Successful use of ofatumumab in two cases of early-onset juvenile SLE with thrombocytopenia caused by a mutation in protein kinase C δ

Abstract

BackgroundWe previously described an endogamous Pakistani kindred in whom we identified a novel homozygous missense mutation in the PRKCD gene encoding for protein kinase C δ (PKCδ) as a cause of monogenic systemic lupus erythematosus (SLE). PKCδ has a role in the negative regulation of B cells. Given the nature of the disease, a logical targeted therapeutic approach in these patients is B cell depletion. Indeed, the 3 siblings all had a marked clinical response and resolution of symptoms with rituximab, although 2 of the siblings had severe reactions to rituximab thus precluding further treatment with this. We therefore describe the first successful use of ofatumumab for this rare form of monogenic SLE.Case presentationAll three affected siblings presented with SLE before the age of 3-years with lethargy, intermittent fever, thrombocytopenia, cutaneous involvement, alopecia, and hepatosplenomegaly. Tubulointerstitial nephritis was also present in 1 of the siblings. Homozygosity mapping followed by whole exome sequencing identified a homozygous missense mutation in PRKCD (p.Gly432Trp), subsequently confirmed by Sanger sequencing to be present in all 3 siblings. All 3 patients were initially treated with rituximab, however 2 of the siblings developed severe infusion-related reactions. For subsequent disease flare in these individuals we therefore used an alternative B cell depleting agent, ofatumumab (300 mg/1.73m2 on day 1; 700 mg/1.73m2 on day 15). This resulted in marked clinical improvement in both patients. To the best of our knowledge, this is the first report describing the successful use of ofatumumab for PKCδ deficiency.ConclusionsPKCδ deficiency causes a monogenic form of SLE which responds well to B cell depletion. Ofatumumab is also likely to have a therapeutic role for sporadic juvenile SLE (jSLE) patients intolerant of rituximab.

Pediatric NMOSD: A Review and Position Statement on Approach to Work-Up and Diagnosis

“…In a retrospective review, nine patients with SLE who were treated with ofatumumab at a median age of 16 years (11–18 years) showed clinical improvement with a good safety profile ( 116 ). Additional successful pediatric exposure to ofatumumab has been recently published in two siblings with monogenic SLE before the age of 3 years ( 117 ). There is no published experience on the use of ofatumumab in children with NMOSD yet.…”

B Cells as a Therapeutic Target in Paediatric Rheumatic Disease

“…Clinical trials that directly compare rituximab therapy with methotrexate alone, TNF inhibiting drugs or, where appropriate, anti-IL-6 therapy would be extremely informative to help stratify treatment efficacy when compared to other current treatment strategies. Development of other CD20-targeting monoclonal antibodies is ongoing, recent additions include ofatumumab (104) and veltuzumab, which have a similar mechanism of action to rituximab. Notably, ofatumumab is a fully humanized form of CD20, which has been demonstrated to be effective in adults and children with SLE who have had adverse reactions to rituximab (104).…”

“…Development of other CD20-targeting monoclonal antibodies is ongoing, recent additions include ofatumumab (104) and veltuzumab, which have a similar mechanism of action to rituximab. Notably, ofatumumab is a fully humanized form of CD20, which has been demonstrated to be effective in adults and children with SLE who have had adverse reactions to rituximab (104).…”

The Use of Ofatumumab in Renal Conditions

“…A very interesting case report described three siblings with protein kinase C δ deficiency who presented with SLE before 3 years of age [26]. Two of them developed infusion-related reactions when receiving RTX.…”