoperative... 267

The diagnosis of instability was made from conventional lateral radiographs of the cervical spine in maximum extension and maximum flexion (Karhu et al., 2005; Kauppi & Neva, 1998; Kwek et al., 1998). Functional radiographs were often combined with plain tomography, and later during the study period with computer tomography (CT) or

Radiographs were scored according to Teigland et al (1990) measuring both the anterior subluxation (AS) of atlas relative to axis and the vertical settling (VS) of atlas on axis measured as the so called 'AC distance'. In addition all posterior subluxations (PS) and subaxial subluxations (SS) were registered. The radiographs were not calibrated directly for distance measurements, but all examinations were taken in the same laboratory with the same equipment and with a standard distance and positioning of the head and neck relative to the film during exposures. The numbers and mean values of cervical spine subluxations for the various subgroups of patients are presented in Table 3. Bony ankylosis was

Values are presented as absolute numbers N (proportions) or mean (SD). Student's t-test and chi square test were used for testing group differences for continuous and categorical variables, respectively. Cox Proportional Hazard regression analysis was used to identify possible predictors for survival. As reference point for the time-to-event analyses we used the time at operation. Martingale residuals were used to assess the validity of the models. As the assumption of proportionality of the hazard rates was violated, an interaction term between the indicator for cervical neurology and the time variable 'years survival following

All P-values equal to or below 0.05 were considered statistically significant. Statistical analyses were performed with SPSS software, version 12.0 (SPSS Inc., Chicago), R (R Foundation for Statistical Computing, http://www.R-project.org) and Statistical Analysis

evaluated by examination of ordinary 2-plane cervical radiographs.

Number 75 24 (32) 51 (68) Operated with arthrodesis 67 (89) 18 (75) 49 (96) Arthrodesis Occiput - C1 - C2 12 (16) 4 (17) 8 (16) Arthrodesis C1 – C2 37 (49) 8 (33) 29 (57) Arthrodesis below C1 – C2 18 (24) 6 (25) 12 (24) Laminectomy 31 (41) 11 (46) 20 (39) Postoperative ankylosis 51 (76) 18 (100) 33 (67) Reoperation refixation 3 (4) 1 (6) 2 (4) Reoperation cement removal 1 (1) 0 1 (2) Release nervus occipitalis major 2 (3) 0 2 (4) Table 2. Operated RA Patients with Cervical Subluxation and relevant Neurology. Levels of Fixation, Frequency of Laminectomy and Postoperative Results with Complications and Reoperations. Distribution among Alive and Dead during the Follow-up Period. Absolute

**All Alive Dead** 


The RA diagnosis had been made at the mean age of 41 (SD, 13.7) years. By the end-point date, 51 (68%) patients had died at a mean age of 69 (SD, 9.3) years (Table 1).

Table 1. Various Data of Operated RA Patients with Cervical Subluxation with and without Neurological Symptoms or Signs. Mean Values with Standard Deviations (SD)

The total number of patients with RA and cervical problems operated in the neck during the same period was 217 patients, i.e. 142 patients without relevant, specific neurology.

The follow-up period after surgery till death or to Dec 31st 1999 for all the operated patients (n=217) was mean 8.5 (SD, 5.9) years, for those with relevant neurology (n=75) mean 6.7 (SD, 5.5) years and for those without (n=142) mean 9.8 (SD, 5.8) years. Fifty one (68%) of the patients with relevant neurology, and 93 (65%) of the patients without, died during the follow-up.

The defined selection criteriae for surgical intervention were existing or increasing atlantoaxial or subaxial subluxations above certain limits. The patients had cervical symptoms (e.g paresthesia) or neurological signs (e.g loss of sensibility, paresis or increased reflexes) from radiculopathy or myelopathy in addition to unspecific local pain not responding to conservative treatment. The neurological findings were paresthesia in 35 patients, paresis in 32, acute radiating pain in the arm(s) in 15, hyperreflexia in 14 and difficulties with urinary control in 8 patients. The localisation was in the upper extremity in 63 (84%), in the lower limb in 41 patients (55%) and in both extremity levels in 29 (39%) patients.

The aims of the operations were to remove or reduce neurological symptoms and signs with pain, stabilize the cervical spine to prevent further subluxations both horizontally and vertically, and to prevent future neurological involvement.

The medical treatment for the patients' RA was continued by the referring rheumatologist.

Operative methods changed over time, and different techniques were used with or without decompression of the spinal canal, depending on the type of cervical instability. Initially, atlantoaxial (AA) fusion would also include additional fusion to the occiput (Brattstrom & Granholm, 1976) but later AA fusion included spondylodesis of atlas and axis only. The applied methods consisted of fixation of occiput to atlas and axis in 12 patients (16%; two combined with laminectomy), fixation of atlas to axis only in 37 patients (49%; 5 of these in combination with laminectomy), 18 patients (24%) had a posterior fusion further down the cervical spine (16 of these combined with laminectomy), and 8 had laminectomy only (Table 2). The need for laminectomy was significantly (*p*<0.001) higher in the cohort with cervical neurology (31/75) than in the cohort of patients without (5/142).


Table 2. Operated RA Patients with Cervical Subluxation and relevant Neurology. Levels of Fixation, Frequency of Laminectomy and Postoperative Results with Complications and Reoperations. Distribution among Alive and Dead during the Follow-up Period. Absolute Numbers (percentages)

### **2.2 Radiology**

266 Rheumatoid Arthritis – Etiology, Consequences and Co-Morbidities

The RA diagnosis had been made at the mean age of 41 (SD, 13.7) years. By the end-point

**Operated with Neurology** 

The total number of patients with RA and cervical problems operated in the neck during the

The follow-up period after surgery till death or to Dec 31st 1999 for all the operated patients (n=217) was mean 8.5 (SD, 5.9) years, for those with relevant neurology (n=75) mean 6.7 (SD, 5.5) years and for those without (n=142) mean 9.8 (SD, 5.8) years. Fifty one (68%) of the patients with relevant neurology, and 93 (65%) of the patients without, died during the

The defined selection criteriae for surgical intervention were existing or increasing atlantoaxial or subaxial subluxations above certain limits. The patients had cervical symptoms (e.g paresthesia) or neurological signs (e.g loss of sensibility, paresis or increased reflexes) from radiculopathy or myelopathy in addition to unspecific local pain not responding to conservative treatment. The neurological findings were paresthesia in 35 patients, paresis in 32, acute radiating pain in the arm(s) in 15, hyperreflexia in 14 and difficulties with urinary control in 8 patients. The localisation was in the upper extremity in 63 (84%), in the lower limb in 41 patients (55%) and in both extremity levels in 29 (39%)

The aims of the operations were to remove or reduce neurological symptoms and signs with pain, stabilize the cervical spine to prevent further subluxations both horizontally and

The medical treatment for the patients' RA was continued by the referring rheumatologist. Operative methods changed over time, and different techniques were used with or without decompression of the spinal canal, depending on the type of cervical instability. Initially, atlantoaxial (AA) fusion would also include additional fusion to the occiput (Brattstrom & Granholm, 1976) but later AA fusion included spondylodesis of atlas and axis only. The applied methods consisted of fixation of occiput to atlas and axis in 12 patients (16%; two combined with laminectomy), fixation of atlas to axis only in 37 patients (49%; 5 of these in combination with laminectomy), 18 patients (24%) had a posterior fusion further down the cervical spine (16 of these combined with laminectomy), and 8 had laminectomy only (Table 2). The need for laminectomy was significantly (*p*<0.001) higher in the cohort with cervical

vertically, and to prevent future neurological involvement.

neurology (31/75) than in the cohort of patients without (5/142).

Total number 75 142 217 Female/male 54/21 99/43 153/64 Age at RA diagnosis 41 (13.7) 39 (14.1) 40 (13.9) Age at first visit 60 (11.9) 56 (12.3) 57 (12.3) Age at operation 61 (11.5) 58 (12.0) 59 (11.9) Follow-up period (years) 6.7 (5.5) 9.8 (5.8) 8.5 (5.9) No of dead patients (%) 51 (68) 93 (65) 144 (66) Age at death 69 (9.3) 69 (11.0) 69 (10.5) Table 1. Various Data of Operated RA Patients with Cervical Subluxation with and without

**Operated without** 

**Neurology Total** 

date, 51 (68%) patients had died at a mean age of 69 (SD, 9.3) years (Table 1).

Neurological Symptoms or Signs. Mean Values with Standard Deviations (SD)

follow-up.

patients.

same period was 217 patients, i.e. 142 patients without relevant, specific neurology.

The diagnosis of instability was made from conventional lateral radiographs of the cervical spine in maximum extension and maximum flexion (Karhu et al., 2005; Kauppi & Neva, 1998; Kwek et al., 1998). Functional radiographs were often combined with plain tomography, and later during the study period with computer tomography (CT) or magnetic resonance imaging (MRI).

Radiographs were scored according to Teigland et al (1990) measuring both the anterior subluxation (AS) of atlas relative to axis and the vertical settling (VS) of atlas on axis measured as the so called 'AC distance'. In addition all posterior subluxations (PS) and subaxial subluxations (SS) were registered. The radiographs were not calibrated directly for distance measurements, but all examinations were taken in the same laboratory with the same equipment and with a standard distance and positioning of the head and neck relative to the film during exposures. The numbers and mean values of cervical spine subluxations for the various subgroups of patients are presented in Table 3. Bony ankylosis was evaluated by examination of ordinary 2-plane cervical radiographs.

## **2.3 Statistical analysis**

Values are presented as absolute numbers N (proportions) or mean (SD). Student's t-test and chi square test were used for testing group differences for continuous and categorical variables, respectively. Cox Proportional Hazard regression analysis was used to identify possible predictors for survival. As reference point for the time-to-event analyses we used the time at operation. Martingale residuals were used to assess the validity of the models. As the assumption of proportionality of the hazard rates was violated, an interaction term between the indicator for cervical neurology and the time variable 'years survival following operation' was included in the final model.

All P-values equal to or below 0.05 were considered statistically significant. Statistical analyses were performed with SPSS software, version 12.0 (SPSS Inc., Chicago), R (R Foundation for Statistical Computing, http://www.R-project.org) and Statistical Analysis System (SAS version 9.1.3; Cary, North Carolina, USA).

Increased Mortality Rate in Rheumatoid Arthritis Patients with Neurological Symptoms

relevant neurology operated for involvement of the cervical column (Figure 1).

Fig. 1. Survival for operated RA patients with and without preoperative cervical

neurological symptoms and signs.

or Signs Secondary to Cervical Spine Subluxations – Reduced Mortality if Postoperative... 269

with cervical neurological symptoms or signs. In the group of patients operated without relevant neurology there were only 2 patients with SS. The incidence of severe VS was higher in the group of patients with relevant neurology (*p*=0.04). Interestingly, severe AS was significantly higher in the group of patients without relevant neurology (*p*=0.001) (Table 4). The survival rate of the studied cohort with neurological symptoms or signs was significantly reduced (*p*<0.001) when compared to the cohort of RA patients without


AS - Anterior subluxation

VS - Vertical settling

SS - Subaxial subluxation(s)

Table 3. Cervical Spine Subluxations in Operated RA Patients with and without Neurological Symptoms or signs. Distribution among Alive and Dead during the Follow-up Period. Total Numbers, Mean values with Standard Deviations (SD)
