Background: Patients with connective tissue disorders (CTD) are at increased risk of malignancies, especially lymphoproliferative disorders, both due to chronic inflammatory sequelae and also immunomodulating therapies. The risk of hepato-pancreato-biliary (HPB) malignancies is poorly studied in CTD and this is the first population-based study to estimate this risk. Methods: National Inpatient Database (NIS 1998–2010) was used to identify patients with systemic lupus erythematosus (SLE), discoid lupus (DL), rheumatoid arthritis (RA), juvenile RA, psoriasis, Sjögren's syndrome (SJS), systemic sclerosis (SS) and multiple sclerosis (MS) and demographic data were abstracted. The Standardized Incidence Ratio (SIR) for each malignancy was calculated to assess the true risk. Malignancy data were abstracted and converted to events/year/100,000 and compared against corresponding national incidence rates obtained from Surveillance Epidemiology and End Results (SEER) database. Results: 1,949,776 patients with CTD were identified in NIS database, of whom 4461(0.23%) suffered from at least one HPB cancer. The mean age of CTD patients with cancer was 68.3 years, higher to those without cancer (60.1). The female:male ratio in CTD and HPB cancer was 2.1:1. CTD and HPB cancer was highest in Caucasians. The in-hospital mortality was 7.6% in CTD with HPB cancer, compared to 2.2% in CTD without cancer. Patients with psoriasis are at higher risk of developing any HPB cancer and patients with DL and RA are at increased risk of gallbladder and pancreatic cancer (table). Conclusion: Only three types of CTD are at increased risk for developing HPB malignancies. Advanced age at the diagnosis of HPB cancer in CTD patients might indicate lag phase, which can be utilized with appropriate screening tools for early detection and treatment.Table 1Comparison of demographic characters of patients with connective tissue disorders with and without hepatico-pancreato-biliary malignanciesOverallCTD with HPB malignancyCTD without HPB malignancyN (%)1,949,7764,404 (0.23)1,945,372(99.77)Age60.1 ± 17.368.3 ± 11.760.1 ± 17.3Male: Female1: 3.21: 2.11: 3.2Race Caucasian1,121,648 (57.5)2,692 (61.1)1,118,956 (57.5) African American217,058 (11.1)372 (8.4)216,686 (11.1) Hispanic114,795 (5.9)291 (6.6)114,504 (5.9) Others496,275 (25.5)1050 (23.8)495,225 (25.5)Mortality42,945 (2.2)335 (7.6)42610 (2.2)N; number of patients. Open table in a new tab Table 2Standardized incidence ratio of hepato-pancreato-biliary malignancies in patients with connective tissue disordersGallbladder CaExtrahepatic biliary CaPancreatic CaLiver CaE1.21.912.58.6SLEO0.410.767.464.29SIR34.3139.9159.6749.92DiscoidO2.31.3815.666.45SIR191.9472.72125.3174.99Lupus RAO1.311.6712.955.79SIR109.5188.24103.6267.34Juvenile RAO0.4801.942.92SIR40.49015.5634.23PsoriasisO1.331.9512.9517.89SIR111.04102.63103.56208.09Sjögren's syndromeO1.10.6813.85.79SIR91.6736.01110.4167.4Systemic sclerosisO00.958.735.5SIR050.3169.863.93Multiple sclerosisO0.8450.67.252.07SIR70.4231.535824.09E: Expected events/year/100,000, O: Observed events/year/100,000, SIR = Standardized Incidence Ratio (observed events/expected events × 100). Open table in a new tab N; number of patients. E: Expected events/year/100,000, O: Observed events/year/100,000, SIR = Standardized Incidence Ratio (observed events/expected events × 100).