CME INDIA Presentation by Admin.

Among immunomodulators dexamethasone has made a relevant improvement on survival. But other immunomodulators are yet to show an impact. Recently few studies have shown the potential survival benefit of the JAK-STAT inhibitor tofacitinib on COVID-19 pneumonia. The study showed that adding tofacitinib based anti-inflammatory therapy to a treatment regimen including dexamethasone in COVID-19 pneumonia seems to have potential benefit of improving survival when compared to dexamethasone alone.

20 years down the lane

• The Janus Kinase (JAK)-Signal Transducers and Activator of Transcription (STAT) pathway was discovered about 20 years ago.
• Tofacitinib was the first molecule among JAK-Inhibitors to be available for clinical trials.
• The four JAKs (JAK1, 2, 3 and TYK2) have been shown to be critical components of cytokine-mediated effects.
• A class of drugs—called JAK inhibitors or JAKinibs—that block one or more JAKs has been developed in the last decade, and now numbers >20 members.
• Janus kinase inhibitors are immunomodulators, they are DMARDs (disease-modifying antirheumatic drugs), and they are a subclass of tyrosine kinase inhibitors. They work by modifying the immune system via cytokine activity inhibition.
• JAK inhibitors have been used in some immune-mediated conditions: Psoriasis, Rheumatoid Arthritis, IBD, Single-gene disorders (interferonopathies), Uveitis, etc.

How JAK-Inhibitors work?

• JAK inhibitors prevent JAK activation
• JAKs are the key initiating players of the JAK/STAT pathway. Upon binding of their respective effector molecules (cytokines, IFNs, growth factors and others) to type I and type II receptors, JAKs are activated, and through phosphorylation of themselves and of other molecules (including STATs), they mediate signal transduction to the nucleus.
• The signaling cascade that originates upon binding of the cytokines to their specific receptors is blunted by the action of specific JAK inhibitors.
• JAKs are no longer capable to phosphorylate substrates like STATs and, therefore, cytokine-dependent gene regulation is prevented.

What is the Need for Immunomodulators NOW in second wave?

• Devastation in both urban and rural societies across our country is being seen.
• It is now clear that final outcome of COVID-19 disease depends on the magnitude of immune activation in response to the virus during the second week of illness.
• Detect Early and intervene to dampen the immune mediated cytokine release storm (CRS) is the NEW MANTA.
• The studies done so far in COVID19 patients point to a generalized severe inflammation with no one cytokine identifiable as a key driver.
• So, we need targeted approach to stem the florid immune response associated with COVID-19 illness.

JAK inhibitors available in India

Baricitinib:

• Baricitinib, an orally administered, selective inhibitor of Janus kinase (JAK) 1 and 2.
• Baricitinib inhibits the intracellular signaling pathway of cytokines known to be elevated in severe Covid-19, including interleukin-2, interleukin-6, interleukin-10, interferon-γ, and granulocyte–macrophage colony-stimulating factor.
• It acts against SARS-CoV-2 through the impairment of AP2-associated protein kinase 1 and the prevention of SARS-CoV-2 cellular entry and infectivity.
• It improves lymphocyte counts in patients with Covid-19.
• Baricitinib treatment has been shown to improve oxygenation and a reduction in select inflammatory markers.
• In a randomized trial of 1033 hospitalized patients of covid-19, Remdesivir along with baricitinib reduced the time to recovery (defined as discharge or continued hospitalization without need of oxygen) compared with placebo.

Tofacitinib:

A retrospective study of 269 patients has shown survival benefit of adding tofacitinib with dexamethasone as compared to dexamethasone alone.

Black box warning of Tofacitinib

• JAK inhibitors are also associated with black box warning for thrombo-embolic events.
• It has been debated that short term therapy of ten days is unlikely to escalate the risk.
• Also, co-prescription of anticoagulants in most COVID19 patients with intermediate to high thrombotic risk factors is standard of care and would balance the thrombotic risk with JAK inhibitors.

How to use?

• Start after 48 hours of initiation of steroid therapy, where CRP fails to decrease by 50% from baseline, or signs of clinical deterioration like persistence of fever or hypoxemia are noted on close follow up.
• Two drugs are available, any one of them can be used:
  • Tab Baricitinib 4 mg once daily for 10 days(*Renal modification – 2mg once daily if GFR is between 30 to 60ml/ml/min, avoid if GFR < 30 ml/min)  Cost : 4mg tab, 30Rs /tab.
  • Tablet Tofacitinib 10 mg twice daily for 10 days (* avoid if GFR <30ml/min).

CME INDIA Learning Points

• Emerging data suggest that disease severity may be due in part to a dysregulated inflammatory response.
• Mitigating the immune response and preventing a hyperinflammatory state is likely to improve clinical outcomes
• For the Initial Viral Replicative Phase of Illness (First 5 days of illness) Rheumatological association of Gujrat strongly recommends AGAINST the use of steroids or any other immunomodulatory medicines during this period.
• For the Inflammatory Phase of Illness (From Day 6 of onset of symptoms) Immunomodulatory Treatment is recommended for the covid-19 positive patients with any of the following signs of deterioration (after exclusion of alternative causes like secondary infections etc):
  • SpO2 below 94% at rest on room air.
  • SpO2 falling by > 4% from baseline after 6-minute walk at normal pace.
  • CRP > 30 mg/l; or Doubling of CRP from baseline in second week of illness (if baseline values available).
  • HRCT Severity score >9 score.

[*Isolated D-Dimer elevations above 2-times the upper limit of normal or above 1000ng/ml at presentation or a rising trend in serial reports – should warrant only anticoagulation therapy.]

• It has been recommended to start anticoagulation treatment for all patients on JAK inhibitors who have intermediate or high-risk factors for thrombosis. Drug and duration should be decided on Individual basis, based on age, risk factors and D-Dimer levels. (Risk Factors: reduced mobility, active cancer, prior history of DVT, prior h/o anti-phospholipid antibody syndrome, elevated D-dimer levels (>2 times the upper limit of normal).
• Second wave Treatment protocol: A solid model to move forward:
  1. Anticoagulant therapy.
  2. Antiviral therapy.
  3. Anti-inflammatory with Baricitinib: or Tofacitinib, whether or not combined with a short course of dexamethasone.
• New paper shows that Baricitinib plus Remdesivir was superior to Remdesivir alone in reducing recovery time and accelerating improvement in clinical status, notably among patients receiving high-flow oxygen or non-invasive mechanical ventilation. The combination was associated with fewer serious adverse events.

Note: At present most of the standard protocols do not recommend JAK inhibitors. Recently it has become available in India. This article only analyses the status of JAK inhitors to explore its use. You are adviced to follow the standard protocol.

CME INDIA Tail Piece

References:

1. Horby P, Campbell M, Staplin N, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. February 11, 2021 https://doi.org/10.1101/2021.02.11.21249258.
2. Maroun E. Hayek, Michael Mansour, Harrison Ndetan, Quentin Burkes, Robert Corkren, Ammar Dulli, Reya Hayek, Karim Parvez, Satwinder Singh Anti-Inflammatory treatment of COVID-19 pneumonia with tofacitinib alone or in combination with dexamethasone is safe and possibly superior to dexamethasone as a single agent in a predominantly African American cohort. https://doi.org/10.1016/j.mayocpiqo.2021.03.007 Reference: PIQO 330 To appear in: Mayo Clinic Proceedings.
3. M.D., M.P.H., Thomas F. Patterson, M.D., Aneesh K. Mehta, M.D.,etal.,for the ACTT-2 Study Group Members^* Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19 March 4, 2021 N Engl J Med 2021; 384:795-807
   DOI: 10.1056/NEJMoa203199.
4. Furumoto Y, Gadina M. The arrival of JAK inhibitors: advancing the treatment of immune and hematologic disorders. BioDrugs. 2013;27(5):431-438. doi:10.1007/s40259-013-0040-7.

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