Background: JAK-inhibitors (jakinibs) in the greater context
Much of the harm from infections is mediated by hyperactive inflammatory reactions. To date, most research has focused on two classes of medications to treat this:
- Corticosteroids have the advantage of being cheap, widely available, and often effective. The disadvantage is that corticosteroids modulate innumerable molecular pathways, thereby causing a variety of side effects.
- Monoclonal antibodies which inhibit a single cytokine have the advantage of molecular precision. These agents provide more focused inhibition of a single pathway, thereby avoiding the broad side effect profile of corticosteroids. Unfortunately, inhibiting a single cytokine among a network of hyperactive cytokines often has minimal effect. Monoclonal antibodies are also exceedingly expensive and have limited availability.
JAK-inhibitors may offer a compromise between these two extremes:
- JAK-inhibitors block several cytokine pathways. For example, JAK1/2 inhibitors block signaling via numerous cytokines, including IL-2, IL-6, IL-12, and interferons. This provides broader spectrum activity than inhibition of a single cytokine, potentially allowing JAK-inhibitors to be more effective than monoclonal antibodies.
- JAK-inhibitors affect fewer pathways than steroid, potentially allowing JAK inhibitors to have a more favorable side effect profile (e.g., no myopathy or delirium).
- JAK-inhibitors are small-molecule inhibitors which may be manufactured in bulk quantity and administered orally. Although these agents are currently expensive, over time their price is likely to decrease.
JAK inhibitors are relatively new medications. For example, baricitinib was FDA-approved in 2018 and ruxolitinib was approved in 2011. Ruxolitinib has recently demonstrated efficacy against hemophagocytic lymphohistiocytosis (HLH) in several case series, with an impressive efficacy/toxicity ratio.1–4 The application of JAK-inhibitors to other forms of hyperinflammation could open exciting new avenues into the treatment of critical illness.
Clinical evidence on baricitinib in COVID-19
ACTT-2 Trial: Baricitinib plus remdesivir for hospitalized adults with COVID-19
This is a multi-center, placebo-controlled RCT evaluating the effect of baricitinib when added to remdesivir (remdesivir plus placebo vs. remdesivir plus baricitinib).5 Patients weren’t allowed to receive steroid for treatment of COVID-19 (the trial was performed prior to publication of the RECOVERY trial). Since remdesivir probably has minimal effect on COVID-19, this trial is essentially a double-blind RCT investigating the use of baricitinib against COVID-19.
1,033 patients were included, many of whom were minimally ill (table above). The primary endpoint was time to recovery, which was one day shorter in patients treated with baricitinib. So the primary endpoint was statistically positive, but only with a small difference.
Secondary endpoints were more clinically meaningful and a bit more impressive:
- Among patients not requiring oxygen at baseline, treatment with baricitinib reduced the development of hypoxemia (23% vs. 40%).
- Among patients who weren’t intubated at baseline, treatment with baricitinib reduced the need for intubation (10% vs. 15%).
- There was a nonsignificant trend towards reduced 28-day mortality among patients treated with baricitinib (5.1% vs 7.8%, p=0.1).
Baricitinib appeared to be safe. Specifically:
- Significantly fewer “severe adverse events” were recorded in the baricitinib group than in the placebo group! You’re doing pretty well when you’re safer than placebo. This highlights the importance of performing placebo-controlled trials (without a placebo group all adverse events may be incorrectly attributed to the novel intervention).
- Fewer infections occurred in the baricitinib group.
- There was no significant difference in venous thromboembolic events between groups.
The primary limitation to applying this trial currently is that it was performed prior to widespread utilization of dexamethasone (with ~10% of patients receiving steroid). Consequently, the study cannot address the question of whether to use baricitinib in combination with steroid.
Cantini F et al. Beneficial impact of Baricitinib in COVID-19 moderate pneumonia: multicentre study
This is an observational, multicenter study describing outcomes of hospitalized patients treated with baricitinib (4 mg/day for two weeks) versus hydroxychloroquine (both in combination with lopinavir/ritonavir).6 Steroid administration was not allowed. At baseline, the groups were well matched and not very ill (inclusion required a saturation >92% on room air; patients were treated a median of seven days from symptom onset).
Outcomes are shown below. Patients in the baricitinib group were significantly less likely to require ICU admission and less likely to die. The baricitinib group showed more rapid improvement across a variety of clinical indices (e.g., oxygen saturation and various symptoms). Treatment with baricitinib correlated with increases in lymphocyte count and decreases in C-reactive protein and IL-6 levels.
This study has numerous limitations (e.g., lack of randomization and use of hydroxychloroquine as a control – although hydroxychloroquine is arguably an expensive placebo for COVID-19). However, the interpatient biological endpoints are rather convincing. Without baricitinib therapy, levels of C-reactive protein and IL-6 didn’t decrease over the first week of illness – whereas these levels dropped rapidly in the baricitinib group.
Stebbing J et al. JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality
This study includes a propensity-matched comparison of 83 patients treated with baricitinib, compared to 83 matched control patients.7 A number of important variables were used to generate two groups with closely aligned characteristics:
Use of baricitinib was associated with a reduction of the primary endpoint (deterioration leading to death or mechanical ventilation), 17% vs. 35% with p <0.001.
As a retrospective, propensity-matching study this cannot prove causality (because the possibility always exists that confounding occurred due to unidentified variables). Nonetheless, this supports the utility of baricitinib. Most notably, it suggests that baricitinib may be useful even among patients being treated with steroid (since 85% of patients were also treated with steroid).
Rodriguez-Garcia JL et al. Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study
This is a retrospective cohort study comparing patients treated with steroid alone, versus steroid plus baricitinib.8 Groups were reasonably well matched at baseline, with patients in the baricitinib group being slightly sicker (as might be expected, since the decision to use baricitinib was based on clinical judgement).
Patients treated with baricitinib were more likely to be weaned off oxygen (table below). There were no differences in mortality.
As a retrospective cohort study, this study has numerous limitations. However, it does lend further support to the concept that baricitinib provides benefit even when added to corticosteroid. Implications regarding long-term functional endpoints are notable.
Mechanism of action of baricitinib for COVID-19
Baricitinib has roughly two potential mechanisms of action against COVID-19:
- Baricitinib is an inhibitor of JAK-1 and JAK-2, which may dampen proinflammatory cytokine signaling (figure above).
- Baricitinib inhibits AP2-associated protein kinase 1 (AAK-1), which regulates endocytosis in alveolar type II cells. This could potentially reduce viral replication.9
However, several lines of evidence suggest that any impact on viral replication is not clinically relevant:
- Studies of related viruses suggest that blockade of AAK-1 may be inadequate to inhibit viral entry into cells.10
- One study involving in vitro liver organoids did suggest a mild reduction in viral replication due to baricitinib.7 However, in a study involving macaques infected with COVID, baricitinib did not affect viral titers.11
- Baricitinib is effective in later-stage disease (e.g., patients who are on high-flow nasal cannula). The primary driver of illness at this disease stage is an immune hyperresponsiveness to COVID-19. Thus, antiviral therapies generally have minimal effectiveness in this disease stage.
Consequently, it’s likely that other JAK-1/JAK-2 inhibitors would have similar efficacy against COVID-19 (e.g., ruxolitinib). However, further evidence is needed to establish this. To date, most studies have focused on baricitinib due to its potential antiviral activity.
Pharmacology of baricitinib
Baricitinib is a small-molecule agent which is available in tablet form. It is well absorbed, with a bioavailability of ~80%.
Baricitinib is mostly (75%) cleared by the kidneys with a half-life of about 6-9 hours. The short half-life is both a strength and a weakness. If a complication from baricitinib were to arise, the drug could be withdrawn rapidly. However, discontinuation of baricitinib could theoretically lead to a resurgence of hyperinflammation.
The usual dose of baricitinib for COVID-19 is 4 mg daily. Among patients with renal insufficiency, it should be dose-reduced:
- GFR 30-60 ml/min: 2 mg daily
- GFR 15-30 ml/min: 1 mg daily
Probenecid inhibits baricitinib excretion by the kidney by about 50%. Therefore, in patients receiving probenecid, the dose of baricitinib should be reduced by 50%.12 In the context of a baricitinib shortage, probenecid co-administration could be used to double the number of patients who could be treated with baricitinib.
Safety concerns and contraindications
JAK inhibitors may cause lymphopenia, anemia, and neutropenia when used to treat rheumatoid arthritis. However, within the context of COVID-19 infection, effects on cell lines appear to be different. Specifically, due to improved treatment of the COVID-19 infection, JAK-inhibitors may actually improve some cytopenias.
- Lymphocytopenia: In the context of acute COVID-19, JAK-inhibitors appear to increase in the lymphocyte count. Two studies have found that baricitinib increases the lymphocyte count (Cantini et al. discussed above, and Bronte et al. shown below).13 One prospective multicenter RCT similarly demonstrated that ruxolitinib increased the lymphocyte count.14 Although lymphopenia is generally considered a contraindication to using baricitinib, among COVID-19 patients lymphopenia may be more accurately considered an indication to use baricitinib.
- Neutropenia: Studies don’t seem to show that baricitinib substantively affects neutrophil count among patients with COVID. Many references recommend avoiding baricitinib in patients with an absolute neutrophil count below 500 cells/mm3. Severe neutropenia is uncommon among COVID patients, so this is unlikely to be a relevent issue.
- Anemia: JAK inhibitors could theoretically promote anemia due to reduced bone marrow synthesis of erythrocytes. This is a minimal effect which is unlikely to be clinically significant when considering the short duration of therapy (up to 14 days). Additionally, critically ill patients with COVID and acute inflammation probably have inhibited erythropoiesis regardless. Case series demonstrate no difference in hemoglobin concentrations due to baricitinib.15
There is no free lunch. Suppressing the proinflammatory cytokine system will inevitably be associated with some sort of increased susceptibility to infection. This is true of any immunomodulatory therapy (e.g., steroid, tocilizumab).
It’s a bit more complicated, though. Patients with septic shock often undergo an initial phase of immune hyperactivation, which is followed by a subsequent phase of immunoparalysis (i.e., Compensatory Anti-inflammatory Response Syndrome, or CARS). It’s conceivable that by blunting the initial immune hyperactivation, baricitinib could also blunt the subsequent immunoparalysis phase. This concept is supported by the ability of baricitinib to increase lymphocyte counts. So, in addition to causing some opportunistic infections, it’s also conceivable that baricitinib could prevent delayed infections.
What evidence do we have?
- The rheumatology literature shows that baricitinib causes only a tiny increase in opportunistic infections. When used for prolonged therapy among outpatients, baricitinib causes a slight increase in infection with herpes simplex virus and varicella zoster virus (~5 infections per person-year).16 Exposure to baricitinib for one or two weeks might therefore be expected to cause only a very small increase in infection.
- In the context of rheumatoid arthritis, opportunistic infections are associated with lymphopenia.10 Given that baricitinib increases lymphocyte counts in the context of COVID-19, this could imply that such opportunistic infections might not be such a problem.
- In the ACTT-2 trial, baricitinib caused a reduction in the rate of new infections (6% vs. 11%; p=0.003).5
The reason that baricitinib reduced infection in ACTT-2 remains unclear. It’s likely that this is simply a result of avoiding intubation and thereby avoiding ventilator-associated pneumonia (VAP). It’s also conceivable that it could relate to normalization of the immune system, thereby avoiding immunoparalysis.
Outpatient experience with baricitinib reveals that it causes a very small increase in venous thromboembolic events. In the context of a hospitalized patient with COVID-19, baricitinib might be expected to have three effects on the risk of venous thromboembolic disease:
- Baricitinib has prothrombotic effects, causing a risk of venous thromboembolism of roughly 0.6 per one hundred patient-years among patients with rheumatoid arthritis.10 This might relate to barcitinib’s stimulating an increase in platelet counts.
- Baricitinib reduces intubation rate and accelerates recovery among COVID-19 patients. This would be expected to reduce immobility and thereby reduce the risk of venous thromboembolic disease.
- Patients with COVID-19 experience a prothrombotic state due to increased systemic inflammation. By dampening inflammation, baricitinib could treat the underlying prothrombotic state and thereby reduce the risk of venous thromboembolic disease. For example, Rodriguez-Garcia et al. found that baricitinib accelerated the reduction in D-dimer levels.8
The ACTT-2 trial found no significant difference in thromboembolic events among patients treated with baricitinib. Overall, it seems unlikely that baricitinib would cause clinically problematic venous thromboembolic disease (given considerations #2 and #3 above).
Liver function test abnormalities
Just about anything in life can cause liver test abnormalities, and this is true of medications. In ACTT-2, patients treated with baricitinib were less likely to develop elevated AST (2% vs. 3%), less likely to develop ALT elevation (1.2% vs. 1.8%), and less likely to develop bilirubin elevation (0.4% vs. 1.6%).5 Hepatic toxicity is always possible for any drug, but this doesn’t seem to be a substantial problem.
So where does this leave us regarding the actual contraindications for baricitinib? The use of baricitinib in COVID-19 is new, so it’s impossible to construct a definitive list of contraindications. For now, the following might be considered contraindications:
- Absolute neutrophil count <500 cells/mm3.
- Active severe infection (e.g., known tuberculosis or invasive fungal infection).
- Substantial immune dysfunction (e.g., AIDS, TNF-inhibitors, chemotherapy).
- Severe renal failure (e.g., glomerular filtration rate <15 ml/min).
- Pregnancy (little human data; some evidence of toxicity in animals).
Baricitinib plus dexamethasone?
Dexamethasone is currently the front-line immunomodulator therapy for hypoxemic patients with COVID-19 (based on established mortality benefit in the RECOVERY trial). The clinical question is thus whether baricitinib should be added in combination with dexamethasone.
Currently we lack prospective RCT-level evidence to answer this question. Available data from Stepping et al. and Rodriguez-Garcia et al. (explored above) suggests that baricitinib is beneficial among patients treated with steroid. Another retrospective study similiarly suggested that the combination of ruxolitinib plus steroid was beneficial.17
The primary concern involving the combination of dexamethasone and baricitinib is that excessive immunosuppression could increase the risk of opportunistic infections. This is a valid concern which deserves further investigation. However, this fear is probably overblown, for the following reasons:
- Dexamethasone 6 mg/day isn’t a very high dose of steroid (it’s equivalent to 40 mg prednisone).
- Neither baricitinib nor dexamethasone has been associated with an increase in opportunistic infection when utilized for COVID-19 patients. Baricitinib caused a reduced risk of secondary infection in ACTT-2 (discussed above). The use of high doses of dexamethasone (20 mg/day) in CODEX trial was likewise associated with a reduced risk of secondary infection.18
- Combining a steroid with an immunosuppressive agent (e.g., azathioprine) is a common practice in medicine. The risk of opportunistic infection is often increased, but generally tolerable (especially for a short time-frame).
Currently, there is no simple answer regarding whether to add baricitinib to dexamethasone. This decision may be made for each individual patient, possibly with the help of rheumatology consultation. Factors which may favor the addition of baricitinib may include:
- More severe disease (e.g., patient on high-flow nasal cannula or mechanical ventilation).
- Greater systemic inflammation (e.g., C-reactive protein over ~100 mg/dL).
- More severe lymphopenia (e.g., absolute lymphocyte count <0.8 billion/L or neutrophil/lymphocyte ratio >5).
- Clinical failure of dexamethasone (e.g., worsening hypoxemia and rising C-reactive protein despite dexamethasone).
- Adequate supply of baricitinib to provide it to all patients who could potentially benefit.
- Baricitinib is a JAK-inhibitor which blocks many of the cytokine pathways involved in hyperinflammation caused by COVID-19.
- The ACTT-2 trial demonstrated that baricitinib hastened recovery and reduced the need for intubation. The safety profile was very good (with a reduction of infections seen in patients treated with baricitinib, and no significant difference in the risk of venous thromboembolism).
- Retrospective and propensity-matched studies of baricitinib report similar results. Two studies suggested benefit from baricitinib even among patients treated with steroid.
- Whether to add baricitinib on top of dexamethasone remains controversial, given a lack of direct RCT-level evidence. Currently the decision may need to be personalized (e.g., incorporating individual aspects of the patient and multidisciplinary consultation).
- Multicenter RCT evaluating ruxolitinib for COVID-19 (PulmCrit)
- Jakinibs for hemophagocytic lymphohisticotyosis (IBCC)
- Jakinibs for influenza-induced HLH (IBCC)
- 1.Gálvez A, Javalera R. Ruxolitinib as first-line therapy in secondary hemophagocytic lymphohistiocytosis and HIV infection. Int J Hematol. 2020;112(3):418-421. doi:10.1007/s12185-020-02882-1
- 2.Zandvakili I, Conboy C, Ayed A, Cathcart-Rake E, Tefferi A. Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: A second experience. Am J Hematol. 2018;93(5):E123-E125. doi:10.1002/ajh.25063
- 3.Wang J, Wang Y, Wu L, et al. Ruxolitinib for refractory/relapsed hemophagocytic lymphohistiocytosis. Haematologica. 2020;105(5):e210-e212. doi:10.3324/haematol.2019.222471
- 4.Ahmed A, Merrill S, Alsawah F, et al. Ruxolitinib in adult patients with secondary haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial. Lancet Haematol. 2019;6(12):e630-e637. doi:10.1016/S2352-3026(19)30156-5
- 5.Kalil A, Patterson T, Mehta A, et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. Published online December 11, 2020. doi:10.1056/NEJMoa2031994
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- 7.Stebbing J, Sánchez N, Falcone M, et al. JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. Sci Adv. Published online November 13, 2020. doi:10.1126/sciadv.abe4724
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