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

Tue Nov 8 01:03:23 EST 2016

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<mailto:mikko.seppanen at hus.fi> and I will tell you some more plus Mike's e-mail)

Mikko

Oyl Mikko Seppänen
Harvinaissairauksien yksikkö (HAKE)
[cid:]

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<mailto: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<mailto: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/0BzdY4kb1eMzvNGxwdzF4aWk0YVE?gsessionid=JgIfFenSdExWvx9kKrrouJdfihqhi94-&sort=13&direction=a

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