key: cord-323910-lms3xw4k
authors: Putman, Michael; Chock, Yu Pei Eugenia; Tam, Herman; Kim, Alfred H.J.; Sattui, Sebastian E.; Berenbaum, Francis; Danila, Maria I.; Korsten, Peter; Sanchez‐Alvarez, Catalina; Sparks, Jeffrey A.; Coates, Laura C.; Palmerlee, Candace; Peirce, Andrea; Jayatilleke, Arundathi; Johnson, Sindhu R.; Kilian, Adam; Liew, Jean; Prokop, Larry J.; Murad, M. Hassan; Grainger, Rebecca; Wallace, Zachary S.; Duarte‐García, Alí
title: Antirheumatic Disease Therapies for the Treatment of COVID‐19: A Systematic Review and Meta‐analysis
date: 2020-08-02
journal: Arthritis Rheumatol
DOI: 10.1002/art.41469
sha: 
doc_id: 323910
cord_uid: lms3xw4k

OBJECTIVE: Antirheumatic disease therapies have been used to treat coronavirus disease 2019 (COVID‐19) and its complications. We conducted a systematic review and meta‐analysis to describe the current evidence. METHODS: A search of published and preprint databases in all languages was performed. Included studies described one or more relevant clinical outcomes in five or more people who were infected with SARS‐CoV‐2 and were treated with antirheumatic disease therapy between 01/01/2019 and 05/29/2020. Pairs of reviewers screened articles and extracted data and assessed risk of bias. A meta‐analysis of effect sizes using the random‐effects models was performed when possible. RESULTS: The search identified 3,935 articles, of which 45 were included (4 randomized controlled trials, 29 cohort studies, and 12 case series). All studies evaluated hospitalized patients and 29 out of 45 had been published in a peer‐reviewed journal. In a meta‐analysis of three cohort studies with a low risk of bias, hydroxychloroquine use was not significantly associated with mortality (pooled hazard ratio (HR) 1.41, 95% confidence interval (CI) 0.83‐2.42). In a meta‐analysis of two cohort studies with some concerns/high risk of bias, anakinra use was associated with lower mortality (pooled HR 0.2, 95% CI 0.1‐0.4). Evidence was inconclusive with regard to other antirheumatic disease therapies and the majority of other studies had a high risk of bias. CONCLUSION: In this systematic review and meta‐analysis, hydroxychloroquine use was not associated with benefit or harm with regard to COVID‐19 mortality. The evidence supporting the effect of other antirheumatic disease therapies in COVID‐19 is currently inconclusive.

Several antirheumatic disease therapies have emerged as potential treatments for coronavirus disease 2019 , the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There has been particular interest in the antimalarial agents hydroxychloroquine (HCQ) and chloroquine (CQ) (1) , which may inhibit SARS-CoV-2 replication by elevating endosomal pH or altering the glycosylation of the ACE2 receptor. (2) After preliminary evidence also suggested a clinical benefit for HCQ (3) , public acquisition resulted in shortages (4, 5) .

More recently, a now-retracted study by Mehra et al. reported an association between HCQ use and increased mortality (6, 7) . Both concern for this potential risk and the aforementioned HCQ shortages have negatively impacted patients who take HCQ for rheumatic diseases.

Antirheumatic disease therapies may also mitigate the hyperinflammatory state caused by SARS-CoV-2 infection, which has been associated with elevated levels of inflammatory cytokines (8, 9) Therapies that directly target the inflammatory cascade, including interleukin-6 (IL-6) inhibitors, interleukin 1 (IL-1) inhibitors, and glucocorticoids, have been widely adopted in clinical practice prior to the publication of ongoing randomized controlled trials (RCTs). Similar considerations have led to speculation that tumor necrosis factor (TNF) inhibitors and the Janus kinase inhibitor baricitinib may be beneficial (10) (11) (12) . Recent systematic reviews have primarily focused on antimalarial therapy (13, 14) , and no reviews to date have performed a meta-analysis of recently published large observational studies of antirheumatic disease therapies.

In this systematic review and meta-analysis, we identified and summarized published and pre-print original scientific articles that described the use of antirheumatic disease therapies for the treatment of COVID-19.

This systematic review was performed according to the Cochrane Handbook for Systematic Reviews of Interventions (15) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (16) and the Synthesis without Meta-Analysis (SWiM) guidelines (17) .

The protocol was registered on the International Prospective Register of Systematic Reviews (CRD42020176896) (18) . Given the rapid development of new evidence, all articles available on the preprint servers medRxiv, bioRxiv and ChinaXiv were also included. Coronavirus resource centers of The Lancet, JAMA, and the New England Journal of Medicine were hand searched until 05/29/2020. The studies that were identified as preprints were replaced by peer-reviewed published versions if available and identified by 05/23/2020. A detailed search strategy is available in the Supplemental Appendix.

Original eligibility criteria were refined after review of the initial search (18) . The final eligibility criteria were (1) Included 5 or more people infected with SARS-CoV-2; (2) antirheumatic disease therapy (Supplemental Appendix); (3) published after January 1st, 2019; (4) original research; (5) had one of the following outcomes: Death, ventilator-free days, escalation of care (ICU transfer), length of hospital stay, symptom resolution, viral clearance. Studies that did not present primary data (i.e., editorials, opinions, meta-analysis, and reviews) were excluded.

Four patient research partners who have had COVID-19 -two patients with an autoimmune disease and two rheumatologists -were involved throughout the project. Patient research partners participated in the selection of outcomes and the drafting of the manuscript.

Pairs of reviewers working independently (FB, YPC, AD, MD, AK, PK, MP, HT, CS, SS, JS) evaluated eligibility based on review of abstracts and titles. Records with disagreements on inclusion/exclusion were included in full text review. Pairs of the same reviewers working independently evaluated full text articles. Disagreements were resolved by consensus discussion and, if necessary, by involving a third reviewer. Abstract, title and full text review were conducted on DistillerSR software (Evidence Partners, Ottawa, Ontario, Canada). A standardized extraction tool was developed by consensus and refined after preliminary testing over a subset of the full text articles. The extraction tool included a full description of study characteristics, the medications patients received (dose, frequency, route), and the inferences made in each study. Pairs of reviewers extracted data independently and differences were reconciled by the corresponding authors (MP, AD).

Two reviewers (MP, AD) working independently assessed the risk of bias. Randomized controlled trials (RCT) were assessed using the Risk of Bias 2.0 tool (19) and reported using the recommended three point ordinal scale ("High risk of bias," "Some concerns", "Low risk of bias"). Cohort studies were assessed using the Newcastle-Ottawa Scale (20) . The comparability domain of the Newcastle-Ottawa Scale was the primary differentiation point for study risk of bias in this context and was used to determine global risk of bias ("High risk of bias" for 0 points, "Some concerns" for one point, "Low risk of bias" for two points) (21). Disagreements were resolved by consensus discussion. Studies were defined as case series if they did not include an unexposed group and were deemed to have a high risk of bias by default (22, 23) .

This article is protected by copyright. All rights reserved When more than one study reported (1) the same outcome for (2) the same antirheumatic therapy and (3) reported an estimate of effect size, we performed a meta-analysis. Adjusted effect size estimates were used if available. Otherwise, unadjusted effect size estimates were used. Each study was weighted based on its log-transformed inverse variance. The meta-analysis was conducted using the random-effects models due to expected clinical and methodological heterogeneity (24) .

The I 2 statistic was calculated to describe heterogeneity. All analyses were conducted using RevMan

We grouped the studies by antirheumatic disease therapy and outcomes. The data were synthesized narratively and in tables. For reporting purposes and due to the methodological diversity of the studies, we prioritized results for summary and synthesis based on study design (RCT > cohort studies > case series), risk of bias assessment (low risk > some concerns > high risk) and relevance of the outcome (e.g. mortality > viral clearance). Given substantial heterogeneity of study design and reporting, we used the vote counting method as described in the Cochrane handbook to summarize the direction of the effect for a given outcome (25) .

The initial search was performed on 03/17/2020 and identified 1,315 studies, including 290 studies in the peer-reviewed published literature and 1,025 in preprint archives. An updated search was performed on 05/07/2020 and identified an additional 2,614 studies, including 622 studies in the published literature and 2,618 in the preprint archives. Six additional studies were identified prior to 05/29/2020 by hand search and were included in the second extraction. After title and abstract screening, 3,660 were excluded. Out of 275 articles included for full text review, 230 were excluded and 45 were included in qualitative review. One study identified by hand count was subsequently retracted and therefore removed (6, 7) . Six of these were also eligible for meta-analysis (Supplement Figure 1 ).

We included four RCTs, 29 cohort studies, and 12 case series. Sixteen studies had been posted to a preprint archive only and 29 had been published in a peer-reviewed journal. Studies were conducted in China (22) , France (10), Italy (5), USA (4), Brazil (1), the United Arab Emirates (1), Iran (1), and Qatar (1). All studies evaluated hospitalized patients with COVID-19 (Supplementary Appendix, Table 1 ). Of the four RCTs included, all four had a high risk of bias. Of the 29 cohort studies, six had low risk of bias, five had some concerns, and 18 had a high risk of bias. (Supplementary Appendix, Table 2 , Table 3 ).

Fourteen studies assessed HCQ, including two RCTs, seven cohort studies, and five case series (Table 1) . Three cohort studies (pooled n = 932) evaluated mortality and were included in quantitative synthesis (26) (27) (28) . In the meta-analysis, HCQ use was not associated with a significant risk of death (pooled HR 1.41, 95% CI 0.83-2.42) ( Figure 1A ). Two cohort studies (pooled n = 1549) evaluated a composite risk of invasive mechanical ventilation and mortality and were included in quantitative synthesis (28, 29) . HCQ use was not associated with the pooled composite outcome (HR 1.41, 95% CI 0.83-2.42) ( Figure 1B ). All studies included in the quantitative synthesis had a low risk of bias.

This article is protected by copyright. All rights reserved 

Five studies assessed CQ, including two RCTs, two cohort studies and one case series (Table 1) .

One RCT by Borba et al. assessed mortality (33) and was stopped early due to a safety signal that suggested a higher rate of mortality with a higher dose of chloroquine. It had a high risk of bias and did not include a placebo group as a comparator.

An RCT by Huang et al. that compared CQ to lopinavir/ritonavir found that participants on CQ were twice as likely to be discharged (34) , and a cohort study by Huang et al. reported a significantly shorter duration of fever (35) . The same two studies also addressed SARS-CoV2 clearance. The RCT reported a higher likelihood of clearance with CQ as opposed to ritonavir/lopinavir, while the Accepted Article cohort study reported a shorter time for viral clearance. A cohort study by Chen et al. found no significant change in viral clearance at 14 days (36) . All studies assessing viral clearance had a high risk of bias and by vote counting had the same direction of effect toward a shorter time for viral clearance.

Seven studies assessed tocilizumab, an interleukin-6 receptor inhibitor, including three cohort studies and four case series; one case series assessed the interleukin-6 inhibitor siltuximab ( 

Fourteen studies assessed glucocorticoid use, including 13 cohort studies and one case series (Table 3) . Nine cohort studies evaluated mortality and glucocorticoids. There was variability regarding timing of glucocorticoid use and COVID-19 disease severity. By vote counting, the direction of effect was positive in one-third of the studies and negative in the remaining two-thirds.

One cohort study by Wang et al. found a higher rate of a composite outcome of ICU admission or mortality (36) . Two cohort studies both found a lower rate of escalation of care (40, 41) . The study by Wang et al. showed a shorter hospitalization time with methylprednisolone, but a cohort study by Fadel et al. did not. Three cohort studies evaluated SARS-CoV-2 clearance. One study found a significantly increased time to viral clearance (42) , and 2 studies found no significant difference (43, 44) . Eleven of the 14 studies had a high risk of bias.

Three studies assessed the interleukin-1 inhibitor anakinra, including two cohort studies and one case series ( Table 4 ). The two cohort studies (pooled n = 141) evaluated mortality and were included in the quantitative analysis (45, 46) . Anakinra was associated with a significantly lower risk of

This article is protected by copyright. All rights reserved mortality (pooled HR 0.2 CI 0.1-0.4) as compared to the standard of care (Figure 2 ). The study by Cavalli et al. also found a lower rate of a composite endpoint of mechanical ventilation or death but did not find a difference with regard to ventilator-free survival at 21 days. The study by Cavalli et al.

had a high risk of bias, while the study by Huet et al. had some concerns.

Four cohort studies evaluated mortality and the use of intravenous immunoglobulin (IVIG) ( Table 4) .

One study reported a lower risk of mortality at 60 days with IVIG, while two other cohorts found no difference in survival (47) (48) (49) . In a study of patients with cirrhosis and COVID-19, there was no difference in mortality between IVIG users and non-users (50) . The direction of effect was split evenly by vote counting. The cohort study by Shao et al. had some concerns and the other three studies had a high risk of bias.

One cohort study with a high risk of bias found no significant difference in ICU transfer at 2 weeks, but higher rate of discharge at week two among patients who received baricitinib (51) ( Table 4 ).

This article is protected by copyright. All rights reserved DISCUSSION In this systematic review and meta-analysis of antirheumatic disease therapies for the treatment of COVID-19, the use of hydroxychloroquine was not associated with mortality. The effects of other antirheumatic disease therapies were frequently contradictory with respect to mortality, escalation of care, discharge, clinical improvement, and SARS-CoV-2 clearance. This may reflect important limitations of the included studies, the majority of which had small sample sizes and inadequate or absent comparator groups. Many also relied upon viral clearance as their primary outcome measure, a surrogate measure which may not be clinically relevant. These results extend recent systematic reviews of hydroxychloroquine (13, 14) , to a broader range of antirheumatic disease therapies and complement guidance from the American College of Rheumatology that focused on patients with rheumatic diseases (52) .

Despite limitations of the available evidence, patterns have begun to emerge. Contrary to early enthusiasm for hydroxychloroquine (1, 4) , in this meta-analysis hydroxychloroquine use was not associated with a mortality benefit in people with COVID-19. These findings are in agreement with general observations from another systematic review (13) and from a recently published RCT that assessed post exposure prophylaxis (53). In contrast to a now-retracted study by Mehra et al., hydroxychloroquine use was not associated with increased mortality (6, 7) . This may reassure patients with rheumatic diseases, who were understandably concerned about taking hydroxychloroquine after these apparently unverifiable data were published. Definitive data from large randomized trials are expected to be published soon, including the National Institutes of Health (NIH) sponsored ORCHID trial, the RECOVERY trial from the United Kingdom, and the World Health Organization (WHO) Solidarity trial. All three trials recently halted enrollment and have reported a lack of benefit in press releases (54) (55) (56) . Overall, our findings and other data support a growing consensus that antimalarial therapies for COVID-19 should be limited to use in ongoing clinical trials (57, 58) .

Therapies that target the hyperinflammatory state of COVID-19, including IL-1 and IL-6 inhibitors, have been widely used despite a relative paucity of data. Results from our meta-analysis of two studies found an association between anakinra and lower mortality, but this should be interpreted Accepted Article with caution. One study did not adequately control for confounders, and the other study used a historical cohort as a comparator group (45, 46) . Neither study provided adequate evidence to support widespread use of drugs inhibiting IL-1 for treatment of COVID-19, which must await high quality evidence from ongoing RCTs. The available data for IL-6 inhibition were similarly limited. Few studies of IL-6 inhibitors used an adequate comparator, and the results of IL-6 inhibitor studies were frequently conflicting. It should be noted that both IL-1 and IL-6 inhibitors were typically used for patients with moderate to severe acute respiratory distress syndrome. Selection bias, publication bias, and confounding by indication may have influenced purported associations. Press releases from ongoing RCTs have been encouraging, but peer-reviewed data will be essential in determining the role of these therapies.

Glucocorticoids have also been widely used in hospitalized patients with COVID-19. As with IL-1 and IL-6 inhibitors, they typically have been reserved for patients with moderate to severe disease, likely biasing risk estimates. Overall, no definitive conclusions could be drawn from our data synthesis.

Small studies with inadequate or absent comparator groups generally suggested no difference with regard to mortality. Those that included a comparator had conflicting findings, and none were assessed as having a low risk of bias. After the final date of our search, preliminary findings from the adaptive RECOVERY trial, which assessed dexamethasone in hospitalized patients with COVID-19, were posted to medRxiv (59) . While preprint data that have not undergone peer review should be interpreted with caution, the RECOVERY trial was well designed and observed a significant reduction in mortality at 28 days in patients randomized to receive open label dexamethasone as opposed to usual care (age-adjusted rate ratio 0.83, confidence interval 0.74-0.92). These data support current recommendations for prescribing glucocorticoids in a select group of patients with COVID-19 (57, 60, 61) .

Intravenous immunoglobulin (IVIG) and baricitinib have also been studied. One study with an inadequate comparator found an association with IVIG use and lower mortality at 60 days. Only one small cohort study with a high risk of bias evaluated baricitinib. It found no difference with respect to escalation of care, but patients who received baricitinib were more likely to be discharged at two weeks. Although it did not meet inclusion criteria, we identified one case series of eculizumab use in 4 patients (62), all of whom recovered.

This article is protected by copyright. All rights reserved These limitations notwithstanding, this comprehensive systematic review and meta-analysis suggests that hydroxychloroquine use is not associated with benefit or harm with regard to COVID-19 mortality. Antirheumatic disease therapies should be investigated further in randomized controlled trials. In the interim, physicians should be cautious in offering off label antirheumatic disease therapies to patients with COVID-19 based on the currently available literature. * Bias assessment using the Newcastle-Ottawa Scale; case series assumed to be high risk by default †Direction of effect quantified using the Cochrane vote counting method for data synthesis. Studies eligible for quantitative synthesis and case series were excluded Abbreviations: Odds ratio (OR); confidence interval (CI); hazard ratio (HR); acute respiratory distress syndrome (ARDS); glucocorticoids (GC); standard of care (SoC); intensive care unit (ICU); invasive mechanical ventilation (IMV); not applicable (NA) 

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Roumier (37) Cohort ( * Bias assessment using the Newcastle-Ottawa Scale; case series assumed to be high risk by default †Direction of effect quantified using the Cochrane vote counting method for data synthesis. Studies eligible for quantitative synthesis and case series were excluded Abbreviations: Hazard ratio (HR); confidence interval (CI); tocilizumab (TCZ); odds ratio (OR); invasive mechanical ventilation (IMV); intensive care unit (ICU); standard of care (SoC); arterial partial pressure oxygen to fractional inspiration ratio (P/F); not applicable (NA)

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Shao (47) 

Cantini (51) Cohort (24) No difference in ICU transfer at week 2 with baricitinib (0% vs. 33% SoC, p = 0.09) High +

Cantini (51) Cohort (24) Higher rate of discharge at week 2 with baricitinib (58% vs 8% SoC, p = 0.03) High +