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Introduction Anti-Ku antibodies are rare myositis-associated antibodies directed against a DNA-binding heterodimer involved in DNA repair. Anti-Ku positivity may be associated with a distinct clinical phenotype in autoimmune diseases and, when present in isolation from other autoantibodies, may represent a distinct clinical syndrome, characterized primarily by musculoskeletal and cutaneous manifestations. Current literature primarily includes studies on Asian and Caucasian populations, with limited data available on Hispanic individuals. We aim to describe the clinical and serology of anti-Ku-positive patients within a Hispanic cohort.Material and Methods We conducted a cross-sectional study at the Dr. José Eleuterio González University Hospital in Monterrey, Mexico, between February 2016 and December 2023. Patients with moderate or strong positivity for anti-Ku antibodies were included, using the EUROLINE autoimmune inflammatory myopathies panel. Demographic, clinical, and serological data were obtained from medical records. Patients with weak or borderline positivity, duplicate records, or insufficient follow-up were excluded. Approved by the institutional ethics committee.Results Eight patients were included, with a median age of 46 (IQR: 32.5 – 64.75). Seven (87.5%) were women. Three patients were diagnosed with anti-Ku syndrome. Other rheumatic diagnoses included overlap syndrome (systemic lupus erythematosus (SLE)/rheumatoid arthritis (RA), n=3), systemic sclerosis (SSc), and SLE (n=1 each). In our cohort, all patients reported articular involvement during their clinical evolution. Skin involvement (alopecia, malar rash, and hyperpigmentation) was present in seven patients. Sicca symptoms and Raynaud’s were present in five (62.5%) and four (50%) patients, respectively. Four patients (50%) had increased muscle enzymes. Three patients had cardiac involvement, and one had lung involvement. Anti-Ro52 was the most common overlapping antibody (50%). We identified three antibody subgroups: anti-Ro-52 ± MDA5/NXP2/U1-RNP (n=4), often associated with Raynaud’s and cardiac involvement, including the only death; isolated anti-Ku (n=3), with predominantly articular and sicca symptoms, and anti-cN1A (n=2), associated with SLE and cutaneous features. Compared to international cohorts, our patients shared similar articular symptom prevalence (France: 83%, Italy: 86%, Germany: 80%) and Raynaud’s rates (Portugal: 40.7%, France: 43%, Italy: 66.7%, ours: 50%). However, ILD was less frequent (25%) than in other international cohorts (up to 58%). All patients received corticosteroids.Conclusions Clinical manifestations largely mirrored data from other international cohorts, particularly in articular manifestations and Raynaud’s symptoms. Antibody clustering may reveal phenotypes with distinct prognoses. Our findings underscore the importance of considering autoantibody profiles in risk stratification and individualized treatment. Larger studies are needed to define clinical implications in this population.