Abstracts vom weltgrößten Rheumatologenkongress, das American College of Rheumatology (ACR 2003) in Orlando zu Remicade: Spondylitis ankylosans

Two Year Follow Up Results of a Controlled Trial of the Anti-TNF Alpha Antibody Infliximab in Active Ankylosing Spondylitis
Category:  27 Spondylarthropathies
Jan Brandt1, Joachim Listing2, Rieke Alten3, Gerd Bumester4, Erika Gromnica-Ihle5, Herbert Kellner6, Matthias Schneider7, Helmut Sörensen8, Henning Zeidler9, Joachim Sieper1, Jürgen Braun10. 1Benjamin Franklin Hospital, Free University Berlin, Berlin, Germany; 2German Rheumatism Research Center Berlin, Berlin, Germany; 3Schlosspark-Clinic, Berlin, Germany; 4Charité, Humboldt University, Berlin, Germany; 5Rheumatology-Hospital Berlin-Buch, Berlin, Germany; 6Ludwig-Maximilians-University, Munich, Germany; 7Heinrich Heine University, Düsseldorf, Germany; 8Immanuel Hospital, Berlin, Germany; 9University of Hannover, Hannover, Germany; 10Rheumatology Center, Herne, Germany
 

Background: In the initial double-blind randomised controlled part of this study the clinical efficacy of the anti-tumor necrosis factor alpha (TNF) antibody infliximab in patients with active and severe ankylosing spondylitis (AS) was demonstrated in a multicenter trial over 3 months. The data of the open extension over 1 year has suggested ongoing benefit.
Purpose: To assess the long-term efficacy and safety of infliximab over 2 years.
PATIENTS AND METHODS: Out of the 70 patients initially included in the placebo controlled phase, 54 patients entered the second year of the observational phase of the study. All patients continously received 5 mg/kg infliximab iv. every 6 weeks until week 102. Disease activity (by BASDAI), BASFI (Functional Index), BASMI (Metrology Index), quality of life by the SF-36 and CRP were assessed.
Results: At week 102, there were 49 completers (70%) and 21 drop outs: 14 due to adverse events (AEs), 3 due to lack of efficacy and 4 because of other reasons incl. non-compliance. The magnitude of improvement of disease activity was sustained in every outcome measure assessed until week 102. In an intention to treat analysis 43.5% of the patients reached an 50% improvement of the BASDAI at week 102. In the completer analysis, a sustained decrease of the disease activity at baseline was observed: the mean BASDAI at week 0 was 6.4 ± 1.3, at week 54 2.5 ± 1.7, and at week 102 2.6 ± 2.0. Importantly, at week 102 26.5% of the completers were in partial remission according to the ASAS criteria. The following AEs were observed: tuberculosis (1), transient allergic granulomatosis of the lung (1), chronic polyarthritis (1), transient symmetric polyarthritis with development of antinuclear- but no anti-DNA antibodies (2), mild skin lupus (1), transient mild leucopenia (1), moderate elevation of liver enzymes (1), herpes zoster (1), pancreatitis (1), and infusion related reactions (4).
Conclusion: This study shows that treatment with infliximab is very efficacious in patients with active AS over two years. After two years 70% of the patients are still being treated with infliximab with ongoing benefit, no further increase in side effects and no indication of loss of efficacy were observed. This possibly argues against a major role of anti-infliximab antibodies in patients on continous herapy. Therapy of active AS with infliximab is a major breakthrough in rheumatology.

Two-year-follow Up Data of Infliximab Therapy in Patients with Active Ankylosing Spondylitis: Socioeconomic Consequences
Category:  27 Spondylarthropathies
Jan Brandt1, Joachim Listing2, Rieke Alten3, Gerd Burmester4, Erika Gromnica-Ihle5, Herbert Kellner6, Matthias Schneider7, Helmut Sörensen8, Henning Zeidler9, Martin Rudwaleit1, Joachim Sieper1, Jürgen Braun10. 1Benjamin Franklin Hospital, Free University Berlin, Berlin, Germany; 2German Rheumatism Research Center Berlin, Berlin, Germany; 3Schlosspark-Clinic, Berlin, Germany; 4Charité, Humboldt University, Berlin, Germany; 5Rheumatology-Hospital Berlin-Buch, Berlin, Germany; 6Ludwig-Maximilians-University, Munich, Germany; 7Heinrich Heine University, Düsseldorf, Germany; 8Immanuel Hospital, Berlin, Germany; 9University of Hannover, Hannover, Germany; 10Center of Rheumatology Ruhrgebiet, Herne, Germany

Background: Patients with ankylosing spondylitis (AS) are at increased risk for unemployment, a higher frequency of sick leave, work disability and early retirement. Therapy with the anti-tumor necrosis factor a antibody infliximab was found to be long-term efficacious in active AS patients over two years.
Purpose: To assess whether infliximab therapy can improve the socioecomomic outcome of AS patients.
PATIENTS AND METHODS: At baseline, 70 patients with proven AS in an active stage of disease had been randomized into 2 groups who received either 5 mg/kg infliximab i.v. or placebo for 12 weeks. Thereafter, in an open extension phase, infliximab was given every 6 weeks to all patients until week 102. The status of education, profession, work status, and days of sick leave were assessed at baseline and after one and two years, respectively.
Results: There were 54 completers (78%) after 1 year and 49 (70%) after 2 years all with sustained improvement. The educational level of the patients was: academic (university degree) in 39%, apprenticeship or college in 22% and middle or elementary school in 38% of the patients. The total number of patients with gainful employment (n=30) who were on sick leave at all decreased from 9 (30%) at baseline to 2 (7%; p<0.05) and 3 (10%; p=0.11) patients at week 54 and 102. The mean days of sick leave assessed during the last 3 months decreased from 6.9 ± 13.0 at baseline to 0.3 ± 1.6 (p < 0.05) after one year and 2.5 ± 9.0 (p>0.05) after two years of treatment. During the year prior to the start of the trial patients had been hospitalised for a mean of 3.8 weeks. This was reduced to 1.7 weeks after one year during treatment with infliximab. The result at year 2 will be presented at the ACR.
Discussion: Treatment with infliximab has not only definite clinical efficacy but seems to reduce the number of days of sick leave and also to decrease the number of weeks of hospital admissions. These data suggest that infliximab may decrease direct and indirect costs caused by AS. Cost effectiveness analyses need to be performed.

The Burden of AS and the Cost-Effectiveness of Treatment
Category:  27 Spondylarthropathies
Presentation Time: Monday, 3:00 p.m. - 3:15 p.m.
G. Kobelt1, P. Andlin-Sobocki2, L. Jönsson2, S. Brophy3, A. Calin4, J. Braun5. 1Karolinska Institute, Stockholm, Sweden; 2Stockholm Health Economics, Stockholm, Sweden; 3Bath University, Bath, United Kingdom; 4Royal National Hospital for Rheumatic Diseases, Bath, United Kingdom; 5Rheumazentrum Ruhrgebiet, Herne, Germany

Introduction: In the past, treatment options for AS have been limited, and the introduction of new treatments such as infliximab will therefore have an impact on health care budgets. Consequently, it is important to assess the current burden of the disease and estimate the cost-effectiveness of using new treatments such as infliximab.
Methods: A cross-sectional retrospective observational study was performed in 2300 patients who had participated in a population survey between 1992-1994 at the University of Bath, and a cohort of 700 patients regularly followed at the Royal National Hospital for Rheumatic Diseases in Bath for up to 9 years. Patients answered a detailed questionnaire concerning their resource utilisation during the past 3 months, as well as current functional status (BASFI), disease activity (BASDAI) and QoL (utility, EQ-5D). Mean costs and utility were estimated using a regression model including age, gender, disease duration, disease activity and functional status. Annual disease progression was estimated using both cohorts.
Cost-effectiveness of infliximab was modelled using a 3-month placebo controlled clinical trial with open 1-year extension, over a total timeframe of 2 years. In the model, costs and utility controlled for disease severity (BASFI and BASDAI) as well as age from the observational study were assigned to individual patients.
Results: An answer to the questionnaires was received from 57% of patients. The mean age of the sample was 57 (11.2), 74% were male and mean disease duration was 30.2 (11.7) years. Mean BASDAI and BASFI were 4.21 (2.31) and 4.44 (2.76) respectively, and mean utility was 0.67 (0.21). Mean total costs were estimated at 6765 (166) £, with indirect costs representing 58%. Work capacity in the group below 65 years of age ranged from 85% to 26%, depending on the severity of the disease.
Using the clinical trial in the two-year model, mean costs for untreated patients are estimated at 25128 £, with direct costs accounting for 57%. For the infliximab group, mean costs (excluding treatment) are estimated at 17240 £, a reduction of 31%. Thus, a part of the treatment cost was offset by savings in other resources (7888 £), leaving an incremental cost of 6214 £. Treatment increased the number of quality-adjusted live years (QALYs) from 1.19 in the untreated group to 1.37 QALYs, leading to a cost per QALY gained of 35400 £ for the first year of treatment. Sensitivity analysis using infliximab maintenance treatment (9 infusions instead of 10 during the first year) leads to a cost per QALY of 34800 £. Cost-effectiveness ratios decrease in patients groups with more severe and more active disease.
Conclusions: Indirect costs dominate the cost of AS. The cost of treatment with infliximab is partly offset by reductions in the cost of the disease. Patients quality of life is increased and the cost per QALY gained is in the vicinity of 35000 £

Anti-TNF Alpha Therapy In Ankylosing Spondylitis. Can We Predict A Good Clinical Response?
Category:  27 Spondylarthropathies
Martin Rudwaleit1, Joachim Listing2, Jan Brandt1, Juergen Braun3, Joachim Sieper1. 1University Hospital Benjamin Franklin, Berlin, Germany; 2Epidemiology, Deutsches Rheumaforschungszentrum, Berlin, Germany; 3Rheumazentrum Ruhrgebiet, Herne, Germany

Purpose: TNFalpha blockers have been shown in recent controlled trials to be a highly effective therapy for patients with active ankylosing spondylitis (AS). It is not known which AS patients are more likely to respond to such therapy which is of interest given the risk of side effects and high costs of treatment.
METHODS: Patients with active AS participated in two placebo-controlled randomized trials conducted in Germany with infliximab and etanercept, respectively. For inclusion in either trial patients had to have high disease activity (BASDAI>4) despite treatment with NSAIDs. A good clinical response was defined as a 50% improvement of the initial BASDAI (BASDAI 50) after 12 weeks of treatment with either drug. For statistical analysis data from both trials (infliximab n=70, etanercept n=30) were combined. Logistic regression likelihood ratio tests (LRT; univariate and multivariate) and chi-squared tests were performed.
Results: A good clinical response (BASDAI 50) was achieved by 55/99 (55.6%) of the patients. Among patients with a short disease duration of 20 yrs (n=9/29). Patients with high disease activity and high levels of CRP were also more likely to achieve a good response: 29% of patients with initial BASDAI of 4-5 achieved a BASDAI 50 compared to 61% of patiens with a BASDAI >5 (p=0.17). While a CRP cut-of level of 10mg/l did not significantly differentiate between responders and non-responders (60% vs 45%) a cut-of level of 30 mg/l revealed differences (75% vs 48%; p=0.024). Univariate analysis revealed that a shorter disease duration (LRT 9.1; p=0.003), a lower BASFI (LRT 7.2; p=0.007), younger age (LRT 6.9; p=0.009), elevated ESR (LRT 4.5; p=0.033), and elevated CRP (LRT 4.5; p=0.035) were predictors of a good response to treatment. The best multivariate model built by stepwise regression contained the covariables (prediction parameters) disease duration, BASFI, BASDAI, and CRP.
Conclusion: In AS, a shorter disease duration, a lower BASFI, and a higher BASDAI may be valuable predictors of a good clinical response to TNF blockers. An explanation may be less structural damage having already occurred in such patients. Particularly high CRP levels are also associated with a good clinical response to anti-TNF therapy.

How To Diagnose Axial Spondyloarthritis Early?
Category:  27 Spondylarthropathies
Martin Rudwaleit1, Juergen Braun2, Muhammad A. Khan3, Désirée van der Heijde4, Joachim Sieper1. 1University Hospital Benjamin Franklin, Berlin, Germany; 2Rheumazentrum Ruhrgebiet, Herne, Germany; 3Case Western Reserve University, Cleveland, OH; 4Maastricht University, Maastricht, Netherlands

Purpose: Chronic low back pain, one of the earliest manifestations of axial spondyloarthritides (SpA), particularly ankylosing spondylitis (AS), precedes the development of radiographic sacroiliitis, sometimes by many years. Since chronic low back pain results from many different causes we sought to assign disease probabilities and to develop an algorithm which may help the clinician make an early diagnosis of axial SpA with a high degree of confidence.
Methods: Clinical SpA features of axial SpA include inflammatory back pain (IBP), enthesitis, arthritis, dactylitis, acute anterior uveitis, a positive family history, and good response to NSAIDs. Associated laboratory findings include elevated acute phase reactions, HLA-B27 association, and abnormalities on skeletal imaging. We determined the sensitivities and specificities of these parameters based on published studies and calculated likelihood ratios. For our analysis we used a figure of 5% prevalence of axial SpA among patients with chronic low back pain attending primary care physicians, based on a published report. We then determined the probabilitiy of the presence of axial SpA depending on the presence or absence of each of the above mentioned clinical features of SpA. A probability of at least 90% (post test odds of 9 or more) was considered a high enough degree of confidence for making a diagnosis of axial SpA in our proposed algorithm.
Results: The presence of inflammatory features of the patient’s back pain increases the probability of axial SpA from the background 5 % prevalence to 14 %. We found that the further presence of at least 2 to 3 SpA features was in general necessary to increase the probability of axial SpA to 90%. Among these features of SpA, which can be clinical manifestations alone, or laboratory or imaging procedures (such as HLA-B27 or MRI, respectively), the highest LR were obtained for acute anterior uveitis, HLA-B27, and MRI, reflecting the high utility of these parameters as aids to diagnosis. Using all of these parameters we have developed two kinds of diagnostic algorithms, one of them for the experienced rheumatologist, and the other for primary care physicians.
Conclusion: We present a novel approach to help clinicians diagnose with a high degree of confidence axial SpA at an early stage in patients with IBP who lack radiographic sacroiliitis.

Disease Activity, Severity, And Function In Patients With Early Ankylosing Spondylitis And Undifferentiated Axial Spondyloarthritis
Category:  27 Spondylarthropathies
Martin Rudwaleit1, Joachim Listing2, Elisabeth Maerker-Hermann3, Henning Zeidler4, Angela Zink2, Juergen Braun5, Joachim Sieper1. 1University Hospital Benjamin Franklin, Berlin, Germany; 2Epidemiology, Deutsches Rheumaforschungszentrum, Berlin, Germany; 3Horst Schmidt Kliniken, Wiesbaden, Germany; 4Medical School, Hannover, Germany; 5Rheumazentrum Ruhrgebiet, Herne, Germany

Purpose: In Ankylosing spondylitis (AS), very little is known about disease activity, severity, and function in patients with early disease and in patients with axial spondyloarthritis (SpA) who yet have not developed radiographic sacroiliitis.
Methods: The German Spondyloarthritis Inception Cohort (GESPIC) is a prospective observational study on SpA patients with early disease. Patients are classified as AS or axial SpA according to the modified New York criteria or ESSG criteria, respectively. A maximum duration of symptoms of 10 yrs for AS and 5 years for axial SpA without definite radiographic sacroiliitis is required for inclusion in this cohort. Disease activity, function, spinal mobility, and quality of life are assessed by validated instruments. For statistical analysis chi-squared tests and t tests were performed.
Results: The early stage of disease is well reflected by the mean duration of symptoms of 6.2 (SD 2.5) yrs among 138 AS patients and 3.7 (SD 2.4) yrs among 57 axial SpA patients (p<0.001). Axial SpA patients were younger (axial SpA 35.4 (SD 9.8) yrs vs. AS 39.5 (SD 10.3) yrs; p=0.01), and had less restriction of spinal and thoracic mobility as assessed by BASMI (axial SpA 1.3 (SD 0.17) vs. AS 1.8 (SD 0.15); p=0.003) and by thorax expansion (axial SpA 5.3 (SD 2.0) cm vs. AS 4.4 (SD 2.0) cm; p=0.006) compared to AS patients. There were no significant differences between axial SpA and AS regarding disease activity (BASDAI 4.3 vs 3.8; patient global 5.0 vs 4.9), function (BASFI 2.7 vs 3.2, Hannover questionnaire on function 78.3 vs 76.5), quality of life (SF 12 physical health 39.3 vs. 38.3, SF 12 mental health 43.0 vs. 46.7) and use of NSAIDs (64.9% vs 65.2%). The overall impact of disease as assessed by the physician was slightly lower in axial SpA than in AS patients (physician global: axial SpA 3.8 (SD 1.7) vs AS 4.6 (SD 2.2); p=0.012).
Conclusion: Disease activity, quality of life, and need of medical treatment are similar in patients with AS and in patients with axial SpA without radiographic sacroiliitis. However, compared to fully established AS, patients with axial SpA exhibit better spinal mobility probably reflecting shorter disease duration and less damage. The similar burden of disease lends support to consideration of anti-TNF therapy not only in AS but also in patients with early axial SpA.

Structural Damage Assessed on Radiographs in Patients with Ankylosing Spondylitis (AS) Steadily Increases over Time
Category:  27 Spondylarthropathies
Désirée M. F. van der Heijde1, Astrid Wanders1, Anneke Spoorenberg1, Sjef van der Linden1, Maxime Dougados2, Hille van der Tempel3, Herman Mielants4, Robert Landewé1. 1University Hospital Maastricht, Maastricht, Netherlands; 2Hospital Cochin, Paris, France; 3Maasland Hospital, Sittard, Netherlands; 4University Hospital Gent, Gent, Belgium

Introduction: The natural progression of structural damage assessed on radiographs in AS is unknown. It is often considered of less importance and at a lower rate as compared to rheumatoid arthritis.
Aim: To assess the progression of radiographic damage in a prospective cohort of AS .
Methods: Consecutive patients at 4 rheumatology centres were followed according to a fixed protocol (OASIS) and radiographs were obtained at baseline, after one, two and four years of follow-up. Films of lateral cervical and lumbar spine were scored according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS; range 0-72) by one observer with known chronology of the films.
Results: Radiographs of 133 patients (out of the original 217) were available for baseline, 1, 2 and 4-year follow-up. Baseline data for the patients with complete and incomplete data were similar. The progression during various time periods is presented in the figure. The percentage of patients showing progression is increasing steadily by each time interval. More than 55% of the patients show progression (mSASSS units >0) in a 4-year period. Also the amount of progression is increasing by each follow-up period. The mean (SD) progression is 1.53 (2.72), 2.59 (4.29), and 4.43 (6.39) in the 1, 2, and 4-year interval respectively.
Conclusion: Unlike the general perception, a large proportion of patients with AS show progressive structural damage over a 4-year period. This considerable amount of progression becomes apparent only if scored by a sensitive scoring method including both cervical and lumbar spine.

Abstracts vom weltgrößten Rheumatologenkongress, das American College of Rheumatology (ACR 2003) in Orlando zu Remicade: Psoriasis Arthritis

The One Year Results of the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT)
Category:  27 Spondylarthropathies
Presentation Time: Saturday, 5:15 p.m. - 5:30 p.m.
Christian Antoni1, Arthur Kavanaugh2, Bruce Kirkham3, Gerd Burmester4, Bernhard Manger1, Udo Schneider4, Zuhre Tutuncu2, Wolfgang Ebner5, Sigfrid Wassenberg6, Daniel Furst7, Jerry Molitor8, Edward Keystone9, Daphna Gladman10, Michael Weisman11, Daniel Wallace11, Joachim Kalden1, Josef Smolen5. 1Friedrich-Alexander-University, Erlangen, Germany; 2UCSD Rheumatology CIT, San Diego, CA; 3Guys Hospital, London, United Kingdom; 4Charité, Berlin, Germany; 52nd Dep of Med Lainz, Vienna, Austria; 6Ev. Fachkrankenhaus, Ratingen, Germany; 7Rheumatology Div. UCLA, Los Angeles, CA; 8Rheumatology Virgina Mason Med. Ctr., Seattle, WA; 9Mt Sinai Hospital, Toronto, ON, Canada; 10Ctr for Prognosis Studies, Toronto, ON, Canada; 11Cedars-Sinai Med Ctr, Los Angeles, CA

Purpose: To assess the safety and efficacy of infliximab in psoriatic arthritis over one year of treatment.
Methods: 102 patients with psoriatic arthritis (≥5 active joints) were included in a randomized double blind trial comparing infliximab with placebo over 16 weeks, followed by open treatment through week 50. Treatment arms were infliximab (5mg/kg) or placebo at week 0, 2, 6 and 14 and open label treatment for both arms with 5 mg/kg infliximab every 8 weeks thereafter. To preserve the blind, patients initially on placebo received blinded doses of infliximab at weeks 16 and 18. Patients were allowed, but not required stable comedication with DMARDs, NSAID and steroids ≤ 10 mg/day. We report the week 50 results.
Results: Of 102 patients, 88 completed according to protocol; 93 patients had a week 50 evaluation and have been included in this efficacy evaluation. Of the 14 patients discontinuing, 7 were due to AE (1 each: infusion reaction, joint infection, tendon rupture, elevated LFTs, asthma attack, meningioma), 6 due to lack of efficacy/withdrawal of consent and 1 lost to follow up. Regarding efficacy, the infliximab group had an ACR20 response of 69% at week 16 and 72% at week 50. At these same time points, the ACR50 was 49% and 54%, and the ACR70 29% and 35%. In the placebo group, the ACR20 was 8% at week 16; after swithcing to active treatment, the ACR20 increased to 77% at week 50. Similarly, the ACR50 and ACR70 increased from from 0% at week 16 to 49% and 30% (respectively, week 50) after switching to active treatment. Among patients with a baseline PASI ≥ 2.5, inflixmab treated patients improved their mean PASI from 8.4 to 1.6 at week 16; the PASI was maintained at 1.8 at week 50. Placebo treated patients worsened from a PASI 8.4 to a mean of 9.3 at week 16; but after switching to active treatment improved to a PASI of 2.3 at week 50. In the infliximab group, 12 of 14 patients improving their PASI by ≥ 75% at week 16 sustained this through week 50. Among placebo patients, after the switch, 8 of 16 had an improvement in PASI of ≥ 75% (week 50).
Conclusion: The rapid improvements in psoriatic skin and synovial lesions seen with infliximab treatment at week 16 were sustained through week 50. After switching to active treatment at week 16, the placebo group showed consistent response rates. The safety profile was good, and consistent with reported AE rates.

Infliximab Improves Signs of Plaque Psoriasis in Patients with Psoriatic Arthritis.
Category:  17 RA—treatment
Alan Menter1, Robert Evans2, Lisa T. Dooley2, Kamlesh Patel2, Cynthia Guzzo2, Robert Matheson3. 1Baylor University Medical Center, Dallas, TX; 2Centocor, Inc., Malvern, PA; 3Oregon Medical Research Center, Portland, OR

Purpose: Psoriatic arthritis is a chronic inflammatory condition that affects both the skin and joints. Tumor necrosis factor alpha (TNF-alpha), a primary mediator of general inflammation, plays a key role in the pathogenesis of both the articular and skin inflammatory components. Infliximab (IFX) is a chimeric, anti-TNFα monoclonal antibody that specifically neutralizes both bound and secreted forms of TNFα. Previous studies have demonstrated improvement in both rheumatoid arthritis when IFX is used in combination with MTX and in psoriasis when IFX used as monotherapy. This abstract assesses the effects of IFX induction therapy on plaque psoriasis in patients with PsA.
Methods: In a retrospective analysis of a Phase II, multicenter, randomized, double-blind, placebo-controlled trial evaluating IFX induction therapy in patients with plaque-type psoriasis, 78 patients had PsA as identified by medical history. These Patients were treated with placebo or 3 or 5 mg/kg IFX at weeks 0, 2 and 6. Improvement from baseline in psoriatic lesions was assessed using the Psoriasis Area and Severity Index (PASI) and Physician Global Assessment (PGA). Proportions of PASI responders (≥75 % improvement in PASI) marked responders (≥90 % improvement in PASI), and patients achieving a PGA score of minimal or clear in the IFX dose groups were compared with that of the placebo group at week 10 using a chi-square test.
Results: At week 10, a clinically significant improvement in psoriasis was noted in patients treated with IFX compared with those treated with placebo, with 89.7% of patients in the 5 mg/kg group being rated as having minimal/clear disease.
Conclusion: IFX treatment resulted in a highly significant greater improvement compared with placebo in all measures of efficacy for plaque psoriasis in patients with concurrent PsA.