Sir, Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome (MIM no. 604416) is an autosomal dominant autoinflammatory disease caused by mutations in the PTSTPIP gene [1]. Historically, it had been described as streaking leucocyte factor disease [2]. PAPA syndrome is characterized by recurrent sterile arthritis that usually occurs after minor trauma, but also spontaneously [3]. It is a self-limiting disease, but can lead to serious joint destruction. No effective treatment has been published so far, although steroids have been effective in some cases. Here we describe the effect of recombinant human interleukin (IL)-1 receptor antagonist (anakinra, Kineret®) in a case of PAPA syndrome-associated arthritis refractory to steroids.

A 16-yr-old boy presented in a local hospital with a swollen and painful right ankle 2 weeks after a minor traffic accident resulting in a superficial laceration on his knee. He, his father and three of his six siblings suffer from recurrent sterile arthritis. In addition, they have mild acne, mainly around the nose. Recently, this family was diagnosed as having PAPA syndrome, confirmed by a heterozygous A230T mutation in the PTSTPIP1 gene (the genetic confirmation kindly performed by I. Aksentijevich, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH Bethesda, MD, USA). Therefore, the patient was suspected of having a flare of arthritis associated with PAPA syndrome and he received intra-articular steroids (40 mg triamcinolone hexacetonide) twice with a 1-week interval, but without any effect.

He was referred to our paediatric rheumatology department. On examination, the right ankle was swollen and painful, and showed limitation of movement. Besides mild anaemia, an ESR of 85 mm/h and a CRP of 144 mg/l, there were no abnormal laboratory findings. Blood cultures and a culture of an aspirate from the right ankle remained sterile. Since PAPA syndrome is associated with elevated IL-1β production [4], we decided to treat him with anakinra, a recombinant human IL-1 receptor antagonist (1 mg/kg per day subcutaneously for 1 week). After a few days, the swelling and pain diminished, and it resolved completely within 1 week. In addition, laboratory results returned to normal (Fig. 1a). Five and 7 months later, the boy developed acute inflammation of his right knee joint spontaneously and after sports, respectively. Within a day, treatment with anakinra was resumed. Two days later, he was free of symptoms (Fig. 1b and c).

Fig. 1.

(a) Clinical symptoms described as pain, swelling, restricted flexion and extension of the right ankle in relation to treatment and laboratory findings. 1 = start of symptoms; 2 = first intra-articular depot (40 mg triamcinolone hexacetonide); 3 = second intra-articular depot; 4 = start of anakinra (1 mg/kg). (b) Right knee at presentation. (c) Right knee 1 week after starting treatment with anakinra. This figure may be viewed in colour as supplementary data at Rheumatology Online.

Fig. 1.

(a) Clinical symptoms described as pain, swelling, restricted flexion and extension of the right ankle in relation to treatment and laboratory findings. 1 = start of symptoms; 2 = first intra-articular depot (40 mg triamcinolone hexacetonide); 3 = second intra-articular depot; 4 = start of anakinra (1 mg/kg). (b) Right knee at presentation. (c) Right knee 1 week after starting treatment with anakinra. This figure may be viewed in colour as supplementary data at Rheumatology Online.

PAPA syndrome belongs to the recently recognized group of hereditary autoinflammatory disorders. Other members include familial Mediterranean fever (FMF), the hyper-IgD and periodic fever syndrome and cryopyrin associated disorders, such as the Muckle–Wells syndrome. Although the precise pathogenesis of these diseases is only partly understood, increased IL-1β production is a common feature [4, 5]. The mutations described in PAPA syndrome result in a mutated CD2BP1 (CD2 binding protein 1, also known as PSTPIP1; proline–serine–threonine phosphatase interacting protein). The function of CD2BP1 is not completely understood, but mutations can lead to decreased apoptosis, explaining the observed accumulation of neutrophil-rich material [6]. In addition, it has been suggested that PAPA syndrome intervenes in the same pathway as FMF. In FMF, there is a mutation in the gene encoding pyrin. The mutated CD2BP1 in PAPA syndrome has increased interaction with pyrin. The effect of this interaction is similar to that of mutated pyrin, resulting in decreased apoptosis and elevated IL-1β levels, as seen in FMF [7]. Recently, anakinra appeared to be highly effective in patients with Muckle–Wells syndrome [8, 9]. We observed that anakinra effectively aborts arthritis flares associated with PAPA syndrome. In the first arthritis flare the improvement could be spontaneous or due to a delayed effect of earlier steroid treatment. However, the speed of amelioration after the first administration of anakinra favours its effectiveness. This was further supported by the immediate clinical response to anakinra at the next two disease flares. PAPA syndrome is exceedingly rare in comparison with, for example, septic arthritis. Therefore the diagnosis rests on the initial repeated exclusion of joint infection in addition to genetic testing. However, when the diagnosis is established the availability of effective systemic therapy spares the patient repeated arthrocenteses for culture and local steroid deposits.

In summary, anakinra appears to be an effective therapy to treat disease flares in PAPA syndrome. Anakinra has previously been employed in other inflammatory diseases for maintenance treatment, but never intermittently to abort disease flares. Our observation shows that further study of intermittent administration of anakinra to treat flares of episodic autoinflammatory disorders is both rational and necessary.

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The authors have declared no conflicts of interest.

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Author notes

Department of Pediatric Immunology and Rheumatology and 1Department of General Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Suite 03.063.0, P.O. Box 85090, 3580AB, Utrecht, The Netherlands

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