Home Page - About the Arthritis Center -Hopkins Rheumatology - Myositis Center - Vasculitis Center - Scleroderma Center
| |
 
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Jon Giles, M.D. and Clifton Bingham, M.D.
Psoriatic Arthritis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ankylosing Spondylitis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Abstract 1169: Additional Human Beta-2m Curbs HLA-B27 Heavy Chain Misfolding and Promotes Arthritis and Spondylitis but not Colitis in Male B27 Transgenic Rats Although the association between the gene encoding HLA-B27 and spondylitis, arthritis, and colitis is well recognized, the molecular link between the protein and the development of the clinical phenotype is not understood. Previous work from these authors has identified that heavy chain proteins encoded by HLA-B27 tend to misfold, forming homodimers, which may be one of the pathogenic steps leading to disease. Here, Tran et al test the hypothesis that B27 misfolding will be reduced if stabilizing beta-2 microglobulin is present in excess, and further, that prevention of misfolding will prevent disease from occurring in a rat model of B27-associated disease. Methods: The L33.3 rat line, prone to colitis, orchitis, and occasional spondylitis, was bred with the healthy 282-2 line, which is know to overexpress beta-2 microglobulin, to observe the phenotypic changes associated with excess beta-2 microglobulin in the setting of B27 associated disease. Results: Contrary to the a priori hypothesis, crossing the L33.3 and 282-2 rat lines resulted in an increase in the prevalence and severity of B27 associated spondylitis, peripheral arthritis, and orchitis (but not colitis) . A second cross breeding experiment of 282-2 with a line that is disease prone only when homozygous (21-3), showed spondylitis and arthritis, but not colitis, only in male offspring that was not seen when 282-2 rates were cross bred with a disease resistant control line. Splenocytes from the 282-2 x 21-3 rates demonstrated 50% less dimmer formation of B27 heavy chains and a 2.5-fold increase in B27 heavy chain folding compared to 21-3 rats. Triggering of protein unfolding was seen in the L33.3 and 21-3 rats, but not in the 21-3 rats crossed with the 282-2 line. Conclusions: In a rat model of B27 associated disease, addition of excess beta-2 microglobulin appears to prevent B27 heavy chain misfolding and diminish the triggering of protein unfolding. Decreasing B27 misfolding and diminishing the triggering of protein unfolding is able to decrease colitis, but is associated with an increase in spondylitis and peripheral arthritis. Editorial Comment: These results are interesting as much for the new questions that are presented than for the ones that are answered. The findings that phenotypic features of B27 associated disease, at least within the confines of this rat model, may be different depending on more or less B27 misfolding is very novel and suggests that B27 disease may be characterized by a complex dysregulation of proteins rather than just a simple increase or decrease in the expression of pathogenic proteins. Further, pathogenic processes may be different given different target tissues. This, of course, adds many new layers of complexity to the study and understanding of this already complex disease process. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Abstract 691 Adalimumab Therapy Results in Significant Reduction of Signs and Symptoms in Subjects with Ankylosing Spondylitis: The ATLAS Trial Abstract 483 Major Clinical Response and Partial Remission in Ankylosing Spondylitis Subjects Treated with Adalimumab: The ATLAS Trial Abstract 490 Adalimumab Improves Health-Related Quality of Life in Patients with Active Ankylosing Spondylitis-The ATLAS Trial Background: Ankylosing spondylitis (AS) is an immune-mediated disease state in which tumor necrosis factor (TNF) is present in increased concentrations in the axial and peripheral joints. Adalimumab (ADA) is a fully human, monoclonal antibody that targets TNF. This study evaluated the efficacy of ADA vs. placebo (PBO) in patients with active AS. Methods: Adalimumab Trial Evaluating Long-term Efficacy and Safety in AS (ATLAS) was a randomized, PBO-controlled, double-blind, study conducted in the US and Europe. Patients with active AS who had an inadequate response to at least one NSAID or DMARD were eligible to enroll. Patients were randomized to receive either ADA 40 mg every other week or placebo for 24 weeks. After the Week 12 assessment, patients not achieving an ASAS20 response were eligible for early escape therapy with ADA, but were considered nonresponders in the analysis. Efficacy was assessed using the ASessment in AS (ASAS) International Working Group criteria (the Bath AS Disease Activity Index [questions 5 and 6; BASDAI], Total Back Pain [TBP], the Bath AS Functional Index [BASFI], and the Patients Global Assessment of disease activity [PGA]) and BASDAI 50. The primary endpoint was ASAS20 response at Week 12. Results: 315 patients (208 ADA, 107 PBO) were enrolled. Baseline characteristics were similar between ADA and PBO arms. ASAS20, 50, and 70, and BASDAI 50 responses for ADA patients were significantly better than PBO at Weeks 12 and 24 at 12 and 24 weeks.
It is of note that the results in the table above were in the abstract though there were slight differences in the numbers in the presentation at ACR that did not affect the magnitude of response or significance of results. ASAS20 responders for ADA were seen as early as 2 weeks vs. PBO (p<0.05). Also, ADA patients showed significant improvements vs. placebo for BASDAI, TBP, BASFI, and PGA at Weeks 12 and 24. Early escape therapy was chosen by 50% of PBO and 26% of ADA patients at Week 12. Adverse events (AE), serious and severe AEs were comparable between both groups, though there were higher LFTs seen in the ADA groups, the magnitude of these changes were small. No serious infectious AE was present in ADA. No malignancies or deaths occurred. Conclusions: Adalimumab as monotherapy, administered 40 mg every other week, was efficacious in reducing the signs and symptoms of active AS during this 24-week period. Adalimumab was safe and well-tolerated. Editorial Comment: These data demonstrate the efficacy of Adalimumab in the treatment of AS further demonstrating the important role of TNF in the pathogenesis of this disease. Additional data were presented at ACR that showed more patients had achieved an improvement in 5 of 6 domains of the ASAS Criteria (ASAS 5/6) in 48.6% and 44.7% of ADA-treated patients and in 13.1% and 12.1% of placebo treated patients at 12 and 24 weeks respectively. Also more patients were in ASAS Partial remission with ADA than PBO 20.7%/22.1% vs 3.7%/5.6% as 12 and 24 weeks, respectively (Abstract 483). In parallel with the improvements in signs and symptoms, additional data were presented showing improvements in health-related quality of life with ADA as recorded by the physical component scale of the SF-36 and AS Quality of Life score (Abstract 490). The ability to demonstrate ASAS70, ASAS5/6, and ASAS Partial remissions in patients with active AS represent clinically relevant improvements in signs and symptoms that are paralleled by improvements in quality of life. These data further support the evolving treatment recommendations that advocate earlier institution of the TNF antagonist class for therapy of patients with AS. The long term radiographic implications of symptomatic disease control remains to be seen. Abstract 1708 Radiographic Results from a Long-Term Multicenter Trial of Etanercept (ENBREL) in Patients with Ankylosing Spondylitis Purpose: Several double-blind, placebo-controlled studies in patients with Ankylosing Spondylitis (AS) have shown that etanercept reduced disease activity measured by multiple variables including Assessment in Ankylosing Spondylitis (ASAS) 20, 50 and 70. However, there is limited data on radiographic progression. This study evaluated radiographic progression in patients with AS after one year of etanercept. Methods: This was a 2-year open-label, multicenter extension study of adult subjects with AS preceded by a 3-month double-blind, placebo-controlled trial. The study was designed to provide long-term safety and efficacy data, including radiographic outcomes in patients treated with etanercept. 81 subjects from the original blinded study who met the completion requirements were enrolled into this treatment extension and received etanercept 25mg twice weekly for up to 96 weeks. X-rays of cervical and lumbar spine taken at baseline in the double-blind study were compared with films taken at week 48 of the extension, or at early termination, to assess the degree of radiographic progression in these patients. Radiographic data from subjects with valid baseline and post-baseline images were included in the analysis (N = 70 for cervical spine and N=68 for lumbar spine). All images were scored in a blinded fashion, without information on time sequence, by an independent reader using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) method. Paired t-tests were used to test within group changes from baseline. Results: Mean mSASSS scores at baseline in the double-blind, placebo-controlled study for cervical, lumbar and overall spine were 9.8, 5.7 and 15.1, respectively. Mean (S.E.) mSASSS change from baseline to week 48 or early termination was 0.1 (+ 0.1) for cervical spine, -0.1 (+ 0.1) for lumbar spine and 0.1 (+ 0.2) for overall x-ray scores. Most patients exhibited no change in their scores as noted by the median change of 0.
Conclusions: In this one year open label study of treatment with etanercept 25 mg twice weekly, patients with AS appeared to show no radiographic progression of disease. Editorial comment: Though this study demonstrates that there is no plain radiographic progression in this group of AS patients over 1 year treated with Etanercept, there is no control group that is either untreated or treated with other non-biological therapies for reference. While clinical trials in RA have devised expected rates of radiographic progression based on entering Sharp scores and duration of disease, it is unclear that a similar extrapolation exists for AS to put these results in context. If the rate of change is slow on the individual level, then mean changes may not readily be seen without larger sample sizes. Analysis of each individual patient and the evaluation of the numbers of progressors, as reported for RA studies, may help in the interpretation of these results as well. Given the clinical benefits of TNF antagonists in the treatment of axial disease in AS, and the evolving treatment recommendations suggesting that TNF antagonists are important in the early management of disease, performing a longer term study of patients with a proper control group may be difficult, thus defining an appropriate reference historical control may be the best available comparison. The incorporation of other imaging modalities such as MRI, which have in small series shown improvement in findings of enthesopathy and bone marrow lesions, do suggest the TNF antagonists are affecting the biology of AS in addition to improving signs and symptoms. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Psoriatic Arthritis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Abstract 690 Alefacept (Amevive®) in Combination with Methotrexate for the Treatment of Psoriatic Arthritis Background: Alefacept (Amevive; ALF) is approved for the treatment of psoriasis and acts by inhibiting an interaction between antigen presenting cells and memory effector T lymphocytes resulting in inhibition of T cell activation and proliferation, especially CD4-bearing lymphocytes. ALF is a dimeric fusion protein that consists of the extracellular CD2-binding portion of the human leukocyte function antigen-3 (LFA- 3) linked to the Fc portion of human IgG1. Previous open label studies have shown clinical efficacy in psoriatic arthritis, and decreases in both lymphocyte infiltration and CD68 macrophage infiltration has been demonstrated in response to alefacept in synovial tissue biopsies (Kraan MC, van Kuijk AW, Dinant HJ, Goedkoop AY, Smeets TJ, de Rie MA, Dijkmans BA, Vaishnaw AK, Bos JD, Tak PP. Alefacept treatment in psoriatic arthritis: reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis. Arthritis Rheum. 2002 Oct;46(10):2776-84) The objective of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of alefacept (ALF) in combination with methotrexate (MTX) for the treatment of psoriatic arthritis (PsA). Methods: Patients ages 18-70 years with active PsA (>3 swollen joints and >3 tender joints) despite treatment with MTX (>10 mg/week to >25 mg/week) for >3 months, with a stable dose for >4 weeks prior to enrollment were eligible. Randomization (2:1, alefacept:placebo) was stratified based on body surface area involvement (BSA) of psoriasis (>3% or <3%). Alefacept (15 mg) was administered intramuscularly once weekly for 12 weeks, followed by a 12-week observation period. All patients continued to receive their stable dose of MTX throughout the 24-week study period. Allowed concomitant therapies were stable doses of corticosteroids (<10 mg/day of prednisone or equivalent) and NSAIDs. Psoriasis Area and Severity Index (PASI) and Physician Global Assessment (PGA) were used as measures of psoriasis activity in patients who had psoriasis involving >3 % BSA. The primary efficacy endpoint was the proportion of patients achieving ACR20 at week 24. Safety assessments included hematology and lymphocyte subset analysis. Adverse events were monitored throughout the study. Results: 185 patients were randomized to receive either ALF-MTX (n=123) or placebo-MTX (n=62). Mean MTX doses were 13.7 mg in the Alefacept and 14.6 mg in the placebo group. Week 24 results (12 weeks after ALF dosing was completed) are presented below:
At week 24, the mean decrease in tender-joint count was 31% in the ALF-MTX group and 18% in the placebo-MTX group, and the mean decrease in swollen-joint count was 46% in the ALF-MTX group and 34% in the placebo-MTX group. In patients evaluable for psoriasis endpoints (n=87), significant improvement was noted in the ALF-MTX group, with 53% of these patients achieving PASI 50 at week 14 compared with 17% of those receiving placebo-MTX (P<0.001). PASI 75 was achieved by 22% of ALF-MTX-treated patients, and 10% of placebo-MTX-treated patients (P=NS). Adverse events were similar between treatment groups; those occurring in >5% of patients in either group included back pain, nasopharyngitis, URI, nausea, and increased alanine transaminase (ALT). Less than 2% of patients receiving ALF-MTX discontinued treatment due to treatment-related adverse events. There were no serious infections or malignancies in the alefacept-MTX group. Expected reductions in CD4 lymphocytes were seen in alefacept treated groups. Conclusions: These results suggest that alefacept in combination with MTX is a safe and effective treatment for PsA. Editorial Comment: This study provides important safety and efficacy information regarding the combination of alefacept with methotrexate. Whereas studies in psoriasis patients evaluated the effect of alefacept alone, it was important to determine if additive toxicity would be seen in combination with methotrexate in patients with psoriatic arthritis. The results presented would suggest that no untoward safety signal was seen with this combination over the 6 months of the study. The data presented suggest that there is clinical efficacy for alefacept in reducing signs and symptoms of active psoriatic arthritis patients with continuing disease activity in spite of methotrexate. Efficacy results were also presented for open label retreatment of patients with a second course of alefacept for 12 weeks followed by a second 12 week observation period demonstrating a further improvement from baseline at the ACR50 and 70 levels. Data was also briefly presented in this oral presentation showing a reduction of radiographic progression (measured by modified total sharp score) in patients who received alefacept compared to placebo; however the time period of this measurement and the statistical significance of the differences were not elaborated. The data presented would suggest that the recommendation to carefully follow CD4+ T-lymphocyte counts is especially important with concomitant immunosuppressives, as well as attention to CD4 lymphocytopenia that may predispose patients to opportunistic infection. All studies to date have looked at only 12 weeks of treatment followed by 12 weeks off treatment; thus the safety of continuous treatment with alefacept is unknown. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TNF Antagonists in Psoriatic Arthritis The data at ACR 2005 represent extensions of the above studies that were carried out over 1 year with additional clinical and radiographic outcomes. As has previously been demonstrated with etanercept (Mease et al Arthritis Rheum 2004; 50: 2264-2272), we continue to see that psoriatic arthritis is a modifiable disease with the use of TNF antagonist therapy as judged by modified Sharp scoring of plain radiographs. Infliximab Infliximab Abstract 487 Infliximab Therapy Results in Sustained Improvement in Functional Status and Quality of Life in Patients with Psoriatic Arthritis- Results from the IMPACT 2 Study Abstract 486 Sustained Improvement in Clinical Measures of Psoriatic Arthritis in Infliximab-Treated Patients: 1 Year Results from IMPACT 2 We have previously seen data demonstrating that infliximab (IFX) is effective in improving signs and symptoms of psoriatic arthritis. Results from the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) have been reported and some results previously reviewed. (Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, Schneider U, Furst DE, Molitor J, Keystone E, Gladman D, Manger B, Wassenberg S, Weier R, Wallace DJ, Weisman MH, Kalden JR, Smolen J. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum. 2005 Apr;52(4):1227-36) This study demonstrated that infliximab at 5 mg/kg every 8 weeks after loading doses at 0, 2, 6 weeks, improved signs and symptoms, including swollen and tender joints, composit indices, and skin disease in addition to dactylitis and enthesitis in patients with active psoriatic arthritis. (see ACR 2004 highlights) The results of IMPACT2, a larger placebo controlled study of 200 patients with moderately severe psoriatic arthritis, have also been previously reviewed in our ACR 2004 highlights (abstracts 1635 & 1637)and our Eular 2005 highlights (abstract OP0169). Additional data were presented at ACR 2005 with longer term clinical and radiographic follow up from this study at 1 year. Methods: This was a 1 year double-blind, placebo-controlled trial. Patients with active (> 5 joints) PsA were randomized (1:1) to receive IFX 5 mg/kg at wks 0, 2, 6, and every 8 wks through wk 46 or placebo at wks 0, 2, 6, 14, and 22. Concomitant MTX at stable doses was permitted. Placebo-treated pts with less than 10% improvement in both swollen and tender joints entered early escape and received IFX 5 mg/kg at wks 16, 18, and 22 (N=47). At wk 24, all placebo pts who did not qualify for early escape, received IFX at wk 24, 26, 30, 38 and 46. Pts randomized to IFX who had less than 20% improvement in combined tender and swollen joint count were dose escalated to receive IFX 10 mg/kg at wks 38 and 46. Function was assessed using the HAQ, and SF-36. Formal assessments of dactylitis and enthesopathy were also performed. Radiographs of the hands and feet were obtained at wk 0, 24, and 54 and evaluated by the modified Van der Heijde-Sharp method. Results: 200 pts were enrolled. At baseline, the median pt age was 47 years, PsA duration was 5.5 years. Baseline tender joints were 23, and swollen joints were 12. Dactylitis was recorded at baseline in 40%/41% of PBO/IFX patients respectively, and enthesopathy in 35%/42%. Baseline mean and median HAQ was 1.1. At week 24, 54% of IFX treated patients and 16% of PBO treated patients had achieved an ACR20 (p<0.001). The proportion of patients with dactylitis and enthesopathy was significantly lower in IFX-treated patients vs PBO at week 24. The median percent improvement from baseline in HAQ at 14 weeks was 42.9% in the IFX group and 0% in the PBO group. After placebo patients were switched to receive infliximab at 24 weeks, the median percent improvement in HAQ from baseline 45.5% compared to 50% of the patients maintained on IFX from the start of the study. HAQ improved by more than 0.3 in 58.9% of IFX treated patients and in 53% of patients who received PBO then IFX. Baseline mean +/- SD (median) total vdH-S score was 39.09 +/- 82.83 (4.50) for IFX and 30.29+/-61.43 (6.00) for placebo. At wk 24, IFX-treated pts had significantly less radiographic damage at wk 24 than pts receiving placebo, as measured by the mean ( SD) change from baseline in total vdH-S score (-0.70 + 2.53 vs 0.82 + 2.62, p<0.001). In the placebo group, 12 pts demonstrated progression in total vdH-S score above the smallest detectable change (SDC=2.69) at wk 24 vs 3 pts in the IFX group (p=0.017). In pts continued on IFX through wk 46, the mean (SD) change from baseline at wk 54 was -0.94 (3.40) vs 0.53 (2.60) in pts who crossed over from placebo to IFX (p=0.001). IFX randomized pts and placebo pts who crossed over to IFX at wk 16 or 24 had an improvement in total score of -0.24 (2.45) and -0.29 (1.98), respectively, from wk 24 to 54. No differences were observed in PsA-characteristic features including pencil-in-cup deformities and gross osteolysis. There were no opportunistic infections, serious infusion reactions, CHF, or clinically significant liver damage, though 6 IFX treated patients had more than 1 markedly abnormal ALT elevation compared to 0 PBO patients. Conclusion: Infliximab treatment of psoriatic arthritis patients results in significant improvements in clinical parameters, functional assessments, and inhibited radiographic progression in as early as 24 wks. Radiographic improvement continued through 1 year. Improvement in radiographic scores was observed in placebo pts who initiated IFX after a 16-24 wk delay but was less than that observed in pts who initiated IFX at the start of the study. Adalimumab Abstract 500 Clinical Efficacy and Safety of Adalimumab for Psoriatic Arthritis: 48-Week Results of ADEPT Methods: The ADEPT study (Adalimumab Effectiveness in Psoriatic Arthritis Trial) was conducted to assess the efficacy of Adalimumab (ADA) 40 mg every other week versus placebo (PBO) over 24 weeks. The data presented at ACR 2005 are from an open label extension of the original 6-month study. More than 300 patients with longstanding, moderately to severely active PsA, were enrolled in an initial 6 month placebo-controlled study, followed by an open label roll over to active treatment with adalimumab. Patients were stratified in the initial randomization according to methotrexate (MTX) use. During the open-label period, after 12 weeks of therapy, patients who had an inadequate response were permitted to increase to ADA 40 mg every week, but data from these patients used the nonresponder imputation for ACR and PASI, and last observation carried forward for HAQ. Radiographs of the hands and feet were obtained at baseline, 6 months, and at 1 year over one year and evaluated by the modified total Sharp score that evaluated additional joints affected by PsA (e.g. DIPs) and expanded numerical scales to evaluate osteolysis. For missing radiographs at 48 weeks, results from 24 weeks were carried forward. Results: Enrolled patients had clinically active disease with 14.3 swollen (76 possible) and 23.9-25.8 tender joints (78 possible). Clinical responses of the patients who were rolled over from PBO treatment to open label active ADA treatment were similar to the responses seen in the ADA treated group over the first six months. Twelve patients escalated to weekly ADA at Week 36, of whom 3 (25%) achieved an ACR20 response at Week 48. Baseline use of MTX did not affect the clinical response.
Patients had significant preexisting radiographic damage and were well matched between treatment groups with baseline mTSS, ERO, JSN in ADA vs PBO 22.7 vs 19.1, 11.4 vs 10.0, and 11.2 vs 9.2, respectively. Whereas the patients in the placebo group had significantly more progression (+ 1.0) as measured by mean mTSS in the first 24 weeks than the ADA (-0.1), p<0.001, when the patients initially treated with placebo were moved to active treatment, there was a reduction in their additional progression that was decreased to the rate of the patients maintained on ADA from the beginning of the study (mean change in mTSS, 0.1 in ADA (0-48 weeks) and Placebo-ADA (24-48 weeks). An additional analysis not reported in the abstract demonstrated that, while all patients receiving ADA had less radiographic progression than Placebo or MTX treated patients, patients receiving MTX in combination with ADA had less radiographic progression than those receiving ADA alone. ADA was generally well-tolerated. The safety profile during the open-label therapy was consistent with that reported for the initial 24 wks and that described for ADA in RA studies. Conclusions: Adalimumab therapy was effective in treating the signs and symptoms and in controlling radiographic progression of patients with PsA when administered over 48-wk. Editorial Comments: We continue to appreciate from these studies that psoriatic arthritis affects function, quality of life, and is a potentially destructive disease. As has been the case for TNF antagonist therapy in rheumatoid arthritis, all three available TNF antagonists appear to have quite similar efficacy in the treatment of psoriatic arthritis, both in terms of clinical outcomes as well as in terms of slowing of radiographic progression affording patients and practitioners several options in the management of disease. While differences in drugs versus placebo are seen according to mean changes in radiographic progression, as is the case in rheumatoid arthritis, the majority of patients do not show progression over the short term. Defining the parameters that identify patients with an aggressive phenotype of PsA remains a challenge. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ((top of page)) (next page)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
