Spondyloarthropathy
At this year's meeting investigators from several countries reported favorable results of TNFainhibition therapy for spondyloarthropathies, particularly ankylosing spondylitis and psoriatic arthritis. Three studies reported longer term data on earlier published trials (Abstracts 207, 208, 2019), each demonstrating continued safety and efficacy of TNFatherapy. Two new studies, (Late Breaking Abstract and Abstract 209) showed dramatic MRI improvements with therapy, underscoring the need to further investigate the longterm significance of MRI changes. Future trials are needed to clarify the role of TNFainhibition as disease modifying therapy for spondyloarthropathies.
- Etanercept
- Infliximab
- Basic Science (abstract review by Antony Rosen)
- in the Treatment of Psoriatic Arthritis
- in the Treatment of Ankylosing Spondylitis
- in the Treatment of Resistant Spondyloarthropathy
in the Treatment of Psoriatic Arthritis
Abstract #2019 Enbrel (etanercept) in the Treatment of Psoriatic Arthritis (PsA) and Psoriasis P Mease. Seattle, WA.
Overview of Study: In this study, Mease reports 6 month open-label data on 58 of 60 patients who completed a 3 month randomized, double-blind, placebo-controlled trial of Enbrel 25mg (n=30) vs. placebo (n=30) subcutaneous twice a week (Mease Lancet 2000;356;385-90). Initial entry criteria included: 1) presence of psoriasis, 2) arthritis in > 3 swollen and tender joints, and 3) inadequate response to current therapy. Outcome measures included: 1) Psoriatic Arthritis Response Criteria (PsARC)* 2) ACR response critieria, and 3) Psoriasis Area and Severity Index (PASI). Methotrexate, NSAIDS, and steroids were maintained at stable doses.
Summary of Findings after 3 months Blinded Phase: 87% of Enbrel-treated patients vs. 23% of placebo-treated patients had improved according to PsARC criteria. The percent of Enbrel vs. placebo-treated patients who achieved ACR 20, 50, 70 responses were as follows: 73% vs. 13%; 50% vs. 3%; 13% vs. 0%. The median percent improvement in PASI in Enbrel vs. placebo-treated patients was 46% vs. 9% (p<0.003).
Summary of Findings after 6 months Open Label Extension: Fifty-eight patients from the 3 month blinded phase of the trial continued in the open label extension phase. All patients received Enbrel 25mg twice weekly. 24/28 (86%) patients in placebo and 26/30 (87%) Enbrel patients completed the 6 month extension. The patients initially treated with Enbrel maintained their response according to PsARC, with additional patients showing improvement according to ACR criteria. Two-thirds of placebo-treated patients showed improvement once treated with Enbrel, a response similar to but not as pronounced as patients originally treated with Enbrel. Methotrexate-treated patients responded no differently than those not taking methotrexate.
| n=50 | ACR 20 | ACR 50 | ACR 70 |
| Placebo/Enbrel | 61% | 46% | 25% |
| Enbrel/Enbrel | 87% | 63% | 33% |
Methotrexate was discontinued in 25% and decreased in 43%. Prednisone was discontinued in 67% of patients and decreased in 67%. PASI scores also improved in all Enbrel treated patients (median percent improvement 62%).
Adverse events included minor infections in 47%. Injection site reactions in 14%. One patient developed a multiple sclerosis-like illness and elected to continue etanercept therapy without progression of symptoms occurring.
Editorial Comment: This study provides encouraging results on the long-term management of psoriatic arthritis and psoriasis with Enbrel. Patients in this open-label trial continued to respond favorably over time, with the number of patients achieving ACR 70 more than doubling in one year. The results of a recently completed 200 patient, multi-center trial of Enbrel in psoriatic arthritis is anxiously awaited.
*PsARC:Improvement in at least 2 of 4 criteria: 1) physician global assessment, 2) patient global assessment, 3) tender joint count, 4) swollen joint count; improvement in at least 1 of 2 joint scores; no worsening in any criteria.
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Abstract #35 Efficacy of Etanercept in Refractory Psoriatic Arthritis (PsA) M Cuellar E Mendez, R Collins, S Burford, L Espinoza. New Orleans, LA.
Overview of Study: This study was an open-label trial of etanercept 25mg twice weekly in 12 patients with PsA who had failed methotrexate alone or in combination with cyclosporin A (n=5), sulfasalazine (n=6), leflunomide (n=1), azathioprine (n=1), prednisone (n=2) (median number of previous DMARDS: 2.5, range 2.0 to 6.0). All DMARDS were discontinued except methotrexate < 20mg. Treatment response was defined as improvement in at least 2 of 4 criteria: patient and physician global assessment, tender and swollen joint count. Skin involvement was assessed using the Psoriasis Area and Severity Index (PASI). The ACR response criteria, including the HAQ, ESR, and CRP were also measured. Mean follow-up time was 10 months (range 5-14 months).
Summary of Findings: There were 8 men and 4 women with an average disease duration of 17 years for skin (range 10 to 35 years) and 10 years for arthritis (range 2 to 21 years). At 24 weeks, ACR 20 was achieved in 83% of patients; 67% achieved ACR 50; and 58% achieved ACR 70. At the time of the abstract presentation, 10 month follow-up data on all 12 patients was available: complete remission of disease (skin, nails, joints, normal ESR and CRP) was achieved in 10 of 12 patients (83%). Two of 12 patients (17%) did not improve on etanercept and required higher doses of methotrexate.
| Pre-treatment with etanercept |
Post-treatment with etanercept |
|
| PASI score | 8 +/- 6 | 1 +/- 1 |
| Tender joint count* | 23.5 | 4.0 |
| Swollen joint count* | 13.5 | 5.0 |
| HAQ* | 1.4 | 0.2 |
| ESR* | 41 | 12 |
| CRP* | 15.5 | 3.0 |
| # patients on methotrexate** | 12 | 6 |
*mean values; range not reported; no statistical analysis
**4 patients discontinued
Adverse reactions were generally minor. Etanercept was discontinued during one case of pneumonia and was restarted after 2 weeks.
Conclusion: Etanercept was safe and effective in the majority of patients treated for psoriatic arthritis and psoriasis.
Editorial Comment: The efficacy of etanercept in this trial appeared to be considerably higher than reported in the trial by Mease et al. This is a much smaller open-label study, and therefore must be interpreted with caution. However, the favorable results once again support the role of TNF-ainhibition in the treatment of psoriatic arthritis.
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in the Treatment of Akylosing Spondyllitis
Abstract #2020 Etanercept in the Treatment of Ankylosing Spondylitis: A Randomized, Double-Blind, Placebo-Controlled Study J Gorman, K Sack, J Davis. San Francisco, CA.
Overview of Study: This is an ongoing 4 month randomized controlled trial of etanercept 25 mg twice weekly in patients with moderately severe active ankylosing spondylitis (AS) (modified New York Criteria) despite treatment, followed by a 6 month open-label extension of etanercept. Therapy with NSAIDS and/or DMARDs (prednisone < 10mg, sulfasalazine, methotrexate, azathioprine, and/or gold) is continued at stable doses 4 weeks pior to and during the study. Primary outcome measures include: 1) Bath Ankylosing Spondylitis Functional Index (BASFI), 2) visual analog scale (VAS) of nocturnal spinal pain, 3) duration of morning stiffness, 4) patient global assessment (PtGA), 5) swollen joint count (SJC). Response is defined as > 20% improvement in 3 of 5 criteria, one of which must be morning stiffness or spinal pain, without worsening in any other criteria.
Summary of Findings: Sixteen of the 40 patients planned for enrollment have entered the trial. Enrolled patients were mostly men (75%), caucasian (82%), and HLA-B27 positive (94%). The mean age was 39 years with a disease duration of 12 years. At the time of enrollment into the study, half the patients were taking 2 or more medications for their disease. 63% patients had failed at least one DMARD (average 1.8). Eleven patients have completed the blinded phase, all of whom have entered the open-label extension. Seven of these 11 patients have completed the open phase.
Clinical Response with Etanercept in 6 month Open-Label Extension (n=7)
| Outcome Measure | AM Stiffness | Spinal Pain | BASFI | PtGA | SJC |
| Mean % Improvement | 92.3 | 68.2 | 55.7 | 47.9 | 59.1 |
No serious adverse events were noted, however, injection site reactions occurred in 29% of patients.
Conclusion: The results of the open-label extension suggests that etanercept is safe and effective in the treatment of AS.
Editorial Comment: This is very preliminary data on a small number of patients completing the open-label portion of the trial. However, etanercept seems promising for the treatment of AS. The final analysis of both the blinded and open-label phase will provide more definitive results on symptoms and functional outcome.
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in the Treatment of Resistant Spondyloarthropathy
Abstract #209 A Clinical and MRI Assessment of the Efficacy of the Recombinant TNF alpha receptor:Fc Fusion Protein Etanercept in the Treatment of Resistant Spondyloarthopathy H Marzo-Ortega, D McGonagle, P O'Connor, S Burns, R Wakefield, P Emery. Leeds, West Yorkshire, United Kingdom.
Overview of Study: This is a pilot study of 10 spondyloarthropathy patients (European criteria) with inflammatory back pain, peripheral arthritis, and elevated inflammatory lab markers who failed DMARD therapy. Patients received etanercept 25mg twice weekly over 6 months. Patients on methotrexate were maintained at a stable dose, but other DMARDS were discontinued 4 weeks prior to study entry. Outcome measures were performed every 4 weeks and included visual analog scale for day and night back pain, Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Quality of Life Measure (ASQoL), Leeds Disability Questionnaire (LDQ), Schober's and chest expansion measurements, and fat suppressed MRI of lumbar spine, sacroiliac joint, and affected peripheral joints. MRI scans were performed at study entry and at 6 months, and were scored blindly for the presence of bone edema/enthesitis, effusion, and synovitis.
Summary of Findings: The mean age of the 10 enrolled patients was 40 years; the mean disease duration was 10 years (range 8 months to 34 years); the median C-reactive protein was 43.5; 80% were HLA B27 positive. The diagnoses included ankylosing spondylitis (n=7), Crohn's disease (n=2), and undifferentiated spondyloarthropathy (n=1). All measured outcome measures improved over the 6 months of the trial, including chest expansion and Schober's flexion. At 9 month follow-up, 6 patients flared after stopping etanercept (median time to flare was 6 weeks). The undifferentiated spondyloarthropathy patient is in remission off of medications.
| n=10 | Baseline | 6 months |
| VAS night* | 46 | 15 |
| VAS day* | 64 | 5 |
| BASFI (0-10)* | 7.8 | 5.1 |
| BASDAI (0-10)* | 5.4 | 1.7 |
| ASQoL* | 14 | 5 |
| LDQ | 28 | 22 |
| Morning stiffness (minutes) | 120 | 5 |
| Swollen joint count | 2 | 0 |
*p<0.05
MRI Scores of Axial Skeleton
| Baseline | 6 months | |
| Bone edema at SIJ | 4.5 | 1.5 |
| Sclerosis at SIJ | 1.0 | 0 |
| Spinal lesions | 1.0 | 0 |
No major adverse reactions were reported. One patient developed a positive ANA at 12 weeks, which disappeared at 24 weeks. During the trial, hypertension developed in one patient and uveitis in another.
Conclusions: Significant improvement in clinical signs and symptoms of spondyloarthropathy, as well as imaging, were achieved during etanercept therapy.
Editorial Comment: This pilot study is one of a few recent trials reporting the favorable effect of TNFa inhibition on MRI findings in AS. Criteria for scoring MRI changes need to be standardized and the longterm significance of these findings have yet to be determined.
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Infliximab
Late-Breaking Abstract Clinical Predictors of Response to Treatment with Infliximab in Ankylosing Spondylitis (AS) M Stone, D Salonen, U Payne, M Lax, V Lapp, R Inman. Toronto, Canada.
Overview of Study: This is an open-label study of 22 patients with active AS (modified New York Criteria) who were unresponsive to treatment with NSAIDS (n=4) or NSAIDS+DMARDS (n=18). Medication was unchanged for at least 2 weeks prior to study entry, and included: NSAIDS (n=22), methotrexate < 15mg (n=10), sulfasalazine <2 gm (n=15), prednisone (n=4). Infliximab 5mg/kg was administered intravenously at 0, 2, 6, and 14 weeks. Assessment of response was determined by the following measures: Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), physician and patient global assessments, Health Assessement Questionnaire (HAQ), and clinimetrics (chest expansion, Schober's, tender joint count, swollen joint count), and laboratory tests (ESR, C-reactive protein, haptoglobin). A primary outcome response was defined as a 20% improvement in 6/9 functional measurements. A secondary outcome response was defined as at least a 20% improvement in the clinimetrics. All patients had radiographs and 8 patients had MRI with gadolinium at baseline and following each infusion.
Summary of Findings: The mean age of the 22 patients (19 men, 3 women) was 39 years, the mean duration of disease was 9.2 years; all were HLA B27 positive. Most patients had both peripheral and axial disease (73%), 9% had peripheral disease only, and 18% had only axial disease. Patients were divided into two groups based on their response to therapy: Group A (n=18) had a >20% improvement in all functional measures, while Group B (n=4) had >20% improvement in only half of these measures. Group A patients had statistically significant shorter duration of disease compared to Group B (7.7 vs. 14 years), and better baseline clinical measures. There was no difference in methotrexate use between the two groups. In all 8 patients scanned, MRI gadolinium enhancement disappeared as early as 2 days after the first infusion. Adverse reactions included headaches, bruising, and upper respiratory infections, none of which necessitated a discontinuation of therapy. Eleven patients developed positive ANA (dsDNS negative) early in treatment, but at 4 months, only 2 patients had positive ANA.
Conclusion: Patients who have earlier disease and less restricted motion on exam have a better response to infliximab.
Editorial Comments: This is a relatively large trial in which the majority of AS patients improved on infliximab. The study emphasizes the importance of starting therapy early in the disease course in order to achieve the greatest effect. MRI changes in this study were detected very early using gadolinium enhancement. Additional information from this and other studies of the significance of MRI changes as well as the predictors of response to therapy with TNFa inhibition is needed.
Abstract #208 Anti-TNFaTreatment of Patients with Severe Ankylosing Spondylitis - A One Year Follow Up J Brandt, H Haibel, J Reddig, J Sieper, J Braun, Munich, Germany.
Overview of Study: This is a one year follow-up of an open label pilot study of 11 patients with active AS and severe pain (modified New York criteria) who received infliximab 5mg/kg at 0, 2, and 6 weeks. At baseline patients had a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) >4 (scale 0 to 10) and a Visual Analogue Scale (VAS) for pain >4. DMARDS were discontinued 4 weeks and steroids 2 weeks prior to study entry (NSAIDS were continued). Clinical response was measured by the BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index BASMI), VAS for spinal pain, a global health survey (SF 36), CRP, ESR, and IL-6. MRI scans were performed in 5 patients.
Summary of Findings after 3 months (J Brandt Arthritis Rheum 2000 43:1346-52): The mean age was 36 years, the median disease duration 5 years. One patient dropped out after the first infusion because of a rash and tonsillitis. The ten patients who completed the 3 infusions experienced a marked improvement in most parameters (>50% improvement in 9/10 patients at weeks 2 and 4). Two of the 3 patients who had a follow-up MRI showed decreased inflammation 2 to 6 weeks after the third infusion. NSAIDS doses required by patients were <50% of that taken prior to the study, and half of patients stopped NSAIDS completely. Improvement persisted in 8 of 10 patients at 12 weeks follow-up.
| *p<0.05; median values; n=10 | Week 0 | Week 12 |
| BASDAI* | 6.5 | 2.4 |
| BASFI* | 5.3 | 2.4 |
| BASMI | 3.0 | 1.5 |
| VAS for back pain*#042; | 7.8 | 2.5 |
| CRP* | 15.5 | <6 |
| ESR> | 32 | <15 |
Summary of Findings after One Year: After completion of the 3 month trial, patients received a fourth infusion of infliximab if they experienced a disease relapse defined as an increase in the BASDAI score of > 80% of their baseline score, and a fifth and sixth infusion if the BASDAI score increased by > 60% of baseline. One patient is in remission 11 months after the initial 3 infusions. For the remaining 9 patients, the median time before requiring a fourth infusion was 12 weeks. Treatment effect persisted for a median of 7 weeks (range 2 to 25) prior to a fifth infusion, and a median of 6 weeks prior to a sixth infusion (range 2 to 16).
At one year follow-up, 3 of the original 11 patients had withdrawn from the study because of recurrent severe urticarial exanthema. One patient developed a high titer ANA. Uncomplicated infections occurred in 9 patients (tonsillitis, otitis, sinusitis, enteritis, herpes labialis).
Conclusion: Anti-TNFatherapy is effective for longterm treatment of AS, but must be administered on average every 6 weeks to maintain a response.
Editorial Comment: This is one of the longest trials to date of TNFa inhibition in AS which showed that ongoing therapy is required at regular intervals to maintain efficacy. The appropriate dose and length of time between infusions may vary in each individual. Clearly some patients experience significant side effects.
Abstract #207 Effects of Tumor Necrosis Factor a Blockade with Infliximab in Patients with Spondyloarthropathy: An Open Pilot Study. F Van den Bosch, E Kruithof, D Baeten, F De Keyser, H Mielants, E Veys, Belgium.
Overview of Study: This is a follow-up report of an open-label trial of infliximab in 21 patients with spondyloarthropathy treated with infliximab at weeks 0, 2 and 6 (Van den Bosch F et al, Ann Rheum Dis 2000; 59:428-433). Patients received additional infusions every 14 weeks after the third infusion. Entry criteria required patients to have active disease defined as 1 swollen joint, 1 active tendinitis, 1 dactylitis or typical nocturnal pain. DMARDS (methotrexate, average dose 12.5mg; sulfasalazine) were discontinued 4 weeks prior to study entry. NSAIDS and prednisone <10mg were permitted provided that the doses were stable 4 weeks prior to and during the study. Assessment of response to therapy included global, peripheral joint, and axial measures; ESR, C-reactive protein (CRP); and Psoriasis Area and Severity Index (PASI). Follow-up was 8.5 months.
Summary of Findings: The mean age of the patients was 39 years; the mean duration of disease was 17 years. Categories of spondyloarthopathy were as follows: ankylosing spondylitis (n#3), ankylosing spondylitis with peripheral arthritis (n#7), psoriatic arthritis (n#9), and undifferentiated spondyloarthopathy (n#2). Nine of the ten patients with axial disease were HLA-B27 positive. Statistically significant improvement in global and peripheral assessments occurred as early as 3 days after the first infusion. Response was sustained through week 34. Axial measures significantly improved starting at week 2 through week 34. Psoriatic skin disease significantly improved at 3 months in 8 of 9 psoriatic arthritis patients. By week 34 there was a trend toward worsening symptoms.
Global and Peripheral Assessments (median values)
| Baseline* | Week 2* | Week 6* | Week 12 | Week 20* | Week 34* | |
| Patient Global | 57 | 23 | 11 | 10 | 10 | 24 |
| Physicial Global | 57 | 23 | 11 | 10 | 14 | 20 |
| ESR | 44 | 6 | 5 | 4 | 7 | 17 |
| CRP | 4.6 | 0.3 | 0.2 | 0.5 | 0.6 | 2.2 |
| VAS pain(0-100) | 75 | 27 | 10.5 | 12 | - | - |
| Morning stiffness | 90 min | 5 | 10 | 5 | - | - |
| Tender joint count | 6 | 2 | 0 | 0 | 1 | 0.5 |
| Swollen joint count | 3.5 | 1 | 0 | 0 | 0 | 0 |
*infusion given; all parameters statistically significantly improved compared to baseline
No patients withdrew from the study. Twelve patients experienced minor side effects including nausea, headache, dizziness. ANA were positive in 63% of patients, and anti-ds DNA became positive in 23%. No lupus-like illnesses developed.
Conclusion: Infliximab therapy produced significant improvement in both axial and peripheral manifestations of spondyloarthopathy for up to 9 months.
Editorial Comment: This study provides additional longterm data on safety and efficacy of TNFainhibition in AS and psoriatic arthritis. Both axial and peripheral manifestations improved with infliximab. By the eighth month of therapy, response to infliximab began to decline. The ANA and anti-ds DNA seroconversion is concerning, and raises questions about safety. We await futire reports regarding safety and optimum doing intervals from this ongoing trial.
Basic Science
Abstract # 1181 The Role of Natural Killer (NK) cells in HLA-B27-Associated Arthritis E Marietta, T Trejo, H Luthra, C David. Minnesoto.
This abstract, from an outstanding group, reports interesting and potentially very important observations about the potential mechanisms of HLA B27-associated syndromes. There has always been great difficulty inducing self-sustaining arthritis in mice expressing human HLA-B27 and human b2-microglobulin. Human HLA B27-associated disease is also characterized by a diverse spectrum of phenotype, spanning periodic flares or unremitting disease, suggesting that factors other than B27 itself play a role in disease propagation. These investigators therefore addressed whether additional immune regulatory systems play a role in B27-associated arthritis. Using a transgenic approach in a mouse model of B27-associated arthritis, they examined the role of NKB1, an NK inhibitory receptor which recognizes B27 in vitro. They showed that mice expressing this inhibitory receptor develop a progressively debilitating arthritis, in contrast to mice without NKB1, which develop only minor joint disease.
Editorial Comment: Although the mechanism responsible for this observation is still unclear, the data focus attention on a potentially important role for cells expressing NKB1 in B27-associated arthritis. The studies also represent the next quantum in terms of understanding the mechanisms of this group of diseases, and may identify important pathways amenable to therapy that have been previously unappreciated.
