Rheumatology Advance Access originally published online on June 26, 2006
Rheumatology 2006 45(9):1171-1173; doi:10.1093/rheumatology/kel178
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Successful treatment using tacrolimus (FK506) in a patient with TNF receptor-associated periodic syndrome (TRAPS) complicated by monocytic fasciitis
First Department of Internal Medicine, Nagasaki University Hospital of Medicine and Dentistry, Graduate School of Biomedical Sciences, Nagasaki University and 1Nagasaki University School of Health Sciences, Nagasaki, Japan
Correspondence to: Hiroaki Ida, MD, PhD, The First Department of Internal Medicine, Nagasaki University Hospital of Medicine and Dentistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. E-mail: idah{at}net.nagasaki-u.ac.jp
SIR, Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant inherited disease characterized by prolonged episodes of periodic fever and localized inflammation [1]. Although TRAPS was initially described in the pedigree of a large Irish/Scottish family with a periodic inflammatory condition, mutations in TNFRSF1A have now been found in many ethnic backgrounds, including Japanese, African Americans and Mediterranean populations [2]. The hypothetical pathogenesis of TRAPS is defective TNFRSF1A shedding from cell membranes in response to a stimulus including TNF-
. This mechanism has recently been shown to account for a minor population of TRAPS patients, and other mechanisms are thus needed to explain the disease [3]. Regarding the treatment of TRAPS, glucocorticoids can decrease the symptoms in most patients, but they do not decrease the frequency of attacks [1]. Clinical trials using etanercept, a TNFRSF1B receptor-immunoglobulin fusion protein, for TRAPS patients have shown that it can decrease both the attack frequency and the corticosteroid dose [4]. Etanercept may thus be useful as a treatment for TRAPS attacks; however, some patients do not respond to this drug [4, 5].
We previously reported a TRAPS patient associated with systemic lupus erythematosus (SLE) with a novel TNFRSF1A mutation (T61I) [6]. A family study and the known high prevalence in the general population (3%; nine healthy Japanese individuals out of 300 in our recent study) show that the T61I mutation has low penetrance, resembling the R92Q mutation [1, 6]. This patient was complicated by monocytic fasciitis in both thighs, which was confirmed by immunohistological studies (CD68-positive cells were seen to infiltrate the fascia) [6, 7]. Our previous data demonstrated that her TRAPS symptoms were not correlated with the serum level of TNF-, because continuous elevation of serum TNF- was observed for more than 3 yrs in spite of prednisolone administration. As TNF- was mainly produced by monocytes, we speculated that her continuous high serum level of TNF- was due to monocytic fasciitis in both thighs. This same Japanese female TRAPS patient, who is now 29 yrs old, was followed up at the First Department of Internal Medicine, Nagasaki University Hospital of Medicine and Dentistry, Japan. She was treated with prednisolone for a long time; however, continuous recurrent fever and inflammatory signs were observed. As high fever and increased, C-reactive protein (CRP) levels continued for more than 3 months in spite of the administration of 10 mg of prednisolone, and so we added another 5 mg of prednisolone, thus resulting in a total dosage of 15 mg of prednisolone on 14 January 2004 (Fig. 1). Thereafter, the high fever diminished and the serum level of CRP decreased; however, the serum level of TNF- was still very high and high-intensity signals in the fascia remained clearly detected by short tan inversion recovery (STIR) magnetic resonance imaging (MRI) (Fig. 1).
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Tacrolimus (FK506) is an immunosuppressive drug, which is widely used in transplantation, rheumatoid arthritis and atopic dermatitis. The immunosuppressive effects of tacrolimus have been reported by both us and other groups [8–10]. The action of this drug is mainly the suppression of activated T-cells via calcineurin inhibition [10]. The suppression of T-cell activation leads to an inhibition of a subsequent production of inflammatory cytokines, such as TNF-
, IL-1ß, IL-6, etc. [9, 10]. Further examinations will be needed for its direct effect in cytokine-producing cells. To inhibit the serum level of TNF- in this TRAPS patient, we used 3 mg of tacrolimus in addition to 15 mg of prednisolone. Figure 1 shows that serum level of CRP, TNF-, soluble TNFRSF1A and soluble TNFRSF1B were decreased after the administration of tacrolimus. Interestingly, after 4 months and 2 weeks of this tacrolimus treatment, the high-intensity signals in fascia were found to be almost undetectable by MRI. The proteinuria, which was thought to be the only SLE symptom observed at this time, decreased from 3.68 g/day (30 April 2004) to 1.40 g/day (27 September 2004) while the patient was being treated with tacrolimus, thus suggesting that this drug was also effective for lupus nephritis. Because continuous high-intensity signals detected by MRI had been observed nine times from November 2000, while, in addition, high serum levels of TNF- continued [6], it is unlikely to assume that the spontaneous remission of TRAPS and monocytic fasciitis may have occurred during this period (after tacrolimus treatment). In this case, tacrolimus may prevent the TNF- release from monocytes by inhibiting the inflammation of fascia in both thighs, thus demonstrating this to be a new strategy for targeting TNF--producing cells rather than neutralizing the serum TNF- (i.e. etanercept). Tacrolimus might therefore be a potentially useful drug for TRAPS patients, especially in those complicated by monocytic fasciitis.
The authors have declared no conflicts of interest.
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