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15 Articles in Volume 20, Issue #6
20/20 with Mark Wallace: Where Cannabis Fits into Pain Practice
A Commentary on Opioid Stewardship: Fentanyl, Sufentanil, and Perioperative Pain
Adherence and Relapse – How to Maintain Long-Term Gains in Patients with Chronic Conditions
Advanced Practice Matters with Theresa & Jeremy: COVID, Pain, and Power
Analgesics of the Future: Inside the Potential of Janus Kinase Inhibitors
Application Note: Using Photobiomodulation to Treat Trigeminal Neuralgia
Case Report: Quadratus Lumborum Block for Managing Pathologic Pain to the Hip
Chronic Pain and the Short-term Effects of Medical Cannabis
Differential Diagnosis: Polymyalgia Rheumatica or Rheumatoid Arthritis
Genicular Nerve Blocks: Field Tips on Prognostic Value and Technical Considerations
Guideline Update: ACR Promotes Pharmacologic Treatment for Osteoarthritis
Navigating New York's Medical Marijuana Program: A Patient Handout
Person-Centered Care: Lessons from the VA’s Whole Health Model
Psychedelics for Chronic Pain: Is It Time?
Resident’s Corner: What Pain Medicine Education is Missing in the COVID Era

Analgesics of the Future: Inside the Potential of Janus Kinase Inhibitors

A safety and efficacy review of these new oral medications for refractory rheumatoid arthritis and psoriatic arthritis.

Janus kinases (JAKs) are cytoplasmic protein tyrosine kinases that have the critical function of signal transduction of type I and type II cytokines to the nucleus from plasma membrane receptors. There are four types: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Notably, they are docked on the intracellular tails of transmembrane receptors for important inflammatory cytokines including IL-2, IL-6, IL-12, IL-21, IL-23, interferon gamma (IFNy), IFN-alpha, IFN-beta, among many others.

They then interact with other signal transducers − signal transducer and activator of transcription (STATs) − which then dimerize and translocate into the nucleus. In turn, there are seven STATs (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6) and through multiple combinations with JAKs, they play essential roles in numerous autoimmune pathogenesis processes. For this reason, blockade of certain JAK-STAT pathways has become an emerging and promising therapeutic target. Janus kinase inhibitors are targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARDs) that decrease transduction signaling by these cytokines to the nucleus that results in a reduced inflammatory response.1,2

There are three JAK inhibitors approved by the FDA for the treatment of rheumatoid arthritis (RA) (see Table I). Tofacitinib (Xeljanz) was the first JAK inhibitor approved in 2012, followed by baricitinib (Olumiant) in 2018, and most recently, upadacitinib (Rinvoq) in 2019. Filgotinib is a JAK inhibitor that was recently reviewed by the agency. FDA rejected the application in August 2020 due to safety concerns regarding sperm parameters and risk versus benefit assessment. FDA requested additional data from two ongoing clinical trials (MANTA and MANTA-Ray);3,4 filgotinib may not be refiled with FDA until 2021. Unlike most biologic disease-modifying anti-rheumatic drugs (bDMARDs), JAK inhibitors are taken orally rather than by subcutaneous injection or intravenous infusion, which may provide significant convenience to patients. 

 

 

American College of Rheumatology (ACR) guidelines for rheumatoid arthritis generally recommend conventional disease-modifying anti-rheumatic drugs (cDMARDs) as a first-line pharmacotherapy for RA except when patients have contraindications for these drugs. If optimal disease control cannot be achieved with cDMARDs in 3 to 6 months, the next step of therapy options are:

  1. combination cDMARDs
  2. bDMARDs monotherapy
  3. tsDMARDs monotherapy
  4. combination of cDMARD(s) with bDMARD
  5. combination of cDMARD(s) with tsDMARD.5

This article will review the efficacy and safety of JAK inhibitors as well as its place in therapy. 

 

Tofacitinib

Tofacitinib preferentially inhibits JAK-1 and JAK-3. Tofacitinib is indicated for the treatment of moderate to severe RA in patients who have not adequately responded to methotrexate (MTX) or have developed significant MTX side effects. Tofacitinib is also approved for psoriatic arthritis (PsA) and ulcerative colitis (UC). Tofacitinib and all other JAK inhibitors should not be taken in combination with bDMARDs or potent immunosuppressants, such as azathioprine or cyclosporine, because of additionally increased risk of infections. 

The efficacy of tofacitinib was evaluated in a series of ORAL (Oral Rheumatoid Arthritis triaL) studies. Fleischmann evaluated different tofacitinib treatment regimens in patients with an inadequate response to one or more non-biologic or biologic DMARDs. The treatment regimens were: 5 mg tofacitinib twice daily for 6 months, 10 mg tofacitinib twice daily for 6 months, placebo for 3 months followed by 5 mg tofacitinib twice daily for 3 months, or placebo for 3 months followed by 10 mg tofacitinib twice daily for 3 months, with 4:4:1:1 ratio.4 Three primary endpoints were evaluated after 6 months of therapy: the ACR scale (ACR20), Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and the remission defined by Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-ESR), which is score of less than 2.6.6

Statistical significance was achieved in favor of tofacitinib groups. ACR 20 was achieved in 65.7%, 59.8%, and 26.7% in 10 mg twice daily, 5 mg twice daily, and combined placebo groups. HAQ-DI score reduction was -0.57, -0.50, and -0.19 points in 10 mg twice daily, 5 mg twice daily, and combined placebo groups. The percentage of patients with a DAS28-ESR of less than 2.6 was, however, not significantly different between tofacitinib treated groups versus placebo (8.7%, 5.6%, 4.4% in 10 mg twice daily, 5 mg twice daily, and combined placebo). The authors concluded that tofacitinib monotherapy demonstrated reductions of RA symptoms with improvement in physical function.6 Subsequent reports from the ORAL series demonstrated that tofacitinib provided additional benefit to patients who had an inadequate response to MTX and Tumor Necrosis Factor alpha inhibitor (TNFai).7-10   

Adverse reactions include increased risk for infection, notably to viral infections due to its inhibition of JAK1 and JAK2, which are involved in IFNy signaling. Because of this, studies have shown higher incidences of herpes zoster infections. Other notable adverse reactions include   LDL cholesterol increase, transaminitis, neutropenia, and declines in kidney function. All were observed during clinical trials of tofacitinib and are considered to be a class effect of JAK inhibitors. The one exception here is neutropenia, which is entirely due to JAK2 inhibition.1 These clinical trials were not adequately powered to provide statistical inference concerning side effects; however, through post-marketing surveillance, side effect information has been updated. US boxed warnings of tofacitinib include increased risk of serious infections, malignancy, thrombosis (deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, and cardiovascular death. 

 

Baricitinib

Baricitinib, preferentially selective for JAK1 and JAK2 inhibition, was approved in June 2018. Baricitinib is indicated for the treatment of adults with moderately to severely active RA who have had an inadequate response to one or more TNFai therapies. The RA-BUILD11 and RA-BEACON12,13 trials evaluated baricitinib 2 mg per day in comparison to placebo. For patients who had inadequate responses to cDMARDs, baricitinib 2 mg daily showed significant difference benefit compared to placebo in achieving low disease activity and remission in Disease Activity Score 28-joint count C reactive protein (DAS28-CRP).11 The BEACON trial enrolled RA patients with an inadequate response to biologics. Baricitinib showed significant efficacy in ACR50 at week 12 compared to placebo (20% vs 8% respectively). 

Baricitinib trial data suggested that the peak effect of baricitinib 2 mg may be reached at 16 to 24 weeks from the initiation of medication,12-15 and that it may be more appropriate to assess the effectiveness in 16- to 24-week timeframe from the initiation of baricitinib in clinical practice.  

Both 4 mg daily and 2 mg daily were assessed in clinical trials. Serious adverse events reported during clinical trials in the higher dose group included thrombotic events (fatal thrombosis and ST-segment elevation myocardial infarction) and non-melanoma skin cancer. Although the statistical significance of these adverse events could not be determined due to inadequate power, these trends raised a concern that FDA approved baricitinib 2 mg dose only. The FDA has also required post-marketing long term safety studies to further assess the rare potential side effects. Through these efforts, it was found that compared with TNFai, there is no difference in increased thrombotic events for 2 mg daily dose of baricitinib compared to tofacitinib.1

 

Upadacitinib

Upadacitinib is a JAK inhibitor that primarily acts on JAK 1. It is approved for the treatment of moderate to severe RA in adults with an inadequate response or intolerance to MTX. The recommended dose of upadacitinib is 15 mg (extended-release formulation) once daily by mouth. 

Upadacitinib was approved by the FDA on the basis of the following SELECT trials (not to be confused with the SELECT trials for prostate cancer). Both 15 mg and 30 mg doses were tested in the SELECT trials, but only the 15-mg daily dose was approved by FDA. The SELECT-MONOTHERAPY trial16 was performed in patients with active RA who had a 3-month or longer treatment history with MTX and experienced either inadequate efficacy or intolerance. This study showed that upadacitinib monotherapy with 15 mg daily was superior to MTX monotherapy in ACR50 response, DAS28-CRP (in terms of low disease activity or remission), and change from baseline of HAQ-DI.

The SELECT-COMPARE trial was performed in RA patients with joint erosions who had an inadequate response to MTX.17 In this trial, upadacitinib (15 mg daily) plus MTX was compared to adalimumab (40 mg every 2 weeks) plus MTX. Upadacitinib showed benefit over adalimumab in ACR50, DAS28-CRP low disease activity, and remission rates at 12 weeks. 

The SELECT-BEYOND trial18 enrolled patients with an inadequate response to previous bDMARDs. More patients receiving upadacitinib achieved ACR50 compared to placebo at week 12. Upadacitinib showed favorable results in several secondary outcomes including onset of efficacy and ACR20 response. The ACR20 and ACR50 responses persisted for 24 weeks in those who were continued on upadacitinib.

 

Filgotinib

Filgotinib is an investigational tsDMARD that selectively inhibits JAK1. Currently, this drug has not been approved by the FDA for use with RA.A recent Phase 3 placebo-controlled trial17 evaluated ACR20 in 449 RA patients who were randomly assigned to filgotinib 200 mg once daily, 100 mg once daily, or placebo for 12 weeks. The difference between the filgotinib groups vs placebo was 35% (95% CI, 24%-46%) and 26% (95% CI, 15%-38%) for filgotinib 200 mg and 100 mg, respectively (P < 0.001 for both comparisons).  Filgotinib groups showed better effectiveness than placebo in secondary outcomes: HAQ-DI, DAS28-CRP of 3.2, 36-item Short-Form Health Survey Physical Component, Functional Assessment Chronic Illness Therapy-Fatigue scores, ACR50, and ACR 70. 

Serious adverse events occurred in 5% or less in both filgotinib groups and the placebo group. The study drug was discontinued in less than 4% in all three groups. Infections were more common in patients receiving filgotinib (53 patients [36.1%] receiving 200 mg and 52 patients [34%] receiving 100 mg) compared to placebo (38 patients [25.7%]). Although the filgotinib groups had a higher frequency of side-effects and drug discontinuation, the statistical significance of these findings could not be determined due to inadequate power. 

 

Discussion

JAK inhibitors are orally administered medications that are effective for rheumatoid arthritis.   Clinical trials with these agents have enrolled patients with slightly different clinical characteristics. There have been no head-to-head comparative trial of specific JAK inhibitors.  There is also limited data available comparing the efficacy of JAK inhibitors and biologic DMARDs.18  Although JAK inhibitors are orally administered, their magnitude of efficacy and frequency of side effects are more comparable to injectable biologic DMARDs than conventional DMARDs.  

Infection risk, malignancy, and thrombosis are serious side effects associated with all JAK inhibitors regardless of which enzyme subtypes they inhibit. For malignancy risk, there is yet not enough long-term surveillance to truly assess and define the actual risk, if any. As for the risk of thrombosis, it remains a concern to vocalize in patient encounters but whether it is due to the medication itself or if it is an inherent risk of uncontrolled disease remains unclear. The current published clinical trials have had limited power to detect rare side effects of these medications.  The FDA has required post-marketing surveillance to further assess the side effect profiles of these agents. 

Each JAK inhibitor has slightly different nuances in terms of drug interactions. Both tofacitinib and upadacitinib serum levels increase with CYP3A4 inhibitors. CYP3A4 inducers such as rifampin may lead to loss or reduced clinical response of tofacitinib and upadacitinib. Baricitinib serum levels increase with strong organic anion transport 3 (OAT3) inhibitors such as probenecid. Tofacitinib exposure increases with CYP2C19 inhibitors and may lose therapeutic effects with concomitant use of CYP2C19 inducer. 

Severe immunosuppression may occur when JAK inhibitors are concomitantly used with biologic DMARDs, or potent immunosuppressive drugs such as azathioprine, tacrolimus, or cyclosporine. There is insufficient data on JAK use during pregnancy or breastfeeding; thus, a specialist should be consulted when considering use in such patients. Herpes zoster vaccination is recommended for patients age 50 yeard or older, 2 to 4 weeks prior to the initiation of JAK inhibitors. 

Several RA clinical trials involving JAK inhibitors suggest that this class of drug is useful for patients who fail or inadequately respond to cDMARDs and/or TNFai. JAK inhibitors would be an option for patients who prefer oral administration over injection or infusion biologic medication. It is important to share efficacy data and the side-effect risks of JAK inhibitors with patients before initiating this therapy.

 

Experts Weigh In: Review by PPM Editors-at-Large Jeff Gudin, MD, and Jeffrey Fudin, PharmD

There is accumulating evidence to suggest that targeting the Janus kinase signal (JAK) transducer pathway may improve pain outcomes in rheumatoid arthritis, but there is little evidence for effectiveness in other pain syndromes thus far. It is difficult for us to translate the available data as it is both limited and complex. As with all types of pain, we need a better understanding of the underlying mechanisms when determining the most appropriate treatment approach. Chronic pain is a multifactorial experience, resulting from a complex interaction between genetics, psychology, comorbidities, tissue pathology, and alterations in both peripheral and central pain processing. In recent years, the JAK-STAT pathway has been recognized as a pivotal component both in the inflammatory process and in pain amplification in the CNS.
 

It is important to recognize that as a class, JAKs could be an important stepping-stone for many potential therapies of the future, as our knowledge of the inflammatory process continues to unravel at the cellular level.  Having access to novel synthetic DMARDs avoids antibody production ordinarily seen with more traditional chimeric and humanized monoclonal antibody therapeutics used for many inflammatory disorders whether or not related to chronic pain syndromes.

We commend the authors on a well-written summary of the available agents. We offer 4 out of 5 Stars* for the potential of this class of drug and look forward to data in the future that may support treating peripherally and centrally mediated (neurogenic) inflammatory pain conditions.

*Star-rating based on: novelty, risk-benefit ratio, clinical utility, scientific rigor of studies, and market potential, along with the reviewer’s expertise and opinion. 

 

See also a debate from ACR 2020 on JAKs versus TNF for rheumatoid disease.

 

Prior Analgesics of the Future Colulmns

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Analgesics of the Future: NKTR-181
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