key: cord-0890624-zeqax0il authors: Mahil, S. K.; Yates, M.; Langan, S. M.; Yiu, Z. Z.; Tsakok, T.; Dand, N.; Mason, K. J.; McAteer, H.; Meynall, F.; Coker, B.; Vincent, A.; Urmston, D.; Vesty, A.; Kelly, J.; Lancelot, C.; Moorhead, L.; Bachelez, H.; Bruce, I. N.; Capon, F.; Contreras, C. R.; Cope, A. P.; De La Cruz, C.; Di Meglio, P.; Gisondi, P.; Hyrich, K.; Jullien, D.; Lambert, J.; Waweru, H.; Marzo-Ortega, H.; McInnes, I.; Naldi, L.; Norton, S.; Puig, L.; Spuls, P.; Sengupta, R.; Torres, T.; Warren, R. B.; Weinman, J.; Griffiths, C. E.; Barker, J. N.; Brown, M. A.; Galloway, J. B.; Smith, C. H. title: Risk mitigating behaviours in people with inflammatory joint and skin disease during the COVID-19 pandemic differ by treatment type: a cross-sectional patient survey date: 2020-11-07 journal: nan DOI: 10.1101/2020.11.05.20226662 sha: 45cb9b7f4944d6ee3ef2cbc633fa1446f6f70260 doc_id: 890624 cord_uid: zeqax0il Objectives Registry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse COVID-19 outcomes compared to patients receiving no systemic treatments. We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation. Methods Online surveys were completed by individuals with Rheumatic and Musculoskeletal Diseases (RMD) (UK only) or psoriasis (globally) between 4th May and 7th September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterised international variation in a mixed effects model. Results Of 3,720 participants (2,869 psoriasis, 851 RMD) from 74 countries, 2,262 (60.8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term shielding). A greater proportion of those receiving targeted therapies (biologics and JAK inhibitors) reported shielding compared to those receiving no systemic therapy (adjusted odds ratio [OR] 1.63, 95% CI 1.35-1.97) and standard systemic agents (OR 1.39, 95% CI 1.22-1.56). Shielding was associated with established risk factors for severe COVID-19 (male sex [OR 1.14, 95% CI 1.05-1.24], obesity [OR 1.38, 95% CI 1.23-1.54], comorbidity burden [OR 1.43, 95% CI 1.15-1.78]), a primary indication of RMD (OR 1.37, 95% CI 1.27-1.48) and a positive anxiety or depression screen (OR 1.57, 95% CI 1.36-1.80). Modest differences in the proportion shielding were observed across nations. Conclusions Greater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk mitigation strategies and may help inform updated public health guidelines as the pandemic continues. What is already known about this subject? • At the beginning of the COVID-19 pandemic, patients with immune mediated inflammatory diseases (IMIDs) on targeted systemic immunosuppressive therapy were considered to be at higher risk of severe COVID-19. Subsequent registry data suggest that this may not the case. • Here we characterise shielding behaviour in patients with IMIDs from a global survey. We identified that targeted systemic therapy associates with increased shielding behaviour, as do demographic risk factors for severe COVID-19 including male gender and obesity. • Shielding behaviour varies across nations, albeit modestly when case-mix is taken into account. • Variable shielding behaviour amongst patients with IMIDs may be an important confounder when considering differential COVID-19 risk between therapy types, so should be accounted for in analyses where possible. The COVID-19 pandemic, caused by the highly infectious SARS-CoV-2 virus, represents an unprecedented global health crisis 1, 2 . Death from COVID-19 is associated with male gender, older age, Asian/Black ethnicity, and coexisting conditions including cardiovascular disease and obesity 3, 4 . Guided by international recommendations from the World Health Organization (WHO), public health risk mitigating measures such as social/physical distancing were introduced early in the pandemic to limit community transmission of COVID-19 5-8 . The WHO also recommended more stringent protection measures to reduce exposure risk in groups at higher risk of severe COVID-19 9 . This was referred to as 'shielding', and in the UK, was incorporated into Government policy where individuals classed as clinically extremely vulnerable were advised to physically isolate at home and avoid face-to-face interactions 7 . Informed by pre-COVID-19 observational studies on drug-related risks of serious infection [10] [11] [12] [13] , individuals with immune-mediated inflammatory diseases (IMIDs) receiving drugs that affect the immune system were considered at higher risk of severe COVID-19 14, 15 . Whilst limited evidence has been published to date on drug-specific COVID-19 risks in IMIDs, rheumatoid arthritis, systemic lupus erythematosus and psoriasis were collectively suggested as risk factors for death using UK primary care data linked to hospital records from 17 million adults 3 . Global clinician-reported registry data in rheumatic diseases, psoriasis and inflammatory bowel disease have further suggested a differential risk of severe COVID-19 associated with different treatment types. In particular, use of targeted systemic therapies (biologics and Janus Kinase [JAK] inhibitors) was associated with a reduced risk of adverse COVID-19 outcomes, compared with no treatment or standard systemic agents [16] [17] [18] . It remains unclear if this is attributable to therapeutic modulation of the host antiviral immune and inflammatory response (i.e. biological mechanisms) or enhanced shielding behaviour in patients receiving targeted therapies (resulting in a lower infectious dose of SARS-CoV-2). There is an urgent need to address this knowledge gap since targeted and standard systemic therapies represent the mainstay of treatment in moderate to severe IMIDs. Rheumatic and musculoskeletal diseases (RMDs) and psoriasis are common IMIDs that are closely related; psoriasis is the commonest immune-mediated skin disease associated with inflammatory arthritis, both conditions have a high prevalence of multimorbidity and are effectively treated with targeted and standard systemic therapies. We focused on RMDs and psoriasis as representative IMIDs and used global self-report survey data to explore the notion that individuals receiving different types of treatment exhibit distinct risk mitigating behaviours in the pandemic. Two online self-report surveys with aligned questions, permitting a combined analysis of data, were developed for people with psoriasis (Psoriasis Patient Registry for Outcomes, . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted November 7, 2020. ; Data were extracted on 7th September 2020 and analyzed using Stata version 16. Continuous variables were reported using means and standard deviations (SD), and categorical/dichotomous variables as numbers and percentages. To account for partially completed surveys, respondents who completed more than 50% of variables were included. Individuals completing CORE-UK and PsoProtectMe were classified as having a primary diagnosis of RMD and psoriasis, respectively. We characterised the demographic, socio-economic and disease-specific factors associated with the primary outcome of shielding behaviour in the pandemic. The key exposure measure was IMID treatment type in the pandemic, comprising 3 mutually exclusive categories: (1) Targeted therapy: biologics and JAK inhibitors (TNF inhibitors: adalimumab, certolizumab pegol, etanercept, infliximab, golimumab; IL-17 inhibitors: brodalumab, ixekizumab, secukinumab; IL12/IL-23p40 or IL-23p19 inhibitors: guselkumab, risankizumab, tildrakizumab, ustekinumab; IL-6 inhibitors tocilizumab, sarilumab; JAK inhibitors: baricitinib, tofacitinib); (2) Standard systemic therapy (methotrexate, ciclosporin, azathioprine, mycophenolate mofetil, fumaric acid esters/dimethylfumarate, sulfasalazine, leflunomide, acitretin, apremilast, chloroquine, hydroxychloroquine, prednisolone, tacrolimus); Two sensitivity analyses were performed on the fully adjusted multivariable regression models: (1) Multiple imputation using iterative chained equations with 20 sets of imputed . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 7, 2020. ; data to account for missing covariate data; (2) Exclusion of respondents on no systemic therapy, with standard systemic therapy becoming the reference group. Adherence data was included as a covariate in this model. As the COVID-19 pandemic progressed in countries over different time periods, we hypothesised that the impact of time on the relationship between treatment and shielding behavior would vary between countries. To explore this, unadjusted estimates of shielding over time by treatment group were plotted for UK and non-UK survey respondents. Based on these plots we re-ran the multivariable model with UK respondents only including time as an interaction term with treatment, and as a fixed covariate, with a comparison of model fit. Time was converted to a binary variable, before or after 30th June. Shielding in the UK appeared to decrease after this date, which also coincided with the reopening of hospitality across the UK. To characterise international variations in shielding behaviour, a mixed effects logistic regression model was executed with country of residence as a random effect. The random effect captures the difference between national and overall sample means, enabling estimation of case-mix adjusted rates. The national effects on shielding were visualised using a caterpillar plot 21 . Self-reported data from 3,720 individuals with a primary diagnosis of RMD (851, 22.9%) or psoriasis (2869, 77.1%) were available from 74 countries (including UK (2,578, 69.4%), Portugal (200, 5.4%), USA (165, 4.5%)) (demographic/clinical/socio-economic descriptions, CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 7, 2020. ; COVID-19 reported shielding (143 of 257, 55.6%), compared to those without COVID-19 (2,051 of 3,352, 61.2%). Overall, 2,262 participants (60.8%) reported shielding. Of To account for missing data (Table 1 ), the multivariable model was rerun following multiple imputation. The magnitude and direction of associations did not change substantially (Table S2 ). . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 7, 2020. ; The model was also rerun excluding respondents on no systemic therapy, using standard systemic therapy as the reference group. The association between targeted therapy and shielding was preserved (OR 1.39, 95% CI 1.23 to 1.56). Therapy non-adherence was not associated with shielding (Table S3 ). The influence of time (survey completion date) on shielding behaviour was explored across treatment groups. Estimated shielding behaviour generally decreased over time, however time had a differential impact in the UK ( Figure S1 ) compared with non-UK countries ( Figure S2 ). The multivariable model was therefore rerun with UK respondents only, first including time as a fixed covariate and secondly as an interaction term with treatment. The association between targeted therapy and shielding was preserved, with better model fit for the interaction term (further details in supplementary material). A greater proportion of participants in the UK reported shielding compared to those elsewhere (63.3%, versus 55.0%). However, UK participants were also less likely to receive a targeted therapy (23.4%, versus 28.4%). A mixed effects model further showed modest variation around the sample mean in the proportion shielding in different countries, indicating broadly similar risk mitigating behaviours (Figure 3 ). Shielding was more prevalent in the UK, Canada and Argentina, but less prevalent in Portugal and Japan. We present global self-reported data on risk mitigating behaviours in 3,720 individuals with inflammatory joint and skin disease across 74 countries. Established risk factors for severe COVID-19 outcome including male sex, obesity and comorbidity burden were associated with stringent risk mitigating behaviour (classified here under the umbrella term 'shielding', encompassing self-reported shielding, quarantine, staying home or distancing within the home). Notably, use of targeted therapies (biologics and JAK inhibitors) was associated with shielding in comparison with no systemic therapy or standard systemic therapy. Although the differences in shielding behaviours across treatment groups in UK respondents were preserved when time was used as an interaction term, the observed decline in estimated shielding behaviour over time may help inform updated public health guidelines as the pandemic continues. Our dataset is based on a large sample of individuals self-reporting RMD and psoriasis. Since there was no healthcare professional/record validation of survey responses, it is . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 7, 2020. ; reassuring that key risk factors for severe COVID-19 in the general population such as male sex and obesity were associated with shielding. This is in keeping with public health messaging during the pandemic, and indicates a representative and generalizable sample. Shielding was recommended in groups of individuals deemed at higher risk 7,9 on the premise that this would reduce the risk of COVID-19 transmission. More recently, evidence has emerged indicating shielding may also result in a less severe course of COVID-19 by reducing the frequency and intensity of exposures to SARS-CoV-2, thus lowering the infectious dose 22 . There is a growing body of evidence indicating that SARS-CoV-2 viral load positively correlates with disease severity 23, 24 , and that in animal models, greater SARS-CoV-2 dose at exposure correlates with higher viral load and worse outcomes 25 . Notably, increasing age was not associated with shielding behaviour in our dataset. This finding is in keeping with a recent international study of 8,317 individuals from the general population showing that age did not predict whether individuals took health precautions (mask wearing, social distancing, handwashing, staying home) 20 . Instead, beliefs that taking health precautions are effective and a concern for one's own health were important predictors. Consistent with this, we identified an association between shielding and anxiety/depression. A larger proportion of participants also reported shielding compared to those advised to shield, which may reflect the elevated rates of self-reported anxiety. Anxiety and depression has also been reported in previous observational studies, underscoring the mental health burden of the pandemic (which may at least in part be due to the impact of social isolation) [26] [27] [28] . While this finding suggests accurate and representative data capture, more data are required on the severity and temporality of anxiety and depression. Our study indicates a greater likelihood of shielding overall in individuals with a primary diagnosis of RMD compared with psoriasis, however the reasons underlying this are not clear. It may be attributable to differences in illness perception 29 , use of treatments and prevalence of comorbidities. IMID-specific COVID-19 risks are unknown, and neither RMD nor psoriasis were included in WHO and national public health shielding recommendations per se 7, 9 . The reasons underlying differences in shielding behaviours between treatment groups, including patient perceptions of COVID-19 risk, also warrant further study. Although there is a paucity of data on treatment-related beliefs in psoriasis, recent single centre crosssectional patient survey data in inflammatory bowel disease indicate patients perceive biologics to be riskier than other therapies 29 . These perceptions may influence shielding behaviours and are important to address during patient-clinician interactions. Our global data on shielding behaviour builds on the findings from a recent single centre audit of 1,693 UK patients with rheumatic diseases 26 . Forty six percent self-reported . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 7, 2020. ; shielding, however shielding among different treatment groups was not explored. In line with our findings, the audit found that a lower proportion of individuals with COVID-19 shielded (39%) compared to those without COVID-19 (47%). Our study also complements emerging findings from international clinician-reported registries, indicating differences in COVID-19 outcomes between different treatment types. Among 600 patients with rheumatic diseases and COVID-19 reported to the COVID-19 Global Rheumatology Alliance registry 17 , biologic/targeted synthetic systemic drug use was associated with lower odds of being hospitalized compared to patients receiving no systemic therapies. This effect was largely driven by TNF inhibitors since most patients on biologics were receiving this sub-group. A decreased risk of hospitalization or death was also associated with TNF inhibitor biologics compared with no treatment among 525 patients with inflammatory bowel disease and COVID-19 reported to SECURE-IBD 16 . In contrast, the standard systemics sulfasalazine or 5aminosalicylate were associated with a higher risk of hospitalization or death. Our previously published study of 374 patients with psoriasis and COVID-19 reported to the PsoProtect registry further suggested an association between biologics (pooled data on TNF, IL-17 and IL-23 inhibitors) and reduced risk of hospitalization, compared to standard systemic therapies 18 . Although exploration of possible biological mechanisms underlying these associations is warranted (e.g. cytokine-targeted biologics may attenuate a severe systemic inflammatory response to COVID-19 30 ), our current study highlights shielding behaviour as an important unmeasured potential mediator in these datasets. The differences in shielding behaviours across treatments supports the notion that greater protective shielding behaviour (resulting in a lower infectious dose of SARS-CoV-2) in those receiving targeted therapies may account, at least in part, for the observed associations. Thus conclusions from clinicianreported registry data about medication-related COVID-19 risk should be interpreted in this context, and further research efforts are required to quantify potential mediation through shielding. A greater proportion of participants from the UK reported shielding compared with those elsewhere, which may reflect cross-national differences in public health messaging. However, these data should be interpreted with caution since our dataset is dominated by UK participants. Due to limited capture of socioeconomic data, we were unable to fully adjust for this confounder in the analysis, however we did identify that household density was inversely associated with shielding. Both shielding behaviour and clinical decision making around systemic therapies globally (including access to medications) may be influenced by socioeconomic variables such as income and education 31, 32 , which may in turn influence outcome of COVID-19 4 . Linkage between health, social, behavioural and employment data should thus be prioritised in future research. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 7, 2020. ; Collecting data via an online survey may have limited participation to more tech-literate individuals and those more connected to media. The study sample was mostly female (as expected in survey-based studies), of white ethnicity, and self-reported their diagnoses, which further limits the generalizability of the results. Ascertainment bias may overestimate the overall proportion shielding, since those more concerned about COVID-19 risk may be more likely to participate. Our sample, in which a greater proportion reported receiving . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 7, 2020 . T a b l e 1 . ' S h i e l d e d ' r e f e r s t o p a r t i c i p a n t s w h o q u a r a n t i n e d a n d s e l f -i s o l a t e d . I n f l a m m a t o r y a r t h r i t i s i n c l u d e d a n y p a r t i c i p a n t w i t h a d i a g n o s i s o f r h e u m a t o i d a r t h r i t i s o r p s o r i a t . It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 7, 2020. . It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 7, 2020. F i g u r e 3 . C a t e r p i l l a r p l o t o f o b s e r v e d a n d e s t i m a t e d r i s k m i t i g a t i n g b e h a v i o u r , b y n a t i o . It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 7, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 7, 2020. ; https://doi.org/10.1101/2020.11.05.20226662 doi: medRxiv preprint Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy OpenSAFELY: factors associated with COVID-19 death in 17 million patients Ethnic differences in COVID-19 infection, hospitalisation, and mortality: an OpenSAFELY analysis of 17 million adults in England COVID-19) Guidance on shielding and protecting people who are clinically extremely vulnerable from COVID-19 Overview of public health and social measures in the context of COVID-19: interim guidance Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis: Results From the Psoriasis Longitudinal Assessment and Registry (PSOLAR) Safety of synthetic and biological DMARDs: a systematic literature review informing the 2016 update of the EULAR recommendations for management of rheumatoid arthritis Serious infection across biologic-treated patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly Identifying rheumatic disease patients at high risk and requiring shielding during the COVID-19 pandemic Dermatology Advice Regarding Medication Acting on the Immune System: Adults, Paediatrics and Young People. 1, 2 Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry Factors associated with adverse COVID-19 outcomes in patients with psoriasis -insights from a global registry-based study Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support Predictors of COVID-19 voluntary compliance behaviors: An international investigation A brief introduction to mixed effects modelling and multi-model inference in ecology Inoculum at the time of SARS-CoV-2 exposure and risk of disease severity SARS-CoV-2 viral load predicts COVID-19 mortality Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development COVID-19 prevalence and the impact on quality of life from stringent social distancing in a single large UK rheumatology centre Mental health in the UK during the COVID-19 pandemic: cross-sectional analyses from a community cohort study Mental Health and the Covid-19 Pandemic Patients' Perceive Biologics to Be Riskier and More Dreadful Than Other IBD Medications Accumulating evidence suggests anti-TNF therapy needs to be given trial priority in COVID-19 treatment Combating COVID-19: health equity matters Patients' demographic and socioeconomic characteristics influence the therapeutic decision-making process in psoriasis We are very grateful to the patients who have contributed to PsoProtectMe and CORE-UK.We would like to acknowledge the professional and patient organizations who supported or promoted PsoProtectMe and CORE-UK (Table S1 ). We are grateful for the input of Prof Lars Iversen, Prof Nick Reynolds, Prof Joel Gelfand, Ms Christine Janus. We are also incredibly thankful to Engine Group UK for their generous creative input and website expertise.