Autoimmune hemolytic anemia

Summary

Autoimmune hemolytic anemia (MONDO:0020108) is a disease (an umbrella term covering 7 Mondo subtypes) with 2 cohort genes and 53 clinical trials. Top therapeutic interventions include acalabrutinib, luspatercept, and tacrolimus anhydrous.

At a glance

• Prevalence: 1-5 / 10 000 (Denmark) [Orphanet-validated]
• Umbrella term: 7 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 4
• Clinical trials: 53

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	2.02	Europe	Validated
Annual incidence	1-9 / 100 000	2.02	United States	Validated
Point prevalence	1-5 / 10 000	11	Denmark	Validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autoimmune hemolytic anemia
Mondo ID	MONDO:0020108
EFO	EFO:1001264
MeSH	D000744
OMIM	205700
Orphanet	98375
DOID	DOID:718
ICD-11	1834341306
NCIT	C34378
SNOMED CT	413603009
UMLS	C0002880
MedGen	1918
GARD	0005870
MedDRA	10002046
NORD	774
Is cancer (heuristic)	no

Also known as: acquired autoimmune hemolytic anaemia · acquired autoimmune hemolytic anemia · AHA · AIHA · anaemia hemolytic autoimmune · anemia hemolytic autoimmune · Anemia, Hemolytic, Acquired Autoimmune · autoimmune haemolytic anemia · autoimmune hemolytic anemia · familial auto-immune hemolytic anaemia (subtype) · familial auto-immune hemolytic anemia (subtype) · idiopathic autoimmune hemolytic anaemia · idiopathic autoimmune hemolytic anemia · immuno-hemolytic anaemia · immuno-hemolytic anemia

Data availability: 4 ClinVar variants · 6 cell lines.

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › autoimmune disorder of blood › autoimmune hemolytic anemia

Related subtypes (1): primary thrombocytopenia

Subtypes (7): Evans syndrome, autoimmune hemolytic anemia, cold type, neonatal autoimmune hemolytic anemia, autoimmune hemolytic anemia, warm type, mixed-type autoimmune hemolytic anemia, drug-induced autoimmune hemolytic anemia, giant cell hepatitis with autoimmune hemolytic anemia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

3 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
977213	NM_003745.2(SOCS1):c.24del (p.Ala9fs)	LOC130058479	Pathogenic	criteria provided, single submitter
977214	NM_003745.2(SOCS1):c.476_480dup (p.Met161fs)	SOCS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1339649	NM_138636.5(TLR8):c.1715G>T (p.Gly572Val)	TLR8	Pathogenic	criteria provided, single submitter
1339650	NM_138636.5(TLR8):c.2498T>C (p.Phe833Ser)	TLR8	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TLR8	Orphanet:675628	TLR8-related inflammation-severe neutropenia-bone marrow failure-lymphoproliferation syndrome
SOCS1	Orphanet:619948	Early-onset autoimmunity-autoinflammation-immunodeficiency syndrome due to SOCS1 haploinsufficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TLR8	HGNC:15632	ENSG00000101916	Q9NR97	Toll-like receptor 8	clinvar
SOCS1	HGNC:19383	ENSG00000185338	O15524	Suppressor of cytokine signaling 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TLR8	Toll-like receptor 8	Endosomal receptor that plays a key role in innate and adaptive immunity.
SOCS1	Suppressor of cytokine signaling 1	Essential negative regulator of type I and type II interferon (IFN) signaling, as well as that of other cytokines, including IL2, IL4, IL6 and leukemia inhibitory factor (LIF).

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TLR8	Other/Unknown	no		TIR_dom, Cys-rich_flank_reg_C, Leu-rich_rpt
SOCS1	Scaffold/PPI	no		SH2, SOCS_box, SOCS1_SH2

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1
endocervix	1
sperm	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TLR8	174	broad	marker	monocyte, mononuclear cell, leukocyte
SOCS1	211	ubiquitous	marker	type B pancreatic cell, sperm, endocervix

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TLR8	3,532
SOCS1	3,435

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TLR8	Q9NR97	39

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SOCS1	O15524	84.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Trafficking and processing of endosomal TLR	1	407.9×	0.019	TLR8
Regulation of IFNG signaling	1	407.9×	0.019	SOCS1
Regulation of KIT signaling	1	300.5×	0.019	SOCS1
Signaling by CSF3 (G-CSF)	1	285.5×	0.019	SOCS1
Growth hormone receptor signaling	1	237.9×	0.019	SOCS1
Regulation of IFNA/IFNB signaling	1	219.6×	0.019	SOCS1
Inactivation of CSF3 (G-CSF) signaling	1	219.6×	0.019	SOCS1
Interleukin-7 signaling	1	158.6×	0.024	SOCS1
Signaling by SCF-KIT	1	124.1×	0.026	SOCS1
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	92.1×	0.026	TLR8
Toll Like Receptor TLR6:TLR2 Cascade	1	87.8×	0.026	SOCS1
Toll Like Receptor 2 (TLR2) Cascade	1	86.5×	0.026	SOCS1
Toll Like Receptor TLR1:TLR2 Cascade	1	84.0×	0.026	SOCS1
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1	76.1×	0.026	SOCS1
Interferon alpha/beta signaling	1	76.1×	0.026	SOCS1
Toll Like Receptor 4 (TLR4) Cascade	1	65.6×	0.026	SOCS1
Interferon gamma signaling	1	62.8×	0.026	SOCS1
Toll-like Receptor Cascades	1	62.1×	0.026	SOCS1
Interferon Signaling	1	60.1×	0.026	SOCS1
Interleukin-4 and Interleukin-13 signaling	1	51.4×	0.029	SOCS1
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	44.6×	0.032	TLR8
Class I MHC mediated antigen processing & presentation	1	35.0×	0.039	SOCS1
Signaling by Interleukins	1	32.1×	0.040	SOCS1
Signaling by Receptor Tyrosine Kinases	1	25.8×	0.048	SOCS1
Cytokine Signaling in Immune system	1	20.4×	0.058	SOCS1
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.061	SOCS1
Adaptive Immune System	1	14.9×	0.073	SOCS1
Innate Immune System	1	12.8×	0.082	SOCS1
Immune System	1	6.5×	0.153	SOCS1
Signal Transduction	1	5.1×	0.187	SOCS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
toll-like receptor 8 signaling pathway	1	2808.7×	0.005	TLR8
negative regulation of CD8-positive, alpha-beta T cell differentiation	1	2808.7×	0.005	SOCS1
positive regulation of CD4-positive, alpha-beta T cell differentiation	1	1404.3×	0.007	SOCS1
positive regulation of regulatory T cell differentiation	1	468.1×	0.012	SOCS1
negative regulation of receptor signaling pathway via JAK-STAT	1	443.5×	0.012	SOCS1
immunoglobulin mediated immune response	1	351.1×	0.012	TLR8
positive regulation of interferon-alpha production	1	324.1×	0.012	TLR8
toll-like receptor signaling pathway	1	300.9×	0.012	TLR8
positive regulation of innate immune response	1	263.3×	0.013	TLR8
macrophage differentiation	1	234.1×	0.013	SOCS1
positive regulation of interferon-beta production	1	195.9×	0.013	TLR8
negative regulation of insulin receptor signaling pathway	1	187.2×	0.013	SOCS1
canonical NF-kappaB signal transduction	1	183.2×	0.013	TLR8
cellular response to amino acid stimulus	1	153.2×	0.014	SOCS1
cell surface receptor signaling pathway via JAK-STAT	1	145.3×	0.014	SOCS1
positive regulation of interleukin-1 beta production	1	129.6×	0.014	TLR8
regulation of cytokine production	1	123.9×	0.014	SOCS1
positive regulation of interleukin-8 production	1	122.1×	0.014	TLR8
positive regulation of type II interferon production	1	112.3×	0.014	TLR8
cellular response to mechanical stimulus	1	108.0×	0.014	TLR8
fat cell differentiation	1	90.6×	0.016	SOCS1
positive regulation of interleukin-6 production	1	83.4×	0.016	TLR8
response to virus	1	72.0×	0.018	TLR8
cytokine-mediated signaling pathway	1	65.3×	0.019	SOCS1
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.033	TLR8
defense response to virus	1	34.7×	0.033	TLR8
protein ubiquitination	1	20.7×	0.053	SOCS1
intracellular signal transduction	1	19.1×	0.054	SOCS1
inflammatory response	1	18.9×	0.054	TLR8
innate immune response	1	16.8×	0.059	TLR8

Therapeutics

Drugs indicated for this disease

1 approved, 7 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Sutimlimab	Approved (phase 4)
Cyclosporine	Phase 3 (in late-stage trials)
Ianalumab	Phase 3 (in late-stage trials)
Obexelimab	Phase 3 (in late-stage trials)
Parsaclisib	Phase 3 (in late-stage trials)
Pegcetacoplan	Phase 3 (in late-stage trials)
Prednisolone	Phase 3 (in late-stage trials)
Rituximab	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): ANX-005, Alemtuzumab, Batoclimab, Bendamustine, Bortezomib, Eculizumab, Fludarabine, Fostamatinib, Ibrutinib, Ixazomib, Nipocalimab, Prednisone, Rilzabrutinib, Sirolimus, Sovleplenib, Zanubrutinib.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TLR8	8	2
SOCS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VESATOLIMOD	2	TLR8
MOTOLIMOD	2	TLR8
RESIQUIMOD	2	TLR8
GSK-2245035	2	TLR8
SELGANTOLIMOD	2	TLR8
AFIMETORAN	2	TLR8
ENPATORAN	2	TLR8
MHV-370	2	TLR8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TLR8	395	Binding:378, Functional:16, ADMET:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TLR8	395

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

8 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
VESATOLIMOD	2	TLR8
MOTOLIMOD	2	TLR8
RESIQUIMOD	2	TLR8
GSK-2245035	2	TLR8
SELGANTOLIMOD	2	TLR8
AFIMETORAN	2	TLR8
ENPATORAN	2	TLR8
MHV-370	2	TLR8

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	TLR8
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SOCS1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SOCS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 53.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	19
PHASE1	14
PHASE2	10
EARLY_PHASE1	4
PHASE3	3
PHASE1/PHASE2	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03918265	PHASE4	UNKNOWN	Tacrolimus Treatment for Refractory Autoimmune Cytopenia
NCT05057468	PHASE3	RECRUITING	Second-line Treatment of Primary Autoimmune Hemolytic Anemia
NCT07086976	PHASE3	RECRUITING	A Study to Investigate the Efficacy, Safety, and Pharmacokinetics of Oral Rilzabrutinib Compared With Placebo in Participants 18 Years of Age and Older With Warm Autoimmune Hemolytic Anemia
NCT05057481	PHASE3	UNKNOWN	Reappraisal of the Therapies of Refractory Autoimmune Hemolytic Anemia in Systemic Lupus Erythematosus
NCT04657094	PHASE2	ACTIVE_NOT_RECRUITING	Acalabrutinib for the Treatment of Relapsed or Refractory Autoimmune Hemolytic Anemia in Patients With Chronic Lymphocytic Leukemia
NCT05089227	PHASE2	RECRUITING	Efficacy of Prolonged Anticoagulation for Primary Prevention of Venous Thromboembolic Disease in Autoimmune Hemolytic Anemia: a Prospective, Phase II, Randomized, Multicenter Study
NCT05694312	PHASE2	RECRUITING	Ibrutinib for the Treatment of AIHA in Patients With CLL/SLL or CLL-like MBL
NCT07175493	PHASE1/PHASE2	RECRUITING	A Study of CM336 in Patients With Relapsed or Refractory Autoimmune Cytopenia
NCT07190261	PHASE2	NOT_YET_RECRUITING	A Single-arm Phase 2 Prospective Clinical Study of Enatumab in the Treatment of Relapsed/Refractory Warm Antibody Autoimmune Hemolytic Anemia
NCT07453368	PHASE2	NOT_YET_RECRUITING	Orelabrutinib in the Treatment of Relapsed/Refractory AIHA
NCT07603557	PHASE2	NOT_YET_RECRUITING	Study of Zola-cel (BMS-986353), in Participants With Autoimmune Cytopenia (Breakfree-AiCE)
NCT02389231	PHASE1/PHASE2	TERMINATED	Evaluating the Interest of Interleukine-2 for Patients With Active Warm Hemolytic Anemia Resistant to Conventional Treatment
NCT02689986	PHASE2	COMPLETED	Bendamustine and Rituximab Combination Therapy for Cold Agglutinin Disease
NCT03538041	PHASE2	COMPLETED	A Study of INCB050465 in Participants With Autoimmune Hemolytic Anemia
NCT04039477	PHASE2	WITHDRAWN	A Phase 2 Study to Evaluate the Safety and Efficacy of KZR-616 in Patients With AIHA and ITP
NCT04083014	PHASE2	COMPLETED	Single-dose Anti-CD20 Antibody With Bortezomib for Relapsed Refractory Autoimmune Hemolytic Anemia
NCT06231368	PHASE1	ACTIVE_NOT_RECRUITING	CNCT19 for Patients With Autoimmune Hemolytic Anemia After Failure ≥3 Lines of Therapy.
NCT06733610	PHASE1	RECRUITING	CAR T-cell Therapy Targeting CD19 and BCMA in Patients with AIHA Who Have Failed ≥3 Lines of Therapy.
NCT06770504	PHASE1	NOT_YET_RECRUITING	A Study of YTS109 Cell Injection in Subjects With Relapsed/Refractory Autoimmune Hemolytic Anemia
NCT06978738	PHASE1	NOT_YET_RECRUITING	UCAR T-cell Therapy Targeting CD19/ BCMA in Patients With Relapse/ Refractory Autoimmune Diseases
NCT07287930	PHASE1	NOT_YET_RECRUITING	A Study of YTS109 Cell in Subjects With Relapsed/Refractory Autoimmune Hemolytic Anemia
NCT07453836	PHASE1	NOT_YET_RECRUITING	Research on YTS109 Cell in Patients With Recurrent/Refractory Autoimmune Hemolytic Anemia
NCT07574073	PHASE1	NOT_YET_RECRUITING	CD20 Monoclonal Antibody Combined With BTK Inhibitor for the Treatment of Refractory Immune-related Cytopenia
NCT07585071	PHASE1	NOT_YET_RECRUITING	IASO206 in Patients With Relapsed/Refractory Autoimmune Hemolytic Anemia
NCT00001630	PHASE1	COMPLETED	Treatment of Autoimmune Thrombocytopenia (AITP)
NCT04269551	PHASE1	COMPLETED	A Safety and Tolerability Study of BIVV020 in Adults With Cold Agglutinin Disease
NCT04802057	PHASE1	TERMINATED	Safety and Tolerability Study in Adults With Cold Agglutinin Disease Previously Treated With SAR445088 or Never Treated With SAR445088
NCT05676697	PHASE1	TERMINATED	PI3K Delta Inhibitor in Relapsed / Refractory Autoimmune Hemolytic Anemia Patients After Receiving Two or More Lines of Therapy
NCT06212154	PHASE1	UNKNOWN	CAR-T for Autoimmune Hemolytic Anemia Patients Who Have Failed Three or More Lines of Therapy
NCT07075484	PHASE1	COMPLETED	A Study of YTS109 Cell in Subjects With Relapsed/Refractory Autoimmune Hemolytic Anemia
NCT06888960	EARLY_PHASE1	RECRUITING	Safety Study of CC312 in Autoimmune Disease Patients
NCT07205315	EARLY_PHASE1	RECRUITING	A Clinical Study Evaluating the Safety and Efficacy of GT801 Injection in Adult Patients With Relapsed/Refractory CD19-positive B-cell Hematologic Malignancies and Autoimmune Hemolytic Anemia
NCT07441525	EARLY_PHASE1	RECRUITING	UCAR-T Targeting CD19/BCMA in Subjects With Autoantibody-Mediated Autoimmune Benign Hematological Diseases
NCT05263817	EARLY_PHASE1	UNKNOWN	A Clinical Study of CD19/BCMA CAR-T Cells in the Treatment of Refractory POEMS Syndrome, Amyloidosis, Autoimmune Hemolytic Anemia, and Vasculitis
NCT02877706	Not specified	RECRUITING	French Registry of Adult Patients With Immune Thrombocytopenia and Autoimmune Hemolytic Anemia
NCT04005638	Not specified	RECRUITING	Biological Bank for the Patients Followed in a Constitutive Reference Center for Autoimmune Cytopenia
NCT04814394	Not specified	NOT_YET_RECRUITING	The Significance of Release of T-follicular Helper and T-follicular Regulatory Cells in Autoimmune Haemolytic Anemia Before and After Tratment
NCT05931718	Not specified	RECRUITING	Prospective Evaluation of Diagnosis and Treatment of Patients With Autoimmune Cytopenias Including Autoimmune Hemolytic Anemia, Immune Thrombocytopenia, and Chronic Idiopathic/Autoimmune Neutropenia
NCT05937828	Not specified	RECRUITING	OBS’CEREVANCE: French Cohort of Pediatric Autoimmune Cytopenia
NCT06921980	Not specified	RECRUITING	Brain Function and Psychological Changes Related to Cell Therapy for Autoimmune Hemolytic Anemia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ACALABRUTINIB	4	1
LUSPATERCEPT	4	1
TACROLIMUS ANHYDROUS	4	1
PARSACLISIB	3	2
RILIPRUBART	3	2
RILZABRUTINIB	3	1
LINPERLISIB	2	1
ZETOMIPZOMIB	2	1
ZOLACABTAGENE AUTOLEUCEL	1	1
CHEMBL4747506	0	1
CHEMBL5187554	0	1
CHEMBL5276925	0	1