Reversal of moderate to severe disease is now possible thanks to new treatments.
Complex and evolving treatments have revolutionised the treatment of moderate to severe alopecia areata (AA). This autoimmune disorder of hair loss, which was previously refractory to treatment, can now be reversed.
Baricitinib, a JAK 1/2 inhibitor, was FDA approved (June 2022) and TGA approved (May 2023) for the treatment of severe AA. It was data from the BRAVE AA1 and BRAVE AA2 studies that led to these approvals. The BRAVE AA studies are two independent international randomised double- blinded placebo-controlled phase 3 studies looking at the safety and efficacy of baricitinib in severe AA.
A recent publication (Am J Clin Dermatology Kwon et al) looked at participants in the BRAVE studies who were treated with baricitinib from randomisation and continued on their assigned doses through to week 52. In both studies there was a dose-dependent increase in proportion of patients achieving SALT (severity of alopecia tool) score of 20 (individual has regrown 80% of scalp hair) or better through week 52.
Around 40% of patients treated with baricitinib 4mg achieved this endpoint at week 52 in each study.
The BRAVE AA clinical trials have also reported improvement in both eyebrow and eyelash hair in patients who had substantial loss of these hairs at baseline. In both studies, by week 52, regrowth (implying full or minimal gaps) with 4mg baricitinib for brows ranged between 39.4% and 44% and for lashes between 22.8% and 50.7%.
The BRAVE studies have further helped us understand the biology of responders to treatment, with three response patterns being noted namely early responders (4-12 weeks), gradual responders (12-36 weeks) and late responders (36-52 weeks). Studies have shown that 48% of those treated with 4mg baricitinib, and 28% on 2mg baricitinib, were early and gradual responders. Early response was more frequent among patients with severe AA (SALT score 50-94) compared to those with very severe AA (SALT score 95-100).
Better treatment response was noted in individuals with a shorter duration of current episode of AA, regardless of baseline disease severity implying early intervention allows for improved treatment efficacy.
Longer duration of current AA episode (?4 years) and very severe AA (SALT score 95-100) were more commonly observed amongst non-responders. The understanding off these timelines and response patterns can be helpful when managing patients’ expectations for scalp hair regrowth.
We have published recent experiences with baricitinib at Sinclair Dermatology.
We reported on the treatment of AA of the beard (BAA) with baricitinib in 60 patients (JAAD, Moussa et al). In this retrospective review, 45.7% of patients with partial BAA experienced complete regrowth, compared to 21.4% with total beard loss.
Patients with no beard regrowth also failed to regrow scalp hair (66.7%), while 54.2% of those with complete beard regrowth also experienced full scalp regrowth.
These findings suggest that those with alopecia totalis and co-existing beard loss have a poorer prognosis and less regrowth on treatment, and that there is a strong correlation between the extent of beard and scalp regrowth in the same individual.
We have safely and successfully managed both adolescents and pre-adolescents with severe AA. A retrospective review (JAAD Moussa et al) of 29 adolescents, aged 12-17 years, with moderate to severe AA treated with baricitinib (mean dose 3.9mg/d) and low dose oral minoxidil (mean dose 0.7mg/d). Median baseline SALT score was 80, and 79% of patients experienced partial or complete scalp regrowth with a median percentage change in SALT score of 93%.
Complete or near complete eyebrow and eyelash regrowth was noted in 78% and 80% respectively.
No patient required dose reduction or discontinuation due to adverse events. In addition, we report a retrospective longitudinal cohort study (BJD Asfour et al) of 19 pre-adolescent patients with a median baseline SALT score of 94.
Following treatment with a median dose of 4mg of baricitinib, the mean reduction in SALT was 68. Furthermore, 25% of children achieved SALT 0 (complete regrowth) and 50% achieved SALT <20. There were no dose modifications or discontinuations due to adverse events. Eyebrow regrowth was achieved in 9 out of 11 and eyelash regrowth in 9 out of 10.
We also conducted a retrospective study (JAAD Kazmi et al) assessing the outcome of switching between tofacitinib (pan JAK inhibitor) and baricitinib in patients with AA. Seventy-three patients received tofacitinib first. Of these, 30 achieved complete hair regrowth while 35 responded partially and eight had no response.
Among the 30 complete responders, 16 were changed to baricitinib during the covid-19 pandemic, due to safety perceptions, and remained in complete remission.
Nine initial tofacitinib complete responders experienced relapse on therapy and switched to baricitinib, with five experiencing full hair regrowth and four having partial hair regrowth. All 35 tofacitinib partial responders were switched to baricitinib and 10 experienced complete regrowth.
Among the eight patients who failed to regrow hair despite tofacitinib therapy, two had a partial response and six had no response upon switching to baricitinib.
It appears that partial responders to tofacitinib or those who relapse on tofacitinib may benefit from switching to baricitinib while those who fail to regrow any hair with one JAK inhibitor may be less likely to respond to a second JAK inhibitor.
While baricitinib is the only JAK inhibitor approved by the both the FDA and TGA for the treatment of AA, ritlecitinib (JAK 3 inhibitor) and deuroxolitinib (JAK 1/2 inhibitor) have received breakthrough therapy designation in the United States.
A recent systematic review and meta-analysis comparing the efficacy and safety of JAK inhibitors: baricitinib, ritlecitinib, brepocitinib (TYK 2 and Jak 1/2 inhibitor) and deuruxolitinib looked at five randomised studies of these four agents. The authors (JEADV Barati et al) concluded that baricitinib 4mg a day and deuruxolitinib 12mg twice daily appear to be superior treatments.
There were, however, only five studies in the meta-analysis, the numbers of patients in each study were markedly different – baricitinib (1310), ritlecitinib (48), brepocitinib (47), and deuruxolitinib (149).
In addition, the baricitinib trial was 36 weeks in duration compared to 24 weeks for the other agents. We now understand that longer treatment periods in AA lead to greater efficacy.
Since this meta-analysis, data from a phase 2b-3 study published in The Lancet (King et al) looked at the safety and efficacy of ritlectinib in 718 adults and adolescents with AA who were randomly assigned to receive oral ritlecitinib or placebo once-daily. At week 24, between 14% and 31% of those assigned 30mg or 50mg ritlecitinib achieved a SALT 20 (80% scalp coverage) and the percentage of patients achieving or exceeding this end point increased through to week 48.
More randomised trials with identical inclusion criteria, dose and duration of treatment and similar participant numbers will be required to confirm efficacy and safety between current JAK inhibitors.
There are also recent reports of existing and new JAK inhibitors, proving safe and effective in the treatment of AA.
Upadacitinib (JAK 1 inhibitor) is approved to treat moderate to severe rheumatoid and psoriatic arthritis and moderate to severe atopic dermatitis. There have been numerous reports of the uses of upadacitinib in patients with AA despite no clinical trials conducted as yet.
A recent retrospective case series (JAAD Johnston et al) reported complete hair regrowth in three patients on 30mg upadacitinib daily after three to eight months. Our personal experience with upadactinib is favourable too, however further studies are warranted to evaluate efficacy.
A randomised double-blind placebo-controlled phase II study has recently published (JAAD Zhou et al) evaluating the efficacy and safety of ivarmacitinib (a JAK 1 inhibitor), in adults with alopecia areata with greater than 25% scalp hair loss.
At week 24 the percentage change in SALT from baseline was 19% in placebo group versus 56% and 51% in those receiving ivarmacitinib 4mg and 8mg respectively. There has been a single report of alopecia areata responding to filgotinib (JAK 1 inhibitor) in a patient with Crohn’s disease and this highlights the potential for repurposing JAK inhibitors for other medical conditions.
An update on the treatment of AA with JAK inhibitors would be incomplete without an update on safety information recently released by the TGA. Based on results from a post-marketing safety study with tofacitinib (pan JAK inhibitor) the TGA has issued a class-wide boxed warning for JAK inhibitors baricitinib, upadacitinib and tofacitinib used in the treatment of chronic inflammatory disorders.
The ORAL surveillance study looked at the safety of tofacitinib (5mg and 10mg twice daily) versus tumour necrosis factor inhibitor (TNF) in patients with rheumatoid arthritis.
Findings from the study revealed higher incidence of MACE, VTE, malignancies (lung cancer, lymphoma, non-melanoma skin cancer), serious infections and all-cause mortality in those treated with tofacitinib compared to TNF.
The warnings have, however, been extrapolated to all JAK inhibitors.
It is worthwhile noting that all patients in the ORAL surveillance study had rheumatoid arthritis, were over 50 years of age and all had at least one cardiovascular risk factor. In addition, all were on, or had been on immune suppression including prednisolone.
The FDA issued these black box warnings regarding MACE and VTE in 2021 and for this reason were already considered in our AA patient selection and counselling, but as with all systemic agents, the prescribing physician needs to consider the risks and benefits for each patient before embarking or continuing JAK inhibitor therapy.
Dr Eisman is a British/South African-trained dermatologist who has had more than 20 years’ experience dermatology. In 2012, she relocated with her family to Melbourne and practices at Sinclair Dermatology, where she has an interest in alopecia and hair disorders. Dr Eisman has been a principal investigator in more than 50 clinical trials at Sinclair Dermatology’s Clinical Trial Centre. She currently serves as treasurer and board member of the Australian Wool and Hair Research Society.
References available on request.