[CIS PIDD] [cis-pidd] Cutaneus Vasculitis Presenting as Purpura Fulminans in an ALPS-like / SLE / Sarcoid pt

Tue Nov 8 01:49:22 EST 2016

Thank you Mikko!

We will try to get new tissue samples and look for LGL cells.
When I first saw the rash I was also considering acquired protein C or
protein S deficiency (reminded me warfarin induced fulminant purpura). and
I was also thinking that a patient who makes antibodies against neutrophils
could also make antibodies against different proteins, but sh has stone
cold normal coagulation in any way we checked it.
I didn't think about ADA2 (I should have, sorry). I know that it was
described in several Jewish families in Israel. Not that it means much but
the patient isn't Jewish.

I will contact Dr. Michael Hershfield.

Thank you very much again!

David

On Tue, Nov 8, 2016 at 8:00 AM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
wrote:

> Hi David,
>
> The lack of thrombocytopenia is baffling.
> Besides hunting for bacteria in tissue biopsies...:
>
> Since livedo reticularis is pathophysiologically related - in a sense -  I
> would start looking for things like CECR1, STAT3 GOF, TMEM173 and other
> interferonopathies, also for NFKB1 - for starters.
>
> I would also search for LGLs in liver biopsy, BM biopsy and peripheral
> blood.
>
> CECR1 / DADA2 has been reported to be rather "common" in Israel and its
> clinical pheotypic variation seems huge. An "easy" way to exclude it would
> be to send a dried plasma spot / serum to Michael Hershfield at Duke's.
>
> Other lines of thought would be for example
> -  protein C deficiency and infection or
> -  a paraneoplastic phenomenon unrelated to LGL lymphoproliferation
>
> (David, send directly an e-mail to mikko.seppanen at hus.fi and I will tell
> you some more plus Mike's e-mail)
>
> Mikko
>
> Oyl Mikko Seppänen
> Harvinaissairauksien yksikkö (HAKE)
>
> Head, Rare Disease Center,
> Helsinki University Hospital (HUH)
> FINLAND
>
> phone +358 947180201
> GSM +358 50 4279606
> fax +358 9 47174703
>
> CIS-PIDD <cis-pidd at lists.clinimmsoc.org> kirjoitti 7.11.2016 kello 17.50:
>
> Here's the link again:
>
> https://drive.google.com/drive/folders/0BzdY4kb1eMzvNGxwdzF4aWk0YVE?
> usp=sharing
>
> Thanks!
>
> On Mon, Nov 7, 2016 at 4:52 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
> wrote:
>
>> Dear friends,
>> I would appreciate your thoughts and suggestions regarding a patient I
>> saw a week and a half ago.
>> I apologize but it is going to be a long one.
>>
>> This is a 29y/o female with 2-3 yrs history of hepatosplenomegaly,
>> lymphadenopathy, granoulomatous disease, autoimmune neutropenia  and
>> elevated % of DN ab T cells.
>>
>> The patient underwent an evaluation for bariatric surgery 3 years ago
>> when an abdominal US revealed an incidental finding of enlarged spleen.
>> That triggered an intensive work up to rule out malignancy / infection /
>> autoimmunity. She even underwent exploratory laparoscopy + several bone
>> marrow Bx all showed epithelioid histiocytic granulomatous inflammation,
>> which at least in the liver were surrounded by lymphocytes. At this point -
>> her working diagnosis is extra pulmonary sarcoidosis.
>>
>> Early in 2015 the pt was admitted several times with neutropenic fevers.
>> It was assumed that neutropenia is either drug related or  part of her
>> sarcoidosis. She also had mild thrombocytopenia (around 100-130K) and mild
>> (Coombs negative) anemia (Hb ~9-10). BM Bx again showed the same
>> granulomatous disease, with hypercellular marrow, M:E ratio of >5 and
>> increased megakaryocyte count (suggesting peripheral destruction?
>> hypersplenism??).
>> Later she was found to have anti neutrophilic antibodies, but at that
>> point she was started on prednisone 1mg/kg and GCSF.
>>
>> Was kept on high dose prednisone for several month with very slow
>> tapering to 7mg/day. As for the nuetrophils - she still requires GCSF every
>> couple of week. She was kept out of the hospital with no fevers or
>> admissions for almost a year, but in the last 3 months was again admitted
>> twice for neutropenic fever.
>>
>> Labs - a lot over the years but to summarize, here are the most
>>  important ones (I think):
>>
>>
>> 2/2015:
>> ANA= >1:640 Dense Fine Speckeled - considered false positive as direct IF
>> was negative.
>> dsDNA – 51.1H but a second one was negative.
>> ANCA – Neg
>> RF – Neg
>>
>> IgG-2040mg/dL H
>> IgM – 309mg/dL H
>> IgA – 451 H
>> IgG Subclasses: IgG1 - 1170*; IgG2 – 155* (L); IgG3 – 42; IgG4 -3
>> C3 - 1.49 N
>> C4 - 0.08L + 0.09L on repeated testing
>>
>> Serology for Q fever, Bartonella, Toxo and almost every other pathogen
>> were all negative (TB was tested over and over again and was always
>> negative) - and I think that any infectious disease would have been
>> identified by now, especially with a long high dose steroid treatment.
>>
>> 8/2016:
>> Ds DNA – 12.7 N
>> ENA – 2.0 H with mildly elevated anti-Sm.
>> ANA is again positive (don't have the exact titer) but this time the
>> pattern is homogenous - goes better with SLE.
>> IgG 2020mg/dL; IgM 335mg/dL; IgA 489mg/dL
>> ACE – 97 - mildly elevated (N<80)
>>
>> 9/2016 – Lymphocyte subsets:
>> Toatl CD3 – 945, CD4 – 344, CD8 – 430, CD4/CD8 ratio 0.8, CD20 – 172,
>> *Double Negative CD3+ab+  6%*
>>
>> HLA-DR – 46%
>>
>>
>> She also has very low HDL (17), but normal vitamin B12 (~400). I do not
>> have IL18 or IL10 levels.
>>
>> On PE - the patient is a bit pale and tachypneic, and the most
>> significant finding is huge spleen and liver. I did not find enlarged LN in
>> other places, although imaging studies showed enlarged abdominal LN -
>> mostly periportal and retroperitoneal.
>>
>> At this point, and assuming that the patient does not have a
>> lymphoproliferative disorder, I decided to call her an ALPS-like - even
>> though the granulomatoues disease does not fit well to the overall picture.
>> I was considering starting her on either MMF or Rapamycin based on the
>> presence of cytopenia (requiring frequent GCSF), huge hepatosplenomegaly
>> and elevated DNT cells.
>>
>> I would appreciate your thought whether it makes sense - would you even
>> call her APLS?
>>
>> But here is the twist...
>>
>> I first saw the patient a week and a half ago (10-27). 3 days later,
>> before we even made any changes to her medical treatment, the patient gets
>> her flu shot.
>>
>> The next day I get a call from the ER - the patient is seen with mild
>> purpuric rash. The rash is painful. Her CBC is without any change - plt
>> 125K as always, ANC - 1300 as always, Hb - 9.2 as always, PT, PTT is
>> normal, no fever. I was afraid that with her law neutrophils she might
>> catch something in the hospital (it was already late afternoon) so I sent
>> her home with 60mg of prednisone, gave her my phone number and asked her to
>> come to clinic the next morning.
>> Next morning she shows up with fulminant purpura - very painful, but
>> again - her lab is almost without any change. No evidence for DIC what so
>> ever, no fever - cultures so far are negative, no evidence for hemolysis on
>> lab or blood smear, plt counts are stable, hemoglobin is table, neutrophils
>> are stable, no evidence for any other organ involvement other than skin
>> (normal LFTs, normal kidney functions and normal urine sed). CRP is 20
>> (normal range <5). Skin biopsy is pending.
>> We decided that no matter what the underlying diagnosis is (and the
>> options are SLE / sarcoidosis / ALPS-like), right now she has cutaneous
>> vasculitis and we started her on 3 days of pulse methylprednisolone
>> (1gr/day) which she completed yesterday. Other than her CRP that went down
>> from 20 to 5 (N), it is very difficult to see any improvement and pain is a
>> dominant issue here.
>>
>> As the next step, we are considering either rituximab or plasmapheresis,
>> mostly because she has very high total antibody levels and we assume that
>> the underlying mechanism might be antibody mediated (immune complex? we
>> don't have kidney injury or arthritis).
>>
>> I am a attaching a link to few pictures. My major concern right now is
>> that she will develop skin necrosis and secondary sepsis, and that's why I
>> don't feel very strong about adding more immunosuppression but would love
>> to hear your thoughts and suggestions regarding the underlying diagnosis
>> and other treatment option.
>>
>>
>> Update - as I'm writing - preliminary report of the skin biopsy indeed
>> suggests vasculitis.
>>
>>
>> Thank you very much!
>>
>> David Hagin,
>>
>>
>> Tel-Aviv Sourasky Medical Center,
>> Tel-Aviv, Israel
>>
>>
>> https://drive.google.com/drive/u/0/mobile/folders/0BzdY4kb1e
>> MzvNGxwdzF4aWk0YVE?gsessionid=JgIfFenSdExWvx9kKrrouJdfihqhi9
>> 4-&sort=13&direction=a
>>
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