Standardized incidence ratios and risk factors for cancer in patients with systemic sclerosis: Data from the Spanish Scleroderma Registry (RESCLE)

Autoimmunity Reviews 21 (2022) 103167 Available online 2 August 2022 1568-9972/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/). Standardized incidence ratios and risk factors for cancer in patients with systemic sclerosis: Data from the Spanish Scleroderma Registry (RESCLE) Cristina Carbonell a , Miguel Marcos a , * , Alfredo Guill´ en-del-Castillo b , Manuel Rubio-Rivas c , Ana Argibay d , Adela Marín-Ballv´ e e , Ignasi Rodríguez-Pint´ o f , Maria Bald` a-Masmiquel g , Eduardo Callejas-Moraga h , Dolores Colunga i , Luis S´ aez-Comet j , Cristina Gonz´ alez-Ech´ avarri k , Norberto Ortego-Centeno l , Bego˜ na Marí-Alfonso h , Jos´ e-Antonio Vargas-Hitos m , Jos´ e-Antonio Todolí-Parra n , Luis Trapiella i , María-Teresa Herranz-Marín o , Mayka Freire p , Antoni Castro-Salom´ o q , Isabel Perales-Fraile r , Ana-Bel´ en Madro˜ nero-Vuelta s , María-Esther S´ anchez-García t , Manuel Ruiz-Mu˜ noz u , Andr´ es Gonz´ alez-García v , Jorge S´ anchez-Redondo w , Gloria de-la-Red-Bellvis x , Alejandra Fern´ andez-Luque y , Alberto Muela-Molinero z , Gema-María Lled´ o aa , Carles Tolosa-Vilella h , Vicent Fonollosa-Pla b , Antonio-Javier Chamorro a , 1 , Carmen-Pilar Sime´ on-Aznar b , 1 , on behalf of RESCLE Investigators, Autoimmune Diseases Study Group (GEAS) 2 a Department of Internal Medicine, Hospital Universitario de Salamanca, Universidad de Salamanca-IBSAL, Salamanca, Spain b Unit of Autoimmune Diseases, Department of Internal Medicine, Hospital Universitario Vall d’Hebron, Barcelona, Spain c Unit of Autoimmune Diseases, Department of Internal Medicine, Hospital Universitario de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain d Unit of Systemic Autoimmune Diseases and Thrombosis, Department of Internal Medicine, Complejo Hospitalario Universitario de Vigo. Vigo, Pontevedra, Spain e Unit of Autoimmune Diseases, Department of Internal Medicine, Hospital Clínico Universitario Lozano Blesa, IIS Arag´ on. Zaragoza, Spain f Department of Internal Medicine, Hospital Universitario Mútua Terrassa, Terrassa, Barcelona, Spain g Unit of Systemic Autoimmune Diseases, Department of Internal Medicine, Consorci Hospitalari de Vic. Vic, Barcelona, Spain h Department of Internal Medicine, Parc Taulí, Hospital Universitario, Sabadell, Barcelona, Spain i Department of Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain j Department of Internal Medicine, Hospital Universitario Miguel Servet, Zaragoza, Spain k Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, University of the Basque Country, Barakaldo, Spain l Inst Invest Biosanitaria Ibs Granada. Department of Internal Medicine, Unit of Systemic Autoimmune Diseases. Department of Medicine, Facultad de Medicina. Hospital Universitario San Cecilio. Granada. Spain m Department of Internal Medicine. Hospital Universitario Virgen de las Nieves. Granada, Spain n Department of Internal Medicine. Hospital Universitario y Polit´ ecnico La Fe. Valencia, Spain o Department of Internal Medicine. Hospital General Universitario "J.M. Morales Meseguer", Murcia, Spain p Unit of Autoimmune Diseases, Department of Internal Medicine. Hospital Clínico Universitario de Santiago. Santiago de Compostela, A Coru˜ na, Spain q Department of Internal Medicine. Hospital Universitario Sant Joan. Reus, Tarragona, Spain r Department of Internal Medicine. Hospital Universitario Rey Juan Carlos. M´ ostoles, Madrid, Spain s Department of Internal Medicine. Hospital General San Jorge. Huesca, Spain t Department of Internal Medicine. Hospital Universitario Virgen de Valme. Sevilla, Spain u Department of Internal Medicine. Hospital Universitario Fundaci´ on Alcorc´ on. Alcorc´ on, Madrid, Spain v Department of Internal Medicine. Hospital Universitario Ram´ on y Cajal. Madrid, Spain w Department of Internal Medicine. Hospital Universitario de M´ ostoles. M´ ostoles, Madrid, Spain x Unit of Systemic Autoimmune Diseases, Department of Internal Medicine. Fundaci´ o Hospital de l’Esperit Sant. Santa Coloma de Gramenet, Barcelona, Spain y Department of Internal Medicine. Hospital de Mollet. Mollet del Vall` es, Barcelona, Spain z Department of Internal Medicine. Complejo Asistencial Universitario de Le´ on. Le´ on, Spain aa Department of Autoimmune Diseases. Hospital Clinic. Barcelona, Spain * Corresponding author. E-mail address: [email protected] (M. Marcos). 1 Both authors are co-senior authors of this manuscript. 2 See Appendix 1 for members of the RESCLE Registry. Contents lists available at ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev https://doi.org/10.1016/j.autrev.2022.103167 Received 27 July 2022; Accepted 31 July 2022 Autoimmunity Reviews 21 (2022) 103167 2 ARTICLE INFO Keywords: Systemic sclerosis Cancer Anticentromere antibody Primary biliary cholangitis ABSTRACT Aim: Patients with systemic sclerosis (SSc) are at increased risk of cancer, a growing cause of non–SSc-related death among these patients. We analyzed the increased cancer risk among Spanish patients with SSc using standardized incidence ratios (SIRs) and identified independent cancer risk factors in this population. Material and methods: Spanish Scleroderma Registry data were analyzed to determine the demographic characteristics of patients with SSc, and logistic regression was used to identify cancer risk factors. SIRs with 95% confidence intervals (CIs) relative to the general Spanish population were calculated. Results: Of 1930 patients with SSc, 206 had cancer, most commonly breast, lung, hematological, and colorectal cancers. Patients with SSc had increased risks of overall cancer (SIR 1.48, 95% CI 1.36–1.60; P <0.001), and of lung (SIR 2.22, 95% CI 1.77–2.73; P <0.001), breast (SIR 1.31, 95% CI 1.10–1.54; P =0.003), and hematological (SIR 2.03, 95% CI 1.52–2.62; P <0.001) cancers. Cancer was associated with older age at SSc onset (odds ratio [OR] 1.22, 95% CI 1.01–1.03; P <0.001), the presence of primary biliary cholangitis (OR 2.35, 95% CI 1.18–4.68; P =0.015) and forced vital capacity <70% (OR 1.8, 95% CI 1.24–2.70; P =0.002). The presence of anticentromere antibodies lowered the risk of cancer (OR 0.66, 95% CI 0.45–0.97; P =0.036). Conclusions: Spanish patients with SSc had an increased cancer risk compared with the general population. Some characteristics, including specific autoantibodies, may be related to this increased risk. 1. Introduction Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vascular and immunological changes that alter the normal architecture of tissues and lead to the development of fibrosis [1,2]. The leading causes of death related to SSc are mainly secondary to lung involvement, including pulmonary hypertension and interstitial lung disease (ILD). However, improvement of the management of patients with SSc and the increase in survival in recent decades have contributed to the reduction of SSc-related causes of death in favor of non–SScrelated deaths in this population. Among the most frequent of these is death from cancer, the rate of which ranges from 5% to 30% [3–7]. Recent series show a temporal trend of an increasing cancer prevalence among patients with SSc. Although conflicting results have been reported, likely due to the heterogeneity of study designs and differences among study populations, most authors describe breast, lung, and hematological cancers as most prevalent. Several studies have shown that the incidence of these neoplasias is higher among patients with SSc than in the general population [8–10], likely due to factors such as the existence of a hyperinflammatory chronic state, genetic factors, use of immunosuppressive therapies, and the presence of SSc-related autoantibodies [11,12]. Several cancer risk factors among patients with SSc have been identified, although evidence is scarce. For instance, anti–polymerase RNA III (anti-RNAP III) and anti–Scl-70 antibodies have been described as risk factors for lung cancer in several cohorts of patients [13–18], but evidence for many other factors has not been consistently reproduced. In addition, patients’ sex, geographical location, and ethnic background should be considered when analyzing the risk of cancer, reinforcing the need for further and more precise epidemiological studies of the risk of SSc-related cancer in different regions [19,20]. Such data will aid the development of preventive programs and identification of susceptible patients at risk of specific cancers. Thus, the aims of this study were to examine the increased risk of cancer among Spanish patients with SSc through the analysis of standardized incidence ratios (SIRs), and to define independent risk factors for cancer in this population. 2. Material and methods 2.1. Study design We analyzed data from a nationwide multicenter observational SSc registry in Spain (Registro Espa˜ nol de eSCLErodermia [RESCLE]), managed by the Autoimmune Diseases Study Group of the Spanish Society of Internal Medicine. 2.2. Patients and data collection Included patients with SSc met the 2013 American College of Rheumatology/European League Against Rheumatism criteria [21] and/or the modified criteria proposed by LeRoy and Medsger [22] in 1988, to avoid missing patients with sclerosis sine scleroderma who did not meet the former. Data were collected retrospectively until 2006 and prospectively thereafter until October 2018. Forty hospitals nationwide contributed to the registry during this period. All participating centers obtained local ethics committee approval. According to the RESCLE protocol, data on patients’ demographic and clinical characteristics, mortality, specific and other SSc-related autoantibodies, diagnostic procedures, SSc-related treatments, and cancer were collected when patients were included in the study and updated annually. Disease onset was defined as the appearance of the first clinical manifestation of SSc, and each SSc diagnosis was recorded on the date on which the first physician determined the presence of the disease. ILD was defined by the detection of a pulmonary interstitial pattern by high-resolution computed tomography [23]. Pulmonary hypertension (PH) was defined as systolic pulmonary arterial pressure (PAP) >40 mmHg, detected by Doppler echocardiography or when mean PAP ≥25 mmHg by right catheterization, which was the definition in use during the study period [24]. Detailed definitions of SSc cutaneous subsets, clinical features, organ involvement, nailfold capillaroscopy patterns, immunological features, and SSc- and non–SScrelated causes of death have been published elsewhere [25]. The performance of autoantibody analysis depended on the availability of analytical tools in each participating center. To analyze relationships between pharmacological treatments and cancer development, data on the treatments used for conditions related to autoimmune disease prior to neoplasm appearance were collected. Data regarding the cancer location, histological type, and date of diagnosis were also collected. Multiple neoplasias were those that appeared in more than one location in the same patient, but data on the time elapsed between their appearance were not available. Cancer-associated scleroderma was defined as tumor occurrence from 3 years before to 3 years after scleroderma onset [16]. 2.3. Statistical analyses Data are presented as means and standard deviations (SDs) for normally distributed continuous variables, as medians with interquartile ranges for non-normally distributed continuous variables, and as numbers and percentages for categorical variables. Qualitative variables were compared using χ 2 and Fisher’s exact-tests, and quantitative variables were compared using Student’s t-test and the Mann–Whitney U test. SIRs with exact Poisson 95% confidence intervals (CIs) were C. Carbonell et al. Autoimmunity Reviews 21 (2022) 103167 3 calculated as ratios of cancer incidence in patients with SSc (observed cases) to that in the general Spanish population (expected cases), weighted according to age and sex. Cancer incidence data for Spain were obtained from the GLOBOCAN database of incident cancers (September 2018 version) of the Global Cancer Observatory platform of the International Agency for Cancer Research [26]. Univariable and multivariable logistic regression was used to determine the associations of different variables with cancer. Variables with P values <0.05 in the univariable analysis and those deemed to be of clinical significance to the outcome were included in the multivariable logistic regression analysis. Kaplan–Meier curves and Mantel–Cox analysis were used to estimate cumulative survival from the time of the first SSc symptom in SSc patients with cancer compared with patients without this diagnosis. Two-tailed P values ≤0.05 were considered to be significant. 3. Results 3.1. Characteristics of patients with SSc with and without cancer The cohort consisted of 1930 patients with SSc, of whom 206 (10.7%) had neoplasias (Table 1). The mean age at the time of cancer diagnosis was 62.0 (SD 12.9) years, and patients with cancer had a mean age at the time of SSc diagnosis of 57.8 (SD 13.9) years. Those who developed cancer were older than those who did not at the times of SSc onset (49.3 [SD 17.0] vs. 45.9 [SD 16.1] years, P =0.001) and SSc diagnosis (57.8 [SD 13.9] vs. 51.9 [SD 15.6] years, P <0.001). In addition, the time from symptom onset to SSc diagnosis was longer in patients with cancer. 3.2. Cancer locations and temporal associations between cancer and SSc The most frequent malignancies were breast (n =47 [22.8%]), lung (n =29 [14.1%]), hematological (n =20 [9.7%]), colorectal (n =18 [8.7%]), and uterine (n =14 [6.8%]) cancers. Locations for which fewer than 10 cancer cases were recorded included the kidney, prostate, ovary, brain, stomach, esophagus, pancreas, oropharynx/larynx, and bladder. Overall, adenocarcinoma was the most common histological type (n = 78 [42.3%]), followed by squamous carcinoma (n =17 [10.8%]). Fig. 1 shows the temporal relationship between cancer occurrence and both the clinical onset of SSc and SSc diagnosis. Considering clinical onset of SSc, 34 (18.9%) tumors were considered to be cancer-associated scleroderma (Fig. 1A). One hundred thirty-three (70%) cases of cancer were diagnosed after the diagnosis of SSc and two temporal trends were noted: 48 (25.2%) tumors developed three years after SSc diagnosis and 49 (26%) tumors developed 10 years after SSc diagnosis (Fig. 1B). 3.3. Risk of cancer among patients with SSc compared with the general population The global cancer risk was greater in our cohort of patients with SSc than in the general population (SIR 1.48, 95% CI 1.36–1.60; P <0.001; Table 2). In addition, the incidences of lung (SIR 2.22, 95% CI 1.77–2.73; P <0.001), breast (SIR 1.31, 95%CI 1.10–1.54; P =0.003), and hematological (SIR 2.03, 95% CI 1.52–2.62, P <0.001) cancers were higher in the SSc cohort. No overall increased risk was observed for colorectal cancer (SIR 1.12, 95% CI 0.84–1.45; P =0.388). An increased risk of colorectal cancer was noted for women (SIR 1.57, 95% CI 1.17–2.04; P =0.004), whereas men had no increased risk of colorectal (SIR 0.94, 95% CI 0.71–1.19; P =0.643) or hematological (SIR 0.94, 95% CI 0.62–1.33; P =0.829) cancer. 3.4. Cancer risk factors Regarding lung involvement, these patients also had more PH (41.1% vs. 28.6%, P =0.010) and ILD (52.7% vs. 40.5%, P <0.001). Patients with cancer had worse respiratory function test results, Table 1 Demographic and clinical characteristics of patients with SSc with and without cancer. Patient characteristics SSc patients without cancer SSc patients with cancer P n =1729 n =206 n/N (%) n/N (%) Demographics Female 1534 /1724 (89.0) 177 /206 (85.9) 0.201 Age at SSc onset, years (SD) 45.9 (16.1) 49.3 (17.0) 0.007 Age Diagnosis of SSc 51.9 (15.6) 57.8 (13.9) <0.001 Follow-up since first clinical manifestation, years (SD) 14.1 (11.5) 18.1 (14.5) 0.005 Years from onset SSc to 6.3 (8.9) 8.7 (13.0) 0.017 diagnosis, years (SD) Limited SSc 1019 (59.5) 128 (63.7) 0.255 Diffuse SSc 351 (20.5) 44 (21.9) 0.645 SSc sine scleroderma 184 (10.7) 21 (10.4) 1.000 Very early SSc 43 (2.5) 1 (0.50) 0.080 Pre-SSc 117 (6.8) 7 (3.5) 0.070 Smoking history Current 190 /1442 (13.2) 19 /190 (10.0) 0.249 Ex smoker 248 /1442 (17.2) 42 /190 (22.1) 0.106 Non smoker 1004 /1442 (69.6) 129 /190 (67.9) 0.616 Arterial hypertension 451 /1455 (31.0) 77 /190 (40.5) 0.010 Clinical manifestations Peripheral vascular involvement Raynaud’s phenomenon 1641 /1713 (95.8) 191 /205 (93.2) 0.105 Digital ulcers 667 /1720 (38.8) 74 /205 (36.1) 0.495 Telangiectasias 975 /1713 (56.9) 122 /205 (59.5) 0.502 Acrosteolysis 96 /1161 (8.3) 14 /122 (11.5) 0.233 Musculoskeletal Calcinosis 351 /1717 (20.4) 45 /204 (22.1) 0.583 Arthritis 239 /1163 (20.6) 31 /122 (25.4) 0.242 Myositis 152 /1165 (13.0) 18 /123 (14.6) 0.578 Tendinitis 62 /1161 (5.3) 13 /123 (10.6) 0.026 Joint contractures 120 /639 (18.8) 20 / 76 (26.3) 0.127 Digestive involvement Esophageal motility disorders 1001 /1702 (58.8) 126 /204 (61.8) 0.451 Barret’s esophagus 41 /783 (5.2) 2 /90 (2.2) 0.303 Esophagitis 152 /506 (30.0) 25 /70 (35.7) 0.336 Gastritis 218 /1167 (18.7) 30 /142 (21.1) 0.496 Intestinal involvement 125 /1164 (10.7) 19 /142 (13.4) 0.323 Malabsorption 99 /1435 (6.9) 17 /159 (10.7) 0.105 Primary biliary cholangitis 72 /1708 (4.2) 18 /203 (8.9) 0.007 Lung involvement ILD 694 /1714 (40.5) 108 /205 (52.7) <0.001 FVC (%) in ILD, mean (SD) 75.9 (23.0) 74.3 (23.6) 0.514 FVC <70% in ILD, mean (SD) 254/633 (40.1) 48/98 (49.0) 0.100 FVC (%), mean (SD) 87.0 (22.5) 82.4 (23.4) 0.042 DLCO (%), mean (SD) 77.4 (42.2) 66.1 (22.5) 0.430 DLCO / AV (%), mean (SD) 82.8 (42.7) 75.4 (22.7) 0.104 ILD with FVC <70% 316 /1484 (21.3) 57 /171 (33.3) <0.001 Ground glass pattern 370 /1040 (35.6) 65 /158 (41.1) 0.184 Reticular pattern 334 /1127 (29.6) 63 /163 (38.7) 0.023 PH (echocardiographic data) 262 / 917 (28.6) 44 /107 (41.1) 0.010 PH (catheterization) 128 / 176 (72.7) 23 / 34 (67.6) 0.538 Cardiac involvement (continued on next page) C. Carbonell et al. Autoimmunity Reviews 21 (2022) 103167 4 specifically a decrease in the forced vital capacity (FVC) to <70% of the expected value (33.3% vs. 21.3%, P <0.001), and a greater frequency of the radiological reticular pattern (38.7% vs. 29.6%, P =0.023). The frequency of arterial hypertension was greater among patients with SSc with than among those without cancer (40.5% vs. 31.0%, P =0.010). Regarding cardiac involvement, a larger proportion of patients with cancer had left ventricular diastolic dysfunction (48.0% vs. 33.3%, P = 0.001). And at the digestive level, primary biliary cholangitis (PBC) was more common among patients with cancer (8.9% vs. 4.2%, P =0.007). Patients with cancer had higher frequencies of positivity for anti-RNAP III (23.8% vs. 10.4%, P =0.019) and anti-PM-Scl (13.4% vs. 7.0%, P = 0.024) antibodies, but a lower frequency of anti-centromere antibodies (ACAs; 40.8% vs. 49.3%, P =0.033). Among SSc treatments (used before the appearance of neoplasia in cases of cancer), calcium antagonists (28.6% vs. 47.3, P <0.001), proton pump inhibitors (PPIs; 33.0% vs. 47.9%, P <0.001), antiplatelet drugs (18.4% vs. 27.3%, P =0.006), specific vasodilators (9.7% vs. 22.4%, P <0.001) and immunosuppressants (12.1% vs. 18.7%, P =0.021), in particular azathioprine (2.4% vs. 5.8%, P =0.049) and mycophenolate (4.9% vs. 9.7%, P =0.021), were used significantly less frequently for patients with than for those without cancer (Table 3). No differences between SSc patients with and without cancer were detected according to SSc subtype or capillaroscopic pattern. In the multivariable logistic regression analysis, variables significantly associated with higher risk of cancer were older age at the time of SSc onset (odds ratio [OR] 1.22, P <0.001), and the presence of PBC (OR 2.35, P =0.015), ILD with FVC <70% of the expected value (OR 1.83, P =0.002). The presence of ACAs (OR 0.66, P =0.036), the use of calcium channel blockers (CCBs; OR 0.54, P =0.002), and the use of pulmonary vasodilators (OR 0.46, P =0.006; Table 4) were associated with a lower risk of cancer. 3.5. Risk factors for different types of cancer Independent risk factors for cancer in patients with SSc by location are shown in Table 4. 3.5.1. Breast cancer The breast was the most frequent tumor location; the prevalence in our cohort was 2.6% (n =47, all female). Patients with breast cancer were older than those without cancer at the time of SSc onset (58.9 vs. 51.9 years, P =0.004). In the multivariable logistic regression analysis, independent risk factors for the development of breast cancer were puffy hands as the first manifestation of SSc (OR 6.40, P =0.005), the presence of PBC (OR 5.71, P <0.001), ILD (OR 3.29, P <0.001), the presence of anti-Ro antibody (OR 2.14, P =0.048), less use of immunosuppressants (OR 0.19, P =0.027), and less use of PPIs (OR 0.24, P <0.001). 3.5.2. Lung cancer The prevalence of lung cancer in the cohort was 1.2%. Twenty-seven (96.4%) cases of lung cancer occurred after SSc diagnosis. In the multivariable logistic regression analysis, lung cancer was associated with older age at the time of SSc onset (OR 1.06, P =0.002) and the presence of anti-Scl-70 antibodies (OR 2.61, P =0.049), whereas the Table 1 (continued) Patient characteristics SSc patients without cancer SSc patients with cancer P n =1729 n =206 n/N (%) n/N (%) LVEF <50% 30 /1304 (2.3) 6 /175 (3.4) 0.428 LVEF (%), mean (SD) 63.4 (6.9) 62.9 (8.2) 0.214 PAPs (mm Hg), mean (SD) 36.8 (17.6) 39.8 (15.4) <0.001 TRV, mean (SD) 2.3 (0.9) 2.4 (0.9) <0.001 VI diastolic dysfunction 345 /1037 (33.3) 60 /125 (48.0) 0.001 Pleural effusion 100 /1266 (7.9) 13 /172 (7.6) 1.000 Pericarditis 72 /823 (8.7) 9 /100 (9.0) 0.853 Ischemia 100 /826 (12.1) 19 /100 (19.0) 0.058 Conduction disturbances 177 /826 (21.4) 30 /99 (30.3) 0.055 Kidney involvement Scleroderma renal crisis 38 /1716 (2.2) 4 /204 (2.0) 1.000 Other manifestations Sicca syndrome 125 /1416 (8.8) 15 /185 (8.1) 0.890 Peripheral neuropathy 492 /1719 (28.6) 70 /203 (34.5) 0.087 Fulfilment of ACR SSc criteria 1359 /1480 (91.8) 174 /189 (92.1) 1.000 SSc, systemic sclerosis; SD, standard deviation; ILD, interstitial lung disease; FVC, forced vital capacity; DLCO, diffusing capacity of the lung for carbon monoxide; AV, alveolar volume; PH, pulmonary hypertension; LVEF, left ventricular ejection fraction; PAPs, systolic pulmonary artery pressure; TRV, ventricular repolarization disorder; ACR, American College of Rheumatology. Clinical onset of SSc 35 1>10 -3 -5 -1 <10 Years Cancers n (%) 24 (12.6) 10 (5.2) 13 (6.8) 11 (5.8) 16 (8.4) 32 (16.8) 8 (4.2) 28 (14.7) 49 ( 25.7) SSc diagnosis Cancers n (%) 10 (5.6) 5 (2.8) 10 (5.6) 3 (1.7) 8 (4.4) 13 (7.2) 18 (10.0) 28 (15.6) 85 (47.2) 35 1>10 -3 -5 -1 <10 Years A B 0 0 Fig. 1. A. Temporal relationship between cancer occurrence and the clinical onset of systemic sclerosis (SSc). B. Temporal relationship between cancer occurrence and SSc diagnosis. C. Carbonell et al. Autoimmunity Reviews 21 (2022) 103167 5 presence of ACAs protected against lung cancer development (OR 0.15, P =0.018). 3.5.3. Hematological cancer The prevalence of hematological malignancies was 1.1%. In the multivariable logistic regression analysis, these malignancies were associated with older age at the time of SSc onset (OR 1.06, P =0.003). The development of this neoplasia was associated with cardiac involvement, specifically a larger proportion of conduction disorders (5/ 7 [71.4%] vs. 177/826 [21.4%], P =0.007), and left ventricular diastolic dysfunction (7/10 [70.0%] vs. 345/1037 [33.3%], P =0.036), but these results could not be confirmed in the multivariate analysis. 3.5.4. Colorectal cancer The prevalence of colon cancer was 1%. In the multivariable logistic regression analysis, colorectal cancer was associated with ILD with FVC <70% of the expected value (OR 5.21, P =0.007), whereas the use of PPIs protected against the development of this cancer (OR 0.18, P = 0.031). 3.5.5. Multiple neoplasias Seventy-two patients had more than one type of neoplasm. Risk factors for multiple neoplasias were older age at the time of SSc onset (OR 1.05, P <0.001) and ILD with FVC <70% of the expected value (OR 2.72, P <0.001), whereas the use of aspirin protected against multiple neoplasia development (OR 0.29, P =0.005). 3.6. Mortality, causes of death, and survival In total, 355 (18.4%) patients (284 [16.5%] without and 71 [34.5%] with cancer) died (Table 3). Of these deaths, 171 were considered to be SSc related, 163 were not, and the cause of death was unclear or unknown in 21 cases. A total of 38 patients died because of cancer. SSc-related deaths were slightly more common than non–SSc-related deaths (171/355 [48.2%] vs. 163/355 [45.6%]). The most prevalent cause of death was pulmonary involvement, specifically PH and ILD, representing 16.6% and 11.3% of deaths, respectively; cancer ranked third, representing 10.7% of all deaths. The mortality rate was higher for patients with than for those without cancer (71/206 [34.5%] vs. 284/1724 [16.5%], P <0.001). Significantly fewer SSc-related deaths occurred among patients with than among those without neoplasia (15/66 [22.7%] vs. 156/268 [58.2%], P <0.001). The primary causes of death among patients with cancer were non–SSc related (77.3%), most commonly cancer (38/71 [53.5%]), followed by sepsis (3/71 [4.2%]). The primary causes of death among patients with SSc without cancer were SSc related (58.2%), most commonly PH (54/284 [13.4%]), ILD (38/284 [19.0%]), and PH with ILD (23/284 [8.1%]). Cumulative survival rates among patients with cancer declined from 92.5% at 5 years to 68.4% at 20 years and 53.0% at 30 years after the onset of the disease compared with those of patients without cancer (Table 3, Fig. 2). 4. Discussion This report is the first description of the analysis of multicenter data on the characteristics of patients with cancer and SSc in Spain, and the evaluation of the risk of neoplasia in this population. We found an increased global risk of cancer among patients with SSc relative to that in the general population, as well as increased risks of specific cancer types (lung, breast, and hematological). Factors associated with the greater risk of cancer were the presence of PBC and moderate or severe ILD, whereas the presence of ACAs was associated with a reduced cancer risk. Our findings agree with reports that the most prevalent cancers in patients with SSc are breast, lung, and hematological malignancies [8–10]. Most reports published before 2014 describe lung cancer as the most frequent neoplasm, followed by breast cancer [27–34]. This relationship is reversed in most recent studies, coinciding with our results [16,35–39]. The increased detection of breast neoplasia, facilitated by screening established in the last decade, may have contributed to this change. Hematological cancers have consistently ranked as the second or third most common cancer type in patients with SSc in many studies [13,27,28,34,35,39–43]. Colorectal cancer among patients with SSc is poorly represented in the literature [8], although it ranked fourth, as in the present study, in a recent multicenter Australian study with a large sample size [39]. In addition, cancer was the third leading cause of death in our series, and cancer diagnosis was associated with greater all-cause mortality. These findings are consistent with those from other cohorts, highlighting the relevance of this association [4,5,39]. According to our SIR calculation, patients with SSc had a 1.5-times greater risk of cancer compared with the general population in Spain. This increased risk was confirmed for lung, hematological, and breast cancers, and for colorectal cancer among women. Consistent with these results, the global risk of cancer has been reported to be increased in patients with SSc (by 1.5–4 times that in the general population), and increased risks of lung and hematological neoplasms have been reported [8–10]. Conflicting results have been found for breast cancer, with some studies showing an association [17,32,42] but others, including three meta-analyses [8–10], have failed to confirm this finding [28,39,44]. Differences in screening programs or inclusion criteria among studies may have contributed to this discrepancy. In our analysis of the clinical manifestations of autoimmune disease, the presence of PBC was associated with cancer in general and with breast cancer in particular; such results have not been reported previously for an SSc cohort but the association of PBC and breast cancer have been noticed in the general population [45]. PBC and limited SSc are known to coincide as Reynolds syndrome [46]. The estimated prevalence of SSc in patients with PBC is 5–15%, and that of PBC in patients Table 2 Overall cancer risk and risk of cancer by location for patients with systemic sclerosis compared with the general population. Location Observed cases Expected cases SIR P* Total Global cancer 572.2 387.7 1.48 (1.36–1.60) <0.001 Lung 86.7 39.1 2.22 (1.77–2.73) <0.001 Breast 143.2 109.3 1.31 (1.10–1.54) 0.003 Colorectal 54.4 48.5 1.12 (0.84–1.45) 0.388 Hematological 56.4 27.8 2.03 (1.52–2.62) <0.001 Global cancer 548.4 322.5 1.70 (1.56–1.85) <0.001 Lung 70.4 20.3 3.47 (2.69–4.36) <0.001 Woman Breast 143.2 109.3 1.31 (1.10–1.54) 0.003 Colorectal 52.8 33.7 1.57 (1.17–2.04) 0.004 Hematological 55.5 22.4 2.48 (1.87–3.22) <0.001 Men Global cancer 783.0 469.2 1.67 (1.55–1.79) <0.001 Lung 191.0 61.0 3.13 (2.70–3.61) <0.001 Colorectal 61.5 65.6 0.94 (0.71–1.19) 0.643 Hematological 29.0 30.9 0.94 (0.62–1.33) 0.829 SIR, standardized incidence ratio. Global cancer refers to the total number of cancers in all locations. *Null hypothesis, SIR =1; alternative hypothesis, SIR ∕= 1. The data on observed and expected values correspond to the incidence rate per 100,000 person-years. C. Carbonell et al. Autoimmunity Reviews 21 (2022) 103167 6 Table 3 Immunological and treatment-related features, causes of death, and survival in patients with systemic sclerosis with and without malignancy. Patient characteristics SSc patients without cancer SSc patients with cancer P n =1729 n =206 n/N (%) n/N (%) Autoantibodies Scleroderma-specific antibodies ANA determinations 1603 /1721 (93.1) 187 /205 (91.2) 0.312 Speckled pattern 523 /1559 (33.5) 59 /179 (33.0) 0.933 Centromeric pattern 511 /1559 (32.8) 53 /179 (29.6) 0.448 Homogeneous pattern 197 /1559 (12.6) 28 /179 (15.6) 0.289 Nucleolar pattern 222 /1559 (14.2) 22 /179 (12.3) 0.570 Nucleolar / speckled pattern 59 /1559 (3.8) 7 /179 (3.9) 0.838 Homogeneous / nucleolar pattern 47 /1559 (3.0) 10 /179 (5.6) 0.075 Topoisomerase I (Scl-70) 305 /1534 (19.9) 41 /190 (21.6) 0.566 Centromere 761 /1545 (49.3) 73 /179 (40.8) 0.033 RNAP III 39 / 376 (10.4) 10 / 42 (23.8) 0.019 PM-Scl 65 / 922 (7.0) 15 /112 (13.4) 0.024 Ro 214 /1528 (14.0) 31 /190 (16.3) 0.380 La 57 /1511 (3.8) 6 /191 (3.1) 0.839 Sm 16 /1483 (1.1) 3 /181 (1.7) 0.453 RNP 88 /1506 (5.8) 6 /184 (3.3) 0.174 Mitochondrial 96 / 837 (11.5) 16 /112 (14.3) 0.434 Thyroid 125 / 477 (26.2) 10 / 60 (16.7) 0.117 Ku 10 / 355 (2.8) 2 / 45 (4.4) 0.633 Rheumatoid factor 287 /1253 (22.9) 33 /153 (21.6) 0.760 Citrullinated anti-cyclic peptide 18 / 297 (6.1) 1 / 41 (2.4) 0.489 ANA positive and negative ATA, ACA, anti-RNAP III and anti-PM-Scl 89 / 308 (28.9) 9 / 33 (27.3) 1.000 Treatment Calcium antagonists 815/ 1724 (47.3) 59/ 206 (28.6) <0.001 Antiplatelet 471/ 1724 (27.3) 38/ 206 (18.4) 0.006 ASA 426/ 1724 (24.7) 32/ 206 (15.5) 0.003 Anticoagulants 98/ 1724 (5.7) 10/ 206 (4.9) 0.749 Specific vasodilators 387/ 1724 (22.4) 20/ 206 (9.7) <0.001 ERA 323/ 1724 (18.7) 17/ 206 (8.3) <0.001 PDF-5 149/ 1724 (8.6) 6/ 206 (2.9) 0.003 PGL 109/ 1724 (6.3) 4/ 206 (1.9) 0.007 Antifibrotic 103/ 1724 (6.0) 14/ 206 (6.8) 0.642 Immunosuppressants 322/ 1724 (18.7) 25/ 206 (12.1) 0.021 Azathioprine 100/ 1724 (5.8) 5/ 206 (2.4) 0.049 Cyclosporine 8/ 1724 (0.5) 1/ 206 (0.49) 1.000 Phosphamide cycles 117/ 1724 (6.8) 12/ 206 (5.8) 0.767 Methotrexate 83/ 1724 (4.8) 6/ 206 (2.9) 0.290 Mycophenolate 168/ 1724 (9.7) 10/ 206 (4.9) 0.021 Tacrolimus 17/ 1724 (1.0) 1/ 206 (0.49) 0.712 Biological therapy 41/ 1724 (2.4) 2/ 206 (0.97) 0.313 Rituximab 33/ 1724 (1.9) 2 / 206 (0.97) 0.576 Anti-TNF 3/ 1724 (0.2) 0/ 206 (0) 1.000 PPI 826/ 1724 (47.9) 68/ 206 (33.0) <0.001 Corticosteroids 431 (25.0) 42 (20.4) 0.170 NSAID 61 (3.5) 3 (1.5) 0.147 Antioxidants 79 (4.6) 7 (3.4) 0.591 Antimalarials 132 (7.7) 11 (5.3) 0.262 ACEI 251/ 1724 (14.6) 22/ 206 (10.7) 0.139 ARA II 171/ 1724 (9.9) 13/ 206 (6.3) 0.103 SSRI 115/ 1724 (6.7) 6/ 206 (2.9) 0.033 Causes of death Total deaths 284 /1724 (16.5) 71 /206 (34.5) <0.001 SSc-related deaths 156 /284 (54.9) 15 /71 (21.1) 0.001 ILD 38 /284 (13.4) 2 /71 (2.8) 0.011 PH 54 /284 (19.0) 5 /71 (7.0) 0.013 PH and ILD 23 /284 (8.1) 3 /71 (4.2) 0.319 ILD/ PAH / PH and ILD 115 /284 (40.5) 10 /71 (14.1) <0.001 Scleroderma renal crisis 17 /284 (6.0) 1 /71 (1.4) 0.140 Arrhythmias 4 /284 (1.4) 0 /71 (0) 0.588 Ischemic cardiomyopathy without CVRF 6 /284 (2.1) 1 /71 (1.4) 1.000 Sepsis 2 /284 (0.7) 0 /71 (0) 1.000 Other causes related to SSc 12 /284 (4.2) 3 /71 (4.2) 1.000 Non-SSc related deaths 112 /284 (39.4) 51 /71 (71.8) 0.05 Stroke 3 /284 (1.1) 0 /71 (0) 1.000 Chronic renal failure 3 /284 (1.1) 0 /71 (0) 1.000 COPD 2 /284 (0.7) 0 /71 (0) 1.000 Sepsis 19 /284 (6.7) 3 /71 (4.2) 0.587 Pulmonary embolism 4 /284 (1.4) 0 /71 (0) 0.588 Neoplasia 0 /284 (0) 38 /71 (53.5) <0.001 Arrhythmias 2 /284 (0.7) 0 /71 (0) 1.000 (continued on next page) C. Carbonell et al. Autoimmunity Reviews 21 (2022) 103167 7 with SSc is 2–4.7%, higher than in the general population. Although we cannot explain the relationship between autoimmunity and overall or breast cancer, the presence of PBC in patients with SSc can be considered to be a risk factor for the development of cancer. Another relevant finding of this study is the association in a multivariable analysis between cancer and ILD with FVC <70% of the expected value. Other authors have reported worse SSc prognoses with more severe lung disease [47] and a greater risk of lung cancer in patients with ILD and SSc [12,28,30,32]. As lung disease is caused by endothelial cell injury and subsequent vascular damage, cancer development in this setting may be related to increased inflammation, although more data are needed to confirm this association. The main result of our multivariable analysis of antibody associations with cancer was that the presence of ACAs was significantly less frequent in patients with SSc and cancer than it was in those without cancer. This finding is consistent with the results of Igusa et al. [16] among patients with SSc, who reported that patients with ACA positivity had a lesser risk of cancer development during follow-up (SIR 0.59, 95% CI 0.44–0.76). Other authors have also reported that the presence of ACAs reduces the cancer risk compared with the presence of other autoantibodies [13]. In contrast, Higuchi et al. [48] identified this autoantibody as a risk factor for cancer, although their sample was small (45 patients, of whom 7 had neoplasias). Overall, the data clearly suggest that ACAs are associated with a reduced risk of cancer among patients with SSc. As the presence of this autoantibody has been correlated with a less severe form of SSc and improved survival, the presence of less severe organ damage and reduced inflammation may explain the association [49–51]. Anti-RNAP III has also been reported to be a risk factor for cancer [13–16,52,53]. Given the small number of patients with this autoantibody in our cohort, assessment of its significance in a multivariable analysis in this study was difficult. Our multivariable analysis revealed the novel finding that anti-Ro was a risk factor for breast cancer, and that anti-Scl-70 was a risk factor for lung cancer, confirming previously reported associations [17,18,28]. Although the significance of these relationships was limited by the sample size and the performance of multiple comparisons, the detection of certain autoantibodies or combinations thereof may aid the identification of patients at greater risk of cancer [15,16,54]. We also identified the late onset of SSc as a risk factor for neoplasia, as reported previously [15,32,42]. This relationship may be explained by the likelihood that immunosenescence favors carcinogenesis in the context of this disease. Finally, we found several associations between certain drugs (CCBs, PPIs, and acetylsalicylic acid [ASA]) and a reduced risk of cancer. We observed an inverse association between CCB use and the risk of cancer; other authors have reported otherwise [39]. Bernal Bello et al. [55] noted that CCB use among patients with SSc and cancer has rarely been analyzed, whereas several studies have analyzed the relationship between CCB use and breast cancer in general populations; controversial results have been reported, and no clear pathogenic explanation can be offered for either finding. The observed protective effect of ASA against multiple neoplasias in our cohort aligns with the protective effect of this drug against cancer in the general population [56] and other SSc cohorts [35,57]. Aspirin may inhibit eicosanoid pathways, leading to the reduced release of thromboxane-mediated tumor growth factors that modulate apoptosis and cell proliferation [58]. Further studies are needed to analyze the role of this drug in carcinogenesis among patients Table 3 (continued) Patient characteristics SSc patients without cancer SSc patients with cancer P n =1729 n =206 n/N (%) n/N (%) Ischemic cardiomyopathy 1 /284 (0.4) 0 /71 (0) 1.000 Other causes not related to SSc 78 /284 (27.5) 10 /71 (14.1) 0.021 Unknown 16/284 (5.6) 5/71 (7.0) 0.673 Cumulative survival since the first symptom of SSc (N =1820) 5 years 0.960 0.925 0.038 10 years 0.919 0.878 0.073 20 years 0.806 0.684 0.001 30 years 0.682 0.530 <0.001 SSc, systemic sclerosis; ANA, antinuclear antibody; RNP, ribonucleoprotein; RNAP III, RNA polymerase III; ATA, anti-topoisomerase antibody; ACA, anti-centromere antibody; ASA, acetylsalicylic acid; ERA, endothelin I receptor antagonist; PDF-5, phosphodiesterase 5 inhibitor; PGL, prostaglandins; TNF, tumor necrosis factor; PPI, proton pump inhibitor; NSAID, non-steroidal anti-inflammatory drugs; ACEI, angiotensin converting enzyme inhibitors; ARA II, angiotensin II receptor antagonist; SSRI, selective serotonin reuptake inhibitor; ILD, interstitial lung disease; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; CVRF, cardiovascular risk factors; COPD, chronic obstructive pulmonary disease. Table 4 Independent risk factors for cancer in patients with SSc by location, as determined by multivariate analysis. Cancer location Risk factor OR 95% CI P Global cancer (n = 206) Increasing age at SSc onset 1.22 1.01–1.03 <0.001 PBC 2.35 1.18–4.68 0.015 ILD with FVC <70% 1.83 1.24–2.70 0.002 ACA 0.66 0.45–0.97 0.036 Use of calcium channel blockers 0.54 0.37–0.79 0.002 Use of specific vasodilators 0.46 0.26–0.80 0.006 Breast cancer (n = 47) Puffy hands 6.40 1.73–23.64 0.005 PBC 5.71 2.16–15.09 <0.001 ILD 3.29 1.69–6.39 <0.001 Anti-Ro antibody 2.14 1.01–4.56 0.048 Use of immunosuppressants 0.19 0.04–0.83 0.027 Use of PPI 0.24 0.11–0.54 <0.001 Lung cancer (n =29) Increasing age at SSc onset 1.06 1.02–1.10 0.002 Anti-Scl-70 antibodies 2.61 1.00–6.79 0.049 ACA 0.15 0.03–0.72 0.018 Hematological cancer (n =20) Increasing age at SSc onset 1.06 1.02–1.09 0.003 Colorectal cancer (n =18) ILD with FVC <70% 5.21 1.57–17.33 0.007 Use of PPI 0.18 0.04–0.85 0.031 Multiple neoplasias (n =72) Increasing age at SSc onset 1.05 1.03–1.07 <0.001 ILD with FVC <70% 2.72 1.54–4.72 <0.001 Use of ASA 0.29 0.12–0.68 0.005 SSc, systemic sclerosis; OR, odds ratio; CI, confidence interval; PBC, primary biliary cholangitis; ILD, interstitial lung disease; FVC, forced vital capacity; ACA, anti-centromere antibody; PPI, proton pump inhibitors; ASA, acetylsalicylic acid. C. Carbonell et al. Autoimmunity Reviews 21 (2022) 103167 8 with SSc. Apart from the limitations mentioned above, including the small samples available for some neoplasias, we acknowledge that data on some potential risk factors for specific cancers (e.g., alcohol use or family history of cancer) were not collected in this study. Despite these limitations, the main strength of our study lies in the multicentric design, the overall large sample relative to those of other observational studies, and, to our knowledge, the first use of SIRs to examine a cohort of Spanish patients with scleroderma and cancer. In summary, our work clearly shows that patients with SSc have an increased risk of cancer compared with the general population. Patients with late-onset SSc, those with moderate ILD defined as FVC <70%, and those with ACA negativity are at increased risk of cancer. These data may help to identify SSc patients at high-risk of cancer for screening. Author contributions Conceptualization, formal analysis, methodology, supervision, writing-review: CPS and AJC. Data curation, formal analysis, investigation, writing original draft: CC. Formal analysis, supervision, writingoriginal draft and review: MM. Data curation and writing-review: AGC, MRR, AA, AMB, IRP, MBM, ECM, DC, LSC, CGE, NOC, BMA, JAVH, JATP, LT, MTHM, MF, ACS, IPF, ABMV, MESG, MRM, AGG, JSR, GRB, AFL, AMM, GML, CTV, VFP. All authors revised the manuscript for critical important content and approved the final version. Funding This work was financed in part by the Autoimmune Diseases Study Group of the Spanish Society of Internal Medicine. Declaration of Competing Interest The authors declare that they have no conflict of interest, including any financial, personal, or other relationship within 3 years of beginning this research with a person or organization that could have inappropriately influenced, or be perceived to influence, this work. Appendix 1. 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