A Compendium of Intralesional Therapies in Nail Disorders

Abstract

Nail unit is a complex skin appendage offering natural barrier to drug penetration by virtue of its unique anatomy. This is the reason why topical as well as oral therapies can be largely ineffective when dealing with nail diseases. Intralesional (injectable therapies) offer a practical solution in this scenario. This review aims to summarise the role of different injectable drugs in various nail unit disorders. Various types of intralesional therapies in the nail unit, their techniques of administration, appropriate drugs to be used and optimum treatment protocols are summarised.

Introduction

The nail is a complex skin appendage. Being one of the most visible appendages, its disfigurement has a significant impact on the self-esteem and self-image of the sufferer. Hence, it becomes imperative to treat nail afflictions because the patients specifically request for it. However, at the same time, the unique anatomy of the nail ensures that there are difficult to penetrate, sanctuary sites within the nail unit. For example, the proximal nail fold formed by a double layer of skin, thrown back upon itself [Figure 1] protects, and largely masks the underlying nail matrix. Similarly a thick, relatively impervious nail plate overlies the nail bed epithelium. As a result, the germinative portions of the nail unit (largely the nail matrix; and to a much lesser extent, the nail bed) are both shielded very effectively against environmental insults. Paradoxically, this very protection comes in the way of effective drug delivery for treating dermatoses affecting the nail unit. Thus, for an effective topical therapy across the nailplate, ungual drug permeation needs to be enhanced.[1]

Figure 1.

Sagittal section of the nail unit. The germinative portions (mainly the nail matrix and to some extent the nail bed) are effectively shielded from topical drug penetration

There is a significant risk of treatment failure when it comes to treating nail disorders. We know that upto 20–30% cases of onychomycosis fail to respond to treatment with systemic, topical or combination drug therapy with the very same drugs which are otherwise effective against the fungi invitro.[2] This is mostly due to a poor bioavailability at the affected sites within the nail unit. Other conventional modes of therapy, including phototherapy, do not work that well in the nail unit either. Additionally, prolonged duration of treatment and antecedent risks involved with systemic therapy means that it may not be justifiable for patients with predominant or isolated nail involvement. To ensure optimal bioavailability of effective medications, this compromised conventional drug delivery in nail diseases needs to be circumvented. The present review aims to offer practical solutions to this end.

Intralesional Therapy in Nail Disorders

Over the years, various methods have been used to enhance drug delivery within the nail unit. These are summarised in Table 1. Among these, intralesional administration of drugs is a form of ‘targeted therapy’offering specific advantages in this complex appendage. As explained above, the germinative portion of the nail unit needs to be targeted for treating inflammatory nail dystrophies and the best way to reach it is injectable administration of drugs. This bypasses the need for systemic administration (thus minimising potential systemic side effects) or topical administration (which is anyways highly compromised). It aids deposition of a drug depot ensuring prolonged action at the site where it matters the most. The rationale for intralesional therapies in nail disorders is summarised in Table 2.

Table 1.

Various methods used to enhance drug delivery within the nail unit

Table 2.

Rationale for intralesional therapy in nail disorders

Preparation for the procedure

As the administration of nail injections is expected to be moderately painful under the best of circumstances, as well as excessively painful for some; the patient is to be prepped accordingly. Most of the patients would agree to try out the injections and continue to take them at prescribed intervals without requesting for anaesthesia (author's personal experience). For those requesting pain relief there are various techniques and tricks available to minimise procedure-related pain. These are summarised in Table 3.

Table 3.

Tips and tricks to minimise pain during nail injections

Contraindications to injectable therapies

There are no absolute contraindications to this form of therapy. However, one should be careful about any visible focus of infection at the site or in the vicinity (even though injectables are often used for infectious conditions like warts and chronic paronychia). Signs or symptoms of peripheral ischaemia or peripheral vascular compromise should always be ruled out. The use of sterile needles is imperative to prevent the spread of blood-borne infections including the dreaded HIV.

Expectation alignment

A key aspect while starting intralesional drug therapy in nail unit is to provide realistic expectations to the patient. They should be made to understand the need for prolonged duration of therapy and monthly follow-ups. It should be impressed upon them that practically no improvement may be visible for the initial 2–3 months (or even longer in toe nails). The need for maintenance therapy in most of the inflammatory nail dystrophies should also be explained; as well as the possibility of suboptimal or no response needs to be reinforced.

Drugs found useful for injection in the nail unit

Over the years, various drugs which have been tried for injecting in the nail unit are summarised below:

1. Triamcinolone acetonide (TA):[13,14,15] Intralesional TA in the proximal nail fold has been used as a treatment modality in patients with trachyonychia/twenty-nail dystrophy, nail lichen planus or nail psoriasis. It is used in strengths varying from 2.5–10mg/ml. Predominant side effects include proximal nail fold hypopigmentation and atrophy. TA injected into the proximal nail fold area is a useful, cheap and efficacious treatment for dermatoses affecting the nail unit

2. Methotrexate:[16,17,18] It has been used in cases with nail psoriasis, not responding to other commonly used treatment modalities. Side effects include pain and slight injection site discolouration. There is also a need to keep track of the cumulative dose to assess systemic effects. Nail bed injections of methotrexate are a safe and effective therapy for isolated nail psoriasis with both the nail bed and the matrix changes responding well

3. Terbinafine:[19] Intralesional administration of controlled-release microspheres incorporating terbinafine has been tried as an alternative mode of treating onychomycosis. This is a single study evaluating such a formulation

4. Bleomycin:[20,21,22,23,24] Intralesional bleomycin has been used as an effective treatment for periungual warts. Bleomycin hydrolase responsible for inactivating the drug is found in very small amounts in skin. Thus a significant amount of the active drug becomes available at the site of action when injected intralesionally. It can be injected by multiple-puncture technique using a bifurcated vaccination needle; however, intralesional administration as detailed below has been found to have a very high success rate.[23] Potential side effects include extravasation into normal skin, extensive necrosis, scarring, pigmentary changes, nail damage and Raynaud's phenomenon[24]

5. Measles, Mumps and Rubella (MMR) Vaccine:[25] This offers a safe and effective immunotherapy tried in cutaneous warts by eliciting a strong immune response against human papillomavirus (HPV). The same can be used for ungual warts as well. The technique is simple and cost-effective with good efficacy and tolerability, less side effects and lower relapse rate

6. Cyclosporine:[18] Intramatricial cyclosporine has rarely been used in nail psoriasis in the dosage of 50 mg/ml. In a recent study conducted by Mittal and Mahajan, it was reported that difference in efficacy of intramatricial TA, methotrexate and cyclosporine in nail psoriasis, was not statistically significant. However, methotrexate yielded the best results with the maximum number of nails showing complete recovery.[18] On the other hand, nails treated with intramatricial cyclosporine demonstrated the maximum number of side effects, including severe pain which can decrease patient compliance

7. Vitamin D3:[26] This is a form of immunotherapy for warts. Vitamin D3 (0.2 ml, 15 mg/ml) is injected at the base of the wart after giving local anaesthesia. The injections are repeated at 2 weekly intervals till wart clearance. The authors had demonstrated good amount of clearance in cutaneous warts as well as a few periungual warts.[26]

Techniques for Intralesional Therapy

Depending on the targeted area of drug administration, intralesional therapy in nail diseases can be of various types. The nail being a complex appendage, different parts of the nail unit impact the growth of nail plate differently. This can be easily deciphered by a trained observer. For example, changes in the nail plate (like pitting or onychorrhexis) are a result of inflammation affecting the nail matrix which thus needs to be treated. Similarly, nail bed changes like onycholysis, subungual debris or salmon patch necessitate the site of administration to be the nail bed. The predominant clinical feature along with the type of injection required are summarised in Table 4.

Table 4.

How nail features guide the mode of injectable therapy

Once the appropriate site for treatment is chosen, it further determines the mode of administration and type of injection to be given. The procedure to be followed for various intralesional nail injections and the expected results are summarised below.

Intramatricial therapy (nail matrix injections)

This involves direct administration of the drug into the nail matrix area.

Indications

Dermatoses affecting the germinative nail matrix, e.g., nail psoriasis, nail lichen planus and trachyonychia.[27] The nail changes which suggest the need for treating nail matrix are summarised in Table 4.

Drugs administered

TA (2.5–10 mg/ml) is the most commonly administered drug by this route. There are reports of methotrexate (25 mg/ml) and cyclosporine (50 mg/ml) also being used with good efficacy.[18]

Procedure

The patient is explained the procedure and expected results beforehand and an informed written consent is taken. For consenting patients, a complete pre-procedure evaluation and photographic documentation is done prior to starting injections.

The injections are preferably given with the patient in a lying down position. We generally ask the patient to lie prone and extend the hand/foot to be injected towards the operator. These injections are administered with a 1ml syringe. We prefer the use of insulin syringes as they have a longer needle designed for ‘subcutaneous administration’ of insulin as compared to the tuberculin syringe which is designed for ‘intradermal administration’. Most commonly a 30–31 G needle with 6–8mm length is chosen. The needle should be built-in the syringe to enable injection under pressure, preventing any needle dislodgement or backsplash.

The local area is cleaned with spirit and povidone iodine. The point of injection is 2mm below and lateral to the junction between the lateral and proximal nail folds. We inject with the needle entering almost parallel to the skin surface; inserting it further till there is a feeling of loss of resistance. The needle is advanced upto the middle of PNF [Figure 2]. An aspiration is attempted to ensure that no blood vessel has been entered accidentally. Thereafter, the drug is slowly infused to raise a semilunar blanch arising from the lunula. This blanch is the endpoint of injection and no more than 0.1–0.2 ml of the drug can usually be administered in an average sized nail (personal observation) [Figure 3–c]. After withdrawing the needle, sustained pressure is maintained at the injection site for 1–2 min to ensure adequate haemostasis which prevents subungual haematoma formation.

Figure 2.

Schematic diagram of intramatrix injections. The arrow represents the direction of entry of the needle while the arrow head shows the final position of the bevel underneath the proximal nail fold. The green zone is the expected area over which the drug is infiltrated

Figure 3.

Steps of intramatricial injection. (a) 30G needle with built-in insulin syringe is parallel to the skin with the bevel side up. (b) The needle has entered and the bevel is now placed in the matrix area. (c) The blanch arising from the proximal nail fold and covering the lunula can be well appreciated

The injections are generally repeated at 4 weekly intervals initially (shorter intervals for methotrexate), till a desired improvement is seen. Thereafter, the frequency of injections is reduced, i.e., the inter-injection interval is prolonged to 6–8 weeks to enable maintenance of response and prevention of relapses. Periodic photography (preferably before each administration) helps in monitoring progress and detecting development of side effects.

Results

Representative results are demonstrated in Figure 4a–c.

Figure 4.

Response to intramatricial triamcinolone injections in nail lichen planus. (a) Patient with nail lichen planus with involvement of the proximal nail fold and prominent matricial changes. (b) Improvement seen at the end of 2 months. (c) At the end of 6 months

Intrabed therapy (nail bed injections)

This involves direct administration of the drug into the nail bed area and is reserved for cases showing more distal changes in the nail unit.

Indications

Indications for this form of therapy include dermatoses affecting the sterile nail matrix or the nail bed. Most common among these is nail psoriasis with characteristic changes like salmon patch, oil-drop sign, distal onycholysis and subungual hyperkeratosis. The more distal the change is, the less likely it is to respond to intramatrix injections.[16] Another disorder producing prominent nail bed involvement is nail lichen planus.

Drugs administered

TA (2.5–10 mg/ml) is the most commonly administered drug. Methotrexate has also been used.[16,17,18]

Procedure

Nail bed injections are expectedly more painful than nail matrix injections. This is because the nail bed is an enclosed compartment, hence, more sensitive to drug infiltration. Also, the needle needs to reach a more distal area than the nail matrix injections. should.[14,28]

The pre-procedure evaluation, consent and documentation remain the same as that for nail matrix injections. The injections should be given with the patient in a lying down position and are administered with 1ml insulin syringe, with built-in longer needle. The proximal nail fold is cleaned and prepped. The point of injection is slightly more medial than the nail matrix entry point while the angle of insertion remains the same [Figure 5]. The needle is directed towards the digital tip and advanced towards the centre of the nail bed, carefully avoiding the ungual process on the way [Figure 6a–c]. After attempting aspiration the intended drug is slowly infused to raise a more distal blanch in the nail bed area, this being the end point of injection. Roughly 0.1–0.2 ml of the drug can usually be administered in an average-sized nail (personal observation). Sustained pressure after withdrawing the needle is essential to ensure adequate haemostasis. The injections can be repeated at 4 weekly intervals like nail matrix injections and then spaced out as above.

Figure 5.

Schematic diagram of intrabed injections. The arrow represents the direction of entry of the needle while the arrow head shows the final position of the bevel underneath the nail plate. The green zone is the diamond-shaped area of drug infiltration

Figure 6.

Steps of intrabed injection. (a) 30G needle with built-in insulin syringe is positioned more medially with the bevel side up. The needle enters parallel to the skin surface. (b) The needle has been inserted and is in situ for final drug infiltration. (c) The blanch in the nail bed area can be seen. It marks the endpoint of the injection

Results

For disorders like nail bed psoriasis with prominent distal onycholysis and subungual hyperkeratosis, nail bed injections produce effective results [Figure 7a–c]. Nail bed methotrexate injections have been particularly found useful [Figure 8a–c].

Figure 7.

Response to intrabed triamcinolone injections in nail psoriasis. (a) Patient with nail psoriasis showing predominantly distal changes in the form of distal onycholysis, subungual hyperkeratosis and splinter haemorrhages. (b) Improvement seen after two sittings at 4 weekly intervals. (c) At the end of 6 months

Figure 8.

Response to intrabed methotrexate injections in nail psoriasis. (a) Another patient with prominent nail bed changes. (b) Improvement seen after three sittings at 3 weekly intervals. (c) At the end of 15 weeks. Notice the dot like discolouration in the nail bed which was the point of infiltration of methotrexate

Hyponychial injections

Indications

This approach is even more painful and is not routinely recommended,[29] It can be used under digital anaesthesia, especially to target inflammatory nail changes like distal onycholysis and subungual hyperkeratosis. This is because, for very large nails like the great toenail, even nail bed injections may not be very effective in infiltrating the drug upto the affected distal nail bed. Similarly for distally placed subungual warts, the hyponychial entry may be used.

Drugs administered

TA (inflammatory nail diseases) and bleomycin (warts) can be used.

Procedure

Being a more painful process, it is recommended to give this injection under digital anaesthesia.[29]

After giving a proximal digital block (at the base of the digit bilaterally), it is advisable to wait for 5–10 min before the digital anaesthesia takes effect. Insulin syringe is used with the patient in a lying down position.

The distal nail fold and subungual area (hyponychium) is cleaned with alcohol and povidone iodine. The point of injection is in the middle of the distal nail fold (about 1–2mm below the nail plate) [Figure 9]. The needle is inserted perpendicular to the distal nail fold and then advanced proximally to ensure that the tip infiltrates the drug in the affected nail bed. Sustained pressure on the digital tip is again needed after withdrawing the needle to ensure adequate haemostasis.

Figure 9.

Schematic diagram of hyponychial injections. The arrow represents the needle entering from the distal nail fold, beneath the distal free edge of the nail plate. Depending on the length of penetration, the green zone shows the area of drug infiltration

Results

For distal onycholysis with nail bed psoriasis this technique of injection may be particularly useful [Figure 10a–c].

Figure 10.

Response to hyponychial methotrexate injections in nail psoriasis. (a) There is predominantly distal nail loss with scaling involving the distal nail folds. (b) Improvement seen after two sittings at 3 weekly intervals. (c) At the end of 15 weeks

Translesional injections

Indications

Translesional administration of drugs is needed for space occupying lesions in the nail unit. This includes periungual or subungual warts or myxoid pseudocysts arising under the proximal nail fold.

Drugs administered

Bleomycin (1–3 U/ml) has been extensively studied for warts in ungual location; while TA (10–40 mg/ml) injections aid the regression of smaller myxoid pseudocysts. Vitamin D3 (0.2 ml, 15 mg/ml) has also been injected in periungual warts.[26]

Procedure

With the patient in a prone position, and the affected hand being extended towards the operator, the needle is inserted into the substance of the lesion (wart or cyst). Thereafter, the solution is injected under pressure [Figure 11]. To prevent needle dislodgement or backsplash, it is imperative that a Luer-locked syringe or insulin syringe with a built-in needle is used. The backsplash is particularly likely during bleomycin injections in warts due to the fissured surface of warts (personal observation). Thus, it is advised to use eye protection during this procedure. The amount of drug to be infiltrated is dependent on the size of the lesion being injected. For bleomycin injection in warts, the endpoint is blanching/yellowish appearance of the wart. For larger warts, multiple injections may be needed to adequately infiltrate all the sectors. The injection of triamcinolone in a myxoid pseudocyst produces its blanching and swelling.

Figure 11.

Schematic diagram of translesional injections. The arrow represents the needle position, which enters the affected area, in this case the subungual and periungual warts. Appropriate angulation depending on the vertical dimensions of the lesion is used for entry. Depending on the depth and length of penetration, the green zone shows the area infiltrated by the drug injected

Translesional multiple punctures have been used by some authors to distribute the drug throughout the wart tissue. The depth of the injection is controlled in this technique, thus avoiding accidental administration into the dermis. However, this technique cannot be employed for wart tissue covered under the nail plate, leading to lower efficacy and higher recurrences. Translesional administration hence remains the procedure of choice.

There are isolated reports of a controlled-release drug delivery system which can be injected in the nail unit. It involves the use of injectable, biodegradable polymer [poly (lactide-co-glycolide) (PLGA) microspheres] which can be injected intralesionally.[9] These drug-impregnated polymers then ensure a controlled and sustained release of terbinafine for prolonged periods which is required for treating onychomycosis. This has been projected as a potential alternative mode of treatment.[19]

Results

Some of the results produced with translesional drug administration of bleomycin [Figure 12a and b] and triamcinolone [Figure 13a–c] are shown.

Figure 12.

Response to translesional bleomycin injections in ungual warts. (a) Multiple and variable sized subungual and periungual warts in the distal and lateral nail folds, causing marked distal onycholysis and lifting up of the nail plate. (b) Improvement seen after eight injections at 2 weekly intervals. Most of the lesions have completely resolved. However, there is persistence of subungual discolouration suggestive of subungual haematoma or trapped debris

Figure 13.

Response to translesional triamcinolone injections in a pseudo-myxoid cyst. (a) A large pseudo-myxoid cyst arising under the proximal nail fold and producing pressure induced changes in the nail plate. (b) Intralesional triamcinolone acetonide produces blanching and distension of the cyst. (c) At the end of 2 weeks, there is substantial reduction in the size of the lesion

Dermojets are high pressure, needleless injection techniques. Some patients prefer these due to less pain caused as compared to injectable therapy,[30]; However, use in clinical practice is not very common.[28] The probable reasons include varying efficacy of different devices and the risk of side effects like backsplash and spread of infections, formation of epidermal inclusion cysts and so on.[30,31]

The efficacy of intralesional therapies in nail unit have been evaluated sparsely over the years. Table 5 summarises the studies available in this regard with different drugs being used for various nail unit diseases.

Table 5.

Efficacy of intralesional therapy in various nail disorders

Side Effects of Intralesional Therapy

The main disadvantage of intralesional injection in nail unit is the pain experienced at the site of injection. This is also the major reason for lower patient compliance and relatively poor acceptability in general dermatologic practice. Other than this, sideeffects are minimal. At times, subungual haematoma formation can occur, the incidence of which can be minimised by ensuring appropriate haemostasis after withdrawing the needle [Figure 14]. Proximal nail fold hypopigmentation and/or atrophyhave been seen with injections of TA [Figure 15a and b]. Matrix injections may occasionally produce deleterious effects causing disturbed nail growth. However, all these complications are largely preventable and fortunately reversible. The risk of hypersensitivity reactions has to be kept in mind and prior history needs to be carefully sought. Apprehensive patients may experience vasovagal syncope occasionally; hence the injections should be administered in a proper setup, with adequate positioning of the patient as well as readiness to handle dermato-surgical emergencies. Nicolau syndrome following intramatricial triamcinolone has been reported as a rare complication.[38]

Figure 14.

Subungual haematoma seen post-nail bed injections

Figure 15.

(a) Hypopigmentation and atrophy involving the proximal nail fold seen secondary to intramatricial injections. (b) Partial resolution and improvement can be seen after 2 months

Conclusions

In the present era of ‘injectables’, intralesional/injectable therapies in nail unit offer a viable method of ‘targeted administration’ of drugs. Drugs like TA, methotrexate or bleomycin can be effectively administered to the affected part of the nail unit. Careful precautions and preparation with thorough attention to the injection technique is very useful in optimising treatment outcomes and minimising side effects associated with the procedure. Though they are commonly used, there is very less data available in literature as of now, regarding their efficacy. Future controlled studies comparing injection techniques or treatment protocols can help standardise these treatment options.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.