|Ahead of print publication
Oral tofacitinib: Contemporary appraisal of its role in dermatology
Sidharth Sonthalia1, Parul Aggarwal2
1 Medical Director and Senior Consultant Dermatologist, Department of Dermatology and Dermatosurgery, Skinnocence: The Skin Clinic and Research Center, Gurugram, Haryana, India
2 Consultant Dermatologist Dermatologist, Department of Dermatology and STD, Skinalive Clinic, New Delhi, India
|Date of Web Publication||29-May-2019|
1775, Sector 10/A, Gurugram - 122 001, Haryana
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Tofacitinib, an oral Janus kinase inhibitor (Jakinib), is an emerging treatment modality whose well-established efficacy in systemic inflammatory diseases is now being actively explored for cutaneous disorders (arising due to the patient's dysimmune responses) that are not responding to and/or sustaining intolerable adverse effects with the classical immunosuppressives and other targeted therapies such as the biologics. The most common dermatoses for which oral as well as topical Jakinibs such as tofacitinib have been evaluated and are being used albeit as an off-label indication include psoriasis, psoriatic arthritis, alopecia areata, vitiligo, and atopic dermatitis. This article provides a succinct review on the current status of oral tofacitinib in dermatology through literature search of PubMed database and stresses on the need for further evidence generation to define the drug's place in the therapeutic arsenal of dysimmune cutaneous disorders.
Keywords: Alopecia areata, atopic dermatitis, Jakinib, Janus kinase inhibitors, psoriasis, psoriatic arthritis, tofacitinib, vitiligo
|How to cite this URL:|
Sonthalia S, Aggarwal P. Oral tofacitinib: Contemporary appraisal of its role in dermatology. Indian Dermatol Online J [Epub ahead of print] [cited 2019 Aug 21]. Available from: http://www.idoj.in/preprintarticle.asp?id=259299
| Introduction|| |
Tofacitinib, an immunomodulator of Janus kinase inhibitor (Jakinib) family, blocks tyrosine kinases of the Janus family. Janus kinase-signal transducer and activator of transcription (JAK/STAT) is an intracellular pathway that drives downstream signaling of several pro-inflammatory pathways. The well-established efficacy of Jakinibs in inflammatory disorders, particularly rheumatoid arthritis (RA) and ulcerative colitis (UC), suggests the potential of their positive effects in a myriad of inflammatory dermatoses as well.
Jakinibs constitute an attractive and preferable option as a targeted therapy over biologics, owing to inhibition of signaling from multiple cytokines, unreported potential of generating neutralizing antibodies, and the ease of administration by oral and topical routes. The aim of this paper is to provide a review of studies exploring their use (tofacitinib as the prototype) in dermatology.
| Methods|| |
A literature search was performed without the use of filters on PubMed with the following set of keywords: tofacitinib dermatology, tofacitinib skin disorders, JAK inhibitors dermatology, JAK inhibitors skin, tofacitinib psoriasis, tofacitinib psoriatic arthritis, tofacitinib alopecia, tofacitinib vitiligo, and tofacitinib atopic dermatitis. Articles from year 2001 to 2018 were reviewed, and 149 search results and their references were obtained. Criteria for consideration of search articles for inclusion purpose in the review were based on mutual decision of both the authors as per their relevance to the journal. After data extraction, information pertaining to the different subsections were processed and reorganized in the form of this narrative review. An attempt was made to objectivize the article by summarizing the content in tables.
Mechanism of action of tofacitinib: The JAK/STAT pathway
JAKs are intracellular enzymes that bind to the cytoplasmic domains of many cytokine receptors. The JAK/STAT signaling pathway is involved in many inflammatory skin diseases [Figure 1], particularly those resulting from type I/II cytokine receptors-associated cytokines.
|Figure 1: Type I/II cytokine receptors lack intrinsic kinase activity and signal through the cytoplasmic Janus kinases (JAK1, JAK2, JAK3, and TYK2) along with the DNA-binding proteins called signal transducers and activators of transcription (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6). Upon engagement of extracellular ligands with the receptors, intracellular JAK proteins become activated and phosphorylate STAT proteins which dimerize and translocate to the nucleus to regulate gene expression. Jakinibs interfere with the cytokine signal transduction to bring about their antiinflammatory effects|
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The major cutaneous and associated disorders that have shown the most promising results with tofacitinib and other Jakinibs include psoriasis and psoriatic arthritis (PsA), alopecia areata (AA) and variants including AA totalis (AT) and AA universalis (AU), atopic dermatitis (AD), and vitiligo. Anecdotal reports have also suggested their efficacy in cutaneous lupus erythematosus, dermatomyositis, chronic actinic dermatitis, erythema multiforme, hypereosinophilic syndrome, cutaneous graft-versus-host disease, pyoderma gangrenosum (PG), lichen planus, and Sjogren's syndrome, amongst others.
Types of Jakinibs
Four JAK isoforms are known: JAK1, JAK2, JAK3, and TYK2. While JAK1, JAK2, and TYK2 bind to many cytokine receptors, JAK3 only binds one subunit, the common gamma chain. This shared receptor subunit is used by a small family of cytokines that includes interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. While first-generation Jakinibs (tofacitinib, ruxolitinib, baricitinib) block multiple JAKs, the second generation (decernotinib, experimental agents such as VX-509, GLPG0634) target a particular JAK. Specific Jakinibs are associated with less adverse events (AEs), particularly serious infections and cytopenias. [Table 1] summarizes the current US Food and Drug Administration (FDA) approved indications of first-generation Jakinibs, with psoriatic arthritis representing the only skin-associated disorder for which oral tofacitinib is currently approved. Second-generation Jakinibs are currently being evaluated in phase II studies. Tofacitinib, a JAK 1/3 inhibitor, is the most studied Jakinib in cutaneous diseases. As it blocks JAK2 only weakly, the JAK2-blockade associated hematological AEs are much lesser with this drug. The key pharmacological concepts of tofacitinib are detailed in [Table 2].
|Table 1: List of first-generation oral Jakinibs currently US FDA-approved for human use|
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| Clinical Use of Oral Tofacitinib in Skin Disorders: an Appraisal|| |
JAK/STAT-dependent cytokines IL-12 and IL-23 are principle mediators of psoriasis, the first cutaneous disease evaluated for treatment with tofacitinib. Their upstream blockade by tofacitinib indirectly decreases IL-17 levels. Results from multiple placebo-controlled and comparative randomized controlled trials (RCT) have established good efficacy of tofacitinib in psoriasis.,,,,,, The therapeutic outcome with 5 or 10 mg tofacitinib was significantly better than placebo and comparable or superior to etanercept.,, Results of a long-term extension study involving 2867 psoriatic patients who were administered tofacitinib 5–10 mg twice daily as per a specific protocol of 3+ months showed that 52–62% patients achieved 75% improvement in Psoriasis Area and Severity Index (PASI75) through month 54. General and serious AEs were reported in 82.5% and 13.7% patients, respectively; 13.9% discontinued the drug owing to AEs. Twenty-nine deaths occurred during the study, of which nine were considered potentially related to tofacitinib, malignancy being the most common cause. In an aggregate data model-based meta-analysis that quantitatively evaluated the time-course and treatment effects of systemic agents for psoriasis, tofacitinib 10 mg twice daily showed PASI75 and PASI90 response rates comparable to cyclosporine, noninferior or better than methotrexate and better than acitretin and apremilast.
PsA is a US FDA-approved indication of oral tofacitinib with evidence of efficacy of tofacitinib being better than placebo and comparable to adalimumab. The drug also showed improvement in patients not responding despite 6 months treatment with at least one TNF-α inhibitor. Although results were better with the higher dose (10 mg twice-a-day), 5 mg twice daily is currently the preferred dose for PsA owing to better safety.
The serendipitous discovery of tofacitinib as a treatment for AA led to further exploration. JAK-STAT-dependent cytokines interferon (IFN)-γ and IL-15 drive activation of autoreactive CD8 T cells that are crucial in the pathogenesis of AA. Improvement of >50% in Severity of Alopecia Tool (SALT) score has been reported in 32–66% patients treated with tofacitinib.,, The efficacy varies with disease severity, drug dosage, and adjuvant treatments. Better overall outcomes were reported in patchy AA (versus AT/AU), with 10 mg twice daily (instead of 5 mg twice daily), and with concomitant oral steroids., Relapses were frequent but responded to higher doses and/or corticosteroid addition. The well-known waxing-and-waning and relapsing course of severe variants of AA such as AT and AU (despite the use of tofacitinib) mandates thorough pretreatment counseling of the patient and/or guardians about the possibility of waning treatment response, possible need for dosage increment, and unpredictability of relapse following cessation of therapy. Tofacitinib has been reported to provide similar efficacy as oral ruxolitinib, higher efficacy than contact immunotherapy, and better tolerability than conventional immunosuppressive treatments (corticosteroids ± cyclosporine) in AA., In addition, the drug has demonstrated improvement in nail symptoms of AA. The longest reported duration of treatment with tofacitinib in AA/AT/AU is 18 months.,
Tofacitinib inhibits IFN-γ signaling, which drives the CD8 T cell-mediated melanocyte destruction. Satisfactory re-pigmentation has been reported with 5–10 mg twice daily, with better outcome seen in sun-exposed areas and concomitant narrowband ultraviolet B (NB-UVB) therapy.,
Tofacitinib decreases IL-4, IL-5, and IL-13 signaling involved in the pathogenesis of AD.,, It additionally reduces AD-associated pruritus, because JAK signaling in nerves critically regulates AD-associated itch.
Recent anecdotal reports and short case series have demonstrated efficacy of tofacitinib in certain other cutaneous disorders as well. Oral tofacitinib 5–10 mg twice daily given to three patients with Crohn's disease (primarily for associated severe inflammatory arthritis) and PG refractory to biologics, resulted in resolution of all PG lesions in 12 weeks. Oral tofacitinib 5 mg two to three times daily given for 2–19 months in combination with other immunomodulatory therapies such as low-dose methotrexate reportedly produced significant improvement in patients with generalized deep morphea and eosinophilic fasciitis nonresponsive to corticosteroids, and in patients with treatment-recalcitrant lichen planopilaris.,
A review of major studies evaluating the efficacy and safety of oral tofacitinib in specific dermatoses is detailed in [Table 3].
|Table 3: Review of the efficacy and safety profile of oral tofacitinib reported in major clinical studies for Jakinib-responsive dermatological disorders|
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| Oral Versus Topical Tofacitinib|| |
The AEs associated with oral Jakinibs may be offset with their topical formulations. Topical tofacitinib (TT), most commonly used as a 2% ointment with/without penetration enhancers, demonstrated modest improvement in psoriasis and AD. In psoriasis, lower concentrations (0.02, 0.2, and 1%) showed efficacy comparable to 2% formulation. In a 24-week, open-label pilot study of 10 patients with AA treated with tofacitinib 2% ointment applied twice daily, 3 patients experienced hair regrowth with a mean decrease of 34.6% in SALT score. The response was less than oral tofacitinib but similar to that reported with clobetasol 0.05% ointment under occlusion. Although results in AA/AT/AU have been modest and conflicting, TT may be a favorable treatment option to induce hair regrowth in locations such as eyebrows and eyelashes. A near complete regrowth of eyelashes was reported with tofacitinib 2% solution by 4 months in a patient who had used multiple ineffective prior modalities. At the time of authoring this review, there was no report published in indexed literature of TT in vitiligo, although topical ruxolitinib demonstrated decent efficacy in facial lesions of vitiligo. The vehicle of the topical formulation impacts the efficacy; better results were reported with liposomal-based TT. The most common AEs seen with TT were erythema, hyperpigmentation, transient acne, and minor and reversible laboratory abnormalities. A succinct review on the current status of topical Jakinibs for inflammatory dermatoses is advised for further reading for interested readers.
| Use in Specific Populations|| |
The use of oral tofacitinib in special populations,,,, has been summarized in [Table 4].
AEs reported with oral tofacitinib
The six major groups of AEs associated with tofacitinib that dermatologists should be aware and vigilant about have been summarized in [Table 5] and include:
|Table 5: Oral tofacitinib: Reported AEs (from studies done in dermatologic indication plus other indications)|
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- Infections: Cutaneous/Systemic; new onset/reactivation of latent infections; nasopharyngitis/severe infections; opportunistic infections (OIs)
- Malignancies: Solid organ cancers, lymphoproliferative malignancies including lymphomas, cutaneous including nonmelanoma skin cancers (NMSC) and melanoma
- Gastrointestinal: Gastrointestinal perforations and obstruction
- Laboratory abnormalities: Hematological, liver derangement with enzyme elevations, dyslipidemia
- Hypersensitivity reactions and miscellaneous: Urticaria, angioedema, headache, hypertension, distal symmetric polyneuropathy, and musculoskeletal complaints such as arthralgia, back pain, and pain in extremities
- Drug interactions: As such tofacitinib does not cause any significant inhibition or induction of the major human drug-metabolizing Cytochrome P450s (CYPs), but its pharmacokinetics and effects/adverse effects may be altered by drugs affecting CYP isoforms. The important drug interactions that must be known to a dermatologist prescribing oral tofacitinib have been mentioned in [Table 6].
Inhibition of multiple JAKs by tofacitinib suggests a high risk for infections and malignancies. Interestingly, clinically observed toxicity is limited, probably attributable to rapid kinetics of action. The most common AEs reported with oral tofacitinib include upper respiratory tract infections, headache, diarrhea, and reactivation of viral infections (particularly herpes zoster). Risk of disseminated disease and serious infections is more with higher dose (10 mg BD) and with concomitant immunomodulators (methotrexate or corticosteroids) necessitating more cautious monitoring.
Reactivation of latent tuberculosis (TB) infection (LTBI) has been reported in patients with systemic inflammatory disorders such as RA., India is endemic for TB and one of the high background TB incidence rate (IR) countries (TB IR >0.05/100 patient-years). As per a review of phases II and III and long-term extension clinical trial data from the tofacitinib RA program, 26 out of 5675 RA patients (0.45%) on tofacitinib (phase II studies) developed active TB as an OI. Of these 26 patients, 21 (81%) belonged to TB-endemic countries like India. Majority of cases developed in patients treated with high doses (10 mg BD). Secondly, of the phase III study cohort, 263 patients were diagnosed with LTBI by one of the following LTBI screening tests—QuantiFERON-TB Gold In-Tube (QFT-IT; Quest Diagnostics) or tuberculin skin test (TST; positive if induration ≥5 mm), and all of them received concomitant Isoniazid (INH) prophylaxis that guarded them from developing active TB. Also, while tofacitinib-treated patients using INH were slightly more likely to develop small elevations in liver enzymes during therapy, they were no more likely to develop significant liver transaminases elevation (>3× upper limit of normal) during therapy than tofacitinib-treated patients not using INH. However, it is important to note that active TB with/without prior LTBI has till now not been reported as an AE of tofacitinib treatment for any dermatoses from India or the globe. Although speculative, this dichotomy may result from many factors—overall less pool of patients treated till now (compared to RA), lack of screening for LTBI, lack of active surveillance for active TB during and after treatment, reporting bias, lower doses and treatment duration used relative to RA, lesser incidence of the use of concomitant immunomodulatory therapies, higher doses, and the fact that majority of the published studies on tofacitinib use for skin disorders hail from TB-nonendemic and low TB IR countries. Thus, it may be premature to comment on this risk any further as of now. Till then, the recommended guidelines of pretreatment evaluation for latent and active TB and administration of INH treatment (if required) with annual screening for TB should be followed in all patients planned for oral tofacitinib treatment for any skin disorder. [Table 7] summarizes the current recommendations regarding the risk of latent/active TB and use of oral tofacitinib.
|Table 7: Guidelines for oral tofacitinib treatment and risk of tuberculosis (TB)|
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Malignancies, most commonly cancers involving the prostate, lungs, breast, and NMSC have been reported in tofacitinib studies, with the risk being comparable to that observed with other targeted immunosuppressive therapies., Lymphomas and Epstein Barr virus-associated posttransplant lymphoproliferative disorders have been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressive medications. Targeted screening with personal and family history of malignancy, including NMSC and other risk factors such as past treatment with UVB, merits consideration in high-risk patients before tofacitinib administration. Long-term studies are warranted to evaluate the specific risk of malignancy induction with oral tofacitinib in cutaneous disorders.
Gastrointestinal perforation has been reported; risk factors being history of diverticulitis, concomitant intake of nonsteroidal antiinflammatory drugs, oral corticosteroids. Although rare, there is a possibility of gastrointestinal obstruction due to the nondeformable XR preparation in patients with preexisting severe pathologic or iatrogenic gastrointestinal narrowing.
Laboratory derangements may occur. Cytopenias are generally not common with tofacitinib (due to weak JAK2 inhibition), particularly in patients with healthy bone marrow reserves. However, anemia, and fall in red blood cells, neutrophil and lymphocyte counts have been reported in studies of tofacitinib given for RA and UC. Elevations in creatine phosphokinase enzyme and liver enzymes (transaminases) greater than three times the upper limit of normal have been observed in patients treated with tofacitinib. Dys/hyperlipidemia with minor elevations in low-density lipoprotein, high-density lipoprotein, and total cholesterol and serum triglyceride levels are well known with this drug. Despite an increased risk of hypertension and dyslipidemia, an increased risk of major adverse cardiovascular events has not been reported. Tofacitinib-induced hyperlipidemia may last for up to 12 weeks followed by stabilization. Persistent hyperlipidemia should be treated as per standard clinical guidelines, e.g., National Cholesterol Educational Program (NCEP). Use of lipid lowering agents such as statins improves the dyslipidemia, although regular monitoring of hepatic enzymes becomes mandatory in such cases.
Drug hypersensitivity presenting as angioedema and urticaria have been observed in post marketing experience.
Dose-dependent adverse reactions (seen more in patients treated with 10 mg twice daily than 5 mg twice daily) include herpes zoster infections, serious infections, and malignancy induction, particularly NMSC.
| Contraindications and Precautions|| |
While there are no contraindications for tofacitinib per se, in [Table 8] we have listed conditions in which treatment should not be initiated (may be construed as “absolute contraindications”), conditions in which tofacitinib should preferably be started if the required benefit outweighs the risk (may be construed as “relative contraindications”—treatment may be given but only after discussion about possible adverse issues with the patient and with extra cautious and close clinical and/or laboratory monitoring), and situations that warrant temporary or permanent interruption of the treatment.
|Table 8: Conditions in which oral tofacitinib should not be started, may be given with caution and close monitoring, and situations warranting interruption of treatment,|
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[Table 9] summarizes the recommended guidelines for monitoring treatment with oral tofacitinib, independent of therapeutic indication.,,[Table 10] describes the Child-Pugh Score, to be applied for monitoring patients with hepatic impairment.
| Availability in India|| |
While topical formulations are not available in India, oral tablets of the innovator brand XELJANZ®/XELJANZ XR® manufactured by Pfizer have become recently available. Tablets of three doses and types (instant release versus XR-extended release) that are internationally available include:
- 5 mg tofacitinib
- 10 mg tofacitinib.
XELJANZ XR® Tablets:
Patients treated with XELJANZ 5 mg twice daily may be switched to XELJANZ XR 11 mg once daily, the day following the last dose of XELJANZ 5 mg.
| Conclusion|| |
Based on current literature, tofacitinib holds a significant potential to broaden the treatment options for many chronic inflammatory dermatoses with unmet medical needs. Although the absence of data on long-term efficacy, frequent post-cessation relapses, inadequately evaluated safety issues, and high cost limit its use, the drug's ability to induce rapid improvement and the reported clinical toxicity being much lesser than the predicted potential have added tofacitinib and its congeners to the ever-expanding therapeutic armamentarium of inflammatory dermatoses. Multicentric well-designed controlled studies are needed to address the gaps regarding the ideal dosing, treatment duration, and safety profile of tofacitinib. Innovative research in development of better topical formulations and more selective Jakinibs offer the potential of harnessing better efficacy with lesser AEs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]