负荷剂量英夫利昔单抗治疗强直性脊柱炎的临床疗效及疗效预测因素分析

目的 探讨负荷剂量的抗肿瘤坏死因子(TNF)-α单克隆抗体英夫利昔单抗治疗强直性脊柱炎(AS)的临床疗效和达到临床疗效的预测因素.方法 本研究以一项2个中心的开放性Ⅱ期临床试验为基础,纳入确诊的AS患者,并且处于疾病活动期,即Bath AS疾病活动指数(BASDAI)和脊柱痛评分均≥4.患者分别在试验的第0、2、6周静脉滴注英夫利昔单抗5 mg/kg,在10周时对其临床疗效进行评估,以10周时是否达到ASAS 20,ASAS 40和BASDAI 50为疗效标准,对人口学参数[性别、年龄、病程、人类白细胞抗原(HLA)-B27阳性与否]和基线时疾病活动指标[BASDAI、脊柱炎症、脊柱痛VAS、夜间痛VAS、患者总体评估指数、BASFI、BASMI、肌腱端指数、整体关节肿胀指数、扩胸度、红细胞沉降率(ESR)和C反应蛋白(CRP)和BASRI]17个指标进行Logistic单因素和多因素疗效预测分析.结果 63例患者(男性占79%,平均年龄32岁,平均病程10年,HLA-B27阳性占90%)纳入并完成研究,第10周试验结束时,84%的患者达到ASAS 20改善;.75%的患者达到ASAS 40改善;70%的患者达到BASDAI评分改善＞50%.Logistic单因素和多因素分析显示:人口学参数和基线时疾病活动指标均未显示能预测患者的疗效.结论 英夫利昔单抗治疗AS疗效明显,基线时的人口学参数、疾病活动性的临床和实验室指标不能预测疗效.     

Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT)

OBJECTIVE: The signs and symptoms of ankylosing spondylitis (AS) respond inadequately to nonsteroidal antiinflammatory drugs, corticosteroids, and disease-modifying antirheumatic drugs in quite a number of patients. Tumor necrosis factor inhibitors have demonstrated success in reducing AS disease activity in a limited number of clinical trials. The objective of this multicenter, randomized, placebo-controlled study was to evaluate the efficacy and safety of infliximab in patients with AS. METHODS: Patients were randomly assigned to receive infusions of placebo or 5 mg/kg infliximab at weeks 0, 2, 6, 12, and 18. Efficacy was assessed using the ASsessment in Ankylosing Spondylitis (ASAS) International Working Group criteria, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), night pain, patient's global assessment, the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Metrology Index (BASMI), chest expansion, the Mander enthesis index, the total swollen joint index, the C-reactive protein level, and the Short Form 36 (SF-36) health survey questionnaire. The primary end point in this study was the proportion of patients with a 20% improvement response according to the ASAS International Working Group criteria (ASAS20 responders) at week 24. RESULTS: Of the 357 patients screened, 201 were assigned to receive 5 mg/kg infliximab and 78 were assigned to receive placebo. After 24 weeks, 61.2% of patients in the infliximab group were ASAS20 responders compared with 19.2% of patients in the placebo group (P < 0.001). Clinical benefit was observed in patients receiving infliximab as early as week 2 and was maintained over the 24-week study period. Patients receiving infliximab also showed significant improvements in the BASDAI, BASFI, BASMI, chest expansion, and physical component summary score of the SF-36. Adverse events were reported by 82.2% of patients receiving infliximab and by 72.0% of patients receiving placebo; however, most adverse events in both treatment groups were mild or moderate in severity. CONCLUSION: Infliximab was well tolerated and effective in a large cohort of patients with AS during a 24-week study period.     

Effectiveness of reducing infliximab dose interval in non-responder patients with refractory spondyloarthropathies. An open extension of a multicentre study

OBJECTIVE: To evaluate the therapeutic effectiveness of reducing the infliximab dose interval to 6 weeks in spondyloarthropathy patients not responding to 5 mg/kg every 8 weeks. METHODS: After 30 weeks of infliximab therapy, 25 patients were classified as responders [Bath Ankylosing Spondylitis Activity Index (BASDAI) <4 cm or ESR <30 mm/h and CRP <5 mg/l, n = 15; group A] or non-responders (patients who did not achieve the response established for group A; n = 10; group B). Responders continued on 5 mg/kg every 8 weeks and non-responders decreased the dose interval to 6 weeks. BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI), ESR, CRP and ankylosing spondylitis assessment (ASAS) criteria were used to assess response. RESULTS: At 62 weeks, 11 of 15 patients (73.3%, 95% confidence interval = 44.9-92.2%) from group A and three of 10 patients (30%, 95% confidence interval = 6.7-65.2) from group B were responders (P = 0.049). Eighty per cent (eight of 10 patients from group A) and 22.2% (two of 9 patients from group B) achieved 50% BASDAI improvement (P = 0.023), and nine of 11 patients (81.8%) and four of 10 (40%) from groups A and B, respectively, reached ASAS20 at 62 weeks (P = 0.08). CONCLUSION: Patients on infliximab 5 mg/kg every 8 weeks with persistent disease activity may benefit from reducing the dose interval to 6 weeks.     

Efficacy and safety of infliximab in patients with ankylosing spondylitis: Results of a randomized,placebo‐controlled trial (ASSERT)

Objective

The signs and symptoms of ankylosing spondylitis (AS) respond inadequately to nonsteroidal antiinflammatory drugs, corticosteroids, and disease‐modifying antirheumatic drugs in quite a number of patients. Tumor necrosis factor inhibitors have demonstrated success in reducing AS disease activity in a limited number of clinical trials. The objective of this multicenter, randomized, placebo‐controlled study was to evaluate the efficacy and safety of infliximab in patients with AS.

Methods

Patients were randomly assigned to receive infusions of placebo or 5 mg/kg infliximab at weeks 0, 2, 6, 12, and 18. Efficacy was assessed using the ASsessment in Ankylosing Spondylitis (ASAS) International Working Group criteria, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), night pain, patient's global assessment, the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Metrology Index (BASMI), chest expansion, the Mander enthesis index, the total swollen joint index, the C‐reactive protein level, and the Short Form 36 (SF‐36) health survey questionnaire. The primary end point in this study was the proportion of patients with a 20% improvement response according to the ASAS International Working Group criteria (ASAS20 responders) at week 24.

Results

Of the 357 patients screened, 201 were assigned to receive 5 mg/kg infliximab and 78 were assigned to receive placebo. After 24 weeks, 61.2% of patients in the infliximab group were ASAS20 responders compared with 19.2% of patients in the placebo group (P < 0.001). Clinical benefit was observed in patients receiving infliximab as early as week 2 and was maintained over the 24‐week study period. Patients receiving infliximab also showed significant improvements in the BASDAI, BASFI, BASMI, chest expansion, and physical component summary score of the SF‐36. Adverse events were reported by 82.2% of patients receiving infliximab and by 72.0% of patients receiving placebo; however, most adverse events in both treatment groups were mild or moderate in severity.

Conclusion

Infliximab was well tolerated and effective in a large cohort of patients with AS during a 24‐week study period.

     

Low-dose infliximab treatment for ankylosing spondylitis--clinically- and cost-effective

OBJECTIVES: Infliximab has been shown to be effective in the treatment of ankylosing spondylitis (AS) when treated in a dose of 5 mg/kg at 6 weekly intervals. This dose of infliximab has not been determined by any structured randomized trials and has significant cost implications. We describe our experience of treating AS with low-dose infliximab (3mg/kg at 8 weekly intervals). The efficacy and cost implications are discussed. METHODS: Patients who had active AS [Bath AS Disease Activity Index (BASDAI) > or = 4] were treated with infliximab 3 mg/kg at 0, 2, 6 weeks and thereafter at 8 weekly intervals. Response to treatment was defined as 50% improvement in BASDAI. Other response criteria such as ASAS 20, 40 and five of the six criteria were also assessed. Direct drug costs for infliximab were determined. RESULTS: Twenty-two consecutive AS patients received infliximab. All 22 completed treatment for 3 months, 15 patients for 6 months and 14 for 12 months. Mean age was 45 years (range 21-62) and mean disease duration 14.5 years (range 2-43). Of the patients, 54% achieved a 50% BASDAI response at 3 months and the benefit was sustained at 12 months in 63%. Similar response rate was seen with the other assessment criteria. Direct drug costs were significantly lower when low-dose infliximab regimen was used. CONCLUSIONS: Low-dose infliximab (3 mg/kg at 8 weekly infusions) is effective in the treatment of AS. Higher doses are required in a small proportion of patients when treatment is only partially effective. Titrating the dose and frequency of infusions may be required in individual patients to achieve optimal response. Using low-dose infliximab has significant economic implications.     

Multicenter validation of the value of BASFI and BASDAI in Chinese ankylosing spondylitis and undifferentiated spondyloarthropathy patients

The objectives of this study were to evaluate the reliability of Bath ankylosing spondylitis functional index (BASFI) and Bath ankylosing spondylitis disease activity index (BASDAI) in Chinese ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA) patients. 664 AS patients by the revised New York criteria for AS and 252 USpA patients by the European Spondyloarthropathy Study Group criteria were enrolled. BASDAI and BASFI questionnaires were translated into Chinese. Participants were required to fill in BASFI and BASDAI questionnaires again after 24?h. Moreover, BASDAI and BASFI were compared in AS patients receiving Enbrel or infliximab before and after treatment. For AS group, BASDAI ICC: 0.9502 (95% CI: 0.9330?C0.9502, ???=?0.9702), BASFI ICC: 0.9587 (95% CI: 0.9521?C0.9645, ???=?0.9789). For USpA group, BASDAI ICC: 0.9530 (95% CI: 0.9402?C0.9632, ???=?0.9760), BASFI ICC: 0.9900 (95% CI: 0.9871?C0.9922, ???=?0.9950). In the AS group, disease duration, occipital wall distance, modified Schober test, chest expansion, ESR, and CRP showed significant correlation with BASDAI and BASFI (all P?<?0.01). In the USpA group, onset age, ESR, and CRP were significantly correlated with BASDAI (all P?<?0.05), while modified Schober test, ESR, and CRP were significantly associated with BASFI (all P?<?0.05). The change in BASDAI and BASFI via Enbrel or infliximab treatment showed a significant positive correlation (P?<?0.01). The two instruments have good reliability and reference value regarding the evaluation of patient??s condition and anti-TNF-?? treatment response.     

Six months open label trial of leflunomide in active ankylosing spondylitis

OBJECTIVE: To examine the potential therapeutic effects of leflunomide in patients with active AS in an open label study. PATIENTS AND METHODS: Twenty patients with AS fulfilling the 1984 modified New York criteria with a Bath AS Disease Activity Index (BASDAI) >3 were given leflunomide for 6 months. Clinical outcome assessments included disease activity (BASDAI), function (BASFI), metrology (BASMI), patient's and physician's global assessment, peripheral joint assessment, quality of life (SF-36), global pain, and CRP. Primary end point was a reduction of disease activity as measured by the BASDAI of >25% at 6 months. RESULTS: A BASDAI 25% improvement was noted in 5/20 (25%) patients and a BASDAI 50% improvement in 4/20 (20%) patients. The absolute BASDAI did not change significantly over the 6 month study (4.9 at baseline v 4.3 at week 24, p>0.05). Similarly, no significant change was found for the BASFI, BASMI, patient's and physician's global assessment, SF-36 mental component, and CRP. For the 10 patients with peripheral arthritis, the mean number of inflamed joints was significantly reduced from 1.7 at baseline to 0.9 at week 12 (p = 0.034) and 0.2 at week 24 (p = 0.039). CONCLUSION: In this open study of patients with active AS only those with peripheral arthritis improved significantly with leflunomide treatment. Axial symptoms did not improve.     

Multicenter open-label study with infliximab in active ankylosing spondylitis over 28 weeks in daily practice

OBJECTIVE: The aim of this study was to prospectively investigate the therapeutic efficacy and safety of infliximab therapy in NSAID-refractory AS patients, with special emphasis on impact on quality of life in daily practice. PATIENTS AND METHODS: 101 AS patients with active disease (mean Bath ankylosing spondylitis activity index (BASDAI) 6.3, range 4.0-9.8) were enrolled in an open label study. Infliximab 5 mg/kg body weight was administered intravenously at week 0, 2, 6, 12, 18 and 24 followed by a final assessment at week 28. Clinical assessments included quality of life (SF-36, primary endpoint), disease activity (BASDAI), function (BASFI), metrology (BASMI), patients' and physicians' global, pain, work productivity (WPAI) and CRP. RESULTS: Using an intention to treat (ITT) analysis, the mean SF-36 physical health component improved from 27.6 at baseline to 40.9 at study end (p<0.001), the mean SF-36 mental health component improved from 44.4 at study entry to 53.0 at final assessment (p<0.001). The Assessment of AS (ASAS-) 20 short-term improvement criteria were reached by 80.2% of patients, ASAS 40 by 60.4% and the ASAS criteria for partial remission were reached by 27.7% of patients. A BASDAI 50% improvement was found in 66.3% of patients. Comparable significant improvements were found for mean BASDAI; BASFI, BASMI, patients' and physicians' global, general pain, CRP and WPAI. 11.8% of patients stopped therapy because of side effects. CONCLUSIONS: Infliximab showed high efficacy and safety when used by non-specialised rheumatologists in daily practice.     

Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor alpha monoclonal antibody infliximab

OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) has been detected in sacroiliac joint biopsy specimens from patients with spondylarthropathy. The present open pilot study was undertaken to test the efficacy of the anti-TNFalpha monoclonal antibody infliximab in the treatment of active ankylosing spondylitis (AS). METHODS: Eleven patients with AS of short duration (median 5 years, range 0.5-13 years) that had been active for at least 3 months (range 3-72 months) were treated with 3 infusions of infliximab (at weeks 0, 2, and 6), in a dosage of 5 mg/kg. Ten of the 11 patients had elevated C-reactive protein (CRP) levels (>6 mg/liter) before treatment; these elevations were known to have had persisted > 1 year in at least 3 patients. The Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI), pain as measured on a visual analog scale, and the Bath AS Metrology Index (BASMI) were assessed. Quality of life was assessed using the Short Form 36 instrument. Laboratory markers of disease activity, including interleukin-6 (IL-6) levels, were determined. Dynamic magnetic resonance imaging (MRI) of the spine was performed in 5 patients. RESULTS: One patient withdrew from the study due to the occurrence of urticarial xanthoma 8 days after the first infusion. At study enrollment, 3 of 5 patients had evidence of spinal inflammation (spondylitis and spondylodiscitis) as detected by MRI; followup MRI 2-6 weeks after the third infusion revealed improvement in 2. Improvement of > or = 50% in activity, function, and pain scores was documented in 9 of 10 patients; the median improvement in the BASDAI after 4 weeks was 70% (range 41-94%). This clear-cut benefit lasted for 6 weeks after the third infusion in 8 of 10 patients. The median CRP level decreased from 15.5 mg/liter (range <6-90.8) to normal, and the median IL-6 level from 12.4 mg/liter (range 0-28.4) to normal (<5). There was improvement in all 9 SF-36 concepts; the improvement was significant for 6 concepts. CONCLUSION: These data suggest that anti-TNFalpha therapy is very effective for several weeks in AS. Whether this therapy, in addition to its antiinflammatory effect, prevents ankylosis remains to be determined.     

Successful short term treatment of severe undifferentiated spondyloarthropathy with the anti-tumor necrosis factor-alpha monoclonal antibody infliximab

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) has been detected in sacroiliac joints of patients with spondyloarthropathies (SpA). Anti-TNF-a therapy has been efficacious in patients with active ankylosing spondylitis (AS) and psoriatic arthritis. Similar to these SpA subtypes, therapeutic options in undifferentiated SpA (uSpA) are also limited. We tested the efficacy of the monoclonal anti-TNF-alpha antibody infliximab in patients with active and severe uSpA in an open observation trial. METHODS: Six patients with uSpA were treated with 3 infusions of infliximab in a dosage of 3 (n = 3) or 5 mg/kg (n = 3) at Weeks 0, 2, and 6. The total observational period was 12 weeks. The Bath AS Disease Activity Index (BASDAI), the Functional Index (BASFI), pain on a visual analog scale, the Bath AS Metrology Index (BASMI), and quality of life (SF-36) were assessed before, during, and after therapy. RESULTS: Significant improvement at Day 1 after the first infusion lasting until Week 12 was reported by 5/6 patients. Improvement of > or = 50% in all activity, function, pain, and swollen joint scores was observed in the patients taking 5 mg/kg. The 3 mg/kg dose was less effective, resulting in > or = 15% improvement in outcome variables. Peripheral arthritis, enthesitis, and spinal symptoms improved equally. C-reactive protein dropped in 4 patients. Health related quality of life increased. No serious side effects or infections occurred. CONCLUSION: These observations suggest that anti-TNF-alpha therapy has significant short term efficacy in patients with severe uSpA.     

Two year maintenance of efficacy and safety of infliximab in the treatment of ankylosing spondylitis

OBJECTIVE: To obtain results of the second year extension of an original 3 month randomised, placebo controlled trial (and the 1 year extension study) assessing the use of infliximab, a monoclonal antibody to tumour necrosis factor alpha, for the treatment of patients with ankylosing spondylitis (AS). METHODS: Of the 54 patients with AS who completed the first year of the study, 52 continued to receive infliximab 5 mg/kg every 6 weeks up to week 102. The primary end point was the proportion of patients achieving at least 50% improvement from baseline in the Bath AS Disease Activity Index (BASDAI) at week 102. Other assessments included patient and physician global assessments, quality of life as assessed by Short Form-36, Bath AS Functional Index, Bath AS Metrology Index, and C reactive protein (CRP). RESULTS: Improvement in signs and symptoms of AS seen during the first year of the study was sustained during the second year. Forty nine patients (71% of 69 enrolled patients and 49/52 (94%) patients who started year 2) completed the study up to week 102. Thirty (58%) patients achieved at least 50% improvement from baseline in the BASDAI score at week 102. Scores for other efficacy assessments were similar at weeks 54 and 102. Median CRP levels remained low at weeks 54 and 102 (3.9 and 4.3 mg/l, respectively). Side effects during the second year of the study were similar to those of the first year of treatment with infliximab. CONCLUSIONS: Patients with AS treated for 2 years with infliximab 5 mg/kg exhibited a good and durable clinical response.     

Persistent clinical response to the anti-TNF-alpha antibody infliximab in patients with ankylosing spondylitis over 3 years

OBJECTIVE: Infliximab, a monoclonal antibody against tumour necrosis factor alpha (TNF-alpha), is approved in Europe for the treatment of patients with active ankylosing spondylitis (AS) who have responded inadequately to conventional therapy. This report provides analyses from a 3-yr extension study, as a follow-up to both the 1- and 2-yr open label extensions of the original 3-month randomized controlled trial of infliximab in patients with AS. METHODS: Of the 49 patients with AS who completed the second year of the study, 46 continued treatment with infliximab 5 mg/kg every 6 weeks up to week 156. The Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index, the Bath AS Metrology Index, patient's and physician's global assessments, quality of life (Short Form-36), C-reactive protein (CRP) and erythrocyte sedimentation rate were assessed throughout the study period. RESULTS: The improvement of signs and symptoms observed in the majority of the patients during the first and second year was sustained throughout the third year of the study. Forty-three patients (62% of the 69 patients enrolled at baseline and 93% of the patients who started the third year) completed week 156. In the intention-to-treat analysis, an ASAS '5 out of 6' and ASAS 40% response was seen by 46% and 50% of the patients, respectively. The scores for other efficacy assessments were similar to the values observed at weeks 54 and 102. Median CRP levels remained low (1.5 mg/l at week 156). There were no relevant side-effects and no discontinuation because of drug-related adverse events during the third year of the study. CONCLUSIONS: Patients with AS receiving infliximab for 3 yr showed a durable clinical response without loss of efficacy. Long-term infliximab treatment was well tolerated by patients in this study.     

Effectiveness of a modified dosing regimen with a lower maintenance dose of infliximab in the treatment of patients with ankylosing spondylitis and spondyloarthropathy

Objective: Anti‐tumour necrosis factor therapy offers hope to patients with ankylosing spondylitis (AS) and spondyloarthropathy (SpA) refractory to conventional disease‐modifying antirheumatic drugs (DMARDs). However, it is expensive with the standard recommended dosing (5 mg/kg) every 6–8 weeks. We assess the effectiveness of treating AS and SpA with a modified lower maintenance dosing regimen of infliximab. Methods: An open‐labelled, prospective trial with subjects recruited from a local tertiary hospital. Patients either fulfilled the modified New York criteria for classification of ankylosing spondylitis (AS) or European Spondyloarthropathy Study Group (ESSG) classification criteria for SpA with active disease. After induction with infliximab at 5 mg/kg at week 0 and 2 (induction period), patients were given 3 mg/kg at week 6 and then 8‐weekly (maintenance period) to 22 weeks. The patients were assessed with a standard protocol to 30 weeks. Erythrocyte sedimentation rate, c‐reactive protein, Visual Analogue Scale (VAS) pain score, VAS global health score (GH), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) were recorded. The Ankylosing Spondylitis Assessment (ASAS) 20, ASAS 40 and ASAS 5/6 were determined at the end of the study. Results: Eighteen Chinese patients were recruited (16 AS, 2 SpA; M : F 8 : 10), with the mean age of 38.2 years and mean disease duration of 8 years. Nine patients had extra‐articular manifestations (9 uveitis, 1 aortic valve insufficiency, 1 colitis). Thirteen of these were on concurrent DMARDs. When comparing baseline with 6, 14, 22 or 30 weeks, erythrocyte sedimentation rate, c‐reactive protein, VAS pain, VAS GH, BASDAI and BASFI all achieved a statistical significant reduction. Half of the patients (9/18) achieved ASAS20 and ASAS40, whereas 61.1% (11/18) achieved ASAS5/6 at the end of the study. Partial remission was achieved in 22.2% (4/18) of subjects studied. Improvement in VAS pain score, VAS GH and BASFI after the induction period was sustained during the maintenance period. Conclusion: The modified dosing regimen with a lower maintenance dosage of infliximab was feasible and effective in the treatment of spondyloarthropathy. This would allow more patients to access and afford the therapy. A larger cohort with longer follow‐up would be useful to assess structural changes as well as confirmation of our current findings.     

Infliximab in ankylosing spondylitis: a prospective observational inception cohort analysis of efficacy and safety

OBJECTIVE: Infliximab, a neutralizing antibody to tumor necrosis factor-alpha, appears to be effective therapy in ankylosing spondylitis (AS), although treatment is costly and serious infections are an increasing concern. We investigated the efficacy and tolerability of infliximab in a prospective observational inception cohort of patients with nonsteroidal antiinflammatory drug-refractory AS seen in both university and community based practice. We also used a lower dose, 3 mg/kg, than has been evaluated to date in AS. METHODS: We included all consecutive patients with AS starting infliximab therapy 3 mg/kg i.v. at 0, 2, and 6 weeks and q 2 months between April 2000 and October 2001. Data were systematically collected at baseline, 14 weeks, and 1 year, or at withdrawal, and included demographic characteristics, Bath AS indexes (BASDAI, BASFI, BASGI, BASMI), adverse events, and reasons for withdrawal. Laboratory measures included erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum matrix metalloproteinases (MMP) 1 and 3, and serum human cartilage glycoprotein-39 (YLK-40). The first 6 consecutive patients were also studied by several magnetic resonance sequences, including dynamic MRI with gadolinium augmentation of affected joints. Maximal rate of augmentation was determined at baseline and 84 days. Analysis was by intention-to-treat. RESULTS: Twenty-one patients (m:f = 17:4), mean age 42.5 years (range 24-66), mean disease duration 13.8 years (range 3-26), were studied: 13 had active peripheral synovitis at baseline. Mean followup was 47.5 weeks (range 10-77). Four patients withdrew, 2 for serious adverse events (septic osteomyelitis and severe hypersensitivity after 3 and 2 infusions, respectively), one for lack of efficacy, and one lost to followup. Three patients required an increased dose to 5 mg/kg after 14 weeks. Efficacy data were available on 17 patients at 14 weeks; mean BASDAI improved significantly from baseline (6.2) to 14 weeks (2.8) (p < 0.001), with 10 patients (58.8%) showing at least 50% improvement (range 0-99.6%). Significant reduction in mean BASFI (43.4%; p < 0.001), BASGI (44%; p = 0.001), ESR (55%; p < 0.001), and CRP (63.5%; p = 0.01) was evident. Complete remission of peripheral joint disease was seen in 5 of 11 (45.4%) patients evaluated at 14 weeks and maximal rate of MRI defined gadolinium augmentation was significantly decreased (p = 0.04). Reductions in serum YKL-40 and MMP-1 and 3 were nonsignificant, but significant correlations were observed between changes in BASDAI, ESR, CRP, and changes in serum levels of MMP-3 and YKL-40 (p < 0.005 to p < 0.05). Followup data on 8 patients completing 1 year of therapy revealed continued efficacy at a dose of 3 mg/kg every 8 weeks. CONCLUSION: Infliximab appears to be effective and well tolerated for both axial and peripheral joint disease in AS even at lower doses than those examined to date. Suppression of markers of cartilage degradation/turnover commensurate with reductions in clinical and laboratory measures of disease activity suggests that these markers should be further validated as surrogates for structural damage in AS. Controlled trials are warranted to further assess the potential of this agent in ameliorating structural damage.     

Efficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging study

OBJECTIVE: To determine the efficacy of anakinra, an interleukin 1 receptor antagonist in active ankylosing spondylitis (AS), and to investigate the effect of anakinra treatment on spinal enthesitis/osteitis using magnetic resonance imaging (MRI). METHODS: A 3 month open label study of anakinra (100 mg subcutaneous injection daily) was carried out in nine patients with active AS who had back pain and an increased acute phase response, and who had failed to respond to at least one non-steroidal anti-inflammatory drug. Clinical assessment included the Bath AS Functional Index (BASFI), Bath AS Disease Activity Index (BASDAI), and AS Quality of Life (ASQoL) before and after treatment. Fat suppressed MRI of the spine and sacroiliac joints was performed with a 1.5 T scanner at baseline and at 3 months to determine the effect of treatment on spinal enthesitis/osteitis. RESULTS: Significant improvement was found in the BASFI (median baseline 5.88, 3 months 3.63, p = 0.021), BASDAI (median baseline 5.63, 3 months 3.48, p = 0.028), ASQoL (median baseline 12, 3 months 8, p = 0.011) and laboratory measures reflecting inflammation, with C reactive protein (median baseline 31 mg/l, 3 months 17 mg/l, p = 0.036) and erythrocyte sedimentation rate (median baseline 19 mm/1st h, 3 months 15 mm/1st h, p = 0.008) also showing significant improvement. Six patients (67%) achieved the Assessments in AS (ASAS) Working Group criteria of 20% improvement. Of the 38 regions of enthesitis/osteitis determined by MRI at baseline, 23 (61%) either improved or regressed completely. CONCLUSIONS: This open label pilot study suggests that anakinra is effective in controlling the clinical manifestations of AS. The clinical response was reflected by an improvement in MRI determined spinal enthesitis/osteitis.     

Efficacy of methotrexate in ankylosing spondylitis: a randomized, double blind, placebo controlled trial

OBJECTIVE: To evaluate the efficacy and safety of methotrexate (MTX) compared with placebo in patients with active ankylosing spondylitis (AS). METHODS: This 24 week, double bind, randomized, placebo controlled trial compared the response between MTX 7.5 mg/week or placebo in patients with active AS. The primary outcome measure was a composite index of improvement in 5 of the following scales: severity of morning stiffness, physical well being, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), the Health Assessment Questionnaire for Spondyloarthropathies (HAQ-S), and physician and patient global assessment of disease activity. RESULTS: Seventeen patients received MTX and 18 placebo. In the intention-to-treat analysis at 24 weeks, 53% of patients in the MTX group had a treatment response, compared with 17% in the placebo group (p = 0.03). We observed significant improvements with MTX in physical well being (p = 0.009), BASDAI (p = 0.02), BASFI (p = 0.02), physician global assessment (p < 0.001), patient global assessment (p = 0.03), and HAQ-S (p = 0.02). In the adjusted analysis only MTX determined the improvement in the primary outcome. At the end of the trial, one patient with MTX withdrew due to a lack of compliance, and one with placebo due to a lack of efficacy. We did not observe significant differences in rates of side effects between the 2 groups. CONCLUSION: MTX is safe and effective for patients with AS. Longterm studies are needed to evaluate the permanence of its benefit.     

Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: an open,observational, extension study of a three-month,randomized, placebo-controlled trial

OBJECTIVE: Treatment of ankylosing spondylitis (AS) with infliximab, an anti-tumor necrosis factor alpha monoclonal antibody, was shown to be efficacious in patients with active disease during a 3-month treatment period. The purpose of this study was to evaluate the efficacy and safety of infliximab treatment of AS for a 1-year period. METHODS: This study was an open, observational, extension study of a 3-month, randomized, placebo-controlled trial. All patients who had tolerated infliximab (infliximab/infliximab group) or placebo (placebo/infliximab 12-week crossover group) therapy for 3 months entered the open extension trial (n = 65). Infliximab was administered at a dosage of 5 mg/kg every 6 weeks after the induction phase (weeks 0, 2, and 6). The primary end point was a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). RESULTS: At week 54, a total of 54 of the 69 patients (78%) continued to take infliximab. The intent-to-treat primary efficacy analysis at week 54 showed that 47% of patients in the infliximab/infliximab group (95% confidence interval 31-63) and 51% of the patients in the placebo/infliximab group (95% confidence interval 36-67) achieved 50% improvement in BASDAI scores. In the analysis of those who completed the study, the mean BASDAI scores improved between weeks 0 and 54 in both treatment groups: from 6.6 to 2.4 in the infliximab/infliximab group and from 6.3 to 2.6 in the placebo/infliximab group. The dosage of nonsteroidal antiinflammatory drugs was reduced in approximately 70% of the patients. There were significant improvements in measures of functioning, metrologic parameters, and quality of life. Between weeks 12 and 54, a total of 4 patients had serious adverse events that were possibly related to infliximab and resulted in their discontinuing the study. CONCLUSION: Infliximab therapy in AS patients resulted in a rapid and significant improvement in BASDAI scores (>50% improvement) and a durable response for 1 year. The safety profile of infliximab in AS was comparable to that observed in the postmarketing experience for the approved indications.     

Infliximab,a TNF-alpha antagonist treatment in patients with ankylosing spondylitis: the impact on depression,anxiety and quality of life level

The objective of this study was to assess the effect of infliximab on depression, anxiety and quality of life in patients with active ankylosing spondylitis (AS). In this 6-week longitudinal study, 16 patients with AS were assessed. Active disease as defined by BASDAI ≥4.0 was sought for inclusion. Infliximab was administered 5 mg/kg at 0, 2 weeks and 6 weeks. Collected data included age, sex and date of onset of rheumatologic disease. Activity of disease was measured using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Biological activity was evaluated with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). ESR and CRP were assessed at baseline and day 42. The Hospital Anxiety and Depression scale (HADS), Beck Depression Inventory (BDI) and 36-item Short Form Health Survey (SF-36) were used to evaluate anxiety, depression and quality of life. BASDAI, SF-36, HADS and BDE were assessed prior to the initial infliximab dose and at 2nd, 14th and 42nd day. Seven (43.8%) AS patients had depression scores above the cut off value for both the HADS depression (HADS-D) and BDI and 4 (25 %) had high HADS anxiety scores at baseline. Significant time effect for BDI and HADS-D scores were observed. Although significantly lower BDI scores were found after first, second and third infusions of infliximab, compared to initial score, the significant decrease in HADS-D appeared after second and third infusions. A significant time effect for HADS-anxiety scores were found as well. All of the subscales of SF-36 improved significantly during the course, with an exception of role emotional, for which the difference approached to the significance. The change in BASDAI scores and CRP and ESR, in the treatment process, were not correlated with the change in depression and anxiety scores. Infliximab which is an anti-TNF-α drug, may be effective in the treatment of depression accompanying AS. Possible implications for the treatment of major depressive disorder were discussed, as well.     

Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor alpha blockers in ankylosing spondylitis

BACKGROUND: TNFalpha blockers have been shown to be highly efficacious in patients with active ankylosing spondylitis (AS). OBJECTIVE: To identify parameters predicting the clinical response to TNF blockers in AS. METHODS: Patients with active AS participated in two placebo controlled, randomised trials conducted in Germany with infliximab (n = 69) and etanercept (n = 30), respectively. For inclusion in either trial patients had to have high disease activity (BASDAI >or=4) and a spinal pain score (numerical rating scale 0-10) >or=4 despite treatment with NSAIDs. A major clinical response was defined as a 50% improvement of the initial BASDAI (BASDAI 50) after 12 weeks' treatment with active drug. Logistic regression likelihood ratio tests (univariate and multivariate), Student's t test, and chi(2) tests were performed. RESULTS: Univariate analysis showed the following to be predictors of a major response (BASDAI 50) to treatment: shorter disease duration (p = 0.003); lower BASFI (p = 0.007); younger age (p = 0.009); raised ESR (p = 0.033); raised CRP (p = 0.035). After adjustment for disease duration, BASFI, ESR, and CRP, but not age, remained significantly associated. After adjustment for disease duration and for BASFI, ESR, CRP, and in addition, a higher BASDAI were significantly associated with response. The best multivariate model built by stepwise regression contained the covariables disease duration, BASFI, BASDAI, and CRP. CONCLUSION: A shorter disease duration, younger age, and a lower BASFI are predictors of a major clinical response to TNF blockers in active AS. Raised CRP and a higher BASDAI may also be valuable predictors. These data need to be confirmed in further studies.