Clinical Information

The presence of anti-centromere antibody (ACA) is associated with antinuclear antibody and demonstrates a characteristic discrete nuclear speckled staining pattern of both interphase nuclei and metaphase chromatin on HEp-2 substrate by indirect immunofluorescence assay (IFA).(1,2) ACA has a broad specificity for the centromere–kinetochore macro-complex.(2) Several putative epitopes associated with this autoantigenic complex have been described with CENP-A (18 kDa), CENP-B (80 kDa), CENP-C (140 kDa, and CBX as the main targets.(1-4) The CENP-B antigen is believed to be the primary autoantigen in systemic autoimmune diseases and is recognized by most, if not all, sera that contain centromere antibodies.(1-4) Together with anti-Scl 70 and anti-RNA polymerase III autoantibodies, ACA is recommended for the diagnostic classification systemic sclerosis (SSc) by the American College of rheumatology/European League Against Rheumatism collaborative initiative.(5)

Historically, ACA has been associated with SSc but also occur in varying frequencies in autoimmune diseases such as Sjögren's syndrome (SjS), primary biliary cholangitis (PBC), PBC overlap disease, or overlap connective tissue disease (CTD), and rheumatoid arthritis.(1-7) ACA is the most detected SSc-specific autoantibody and it is typically associated with the limited cutaneous SSc (lcSSc), previously referred to as CREST syndrome which is comprised of calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia.(1,3,6,8) In addition, ACA has a higher frequency in Caucasian than in African American or Asian cohorts.(1,7,8) The lcSSc is characterized by skin fibrosis of the fingers (sclerodactyly) and, in some cases, of the face and neck or the skin distal to the elbows and/or knees, sparring the upper arms, upper legs, or trunk.(1,7,8) Based on the autoantibody and cutaneous phenotypic characterization, ACA-positive patients with lcSSc generally have the highest 20-year survival, lowest incidence of clinically significant pulmonary fibrosis, scleroderma renal crisis, and lowest incidence of cardiac SSc.(2,5,7,8)

In addition to SSc, ACAs occur in patients with SjS, rheumatoid arthritis, PBC overlap, or overlap CTD.(1-7) Recent studies aimed at determining the fine specificities ACA in different CTD demonstrated comparative frequencies to CENP-B, the major ACA target.(2,4) In both studies, ACA recognize centromere “complex” rather than individual protein, and this feature is common among patients with Sjogren’s syndrome, SSc and PBC.

In routine clinical evaluation, ACA as well as ACA-specific for CENP-B and CENP-A, can be detected using a variety of methods.(1,9,10) The ACA detected using HEp-2 substrate by IFA, broadly defines a heterogeneous population of centromeric proteins (centromere-kinetochore macro-complex) while most solid-phase immunoassays for clinical evaluation are designed with mainly CENP-B antigen.(10)