PID and autoimmunity, treatment options
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1 PID and autoimmunity, treatment options Alain Fischer Hôpital Necker Enfants Malades, Inserm, Université Paris-Descartes, Institut Imagine, Collège de France, Paris
2 PID, monogenic diseases and autoimmunity 146 monogenic diseases causing autoimmunity and/or inflammation! (#45 % of identified PID) Frequency of autoimmunity in PID patients Pathophysiology is revealing mechanisms of autoimmunity Targeted therapeutics?
3 Frequency of autoimmunity/inflammation in PID patients French registry CEREDIH A systematic survey ( from 09/2013) Study population cases Male gender 57.9 % Age (years) 20 9 ; 38 Autoimmunity : 24.5% n=903 % B CVID 18.7 B non CVID 26.8 T SCID 7.3 T CID 15.3 T others 16.1 Innate 14.8
4 Nature and frequency of events n= % Cytopenias Gastrointestinal disorders Skin Rheumatologic disorders Endocrine disorders Lung Eye Kidney Vasculitis and other systemic disorders Neurologic disorders Urologic disorders Other Total 852
5 Distinct gene mutations, distinct autoimmune manifestations CTLA4 LRBA STAT3 IPEX WAS ALPS APDS APECED AI. Anemia Thrombopenia Neutropenia Enteropathy Lung disease Diabetes Polyarthritis Neurol. disease Hepatitis Vasculitis Glomerulonephritis Uveitis Hypoparathy. Adrenal Insuff. Thyroiditis Hypogondism Gastritis Alopecia Skin, others Vitiligo % : > 33 > 75
6 Impact on survival
7 Impact on survival as a function of PID diagnosis CVID Other B cell PID T cell PID Innate PID
8 Impact of autoimmunity pre HSCT on survival post HSCT
9 PID, monogenic diseases and autoimmunity Targeted therapeutics? Hematopoietic stem cell transplantation
10 Targeted therapies IL1 inhibitor autoinflammatory syndromes JAK1,2 inhibitors STING gof STAT1 gof IL6 inhibitor STAT3 gof CTLA4 Ig CTLA4, LRBA deficiencies PI3K inhibitors PI3K gof (APDS) mtorc inhibitors mtorc inhibitors FAS, FASL (ALPS) lof : loss of function, gof : gain of function
11 Blockade of interferon type I signaling Example: gain of function of STING ADN ADN JAK inhibitor T Junt & W Barchet, Nature Reviews Immunology
12 Benefit of JAK/2 inhibitor in SAVI, GOF of STING 11pts 5-40 months follow up, median 22 months efficacy ++, albeit not complete safe B. Neven, ML Fremont
13 Effect of HSCT on SAVI manifestations Haplo-id HSCT (age) 28 months Full chimerism 22 years TMEM173 mutation p.n154s lung disease Pre HSCT Post HSCT interferon signature prior to Ruxotilinib after 70 days of treatment Skin vasculitis calcifications brain + 7 years
14 Effect of HSCT on SAVI. Interpretation Hematopoïetic origin : lung lesions most IFN signature Extrahematopoïetic origin : skin vasculitis and brain calcifications STING in endothelial cells?
15 Targeted therapies IL1 inhibitor autoinflammatory syndromes JAK1,2 inhibitors STING gof STAT1 gof IL6 inhibitor STAT3 gof CTLA4 Ig CTLA4, LRBA deficiencies PI3K inhibitors PI3K gof (APDS) mtorc inhibitors mtorc inhibitors FAS, FASL (ALPS) lof : loss of function, gof : gain of function
16 Therapeutic strategy for CTLA4 deficiency Ligand competition CD28 CTLA4-Ig Prevention of CD80/86 interaction with CD28 when CTLA4 is defective CD80/86 Adapted from L.S.K. Walker et al, Nature Reviews Immunol., 2011
17 Treatment of CTLA4 and LRBA deficiencies by CTLA4Ig Paris experience, B. Neven 14 patients, 10 CTLA4, 4 LRBA teenagers and adult patients 7.5mg/kg to 20mg/kg / 2 weeks median, f. up 14 months well tolerated positive effects on lung, cytopenia,+/- liver better when treated early, high dose
18 Targeted therapies IL1 inhibitor autoinflammatory syndromes JAK1,2 inhibitors STING gof STAT1 gof IL6 inhibitor STAT3 gof CTLA4 Ig CTLA4, LRBA deficiencies PI3Kd inhibitors PI3K gof (APDS) mtorc inhibitors mtorc inhibitors FAS, FASL (ALPS) lof : loss of function, gof : gain of function
19 Phosphoinositide 3 kinase signaling pathway and PID TCR/BCR CD28 PIP2 PIP3 p85 a,b.. P110d gof mutations APDS 1,2 AKT-P Ongoing trials PI3K inhibitor mtor proliferation, activation lymphoproliferation,autoimmunity senescence
20 Treatment of APDS with a PI3Kd inhibitor 6 pts 12 weeks PI3Kd inhibitor (leniolisib) Improvement of lymphoproliferation Normalization of transitional and naive B cells Decreased serum IgM Reduction of senecent T cells Another trial (UCB) But,
21 A potential risk of PI3Kd inhibitor? (CLL,..) Nature 2017
22 A risk of PI3Kd inhibitor usage to treat APDS? et al Nature 2017 pre post Mutations frequency Patients with CLL treated by a PI3Kd inhibitor Cautious usage, restricted to a prehsct period?
23 PID, monogenic diseases and autoimmunity Targeted therapeutics Hematopoietic stem cell transplantation? European data base since PID pts, 5503 transplants 88 centers, 26 countries 110 pts with autoimmunity as predominant manifestation
24 HSCT for PIDs in Europe Autoimmune/inflammatory PIDs Disease n patients IPEX 35 IPEX, FOXP3 18 IPEXlike 17 Inflammatory bowel disease 23 IL10 10 IL10RA 2 IL10RB 9 UNKNOWN 2 ALPS 18 CTLA4 deficiency 10 LRBA deficiency 3 STAT3 GOF 6 Other PID with AI 15 Total 110
25 HSCT for PIDs in Europe Results: Autoimmune/inflammatory PIDs n MSD MMRD MUD MMUD Alive Died Alive Died Alive Died Alive Died median Fup (years) n median Fup (years) n median Fup (years) n median Fup (years) IPEX 7 1, IBD ALPS CTLA4/LRBA STAT3 GOF 1 na 1 na Other Total Need for detailed analysis, but rather encouraging!
26 Classic immunosuppression, targeted therapy, HSCT? Disease by disease (extra hematopoietic manifestations..) Patient by patient: severity course, type of manifestations Drugs toxicity (short/long term) Donor availability Studies required +++ Short term versus long term strategy, i.e. targeted then HSCT?
27 F. Rieux Laucat A. Magerus-Chatinet N. Jeremiah L. Barnabei M. Moncan MC. Stolzenberg G. De Saint Basile S. Kracker B. Bader-Meunier P. Quartier E. Levy CM. Besnard B. Neven D. Moshous Y. Crow ML. Fremond N. Mahlaoui J. Provot JP. Jais A. Alcais A. Lankaster V. Courteille All centers! C Picard
28 Risk persists all over life!
29 Occurrence of autoimmune/inflammatory events as a function of PID diagnosis group and age
30 HSCT for PIDs in Europe Autoimmune/inflammatory PIDs & donor MSD MRD MMRD MUD MMUD na Total IPEX IBD ALPS CTLA4/LRBA STAT3 GOF Other Total
31 HSCT for PIDs in Europe Autoimmune/inflammatory PIDs Total ALPS CTLA4 LRBA IBD IPEX STAT3 GOF OTHER Total
32 HSCT for PIDs in Europe Autoimmune/inflammatory PIDs & country IPEX IBD ALPS CTLA4 d. LRBA d. STAT3 GOF Other PID with AI Total Austria 1 1 Belgium 1 2 Czech rep Denmark 1 1 France Germany Hungary 1 1 Italy 3 3 Poland Russia 1 1 Spain 2 2 Sweden 1 1 Switzerland 1 1 The Netherlands 1 1 Turkey 2 2 UK Total
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