SEARCH

SEARCH BY CITATION

Keywords:

  • Ankylosing spondylitis;
  • Etanercept;
  • Health-related quality of life;
  • Short Form 36

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Objective

To assess the impact of ankylosing spondylitis (AS) on patient health-related quality of life (HRQOL) relative to both the general US and chronically-ill populations, and to evaluate whether etanercept therapy can reverse impairments in HRQOL due to AS.

Methods

Two AS patient populations were evaluated: patients with AS from a US clinical trial who were randomized to receive either etanercept (n = 20) or placebo (n = 20) for 16 weeks, and placebo-treated patients from a multinational sample who subsequently received etanercept (n = 129) during a 48-week, open-label extension study. A sample from the US general population and patients with other medical conditions derived from the National Survey of Functional Health Status were used as comparators to evaluate the relative impact of active AS on HRQOL, as measured by the Short Form 36 (SF-36) questionnaire.

Results

At baseline, patients with AS in both the US and multinational samples had significantly lower scores than the US general population on all 8 SF-36 scales. Compared with patients with other medical conditions, patients with AS had the lowest scores in the physical domains—Physical Functioning, Role Physical, and Bodily Pain. Impairments in SF-36 scores for psychosocial domains, such as Social Functioning, Role Emotional, and Mental Health, were somewhat less pronounced in patients with AS. Treatment with etanercept significantly improved the HRQOL of patients with AS on all 8 SF-36 scales, especially in the same physical domains that showed the greatest impairments prior to treatment (Physical Functioning, Role Physical, and Bodily Pain).

Conclusion

Patients with active AS despite conventional therapy have significantly reduced HRQOL across a wide range of domains. These reductions are most pronounced in the physical domains and exceed those seen in many other chronic diseases. Etanercept therapy significantly improves patient HRQOL, indicating that decrements in HRQOL due to AS may be at least partly reversible.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Ankylosing spondylitis (AS) is the most frequently occurring subtype of the seronegative spondylarthritides (1). Of the 5 subtypes, which also include spondylitis associated with psoriasis and inflammatory bowel disease, reactive arthritis, and undifferentiated spondylarthropathy, AS has the most severe outcome, with a variable prognosis and disease activity that includes acute flares and periods of remission (2).

AS is characterized by axial skeletal ankylosis and inflammation at the insertions of tendons (enthesitis), and occasionally by peripheral arthritis (3). The lumbar and thoracic spine are more commonly involved than the cervical spine, resulting in inflammatory low back pain and stiffness, as well as limited range of spinal movement and chest expansion (2). Affected individuals also experience peripheral joint pain and swelling, localized tenderness related to enthesitis, anterior uveitis, fatigue, and morning stiffness.

A recent study revealed that the extent of pain and disability among patients with AS was similar to patients with rheumatoid arthritis (RA) (4). In another study, Chorus et al demonstrated that although patients with RA reported worse physical health than patients with AS, those with AS reported worse mental and emotional wellbeing (5). Overall, patients with RA and AS experienced similar physical limitations, including work-related activities. However, because the onset of AS occurs between the ages of 20 and 30 years, the average duration of disease is longer in comparison with diseases such as RA that manifest later in life (1, 6). Patients with AS experience chronic pain and stiffness, which, in turn, limits their abilities to perform various activities of daily living. The disease may also compromise patients' ability to sleep, thus impairing mood and performance of tasks during the day. Consequently, AS may adversely affect their health-related quality of life (HRQOL). In fact, other studies have reported similar reductions in quality of life in patients with AS, especially in those with less education (7).

Although traditional therapies have been used to manage the symptoms of the disease, none has been shown to slow the progression of axial disease in patients with AS (2). Recent studies have shown that tumor necrosis factor α (TNFα) appears to play an important role in the pathogenesis of AS and other forms of spondylarthritis (8–12). Studies have also demonstrated that patients with spondylarthropathies, including psoriatic arthritis, reactive arthritis, and AS, who were treated with etanercept (a recombinant human TNF receptor [p75]–Fc fusion protein [Enbrel; Immunex, Seattle, WA]) (1, 3, 13–17) had significant reductions in disease activity (18). Although the clinical efficacy of etanercept has been demonstrated (3, 15), the effect of these improvements on HRQOL in treated patients remains unknown.

In this analysis, the HRQOL for 2 different samples of patients with AS is compared with that of individuals from a nationally representative sample of the general population. The objectives of this analysis were to assess the impact of active AS on different dimensions of HRQOL; to compare the decrement in HRQOL seen in patients with AS despite conventional therapy with the decrement in HRQOL seen in patients with other chronic illnesses; and to evaluate whether the impairment in HRQOL caused by AS is reversible with etanercept therapy.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Patient population

The first part of this analysis compared 2 different samples of patients with AS (US sample, multinational sample) (3, 15) with a nationally representative sample (US norms) reflecting the US general population (derived from responses to the National Survey of Functional Health Status [NSFHS]) (19, 20), as well as NSFHS respondents reporting other chronic diseases and medical conditions. These samples will be discussed separately.

Sample of patients with AS

Patients with AS came from 2 clinical trials of etanercept therapy. Details about the study population selection and inclusion/exclusion criteria for the controlled portions of these trials are published separately (3, 15). Briefly, men and women were included in the clinical trials if they were at least 18 years of age and had met the modified New York Clinical Criteria for definite AS (3, 15, 21). Patients in the 2 studies were allowed to continue taking nonsteroidal antiinflammatory drugs, oral corticosteroids (≤10 mg/day), methotrexate, and sulfasalazine at stable doses during the trials.

US sample of AS patients

The US sample came from a randomized, double-blind, placebo-controlled study in which patients with active, inflammatory AS, despite conventional therapy, received twice-weekly subcutaneous injections of etanercept (25 mg) or placebo for 16 weeks (3). Forty patients were recruited from rheumatology practices in northern California. The trial was conducted from July 1999 to December 2001, and all patients provided written informed consent. Patients in the US sample completed the HRQOL assessment at baseline and after 16 weeks.

Multinational sample of AS patients

The multinational sample came from an open-label followup to a phase 3, 24-week, randomized, double-blind, placebo-controlled trial of etanercept therapy in patients with active, inflammatory AS despite conventional therapy (15). The HRQOL assessment (Short Form 36 [SF-36]) was not included in the phase 3 trial, but was included for all patients in the open-label followup. Because etanercept therapy may affect the HRQOL status, only patients who had received placebo in the phase 3 trial were analyzed at followup. These patients completed the HRQOL assessment at baseline of the open-label study (i.e., after they had completed 24 weeks of blinded treatment with placebo) and after 48 weeks of open-label treatment with etanercept (25 mg twice weekly).

Sample of the US general population and patients with other chronic diseases

Data for the US norms sample came from responses to the NSFHS, a 1990 cross-sectional survey that was used to create US general population estimates for the SF-36 (19, 20, 22). The NSFHS was drawn from a comprehensive random sample of 2,474 noninstitutionalized adults in the US who provided HRQOL and health history information. The survey, which was conducted via mail or telephone, had a high response rate (77.1%). Previous research comparing respondents to the NSFHS with US general population estimates from the National Center for Health Statistics supported the representitiveness of the NSFHS with regard to sociodemographic characteristics (e.g., age and sex) (19).

Subsamples of the NSFHS consisting of patients with a variety of self-reported disease states were used as comparators to assess the impact of AS relative to these other chronic conditions. In the NSFHS, respondents were asked, among other questions, whether a doctor had ever told them that they had hypertension, congestive heart failure, and diabetes. In addition, they were asked if they now had arthritis or any kind of rheumatism, and limitations in the use of an arm or leg (missing, paralyzed, or weakness). Positive responses to these questions were used to categorize respondents in the following disease states: hypertension (n = 701), congestive heart failure (CHF; n = 93), diabetes (n = 156), arthritis (n = 862), and missing or limited use of a limb (n = 274). Because these disease states are based on self report, they may include patients with a wide range of disease activity as well as some patients who may be incorrectly defined.

Instruments used for assessment of HRQOL

HRQOL was assessed using the SF-36, a widely used measure assessing HRQOL (20, 22). The SF-36 was chosen for its multidimensionality, brevity, and its prior successful application in a variety of diseases. Responses to the 36 items are considered to assess a number of HRQOL domains. These domains range from those reflecting predominantly physical wellness, including Physical Functioning, the ability to perform expected Physical Roles, degree of Bodily Pain, and overall sense of General Health, to those reflecting predominantly social and emotional wellbeing, including overall sense of Vitality, ability to function in social roles (Social Functioning), ability to perform expected emotional and social roles (Role Emotional), and overall sense of Mental Health.

Completion of the SF-36 generally takes 5–10 minutes, although elderly patients may require up to 15 minutes (20). The reliability and validity of the instrument were confirmed in an initial sample of 3,445 patients with chronic medical and psychiatric conditions, as well as in a number of subsequent studies (20). Scoring of each scale ranges from 0 to 100, with higher scores indicating better HRQOL and positive change scores indicating improved HRQOL. A difference of 5 points in an SF-36 scale is considered “clinically and socially relevant” (20).

Statistical analysis

Comparisons of HRQOL between patients with AS and the US general population, as well as comparisons with patients with other chronic conditions (hypertension, CHF, diabetes, arthritis, and missing or limited use of a limb), were based on regression-adjusted means for the SF-36 questionnaire. Changes in SF-36 scale scores after etanercept use were evaluated to determine if treatment with etanercept can reverse the decrements in HRQOL caused by AS.

Initially, to control for multiple comparisons, a multivariate analysis of variance (MANOVA) test of the 8 SF-36 scales was performed to compare patients with AS versus US norms and patients with AS versus those with other chronic diseases. If the test was statistically significant (P < 0.05), then each scale was analyzed using regression analysis (SAS PROC GLM, version 8; SAS Institute, Cary, NC) with adjustments for age and sex. Because the comparisons were only conducted if the initial MANOVA test result was statistically significant, there were no additional adjustments for multiple comparisons.

Comparisons between patients in each of the 2 AS samples and the US norms were made by pooling the samples and conducting regression analyses with covariates for age and sex. Hypothesis tests of the effect of AS were conducted using a 2-tailed t-test. Comparisons between the 2 AS samples and patients with chronic diseases were performed similarly, again pooling the samples and using regression analyses with covariates for age and sex and dummy variables for each chronic disease of interest. Hypothesis tests to compare AS with each of the other diseases were conducted using 2-tailed t-tests.

Comparisons of the change in SF-36 scores were conducted differently for the 2 studies. In the US sample, the change from baseline was compared between patients who received etanercept and those who received placebo. Hypothesis tests were conducted using the Wilcoxon rank sum test. In the multinational sample, there was no control group, so t-tests of the change in each SF-36 scale were conducted to assess the significance of the change from baseline.

To assess the relationship between initial deficits in HRQOL and subsequent improvements from therapy, the Pearson correlation was calculated between the initial mean differences for the SF-36 scales between patients with AS and US norms, and the subsequent mean changes due to etanercept treatment. A high correlation would indicate that the SF-36 scales where patients with AS showed the greatest mean deficits were the same scales that showed the greatest improvements with etanercept therapy.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Patients

There were a total of 40 patients from the US sample (3) and 129 from the multinational sample (15) (Table 1). Patients in both samples were predominantly white men who have had long-standing AS (range 9–15 years). Mean age ranged from 38 to 43 years.

Table 1. Baseline characteristics of patients by treatment group and concomitant medications (3, 15)*
Baseline characteristicsUS sampleMultinational sample
Etanercept (n = 20)Placebo (n = 20)Etanercept (n = 129)
  • *

    NA = not available.

  • No statistically significant differences between the 2 groups.

  • Defined as at least 1 swollen joint.

  • §

    Defined as the receipt of more than one concomitant medication for the treatment of ankylosing spondylitis.

Male, %659074
White race, %757091
Age, mean ± SD years38 ± 1039 ± 1043 ± 11
Duration of disease, mean ± SD years15 ± 1012 ± 99 ± 9
Peripheral-joint involvement, %6060NA
Concomitant medications, %   
 Nonsteroidal antiinflammatory drugs8095NA
 Corticosteroids2510NA
 Disease-modifying antirheumatic drugs4035NA
 Combination therapy§4535NA
AS patients versus the US general population

As shown in Figure 1, SF-36 scores were remarkably consistent between the US sample and the multinational sample, with only the Role Physical scale showing a significant difference between the 2 AS samples.

thumbnail image

Figure 1. Baseline mean Short Form 36 scores in patients with ankylosing spondylitis (AS) versus US general population (US norms) (19, 20). Mean scores were significantly lower for AS patients in both the US and multinational samples compared with the US general population (US norms). PF = Physical Function; RP = Role Physical; BP = Bodily Pain; GH = General Health; VT = Vitality/Energy; SF = Social Functioning; RE = Role Emotional; MH = Mental Health. * P < 0.0001 for AS patients in either the US or the multinational sample versus US norms.

Download figure to PowerPoint

Both samples of patients with AS showed statistically-significant lower scores for HRQOL on all 8 scales of the SF-36 compared with norms from the US general population. The differences in SF-36 scale scores were most pronounced for the physical domains, such as Physical Functioning, Role Physical, and Bodily Pain, and somewhat less so for the psychosocial domains such as Role Emotional and Mental Health. The magnitude of the difference between patients with AS and US norms ranged up to 62.5 points and exceeded the clinically and socially relevant difference of 5 points for each of the 8 SF-36 scales. To illustrate the difference, the 36-point difference between the mean Physical Functioning score for US norms and the multinational sample is similar in magnitude to the difference between mean scores for a 21-year-old man and a 70-year-old man (i.e., the effect of aging almost 50 years).

AS patients versus patients with other chronic medical conditions

Patients with AS generally had lower SF-36 scores compared with patients with most other medical conditions, especially in the physical domains (Figure 2). Mean scores for the US norms are also included for comparison. Compared with patients with self-reported hypertension, diabetes, or arthritis, patients with AS in either the US or the multinational sample had lower mean scores for all of the 8 SF-36 scales, 7 of which were statistically significant (the exception being Mental Health). Differences between patients with AS and those with missing or limited use of a limb were similar but slightly smaller, with AS patients reporting lower mean scores for 7 of the 8 SF-36 scales, 5 of which were statistically significant. Compared with patients with CHF, patients with AS generally had lower mean scores for the more physical HRQOL domains (Physical Functioning, Role Physical, and Bodily Pain), but generally had higher mean scores for the more psychosocial domains (Social Functioning, Role Emotional, and Mental Health). Overall, the largest differences between patients with AS and the comparators were seen in the Role Physical scale, and the smallest differences were seen in the Mental Health scale.

thumbnail image

Figure 2. Mean Short Form 36 scores in patients with ankylosing spondylitis (AS) versus the US general population (US norms) and patients with other medical conditions (19, 20). CHF = congestive heart failure; Diabetes = diabetes mellitus; Limb = missing or limited use of a limb; vs = versus. P < 0.0001 AS patients in US Sample versus comparators with the following exceptions: Physical Functioning AS (US Sample) vs CHF P = 0.0003; Role Physical AS (US Sample) vs AS (Multinational) P = 0.0102; AS (US Sample) vs CHF P = 0.0059; Bodily Pain AS (US Sample) vs limb P = 0.0002; General Health AS (US Sample) vs diabetes P = 0.0013; AS (US Sample) vs limb P = 0.0021; Vitality/Energy AS (US Sample) vs diabetes P = 0.0074; Social Functioning AS (US Sample) vs diabetes P = 0.0032; Role Emotional AS (US Sample) vs hypertension P = 0.0157; AS (US Sample) vs arthritis P = 0.0281; AS (US Sample) vs US Norms P = 0.0016; Mental Health AS (US Sample) vs US Norms P = 0.0262. P < 0.0001 in AS patients in Multinational Sample vs comparators with the following exceptions: Role Physical AS (Multinational) vs AS (US Sample) P = 0.0102; General Health AS (Multinational) vs diabetes P = 0.0011; AS (Multinational) vs limb P = 0.0017; Vitality/Energy AS (Multinational) vs limb P = 0.0055; Role Emotional AS (Multinational) vs arthritis P = 0.0003; AS (Multinational) vs diabetes P = 0.0309; Mental Health AS (Multinational) vs CHF P = 0.0406; AS (Multinational) vs US Norms P = 0.0002.

Download figure to PowerPoint

Improvement in HRQOL scores for AS patients following etanercept therapy

Treatment with etanercept improved the SF-36 scores, with increases seen in all 8 scales at week 16 for patients in the US sample and at week 48 for patients in the multinational sample (Figure 3).

thumbnail image

Figure 3. Mean change in Short Form 36 scores for patients with ankylosing spondylitis (AS) following etanercept therapy. A, Mean change from baseline for etanercept-treated AS patients and placebo controls in the US sample at 16 weeks. Compared with the placebo controls, significant improvement from baseline were observed in the PF (P = 0.0045), the RP (P = 0.0166), the BP (P = 0.0139), the VT (P = 0.0154), and the SF (P = 0.0007) scales. B, Mean change from baseline for etanercept-treated AS patients in the multinational sample at 48 weeks. See Figure 1 for abbreviations.

Download figure to PowerPoint

In the US sample, patients receiving etanercept therapy reported improvements in all 8 SF-36 scores that exceeded those for patients receiving placebo; the differences in improvement were statistically significant in 5 scores (Figure 3A). The most significant effects were observed in the Physical Functioning (P = 0.0045), Role Physical (P = 0.0166), Bodily Pain (P = 0.0139), and Social Functioning (P = 0.0007) scores.

For patients in the multinational sample, etanercept therapy greatly improved patient HRQOL in all 8 SF-36 scales at week 48 (Figure 3B). Improvements in these scales exceeded 5 points in each case and were all statistically significant. Again the greatest effects were seen in the more physical HRQOL scales, with the largest improvement seen in the Role Physical scale.

Figure 4 provides a comparison of SF-36 scores between the US norms and the 2 samples of patients with AS at both pretreatment and posttreatment. Improvements from etanercept therapy reduced the gap in HRQOL between the US norms and the patients with AS. The largest improvements in HRQOL scores were observed in those domains that showed the greatest gaps at baseline. For example, the difference in Role Physical scores between US norms and patients with AS in the multinational sample narrowed from 45.3 at baseline to 17.5 after 48 weeks of etanercept therapy. The improvements from etanercept therapy reduced the baseline deficits by more than half for 6 of the 8 SF-36 scales, with only Physical Functioning and General Health showing a smaller gain. The Pearson correlation between mean baseline HRQOL deficits and subsequent improvements with etanercept therapy was positive and statistically significant (Pearson correlation = 0.876, P < 0.0001).

thumbnail image

Figure 4. Mean Short Form 36 scores patients with ankylosing spondylitis (AS) before and after etanercept therapy versus scores in the US general population (US norms) (19, 20). AS Sample includes only those patients who received etanercept therapy (n = 20). See Figure 1 for abbreviations. P values denote statistically significant differences in SF-36 scores between AS Patients (Post-Therapy) and US Norms. *P < 0.0001 AS patients in either the US Sample or the Multinational Sample versus US Norms. ** P = 0.0005; AS patients in the US Sample versus US Norms. *** P = 0.0006; AS patients in the US Sample versus US Norms.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

The major findings of this study are as follows: HRQOL is significantly impaired in patients with active AS; the magnitude of this decrement is greater than the decrements seen in patients with other chronic conditions such as diabetes, arthritis, and hypertension; reductions in HRQOL are most pronounced in the more physical HRQOL domains, but are evident in the psychosocial domains as well; and therapy with etanercept is associated with significant improvements in HRQOL, indicating that decrements due to AS may be at least partly reversible. These results are robust in that they were consistent across 2 independent samples with different designs and sources of patients.

Patients with active AS have greatly reduced HRQOL because of a variety of symptoms, such as inflammatory low back pain and stiffness, fatigue, and a limited range of spinal movement and chest expansion. Given the early onset of the disease during the prime age of a patient's life, and the subsequent progression towards disability with very few therapeutic alternatives, it is not surprising that patients with AS have such diminished HRQOL. As spinal mobility is progressively lost, the difficulties in performing simple, physical routines place a huge burden on these patients that extends beyond the physical hardship, and compromises the patient's mental functional status. These findings underscore the severity with which AS can manifest, usually leading to diminished physical and mental health status.

In this study, we also found that treatment with etanercept can reverse the decline in HRQOL seen in patients with active AS, thus providing hope for patients who previously lacked an effective treatment for reducing disease activity. In a study of 11 patients, similar results have been reported with another anti–TNF agent, infliximab (23). Although the estimated mean improvements in HRQOL scores described here are considered clinically and socially relevant (over 5 points), the full impact of etanercept therapy may be even greater with longer treatment. After less than 1 year of treatment, patients' mean scores had improved by >50% of the mean baseline differences for 6 of the 8 SF-36 scales. Additional studies will be necessary to determine if the HRQOL reduction can be sustained and even improved upon with continued etanercept treatment.

Active AS severely reduces HRQOL. These reductions are most pronounced in the more physical domains, but are evident in psychosocial domains as well. Effective therapy can reverse these impairments and substantially improve patients' lives.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

The authors would like to thank Ting Chang, Deepa Lalla, and Karin Klink for help in the drafting of this manuscript, and Yonggang Zhao, Allison Webb, Steve Lund, Maureen Fitzpatrick, and Anne Marie Duhme for administrative, technical, or material support.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  • 1
    Braun J, Sieper J. Therapy of ankylosing spondylitis and other spondyloarthritides: established medical treatment, anti-TNF-alpha therapy and other novel approaches. Arthritis Res 2002; 4: 30721.
  • 2
    Toussirot E, Wendling D. Current guidelines for the drug treatment of ankylosing spondylitis. Drugs 1998; 56: 22540.
  • 3
    Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 2002; 346: 134956.
  • 4
    Zink A, Braun J, Listing J, Wollenhaupt J. Disability and handicap in rheumatoid arthritis and ankylosing spondylitis: results from the German rheumatological database: German Collaborative Arthritis Centers. J Rheumatol 2000; 27: 61322.
  • 5
    Chorus AM, Miedema HS, Boonen A, van der Linden S. Quality of life and work in patients with rheumatoid arthritis and ankylosing spondylitis of working age. Ann Rheum Dis 2003; 62: 117884.
  • 6
    Brandt J, Sieper J, Braun J. [Treatment of ankylosing spondylitis and undifferentiated spondyloarthritis with TNF alpha-antagonists]. Z Rheumatol 2003; 62: 21827. In German.
  • 7
    Ward MM. Health-related quality of life in ankylosing spondylitis: a survey of 175 patients. Arthritis Care Res 1999; 12: 24755.
  • 8
    Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbst H, et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum 1995; 38: 499505.
  • 9
    Canete JD, Llena J, Collado A, Sanmarti R, Gaya A, Gratacos J, et al. Comparative cytokine gene expression in synovial tissue of early rheumatoid arthritis and seronegative spondyloarthropathies. Br J Rheumatol 1997; 36: 3842.
  • 10
    Gratacos J, Collado A, Filella X, Sanmarti R, Canete J, Llena J, et al. Serum cytokines (IL-6, TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and severity. Br J Rheumatol 1994; 33: 92731.
  • 11
    Grom AA, Murray KJ, Luyrink L, Emery H, Passo MH, Glass DN, et al. Patterns of expression of tumor necrosis factor α, tumor necrosis factor β, and their receptors in synovia of patients with juvenile rheumatoid arthritis and juvenile spondylarthropathy. Arthritis Rheum 1996; 39: 170310.
  • 12
    Toussirot E, Lafforgue P, Boucraut J, Despieds P, Schiano A, Bernard D, et al. Serum levels of interleukin 1-beta, tumor necrosis factor-alpha, soluble interleukin 2 receptor and soluble CD8 in seronegative spondylarthropathies. Rheumatol Int 1994; 13: 17580.
  • 13
    Brandt J, Khariouzov A, Listing J, Haibel H, Sorensen H, Grassnickel L, et al. Six-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis. Arthritis Rheum 2003; 48: 166775.
  • 14
    Braun J, Brandt J, Listing J, Rudwaleit M, Sieper J. Biologic therapies in the spondyloarthritis: new opportunities, new challenges. Curr Opin Rheumatol 2003; 15: 394407.
  • 15
    Davis JC Jr, van der Heijde D, Braun J, Dougados M, Cush J, Clegg DO, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 2003; 48: 32306.
  • 16
    Mease PJ. Disease-modifying antirheumatic drug therapy for spondyloarthropathies: advances in treatment. Curr Opin Rheumatol 2003; 15: 20512.
  • 17
    Mease PJ, Kivitz AJ, Burch FX, Siegel EL, Cohen SB, Ory P, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 2004; 50: 226472.
  • 18
    Calin A, Garrett S, Whitelock H, Kennedy LG, O'Hea J, Mallorie P, et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol 1994; 21: 22815.
  • 19
    Thalji L, Haggerty CC, Rubin R, Berckmans TR, Pardee BL. 1990 national survey of functional health status: final report. Chicago (IL): National Opinion Research Center; 1991
  • 20
    Ware JE Jr, Snow KK, Kosinski M. SF-36 health survey: manual and interpretation guide. Lincoln (RI): Quality Metric Inc.; 2000.
  • 21
    Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria. Arthritis Rheum 1984; 27: 3618.
  • 22
    Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30: 47383.
  • 23
    Brandt J, Haibel H, Cornely D, Golder W, Gonzalez J, Reddig J, et al. Successful treatment of active ankylosing spondylitis with the anti–tumor necrosis factor α monoclonal antibody infliximab. Arthritis Rheum 2000; 43: 134652.