Rheumatology and
1 Physiotherapy Departments, Royal Liverpool University Hospital,
2 Rheumatology Department, Countess of Chester Hospital and
3 Rheumatology Department, University Hospital Aintree, UK
SIR, Ankylosing spondylitis (AS) is a chronic inflammatory condition that causes chronic back pain and spinal fusion, often resulting in severe disability and increased morbidity. Whilst non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of treatment, they only offer symptomatic aid and there is a pressing need for drugs that affect the disease process itself. Of potential disease modifying drugs, sulphasalazine [1] has shown some short-term benefit in alleviating symptoms of spinal pain and morning stiffness, but this appears to be transient at best. Methotrexate, used extensively in rheumatoid arthritis [2], has also shown some promise in the treatment of AS. In an open study [3], improvement in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) and reduction of symptoms of pain were demonstrated in patients with AS taking methotrexate; however this study only involved 11 patients and, whilst intriguing, was too small to draw valid conclusions. We therefore set out to design a randomized, double-blind, placebo-controlled observer study to determine the potential role of methotrexate in controlling disease activity for patients with AS using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) [4], and to assess any improvement in metrology using the Bath Ankylosing Spondylitis Metrology Index (BASMI) [5].
The study was conducted, after full ethical approval by the Liverpool Research Ethics Committee, at the Rheumatology Departments of The Royal Liverpool University Hospital and the Countess of Chester Hospitals. Patients of either sex, aged between 18 and 60 years, with severe AS fulfilling the modified New York criteria [6] were included. Active disease was defined as the presence of at least two of the following symptoms, despite treatment with NSAIDs and/or other disease-modifying anti-rheumatic drugs (DMARDs): (i) morning stiffness of at least 30 minutes; (ii) disturbed sleep due to pain and stiffness; (iii) peripheral arthritis; (iv) ESR >30 mm in the 1st hour, or CRP >20 mg/l; (v) spinal pain; and (vi) pain in both buttocks during the day or night.
Discontinuation of sulphasalazine or other DMARDs for at least 4 weeks before study entry, and adequate contraception during and 6 months after methotrexate treatment was required. Patients were excluded in cases of: (i) serious systemic disease, malignancies, impaired organ function or serious infections; (ii) pregnancy and breast feeding; (iii) mental disorders; (iv) alcohol or drug abuse; and (v) history of intestinal disease.
The study took the form of a double-blind, placebo-controlled observer study that ran for a period of 24 weeks, the purpose or which was to assess the efficiency of methotrexate. Patients were randomized to receive oral methotrexate 10 mg weekly, or placebo, for 24 weeks. Patients were assessed every 4 weeks for 24 weeks. Disease activity and metrology were measured using the BASDAI and BASMI, respectively.
At each visit the following variables were assessed: (i) BASDAI; (ii) BASMI; (iii) laboratory variables (ESR and CRP, full blood count, serum creatinine and liver function tests); and (iv) side effects related to study medication, assessed by direct questioning or given as spontaneously reported complaints.
Change scores were computed as the difference between the baseline score and the mean of the final 3-month observations. Differences between change scores for the two drug treatments (methotrexate and placebo) were tested using the MannWhitney U-test.
A total of 30 patients entered the study and 28 patients completed the assessments for the duration of the study. Patient characteristics are shown in Table 1. Only two patients failed to complete the study; one moved out of the locality and the other discontinued after 16 weeks due to side effects of nausea, rhinorrhoea and headache. Before and after figures for BASDAI, BASMI and CRP are shown for patients given methotrexate for 24 weeks, and for those given placebo for 24 weeks in Tables 2
and 3
, respectively.
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In this 24 week, double-blind, placebo-controlled study of methotrexate in AS, there did not appear to be a significant benefit of methotrexate treatment compared with placebo. This is in contrast to two small open studies that suggested methotrexate might improve clinical symptoms [7, 8]; however, these studies did not demonstrate any improvement in axial measurements.
Our results may reflect the fact that, in the majority of patients, treatment was commenced at a relatively late stage in the disease, with 23 patients having a disease duration of 10 years, and only six patients having symptoms for <15 years. If disease is to be modified, it is possible that this might best be achieved early on. Indeed, the two patients in our study who chose to continue on methotrexate after 24 weeks, due to symptomatic benefits, had relatively earlier disease. In addition, it is also possible that higher doses of methotrexate are required in AS. Larger, multicentre studies are therefore required to test these further and to define a potential role for methotrexate in AS fully.
Notes
Correspondence to: B. Roychowdhury, Consultant Rheumatology, Cumberland Infirmary, Carlisle CA2 7HY, UK.
References