[CIS PIDD] [cis-pidd] C4 deficiency, Cryoglobulinemia and Hypogammaglobulinemia

[CIS-PIDD]

Dear David, 

your case is very interesting and I would have some
thoughts about it: 

- Given that your patient wasn't treated with
Rituximab, I suppose that the most probable cause of her
hypogammaglobulinemia is the immunosuppressive treatment (+ renal loss
during episodes of important proteinuria?). What about her IgA and IgM
levels or B cells ? A recent paper from Klaus Warnatz (J Clin Immun
2016) showed the differences between primary and secondary antibody
deficiency due to glucocorticoid therapy (most of the patients with
persistent hypogammaglobulinemia had isolated IgG deficiency).
 However,
with cryo and hypogamma one should exclude also a hematologic
malignancy… 

- The presence of cryoglobulins could cause false positive
hypogammaglobulinemia but you can prevent that with collecting and
working blood samples at 37°C. 

- The cryoglobulins were typed? Which
type of cryoglobulinemia does she have? Rheumatoid factor? How about her
C3 levels? I suppose she is also negative for HBV and autoimmunity (esp.
SLE that can be associated with C4 deficiency)? 

- Given the two
pneumonia episodes and her IgG levels, I would start IVIG replacement
therapy (please note that there are some reports of increased immune
complex precipitation and worsening after high dose IVIG in patients
with cryoglobulinemia). 
Unfortunately C4 deficiency also increases
susceptibility to bacterial infection.

Sincerely,

Milica Mitrevski 


--

Milica Mitrevski, MD, PhD 
Clinical Immunology and Allergy
Specialist
 Sapienza University of Rome 
Department of Clinical Medicine
Viale dell'Università 37, 00185 Rome, Italy 
tel: +39 349 5622376
 mail:
mitmilica at tiscali.it 

Il 29.11.2016 19:51 CIS-PIDD ha scritto: 

>
Hello, 
> I yesterday saw a very interesting case of a 31 y/o lady who
was admitted due to severe lower limb skin ulcers, with which she was
struggling in the last 3 months. 
> She was first presented at the age
of 14 with purpura and proteinuria and was later diagnosed with
cryoglobulinemia (HCV negative). She was treated with pulse
methylprednisolone for the acute phase and was kept on prednisone +
azathioprine/MMF for maintenance. 
> Over the years she suffered several
exacerbations with heavy proteinuria and responded each time to pulse
steroid treatment. Between exacerbation she is stable on prednisone
(12.5mg) + azathioprine which was later switched to MMF (3g/day). 
>
Over the years complement levels were checked numerous times and she
always had undetected C4 level. At one point she had some genetic
testing which according to her confirmed C4 deficiency. So I think it
makes sense and should explain the Cryo. 
> But, she also had her
antibody levels checked, and in the last two years (all that was
available for me to see) her IgG levels are always between 200-300mg/dL.
I assume this is secondary to prolonged immunosuppression, together with
complement deficiency which might as will impair antibody production. 
>
Infection wise - she was free of any significant infection until a year
and a half ago. In the last 18 months she had two pneumonias, one of
them with Q fever. No other infections. 
> I was planning to start her
on IVIg, but then spoke with her nephrologist (she was followed at a
different hospital) who told me she had hypogammaglobulinemia for 10
years now. The reason they didn't start her on replacement therapy was
that she did not have significant infections (I think that pneumonias
should count for something). 
> I would love to get some input on
several issues: 
> 1. Any reason to hold Ig replacement therapy? 
> 2.
Would you consider other explanation for the hypogam - other than
prolonged immunosuppression? 
> 3. Do you think that the presence of
cryoglobulins could cause false positive hypogammaglobulinemia (IgGs
precipitate together with the cryo?). 
> 4. Severe hypogammaglobulinemia
and skin ulcers - she did not improve with more intense
immunosuppression. Would you look for Helicobacter bilis, similar to
what was described in XLA patients? 
> Thank you very much for your time
and thoughts, 
> David Hagin 
> Tel-Aviv Medical Center 
> 
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--

Milica Mitrevski, MD, PhD Clinical Immunology and Allergy
Specialist Sapienza University of Rome Department of Clinical Medicine
Viale dell'Università 37, 00185 Rome, Italy tel: +39 06 49972036 +39 349
5622376 mail: mitmilica at tiscali.it   


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