2 x 1mL micro-collect (minimum)
Normal result: Negative (all targets)
Service implemented: 1 August 2022
Assay: EUROLINE Autoimmune Inflammatory Myopathies 16 antigens with additional cN-1A and HMGCR (IgG).Platform: EUROBlot One
Methodology: Line Immunoassay
Idiopathic inflammatory myopathies cause inflammation of the skeletal musculature giving rise to accentuated muscle weakness. They are considered rare, having an incidence of 1-6 per 100,000 in a 2:1 female to male prevalence. Both adults and children can be affected. They can be divided into polymyositis [PM] (30%), dermatomyositis [DM] (30%), immune mediated necrotising myopathies [IMNM], sporadic inclusion body myositis [sIBM] and overlap myositis associated with other autoimmune diseases (20%), notably RA, SLE and MCTD. Often in elderly patients, DM and PM are paraneoplastic in origin, with symptoms often present before tumour detection.
Histologically, the myositidies can be purely diffuse interstitial without fibre destruction or focal damage with defined muscle fibre infiltrates and lesions.
PM is an inflammatory disease of the skeletal muscles with perivascular lymphocytic infiltration. Involvement of the skin transforms the disease to DM. Typical symptoms of PM are recurring bouts of fever, muscle weakness, arthralgia, difficulty swallowing, involvement of the inner organs and possibly Raynaud?s syndrome. In DM patients there is purple coloured exanthema on the eye lids, nose bridge and cheeks, periorbital oedema, local erythema and scaly eczema dermatitis.
Sporadic inclusion body myositis (sIBM) is part inflammatory, part degenerative. The accumulation of tau protein is identical to that found in Alzheimer?s patients. Although there is no cure and standard corticosteroid therapies are ineffective, rarely do afflicted patients die from sIBM, rather they die from complications of the myositis (e.g. pneumonia). The antibody cN-1A is considered a diagnostic marker for sIBM although antibodies are found in approximately 5% of healthy individuals.
Patients on statins may develop myopathy and symptoms disappear on discontinuation of statin medication. However, a small proportion develop antibodies to HMG-CoA reductase resulting in IMNM where discontinuation of statins is ineffective. HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) catalyses the conversion of HMG-CoA into mevalonic acid, an important step in cholesterol biosynthesis. The expression of HMGCR is upregulated by statins. Patients with anti-HMGCR myositis present with severe necrosis of the muscle fibres with only a few inflammatory infiltrates. Muscle weakness is present with high creatine kinase levels. Response to immunotherapy is good but relapse is common if it is discontinued. Younger patients have a more severe clinical course than older patients.
The synthetase syndrome is a subset of autoimmune myopathies caused by autoantibodies directed against translational RNA synthetases (tRNA?s). They include Jo-1, PL-7, PL-12, EJ and OJ. Approximately 20% of patients with the synthetase syndrome present with fever either at onset or relapsing. The vast majority (>90% )have myositis, usually proximal, indications of which are difficulty standing up and / or climbing stairs. Around half have polyarthritis affecting the small joints of hands and feet. If Jo-1 antibody is present, interstitial lung disease (ILD) usually develops, the clinical course of which is severe with a poor prognosis. ?Mechanics hands? characterised by thickening of the skin tips and margins of the fingers is present in approximately 30% of patients and Raynauds phenomena is seen in approximately 40% of patients with the syndrome.
The myositis antibodies are divided into myositis specific antibodies [MSA] e.g. synthetase, SRP, HMGCR, Mi-2 which are only associated with inflammatory myopathies and the myositis associated antibodies [MAA] e.g. Ro52, PL-ScL, U1RNP. Ku which are also associated with other systemic autoimmune conditions.
Corticosteroids (typically prednisone) are the first choice therapy and, with the exception of sIBM are effective.
The
following Table details individual antibodies, their clinical association and
ANA association.
The ANA pattern classification (AC-
x)
is from the International body (ICAP)
https://www.anapatterns.org/
|
Target |
Myositis antibody Group |
Clinical association |
ANA association |
Other comments |
|
Mi-2 alpha Chromodomain-helicase-DNA binding protein 3 |
MSA |
DM (20%) |
Nuclear fine speckled (AC-4) |
|
|
Mi-2 beta Chromodomain-helicase-DNA binding protein 4 |
MSA |
DM (20%) |
Nuclear fine speckled (AC-4) |
More frequently detected in adult onset DM patients |
|
TIF 1 gamma Transcriptional intermediary factor -1 gamma |
MSA |
DM (15%) |
Nuclear fine speckled (AC-4) |
In 50-60% DM patients who are TIF 1 gamma antibody positive there is an association with malgnant disease (e.g. pancreatic carcinoma). The presence of TIF 1gamma in juvenile DM is not associated with malignancy |
|
MDA 5 Melanoma differentiation ?associated gene 5 |
MSA |
DM (all 15-25%) >95% of patients with amyopathic DM |
Negative or cytoplasmic based fine speckling (AC-20) |
Amyopathic DM - prominent skin changes with only minimal muscle invovement. There are systemic features with rapidly progressive ILD |
|
NXP 2 RNA and nuclear matrix binding protein 2 |
MSA |
Juvenile PM / DM (20-30%) Adult PM / DM (1%) |
Multiple nuclear dots (AC-6) |
Associated with juvenile DM. Clinical features may include severe muscle weakness, calcinosis, joiny contractures, intestinal vasculitis. Adult cases may be carcinoma associated (breast, uterine, pancreatic) |
|
SAE 1 SUMO activating enzyme subunits 1 |
MSA |
DM (8%) |
Nuclear fine speckled (AC-4) |
In adult DM, 5% cases have ILD. Cutaneous features may precede muscle involvement. |
|
SRP Signal recognition particle |
MSA |
IMMN (anti-SRP syndrome) |
Cytoplasmic based dense fine speckling (AC-19) |
|
|
Jo-1 Histidyl-tRNA synthetase |
MSA |
PM (20-60%) |
Cytoplasmic fine speckled (variable expression) (AC-20) |
Seen in patients with synthetase syndrome Frequently associated with ILD If Jo-1 is specific, expect to have Ro52 reactivity |
|
PL-7 Threonyl-tRNA synthetase |
MSA |
Myositis (5-10%) |
Cytoplasmic fine speckled (variable expression) (AC-20) |
Seen in patients with synthetase syndrome
|
|
PL-12 Alanyl-tRNA synthetase |
MSA |
Myositis (5%) |
Cytoplasmic fine speckled (variable expression) (AC-20) |
Seen in patients with synthetase syndrome
|
|
EJ Glycyl-tRNA synthetase |
MSA |
PM (1-5%) |
Cytoplasmic fine speckled (variable expression) (AC-20) |
Seen in patients with synthetase syndrome |
|
OJ Isoleucyl-tRNA synthetase |
MSA |
PM (1-5%) |
Cytoplasmic fine speckled (variable expression) (AC-20) |
Seen in patients with synthetase syndrome |
|
cN-1A Cytosolic 5'-nucleotidase 1A |
MSA |
sIBM (35%) PM (75%) DM (15%) |
Unknown |
While considered a marker for sporadic inclusion body myositis, is also seen in other CTD's and 5% of healthy individuals |
|
HMGCR 3-hydroxy-3-methylglutaryl coenzyme A reductase |
MSA |
Necrotising myositis (75%) |
Negative or Cytoplasmic based speckling (AC-20) |
Most but not all cases are related to statin use |
|
|
||||
|
Ku DNA binding, non-histone protein |
MAA |
Seen in idiopathic inflammatory myopathy |
Nuclear fine speckled (AC-4) |
Associated with increased frequency of vasculitis and pulmonary hypertension. Seen in other CTD's notably SLE and Systemic sclerosis. |
|
PM-ScL Proteins (75 kDa and 100 kDa) of the nucleolar PM-ScL macromolecular complex PM-1) |
MAA |
Paients with PM / DM and or SSc overlap syndrome (50-70%) |
Nuclear: Homogeneous and Nucleolar pattern (AC-8) |
The two proteins of differing molecular weights (75kDa and 100kDa) are not separately reported. If either is reactive, the target is reported as positive. |
|
Ro52 Zinc binding protein as a member of the tripartite motif (TRIM) family
|
MAA |
Myositis patients (25%) |
No specific ANA pattern is associated with this target |
Also in many other rheumatic and non-rheumatic diseases. In isolation likley to be of little clinical significance. **Refer to Jo-1 target |
References
1. Up to Date accessed 15/4/2022 (Dr. R. Steele)
2. www.anapatterns.org accessed 15/4/2022 (Dr. R. Steele)
3. EUROLINE Autoimmune Imflammatory Myopathies 16 antigen with cN-1A and HMGCR test instructions
4. Palterer B et al. Bench to bedside review of myositis autoantibodies. Clin Mol Allergy (2018); 126 (5): https://doi.org/10.1186/s12948-018-0084-9
5. Tebo AE. Autoantibody testing in idioppathic inflammatory myopathies. The Journal of Applied Laboratory Medicine (2022); 7 (1): 387-390. https://doi.org/10.1093/jalm/ifab149
Dr. Richard Steele, Immunopathologist RSteele@adhb.govt.nz
Dr. Rohan Ameratunga, Immunopathologist RohanA@adhb.govt.nzSend 1 x 3.5mL centrifuged SST blood specimen, transported with standard chiller pack(s).
If separated serum is sent, use the same transport conditions with a minimum specimen volume of 750uL (0.75mL)