Onychomycosis is a typical nail disease, accounting for 50% of abnormal nails¹. It is prominent in South Korea, causing 10% of all dermatological out-patient cases². The major treatment options include topical and oral antifungal medications. Single topical agents are inadequate for onycho- mycosis because they exhibit limited penetration to the nail plate. Oral antifungal therapies are found to be the most effective treatment options; however, they have limited use due to slow responses, high recurrences, and adverse effects, with a failure rate of about 30%³. Meanwhile, the appli- cation of laser treatment continues to gain attraction as an alternative treatment option with many advantages, such as relatively fast response, fewer side effects, and avoidance or mitigating the duration of oral therapy⁴. Among the several laser equipment types, the 1,064-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser is a laser device that reaches the nail plate and bed, facilitating superheating of the fungal materials and suppressing their growth⁵. However, some patients are refractory to laser monotherapy. Thus, combination therapy has garnered considerable interest, given its potential for drug synergy and prevention of antifungal resistance_⁶. To date, few analyses have contrasted the com- bination of laser and oral drugs with oral monotherapy for laser non-responders after different cycles of laser treatment, offering clinicians guidance on whether it is better to combine oral drugs with laser treatment or entirely switch to oral drugs if laser treatment fails. Therefore, we undertook this retrospective study to assess the efficacy and safety of oral drug intervention for non-responders to laser therapy and compare the efficacy of the integration of laser and oral drugs with that of oral monotherapy.

1. Study population

A retrospective review of electronic charts was conducted for patients with onychomycosis, who visited the Department of Dermatology at Kyung Hee University Medical Center between September 2021 and September 2022, and were treated with Nd:YAG laser for at least four sessions (PinPointe foot laser, CYNOSURE, US) and were subsequently switched to oral drugs or continued laser treatment combined with oral drugs. We analyzed the records of 72 patients. The research was authorized by the Institutional Review Board of the hospital (2021-09-034) and was executed following the principles of the Declaration of Helsinki.

Patients were exempted based on the following criteria: irregular visits, much far from the visit interval, termination of treatment by the patient, inadequate data for photographs, oral antifungal therapy within 6 months before the study, nail discoloration facilitated by factors other than a fungus or Candida, and psoriasis and lichen planus of the nail plate. After applying the exclusion criteria, 52 patients were screened, and finally, 20 patients were enrolled in the study.

2. Study design

The final 20 patients were categorized into two groups based on the investigator's global assessment (IGA) re- sponse⁷: the laser non-responder group and the laser partial-responder group. The laser non-responder group comprised older patients with an IGA score of 0 (worse, deterioration from baseline) or 1 (poor, <24% improvement) after four sessions of laser treatment, whereas the laser partial-responder group comprised nine patients with IGA scores of 2 (fair, 25~49% improvement), 3 (good, 50~89% improvement), and 4 (excellent, 90~99% improvement). No patient had an IGA score of 5 (cleared, 100% remission except for residual manifestations) that conformed to the absence of demand for additional oral treatment. Ten patients received oral anti- fungal drugs in combination with the ongoing laser therapy, and the other ten patients were switched to oral drugs with no additional laser sessions, as illustrated in Fig. 1.

Figure 1. Diagram showing the categorization of the study population

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Concerning the laser treatment protocol, nails thicker than 2 mm were mechanically debrided using a nail grinder before treatment. The parameter settings of the laser were wave- length, 1,064 nm; pulse energy, 200 mJ; pulse duration, 0.1 ms; spot size, 1.5 mm; frequency, 30 Hz, and temperature, 40~60℃. The laser beam was moved spirally to cover the entire nail plate. The procedure was conducted twice following a 2-min pause. The patients were treated at 1-month intervals for a total of four sessions.

For oral therapy, three antifungal drugs were given, with a dose was 250 mg a day of terbinafine, 200 mg a day of itraconazole, and 150 mg a week of fluconazole. In the aspect of itraconazole, two patients were treated with pulse therapy comprising 200 mg twice daily for 1 week followed by a 3-week off. Terbinafine was given to most patients (15/20), followed by itraconazole (3/20) and fluconazole (2/20).

3. Outcome assessment

The major outcome of this study was to evaluate clinical efficacy by calculating IGA response based on modifications in the onychomycosis severity index (OSI)^7,8. The OSI scoring system highlights the infected area, proximity to the nail matrix, dermatophytoma, and subungual hyperkeratosis⁸. To demonstrate statistically significant improvement, a clinical cure was outlined as IGA scores 3, 4, and 5, which indicates an improvement of more than 50%. For baseline mycological evaluation, four different modalities were conducted: fungus culture, potassium hydroxide (KOH) smear, nail periodic acid schiff (PAS), and reflectance confocal microscopy (RCM). We deemed the outcome of mycological evaluation as "positive" if at least one test revealed a positive result, considering the high specificity and relatively low sensitivity of each test⁹. Outcome evaluations were conducted at baseline and 3 months after treatment. 3 months after the final analysis, the patients were asked to visit the hospital to detect recurrence, which was defined as the emergence of clinical evidence of infection, considering color change, thickness, and dermato- phytoma. The entire process and the evaluation period are depicted in Fig. 2. Furthermore, we attempted to determine the factors influencing laser treatment failure. Important variables included age, sex, chronic illness, concomitant drugs, nail site, clinical type, and baseline mycological evaluation.

Figure 2. Diagram depicting the evaluation process at baseline and at 3 months and assessment of recurrence at 6 months

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4. Safety evaluations

Patients were asked to mention any adverse effects at all follow-up visits, ranging from baseline evaluation to 6 months.

5. Statistical analysis

All statistical analyses were conducted using SPSS software (version 20.0; SPSS Inc., Chicago, IL, USA). Because the pro- portion of patients is less than 30, we applied Wilcoxon Signed-Rank Test to contrast clinical improvement between the intervention modalities of oral therapies and the Mann-Whitney U-test to assess combining therapy and oral monotherapy in the laser non-responder group. Furthermore, we employed a chi-square test to determine factors affecting the output of laser treatment. Statistical significance was set at p-value < 0.05.

1. Demographic information

Twenty patients were chosen according to the inclusion criteria. The mean age of the patients was 55.2 (± 12.4) years. The most widespread chronic illness was urticaria equally accompanied by hypertension and diabetics mellitus (DM) and the most predominantly co-used drug was an antihistamine. The total number of affected nails was 99, with an average of 4.9 nails per patient, and the great toenail was the most constantly affected. The most prevalent clinical type was distal lateral subungual onychomycosis (14/20 patients). All patients were treated with topical efinaconazole. According to the presumption of the baseline mycological evaluation presented above, 14 patients demonstrated mycologically positive results, which were, when we assess them more exclusively, 11 positivity of KOH, 6 positivity of fungus culture, and 7 positivity of PAS or RCM. The most predominant species discovered by fungus culture was Tinea rubrum (3/7), followed by Fila- mentous fungi (2/7). The demographic information of the patients categorized according to treatment modalities is presented in Table 1.

2. Comparison of the impact of oral antifungal intervention between laser non-responders and partial responders

Eleven laser non-responders and nine laser partial re- sponders were measured to determine the influence of oral therapies. In the laser non-responder group, merging with or switching to oral antifungal drugs was considerably effective in a clinical evaluation with the elevation of mean IGA from 0.82 to 2.09 (Z = -2.481, p = 0.013). The clinical cure rate, which is the percentage of patients achieving a predefined clinical cure, rose from 0% to 45.5% after oral therapies. In contrast, the laser partial-responder group did not attain a statistically significant change (Z = -0.707, p = 0.480). The change in mean IGA indicated a decline of 0.3, which implies an ironically partial deterioration after an oral intervention.

3. Comparison between combining and switching to oral treatments in the laser non-responder group

Among the 11 laser non-responders, 6 patients were treated with combination therapy (laser plus oral antifungal drugs), while the other 5 were treated with oral monotherapy. Patients who received combination therapy demonstrated a 2.5 increase in the mean IGA score, but those who received oral monotherapy expressed only an increase of 1.6 (Fig. 3). This implied that combining oral drugs was more efficient than explicitly switching to oral drugs from laser treatment alone, although this was not statistically significant (Z = -1.324, p = 0.247). The comprehensive IGA responses based on the OSI are highlighted in Table 2.

Figure 3. A colored onychomycotic nail of a patient treated with laser and oral combination therapy clinically improved better than with laser monotherapy in color, subungual hyperkera- tosis, and dermatophytoma.

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4. Factors affecting failure of laser treatment

We could not detect any statistically significant factor influencing the output of laser treatment regarding sex, age, chronic illness, concomitant drugs, number, site of affected nails per patient, and clinical type. However, we determined statistical significance in baseline mycological analysis, of which the positive result denoted a higher likelihood of failure of laser treatment (χ2 = 5.089, p = 0.024).

5. Adverse events

Regarding safety, no particular adverse events occurred. There were two cases of recurrence only in patients treated with switching therapy and none in those treated with combined therapy.

The treatment of onychomycosis primarily includes oral and topical antifungal drugs¹⁰. A single topical antifungal drug is inadequate for the complete removal of the fungus, and oral antifungal drugs are strongly demanded not only for their supportive and synergistic effect with the topical agent but also for application as a single therapy¹¹. However, their long-term use is minimized when patients are immunocom- promised, hepatopathic, nephropathic, or poly medicated. Furthermore, not every patient is satisfied with their efficacy. Oral antifungal drugs are known to be potent in eradicating fungi, meaning they have a good fungicidal effect; however, they are ineffective in attaining rapid and long-lasting clinical improvement, including nail color and thickness^12,13. Despite the excellent mycological cure rate linked to oral antifungal drug use, a 5-year follow-up study revealed that 53% and 23% of the patients who achieved mycological cure at 12 months after oral itraconazole and terbinafine, respectively, had mycological relapse or reinfection¹⁴.

Lately, several studies have attempted to substitute this treatment with laser treatment to improve the cure rate, reduce adverse effects, and eliminate drug-resistant patho- gens. Although there are different types of lasers available, 1,064 nm Nd:YAG laser therapy is simple, quick, minimally invasive, and comparably well tolerated^5,15. The laser is also conducive for multiple fungal species¹⁶. Unlike Q-switched or short-pulse Nd:YAG lasers, long-pulse (ms) Nd:YAG laser has been studied extensively and is known to indicate a mycological cure rate of more than 70% and a clinical cure rate of 50% after 6 months of treatment¹⁷. Based on these similar robust research outputs, the Ministry of Food and Drug Safety in South Korea authorized the use of a long-pulse 1,064 nm Nd:YAG laser for onychomycosis¹⁷. A retrospective study of 30 patients with onychomycosis proposed that the Nd:YAG laser offers effective treatment, as demonstrated by its significant mycological and clinical clearance¹⁸. However, some patients remain refractory to laser monotherapy. A review of 24 laser trials on onychomycosis revealed that there was little evidence supporting the use of lasers for clinical cure¹⁹. In a systematic review of 25 randomized controlled trials on laser monotherapy, a complete cure was not found in any study, and mycologic cure was examined in only one study²⁰. Furthermore, laser treatments are not cheap, are generally not insured, and typically require multiple monthly or biweekly sessions²¹. Therefore, it is essential to integrate laser treatments with other interventions.

Studies comparing laser and oral combination therapies with oral monotherapy are meager. A recent study by Khater et al. evaluated the efficacy of combined Nd:YAG laser treat- ment and itraconazole versus that of itraconazole solely and indicated that clinical cure expressed better results in group II (laser and itraconazole) than in group 1 (itraconazole alone). However, the mycological cure did not reveal a substantial difference between the groups²². In 2016, Li et al. described that a combination of itraconazole and laser therapy was suggested for severe onychomycosis, whereas single medi- cation and combination treatments revealed no difference in patients with mild or moderate onychomycosis²³. In 2014, Xu et al. indicated that combined treatment was better than either oral therapy or laser treatment and was particularly effective in the first 3 months of treatment¹².

First, we equipped the study to present evidence that add- itional oral drugs benefit laser non-responders more than partial laser responders. Consistent with our expectations, regardless of the method of oral intervention, both combination and oral monotherapy were substantially effective only for non-responders. This implies that patients who are satisfied with laser treatment even slightly are better able to keep it up, instead of considering other options. However, in cases where a patient does not appear to be the right fit for laser therapy, integrating and switching to oral drugs may be a good alternative option.

Second, we attempted to identify whether combining or switching to oral drugs was preferable for laser non-responders, and our analysis showed that combining oral drugs seemed to be superior to switching to oral drugs alone. Two cases of recurrence occurred only in the oral monotherapy group. The mechanism of long-pulsed Nd:YAG lasers are not exten- sively known; however, different hypotheses have been pro- posed. Local hyperthermia influences protein denaturation and fungal apoptosis. Furthermore, laser waves are selectively absorbed by melanin on fungal cell walls, thus inhibiting fungal growth and influencing the growth of infected nails²³. An in vitro study revealed that a long-pulsed 1,064-nm Nd:YAG laser can effectively hinder the growth of Tinea rubrum²⁴. In contrast, oral antifungal drugs inhibit the activity of sterol 14α demethylase, which can obstruct the synthesis of ergosterol, a crucial component of fungal cell membranes²³. Considering the different mechanisms of action, the syner- gistic impacts of oral drugs and lasers appear to play no role in improving efficacy and reducing recurrence. Therefore, it is rational to presume that combination therapy can shorten the treatment duration of oral drugs and achieve broader antifungal coverage while preserving the same efficacy²⁵. A large-scale systematic review in 2022 demonstrated a signifi- cant clinical benefit of laser and oral combination therapy over monotherapy in almost all studies (14/15, 93.3%)⁶.

Despite the many advantages of combination therapy over monotherapy, there are still some safety issues. The above-mentioned systematic review revealed that there was a greater number of studies on the adverse events linked to combination therapy than with monotherapy6. Most adverse events were mild-to-moderate burning sensation and pain. However, most sample sizes were small, and the monotherapy comprised a topical drug or placebo, not an oral drug. It is obscure whether the adverse events were linked to the combinational effect of treatment or the procedure itself, like the super- heating by the high thermal energy of the laser. No severe adverse events, except for the temporary elevation of hepatic function, were observed in any of the studies on the com- bination therapy of laser and oral drugs^12,22,23. In our study, no explicit adverse events occurred in either group. Therefore, combination therapy is generally well accepted.

Furthermore, we attempted to determine several differential points for distinguishing laser responders from laser non-responders. The baseline mycological result was the only substantial factor that impacted the effectiveness of laser treatment. Therefore, when we discover a patient whose baseline mycological evaluation is negative, but who is clinic- ally and circumstantially believed to be an onychomycosis patient, we would be more encouraged to consider laser treatment.

This study had several limitations, including the small proportion of cases, incomplete mycological data, uneven distribution of sex, clinical types, and application of antifungal oral drugs with different cure rates, which can be attributed to the inherent characteristic of this retrospective study. We had to use a non-parametric statistic test because of the small number of patients less than 30. We mostly relied on clinical clues highly indicative of onychomycosis to validate the diagnosis of onychomycosis without conducting myco- logical examinations for all patients; however, the risk of misdiagnosis was lowered by excluding possible differential diagnoses, such as nail lichen planus and psoriasis, during patient screening¹⁰. Furthermore, this study tracked recurrence for only 6 months. Considering the high recurrence rate of oral monotherapy, studies with longer follow-ups are required to optimize treatment regimens¹⁴. Based on this analysis, a prospective study designed to complement such limitations will be required soon.

Laser treatment is particularly beneficial for older, immuno- compromised, uncontrolled DM, hepatopathic and nephro- pathic patients, for whom long-term oral drugs could pose some risk. However, when a patient is refractory to laser therapy, integrating oral drugs with laser therapy could be beneficial for efficacy, recurrence, and safety.