Investigations and treatment of photodermatoses

Morphology of the lesions

Histopathology

This is useful in differentiating many conditions, especially PMLE from SCLE and actinic reticuloid (AR) from mycosis fungoides. A study by Megahed and Schaller has described the utility of histopathology in various photodermatoses.^[5] They concluded that histopathology does not have pathognomonic diagnostic features for most conditions, though diagnostic pointers are available for PMLE (prominent papillary edema) and phototoxic dermatitis (sunburn cells). For example, SU cannot be differentiated from urticaria and HV can be mistaken for bullous phototoxic contact dermatitis, bullous irritant contact dermatitis, or hand,foot mouth disease. Most other conditions have non-specific histopathology.^[5] Table 2 denotes the utility of histopathology in the diagnosis of various photodermatoses.^[1,3,5,6]

Photo-testing

This is primarily used in the diagnosis of immunological photodermatoses such as CAD, SU, and PMLE. This helps in determining the action spectrum of the condition so as to avoid the implicated spectrum and to plan the treatment.^[7]

Procedure

The patient should avoid topical and systemic steroids and other immunosuppressants for at least two weeks and antihistamines for two days prior to the test. A photo opaque template with multiple 2 × 2 cm windows is placed on the shaved, uninvolved back of the patient. Upper arm or forearm can also be used. The skin is then exposed to increasing dose of UVA, ultraviolet B (UVB), or visible light (VL).

For UVA testing, the following may be used as a source of UVA: High output fluorescent black light used for psoralen with ultraviolet A (PUVA) therapy, PUVA chamber with the patient in the center, or metal halide lamps (UVASUN 320– 400 nm). The doses given are 3, 6, 12, and 18 J/cm².

For UVB testing, broadband UVB lamps or fluorescent lamps (Philips TL 20 W/12, 285–350 nm) are used and the UVB dose used starts from 6 mJ/cm², proceeding to 12, 24, 36, 48, 72, 96, and 108 mJ/cm². A solar simulator was used earlier for calculating the minimal erythema dose (MED) [Figures 1 and 2].

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Figure 1:

MED testing using solar simulator. MED: Minimal erythema dose.

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Figure 2:

MED obtained using solar simulator. MED: Minimal erythema dose. SS: Solar simulator, WS: Whole spectrum.

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A solarimeter or a slide projector can be used for VL testing and has to be placed 30 cm away from the skin surface. To avoid heat, a water filter is suggested to be placed in front of the light source. The exposure times are 15, 30, 45, and 60 minutes. Elimination of heat rays using water bath will negate the chance of developing heat-induced urticaria.

An immediate reading at 20 min rules out SU. The lowest irradiation that induces wheal is defined as the minimal urticaria dose (MUD). After 24 h, MED for UVA, UVB, or VL is calculated. MED is defined as the dose that induces just perceptible erythema covering the entire irradiated surface [Figure 3].

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Figure 3:

MED to UVB at 30J and to UVA at 300J in CAD. MED: Minimal erythema dose, CAD: Chronic actinic dermatitis, UVA: Ultraviolet A, UVB: Ultraviolet B.

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Provocative testing

In conditions such as PMLE, HV, or EPP, lesions may be induced by provocative testing. This is especially effective where MED is suspected to be normal. The same site is exposed to UVA, UVB, or VL for three–four consecutive days at 80% of MED with a subsequent 10%–20% increase.^[7] Lesions occur within 24 hours and biopsy may be done if required. This method is not very logistical or popular as the patient has to visit the hospital or clinic daily for 4–5 days. Photoprovocation is positive in 60–70% of cases of AP.^[14]

Phototesting and photoprovocative testing have also been used to establish the protective role of sunscreens in photodermatoses.^[11]

Photopatch testing

This is used to identify allergens or photoallergens that can exacerbate photodermatoses in suspected cases of photoallergic contact dermatitis (PACD) and is also often positive in CAD.^[15] The methodology is the same as patch testing, with allergens being applied in duplicate so that one set can be irradiated by UVA light. Various preformed series of photoallergens are available.^[16] There is no Indian series, though European, Scandinavian, and extended European series are available.^[17,18]

A photopatch test series ideally contains sunscreens, NSAIDs, cosmetics, and often the patient’s products. In addition to photoallergen series, any suspected product the patient is exposed to, or used by the patient can also be applied in duplicate patches, in sufficient dilution using a suitable substrate after referring to the standard pharmacopeia textbooks.

Interpretation

The results are interpreted according to the International Contact Dermatitis Reading Group (ICDRG) criteria as varying degrees of erythema, papules, and vesicles.^[20] [Figure 4].

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Figure 4:

Photo patch test showing contact allergy to parthenium and photocontact allergy to perfume mix. WS: Whole spectrum, MED: Minimal erythema dose, UVB: Ultraviolet B.

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Photopatch test is expected to be positive in photoallergic dermatoses and may occasionally be positive in CAD. There can be photoaggravation as well as photoaugmentation; in photoaggravated reaction, there is contact allergy with photoaggravation whereas photoaugmented reactions have both contact as well as photocontact allergic reactions.^[18]

Table 3 shows various common scenarios of photopatch test readings.

Table 3: Common scenarios in photopatch testing.

Clinical diagnosis	Patch test	Photo patch test (Irradiated site)
No allergy	−ve	−ve
ACD	+	+
PACD	−ve	+
Both ACD and PACD	+	++

ACD: Allergic contact dermatitis, PACD: Photoallergic contact dermatitis

Rai and Thomas have done photopatch testing in 35 photodermatitis patients, using 14 J/cm² UVA irradiation, and found 51% photopatch test positivity with both PACD and photoaggravation to parthenium.^[21] A European multicentric study yielded 19.4% positivity in 200 subjects, mostly to topical NSAIDs (ketoprofen and etofenamate) and organic UV absorbers (octocrylene, benzophenone-3, and butyl methoxydibenzoylmethane). Allergic contact dermatitis (ACD) was seen in 5% cases.^[22] Data from 1129 patients from 45 centers spanning five years concluded that NSAIDs, sunscreens, disinfectants, fragrances, and phenothiazines caused photoallergy, whereas phototoxicity was attributed to chemicals such as promethazine, chlorpromazine, fenticlor, balsam of Peru, wood tar, and perfumes. However, many reactions lacked relevance for the patients.^[23]

Miscellaneous tests

Serum immunoglobulin E is elevated in up to 50% of cases of severe AP.

Occasional Sezary cells in peripheral smear may be seen in CAD.

Other serological tests: ANA, anti-Ro, anti-La, HIV, especially in younger individuals to rule out autoimmune connective tissue diseases.^[24]

Tzaneva et al. showed that although, up to 11.7% of PMLE patients show ANA positivity, none progress to SLE;^[25] hence, ANA testing need not be performed unless there is a strong suspicion of autoimmune connective tissue disease otherwise.

Porphyrin levels can either confirm or rule out porphyrias. Microcytic anemia with elevated iron levels, cholelithiasis, and cholestasis may also be seen in porphyrias.^[1]

Immunohistochemistry shows T-cell cytotoxic molecules and monoclonality of T-cell receptor genes in Epstein Barr-related HV like reactions. This may be used to differentiate from idiopathic HV. TCR gene rearrangements, Ki-67 index, and lactate dehydrogenase levels may also be used.^[26,27]

Targeted next-generation sequencing tests, DNA repair function tests using cultured fibroblasts can be used to investigate Xeroderma pigmetosum types and variants, and for atypical cases.^[28]

Polarized light microscopy of hair reveals the tiger tail pattern of altering light and dark bands in trichothiodystrophy. Common photodermatoses and investigations are shown in Table 4.

General principles

All patients of photodermatoses should follow strict photoprotection by means of clothing, hats, shawls, sunglasses, and avoidance of direct sun exposure. Broad-spectrum sunscreen may be used wherever indicated, provided that there is no photocontact dermatitis. Window films that block UVA and VL to some extent can be used in cars and home window panes. Clothing that is especially suitable to prevent UV light entry is available, with a specific ultraviolet protection factor (UPF) protection factor mentioned; higher the UPF, better the protection. Clothing treated with broad spectrum UV absorbers is also available.^[29] In case of sunburn such as reactions, cold compresses, antihistamines, analgesics, and bland emollients are to be used. Avoidance of all known allergens, photoallergens, and photosensitizing drugs is the norm in conditions of photoallergy, phototoxicity, and severe photosensitivity like CAD. Even broad-spectrum sunscreens should preferably be used only after ruling out sunscreen allergy.^[1] Topical steroids may be applied to the skin lesions, depending on the area and severity of involvement, and may be tapered and stopped based on the response. Some commonly available topical steroids in increasing order of potency are hydrocortisone acetate 1%, desonide 0.05%, hydrocortisone butyrate 0.1%, mometasone furoate 0.1%, fluticasone propionate 0.05%, betamethasone valerate 0.1%, betamethasone dipropionate 0.05%, clobetasol propionate 0.05%, halobetasol propionate 0.05% available as lotion, cream, and ointment.^[30] Topical calcineurin inhibitors such as tacrolimus 0.01% ointment or lotion can also be used.

PMLE

For extensive and severe PMLE, short course of oral steroids, or steroid-sparing agents like hydroxychloroquine (HCQ) sulfate (200–300 mg/day), azathioprine (0.8–2.5 mg/kg/day), cyclosporine (3–5 mg/kg/day), or even thalidomide has been tried.^[3,6] Topical antioxidants have been evaluated and found to be effective in UVA and UVB-mediated photodermatoses by reducing MED as well as minimal phototoxic dose. Topical tocopherol has been used in PMLE.^[31] Oral polypodium leucotomos extract 240 mg twice daily started 15 days before sun exposure, and continued throughout is reported to be beneficial by Caccialanza et al.^[32] Afamelanotide, an alpha melanocyte-stimulating hormone analog, is a promising drug that has completed phase III clinical trials in PMLE, and acts via skin pigmentation, DNA repair, and antioxidant repair. It is available as a 20 mg subcutaneous implant.^[33] In CAD, the patient should avoid contact and photocontact allergens as well as potent photosensitizers. Sunscreen allergy should be ruled out. Azathioprine, cyclosporine, mycophenolate mofetil (MMF), and even tofacitinib have been tried in CAD.^[34] Bhari and Gupta have attempted overnight application of 0.1% tacrolimus under occlusion in resistant CAD.^[35] Photoallergic reactions can be treated similar to ACD with topical or oral steroids and steroid sparing agents. If every severe and extensive, a short course of oral steroids, approximately 0.25–0.5 mg/kg equivalent of prednisolone may be required, with due precautions. Polypodium leucotomos, pentoxifylline, cyclosporine, azathioprine in immunosuppressive doses, thalidomide 50–100 mg/day, and even Dupilumab have been tried in CAD and resistant AP cases.^[36] Eickstaedt et al. reported clearance of recalcitrant AP with Dupilumab.^[37]

SU

Non-sedative antihistamines along with photoprotection form the first-line treatment followed by phototherapy. Omalizumab 300 mg s/c at 4 weeks interval is effective, especially in refractory cases of SU.^[38] Prophylactic use of antihistamines 1 h before sun exposure can prevent lesions. Cimetidine, doxepin, leukotriene antagonists, intravenous immunoglobulin (400 mg/day for 5 days), and cyclosporine (3–5 mg/kg/day) have also been tried.^[3]

AP is often resistant to treat even with phototherapy, and if so, thalidomide is the treatment of choice and can be started at 100–200 mg/day and later tapered to 50 mg once in 2–3 days.^[3,4]

Porphyrias

Cholestyramine can bind to, and excrete protoporphyrins in feces. Oral beta-carotene, activated charcoal, colestipol, cimetidine, and plasmapheresis are other modalities. For porphyria cutanea tarda, avoid alcohol, smoking, and added estrogens. Phlebotomy, which reduces iron-mediated uroporphyrinogen decarboxylase inhibition and low-dose HCQ (100 mg twice a week), is also tried.

Afamelanotide that stimulates melanin production and increases the light tolerance, is considered the currently most effective treatment. In porphyrias, it is given as a 60 mg s/c depot injection every 60 days.^[39] Liver and bone marrow transplantation are end-stage options.

Long-term oral retinoids (isotretinoin and acitretin) and topical imiquimod are tried in Xeroderma pigmentosum, to prevent cutaneous malignancy.

Sunscreens with T4 endonuclease V bacterial DNA repair enzyme or with photolyases can reduce development of actinic keratoses and cutaneous malignancies, but are not in wide use.^[40] Regular cutaneous, neurological, and ophthalmologic checkups should be carried out, and any malignancies should be removed at the earliest.

Mechanism

Hardening induced by phototherapy results in downregulating the immune response to neoantigens formed during the disease process.^[42] There is also disruption in antigen presentation and secretion of inhibitory cytokines.^[43] In SU, it works by downregulation of immunoglobulin E production and inhibition of mast cell degranulation.^[8] Photodermatoses managed by phototherapy include PMLE, SU, AP,^[44] chronic actinic dermatitis, porphyria,^[45] and HV.^[46] Contra-indications to phototherapy include patients with SLE, Xeroderma pigmentosum.

Protocol

Patients should be explained the procedure, the mechanism, cost, need for multiple sessions, and the possible side effects, including tanning. If possible, proceed with MED testing to know the degree of photosensitivity.

In patients with severe photosensitivity, especially in CAD, some authors recommend a short course of oral steroids for 8–10 days, at approximately 0.6–0.8 mg/kg body weight equivalent of prednisolone, from the day before initiation of phototherapy.^[8]

For those with normal MED, starting dose is based on the skin type, or the protocol of the respective phototherapy unit, and subsequent increment is 10–15%/session, with 2–3 sessions/week.

Photo therapy

UVA1 is not available freely in India. However, if attempted, MUD for UVA1 should be elicited, and therapy should be started with 50% of the same. If not, start with 10 J/cm² with increments of 5–10 J/cm² until a total dose of 20 J/cm². Only photo-exposed sites may be treated, so as to minimize the chance of anaphylaxis.

Narrow-band ultraviolet B (NB-UVB) is currently the phototherapy of choice, due to its lesser side effects and ease of administration. The starting dose varies depending on skin type, but can be anywhere between 200 and 300 mJ/cm² for Indian skin. Treatments are spaced at two to three –3/week for a total of 15 sessions. Patients may then be advised to expose to 20–30 min of cumulative weekly midday sun exposure to maintain the hardening PUVA therapy has been used for CAD, but at a lower dose of 0.5 J/cm², with 2–3 treatments/week to a total of 15–20 treatments.

In SU, UVA1, PUVA, or NB-UVB may be used.^[8] Phototherapy has also been successfully tried in AP, HV, and EPP.^[8]

PMLE

Phototherapy is well known to induce prophylactic protection in PMLE. Aslam et al. evaluated the effect of desensitization using phototherapy in 79 patients and found that 91% patients found it to be effective.^[47]

CAD

A pilot study on UVA rush hardening in six patients with CAD was conducted by Wang et al., in which patients were exposed to multiple UVA sessions at 1-h intervals for 4–5 days, and subsequent maintenance doses at 1–2 weeks, and this was found to be effective.^[48]

SU

There are various studies that have found good outcomes with phototherapy using NB-UVB^[49,50] as it is more widely available.

Points to note

• Most photodermatoses are in the UVA spectrum.

• UVB-responsive dermatoses are more easily prevented, as UVB does not penetrate glass, and broad-spectrum sunscreen is helpful.

• Even potent UVA sunscreen may not fully prevent PMLE if there is a very low UVA threshold.

• Sensible, general sun protection behavior should be reiterated to the patient at every visit.

• Sunscreens are not protective in the VL range; hence, conditions like EPP or SU may require physical protection with clothes, cap, and shawl.

• Rarely, even fluorescent lamps can exacerbate CAD; then, LED lamps are a safer alternative.

• Water, snow,and sand can reflect sunlight, hence extra caution to be taken. Tanning beds to be avoided.

• Vitamin D supplementation is essential in those on prolonged photoprotection.

• Phototherapy is used diagnostically as well as therapeutically; NB-UVB is the most widely used

• Biological therapy is evolving with molecules like dupilumab, omalizumab being explored in certain indications.

• Promising drugs like afamelanotide are under consideration.