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Baricitinib

Editor: Fred J. Balis Updated: 7/27/2022 4:26:07 PM

Indications

Baricitinib is a disease-modifying antirheumatic drug (DMARD), and FDA approved for treating adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to other disease-modifying antirheumatic drugs (DMARDs), including TNF antagonist therapies. Several clinical trials have shown marked clinical improvement and inhibition of the disease's progression compared to placebo.[1][2]

Off-label use: Based on a clinical trial in 2020, the FDA has issued an emergency use authorization for baricitinib in combination with remdesivir for the treatment of COVID-19 in hospitalized patients requiring supplemental oxygen invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[3] Baricitinib is not FDA-approved as a stand-alone treatment for COVID-19.  

Future use: Clinical trial (BREEZE-AD7) has shown the efficacy of baricitinib and topical corticosteroids in improving signs and symptoms of severe atopic dermatitis.[3] It is currently under review by FDA for approval.  Similarly, clinical trials have shown promising results of baricitinib in the treatment of alopecia areata.[2]

Mechanism of Action

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Mechanism of Action

Baricitinib is an oral selective and reversible inhibitor of Janus Kinases (JAKs). Janus Kinase is an intracellular enzyme that belongs to the tyrosine-protein kinase family and modulates signals from cytokines and growth factor receptors involved in immune cell function.[4] 

There are four JAK proteins (JAK 1, JAK 2, JAK 3 and TYK2). These proteins pair differently in different cell receptors and form homodimers or heterodimers. These JAK dimers phosphorylate the transcription proteins (STATs) and activate intracellular activity, including gene transcription, of inflammatory mediators leading to an autoimmune response.[5] 

Baricitinib has a higher affinity for JAK1 and JAK2. It inhibits the JAK proteins, prevents phosphorylation and activation of STATs, and modulates the signaling pathway of various interleukins, interferons, and growth factors. Baricitinib also decreases the proliferation of JAK1/JAK2 expression in mutated cells and induces cell apoptosis.  

Administration

Baricitinib is administered orally in two formulations, 2 mg or 4 mg. The recommended dosage for rheumatoid arthritis is 2 mg oral daily, and in COVID 19 infection, 2 mg oral baricitinib was evaluated in clinical trials with 10 to 14 days of antiviral therapy.[6] Baricitinib is absorbed quickly from the gut and has a bioavailability of approximately 97%. Its plasma protein binding capacity is around 50%. It reaches its peak plasma concentration in about 0.5 to 3 hours with an average time of 1.5 hours. Administration with the food has not been proven to affect the peak plasma concentration.[7]

In clinical pharmacology trials, approximately 75% of the drug has renal clearance, and 20% is eliminated through the gut. The elimination half-life of baricitinib is about 12 hours in patients with rheumatoid arthritis with a renal clearance of around 12L/hour.[7] Only 10% of the drug is metabolized in the liver via oxidation by CYP3A4 and OAT3. Probenecid, a potent inhibitor of OAT3, results in a two-fold increase in baricitinib blood levels; therefore, patients on probenecid should reduce the dose to half.  

Dose Adjustment 

As baricitinib is mainly excreted via the kidneys, in patients with moderate renal impairment with glomerular filtration rate (GFR) between 30 to 60 mL/minute /1.73 m^2, the dose should be reduced to 1 mg oral daily. The drug is not recommended for patients who have GFR less than 30 mL/minute /1.73 m^2.  

Mild to moderate liver impairment does not require any dose adjustment. Baricitinib should be avoided in patients with severe hepatic impairment due to a lack of clinical data.[8]

No specific dose adjustment has been recommended for the geriatric population.

Adverse Effects

Baricitinib is generally considered safe and well-tolerated, but it can increase the risk of serious infections as it is an immunosuppressive drug. The most common infections are upper respiratory and urinary tract infections, but there is also an increased incidence of herpes zoster infections. Among opportunistic infections, tuberculosis, histoplasmosis, pneumocystosis, candidiasis, BK virus infection, and cytomegalovirus infections have been reported.[9] 

Baricitinib is reportedly associated with bone marrow suppression and hematological abnormalities, including anemia, neutropenia, and lymphopenia, and requires regular lab monitoring. Another side effect that has typically been observed after 12 weeks of use of baricitinib is an increase in mean cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels without elevation of LDL to HDL ratio. A rise in CPK levels has also been observed in some patients.[10][11]

 In clinical trials and post-marketing surveillance, deep vein thrombosis and pulmonary embolism were also observed.[12] A small percentage of patients also developed malignancies, including lymphoma and skin cancers.[1] 

Among gastrointestinal side effects, nausea, vomiting, abdominal pain have been commonly reported. However, serious side effects such as GI perforation are rare but have been reported in patients with prior history of diverticulitis. Transient elevation in liver enzymes has been observed with baricitinib as compared to placebo.[10]

Baricitinib use in human pregnancy is not well studied yet.[13] As per clinical data in animal studies, baricitinib is associated with low fetal birth weight and teratogenicity. Baricitinib was found to be excreted in rat milk during trials; no data is available on its presence in human milk, so it should be avoided in breastfeeding mothers. Similarly, animal studies have suggested the potentially harmful effect of baricitinib on female fertility with no specific effect on male spermatogenesis.

Contraindications

Patients with severe active local or systemic infections, including hepatitis, HIV, or fungal infections, should avoid its use until the active infection has been adequately treated. It should not be used in patients with active tuberculosis.[9][11] 

Baricitinib is contraindicated in patients with chronic kidney disease with GFR less than 30 mL/minute /1.73 m^2. It is not recommended for patients with severe hepatic impairment.  

Patients with significant anemia with hemoglobin below 8mg/dL, lymphopenia with absolute lymphocyte count (ALC) less than 500 cells/mm^3, or neutropenia with absolute neutrophil count (ANC) less than 1,000 cells/mm^3 should avoid Baricitinib until the counts recover.[10]

Baricitinib should not be used in combination with biologic disease-modifying antirheumatic drugs. Due to the lack of clinical data on human pregnancy and breastfeeding, it's been recommended to avoid its use during pregnancy and nursing. Female patients of reproductive age should use effective contraception and should inform their clinicians if they become pregnant.

Monitoring

Patients should be evaluated for latent tuberculosis infection before and during therapy. If positive for latent tuberculosis, start treatment for latent tuberculous before initiating the drug.  

The impact of baricitinib on chronic viral hepatitis reactivation is unknown as patients with active hepatitis B or C infection were excluded from clinical trials. Patients with positive hepatitis B core antibody and negative Hepatitis B surface antigen should be monitored closely for expression of hepatitis B virus DNA.[14]

Liver function tests should be done at baseline, every four weeks for the initial twelve weeks, and then every three months. For patients who develop significant elevation of transaminases, 5x ULN for aspartate aminotransferase (AST) and Alanine aminotransferase (ALT), the drug should be stopped immediately.[10][15] As treatment with baricitinib is associated with hyperlipidemia, lipid profile assessment is recommended in all patients after 12 weeks of initiation of the drug, followed by management as per standard guidelines.[16][11]

Similarly, a patient needs to have a baseline complete blood count (CBC) with differential before initiating baricitinib. This needs to be repeated every four weeks for the first three months, followed by regular CBC monitoring every three months to monitor bone marrow toxicity.  

The clinician needs to determine the dose as per GFR, so baseline renal function tests (RFTs) are required, followed by periodic RFTs every three months. Due to its risk of skin cancer, an annual skin cancer screening examination is also recommended.  

Live vaccines are contraindicated in patients using baricitinib, and immunization status should be current before starting the drug.[17] If patients require any live vaccine, the time interval between initiation of the drug and live vaccine should be according to the current vaccination clinical guidelines. Patients should be monitored for reactivation of herpes zoster infection during therapy.  

Toxicity

In clinical trials, single doses up to 40 mg and multiple doses of up to 20 mg for ten days were evaluated, but no dose-limiting toxicity was observed. Adverse events were similar to those with lower doses, including nausea, vomiting, recurrent infections, hypersensitivity reactions, and myelosuppression. In case of overdose, patients should be monitored for signs and symptoms of adverse reactions and seek medical attention accordingly.[18]

Enhancing Healthcare Team Outcomes

For the best patient outcomes, there should be open communication between the healthcare team and patients regarding close monitoring for the development of adverse reactions. 

  • Patients should undergo proper screening of viral hepatitis and tuberculosis before initiating the drug. Patients should be advised to inform their clinicians of any signs and symptoms related to infection and especially if they travel to areas with increased prevalence of tuberculosis.  
  • Clinicians have to make sure patients are up to date on immunizations before initiation of the drug.  
  • Baseline CBC with differential, LFTs, and RFTs should be acquired before initiating the drug, and regular monitoring should be ensured for dose adjustments. The lipid panel should be monitored after the initiation of the drug. Patients should be encouraged to have regular follow-up visits.  
  • Clinicians should be paying special attention to any signs of active infection at every visit. In case of any serious infection, including reactivation of herpes zoster, the drug should be discontinued.
  • For patients who have a history of deep venous thrombosis or pulmonary embolism, baricitinib should be used cautiously. Patients should be educated on signs and symptoms of the development of blood clots and advised to seek immediate medical attention accordingly.
  • Clinicians should use baricitinib with caution in patients with a history of diverticulitis and should have a lower threshold to rule out gastrointestinal perforation in cases of abdominal pain and advise patients to seek emergent help in that case.  
  • Clinicians should avoid baricitinib in pregnant patients and educate patients on effective contraception before starting the drug, and in case of pregnancy, patients should contact their providers immediately.
  • Patients should be educated on the potential side effects of the development of skin cancers and lymphoma. 

In summary, baricitinib is a relatively new addition to the disease-modifying antirheumatic drugs, the JAK inhibitors family, with promising results. For effective outcomes, it needs the collaborative efforts of an interprofessional team, including patients, nursing staff, pharmacists, and specialists. Nursing staff in primary care and specialist office can monitor the patient's compliance to the drug and screen for any possible side effects in collaboration with the coordinating clinicians. Pharmacists can ensure adequate drug dosing considering patient's comorbidities and provide feedback regarding its drug interactions. Other specialists like infectious disease specialists, hematologists, gastroenterologists' consults can be obtained if the patient develops any potential adverse effects. Any signs and symptoms of toxicity should be taken seriously to improve the outcome and decrease morbidity. 

References


[1]

. Correction: Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Annals of the rheumatic diseases. 2017 Sep:76(9):1634. doi: 10.1136/annrheumdis-2016-210094corr1. Epub     [PubMed PMID: 28798079]


[2]

Phan K, Sebaratnam DF. JAK inhibitors for alopecia areata: a systematic review and meta-analysis. Journal of the European Academy of Dermatology and Venereology : JEADV. 2019 May:33(5):850-856. doi: 10.1111/jdv.15489. Epub 2019 Apr 10     [PubMed PMID: 30762909]

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[6]

Huang F, Luo ZC. Risk of Adverse Drug Events Observed with Baricitinib 2 mg Versus Baricitinib 4 mg Once Daily for the Treatment of Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2018 Oct:32(5):415-423. doi: 10.1007/s40259-018-0304-3. Epub     [PubMed PMID: 30203252]

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Level 1 (high-level) evidence

[8]

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Level 3 (low-level) evidence

[9]

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[10]

Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, Del Carmen Morales L, Reyes Gonzaga J, Yakushin S, Ishii T, Emoto K, Beattie S, Arora V, Gaich C, Rooney T, Schlichting D, Macias WL, de Bono S, Tanaka Y. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. The New England journal of medicine. 2017 Feb 16:376(7):652-662. doi: 10.1056/NEJMoa1608345. Epub     [PubMed PMID: 28199814]


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Taylor PC, Kremer JM, Emery P, Zuckerman SH, Ruotolo G, Zhong J, Chen L, Witt S, Saifan C, Kurzawa M, Otvos JD, Connelly MA, Macias WL, Schlichting DE, Rooney TP, de Bono S, McInnes IB. Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies. Annals of the rheumatic diseases. 2018 Jul:77(7):988-995. doi: 10.1136/annrheumdis-2017-212461. Epub 2018 Feb 20     [PubMed PMID: 29463520]


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Verden A, Dimbil M, Kyle R, Overstreet B, Hoffman KB. Analysis of Spontaneous Postmarket Case Reports Submitted to the FDA Regarding Thromboembolic Adverse Events and JAK Inhibitors. Drug safety. 2018 Apr:41(4):357-361. doi: 10.1007/s40264-017-0622-2. Epub     [PubMed PMID: 29196988]

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Level 3 (low-level) evidence

[14]

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[15]

. Baricitinib. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012:():     [PubMed PMID: 31643344]


[16]

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Level 2 (mid-level) evidence

[17]

Furer V, Rondaan C, Heijstek MW, Agmon-Levin N, van Assen S, Bijl M, Breedveld FC, D'Amelio R, Dougados M, Kapetanovic MC, van Laar JM, de Thurah A, Landewé RB, Molto A, Müller-Ladner U, Schreiber K, Smolar L, Walker J, Warnatz K, Wulffraat NM, Elkayam O. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Annals of the rheumatic diseases. 2020 Jan:79(1):39-52. doi: 10.1136/annrheumdis-2019-215882. Epub 2019 Aug 14     [PubMed PMID: 31413005]


[18]

Peng L, Stebbing J, Wang YJ. Reply to letter to the editor: baricitinib and toxicity is a rare occurrence. Expert opinion on drug safety. 2020 Oct:19(10):1371-1372. doi: 10.1080/14740338.2020.1812192. Epub 2020 Aug 24     [PubMed PMID: 32804556]

Level 3 (low-level) evidence