Ruxolitinib a cancer drug restores hair growth in Alopecia areata

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Alopecia areata causes hair loss for more than 6.5 million people in the US. Now, researchers have discovered that a drug already approved by the Food and Drug Administration for treatment of a rare bone marrow disease - Ruxolitinib - could restore hair growth in these patients. The research team, led by Dr. Raphael Clynes and Angela M. Christiano of Columbia University Medical Center (CUMC), recently published the initial findings of their ongoing clinical trial in the journal Nature Medicine.

Alopecia areata is a disease whereby the immune system attacks hair follicles - the parts of the skin from which hair grows. The hair follicles send a "danger signal" to immune cells, which encourages them to launch an attack on the follicles. The majority of people with this disease experience bald patches over their head, face and body, although the condition can cause total hair loss in some cases.  It is found that a certain set of T cells responsible for attacking hair follicles.

Ruxolitinib (INC424, INCB18424, trade names Jakafi and Jakavi, by Incyte Pharmaceuticals and Novartis) is an FDA Approved  prescription only oral drug for the treatment of intermediate or high-risk myelofibrosis, a type of bone marrow cancer. It is also being investigated for the treatment of other types of cancer (such as lymphomas and pancreatic cancer), for polycythemia vera, for plaque psoriasis. In November 2011, ruxolitinib was approved by the U.S. Food and Drug Administration (FDA) for the treatment of intermediate or high-risk myelofibrosis



Reported Mechanism of Action of Ruxolitinib is as a Janus kinase inhibitor with selectivity for subtypes JAK1 and JAK2 of this enzyme.  JAK1 and JAK2 recruit signal transducers and activators of transcription (STATs) to cytokine receptors leading to modulation of gene expression.

In this above mentioned study, the researchers report on the findings of a small, open-label clinical trial of ruxolitinib on patients with moderate-to-severe alopecia areata, defined as having more than 30% hair loss.
Early results of the trial revealed that in three of the participants, hair growth was fully restored within 4-5 months of treatment initiation. Furthermore, the T cells that attack the hair follicles were no longer present in the participants' scalps.

The reported side effects of Ruxolitinib have included herpes zoster (shingles) (1.9%),  weight gain (7.1%). Laboratory abnormalities have included alanine transaminase (ALT) abnormalities (25.2%), aspartate transaminase (AST) abnormalities (17.4%), and elevated cholesterol levels (16.8%)

New treament for Alopecia universalis

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Alopecia universalis occurs in approximately one in every 200,000 people. It is thought to be an auto immune disorder and can affect anyone at any age, long considered untreatable.

An arthritis drug Tofacitinib citrate (trade names Xeljanz and Jakvinus, formerly tasocitinib or CP-690550 & developed at Pfizer) was used to treat the 25-year-old man Kyle Rhodes from Killingworth who had lost most of his hair of the scalp, face and body by his 18^th birthday, after getting alopecia universalis – a disease there is currently no long-term treatment or cure for. The only hair on his body was within the psoriasis plaques on his head.

Kyle Rhodes visited Assistant Professor of Dermatology at Yale University School of Medicine, Dr. Brett King late last summer, seeking help for a severe case of plaque psoriasis & associated Alopecia universalis. The man had not grown hair for seven years. However, after being treated with Tofacitinib just three months, he had regrown a head of hair, eyebrows, eyelashes, some facial hair and armpit hair. This is a huge step forward in the treatment of patients with this condition.

The patient's head a) before treatment with Tofacitinib, b) two months into treatment, c) five months into treatment, and d) eight months into treatment. Yale University

King believed it might be possible to address both diseases simultaneously using an existing FDA-approved drug for rheumatoid arthritis called Tofacitinib citrate. The drug had been used successfully for treating psoriasis in humans. It had also reversed alopecia areata, a less extreme form of alopecia, in mice as studied (but not published) by Columbia University scientist Angela Christiano.

  

After two months on Tofacitinib at 10 mg daily, the patient’s psoriasis showed some improvement, and the man had grown scalp and facial hair — the first hair he’d grown there in seven years. After three more months of therapy at 15 mg daily, the patient had completely regrown scalp hair and also had clearly visible eyebrows, eyelashes, and facial hair, as well as armpit and other hair. By eight months there was full regrowth of hair, The patient has reported feeling no side effects, and lab test showed no abnormalities, either.

It is believed that Tofacitinib appears to spur hair regrowth in a patient with alopecia universalis by turning off the immune system attack on hair follicles that is prompted by the disease.

King has submitted a proposal for a clinical trial involving a cream form of tofacitinib as a treatment for alopecia areata. A topical formulation has yet to be developed and will be difficult to develop due to the large size of the molecule involved and consequent difficulty in penetrating the scalp skin.

The paper is titled “Killing Two Birds with One Stone: Oral Tofacitinib reverses Alopecia Universalis in a Patient with Plaque Psoriasis.”



Mechanism of action

Tofacitinib is an inhibitor of the enzyme janus kinase 3 (JAK3), & it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription.

Recently it has been shown in a murine model of established arthritis that Tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. Tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3. In November 2012, the U.S. FDA approved Tofacitinib for treatment of rheumatoid arthritis. Once on the market, rheumatologists complained that the $2,055 a month wholesale price was too expensive.

Possible side effects:
The most important side effects in Phase II studies were increased blood cholesterol levels and neutropenia. Phase III trials testing the drug in rheumatoid arthritis started in 2007 and are scheduled to run until January 2015. In April 2011, four patients died after beginning clinical trials with tofacitinib. By April 2011, three phase III trials for RA had reported positive results. In November 2012, the U.S. FDA approved Tofacitinib "to treat adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to, or who are intolerant of, Methotrexate." A boxed warning that goes along with this approval warns patients that they are at higher risk of opportunistic infections, tuberculosis, cancers and lymphoma.

* This case report was publishes in Journal of Investigative Dermatology on 18^th June 2014 by Dr. Brett King & Brittany G Craiglow at Yale University School of Medicine: online available at: http://www.nature.com/jid/journal/vaop/naam/pdf/jid2014260a.pdf

The paper is titled “Killing Two Birds with One Stone: Oral Tofacitinib Reverses Alopecia Universalis in a Patient with Plaque Psoriasis.”



Does hair transplant for hair loss or baldness Reduce the cardiac ( heart) risk?

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Studies show that Minoxidil, Finasteride or hair transplant for baldness is not going to change the risk of hear disease in bald people.Baldness is only a diathesis in people with heart ailment and it is not a predisposing condition for heart disease as atherosclerosis or diabetes, hypertension or smoking.

What is the connection of Hair loss or Baldness to heart, Diabetes, blood pressure and Prostate cancer risk?

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In 6 studies of 37000 men in Tokyo University published in British Medical Journal recently it was observed that

1. Crown baldness at age below 50 s associated with heart disease more as a diathesis but not necessarily a predisposing factor such as hypertension, diabetes, obesity, Cholesterol & smoking. Smoking can have about 200%, high blood pressure can have up to 100% increased risk where as below 50 years crown baldness of over 10 years can increase the risk of heart disease as much as 44%

2.Frontal baldness is not associated with such a risk. But more the crown baldness the more is the risk of heart disease.

3. Crown baldness may be used as a marker especially vigilant about controlling other risk factors like blood pressure, diabetes, or cholesterol

3. The association could be due to male hormones testosterone, which may be responsible for more atherosclerosis deposit in arteries besides being the cause of baldness but need to be verified by more studies

4.Studies have suggested that balding men are more likely to also have high blood pressure and insulin resistance, which often leads to diabetes. Those relationships really do need additional study. But it's more important to pay attention to your waistline than your hairline.

5. Minoxidil, Finasteride or hair transplant for baldness is not going to change the risk of hear disease in bald people.

6. In a recent study at University of Pennsylvania on 537 African American people it was found that balding African-American men are at higher risk for developing prostate cancer at an earlier age, if they developed even frontal balding below the age of 50 years. Whether there is any Genetic or hormonal links between 2 conditions need to be assessed my more studies.

Why so many Doctors wants to Learn FUE Technique?

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In last few years there is a turn around from conventional strip surgery to FUE procedure. This is mainly due to advantages of minimally invasive surgery of FUE as it does not involve stitches and therefore has practically no pain after procedure, there is no stitch mark involved, there is freedom to keep short hair style and the recovery is much faster and post procedure restrictions are minimal compared to the Old strip procedure. This and few other reasons why there is a sudden 50 to 60% surge in the demand of this procedure in last 3 years. Many doctors are not trained for this relatively new but highly sough after procedure. Since FUE is a more demanding procedure from technical point of view and needs extra training to master this technique which is in high demand.

Interview of Dr. Mahadevia on V- TV on 26th February 2012

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Dr. Mahadevi'a  Live interview by V- TV on 26th February 2012 on Hair Transplant

BHT after 1 year video- Presentation Surat GAPSCON 2012 at Surat

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Dr. Mahadevi'a  was invited for presentation of his work on Body Hair Transplant on 19th February 2012:

Follica may be next breakthrough in hair growth treatment?!

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Follica has raised money to begin a human trial of its hair cloning technology. According to the company’s website, the company has obtained “an exclusive, worldwide license from the University of Pennsylvania to develop and commercialise a breakthrough technology that has been demonstrated to stimulate the genesis and development of new follicles.” It is announced it had completed a $5.5 million Series A financing round.

Is this a first successful Human Hair cloning?

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Scientists in Berlin have used human adult stem cells to develop hair follicles using 3 D Biodegradable Scaffold, from which hair then grows naturally. The treatment provides new hope for people suffering from hair loss.Only a few hair follicles would need to be taken from the"patient"and used to generate as much new hair as is needed, which can then be grafted.
check this video:
http://youtu.be/iAS_k1IrJpA

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Restoration Robotics, Inc., MOUNTAIN VIEW, California, a medical device company, has on 14th March 2011 announced that they have received 510K clearance from (FDA) for a ROBOT  for harvesting hair follicles from the scalp in men diagnosed with androgenetic alopecia (male pattern hair loss) with black or brown straight hair.  The name of the Robot for this technology is ARTAS™ System.

ARTAS™ is a physician-controlled, state-of-the-art, interactive, computer-assisted system that enables harvesting of hair follicles during hair restoration procedures. It combines several features including a video image-guided robotic arm, special imaging technologies, small dermal punches, force sensor, robotic arm,and a computer interface. The ARTAS™ System is capable of identifying and harvesting individual follicular units to implement the follicular unit extraction (FUE) technique. The software that runs the instrument helps the surgeon target follicular units for extraction and also uses stereoscopic video images to guide the needle mechanism and robotic arm.

The robotic harvesting technique resembles that of follicular unit extraction ( FUE). The donor area, as in FUE is cropped to short length to enable the stereo camera system to visualize hair follicles. The imaging algorithms are capable of identifying follicular unit, determining their type (1 hair FU, 2 hair FU, 3 hair FU etc.) and calculating the angle, orientation & location of each follicular unit on the scalp surface. Using this position  & location data, the imaging system semi autonomously guides the robotic arm & mechanism to core & extract follicular units one at a time; The punch size is 1mm in ID. The coring of the follicular units is enabled by a proprietary punch designed that aims to minimize transaction rate. The system, using a feature called visual servoing, continuously tracks & adjusts to patient movement so that harvesting of targeted follicular units is precise. Based on inputs by the user, the degree of automation can be adjusted, e.g. the system may be configured to harvest 10-20 grafts sequentially. The harvested follicular unit may then be automatically transported to a vial where it is kept moist and cool. It may be possible to achieve harvest speed of up to 1000 grafts in an hour.

The Benefits
There is growing interest in FUE because of its many patient benefits, such as less discomfort and a quicker return to normal activities. The ARTAS™ System solves many of the technical challenges experienced by physicians currently attempting the FUE procedure which gives physicians and patients new choice. Rapid healing and lack of a linear scar, which makes this procedure different from the strip method.

Limitations:
The Robot is approved for only straight back and brown hairs and for those with curly , gray or blond hair may have to wait for some later date.

On a personal communication it was mentioned that the system may harvest up to 1000 grafts in an hour with Transaction rate under 6%.

For more :    www.restorationrobotics.com.

Effect on Graft survival of Dense packing

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Check this research paper: double click the picture to read it in separate view

Add caption

Well we can do up to 60 per sq. cm but we do not recommend it because of significantly reduced survival rate if transplanted over 30 per sq. cm. Check the attached pdf file of the research paper: For example, if grafts are placed at a density of 50 FU/cm2 but only grow at a density of 40 FU/cm2, the results would still look good to the eye because a density of 40 FU/cm2 looks good. However, in reality this represents a loss of 20 percent of the grafts, which is unacceptable in hair transplantation due to the limited donor supply.

Transplanting Crown

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Transplanting in crown with early hair loss has following drawback in your case at this stage and age of hair loss;
1. The miniaturized weak existing hairs in this area may not be able to sustain the surgery and some of them may be lost sometime after this procedure ( shock loss)
2. The Transplant may be possible between the existing hairs so we can only put small number of hairs without damaging the existing hairs
3. If you lose more hair in future around the area of transplant you will have central are of transplanted hair with surrounding halo of no hairs ; this will not look natural.
4. You can certainly improve the area by use of medications then why you need surgery?

 Photo from: http://www.bernsteinmedical.com/hairtransplantblog/can-the-hair-grafts-be-packed-together-densely/

Astressin-B Potential new treatment for hair loss & gray hair

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According to an article published in on line journal Plosone.org Million Mulugeta, D.V.M., Ph.D., co-director of UCLA’s preclinical stress biology research program at the University of California, Los Angeles, claim that they have uncovered a promising hair-loss treatment & may have the potential to affect hair color, including gray hair..

The experiment wasn’t focused on hair loss. Instead, it was designed to study a chemical compound that blocks the effects of stress on the gut.

The research team, during a study of the effect of a compound called Astressin-B while conducting stress-hormone experiments on mice that typically develop head-to-tail baldness as a result of being genetically altered to overproduce a stress hormone (The mice used in the experiments had been genetically altered to overproduce a stress hormone called corticotrophin-releasing factor, or CRF. Corticotropin-releasing factor over-expressing (CRF -OE)-mice that display phenotypes of Cushing's syndrome and chronic stress, including alopecia. CRF-OE mice develop bilateral symmetric hair loss in adulthood). The goal of the experiments was to study the effect of Astressin-B ((5 µg/mouse) injected peripherally once a day for 5 days) to determine whether it would block the effects of stress on the colon but accidental finding was the mice treated with Astressin –B had recovered the full cover of fur on the back in few weeks compared to the placebo ( injected with saline) given mice which did not recover. A sterssin-B induced pigmentation and hair re-growth that was largely retained for over 4 months (a significant period for average 2 years life of mouse) when mice were killed Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that Astressin-B revived the hair follicle from the telogen to anagen phase.

The team repeated the experiment several times and got the same results — bald mice grew new hair in a few weeks. The researchers also injected the compound into young mice before they went bald. Those mice never lost their fur.

The researcher said the compound appears to have affected the mice skin pigment as well as spurred hair growth. This could mean Astressin-B has the potential to affect hair color and gray hairs. Majority of Pigments were regained by about 1 week and the hair was regained by about 2 weeks

Temporary blockade of the CRF receptors could thus be a breakthrough therapy for alopecia particularly for patients in acute (chemotherapy, traumatic stressful events) or chronic stress setting.

Findings of a mouse study may not be applicable to humans, but results may spur more study of the role stress might play in human hair loss. Hair growth cycles are very different in mice and humans, so one could draw only limited conclusions from the research

The research would probably be useful only for hair loss related to stress, likes that caused by one-time events, rather than as a treatment for genetic baldness.