A New Study highlights Striking “Scalp Only” Inflammatory Pattern — Donovan Hair Clinic

A new study set out to evaluate patterns of inflammation in frontal fibrosing alopecia and to compare those patterns to what is found in other known inflammatory conditions such as alopecia areata and psoriasis.

Inflammation in patients with frontal fibrosing alopecia was found to be largely limited to the scalp with inflammatory closely linked to fibrosis but no systemic inflammation.

Dubin et al, 2022

Authors from New York set out to determine how FFA differed from alopecia areata and patients without immune based hair loss using broad molecular profiling and to identify biomarkers linked to disease severity. The authors assessed 33,118 genes in scalp using RNA sequencing and 350 proteins in serum using high-throughput proteomics.

There were 38 patients in the study including 12 with FFA, 18 patients had alopecia areata and 8 controls. 4.5 mm biopsies were taken from patients.


The authors found 1218 genes differentially expressed in the scalp of patients with FFA compared to alopecia areata. Those most significantly altered included markers related to Th1 (IFNg/CXCL9/ CXCL10), T-cell activation (CD2/CD3/CCL19/ICOS), fibrosis (CXCR3/FGF14/FGF22/VIM/FN1), T-regulatory (FOXP3/TGFB1/TGFB3), and Janus kinase/JAK (JAK3/STAT1/STAT4). Activation of the JAK STAT pathway seemed to correlate well with fibrosis. In other words, the greater and greater the degree of activation of the JAK STAT pathway the greater the expression of fibrosis related genes. Significant correlations were found between scalp biomarkers (IL-36RN/IL-25) and FFA severity. In general, there was more robust inflammation in the scalp of FFA compared to alopecia areata.

Biopsies from FFA Patients Do Not Show Upregulation of Proteins in the Serum

Surprisingly, the authors found just 1 upregulated differentially expressed protein in the serum in FFA patients compared to control serum. This was the apoptosis-related gene ADM). This differed considerably from other inflammatory conditions like alopecia areata where there were 73 proteins differentially expressed, and atopic dermatitis where there were 45 proteins differentially expressed and psoriasis where there were 47 proteins differentially expressed.

Unlike in other inflammatory conditions, there was a lack of immune activation and atherosclerosis type signalling in FFA. Although FFA had more inflammatory expression in the scalp than aloepecia areata, alopecia areata had far more inflammation in the serum than FFA.


Overall, the authors propose that frontal fibrosing alopecia is a condition in which robust inflammation is limited to the scalp. Moreover, they propose it is a very different inflammatory condition to other known inflammatory conditions, like alopecia areata atopic dermatitis and psoriasis that involve systemic inflammation, including elevation of cardiovascular-related markers.

Overall, fibrosis is very much a part of the pathogenesis of FFA and it seems that the JAK/STAT pathway is closely linked to pathways driving fibrosis.

The Many Unknowns that Remain

There are a few unknowns which will need to be addressed in further studies:

1) Are patients with FFA truly at increased risk of heart disease?

If we believe that LPP and FFA are closely related, then we can’t neglect the data that suggests patients with LPP might have an increased risk of heart disease. Compared to controls, patients with LPP had a 1.7 fold increased risk of coronary artery disease, a 1.5 fold increased risk of heart attacks and 1.6 fold increased risk of strokes. Is FFA a heart disease free version of LPP? We just don’t know. More studies will be needed.

2) Do we accept that FFA is a ‘scalp only’ disease?

FFA is not truly a scalp only disease given that eyebrows, eyelashes, body hairs and facial papules and facial atrophy is seen. Is it only local inflammation driving these changes? Is fibrosis just as relevant at these sites where we can see improvement in eyebrows sometimes. More studies will be needed.

3) Are these systemic associations we feel are relevant really true associations?

If FFA is truly a scalp or skin limited disease with no systemic inflammation, why do we see an increased risk of early menopause, lichen sclerosis, low androgen levels. More studies will be needed.

4) How do we tie in the increase risk of rosacea among FFA patients?

If FFA is truly a scalp or skin limited disease with no systemic inflammation, why do we see an increased risk of rosacea in women with FFA. Rosacea is linked to systemic inflammation.

In 2019, Moreno-Arrones and colleagues recently conducted a multicentre case-control study and recruited 335 individuals with FFA and 329 patients who did not have FFA. Women with FFA were found to have a nearly two fold greater incidence of rosacea compared to women without FFA (OR = 1.91; 95% CI 1.07-3.39). Porriño-Bustamante and colleagues also recently performed their own cross sectional study which included 99 women with frontal fibrosing alopecia and 40 controls. 62 % of women with FFA had rosacea compares to 30% of women without FFA. Women with more advanced stages of FFA were the most likely to report having rosacea compared with women with less advanced stages.

More studies will be needed.

5) If FFA is not really a systemic disease, why can systemic medications trigger the disease?

If FFA is truly a scalp or skin limited disease with no systemic alterations, why can systemic medications like tamoxifen increase the risk of FFA so dramatically. The same authors found additional data that interruption of estrogen signalling may have a role – the anti-estrogen tamoxifen was found to be associated with a nearly 15 fold greater risk of developing FFA.

Other systemic medications with a completely different mechanism can also induce FFA. In 2019, King et al described a 62-year-old woman who developed persistent FFA while on ustekinumab for treatment of preexisting psoriasis. The suggestion here was that blockage of IL-12 and IL-23 (the targets of ustekinumab) might carry some sort of risk to trigger FFA in some patients.

More studies will be needed.

6) Do patients with FFA truly have an increased risk of early menopause?

If FFA is truly a scalp or skin limited disease with no systemic alterations, what do we do with the information showing that women with FFA are at increased risk for premature menopause. Premature menopause is defined as menopause occurring in women under 40 years of age. Overall, about 1 % of women in the general population have premature menopause making the condition not really all that rare. A 2014 study by Dr Vano Galvan suggested that 14 % of women with FFA may have early menopause.

A 2018 case control study by Buendia-Castrano and colleagues showed that menopause occurred earlier in women with FFA. This data came from examining records of 104 female FFA patients and 208 controls.

More studies will be needed.

7) If FFA is a “scalp only” disease, why do patients with FFA seem to be at increased risk for having so many autoimmune diseases?

If FFA is to be viewed as a scalp limited disease, how to be reconcile the fact that autoimmune diseases like thyroid disease seem to be increased in FFA and possibly other autoimmune diseases like oral lichen planus, nail lichen planus, lichen sclerosis, discoid lupus, and possibly psoriasis.


All in all, this is a fascination study, and undoubtedly top study for 2022. All really good studies open the door to many more questions and certainly this study is no exception in this regard.


Dubin C et al. Scalp and serum profiling of frontal fibrosing alopecia reveals scalp immune and fibrosis dysregulation with no systemic involvement. J Am Acad Dermatol. 2022 Mar;86(3):551-562. doi: 10.1016/j.jaad.2021.05.016


Moreno-Arrones OM, et al. Clin Exp Dermatol. 2019.
Porriño-Bustamante ML, et al. Acta Derm Venereol. 2019.

Buendia-Castrano D et al. Hormonal and Gynecological Risk Factors in Frontal Fibrosing Alopecia: A Case-Control Study. Skin Appendage Disord. 2018 Oct;4(4):274-276. doi: 10.1159/000484210. Epub 2017 Dec 8.

Imhof et al. Frontal Fibrosing Alopecia in Women: The Mayo Clinic Experience With 148 Patients, 1992-2016. Mayo Clin Proc. 2018 Nov;93(11):1581-1588. doi: 10.1016/j.mayocp.2018.05.036.

King et al. Onset of frontal fibrosing alopecia during inhibition of Th1/17 Pathways with ustekinumab.mDermatol Online J . 2019 Jul 15;25(7):13030/qt8nw631wq.

Vano-Galvan et al. Frontal fibrosing alopecia: a multicenter review of 355 patients. J Am Acad Dermatol. 2014 Apr;70(4):670-678. doi: 10.1016/j.jaad.2013.12.003. Epub 2014 Feb

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