Rheumatology Advance Access originally published online on October 25, 2007
Rheumatology 2007 46(12):1860-1862; doi:10.1093/rheumatology/kem258
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Mevalonate kinase deficiency syndrome with structural damage responsive to anakinra
1Department of Rheumatology, Rouen University Hospital, 76031 Rouen Cedex, 2Inserm Unit 519, IFR23, University of Rouen Medical School, 76183 Rouen Cedex and 3Department of Pediatric Immuno-Hemato-Rheumatology, Necker–Enfants-Malades Hospital, 75743 Paris Cedex 15, France
Correspondence to: T. Lequerré, Department of Rheumatology, Rouen University Hospital, 76031 Rouen Cedex, France. E-mail: thierry.lequerre{at}univ-rouen.fr
SIR, mevalonate kinase deficiency (MKD) syndrome is an autosomal recessive autoinflammatory disorder caused by mutations in the MVK gene. We describe the first case of MKD syndrome with structural damage successfully treated with anakinra.
A 32-year-old French Caucasian woman experienced relapsing flares of progressively destructive bilateral and symmetrical polyarthritis involving small and large joints with morning stiffness (lasting 2–4 h). Synovial fluid, drained several times, was inflammatory and contained an average of 30 000 leucocytes/mm3 (98% neutrophils), without crystals or bacteria. X-rays detected joint-space narrowing and erosions in several joints (Fig. 1). She had three or four polyarthritis attacks/year, each lasting 2–3 weeks, associated with fever (38–39°C), chills, fatigue, headaches, maculopapular rash, diarrhoea, vomiting with severe abdominal pain (macroscopically inflammatory peritonitis without bacteria), splenomegaly, bronchopneumopathy, elevated ESR (40–100 mm/1st h) and high CRP (50–200 mg/l). Since childhood, no autoantibodies (rheumatoid factor, antinuclear antibodies, anti-citrullinated antibodies) have ever been detected.
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The extra-articular symptoms started at 3 months (1974) with flares occurring at irregular intervals; atypical systemic juvenile idiopathic arthritis (aSJIA) was diagnosed, but was reconsidered in 2004 when laboratory investigations showed high serum immunoglobulin D (IgD) [166.4 mg/l (28.2<normal range<141 mg/l)], elevated mevalonaciduria [19.2 mmol/mol of creatinine (normal range<1.3 mmol/mol)] and low mevalonate kinase activity in lymphocytes [0.7 µkat/kg of protein (2.5<normal range<7.8 µkat/kg)]. Sequencing of the 10 MVK-gene exons detected a four-base deletion (c.475–478 delACTG) and an undescribed Q390P mutation, but no mutations were found in the genes encoding cold-induced autoinflammatory syndrome 1 (CIAS1) or tumour necrosis factor-receptor–1A (TNFR1A). MKD or hyper-IgD syndrome (HIDS) was diagnosed.
Because of earlier successive failures of sulfasalazine, leflunomide and etanercept before MKD diagnosis, and corticoid dependency since childhood (5–10 mg/day), subcutaneous IL-1Ra (100 mg/day; anakinra) was started and has been continued since July 2005. Most disease manifestations regressed dramatically (joint pain with morning stiffness resolved completely; ESR and CRP normalized) and no new flares have occurred. In November 2005, erysipela led to anakinra interruption and a typical MKD flare ensued (CRP, 200 mg/l; ESR, 100 mm/1st h; serum IgD, 478 mg/l; mevalonaciduria, 9 mmol/mol of creatinine). Anakinra reintroduction obtained complete resolution of all clinical manifestations and normalization of biological parameters. This response has persisted for 
14 months. IL-1Ra is well tolerated. In January 2006, the patient was able to stop corticosteroids.
Until 2004, this patient's polyarthritis and joint destructions were thought to be aSJIA. During childhood, her IgD level was slightly above normal only once, which was insufficient to diagnose HIDS. Extensive clinical investigations failed to discover any definitive microbiological or immunological abnormalities. Recent genetic identification of autoinflammatory disorders and biological investigations established MKD and HIDS during flares. The severe structural damage of her atypical MKD broadens the spectrum of this disease and contributed to its late diagnosis. Indeed, 80% of HIDS patients have arthralgias and joint flares but destructive arthritis is extremely uncommon. Joint involvement usually consists of symmetrical non-destructive oligoarthritis of enlarged joints in 68% of the patients [1–4]. A continuously high serum IgD (>100 IU/ml or 141 mg/l) constitutes a unique hallmark of HIDS, but is not HIDS-specific and can be observed in TNF-receptor-associated periodic syndrome or Mediterranean fever. The precise role of IgD in HIDS pathogenesis has not yet been elucidated and the serum IgD level in HIDS is not correlated with disease severity or frequency of attacks. The abnormal immunoglobulin pattern in HIDS is not specific to IgD, since >80% of patients also have high IgA levels, meaning elevated IgG levels could be an epiphenomenon. Thus, MKD diagnosis is based on the detection of elevated mevalonate excretion in urine alone or in combination with increased IgD. In accordance with the literature, our patient suffered successive therapy failures [5]. Anakinra effectively achieved 42.1% fewer fever peaks/month with CRP and ESR normalization in two patients [6, 7]. To the best of our knowledge, this is the first report of successful and sustained anakinra efficacy against clinical and biological symptoms of MKD syndrome with structural damage that was confirmed by the spectacular regression of an MKD relapse suffered after its temporary withdrawal.
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The authors thank Janet Jacobson for her valuable advice in editing the manuscript.
Disclosure statement: The authors have declared no conflicts of interest.
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TopAcknowledgementReferences |
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