Monday August 18 2014
Patients treated for alopecia with ruxolitinib responded well
“Alopecia sufferers given new treatment hope with repurposed drug,” The Guardian reports.
Alopecia is a type of autoimmune condition where the body’s own immune cells start to attack the hair follicles for an unknown reason, leading to hair loss.
This new research actually involved two phases, one involving mice and one involving humans.
The researchers identified the specific type of immune cell (CD8+NKG2D+ T cells) that is involved in this autoimmune process, and identified the signalling pathways that stimulate the activity of these cells.
The researchers then demonstrated that using molecular treatments to block these signalling pathways was effective in preventing and reversing the disease process in mice genetically engineered to develop alopecia.
These findings in mice were followed by promising results in three people with moderate to severe alopecia. These people were treated with ruxolitinib, which is currently licensed in the UK to treat certain bone marrow disorders. All three patients demonstrated “near-complete hair regrowth” after three to five months of treatment.
This promising research is in very early stages. Ruxolitinib has been tested in only three people with alopecia, which is far too small a number to make any solid conclusions about the effectiveness or the safety of this treatment in people with alopecia.
The safety and efficacy would need to be tested in many further studies involving larger numbers of people, and it would also need to be tested against other currently used treatments for alopecia, such as steroids.
Where did the story come from?
The study was carried out by researchers from Columbia University in New York. The study received various sources of financial support including US Public Health Service National Institutes of Health, the Columbia University Skin Disease Research Center, the Locks of Love Foundation and the Alopecia Areata Initiative.
The study was published in the peer-reviewed scientific journal Nature Medicine.
The media gives varied reports of this study. The Mail in particular is overly premature, as the current study is a very long way away in terms of research steps before knowing whether there could be a new “standard treatment for the condition”.
Also, references to a “baldness pill” are potentially misleading as they could lead people to think that this treatment, or similar, would be effective against the most common type of baldness, male pattern baldness.
What kind of research was this?
This was a laboratory and mouse study that aimed to examine the cellular processes that cause alopecia and to try and investigate a treatment to reverse the process.
Alopecia is a condition where body hair falls out, ranging from just a patch of hair on the head to the entire body hair. It is understood to be a type of autoimmune condition where the body’s own immune cells start to attack the hair follicles. Causes are not completely understood, with associations with stress and genetics speculated. Unfortunately, although various treatments may be tried (most commonly corticosteroids) there is currently no cure for alopecia.
The autoimmune process is thought to be driven by T lymphocyte cells (a type of white blood cell). Previous laboratory studies in mouse and human models have shown that transfer of T cells can cause the disease. However, effective treatments are said to be limited by a lack of understanding of the key T cell inflammatory pathways in alopecia.
The researchers had previously identified a particular subset of T cells (CD8+NKG2D+ T cells) surrounding hair follicles in alopecia, as well as identifying certain signalling molecules that seem to stimulate them. In this study, the researchers aimed to further investigate the role of these specific T cells using a group of mice genetically engineered to spontaneously develop alopecia, and also human skin samples.
What did the research involve?
First of all the researchers examined skin biopsies from genetically engineered mice that had developed alopecia to confirm that these specific CD8+NKG2D+ T cells were infiltrating the hair follicles. They confirmed that there was an increase in numbers of these specific T cells, increase in total number of cells, and also noticed that there was an increase in growth of lymph nodes in the skin. They found that the type of T cell infiltrating the skin and infiltrating the lymph nodes was the same. They examined the genetic profile of these T cells from the lymph nodes.
They then looked into the role of these specific T cells in disease development by transferring these specific T cells, or overall cells from the lymph nodes, into thus far healthy genetically engineered mice that had not yet developed alopecia.
This was in order to confirm that the CD8+NKG2D+ T cells were the dominant cell type involved in the development of the disease and were sufficient to cause the disease.
The researchers then examined the gene activity in skin samples from the genetically engineered mice, and from humans with alopecia.
They identified several genes that were overexpressed around the areas of alopecia, as well as several signalling molecules that are drivers of this abnormal T cell activity, including interleukins 2 and 15, and interferon gamma.
The researchers therefore then wanted to see whether using drug treatments that could block these signalling molecules would prevent disease development.
To do this they grafted skin from mice that had developed alopecia on to the backs of mice who had not yet developed the condition. They then tested the effectiveness of drug treatments that can block the signalling molecules to see if they could prevent or reverse the disease.
Finally, they followed their results in mice with tests in three people with alopecia.
What were the basic results?
When currently healthy mice were grafted with the skin of mice who had developed alopecia, 95-100% of them developed alopecia within 6 to 10 weeks. Giving antibodies to neutralise interferon gamma at the time of grafting prevented alopecia development. Giving antibodies to block interleukins 2 and 15 had a similar effect.
However, though the researchers could prevent development if given at the same time, none were able to reverse the process if given after alopecia had developed.
They then investigated whether they could block other signalling molecules that are involved in the downstream pathway from interferon gamma (called JAK proteins). Ruxolitinib (currently licensed in the UK to treat certain bone marrow disorders) is a molecule that blocks JAK1/2 proteins. Tofacitinib is another molecular treatment (not currently licensed for any condition in the UK) that blocks another (JAK3). When these two treatments were given at the same time the alopecia skin samples were grafted on to the healthy mice, the mice no longer developed alopecia.
The researchers then tested whether giving tofacitinib seven weeks after grafting could reverse alopecia. Treatment did result in “substantial hair regrowth” all over the body and reduced numbers of T cells, which persisted for a few months after stopping treatment. They also tested whether these two JAK inhibitor treatments were effective when topically applied (rubbed into the skin on the back) instead of given by mouth, and found that they were, with hair regrowth occurring within 12 weeks.
The human tests involved three people with moderate to severe alopecia who were given 20mg of ruxolitinib by mouth twice daily.
All three people demonstrated “near-complete hair regrowth” within three to five months of treatment.
No information on whether these people developed side effects was provided in the study.
How did the researchers interpret the results?
The researchers conclude that their results demonstrate that CD8+NKG2D+ T cells are the dominant cell type involved in the disease process of alopecia. They say that “the clinical response of a small number of patients with alopecia to treatment with the JAK1/2 inhibitor ruxolitinib suggests future clinical evaluation of this compound or other JAK protein inhibitors currently in clinical development is warranted”.
This is valuable laboratory research that identifies the specific type of immune cell (CD8+NKG2D+ T cells) that is involved in the disease process of alopecia. It further identifies several signalling molecules that are drivers of this T cell activity.
The researchers then demonstrate that giving two molecular treatments to block the signalling molecules – ruxolitinib (currently licensed in the UK to treat certain bone marrow disorders) and tofacitinib (not currently licensed for any condition in the UK) – were effective in preventing and reversing the disease process in mice with alopecia.
These findings in mice were followed by promising results in three people with moderate to severe alopecia who were treated with ruxolitinib. All three patients demonstrated “near-complete hair regrowth” after three to five months of ruxolitinib treatment.
These are promising results into the study of potential treatments for this devastating autoimmune condition, which currently has no cure.
However, it is important to realise that this research is in the very early stages. So far ruxolitinib treatment has been tested in only three people with alopecia, which is far too small a number to make any solid conclusions about the effectiveness or the safety of this treatment in people with alopecia. This drug is currently not licensed for use in this condition. It would need to go through many further clinical trial stages in larger numbers of people with alopecia. It would also need to be tested for safety and efficacy against other currently used treatments for alopecia, such as steroids.
Overall there is some way to go before we could know whether ruxolitinib holds real promise as a treatment for alopecia.
Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.