Article Text

Immunomodulatory therapies for SARS-CoV-2 infection: a systematic literature review to inform EULAR points to consider
  1. Alessia Alunno1,
  2. Aurélie Najm2,
  3. Xavier Mariette3,
  4. Gabriele De Marco4,5,
  5. Jenny Emmel6,
  6. Laura Mason6,
  7. Dennis G McGonagle4,5,
  8. Pedro M Machado7,8,9
  1. 1Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy
  2. 2Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
  3. 3Department of Rheumatology, Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, INSERM UMR1184, Le Kremlin Bicêtre, France
  4. 4Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, Leeds, UK
  5. 5The NIHR Leeds Biomedical Research Centre, Chapel Allerton Hospital, Leeds, UK
  6. 6Library & Evidence Research Centre, Medical Education, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  7. 7Department of Rheumatology, Northwick Park Hospital, London North West University Healthcare NHS Trust, London, UK
  8. 8Centre for Rheumatology & Department of Neuromuscular Diseases, University College London, London, UK
  9. 9National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC), University College London Hospitals (UCLH) NHS Foundation Trust, London, UK
  1. Correspondence to Dr Alessia Alunno, Rheumatology Unit, Department of Medicine, University of Perugia, 06123 Perugia, Umbria, Italy; alessia.alunno82{at}gmail.com

Abstract

Objective To summarise the available information on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection.

Methods As part of a European League Against Rheumatism (EULAR) taskforce, a systematic literature search was conducted from January 2019 to 11 December 2020. Two reviewers independently identified eligible studies according to the Population, Intervention, Comparator and Outcome framework and extracted data on efficacy and safety of immunomodulatory agents used therapeutically in SARS-CoV-2 infection at any stage. The risk of bias was assessed with validated tools.

Results Of the 60 372 records, 401 articles were eligible for inclusion. Studies were at variable risk of bias. Randomised controlled trials (RCTs) were available for the following drugs: hydroxychloroquine (n=12), glucocorticoids (n=6), tocilizumab (n=4), convalescent plasma (n=4), interferon beta (n=2), intravenous immunoglobulins (IVIg) (n=2) and n=1 each for anakinra, baricitinib, colchicine, leflunomide, ruxolitinib, interferon kappa and vilobelimab. Glucocorticoids were able to reduce mortality in specific subsets of patients, while conflicting data were available about tocilizumab. Hydroxychloroquine was not beneficial at any disease stage, one RCT with anakinra was negative, one RCT with baricitinib+remdesivir was positive, and individual trials on some other compounds provided interesting, although preliminary, results.

Conclusion Although there is emerging evidence about immunomodulatory therapies for the management of COVID-19, conclusive data are scarce with some conflicting data. Since glucocorticoids seem to improve survival in some subsets of patients, RCTs comparing glucocorticoids alone versus glucocorticoids plus anticytokine/immunomodulatory treatment are warranted. This systematic literature review informed the initiative to formulate EULAR ‘points to consider’ on COVID-19 pathophysiology and immunomodulatory treatment from the rheumatology perspective.

  • therapeutics
  • inflammation
  • immune system diseases
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Key messages

What is already known about this subject?

  • The SARS-CoV-2 pandemic is a global health problem. Aberrant host immune response plays an important role throughout the course of mild, moderate and severe COVID-19.

  • There is intense investigation to explore the utility of immunomodulatory drugs commonly used in the rheumatology arena as agents that may mitigate against COVID-19 to improve disease prognosis.

What does this study add?

  • Robust and reliable evidence of the efficacy of immunomodulatory therapies is scarce, but results from randomised controlled trials (RCTs) ruled out any benefit of hydroxychloroquine at any stage of SARS-CoV-2 infection while demonstrating the ability of some glucocorticoids to reduce mortality in specific patient subsets with severe COVID-19.

  • Data from RCTs on tocilizumab are conflicting, and definite conclusions cannot be drawn at this point in time. Anakinra was not effective in the only available RCT, while baricitinib+remdesevir was effective in specific patient subgroups (patients with non-invasive ventilation) in the only available RCT.

  • Evidence for several immunomodulatory compounds is scarce, and data from RCTs are required to elucidate their role in the context of different phenotypes of SARS-CoV-2 infection.

How might this impact on clinical practice or future developments?

  • This systematic literature review evaluated the evidence pertaining to immunomodulatory drugs where there is some evidence for efficacy in severe COVID-19 and a good safety profile thus far.

  • Further evidence is needed regarding the optimal use and consideration of combination therapies for severe disease in a rapidly evolving arena.

Introduction

SARS-CoV-2 infection encompasses a heterogeneous clinical picture ranging from asymptomatic to multisystem life-threatening manifestations. Although the majority of patients experience only mild to moderate symptoms, a relevant proportion of infected subjects may develop respiratory failure, acute respiratory distress syndrome and death.1 2 The severest forms of COVID-19 pneumonia are associated with severe pulmonary inflammatory responses, including oedema and inflammatory cell infiltration with severe alveolitis and associated pulmonary immunothrombosis. Beside the specific pathogenic effect of SARS-CoV-2, the immune response may be deleterious and excessive since postmortem studies may show excessive immune activation but a paucity of evidence for active viral alveolitis. A vicious circle encompassing the intrapulmonary release of proinflammatory mediators, along with the aberrant activation of immune cells, coagulopathy and histological evidence of haemophagocytosis in patients with more severe COVID-19 demonstrated some features that resembled the macrophage activation syndrome (MAS) also known as secondary haemophagocytic lymphohistocytosis (sHLH).3 4

Rheumatologists routinely use immunomodulatory drugs and are well aware of conditions like MAS/sHLH that may be observed as a complication of autoimmune or inflammatory rheumatic and musculoskeletal diseases (RMDs). On this basis, a large number of immunomodulatory drugs used in rheumatology for years have been investigated in SARS-CoV-2 infection, particularly severe COVID-19. This systematic literature review (SLR) was performed to inform the EULAR taskforce responsible for developing the points to consider (PtC) on COVID-19 pathophysiology and immunomodulatory treatment as viewed from the rheumatology perspective. Specifically, the SLR aimed to summarise the available information on the use of immunomodulatory drugs for the management of SARS-CoV-2 infection at any stage.

Methods

Search methodology

The EULAR task force that developed PtCs on COVID-19 pathophysiology and immunomodulatory treatment from the rheumatology perspective outlined the scope of the systematic literature search, according to the Population, Intervention, Comparator and Outcome approach.5 Based on a set of research questions encompassing the pathogenesis of SARS-CoV-2 infection, its management with immunomodulatory agents and its possible role as trigger of new-onset RMDs, three separate searches (online supplemental text S1−S4) were performed. The searches were performed in MEDLINE, Embase, The Cochrane Database of Systematic Reviews, CENTRAL and CINAHL. The searches on pathogenesis and RMDs were conducted up to 2 November 2020, while the one on immunomodulatory treatment up to 11 December 2020. The PubMed Similar Articles tool was also used, and a crosscheck of the key scientific journals in general medicine and immunology was performed. Non peer-reviewed literature was excluded given this SLR aimed at informing recommendations. However, given the rapid evolution of knowledge on COVID-19 treatment, a parallel hand search of ‘grey literature’ consisting only of RCT not yet published in peer-review journals but accessible in press releases or in extenso in preprint repositories was performed. These not yet published RCTs are presented separately and were not used to inform the PtC. In order to ensure this SLR to be as comprehensive as possible and provide an overview of all evidence (regardless of the level), no restriction to specific study design (eg, randomised controlled trials (RCTs)) was defined. The results of the search focused on the pathogenesis of SARS-CoV-2 infection are published elsewhere.

Study selection, data collection and assessment of risk of bias (RoB)

Briefly, original research articles of any study design, published in English, in peer-reviewed journals and addressing adults with proven SARS-CoV-2 infection treated with one or more immunomodulatory agent were eligible (online supplemental text S4). Two reviewers (AA and AN) independently assessed titles and abstracts according to the predetermined eligibility criteria, followed by full-text review. The agreement between reviewers, calculated with the Cohen’s kappa, was 0.95. Discrepancies were resolved by discussion. The task force methodologist (PMM) was consulted in the case of uncertainties. Data on patient characteristics, investigated drug administration scheme and comparators and outcomes were extracted. The RoB was assessed using validated tools according to the study design (online supplemental text S5). Only the results pertaining to immunomodulatory therapies are presented here.

Results

Of the 60 372 records yielded by the three searches, 700 were selected for full-text review and seven additional articles were identified by cross-referencing. Of these, 401 articles on 33 therapeutic strategies met the inclusion criteria for the research questions on immunomodulatory treatment of COVID-19 (online supplemental tables S1−S3). Robust evidence was mostly available for moderate to severe/critical COVID-19. The best evidence available for each compound is shown.

Immunomodulatory therapies with evidence on severe (patients on oxygen therapy) or critical (patients in intensive care unit (ICU)) COVID-19

Data from RCTs

A total of 39 RCTs, all at high or unclear RoB, evaluating 13 therapeutic approaches in severe/critical COVID-19 were retrieved by the SLR (online supplemental table S4).

Glucocorticoids
Efficacy

Of the six RCTs on glucocorticoids in severe/critical COVID-19, two investigated dexamethasone (DEX) (one at unclear and one at high RoB), two investigated methylprednisolone (MTP) (one at unclear and one at high RoB) and two investigated hydrocortisone (HCT) (both at unclear RoB). Most of the studies included severe and critical patients with between 15% and 100% of subjects requiring invasive mechanical ventilation (IMV).6–11 In one study at high RoB, none of the patients needed IMV at enrolment.11 This, along with the variability of other inclusion criteria, the use of different compounds (eg, long acting vs short acting) and different schedule may have contributed to the conflicting results for the majority of outcomes in the overall analysis (tables 1 and 2). Conversely, subgroup analyses revealed positive results for two (DEX and MTP) out of three compounds with regard to mortality (figure 1). The study from the RECOVERY Collaborative Group (unclear RoB) enrolled 6425 patients with severe COVID-19 of which 2104 were assigned to receive DEX in addition to standard of care (SOC) and 4321 to receive SOC only.6 The two groups were comparable with regard to need of oxygen therapy/non-invasive or IMV at randomisation. The addition of DEX to SOC reduced mortality but only in patients requiring respiratory support. Likewise, the addition of MTP to SOC in a study at unclear RoB was able to reduce mortality in patients aged 60 years or over.7 HCT failed to show benefit in reducing mortality in both studies.9 10 Importantly, the RECOVERY trial also reported that in patients not receiving oxygen therapy, DEX may have a possible (even if not statistically significant) deleterious effect on mortality (OR=1.22, 95% CI 0.93 to 1.61, p=0.14).6

Table 1

Effect of immunomodulatory drugs on mortality, assessed by randomised controlled trials, in moderate to severe COVID-19 (with oxygen therapy) and in critical COVID-19 (patients in ICU)

Table 2

Effect of immunomodulatory drugs on invasive and non-invasive ventilation and on oxygen support, assessed by randomised controlled trials, in moderate to severe COVID-19 (with oxygen therapy) and in critical COVID-19 (patients in ICU)

Figure 1

Forest plots showing the risk ratio (RR) and 95% CI for mortality in randomised controlled trials divided by intervention. The latest follow-up available is reported in the timing column. Panel A shows RRs in overall cohorts, panel B shows overall cohorts and subgroup analysis in studies assessing glucocorticoids and panel C shows all studies on tocilizumab (including grey literature).

The two studies on DEX yielded conflicting results with regard to the need of IMV; however, a lack of stratification of inpatients with mild to moderate pneumonia receiving oxygen therapy did not allow us to untangle the effect of DEX in patients requiring a low rate of oxygen (1–2 L/min) from the effect in those requiring higher rate (3–15 L/min). In addition, the studies on MTP and HCT assessing the need of IMV7 10 found no beneficial effect of these compounds. One additional study on HCT in patients with COVID-19 requiring oxygen therapy ≥10 L/min (COVID-19 STEROID) emerged from the search of the ‘grey literature’, reporting no benefit of HCT on 28-day all-cause mortality.12

Safety

Only one study identified safety concerns related to glucocorticoids use in severe COVID-19 with a reported increased insulin use at day 7 in patients treated with MTP+SOC compared with SOC.7 The other RCTs reported either no difference between groups8 or descriptive information without statistical assessment of differences (table 3).9–11

Table 3

Safety of immunomodulatory drugs assessed by randomised controlled trials in moderate-to-severe COVID-19 (with oxygen therapy) and in critical COVID-19 (patients in ICU)

Hydroxychloroquine
Efficacy

Of the nine RCTs on hydroxychloroquine (HCQ) in severe COVID-19, three studies at high RoB did not report any information regarding the proportions of patients requiring oxygen therapy/NIMV/IMV,13–15 two studies reported NIMV/IMV as exclusion criterion16 17 and four studies detailed the proportion of enrolled patients received either oxygen therapy, NIMV or IMV.18–21 The studies assessing mortality,13 16 18–20 three at unclear and one at high RoB, agreed that the addition of HCQ to SOC did not provide any beneficial effect. As far as clinical severity is concerned, HCQ did not reduce the need of IMV,13 16 19 but one RCT at unclear RoB demonstrated a higher risk of progression to IMV in patients treated with HCQ+SOC compared with SOC only18 (tables 1 and 2). From the parallel hand search in the ‘grey literature’, we identified one additional RCT on HCQ that was prematurely discontinued due to inefficacy—the ORCHID trial.22

Safety

Two studies at unclear RoB alerted on safety issues regarding HCQ. Overall, more adverse events occurred in the HCQ-treated groups. One study reported higher frequency of QTc prolongation and elevation in liver enzyme levels in HCQ-treated patients.16 The other study reported a greater risk of death in HCQ-treated patients, either from non-SARS-CoV-2 infections or from cardiac causes, although the incidence of arrhythmias was similar across groups.18 It is important to mention that the schedule of HCQ in the above-mentioned RCTs was higher than that used in rheumatology practice (eg, a stable dose of 800 mg/day or 800 mg/day for a few days followed by 400 mg/day). Furthermore, the combination with other drugs that could prolongate the QT interval such as azithromycin may account for the safety concerns.

Tocilizumab
Efficacy

Three RCTs on tocilizumab (TCZ) at unclear RoB were retrieved.23–25 In all studies, NIV/IMV represented an exclusion criterion; however, only the CORIMUNO-19 trial excluded also hospitalised patients without need of oxygen therapy, focusing only on patients requiring at least 3 L/min oxygen therapy. In this regard, the observed mortality at day 28 in the former two RCTs was rather low (2%–5%), suggesting that they may have enrolled milder patients than CORIMUNO-19. In Stone’s study, 16% of patients did not receive oxygen therapy. While Stone et al24 and Salvarani et al25 failed to demonstrate any benefit from the addition of TCZ to SOC for all the outcomes assessed, the CORIMUNO-19 trial demonstrated benefit of adding TCZ to SOC with regard to lower progression to NIV, IMV or death, although day-28 mortality did not differ between groups.

Two additional RCTs on TCZ were identified in the ‘grey literature’. The EMPACTA trial, using the same inclusion criteria as CORIMUNO-19, met the composite primary outcome of death or IMV at day 28 and was published in The New England Journal of Medicine on 17 December 2020.26 Conversely, the COVACTA trial did not show a benefit in terms of clinical improvement or mortality in the overall population. Unlike the above-mentioned studies, NIV/IMV were not an exclusion criteria in COVACTA, and of note, 65%–70% of patients were receiving either of the two.27 However, positive results were reported in a post hoc analysis with a significantly lower proportion of patients experiencing clinical failure in the subgroup not receiving IMV at randomisation (table 4). In patients recently admitted to ICU within 1 day, the REMAP-CAP study was prematurely stopped because of positive results on hospital mortality with TCZ (28% for TCZ vs 35.8% for controls) and on day 90 survival with TCZ: (median HR=1.59 (1.24 to 2.05), probability of superiority of TCZ >99.9%) (table 4).28 Lastly, an RCT reporting that TCZ was not superior to SOC in improving clinical outcomes at 15 days was published on 22 January 2021.29

Table 4

’Grey literature’ concerning randomised controlled trials

Safety

The safety profile of TCZ was good, with the study by Stone et al24 showing fewer serious infections in the TCZ group in spite of an increase rate of neutropaenia.

Anakinra
Efficacy

One RCT assessed anakinra in patients with COVID-19 requiring at least 3 L/min oxygen therapy (CORIMUNO-19) and was published online in The Lancet Respiratory Medicine on 22 January 2021.30 The addition of the drug to SOC failed to improve survival without NIV (including high-flow oxygen) or IMV at day 14 or survival at day 90.

Safety

From a safety perspective, there was a numerical increase of serious infections in the anakinra group.

Baricitinib
Efficacy

At present, the only RCT available on baricitinib in SARS-CoV-2 infection compared remdesevir+baricitinib versus remdesevir+placebo.31 Patients receiving remdesevir+baricitinib had a median time to recovery of 7 days, as compared with 8 days in the remdesevir+placebo group (rate ratio for recovery: 1.16; 95% CI 1.01 to 1.32; p=0.03), which is statistically significant but clinically probably not meaningful, except in the subgroup of patients with a baseline NIV (including high flow oxygen) in whom median time to recovery was 10 days with the combination therapy, as compared with 18 days in the remdesivir only control group (rate ratio for recovery: 1.51; 95% CI 1.10 to 2.08). It is important to note that the global mortality in the ACTT-2 trial was lower (around 5%) than in other trials like the RECOVERY DEX trial (around 20%) that might explain the modest effect size observed in ACTT-2. Interestingly, the ACTT-4, evaluating the combination of baricitinib and remdesivir compared with DEX and remdesivir is currently ongoing.32

Safety

The incidence of adverse events was similar in the two treatment groups.

Other immunomodulatory drugs
Efficacy

The SLR yielded three publications on two RCTs on interferon (IFN) beta,33–35 one on the Janus kinase inhibitor ruxolitinib,36 one on anti-C5a vilobelimab,37 one on colchicine,38 two on IVIg39 40 and three on convalescent plasma.41–43 The studies on vilobelimab and colchicine were at unclear RoB, while all the others were at high RoB. The studies on IFN-beta provided conflicting results on mortality and other clinical outcomes (tables 2 and 3).33–35 No differences on mortality or in the need of IMV were observed in patients treated with ruxolitinib,36 while IVIg reduced mortality in hospitalised patients requiring NIMV/IMV.39 The addition of colchicine to SOC allowed a larger number of patients to achieve cumulative event-free 10-day survival, using a composite outcome including mortality or need of IMV, and a lower number of patients displayed clinical deterioration.38 However, patients with a slightly milder phenotype not requiring IMV were enrolled. On 24 January 2021 the results of the large COLCORONA trial have been released highlighting that colchicine reduced hospitalisation, use of ventilation and mortality.44 Vilobelimab was not effective on any of the outcomes assessed (table 4). All studies on convalescent plasma failed to show any efficacy on 28-day mortality, progression to severe disease42 or clinical improvement at 2841 or 3043 days. On the day of submission of this article, a press release announced that the phase III RUXCOVID study evaluating ruxolitinib+SOC compared with placebo+SOC in patients with COVID-19 did not meet its primary endpoint of reducing the number of hospitalised patients with COVID-19 who experienced severe complications (death, mechanical ventilation or ICU care).45 Finally, a press release on 2 July 2020 reported the failure of a phase III trial assessing sarilumab in critical patients (requiring IMV) with COVID-19,46 while in the above-mentioned REMAP-CAP study (grey literature) assessing TCZ and sarilumab demonstrated efficacy of the latter in improving survival and other outcomes.28

Safety

Ruxolitininb and vilobelimab and convalescent plasma showed a good safety profile. Conversely, data were conflicting for IFN-beta, not reported for IVIg and worse safety profile for colchicine since authors highlighted a higher frequency of diarrhoea in colchicine-treated patients.

Data from prospective or retrospective controlled studies

Prospective controlled studies were identified as best available evidence for eight therapeutic strategies, three of which using a combination of two immunomodulatory drugs (online supplemental table 5).

Glucocorticoids+TCZ
Efficacy

Three studies assessed this therapeutic strategy.47–49 Ramiro et al47 enrolled patients requiring any kind of oxygen support, reporting that the proportion of patients receiving IMV was higher in the cohort of patients treated with SOC versus those receiving TCZ (15% vs 1%). The treatment protocol included sequential MTP and TCZ, the latter added if lack or clinical response to MTP within 2–5 days. Historical control groups were identified among patients referred to the same centre in the previous month and receiving SOC only. Significant positive effects were observed in the TCZ+MTP group with regard to mortality, IMV, oxygen support, clinical improvement and time to discharge. Of note, day-28 mortality rate in the control group was high (48%).

Likewise, Sanz Herrero et al49 compared patients receiving TCZ either monotherapy or in combination with MTP and reported that combination therapy was superior to monotherapy in reducing the risk of death. On the contrary, Gupta et al50 reported that the association between TCZ treatment and mortality was similar in patients having received or not glucocorticoids on ICU admission (HRs (95% CI) 0.68 (0.46 to 0.99) and 0.71 (0.53 to 0.96)), respectively.

Safety

One study at unclear RoB reported that although the overall rate of adverse events was comparable in the treatment groups, there was a trend towards more pulmonary embolism in the TCZ+glucocorticoids group (p=0.059). Arrhythmias occurred less frequently, although not significantly, in the TCZ+glucocorticoids group (p=0.265).47

Glucocorticoids+baricitinib
Efficacy

The combination of baricitinib and glucocorticoids added to SOC was assessed in a study at high RoB.51 Patients with severe COVID-19, half of which were receiving NIV (IMV was an exclusion criterion) received three consecutive days of pulse MTP therapy (80, 125 or 250 mg/day) followed by prednisone at a starting dose of 30 mg/day tapered until discontinuation within 7–10 days. Those receiving only MTP were compared with those receiving also baricitinib from day 3 (2 or 4 mg/day), and the combination therapy (regardless of the baricitinib dose) was linked to more pronounced clinical improvement, a lower use of supplemental oxygen both at discharge and 1 month later was compared with MTP+SOC.

Safety

A number of adverse events occurred in the two treatment groups, including infectious and cardiac adverse events, but the authors did not flag any specific scenario attributable to baricitinib. Of particular interest, occurrence of venous thromboembolism, a class warning for JAK inhibitors, was similar in the two treatment groups.

Other immunomodulatory drugs

A few small prospective studies at variable RoB evaluated mavrilimumab,52 lenzilumab,53 eculizumab,54 sarilumab,55 recombinant human IL-756 and the combination of ruxolitinib+eculizumab,57 ruxolitinib+glucocorticoids58 and cyclosporin+glucocorticoids.59 However, none of them provided solid positive results.

One retrospective controlled study of infliximab at high RoB showed comparable mortality rate and need of IMV in 17 patients with COVID-19 treated with SOC versus seven patients receiving infliximab in addition to SOC. In the ‘grey literature’, we came across other ongoing studies with infliximab (ACTIV-1: NCT04593940 and CATALYST: ISRCTN40580903) and adalimumab (AVID-CC: ISRCTN33260034).60 One retrospective study explored anakinra in combination with glucocorticoids reporting a possible benefit in reducing mortality.61

Data from non-controlled studies

Canakinumab was evaluated in one retrospective non-controlled study and one case report,62 63 tesidolumab was assessed in one retrospective study64 and itolizumab was assessed in a prospective non-controlled study.65 These studies showed favourable, although very preliminary results, that required to be confirmed in controlled studies.

Immunomodulatory therapies with evidence on mild COVID-19 (without oxygen therapy)

Six immunomodulatory strategies were assessed in RCTs at high or unclear RoB enrolling patients with mild to moderate COVID-19 (table 5).

Table 5

Effect and safety of immunomodulatory drugs assessed in mild COVID-19 (without oxygen support)

Hydroxychloroquine

Efficacy

Five RCTs evaluated HCQ in mild to moderate COVID-19,17 21 66–68 but none of them demonstrated any benefit with the addition of this drug to SOC (including in milder non-hospitalised patients.66 67

Safety

In line with what was reported from studies in severe COVID-19, the RCTs enrolling mild to moderate COVID-19 highlighted safety concerns for HCQ since a higher number of adverse events were observed in the HCQ-SOC group compared with SOC.

Other immunomodulatory drugs

Two small RCTs at high RoB reported on leflunomide.69 70 One study observed no difference in length of hospital stay,69 while conflicting results were reported by both studies with regard to a possible effect on negative conversion of SARS-CoV-2. Safety concerns were raised by one of the studies with increased liver enzymes in leflunomide-treated patients.70

IFN-alpha71 and IFN-kappa72 reduced the time to negative conversion of SARS-CoV-2 in two studies. Two prospective studies on baricitinib at high RoB provided conflicting results for every assessed outcome and only agreed on the fact that addition of baricitinib to SOC did not worsen the safety profile of the therapeutic strategy.73 74 One small study evaluated TCZ+favipavir demonstrating positive effects on lung inflammation.75

Discussion

Our SLR has shown that despite the large bulk of articles investigating several immunomodulatory drugs for the treatment of SARS-CoV-2 infection, most studies are at high or unclear RoB, and robust evidence on efficacy is available only for a few drugs and for a low number of outcomes. In particular, data from RCTs showed that the addition of HCQ to SOC was not beneficial at any stage of SARS-CoV-2 infection, while glucocorticoids may reduce mortality in some subgroups of patients with moderate, severe or critical COVID-19. The latter evidence is mainly driven by the large RECOVERY trial.6 Regarding TCZ, three available RCT were positive, but three other RCTs are negative. Thus, TCZ could have a place in some specific subgroups that remain to be determined.23 76

The SLR identified a number of pitfalls that prevented the comparison of retrieved studies and constrains results interpretation. First, heterogeneity of inclusion criteria even in studies claiming to assess the same patient subgroup (eg, severe COVID-19) was often observed. In fact, various parameters, such as the partial pressure of oxygen (PaO2)/fractional inspired oxygen ratio, C reactive protein level and peripheral oxygen saturation to cite a few, with different cut-off values, have been used to classify patients contributing to a relevant selection bias. We tried to overcome this issue and harmonise the presentation of results using a framework inspired by one the WHO scales.77

In RCTs, the definition of ‘standard of care’ was also highly variable making data interpretation difficult. Every immunomodulatory drug that has been assessed was added on top of SOC and compared (with a few exceptions) with SOC alone. However, in COVID-19, SOC changed rapidly, and the approaches recommended as SOC in March 2020 were not the same as in the subsequent months. Moreover, other factors such as local/national regulations or recommendations, criteria for hospital admission/IMV or differing drug availability increased study variability even if published within the same timeframe. In addition, in some studies, the treatment, including glucocorticoids, interferon or other immunomodulatory drugs, was left at the discretion of the treating physician, meaning that a subgroup of the intervention group could receive other drugs in a non-standardised manner, subsequently affecting the interpretability of the results.

In prospective observational studies, the main pitfall was that the control groups were often historical and thus not comparable with the studied group, even if adjusted for baseline characteristics, given the rapid evolution in the treatment of the disease. Finally, yet importantly, study outcomes along with the timing of their assessment largely varied across studies.

In conclusion, this SLR informed the EULAR initiative to formulate PtC on COVID-19 pathophysiology and immunomodulatory therapies. However, the results of the present SLR also underscored the need of RCTs with standardised inclusion criteria and outcomes in order to robustly elucidate the effect of immunomodulatory drugs at different stages of SARS-CoV-2 infection and ultimately improve the care and prognosis of affected people. Another important aspect to be further explored is the identification of factors predicting efficacy of the selected drug(s) in a specific population.

References

Supplementary materials

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Footnotes

  • Handling editor Désirée van der Heijde

  • Twitter @pedrommcmachado

  • AA and AN contributed equally.

  • Contributors All authors contributed and finally approved the current manuscript.

  • Funding This work was funded by European League Against Rheumatism (CLI122). PMM is supported by the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre.

  • Disclaimer The views expressed are those of the authors and not necessarily those of the (UK) National Health Service, NIHR or the Department of Health.

  • Competing interests XM has received consulting and/or speaker’s fees from BMS, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Servier and UCB, all unrelated to this manuscript. DGM has received consulting and/or speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, all unrelated to this manuscript. PMM has received consulting and/or speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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