Correspondence
Correction
Inhibition of Tumor Necrosis Factor α and Ankylosing Spondylitis
N Engl J Med 2003; 348:359-361January 23, 2003
- Article
To the Editor:
In a recent multicenter trial, Gorman et al. (May 2 issue)1 found that 80 percent of patients with active ankylosing spondylitis had a favorable response to etanercept. Equivalent results are obtained with infliximab.2 Data on uveitis are still lacking. We report a case of severe uveitis in a 45-year-old man that improved with infliximab.
In 1986, the patient was given a diagnosis of HLA-B27–positive ankylosing spondylitis. Since 1993, he had had recurrent bilateral anterior uveitis, leading to functional blindness of the right eye despite the use of antiinflammatory drugs, including corticosteroids. When he was seen in May 1996 because of persistent joint and eye inflammation, he was treated with 60 mg of prednisone per day and 15 mg of methotrexate per week; the dose of prednisone was then tapered. Despite an increase in the dose of methotrexate up to 25 mg per week, bilateral uveitis relapsed. Methotrexate treatment was discontinued in April 2001 because of lack of efficacy and alcoholic hepatitis.
In July 2001, a new relapse led to the initiation of treatment with intravenous cyclophosphamide at a monthly dose of 1000 mg. In January 2002, after six pulses of cyclophosphamide, severe uveitis occurred in the left eye, with a decrease in visual acuity from 10/10 to 5/10 and cystoid macular edema. After three pulses of methylprednisolone, 5 mg of infliximab per kilogram of body weight was administered on day 1, day 8, day 15, and at eight weeks. Cystoid macular edema decreased, visual acuity improved to 10/10, and ocular inflammation disappeared. The dose of oral prednisone was regularly and rapidly reduced to 25 mg per day without relapse. These findings suggest that inhibitors of tumor necrosis factor α (TNF-α) could be effective in the treatment of uveitis associated with ankylosing spondylitis, as they are for uveitis associated with Crohn's disease3 or Behçet's disease.4
4 ReferencesBouchra Asli, M.D.
Bertrand Wechsler, M.D.
Claire Lemaître, M.D.
Pitié-Salpêtrière Hospital, 75651 Paris, CEDEX 13, France
bertrand.wechsler@psl. ap-hop-paris. fr 1
Gorman JD ,Sack KE ,Davis JC Jr . Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor α. N Engl J Med 2002;346:1349-1356
Full Text | Web of Science | Medline2
Braun J ,Brandt J ,Listing J , et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002;359:1187-1193
CrossRef | Web of Science | Medline3
Fries W ,Giofre MR ,Catanoso M ,Lo Gullo R . Treatment of acute uveitis associated with Crohn's disease and sacroileitis with infliximab. Am J Gastroenterol 2002;97:499-500
CrossRef | Web of Science | Medline4
Sfikakis PP ,Theodossiadis PG ,Katsiari CG ,Kaklamanis P ,Markomichelakis NN . Effect of infliximab on sight-threatening panuveitis in Behcet's disease. Lancet 2001;358:295-296
CrossRef | Web of Science | Medline
To the Editor:
The role of TNF-α in ankylosing spondylitis is better understood than its role in rheumatoid arthritis. The predominant inflammatory cell at sites of acute enthesitis and osteitis is the macrophage, and a high level of expression of TNF-α has been shown at these sites. Animal models that demonstrate the efficacy of inhibiting tumor necrosis factor (TNF) are arguably better models for the pathogenesis of ankylosing spondylitis than for that of rheumatoid arthritis, and overexpression of TNF leads to a disease reminiscent of ankylosing spondylitis.1 Evidence in the article by Gorman et al. suggests that up to 80 percent of patients with ankylosing spondylitis have a response to etanercept, as compared with patients with rheumatoid arthritis, who may not have a response — suggesting that TNF-α has a more central role in the pathogenesis of ankylosing spondylitis. We do not believe it is possible to extrapolate observations from peripheral synovial tissue to the enthesitis that characterizes spinal disease in ankylosing spondylitis. In addition, synovitis may be secondary to the release of TNF from these lesions.2
In contrast to the report of Gorman et al., we reported that fatigue improved by 57 percent in patients with ankylosing spondylitis who were treated with etanercept for 24 weeks, and this improvement was mirrored by improvement in spinal inflammatory lesions as determined by magnetic resonance imaging.3 With regard to the many unanswered questions pertaining to the use of biologic agents in patients with ankylosing spondylitis, the pivotal issue is whether suppression of inflammation prevents new bone formation and ankylosis, the chief cause of chronic disability in patients with this disease.
3 ReferencesHelena Marzo-Ortega, M.D.
Paul Emery, M.D.
Dennis McGonagle, M.D.
University of Leeds, Leeds LS2 9NZ, United Kingdom
medhmo@leeds.ac. uk 1
Crew MD ,Effros RB ,Walford RL ,Zeller E ,Cheroutre H ,Brahn E . Transgenic mice expressing a truncated Peromyscus leucopus TNF-alpha gene manifest an arthritis resembling ankylosing spondylitis. J Interferon Cytokine Res 1998;18:219-225
CrossRef | Web of Science | Medline2
McGonagle D ,Gibbon W ,Emery P . Classification of inflammatory arthritis by enthesitis. Lancet 1998;352:1137-1140
CrossRef | Web of Science | Medline3
Marzo-Ortega H ,McGonagle D ,O'Connor P ,Emery P . Efficacy of etanercept in the treatment of the entheseal pathology in resistant spondylarthropathy: a clinical and magnetic resonance imaging study. Arthritis Rheum 2001;44:2112-2117
CrossRef | Web of Science | Medline
Author/Editor Response
Regarding the report by Dr. Asli and colleagues of the successful treatment with infliximab of a case of HLA-B27–associated uveitis: although randomized, controlled studies of anti-TNF therapies for this indication are lacking, the use of these agents for the treatment of inflammatory eye disease is being increasingly reported.1,2
In an open-label study of etanercept in the treatment of spondyloarthritis, Dr. Marzo-Ortega and colleagues reported substantial improvement in fatigue. In their study, fatigue was measured by a single question from the Bath Ankylosing Spondylitis Activity Index.3 Responses to this question about fatigue correlate significantly with responses to the eight components of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36) that we used,4 in six of which there was significant improvement with etanercept therapy in our trial. There may be several suitable measures of fatigue in patients with ankylosing spondylitis,4 but at the time our study was initiated, no instrument had been deemed relevant by the Assessments in Ankylosing Spondylitis Working Group.5
We would like to make a correction to the response rate among etanercept-treated patients in our trial. One patient in the etanercept group during the randomized portion of the study was inadvertently classified as having had a response at four months. Although the patient had greater than 20 percent improvement in the duration of morning stiffness (33 percent), nocturnal spinal pain (65 percent), patient's global assessment of disease activity (25 percent), and Bath Ankylosing Spondylitis Functional Index (49 percent), the swollen-joint score had increased from 0 to 2 by the end of the study. According to the intention-to-treat principle with the last value carried forward, the percentage of patients in the etanercept group with a response to treatment (reported at the bottom of the left-hand column on page 1351, in Table 2, and in Figure 1 of our article) should be 75 percent instead of 80 percent, with a corrected P value of 0.01 by Fisher's exact test (two-tailed). We regret the error.
5 ReferencesJennifer D. Gorman, M.D.
Kenneth E. Sack, M.D.
John C. Davis, Jr., M.D., M.P.H.
University of California, San Francisco, San Francisco, CA 94143
jdavis@medicine.ucsf. edu 1
Smith JR ,Levinson RD ,Holland GN , et al. Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum 2001;45:252-257
CrossRef | Web of Science | Medline2
Reiff A ,Takei S ,Sadeghi S , et al. Etanercept therapy in children with treatment-resistant uveitis. Arthritis Rheum 2001;44:1411-1415
CrossRef | Web of Science | Medline3
Garrett S ,Jenkinson T ,Kennedy LG ,Whitelock H ,Gaisford P ,Calin A . A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994;21:2286-2291
Web of Science | Medline4
van Tubergen A ,Coenen J ,Landewe R , et al. Assessment of fatigue in patients with ankylosing spondylitis: a psychometric analysis. Arthritis Rheum 2002;47:8-16
CrossRef | Web of Science | Medline5
van der Heijde D ,Calin A ,Dougados M ,Khan MA ,van der Linden S ,Bellamy N . Selection of instruments in the core set for DC-ART, SMARD, physical therapy, and clinical record keeping in ankylosing spondylitis: progress report of the ASAS Working Group: Assessments in Ankylosing Spondylitis. J Rheumatol 1999;26:951-954
Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Nikos N. Markomichelakis, Panagiotis G. Theodossiadis, Eygenia Pantelia, Semina Papaefthimiou, George P. Theodossiadis, Petros P. Sfikakis. (2004) Infliximab for chronic cystoid macular edema associated with uveitis. American Journal of Ophthalmology 138:4, 648-650
CrossRef2
Eric B. Suhler, Tammy M. Martin, James T. Rosenbaum. (2003) HLA-B27???associated uveitis: overview and current perspectives. Current Opinion in Ophthalmology 14:6, 378-383
CrossRef
