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A 26 week randomised, double blind, placebo controlled exploratory study of sulfasalazine in juvenile onset spondyloarthropathies
  1. R Burgos-Vargas1,
  2. J Vázquez-Mellado2,
  3. C Pacheco-Tena2,
  4. A Hernández-Garduño3,
  5. M V Goycochea-Robles2
  1. 1Research Division, Hospital General de Mexico
  2. 2Rheumatology Service, Hospital General de Mexico
  3. 3Department of Clinical Research, Hospital General de Mexico
  1. Correspondence to:
    Professor R Burgos-Vargas, Dirección de Investigación, Hospital General de Mexico, Dr Balmis 148, México DF 06726;
    burgosv{at}attglobal.net

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Juvenile onset spondyloarthropathies (SpA) comprise a group of conditions, characterised by recurrent episodes of arthritis and enthesitis that may lead to structural changes and functional impairment.1 Except for mild to moderate cases, the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) appears limited and glucocorticoids may induce severe adverse events. According to open trials,2–6 sulfasalazine (SSZ) appears to be a good alternative for treating juvenile onset SpA. Consequently, we conducted a phase III, exploratory, 26 week prospective, randomised, double blind, placebo controlled trial of SSZ in active juvenile SpA.

PATIENTS AND METHODS

Patients with the seronegative enthesopathy and arthropathy syndrome (SEA)7 or ankylosing spondylitis (AS)8 (onset age 16 years; current age 20 years) fulfilling the three following criteria despite stable NSAID treatment in the previous four weeks were enrolled in the trial: (a) ≥4 active joints; (b) ≥3 tender entheses; and (c) erythrocyte sedimentation rate (ESR) ≥25 mm/1st h. Exclusion criteria were diarrhoea, inflammatory bowel disease, mucositis, psoriasis, previous use of SSZ, sulphonamide or salicylates hypersensitivity, and concomitant diseases. The study was approved by the Institutional Review Board and parents and patients signed an informed consent.

Patient allocation into the group receiving SSZ or placebo was generated through a random number table; randomisation was restricted by blocks of four (ratio 1:1). Patients received identical tablets of 500 mg enteric coated SSZ or placebo (Kabi-Pharmacia, Sweden) in numbered containers according to the next available number. Except for one of the investigators, all study personnel were unaware of the treatment assignment. Recruitment lasted 18 months.

Daily doses of SSZ and placebo escalated from two tablets in the first week and three in the second to four tablets in the third week. Children weighing less than 30 kg received 30–60 mg/kg/day from the first to the third week.

Patients were allowed to continue receiving stable doses of NSAIDS or prednisone (10 mg/day) in the initial three months. NSAID dose change or prednisone addition to treatment qualified for lack of efficacy in the post hoc analysis. Paracetamol (<1 g/day), but no intra-articular or intralesional injections, was allowed for severe pain.

The number of active joints—defined by soft tissue swelling and tenderness when pressing or pain when moving the joints—was the primary outcome variable. Secondary variables included patient and doctor Likert scale assessments of efficacy (marked improvement or improvement, no change, or worsening) and health (very good, good, fair, or bad); pain severity on a 100 mm visual analogue scale; tender joints and entheses counts (excluding the tarsus); mid-foot swelling and tenderness; American College of Rheumatology functional class; ESR; anterior spinal flexion; and duration of morning stiffness. Clinical and laboratory examinations were performed monthly.

Data were analysed on the basis of the intention to treat principle. Baseline versus final values were analysed by paired t test or Wilcoxon's signed rank, and SSZ versus placebo by t test or Mann-Whitney test. The significance level was fixed at p<0.05.

Thirty three patients (27 male, six female; mean age 15.9 (SD 3.9) years; 20 with SEA syndrome, 13 with AS) received SSZ (n=17) or placebo (n=16). Two patients receiving SSZ and three receiving placebo were lost to follow up; treatment of two more receiving SSZ and eight receiving placebo was prematurely discontinued in the post hoc analysis because of lack of efficacy. The sample size has a post hoc statistical power of 11% for the number of active joints.

RESULTS AND DISCUSSION

Group characteristics—including the proportion with SEA syndrome and AS in each group—were comparable at baseline. Most variables in the SSZ and placebo groups improved significantly, but differences between groups were only significant in the doctor and patient assessments of improvement (table 1) and the number of changes of concomitant treatment (2 v 8; p=0.026). Four patients receiving SSZ and two receiving placebo had mild or moderate epigastric pain not requiring specific treatment or withdrawal from the study.

Table 1

Intragroup changes of selected outcome variables in the intention to treat analysis

Although the lack of further differences between the groups may result from the small number of patients enrolled because of restrictions in the inclusion criteria, the high rate placebo response similar to that seen in adult onset SpA studies,9,10 and additional factors, including the natural course of the disease, the results of this trial suggest that SSZ may be useful in active juvenile onset SpA.

Acknowledgments

Supported (in part) by Kabi-Pharmacia, Sweden.

REFERENCES

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