short report Risk of recurrent venous thromboembolism in patients with autoimmune diseases: data from the Registro Informatizado de Enfermedad TromboEmbo  lica (RIETE) registry Jaime Borjas Howard,1 Summary Pablo Ruiz-Sada,2 Karina de Leeuw,3 Luciano L opez-Jimenez,4 Carme Font,5 Autoimmune disease is a risk factor for first incident venous thromboembolism Pablo Javier Marchena,6 (VTE). However, data on the risk of recurrent VTE in people with autoimmune Olga Madridano,7 disease is sparse. We explored the risk of recurrent VTE using the RIETE registry, Philippe Debourdeau,8 Karina Meijer,1 comparing people with autoimmune disease (n = 1305) to those without (n = Manuel Monreal9,10 and the Registro 50608). Overall rates were 6.5 and 5.1 recurrent VTE/100 years for patients with Informatizado de Enfermedad autoimmune disease vs controls, respectively. After adjustment for sex and unpro- TromboEmb olica (RIETE) Investigators voked/provoked VTE yielded an adjusted hazard ratio of 1.29 (95%CI 1.03-1.62). 1 Department of Hematology, University The analysis was limited by short median follow up time (161 days overall), pre- Medical Centre Groningen, University of cluding definitive conclusions on recurrent VTE risks. Groningen, Groningen, the Netherlands, 2 Keywords: venous thrombosis, autoimmune disease, risk factors. Department of Internal Medicine, Hospital Reina Sofıa, Tudela, Navarra, Spain, 3 Department of Rheumatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands, 4 Department of Internal Medicine, Hospital Universitario Reina Sofıa, Cordoba, 5 Department of Medical Oncology, Hospital Clınic, Barcelona, 6Department of Internal Medicine and Emergency, Parc Sanitari Sant Joan de Deu-Hospital General, Barcelona, 7Department of Internal Medicine, Hospital Universitario Infanta Sofıa, Madrid, Spain, 8Department of Supportive Care Oncology, Institut Sainte Catherine, Avignon, France, 9Department of Internal Medicine, Hospital Germans Trias i Pujol, Universidad Autonoma de Barcelona, Barcelona, Spain, and 10Chair of Thromboembolic Diseases, Universidad Catolica de Murcia, Universidad Autonoma de Barcelona, Barcelona, Spain Received 17 March 2021; accepted for publication 19 April 2021 Correspondence: Jaime Borjas Howard, Department of Hematology, University Medical Centre Groningen, University of Groningen, the Netherlands. E-mail: j.f.borjas.howard@umcg.nl ª 2021 The Authors. British Journal of Haematology published by British Society for Haematology First published online 2 June 2021 and John Wiley & Sons Ltd. British Journal of Haematology, 2021, 194, 195–199 doi: 10.1111/bjh.17549 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Short Report A full list of the RIETE investigators is given in the appendix. therapy and who subsequently stopped anticoagulant therapy Introduction were included. One of the central issues surrounding management of venous thromboembolism (VTE) is to estimate the risk of recurrent Data collection methods VTE. This informs whether anticoagulant treatment should be continued indefinitely or whether a limited duration is more Data in RIETE are recorded on to a computer-based case appropriate.1 Although much research has concentrated on the report form at each participating hospital and submitted to a use of biomarkers for all patients with VTE, it would be impor- centralised co-ordinating centre. tant to understand how relatively highly prevalent risk factors for VTE influence recurrence risk as well. Autoimmune dis- Exposure eases are such a risk factor: depending on definition, preva- lence of autoimmune disease is 5–9% among the general The main exposure of interest was autoimmune disease. population2 and because they are a risk factor for VTE they are Within the registry, this included inflammatory bowel disease expected to be over-represented in populations with VTE. A (ulcerative colitis/Crohn’s disease), systemic lupus erythemato- recent systematic review concluded that there is insufficient sus, Behcßet’s disease, temporal arteritis, rheumatoid arthritis, evidence to say whether autoimmune disease is associated with ankylosing spondylitis, polymyalgia rheumatica and vasculitis. a higher risk of recurrent VTE, with only some moderate qual- ity evidence available for the risk of recurrence in patients with inflammatory bowel disease and Behcßet’s disease.3 Part of the Outcome issue identified is that each separate autoimmune disease is rel- Recurrent deep vein thrombosis was adjudicated by treating atively rare, making this relatively small subgroups of people physicians and is defined as a new non-compressible vein suffering from VTE. To gather sufficient data on recurrence segment, or an increase of the vein diameter of >4 mm com- risk of VTE in these single diseases, it is likely that national- pared with last available measurement on ultrasonography. scale or even multinational-scale co-operation would be Recurrent pulmonary embolism is defined as a new needed. A different approach would be to use existing VTE ventilation-perfusion mismatch or new intraluminal filling registries, which would likely document comorbidities, and defect on relevant imaging.5 consider autoimmune disease as one entity despite their heterogeneity in disease presentation and severity. The Regis- tro Informatizado de Enfermedad TromboEmb olica (RIETE) Confounders registry has extensive data during treatment, and showed no Sex and provoking factors were considered to be confounders. difference in occurrence of VTE and/or bleeding during this Provoking factors were modelled as categorical variables, with period in these patients.4 In the present study, we analysed the the following three categories: unprovoked (no clear provoking risk of recurrent VTE in patients with autoimmune diseases factor), cancer-associated (active cancer, irrespective of pres- using the RIETE registry after withdrawing treatment. ence of other provoking factors) or provoked (associated with surgery in the 2 months prior to VTE, immobilised for Patients and methods >4 days, use of oestrogen and/or pregnancy). The RIETE registry has been described previously.5 In short, it is an ongoing, multicentre, international registry of consec- Statistical analysis utive patients with objectively confirmed acute VTE (Clini- calTrials.gov identifier: NCT02832245). Multiple centres Rates were calculated by dividing events by total years of enrol patients at the time that they have a VTE and extensive follow-up. clinical data are collected including medication use, labora- Cumulative incidences were estimated accounting for tory measurements and comorbidities. Participants are subse- competing risk of death. quently followed-up during treatment. Cause specific hazard estimates were estimated using Cox proportional hazards regression, adjusted estimates were arrived at by adjusting for sex and index event type (pro- Participants voked/cancer associated/unprovoked). Patients who entered the registry with a first episode of VTE Post hoc, the data showed a high rate of censoring, mean- and who did not have a recurrence during anticoagulant ing that data from late follow-up would not only be an 196 ª 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. British Journal of Haematology, 2021, 194, 195–199 Short Report Table I. Participants after exclusion of people with venous throm- boembolism prior to registry entry or who had a recurrence during Results anticoagulant therapy. After exclusion of RIETE participants who did not enter the Autoimmune No autoimmune registry with a first VTE and exclusion of participants who disease disease had a recurrence during use of anticoagulants, 51 913 partic- ipants remained. Of these >2% had one of the mentioned Patients, N 1305 50608 Inflammatory bowel 275 (21) autoimmune diseases. Baseline characteristics are shown in disease, n (%) Table I. As expected, there was a slightly higher proportion Systemic lupus 97 (7) of females in the autoimmune group and a higher propor- erythematosus, n (%) tion of unprovoked index VTEs. Excluded participants with Behcßet’s disease, n (%) 18 (1) autoimmune disease had a similar sex ratio (41% male). Temporal arteritis, n (%) 74 (6) The median follow-up across the whole cohort was Other vasculitis, n (%) 148 (11) 161 days, with three-quarters being censored after 335 days, Rheumatoid arthritis 459 (35) with only slightly longer follow-up for participants with Ankylosing spondylitis 42 (4) autoimmune disease (median 181 days, third quartile Polymyalgia rheumatica 225 (17) 371 days). Rates considering all follow-up and only early Clinical characteristics follow-up are shown in Table II. Age, years, mean (SD) 66 (17) 68 (18) Male gender, n (%) 477 (36) 24391 (48) Cumulative incidence plots are shown in the supplemen- Anti-phospholipid antibodies 11 (1) 26 (0) tary appendix, showing overall cumulative incidence and Initial VTE presentation cumulative incidences stratified by sex and within the unpro- DVT only, n (%) 505 (39) 20491 (40) voked stratum. In the overall analysis, cumulative incidence Pulmonary embolism* 800 (61) 30117 (60) rates at 1, 2 and 5 years were 58%, 125% and 265% for VTE type participants with autoimmune disease and 48%, 90% and Unprovoked 742 (57) 23021 (45) 221% for participants without autoimmune disease. In the Active cancer 143 (11) 11117 (22) analysis stratified by sex, it appeared that females with Other provoking factors 420 (32) 16470 (33) autoimmune disease had a particularly higher risk of recur- DVT, deep venous thrombosis; SD, standard deviation; VTE, venous rent VTE as compared to other strata. thromboembolism. Table II also shows the results of the Cox proportional haz- *With or without DVT. ards regression analysis, estimating an approximately 30–40% higher hazard of recurrent VTE after adjustment for sex and type of index event. However, limiting the analysis to only the implausible extrapolation of risk estimates from the initial first year follow-up attenuated the association to a 20% higher risk set, but also there was some concern that there might be hazard, with the confidence interval including a null effect. selective follow-up for participants with autoimmune disease: None of the models showed any evidence of violation of pro- it was deemed more likely that these patients would have portional hazards for the variable autoimmune disease. A post ongoing care in the hospital that participated in the registry, hoc subgroup analysis of the most prevalent autoimmune dis- so there would be more information available distorting eases was done to explore whether the average effect of results. Therefore, a sensitivity analysis including only the autoimmune disease was being driven by one particular dis- early follow-up period was performed. ease. This was not the case (results in the appendix). Table II. Rates and hazard ratios of recurrent venous thromboembolism. Events, n Follow-up, years Rate, n/100 years Unadjusted HR (95% CI) Adjusted* HR (95% CI) Total follow-up available No autoimmune disease 2204 42813 5 1 (4 9–5 4) Ref. Ref. Autoimmune disease 77 1179 6 5 (5 2–8 1) 1 29 (1 03–1 62) 1 33 (1 06–1 67) Only first 2 years No autoimmune disease 1691 33463 5 1 (4 8–5 3) Ref. Ref. Autoimmune disease 64 954 6 7 (5 3–8 5) 1 34 (1 04–1 72) 1 37 (1 06–1 76) Only first year No autoimmune disease 1337 25829 5 2 (4 9–5 5) Ref. Ref. Autoimmune disease 44 724 6 1 (4 6–8 1) 1 18 (0 88–1 60) 1 22 (0 91–1 65) CI, confidence interval; HR, hazard ratio. *Adjusted for sex and unprovoked/cancer-provoked/provoked venous thromboembolism. ª 2021 The Authors. British Journal of Haematology published by British Society for Haematology 197 and John Wiley & Sons Ltd. British Journal of Haematology, 2021, 194, 195–199 Short Report In conclusion, the present study suggests a higher risk of Discussion recurrent VTE in patients with the selected autoimmune dis- The present results suggest that participants with the studied eases, especially in women. However, several limitations pre- autoimmune diseases are at a higher risk of recurrent VTE clude making confident conclusions. Future large-scale than controls. This is the first study to produce such a large- studies using routinely collected data are needed to obtain scale analysis of recurrent VTE in participants with autoim- more reliable estimates. mune disease. Indeed, the previous studies that included patients with a first VTE had a sample size of 116 patients (inflammatory bowel disease)6 and 296 patients (Behcßet’s Acknowledgements disease).7 Karina Meijer received research support from Bayer, Sanquin The main limitation of the present analysis relates to the and Pfizer; speaker fees from Bayer, Sanquin, Boehringer fact that the registry was not designed to assess recurrent Ingelheim, BMS and Aspen; consulting fees from UniQure VTE, mainly due to short follow-up times: three-quarters of (all fees go to the institution) outside of the current work. participants were censored before 1 year of follow-up, ques- The authors have not received any specific funding for this tioning the validity of estimates derived after this time point. work. We amended analyses accordingly. At high censoring rates, a further concern is differential loss to follow-up. In this speci- fic setting, it is plausible that, given the chronic nature of Author contributions autoimmune diseases, these participants may be followed in Jaime Borjas Howard designed the research, analysed the the same centre by a rheumatologist, whilst this may not be data and wrote the manuscript; Pablo Ruiz-Sada, Luciano the case for other participants without disease raising con- Lopez-Jimenez, Carme Font, Pablo Javier Marchena and Phi- cern about detection bias. However, the direction of this bias lippe Debourdeau were involved in data collection and is unclear: participants with autoimmune disease may have a reviewed drafts of the manuscript; Karina Meijer and Karina both inflated numerator (events reported) and denominator de Leeuw designed the research and reviewed drafts of the (follow-up time). Limiting follow-up time to 1 year attenu- manuscript; Manuel Monreal supported data acquisition and ated the hazard ratio, suggesting that this mainly led to an analysis and reviewed drafts of the manuscript. overestimation of relative risk. Therefore, although the results follow the expected direction of effect (higher risk of recur- rence in people with autoimmune disease) they should be Conflict of interest interpreted with caution. The present study highlights the challenges in investigat- All the other authors declare no conflict of interest. ing the risk of recurrent VTE in subgroups of patients. On the one hand, existing dedicated recurrent VTE cohort stud- Supporting Information ies [e.g. the Austrian Study on Recurrent Venous Throm- boembolism (AUREC)]8 will have insufficient participants Additional supporting information may be found online exposed to autoimmune disease for a meaningful analysis, in the Supporting Information section at the end of the let alone whether autoimmune disease is reliably ascertained article. as an exposure. In turn, within any cohort dedicated to a Fig S1. Cumulative incidence of recurrent venous throm- single autoimmune disease, we can only expect a small boembolism, stratified by autoimmune disease and sex. minority to have had a VTE. This implies that larger datasets Table SI. Subgroup analysis of recurrent venous throm- will have to be used. Routinely collected datasets with long- boembolism in the largest autoimmune disease groups. term follow-up come to mind, e.g. data collected at general practitioner practices. Here, problems are likely to arise with References ascertainment of the recurrent VTE outcome; validity of diagnostic codes for a recurrent VTE episode would have to 1. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel be validated. We are aware of one study that collected gen- report. Chest. 2016;149:315–52. eral VTE recurrence trends using a GP records database in 2. Cooper GS, Bynum ML, Somers EC. Recent insights in the epidemiology of the UK.9 autoimmune diseases: improved prevalence estimates and understanding of Finally, it is important to stress that the present study cov- clustering of diseases. J Autoimmun. 2009;33:197–207. ered only a specific subset of autoimmune disease collected 3. Borjas-Howard JF, Leeuw K, Rutgers A, Meijer K, Tichelaar VY. Risk of recurrent venous thromboembolism in autoimmune diseases: a systematic in RIETE. Estimates from the present study cannot be review of the literature. Semin Thromb Hemost. 2019;45:141–9. extrapolated to autoimmune diseases that have typically less 4. Sada PR, L opez-N un~ez JJ, Samperiz A, Soto MJ, Pedrajas JM, Porras JA, systemic involvement, e.g. autoimmune thyroiditis, celiac dis- et al. Venous thromboembolism in patients with autoimmune disorders: ease or psoriasis. findings from the RIETE registry. Angiology. 2020;71:131–8. 198 ª 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. British Journal of Haematology, 2021, 194, 195–199 Short Report 5. Bikdeli B, Jimenez D, Hawkins M, Ortız S, Prandoni P, Brenner B, et al. 8. Kyrle PA, Kammer M, Eischer L, Weltermann A, Minar E, Hirschl M, et al. Rationale, design and methodology of the computerized registry of The long-term recurrence risk of patients with unprovoked venous throm- patients with venous thromboembolism (RIETE). Thromb Haemost. boembolism: an observational cohort study. J Thromb Haemost. 2018;118:214–24. 2016;14:2402–9. https://doi.org/10.1111/jth.13524. 6. Novacek G, Weltermann A, Sobala A, Tilg H, Petritsch W, Reinisch W, 9. Martinez C, Cohen AT, Bamber L, Rietbrock S. Epidemiology of first et al. Inflammatory bowel disease is a risk factor for recurrent venous and recurrent venous thromboembolism: a population-based cohort thromboembolism. Gastroenterology. 2010;139:779–87. study in patients without active cancer. Thromb Haemost. 2014;112: 7. Desbois AC, Wechsler B, Resche-Rigon M, Piette JC, Huong DLT, Amoura 255–63. Z, et al. Immunosuppressants reduce venous thrombosis relapse in Behcßet’s disease. Arthritis Rheum. 2012;64:2753–60. ª 2021 The Authors. British Journal of Haematology published by British Society for Haematology 199 and John Wiley & Sons Ltd. British Journal of Haematology, 2021, 194, 195–199