Pneumocystis prophylaxis in ANCA vasculitis Robert Hunter Wellcome Trust Clinical Research Career Development Fellow Honorary Consultant In Renal Medicine @renalrob

Pneumocystis prophylaxis in ANCA vasculitis Overview: Risk of PCP in ANCA vasculitis A case Prophylaxis regimens Trimethoprim-sulfamethoxazole desensitisation Questions: Who should receive PCP prophylaxis? What should we do when patients are allergic to TMP-SMX?

PCP in ANCA vasculitis Jarrousse (1993) Guillevin (1997) Reinhold-Keller (2000) Bligny (2002) Booth (2003) Charles (2011) Guillevin (2014) Edinburgh registry PCP in ANCA vasculitis We have 1012 patient-years and 2 cases = 0.2 cases per 100 patient-years Consider epidemic vs. sporadic Outbreak in 2015 in Aberdeen, Birmingham, Cambridge (e.g. 4 cases in Aberdeen) Jarrousse = GPA without prophylaxis Booth = London, renal disease only Guillevin (2014) = MAINRITSAN Charles = French, rituximab only

Case Case of PCP in patient with AAV during maintenance rituximab. Role of T-S desensitisation discussed.

PCP prophylaxis BSR / BHPR EULAR / ERA CANVAS Indication: 1st-line: CYC (grade B) other induction with high- dose GC (grade C) CYC CYC (grade C) RTX (grade C) 1st-line: TMP-SMX 960 mg thrice- weekly 960 mg alt days 480 mg daily 2nd-line: pentamidine or dapsone pentamidine (but NOT routinely) Options: 1) trimethoprim-sulfamethoxazole (daily, thrice-weekly) 2) dapsone 100 mg daily 3) dapsone 100 mg + pyrimethamine 25 mg twice-weekly 4) atovaquone 750 mg daily 5) pentamidine 300 mg nebulised monthly NB dose-adjustments in renal failure and potential interaction between methotrexate and TMP-SMX

TMP-SMX prophylaxis TMP-SMX is effective at preventing PCP (Stern et al., Cochrane Rev, 2016) Adverse reactions lead to discontinuation of TMP-SMX in ~20% Desensitisation is more effective than re-challenge (Lin et al., Cochrane Rev, 2007) Our desensitisation regime: 96 mg daily for 3 days (= 1 ml of 480 mg / 5 ml liquid) 192 mg for 3 days (= 2 ml) 288 mg for 3 days (= 3 ml) 384 mg for 3 days (= 4 ml) 480 mg daily (= 5 ml or convert to tablet) NNT = 19 in non-HIV population with control event rate = 6% = Stern et al, Cochrane 2016 Desensitation is better than re-challenge: NNT = 7 to prevent T-S discontinuation (in HIV population: Lin et al., Cochrane 2007) Reference for discontinuation in 20% is in introduction to Cochrane review 2007 and also Stegeman (NEJM, 1996) Classic protocols last 48 hrs – 5 days (including the three studies reviewed by the 2007 Cochrane review)

Our answers Who should receive PCP prophylaxis? everybody during induction (not only cyclophosphamide) …and for months-years thereafter inclusive (vs. risk-oriented) prescription possible immunomodulatory benefit of TMP-SMX (Stegeman et al., NEJM 1996; Salmela et al., Rheumatology, 2017) What should we do when patients are allergic to TMP-SMX? consider immune context desensitise (13-day regime, steroids, anti-histamines, close monitoring)

Acknowledgments Neeraj Dhaun (Bean) David Kluth Eve Miller-Hodges BHF Intermediate Fellow & Honorary Consultant Nephrologist David Kluth Senior Lecturer in Nephrology & Honorary Consultant Nephrologist Eve Miller-Hodges Specialist Registrar in Nephrology & Vasculitis Fellow Tariq Farrah MRC Clinical Fellow Jin Werne Hah Renal Pharmacist Sadaf Arshad @renalrob