Eculizumab non-response in aHUS

A number of genetic abnormalities are associated with eculizumab non-response. The finding of these abnormalities should prompt stopping treatment with eculizumab.

In addition to diagnostic testing to support a diagnosis of complement-mediated aHUS, the following tests are routinely performed as part of the diagnostic work up in patients with suspected aHUS.

• Single nucleotide polymorphisms (p.R885H; p.R885C) in C5 that associate with non-response to eculizumab. 
• Genetic screening is routinely performed for DGKE and MMACHC as they predict Eculizumab non response and guide alternative therapies.
• Rare familial cases of Eculizumab non responsive TMAs have been described in patients with  INF2 mutations and screening can be performed on request. 

Screening for mutations in THBD  can also be performed on request. 

There is also currently no evidence as to the efficacy of Eculizumab in secondary TMAs or STEC–HUS and consequently NHS England do not fund its use in this situation. The decision to initiate Eculizumab may be made prior to the availability of diagnostic tests: this is to maximise clinical efficacy in patients who subsequently are confirmed to have primary complement mediated aHUS. Identification of an alternative diagnosis (such as secondary TMAs or STEC-HUS) will necessitate withdrawal. 

In patients who present late in the course of complement-mediated aHUS, renal recovery may not be seen. Evidence of renal recovery following Eculizumab therapy has been seen even following 3 months of renal replacement therapy. For this reason a course of 3 months is usually given prior to review for signs of renal recovery. Lack of evidence of renal recovery at this point should necessitate discussion with the national centre as to whether therapy should be continued. This is to minimise the risk of adverse events, in particular meningococcal infection.