Janus kinase (JAK) - Bernstein Medical - Center for Hair Restoration
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Two new studies researching a class of drugs called JAK inhibitors have shown that oral treatment results in significant hair regrowth in patients with alopecia areata, an autoimmune condition that causes non-scarring patches of localized hair loss. Currently there is no cure for alopecia areata, so the possibility of a safe, effective medication is welcome news for thousands of affected patients.

Background

Last year we wrote about how the two new FDA-approved drugs tofacitinib and ruxolitinib act as inhibitors of the family of enzymes called Janus kinase (JAK). ((Harel S, Higgins CA, Cerise JE, Dai Z, Chen JC, Clynes R, Christiano AM. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth. Sci Adv. 2015 Oct; 1(9): e1500973.)) By inhibiting the JAK enzymes, the drugs disrupt intracellular communication to white blood cells, called “T lymphocytes,” and are thus useful in treating alopecia areata. The JAK inhibitors prevented the onset of the disease and reversed the condition, enabling hair to regrow in areas previously devoid of hair.

The 2015 study we referenced – led by renowned alopecia areata researcher Dr. Angela Christiano – showed that topical application of tofacitinib and ruxolitinib in mice resulted in the rapid transition of hair follicles from the telogen (resting) phase of the hair cycle to the anagen (growth) phase. The same study found that tofacitinib encouraged hair follicle development in clumped human dermal papilla (DP) cells, stem cells that are critical in the development of hair follicles. [1]

The Studies

The two new studies were published in September 2016 in the journal JCI Insight, a peer-reviewed journal dedicated to biomedical research.

Tofacitinib

The study of oral tofacitinib – by Crispin, Ko, et al – was a 2-center, open-label, single-arm trial; the first to systematically examine the efficacy of JAK inhibitors as a treatment for alopecia areata. ((Crispin MK, Ko J, Craiglow BG, Li S, Shankar G, Urban JR, Chen JC, Cerise JE, Jabbari A, Winge MG, Marinkovich MP, Christiano AM, Oro AE, King BA. Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata. JCI Insight. 2016;1(15):e89776. doi:10.1172/jci.insight.89776.)) In addition to studying alopecia areata (AA) patients with greater than 50% scalp hair loss, they tested the drug on patients with alopecia totalis (AT), which is the complete loss of scalp hair; alopecia universalis (AU), the loss of scalp and body hair; and ophiasis pattern alopecia areata, hair loss localized to the temporal and occipital scalp. After three months on 5mg tofacitinib citrate, 32% showed up to 50% improvement, and 32% showed greater than 50% improvement. When broken down by subtype of the condition, those with AA improved by 70% on average, those with ophiasis improved by 68%, AT by 11.8%, and AU by 10.5%. They found that following cessation of the treatment, all patients experienced a recurrence of hair loss after an average of 8.5 weeks. Additional trials are necessary to determine the optimal dosage regimen for providing the most long-lasting response.

Ruxolitinib

The study of ruxolitinib – by Mackay-Wiggan, Jabbari, et al – was an open-label clinical trial of 12 patients with moderate to severe alopecia areata. ((Mackay-Wiggan J, Jabbari A, Nguyen N, Cerise J, Clark C, Ulerio G, Furniss M, Vaughan R, Christiano AM, Clynes R. Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata. JCI Insight. 2016;1(15):e89790. doi:10.1172/jci.insight.89790.)) The pilot study tested the use of 20mg oral ruxolitinib twice a day for three to six months; this was followed by three months of monitoring the patients without treatment. Despite the small sample size, the results were striking in that 75% of patients showed a strong response to the medication, with hair regrowth over 50%. After treatment, those who responded to the treatment exhibited a 92% reduction in hair loss. Seven of the nine responders achieved greater than 95% hair regrowth. After stopping treatment hair loss resumed; however, it did not reach the level of hair loss that was present before treatment. This proof-of-concept pilot study showed that ruxolitinib is a safe and effective in reversing the balding effects of alopecia areata.

Conclusion

After showing promise in previous research, scientists have now shown that JAK inhibitors have strong potential to cause substantial hair regrowth in people with alopecia areata; a condition that causes hair loss that can be socially awkward at best and cosmetically disfiguring in severe cases. More studies need to go forward in order to determine which of the two drugs – tofacitinib or ruxolitinib – will be the most effective treatment, and what the proper dosage is for long-term treatment. However, we are hopeful that a medication will be developed for broad use in treating alopecia areata patients.

The other major point of interest following the publication of the series of studies is the potential for JAK inhibitors to treat androgenetic alopecia, or common genetic hair loss. One area that is being discussed is the potential for JAK inhibitors, perhaps in the form of a topical treatment, to stimulate the transition of hair follicles from the resting phase to the growth phase of the hair cycle. Christiano’s research is examining the effects of JAK inhibitors on cultured dermal papilla (DP) spheres. If JAK inhibitors can be used to stimulate DP spheres to grow into mature hair follicles, it may enable hair multiplication techniques to become a viable treatment for common baldness.

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Dr. Angela Christiano and her team of researchers at Columbia University studying the autoimmune disease alopecia areata, have shed new light on how to move hair follicles from their resting stage (telogen) into the growth stage (anagen) in which they can produce normal hairs. The study, published in the October issue of Science Advances, introduces the possibility of a new topical medication for hair growth stemming from a class of chemicals that block enzymes in the Janus kinase (JAK) family. ((Harel S, Higgins CA, Cerise JE, Dai Z, Chen JC, Clynes R, Christiano AM. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth. Sci Adv. 2015 Oct; 1(9): e1500973.)) The findings on the topical application of JAK inhibitors have implications in the treatment of common hair loss as well as alopecia areata, which causes a non-scarring form of localized hair loss.

Scientists had, until now, tried unsuccessfully to use drugs to induce follicles en masse into the anagen phase. The two FDA-approved medications currently used to treat hair loss each use a different approach. Finasteride (Propecia) blocks the conversion of testosterone to dihydrotestosterone (DHT) – the hormone that causes genetically susceptible hair follicles to progressively shrink or miniaturize. Minoxidil (Rogaine) extends the anagen phase, thereby delaying the onset of hair follicle miniaturization. JAK inhibitors could develop into a third major medical option for the treatment of hair loss.

Background: Research Investigating Alopecia Areata

Dr. Christiano, herself diagnosed with alopecia areata, has made several significant breakthroughs involving hair loss and its treatment in the past. Bernstein Medical has written extensively about her study of alopecia areata, hair loss genetics, and hair cloning.

Building on initial research in 1998 implicating a type of white blood cell known as “T lymphocytes” in the development of alopecia areata, ((Gilhar A, Ullmann Y, Berkutzki T, Assy B, Kalish RS. Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice. J Clin Invest. 1998 Jan 1; 101(1):62-7.)) Dr. Christiano and her team set out to find ways to modulate them. In research published in the September 2014 issue of Nature Medicine, they looked at two different FDA-approved chemicals, ruxolitinib and tofacitinib, and how they act as inhibitors of enzymes in the family Janus kinase (JAK). Inhibiting JAK cut off communication to the T cells. Without an accumulation of T cells, alopecia areata could not progress. ((Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, de Jong A, Harel S, DeStefano GM, Rothman L, Singh P, Petukhova L, Mackay-Wiggan J, Christiano AM, Clynes R. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014 Sep; 20(9):1043-9.)) The JAK inhibitors both prevented the onset of the disease, and reversed the condition where it was already established.

The most surprising finding of this study concerned the effect of topically applying the inhibitors.

“We found that topical ruxolitinib and topical tofacitinib were both highly effective in reversing disease in treated lesions (applied to back skin). A full coat of hair emerged in the ruxolitinib- or tofacitinib-treated mice by 7 weeks of treatment, and we observed complete hair regrowth within 12 weeks following topical therapy.”2

Findings: JAK Inhibitors and Hair Growth in Normal Subjects

Having successfully tested JAK inhibitors against alopecia areata, Dr. Christiano and her team sought to investigate JAK inhibition on normal mice and humans.

The researchers applied solutions of tofacitinib and ruxolitinib to one side of the backs of mice with hair in the telogen phase, while the other side was treated with a control solution. Within seven days of treatment, each mouse saw robust hair growth on the treated side, while the control side did not. This indicates a rapid transition of the hair cycle from telogen (resting) to anagen (growth). Furthermore, they found that treatment with JAK inhibitors resulted in “significant proliferation” of hair follicle stem cells, indicating that the inhibitors activated progenitor stem cells within the follicles. The topical application of JAK inhibitors in mice unmistakably resulted in rapid onset of hair growth.

Next, the team looked at the effects of JAK inhibitors on cultured dermal papilla (DP) spheres. In 2013, Dr. Christiano achieved a breakthrough in using an ingenious technique, called a “hanging drop culture.” Using this process, her team caused dermal papilla cells to clump together in a spherical (tear drop) shaped configuration. They found that DP cells in this three-dimensional mass more easily communicate with one another and are then capable of forming new hair follicles. When cultured in a solution containing the JAK inhibitor, tofacitnib, the DP spheres showed an enhanced ability to induce hair follicle development in larger sizes and in significantly greater numbers.

Conclusion/Summary

Topical application of JAK inhibitors leads to the activation and proliferation of hair follicle stem cells and a rapid transition to the anagen phase of the hair growth cycle. This research could be the catalyst for the development of a new topical treatment for hair loss that could potentially benefit individuals who are not indicated for, or who have not seen a positive response from, traditional hair loss medications or are not candidates for hair transplantation. Additionally, JAK inhibitors may be developed into a topical treatment for alopecia areata and potentially other autoimmune conditions that cause localized hair loss or other skin problems. JAK inhibitors might even aid in the development of hair cloning techniques, which could effectively cure hair loss.

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