New Biomarkers for Diagnosis and Follow-up of Patients With LRBA or CTLA4 Deficiencies

Study Overview
=================
Brief Summary
-----------------
Primary immune deficiencies (PID) are a group of chronic diseases characterized by recurrent infections. Apart from recurrent infections, in some of PIDs autoimmunity, allergy or malignancy could be accompanied to the diseases. Recently, the advanced sequencing technologies have led to the identification of a growing number of novel PIDs including the immune dysregulation syndromes caused by loss of function mutations in the LRBA (encoding lipopolysaccharide-responsive beige like anchor protein) and CTLA4 (encoding cytotoxic T lymphocyte antigen 4) genes, which are in common associated with autoimmunity in addition to a predisposition to recurrent infections. PIDs with autoimmune components usually tend to have a more protracted clinical course and poorer prognosis rendering early diagnosis and treatment more crucial. The accurate diagnosis largely relies on the molecular diagnosis due to the significant overlaps between the phenotypic expression of these various genetic defects. The project aims to provide better and early diagnosis for LRBA, CTLA4 deficiencies by using basic and advanced immunological, genetic and molecular assays and rendering an early targeting therapy for patients, discover disease related new pathways and biomarkers that can be helpful during diagnosis and monitoring abatacept targeted therapy responses.

Detailed Description
-----------------
Lipopolysaccharide-responsive beige-like anchor (LRBA) and cytotoxic T lymphocyte protein-4 (CTLA-4) deficiencies are primary immunodeficiency characterized by recurrent sinopulmonary infections with hypogammaglobulinemia, lymphoproliferation and immunodysregulation, which presents by enteropathy, cytopenias and autoimmune endocrinopathy. LRBA plays a pivotal role in the intracellular trafficking of by CTLA4 re-routing it away from lysosomal degradation and back to the cell surface. CTLA-4 is an key immune checkpoint protein that is constitutively expressed on fork-head box P3 (FOXP3)+ regulatory T (Treg) cells and is also induced upon activation of conventional T cells. LRBA deficiency results in very low CTLA4 expression, which explains the phenotypic overlap between LRBA and CTLA4 deficient subjects. Furthermore, reduced Treg cells number and function have been demonstrated in LRBA-deficient patients. Consequent upon this, LRBA deficiency may manifest as an IPEX like disease with early onset autoimmunity. LRBA was originally described as a common variable immune deficiency (CVID)-like disease with autoimmunity. To date, different agents have been applied in the treatment of LRBA and CTLA4 deficiencies, including corticosteroids, intravenous immunoglobulin therapy (IVIG), sirolimus, infliximab, rituximab and azathioprine. Some patients also benefit from hematopoietic stem cell transplantation (HSCT), which can be curative. More recently, studies have suggested the effectiveness of abatacept, a CTLA4-Ig fusion protein, in controlling disease-related immune dysregulatory phenotypes. In addition, some biomarkers like soluble CD25 and circulating T Follicular helper (cTFH) cells were described as useful to monitor patients' disease activity. Nevertheless, the long-term effectiveness of abatacept is not well documented. Also, there is no established consensus as to the dose and frequency of abatacept therapy for the treatment of those diseases and which biomarker is most reliable for follow up of patients. Aims of this current study include: Provide better and early diagnosis for LRBA, CTLA4 deficiencies by using basic and advanced immunological, genetic and molecular assays and rendering an early targeting therapy for patients. Discover disease related new pathways and biomarkers that can be helpful during diagnosis and monitoring abatacept targeted therapy responses.

Official Title
-----------------
Identification of New Immunopathogenic Mechanisms Associated With LRBA or CTLA4 Deficiencies

Conditions
-----------------
LRBA Deficiency, CTLA4 Haploinsufficiency

Intervention / Treatment
-----------------
* Drug: Abatacept Injection [Orencia]


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients diagnosed with LRBA and CTLA4 deficiencies and eligible for the study Patients accept consent to participate in this study and followed prospectively on abatacept treatment. Exclusion Criteria: History of hypersensitivity to abatacept History of acquired immunodeficiency diseases like HIV EBV viremia during the study screening Documented malignancy Current active infectious disease (bacterial or fungal) like tuberculosis Chronic hepatitis B or hepatitis C infections

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| LRBA deficient patients on abatacept<br>These patients will prospectively followed and biological samples collected at baseline as well as periodically every 3 months under therapy. Abatacept will be provided on an off-label basis upon approval of the physician's request of the drug by Turkish Medicines and Medical Devices Agency (TMMDA) of Turkish Ministry of Health. The dosage and interval of the drug is determined according to drug instructions provided by the drug company based on the weight of the patients. | Drug: Abatacept Injection [Orencia]<br>* Patients on abatacept to control disease symptoms<br>|
| CTLA4 haploinsufficient patients on abatacept<br>These patients will prospectively followed and biological samples collected at baseline as well as periodically every 3 months under therapy. Abatacept will be provided on an off-label basis upon approval of the physician's request of the drug by Turkish Medicines and Medical Devices Agency (TMMDA) of Turkish Ministry of Health. The dosage and interval of the drug is determined according to drug instructions provided by the drug company based on the weight of the patients. | Drug: Abatacept Injection [Orencia]<br>* Patients on abatacept to control disease symptoms<br>|
| Control group<br>Age matched healthy control group will be used during the study to determine the reference values of the immunological assays. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Efficacy of abatacept in normalizing symptoms of disease | The symptoms including lymphoproliferation, autoimmunity and chronic diarrhea should be controlled. | 3-9 months | 
| Clinical tolerability of abatacept in patients | Drug related side effects should not be observed (Severe viral or bacterial infections) | 1-24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Discontinuation of other immunosuppressants | Drug used before and after abatacept should be minimized | 3-12 months |