JAKne is on the horizon

By Warren R. Heymann, MD, FAAD
July 27, 2022
Vol. 4, No. 30

If you are like me, you have read much more about JAK inhibitors (JAKi) than have prescribed them. We are all on a learning curve. The rapid introduction of topical ruxolitinib (Opzelura), oral upadacitinib (Rinvoq), and abrocitinib (Cibinqo) for atopic dermatitis (AD), followed by last month’s approval of baracitinib (Olumiant) for alopecia areata (AA) and last week’s approval of ruxolitinib for vitiligo, has been stunning.

Prescribing dermatologists must familiarize themselves with the benefits and risks of these drugs. Although the data prompting black box warnings (serious infections, mortality from sudden cardiovascular death, malignancies, major adverse cardiovascular events, and thrombosis) was derived from older adults with rheumatoid arthritis, they must be addressed. As more data accrues with experience in younger patients treated with JAKi, perhaps these will be modified with time.

In reading these studies, I have been intrigued by acne as an adverse event. Given the ever-expanding list of inflammatory disorders touting the benefit of JAKi (vitiligo, psoriasis, lupus, others), I assumed that acne would benefit from JAKi as well. Perhaps in some circumstances, it might. There is relatively little literature devoted to this topic.

Awad et al analyzed the cutaneous expression of JAK1/2/3 proteins in acne vulgaris to determine the possible role of JAK signaling in acne pathogenesis. They performed a case-control study on 28 patients with inflammatory acne vulgaris vs 20 age- and sex-matched healthy volunteers. Acne severity was assessed using a Global acne severity grading system (GAGS). Skin biopsies were collected from lesional and non-lesional skin of patients and a control group. The expression of JAK1/2/3 proteins was examined by real-time quantitative polymerase chain reaction. JAK1 and JAK3 were overexpressed in acne lesions, compared to non-lesional skin and the control group. No significant difference was found in JAK2 expression between patients and controls. JAK1 and JAK3 showed no significant relation with the patients' age, sex, family history, duration of acne, or GAGS score. The authors suggest that the activation of JAK pathway may play a pivotal role in inflammatory acne, with JAK1 and JAK3 possible being new targets for acne therapy. (1)

I encourage you to read the article by Correia et al, who reviewed the data on acne in AD patients with JAKi. The authors state: “Acne proved to be common with upadacitinib (ABT-494, Rinvoq, Abbvie) and affected up to 13% of patients on upadacitinib 15 mg and up to 17% of patients on upadacitinib 30 mg (Measure Up 1/2). However, 68% had mild acne, mainly characterized by inflammatory papules pustules, and comedones, with few cysts and nodules. Most acne involved the face, and approximately one-third also reported acne on the trunk. Only one patient in the upadacitinib 15 mg group and one patient in the upadacitinib 30 mg group discontinued the study drug because of moderate acne (Measure Up 1). Secondly, acne was often more reported in abrocitinib (PF-04965842, Pfizer) groups who received the 200-mg dose (6.6%) than in others who received the 100-mg dose (2.9%). Nonetheless, it was mild or moderate in all cases. Lastly, only 2.9% of patients across all baricitinib (Olumiant, Eli Lilly) doses studied in the whole BREEZE-AD clinical programs reported the occurrence of acne. The influence of personal and family history regarding acne on the latter’s development remains unclear when associated with JAK inhibitors. Acne is more pronounced in upadacitinib and abrocitinib groups, showing a dose-dependent correlation. In particular, upadacitinib proved to cause more acne in AD studies than in rheumatoid arthritis studies. The younger age of patients in AD studies and the skin examinations performed by the dermatologist can probably explain the increased odds of acne detection.” (2)

In two phase 3 trials involving patients with severe alopecia areata, King et al reported that oral baricitinib was superior to placebo for hair regrowth at 36 weeks, in two phase 3 trials in patients with severe AA.(These trials were funded by Eli Lilly under license from Incyte; BRAVE-AA1 and BRAVE-AA2 ClinicalTrials.gov numbers, NCT03570749 and NCT03899259. I have no conflict of interest — financial or otherwise — for any of the companies mentioned in this commentary). “Acne was more common with baricitinib than with placebo, occurring in 16 of 280 patients (5.7%) with 4-mg baricitinib, 10 of 183 (5.5%) with 2-mg baricitinib, and 1 of 189 (0.5%) with placebo in BRAVE-AA1 and in 11 of 233 patients (4.7%), 9 of 155 (5.8%), and 3 of 154 (1.9%), respectively, in BRAVE-AA2.” (3)

Guo et al performed a meta-analysis of 14 studies including 6 clinical trials and 8 observational studies with 275 AA patients treated with tofacitinib, determining that tofactinib is “reasonably effective.” Their safety analysis was based on 7 studies including 3 clinical trials and 4 observational studies. In the clinical trial group, acne was observed in 13.2%, the second most common adverse reaction, with upper respiratory infections leading the list (56.8%). (4)

This is Dermatology World Insights and Inquiries, and for the topic of acne and JAKi (what I have termed JAKne), I have far more inquiries than insights. Of those that developed acne, was it new onset or a recrudescence? What is the pathomechanism(s)? Will it abate with continued therapy? Should patients with moderate-to-severe acne at baseline receive the drug? Correia et al recommend only topical therapy for comedonal acne and mild to moderate papulopustular acne. They suggest saving systemic therapy for the treatment of severe papulopustular/moderate nodular acne and severe nodular/conglobate acne. (2)

Every patient is unique and therapy must be tailored to their circumstances, desires, and risk tolerance. I suspect that the relatively small risk of acne will not deter motivated patients with severe AA or AD from being treated with JAKi. With increasing experience, we will all have a better sense of the scope and treatment of JAKne.

Point to Remember: Acne is a reported adverse reaction in patients with atopic dermatitis and alopecia areata treated with JAK inhibitors. For most patients, this can be managed with standard acne regimens while receiving the JAK inhibitors. Future research will provide insights regarding acne pathogenesis and treatment.

Our experts’ viewpoint

Brett A. King, MD, PhD, FAAD
Associate Professor, Dermatology
Yale University School of Medicine

Brittany G. Craiglow, MD, FAAD
Associate Professor Adjunct, Dermatology
Yale University School of Medicine

While we are not accustomed to thinking about acne as an adverse effect of medications we prescribe in dermatology, we are fortunate as dermatologists to be experts in treating it. We have treated hundreds of patients with JAK inhibitors (JAKi) over the past 8 years, and we observed acne from the very beginning. Indeed, in an open-label clinical trial of tofacitinib for treatment of alopecia areata (AA), acne occurred in 7.6% of patients. (5) Subsequently, in a 90-patient retrospective review of tofacitinib for AA, acne occurred in 7.8% of patients. (6) We have come to learn a lot about ‟JAKne” during this time.

In our experience, JAKne comprises 3 entities — exacerbation of underlying acne, an acneiform eruption, and JAKi-induced acne — which are distinguished by the presence or absence of acne at the start of JAKi treatment and, in the latter cases, response to treatment of the acne.

1. Exacerbation of underlying acne. Some patients who have acne at the start of treatment will experience worsening disease, including (rarely) nodulocystic acne that merits treatment with isotretinoin. We have yet to encounter a situation in which there has been a concern with using isotretinoin during JAKi treatment of another disease.

2. Transient acneiform eruption. In some patients who develop acne after the start of JAKi treatment — patients who have not had acne in years or decades — appropriate treatment of the acne, most often with topical therapy and/or short courses of oral antibiotics and, rarely, with isotretinoin, will lead to resolution of acneiform lesions, even after acne treatment is stopped (and JAKi continued).

3. JAKi-induced acne. In some patients who have not had acne in years or decades and who develop it anew after the start of JAKi treatment, chronic acne management is required as long as they are taking JAKi.

The spectrum of JAKne includes comedones and inflammatory papules and nodules in a typical acne distribution including face, chest, and back. Although some cases are more clinically suggestive of folliculitis, we have cultured pustules on several patients, all of which have shown normal skin flora.

It is clear from our experience that JAKne management is no different from managing acne in general. Many patients respond well to topical therapy, and some require short courses of oral antibiotics to achieve clearance. In rare cases, isotretinoin is necessary.

When starting a patient on a JAKi, it is important to discuss acne as a potential side effect. If patients have clinically significant acne at baseline, then we like to begin acne treatment concurrently with the JAKi. It seems that such patients are at increased risk of severe acne exacerbation, and, not surprisingly, they are usually teenagers. We have not seen JAKne in any prepubertal patients nor have we ever discontinued a JAKi because of development of acne. Although JAKne may be a nuisance and in some cases may require our patients to take additional systemic therapy, it is very unlikely to be a limiting factor and should certainly not be a deterrent to initiating treatment with JAKi, as these medications have an unparalleled potential to significantly improve the lives of patients suffering from inflammatory skin diseases.

Dr. King had disclosed financial relationships with the following to the AAD at the time of publication: AbbVie, AnaptysBio, Arena Pharmaceuticals, Bristol-Myers Squibb, Concert Pharmaceuticals, Eli Lilly and Company, Equillium, Inc., Horizon Pharma, Inc., Incyte Corporation, Janssen Pharmaceuticals, Inc, Pfizer Inc., Regeneron, Sanofi Genzyme, TWi Biotechnology, Inc.

Dr. Craiglow had disclosed financial relationships with the following to the AAD at the time of publication: Aclaris Therapeutics Inc., Arena Pharmaceuticals, Beiersdorf, Inc., Celgene, Concert Pharmaceuticals, Eli Lilly and Company, EltaMD, Leo Pharma Inc, Pfizer Inc., Regeneron Pharmaceuticals, Inc., Roivant Sciences, Sanofi Genzyme

Full disclosure information is available at disclosures.aad.org.

1. Awad SM, Tawfik YM, El-Mokhtar MA, El-Gazzar AF, Abdel Motaleb AA. Activation of Janus kinase signaling pathway in acne lesions. Dermatol Ther. 2021 Jan;34(1):e14563. doi: 10.1111/dth.14563. Epub 2020 Nov 30. PMID: 33210790.

2. Correia C, Antunes J, Filipe P. Management of acne induced by JAK inhibitors. Dermatol Ther. 2022 Jul 5:e15688. doi: 10.1111/dth.15688. Epub ahead of print. PMID: 35789037.

3. King B, Ohyama M, Kwon O, Zlotogorski A, Ko J, Mesinkovska NA, Hordinsky M, Dutronc Y, Wu WS, McCollam J, Chiasserini C, Yu G, Stanley S, Holzwarth K, DeLozier AM, Sinclair R; BRAVE-AA Investigators. Two Phase 3 Trials of Baricitinib for Alopecia Areata. N Engl J Med. 2022 May 5;386(18):1687-1699. doi: 10.1056/NEJMoa2110343. Epub 2022 Mar 26. PMID: 35334197.

4. Guo L, Feng S, Sun B, Jiang X, Liu Y. Benefit and risk profile of tofacitinib for the treatment of alopecia areata: a systemic review and meta-analysis. J Eur Acad Dermatol Venereol. 2020 Jan;34(1):192-201. doi: 10.1111/jdv.15937. Epub 2019 Oct 10. PMID: 31494993.

5. Kennedy Crispin M, Ko JM, Craiglow BG, Li S, Shankar G, Urban JR, Chen JC, Cerise JE, Jabbari A, Winge MC, Marinkovich MP, Christiano AM, Oro AE, King BA. Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata. JCI Insight. 2016 Sep 22;1(15):e89776.

6. Liu LY, Craiglow BG, Dai F, King BA. Tofacitinib for the treatment of severe alopecia areata and variants: A study of 90 patients. J Am Acad Dermatol. 2017 Jan;76(1):22-28.

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