Efficacy of anti-IL-1 treatment in Majeed syndrome

Abstract

Background and objective: Majeed syndrome is an autosomal recessive disorder characterised by the triad of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia and a neutrophilic dermatosis that is caused by mutations in LPIN2. Long-term outcome is poor. This is the first report detailing the treatment of Majeed syndrome with biological agents and demonstrates clinical improvement with IL-1blockade.

Methods: We describe the clinical presentation, genetic analysis, cytokine profiles and response to biological therapy in two brothers with Majeed syndrome.

Results: Both boys were homozygous for a novel 2-base pair deletion in LPIN2 (c.1312_1313delCT; p.Leu438fs+16X), confirming the diagnosis. Their bone disease and anaemia were refractory to treatment with corticosteroids. Both siblings had elevated proinflammatory cytokines in their serum, including tumour necrosis factor α (TNF-α), however a trial of the TNF inhibitor etanercept resulted in no improvement. IL-1 inhibition with either a recombinant IL-1 receptor antagonist (anakinra) or an anti-IL-1β antibody (canakinumab) resulted in dramatic clinical and laboratory improvement.

Conclusions: The differential response to treatment with TNF-α or IL-1 blocking agents sheds light into disease pathogenesis; it supports the hypothesis that Majeed syndrome is an IL-1β dependent autoinflammatory disorder, and further underscores the importance of IL-1 in sterile bone inflammation.

Figure 1

Clinical findings: MRI abnormalities improve with IL-1 inhibition. (A) MRI with coronal (short tau inversion recovery (STIR)) sequence of sibling A obtained at age 29 months before starting treatment; shows increased signal intensity on STIR images predominantly affecting both metaphyseal regions of the tibiae but with patchy involvement of the diaphyses and epiphyses as well. There is evidence of soft tissue inflammation adjacent to an area of affected bone in the metaphyseal region of the left fibula. (B) MRI STIR sequence 3 months after treatment with canakinumab. (C) Bone marrow from sibling A shows erythroblasts with binucleated (long thin arrows) and nuclear budding (short thick arrows).

Figure 2

Novel mutation in LPIN2: exon 9 forward and reverse sequences are shown for sibling A, sibling B and wild-type. There is a homozygous 2-base pair deletion in exon 9 of LPIN2 seen both in the forward and reverse directions (c.1312_1313delCT; p.Leu438fs+16X).

Figure 3

Inflammatory cytokine response over time relative to treatment of Majeed syndrome with biological agents. Cytokine profiles A and B reflect serum cytokine changes in sibling A and sibling B, respectively. Time zero reflects serum cytokines prior to the initiation of biological therapy. The right-hand panel demonstrates erythrocyte sedimentation rate (ESR) and haemoglobin over time in relation to treatment in sibling A (top) and sibling B (bottom). E, etanercept, A, anakinra, C, canakinumab. Canakinumab dosing was 4 mg/kg every 4 weeks.