Prevalence and Radiographic Progression of Hip Involvement in Patients With Ankylosing Spondylitis Treated With Tumor Necrosis Factor Inhibitors.

OBJECTIVE: To examine the prevalence of hip involvement between sexes in patients with ankylosing spondylitis (AS) treated with tumor necrosis factor inhibitors (TNFi) and to estimate the effect of TNFi on radiographic progression of hip involvement compared to the spine. METHODS: Two hundred ninety-nine patients with AS treated with TNFi (215 men; median age: 43 yrs [IQR 36-52], median disease duration: 7.6 yrs [IQR 2-15]) were evaluated for hip involvement, defined radiographically as Bath AS Radiological Hip Index (BASRI-hip) score ≥ 2. Those who received TNFi for ≥ 2 years (263/299) were assessed for radiographic progression. Radiographs of the pelvis and spine, obtained at baseline (ie, before TNFi initiation), were compared retrospectively to those obtained after 2.5 (SD 0.7) years and 7.0 (SD 2.3) years of TNFi treatment. Both hips were scored by BASRI-hip score and mean joint space width (MJSW). Spinal radiographs were scored by modified Stoke AS Spinal Score (mSASSS). RESULTS: The prevalence of hip involvement at baseline was 113/299 (38%) patients, of whom 87/215 (41%) were male and 26/84 (31%) were female (P = 0.10). In both sexes with hip involvement at baseline, BASRI-hip score and MJSW did not change significantly during follow-up. In males and females without baseline hip involvement, the BASRI-hip score remained unchanged after 2.5 (SD 0.7) years but increased significantly after 7.0 (SD 2.3) years, without reaching the cut-off of 2. In contrast, the MJSW slightly decreased at the 2 follow-up timepoints (ie, after 2.5 and 7.0 yrs). The mSASSS increased significantly during the follow-up in both sexes, regardless of hip involvement. CONCLUSION: In our study, approximately one-third of patients with AS had hip involvement, which seemed to stabilize with TNFi treatment. No sex differences in the prevalence or progression of this manifestation were found.

Fat Mass Lowers the Response to Tumor Necrosis Factor-α Blockers in Patients with Ankylosing Spondylitis.

OBJECTIVE: Our main objective was to assess the relationship between body composition (BC) and response to tumor necrosis factor-α (TNF-α) blocker treatment in patients with ankylosing spondylitis (AS). Our secondary objective was to evaluate the change of BC after treatment, accounting for sex and age. METHODS: All included patients fulfilled the modified New York criteria for AS and were naive to TNF-α blocker. They were followed for at least 6 months after the start of etanercept or adalimumab. The Ankylosing Spondylitis Disease Activity Score containing C-reactive protein (ASDAS-CRP) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were reported. BC was assessed by whole body dual-energy X-ray absorptiometry. Body fat percentage (BF%), fat mass index (FMI), and fat free mass index (FFMI) were reported as absolute values and as percentiles. RESULTS: Forty-one patients were included (61% men). The median followup was 14.3 months (interquartile range 8.4-19.4). After multivariate regression analysis, more fat at baseline (BF%, FMI, or FMI percentile) was significantly related with a lower chance of achieving a clinically important improvement of the ASDAS-CRP or BASDAI after treatment. The body composition did not change significantly after treatment, but there was a trend toward muscle recovery in men (FFMI change from 34.0th to 37.4th percentile). CONCLUSION: Higher body fat content at baseline was independently associated with a worse response to treatment with TNF-α blockers, measured by ASDAS-CRP and BASDAI change, and might contribute to the lower response rates in female patients. Also, there is a trend toward muscle mass recovery in male patients after treatment.

Etanercept Increases Bone Mineral Density in Ankylosing Spondylitis, but Does Not Prevent Vertebral Fractures: Results of a Prospective Observational Cohort Study.

OBJECTIVE: Ankylosing spondylitis (AS) is characterized by chronic inflammation leading to ankylosis, but also to low bone mineral density (BMD) and vertebral fractures (VFx). Treatment with tumor necrosis factor-α blockers decreases inflammation and has shown to be effective in increasing BMD. We studied the effects of etanercept (ETN) on BMD and VFx in patients with AS after 2 years of treatment. Further, we studied changes in bone turnover markers and radiological damage. METHODS: Patients with active AS, treated with ETN for 2 years, were included. BMD lumbar spine and hip were measured at baseline and after 2 years, as well as radiological damage (modified Stoke Ankylosing Spondylitis Spinal Score with the addition of the thoracic spine), VFx (Genant method), and change in bone turnover markers. RESULTS: Forty-nine patients with AS were included. After 2 years of ETN, hip BMD increased by 2.2% (p = 0.014) and lumbar spine BMD by 7.0% (p < 0.001). The Bath Ankylosing Spondylitis Disease Activity Index decreased significantly (p < 0.001), as well as C-reactive protein and erythrocyte sedimentation rate (p < 0.001). Despite ETN therapy, the number of patients with VFx more than doubled (from 6 to 15 patients, p = 0.003). Also, the radiological damage increased significantly over time (from 12.1 to 18.5, p < 0.001); however, no significant change in bone turnover markers was found. CONCLUSION: This prospective longitudinal observational cohort study showed that after 2 years of ETN, BMD of the hip and spine increased significantly, but the number of patients with VFx and the severity of VFx increased as well. Besides that, radiological progression, including the thoracic spine, increased significantly. Thus, the favorable bone-preserving effect is accompanied by unfavorable outcomes on VFx and radiological damage.

Objective evaluation of physical functioning after tumor necrosis factor inhibitory therapy in patients with ankylosing spondylitis: a selection of 3 feasible performance-based tests.

OBJECTIVE: (1) To select a limited number of performance-based tests that are reliable, show improvement in physical functioning after tumor necrosis factor inhibitor (TNFi) therapy in patients with ankylosing spondylitis (AS), and generate information equivalent to the full set of tests, and (2) are feasible for use in daily clinical practice. METHODS: Eight performance-based tests were evaluated. To eliminate redundant testing, the tests that showed adequate reliability, the highest standardized response mean (SRM), and the largest proportion of patients with an improved performance-based physical functioning were selected. The selected tests were combined into a new criterion for improvement in physical functioning (AS Performance-based Improvement; ASPI). The number and percentage of improved patients identified with the ASPI and identified with the full set of performance tests were compared. RESULTS: Reliability for all tests was adequate to excellent (ICC 0.73-0.96). The tests for bending, putting on socks, and getting up from the floor had the highest SRM (0.52-0.74) and showed the largest proportion of improved patients after TNFi therapy. The combination of these 3 tests was feasible in daily clinical practice and showed improved physical functioning after TNFi therapy in 67% of the patients. CONCLUSION: The 3 selected tests are recommended for use in daily practice because they generate information comparable to the full set. They are reliable and feasible, and the combination of these tests showed improved physical functioning after TNFi therapy in 67% of the patients. Evaluation of physical functioning might be improved by adding these tests to other AS outcome measures.

Adalimumab significantly reduces the recurrence rate of anterior uveitis in patients with ankylosing spondylitis.

OBJECTIVE: To investigate whether use of adalimumab decreases the frequency of attacks of anterior uveitis (AU) in patients with ankylosing spondylitis (AS). METHODS: Consecutive patients with AS, visiting an outpatient clinic and treated for at least 12 weeks with adalimumab, were enrolled. The number of attacks of AU in the year before start and during treatment were assessed by patient history and ophthalmological controls. RESULTS: In the 77 patients a total of 52 AU attacks occurred in the year before baseline (68 attacks per 100 patient-yrs), whereas during adalimumab treatment 19 attacks were seen (14 per 100 patient-yrs; reduction rate 80%). Twenty-six patients with AU in the year before start of adalimumab treatment had recurrent attacks, with a median number of 2.0 AU attacks per year [interquartile range (IQR) 1.00-3.00], whereas during treatment this decreased to 10 patients with a median number of 0.56 attacks per year (IQR 0.30-0.75). Hence, the number of attacks per year decreased by 72% (p = 0.000). CONCLUSION: In patients with AS, a significant reduction in the number of AU attacks, as well as in the number of attacks per patient, was observed during adalimumab treatment.

What do we miss? ASAS non-responders on anti-TNF therapy show improvement in performance-based physical function.

OBJECTIVE: A prospective study was conducted in order to establish whether AS patients, who are defined as non-responders after 3 months of anti-TNF therapy, show improvement on performance-based tests of physical functioning. METHODS: At baseline and 3 months after the start of anti-TNF therapy, AS patients completed seven performance-based tests of physical functioning, questionnaires on self-reported physical functioning (BASFI) and disease activity (BASDAI), and a pain and a global patient assessment. The concordance between ≥ 20% intra-individual improvement on the performance-based test of physical functioning and (i) response to anti-TNF therapy [Assessment of SpondyloArthritis International Society 20% (ASAS20) response] and (ii) ≥ 20% intra-individual improvement on self-reported physical functioning (BASFI) was assessed. RESULTS: One hundred AS patients were included, of which 82 patients completed all tests at both time points. After 3 months of anti-TNF therapy, 27 (32.9%) patients were categorized as non-responders according to the ASAS20 response criteria. Improvement in performance-based physical functioning was seen in 13 of the 27 non-responders (48.1%) (i.e. n = 13/82 = 15.9% of the total group). Furthermore, 30 (36.6%) patients showed no improvement on self-reported physical functioning (BASFI). However, 17 of the 30 (56.7%) patients did improve on the performance-based tests of physical functioning (i.e. n = 17/82 = 20.7% of the total group). CONCLUSION: After 3 months of anti-TNF therapy, performance-based tests of physical functioning showed improvement in 48.1% of the ASAS20 non-responders. With these performance-based tests, new information on outcome after anti-TNF therapy can be generated. Using performance-based tests alongside the BASFI could have additional value in the evaluation of outcomes for patients receiving anti-TNF therapy.

Bone formation rather than inflammation reflects ankylosing spondylitis activity on PET-CT: a pilot study.

INTRODUCTION: Positron Emission Tomography - Computer Tomography (PET-CT) is an interesting imaging technique to visualize Ankylosing Spondylitis (AS) activity using specific PET tracers. Previous studies have shown that the PET tracers [18F]FDG and [11C](R)PK11195 can target inflammation (synovitis) in rheumatoid arthritis (RA) and may therefore be useful in AS. Another interesting tracer for AS is [18F]Fluoride, which targets bone formation. In a pilot setting, the potential of PET-CT in imaging AS activity was tested using different tracers, with Magnetic Resonance Imaging (MRI) and conventional radiographs as reference. METHODS: In a stepwise approach different PET tracers were investigated. First, whole body [18F]FDG and [11C](R)PK11195 PET-CT scans were obtained of ten AS patients fulfilling the modified New York criteria. According to the BASDAI five of these patients had low and five had high disease activity. Secondly, an extra PET-CT scan using [18F]Fluoride was made of two additional AS patients with high disease activity. MRI scans of the total spine and sacroiliac joints were performed, and conventional radiographs of the total spine and sacroiliac joints were available for all patients. Scans and radiographs were visually scored by two observers blinded for clinical data. RESULTS: No increased [18F]FDG and [11C](R)PK11195 uptake was noticed on PET-CT scans of the first 10 patients. In contrast, MRI demonstrated a total of five bone edema lesions in three out of 10 patients. In the two additional AS patients scanned with [18F]Fluoride PET-CT, [18F]Fluoride depicted 17 regions with increased uptake in both vertebral column and sacroiliac joints. In contrast, [18F]FDG depicted only three lesions, with an uptake of five times lower compared to [18F]Fluoride, and again no [11C](R)PK11195 positive lesions were found. In these two patients, MRI detected nine lesions and six out of nine matched with the anatomical position of [18F]Fluoride uptake. Conventional radiographs showed structural bony changes in 11 out of 17 [18F]Fluoride PET positive lesions. CONCLUSIONS: Our PET-CT data suggest that AS activity is reflected by bone activity (formation) rather than inflammation. The results also show the potential value of PET-CT for imaging AS activity using the bone tracer [18F]Fluoride. In contrast to active RA, inflammation tracers [18F]FDG and [11C](R)PK11195 appeared to be less useful for AS imaging.

Moving instead of asking? Performance-based tests and BASFI-questionnaire measure different aspects of physical function in ankylosing spondylitis.

INTRODUCTION: Ankylosing Spondylitis (AS) is characterised by limitations in physical function. The Bath Ankylosing Spondylitis Functional Index (BASFI) is considered to be the gold-standard to assess physical function in AS patients. However, the BASFI questionnaire is a self-reported outcome measure and susceptible to subjective interpretation (under- or over-estimation). More objective outcome measures, like performance-based tests, could provide an objective outcome measurement for the evaluation of limitations in physical function. Therefore, the primary aim of this study was to determine the association between performance-based measures and the BASFI questionnaire. METHODS: In this cross-sectional study 126 AS patients completed the BASFI questionnaire and eight performance-based tests based on BASFI-items. Each test received three scores: one for performance (time or points) and a score for exertion and pain experienced during performance (using modified Borg-scale and VAS 0-100 mm, respectively). Linear regression analyses were used to assess the associations between the BASFI questionnaire and performance-based tests. RESULTS: The univariable association between performance and BASFI-score was moderate with a R-square of 0.31 and Beta of 0.56 (p's < 0.05). In a multivariable analysis, the association between performance, exertion and pain on the one hand and BASFI-score on the other was assessed; R-square increased to 0.54: the Beta's for exertion and pain during performance were 0.38 and 0.26, respectively; the Beta for performance decreased to 0.19 (p's < 0.05). CONCLUSIONS: This study demonstrates that alongside actual performance, patients seem to incorporate exertion and pain in their assessment of perceived physical function on the BASFI questionnaire. Performance-based tests could provide an objective outcome measurement for the evaluation of physical function and give relevant new information in addition to the BASFI questionnaire.

Discovertebral (Andersson) lesions in severe ankylosing spondylitis: a study using MRI and conventional radiography.

The objective of this study is to investigate the prevalence of Andersson lesions (AL) in ankylosing spondylitis (AS) patients who will start anti-tumor necrosis factor (TNF) treatment. Radiographs and magnetic resonance imaging (MRI) of the spine were performed before therapy with anti-TNF. ALs were defined as discovertebral endplate destructions on MRI, associated with bone marrow edema and fat replacement or sclerosis, a decreased signal on T1, enhancement after contrast administration (gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA)), and increased signal on T2 and short tau inversion recovery (STIR). Additionally, conventional radiography showed a fracture line, irregular endplates, and increased sclerosis of adjacent vertebral bodies. Fifty-six AS patients were included, 68% males, mean age of 43 years, and mean disease duration of 11 years. The mean bath ankylosing spondylitis disease activity index was 6.4, and 24% of all patients had ankylosis. Only one patient showed a discovertebral abnormality with bone marrow edema of more than 50% of the vertebral bodies adjacent to the intervertebral disk of T7/T8 and T9/T10, a hypodense signal area on T1, and a high signal on STIR. Irregular endplates were depicted, and T1 after Gd-DTPA demonstrated high signal intensity around the disk margins. However, no fracture line was visible on conventional radiology, and therefore, this case was not considered to be an AL. No AL was detected in our AS patients, who were candidates for anti-TNF treatment. One patient showed a discovertebral abnormality on MRI, without a fracture line on conventional radiology. The relative small proportion of patients with a long-established disease might explain this finding for, particularly, an ankylosed spine is prone to develop an AL.

Survival, comorbidities and joint damage 11 years after the COBRA combination therapy trial in early rheumatoid arthritis.

BACKGROUND: COBRA (for 'COmbinatie therapie Bij Rheumatoide Artritis') combination therapy is effective for the treatment of rheumatoid arthritis (RA), but long-term safety is unknown. This study evaluates survival, comorbidities and joint damage in the original COBRA trial cohort. METHODS: In the COBRA trial, 155 patients with early RA were treated with sulfasalazine (SSZ) monotherapy (SSZ group) or a combination of step-down prednisolone, methotrexate (MTX) and SSZ (COBRA group). The current 11-year follow-up study of the COBRA trial invited all original patients and performed protocollised scrutiny of clinical records, questionnaires, physical examination, laboratory and imaging tests. RESULTS: In all, 152 out of 155 patients yielded at least partial data. After a mean of 11 years follow-up, 18 (12%) patients had died, 6 COBRA patients and 12 SSZ patients, HR 0.57 (95% CI 0.21 to 1.52). Treatment for hypertension was significantly more prevalent in the COBRA group (p=0.02) with similar trends for diabetes and cataract. Conversely, hypercholesterolaemia, cancer and infection showed a trend in favour of COBRA. Other comorbidities such as cardiovascular disease and fractures appeared in similar frequency. Radiographic findings suggest as a minimum sustained benefit for COBRA therapy, that is, difference in joint damage but similar subsequent progression rates after 5 years. Imputation to compensate for selective dropout suggests increasing benefit for COBRA, that is, difference in yearly progression rates similar to that seen in the first 5 years of follow-up. CONCLUSIONS: After 11 years, initial COBRA combination therapy resulted in numerically lower mortality and similar prevalence of comorbidity compared with initial SSZ monotherapy. In addition, lower progression of joint damage suggests long-term disease modification.

Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formation.

OBJECTIVES: Correlation of serum trough infliximab levels and antibodies to infliximab (anti-infliximab) with clinical response in ankylosing spondylitis. METHODS: In accordance with the international ASsessment in Ankylosing Spondylitis (ASAS) consensus statement, patients were treated with infliximab (5 mg/kg) every 6 weeks after a starting regimen. Preinfusion sera were collected at baseline, 24 and 54 weeks. At every visit, the 20% improvement response (ASAS-20) was assessed and laboratory tests performed. RESULTS: 24 of the 38 (63%) patients fulfilled ASAS-20 response criteria after 24 weeks of treatment and 21 (53%) after 54 weeks. After 54 weeks, 11 (29%) patients showed undetectable serum trough infliximab levels and detectable anti-infliximab; six of these patients developed an infusion reaction. Anti-infliximab was found significantly more often (p = 0.04) in ASAS-20 non-responders compared with responders at week 54. Serum trough infliximab levels were significantly (p<0.0001) lower in patients with (mean 0.02 mg/l) than in those without (12.7 mg/l) anti-infliximab. CONCLUSIONS: In ankylosing spondylitis, high levels of serum trough infliximab correlated with a good clinical response. Detection of anti-infliximab within 54 weeks is associated with undetectable serum trough infliximab levels, reduced response to treatment and increased risk of developing an infusion reaction.

Efficacy and safety of mesalazine (Salofalk) in an open study of 20 patients with ankylosing spondylitis.

OBJECTIVE: Mesalazine (Salofalk) was found to be effective and showed low toxicity in patients with inflammatory bowel disease. The association of gut lesions and spondyloarthropathy (SpA) is well known and we studied the efficacy and safety of a relatively high dose of mesalazine in patients with ankylosing spondylitis (AS). METHODS: In an open study, mesalazine (3-4 g/day) was prescribed for 24 weeks to 20 patients (aged 18-70 yrs) with active AS, defined as the presence of at least one clinical criterion (morning stiffness > 30 min, peripheral synovitis, enthesopathy, or pain score > 2 on a visual analog scale of 10 cm) and one laboratory criterion [erythrocyte sedimentation rate (ESR) > 20 mm/h or C-reactive protein (CRP) > 20 mg/l]. Data on toxicity and disease activity variables (ESR, CRP, BASDAI, BASFI, BASMI, global assessment, and joint count) were obtained at baseline and after 4, 12, and 24 weeks, and analyzed on an intention-to-treat basis. RESULTS: Study patients had a mean age of 41 years, with mean disease duration of 7.9 years and a mean ESR at baseline of 29 mm/h. After a mean of 9.3 weeks (range 2-22), 8 of the 20 patients prematurely stopped the medication because of adverse effects, mainly gastrointestinal complaints. Twelve patients completed the 24 weeks of the study using a mean dose of 3.2 g/day (range 1-4) mesalazine. Analysis of the data showed improvement in ESR, CRP, and physician's global assessment, but only the change in ESR (29 mm/h on baseline and 25 mm/h at week 24) reached statistical significance (p = 0.03). No change was observed in the other disease activity variables. CONCLUSION: No significant improvement in any disease activity variable of active AS was observed during treatment with Salofalk except for the ESR. Many side effects were seen.

COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention.

OBJECTIVE: The Combinatietherapie Bij Reumatoide Artritis (COBRA) trial demonstrated that step-down combination therapy with prednisolone, methotrexate, and sulfasalazine (SSZ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis (RA). The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time, and to determine which baseline factors could predict outcome. METHODS: All patients had participated in the 56-week COBRA trial. During followup, they were seen by their own rheumatologists and were also assessed regularly by study nurses; no treatment protocol was specified. Disease activity, radiologic damage, and functional ability were the primary outcome domains. Two independent assessors scored radiographs in sequence according to the Sharp/van der Heijde method. Outcomes were analyzed by generalized estimating equations on the basis of intent-to-treat, starting with data obtained at the last visit of the COBRA trial (56 weeks after baseline). RESULTS: At the beginning of followup, patients in the COBRA group had a significantly lower mean time-averaged 28-joint disease activity score (DAS28) and a significantly lower median radiologic damage (Sharp) score compared with those in the SSZ monotherapy group. The functional ability score (Health Assessment Questionnaire [HAQ]) was similar in both groups. During the 4-5 year followup period, the time-averaged DAS28 decreased 0.17 points per year in the SSZ group and 0.07 in the COBRA group. The Sharp progression rate was 8.6 points per year in the SSZ group and 5.6 in the COBRA group. After adjustment for differences in treatment and disease activity during followup, the between-group difference in the rate of radiologic progression was 3.7 points per year. The HAQ score did not change significantly over time. Independent baseline predictors of radiologic progression over time (apart from treatment allocation) were rheumatoid factor positivity, Sharp score, and DAS28. CONCLUSION: An initial 6-month cycle of intensive combination treatment that includes high-dose corticosteroids results in sustained suppression of the rate of radiologic progression in patients with early RA, independent of subsequent antirheumatic therapy.