Therapy-refractory systemic juvenile idiopathic arthritis successfully treated with statins

R. ten Cate, P. H. Nibbering1 and R. G. M. Bredius

Departments of Paediatrics and 1 Infectious Diseases, Leiden University Medical Centre, The Netherlands

Correspondence to: R. G. M. Bredius, Department of Paediatrics, Leiden University Medical Centre, Mailbox 9600, 2300 RC Leiden, The Netherlands. E-mail: r.g.m.bredius{at}lumc.nl

SIR, Systemic juvenile idiopathic arthritis (sJIA), Still's disease, is a disease of unknown aetiology that is characterized by uncontrolled inflammation and results in high spiking fever, rash, serositis and polyarthritis. Multiple immunomodulatory strategies are used for disease control. Here we report for the first time the successful treatment of therapy-refractory sJIA with atorvastatin, which was chosen because of its anti-inflammatory properties and its cholesterol-reducing actions [1; for review see reference 2].

A boy aged 2 yr was diagnosed as having sJIA. After a varicella infection he had full remission for 4 yr. At the age of 6 his disease relapsed following a mild respiratory infection (Fig. 1). He did not respond to steroids, subcutaneous methotrexate or cyclosporin, but developed osteoporosis and radiological joint destruction. At the age of 9 yr autologous stem cell transplantation was performed using high-dose cyclophosphamide, antithymocyte globulin and low-dose total body irradiation. Although initially he showed remission of his arthritis, he relapsed after 7 weeks. The boy became steroid-dependent again, and despite intra-articular steroid injections his polyarthritis remained present. Anti-TNF-{alpha} treatment with infliximab and etanercept was stopped because of lack of effect. Thalidomide was introduced as an immune-modulating agent, but was discontinued after only 2 weeks because of acute renal failure. Finally, the patient was treated with atorvastatin (starting dose 10 mg per day), which was gradually increased to 30 mg per day (1.5 mg/kg/day). Before the start of atorvastatin treatment, the cholesterol level was always within the normal range (3.0–6.0 mmol/l), whereas during treatment it decreased below normal (2.4–2.8 mmol/l). At a dose of 30 mg, the arthritis, functional status and all other clinical and laboratory manifestations improved dramatically (Fig. 1). Most importantly, before the start of treatment he was wheelchair-dependent but now he is a normal and fully active child. In addition, the steroids could be tapered and were stopped completely. He had no documented adverse events.



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FIG. 1. Atorvastatin-induced improvement of disease course of therapy-refractory sJIA. The upper panel shows the time course of CRP and therapeutic interventions, i.e. prednisone, cyclosporin A (csa), methotrexate (mtx), indomethacin (nsaid), infliximab and etanercept infusions (anti-TNF-{alpha}), thalidomide (thal) and autologous stem cell transplantation (ASCT). In the lower panel three PRINTO variables are given: visual analogue scale (VAS, range 0–100 mm) by the paediatrician, VAS by the patient and the number of active joints. A complete list of PRINTO variables is available as supplementary data at Rheumatology Online. After the start of atorvastatin the disease parameters improved gradually, ESR and CRP normalized, and steroids could be tapered and stopped.

 
Statins exert a large variety of potent immunological effects, including inhibition of MHC-II expression and thus MHC-II-mediated T-cell activation. It also reduces T cell-proliferation in response to antigens and inflammatory responses [1; for review see reference 2]. Based on this information, statins have been given with positive outcome to patients with multiple sclerosis, systemic lupus erythematosus and to recipients of solid organ transplants [35]. Although sJIA can lead to alterations in lipid metabolism, the use of statins in children with sJIA has never been reported. The promising response in this patient warrants a trial with statins in sJIA patients and raises questions about the mechanisms underlying this disease. Although it is unlikely, spontaneous remission of the disease in this patient cannot be excluded. Finally, for the better understanding and early detection of possible side-effects in patients, the effects of statins on cholesterol synthesis and immunological parameters require monitoring.

The patient was started on atorvastatin after we had obtained written informed consent from both parents and the patient. In addition, written permission was given for publication of this case. The medical ethics committee of the Leiden University Medical Centre allowed the treatment of this patient with atorvastatin.

The authors have declared no conflict of interest.

    Supplementary data are available at

    Rheumatology Online.

References

  1. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6:1399–402.[CrossRef][ISI][Medline]
  2. Weitz-Schmidt G. Statins as anti-inflammatory agents. Trends Pharmacol Sci 2002;23:282–6.
  3. Stuve O, Youssef S, Steinman L, Zamvil SS. Statins as potential therapeutic agents in neuroinflammatory disorders. Curr Opin Neurol 2003;16:393–401.[CrossRef][ISI][Medline]
  4. Johnson BA, Iacono AT, Zeevi A, McCurry KR, Duncan SR. Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 2003;167:1271–8.[Abstract/Free Full Text]
  5. Abud-Mendoza C, de la Fuente H, Cuevas-Orta E, Baranda L, Cruz-Rizo J, Gonzalez-Amaro R. Therapy with statins in patients with refractory rheumatic diseases: a preliminary study. Lupus 2003;12:607–11.[CrossRef][ISI][Medline]
Accepted 12 March 2004





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