Association of Anti–Topoisomerase I Antibodies of the IgM Isotype With Disease Progression in Anti–Topoisomerase I–Positive Systemic Sclerosis

Abstract

Objective Anti–topoisomerase I (anti–topo I) autoantibodies in systemic sclerosis (SSc) are associated with diffuse skin involvement and interstitial lung fibrosis. Thus far, however, the relationship between anti–topo I antibody response and disease course has not yet been fully evaluated. This study was undertaken to gain insight into the association between characteristics of the anti–topo I antibody response and clinical disease course in SSc patients positive for anti–topo I antibodies. Methods Levels of anti–topo I IgG, anti–topo I IgM, and anti–topo I IgA were assessed in consecutive serum samples obtained from patients at baseline who were positive for anti–topo I IgG in the Leiden Combined Care In Systemic Sclerosis (CCISS) cohort. One‐year disease progression was defined by a relevant increase in modified Rodnan skin thickness score (MRSS), decline in pulmonary function, development of digital ulcers, renal crisis, and pulmonary hypertension, and/or mortality. Validation was performed in SSc patients who were positive for anti–topo I from the Oslo University Hospital and University Hospital Zurich. Results Of the 103 patients with anti–topo I IgG in the CCISS cohort, clinical data were available to assess 1‐year disease progression in 81 patients. Of these 81 patients, 23 (28%) had disease progression. At baseline, patients with disease progression were significantly more often anti–topo I IgM–positive than those who did not experience disease progression (21 [91%] of 23 versus 33 [57%] of 58; P < 0.01). This finding was confirmed in the independent validation samples. Conclusion In SSc patients who were anti–topo I IgG–positive, presence of anti–topo I IgM, which might be considered as a surrogate for an ongoing autoreactive B cell immune response, is associated with disease progression.

Effects of Immunoglobulins G From Systemic Sclerosis Patients in Normal Dermal Fibroblasts: A Multi-Omics Study

“…Most of them have nuclear targets and are SSc-specific ( 3 ). Some studies suggested that IgG ATA+ titers correlate with severity, and recent data showed that IgM ATA+ titers are associated with disease activity ( 17 , 18 ). Finally, autoantibodies have been found in the sera of individuals years before SSc onset ( 19 ).…”

Pathogenetic Aspects of Systemic Sclerosis: A View Through the Prism of B Cells

“…Data indicate that ATAs can bind directly to the surface of fibroblasts in SSc patients, but it remains unknown whether this binding could lead to fibroblast activation (49). Another study associated the presence of IgM ATAs with disease progression in ATA (+) SSc patients, but no pathogenetic involvement has been yet established (50) (51). Through a series of experiments, the authors showed that Topo I could bind directly to fibroblasts and recruit ATAs.…”

Kidney Involvement in Systemic Sclerosis

“…Other reports pointed out the frequent presence of anti-RNA-Polymerase III antibodies in patients who developed SRC [ 19 , 56 ]. Anti-topoisomerase1 antibodies are instead associated with disease progression and poor outcome of SRC [ 20 , 57 ]. The use of high doses of corticosteroids has been associated with an increased risk of SRC, as demonstrated by several retrospective studies [ 49 , 50 , 58 ].…”

“…The upregulated B cells lead to the production of a plethora of autoantibodies, such as anti-topoisomerase I and anti-centromere antibodies. While anti-topoisomerase I antibodies are usually associated with diffuse and severe SSc [ 18 , 19 , 20 ], anti-centromere antibodies are associated with the CREST syndrome or lcSSc [ 21 , 22 ]. Among other autoantibodies, those targeting endothelial cells, including endothelin type A receptor and angiotensin II type I receptor, induce activation or apoptosis of endothelial cells [ 23 ].…”