Two pathogenic CIAS1 mutations and plasma cytokine profile in a Finnish patient with familial cold autoinflammatory syndrome responsive to anakinra

We report on a Finnish patient with familial cold autoinflammatory syndrome (FCAS) who had two missense mutations in the CIAS1 gene. Each of them has been reported previously in association with FCAS. The patient responded well to anakinra therapy. This is the first family from Finland to be described with FCAS. Mutations of CIAS1, the gene encoding cryopyrin/ NALP3, lead to a spectrum of autosomal dominant autoinflammatory disorders that, in order of severity from mild to severe, include familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and chronic infantile neurological cutaneous and articular (CINCA) syndrome, which is also known as neonatal-onset multisystem inflammatory disease (NOMID) (1–4). The efficacy of the interleukin (IL)-1 receptor antagonist anakinra in the treatment of these disorders has been demonstrated recently (5–7). Cryopyrin is a key regulator of IL-1b production. The levels of proinflammatory cytokines in one NOMID patient were reported to be high in the cerebrospinal fluid whereas the corresponding serum levels were low, suggesting local activation of intrathecal macrophages (8). In another NOMID case the levels of cytokines, but not IL-1b, were elevated (9). Serum IL-1b was undetectable, again suggesting local production of this cytokine. Active IL-1b was also shown to be available at the disease site in affected FCAS skin (7). There is one previously published case of CINCA syndrome in Finland, which was included in a series of paediatric cases (10). Here we report on a Finnish patient with FCAS. A 42-year-old woman presented at the outpatient clinic of Kuopio University Hospital with a history of intermittent episodes of urticaria-like rash, arthralgia, and fever spikes up to 38–39 C̊. The symptoms had a diurnal pattern, being more serious during the daytime and lasted from hours to weeks depending on exposure to the cold. There was an itchy rash on the face, extensor sides of the upper extremities, buttocks, thighs, and calves, and pain in the metacarpophalangeal (MCP) joints, wrists, knees, and metatarsophalangeal (MTP) joints, which were occasionally swollen. The symptoms had begun in childhood and had become more devastating with increasing age. Laboratory tests revealed a normal blood count, an erythrocyte sedimentation rate (ESR) of 7 mm/h, and a C-reactive protein (CRP) level of 19 mg/L. Complement C3 was low at 0.68–0.80 g/L (normal range 0.84–2.0 g/L) and C4 was 0.12–0.15 g/L (normal range 0.14–0.41 g/L). Rheumatoid factor, anti-nuclear and anti-cytoplasmic antibodies were negative. The symptoms of the affected persons in the family appeared to be similar. The family history with six other similarly affected persons suggested autosomal dominant inheritance. Sequence analysis of exons 1–5 of the TNFRSF1A gene did not reveal any disease-causing mutations. Subsequent sequence analysis of exons 1–9 of the CIAS1 gene revealed two missense mutations: c.592GwA (p.Val198Met) and c.1058TwC (p.Leu353Pro). The same mutations were also detected in the DNA sample of the patient’s affected father, indicating that both mutations are located on the same allele. The L353P mutation is a common FCAS mutation, and V198M has been found in several families with MWS or FCAS (1–3). The patient improved within 24 h of commencing treatment with anakinra 100 mg/day, and she remained symptom free in the cold weather. A trial of every-other-day therapy with anakinra 100 mg was successful. Serum IL-1b, IL-6, and tumour necrosis factor (TNF)-a levels (R&D Systems, Minneapolis, MN, USA) before and during treatment were low, as shown in Table 1. Withdrawal of anakinra resulted Departments of Medicine and Clinical Chemistry, Kuopio University Hospital, Kuopio, Finland, Department of Medical Genetics, University Medical Center Utrecht (UMC), The Netherlands and Department of Clinical Genetics, Kuopio University Hospital, Kuopio, Finland