Safety And Efficacy Of Tazarotene Health And Social Care Essay

Nail involvement is a common, devastating and embarrassing feature in the course of psoriasis. Nail psoriasis has a substantial psychosocial impact that affects quality of life as a result of pain, poor cosmetic appearance and diminished self-esteem. The associated pain in turn can lead to a decline in activities of daily living. Treatment results for nail psoriasis are almost always unsatisfactory and until now there is no standardized treatment regimen. Although much advancement has been made in the management of the disease, nail psoriasis continues to pose a challenge to the dermatologist. Consequently, new approaches to this condition should be investigated.

Psoriasis, a common, inflammatory, multisystem disease, is often viewed negatively by many cultures. It is a chronic skin disease that affects millions of people throughout the world. Influenced by both environmental and genetic factors, the prevalence of this multi-factorial disease in the United States is estimated to be between 2.1% and 2.6%. [1] In the Philippines, an estimated 1 to 2% or between 1 to 2 million of the Philippine population are affected. [2] 

Beyond an incapacitating skin ailment with a large negative impact on health related quality of life, psoriasis is now linked with a number of systemic and behavioral co-morbidities in many patients. [3] Its burden extends beyond physical manifestations and includes significant social, behavioral, and psychologic consequences. It impairs sleep, walking, sitting and standing for long periods, sexual activities, and performance of occupational responsibilities especially with the use of the hands. [4] It usually involves several nails of both fingernails and toenails.

While skin manifestations are the most characteristic findings of psoriasis, nail involvement is an often-overlooked clinical symptom of the disease. Approximately 50% of all patients develop characteristic nail changes as a clinical correlate of psoriatic inflammation of the nail matrix and/or nail bed. [5] If left untreated it may progress to an encumbering nail disease, which leads to significant functional impairment. The incidence cumulatively increases to 80-90% over a life time. [6] 

There is a relatively broad spectrum of manifestations related to nail psoriasis since the clinical signs associated with it can be attributed to a number of specific structures within the nail unit. It ranges from pitting and crumbling of the nail plate to discoloration and hemorrhages within the nail bed. One study by Tham et al [7] showed that pitting was the most common sign of psoriasis, followed by onycholysis then subungual hyperkeratosis and nail bed discoloration as the least common.

The most commonly used method to assess the severity of nail involvement is the Nail Psoriasis Severity Index (NAPSI). It is a reproducible, numeric, objective tool to evaluate the severity of nail matrix psoriasis and nail bed psoriasis by area of involvement in the nail unit. The NAPSI is used during clinical trials for assessing response to treatment of psoriatic nails. A modified NAPSI was proposed to allow clinically meaningful nail changes to be captured consistently and reliably just as Psoriasis Area and Severity Index (PASI) has been shown to be effective with high overall interrater and intrarater reproducibility.

In an interview with 1,728 patients with psoriasis last 1996 by Baran [8] , 93% of cases considered nail psoriasis a significant cosmetic handicap, 58% found that it interfered with their job and 52% had pain as a symptom. Nail psoriasis tends to be persistent and refractory to treatment, and so it is comprehensible that a standardized therapeutic regimen does not currently exist. [9] Therapeutic options for nail psoriasis are very limited and response to therapy can sometimes take years. A faster, better, and more sustained response to therapy in nail psoriasis have been described for systemic therapeutics and in particular for biologics. [10] 111213All these drugs have a serious toxicity potential.

Even though the use of topical medications is effective and safe on specific nail dystrophies, there remains a need for more well-documented and well-controlled studies within the literature. The conventional treatment options for nail psoriasis comprise topical vitamin D3 analogs [14] 1516and topical and intralesional corticosteroids. [17] 1819There are studies using anthralin, [20] retinoids, [21] 22235-fluorouracil, [24] cyclosporine, [25] and psoralen plus ultraviolet A [26] aside from the conventional therapy.

Current literature has shown significant findings for the use of topical therapy for nail psoriasis however available studies lack sufficient power to extrapolate a standardized therapeutic regimen. Recently, various articles have appeared reporting the usefulness of tazarotene for the treatment of nail psoriasis. [27] 22

Tazarotene is a selective retinoid that has established efficacy in clinical trials for the topical treatment of psoriasis. [28] 29It was seen to affect the pathogenesis of psoriasis through three major mechanisms: reduction in keratinocyte proliferation, normalization of abnormal keratinocyte differentiation, and a decrease in the expression of inflammatory markers. 29

Tazarotene exerts its effects in the primary abnormalities associated with psoriasis by normalizing epidermal differentiation and exhibiting a potent anti-proliferative effect. [30] Improvement of nail changes is probably due to the exertion of these well-documented properties on the nail bed cells and nail matrix. In the randomized controlled studies of Rigopoulos, et al 23 and Scher et al (22) it has been shown that tazarotene is a valuable topical drug with mild to moderate adverse events that which leads to prolonged remission.

The application of laser treatment for nail psoriasis had been studied since 2009 and was found to be well-tolerated and effective. The Pulsed Dye Laser or PDL is widely accepted for the management of vascular ectatic disorders. [31] It utilizes a concentrated beam of light that focuses at the blood vessels in the skin and nails. The light is able to travel through tissues and nail plates aims at specific targets without injury to adjacent normal skin or nail. It normalizes epidermal proliferation and reduces the number of cytotoxic T cells in the epidermis and helper T cells in the dermis which helps improve the clinical signs of psoriasis. [32] 33

The need for clinical trials and well-documented substantiation regarding these treatment options is imperative so as not to leave clinicians and patients with a vague and unverified approach to the best possible treatment for nail psoriasis. This study will determine the safety and efficacy of the use of Tazarotene 0.05% gel alone or in combination with the 595nm pulsed dye laser to a commonly ignored and challenging nail disease.

REVIEW OF RELATED LITERATURE

Psoriasis is an unremitting, incurable skin condition that causes considerable pain and morbidity. It varies significantly in severity, ranging from mild localized forms to more severe erythrodermic types. [34] While skin symptoms are the most characteristic manifestations of psoriasis, nail involvement is an often unnoticed entity of the disease. Fifty percent of patients with psoriasis have concomitant nail psoriasis, with a lifetime incidence of 80% to 90%. [35] Nail findings are more common in patients with psoriatic arthritis. [36] In patients with no diagnosis of psoriatic arthritis, 38% of children [37] and 39–46% of adults [38] and are reported to have nail involvement, as compared with 83–100% of patients with psoriatic arthritis. [39] 40

The fingernails are more often affected than the toenails which can be due to repeated trauma (Koebner phenomenon), particularly in manual workers. [41] Psoriasis can affect any element of the nail apparatus—nail matrix or bed, or both—and as a result will have varied clinical manifestations according to the affected part. [42] It has lately been shown that patients with nail psoriasis are negative for the HLA-Cw*0602 allele on chromosome 6, as well as being late-onset cases of psoriasis that display a severe course. [43] 

Although made up of dead, keratinized cells, the nail is functionally incorporated with the musculoskeletal system [44] that performs a myriad of functions. In the article by McGonagle et al, (44) they reviewed how the nail is physiologically linked to the numerous distal interphalangeal joint structures and distal phalanx, including the collateral ligaments and extensor tendon fibres. It has been proven that the collateral ligaments develop an integrated structure on the sides of the joint and the extensor tendon continues from its bony insertion to encase the nail root helping to attach the nail margins. This continuum of connective tissue structures join a thick periosteum on the distal phalanx with several cutaneous ligaments that attach the fatty pads of the finger pulp to the skin, explaining the close association of nail involvement in psoriatic arthritis. In addition to protecting the fingertips from injury, the nail plate exerts a pressure that opposes the volar side of the terminal phalanx, which contributes to the enhanced sensory discriminatory ability of the fingertips. [45] 

The nail unit comprises the nail plate and four epithelial structures: the proximal nail fold (a continuation of the digital skin that folds underneath itself to protect the matrix), the nail bed (the epithelium under the nail plate), the matrix (from which the nail plate arises), and the hyponychium (the epithelium underneath the free edge of the nail plate). Each of these epithelial structures can be affected by psoriasis over differing time scales, which accounts for the variability of the clinical presentation of nail psoriasis. Clinical studies tend to focus on nail matrix psoriasis and nail bed psoriasis. The former has the following four main characteristics: pitting (small depressions in the uppermost layers of the nail plate); leukonychia (smooth-surfaced lesions giving the nail a whitish appearance); red spots in the lunula; and nail plate crumbling. While the latter comprises: subungual hyperkeratosis ("nail thickening" with hyperproliferation of keratinocytes underneath the nail plate); onycholysis (separation of the nail plate and nail bed); oil-drop or salmon-spot discolouration (serum-filled lesions within the nail bed); splinter hemorrhages (minute lesions along the junction of the dermis and epidermis). [46] 

The nail psoriasis severity index (NAPSI) is a simple grading that includes extent of involvement and location in the nail unit of the psoriatic pathologic changes. It can be applied either to all of a patient's affected nails or to a specified target nail.  Simply put, live assessment of each quadrant of the nail is graded for the presence or absence of nail matrix disease (score 0-4) consisting of pitting, leukonychia, red spots in lunula, and nail plate crumbling and nail bed psoriasis (score 0-4) for the presence of oil drop [salmon patch] discoloration, onycholysis, nail bed hyperkeratosis, splinter hemorrhage and nail bed hyperkeratosis. The sum of the scores for all of the fingernails is the nail psoriasis severity score for that patient at that time. As an alternative, a target nail can be chosen and graded by means of evaluation for the presence of all 8 criteria in each quadrant of the nail (score 0-32). [47] (Fig. 1)

A more sensitive scoring system to assess nail disease activity is with the use of the mNAPSI. Parrish, et al [48] noted concerns that the original NAPSI might not have the sensitivity to capture meaningful clinical improvements. In addition to proposing a more qualitative system to improve sensitivity, they proposed using one target nail through photographic analysis, which would decrease the time needed to complete the assessment. The mNAPSI has high overall interrater and intrarater reproducibility but so far the modifications have not been validated. (Fig. 2)

A diagnosis of nail psoriasis is established clinically, and thus it is important to examine the rest of the skin in order to identify psoriatic plaques. Sometimes the only phenotypic manifestation of psoriasis is found in the nails but it is also common for nail psoriasis to coexist with lesions on the scalp and gluteal cleft and psoriatic arthritis. From a clinical point of view, the presence of oil spots, deep, irregular pits and onycholysis surrounded by a salmon stain is highly suggestive of psoriasis. 42

Treatment of nail psoriasis can be challenging for both the patient and the dermatologist. Response to therapy can sometimes take years because of the slow growth of the nail plate. The conventional treatment options for nail psoriasis include

intralesional and topical corticosteroids and topical vitamin D3 analogs. However, the difficulty in achieving adequate antipsoriatic concentrations at the site of the inflammatory process is limiting the feasibility of topical therapy. [49]  

Randomized trials on tazarotene for nail psoriasis have used the 0.1% gel or cream preparation. In the study entitled "Tazarotene cream in the treatment of psoriasis:

Two multicenter, double-blind, randomized, vehicle-controlled studies of the safety and

efficacy of tazarotene creams 0.05% and 0.1% applied once daily for 12 weeks" by Weinstein G., et al, [50] the authors found out that differences in clinical success rates between tazarotene 0.1% and 0.05% were generally not statistically significant. The 0.1% preparation is commonly associated with a fairly greater degree of local irritation than the 0.05%. [51] It is one of the primary aims of this study to evaluate the effectiveness and safety of tazarotene 0.05% gel, the only preparation available in the country at this time.

An electronic search through PubMed using the search term "tazarotene randomized controlled trial AND nail psoriasis" yielded three hits. Scher et al (22) have shown that tazarotene was consistently more effective than vehicle in reducing onycholysis in occluded nails and non-occluded nails at week 24; tazarotene was also more effective than vehicle in reducing pitting in occluded nails. However, outcome measures for the said study did not include the nail psoriasis severity index (NAPSI) which is the standard assessment system for the condition. There was also no mention of percentage of patients achieving clinical goals.

Rigopoulos et al 23 undertook a study in which 46 patients with nail psoriasis were randomly assigned to 2 groups, one treated with 0.1% tazarotene cream under occlusion each night for 12 weeks and the other treated with 0.05% clobetasol propionate cream under the same conditions. They observed a significant time-effect improvement in subungual hyperkeratosis, onycholysis, oil spots, and pitting in both groups after 12 weeks of treatment. The authors used an independent scoring for target nails but only for four out of the eight parameters studied in NAPSI.

In a randomized, open-label study by Bianchi et al, (27) 19 out of 25 patients showed good clinical response with Tazarotene 0.1% gel for the treatment of psoriasis of the fingernails and toenails. There was a statistically significant ‘Visual Assessment Score’ reduction for specific signs at 12 weeks from baseline.

Another search through PubMed using the terms "pulsed dye laser AND nail psoriasis" yielded three citations. All three studies showed compatible results suggesting that PDL treatment can be considered as an alternative treatment for nail psoriasis because it is safe, well-tolerated and efficacious showing good and sustainable improvement even after the study period.

Treewittayapoom, et al [52] compared the effect of different pulse durations in the treatment of nail psoriasis with 595-nm pulsed dye laser using intrapatient left-to-right comparison design in 20 patients with bilateral nail psoriasis. There was no significant difference found between the two pulse duration groups but more importantly, there was a significant reduction in overall NAPSI, nail matrix NAPSI, and nail bed NAPSI scores in both groups after six months.

In a study done by Fernández-Guarino and colleagues [53] last 2009 comparing pulsed dye laser and photodynamic therapy in 14 patients, a decrease in NAPSI score was observed with both treatments. No statistical differences were found between the two methods and between nail matrix and nailbed NAPSI scores.

Oram, et al [54] evaluated the effect of PDL alone in the treatment of nail psoriasis. Statistical analysis of NAPSI scores of five patients before and after treatment showed significant difference. The nail bed lesions like onycholysis and subungual hyperkeratosis responded best to the treatment. Lack of blinding and comparison and the small number of respondents are the limitations of the study.

A need for more randomized controlled trial is essential to validate the anecdotal reports of tazarotene and pulsed dye laser and combination therapy, as will be studied in this paper, for the treatment of nail psoriasis.

Definition of terms:

Nail plate- a rectangular, translucent, and relatively inflexible structure that overlies the distal digits of the hands and feet. It is a continuation of the skin of each digit (the dorsal surface) that folds underneath itself, resting above the nail matrix (the ventral surface) (Fig 3)

Nail matrix. The nail matrix, along with lesser contributions from the nail bed, is responsible for forming the entire length of the nail plate (Fig 4). It

can be divided into 3 regions: the dorsal section of the matrix contributes to the most superficial layers of the nail plate whereas the intermediate region of the matrix forms the deeper layers. Lastly, the ventral subdivision is the most distal part of the nail matrix and it is contributed by the nail bed.

Nail bed. The nail bed is the area underneath the nail plate that is between the lunula and the hyponychium

Hyponychium. The hyponychium is located underneath the free edge of the nail plate

Pits- or dimples in the nails are punctate depressions that are generally multiple and irregular. They are due to focal and transient disease of the proximal matrix and correspond to islands of parakeratosis that are eliminated when the nail appears, leaving behind a depression in the nail plate (Fig 5)

Leukonychia- a partial whitish coloration of the nail plate as a consequence of disease of the intermediate matrix (Fig 6)

Beau Lines- appear as transverse grooves, often deeper in the central nail plate, that move distally with nail growth (Fig 7)

Onycholysis- distal nail plate is lifted away from the nail bed and produces a whitish area of varying size that is surrounded by an erythematous collar or an "oil spot," a sign that is highly suggestive of psoriasis and helps to rule out other causes of onycholysis (Fig 8)

Subungual Hyperkeratosis- Along with onycholysis, subungual hyperkeratosis is a very common manifestation of nail psoriasis (Fig 9), and both may often be present in the same patient. It occurs as a result of excessive proliferation of parakeratotic cells that form a dense, pulverulent, whitish mass that causes distal lifting of the nail plate.

Oil Spots or Salmon Patches- the only lesions that are exclusive to nail psoriasis; they appear as round or oval orange colored areas in the center of the nail plate (Fig 10)

Splinter Hemorrhages- are linear and distal with a threadlike appearance (Fig 11)

Acropustulosis- presents with periungual or subungual pustules in the context of acrodermatitis continua of Hallopeau or, less often, localized or generalized pustular psoriasis (Fig 12)

Paronychia- is associated with erythematous scaly lesions that affect the proximal and/or lateral edges of the nail, generally alongside lesions of the matrix or nail plate (Fig 13)

RESEARCH QUESTION: Among Filipino patients with nail psoriasis, what is the safety and efficacy of Tazarotene 0.05% gel with monthly short-pulsed 595-nm pulsed dye laser vs. Tazarotene 0.05% gel alone in the treatment of nail psoriasis?

OBJECTIVES: GENERAL: To evaluate the safety and efficacy of Tazarotene 0.05% gel with monthly short-pulsed 595-nm pulsed dye laser vs. Tazarotene 0.05% gel alone in the treatment of nail psoriasis

SPECIFIC:

To evaluate nail changes using the nail psoriasis severity index (NAPSI) and modified nail psoriasis severity index (mNAPSI).

To determine the time to clinical response of Tazarotene 0.05% gel with monthly short-pulsed 595-nm pulsed dye laser vs. Tazarotene 0.05% gel alone in the treatment of nail psoriasis.

To determine the adverse effects of Tazarotene 0.05% gel with monthly short-pulsed 595-nm pulsed dye laser vs. Tazarotene 0.05% gel alone in the treatment of nail psoriasis.

To obtain patient satisfaction level at the end of the treatment period.

SIGNIFICANCE OF THE STUDY

Nail involvement is a common, devastating and embarrassing feature in the course of psoriasis. Nail psoriasis has a substantial psychosocial impact that affects quality of life as a result of pain, poor cosmetic appearance and diminished self-esteem. The associated pain in turn can lead to a decline in activities of daily living. Results of treatment of nail psoriasis are unsatisfactory and until now there is no standardized treatment regimen. Although much advancement has been made in the management of the disease, nail psoriasis continues to pose a challenge to the dermatologist. Consequently, new approaches to this condition should be investigated.

NULL HYPOTHESES:

1. There is no significant difference in safety and efficacy between TAZAROTENE 0.05% GEL WITH MONTHLY SHORT PULSED 595-nm PULSED DYE LASER and TAZAROTENE 0.05% GEL ALONE IN THE TREATMENT OF NAIL PSORIASIS ?

2. There is no significant difference in time to clinical response between Tazarotene 0.05% gel with monthly short-pulsed  595- nm pulsed dye laser and Tazarotene 0.05% gel alone in the treatment of nail psoriasis?

METHODOLOGY

RESEARCH DESIGN: This is an experimental, prospective, randomized, single-blind, intrapatient, left-to-right controlled trial.

SETTING: The study will be conducted at the Outpatient Clinic of the Department of Dermatology of Southern Philippines Medical Center (SPMC) and among the Psoriasis Club members of the said hospital from March-August 2013. The study will be approved by the Institutional Review Board of SPMC.

PARTICIPANTS

INCLUSION CRITERIA:

Male and female patients aged 18 to 75

In good general health with bilateral fingernail psoriasis affecting at least two fingernails with at least 3 of the following characteristics: pitting, onycholysis, subungual hyperkeratosis, leukonychia, nail plate crumbling/loss, splinter hemorrhages, or nailbed discoloration

Absence of topical or systemic treatment and/or phototherapy for nail psoriasis for at least four weeks

Negative direct mycological examination for fungus prior to the commencement of the study

EXCLUSION CRITERIA:

Clinical diagnosis of active psoriatic arthritis and pustular psoriasis of the nail apparatus including acrodermatitis continua of Hallopeau

Patients who are currently receiving topical antipsoriatic agents on the nail unit, systemic therapy or phototherapy for psoriasis for at least four weeks

Patients who are pregnant or lactating

Individuals who had a history of photosensitivity or keloid formation

Interventions and Comparisons

The initial screening will include medical history taking and physical examination. In cases that presented with subungual hyperkeratosis, onycholysis, or nail plate crumbling, or when onychomycosis was a differential diagnosis, a KOH preparation will be done. Psoriasis Area and Severity Index (PASI) score will be obtained at baseline. (Fig 14)

Right and left hands of patients will be randomly assigned to two groups. For the first group, Tazarotene 0.05% gel (Tazret) will be applied to the affected nail plates, periungual skin and surrounding nail folds with occlusion at bed-time for up to 12 weeks. Occlusion will be done after application of the cream, using a hypoallergenic tape provided by the researcher. Patients will be advised to trim their fingernails up to the hyponychium weekly or more frequently upon noticing nail growth from the hyponychium before Tazarotene is applied. The patients will be then be seen at weeks 2, 4, 8 and 12. Post-treatment evaluations will be performed by the researcher at weeks 16, 20, and 24.

The fingernails in the second group will be treated with monthly pulses of the 595-nm pulsed dye laser with the following parameters: 7-mm spot size, 0.45-millisecond pulse duration, fluence of 6 J/cm2, cryogen spurt of 20 milliseconds with a 10-millisecond delay. These parameters were implemented in the study done by Dr. Chanitwan Treewittayapoom, et al 52 which showed no significant difference in terms of efficacy between the longer and shorter pulse duration of the PDL. Ten percent overlapping of adjacent layers of spots will be applied, two passes on the lunula, and proximal and lateral nailfolds. This will be done on the day of enrollment to the study and after every four weeks for 12 weeks. Additionally, they will also be given Tazarotene 0.05% gel (Tazret) and will be directed to apply the medication in the same way as in group 1. However, they will be asked not to apply the Tazarotene 0.05% gel on the day of laser treatment and instead apply it the next day at nighttime as previously instructed. This will be observed for the entire duration of the study. Should there be any adverse events noted from the topical medicine, like peeling and erythema of nail folds, irritation of skin on finger, periungual irritation or paronychia among others, a rest period of one to two weeks will be allotted or as deemed necessary by the investigator.

Washout periods will be six weeks for intralesional corticosteroids and UVB or psoralen plus UVA phototherapy, four weeks for topical fingernail medications and investigational drugs and 12 weeks for systemic antipsoriatic medications.

Total and target NAPSI and mNAPSI scores and digital photography of the nails will be performed and taken at baseline and at every monthly visit for three months for both groups. It will be taken before the treatment session. A dermatologist who is not involved in the study protocol will do the assessment noting the clinical change after each treatment from live assessments and digital photographs, using the NAPSI and mNAPSI respectively.

For the NAPSI, the nail is divided with imaginary horizontal and longitudinal lines into four quadrants. Each quadrant is evaluated and scored for the presence or absence of nail matrix involvement (pitting, leukonychia, red spots in lunula, and nail plate crumbling) and nail bed involvement (onycholysis, splinter hemorrhages, oil drop [salmon patch] discoloration, and nail bed hyperkeratosis). The sum of these two scores is the NAPSI score. (See figure below)