Successful Response to a Combination of Intralesional Methotrexate and Fractional CO₂ Laser in Refractory Alopecia Areata: Case Report

Abstract

Introduction

Refractory cases of alopecia areata (AA) may be considered a therapeutic challenge. Intralesional methotrexate (IL-MTX) has been used in other dermatological diseases rather than AA. Likewise, its topical use as an immunosuppressant drug may be of interest for the control of the lymphoid infiltrate in AA. On the other hand, the use of fractional ablative laser is supported in literature as an alternative or complementary treatment in AA, whilst the generation of columns of thermal damage may favour the migration of cells and cytokines that are beneficial.

Case Presentation

In this paper, we present 2 cases in which IL-MTX and ablative fractional CO₂ laser were combined with excellent outcomes.

Conclusion

Previous research encompasses a total of 23 patients. Most patients presented with patchy AA. The doses administered ranged from 2.5 to 50 mg with an average frequency of 3 weeks. On average, most patients required a minimum of 3 sessions. One case employed 1% topical methotrexate ointment. Adverse local events were mild and transient. In conclusion, the concomitant application of these treatments has not been reported previously. Specific recommendations relating to the appropriate dosing of the drug, frequency of administration, and requirements for analytical control studies should be determined in further studies.

Established Facts

• With regards to alopecia areata (AA), intralesional methotrexate (IL-MTX) may be an interesting alternative to corticosteroids; showing a better medium-term response rather than the classical intralesional triamcinolone.

• A good response to ablative fractional CO₂ laser (AFCO₂L) in monotherapy in AA as well as in combination with triamcinolone acetonide has been reported.

• IL-MTX and AFCO2L have been used independently before in the literature in the treatment of AA.

Novel Insights

• The combination of IL-MTX and AFCO2L may have a beneficial synergistic effect in patient's refractory to AA.

• IL-MTX for AA in adults is safe and spares the possible systemic adverse effects of MTX use. Its vehiculation by fractional CO₂ laser therapy, in addition to the intrinsic benefits of the technique, could be advantageous by shortening the response time.

Introduction/Literature Review

Dealing with refractory cases of alopecia areata (AA) has proven to be a therapeutic challenge. The combined use of ablative fractional CO₂ laser (AFCO₂L) and the application of intralesional methotrexate (IL-MTX) can be an effective therapeutic tool, but has not been reported previously. Here, we present 2 cases with complete hair regrowth after patients received the combination of both therapies. We also present the published experience on the intralesional application of methotrexate in AA.

Case Report

Case 1

A 38-year-old woman consulted for a long-standing 3-year history of patchy AA, refractory to oral corticosteroid pulses and intralesional triamcinolone (IL-TrA). Physical examination revealed a 9 × 6 cm occipital plaque (Fig. 1a), with cadaveric hairs on its periphery on dermoscopy. Treatment with 15 mg of IL-MTX was started, with administration every 2 weeks, preceded by two passes with AFCO2L (10,600 nm; CO₂RE Candela®) with 5% coverage and a fluence of 288 J/cm², a core of 51 mJ (Fig. 1a, b). The drug was delivered in small aliquots of product, leaving intradermal deposits of 0.1–0.3 mL per spot. The weekend pulse treatment with 2 mg of dexamethasone was continued. After the second session, incipient hair regrowth was accomplished and recovery ad integrum with white hairs was reached by the 16th week (Fig. 1c-e).

Fig. 1.

a Occipital long-standing AA patch in a 38-year-old woman. b Immediate erythema and ablative microchannels after fractional laser therapy. c Hair regrowth after therapy. d, e Dermoscopy images showing villous white hairs in the middle of the plaque and terminal hairs at the periphery.

Case 2

An 18-year-old patient with a failed multitarget treatment for 4 years and a patchy AA history. Among the compendium of unsuccessful drugs previously employed were oral minoxidil, long-term periods of prednisone, IL-TrA, topical mometasone, and platelet-rich plasma. Two large growing parietal plaques (right 15 × 18 cm; left 10 × 4 cm) revealed a very positive hair pull test at the edge despite the immunosuppressive drugs (Fig. 2a, c). A dual treatment protocol was performed, composed of 15 mg of IL-MTX every 20 days and AFCO₂L dosed in accordance with the parameters of case 1. Meanwhile, a 3-day treatment with prednisone 30 mg was maintained. Improvement became apparent from the first session and a complete response was achieved by week 22 since the start of the treatment (Fig. 2b, d). Both patients were subjected to blood tests before and after the procedure, and neither of them showed abnormalities or local complications during treatment.

Fig. 2.

a, c Alopecic biparieto-temporal patch in an 18-year-old woman, adnexal dermoscopy image showing cadaveric hairs (*) and black dots (arrow) corresponding to activity of the disease. b, d Repopulated plaques with almost total coverage of the alopecic area and absence of inflammatory dermoscopy data (adnexal picture b).

Discussion

The application of AFCO₂L creates small columns of thermal damage surrounded by unscathed skin. As the energy target is mainly water, damage to the stratum corneum is minimal. Reepithelialization is initiated within the immediate 24 h following the procedure, through stimulation of dermal papilla cells, as well as via the migration of cells and cytokines to the affected areas [1]. The foundational characteristic triggering the use of AFCO₂L in the treatment of AA lies primarily in its ability to induce apoptosis of the T-cells that compose the inflammatory infiltrate at the level of the hair bulb. It also favours the promotion of follicles to the anagen phase (activating the Wnt/β-catenin signalling pathway) together with the arrest of telogen phase [2, 3]. Moreover, hair follicle neogenesis from non-hair stem cells as a consequence of the post-laser induced healing process has already been demonstrated in murine models [2].

The use of AFCO₂L in AA, both in monotherapy and in combination with triamcinolone acetonide, was reported in the study by Perper et al. [4]. The authors relied on energy settings varying from 10 to 60 mJ/spot, applying a density of 75–150 spots/cm² with variable outcomes. As El-Husseiny et al. [5] pointed out in their half-half study, further research is required to compare the effectiveness of laser therapy versus IL-TrA.

Moreover, the use of this technology in combination with the vehiculation of hydrophilic molecules (i.e., methotrexate) favours their absorption. In addition, higher fluences result in greater channel depths and higher rates of absorption.

The penetration of a drug through the skin is related to its diffusion coefficient. This parameter depends on the interaction between the molecule and the tissue, the concentration gradient of the molecule, and the diffusion pathway, as described by Fick's law of diffusion. The ablation channels generated by AFCO2L disrupt the stratum corneum, exposing the drug to a tissue with a different diffusion coefficient and reducing the diffusion length, thus enabling topical delivery of MTX at a higher rate of absorption [5]. The role of the thickness of the coagulation zone generated around the ablation column has also been studied. It was found that absorption is greater when a coagulation zone is generated, although smaller thicknesses favour a better uptake [6, 7]. However, it should be noted that the use of topical MTX differs from the intradermal administration in the cases presented, and the creation of these coagulation columns may, as described above, favour its absorption. In vitro studies performed by evaluating the quantitative and qualitative properties of the transport kinetics of AFCO₂L-assisted topical MTX suggest that this could constitute a possible suitable alternative to systemic MTX for some skin disorders [8]. It has also been shown that tissue concentrations of methotrexate in the target organ, the skin, are significantly higher with laser assisted delivery compared to high-dose intravenous administration.

Few cases have been reported in the academic literature in which intralesional MTX was used in the management of AA. By contrast, this technique has been used in other dermatological diseases, ranging from psoriasis to lymphomatoid papulosis, mycosis fungoides, and vitiligo [9]. The few publications in this area have been included in Table 1 [10, 11]. All cases employed MTX in monotherapy, with a mean patient age of 24 years old and a patchy presentation of AA, apart from one AA totalis [10]. The administered doses ranged from 2.5 to 50 mg and with an average dosage frequency of 3 weeks (2–4 weeks). All patients required at least 3 sessions and a maximum of 5 to achieve quasitotal hair regrowth (evaluated at week 24). Ahmed et al. [12] used a 1% topical presentation applied twice per day for a period of 2 months. Adverse local events included minimal pain and burning, redness, hyperpigmentation, and erosion and were resolved within a few days. Blood cell count alterations were not found in any case.

Table 1.

Previous reported literature of IL-MTX in AA, including our 2 cases in combination with fractional ablative laser

Author	Ν, gender	Age+- DS (range)	Areata subtype	Duration of AA median, months	Lapse without treatment previous IL MTX	Previous treatments	Concomitant treatments	Dose of methotrexate	Frequency	Sessions, n	RGS* or regrowth signs	BCC	Adverse events
Elsaie and Hasan et al. [10]	1, male	12 years-old	AA totalis	NR	1 month	Topical corticosteroids Systemic corticoids Diphenciprone Azathioprine Minoxidil 5%	None	MTX 50 mg/2 mL vial, intradermal injections of 0.01 mL/cm2 at 2 cm intervals	Monthly	3	Started at: 4 weeks RSG score 3 after 24 weeks of first injection	Not altered	Minimal pain and stinging on injection
Hamdino et al. [11]	20, males	32 +- 9.05 years-old (19–47)	Patchy Localized AA	5	3 months	NR	None	MTX 25 mg/mL vial, intradermal injections of 0.02 mL per site at cm intervals Maximum dose/session: 0.1–0.2 mL (2.5–5 mg)	Every 3 weeks	4	RSG score 4: 65% after 24 weeks of first injection	Not altered	Hyperpigmentation (45%), erythema (10%), erosion (5%). Transient and gradually disappeared
Ahmed et al. [12]	2, NR	NR	Patchy Localized AA	2	Naive	None	None	Topical 1% methotrexate gel	NA	Twice daily for 2 months	Black terminal hairs and mild scaling	Not altered	Mild, tolerable burning, scaling, and redness
Ana Rodriguez-Villa Lario et al.	2, female	28 years-old (18–38)	Patchy Localized AA	>6	None	Topical corticosteroids Systemic corticoids Intralesional Minoxidil 5%	A: Dexamethasone B: Prednisone A, B: AFCO2L (10.600 nm), 2 passes, 5% de cobertura y fluencia de 288 J/cm2, core de 51 mJ	MTX 15 mg/0.3 mL Intradermal injections of 0.02 mL per site at 2 cm intervals Maximum dose/session: 0.3 mL (15 mg)	A: every 2 weeks B: every 3 weeks	A: 4 B: 5	A: Vellous and black terminal hairs by week 4 B: Vellous hairs by week 3	Not altered	Transitory pain, redness, mild transitory hyperpigmentation

NR, not referred; RGS, regrowth scale.

^*RGS: 0 score (regrowth <10%), 1 score (regrowth 11%–25%),2 score regrowth 26%–50%), 3 score (regrowth 51%–75%), and 4 score (regrowth ≥75%).

Hamdino et al. [11] made an interesting comparison when evaluating the efficacy of local MTX versus classical IL-TrA. Their work found a worse short-term response at week 12 for MTX-IL. However, their analysis showed a better response in the medium term in the reevaluation at 6 months from the start of treatment. Hence, 65% of the IL-MTX population had reached stage 4 in the hair regrowth scale (regrowth ≥75%) compared to 50% in the IL-TrA group.

Therefore, our cases combine these two novel therapies, AFCO₂L with IL-MTX, in order to achieve more effective results. In addition, despite maintaining the systemic corticosteroids, the conjunction of both treatments did not lead to an increase in adverse events. The parameters applied (5% coverage, 70 spots/cm² with 1.8 mm wide/spot, 51 mJ, and overlap 2) with a medium dose of IL-MTX (15 mg) may prove to be a safe strategy providing faster hair regrowth results than in previous cases, while reaching a mean resolution by week 19. Of course, we cannot rule out the possibility that the favourable evolution of the condition is due to the maintenance of the corticoid therapy, as this is the gold standard treatment of AA. The limitations of the study include the small number of cases and the absence of follow-up. In addition, the concomitant use of systemic corticosteroid therapy in our patients can be understood as a favourable outcome bias, as we mentioned before.

In conclusion, IL-MTX for AA in adults is safe and spares the possible systemic adverse effects incurred with the use of MTX. Its vehiculation by fractional CO₂ laser therapy, in addition to the intrinsic benefits of the technique, could be advantageous for a number of reasons. Given the synergy of the therapies applied, IL-MTX can shorten response without an apparent increase in the profile of adverse events. The mean dose and frequency of application of the drug are still unknown and should be established in further studies.

Statement of Ethics

Written informed consent was obtained from the patients for the publication of this case report and any accompanying images. All the patients (or parent/legal guardian) have provided written consent to publish the details and photos of their cases. The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors did not receive any funding.

Author Contributions

All the authors contributed equally in drafting the manuscript. Dr. Rodriguez-Villa made manuscript corrections.

Data Availability Statement

The data used to support the findings of this study are included within the article.

Funding Statement

The authors did not receive any funding.