EFFICACY OF TARGETED PHOTOTHERAPY IN IDIOPATHIC GUTTATE HYPOMELANOSIS
Dissertation Submitted to
THE TAMILNADU DR. M.G.R. MEDICAL UNIVERSITY
In the fulfilment of the regulations for the award of the degree
M.D. DERMATOLOGY, VENEREOLOGY AND LEPROLOGY BRANCH – XX REG. NO. 201730353
DEPARTMENT OF DERMATOLOGY, VENEROLOGY AND LEPROLOGY
PSG INSTITUTE OF MEDICAL SCIENCE AND RESEARCH THE TAMILNADU DR.M.G.R.MEDICAL UNIVERSITY CHENNAI,
TAMILNADU
MAY 2020 EFFICACY OF TARGETED PHOTOTHERAPY IN IDIOPATHIC GUTTATE HYPOMELANOSIS
In the fulfilment of the regulations for the award of the degree
M.D. DERMATOLOGY, VENEREOLOGY AND LEPROLOGY BRANCH – XX REG. NO. 201730353
GUIDE
Dr. SHANMUGASEKAR C, MD DEPARTMENT OF DERMATOLOGY, VENEREOLOGY AND LEPROLOGY
PSG INSTITUTE OF MEDICAL SCIENCE AND RESEARCH
THE TAMILNADU DR.M.G.R.MEDICAL UNIVERSITY CHENNAI,
TAMILNADU
MAY 2020
CERTIFICATE
This is to certify that the thesis entitled “EFFICACY
OF TARGETED PHOTOTHERAPY IN IDIOPATHIC
GUTTATE HYPOMELANOSIS” is a bonafide work of
Dr. KANNAN .P done under the direct guidance and supervision of
Dr. SHANMUGASEKAR .C MD, in the department of Dermatology,
Venereology and Leprology, PSG Institute of Medical Sciences and
Research, Coimbatore in fulfillment of the regulations of Dr.MGR
Medical University for the award of M.D. degree in Dermatology,
Venereology and Leprology.
Dr. REENA RAI Dr. RAMALINGAM Professor DEAN Dept. of DVL
DECLARATION
I hereby declare that this dissertation entitled “EFFICACY
OF TARGETED PHOTOTHERAPY IN IDIOPATHIC
GUTTATE HYPOMELANOSIS” was prepared by me under the direct guidance and supervision of Dr. SHANMUGASEKAR .C MD,
PSG Institute of Medical Sciences and Research, Coimbatore.
The dissertation is submitted to the Tamilnadu Dr.MGR Medical
University in fulfillment of the University regulation for the award of
M.D. degree in Dermatology, Venereology and Leprology. This dissertation has not been submitted for the award of any other Degree or
Diploma.
DR. KANNAN .P
CERTIFICATE BY THE GUIDE
This is to certify that the thesis entitled “EFFICACY
OF TARGETED PHOTOTHERAPY IN IDIOPATHIC
GUTTATE HYPOMELANOSIS” is a bonafide work of
Dr. KANNAN .P done under my direct guidance and supervision in the department of Dermatology, Venereology and Leprology, PSG
Institute of Medical Sciences and Research, Coimbatore in the fulfillment of the regulations of Dr.MGR Medical University for the award of MD degree in Dermatology, Venereology and Leprology.
Dr. SHANMUGASEKAR .C Professor Dept. of DVL
PLAGIARISM TOOL
CERTIFICATE – II
This is to certify that this dissertation work titled
“EFFICACY OF TARGETED PHOTOTHERAPY IN
IDIOPATHIC GUTTATE HYPOMELANOSIS” of the candidate Dr. KANNAN P. with registration Number
201730353 for the award of In the branch of MD degree in
Dermatology, Venereology and Leprology. I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion pages and results shows 14 percentage of plagiarism in the dissertation.
Guide & Supervisor Sign with Seal,
ACKNOWLEDGEMENT
The successful completion of my dissertation would not have been possible without the contribution of many people to whom, I would like to express my deep sense of gratitude.
First and foremost, I am very grateful to my guide,
Dr. Shanmugasekar .C for his timely advice and guidance at various stages of my dissertation.
I am very grateful to Dr. Reena Rai, Dr. Mahadevan K,
Dr. Priya S, and Dr. Setu Mittal for their continuous support and encouragement.
I would like to make a special mention of Dr. Ryan Raju,
Dr. Iyshwariya, Dr. Steffi, Dr. Geoni, Dr. Mohankumar Dr. Sri
Rathna Maheswari and Dr. Janani, Dr. Yuvasri who were not only wonderful seniors, but also very good friends. I would also like to thank my juniors Dr. Sudha, Dr. Krishna Priya, and Dr. Lakshmi
Prabha, Dr. Shenbagaraj, Dr. Harish, Dr. Nithya, Dr. Sushmitha,
Dr. Vinitha who helped me in the completion of my dissertation by taking care of my other responsibilities towards the department.
I would take this as a great opportunity to thank all my patients without whose consent, I would not have been able to complete this study.
I would like to exceptionally thank Dr. Anjali, Dr. Bede Anand,
Dr. Arunprasath, for always being there for me and for being a constant source of support and motivation.
I would be failing in my duty if I do not immensely thank my beloved parents for making me what I am today, and offering constant support all along without which this thesis would not have been completed.
TABLE OF CONTENTS
SL.NO. CONTENT PAGE NO.
1 INTRODUCTION 1
2 AIMS AND OBJECTIVES 2
3 REVIEW OF LITERATURE 3 - 65
4 MATERIALS AND METHODS 66 - 71
5 RESULTS 72 - 73
6 DISCUSSION 74 - 79
7 CONCLUSION 80
8 BIBLIOGRAPHY
9 ANNEXURES
Clinical Photographs
Consent Forms
Proforma
Master chart
List of Abbreviations
LIST OF TABLES
SL.NO. CONTENT PAGE NO.
DIFFERENTIAL DIAGNOSIS OF 1 GUTTATE LEUCODERMA 30
LIST OF FIGURES
SL. PAGE CONTENT NO. NO. 1 MELANOCYTE DEVELOPMENT AND 5 MIGRATION
2 MELANIN SYNTHESIS 8
3 MELANOSOME TRANSFER TO 10 KERATINOCYTES
4 EPIDERMAL MELANIN UNIT 11
5 DERMOSCOPIC APPEARANCE OF IGH 24
6 UVR DEPTH OF PENETRATION 42
7 EFFECTS OF PHOTOTHERAPY AND 43 PHOTOCHEMOTHERAPY
INTRODUCTION
INTRODUCTION
Idiopathic guttate hypomelanosis (IGH) is a commonly acquired guttate leukoderma, affecting the elderly population.(1) With multiple, discrete round to oval sharply defined round to oval depigmented porcelain – white macules, approximately 2-5 mm diameter.
Melanocytopenic hypomelanosis is considered to be the basic pathomechanism for idiopathic guttate hypomelanosis.
Clinical feautures include multiple, discreet round to oval, sharply defined hypopigmented to depigmented porcelain-white macules commonly over the extremities, usually ranging from 2-5 mm in diameter with increasing number with age.(2,3)
Commonly involved areas include extensor forearms and pretibial areas, usually sparing of the face and trunk.[3,4]
It is considered as a benign condition, patients typically seek medical attention for their cosmetic concerns only to be reassured regarding its natural course.
Treatment of this skin condition still remains unsatisfactory even though newer treatment modalities are being described.
AIM OF THE
STUDY
AIM OF THE STUDY
To assess the effect of a targeted phototherapy in idiopathic guttate hypomelanosis.
REVIEW OF LITERATURE
REVIEW OF LITERATURE
MELANOCYTES
Melanocytes are heterogeneous group of specialized cells of the human epidermis. They originate from embryonic cells named neural
5 crest cells (NCC) and produce the pigment called melanin .
During embryogenesis, Melanoblasts originate in neural crest, migrate first to dermis & then to basal lamina of epidermis.
Immunocytochemical marker studies with melanocyte‐specific antibody showed melanoblasts appear in epidermis by 7 weeks gestation.
In the human body melanocytes are present in basal layer of the epidermis, hair bulb and outer root sheath of hair follicle, and give a color of these structures. Melanocytes are also seen in the iris, inner ear,
6,7 nervous system, heart, adrenal glands and various organs .
They contain oval nuclei slightly smaller than that of surrounding keratinocytes. In hematoxylin and eosin (H&E)–stained sections they give processing artefact of a clear halo of cytoplasm.
The life cycle of melanocytes consists of multiple steps including:
1) Lineage specification from embryonic neural crest cells
(melanoblasts),
2) Migration and proliferation of melanoblasts,
3) Differentiation of melanoblasts into melanocytes,
4) Maturation of melanocytes (melanin production),
5) Transport of mature melanosomes to keratinocytes
6) And eventual cell death.
The embryonic origin of epidermal and hair melanocytes are similar but development is different 8,9.
The microscopic analysis of the mature melanocytes show oval or fusiform, dendritic cells, smaller than keratinocytes with clear halo of cytoplasm in H&E staining. Melanin is produced by melanosomes which are special membrane-bound organelles in the cytoplasm of melanocytes10.
Fig.1 MELANOCYTE DEVELOPMENT AND MIGRATION
One melanocyte is in contact with 36 basal and suprabasal keratinocytes; this group of cells forms an epidermal melanin unit 11.
The number of melanocytes per unit of surface area varies at different body sites but there is no difference in the density of melanocytes in different races. The racial differences are due to the distribution and size of melanosomes within keratinocytes12.
MELANIN BIOSYNTHESIS
Melanins are synthesized in melanosomes of melanocytes and are classified into two main groups: 1) the brown to black insoluble high molecular weight eumelanins, 2) the yellow to reddish‐brown alkali‐soluble low molecular weight phaeomelanins. oxidation of the common amino acid tyrosine by tyrosinase produce DOPA and dopaquinone. Dopaquinone further converted to eumelanins or phaeomelanins.
These two types of melanin are different in size, shape and packaging of their granules.
Eumelanosomes have a more elliptical form, and phaeomelanin has a rounded contour. Eumelanin or phaeomelanin production is determined primarily by the melanocortin 1 receptor, which is itself under the control of α‐MSH and agouti signal protein 13,14.
EUMELANIN SYNTHESIS
Dopaquinone is a highly reactive intermediate it spontaneously undergoes intramolecular cyclization to form cyclodopa in the absence of sulfhydryl compounds. Then undergoes redox exchange between cyclodopa and dopaquinone to form the red intermediate, dopachrome, and dopa. Dopachrome decorboxylates to form 5,6‐dihydroxyindole
(DHI) and to a lesser extent to 5,6‐dihydroxyindole carboxylic acid
(DHICA).
DHI and DHICA are further oxidized and polymerized to form eumelanins. Dopachrome tautomerase and Tryp1 (DHICA oxidase) are also having a role alongside tyrosinase in the regulation and promotion of eumelanogenesis.15
PHAEOMELANIN SYNTHESIS
Phaeomelanins contain sulphur and nitrogen and are formed from cysteinyldopa. Oxidation of the thiol adducts leads to the formation of benzothiazine intermediates and then phaeomelanin. Most melanin pigments in skin contains mixtures or copolymers of eumelanins and phaeomelanins. In addition some phaeomelanin‐like pigments may be structural variants of eumelanins16.
Fig.2 MELANIN SYNTHESIS
MELANOSOME TRANSPORT
The melanosomes are transported in melanocytes from the cell
Centre (perikaryon) to the tips of melanocyte dendrites. Melanosome transport depends upon effective dendrite formation by melanocytes.
UVR and MSH are both known to augment this process17.
Melanocyte dendrite formation requires actin polymerization, which is controlled by the activity of the small guanosine triphosphate
(GTP)‐binding proteins Rac and Rho 18-20.
Direct visualization of melanosome trafficking by video microscopy has revealed melanosomes transport takes place on microtubules 19,20.
This process is driven by microtubule associated proteins 1) dyneins and 2) kinesins 23,24.
Dyneins mediate retrograde transport of melanosomes away from the melanocyte dendrites, kinesins mediated microtubule cause anterograde transport. Both dynein and kinesin remain bound to the melanosomes and their regulation modifies the direction of melanosome movement along the microtubules25.
Myosin Va, Rab27a and Mlph are the three individual proteins work together in the final stages of melanosome trafficking.
Fig . 3 MELANOSOME TRANSFER TO KERATINOCYTES
MELANOSOME TRANSFER TO KERATINOCYTES
Transfer of melanosomes from melanocytes to neighboring keratinocytes is an essential step in normal pigmentation.
UV radiation and melanocyte‐stimulating hormone (MSH) stimulate melanosome transfer. Possible mechanisms include exocytosis, cytophagocytosis, fusion of plasma membrane and transfer by membrane vesicles26.
Fig .4 EPIDERMAL MELANIN UNIT
PHYSIOLOGICAL HYPERMELANOSIS (TANNING IN
RESPONSE TO UV RADIATION)
Tanning is the term used for the pigmentary changes of the skin following exposure to UV radiation. It occurs in three distinct phases :
1) Immediate pigment darkening (IPD),
2) Persistent pigment darkening (PPD) and
3) Delayed tanning.
IPD occurs within 5-10 minutes in response to low doses of UVA and manifests as grey‐brown pigmentation. It typically fades within 10–
20 min.
IPD is believed to result from oxidation and redistribution of pre- existing.
Melanin from the perikaryon to melanocyte dendrites. Higher doses of UVA causes PPD which lasts for 2–24 h. This pigmentation is brown and is also caused by oxidation and redistribution of pre‐existing melanin to dendrites. Delayed tanning involves the formation of new melanin due to an increased epidermal melanocytes and increased activity.
Both UVA and UVB are able to induce delayed tanning, but UVB is more effective.
Delayed tanning becomes visible about 3-4 days after UV exposure and persists for 1–2 weeks and gradually fading as keratinocytes are shed from the skin surface.
Tanning and DNA damage are closely associated. Repeated suberythemal doses of UV light induce tanning and also induce DNA damage 27.
Tanning salon exposure has also been shown to induce cyclobutane pyrimidine dimmers and p53 protein expression in epidermal keratinocytes, these changes are linked with the early stages of cutaneous carcinogenesis28.
GUTTATE LEUKODERMA
INTRODUCTION
Guttate was derived from the Latin term “gutta” (a drop) and
“guttatus” (speckled), guttate leukoderma refers to “drop-like” hypopigmentation.
The degree of hypopigmentation varies from hypopigmentation - to depigmentation depending on the underlying pathology.
Patients with guttate hypomelanosis, has to be ascertained whether it is present from birth or acquired later in life. Then the lesions has to be examined to evaluate the textural change of the lesions.
A careful history should be elicited regarding relevant family history, preceding history of infection, injury, pruritus, inflammation, exposure to toxins, as well as associated other comorbidities.
The differential diagnosis for guttate leukoderma is vast and ranging from inherited to acquired disorders, idiopathic guttate hypomelanosis (IGH) is the commonest of guttate leukoderma.
IDIOPATHIC GUTTATE HYPOMELANOSIS
Idiopathic guttate hypomelanosis (IGH) is a commonly acquired guttate leukoderma, affecting the elderly population.1 With multiple, discrete round to oval sharply defined round to oval depigmented porcelain – white macules, approximately 2-5 mm diameter.
Melanocytopenic hypomelanosis is considered to be the basic pathomechanism for idiopathic guttate hypomelanosis.
Commonly involved areas include extensor forearms and pretibial areas, usually sparing of the face and trunk.3,4
EPIDEMIOLOGY
In 1951 Costa described this condition as “symmetric progressive leukopathy of the extremities.”29
In 1951 the term IGH was coined by Cummings and Cottel. 30
IGH commonly seen in the the older population. As age increases number of lesions also increasing.
There is increase in the probability of acquiring IGH with advancing ages, ranging from 47% (31–40 years) to 97% (81–90 years).31
The earliest case being reported at 3 years of age.32
ETIOLOGY AND PATHOGENESIS
The exact etiology remains unclear. several factors have been proposed such as senile degeneration, chronic UV exposure, genetics, trauma, autoimmunity, and local inhibition of melanogenesis.
SENILE DEGENERATION
Increased prevalence of IGH is seen in the elderly population. This might be due to the normal aging process related degenerative changes.
Gradual progressive reduction in the number of melanocytes with increasing age of about 10% to 20% per decade has been demonstrated in several studies.33
Several studies suggest that age related somatic mutation in the melanocytes are being involved in the pathogenesis.34
Both reduced density and defective melanocytes (structural and functional) are also responsible for IGH, these are characteristic changes include dilatation of the endoplasmic reticulum, swelling of the mitochondria, less or absent dendrites, and limited number of melanosomes.32,35
The role of defective keratinocytes which fail to phagocytose the melanosomes are also suggested by some authors, as an additional etiologic factor.35 The histologic evidence of skin aging compared to the surrounding skin such as epidermal atrophy, rete ridge flattening, and reduced epidermal keratosis also further collaborates the role of senelity.29
CHRONIC ULTRAVIOLET (UVR) EXPOSURE
There is a causal role of chronic exposure to ultraviolet (UV) rays has been proposed as an etiology factor for IGH lesions, as it occur more frequently on the sun-exposed areas.
Increased occurrence on IGH on skin has been reported in several studies, which might be due to the exposure to phototherapy (NBUVB or
PUVA).29
Histopathology and ultrastructural studies of IGH lesions, which have demonstrated solar elastosis in almost 70% of the IGH lesions, which is a histologic marker of chronic UV exposure.29
Perivascular monocytic infiltration has also been observed in the
IGH lesions, which suggests IGH lesions are inflammatory in nature.31
Paradoxically, very few lesions has been reported in constantly sun exposed areas such as face and neck. probably due to the textural difference and thickness of the facial and neck skin, and these lesions have also been reported from sites which are minimally exposed to sun.35
GENETIC FACTORS
Role of Genetic predisposition as an etiologic factor has been found in two studies. It is evidenced by the development of IGH on sun- protected areas, in younger patients and falabella et al33 found a high prevalence of IGH lesions among a family of IGH patients.
Association between IGH and human leukocyte antigen-DQ3 has been demonstrated in a study conducted on renal transplant patients. No correlation has been demonstrated with human leukocyte antigen-DR8 with IGH.36 In addition, some studies reported positive family history with increased frequency of IGH.37
LOCAL TRAUMA
IGH lesions occur most commonly over the anterior tibial surfaces and sometimes over the lower central region of the back. Both these areas are vulnerable to local trauma owing to the fact that they have minimum subcutaneous tissue (persons using body scrubs). The etiologic role of local trauma is supported by the higher prevalence of IGH in these areas.29
AUTOIMMUNE PROCESS
Wilson et al tested circulating autoantibodies in IGH patients and proposed autoimmune factors as a possible etiologic factor.38 They demonstrated the presence of autoantibodies against gastric parietal cells in one-third of IGH patients.
However, there was no association of increased prevalence of autoimmune diseases in IGH patients or their relatives. antinuclear, antithyroglobulin, and other autoantibodies are also normal in these patients. Positive antibodies to gastric parietal cells can be seen normally as an age-related change. However, further studies are needed to validate this evidence.
LOCAL INHIBITION OF MELANOGENESIS
Few studies have hypothesized that local inhibition of melanogenesis as a causal factor for the pathogenesis of IGH. Study conducted by Falabella et al33 who grafted normal skin grafts over the
IGH lesions, at 18 months follow up the grafted skin showed depigmentation without spreading to the surrounding areas.
CLINICAL FINDINGS
IGH lesions are clinically manifests as discreet, sharply demarcated, porcelain-white, round-to oval, smooth (only color change, without textural abnormality) asymptomatic macules, it varies in size from 0.5 to 6mm in diameter, rarely lesions may reach up to 2.5 cm.29 generally these lesions do not increase in size or coalesce; however, Gradual enlargement of the lesions in 16% of their patients has been reported by Shin et al.31
The number of lesions in a single patient may range from one to more than 100. If IGH lesions was found in young patients total number of lesions are usually less than 5 and size of the lesions are also usually small around 2 mm. in contrast to numerous (>30–50) and larger lesions
(3–5 mm) were commonly found in older individuals (>50 years).33
IGH lesions usually seen over the sun-exposed areas of our body, such as extensor surfaces of arms and shins and sometimes it can also present as widespread lesions. Involvement of the trunk, face, and neck is rare.
In case of facial lesions, it is commonly involving over the mandibular zone than the central part. Study conducted by Shin et al.31 have demonstrated lesions in both sun-protected and exposed areas in almost three-fourth of their patients. The hairs within the lesions are usually not affected.1,29 usually there are associated photodamage changes in the surrounding skin such as lentigenes and xerosis also noted.1
Kumarasinghe39 conducted a study and have described three morphological variants of IGH lesions:
1) Solitary or multiple hypopigmented macules on a background of
sun-damaged skin in sun-exposed areas.
2) Solitary ivory white, stellate, well-circumscribed, sclerotic macules
related to sun exposure, which can also be seen over both sun
exposed/sun-protected areas.
3) Small well-circumscribed hypopigmented macules with
hyperkeratotic flat crust, with usually having a scalloped border.
Furthermore, detailed studies are needed to confirm whether these morphological varients share the same pathogenesis, or are different entities.
AGNOSIS
IGH is typically a clinical diagnosis made on the basis of history and physical examination of the lesions. Physical examination should be performed under both visible light and UV light of about 365-nm wavelength with Wood’s lamp. Since these lesions may not be conspicuous under visible light in light-skinned individuals.1 Under
Wood’s lamp examination, these lesions show enhanced depigmentation, confirming reduced pigmentation. dermoscopy and histopathology investigations can also be perfomed. However, these investigations are not routinely needed.
DERMOSCOPY
Dermoscopy or epiluminescence microscopy appears to be a noninvasive method to improve the diagnostic precision in difficult cases.
A recent study by Ankad and Beergouder40 in 2015 has described four dermoscopic patterns of to IGH lesions, namely, amoeboid, feathery, petaloid, and nebuloid patterns were frequently noticed in 46.66,40,
23.33, and 3.33 % of lesions respectively . However, the combination of all these dermoscopic patterns was observed in 13.3% of the patients. A clinical correlation has also been deciphered.
Feather like striations were commonly observed in older IGH lesions and the nebuloid pattern, an indistinct borders in commonly seen in newer lesions and also among elderly patients.
Fig .5 DERMOSCOPIC APPEARANCE OF IGH
HISTOPATHOLOGY
Histopathological examination is not usually performed to confirm the diagnosis. Rarely indicated in cases of diagnostic dilemma. A study by Kim et al.33 has proposed hyperkeratosis (38.3%), flattened rete ridges
(14.9%), epidermal atrophy(10.6%), and acanthotic epidermis (10.6%) were features of IGH lesions. However, epidermal atrophy was more often observed in non sun-exposed areas than sun-exposed areas, which was statistically significant.29
Regarding the pigmentary dilution reduced number of melanocytes and irregular distribution are noticed in the IGH lesions. in IGH lesions the melanocytes have been found to be large in size(retained pigment due to abnormal uptake by keratinocytes) with changes in dendritic processes which are small and retracted.42 study by Joshi43 have described a characteristic skipped areas of retained melanin in the basal layer alternating with large areas of melanin loss” in the lesions of IGH in histopathology.
These findings have been confirmed by 3,4-dihydroxyl-L- phenylalanine (DOPA) staining.4,17-19 Fontana-Masson staining by kim et al,42 and immunohistochemical studies (reduced level of melanocyte markers such as NKI/beteb and MART-1).
A thicker grenz zone with increased glycosaminoglycans compared to surrounding normal skin were observed with hale staining in histopathology. Abundance amount of thick, curled, branched elastic fibers called elastosis in the dermis was also observed by luna stain.43
ULTRASTRUCTURAL FINDINGS/ELECTRON MICROSCOPY
Ultrastructural study of the lesions with electron microscopy demonstrated,
1) Melanocyte degeneration,
2) Decreased numbers of melanosomes,
3) Attenuation or absence of melanocyte dendrites, 4) Dilatation of the endoplasmic reticulum, and
5) Swelling of the mitochondria.42,44
On the contrary, Kakepis et al45 have demonstrated abnormal reduction in the phagocytic activity of the keratinocytes, which results in reduced uptake of melanosomes, despite the fact that density and structure of the melanocytes are normal. According to this study they have proposed that etiology of IGH is due to dysfunctional keratinocytes rather than abnormal melanocytes.
TREATMENT
IGH is a benign condition, but in the darker skin types it leads cosmetic concerns and the resulting psychological trauma. Many patients often seek dermatological treatment to allay their anxiety. Counselling regarding the benign course of this disease is of paramount importance, which usually warrants no therapeutic intervention.
Though several treatment modalities have been tried for this condition over time for rapid resolution of these lesions, currently no standard treatment exists for IGH; however, various studies have tried with several medical and surgical/physical modalities.
MEDICAL TREATMENTS
TOPICAL CALCINEURIN INHIBITORS
Topical calcineurin inhibitors have been studied and induce repigmentation in IGH lesions. Asawanonda et al.46 have documented the beneficial effect of 1% pimecrolimus cream, whereas Rerknimitr et al.47 have reported repigmentation with 0.1% topical tacrolimus after 2 and 6 months, respectively, both these drugs applied twice daily. Subjective and objective (measurement by colorimeter for the luminosity scale) assessments in both the studies have shown statistically significant improvement than placebo.
Three mechanisms have been proposed to involve in the repigmentation following topical treatment: ability to stimulate tyrosinase which results in 1)Increased synthesis of melanin, 2)Increased proliferation and migration of melanocytes to the depigmented site
3)Immunosuppressive action suppressing various chronic inflammatory pathways due to senile degeneration.
TOPICAL RETINOIDS
A cohort study 43 performed on 40 Caucasian women by pagnoni et al showed significant improvement of IGH lesions after applying topical tretinoin once nightly for 4 months Topical retinoids 0.025% tretinoin once nightly for 1 week, then 0.05% tretinoin for 1 week, and 0.1% tretinoin until completing the 4-month period 100% (40/40) of the lesions clinically disappeared after 4 months.
INTRALESIONAL CORTICOSTEROIDS
Intralesional corticosteroids were first tried by Falabella et al.33 almost 3 decades back, for the treatment of this condition along with lesional grafting of normal skin. Pigmentary response was noted in all grafted cases, with or without intralesional corticosteroids. The local immunosuppressive effect of corticosteroids may result in its therapeutic efficacy. A short follow-up period of 6 months was a limiting factor.
However, the authors failed to find any evidence of increased melanization in the lesions.
CHEMICAL PEELING
Spot peeling with 88% phenol (once a month, for 3 months) has been tried successfully by Ravikiran et al48 who demonstrated repigmentation in almost 64% of lesions at the end of study. Persistent crust formation (>15 days), postinflammatory hyperpigmentation, ulceration, secondary infection, and scarring were the most common reported adverse effects, respectively.
Although exact mechanism of action is not known, two modalities have been proposed by the authors inactivation of an inhibitory enzyme or chemokine or destruction of the epidermal keratinocytes, thus subsequently normalizing the process of melanocyte uptake once new keratinocytes are formed.
Take home message: Topical spot-peeling with 88% phenol is a safe, effective, and inexpensive treatment modality for this condition; however, this substance must be used cautiously to avoid associated cardiac toxicity.29
SURGICAL AND OTHER PHYSICAL MEASURES
CRYOTHERAPY
Cryotherapy has been proposed by several authors as an effective treatment modality for IGH.40,49 Repigmentation has been observed in
>90% of the treated lesions after 6 to 8 weeks. Initially 10 s of cryo- freezing time was proposed, which resulted in blistering of the lesions.
Subsequently, Kumarasinghe39 has demonstrated similar efficacy with
3 to 5 s of freeze time, without any blister. Ultrastructural studies have demonstrated increased density of melanin and DOPA-positive melanocytes after the procedure, although fewer than in normal skin.29
Although the exact mechanism is debated, inactivation of melanogenesis inhibitory chemokines, destruction of defective epidermis to normalize the uptake of melanocytes by keratinocytes, and/or postinflammatory hyperpigmentation are considered to the possible modes of action.29
TABLE. 1 DIFFERENTIAL DIAGNOSIS OF GUTTATE LEUCODERMA Conditions with textural change Conditions without textural change Achromic verruca plana Bier’s spots (psuedoleukoderma angiospasticum) Clear cell papulosis Chronic arsenicpoisoning Cutaneous popular mucinosis Cole disease Epidermodysplasia Confetti-like lesions in tuberous verruciformis – pityriasis sclerosis versicolor-like lesions Tumor of follicular Dyschromatosis universalis infundibulum hereditaria White fibrous papulosis Dyschromic amyloidosis Dyschromic Exogenous ochronosis Familial white lentiginosis Grover’s disease Idiopathic guttate hypomelanosis Lichen sclerosus etatrophicus Hypopigmented mycosis Darier’s disease Fungoides Lymphomatoid papulosis Generalized Dowling Degos disease Sarcoidosis Dyschromatosis symmterica hereditaria Multiple halo nevi Pityriasis alba Pityriasis lichenoides chronica Pityriasis versicolor Post-inflammatory hypopigmentation Progressive macular hypomelanosis Vitiligo ponctue Xeroderma Pigmentosum DARIER’S DISEASE (DD)
Apart from the classic clinical features of Darier’s disease, guttate leukoderma is also seen over the abdomen, trunk, limbs, hands, and feet in variable degree on patients with pigmented skin.
The pathogenesis of these hypopigmented patches are due to impaired melanin transfer, melanocytic apoptosis due to perturbed cell- cell adhesion and occurring as a subclinical form of brown papules as well as post-inflammatory.50-54 Acantholysis and dyskeratosis, low melanin levels, and reduced melanocyte number are the most frequently reported histological features.55
FAMILIAL WHITE LENTIGINOSIS
It is an acquired disorder clinically characterized by lenticular white macules occurring most frequently in dark-colored individuals of phototype IV–V with a typical distribution on the trunk, neck, hands and on the extensor surface of the upper arms. Histopathological features include lentiginous epidermal hyperplasia with elongated club-shaped rete ridges and an unusual loss of pigmentation. An autosomal dominant or X-linked inheritance is speculated.56-58 COLE DISEASE
Cole disease is a rare autosomal dominant genodermatosis characterized by congenital or early-onset punctate keratoderma associated with irregularly shaped hypopigmented macules, which are typically found over the arms and legs, but not the trunk or acral regions.
Hypopigmented areas of the skin demonstrate hyperkeratosis and normal melanocyte density with a reduction in melanin content in keratinocytes, but not in melanocytes. The ultrastructural changes of melanocytes showing a disproportionately large number of melanosomes in the cytoplasm and dendrites but that keratinocytes showing a paucity of these organelles suggest a defect in melanin transfer.59-62 Mutations in ENPP1, encoding ectonucleotide pyrophosphatase/phosphodiesterase 1, have been implicated.63,64
CLEAR CELL PAPULOSIS
This is clinically characterized by asymptomatic hypopigmented macules or flat-topped papules distributed mainly on the lower aspect of the abdomen or along the milk lines in young children.65,66 The number of skin lesions increases over the first few months or years. Thus, there may be numerous lesions by the time of diagnosis. Clear cell papulosis is more common among the Oriental ethnic groups. Histopathologically, clear cells with a benign appearance are scattered among basal keratinocytes. Clear cells are mucin stain positive and S100 negative.
They also often stain positive with carcinoembryonic antigen, AE 1 + 3, epithelial membrane antigen, cell adhesion molecule 5.2, gross cystic disease fluid protein (GCDFP-15), and cytokeratin 7.67,68
LICHEN SCLEROSUS ET ATROPHICUS (LSA)
Guttate leukoderma in LSA presents as small, ivory, or porcelain- white, shiny, round macules or papules, a few millimeters in diameter.
However, occasionally, they are semitranslucent and resemble mother of pearl. They may be very extensive, involving most of the trunk. Lesions may follow Blaschko’s lines.69
TUMOR OF FOLLICULAR INFUNDIBULUM (TFI)
TFI are benign adnexal tumors that can present as common solitary form or rare eruptive form. The solitary form does not show any distinctive clinical features and frequently misdiagnosed as seborrhoeic keratosis or basal cell carcinoma.70 However, the eruptive form has been described in most reports as symmetrically distributed tumors of variable scaling, hypopigmented macules, and papules with irregular or angulated borders confined to the face, neck, and upper trunk.71 Rarely, the tumors occur on the extremities and buttocks.
Histology shows platelike anastomosing cords of cytologically bland, pale, squamoid, and basaloid epithelium extending from the undersurface of the epidermis. The bulk of the tumor cells show isthmic differentiation. Decreased melanin pigmentation in the tumor cells seen in eruptive form. TFI also shows a unique brush-like network of elastin fibers when stained for elastin fibers
CHRONIC ARSENIC POISONING
The earliest symptoms of chronic arsenic toxicity are the pigmentary changes and the palmar plantar keratosis. Generally, the pigmentary changes start as finely freckled hyperpigmentation and hypopigmentation of the upper chest, arms, and legs described as
“raindrops on a dusty road.” More specifically, this raindrop pattern consists of less pigmented, round spots that are several millimeters in diameter on a background of diffuse hyperpigmentation.72 Patients with chronic arsenic poisoning may also develop multiple malignancies especially squamous cell carcinoma. Furthermore, Unicef Endemic
Arsenicosis Diagnostic Manual has graded the degree of hypopigmentation (as well as hyperpigmentation and hyperkeratoses) in order to form clinical criteria for diagnosis of arsenicosis.73 Grade I
Hypopigmentation that appears on unexposed areas of the body, mainly on the trunk, as symmetrically scattered pale spots the size of pinheads
Grade II Hypopigmentation that is accentuated on unexposed areas of the body, mainly on the trunk, as hypopigmented spots Grade III
Hypopigmentation that occurs on unexposed areas of the body, mainly on the trunk, in an extensive and confluent manner
TUBEROUS SCLEROSIS (TSC)
Hypomelanotic macules are the commonest and earliest cutaneous finding in TSC, often presenting at birth or in infancy. Although the classic presentation is that of an “ash-leaf spot” with a lanceolate shape, they may take on several different forms, including polygonal or round to oval “thumb print” macules.
“Confetti skin lesions” present as a localized area of guttate, hypopigmented, small macules and are a minor criterion for the diagnosis of TSC.74 The prevalence of confetti-like macules has varied widely among studies (2.8–58%).75-78 Clues to the diagnosis of confetti skin lesions include appearance in childhood, lack of scale or preceding rash, and asymmetric involvement.79 SARCOIDOSIS
Hypopigmented macules are a very rare form of chronic cutaneous sarcoidosis.80 Hypopigmented macules have been reported mostly in patients with darker skin.81 Demonstration of granulomas on biopsy is more elusive in these macular lesions than in other cutaneous forms of sarcoidosis, so a high suspicion and repeat biopsies may aid the diagnosis.82
EXOGENOUS OCHRONOSIS SECONDARY TO BLEACHING AGENTS
Classical features of exogenous ochronosis are asymptomatic blue- black macules with textural coarsening and sooty tipped papules on the malar area, temples, inferior cheeks, and neck reported mainly in Asian and African patients.83–86 “Confetti-like” hypopigmented macules interspersed between pigmented macules have been reported in the literature, possibly a side effect from other coexisting bleaching agents such as phenolic or mercurial products in unapproved preparations.85
VITILIGO PONCTUE
Vitiligo ponctue is a rare, unusual variant of vitiligo that presents as discrete, confetti-like amelanotic macules that occur on normal or hyperpigmented skin. However, on its own, arguably, this may not be an actual type of vitiligo, but a form of punctate leukoderma.
When punctate vitiligo coexists with classical vitiligo macules, it is best classified as non segmental vitiligo. Confetti-like depigmentation has also been reported after psoralen plus ultraviolet A (PUVA) therapy in patients with more classic vitiligo, as an adverse effect of PUVA therapy.87
PITYRIASIS ALBA
It is characterized by multiple ill-defined hypopigmented macules and patches (usually 0.5–2 cm in diameter) with fine scaling, typically located on the face but occasionally on the shoulders and arms. These lesions are most obvious in individuals with darkly pigmented skin and/or following sun exposure. Hypopigmentation is thought to result from a low-grade eczematous dermatitis that disrupts the transfer of melanosomes from melanocytes to keratinocytes. Similar hypopigmented lesions can appear upon resolution of more overtly inflamed, erythematous lesions of atopic dermatitis.88
PROGRESSIVE MACULAR HYPOMELANOSIS
Progressive macular hypomelanosis (PMH) is characterized by ill- defined nummular, non-scaly hypopigmented asymptomatic spots on the trunk, often confluent in and around the midline, and rarely extending to the proximal extremities and the neck. Hypopigmentation in PMH has been linked to decreased production of melanosomes, transfer of less melanized melanosomes, and aggregated melanosomes instead of single melanosomes in lesional skin of type V and VI patients.89 It is thought to be due to a subspecies of Propionibacterium acnes. Chapter 10 of this book gives further details of this condition
DYSCHROMIC AMYLOIDOSIS
A rare variant of cutaneous amyloidosis, amyloidosis cutis dyschromica, is characterized by
1) dotted, reticular hyperpigmentation with hypopigmented macules
distributed extensively
2) no or little itch
3) onset before puberty
4) focal subepidermal amyloid deposition.90 Ho et al. reported three cases of primary cutaneous amyloidosis with hypopigmentation as a predominant feature with or without reticular hyperpigmentation, no itching, adult onset, and dermal papillary amyloid deposition.91 The mechanism for hypopigmentation could be pigmentary incontinence rather than the amyloid Deposition.92
CUTANEOUS PAPULAR MUCINOSIS
This localized form of mucinosis presents with small, firm, waxy, ivory-or flesh-colored papules (or nodules and plaques produced by the confluence of papules) confined to few sites only (usually upper and lower limbs and trunk). This entity has been further divided into five subtypes: a discrete form, acral persistent papular mucinosis, self-healing papular mucinosis, papular mucinosis of infancy, and a pure nodular form.93 Histopathologic examination reveals mucin deposition with variable fibroblast proliferation.
EPIDERMODYSPLASIA VERRUCIFORMIS (EV)
EV is a rare genetic disorder that leads to increased susceptibility to cutaneous infections by HPV.94 Clinically it is characterized by polymorphic skin lesions that include widespread, discrete, or confluent papules that resemble flat warts and scaly, pinkish, or hypopigmented guttate macules and thin plaques which resemble pityriasis versicolor. In addition seborrhoeic keratosis-like lesions and premalignant lesions like actinic keratoses that may slowly transform into invasive squamous cell carcinomas develop over the photo-exposed areas.
PITYRIASIS LICHENOIDES CHRONICA (PLC)
PLC presents as erythematous, brownish lichenoid papules with adherent “mica-like” scale that resolve with hypopigmented macules mainly over the trunk and the proximal limbs. Sometimes, these hypopigmented macules are the presenting complaint.95
In summary, guttate leukoderma encompass a wide range of differential diagnoses ranging from idiopathic to infections to malignancy. It can cause considerable distress and anxiety in many patients however benign, especially in pigmented ethnic groups. A careful history and a thorough examination, appropriately complemented by microbiology/ histopathology/ immunohistochemistry, will aid the diagnosis in many cases.
PHOTOTHERAPY
Phototherapy is a form of treatment for skin conditions involving the administration of non‐ionizing radiation (most commonly in the ultraviolet radiation of the electromagnetic spectrum) in a controlled manner to the skin. Photodynamic therapy and laser treatment, which may be regarded as specialized forms of phototherapy.
Phototherapy can be administered as,
• Photochemotherapy • Broadband UVB • Narrowband UVB • UVA1 phototherapy • Excimer laser • Photodyanamic therapy
Ultraviolet radiation is a component of the electromagnetic spectrum with a band of radiation from 200-400 nm. The UVR spectrum is further divided into
• UVC : 200-280 nm
• UVB : 280-315 nm
• UVA : 315-400 nm
• UVA1 : 340 – 400 nm
• UVA2 : 315-340 nm
UVB phototoxicity peaks at 12-24 hours
PUVA phototoxicity peaks at 24-48 hours, even 72 hours
Depth of penetration of UVB : 14 microns.
Depth of penetration of UVA: 140 microns.
FIG .6 UVR DEPTH OF PENETRATION
Fig . 7 EFFECTS OF PHOTOTHERAPY AND PHOTOCHEMOTHERAPY
PHOTOCHEMOTHERAPY (PUVA)
PUVA photochemotherapy includes combination of oral or topical psoralen with exposure to ultraviolet A (320-400nm). It is the photochemical interaction between psoralen and ultraviolet A (UVA) radiation, which has a beneficial effect in psoriasis, vitiligo and other skin diseases. PSORALENS
Psoralen are naturally occurring tricyclic furocoumarin compounds, principally of plant origin such as fruits and vegetables
(limes, lemons, figs and parsnips). Three forms of psoralen are used in photochemotherapy includes, but is also available as a synthetic drug.
1) 8-methoxypsoralen (8-MOP)
2) 5-methoxypsoralen (5-MOP)
3) 4,5,8-trimethylpsoralen(TMP)
4, 5, 8-trimethyl psoralen (TMP, trioxsalen) which is synthetic is less phototoxic after oral administration and is primarily used for the treatment of vitiligo.
2 oral formulations of 8-MOP are used in photochemotherapy, a micronized form that is given at a dose of 0.6 mg/kg 120 minutes prior to
UVA exposure or a dissolved form that is given typically at a dose of 0.4 to 0.6 mg/kg 90 minutes before UVA exposure.
The dissolved preparation is absorbed faster and reaches higher and more reproducible serum levels, it is more commonly employed in
PUVA phototherapy regimens.
Oral administration of methoxsalen (8-MOP) is absorbed from the gastrointestinal tract and produces photosensitivity one hour after taking the dose, reaches it’s peak at about two hours and disappears after about eight hours. 96 The serum half-life of approximately one hour and is rapidly eliminated which prevents photosensitivity.97 topical application of 8-MOP rapidly penetrates the skin and four hours later it can be detected in the urine. The plasma levels of 8-MOP in patients receiving total body topical 8-MOP are comparable to those found during oral ingestion of 8-MOP.98 The plasma concentration of
TMP after bath treatment is low, approximately 1% of the plasma after oral ingestion.
PRINCIPLES OF PUVA THERAPY
The rationale for PUVA therapy is to produce controlled phototoxic reactions which induce remissions of skin diseases. These reactions occur only when psoralens are photoactivated by exposing
UVA.
SOURCES OF UVA RADIATION
Common sources of UVA used for PUVA therapy are fluorescent lamps or high-pressure metal halide lamps. The UVA fluorescent lamp has a maximam emission at 352 nm and emits approximately 0.5 percent in the UVB range. UVA doses are typically given in J/cm 2, it is measured with a photometer with a higher sensitivity at 350 to 360 nm.
TREATMENT PROTOCOLS
PUVASO
Psoralens is typically used along with sunlight as the source of ultraviolet A-rays is known as PUVASOL. In centers where artificial chambers are not available PUVASOL is the most commonly used mode of treatment.
Here the presence of both UVA and UVB in sunlight result in photoaugmentation99 and photoaddition.100 Quantifying UVA is the major disadvantage of solar irradiation when used as the light source. The total amount of UVA reaching the skin at any one time varies widely depending on the season, time of the day, latitude and conditions of the atmosphere. Other disadvantages are lack of privacy, difficulty in monitoring the dose of ultraviolet rays and in addition to ultraviolet A, ultraviolet B, infrared rays and visible light which are not needed for
PUVA therapy may lead to undesirable effects.
UVB in sunlight can increase the thickness of epidermis and this makes the sun exposed skin leathery and this may interfere with the effectiveness. With the use of solarium and a PMA 120 complete privacy can be provided. 101 The main advantages of sunlight as a source of
PUVA is that it is inexpensive and patient need not travel long distance for treatment.
Topical treatment Application of 8-MOP in creams, ointments or lotions followed by UVA irradiation is effective in limited plaque psoriasis and for palmoplantar disease. It can also be used to induce pigmentation over streaks of residual pigmentation following punch grafting and when other measures fail to induce pigmentation.
METHODOLOGY
A lotion containing 0.1 to 1% 8-MOP is applied and exposed to sunlight either immediately or after one to two hours. 102,103 This treatment is given three to four times weekly with UVA dose being gradually increased. Maintenance dose may be needed.
Among the psoralens TMP is most convenient for topical application because of its weak penetrability. 104 The penetrated drug makes photo adducts with DNA molecules even if UVA light is given as soon as the drug is painted resulting in significant inhibition of epidermal
DNA synthesis.102
Advantages of topical psoralen therapy are that systemic side effects can be avoided. The disadvantages are that topical PUVA is laborious and time-consuming, if every lesion has to be treated individually. The adverse effects such as erythema and blisters are more common with topical psoralen application and at the site of treated plaques intense irregular pigmentation may be seen.
BATH WATER DELIVERY OF 8-MOP AND TRIOXSALEN
Bath water psoralen delivery plus UVA has also been found to be equal to or better than local application of psoralen with ointments, creams or lotions.105
Psoralen bath delivery eliminates the laborious application required with other topical modalities. The even skin distribution delivered by bath water leads to even pigmentation. Bath water delivery of 8-MOP was found to be as effective as oral administration of 8-MOP and requirement of UVA radiation is smaller amount than oral administration and also yielded fewer side effects then oral administration.
METHODOLOGY
Bath solutions are prepared in the concentration of 3.75 mg/L. 50 ml of 8-MOP is diluted in 100 liters of bath water . Patients soak for 15 min in this solution and then quickly wipe dry. Immediately patients are given whole body irradiation with UVA, the initial dose depends upon the skin type.
BATH-SUIT DELIVERY OF PSORALEN
In India, use of bath tub is not in vogue and water problem is perennial and most of the attending patients are poor. Hence bath suit therapy is another alternative therapy found to be an effective therapy for psoriasis. 106 Advantages of bath-suit delivery of 8-MOP preparation requires only two liters of water with 0.8 ml of 8-MOP solution when compared to bath water therapy which needs 100 liters of water and 50 ml of 8-MOP. The cost of the drug is less and it is easy and less time- consuming with no systemic side effects when compared to topical psoralen therapy. This treatment can be carried out at home with sunlight as the
UVA source.
Disadvantage of bath-suit delivery are that the entire body surface especially face does not come in contact with the drug and the concentration of the drug may not be uniform in the bath suit.
PUVA TURBAN THERAPY
This therapy has been used in the treatment of alopecia areata.
Methodology: A cotton towel is soaked with a 0.0001% 8-MOP solution
(1 mg/L) at 37 degrees C, wrung gently to remove excess water and wrapped around the patient's head in a turban fashion for 20 min. This is directly followed by UVA radiation. Treatment sessions are three to four times per week. This therapy has been shown to be a well-tolerated and is an efficient therapeutic alternative in the treatment of alopecia areata. 107
ORAL TREATMENT
In oral PUVA, 8-MOP is administered orally (0.6 to 0.8 mg per kilogram body weight) 1 to 3 h before exposure, depending on the absorption characteristics of the particular drug brand. The usual dosage for 5-MOP is 1.2 to 1.8 mg per kilogram of body weight. The initial UVA doses are established by either skin typing or by
MPD testing. 108 Doses are 4, 4.5 or 5 for skin over body and 5 or 6 J/cm 2 for palms and soles. The MPD is defined as the minimal dose of UVA which produces a barely perceptible, well-defined, erythema when template areas of the skin are exposed with increasing doses of UVA ranging from 0.5 to 5 J/cm.2 Erythema readings are performed 72 h after testing, at which time the psoralen phototoxicity reaction usually reaches its peak. The MPD test should be performed on previously nonexposed skin (e.g. buttocks). It is difficult to determine MPD in the Indian skin and therapy is started with a starting dose of 0.5 J/cm 2 and increments can be made every second or third sitting.
Repeated exposures are required to clear PUVA responsive diseases and the frequency of treatments is reduced after satisfactory clearing of disease and the last UVA dose is used as a maintenance dose if maintenance treatment is planned. The duration of this maintenance phase and the frequency of treatments depend on the particular disease being treated and its propensity to relapse.
Eye protection with UVA-blocking glasses (B2 Toric glasses) is required from time of exposure to psoralen until sunset that day A sunscreen with an SPF of at least 15 is required for protection from a psoralen phototoxic reaction. Men should also shield their genitalia.
DISEASES AMENABLE TO PUVA THERAPY
Alopecia areata
Atopic dermatitis
Cutaneous T-cell lymphoma
Parapsoriasis
Pityriasis lichenoides
Dyshidrotic eczema
Graft versus host disease
Polymerphous light eruption
Pityriasis rubra pilaris
Psoriasis
Urticaria pigmentosa
Lichen planus
Palmophantar pustulosis
Vitiligo
SIDE EFFECTS AND CONTRAINDICATIONS
PUVA therapy is contraindicated in patients with photosensitive diseases such as systemic lupus erythematosus and porphyria cutanea tarda because it is based on the photosensitizing effects. PUVA therapy is also contraindicated in pregnant women, because of concerns about possible teratogenicity therapy has both acute and chronic side effects. Acute effects include sunburn reactions, nausea, pruritus, headache and dizziness.
ADVERSE EFFECTS OF PUVA
Premature photoaging
Pigmented macules
Actinic keratoses
Squamous cell carcinoma
Basal cell carcinoma
Anterior cortical cataracts.
ULTRA VIOLET B ( UVB)
TYPES OF UVB
Two types of UVB phototherapy are available:
Narrowband UVB and
Broadband UVB
THERAPEUTIC SPECTRUM
A potential advance in the UVB-based phototherapy has been due to the introduction of fluorescent bulbs (Phillips model TL-01) which deliver UVB in the range of 310 to 315 nm, the a peak radiation from this source at 312 nm. It has a relatively narrow spectrum of emission which results in a reduction in erythemogenic wavelengths in the 290-305 nm range and 5-6 fold increased emission of the longer UVB wavelengths, which results in increased phototherapy index for psoriasis.
MECHANISM OF ACTION
In psoriatics, NB-UVB phototherapy reduces the activity of peripheral natural killer cell, lymphocyte proliferation and immune regulatory cytokine production, by both Th1 (IL-2, IFN-g) and Th2 (IL-
10) T-cell populations. 109,110
In vitiligo, it results in localized immunosupression, stabilization of the depigmenting process, and the stimulation of residual follicular melanocytes. 111,112
DOSING SCHEDULE
Prior to phototherapy, the patients minimal erythema dose (MED) must be determined in order to establish the optimal dosage schedule.
MED is the lowest dose that causes a minimally perceptible erythema reaction after 24 hours of irradiation. Which is determined by standard method.115
A template with 20 apertures (10 on each side) of 1½ × 1½ cm 2 has to be made over the back of a cotton suit used by operation theatre staff. Cotton flaps made over the apertures enables to either shut or keep the apertures open by using the Velcro The source of NB - UVB is whole body phototherapy unit with 24 Philips TL-01 bulbs.
To determine MED a single panel in the whole body unit with 6 bulbs is used whereas for BB-UVB phototherapy, panel with 8 bulbs is used to determine MED to BB. By using photometer the irradiance from the source is determined.
All the apertures are kept open and back is irradiated with 5 mJ of
BB-UVB. One aperture is closed and remaining apertures are closed one after the other after delivering 5 mJ more than the previous aperture.
Same procedure was repeated on the other half of the back starting with
50 mJ of NB - UVB and increasing the dose by 50 mJ for each aperture.
The dosage schedule used for BB - UVB (in mJ) was 5, 10, 15, 20,
225, 30, 35, 40, 45, 50 whereas for NB - UVB (in mJ) was 50, 100, 150,
200,250, 300, 350, 400, 450, 500.
The readings were taken 24 h after exposure since phototoxic effect is peak at 12 to 24 hrs. For 311-nm therapy, the initial dose should be 70% MED in the interest of safety. It is mandatory that MED should be determined before NB-UVB therapy for all condition except vitiligo.
Patients are treated three to five times per week. Although more sittings will be beneficial, two or three sittings per week are more cost effective and hence more acceptable. If the initial dose is tolerated, a 20 percent incremental increase of the previous dose is used at each visit. When a previous treatment results in erythema no treatment is given in the next schedule. Increments every second or third sitting is also effective
(personal observation) possibly because sub erythemogenic dose of UVB is also as effective as erythemogenic dose.
Another approach, as commonly practiced in India, in which first session is initiated in a standard starting dose (280 mJ/cm2), with stepwise increment of the dose of 20% depending upon the erythema development of the patient. Since many patients have higher MED, the first few sittings will be useless for which the patient will pay and in addition the time for response will increase.
In the photodermatoses, dose increment is more cautious with only
10% incremental regimen on sun-exposed sites. 112 In case of mild erythema, the irradiation dose is held constant for subsequent treatments or until resolution of symptoms.
The goal of therapy is to achieve persistent asymptomatic erythema. In case of painful erythema with or without edema/blistering, further treatment is withheld till the symptoms subside.
After resolution of overdose symptoms, the dose administered is
50% of the last dose and subsequent increments should be by 10%. We would like to add a note that the percentages of increments are only recommendation and the physician should be guided by his own experience, patient's comfort and increments can be tailored on case to case basis.
UVB burn is unpleasant and if it occurs during initial phototherapy session the patient is always apprehensive about re-starting therapy. If the
MED is detected at 475 mJ, 450 mJ can be considered as MED especially in Indian skin as erythema may not be detectable. If the patient is sedentary female or has sensitive skin or has atopic diathesis then initial treatment can be 50% of MED instead of 75%. INDICATIONS
Vitiligo
Psoriasis
Atopic dermatitis
Other dermatoses
Prophylactic low dose NB-UVB has been found to be useful in various predominantly UVA induced photosensitivity disorders like polymorphic light eruption, actinic prurigo, hydroa vacciniforme and the cutaneous porphyrias by providing a hardening photoprotective effect.
LONG TERM USE AND ADVERSE EFFECTS
In addition to the expected immediate sunburn effects, chronic NB-
UVB exposure is likely to increase photoageing and the risk of carcinogenesis.113 However, according to a dose response model it has been calculated that the long-term risk for carcinogenesis with its use may be less than that of PUVA therapy. 114 Clinical experience with NB-
UVB is limited for the treatment of vitiligo and currently there is no established safe limit for its maximum safe duration. In children, the maximum duration allowed is 12 months.
BROADBAND UVB PHOTOTHERAPY
High-dose UVB phototherapy using sunlamp bulbs (broadband
UVB) was an effective treatment in many patients with psoriasis. High dose means using a treatment schedule aimed at staying close to or above the erythema threshold of the patient throughout the course of treatment.
NB UVB is more effective than BB UVB. Both can cause sun burn but BB is more likely to burn than NB UVB. The advantage of BB is very short duration of exposure and rapid clearance especially in psoriasis. BB is reported to be carcinogenic especially among whites. This may not be true for our skin. No case of BB induced malignancy is reported from
India. However since lamps are only manufactured in Western countries and since they have abandoned the use of BB UVB and have stopped manufacturing the tubes we have no choice but to stop using the light which is cheaper unless we manufacture the bulb in India.
COMBINATION THERAPY
Phototherapy may be combined with topical or systemic agents to achieve higher clearance rates, longer disease free intervals and a lower carcinogenic risk. 115 Topical agents. Include anthralin, vitamin D analogues, retinoids, glucocorticoids, emollients, saltwater baths and tar. The combination of either broadband UVB or 311 nm UVB therapy with calcipotriol increases the therapeutic efficacy of phototherapy and reduces the irritation caused by calcipotriol.116
Another combination phototherapy of psoriasis is narrowband
UVB irradiation and topical tazarotene gel. The addition of tazarotene broadband or narrowband UVB phototherapy was found to promote more effective, faster clearing of psoriasis when compared to either type of phototherapy alone. 117
Pretreatment with tazarotene gel three times per week for two weeks before phototherapy significantly reduces the mean minimal erythema dose for UVB and the mean UVA exposure required to induce immediate pigment-darkening. Thus, UVB and PUVA therapy can be initiated at lower doses than usual when used in combination with tazarotene. 118
Topical application of emollients alters the optical properties of psoriatic lesions, improve transmission of UVB and leads to increased efficacy. 119 The systemic use of glucocorticoids in combination with photo (chemo) therapy is limited to special indications, such as generalized pustular psoriasis. Also, combination regimens of UVB therapy with methotrexate or cyclosporine A are not advisable, because both substances increase the possibility of UV-induced skin tumors.
Retinoids are the most widely used agents for systemic treatment in combination with phototherapy)
The advantage of combining retinoids and UVB irradiation is two- fold: (1) retinoids exert antipsoriatic effects, which might act synergistically with UVB phototherapy; and (2) they have anticarcinogenic effects and thereby could lower the increased skin cancer risk resulting from long-term UVB therapy. Combination regimens with broadband UVB or oral retinoid therapy together induced improvement in psoriatic patients more quickly than with phototherapy alone and reduced the number of treatments and cumulative UV doses. 120
Similar results were obtained when acitretin, the major metabolite of etretinate, was used in combination with broadband UVB or 311-nm
UVB therapy.
COMBINATIONS OF PSORALEN, UVA AND UVB:
Combinations of PUVA and UVB have shown increased efficacy in the treatment of psoriasis. For recalcitrant disease, a combination of
PUVA and UVB clears psoriasis more rapidly than PUVA or UVB, buttressing the concept that UVB and PUVA have different and perhaps complementary mechanisms. 122 Similarly, 311-nm exposure enhances the phototoxic activity of bath-PUVA. Bath-PUVA with nbUVB clears psoriasis with fewer exposures and lower cumulative UVA doses under the same minimally erythemogenic conditions. 123
Psoralen has not been shown to add to the efficacy of narrow-band
UVB in the treatment of vitiligo. 124
Although PUVB and nbPUVB are efficacious in the treatment of skin disease, neither has established a utility over nbUVB or PUVA alone. The long-term safety of PUVB or nbPUVB remains to be defined.
Further evaluations of psoralen and UVB need to be conducted.
UVA-1 PHOTOTHERAPY
Conventional UVA1 treatment emits wavelengths mainly between
340 and 400 nm, but may also produce scattered radiation >530 nm including infrared irradiation (780-3000 nm). It may be accompanied by extensive heat load predominantly generated by infrared irradiation (780-
3000 nm) and/or insufficient cooling systems of the phototherapy devices. UVA-1 phototherapy is quite expensive and requires a special light source not readily available everywhere. It is used for the treatment of scleroderma, chronic GvHD, extragenital LSA or sclerodermoid rarities and other disorders affecting the connective tissue. 125 It is also effective in the treatment of inflammatory skin diseases such as acutely exacerbated atopic dermatitis, urticaria pigmentosa and disseminated granuloma annulare. 126
EXCIMER LASERS
Excimer 308-nm laser is a laser light source that delivers a specific wavelength (308 nm) of UVB radiation. This is beneficial in the treatment of psoriasis. The UV ray generated by the excimer laser focuses on the psoriatic lesion. The advantages are that healthy skin surrounding the areas of psoriasis is not exposed to radiation; higher dose of radiation can be used to induce a visible reaction in the psoriatic plaque Most clinical studies on the use of excimer laser therapy have focused on patients with localized psoriasis involving less than 10 or 20% of the body. It is used to treat a select group of patients with localized, refractory plaque psoriasis (e.g. patients with thick, scaled plaques on the knees and elbows, which are resistant to any conventional treatment).
127,128 Side effects include erythema, blisters, hyperpigmentation and erosions. Although the risk from excimer laser therapy is unknown, research to date suggests it is less risky than narrowband UVB as it does not expose the whole body to UV radiation.
TARGETED PHOTOTHERAPY
Targeted phototherapy is the localized delivery of ultraviolet radiation (UVR) . it is used in the treatment of localized varients of diseasesof skin using laser or nonlaser devices.129
It is used for skin lesions involving a limited body surface area of the body (<10 percent) or difficult-to-treat anatomical sites.
INDICATIONS FOR TARGETED PHOTOTHERAPY130
Psoriasis
Vitiligo
Atopic dermatitis
Alopecia areata
Mycosis fungoides
Pityriasis lichenoides
Lichen planus
Urticaria pigmentosa
Morphea Scleroderma
Granuloma annulare
Lichen simplex chronicus
ADVANTAGES OF TARGETED PHOTOTHERAPY
1) Exposure of affected skin areas only and sparing of unaffected
areas, which minimizing acute side effects such as erythema and
long-term risk of skin malignancy over unaffected skin.
2) Quick delivery of energy and thereby shortened duration of
treatment
3) Delivery of super-erythemogenic doses (high dose) of radiation
because of the sparing of uninvolved areas of skin , higher doses of
energy can be delivered selectively to the lesions, thereby
enhancing efficacy and achieving faster response.
4) Shorter duration of treatment, which leads to less frequent visits to
clinic, and cost effective.
5) The maneuverable hand piece allows treatment of difficult to reach
areas of affected sites such as scalp, nose, genitals, oral mucosa,
ear, etc.
6) Easy administration for children as delivery is hand-held
7) Occupies less spac
MATERIALS AND METHODS
MATERIALS AND METHODS
STUDY DESIGN
• Interventional study
STUDY PERIOD
• This study was conducted for a period of two years in
patients with idiopathic guttate hypomelanosis.
• After getting approval from ethical committee study was
conducted.
STUDY POPULATION
• Patients with idiopathic guttate hypomelanosis lesions
attending the OPD of Dermatology Venerology and Leprosy.
INCLUSION CRITERIA
➢ Patients older than 18 years
EXCLUSION CRITERIA
➢ Patients with pre existing dermatological conditions that is
exacerbated by ultraviolet radiation
➢ Patients taking medications known to have potential phototoxic
reactions
➢ Current or previous treatment within past 3 months specifically
for IGH
➢ Pregnancy or pregnancy within the past 3 months (can cause
changes in pigmentation)
METHODOLOGY
Idiopathic guttate hypomelanosis patients presenting to dermatology OPD, will be included in the study. Detailed history regarding duration, occupation, systemic illness, past treatment history will be obtained and recorded,
Extent and number of lesions were counted and recorded, after getting informed written consent from IGH patients., minimal erythema dose (MED) was calculated. Initial dose was started at 1 MED and incrementation of 0.5 MED was given on subsequent visits.
Phototherapy was administered weekly twice for 6 weeks for a total of 12 sitings. A single x ray sheet with multiple punched out holes of varying sizes was prepared. The sheet was placed on top of the lesions before administering phototherapy to minimize surrounding pigmentation.
Patients were assessed for extent of repigmentation at the end of 6th week.
METHODOLOGY
CLINICAL ASSESMENT
INFORMED CONSENT
PHOTOGRAPHS/ MED CALCULATION
12 SESSIONS OF TARGETED PHOTOTHERAPY (WEEKLY TWICE FOR 6 WEEKS)
ASSESMENT FOR REPIGMENTATION
All patients were treated with a targeted phototherapy device
(levia). Levia is a nonexcimer source of light which delivers in the wavelength of 300nm to 320 nm. The diameter of Lite spot in the Levia device is 3 cm 2 ( 17 × 17 mm) that can deliver a given dose over a smaller surface area.
MED was calculated by exposing the patient’s back to increasing radiation starting from 100 mj with increments of 50 mj over 10 sites, and the MED was determined after 24 hours.
MED is the lowest dose that causes a minimally perceptible erythema reaction after 24 hours of irradiation.
No topical or oral drugs were used in any of the groups during the study period. Response to treatment was monitored clinically and photographically, which was graded as excellent (≥75% repigmentation), good (50−74% repigmentation) and mild (<50% repigmentation).
1 Worsening of IGH
2 No Improvement (IGH remained stable)
3 Mild improvement of IGH (somerepigmentation on <50% IGH)
4 Good improvement (some repigmentation on >50% or full repigmentation on <75% IGH
5 Excellent repigmentation on >75% IGH
RESULTS
RESULTS
41.70% Male Female 58.30%
PERCENTAGE OF IMPROVEMENT
50% 46% 45% 40% 35% 30% 30% 24% 25% 20% 15% 10% 5% 0% 0% 0% WORSENING OF NO MILD GOOD EXCELLENT IGH IMPROVEMENT
This pilot study included 12 patients(7 females and 5males) with idiopathic guttate hypomelanosis. Majority of the lesions were seen over legs and few over thighs and arm. Lesions over lower extremities were selected. 5 patients were male and 7 patients were females. Two patients lost follow up. Total of 122 lesions were selected for targeted phototherapy out of which 24% (29/122)lesions had 0-50% of improvement, 46% (56/122)lesions had 50-75 % of improvement and
30% (37/122)of lesions had 75-100% of improvement.
The improvement was not uniform in all patients. Lesions seen over the individual patients responded differently. Some lesions had good improvement and other lesions had mild improvement in same patient.
Erythema and pigmentation over the surrounding skin were the common side effects observed in our study . No patients developed severe reactions like blisters.
DISCUSSION
DISCUSSION
Idiopathic guttate hypomelanosis is an acquired, benign leukoderma with unknown etiology. It was first described under this name in 1966 and studies have demonstrated prevalence ranging from
47% to 68%, with one report showing a prevalence of 87% in subjects more than the age of 40.
It clinically presents as scattered porcelain-colored macules with well-defined margins.These lesions must be differentiated from other hypopigmented disorders such as vitiligo, pityriasis versicolor, tuberous sclerosis, guttate morphea, postinflammatory hypopigmentation, and lichen sclerosus et atrophicus.
Histopathology shows hyperkeratosis, an atrophic epidermis, and flattened rete ridges, as well as a decreased melanin content and reduced numbers of melanocytes.
Various modalities of treatment have been reported for the treatment of IGH, but none of these treatments show consistent results.This is the first study using targeted phototherapy for the treatment of IGH.
Ploysangam et al.131 Ortonne et al.132 and Hamada and Saito133 had found that the number of dopa-positive melanocytes in IGH was considerably lower than that in normal skin. In addition, the melanocytes were unevenly distributed throughout the lesion.131
Kim et al. 32 found that the amount of melanin was significantly reduced in the epidermal layers with Fontana–Masson staining.
Moreover, a reduction in the amount of melanin pigment was also represented by a weakened expression of immunohistochemical marker,
NKI/bêteb, and MART-1.
Phototherapy is a common modality used in the treatment of many skin disorders. Conventional phototherapy is available as broad-band ultraviolet (UV) B (290–320 nm) narrow-band UVB (311–313 nm) ,
UVA and more recently, monochromic excimer light (308nm) has been used for treatment of pigmentary disorders.
It is thought that UVB promotes repigmentation through potent immunosuppressive and immunomodulatory effects locally and able to induce melanocyte differentiation and melanin production in the skin.
It has been hypothesized that melanocytes are stimulated by UVB light through keratinocyte release of endothelin-1 and may also stimulate perifollicular dopa-depleted melanocytes to produce melanin.134-137
UVB primarily affects the epidermis and superficial dermis, and there have been no reports of systemic immunosuppression using light therapy.
It has been reported to be effective in cutaneous T-cell lymphoma, prurigo nodularis, localized scleroderma, lichen sclerosus, granuloma annulare, and leukodermas.138
Vitiligo treatment with UVB is well described, and due to the similarities of dyspigmentation between vitiligo and IGH, this treatment protocol was modeled after that protocol. Most successful trials have used a twice weekly treatment regimen for at least 12weeks. In studies involving leukoderma (including chemical leukoderma and pityriasis alba), successful repigmentationwas achieved with 1 to 2 weekly treatments for 12 to 20 weeks.
The safety and efficacy of UVB has been well described. The acute side effects of UVB are predominantly self-limited phototoxicity consisting of localized erythema and/or tenderness that lasts less than 24 hours. Rarely, more severe side effects have been reported that include blistering, pruritus, pain, xerosis, polymorphous light eruption, and herpes simplex virus reactivation.138
Study conducted by Falabella et al33 in 1987 with or without skin graft and inj Intralesional triamcinolone monthly dose for 3 months showed good response in 46.67 % (7/15).
A cohort study performed on 40 Caucasian women by pagnoni et al44 showed significant improvement of IGH lesions after applying topical tretinoin once nightly for 4 months [15] Topical retinoids 0.025 % tretinoin once nightly for 1 week, then 0.05 % tretinoin for 1 week, and
0.1 % tretinoin until completing the 4-month period 100 % (40/40) of the lesions clinically disappeared after 4 months.
Rerknimitr et al139 conducted study with 0.1 % tacrolimus ointment application twice daily for 6 months. 11 % (3/26) of the patients demonstrated some degree of repigmentation. Patients developed transient burning sensation as adverse effect.
Study conducted by Ploysangam et al49 in 1991 with Single application of cryoprobe for 10-seconds showed complete repigmentation in 90.8 % (79/87) of the treated lesions in 6–8 weeks. All of the treated lesions developed blisters.
Shin et al used140 Single session of fractional CO2 laser 42.7 %
(17/40) of the patients showed more than 75 % clinical improvement.
Goldust et al141 used Single session of fractional CO2 laser and 47.9 %
(115/240) of the patients showed more than 75 % clinical improvement.
Adverse reactions include pain , Burning sensation, erythema, and post inflammatory hyperpigmentation
Gordon et al142 performed a longitudinal, split-body controlled, single-blinded pilot study of 6 patients treated with the excimer laser for
12 weeks using a vitiligo protocol. Effectiveness was graded by the blinded observer scale through photographic comparisons at the end of the study. Lesions that received the excimer treatment had significantly higher repigmentation compared with baseline and untreated lesions.
In our study we selected 122 lesions for targeted phototherapy out of which 24% (29/122)lesions had 0-50% of improvement, 46%
(56/122)lesions had 50-75 % of improvement and 30% (37/122)of lesions had 75-100% of improvement with fewer side effects of erytherma and pigmentation over the surrounding lesional skin were the common adverse effects.
This pilot study is a novel approach to a dermatological disease that causes aesthetic concerns in patients. This was the first study to show successful repigmentation of IGH lesions using targeted UVB therapy.
Limitations included a small sample size with minimal variation in
Fitzpatrick skin and lack of extended follow-up.
Long-term follow-up would be recommended in future studies to evaluate if the results are long-lasting and to see if further repigmentation can be achieved by extending the treatment period beyond 6 weeks.
CONCLUSION
CONCLUSION
Targeted phototherapy is a novel safe and effective treatment option for IGH with acceptable cosmetic outcomes.
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ANNEXURES
CLINICAL PHOTOGRAPH
BEFORE
AFTER
BEFORE
AFTER
BEFORE
AFTER
CONSENT FORM
PSG Institute of Medical Science and Research, Coimbatore Institutional Human Ethics Committee INFORMED CONSENT FORMAT FOR RESEARCH PROJECTS
(Strike off items that are not applicable)
I, Dr.KANNAN P, am carrying out a study on the topic: EFFICACY OF TARGETED PHOTOTHERAPHY IN IDIOPATHIC GUTTATE HYPOMELANOSIS – as part of my research project being carried out under the aegis of the Department of: DERMATOLOGY VENEROLOGY & LEPROLOGY
(Applicable to students only): My research guide is: Dr.SHANMUGA SEKAR C
The justification for this study is: UV-B has immunomodulatory effect on melanocytes which causes melanogensis,melanocyte mitogenesis,melanocyte migration. Because of this effect it produces repigmentation. The objectives of this study are:
Primary Objective: To produce repigmentation over hypopigmented macules. Secondary Objective: Quality of life will improve
Sample size: 20
Study volunteers / participants are (specify population group & age group): 18-70 years
Location: Dept. Of Dermatology, PSG IMS&R
We request you to kindly cooperate with us in this study. We propose collect background information and other relevant details related to this study. We will be carrying out:
Initial interview (specify approximate duration):15 minutes.
Data collected will be stored for a period of 3 years. We will / will not use the data as part of another study.
Health education sessions: Number of sessions: N/A
Approximate duration of each session: N/A
Clinical examination (Specify details and purpose): Will be done to assess the extent and number of hypopigmented macules.
Blood sample collection: Specify quantity of blood being drawn: NA
No. of times it will be collected: NA
Whether blood sample collection is part of routine procedure or for research (study) purpose: NA
1. Routine procedure 2. Research purpose
Specify purpose, discomfort likely to be felt and side effects, if any:
Whether blood sample collected will be stored after study period: NA
Whether blood sample collected will be sold: NA
Whether blood sample collected will be shared with persons from another institution: NA
Medication given, if any, duration, side effects, purpose, benefits: NA Whether medication given is part of routine procedure: NA Whether alternatives are available for medication given: NA
Final interview (specify approximate duration): 15 minutes
If photograph is taken, purpose: To record improvement
Benefits from this study: Reduction in number of hypopigmented macules
Risks involved by participating in this study: Mild erythema How the results will be used: For research purpose only
If you are uncomfortable in answering any of our questions during the course of the interview / biological sample collection, you have the right to withdraw from the interview / study at anytime. You have the freedom to withdraw from the study at any point of time. Kindly be assured that your refusal to participate or withdrawal at any stage, if you so decide, will not result in any form of compromise or discrimination in the services offered nor would it attract any penalty. You will continue to have access to the regular services offered to a patient. You will NOT be paid any remuneration for the time you spend with us for this interview / study. The information provided by you will be kept in strict confidence. Under no circumstances shall we reveal the identity of the respondent or their families to anyone. The information that we collect shall be used for approved research purposes only. You will be informed about any significant new findings - including adverse events, if any, – whether directly related to you or to other participants of this study, developed during the course of this research which may relate to your willingness to continue participation.
Consent: The above information regarding the study, has been read by me/ read to me, and has been explained to me by the investigator/s. Having understood the same, I hereby give my consent to them to interview me. I am affixing my signature / left thumb impression to indicate my consent and willingness to participate in this study (i.e., willingly abide by the project requirements).
Signature / Left thumb impression of the Study Volunteer / Legal Representative:
Signature of the Interviewer with date: Witness:
Contact number of PI: 9994049395
Contact number of Ethics Committee Office: 0422 4345818
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PROFORMA
PATIENT PROFORMA
NAME : DATE :
SL. NO:
AGE / SEX :
OP / IP NO :
ADDRESS :
OCCUPATION :
COMPLAINTS :
DIAGNOSIS :
NO. of % of Repigmentation No. of Lesion PATIENTS <50 50-75 75-100
MASTER CHART
S.NO. GENDER AGE
1 MALE 62 LEG, THIGH ARM FOREARM
2 FEMALE 64 LEG
3 FEMALE 68 LEG
4 FEMALE 68 LEG, THIGH
5 MALE 62 LEG
6 MALE 40 LEG
7 FEMALE 49 LEG
8 FEMALE 58 LEG
9 FEMALE 47 LEG
10 MALE 60 LEG
11 MALE 48 LEG
12 FEMALE 69 LEG
ABBREVIATION
8-MOP - 8-METHOXYPSORALEN
5-MOP - METHOXYPSORALEN
DHI - DIHYDROXYINDOLE
DHICA - DIHYDROXYINDOLE CARBOXYLIC ACID
IGH – IDIOPATHIC GUTTATE HYPOMELANOSIS
LSA - LICHEN SCLEROSUS ET ATROPHICUS
MED - MINIMAL ERYTHEMA DOSE
MSH – MELANOCYTE STIMULATIONG HORMONE
NCC – NEURAL CRUST CELLS
PUVA - PSORALEN ULTRAVIOLET A
TMP - 4,5,8-TRIMETHYLPSORALEN
UVA – ULTRAVIOLET A
UVB – ULTRAVIOLET B
UVC - ULTRAVIOLET C
UVR - ULTRAVIOLETRADIATION