A young woman presented with simultaneous features of SLE and atypical hemolytic uremic syndrome. Genetic analysis via whole-exome sequencing revealed no pathogenic or likely pathogenic variants in canonical complement genes (including CFH, CFI, C3, CFB, CD46, THBD, DGKE). Instead, the only immune-regulatory hits of note were two heterozygous IRF5 variants: rs2004640 (c.-12 + 198G>T), a known SLE susceptibility allele, and rs201487893 (c.179A>G, p.Asp60Gly), classified as of uncertain significance with in silico predictions suggesting potential toxicity. The study team reported that rs2004640 can alter splicing and increase IRF5 expression, a mechanism previously associated with elevated type I interferon activity in SLE. The source did not provide functional assays linking these IRF5 variants directly to complement dysregulation in this patient.
The index event began after diarrhea; within two weeks the patient developed oliguria, generalized edema, new-onset hypertension and rapidly declining renal function. On admission labs documented severe renal impairment and laboratory markers consistent with thrombotic microangiopathy: hemoglobin 71 g/L, platelets 8 ×10^9/L, LDH 897 U/L, C3 0.3 g/L, C4 0.03 g/L. Plasma sC5b-9 exceeded 1580 ng/mL (normal 75–219 ng/mL), indicating prominent terminal complement activation. The authors noted a prior history of thrombocytopenia of unknown cause two years earlier; ADAMTS13 activity was not measured during that episode and thus a past TTP event could not be definitively excluded.
Whole-exome sequencing (22,223 genes, including mitochondrial genome) returned no pathogenic variants in known aHUS-associated complement genes. The investigators also reported heterozygous variants of uncertain significance in several renal development or ciliopathy-related genes (NPHP4, ATP6V0A4, DZIP1L, GFRA1), none of which have established links to complement-mediated TMA. The authors therefore framed the IRF5 findings as the most plausible susceptibility factor for an autoimmune background, while explicitly stating these are not established aHUS-causing mutations.
Treatment combined SLE-directed immunosuppression and terminal complement blockade. High-dose intravenous methylprednisolone was given, followed by oral prednisone taper and continued hydroxychloroquine. Weekly eculizumab was initiated. Platelet count rose rapidly after the first eculizumab dose and LDH normalized within one week. Plasma sC5b-9 fell to normal after two weeks, supporting effective terminal complement inhibition. The authors reported that these hematologic improvements occurred independent of blood pressure control, which they interpreted as evidence that complement-mediated TMA was the primary mechanism.
Renal recovery did not occur. Despite hematologic remission, the patient progressed to end-stage renal disease and was placed on maintenance hemodialysis. The paper states no severe infectious complications arose during combined immunosuppression and complement inhibition. The authors also note that routine long-term monitoring of sC5b-9 after discharge was not performed, and they identified this as a limitation.
The investigators proposed, without functional proof, a two-hit model. First, the patient’s rs2004640 IRF5 risk allele may have produced an interferon-high milieu that increased susceptibility to autoimmune activity. Second, an environmental trigger — the antecedent diarrheal illness and concurrent viral exposure reported in the history — may have amplified toll-like receptor and interferon signaling, which in turn could have primed complement activation culminating in TMA with an aHUS phenotype. The authors emphasized this remains hypothetical: no experimental validation linking IRF5 variant-driven interferon signaling to the observed complement activation was reported in the source article.
The report also stressed a practical diagnostic point supported by the presented data: when genetic testing for complement genes is negative, markedly elevated plasma sC5b-9 can confirm terminal complement activation and thereby justify use of C5 inhibition. In this case, rapid hematologic response to eculizumab aligned with measured normalization of sC5b-9.
This is a single-case observation. The authors acknowledged multiple limitations contained in the source: lack of functional studies to validate the IRF5–complement link; absence of ADAMTS13 measurement during the prior thrombocytopenia episode; missing fundoscopy at presentation; incomplete long-term sC5b-9 monitoring post-discharge; and the inability of a lone case to establish causation. The paper called for functional investigations to test whether IRF5 risk variants can mechanistically prime complement-mediated endothelial injury in SLE. The article ends with those concrete open questions rather than broad editorial conclusions.