Rheumatology Complex Case Discussion session Medical Education Centre Southend University Hospital NHS Foundation Trust 14th February 2017 Dr Amin Islam MB MRCP UK, FRCPath UK Consultant Haematologist

Reviewed in haematology clinic 7/9/16 Problem List Thrombocytopenia ?cause Neutropenia resolved Anaemia (? Anaemia of chronic disease ACD)

Past Medical History Sjogren's disease, 2010 but long H/O dry eyes 15 years back Guillain-Barre syndrome with full recovery, 2010 Raynaud’s Stable nodular, right thyroid lobe, 2013 Under investigation by urology team for microscopic haematuria

Medication No know drugs allergies intermittent natural tear eye drop

History and examinations First noticed some bruising in lower limbs in July 2016 Has progressively increased with time Apart from bruising on legs had 2 episodes of blood spots on pillow Had one episode of pink-tinged sputum earlier this week Does not report any gum bleeding, blood blisters or an other mucosal bleeds. No B symptoms On examination today there was no lymphadenopathy or organomegaly.

Blood count: 06/09/16 Hb102 , MCV 91.7 WCC 2.9 Neut 1.87 Plt 35 Ferritin/B12/Folate - normal Total protein 94 Globulin 53 (previously investigated, no paraprotein) Normal bone profile. UES: normal Polyclonally raised immunoglobulin's

Plans and Follow up Explained that we are investigating her thrombocytopenia to look for- Either a bone marrow disorder or an immune mediated process. As symptoms are currently bruising, she is fine to go away on her holiday to France tomorrow return and have a bone marrow test on 20th September, 2016 To be seen back in clinic in 6 weeks' time with the results of the investigations.

HB trend

Neutrophils trend

PLT trend

Further tests done Borderline B12 deficiency corrected orally Immunoglobulins: polyclonally raised BJP :Negative SFLC ratio: Normal DAT: Negative Complement C3 0.85 g/L (0.75 - 1.65 ) Complement C4 * 0.10 g/L (0.14 - 0.54 ) TSH 1.99 mu/L 0.27 - 4.20 Free T4 14.1 pmol/L 12.0 - 22.0

Bone marrow tests

Bone marrow aspirate flow

MRI, marrow signal changes, 2010 Cause?

ANTI DS DNA (EIA) Anti ds DNA (EIA) * 14.0 IU/mL 0.5 - 9.9 ENA PROFILE Anti RNP 70 Not Tested. Anti RNP/Sm Negative Anti Sm Negative Anti SSa (Ro60) +++ Positive Anti Ro52 +++ Positive Anti SSb (La) +++ Positive Anti Scl-70 Negative Anti Centromere B Negative Anti Jo-1 Negative

Pernicious anaemia and Coeliac screen Negative TPMT activity 81 Normal CARDIOLIPIN ANTIBODIES Anti cardiolipin (IgG) 3.9 GPLU/mL 0.5 - 9.9 Anti cardiolipin (IgM) 2.8 MPLU/mL 0.8 - 9.9 Virology : Negative

22nd September rheumatology clinic

7th October 2016 PLT 16 Prednisolone 40 mg started 19th October 2 weeks on prednisolone PLT 18 Prednisolone increased to 60 mg

15th November 2016

Admitted 1/12/16 Admitted with a platelet count of 7 and a 2 day history of epistaxis. No recent symptoms suggestive of infection. This is on a background of newly diagnosed ITP/?lupus cytopenia Not responding to prednisolone. She has recently been started on azathioprine (completed 2 weeks at admission). Admitted for platelet transfusion and IV Immunoglobulins. .

platelet count increased to 22 after 24 hours, however, Hb had dropped further and received 1 unit of blood transfusion platelets were 12 48hours after immunoglobulin treatment. Initiated eltrombopag 25 mg OD

Haematology review 21st December 2016 No bleeding Tapering prednisolone to 5mg Still on AZATHIOPRINE 75mg Eltrombopag 50mg for 2 weeks PLT 10 Discussed option of Rituximab

5th January 2016 PLT 7, HB 77 Admitted for 1st dose of Rituxamab 1gm Had 2 units of RCC Eltrombopag continued AZATHIOPRINE STOPPED

Haematology 11th January 2016 PLT 8, HB 87, wcc 1.5, neut 0.82, lymp .70 Eltrombopag 50 mg continued Tranexamic Acid continued

19th January 2017 HB 66 , WCC* 1.8 , neut 0.87, PLT 9 Had 1 pool PLT, 2 RCC 2nd dose of RITUXMAB 1g

1st February 2017 PLT 6, HB 79, WCC 3.4 Neut 2.39, lymp 0.75 Nose bleeding Transfused 1 pool platelets Long discussion Next line o try Romoplostin (SC TPO agonist) Response 15% may be Wait few more weeks? ?delay response from Rituximab Second opinion?

9th February 2017

10th February 2017 Reviewed at UCLH Under went second marrow Repeat re staging bloods Impression Likely to be bone marrow failure secondary to multiple antibodies or strong immune destruction

What next? And ideas ITP most unlikely here Peripheral destruction Secondary to multiple antibodies But LOW HB with DAT negative Bone marrow failure? But her marrow was hyperactive 5 months ago Might needs combinations of drugs? MMF/Cyclophospahmide/Vincristine? Pasmapheresis? ASCT? CT CNAP? TCR to exclude T Cell lymphoma? PNH screen?

Learning point Immune cytopenia can be frightening for patient and the physicians Only in refractory ITP with bleeding mortality is about 30 % yearly Every effort should be taken to reach a diagnosis Try combinations Ask a friend early