Antisynthetase syndrome (ICD-10 M35.8 + J99.1)

Definition

Anti-synthetase syndrome is a form of muscle inflammation (dermatomyositis or polymyositis), but the lungs are the most important internal body being attacked («Interstitial pulmonary disease").

• The CK (creatine kinase) enzyme need not be elevated as in typical muscle inflammation / myositis
• The anti-synthetase syndrome have additionally typical Antibodies (anti-Jo-1, less frequently anti-PL-7, anti-PL12 or others: anti-EJ, anti-OJ, anti-Zo, anti-Ha-YRS) in blood tests
• The cause of the disease is unknown

Occurrence

Approximately One in three with myositis or dermatomyositis has an antisynthetase syndrome, which corresponds to between five and fifteen new cases of the antisynthetase syndrome in Norway annually. Anti-synthetase syndrome is defined as one rare disease.

• Mean age is 48-55 years when the disease begins, but age between 20 and 80 years is observed
• Women are attacked a little more often than men

History

• The 1980 Jo-1 antibody is described for the first time
• 1983 Compositions of the Jo-1 antibody, lung manifestation and myositis are described
• The 1990 Antisynthesis Syndrome is described (reference Margurie C, 1990)

Symptoms

Increasing heavy breathing (dyspnoea), only at load when going up stairs or steep slopes

• Rheumatic inflammation of the lung tissue (ILD) is detected
• New irritant cough (dry cough)
• Muscle weakness may be absent
• Rash similar to Dermatomyositis occur (Gottron's sign or papules), but Mechanic's Hands with dry, cracked skin on the fingers (see photo below) is more typical (30-40%)
• Arthritis (arthritis) among other things, thumbnails occur at more than 50% and may resemble Rheumatoid arthritis
• Raynaud's phenomenon is quite common (30-50%)
• Fever and night sweats occur, especially in severe lung symptoms
• In some cases, the disease is accidentally detected by pulmonary examination

Diagnosis

Symptoms of lungs, skin and muscles

• CT examinations shows signs of disease (milcky white glass, fibrosis) in the lungs
• Lung function tests (Spirometry and gas diffusion)
  • More about pulmonary disease, please read here (in Danish)
  • Tissue investigation (biopsy) from the lungs is rarely necessary
• MR of thigh muscles have proven useful (reference: Andersson H, 2017)
• The heart muscle is attacked (myocarditis) of 3-4%
• Blood tests
  • ANA (antinuclear antibody) is found in blood tests of approximately 50%
  • anti-SSA antibodies (Ro52) (know by Sjögren's syndrome og SLE) are also not uncommon but less specific to the disease
  • Typical antibodies are anti-Jo-1, less anti-PL-7, anti-PL12 or other anti-EG, anti-OJ, anti-Zo, anti-Ha-YRS in blood samples (please read more below)
  • Muscular disease compatible with Myositis appears at high CK values ​​in blood
• Muscle tissue (biopsy), most often thigh muscle shows inflammation similar to dermatomyositis (perimyseal inflammation). In addition, frequent macrophages occur. Necrotizing myositis is more rare. Infections and other causes of symptoms must be excluded (see below)
• Ultrasound of the heart (echocardiography) done to exclude increased pressure in pulmonary artery vessels (pulmonary hypertension). The occurrence is 8-10%

Diagnostic criteria (suggested) here (in Danish)

• Read more about suggested diagnostic criteria here

Incorrect diagnosis (similar conditions / differential diagnoses)

• Read more about differential diagnosis of antisynthetase syndrome here

The treatment

Before treatment starts

It is important to be well informed of the disease, the treatment goal, and about side effects that may occur

• Infection risk increases during treatment
  • Other causes of reduced immune system are identified (history of disease, white blood cell count, immunoglobulin / IgG)
  • Vaccines for protection against flu and pneumococci (pneumonia) are relevant
  • Latent infections like Tuberculosis (Tbc), hepatitis B og HIV excluded by blood tests
• Disease activity and possible organ damage are recorded for subsequent comparison in order to assess the effect of treatment

Treatment options are depending on the severity of the disease. In case of rapid worsening of the lungs (weeks) it is essential that adequate immunosuppressive treatment is being started quickly. Some serious illnesses show the need for breathing aid respirator (Medical breathing aid) until the medications have an effect.

• Starting treatment with high dosages prednisolone (1mg / kg or maximum 80mg / day) or methylprednisolone (Solu-Medrol) intravenously (in severe cases, the dose is often 500-1000mg / day for three consecutive days
• In severe cases cyclophosphamide (Sendoxan) intravenously every 2-3 week initially as well. If later wish for having children is relevant, please consider freezing of sperm or egg cells / ovarian tissue before start of treatment
• Rituximab (Rixathon, MabThera) (reference: Andersson H, 2015) is off-label Biological treatment in antisynthetase syndrome which has shown promising results both in the case of disease debilitating and as maintenance treatment in some cases
• Azathioprine (Azathioprine) or mycophenolate (CellCept, Myfortic) tablets as «maintenance treatment». Methotrexate, ciclosporin A or immunoglobulins are alternatives
• Pneumocystisprophylaxis with trimethoprim-sulfa / bactim 1 tablet x 1 should be considered
• Pneumococcal and influenza vaccines should be given, preferably at least 2 weeks before treatment commences

Medical prognosis

One can divide the antisynthesis syndrome into three precursors:

• Type I: Acute (10-30%) Pulmonary symptoms with heavy breathing develop during 4 weeks. This is most serious. The treatment is often methylprednisolone (SoluMedrol) intravenously for 3 days followed by prednisolone tablets together with other immunosuppressive therapy. Cyclophosphamide is most often used (Sendoxan) intravenously the first 3-6 months and then transition to azathioprine (Azathioprine) or mycophenolate (CellCept, Myfortic) tablets. Some get rituximab (Rixathon, MabThera) as an alternative. Transient need for respiratory assistance (respirator) is sometimes required until the drugs have achieved effect
• Type II: Chronic (40-50%). Gradually increasing lung disease over weeks or months. Most common form with variable course. The treatment is customized individually and may be as for Type I, but often with lower drug doses or without Sendoxan
• Type III Without Symptoms (20-25%). ODetected at random. If the condition does not show signs of deterioration during controls, no special medication is required

Type I is so serious that some people need respiratory treatment (Medical breathing aid) before treatment effect occurs. Death occurs. Particularly in Type II the course is individual. Overall, it is possible to stop the disease at 25-70%, but 6-40% is relapsed for up to 7 years later. For Type III, the medical prognosis is best.

Antisynthetase Antibodies and their Importance to the Disease

Jo-1 (histidyl tRNA synthetase), most commonly, occurs in 50-80%. Often classical antisynthesis syndrome (lung more than 80%, muscles, skin) and arthritis (arthritis) in 70%

• PL-7 (threonyl tRNA synthetase), 12-20%, often severe lung disease, mild myositis. Raynaud's phenomena
• PL-12 (alanyl tRNA synthetase), 12-20%, often severe lung disease, milder myositis. Raynaud's phenomena
• OJ (isoleucyl tRNA synthetase), 5-10%, Most symptoms of lungs, less frequent myositis. Arthritis occurs
• EJ (glycyl tRNA synthetase), 4-20%, often dermatomyositis, tendency to relapse in the course of the disease
• KS (aspargyl tRNA synthetase), 5%, Most lung disease, none or mild myositis
• Zo (phenylalanyl-tRNA synthetase), less than 1%, data for typical disease course are missing
• Ha / YRS (tyrosyl-tRNA synthetase), less than 1%, data for typical disease progression is missing
• SC (lysyl-tRNA synthetase), less than 1%, data for typical disease progression is missing
• JS (glutamine-tRNA synthetase), less than 1%, data for typical disease progression is missing
• Tryptophanyl antibody, uncertain clinical significance

Other: ACPA / CCP antibodies that are otherwise associated with Rheumatoid arthritis occurs in 6-9% with anti-synthetase syndrome

Follow-up and controls for antisynthetase syndrome

The strongest attacked organs are followed closely

• Lungs
  • Lung function tests at least annually, more often in early stages
  • CT of lungs is done if lung functions are reduced
• Muscles
  • CK (Creative Kinase) is measured in blood samples by controls
• Which joints are possibly swollen is being registered
• Skin changes are recorded
• Inflammation tests (CRP) are measured
• Antibody (e.g., Jo-1): The rash (titer measurements) partly follows the disease activity

Infections

Under severe immunosuppressive treatment (Sendoxan, MabThera, Prednisolon) the immune system is weakened. Risk of common and unusual (opportunistic-) infections increase, which can be very severe, especially with pre-reduced lung function.

• Prevention by giving Pneumococcal vaccine (against pneumonia) and flu vaccine generally recommended.
• Rapid medical evaluation (general practitioner / emergency room) and antibiotic treatment (penicillin or similar) are also recommended if infection symptoms occur.
• Prevention of infection with Bactrim (an antibiotic) for periods may be appropriate.

Medical examination, referral to specialist and for journal writing

• Tips and keywords for the anti-synthetase syndrome here

Literature

• Maturu VN, 2016
• More about the antisynthesis syndrome here (in Danish) (Molberg & Gran) 
• Wikipedia
• Grans Compendium in Rheumatology
• Great Norwegian encyclopedia

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• Bindevevssykdommer.no
• Vaskulitt.no
• revmakompendium.no