Antisynthetase syndrome is a special type of dermatomyositis characterized by acute onset, interstitial pulmonary fibrosis, resistance to standard glucocorticosteroid therapy. The clinical picture consists of fever, signs of fibrosing alveolitis (cough, shortness of breath), Raynaud’s phenomenon (pallor and cyanosis of the fingers). Sometimes there is muscle weakness, arthralgia. The diagnosis is confirmed by the determination of antisynthetase antibodies in the blood, histological studies of lung and muscle biopsies. Therapy is carried out with the help of powerful immunosuppressive and antifibrotic drugs, pulse therapy of GCS. Surgical treatment consists in lung transplantation.
Antisynthetase syndrome (ASS) is not an independent disease, but a subtype of dermatomyositis – a chronic diffuse connective tissue disease from the group of inflammatory myopathies. For dermatomyositis, the predominance of symptoms of damage to skeletal muscles and skin is specific. A distinctive feature of ASS is the predominant involvement of lung tissue in the pathological process. ASS is observed in approximately 20-30% of cases of dermatomyositis and can occur at any age. The incidence peaks at 10-15 years, 45-54 years and 75-84 years. Dermatomyositis is more common in women, while ASS occurs equally in both sexes.
Reasons of antisynthetase syndrome
The exact cause of the ASS has not been established. The etiological role of infectious pathogens is assumed – viral (Coxsackie virus, herpes, picornavirus), bacterial (rickettsia), parasitic (toxoplasma, trichinella). The probability of genetic predisposition to dermatomyositis and ASS is considered. In the course of genetic studies, certain histocompatibility antigens were found in many patients. In particular, ASS is usually associated with HLA B8, DR3, B14. The described cases of morbidity among monozygotic twins and close relatives confirm the hereditary nature of dermatomyositis and ASS. The provoking factors include vaccination, prolonged use of certain medications (antibiotics, insulin), excessive physical activity. The most significant of them is considered to be prolonged insolation.
The main link in pathogenesis is hyperactivation of cellular and humoral immunity. In predisposed individuals, myositis-specific and myositis-associated antibodies are produced under the influence of various triggers. In ASS, antibodies to histidyl-tRNA synthetase have been most studied. As a result of immune autoaggression reactions, cellular infiltration of skeletal muscles occurs, their inflammation with subsequent atrophy.
The resulting immune complexes settle on the endothelium of small-caliber vessels, causing a violation of microcirculation. In the lung tissue, there is an accumulation of lymphocytes, proliferation of mesenchymal cells with excessive release of collagen, which leads to pathological growth of the extracellular matrix and compaction of the lung parenchyma (fibrosis).
According to the degree of muscle involvement in antisynthetase syndrome, amiopathic and hypomyopathic variants are distinguished. There are cross forms with systemic scleroderma, cryoglobulinemic vasculitis. According to the type of lung lesion , the following forms of ASS are distinguished:
- Fast-progressing. The most unfavorable form. The rapid development of respiratory failure, a high frequency of deaths are typical.
- Slowly progressing. Manifests gradually in the form of a slight shortness of breath and an unproductive cough.
- Subclinical. It differs in the almost complete absence of respiratory symptoms in the presence of radiological changes in the lungs.
Symptoms of antisynthetase syndrome
Most often, the antisynthetase syndrome debuts in the spring, it is characterized by an acute onset and course. Fever appears (from subfebrile digits to 39 ° C), minor pain in small joints of the hands, persistent dry cough. Breathing is difficult by the type of mixed shortness of breath: first when performing physical exertion, then in a calm state. Respiratory dysfunction can be caused by both fibrosing alveolitis and functional inferiority of the respiratory muscles (diaphragm, intercostal muscles).
Patients are concerned about muscle weakness, which is especially pronounced when walking up stairs, lifting from a chair, performing household actions (combing hair, dressing, washing). This is due to a stronger inflammatory process in the proximal muscles of the upper and lower extremities. Sometimes, due to the weakness of the muscles of the pharynx, larynx, upper third of the esophagus, hoarseness of voice, dysphagia occur. Articular syndrome occurs in the form of symmetrical minor pains in the wrist joints and small joints of the hands, which quickly pass during treatment.
Specific dermatological signs include a heliotropic rash (purple or purple coloration of the skin of the upper eyelids and around the eyes), papules of the Gottron (flaky, slightly elevated rashes on the skin of the metacarpophalangeal, proximal interphalangeal joints). One of the key skin symptoms of ASS is “mechanic’s hands”: redness, peeling, cracks on the skin of the fingers. Many patients have Raynaud’s syndrome, caused by spasm of the vessels of the fingers with subsequent hyperemia. At low ambient temperature, the color of the fingers of the hands changes (first there is pallor, then cyanosis and redness), accompanied by numbness, pain, tingling.
Most of the complications of antisynthetase syndrome develop due to fibrosing alveolitis and vascular pathologies. Rapidly progressing pulmonary fibrosis in 70% of patients leads to respiratory failure requiring emergency medical intervention. With perifocal edema of the pulmonary vessels, the pressure in the small circle of blood circulation increases (pulmonary hypertension). Prolonged vasospasm in Raynaud’s phenomenon is dangerous with ischemic vasculopathy (necrosis, dry gangrene of the fingers). Functional failure of the muscular apparatus of the pharynx and esophagus can be complicated by aspiration pneumonia. Rare adverse effects of ASS include acute renal failure, the cause of which is the release of a large amount of myoglobin from the muscles with massive inflammation.
Patients with antisynthetase syndrome are treated by rheumatologists and pulmonologists. During physical examination, in particular, palpation of muscles, the patient feels pain. In the case of respiratory insufficiency, lip cyanosis, active participation in breathing of auxiliary muscles, a symptom of drumsticks (cone-shaped thickening of the terminal phalanges of the fingers) attract attention. Additional examination includes:
- Laboratory diagnostic tests. In a general blood test, an acceleration in the rate of erythrocyte sedimentation is detected. Markers of muscle inflammation – creatine phosphokinase, aldolase, lactate dehydrogenase – were elevated in the biochemical analysis. Immunological analyses reveal high concentrations of antinuclear factor, as well as myositis-associated, myositis-specific antibodies to aminoacyl synthetases of tRNA (anti-Jo-1, anti-PL7, anti-PL12).
- X-ray diagnostics. On radiography, CT of the chest organs, cystic clearances, a decrease in the transparency of the pulmonary fields, a mesh deformation of the pulmonary pattern according to the type of “frosted glass” are observed.
- Functional diagnostics. When recording spirography, a decrease in the vital capacity of the lungs is revealed. Needle electromyography is used to determine the low amplitude and duration of action potentials, spontaneous electrical activity of muscle fibers. On the electrocardiogram, minor cardiac arrhythmias are possible (ventricular extrasystole, atrial block).
- Histological studies. For histological confirmation of fibrosing alveolitis, bronchoscopy is performed with a biopsy for further microscopic examination. There is thickening and sclerosis of the alveolar walls, septa, perivascular edema, a large accumulation of lymphocytes. During muscle biopsy, degeneration, atrophy of muscle fibers, their infiltration by lymphocytes and macrophages occur.
Special diagnostic criteria have been developed for a more accurate diagnosis of antisynthetase syndrome. Large criteria include interstitial pulmonary fibrosis, unrelated to environmental factors (allergens, fungal mycelium, silicates) and myositis, verified by histological and laboratory tests. Minor criteria include non-erosive arthritis, Raynaud’s phenomenon, “mechanic’s hands”. The diagnosis is considered reliable in the presence of antisynthetase antibodies in combination with 2 large or 1 large and 2 small criteria.
Antisynthetase syndrome should, first of all, be differentiated with diffuse connective tissue diseases, joint diseases (systemic scleroderma, rheumatoid arthritis). Also, due to the similarity of the clinical picture of ASS with systemic vasculitis accompanied by lung damage, it is necessary to carry out differential diagnosis with nodular polyarteritis, Cherzhd-Strauss syndrome, Wegener granulomatosis. Skin rashes require differentiation with dermatological pathologies, such as eczema, psoriasis, atopic dermatitis. With rapidly progressing pulmonary fibrosis, it is necessary to exclude pulmonary embolism, pneumonia of bacterial or viral etiology.
Treatment of antisynthetase syndrome
All patients are subject to hospitalization in the department of clinical rheumatology, and in case of severe respiratory failure – in the intensive care unit for connection to a ventilator. There is no etiotropic therapy. The main role is given to pathogenetic treatment. There are the following directions of drug therapy ASS:
- Anti-inflammatory. In order to stop inflammation, medications (drugs) with a powerful immunosuppressive effect (mycophenolate mofetil, cyclophosphamide, methotrexate) are prescribed in combination with pulse therapy with glucocorticosteroids (prednisone, methylprednisolone). If they are ineffective, they resort to genetically engineered biological drugs – monoclonal antibodies (infliximab, rituximab), T-lymphocyte stimulation blockers (etanercept, abatacept).
- Antifibose. Traditionally, gamma interferon, D-penicillamine and colchicine are used to suppress fibrosis processes in the lungs. Promising modern antifibrotic drugs are pirfedinone, an inhibitor of fibrotic cytokines, and imatinib mesilate, a specific tyrosine kinase inhibitor.
- Vasoactive. To improve blood circulation in the peripheral vessels and prevent ischemic complications of Raynaud’s syndrome, drugs that improve microcirculation are used – blockers of slow calcium channels (amlodipine, nifedipine) and xanthinol nicotinate. In the aggressive course of Raynaud’s syndrome, these drugs are changed to analogues of prostaglandin E1 (alprostadil).
In case of resistance to pharmacotherapy, extracorporeal procedures (plasmapheresis) are performed, removing circulating antibodies from the blood plasma. With a generalized fibrous process in the lungs, causing severe respiratory failure, as well as the failure of all previous methods of treatment, a life-saving operation is performed – lung transplantation.
Prognosis and prevention
ASS is a severe pathology. The prognosis is mainly determined by the degree of pulmonary fibrosis. With a rapidly progressive form, death occurs in 60-70% of cases from pulmonary insufficiency. The slowly progressing variant proceeds more benign. The frequency of death is 25-30%. A favorable prognosis is observed in patients with a subclinical variant. With timely diagnosis and adequate treatment, mortality in such patients practically does not differ from the general population. Since the etiological factor of antisynthetase syndrome remains unknown, effective preventive measures currently do not exist.