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

Wed Nov 30 17:23:17 EST 2016

Dear David, 

- If you decide to treat your patient with rituximab,
you could try to use low dose of 250 mg/m(2) × 2 that may be as
effective as at higher dosages, most commonly 375 mg/m(2)×4 (results
from our group, Visentini et al, Autoimm Rev 2015) - considering her
hypogamma status. 

- The very unusal fact in this case is the very
early onset of cryoglobulinemia in your patient. What about her family
history? 

- If not done before, given her hypogammaglobulinemia, one
can try also to check directly HCV viremia at 37°C (as for
cryoglobulins). We are doing it routinely at 37°C for blood count, HCV,
complement, immunoglobulins and cryoglobulins analysis. 

Keep me posted
about your patient's findings.

Best,

Milica  

Il 30.11.2016 17:42
CIS-PIDD ha scritto: 

> Hey Milica, 
> Thank you very much for your
suggestions. 
> She was not treated with rituximab, although I think it
could have been the best treatment together with IVIg. I will try to
push for it (just need to make sure first that ulcers are not secondary
to infection). 
> 
> IgM and IgA are lowish but within normal range.
Absolute B cell number is 35, also argues against an artifact. Waiting
for phenotyping results. We will check her IgGs again at 37 degrees. I
like this idea. Will be interesting to see. 
> Bone marrow biopsy looks
normal. 
> Type of cryo - waiting for results 
> C3 level - normal. 
>
I'm as well concerned about worsening her kidney function by adding Igs
in an immune complex disease. I plan to split her IVIg over several days
and follow her kidney functions. 
> Really appreciate your help, 
>
Best, 
> David 
> 
> On Nov 30, 2016, at 01:06, CIS-PIDD wrote:
> 
>>
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 [4] 
>> 
>> 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 [5] 
>> 
>> --- 
>>

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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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