Internal Medicine/Photosensitivity and Other Reactions to Sunlight

Sunlight's Impact on Health
Sunlight, or solar radiation, is a readily noticeable and important element of our environment. It offers us warmth and helps our bodies synthesize vitamin D, but excessive exposure to the sun can also have negative health consequences. Prolonged exposure to sunlight is a leading cause of skin cancer in humans and can weaken our immune systems.

The sun's energy that reaches Earth's surface is composed of various components within the ultraviolet (UV), visible, and infrared spectra. The shorter UV wavelengths below approximately 290 nm are mostly filtered out by the Earth's stratospheric ozone layer, protecting us from the more harmful solar radiation. Concerns about ozone layer depletion due to substances like chlorofluorocarbons have led to international agreements to limit their production.

Measurements of solar energy show significant regional variations due to factors like seasons, the path of sunlight through the atmosphere, altitude, latitude, and the presence of clouds, fog, and pollution.

The key wavelengths of solar radiation that affect human skin are in the UV and visible spectra, ranging from 290 to 700 nm. Additionally, wavelengths beyond 700 nm primarily generate heat and, under certain conditions, can exacerbate the negative effects of UV and visible radiation.

UV Radiation and Skin Structure
Solar UV radiation is divided into UV-B and UV-A segments, ranging from 290 to 400 nm. UV-B, which covers wavelengths between 290 and 320 nm, is the most effective at causing skin redness, commonly known as sunburn. UV-A, spanning from 320 to 400 nm, is about a thousand times less efficient in causing skin redness compared to UV-B.

Visible light, within the 400 to 700 nm range, cannot harm human skin in the absence of photosensitizing chemicals. These chemicals absorb specific wavelengths and initiate photosensitivity reactions. The absorption spectrum of a molecule indicates the wavelengths it absorbs, while the action spectrum shows the wavelengths that produce a response in the presence of incident radiation.

Photosensitivity occurs when a molecule in the skin absorbs energy from photons, becomes excited, and transfers this energy to various structures or to molecular oxygen.

Effects of UVR on Skin Structure and Function

Human skin comprises two main layers: the outer epidermis and the underlying dermis, both vulnerable to sun damage. Various molecules in these layers, such as nucleic acids, proteins, and lipids, can absorb solar energy. The outermost epidermal layer, the stratum corneum, primarily absorbs UV-B, with only a fraction of UV-B wavelengths reaching the dermis. UV-A, however, penetrates more deeply into the skin and can modify structural and matrix proteins, contributing to premature aging, especially in individuals with light skin.

Molecular Targets and Skin Effects from UVR

UV radiation can cause structural changes in epidermal DNA, primarily in keratinocytes and Langerhans cells, forming DNA lesions like cyclobutane dimers and 6,4-photoproducts. Effective repair mechanisms are crucial for preventing skin cancer development. Individuals with defective DNA repair mechanisms, like those with xeroderma pigmentosum, are at a higher risk of skin cancer.

Solar UVR also targets molecular oxygen, producing reactive oxygen species (ROS). ROS can damage skin components through oxidative processes, affecting DNA, lipids, proteins, and enzymes. UVR can also lead to increased cross-linking and degradation of dermal matrix proteins, contributing to photoaging or solar elastosis.

Chromophores and Cutaneous Optics

Chromophores are chemicals that can absorb physical energy and can be endogenous (naturally occurring in the skin) or exogenous (introduced from external sources). Skin's endogenous chromophores include nucleic acids, proteins, lipids, and 7-dehydrocholesterol, a precursor of vitamin D. Exogenous chromophores can include porphyrins, which are normally present in trace amounts but can accumulate in certain diseases, leading to skin damage upon exposure to solar energy.

Porphyrins can generate ROS upon absorbing sunlight, causing skin damage such as erythema, edema, urticaria, or blister formation. Photodynamic therapy (PDT) uses photoexcited porphyrins for targeted destruction of tumor cells in conditions like basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).

Acute Effects of Sun Exposure

Immediate effects of sun exposure include sunburn and vitamin D synthesis. Sunburn, characterized by skin redness, is primarily caused by UV-B and, to a lesser extent, UV-A radiation. It results from an inflammatory response in the skin, involving the release of various cytokines and growth factors, along with the accumulation of ROS. UV-B is particularly efficient at inducing sunburn, but UV-A can contribute to it, especially during midday when UV-A levels are higher.

Sunburn also triggers the formation of "sunburn cells," which are apoptotic keratinocytes attempting to repair DNA damage.

Vitamin D Synthesis and Photocchemistry

UV-B exposure can stimulate the synthesis of vitamin D in the skin. It begins with the photolysis of 7-dehydrocholesterol, converting it into pre-vitamin D3, which then undergoes temperature-dependent transformation into stable vitamin D3. This vitamin is transported through the bloodstream to the liver and kidneys, where it becomes the biologically active hormone, 1,25-dihydroxyvitamin D3.

Vitamin D has various physiological effects, including aiding in calcium metabolism, regulating bone health, and potentially reducing the risk of certain internal malignancies. The debate continues about the risk-to-benefit ratio of sun exposure for vitamin D production. However, the potential risks of skin cancer and photodamage outweigh the benefits, and supplementation is recommended for individuals with vitamin D deficiency, especially as skin's ability to produce vitamin D decreases with age.

Chronic Effects of Sun Exposure: Nonmalignant The visible signs of photoaging, often referred to as dermatoheliosis, encompass characteristics such as wrinkles, uneven pigmentation, visible blood vessels (telangiectasia), and a rough, uneven, and weathered appearance of the skin.

Sunlight plays a significant role in causing photoaging in human skin, and it is likely that reactive oxygen species (ROS) are involved in this process. Sun-associated chronic damage primarily targets the dermis and its connective tissue matrix, leading to a condition known as solar elastosis. This involves a significant increase in the thickened, irregular masses of abnormal elastic fibers. Collagen fibers in the deeper layers of sun-damaged skin also appear clumped together. While the exact mechanisms behind these changes are not fully understood, it is believed that UV-A radiation, which penetrates deeper into the skin, plays a major role. Interestingly, both chronologically aged skin protected from the sun and photoaged skin share molecular features, including damage to connective tissues and elevated levels of matrix metalloproteinases (MMPs), enzymes that break down the extracellular matrix. UV-A radiation induces the expression of certain MMPs, like MMP-1 and MMP-3, which increase collagen degradation and also reduce the expression of type I procollagen mRNA, affecting collagen synthesis. As a result, chronic sun exposure leads to structural and functional alterations in dermal collagen, inhibiting its production and promoting its breakdown. This knowledge has led to the use of high-dose UV-A phototherapy in the treatment of specific skin conditions characterized by localized fibrosis, such as localized scleroderma.

Chronic Effects of Sun Exposure: Malignant Excessive and prolonged exposure of the skin to sunlight is a well-known cause of non-melanoma skin cancers (NMSCs), including squamous cell carcinomas (SCCs), basal cell carcinomas (BCCs), and Merkel cell carcinomas (MCCs). The development of skin cancer follows a multi-step process that involves initiation, promotion, and progression.

Initiation occurs when the DNA of skin cells is structurally altered by factors like UV-B radiation, making them prone to malignant transformation. However, exposure to a tumor initiator, such as UV-B, is necessary but not sufficient for cancer development; other factors are required. Promotion is the next stage, driven by chronic sun exposure, leading to further changes in the initiated cells, clonal expansion, and the development of premalignant growths known as actinic keratoses, which can progress to SCCs. UV-B radiation is considered a complete carcinogen as it can act both as a tumor initiator and promoter. Finally, malignant conversion marks the transition of benign precursors into cancers, involving genetic instability.

On a molecular level, skin cancer is driven by accumulated gene mutations, causing inactivation of tumor suppressors, activation of oncogenes, or reactivation of cellular signaling pathways that are normally active during embryonic skin development, leading to uncontrolled cell proliferation. Studies have shown that UV-induced mutations that drive oncogenesis in SCCs are already present in sun-exposed normal skin, providing a growth advantage to precancerous clones carrying these mutations. These mutations are particularly common in genes influencing the proliferation of epidermal stem cells. The pattern of oncogenic mutations in sun-exposed skin overlaps with those in SCCs but differs from those in BCCs and melanomas. For example, mutations in NOTCH1 are found in approximately 20% of normal sun-exposed skin cells and around 60% of SCCs. Furthermore, mutations in the tumor suppressor gene p53, primarily caused by UVR, can promote skin carcinogenesis.

In contrast to SCCs, BCCs have distinct mutations, primarily involving the tumor-suppressor gene patched or the oncogene smoothened, leading to the activation of the sonic hedgehog signaling pathway. The Wnt/β-catenin signaling pathway is also implicated in skin cancer development. Clonal analysis in mouse models has shown that BCCs originate from stem cells in the interfollicular epidermis and upper hair follicle infundibulum. SCCs can initiate from both interfollicular epidermis and hair follicle bulge stem cells. The transcription factor Myc is associated with both BCCs and SCCs.

Merkel cell carcinoma (MCC), another form of NMSC, is linked to Merkel cell polyoma virus (MCPyV). MCCs can be MCPyV-positive or MCPyV-negative. MCPyV-negative MCCs display high levels of UV-induced signature mutations and tumor suppressor inactivation. MCPyV-positive MCCs result from viral integration into the host genome and mutations in the large T antigen. Both forms of MCC are immunogenic, and some patients with metastatic MCC have shown positive responses to PD-1/PD-L1 immune checkpoint inhibitors.

Global Considerations The incidence of skin cancer varies globally, influenced by geographic location and the predominant skin phototype of the population in each region. For example, Australia experiences high rates of both melanoma and NMSCs due to its sunny climate.

Photoimmunology Exposure to solar radiation leads to immunosuppression, affecting both local and systemic immune responses. Local immunosuppression reduces the immune response to antigens applied at the irradiated site, while systemic immunosuppression affects responses to antigens applied at distant, unirradiated sites. UV radiation targets chromophores in the upper epidermis, including DNA, urocanic acid, and membrane components, initiating immunosuppression. DNA damage induced by UV radiation can inhibit antigen presentation by Langerhans cells. Urocanic acid, which accumulates in the upper epidermis due to the breakdown of the protein filaggrin, undergoes trans-cis isomerization upon UV exposure, contributing to immunosuppression.

Various immunomodulatory factors and cytokines are implicated in UV-induced systemic immunosuppression, including tumor necrosis factor-α, interleukin 4 (IL-4), interleukin 10 (IL-10), and eicosanoids. Additionally, UV radiation can activate Toll-like receptor signaling via damage-associated molecular patterns (DAMPs) released from necrotic keratinocytes.

Chronic sun exposure and the resulting immunosuppression increase the risk of skin cancer, especially in organ transplant recipients who require lifelong immunosuppressive drug regimens. These individuals are at a significantly higher risk of developing skin cancers, emphasizing the importance of photoprotection measures.

Sun exposure can exacerbate autoimmune and inflammatory skin conditions, such as systemic lupus erythematosus (SLE), by promoting DNA damage that may trigger autoantibody production.

In conclusion, skin cancer and various immune-related skin responses are influenced by chronic exposure to UV radiation, affecting both local and systemic immunity. This underscores the importance of sun protection and early detection to mitigate these risks.

Photosensitivity Diseases
To diagnose photosensitivity conditions, it's essential to gather a detailed medical history to understand the duration of symptoms, the time between sunlight exposure and the onset of symptoms, and the age when symptoms began. Certain diseases, like erythropoietic protoporphyria (EPP), often start in infancy or early childhood, while others, such as porphyria cutanea tarda (PCT), tend to appear in one's forties or fifties. A patient's exposure to drugs and chemicals, both topical and systemic, can provide diagnostic clues, as many of these substances can induce photosensitivity through either phototoxic or photoallergic reactions.

Skin examination plays a vital role in diagnosis. Areas naturally shielded from direct sunlight, like the scalp, upper eyelids, and other covered regions, may remain unaffected, while exposed areas exhibit characteristic signs of photosensitivity. These patterns can be helpful in diagnosis, but they are not foolproof. For instance, airborne allergens that settle on the skin can lead to dermatitis in both sun-exposed and shielded areas, complicating diagnosis.

Various dermatological conditions can be triggered or worsened by sunlight exposure, influenced by genetic factors such as DNA repair defects in xeroderma pigmentosum and abnormalities in heme synthesis seen in porphyrias.

Polymorphous Light Eruption (PMLE)

Polymorphous light eruption (PMLE) is the most common type of photosensitivity disorder. Many individuals with PMLE may not seek medical attention as the condition is often temporary, with symptoms arising in the spring upon initial sun exposure but subsiding with continued exposure (a phenomenon known as "hardening"). PMLE is characterized by pruritic (itchy), erythematous (red), and papular (raised) skin lesions that can merge into plaques, typically appearing on sun-exposed areas of the trunk and forearms, with the face being less affected. While the skin findings remain consistent in each recurrence for an individual, there can be significant variations in symptoms among different individuals.

Diagnosis can be confirmed through a skin biopsy and phototesting, where the skin is exposed to UV-A and UV-B radiation to reproduce symptoms. The action spectrum for PMLE usually falls within these portions of the solar spectrum.

Preventing PMLE is essential, and measures include using high-SPF broad-spectrum sunscreens and inducing "hardening" through cautious exposure to artificial UV-B or UV-A radiation or using psoralen plus UV-A (PUVA) photochemotherapy for several weeks before the initial sun exposure in the spring to prevent subsequent PMLE outbreaks during the summer.

Actinic Prurigo

Actinic prurigo is another photosensitivity condition with similarities to PMLE. It typically occurs in the spring, can persist throughout the summer, and extend into the winter months.

Phototoxicity and Photoallergy

Phototoxic and photoallergic reactions result from exposure to drugs and chemicals, which act as chromophores. In both reactions, the substance absorbs energy, becomes photoexcited, and generates tissue-damaging chemical species, including reactive oxygen species (ROS). Phototoxicity is a non-immunologic reaction caused by various drugs and chemicals, while photoallergy involves an immunopathologic process. Phototoxicity and photoallergy reactions can be confirmed through phototest procedures.

Porphyria

Porphyrias are a group of disorders related to heme synthesis abnormalities. Some porphyrins in the body act as potent photosensitizers, absorbing light in the visible spectrum and leading to photosensitivity. The two major categories of cutaneous porphyrias are chronic blistering photosensitivity and acute non-blistering photosensitivity. The latter category includes diseases like erythropoietic protoporphyria (EPP), which causes painful skin burning and stinging upon sun exposure.

The management of these photosensitivity disorders involves various strategies, including eliminating exposure to triggering substances, protecting the skin from sunlight, and, in some cases, using medications to alleviate symptoms or suppress the immune response. For instance, afamelanotide, a synthetic peptide analogue of α-MSH, has been approved by the FDA for treating EPP and can increase skin pigmentation to improve sunlight tolerance. Additionally, β-carotene supplements have shown moderate benefits in increasing sunlight tolerance for some patients with EPP.

Treatment approaches may vary depending on the specific condition and its severity.

Photoprotection
As photosensitivity disorders stem from sunlight exposure, complete avoidance of sunlight could theoretically prevent these conditions. However, this approach is often unfeasible in today's modern lifestyles. Therefore, alternative methods of photoprotection have been explored. The skin naturally provides some photoprotection through structural proteins in the epidermis, especially keratins and melanin. The amount and distribution of melanin in cells are genetically controlled, and individuals with darker skin types (IV-VI) are less prone to acute sunburn and skin cancers. Other forms of photoprotection encompass clothing and sunscreen use. Clothes made of densely woven sun-protective fabrics, regardless of color, offer substantial protection. Covering up with wide-brimmed hats, long sleeves, and trousers can also reduce direct sun exposure.

Sunscreens are now considered over-the-counter drugs, and the FDA has identified category I ingredients as both safe and effective. Sunscreens are rated for their photoprotective capacity based on their Sun Protection Factor (SPF). SPF represents the ratio of time required to produce sunburn erythema with and without sunscreen application. Most sunscreens primarily protect against UV-B but not UV-A. According to the FDA, sunscreens must be categorized as minimal (SPF ≥2 and <12), moderate (SPF ≥12 and <30), or high (SPF ≥30, labeled as 30+).

Broad-spectrum sunscreens contain chemicals that absorb both UV-B and UV-A rays (organic filters). These chemicals soak up UV radiation and transmit the absorbed energy to surrounding cells. For instance, cinnamates, PABA derivatives, and salicylates primarily absorb UV-B, while benzophenones and ecamsule (terephthalylidene dicamphor sulfonic acid) offer protection against both UV-B and UV-A2, and avobenzone primarily guards against UV-A1. In contrast, physical UV blockers such as zinc oxide and titanium dioxide either absorb or reflect UV radiation, providing broad-spectrum protection against both UV-B and UV-A. In addition to light absorption, water resistance significantly affects the sustained photoprotective ability of sunscreens. Sunscreen products with SPF 30 or higher, broad-spectrum coverage, and resistance to water or sweat are recommended for adequate sun protection.

Limiting sun exposure during the day can also provide some photoprotection. Since a significant portion of a person's lifetime sun exposure occurs by age 18, educating parents and young children about the risks of sunlight is important. Reducing exposure at midday can substantially reduce a person's overall UV radiation exposure throughout their life.

Phototherapy and Photochemotherapy
Ultraviolet radiation (UVR) can be used therapeutically. UV-B exposure alone or in combination with topically applied agents can induce remission in various dermatological conditions like psoriasis, atopic dermatitis, and vitiligo. Narrow-band UV-B treatments, utilizing fluorescent bulbs emitting radiation at around 311 nm, have shown enhanced efficacy compared to broad-band UV-B in psoriasis treatment.

Photochemotherapy, where psoralens are topically applied or systemically administered and combined with UV-A (PUVA), is effective in treating psoriasis, early-stage cutaneous T-cell lymphoma, and vitiligo. Psoralens, tricyclic furocoumarins, intercalate into DNA and form adducts with pyrimidine bases when exposed to UV-A, leading to DNA cross-linking. This process is believed to reduce DNA synthesis, contributing to psoriasis improvement. The effectiveness of PUVA in cutaneous T-cell lymphoma treatment is not fully understood but is thought to induce apoptosis in atypical T lymphocyte populations in the skin. Photopheresis, which directly treats atypical lymphocytes in circulation, has been used in severe systemic conditions with circulating atypical lymphocytes, like Sézary syndrome and graft-versus-host disease.

Apart from DNA effects, PUVA therapy stimulates epidermal thickening and melanin synthesis, making it suitable for treating depigmenting diseases like vitiligo. The oral form of 8-methoxypsoralen with UV-A appears most effective, but extensive treatment over 12-18 months may be necessary for satisfactory repigmentation.

The major side effects of long-term UV-B phototherapy and PUVA photochemotherapy resemble those resulting from chronic sun exposure. Nonetheless, these treatment modalities continue to provide excellent therapeutic results. Selecting the most suitable phototherapeutic approach for a specific dermatological condition is crucial. For instance, narrow-band UV-B has been reported to be as effective as PUVA photochemotherapy in treating psoriasis while posing a lower risk of skin cancer development than PUVA.