Ro52 is a member of the tripartite motif-containing (TRIM) family and, hence, is also known as TRIM21. Ro52 is distinct, with no structural homology to Ro60 (also known as TROVE2), 1 although both are major targets of autoantibody responses in several autoimmune connective tissue diseases (CTDs). </p

McHugh, Neil J.

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        Citation for published version:McHugh, NJ 2022, 'Ro52, Myositis, and Interstitial Lung Disease', The Journal of Rheumatology, vol. 50, no. 2,221067, pp. 161-163. https://doi.org/10.3899/jrheum.221067DOI:10.3899/jrheum.221067Publication date:2022Document VersionPeer reviewed versionLink to publicationUniversity of BathAlternative formatsIf you require this document in an alternative format, please contact:openaccess@bath.ac.ukGeneral rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 08. Jul. 2024Ro52 is a member of the tripartite motif-containing (TRIM) family and hence is also known as TRIM21. Ro52 is distinct with no structural homology to Ro60 (also known as TROVE2) (1), although both are major targets of autoantibody responses in several autoimmune connective tissue diseases. Indeed, early studies describing anti-Ro (SSA) do not make a distinction between the separate autoantibody specificities, although they frequently co-exist in conditions such as systemic lupus erythematosus (SLE) and Sjogren’s syndrome and are often accompanied by anti-La (SSB). However, there is compelling evidence that the separate measurement of anti-Ro52 adds important information concerning patient management and outcome, not least in idiopathic inflammatory myopathy (IIM) and interstitial lung disease (ILD).  In the context of IIM anti-Ro52 is regarded as a myositis associated autoantibody (MAA) and can be found in other connective tissue diseases including SLE, Sjogren’s, systemic sclerosis and mixed connective tissue disease (MCTD). In contrast myositis specific autoantibodies (MSA)s are uncommonly encountered in other conditions apart from IIM and rarely coexist in the same patient (2). An important point to note is that MSAs may occur in some manifestations of the IIM spectrum, such as in interstitial lung disease or clinically amyopathic dermatomyositis (CADM) without any apparent muscle involvement, and arguably should be redesignated as myositis spectrum autoantibodies. For instance, some of the rarer anti-tRNA synthetase autoantibodies (anti-PL7 and anti-PL12) may be found in patients with ILD alone, or where ILD is the major disease manifestation (3). The other important example is anti-melanoma differentiation-associated gene 5 (anti-MDA5) previously called anti-CADM140 that typically occurs in patients with CADM and is a major marker for patients at risk of rapidly progressive interstitial lung disease (RP-ILD). The ability of MSAs to identify important sub-phenotypes of IIM is now well established. Their value in determining future disease course, and ideally acting as biomarkers to inform precision medicine is less well developed and ideally requires prospective studies with stratified treatment approaches. Furthermore, it is becoming apparent that the additional presence of a MAA such as anti-Ro52 needs to be taken into consideration. In a study published in this Journal Lv et al report retrospectively on a large regional cohort of 246 patients with myositis associated ILD and positive for anti-MDA5 gathered from 10 centres (4). Anti-Ro52 was present in 158 of the 246 anti-MDA5 patients (64%) and was significantly associated with a higher rate of development of RP-ILD and about twice the mortality rate (29% compared to 16% in anti-Ro52 negative patients). There are major limitations in such a retrospective study including selection bias, treatment effects and the lack of adjustment for person years at risk. Also, anti-Ro52 and anti-MDA5 were measured by line-blot that at best is a semi-quantitative method for measuring autoantibody levels that may be an additional important factor. Nonetheless the findings (and parallel analyses reported separately on the same cohort (5, 6))  are reasonably convincing and lead to conclude there is a degree of heterogeneity in anti-MDA5 positive patients that can be dissected by measuring anti-Ro52. There is also accumulating evidence from other studies in the myositis field that the measurement of anti-Ro52 autoantibodies in addition to other MSAs adds important information, especially in association with either anti-Jo-1 or anti-MDA5. One of the earliest studies comes from a Hungarian cohort reported in 2009 (7) although in this study an ELISA for anti-SSA was used that is not specific for anti-Ro52. A summary of relevant studies including the current report from Lv et al is given in Table one (3, 4, 8-15). All but one study (3)  found that the presence of anti-Ro52 with anti-Jo-1 was associated with more severe ILD and poorer outcome. Notably similar findings were reported in a large US cohort of children with juvenile myositis where ILD is far less common (10) . And in recent studies of three separate large Chinese cohorts the combination of anti-Ro52 with anti-MDA5 was associated with either more frequent RPLD, poorer outcome, and/or higher mortality (13-15). Also of interest is a Japanese prospective study of interstitial pneumonia where patients with CTD were excluded and those with anti-Ro52 autoantibodies alone had worse survival (11). So, despite the variability between studies in the patient populations, and the potential to bias already alluded to in what are mostly retrospective studies, there does seem to be solid evidence that the presence of anti-Ro52 is a poor prognostic indicator in IIM. The case for measurement of anti-Ro52 and its importance in the management of connective tissue diseases becomes even stronger when looking at outcome in ILD associated with connective tissue diseases other than IIM and has been the subject of recent comprehensive reviews (16, 17). In conditions where ILD is relatively frequent such as Sjogren’s syndrome, systemic sclerosis and mixed connective tissue disease the presence of anti-Ro52 is most often associated with an increase in frequency of ILD, that tends to be more severe and generally confers poorer outcome and survival.  Ro52 has several key properties and functions that may help explain why it is a common target for an autoimmune response in connective tissue disease and how that response is linked to the propensity for severe ILD. First, it is known to be highly antigenic (18) and as well is highly expressed in lungs compared to other tissues (17).  Second, Ro52 is likely to play an important role in host responses to viral infections postulated to be initiators of conditions such as in IIM and Sjogren’s syndrome. It has another important role as an immunoglobulin binding protein and the innate clearance of intracellular IgG-bound complex. Ro52 acts as a cytosolic receptor binding to the Fc region of IgG antibodies and hence acts to neutralise and degrade pathogens that antibodies have carried into the cell (16). Ro52 is also an interferon inducible E3 ligase that acts to down regulate interferon transcription factors and by so doing put a check on proinflammatory cytokine responses. In this regard it is worth noting that MDA5 as well is an interferon inducible protein and acts as a cytosolic viral dsRNA sensor. Together Ro52 and MDA5 are involved in effective responses to viral infection through interferon signalling and by virtue of protein-protein interactions may become potential targets for a common autoimmune response. It is also conceivable that anti-Ro52 antibodies may have a direct pathogenic role rather than simply be an imprint of an aberrant autoimmune response although the evidence for such stems mainly from studies of neonatal lupus (16). For instance, anti-Ro52 may block the regulatory activity of Ro52 protein as described above and directly amplify proinflammatory signals mediated through type 1 interferon. It is known that autoantibodies to Ro52 directly inhibit its E3 ligase activity (19) . Ro52 knockout mice develop severe dermatitis and manifestations of lupus and enhanced production of proinflammatory cytokines (20). However regardless of whether anti-Ro52 may have a direct effect, the takeaway measure for clinicians involved in the management of connective tissue disease, and even more so in patients at risk of ILD, is that anti-Ro52 is certainly worth measuring.        1. Itoh K, Itoh Y, Frank MB. Protein heterogeneity in the human Ro/SSA ribonucleoproteins. The 52- and 60-kD Ro/SSA autoantigens are encoded by separate genes. The Journal of clinical investigation. 1991;87(1):177-86. 2. Betteridge Z, Tansley S, Shaddick G, Chinoy H, Cooper RG, New RP, et al. Frequency, mutual exclusivity and clinical associations of myositis autoantibodies in a combined European cohort of idiopathic inflammatory myopathy patients. Journal of autoimmunity. 2019;101:48-55. 3. Pinal-Fernandez I, Casal-Dominguez M, Huapaya JA, Albayda J, Paik JJ, Johnson C, et al. A longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies. Rheumatology. 2017;56(6):999-1007. 4. Lv C, You H, Xu L, Wang L, Yuan F, Li J, et al. Coexisting of anti-Ro52 autoantibodies on anti-MDA5 autoantibodies-positive dermatomyositis is highly associated with rapidly progressive interstitial lung disease and mortality risk. The Journal of rheumatology. 2022. 5. You H, Wang L, Wang J, Lv C, Xu L, Yuan F, et al. Time-dependent changes in RPILD and mortality risk in anti-MDA5+ DM patients: a cohort study of 272 cases in China. Rheumatology. 2022. 6. Xu L, You H, Wang L, Lv C, Yuan F, Li J, et al. Identification of three different phenotypes in anti-MDA5 antibody-positive dermatomyositis patients: implications for rapidly progressive interstitial lung disease prediction. Arthritis & rheumatology. 2022. 7. Vancsa A, Csipo I, Nemeth J, Devenyi K, Gergely L, Danko K. Characteristics of interstitial lung disease in SS-A positive/Jo-1 positive inflammatory myopathy patients. Rheumatology international. 2009;29(9):989-94. 8. Marie I, Hatron PY, Dominique S, Cherin P, Mouthon L, Menard JF, et al. Short-term and long-term outcome of anti-Jo1-positive patients with anti-Ro52 antibody. Seminars in arthritis and rheumatism. 2012;41(6):890-9. 9. Shi J, Li S, Yang H, Zhang Y, Peng Q, Lu X, et al. Clinical Profiles and Prognosis of Patients with Distinct Antisynthetase Autoantibodies. The Journal of rheumatology. 2017;44(7):1051-7. 10. Sabbagh S, Pinal-Fernandez I, Kishi T, Targoff IN, Miller FW, Rider LG, et al. Anti-Ro52 autoantibodies are associated with interstitial lung disease and more severe disease in patients with juvenile myositis. Annals of the rheumatic diseases. 2019;78(7):988-95. 11. Temmoku J, Sato S, Fujita Y, Asano T, Suzuki E, Kanno T, et al. Clinical significance of myositis-specific autoantibody profiles in Japanese patients with polymyositis/dermatomyositis. Medicine. 2019;98(20):e15578. 12. Morita H, Shimizu Y, Nakamura Y, Okutomi H, Watanabe T, Yokoyama T, et al. Auto-antibody evaluation in idiopathic interstitial pneumonia and worse survival of patients with Ro52/TRIM21auto-antibody. J Clin Biochem Nutr. 2020;67(2):199-205. 13. Yang Q, Li T, Zhang X, Lyu K, Wu S, Chen Y, et al. Initial predictors for short-term prognosis in anti-melanoma differentiation-associated protein-5 positive patients. Orphanet journal of rare diseases. 2021;16(1):58. 14. Wen L, Chen X, Cheng Q, Nie L, Xu J, Yan T, et al. Myositis-specific autoantibodies and their clinical associations in idiopathic inflammatory myopathies: results from a cohort from China. Clinical rheumatology. 2022. 15. Gui X, Shenyun S, Ding H, Wang R, Tong J, Yu M, et al. Anti-Ro52 antibodies are associated with the prognosis of adult idiopathic inflammatory myopathy-associated interstitial lung disease. Rheumatology. 2022. 16. Chan EKL. Anti-Ro52 Autoantibody Is Common in Systemic Autoimmune Rheumatic Diseases and Correlating with Worse Outcome when Associated with interstitial lung disease in Systemic Sclerosis and Autoimmune Myositis. Clinical reviews in allergy & immunology. 2022. 17. Decker P, Moulinet T, Pontille F, Cravat M, De Carvalho Bittencourt M, Jaussaud R. An updated review of anti-Ro52 (TRIM21) antibodies impact in connective tissue diseases clinical management. Autoimmunity reviews. 2022;21(3):103013. 18. Burbelo PD, Ching KH, Han BL, Bush ER, Reeves WH, Iadarola MJ. Extraordinary antigenicity of the human Ro52 autoantigen. American journal of translational research. 2010;2(2):145-55. 19. Espinosa A, Hennig J, Ambrosi A, Anandapadmanaban M, Abelius MS, Sheng Y, et al. Anti-Ro52 autoantibodies from patients with Sjögren's syndrome inhibit the Ro52 E3 ligase activity by blocking the E3/E2 interface. The Journal of biological chemistry. 2011;286(42):36478-91. 20. Espinosa A, Dardalhon V, Brauner S, Ambrosi A, Higgs R, Quintana FJ, et al. Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway. The Journal of experimental medicine. 2009;206(8):1661-71.    Table one Summary of studies investigating anti-Ro52 and outcome in myositis and interstitial lung disease  First author Study Population Number Study design Method of detection of anti-Ro52 Findings Vancsa 2009 (7) Hungarian. IIM. 315 total (27 anti-Jo-1, 12 anti-SSA, of whom 8 anti-Jo1 and anti-SSA) Prospective ELISA (for anti-SSA) Combination of anti-Jo1 and anti-SSA associated with more severe course of ILD Marie 2012 (8) French. Consecutive patients with ASS 89 anti-Jo1 of whom 36 anti-Ro52 Retrospective record review ELISA (Ro-SSA) Anti-Ro52 more frequent symptomatic ILD and poorer survival Shi 2017 (9) Chinese. Rheumatology department. Consecutive patients with ASS  124 total of whom 36 anti-Ro52 Retrospective Lineblot (moderate or strong positive) Anti-Ro52 higher frequency of RP-ILD.  Pinal-Fernandez 2017 (3) US Myositis centre cohort testing positive for ASA 169 total of whom 111 anti-Ro52 Prospective ELISA/lineblot/IP Anti-Ro52 more frequent with anti-Jo1 but not associated with more severe ILD Sabbagh 2019 (10)  US multicentre cohort. Juvenile Myositis 371 total of whom 53 anti-Ro52 Cross-sectional with prospective arm ELISA Anti-Ro52 associated with ASA (64%), anti MDA (31%) ILD and poorer outcome  Temmoku 2019 (11) Japanese. DM/PM patient with stable disease 84 total of whom 39 anti-Ro52 Retrospective ELISA   Anti-Ro52 with anti-MDA5 associated with poorer survival Morita 2020 (12) Japanese. Interstitial pneumonia excluding patients with CTD 285 total of whom 29 had anti-Ro52 Prospective cohort with 2 years follow-up Lineblot (at least 2+ positive) Anti-Ro 52 mono-positive had worse survival than anti-Ro52 negative Yang 2021 (13) Chinese. DM, PM or CADM with anti-MDA5  90 total of whom 64 anti-Ro52 Retrospective Lineblot Anti-Ro52 associated with poorer survival Wen 2022 (14) Chinese. Hospitalised with IIM 515 total of whom 124 anti -MDA5, 285 anti-Ro52 (72 with both) Retrospective Lineblot Anti-MDA5 with anti-Ro52 had poorer outcome  Lv 2022 (4) Chinese. Multi-centre myositis-associated ILD cohort with anti-MDA5 246 anti-MDA5 total with 158 anti-Ro52 Retrospective Lineblot Anti-Ro52 associated with higher rate of RP-ILD and mortality Gui 2022 (15) Chinese. IIM-associated ILD 267 total of whom 148 anti-Ro52 and 87 anti-MDA5 Retrospective. Hospital based (respiratory admissions) Lineblot Anti-Ro predictive of RPLD and mortality and more so when present with anti-MDA5  Abbreviations. IIM idiopathic inflammatory myopathy; ILD interstitial lung disease; ASS anti-synthetase syndrome; RP-ILD rapidly progressive interstitial lung disease; ASA anti-synthetase antibody; IP immunoprecipitation; DM/PM dermatomyositis/polymyositis; CTD connective tissue disease; CADM clinically amyopathic dermatomyositis   

Ro52, Myositis, and Interstitial Lung Disease

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Ro52, Myositis, and Interstitial Lung Disease

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