Background Mevalonate kinase deficiency (MKD) is a hereditary autoinflammatory syndrome marked by recurrent attacks of fever and inflammation. Severe enzyme deficiency results in mevalonic aciduria (MA) and milder deficiency in hyperimmunoglobulin D syndrome (HIDS). Treatment remains a challenge.
Objective To observe the effect of the recombinant interleukin-1 receptor antagonist anakinra in patients with MKD.
Methods A prospective observational study was undertaken. Two patients with MA started continuous treatment with anakinra (1–2 mg/kg/day) and nine patients with HIDS chose between continuous treatment and on-demand treatment (starting at first symptoms of attack, 100 mg/day or 1 mg/kg/day for 5–7 days).
Results Anakinra induced partial remission in one patient with MA but there was no response in the other patient with MA. In one patient with HIDS continuous treatment induced complete remission for 7 months but was stopped because of side effects. Eight patients with HIDS preferred on-demand treatment from the start. This induced a clinical response (≥50% reduction in duration) in 8 of 12 treated attacks without a change in attack frequency. Anakinra prevented fever attacks due to vaccination without inhibiting antibody induction. No major side effects were seen.
Conclusions On-demand treatment with anakinra in HIDS decreases the duration and severity of fever attacks. Because of the burden of daily injections and relatively long asymptomatic intervals of HIDS, all patients with HIDS preferred on-demand treatment.
Statistics from Altmetric.com
Mevalonate kinase deficiency (MKD) is a hereditary autoinflammatory disorder caused by mutations in the mevalonate kinase (MVK) gene.1 The associated clinical phenotype ranges from hyperimmunoglobulin D (IgD) and periodic fever syndrome (hyper-IgD syndrome (HIDS), MIM260920) to mevalonic aciduria (MA, MIM251170). Patients with HIDS (residual mevalonate kinase enzyme activity of 0–10%) suffer from lifelong recurrent episodes of fever and inflammation. In MA (residual enzyme activity below detection level) inflammatory episodes are more severe and patients may also have psychomotor retardation, ataxia and failure to thrive. The pathophysiology of MKD is still largely unclear but increased secretion of interleukin 1β (IL-1β) is a central factor.1 2
Until recently, treatment was largely supportive.1 Corticosteroids are used in children with HIDS with varying success; in clinical practice the results are disappointing. Simvastatin produced a statistically significant reduction in the number of days of illness3 but was also disappointing in clinical practice. The tumour necrosis factor (TNF) inhibitor etanercept has been reported in several case reports.4 Lately, inhibition of IL-1β has been shown to be beneficial in a growing number of autoinflammatory disorders.5,–,11 We previously reported a beneficial effect of anakinra on aborting an attack of HIDS provoked by vaccination.12 A beneficial response to continuous treatment with anakinra in MKD has been reported in several cases.4 13,–,16
We describe the results of an observational prospective case series of anakinra in the treatment of MKD. We included patient preference: patients with HIDS were offered an informed choice between continuous treatment and on-demand treatment.
MKD patients with active disease (≥1 attack every 8 weeks) visiting our outpatient clinics were invited to participate. Permission was granted from local ethical committees and written informed consent was obtained. Patients with MA were offered continuous treatment with anakinra. Those with HIDS had the choice between continuous treatment with daily subcutaneous injections or on-demand treatment on 4–7 consecutive days at the time of an attack, depending on the attack duration. For on-demand treatment, patients were advised to start anakinra within 24 h of the first signs of an attack. Children under the age of 16 were given 1 mg/kg/day, to be raised to a maximum of 2 mg/kg/day. Adult patients were given 100 mg/day subcutaneously, to be raised to a maximum of 200 mg/day in case of failure. Patients or their parents were asked to complete a daily symptom score card (rating 12 different symptoms on a scale from 0 to 10), as has been described previously,12 generating a clinical score (CS).
A fever attack was defined as the combination of CS ≥20 with fever (temperature ≥38.0°C) or fever accompanied by at least two symptoms known from previous episodes. The time of CS <20 in the absence of fever was taken as the end of an attack.
During continuous treatment a complete response was defined as complete cessation of fever attacks. In patients treated on-demand a clinical response was arbitrarily defined as a reduction of ≥50% in the duration of treated inflammatory attacks compared with untreated episodes.
Serum was collected from 20 healthy controls and five patients while asymptomatic and 24 h and 48 h after onset of symptoms. A Luminex multiplex bead analysis assay was used for cytokine analysis (IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-18, TNFα and interferon (IFN)γ). Statistical analysis was performed using GraphPad Prism V.4.0 for Windows (Graph Pad Software, San Diego, California, USA).
Eleven of 12 unrelated patients with MKD invited to take part in the study agreed to participate. One patient refused because of fear of injections. The characteristics of the patients are summarised in table 1.
Continuous anakinra in classic MA
In patient 1, anakinra (1 mg/kg) resulted in a clinical response within 24 h but two febrile episodes occurred in the next 19 weeks. Cessation of anakinra during one febrile episode (because of fear of infectious complication) led to a full-blown relapse. Increasing the dose to 2 mg/kg induced complete remission of arthritis and catch-up in growth and development. However, the response was only partial as febrile episodes did recur occasionally and her C reactive protein (CRP) was intermittently elevated. In patient 2, anakinra treatment (2 mg/kg/day) did not result in remission of symptoms and the drug was discontinued after 4 months.
Anakinra in HIDS
Patient 3 was treated continuously with anakinra inducing a complete remission during 7 months (compared with nine fever episodes in the previous 6 months) and a decrease in school absence from 40% to 0%. After he stopped treatment because of painful injections he suffered two fever attacks within 1 month. He subsequently continued with on-demand treatment.
Seven patients (nos 4–10) preferred treatment on-demand from the start; patient 3 was later added to this group. We prospectively observed a total of nine untreated attacks and 12 attacks treated with anakinra (figure 1). In 8 of the 12 treated attacks a clinical response was seen and in the other four attacks the response was a reduction of <50%. When comparing treated with untreated attacks, all aspects of the fever attack were significantly reduced in treated attacks including duration of fever (mean (SD) 2.2 (1.7) days vs 6.3 (1.9) days; p<0.0001), duration of symptoms (3.8 (3.0) days vs 7.3 (3.0) days; p=0.0152), maximum temperature (p<0.0001) and maximum serum CRP concentration (p=0.0004, figure 2A,B). A significant reduction of fever was observed within 24 h.
Three patients (nos 7–9) received DTP vaccinations (diphtheria, tetanus, poliomyelitis; Sanquin, Amsterdam, The Netherlands). In two patients this resulted in a typical fever attack which was successfully treated with anakinra; in the third patient anakinra (initial dose 5 h before vaccination) prevented an inflammatory attack. Adequate antibody titres developed in all patients.
Patient 11 was admitted because of a prolonged fever episode (>19 days). Ten years previously he had had a similar prolonged episode which lasted 2 months before resolving; corticosteroids had been ineffective at that time. Such prolonged attacks are a rare phenomenon in HIDS. Anakinra (100 mg/day) induced complete remission within a few days.
During inflammatory attacks, patients had a significant increase in serum concentrations of IL-5, IL-6, IL-12, IL-13, IL-18, TNFα and IFNγ. Treatment with anakinra decreased the concentration of all these cytokines except IL-18 (see figure S1 in online supplement).
Anakinra in clinical practice
Since this study nine adult patients are currently on this regimen (follow-up 0.5–4 years). They have anakinra at home and start treatment when they recognise attack prodromes for 2–6 days per episode. Anakinra drastically shortens the duration of almost all fever attacks and lessens severity; it does not decrease the frequency of fever attacks. If started >24 h after the first signs of an attack, anakinra is less successful. We observed a decrease in efficacy after 2 months of frequent use of anakinra (>14 days/month) in two patients. Withholding anakinra for 2 months restored the initial response. No patient developed persistent decreased efficacy or adverse reactions.
No major side effects were observed; the only side effects were local injection site reactions and increased frequency of mild upper respiratory tract infections (n=2) which induced one patient to stop on-demand treatment.
On-demand treatment with anakinra in HIDS resulted in a good clinical response in 8 of 12 observed episodes of fever (≥50% reduction in duration to a maximum of 2 days of fever). Evaluation of anakinra in clinical practice corroborates these results, with higher success rates if started within 24 h of onset of prodromes. We have seen no evidence of decreased efficacy even after years of on-demand use of anakinra. There were no serious side effects.
Continuous treatment in children with classical MA was disappointing. This may well be a dosing effect as was suggested in, for example, systemic juvenile idiopathic arthritis17 and cryopyrin-associated periodic syndrome.11 A higher dose of anakinra is now advocated in cases of failure but this was not standard practice at the time of this study.
We included patient preference of treatment modality in our study. All patients with HIDS opted for on-demand treatment. The main reason given was the desire to be free of medication on days of remission. Patients reported feeling more in control of their disease since they were able to intervene when symptoms started instead of suffering helplessly through a fever attack.
A limitation of this study is the fact that treatment was not blinded. Because of interpatient and intrapatient variability, large groups of patients would be necessary for any controlled therapeutic trial of sufficient power; these will be hard to collect because of the low prevalence of this disease. Patients given anakinra before or after vaccination still developed an adequate antibody response, making this a good option for the prevention of disease flares in patients requiring vaccinations.
Because of the burden of daily painful injections, anakinra is not the ideal treatment modality for continuous treatment to prevent attacks in patients with HIDS. Longer acting IL-1 blockers that are currently being tested in phase III studies could overcome this drawback. Continuous treatment with anakinra should probably be advocated over on-demand treatment in patients with HIDS who have very frequent attacks or long-term complications (eg, amyloidosis), although it has not yet been shown that continuous anakinra treatment would prevent these complications.
In conclusion, on-demand treatment with anakinra reduced the severity and duration of symptoms in HIDS attacks when started within 24 h after onset of symptoms.
Funding AS has been supported by a ZonMw VENI grant, and is now recipient of a ZonMW VIDI grant. LK has been supported by the Wilhelmina Children's Hospital research fund. EJB has been supported by a ZonMW program grant.
Competing interests JWMvdM, AS and JF have received consulting fees from Novartis.
Patient consent Not obtained.
Ethics approval This study was conducted with the approval of the Radboud University Nijmegen Medical Centre and University Medical Centre Utrecht in The Netherlands.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.