Standard immunomodulatory and targeted immunotherapies for management of AICs in IEIs
| Genetic defect . | Key clinical features . | Standard immunomodulatory agents . | Targeted therapy . | Target . |
|---|---|---|---|---|
| CTLA4 | AICs, lymphadenopathy, splenomegaly, hypogammaglobulinemia, other organ-specific autoimmunity, lymphoid infiltration of organs, enteropathy, interstitial lung disease | Steroids, sirolimus, CsA, ATG, antibiotics, immunoglobulin replacement, allogeneic HCT | Abatacept rituximab, vedolizumab, anti-TNFα agents | CTLA-4–immunoglobulin anti-CD20 (B cell depleting), α4-β7 integrin TNF-alpha blocker |
| LRBA | AICs, lymphadenopathy, splenomegaly, hypogammaglobulinemia, other organ-specific autoimmunity, lymphoid infiltration of organs, enteropathy with failure to thrive, interstitial lung disease | Steroids, sirolimus, antibiotics, immunoglobulin replacement, allogeneic HCT | Abatacept anti-TNFα agents | CTLA4-Ig, TNFα blocker |
| PI3KCD GOF | Recurrent respiratory infections, bronchiectasis, herpes virus infections, lymphadenopathy, splenomegaly, autoimmune or autoinflammatory manifestations, lymphoid hyperplasia, increased incidence of lymphomas | Steroids, MMF, sirolimus, antibiotics, immunoglobulin replacement, allogeneic HCT | Leniolisib, idelalisib, nemiralisib, ustekinumab | PI3Kδ inhibitor |
| IL-12/23 inhibitor | ||||
| ALPS | Chronic lymphadenopathy, splenomegaly, AICs, increased risk of lymphoma | Steroids, MMF, sirolimus, splenectomy in rare cases and should be avoided, if possible | Rituximab | Anti-CD20 (B cell depleting) |
| PRF1, UNC13D, STX11, STXBP2, RAB27A, LYST* | Hemophagocytosis, fever, splenomegaly, liver dysfunction, inflammatory phenotype with elevated biomarkers, CNS complications in some patients | Dexamethasone, etoposide, CsA, or hydrocortisone with intrathecal methotrexate, allogeneic HCT | Emapalumab-lszg | IFNγ blocker |
| Tadekinig alfa | IL-18BP to neutralize IL-18 | |||
| GATA2 | Viral and bacterial infections, cytopenias, myelodysplasia, myeloid leukemias, pulmonary alveolar proteinosis, lymphedema (Emberger syndrome) | Antibiotics and management of pulmonary disease, allogeneic HCT | None currently | — |
| DKC1, RTEL1, TERC, TERT, other DC gene defects | Triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia in many but not all patients, bone marrow failure, short telomeres, increased risk of malignancies; adult patients have increased risk of idiopathic pulmonary fibrosis and cryptogenic cirrhosis | Allogeneic HCT | Although androgens such as danazol have been used, it is controversial and often not recommended | — |
| CXCR4 GOF | Warts, hypogammaglobulinemia, recurrent respiratory infections, myelokathexis | Immunoglobulin replacement, G-CSF | Plerixafor (AMD3100) | Inhibitor of CXCR4 binding to CXCL12 |
| XIAP | HLH-like features, inflammatory bowel disease, cytopenias, splenomegaly | Allogeneic HCT | Tadekinig alfa | IL-18BP to neutralize IL-18 |
| WAS* | Microthrombocytopenia, eczema, diarrhea, recurrent infections, autoimmunity, increased risk of malignancies, IgA nephropathy, neutropenia with myelodysplasia (GOF variant) | Antibiotics, CsA, cyclophosphamide, high-dose immunoglobulin therapy, steroids, azathioprine, splenectomy, platelet transfusion, allogeneic HCT | Rituximab | Anti-CD20 (B cell depleting) |
| STAT3 GOF | Broad range of autoimmunity, including AICs, lymphoproliferation, hypogammaglobulinemia, enteropathy, interstitial lung disease | Steroids, MMF, tacrolimus, azathioprine, sirolimus, CsA, cyclophosphamide, methotrexate, allogeneic HCT | Anti-TNFα agents, anti-IL1β agents, tocilizumab, ruxolitinib | TNFα blocker, IL-1R antagonist, IL-6R blocker, JAK1/JAK2/STAT inhibitor |
| STK4/MST1 | Overlap with DOCK8 deficiency in some patients, molluscum, warts, bacterial infections, AICs | Antibiotics, antifungals, antivirals, allogeneic HCT | None currently | — |
| Genetic defect . | Key clinical features . | Standard immunomodulatory agents . | Targeted therapy . | Target . |
|---|---|---|---|---|
| CTLA4 | AICs, lymphadenopathy, splenomegaly, hypogammaglobulinemia, other organ-specific autoimmunity, lymphoid infiltration of organs, enteropathy, interstitial lung disease | Steroids, sirolimus, CsA, ATG, antibiotics, immunoglobulin replacement, allogeneic HCT | Abatacept rituximab, vedolizumab, anti-TNFα agents | CTLA-4–immunoglobulin anti-CD20 (B cell depleting), α4-β7 integrin TNF-alpha blocker |
| LRBA | AICs, lymphadenopathy, splenomegaly, hypogammaglobulinemia, other organ-specific autoimmunity, lymphoid infiltration of organs, enteropathy with failure to thrive, interstitial lung disease | Steroids, sirolimus, antibiotics, immunoglobulin replacement, allogeneic HCT | Abatacept anti-TNFα agents | CTLA4-Ig, TNFα blocker |
| PI3KCD GOF | Recurrent respiratory infections, bronchiectasis, herpes virus infections, lymphadenopathy, splenomegaly, autoimmune or autoinflammatory manifestations, lymphoid hyperplasia, increased incidence of lymphomas | Steroids, MMF, sirolimus, antibiotics, immunoglobulin replacement, allogeneic HCT | Leniolisib, idelalisib, nemiralisib, ustekinumab | PI3Kδ inhibitor |
| IL-12/23 inhibitor | ||||
| ALPS | Chronic lymphadenopathy, splenomegaly, AICs, increased risk of lymphoma | Steroids, MMF, sirolimus, splenectomy in rare cases and should be avoided, if possible | Rituximab | Anti-CD20 (B cell depleting) |
| PRF1, UNC13D, STX11, STXBP2, RAB27A, LYST* | Hemophagocytosis, fever, splenomegaly, liver dysfunction, inflammatory phenotype with elevated biomarkers, CNS complications in some patients | Dexamethasone, etoposide, CsA, or hydrocortisone with intrathecal methotrexate, allogeneic HCT | Emapalumab-lszg | IFNγ blocker |
| Tadekinig alfa | IL-18BP to neutralize IL-18 | |||
| GATA2 | Viral and bacterial infections, cytopenias, myelodysplasia, myeloid leukemias, pulmonary alveolar proteinosis, lymphedema (Emberger syndrome) | Antibiotics and management of pulmonary disease, allogeneic HCT | None currently | — |
| DKC1, RTEL1, TERC, TERT, other DC gene defects | Triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia in many but not all patients, bone marrow failure, short telomeres, increased risk of malignancies; adult patients have increased risk of idiopathic pulmonary fibrosis and cryptogenic cirrhosis | Allogeneic HCT | Although androgens such as danazol have been used, it is controversial and often not recommended | — |
| CXCR4 GOF | Warts, hypogammaglobulinemia, recurrent respiratory infections, myelokathexis | Immunoglobulin replacement, G-CSF | Plerixafor (AMD3100) | Inhibitor of CXCR4 binding to CXCL12 |
| XIAP | HLH-like features, inflammatory bowel disease, cytopenias, splenomegaly | Allogeneic HCT | Tadekinig alfa | IL-18BP to neutralize IL-18 |
| WAS* | Microthrombocytopenia, eczema, diarrhea, recurrent infections, autoimmunity, increased risk of malignancies, IgA nephropathy, neutropenia with myelodysplasia (GOF variant) | Antibiotics, CsA, cyclophosphamide, high-dose immunoglobulin therapy, steroids, azathioprine, splenectomy, platelet transfusion, allogeneic HCT | Rituximab | Anti-CD20 (B cell depleting) |
| STAT3 GOF | Broad range of autoimmunity, including AICs, lymphoproliferation, hypogammaglobulinemia, enteropathy, interstitial lung disease | Steroids, MMF, tacrolimus, azathioprine, sirolimus, CsA, cyclophosphamide, methotrexate, allogeneic HCT | Anti-TNFα agents, anti-IL1β agents, tocilizumab, ruxolitinib | TNFα blocker, IL-1R antagonist, IL-6R blocker, JAK1/JAK2/STAT inhibitor |
| STK4/MST1 | Overlap with DOCK8 deficiency in some patients, molluscum, warts, bacterial infections, AICs | Antibiotics, antifungals, antivirals, allogeneic HCT | None currently | — |
ATG, antithymocyte globulin; CNS, central nervous system; CsA, cyclosporin A; DC, dyskeratosis congenita; G-CSF, granulocyte colony-stimulating factor; GOF, gain of function; HLH, hemophagocytic lymphohistiocytosis; MMF, mycophenolate mofetil; PI3Kδ, phosphatidylinositol 3-kinase δ; TNFα, tumor necrosis factor α; WAS, Wiskott-Aldrich syndrome.
Experimental gene therapy is being considered or in early stages for HLH or WAS.