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.


CONCLUSIONS
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.
Maksymowych
Walter P
WP
Department of Medicine, University of Alberta, Edmonton, Canada. walter.maksymowych@ualberta.ca
Jhangri
Gian S
GS
Lambert
Robert G
RG
Mallon
Cathy
C
Buenviaje
Heidi
H
Pedrycz
Ewa
E
Luongo
Rolfe
R
Russell
Anthony S
AS
D054392:Adipokines; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002358:Cartilage, Articular / Q000737:chemistry / Q000473:pathology; D000071451:Chitinase-3-Like Protein 1; D005260:Female; D005500:Follow-Up Studies; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D000069285:Infliximab; D037102:Lectins; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000097:blood; D019278:Matrix Metalloproteinase 3 / Q000097:blood; D008875:Middle Aged; D011446:Prospective Studies; D013167:Spondylitis, Ankylosing / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
D054392:Adipokines; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D037102:Lectins; D000069285:Infliximab; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1