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Antirheumatic Disease Therapies for the Treatment of COVID‐19: A Systematic Review and Meta‐Analysis

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 ≥1 relevant clinical outcome for ≥5 patients who were infected with severe acute respiratory syndrome coronavirus 2 and were treated with antirheumatic disease therapy between January 1, 2019 and May 29, 2020. Pairs of reviewers screened articles, extracted data, and assessed risk of bias. A meta‐analysis of effect sizes using 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 of the 45 studies had been published in a peer‐reviewed journal. In a meta‐analysis of 3 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 (95% CI) 0.83, 2.42]). In a meta‐analysis of 2 cohort studies with some concerns/higher risk of bias, anakinra use was associated with lower mortality (pooled HR 0.25 [95% CI 0.12, 0.52]). 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 regarding COVID‐19 mortality. The evidence supporting the effect of other antirheumatic disease therapies in COVID‐19 is currently inconclusive.


INTRODUCTION
Several antirheumatic disease therapies have emerged as potential treatments for coronavirus disease 2019 (COVID- 19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There has been particular interest in the antimalarial agents hydroxychloroquine (HCQ) and chloroquine (1), which may inhibit SARS-CoV-2 replication by elevating endosomal pH or altering the glycosylation of the angiotensinconverting enzyme 2 (ACE2) receptor (2). After preliminary clearance. Studies that did not present primary data (i.e., editorials, opinions, meta-analysis, and reviews) were excluded.

Patient research partners.
Four patient research partners who have had COVID-19 (2 patients with an autoimmune disease and 2 rheumatologists) were involved throughout the project. Patient research partners participated in the selection of outcomes and the drafting of the manuscript.
Data collection process. Pairs of reviewers working independently (MP, YPEC, HT, SES, FB, MID, PK, CS-A, JS, AK, and AD-G) 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 using DistillerSR software (Evidence Partners). A standardized extraction tool was developed by consensus and refined after preliminary testing on 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 and AD-G).

Risk of bias in individual studies.
Two reviewers working independently (MP and AD-G) assessed the risk of bias. RCTs were assessed using the Risk of Bias 2.0 tool (19) and were reported using the recommended 3-item ordinal scale ("high risk of bias," "some concerns," or "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 a study's risk of bias in this context and was used to determine global risk of bias (0 = high risk, 1 = some concerns, and 2 = low risk) (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).

Data analysis.
When ≥1 study demonstrated the same outcome for the same antirheumatic therapy and showed 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 random-effects models due to expected clinical and methodologic heterogeneity (24). The I 2 statistic was calculated to describe heterogeneity. All analyses were conducted using RevMan 5.3 software.
We grouped the studies according to antirheumatic disease therapy and outcomes. The data were synthesized narratively and in tables. For reporting purposes and due to the methodologic 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 the 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). included in the second extraction. After title and abstract screening, 3,660 studies were excluded. Of the 275 articles included for full-text review, 230 were excluded and 45 were included in qualitative review. One study identified by manual count was subsequently retracted (6,7) and therefore removed. Six of these studies were also eligible for meta-analysis (Supplementary Figure 1, http://onlin elibr ary.wiley.com/doi/10.1002/art.41469/ abstract).
Antimalarial therapy. HCQ. Fourteen studies assessed HCQ, including 2 RCTs, 7 cohort studies, and 5 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 = 1,549) were conducted to evaluate 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 1.03 [95% CI 0.82, 1.29]) ( Figure 1B). All studies included in the quantitative synthesis had a low risk of bias.
Escalation of care and rate of discharge were each evaluated in 1 cohort study. Neither the study by Magagnoli et al assessing the risk of mechanical ventilation (27) nor one by Mahévas and colleagues evaluating discharge at 21 days (28) showed differences among patients with COVID-19 who received HCQ compared to those who did not. Both studies were considered to have a low risk of bias.
Two RCTs and 1 cohort study assessed clinical improvement. An RCT by Tang et al demonstrated no significant difference with regard to symptom alleviation at 28 days (30), while a smaller RCT by Chen et al showed a shorter recovery time with regard to both fever and cough (31). Based on vote counting, the direction of effect in both studies was toward a faster resolution of symptoms. In the aforementioned cohort study by Mahévas et al, researchers also evaluated the proportion of patients who were successfully weaned from oxygen after 21 days and found no significant difference. Both RCTs had a high risk of bias.
With regard to SARS-CoV-2 clearance, the RCT by Tang  Chloroquine. Five studies assessed chloroquine, including 2 RCTs, 2 cohort studies, and 1 case series (Table 1). In an RCT by Borba et al, researchers assessed mortality (33), and the study 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 chloroquine to lopinavir/ritonavir demonstrated that participants receiving chloroquine were twice as likely to be discharged (34), and a cohort study by Huang et al showed a significantly shorter duration of fever in the chloroquine group (35). The same 2 studies also addressed SARS-CoV-2 clearance. The RCT showed a higher likelihood of clearance with chloroquine compared to ritonavir/lopinavir, while the cohort study showed a shorter time for viral clearance. In another cohort study, 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, according to vote counting, had the same direction of effect toward a shorter time for viral clearance.

IL-6 inhibitors.
Seven studies assessed tocilizumab, an IL-6 receptor inhibitor, including 3 cohort studies and 4 case series; 1 case series assessed the IL-6 inhibitor siltuximab (  * Escalation of care included ICU transfer, intubation, and mechanical ventilation. IL-6 = interleukin-6; TCZ = tocilizumab; Pao 2 :Fio 2 = arterial partial pressure oxygen to fractional inspired oxygen ratio (see Table 1 for other definitions). † Bias assessed using the Newcastle-Ottawa Scale; case series assumed to be high-risk by default. ‡ Quantified using the Cochrane vote counting method for data synthesis. Studies eligible for quantitative synthesis and case series were excluded.

Glucocorticoids.
Fourteen studies assessed glucocorticoid use, including 13 cohort studies and 1 case series (Table 3). Nine cohort studies evaluated mortality and glucocorticoids. There was variability regarding timing of glucocorticoid use and COVID-19 disease severity. Based on 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 showed no difference in a composite outcome of ICU admission or mortality (40). Two cohort studies both demonstrated a lower rate of escalation of care (41,42). The study by Wang et al (41) showed a shorter hospitalization time with methylprednisolone, but the cohort study by Fadel (42) et al did not. Three cohort studies evaluated SARS-CoV-2 clearance with glucocorticoids. One study showed a significantly increased time to viral clearance (43), and 2 studies showed no significant difference (44,45). Eleven of the 14 studies had a high risk of bias.
Anakinra. Three studies assessed the IL-1 inhibitor anakinra, including 2 cohort studies and 1 case series ( Table 4). The 2 cohort studies (pooled n = 141) evaluated mortality and were included in the quantitative analysis (46,47). Anakinra was associated with a significantly lower risk of mortality (pooled HR 0.25 [95% CI 0.12, 0.52]), compared to the standard of care (Figure 2). Huet et al (46) also  Table 1 for other definitions). † Bias assessed using the Newcastle-Ottawa Scale; case series assumed to be high-risk by default. ‡ Quantified using the Cochrane vote counting method for data synthesis. Studies eligible for quantitative synthesis and case series were excluded.  High + * Escalation of care included ICU transfer, intubation, and mechanical ventilation. IVIG = intravenous immunoglobulin; BID = twice daily (see Table 1 for other definitions). † Bias assessed using the Newcastle-Ottawa Scale; case series assumed to be high-risk by default. ‡ Quantified using the Cochrane vote counting method for data synthesis. Studies eligible for quantitative synthesis and case series were excluded.

Intravenous immunoglobulin (IVIG).
Four cohort studies evaluated mortality and the use of IVIG (Table 4). One study demonstrated a lower risk of mortality at 60 days with IVIG, while 2 other cohorts demonstrated no difference in survival (48)(49)(50). In a study of patients with cirrhosis and COVID-19, there was no difference in mortality between patients receiving and those not receiving IVIG (51). The direction of effect was split evenly according to vote counting. There were some concerns pertaining to the risk of bias in the cohort study by Shao et al, and the other 3 studies had a high risk of bias.
Baricitinib. One cohort study with a high risk of bias showed no significant difference in ICU transfer at 2 weeks, but there was higher rate of discharge at week 2 among patients who received baricitinib (52) ( Table 4).

DISCUSSION
In this systematic review and meta-analysis of antirheumatic disease therapies for the treatment of COVID-19, the use of HCQ 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 that may not be clinically relevant. These results extend recent systematic reviews of HCQ (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 (53).
Despite limitations of the available evidence, patterns have begun to emerge. Contrary to early enthusiasm for HCQ (1,4), in this meta-analysis, HCQ use was not associated with a mortality benefit in people with COVID-19. These findings are consistent with general observations from another systematic review (13) and from a recently published RCT that assessed postexposure prophylaxis (54). In contrast to reported findings from a now-retracted study by Mehra et al (6,7), HCQ use was not associated with increased mortality. This may reassure patients with rheumatic diseases, who were understandably concerned about taking HCQ 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-sponsored ORCHID trial, the RECOVERY trial from the UK, and the World Health Organization Solidarity trial. All 3 trials recently halted enrollment and have shown a lack of benefit as reported in press releases (55)(56)(57). 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 (58,59).
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 2 studies showed an association between anakinra and lower mortality, but this should be interpreted with caution. One study did not adequately control for confounders, and the other study used a historical cohort as a comparator group (46,47). 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-tosevere 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 published (60). The RECOVERY trial was well designed and showed 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 [95% CI 0.74, 0.92]). These data support current recommendations for prescribing glucocorticoids in a select group of patients with COVID-19 (58,61,62).
IVIG and baricitinib have also been studied. One study with an inadequate comparator showed an association between IVIG use and lower mortality at 60 days. Only 1 small cohort study with a high risk of bias evaluated baricitinib. It demonstrated no difference with respect to escalation of care, but patients who received baricitinib were more likely to be discharged at 2 weeks. Although it did not meet inclusion criteria, we identified 1 case series of eculizumab use in 4 patients (63), all of whom recovered.
Our search did not identify any studies as of May 29, 2020 that evaluated other antirheumatic disease therapies, such as colchicine or TNF inhibitors. Clinical trials are underway to further assess IVIG, baricitinib, and eculizumab, among others (63)(64)(65).
Strengths of this review were a rigorous application of systematic review methodology and a comprehensive search of the literature, which included published and preprint archives | 45 in all languages. Another strength was the inclusion of patients with rheumatic diseases and patients with COVID-19 in the review process. In fact, several members of the review team contracted COVID-19 during the execution of this review.
Our study also had a number of limitations. First, the COVID-19 literature has rapidly expanded and indexing may be delayed, which makes performing a systematic review difficult. At the time of this writing (June 10, 2020), we are not aware of any consequential publications that have been missed. Second, although we used validated risk of bias assessments with 2 reviewers working in parallel, such judgments may be open to interpretation, and use of other validated tools may have led to different conclusions. Third, all of the observational data came from hospitalized patients and may not be generalizable to a broader population. This highlights an important limitation of the literature itself, as we found no studies of outpatients infected with COVID-19 who received antirheumatic disease therapies. Finally, the degree to which publication bias has influenced the current literature was not assessed, but preprint archives were included to mitigate such biases.
These limitations notwithstanding, this comprehensive systematic review and meta-analysis suggests that HCQ use is not associated with benefit or harm with regard to COVID-19 mortality. Antirheumatic disease therapies should be investigated further in RCTs. 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.