Is the use of an invisible infra-red energy (1064nm in wavelength) laser more effective than topical anti fungal agents for the treatment of onychomycosis?
ABSTRACT
Onychomycosis is a common nail pathology affecting the nail plate and nail matrix. It is caused by micro-organisms including yeasts, dermatophytes and non-dermatophyte molds and is believed to affect up to 10% of the general population. It is the most common nail pathology seen in podiatric practice and can cause impaired social interactions, pain, embarrassment and in more extreme cases, difficulties with self-care and footwear fitting.
The main aim of this trial is to discover whether successful treatment of onychomycosis is best achieved with the use of topical agents or infra-red energy laser (1064nm wavelength). Treatment effectiveness will be judged based on whether a mycological cure, clinical cure, or complete cure has been achieved. A mycological cure is indicated by negative potassium hydroxide microscopy and negative culture. A clinical cure is indicated when a clinically completely normal nail is present. A complete cure would be indicated if a clinical cure and mycological cure are achieved simultaneously.
The results of this trial have the potential to improve the evidence base for podiatric treatments used to manage onychomycosis and improve patient outcomes, including better nail health and cosmesis.
1 BACKGROUND & RATIONALE
Onychomycosis is a common fungal infection of the nails that can cause nail plate thickening and discoloration (Singal & Khanna, 2011). The disease is very common in adults and is associated with many predisposing factors including climate, age, socioeconomic status, and occupation, in addition to systemic conditions such as diabetes mellitus, peripheral arterial disease and immunosuppression (Faergemann & Baran, 2003; Hull, 2011). Prevalence of onychomycosis is estimated to be as high as 10 per cent in the general population, 20 per cent in people over 60 years and 50 per cent in those over 70 years (Vlahovic et al., 2018). Dermatophytes are the most common cause of onychomycosis, particularly Trichophyton rubrum (Robres, Aspiroz, Rezusta & Gilaberte, 2015)
Conservative treatment for onychomycoses include regular sharp debridement, application of topical preparations and prescription of oral medications, with a combination therapy of topical and oral medications found to be most effective (Dermnet New Zealand, 2018). Novel treatments for onychomysis using devices include infra-red laser therapy and photodynamic therapy and experimental therapies such as iontophoresis and ultrasound (Dermnet New Zealand, 2018).
Newer topical antiphonals are applied as lacquers for extended duration (up to 1 year). According to Vlahovic et al. (2018), cure rates of newer topical antifungals are:
| Antifungal Agent | Complete Cure Rate | Mycological Cure Rate |
| Tavaborole | 6.5 – 9.1% | 31.1% – 35.9% |
| Efinaconazole | 15.2 – 17.8% | 53.4 – 55.2 |
To be effective, the antifungal agent should penetrate the nail plate and reach the site of infection. Recent evidence suggests that efinaconazole is most effecting in reaching the infection site after transungual and subungual application (Elewski 2015). The effectiveness of subungungual delivery of tavaborole in not yet conclusive (Elewski 2015). Both of these topical treatments are lacquer based therapies applied to the exterior nail plate surface, lateral and proximal nail folds, hyponychium and under-surface of the nail. These preparations are both very expensive, particularly in light of their limited effectiveness. In the USA, for example, efinaconazole 4ml retails at USD 577.36 while tavaborole 4ml retails at USD 608.66.
The effectiveness of a topical antifungal monotherapy is dependent on the active ingredient’s concentration remaining above the minimum inhibitory dose for the infecting organism. Nail lacquers have been shown to be effective as they reduce transonychial water loss and have the potential to induce the germination of dormant and drug-resistant conidia, which help to eradicate the fungus and prevent the recurrence of onychomycosis (Gupta & Simpson, 2012). Gupta and Simpson (2012) found that topical monotherapy is only effective in treating superficial white onychomycosis where less than 50 per cent of the nail plate surface area is affected, without the involvement of the nail matrix. Their study does not examine the effectiveness of topical monotherapy in cases of multiple onychomycotic nails (> 4) or nail matrix involvement.
In contrast to slow-acting nail lacquers, laser therapies are much briefer in duration. For example, one treatment with a 1064nm wavelength infrared laser was delivered in three sessions, each at least three weeks apart, with a topical antifungal cream applied to each treated nail after laser treatment. (Hochman, 2011). This combination therapy saw a negative culture outcome in 87.5 per cent of treated patients, which is a much higher rate of success than that seen with antifungal lacquers.
However, other studies do not reflect similar rates of effectiveness with laser therapies. For example, Lipner (2018) reports that laser treatment results in a lower mycological cure rate (11%) than oral and topical combination therapies (29-61%). It should be noted that systemic oral antifungals carry much greater risks of side effects, drug interactions and liver toxicity compare to laser or conventional topical treatments (Lipner & Sher, 2018). Similarly, Espírito Santo & Deps (2018) found laser therapy less effective for onychomycosis than conventional treatments. The therapeutic response to laser therapy was not satisfactory as only 41 per cent of nails decreased on the onychomycosis severity index, with 50 per cent remaining the same, and severity increasing in 9 per cent of nails (Espírito Santo & Deps, 2018).
In addition, a systematic review of the literature that examined the effectiveness of lasers in the treatment of onychomycosis concluded that current evidence is limited and of inferior methodological quality (Bristow, 2014). Randomised control studies with larger populations and clear design structure would be needed to assess the effectiveness of the intervention (Bristow, 2014)
As these studies demonstrate, the current research on laser therapies and topical antifungal treatments is inconclusive. More research is needed with much larger study populations in order to improve the quality of evidence. Most studies do not report clearly on the age, systemic health and demographic attributes of study populations. There is also a lack of reporting of compliance rates during and after treatment with regard to behavioural changes and changes to local environment (e.g. footwear, hosiery, hygiene). Also, as laser treatment is operator dependent, these results may not be a true indication of how effective the treatment is.
Justification:
This trial will improve the evidence for the effectiveness of laser therapies for onychomycosis treatments in comparison to conservative treatment with topical and oral antifungal agents. Better evidence will offer greater treatment choices to patients with onychomycosis, which is a common condition that is difficult treat and can cause complications and reduced cosmesis.
2 RESEARCH METHODOLOGY
2.1 Objectives and outcome measures
Primary objective:
The main aim of the trial is to identify if 1064-nm infrared laser therapy is more effective at treating onychomycosis compared to topical antifungal agents.
Secondary objective:
To assess self-reported satisfaction with cosmetic improvement.
2.1.1 Outcome measures
The outcomes measured will be whether or not each therapy under study led to a mycological cure, clinical cure, or complete cure. A secondary outcome measure will be patient satisfaction with cosmesis, rated on a scale of 1-10, with 1 being completely happy with the appearance of the affected nail and 10 being completely ashamed, embarrassed and unwilling to wear open-toe shoes as a result.
2.2 Trial design
2.2.1 Trial design
A randomised control trial of one hundred and twenty participants with a two-arm, superiority design.
After obtaining ethics approval, trial participants will be randomly allocated into one of the two groups. Participants will be randomly allocated to either laser treatment or topical antifungal (JUBLIA – efinaconazole 10% nail lacquer). This will be achieved by a computer generated randomisation program. All participants will be given the same information package about treating footwear and drying feet properly. They will be observed and treated over the course of 12 months with monthly appointments to monitor progress. A patient satisfaction form will be administered at each visit and at the conclusion of the trial. Nail samples will also be collected at each visit for culture and potassium hydroxide microscopy. A trial period of 12 months has been chosen as the rate of nail growth is slow (approximately 1-2 mm per month) and varies between participants. Prior to commencement, an initial consultation will take place with a general practitioner (GP) who will prescribe the efinaconazole as appropriate.
2.2.2 Trial setting
The trial will take place at a Sydney podiatry clinic that possesses 2 PinPointe footlaser devices (infrared 1064nm), diamond burs, and diamond nail files. This will be a single centre trial, with multiple podiatrists working from the same clinic. All practitioners will be given instructions on interventions. The location will be advertised through flyers and posters in the local area as well as online via the clinic website and Facebook Group.
2.2.3 Participants
The population is anyone that has been clinically diagnosed with one or more onychomycotic nails. Participants will be recruited from all local private podiatrists, medical practices and public health clinics within a 5km radius of the trial clinic. Participants are eligible for the trial if they have clinically diagnosed onychomycosis in one or more nail and have not treated the condition previously. Participants will be a mix of male and female, and every age group as onychomycosis can affect anyone.
2.2.4 Inclusion criteria
- Any gender
- Any age
- Capable of giving informed consent, or if under 18 years of age with parents’ consent
- Fluent English speaking
- Able to attend the clinic every month
- Has not tried any treatments previously for their onychomycosis
- Positive clinical and mycological diagnosis of onychomycosis
2.2.5 Exclusion criteria
- Pregnancy
- Allergy to latex or any of the trialled medications
- Non English speakers
- Previous wounds
- Neuropathy
- Poor healing
- Peripheral arterial disease
- Anyone that intents to treat the affected nail with other means during the trial.
2.3 Trial Procedures
An initial consultation will take place where a podiatrist will clinically diagnose the affected nail, and take a scraping and nail sample to be sent for culture and potassium hydroxide microscopy. If the patient is deemed suitable, they will have a consultation with a GP who will determine whether to prescribe efinaconazol. If all these requirements are met, the patient will be given the efinaconazole 10% nail lacquer and instructed to apply once daily. Their podiatry appointments will include cutting, filling and reducing the affected nail with either a bur or file.
For those in the laser group, no GP consultation will be necessary and they are able to begin treatment. Treatment will involve cutting, debriding and reducing the nail as much as possible by the podiatrist, followed by a 30 minute session with the laser where the affected area is heated to 55oC in short increments or as tolerated by the patient. Some mild discomfort is expected when applying the laser.
At the beginning of the trial and every subsequent follow up appointment, patients will be asked to give a 1-10 rating on the appearance of their nail. An additional culture and microscopy will also be done at each visit. All appointments will take place in the Sydney clinic. A photograph will be taken and measurements of the fungal infection recorded.
2.3.1 Recruitment
Advertising will be done through placement of flyers and posters in all local private podiatrists, medical practices and public health clinics within a 5km radius of the trial clinic. The trial would also be discussed in depth with the people working within those clinics, so that they may suggest the trial to any patients who fit the trial criteria. Participation is entirely voluntary.
2.3.2 The randomisation scheme
Participants will be randomized through the use of a computer generated system. This will be achieved by participant 1-120 being randomly allocated a number that corresponds to an intervention group.
2.3.3 Blinding
Providers: The care providers will not be blinded as they will need to provide the treatments and monitor the progress through clinical judgement. They will also have to organise a GP consult for the patients that are in the topical group so they can receive more medication.
Assessors: Assessors can be blinded as to which intervention the patient received when conducting the final assessment at the conclusion of the study.
Participants: Participants will be blinded as to what intervention they are receiving. Both groups will be under the impression that they are receiving the intervention being trialled. They will be unaware there is another group.
2.3.4 Baseline data
Each nail will be assessed and defined as:
Mycological infection: Positive potassium hydroxide microscopy and positive culture
Clinical infection: Clinical signs of infection (subungual hyperkeratosis, white or yellow streaks present, crumbling of the affected nail)
Patient satisfaction with the current cosmetic appearance of their affected nail rated 1-10 on the Verbal Analogue Scale (VAS).
2.3.5 Intervention
Group 1: Laser group. Patients here will receive a 30minute laser therapy session once a month, as well as nail reduction.
Group 2: Medicinal group. Patients in this group will apply efinaconazole 10% nail lacquer once daily and receive monthly nail reduction.
Participants will be excluded from the study if they begin any additional treatment for their onychomycosis.
2.3.6 Outcome assessments
Monthly reviews of participants will assess cure rates, reduction in visible area of the affected nail and patient satisfaction. The outcomes will be compared to the results of the baseline assessments at monthly intervals.
2.3.7 Withdrawal criteria
Participants are free to withdraw for any reason throughout the entirety of the trial. Participants who withdraw will be invited to give a reason for their withdrawal, but this will be entirely voluntary.
The clinicians may exclude a participant from the trial if the participant has:
- Commenced another form of treatment for onychomycosis;
- Failed to attend two or more appointments;
- Not been applying the topical antifungal treatment for a significant period (1 month)
2.3.8 Statistics and data analysis
Some previous studies performed around onychomycosis treatments have been smaller sample sizes and results cannot always be generalised. Therefore, this study aims to recruit a larger sample size, with 120 participants, with 60 in each intervention group. This is a feasible number as onychomycosis is the most common nail disorder in the population.
2.3.10 Human Research Ethics Committee (HREC) review
Research will be approved by the University of Newcastle ethics committee prior to any research taking place. All necessary changes will be made to the research proposal if needed. Participants will sign a consent form clearly explaining the goals of the study, activities requested of participants and participant rights.
3 LIMITATIONS
Time of study:
Being such a long study, the potential drop-out rate and loss to follow-up is potentially high. People are often changing jobs, moving or having health or personal issues that may require them to withdraw from the study. An appointment every month is also quite demanding in terms of ensuring they are always able to attend the clinic.
Subjective information:
Relying on the patients score on the VAS to monitor their satisfaction with the appearance of their nails is subjective. Personality types vary significantly and nail appearance might be more important to some than others, leading to them reporting greater dissatisfaction.
Pain during treatment:
The laser treatment causes a small amount of discomfort. Those with lower pain thresholds may not have their fungal nail heated to the correct therapeutic temperature (55oC) and therefore the treatment effect might not be achieved.
Compliance:
This trial relies on compliance for testing the topical antifungal arm of the study. Lacquer must be applied daily and participants could potentially forget, which could reduce the number of cures achieved from this group and give a lower rate of success. Also all patients are required to help treat their fungal nail by giving the treatments the right environment to take effect. This means treating shoes and socks, drying feet properly, avoiding public showers or pools and also cleaning their own bathrooms more diligently. Some patients are unlikely to do this, and hence would reduce the effectiveness of the interventions.
Measured outcomes:
Diagnostic ability of the hydroxide microscopy and cultures are also questionable, with many false negatives occurring due to operator error and mishandling of samples. Clinical signs are also dependent on the practitioner, and a more experienced practitioner may clinically diagnose onychomycosis when a less experienced one would not.
4 POTENTIAL SIGNIFICANCE
The results achieved during this study have the potential to improve evidence based practice for the treatment of onychomycosis and can potentially improve patient outcomes. It may also determine the amount of treatments needed to achieve various cures, and patients’ satisfaction. Laser therapy offers a shorter, easier treatment protocol (albeit more uncomfortable) than a nail lacquer protocol followed daily for a year. Laser therapy is increasing in popularity and may have a reduced cost, depending on the number of sessions required needed in contrast to the expensive efinaconazole topical lacquer.
5 REFERENCES
Bristow, I. (2014). The effectiveness of lasers in the treatment of onychomycosis: a systematic review. Journal Of Foot And Ankle Research, 7(1). doi: 10.1186/1757-1146-7-34
Espírito Santo, R., & Deps, P. (2018). Case Study of Onychomycosis Patients Treated with 1,064-nm Nd:YAG Laser. Case Reports In Dermatology, 10(2), 216-225. doi: 10.1159/000492526
Faergemann, J., & Baran, R. (2003). Epidemiology, clinical presentation and diagnosis of onychomycosis. British Journal Of Dermatology, 149(s65), 1-4. doi: 10.1046/j.1365- 2133.149.s65.4.x
Fungal nail infections | DermNet New Zealand. (2018). Retrieved from https://www.dermnetnz.org/topics/fungal-nail-infections/
Gupta, A., & Simpson, F. (2012). New therapeutic options for onychomycosis. Expert Opinion On Pharmacotherapy, 13(8), 1131-1142. doi: 10.1517/14656566.2012.681779
Hochman, L. (2011). Laser treatment of onychomycosis using a novel 0.65-millisecond pulsed Nd:YAG 1064-nm laser. Journal Of Cosmetic And Laser Therapy, 13(1), 2-5. doi: 10.3109/14764172.2011.552616
Hull, P. (1997). Onychomycosis – Treatment, Relapse and Re-Infection. Dermatology, 194(1), 7-9. doi: 10.1159/000246174
Lipner, S., & Scher, R. (2018). Part II: Onychomycosis: Treatment and Prevention of Recurrence. Journal Of The American Academy Of Dermatology. doi: 10.1016/j.jaad.2018.05.1260
Markinson, B., Monter, S., & Cabrera, G. (1997). Traditional approaches to treatment of onychomycosis. Journal Of The American Podiatric Medical Association, 87(12), 551-556. doi: 10.7547/87507315-87-12-551
Robres, P., Aspiroz, C., Rezusta, A., & Gilaberte, Y. (2015). Usefulness of Photodynamic Therapy in the Management of Onychomycosis. Actas Dermo-Sifiliográficas (English Edition), 106(10), 795-805. doi: 10.1016/j.adengl.2015.10.019
Singal, A., & Khanna, D. (2011). Onychomycosis: Diagnosis and management. Indian Journal Of Dermatology, Venereology, And Leprology, 77(6), 659. doi: 10.4103/0378-6323.86475
Vlahovic, T., Joseph, W., Scher, R., Tosti, A., Plasencia, J., Pariser, D., & Markinson, B. (2018). Diagnosis and Management of Onychomycosis. Journal Of The American Podiatric Medical Association, Vol 106(2), 155-162.
