Cite this asEnriquez JOG, Mendoza CA, Van Oostdam DAH (2023) Anti-synthetase syndrome with positive anti-PL-12 antibodies associated with autoimmune hepatitis: case report and literature review. Open J Orthop Rheumatol 8(1): 008-012. DOI: 10.17352/ojor.000047
Copyright License© 2023 Enriquez JOG, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Antisynthetase Syndrome (ASS) is a rare chronic autoimmune disorder, associated with interstitial lung diseases (the most important feature), such as Dermatomyositis (DM) and Polymyositis (PM). The cause of ASS is unknown. The hallmark of ASS is the presence of serum autoantibodies directed against aminoacyl-tRNA synthetases (anti-ARS involved in protein synthesis). Anti -Jo1 is the most common (20% - 30%); anti-PL12 is present in 2% - 5% of SAS, associated with Interstitial Lung Disease (ILD) in 90%, mainly as Non-Specific Interstitial Pneumonia (NSIP). Autoimmune hepatitis is related to rheumatological diseases (2.7% - 20% in systemic lupus erythematosus, 6% - 47% in primary Sjögren’s syndrome), however, is rare in patients with inflammatory myopathies, and there is no previous reported association with SAS. A literature search was carried out using the PubMed and EMBASE databases in English and Spanish. Our case, a 62-year-old woman who developed polyarthritis, with progressive dyspnea, facial and lower limb edema, proximal muscle weakness, and Raynaud’s phenomenon; high-resolution chest CT, showing pulmonary interstitial disease, consistent with Nonspecific Interstitial Pneumonia (NSIP). She had elevated transaminases and a prolonged prothrombin time, with positive anti-nuclear and anti-smooth muscle antibodies, and was made a diagnosis with autoimmune hepatitis type 1 (HAI). According to this presentation and reports of the literature review, anti-PL12 patients are characteristically associated with a severe phenotype of lung inflammation, that does not necessarily require myositis manifestation. To our knowledge, there is not any case of the antisynthetase syndrome and autoimmune hepatitis reported previously in the literature.
Antisynthetase syndrome (ASS) is defined as a subtype of Idiopathic Inflammatory Myopathies (IIMs) and can be classified according to clinical and/or serologic association to Muscle-Specific Antibodies (SMA), the clinical presentation has a weakness, frequent involvement pulmonary, arthritis, an exceptional pattern in muscle biopsy, fever of unknown origin, typical cutaneous lesions and Raynaud’s phenomenon cover the unique spectrum with aminoacyl-tRNA-synthetases being both the hallmark and the trigger, the most frequent IgG isotype, against the synthetase enzyme, which forms Transfer RNA (tRNA), more frequently affects females (female to male ratio is estimated to be approximately 7:3). Anti-synthetase syndrome (SAS) is uncommon, 8-9 / million, the main clinical manifestations include Polymyositis (PM)/Dermatomyositis (DM), diffuse pulmonary interstitial disease, polyarthritis, Raynaud's phenomenon and "mechanical hands". Aminoacyl tRNA synthetases are cytoplasmatic enzymes, during the translation phase of protein synthesis, they catalyze the binding of specific amino acids to the matching tRNA. In each cell, 20 different synthetases are present, corresponding to a single amino acid . Antisynthetase antibodies can be found in 11.1% - 39.19% of patients with IIM, antibodies have been detected against nine of them, including anti-Jo-1 (histidyl-tRNA synthetase), anti-PL-7 (threonyl), anti- PL-12 (alanyl), anti-EJ (glycyl), anti-OJ (isoleucyl), anti-KS (asparaginyl), anti-Zo (phenylalanyl), anti-Ha (tyrosyl) and most recently anti-asparaginyl (YRS); anti -Jo1 the most common (20% - 30%); anti-PL12 are present in 2% - 5% of SAS, associated with Interstitial Lung Disease (ILD) in 90%, mainly Non-Specific Interstitial Pneumonia (NSIP), identified from 1986 [2,3].
Autoimmune hepatitis is related to rheumatological diseases (2.7% - 20% systemic lupus erythematosus, 6% - 47% primary Sjögren’s syndrome), is rare in patients with inflammatory myopathies, and there is no reported association with SAS.
The patient is a 62-year-old woman who developed polyarthritis, with progressive dyspnea, facial and lower limb edema, and proximal muscle weakness mainly in the lower limbs with an MMT-8 score of 110. She was referred for 2 years with Raynaud’s phenomenon, and in the last month, skin sclerosis from the dorsal aspect of the feet thru the lower third of the legs and generalized hyperpigmentation, without skin sclerosis. Chest examination with decreased breath sounds and basal rales. Complementary laboratory tests included normal blood count, a high Erythrocyte Sedimentation Rate (ESR) of 49 mm, high C-Reactive Protein (CRP) 11 mg/dl, hypertransaminasemia (AST 272 U/L, ALT 326 U/L), alkaline phosphatase 442 U/L, gamma-glutamyltransferase 103 U/ml, total bilirubin 0.5 mg/dl, LDH 460 U/L, albumin 2.2 mg/dl, gamma globulins 4.3 g/dL, elevated creatine kinase (247 U/ml).
Her chest X-ray with a fine bilateral interstitial pattern, which was confirmed through high-resolution chest CT, showing pulmonary interstitial disease, with glass ground areas and grid shadows could be seen under the pleura of bilateral lungs and around the bronchial vascular bundles, abnormalities consistent with Nonspecific Interstitial Pneumonia (NSIP).
There wasn’t any clinical mass or nodules in the breast examination, any pelvic abnormalities in the CT scan, nor serologic tumor markers detected.
In the further work-up of the dyspnea, we found Pulmonary Hypertension (PH) of 32 mmHg, dilatation of the right ventricular cavity, and paradoxical septal motion. Cardiologists suggested that, in absence of a classic pulmonary embolism image in the CT scan, echocardiographic changes were probably due to pulmonary hypertension.
Capillaroscopy with areas of avascularity, mega capillaries, and decreased density. A skin biopsy of the left forearm was done, showing the epidermis with network hyperkeratosis and atrophy, spongiosis, flattening of ridges and pigment loss, and papillary and reticular dermis with basophilic degeneration of the collagen, compatible with dermatomyositis.
Treatment was started with prednisone at a dose of 1 mg/kg, as well as mycophenolic acid, and tacrolimus, with significant improvement in functional and skin lesions, with a progressive reduction in the dose of glucocorticoids.
Simultaneously, she had elevated transaminases and a prolonged prothrombin time, with positive anti-nuclear and anti-smooth muscle antibodies, for which was made a diagnosis of autoimmune hepatitis type 1 (HAI), with negative hepatitis viral markers. The global score for the diagnosis of HAI is + 15 points (definitive HAI in a pre-treatment state).
The main suspicion was either pure dermatomyositis or an overlap syndrome (with autoimmune hepatitis). Positive anti-nuclear antibodies at a 1:1280 dilution with a filamentary fibrillar cytoplasmic pattern, with negative anti-dsDNA, but a positive Anti-Smooth Muscle Antibody (ASMA) 1:80 and negative Anti-Mitochondrial Antibody (AMA). According to the International Consensus on ANA Patterns (ICAP), this pattern of ANA is not typically associated with inflammatory myopathies. The only clinical manifestation we could associate with the former pattern was interstitial pneumonia, in which there is an association with the positivity of anti cytokeratine 19 antibodies .
Three weeks later we obtain the results from the SMA panel, with positive anti-PL-12 (+ + +) and anti-Ro 52 (+ + +) antibodies. Our diagnosis was an overlap syndrome, with the antisynthetase syndrome (anti-PL12 and Ro-52 antibodies) and autoimmune hepatitis; unfortunately, our patient died suddenly before the programmed liver biopsy.
We searched PubMed for original articles, reviews, letters, short communications, and notes in English and Spanish language sources using the following keywords: ("antisynthetase syndrome"[Supplementary Concept] OR "antisynthetase syndrome"[All Fields] OR "antisynthetase syndrome"[All Fields]) AND (("aminoacyl trna synthetases"[MeSH Terms], we reviewed 33 articles, omitted 5 articles because of the inadequate information, and summarized 28 relevant articles. We conducted these literature searches according to the recommended search strategy for narrative reviews.
Our patient presented skin stigmata, generalized hyperpigmentation and heliotrope erythema, arthritis, and progressive dyspnea, besides bilateral radiological interstitial pattern, characteristic of dermatomyositis / antisynthetase syndrome.
Patients with anti-PL-12 antibodies share some clinical characteristics with positive anti-Jo-1 patients. The antibody reacts to the transfer RNA for the amino acid alanine and the alanyl tRNA enzyme, inhibiting aminoacylation with alanine, being this feature is distinctive compared to other types of antisynthetase antibodies. The first clinical description included six patients with a mean age of 52 years and the presence of Raynaud's phenomenon, myositis, lung fibrosis, and one patient with sclerodactyly [3,5]. Patients testing positive for anti-PL-12 and anti-PL-7 antibodies have a higher incidence of ILD and a lower incidence of inflammatory myositis when compared with patients testing positive for anti-Jo-1.
Anti-PL12 patients are associated with a severe phenotype of lung inflammation, that does not necessarily require myositis associated; in a recent cohort the coexistence with muscle and lung involvement was present in 9% at the onset of the disease vs. 65% of exclusive lung involvement; the mean FVC at the onset of the disease is lower than compared to patients with anti-Jo1 and anti PL7 with lung involvement, similar results are reported in other studies. Our patient presented with NSIP, the most frequent tomographic pattern of lung interstitial disease (ILD), followed by an overlap with Organizing Pneumonia (OP), as reported by Debray, et al. .
The presence of anti-Ro-52 as our patient is a common element; anti-synthetase antibodies are generally considered to be mutually exclusive, yet cases of ARS co-occurrence have been described. Antibodies against Ro (including Ro52) are considered the most common type of associated antibodies in ARS-positive patients, occurring in 30% - 65% of cases. In the specific case of anti-PL12, the presence of anti-Ro52 antibody is present in > 25% of the patients. The main association in the presence of ILD, also, in some reports there is a higher activity score of myositis, higher relapses, and a higher proportion of overlap syndrome [7,8,17-28].
Liver dysfunction occurs in 43% of patients with connective tissue disorders. The elevation of CK, DHL and transaminases in patients with inflammatory myopathies is considered to be due to the activity of the disease and rarely to the coexistence of liver injury. There are few case reports of this association, one of primary biliary cholangitis with inflammatory myopathy, and the other with autoimmune hepatitis (Table 1) and nodular regenerative hyperplasia, it is important to mention the damage induced by drugs, however, the level of transaminases and the established therapy have low rates of liver damage, it is not the typical response to it, the titers for ASMA are more characteristic and significant, although it must be recognized that they are not completely specific, viral infections were ruled out.
To our knowledge, there is not any case of the antisynthetase syndrome and autoimmune hepatitis reported previously in the literature.
Similar to anti-Jo1, the prognosis of anti-PL12 ASS seems to be determined by pulmonary involvement, especially in the case of disproportionate pulmonary hypertension, a particularly rare complication of anti-PL12 syndrome. The potential explanation of pulmonary hypertension in our patient may be due to undiagnosed interstitial lung disease and rarely explained with exceptional association with portal hypertension related to liver nodular regenerative hyperplasia. The patient was not submitted to Right Heart Catheterization (RHC).
The prevalence of PH evaluated by RHC in anti-synthetase patients is 8%, 30% (5/16) of the patients had anti-PL12 and only 2 had a positive anti-Ro52 antibody; an interesting fact was that there was an absence of association between the presence of ILD and the development of PH, nor was related with the severity of ILD; the number of patients included was low and only 45% of the patients with a possible diagnosis of PH determined by echocardiogram were submitted to RHC. But this rises the hypothesis that PH could indicate a different mechanism not related to ILD, such as nodular regenerative hyperplasia.
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