Dramatic response after an intravenous loading dose of azathioprine in one case of severe and refractory ankylosing spondylitis
P. Durez3 and
Y. Horsmans1
Department of Rheumatology, Hôpital Erasme, Université Libre de Bruxelles, 808 route de Lennik, B-1070 Brussels and
1 Department of Gastroenterology, Louvain Medical School, Louvain, Belgium
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Abstract
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We describe a 37-yr-old Caucasian male suffering from ankylosing spondylitis (AS) with long-standing severe inflammatory lumbar pain and hip arthritis who was refractory to non-steroidal anti-inflammatory drugs, sulphasalazine and methotrexate up to 25 mg/week. In this patient, administration of an i.v. loading dose of azathioprine (AZA; 40 mg/kg for 36 h followed by 2 mg/kg oral AZA therapy) induced a dramatic response in his clinical condition. Indeed, objective and subjective clinical variables improved within 1 week and were corroborated by a decline in the levels of the inflammatory parameters; anaemia was reported at month 3 but was rapidly reversible. If confirmed, an i.v. loading dose of AZA could represent a valuable alternative in severe and refractory AS, but toxicity of this regimen should be carefully analysed.
KEY WORDS: Ankylosing spondylitis, Intravenous azathioprine
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Introduction
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Ankylosing spondylitis (AS) is a common inflammatory disease, which results in chronic axial skeleton pain, work disability, and increased morbidity [1]. Severe spinal ankylosis with elevated inflammatory laboratory variables occurs in a small proportion of cases and is an adverse prognostic factor [2]. Current therapy includes non-steroidal anti-inflammatory drugs (NSAIDs) and second-line anti-rheumatic drugs [3]. Among them, in AS, the efficacy of only sulphasalazine and methotrexate has been established and still remains controversial [4, 5]. Significant clinical improvement with azathioprine (AZA) has also been reported in patients with severe spondylarthropathy such as psoriatic arthritis [6]. AZA is an effective anti-metabolite immunosuppressive prodrug which has been used in transplantation and autoimmune diseases for 30 yr [7, 8]. AZA is a prodrug that undergoes a complex enzymatic conversion and its oral administration is associated with a prolonged response time [9]. Recently, authors have reported the beneficial use of i.v. AZA administered as a large continuous infusion loading dose which permitted a decrease in response time in patients with Crohn's disease and rheumatoid arthritis [10]. This case report describes a patient with severe and refractory AS who responded dramatically to an i.v. loading dose of AZA therapy.
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Case report
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The patient was a 37-yr-old Caucasian male suffering from AS since 1987. Within 2 yr, he developed severe limitation of spinal motion, including the neck, and showed radiographic evidence of bilateral sacroiliitis and spondylitis. The arthritis also affected his hip joints. There was no family history of spondylarthropathy or any other hereditary disease. He reported chronic alcohol consumption. He possessed HLA-B27 and laboratory tests in 1991 revealed a C-reactive protein (CRP) level of 12 mg/dl and an IgA level of 1250 mg/dl. At this time, no trigger infection was found and ileocolonoscopy (including biopsy findings) revealed no sign of inflammatory bowel disease. He was considered to have idiopathic AS and was first treated with indomethacin (mean daily dose 100 mg) and sulphasalazine (3 g/day) for 6 yr, but had a poor response. In 1995, because of a worsening of his rheumatic condition, methotrexate (up to 25 mg/week) was added with a mild but not sustained biological or clinical efficacy. He also failed to respond to intra-articular corticosteroid injection of the hip and sacroiliac joints.
In June 1998, he was admitted because of a worsening of his back pain and hip arthritis. On examination, his vital signs were normal. Severe neck and lumbar stiffness and limitation of motion of the hip were noted; distance from ground to finger was 45 cm; anteroposterior Schober test was 1.2 cm; the wall to occiput distance was 6.8 cm and chest expansion test showed 3 cm (Table 1
). No psoriasis and no sign of infection were noted.
Abnormal laboratory findings included elevated erythrocyte sedimentation rate (ESR; 100 mm/h) and CRP (9.1 mg/dl). The haemoglobin level was normal, but the mean corpuscular volume was elevated (102 fl). The serum level of immunoglobulins was, respectively, for IgG, IgA and IgM, 1550, 1470 and 259 mg/dl (normal range respectively: 6501500, 70400 and 40250 mg/dl). Liver, renal and thyroid function tests, electrolytes, glucose, muscle enzymes and urinalysis were not remarkable. Hepatitis B, C and HIV serology were negative.
After informed consent and levels of thiopurine methyl transferase (TPMT) up to 10 IU/ml (18.8 IU/ml) (determined following the method described in [11]), continuous infusion of AZA at a dosage of 40 mg/kg for 36 h was administered. After this loading dose, oral AZA was then started at a dose of 2 mg/kg. Indomethacin was maintained. Parameters of disease activity including occiputwall distance, chest expansion, Schober's 10 cm test, fingertip-to-floor distance, visual analogue scale (VAS 0100 mm) for pain and general well-being, duration of morning stiffness and a Dutch functional index for AS [12] were determined at the time blood was drawn for measurement of laboratory variables including 6-TGN levels, an active metabolite of AZA. Within the first week of therapy, the patient felt subjectively well and improvement of most assessed variables (up to 80% for subjective index) was noted (Table 1). Concomitantly, a significant decrease in CRP levels was observed (Fig. 1
) and ESR decreased gradually to 60 mm/h 6 months later. The level of IgA was also reduced to 1050 mg/dl.
The administration of indomethacin (100 mg/day) could be tapered during the trial. No side-effect was reported during the first 3 months. The peak level of 6-thioguanine nucleotide (6-TGN) was obtained after 36 h of the loading dose, decreasing progressively thereafter (Fig. 2
). At 3 months, he presented anaemia (haemoglobin 6 g/dl with a mean corpuscular value of 104 fl, folate and vitamin B12 levels normal), which resolved after discontinuation of AZA. A bone marrow biopsy demonstrated megaloblastic anaemia with the depletion of myeloid cells. Granulocyte and megakaryocyte series presented no morphological changes. This side-effect was rapidly reversible and AZA therapy could be re-introduced after 1 month. In July 1999, no recurrence was noted and the patient was doing well.
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Discussion
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Our observation documents the case of a patient with severe AS refractory to conventional therapy, who dramatically improved after an i.v. loading dose of AZA. AS is the prototype of a heterogeneous group of disorders called spondylarthropathies. While most of the patients have a benign course, some of them can have particularly severe clinical manifestations. Several groups have reported that infectious agents can exacerbate the disease. No concurrent infection was identified in our patient. In such a case of a severe form, the treatment can be based on the use of second-line immunosuppressive agents. Our patient did not respond satisfactorily to sulphasalazine and methotrexate. On the other hand, AZA, an immunosuppressive drug used in arthritis for 30 yr, and apparently safe and beneficial in a few small case series of psoriatic arthritis, has new gained importance in this condition [6]. Recently, the use of an i.v. loading dose of AZA decreased the response time to an oral dose in 12 patients with severe Crohn's disease [10]. Similarly, we observed a dramatic response to this regimen in rheumatoid arthritis within a week and the benefit was sustained over at least 6 months of follow-up without recurrence (personal communication). This effect was accompanied by a tapering of NSAIDs and a progressive reduction of the inflammatory parameters. The reason for the improvement is unclear but could be related to the loading dose. One side-effect was reported after 3 months consisting of megaloblastic anaemia without leucopenia. The myelotoxicity of AZA has been reported in patients with low but also normal TPMT levels [12, 13]. It is possible that this side-effect is related to the rapid increase in red blood cell 6-TGN levels observed in our patient, but also exacerbated by the long-term use of NSAID and the underlying inflammatory process.
In conclusion, a 40 mg/kg i.v. loading dose of AZA for 36 h is effective in AS and may decrease the time to clinical response. The monitoring of 6-TGN could bring some benefit in avoiding significant toxicity better. More experience is needed to draw general conclusions.
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Notes
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3 Correspondence to: P. Durez. 
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Submitted 24 March 1999;
revised version accepted 8 September 1999.