Common variable Immunodeficiency

Transcription

1 Common variable Immunodeficiency In the time of next generation sequencing RCPA Sydney 2018 Klaus Warnatz

2 Disclosures I have received honoraria as a speaker from Shire, Biotest, CSL Behring, LFB Octapharma, Abbott, Pfizer, Merck, Roche. I have participated as a consultant on advisory boards of Baxter, Biotest, CSL Behring, Grifols, LFB. I have received scientific grants from Shire, Biotest, BMS.

3 Definition of CVID ESID register criteria 2014 At least one of the following: *increased infection rate *autoimmune manifestations *granulomatous disease Clinics HD CVID *unexplained polyclonal lymphoproliferation *affected family members with antibody deficiency Ig Serum AND relevant decrease of IgG and IgA with or w/o IgM reduction (at 2 time points; <2SD under the lower level of age matched controls); AND at least one of the following: *poor antibody response to vaccination (and/or absent Isohemagglutinins); i.e. missing protective titers despite recent vaccination Spec Ab/ B cells reduced switched memory B cells (<70% of age matched controls) AND exclusion of secondary hypogammaglobulinemia (s. separate list) AND diagnosis made after the 4. year of life (symptoms can present earlier) Age AND no evidence of a severe T cell deficiency Exclusion

4 The need for a new definition of CVID in Hypogamma LRBA NFkB1... CID ICOS CD19 CSR deficiencies sigad PIK3D GOF Hypogamma of Unknown origin CVID Agamma Bonilla et al, J Allergy Clin Immunol Pract. 2016; 4:38-59.

5 The deflaters view Hypogamma ICOS CTLA4 CD19 sigad CID CSR deficiencies Hypogamma of Unknown origin PIK3D GOF CVID Agamma Picard et al, IUIS PID J Clin Immunol. 2015; 35:

6 Are you no longer a car just because you are a Lamborghini? -cell but not everything with four wheels is a car. Nobody questions the concept of SCID despite genetic diagnoses. Undisclosed source

7 Stratifying the variable Defined by genetics Bona fide CVID CD19 TACI ICOS? Overlapping clinical presentation Usually CID LRBA CTLA-4 NF-kB 1 and 2 Hypomorphic RAG IL2RG reversion STAT1 and 3 GOF ADA2 PI3Kd PKCd Other Hypogamma CD21 BAFF-R incomplete

8 Why bother? Need for genetics? Family Differential diagnosis Impact on therapy expecially in complex CVID Illustrated by cases incomplete

9 Clinical presentation of CVID Overview 249/902 Patients Thrombozytopenia 57 Hemolyt. Anemia 23 Arthritis 19 Vitiligo 17 Celiac like disease 14 Diabetes mellitus 10 Crohn-like 7 Others... Others Autoimmune cytopenia Interstitielle Lungenerkrankung fehlt Skin Enteropathy The numbers in the bars represent absolute counts of patients. (N=902) Endocrinopathy Gathmann et al JACI 2014

10 Clinical classification of CVID There is a strong overlap of autoimmune and inflammatory manifestations Autoimmune cytopenia interstitial lung disease Lymphoproliferation DEFI Cohort (n=287) Chronic enteropathy Bronchiectasis infection only Liver disease Chronic sinusitis Granulomatous disease Mouillot et al J Clin Immunol 2010, Chapel et al JACI 2012

11 Immune dysregulation Pathogenic concepts Disturbed Selection RAG Di George Disturbed Activation ITK PI3Kd (GOF) STIM1 PKCd LAT NFkB1 Altered Treg homeostasis CD25, IL2? CTLA4, LRBA?, März 2018 Increased Danger signals IFN TLR? STAT1/STAT3 ADA2 2 GI Barrier

12 Case report Female patient History: 16y Glomerulonephritis, skin rash, previous AITP Further examination: Splenomegaly+ lymphadenopathy ANA+ DIAGNOSIS of Systemic Lupus Erythematosus Initiation of steroid and MMF therapy 18y Renal function well controlled Recurrent respiratory tract infection Mild Hypogammaglobulinemia B cell phenotype: Reduced switched memory B cells Suspected CVID Genetics: heterozygous GOF PIK3CD mutation E1021K Images are of another patient

13 Activating mutations in the PI(3)kinase catalytic subunit p110d APDS Lucas et al Nat Rev Immunol 2016

14 Activating mutations in the PI(3)kinase catalytic subunit p110d APDS Recurrent respiratory tract infection Bronchiectasis Herpes virus infections Lymphoproliferation Angulo et al Science 2013, Lucas et al Nat Immunol 2013 Coulter et al JACI 2017, Lucas et al Nat Rev Immunol 2016

15 Activating mutations in the PI(3)kinase catalytic subunit p110d APDS PI3Kd inhibitor mtor inhibitor Lucas et al Nat Rev Immunol 2016

16 Case report Female patient 10 y old girl with long-standing EVANS syndrome Therapy: Steroids and high dose immunoglobulins Daily Blood transfusion Chronic mucocutaneous candidiasis (nails, mouth, vagina) Chronic diarrhoea Interstitial lung disease with partial respiratory insufficiency Additional treatments: Rituximab, eculizumab, anakinra (2 HLH) Acquired aplastic anemia ATG and cyclosporine Genetics: STAT1E545K mutation leads to hyperphosphorylation of STAT1. Weihnacht et al JACI 2017, Higgins JACI 2015, Mössner et al J Infect dis 2016

17 Clinical Phenotype in STAT1 GOF Cohort Penetrance nearly 100% Toubiana et al Blood 2016

18 Clinical Phenotype in STAT1 GOF Cohort 5 female patients with SLE 1 patient with scleroderma 4 patients with celiac disease Autoantibodies in 66/157 (42%) 18 ANA 21 anti thyroid 8 anti enterocytes Autoantibodies also seen in asymptomatic carriers (17/84) mostly ANA Toubiana et al Blood 2016

19 Immunological Phenotype in STAT1 GOF Cohort Reduction of sw mem B cells IgG2 and IgG4 TH17 cells (but 18% normal) STAT1 hyperphosphorylation after stimulation with IFN Toubiana et al Blood 2016

20 Targeted therapies in STAT1 GOF Case report STAT1: cytokine and esp. IFN type 1 and 2 signaling Weihnacht et al JACI 2017, Higgins JACI 2015, Mössner et al J Infect dis 2016

21 Targeted therapies in STAT1 GOF Case report Weihnacht et al JACI 2017

22 Targeted therapies in STAT1 GOF Case report cure of Evans syndrome, CMC including diarrhoea and Improvement of Lung function Weihnacht et al JACI 2017

23 Case report female, *1993, Georgia Primary diagnosis 03/2009 with Evans syndrome (AIHA 2006, AITP 2007) Leukopenia 08/2011 (Hepato)Splenomegaly Lymphadenopathy Recurrent Pneumonias (5x since 2008) Lymphocytic interstitial pneumonitis with granulomatous disease and follicular Bronchiolitis (GLILD) Laboratory: Hypogammaglobulinemia Diagnosis: Common variable immunodeficiency CVID Further course: enteropathy and hepatopathy Genetics: CTLA4- insufficiency

24 CTLA4 insufficiency 130 mutation carriers penetrance 66%

25 CVID like disorders with immune dysregulation CTLA-4 insufficiency Clinical presentation Heterozygous insufficiency Kuehn et al Science 2014, Schubert et al Nat Med 2014

26 CTLA-4 insufficiency Therapy Steroids 70% Daily oral steroids 55% High dose/pulse steroid treatment 49% Immunoglobulins 63% Immunosupressants other than steroids 56% Rituximab 30% Abatacept/Belatacept Sirolimus 15% 14% Other Immunosuppressants 43% Prophylactic antibiotics 35% HSCT 14% 0% 10% 20% 30% 40% 50% 60% 70% 80% HSCT n= 12 Deceased Alive and well Long term remission Sirolimus Abatacept Rituximab n= 12 n= 13 n= 25 Response No data Response No response Response No response No data (Schwab et al. submitted) Courtesy of B. Grimbacher

27 Case report Female patient 37 y old patient 16y lymphadenopathy (biopsy no lymphoma), dermatitis 27-28y increased RTIs with a total of 2 pneumonias 29y Diagnosis of CVID: IgG 1.4g/l, IgA and IgM neg 30y Diagnosis of Autoimmune enteropathy (duodenal biopsy) 33y Diagnosis of Autoimmune hemolytic anemia presentation at the CCI: EUROClass B+smB-21lowTRhi, 3% CD45RA+ CD4 T cells, no additional signs of CID Splenomegaly, nodular regenerative hyperplasia of the liver, Noro pos, suspected GLILD 37y severe aphtosis of the mouth Therapy: ivig, steroids for AIHA Genetics: heterozygous NFKB1 frame-shift mutation Diagnosis of NF-kB1 haploinsufficiency

28 NFKB1 deficiency Multiple phenotypes Table of clinical manifestation in NFKB1 removed Because of unpublished data

29 NFKB1 deficiency Multiple phenotypes Kaustio et al JACI 2017

30 Molecular screening of patients with antibody deficiency Impact of Next Generation Sequencing (NGS) N = 451 patients 114 (25%) with informative mutation Michele Proietti, Jessica Rojas, Bodo Grimbacher CCI Genetics Unit

31 Extended diagnostics for humoral ID Assays to screen for monogenetic disorders with CVID-like presentation APDS: ps6 in fresh blood samples CTLA4: to be determined PKCd: to be determined NFkB1: to be determined NFkB2: to be determined STAT1 GOF: ex vivo and pstat1 after IFNg/IFNa stimulation STAT3 GOF: pstat3 not as reliable, SOCS3 mrna, very low IgE IKAROS: To be determined LRBA: Protein staining ADA2: enzyme activity in dry plasma spots Johnson et al Clin Chem 2016

32 Therapeutic implications Targeting therapies HSCT? Evolving pathogenic concepts allow employing new targeted therapies: mtor inhibition PI3K inhibition (for PI3Kd GOF) CTLA4-Ig (CTLA4 /LRBA) RTX (PKCd, CTLA4?) PI3K-inhibitors Specific PI3Kd Abatacept JAK inhibition (Stat-1 GOF, STING,??) TNF inhibition (ADA2) Adapted from Krummey and Ford, Front Immunol, 2012

33 Summary 30-50% of CVID patients show signs of Immune dysregulation (complex form). Immune dysregulation manifests often as autoimmune, inflammatory and lymphoproliferative manifestations. There are different pathogenetic concepts leading to similar manifestations. Several are associated with monogenic disorders like CTLA4 insufficiency, NFKB1/2, STAT1/3 GOF, APDS, (TACI), DADA Because of the overlap of different monogenic disorders, the lack of good diagnostic tests in several cases and the potential impact of a precise diagnosis for the individual and his family NGS should be used for the genetic evaluation of patients presenting with immune dysregulation.

34 Summary cont The need to modulate rather than suppress the immune system is especially valid in this cohort of patients calling for targeted therapies. Management decisions need to be based on all three aspects of clinical, immunological and genetic diagnosis. The clinical presentation leads in most cases of adult PID, but the immunological and genetic diagnosis shall help to adjust the treatment and we need predictive markers. The increasing comprehension of the pathogenic mechanisms will allow tailoring therapies: B cell depletion, mtor inhibition, JAK inhibition (?), CTLA4-Ig, Alternatively also stem cell transplantation which is still performed too late in many CVID patients.

35 Thank you for your attention Prof. Dr. S. Ehl, Prof. B. Grimbacher Prof. Dr. Reinhard Voll AG Warnatz S. Gutenberger I.Stumpf B. Keller S. Unger E.Lee D.Friedmann AG Eibel AG Schamel, Biologie UNI Fr External Collaborations: JL Pasquali, Strassbourg, F AG Grimbacher Inst. of Pathology UK Fr K. Boztug CEMM Vienna, Austria M van der Burg, Erasmus Univ. Rotterdam, NL M.Seidl, G.Kayser P. A. Stepenski, Hadassah Univ., Jerusalem, Israel M.Rizzi A. Schmitt-Graeff, M. Werner Sponsors: DFG TRR130, Trilateral, DACH, BMBF Klaus.warnatz@uniklinik-freiburg.de CVID Outpatient: S. Goldacker C. Echternach M.Klima M. Erler Immune Diagnostics: U.Salzer C.Spee-Mayer