[CIS PIDD] [cis-pidd] NEMO and BID

Wed May 6 18:46:53 EDT 2015

Dear Pere;

Thank you for sharing this very interesting observation.

As you astutely point out, it represents a relatively late presentation for the IBD of NEMO.
Can you share the details of the mutation?

It would seem from the published and ongoing analyses that some mutations are preferentially correlated with the intestinal phenotype.
Particularly, those over the first coiled-coil and C-terminus.
Given the numerous proteins that interact with NEMO directly, this would seem to make some sense: that particular defective signaling/adaptor/scafolding functions of NEMO would be prerequisite to the intestinal phenotype.  The question is, which ones? Your patient may hold an important clue.

I am certainly aware of patients that have presented with a predominantly intestinal disease, but over time they have “collected" other problems.
Your patient again, is a bit older - so it raises curiosity regarding whether this may be a particularly informative (i.e., isolated in functional impact) mutation.

Given the diversity of immune defects attributable to particular NEMO mutations, it would be very interesting to know what specific defects your patient demonstrates.  Given his age and generally well health, one might predict that the immune defects are rather limited and focused.  Again that would be quite informative in the way of potentially helping to unravel the basis of the IBD phenotype in NEMO.

As for treatment:
In my experience steroids have always been the mainstay for NEMO-IBD and typically have been quite effective.  Enteral Budesonide has also been helpful for some.  The fact that your patient is resistant to steroids is somewhat surprising.  We have also had some success with oral vancomycin in concert with steroids.  As the mouse models and human correlative studies have taught us, NEMO insufficient intestinal epithelia is not normal and allows for increased bacterial translocation.  This leads to local inflammation - which is muted to some degree by the defective NEMO present in cells capable of recognizing microorganisms and/or promoting inflammation.  This is also one of the caveats in considering HSCT as it will not replace the defect in the intestinal epithelia, but can potentially provide functioning NEMO sufficient immune cells to the intestine that could potentially make inflammation worse.  In my experience, this effect is most pronounced initially and for a reason unbeknownst to me ameliorates over time (see the case in JACI vol122:p1113).  There are of course many hypotheses one could offer for alteration over time.
With regards to Infliximab, I agree that it is a rather frightening agent to consider in the context of NEMO for the reasons you have raised.  I am aware of one patient who was treated in this way and it was actually quite helpful to him and he did not acquire mycobacterial disease during that time.  That said, personally it is something I would avoid if I could and if I needed to use it I would be sure the patient is on a mycobacterial prophylaxis regimen.

I hope this is of some help and I hope your patient has a favorable outcome.

Very best,

Jordan

Jordan Orange MD, PhD
Chief, Immunology, Allergy and Rheumatology
Director, Center for Human Immunobiology
Texas Children's Hospital
Professor of Pediatrics, Pathology and Immunology
Vice Chair for Research
Department of Pediatrics
Baylor College of Medicine

On Apr 30, 2015, at 4:55 AM, Pere Soler Palacin <psoler at vhebron.net<mailto:psoler at vhebron.net>> wrote:

Dear all, I'd appreciate your inputs on a new case we have. He's a 15 yo boy who was followed by our gastroenterologists due to inflammatory bowel disease (diagnosis was made at 13 years of age due to arthritis and diarrhoea) that was unresponsive to steroids and azathioprine. Then, infliximab was started and PID screening was performed yielding a mutation in the X-linked NEMO gene both mother and sister are carriers of the mutation). My questions are:
- Do you have any experience in NEMo deficiency patients presenting only with Crohn-like phenotype?
- I'm worried about the risk of mycobacteriosis in a patient with NEMO-def receiving infliximab. Would you consider any other therapeutic option?
- The patient is doing clinically well, should SCT be considered in this case?

Thanks in advance and best regards from Barcelona,

P.

Pere Soler Palacín, MD, PhD.
Pediatric Infectious Diseases and Immunodeficiencies Unit. Hospital Universitari Vall d'Hebron
Assistant Professor. Universitat Autònoma de Barcelona (UAB)
Pg. de la Vall d'Hebron, 119-129
08035 Barcelona. Spain.
Tel. 0034934893140  /  Fax 0034934893039

psoler at vhebron.net<mailto:psoler at vhebron.net>  /  34660psp at comb.cat<mailto:34660psp at comb.cat>
Web: www.upiip.com<http://www.upiip.com/>
ORCID ID: http://orcid.org/0000-0002-0346-5570
Scopus Author ID: http://www.scopus.com/authid/detail.url?authorId=55923378300
ResearchGate: http://www.researchgate.net/profile/Pere_Soler-Palacin
LinkedIn: http://es.linkedin.com/pub/pere-soler-palac%C3%ADn/73/918/b16

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