Antisynthetase syndrome

Summary

Antisynthetase syndrome (MONDO:0019344) is a disease with 2 cohort genes and 12 clinical trials. Top therapeutic interventions include azathioprine, cyclophosphamide anhydrous, and efgartigimod alfa.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 4
• Phenotypes (HPO): 44
• Clinical trials: 12

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3.5	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

44 HPO clinical features (Orphanet curated; top 44 by frequency):

HPO ID	Term	Frequency
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002206	Pulmonary fibrosis	Very frequent (80-99%)
HP:0002960	Autoimmunity	Very frequent (80-99%)
HP:0003326	Myalgia	Very frequent (80-99%)
HP:0006530	Abnormal pulmonary interstitial morphology	Very frequent (80-99%)
HP:0012735	Cough	Very frequent (80-99%)
HP:0100614	Myositis	Very frequent (80-99%)
HP:0100749	Chest pain	Very frequent (80-99%)
HP:0000217	Xerostomia	Frequent (30-79%)
HP:0000969	Edema	Frequent (30-79%)
HP:0001097	Keratoconjunctivitis sicca	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001369	Arthritis	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003457	EMG abnormality	Frequent (30-79%)
HP:0030880	Raynaud phenomenon	Frequent (30-79%)
HP:0034143	Anti-threonyl-tRNA synthetase antibody positivity	Frequent (30-79%)
HP:0034145	Anti-alanyl-tRNA synthetase antibody positivity	Frequent (30-79%)
HP:0034146	Anti-glycyl tRNA-synthetase antibody positivity	Frequent (30-79%)
HP:0034147	Anti-aminoacyl-tRNA synthetase antibody positivity	Frequent (30-79%)
HP:0034148	Anti-isoleucyl tRNA-synthetase antibody positivity	Frequent (30-79%)
HP:0034149	Anti-phenylalanyl tRNA synthetase antibody positivity	Frequent (30-79%)
HP:0034150	Anti-tyrosyl-tRNA synthetase antibody positivity	Frequent (30-79%)
HP:0034151	Anti-asparaginyl-tRNA synthetase antibody positivity	Frequent (30-79%)
HP:0034152	Anti-histidyl tRNA synthetase antibody positivity	Frequent (30-79%)
HP:0034153	Anti-cytosolic-5-nucleotidase-1A antibody positivity	Frequent (30-79%)
HP:0100679	Lack of skin elasticity	Frequent (30-79%)
HP:0000988	Skin rash	Occasional (5-29%)
HP:0000989	Pruritus	Occasional (5-29%)
HP:0001373	Joint dislocation	Occasional (5-29%)
HP:0001608	Abnormality of the voice	Occasional (5-29%)
HP:0001659	Aortic regurgitation	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002664	Neoplasm	Occasional (5-29%)
HP:0012819	Myocarditis	Occasional (5-29%)
HP:0100585	Telangiectasia of the skin	Occasional (5-29%)
HP:6001013	Mechanic’s hands	Occasional (5-29%)
HP:6001014	Hiker’s feet	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	antisynthetase syndrome
Mondo ID	MONDO:0019344
EFO	EFO:1001982
MeSH	C537778
Orphanet	81
DOID	DOID:0080744
ICD-11	1572057936
SNOMED CT	445187004
UMLS	C5959873
MedGen	1866768
GARD	0000735
MedDRA	10068801
NORD	1926
Is cancer (heuristic)	no

Also known as: anti-Jo1 syndrome · AS syndrome

Data availability: 4 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › acquired skeletal muscle disease › acquired idiopathic inflammatory myopathy › antisynthetase syndrome

Related subtypes (8): eosinophilic fasciitis, immune-mediated necrotizing myopathy, overlap myositis, inflammatory myopathy with abundant macrophages, idiopathic eosinophilic myositis, juvenile idiopathic inflammatory myopathy, focal myositis, polymyositis

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:

2 association, 1 benign; risk factor, 1 benign; affects; association; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
30126	NC_000011.10:g.1219991G>T	MUC5B	Benign; risk factor	criteria provided, multiple submitters, no conflicts
869138	NC_000002.12:g.112837290A>G	IL1B	association	no assertion criteria provided
869139	NC_000002.12:g.112838252C>G	IL1B	association	no assertion criteria provided
869137	NM_000576.3(IL1B):c.315C>T (p.Phe105=)	IL1B	Benign; Affects; association; other	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MUC5B	Orphanet:171700	Diffuse panbronchiolitis
MUC5B	Orphanet:2032	Idiopathic pulmonary fibrosis
MUC5B	Orphanet:686465	Fibrotic hypersensitivity pneumonitis

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
IL1B	HGNC:5992	ENSG00000125538	P01584	Interleukin-1 beta	clinvar
MUC5B	HGNC:7516	ENSG00000117983	Q9HC84	Mucin-5B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL1B	Interleukin-1 beta	Potent pro-inflammatory cytokine.
MUC5B	Mucin-5B	Gel-forming mucin that is thought to contribute to the lubricating and viscoelastic properties of whole saliva and cervical mucus.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL1B	Other/Unknown	no		IL-1_fam, IL-1_propep, IL1/FGF
MUC5B	Other/Unknown	no		VWF_dom, VWF_type-D, TIL_dom

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
granulocyte	1
monocyte	1
periodontal ligament	1
gall bladder	1
mucosa of transverse colon	1
trachea	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL1B	228	ubiquitous	marker	periodontal ligament, granulocyte, monocyte
MUC5B	171	tissue_specific	marker	trachea, gall bladder, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL1B	8,564
MUC5B	2,659

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IL1B	P01584	64
MUC5B	Q9HC84	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. 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
CASP4-mediated substrate cleavage	1	1142.0×	0.009	IL1B
CASP5-mediated substrate cleavage	1	1142.0×	0.009	IL1B
CLEC7A/inflammasome pathway	1	951.7×	0.009	IL1B
Interleukin-1 processing	1	634.4×	0.010	IL1B
Defective GALNT3 causes HFTC	1	356.9×	0.011	MUC5B
Defective GALNT12 causes CRCS1	1	356.9×	0.011	MUC5B
Defective C1GALT1C1 causes TNPS	1	335.9×	0.011	MUC5B
Termination of O-glycan biosynthesis	1	248.3×	0.011	MUC5B
Pyroptosis	1	211.5×	0.011	IL1B
Dectin-2 family	1	211.5×	0.011	MUC5B
Purinergic signaling in leishmaniasis infection	1	211.5×	0.011	IL1B
C-type lectin receptors (CLRs)	1	119.0×	0.016	MUC5B
Interleukin-10 signaling	1	116.5×	0.016	IL1B
Diseases associated with O-glycosylation of proteins	1	107.7×	0.017	MUC5B
O-linked glycosylation of mucins	1	92.1×	0.018	MUC5B
O-linked glycosylation	1	72.3×	0.022	MUC5B
Diseases of glycosylation	1	65.6×	0.022	MUC5B
Interleukin-1 signaling	1	62.1×	0.022	IL1B
Interleukin-4 and Interleukin-13 signaling	1	51.4×	0.025	IL1B
Diseases of metabolism	1	40.2×	0.031	MUC5B
Innate Immune System	1	12.8×	0.092	MUC5B
Post-translational protein modification	1	9.6×	0.115	MUC5B
Disease	1	6.5×	0.155	MUC5B
Immune System	1	6.5×	0.155	MUC5B
Metabolism of proteins	1	6.2×	0.155	MUC5B

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
positive regulation of cell adhesion molecule production	1	8426.0×	0.003	IL1B
positive regulation of T cell mediated immunity	1	4213.0×	0.003	IL1B
positive regulation of complement activation	1	4213.0×	0.003	IL1B
regulation of nitric-oxide synthase activity	1	4213.0×	0.003	IL1B
positive regulation of RNA biosynthetic process	1	4213.0×	0.003	IL1B
negative regulation of gap junction assembly	1	4213.0×	0.003	IL1B
fever generation	1	2808.7×	0.003	IL1B
monocyte aggregation	1	2808.7×	0.003	IL1B
negative regulation of single-species biofilm formation in or on host organism	1	2808.7×	0.003	MUC5B
smooth muscle adaptation	1	2106.5×	0.003	IL1B
positive regulation of fever generation	1	2106.5×	0.003	IL1B
negative regulation of adiponectin secretion	1	2106.5×	0.003	IL1B
positive regulation of platelet-derived growth factor receptor signaling pathway	1	1685.2×	0.003	IL1B
negative regulation of D-glucose transmembrane transport	1	1685.2×	0.003	IL1B
hyaluronan biosynthetic process	1	1685.2×	0.003	IL1B
negative regulation of lipid metabolic process	1	1685.2×	0.003	IL1B
positive regulation of tight junction disassembly	1	1685.2×	0.003	IL1B
positive regulation of immature T cell proliferation in thymus	1	1404.3×	0.004	IL1B
vascular endothelial growth factor production	1	1203.7×	0.004	IL1B
cellular response to interleukin-17	1	1203.7×	0.004	IL1B
regulation of defense response to virus by host	1	1053.2×	0.004	IL1B
positive regulation of T-helper 1 cell cytokine production	1	1053.2×	0.004	IL1B
positive regulation of prostaglandin biosynthetic process	1	936.2×	0.004	IL1B
positive regulation of prostaglandin secretion	1	936.2×	0.004	IL1B
positive regulation of lipid catabolic process	1	936.2×	0.004	IL1B
regulation of establishment of endothelial barrier	1	936.2×	0.004	IL1B
response to carbohydrate	1	842.6×	0.004	IL1B
negative regulation of synaptic transmission	1	842.6×	0.004	IL1B
positive regulation of heterotypic cell-cell adhesion	1	648.1×	0.005	IL1B
positive regulation of monocyte chemotactic protein-1 production	1	601.9×	0.005	IL1B

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
IL1B	POMALIDOMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IL1B	4	4
MUC5B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
POMALIDOMIDE	4	IL1B
LENALIDOMIDE	4	IL1B
IBERDOMIDE	3	IL1B
AVADOMIDE	2	IL1B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
IL1B	26	Binding:26

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

4 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)
POMALIDOMIDE	4	IL1B
LENALIDOMIDE	4	IL1B
IBERDOMIDE	3	IL1B
AVADOMIDE	2	IL1B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	IL1B
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MUC5B

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)
MUC5B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE3	2
PHASE2/PHASE3	2
PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05523167	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Study to Investigate the Efficacy and Safety of Efgartigimod PH20 SC in Adult Participants With Active Idiopathic Inflammatory Myopathy.
NCT05832034	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Add-on Intravenous Immunoglobulins in Early Myositis
NCT05979441	PHASE3	ENROLLING_BY_INVITATION	A Study to Assess the Long-term Safety and Efficacy of a Subcutaneous Formulation of Efgartigimod in Adults With Active Idiopathic Inflammatory Myopathy
NCT03770663	PHASE3	UNKNOWN	Cyclophosphamide and Azathioprine vs Tacrolimus in Antisynthetase Syndrome-related Interstitial Lung Disease
NCT07391605	PHASE2	RECRUITING	Descartes-08 in Autoantibody Myositis
NCT06613490	EARLY_PHASE1	RECRUITING	An Exploratory Clinical Study of CD19 CAR NK Cells for the Treatment of Refractory Antisynthetase Antibody Syndrome and Rheumatoid Arthritis
NCT05984394	Not specified	RECRUITING	Evaluation of Antigen-specific T Cells in Patients With Antisynthetase Syndrome and Interstitial Lung Disease
NCT07406932	Not specified	NOT_YET_RECRUITING	A Study on the Efficacy and Safety of JAK Inhibitors Versus Calcineurin Inhibitors as Initial Therapy for Interstitial Lung Disease Associated With Antisynthetase Syndrome
NCT04924465	Not specified	UNKNOWN	Evaluation of Interstitial Lung Disease Severity in Patients With Antisynthetase Syndrome According to Specific Autoantibodies Profile
NCT04941547	Not specified	UNKNOWN	Association Between Cancer and Anti-synthetase Syndrome
NCT05691725	Not specified	COMPLETED	Evaluation of Peripheral Neutrophils in Antisynthetase Syndrome
NCT05989399	Not specified	COMPLETED	Evaluation of Circulating Neutrophils in Antisynthetase Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AZATHIOPRINE	4	1
CYCLOPHOSPHAMIDE ANHYDROUS	4	1
EFGARTIGIMOD ALFA	4	1
HUMAN IMMUNOGLOBULIN G	4	1