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Killing Two Birds with One Stone: Oral Tofacitinib Reverses Alopecia Universalis in a Patient with Plaque Psoriasis
Abstract and Figures
Abbreviations: AA, alopecia areata; AU, alopecia universalis; MHC, major histocompatibility complex; RA, rheumatoid arthritis
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... Tofacitinib is a first-generation pan-JAKi, approved by the FDA for use in adults with moderate-to-severe ulcerative colitis, refractory psoriatic arthritis, and refractory rheumatoid arthritis [60]. In 2014, a seminal case report described a patient with simultaneous alopecia universalis and psoriasis who was treated with oral tofacitinib (15 mg/day) [61]. ...
The emergence of biologics and Janus kinase inhibitors (JAKis) has revolutionized the management of immune-mediated skin diseases (IMSDs) through the selective inhibition of key mediators involved in the pathogenic process. In recent years, the enormous potential of these medications has prompted several therapeutic regulatory approvals, predominantly in the adult population. The application of biologics in the pediatric population is comparatively limited. This review provides an up-to-date summary and discussion of current and emerging biologics and JAKis used in the treatment of common pediatric IMSDs, encompassing regulatory approvals and recent trial data.
... Ultimately, this leads to the damage of hair follicles and subsequent hair loss [2,6]. In small clinical studies, JAK inhibitors have demonstrated potential in the treatment of alopecia [7]. ...
Background: Alopecia areata is an autoimmune disorder that causes hair loss in clumps about the size and shape of a quarter. The estimated prevalence of the disorder is approximately 1 in 1000 people, with a lifetime risk of approximately 2 percent. One of the systemic therapies for alopecia areata consists of the use of glucocorticoids or immunosuppressants. Methods: Baricitinib (BCT) is a Janus kinase (JAK) 1 and 2 selective inhibitor used as an immunosuppressant drug. In this study, three olive oil BCT formulations (Oil A, Oil B, and Oil C, which differ in their content in squalene, tocopherol, tyrosol, and hydroxytyrosol) have been developed for topical delivery. The formulations were physicochemically characterized and the in vitro drug release and ex vivo permeation through human skin tissues were assessed. Results: The results showed nearly identical viscosity across all three formulations, exhibiting Newtonian behavior. The mathematical modeling used to describe the drug release profiles was the one-site binding hyperbola for all formulations. Oil-based formulations showed a slow BCT penetration into human skin. Skin integrity remained intact during the experiments, with no signs of irritation or alterations observed. In addition, all the formulations proved their efficacy in vivo. Conclusions: Among the formulations, Oil A demonstrated the highest ability retention capacity (Qr = 1875 ± 124.32 ng/cm²) in the skin, making it an excellent candidate for further investigation in the treatment of alopecia areata.
... In addition, environmental and lifestyle factors, such as using photosensitizers (e.g., psoralens, nonsteroidal anti-inflammatory drugs, or fragrances), further increase this risk [9][10][11]. Current treatment strategies for photodermatitis focus on prevention and symptom management [12], including broadspectrum sunscreens, protective clothing, antihistamines, corticosteroids, and, in severe cases, immunosuppressants [13,14]. Recent advances in photobiology have also stimulated the search for novel therapies to mitigate UV-induced skin damage, such as photoprotection enhancers and antioxidant formulations [15]. ...
Propolis demonstrates diverse pharmacological properties encompassing antimicrobial, anti-inflammatory, antioxidant, immunomodulatory, and wound-healing activities. This study investigated the therapeutic mechanism of propolis against ultraviolet (UV)-induced allergic dermatitis through an integrated approach combining network pharmacology with in vitro experimental validation. The targets of propolis components were conducted through the PubChem, the EMBL-EBI, and SEA Search Server databases, and the disease-associated targets for atopic dermatitis and related allergic conditions were extracted from GeneCards. The overlapping targets between propolis components and UV-induced dermatitis were screened. The Gene Ontology (GO) Enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. The key targets were further validated through ELISA experiments using HSF cells. The results show that there were 28 overlapping targets between propolis and UV-induced allergic dermatitis. The GO enrichment results show that there were 1246 terms of biological functions, 52 terms of cellular components, and 98 terms of molecular functions. KEGG pathway enrichment obtained 110 signaling pathways. The protein–protein interaction (PPI) network showed that TNF, NFKB1, MMP-9, and IL-2 were hub proteins. The ELISA experiment confirmed that propolis reduced the levels of MMP-9 and IL-2 in UBV-induced allergic dermatitis of HSF cells in a dose-dependent manner. These findings provide mechanistic evidence supporting propolis as a promising functional food, dietary supplements, or medicinal agent for UV-induced allergic skin disorders.
... Результаты первого описания эффективности ингибитора JAK при ГА были опубликованы в 2014 г. Показано, в частности, что тофацитиниб, назначенный пациенту с псориазом и сопутствующей универсальной алопецией, привел к полному восстановлению волос в течение 8 мес лечения [34]. Началась новая эра в тера-пии тяжелых форм ГА, которые ранее отличались неблагоприятным прогнозом. ...
Alopecia areata is a chronic genetically determined inflammatory autoimmune disease damaging hair follicles and leading to temporary or persistent nonscarring hair loss. Janus kinase inhibitors have been registered for its management, it allows to personalize the therapy and increase its efficacy by relieving symptoms and positively affecting patients’ quality of life. This group of drugs is considered as the basic one for the treatment of alopecia areata severe forms. The issue of disease relapses after Janus kinase inhibitors cessation and safety of long-term therapy with such drugs are covered.
... JAK inhibitors were first investigated as AA treatment in 2014, when the first patient with alopecia universalis was successfully treated with the JAK inhibitor tofacitinib [31]. Since then, additional case reports, case series, and randomized-clinical trials have shown that JAK inhibitors can be tremendously effective for moderate-to-severe AA. ...
Background
Alopecia Areata (AA) is an autoimmune disorder resulting in non‐scarring hair loss on the scalp, face, and body. AA research has experienced significant advancements within the last century with the discoveries of the autoimmune nature of the disorder and the role of genetic and psychosocial factors. This review provides a comprehensive dive into the history and evolution of AA management with a focus on the recently FDA‐approved JAK inhibitors baricitinib, ritlecitinib, and deuruxolitinib, and sheds light on emerging therapies.
Methods
A search was conducted on PubMed to investigate literature on the history of AA treatment, current AA treatment with a focus on therapy with JAK inhibitors, and the future directions of AA treatment.
Results
Caustic topical agents were used as the main AA therapy until recent decades. The last century saw significant advancements in understanding the etiology of AA as autoimmune, genetic, and psychosocial, influencing the directions of treatment research. In recent years, JAK inhibitors were found to be an effective, systemic AA treatment. Non‐systemic AA therapies such as corticosteroid injections, topical minoxidil, contact immunotherapy, and red‐laser light therapy remain effective treatments. JAK inhibitors continue to be the focus of AA treatment research, although other targets and new treatment modalities are being studied.
Conclusion
The treatment of AA has undergone significant advances within recent years, especially with the application of JAK inhibitors as systemic therapy. Future research should investigate the therapeutic potential of stem cell therapy, gene therapy, and energy‐assisted drug delivery (LEADD) for AA.
Background
Lichen planopilaris (LPP) is a rare, inflammatory condition leading to scarring alopecia, predominantly affecting middle-aged women. Traditional treatments have shown limited efficacy, highlighting the need for novel therapeutic approaches. Tofacitinib, a Janus kinase (JAK) inhibitor, has shown promise in treating various autoimmune diseases, including autoimmune dermatological disorders. This study aims to evaluate the efficacy of tofacitinib in treating patients with LPP.
Methods
We conducted a retrospective, single-center observational study at Shohadaye Tajrish Hospital, reviewing records of 74 patients with biopsy-confirmed LPP who had extensive and treatment-resistant disease. Patients were treated with tofacitinib 5 mg twice daily for at least 16 weeks. Efficacy was assessed using the LPP Activity Index (LPPAI), and adverse events were monitored.
Results
This study evaluated 74 patients with LPP, predominantly female (83.3%), with a mean age of 46.64±8.05 years. The mean LPPAI score significantly decreased from 4.61±1.26 before treatment to 1.73±1.68 after six months (P<0.0001). Response rates varied: 21.62% within 1‒3 months, 24.32% within 3‒6 months, 33.78% within 6‒12 months, and 8.10% within 12‒24 months, with 6.75% showing no response. Adverse effects included headache (8.10%), hyperlipidemia (2.70%), elevated liver enzymes (5.40%), nausea (6.75%), and high blood pressure (4.15%).
Conclusion
Tofacitinib represents a promising treatment for LPP, providing significant improvement in disease activity for most patients. Further research is needed to refine treatment protocols, understand predictors of response, and address gender-specific adverse effects.
Background:
Tofacitinib (CP-690,550) is a novel Janus kinase inhibitor in development as an oral formulation for the treatment of several inflammatory diseases including psoriasis.
Objectives:
This phase 2a study aimed to assess the efficacy, systemic safety, local tolerability and systemic pharmacokinetics of topical tofacitinib in mild-to-moderate plaque psoriasis.
Methods:
Two tofacitinib ointment formulations were evaluated in this multicentre, double-blind, vehicle-controlled trial (NCT01246583). Seventy-one patients were randomized 2 : 1 : 2 : 1 to 2% tofacitinib ointment 1, vehicle 1, 2% tofacitinib ointment 2 and vehicle 2, each administered twice daily for 4 weeks to a single fixed 300 cm(2) treatment area containing a target plaque with or without one or more nontarget plaques and normal skin.
Results:
The primary endpoint of percentage change from baseline in the Target Plaque Severity Score at week 4 demonstrated statistically significant improvement for ointment 1 [least squares mean (LSM) -54.4%] vs. vehicle 1 (LSM -41.5%), but not ointment 2 (LSM -24.2%) vs. vehicle 2 (LSM -17.2%). Secondary endpoints (target plaque area and Itch Severity Item) improved similarly for tofacitinib ointment vs. corresponding vehicle. Adverse event (AE) occurrence was similar across treatment groups. All AEs were mild or moderate and none were serious or led to subject discontinuation. One application-site AE (erythema) was reported. Tofacitinib mean systemic exposure was minimal and was greater for ointment 1 than for ointment 2.
Conclusions:
Tofacitinib ointment 1 was well tolerated and efficacious compared with vehicle for the treatment of plaque psoriasis. Further study of topical tofacitinib for psoriasis treatment is warranted.
Inhibitors of the JAK family of nonreceptor tyrosine kinases have demonstrated clinical efficacy in rheumatoid arthritis and other inflammatory disorders; however, the precise mechanisms by which JAK inhibition improves inflammatory immune responses remain unclear. In this study, we examined the mode of action of tofacitinib (CP-690,550) on JAK/STAT signaling pathways involved in adaptive and innate immune responses. To determine the extent of inhibition of specific JAK/STAT-dependent pathways, we analyzed cytokine stimulation of mouse and human T cells in vitro. We also investigated the consequences of CP-690,550 treatment on Th cell differentiation of naive murine CD4(+) T cells. CP-690,550 inhibited IL-4-dependent Th2 cell differentiation and interestingly also interfered with Th17 cell differentiation. Expression of IL-23 receptor and the Th17 cytokines IL-17A, IL-17F, and IL-22 were blocked when naive Th cells were stimulated with IL-6 and IL-23. In contrast, IL-17A production was enhanced when Th17 cells were differentiated in the presence of TGF-β. Moreover, CP-690,550 also prevented the activation of STAT1, induction of T-bet, and subsequent generation of Th1 cells. In a model of established arthritis, CP-690,550 rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. Furthermore, efficacy in this disease model correlated with the inhibition of both JAK1 and JAK3 signaling pathways. CP-690,550 also modulated innate responses to LPS in vivo through a mechanism likely involving the inhibition of STAT1 signaling. Thus, CP-690,550 may improve autoimmune diseases and prevent transplant rejection by suppressing the differentiation of pathogenic Th1 and Th17 cells as well as innate immune cell signaling.
AE, adverse events; b.i.d., two times-daily dosing; IL, interleukin; JAK, Janus kinase; K16, keratin 16; LSM, least squares mean; PGA, Physician's Global Assessment (of Psoriasis); PLSS, Psoriatic Lesion Severity Sum; q.d., once-daily dosing; SD, standard deviation; SE, standard error
Alopecia areata (AA) is a common autoimmune disease, with a lifetime risk of ∼2%. In AA, the immune systems targets the hair follicle, resulting in clinical hair loss. AA prognosis is unpredictable, and currently there is no definitive treatment. Our previous whole genome expression studies identified active immune circuits in AA lesions, including common γ-chain cytokine and IFN pathways. Since these pathways are mediated through JAK kinases, we prioritized clinical exploration of small molecule JAK inhibitors. In preclinical trials in mice, tofacitinib successfully prevented AA development and reversed established disease. In our tofacitinib trial in 12 patients with moderate to severe AA, 11 patients completed a full course of treatment with minimal adverse events. Following limited response to the initial dose (5mg BID), the dose was escalated (10mg BID) for nonresponding subjects. Eight of 12 patients demonstrated ≥50% hair regrowth while 3 patients demonstrated <50% hair regrowth as measured by SALT score. One patient demonstrated no regrowth. Gene expression profiles and Alopecia Areata Disease Activity Index (ALADIN) scores correlated with clinical response. Our open label studies of ruxolitinib and tofacitinib have shown dramatic clinical responses in moderate-to-severe AA, providing strong rationale for larger clinical trials using JAK inhibitors in AA.
Raymond said in 1892 that "nothing is easier to cure than alopecia areata; one only has to refer to the recent enthusiastic publications...."1 Several current reports of the successful treatment of alopecia areata with dinitrochlorobenzene2-4 have raised the question as to whether treatment effects are directly related to the allergic reaction or to other phenomena associated with an allergic contact dermatitis. We therefore attempted to induce hair growth in patients with alopecia areata by producing an inflammatory nonallergic dermatitis. Anthralin (dithranol) in 0.2% to 0.8% concentrations is known to induce irritant dermatitis without serious side effects.5 This report concerns 32 patients with alopecia areata who were advised to apply anthralin as often as necessary in order to induce a visible but tolerable dermatitis.Patients and Methods
Thirty-two patients ranging in age from 12 to 71 years were treated; 27 were men and five were women. Twenty-four patients
The Janus kinase (JAK) inhibitor, tofacitinib, has shown efficacy for the treatment of psoriasis in a phase IIb trial (A3921047; NCT00678210).
To report haematology data from the phase IIb trial, given the importance of JAK-dependent signalling in haematopoiesis.
Patients with moderate-to-severe chronic plaque psoriasis were randomized to receive tofacitinib 2, 5 or 15 mg, or placebo, twice daily over 12 weeks. Blood samples were collected at screening, baseline, weeks 2, 4, 8 and 12 during treatment, and weeks 14 and 16 during off-treatment follow-up.
Baseline haematology was similar across patients receiving tofacitinib 2 mg (n = 49), 5 mg (n = 49) or 15 mg (n = 49), or placebo (n = 50). Tofacitinib conferred dose-dependent decreases in haemoglobin, haematocrit and red blood cell counts, while reticulocyte counts initially declined, before recovering by week 8, and exceeding baseline levels after treatment cessation. With regard to white blood cells, tofacitinib had no clear dose-dependent effects on basophils or monocytes, but appeared to be associated with transient or reversible dose-dependent decreases in neutrophil and eosinophil counts and transient increases in lymphocyte counts, which were primarily attributable to increases in B cell counts. Natural killer cell counts declined with tofacitinib.
Tofacitinib conferred tolerable, dose-dependent changes in haematological parameters during short-term administration in patients with psoriasis. The effects did not appear to be progressive, and were often transient or reversible. This article is protected by copyright. All rights reserved.
Background
Psoriasis is a chronic, inflammatory skin disease with a significant impact on health-related quality of life (HRQoL). Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator. Objective
This Phase 2b study assessed three tofacitinib dosage regimens vs. placebo to characterize the efficacy and safety of tofacitinib in patients with moderate-to-severe chronic plaque psoriasis. We report the patient-reported outcome (PRO) data. MethodsA total of 197 patients were randomized to tofacitinib 2, 5, 15mg twice daily or placebo for 12weeks. Six PRO questionnaires were completed during the study: Dermatology Life Quality Index, Itch Severity Score (ISS), Short Form-36 questionnaire, version 2 (SF-36), Pain/Discomfort Assessment (PDA), Patient Satisfaction with Study Medication (PSSM) item and Patient Global Assessment of psoriasis. ResultsTreatment with tofacitinib resulted in significant, dose-dependent improvements in several PROs vs. placebo from week 2 onwards. At week 12, least squares mean changes from baseline for Dermatology life quality index, ISS and SF-36 mental component scores were significantly greater for all active drug arms vs. placebo (P<0.05), and significantly greater for tofacitinib 5 and 15 mg for SF-36 physical component scores vs. placebo (P<0.05). At week 12, all dose groups had significantly greater numbers of patients reporting Clear' or Almost clear' on the PtGA vs. placebo. Conclusion
In patients with moderate-to-severe chronic plaque psoriasis, short-term (12-week) treatment with oral twice-daily tofacitinib improves HRQoL outcomes and patient assessment of disease severity and symptoms, with an early onset noted.
Tofacitinib is a novel, oral Janus kinase inhibitor under investigation as a potential treatment for plaque psoriasis.
This Phase 2b, 12-week, dose-ranging study (A3921047, NCT00678210) aimed to characterize the exposure-response, efficacy and safety of tofacitinib vs. placebo in patients with moderate-to-severe chronic plaque psoriasis.
One hundred and ninety-seven patients were randomized. The primary endpoint was the proportion of patients achieving a ≥ 75% reduction in the Psoriasis Area and Severity Index (PASI 75) score at week 12.
At week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25·0% (2 mg; P < 0·001), 40·8% (5 mg; P < 0·0001) and 66·7% (15 mg; P < 0·0001), compared with placebo (2·0%). Significant increases in the proportion of PASI 75 responses were seen by week 4 and were maintained at week 12. Exposure-response over the 0-15 mg tofacitinib twice-daily dose range was successfully characterized. PASI 50, PASI 90 and Physician's Global Assessment response rates were also higher for tofacitinib vs. placebo. The most frequently reported adverse events (AEs) were infections and infestations: 22·4% (2 mg twice daily), 20·4% (5 mg twice daily), 36·7% (15 mg twice daily) and 32·0% (placebo). Discontinuations due to AEs were 6·0%, 2·0%, 4·1% and 6·1% of patients in the placebo, and 2, 5 and 15 mg twice-daily tofacitinib groups, respectively. Dose-dependent increases from baseline in mean serum high-density lipoprotein, low-density lipoprotein and total cholesterol, and decreases in haemoglobin and neutrophils were observed.
Short-term treatment with oral tofacitinib results in significant clinical improvement in patients with moderate-to-severe plaque psoriasis and is generally well tolerated.
We attempted to induce hair growth in patients with alopecia areata by producing an inflammatory nonallergic dermatitis. Anthralin (dithranol) in 0.2% to 0.8% concentrations is known to induce irritant dermatitis without serious side effect. This report concerns 32 patients with alopecia areata who were advised to apply anthralin as often as necessary in order to induce a visible but tolerable dermatitis. The positive and cosmetically good results have encouraged us to continue anthralin treatment, as it is well tolerated by patients and free of serious side effects. It appears to be more effective than topical corticosteroids, as some of our patients were unsuccessfully treated with these preparations before anthralin therapy. However, marked erythema with mild itching is necessary for effective therapy. Our results suggest that anthralin treatment may be useful in cases of alopecia areata with patchy hair loss and cases of alopecia totalis with recent hair loss.