Rheumatology Advance Access originally published online on October 31, 2006
Rheumatology 2006 45(12):1573-1575; doi:10.1093/rheumatology/kel365
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LETTERS TO THE EDITOR |
Three months treatment of active spondyloarthritis with imatinib mesylate: an open-label pilot study with six patients
Department of Internal Medicine, Division of Rheumatology, and 1Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland and 2Rheumatism Foundation Hospital, Heinola, Finland
Correspondence to: Kari Eklund, Helsinki University Central Hospital, Kasarmikatu 11-13, 00130 Helsinki, Finland. E-mail: kari.eklund{at}HUS.fi
SIR, Current conventional anti-rheumatic therapies show limited efficacy in the treatment of spondyloarthritides. Imatinib mesylate (Gleevec®) is a relatively well-tolerated [1] selective inhibitor of tyrosine kinases, which include platelet-derived growth factor receptor, c-kit and macrophage colony-stimulating factor receptor [2]. All of these kinases have been implicated in the pathogenesis of inflammatory synovitis. Recent findings have suggested that imatinib may possess anti-rheumatic activity [3–4]. Therefore, we studied whether imatinib mesylate could have anti-rheumatic activity in the treatment of spondyloarthritides.
Six patients who fulfilled the European Spondyloarthropathy Study Group (ESSG) criteria for spondyloarthropathy [5] were recruited into this 3 months open-label study. Three of the patients had ankylosing spondylitis (AS), one had juvenile AS and two had psoriasis arthropathy (PsA). All the patients with AS were HLA-B27 positive. The mean age of the patients was 34 yrs (range 22–51) and mean duration of the disease 10.3 yrs (range 1–20). All six patients had involvement of peripheral joints. Four of the patients (three AS and one PsA) had inflammatory spinal pain and three of the patients had radiologically verified sacroilitis. All had failed sulphasalazine and methotrexate. Imatinib mesylate was started concomitantly with their current anti-rheumatic medication, which included methotrexate (4/6 patients) and sulphasalazine (1/6). Non-steroidal anti-inflammatory drugs (NSAIDs) (6/6) as well as oral prednisolone (<10 mg/day, 5/6 patients) were continued with stable dose. The local ethical committee approved the study protocol and written informed consent was obtained.
Inclusion criteria included bath ankylosing spondylitis disease activity index (BASDAI)
4 and peripheral joint disease (4 tender and swollen joints). Disease activity visual analog scale (VAS), BASDAI, patient's and physician's global assessment, peripheral joint assessment, Mander enthesis index (MEI) [6], global pain, night pain and C-reactive protein (CRP) were assessed. In case of painful arthritis, local corticosteroid injection was allowed. Two out of five patients who completed the study had 1–3 joints injected with corticosteroid during the first 4 weeks of the study. One patient stopped the treatment at 7 weeks because of a rash. He received corticosteroid injections after 4 weeks, and therefore, due to possible confounding effects, data on week 4 was used instead of the study termination results. Because of the rash the patient never received the full dose (400 mg) of the study drug.
Imatinib treatment was started with 200 mg/day, which was increased during the first 4 weeks to 400 mg/day, which was continued until the end of the study. One patient interrupted the study because of rash after 7 weeks and one patient had temporary interruption of medication because of leucopenia. No significant changes in liver enzyme or creatinine levels were observed. The results were expressed as mean (±S.D.), range, and 95% confidence intervals (95% CIs). CIs were obtained by bias-corrected bootstrapping (1000 replications).
Table 1 shows the outcome measures at baseline and after 1, 2 and 3 months of treatment. All the outcome measures improved. The number of swollen joints decreased in five of the six patients. The mean number of swollen joints decreased from 4.5± 1.0 to 2.3± 1.5 [50± 3%, mean change –2 (95% CI –3 to –1)]. The mean CRP decreased from 62.8± 41.6 mg/l to 34.2± 33.6 mg/l [47± 2%, (mean change –29, 95% CI –41 to –15)]. The enthesitis index decreased from 28.4± 31.3 to 13.7± 20 [mean change –15 (95% CI –28 to –5)]. In three out of six patients, the BASDAI index decreased by >50%. Three of six patients fulfilled the assessment in ankylosing spondylitis (ASAS) 40% improvement criteria. In those patients who completed the study, the mean swollen joint count decreased by 60± 24%, mean CRP by 50± 21%, mean enthesitis index by 64± 23% and mean pain (VAS, mm) by 50± 23%. No serious adverse events were observed during treatment. Leucopenia (1 patient), rash (1 patient) and respiratory infection complicated by sinusitis (1 patient) were recorded as adverse events.
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Favourable response was observed both on symptoms perceived by the patients and on the inflammatory parameters. It is noteworthy that all patients used concomitantly NSAIDs and five out of six used disease-modifying antirheumatic drugs. Four of the patients had inflammatory type of back pain. Although a decrease in night pain was observed, the effect on axial inflammation cannot be evaluated as MRIs were not obtained.
We have previously shown that imatinib induces apoptosis of mast cells in rheumatoid synovial tissue [7] and inhibits proliferation of synoviocytes [8]. Mast cells are a rich source of cytokines, including tumour necrosis factor (TNF)-
, but very little is known about their role in spondyloarthritis. Inflammation in the gut mucosa of AS patients has been implicated in the pathogenesis. As mast cells are abundant in gut mucosa the inhibition of their activity by imatinib could represent one mechanism of action.
Favourable response of imatinib treatment on peripheral arthritis in SpA patients was observed in this small open-label study and thus further studies are warranted.
Imatinib mesylate was kindly provided by Novartis Pharma.
K.K.E. declares that patent application on the treatment of spondyloarthritis with imatinib is pending.
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