Atypical clinical presentation of a subset of patients with anti-RNA polymerase III - non-scleroderma cases associated with dominant RNA polymerase I reactivity and nucleolar staining

Abstract

IntroductionAnti-RNA polymerase III (RNAP III) antibodies are highly specific markers of scleroderma (systemic sclerosis, SSc) and associated with a rapidly progressing subset of SSc. The clinical presentation of anti-RNAP III positive patients, onset of Raynaud's phenomenon (RP) and SSc in unselected patients in a rheumatology clinic were evaluated.MethodsAutoantibodies in sera from 1,966 unselected patients (including 434 systemic lupus erythematosus (SLE), 119 SSc, 85 polymyositis/dermatomyositis (PM/DM)) in a rheumatology clinic were screened by radioimmunoprecipitation. Anti-RNAP III positive sera were also tested by immunofluorescence antinuclear antibodies and anti-RNAP III ELISA. Medical records of anti-RNAP III positive patients were reviewed.ResultsAmong 21 anti-RNAP III positive patients, 16 met the American College of Rheumatology (ACR) SSc criteria at the initial visit but 5 did not; diagnoses were vasculitis, early polyarthritis, renal failure with RP, interstitial lung disease, and Sjögren's syndrome. The first two patients developed rapidly progressive diffuse SSc. An additional case presented with diffuse scleroderma without RP and RP developed two years later. Anti-RNAP III antibodies in these 6 cases of atypical clinical presentation were compared with those in 15 cases of typical (SSc with RP) cases. Anti-RNAP III levels by ELISA were lower in the former group (P = 0.04 by Mann-Whitney test) and 3 of 6 were negative versus only 1 of 15 negative in the latter (P < 0.05 by Fisher's exact test). Three cases of non-SSc anti-RNAP III positive patients had predominant reactivity with RNAP I with weak RNAP III reactivity and had a strong nucleolar staining. Three anti-RNAP III patients, who did not have RP at the initial visit, developed RP months later. Scleroderma developed prior to RP in 5 out of 16 (31%) in the anti-RNAP III group, but this was rare in patients with other autoantibodies. The interval between the onset of RP to scleroderma was short in anti-RNAP III positive patients.ConclusionsAnti-RNAP III antibodies are highly specific for SSc; however, a subset of anti-RNAP III positive patients do not present as typical SSc. The interval between RP and scleroderma in this group is short, and 31% of patients developed scleroderma prior to RP in this group. Anti-RNAP III positive patients may not present as typical SSc and detecting anti-RNAP III may have predictive value.

Prevalence of Anti–RNA Polymerase III Antibodies in Systemic Sclerosis: New Data From a French Cohort and a Systematic Review and Meta‐Analysis

“…In our study, ELISAs resulted in a higher prevalence (13% [95% CI 9-19]) versus immunoprecipitation (7% [95% CI [5][6][7][8][9]) in the overall population, but meta-regression did not reveal a significant association between the type of test (ELISA or immunoprecipitation) and prevalence. When the type of assay was included in the model as a variable, the heterogeneity remained very significant.…”

“…Although anti-RNAP III was identified in 1993 (2,3), data about the clinical impact of these antibodies were limited until enzyme-linked immunosorbent assay (ELISA) kits became available (4,5). Since then, many reports on the prevalence and clinical association of anti-RNAP III in SSc have been published (2)(3)(4)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

Autoantibodies Associated With Connective Tissue Diseases: What Meaning for Clinicians?

“…Anti-RNA polymerase I AAb may also be produced by SSc patients, mainly in association with anti-RNA polymerase III AAb production. Of note, the detection of isolated anti-RNA polymerase I AAb is not associated with SSc ( 169 ). The presence of both anti-RNA polymerase I/III AAb is also associated with cancer and scleroderma renal crisis ( 170 , 171 ).…”

Clinical significance of rare serum autoantibodies in rheumatic diseases: a systematic literature review

“…This allowed the large scale and rapid identification of anti-RNApol antibodies in a clinical diagnostic laboratory setting to identify SSc patients who are at risk for developing SSc with these autoAbs (66,67). Anti-RNApol antibodies are found in 1.1% to 15% of SSc patients (33,36,37,40,41,45,47,49,52,54,68) and anti-RNA polymerase I/III positive patients are more likely to develop dcSSc with pulmonary involvement, joint and tendon involvement, myositis, and a significantly increased risk of scleroderma renal crisis (33,37,40,45,47,49,50,52,62). However, patients with anti-RNA polymerase III antibodies have lower risk of gastrointestinal (GI) manifestations and esophageal dysmotility compared to patients with anti-topo I/Scl70 (40,62), as well as a lower incidence of pulmonary disease (40).…”

“…However, patients with anti-RNA polymerase III antibodies have lower risk of gastrointestinal (GI) manifestations and esophageal dysmotility compared to patients with anti-topo I/Scl70 (40,62), as well as a lower incidence of pulmonary disease (40). A subset of anti-RNA polymerase III positive patients may have an atypical clinical presentation with the onset of scleroderma prior to Raynaud's phenomenon (36). In 2010, Shah et al (69) first reported a possible association of anti-RNA polymerase I/III with the development of malignancy that occurred concomitantly to SSc onset in a small number of US patients.…”