Hair today, gone tomorrow

C&I Issue 5, 2016

Balding eventually affects most men to some extent and 60-70% of women have thinning hair by age 70, often with knock-on effects on their self-esteem and identity. ‘Pretty much everyone who loses their hair would prefer not to,’ says Andrew Messenger, professor of dermatology at the Royal Hallamshire Hospital, Sheffield, UK. ‘The adverse effect of hair loss is mainly on the psyche but, such is the importance of hair, this can be severe and disabling.’

Hair grows from protein cells at the bottom of follicles in the skin. But rather than steadily producing hair, follicles cycle between active (anagen) and dormant (telogen) phases. The active phase typically lasts between two and six years, after which there is a short intermediate phase during which the follicle shrinks and starts to collapse. The dormant phase then lasts for about three months or so, after which the old hair sheds and a new one starts to grow.

Hair loss can result from a number of causes. Androgenetic alopecia (AA), also known as male (or female) pattern baldness, is the most common and is thought to be caused by an increased sensitivity to male hormones – androgens – in the follicles, which leads to a shorter cycle of hair growth, shorter and thinner hair, and a delay in the growth of new hair. The condition, which is progressive and thought to be hereditary, affects an estimated 50m men and 30m women in the US alone.

Underlying medical conditions can also be to blame. Alopecia areata, sometimes called spot baldness because it causes bald spots usually on the scalp, is an inflammatory autoimmune condition in which T-cells attack and destroy hair follicles. The condition can result in total hair loss from the scalp (alopecia totalis) or, in more extreme cases, total hair loss from the body (alopecia universalis). Over 6.6m people in the US have or will develop spot baldness at some point in their lives, according to the US National Alopecia Areata Foundation.

Furthermore, temporary hair loss can be caused by chemotherapy, and permanent hair loss can occur when follicles are destroyed by complications of other conditions such as sclerosis, a hardening of the skin due to the overproduction of collagen.

The British Association of Dermatologists 2012 guidelines suggest a number of treatments to induce hair growth in alopecia areata – including corticosteroids, photochemotherapy and dithranol, a psoriasis ointment – but none has altered the long-term course of the condition. According to consultant dermatologist Matthew Harries at the Salford Royal NHS Foundation Trust, UK: ‘Unfortunately, at present, the treatment options for a number of these conditions are limited. The quality of evidence is generally poor, we cannot predict who will respond to therapies, and accurately recording disease activity and treatment response in some conditions can be challenging. In alopecia areata, for example, the chance of re-growing hair with treatment when extensive hair loss has occurred is low, the hair may fall again in the future even after successful therapy, and more aggressive treatment does not appear to affect the longer term outcomes and chance of recurrence.’

Some good news

The good news is that findings by researchers at Columbia University Medical Center in the US suggest the rheumatoid arthritis drug, tofacitinib, and the bone-marrow cancer drug, ruxolitinib, may have potential as effective hair-loss treatments.

Both drugs block the janus kinase (JAK) family of enzymes. These enzymes are involved in the JAK-STAT reaction pathway within a cell, which produces an immune or anti-inflammatory response. Through initial work involving a genome-wide association study, the researchers identified this pathway as a potential target to prevent T-cell activation. Subsequently, they found that JAK inhibitors block the autoimmune attack in mice. (Nature Medicine, doi: 10.1038/nm.3645).

‘We noticed to our surprise that when we used the drugs topically, the mice regrew their hair much more quickly, much thicker and much darker than when they received the drugs systemically, which gave us the first clue these drugs might be doing something to [the follicles to] influence the hair cycle directly [ie start hairs re-growing more quickly], and not just acting on [blocking] the immune cells,’ explained researcher Angela Christiano at a recent press conference. ‘This is a very unusual effect and there aren’t many drugs that are known to be able to do that,’ she said.

To explore the phenomenon further, the researchers studied the normal hair cycle, both in mice and humans. They found that, when applied directly to mouse and human skin, tofacitinib and ruxolitinib rapidly kick follicles into the active growth phase (Sci. Adv., doi: 10.1126/sciadv.1500973). The drugs also produced longer hair from human hair follicles grown in culture and on skin grafted onto mice.

Separately, Brett King, assistant professor of dermatology at Yale University School of Medicine, US, has reported that oral tofacitinib reverses alopecia universalis in a patient with psoriasis (Science News, doi:10.1038/jid.2014.260).

Christiano says her results suggests JAK inhibitors could potentially influence the start of the human hair cycle as well as extending it, opening up the possibility of treating a wide range of hair disorders, including male/female pattern hair loss and chemotherapy-induced alopecia.

Although the studies are small-scale and preliminary, both Harries and Messenger say the findings are promising, particularly for treating alopecia areata.

Desmond Tobin, professor of cell biology and director of the Centre for Skin Sciences at the University of Bradford, UK, agrees. ‘The results are potentially very exciting indeed, especially as the JAK-STAT inhibitor was administered topically rather than systemically. Safety concerns are particularly relevant in the latter,’ he says. ‘At the moment, this approach appears to be more suitable for immune-mediated conditions like alopecia areata or other cycling hair disorders where the hair follicles may be constrained in the [dormant] phase.’

Whether JAK inhibitors can be used successfully to treat any type of baldness, however, is more speculative. ‘Historically there have been several other compounds that have come and gone that have this similar property of being able to actively and  aggressively start the hair cycle but none is yet on the market for male pattern baldness, so a lot of work still has to be done,’ acknowledges Christiano.

‘Alterations in hair cycling do occur in [male/female] pattern hair loss … and it is conceivable that this could be modulated by JAK inhibition,’ says Messenger. ‘But the main problem in pattern hair loss is that follicles eventually undergo miniaturisation and, as far as we know, this is irreversible.’

‘There may be some utility also in male pattern androgenetic alopecia, but the over-riding androgen effects would not be altered in the longer term I would imagine,’ adds Tobin. ‘Also, it is difficult to see whether a potent immunosuppressive approach would be attractive in the longer term for what is usually viewed as a cosmetic problem.’

The challenge in the UK is the significant costs and safety issues with these drugs, adds Harries. ‘Ruxolitinib costs approximately £40,000/year; tofacitinib is cheaper but not currently available in the EU. Therefore, we cannot really use these drugs at present,’ he says. ‘I have a patient who goes to the US to buy tofacitinib for his AA. An effective topical preparation would be ideal.’

Stem cells – the holy grail for treating hair loss

The ‘holy grail’ for treating hair loss is hair follicle regeneration. Several research groups are working in this area on different techniques.

In 2015, researchers at Sanford-Burnham Medical Research Institute US, showed how they used human pluripotent stem cells to grow new hair — a first step towards the development of a cell-based hair-loss treatment (PLOS One, doi: 10.1371/journal.pone.0116892). Alternative approaches rely on transplanting existing hair follicles from one part of the head to another, but the stem cell method provides an unlimited source of cells from the patient for transplantation and isn’t limited by the availability of existing hair follicles, according to the researchers, who say the next step is to transplant human dermal papilla cells derived from stem cells back into humans.

‘The idea that hair loss can be treated by inducing the formation of new hair follicles has a long history going back to studies done in rats by Colin Jahoda over 30 years ago,’ says Messenger. ‘It is possible in rats and mice but despite many attempts none have been successful in people – yet. Progress is being made, and [the Sanford-Burnham research] is another step on the way. If it can be made to work it will be a big advance but there will still be problems to overcome, [such as] orientating hairs in the right direction [and fully characterising] any risks of implanting stem cell populations into the skin.

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