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

Wed Nov 30 11:42:30 EST 2016

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 <cis-pidd at lists.clinimmsoc.org> 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
> 
>  
> 
> 
> 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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