Cutaneous sarcoidosis successfully treated with PUVA therapy

Introduction

Sarcoidosis is a multi-organ, chronic inflammatory disease of unknown etiology, histopathologically characterized by the formation of non-serous granulomas. Historically, its first description by Jonathan Hutchinson dates back to the second half of the 19^th century and concerns a cutaneous manifestation [1]. After the lungs, the skin is the second most commonly involved organ in sarcoidosis [2, 3]. The disease most often affects young adults of both sexes, with a slight female predominance, according to literature [4]. Two peak incidences in the age ranges of 20–29 years and over 50 years are observed [5]. The incidence (rate) shows considerable regional and racial diversity. The most common nonspecific manifestation of sarcoidosis is erythema nodosum [6]. The specific lesions typically take the form of papules, nodules and plaques located on the face, upper back, and extremities. However, due to the variety of its clinical presentation, the disease has been named the “great imitator” [7]. Treatment most commonly involves topical, intralesional, and systemic corticosteroids, and, if ineffective, immunosuppressants and biologics [8]. Few case reports also address the successful use of phototherapy, including PUVA therapy with psoralen [9].

Objective

The purpose of this study is to present the case of a patient with cutaneous sarcoidosis who achieved complete remission of lesions following PUVA phototherapy.

Case report

A 51-year-old woman with no history of chronic diseases presented to the Dermatology Outpatient Clinic with lesions located on her back that had appeared about 3 months earlier. On physical examination, there were erythematous papular lesions, locally arranged in an annular pattern (fig. 1). Dermoscopically, yellow-orange structureless areas were noted. The patient denied having joint complaints and ophthalmic symptoms. Histopathological examination revealed regular, confluent granulomas without serosity, composed of epithelioid cells with multinucleated cells, located in the superficial and mid-dermis, with a sparse infiltration of lymphocytic cells at the periphery (figs. 2 A, B, 3). Laboratory tests showed neutropenia (1.8 × 10⁹/l), elevated total cholesterol (204 mg/dl) and insufficient 25(OH) vitamin D levels (11.9 ng/ml). Total calcium and angiotensin-converting enzyme (ACE) concentrations were within normal range. Anti-Borrelia burgdorferi IgM and IgG antibodies along with antinuclear antibodies were negative. Quantiferon TB Gold test was negative as well. A chest X-ray and abdominal ultrasound were performed and showed no abnormalities. Based on the correlation of clinical, dermoscopic, and histopathological findings, a diagnosis of cutaneous sarcoidosis was made. Due to the ineffectiveness of very potent topical corticosteroids, PUVA phototherapy with 20 mg of methoxsalen was implemented. After a cycle of 20 UVA irradiations at doses increasing by 0.5 J/cm² from 0.5 J/cm² to 7 J/cm² (total dose 94.5 J/cm²), applied 2–3 times a week, a complete remission of the skin lesions was achieved. The remission was maintained at follow-up visits 1 and 3 months after therapy termination (fig. 4). The patient is under follow-up at the Dermatology Outpatient Clinic.

Discussion

Cutaneous manifestations of sarcoidosis affect about one-third of the patients with this entity [5]. These may precede or accompany the involvement of other organs and may also occur as an isolated form of the disease [6]. There is a higher incidence of sarcoidosis in the African-American population compared to Caucasians [7, 10]. The etiology of lesion formation has not yet been fully elucidated. In genetically predisposed individuals, an excessive immune system response to environmental factors occurs. A number of predisposing HLA variants, as well as genes outside the HLA system, have been identified to date, and the prevalence of a positive family history has been estimated at 1–19% [11]. Sverrild et al. showed that when sarcoidosis was diagnosed in one monozygotic twin, the risk of the other twin to develop the disease was 80 times higher [12]. In the etiopathogenesis of sarcoidosis, the influence of environmental factors, including infectious (especially Mycobacterium tuberculosis, Propionibacterium [Cutibacterium]) factors, as well as non-infectious (organic compounds, e.g. factors pollen, molds, and inorganic compounds such as metal filings of beryllium, titanium, aluminum; insecticides, pesticides, tattoo dyes) agents, is also emphasized [7, 13, 14]. As a result of the immune system’s excessive cellular response to the triggering antigen, antigen-presenting cells (macrophages, dendritic cells) are activated. Antigens enter the cells, and their epitopes are presented via the HLA system to the T lymphocytes, resulting in granuloma formation [7, 15]. The ACCESS study (A Case Controlled Etiologic Study of Sarcoidosis) showed that smoking was a risk-reducing factor [13]. Sarcoidosis is more common in health care workers, people employed in the wood and automotive industries, firefighters, farmers, and soldiers [13]. In recent years, there have been reports of possible induction of the disease by immunomodulatory drugs, such as interferon-a (IFN-a), tumor necrosis factor (TNF) inhibitors, checkpoint inhibitors (nivolumab, among others), and BRAF inhibitors (vemurafenib) [10]. Some researchers have suggested a link between cutaneous sarcoidosis and malignancies. Among patients with confirmed sarcoidosis and a malignancy, a cutaneous manifestation was found in 56.4% of subjects, whereas in patients without an oncologic disease, cutaneous symptoms were present in only 20–25% of subjects [16].
The lesions most often take the form of papules and plaques ranging in color from pink-red, red-brown, to purple [9, 17]. Predisposed areas include the face, neck, and upper back, but lesions can appear in any location. The involvement of parts of the skin after previous trauma, such as scars and tattoos, is also quite typical. Rare manifestations of sarcoidosis have also been described, including presentations mimicking pigmented purpura or a UV-dependent form [18, 19].
The most common dermoscopic features include yellow-orange structureless areas and linear or branching vessels (fig. 5) [20, 21]. Diascopy typically reveals the color formation resembling apple jelly [22]. Confocal microscopy can also be helpful in establishing the diagnosis as well as in selecting an appropriate biopsy site [23].
Skin lesions are the most accessible biopsy material for the diagnosis of sarcoidosis. Histopathological examination reveals non-serous granulomas consisting of epithelial cells located in the dermis, which may be accompanied by minimal lymphocytic or plasmatic infiltrate. Due to the sparse inflammatory infiltration, these granulomas are sometimes referred to as “naked granulomas” [5].
The usefulness of conducting laboratory tests for angiotensin-converting enzyme (ACE) and total calcium, levels of which are typically elevated in patients with systemic sarcoidosis, is unclear in its cutaneous variant. In a retrospective study, Evenson et al. found elevated ACE levels in only 1 out of 13 patients with cutaneous sarcoidosis, while calcium levels were not elevated in any of the 17 patients studied [24].
Due to the multiplicity of clinical pictures, the disease has been named the “great imitator”. Many disorders can phenotypically mimic sarcoidosis as well. The presence of ring-shaped lesions can be differentiated from diseases such as granuloma annulare, fatty necrosis, a cutaneous form of Crohn’s disease, and granulomatous dermatitis [9]. Sarcoidosis in children is rarely described, and Blau syndrome should be ruled out when it is suspected [9].
Skin lesions in the course of sarcoidosis require differentiation from infections, including mycobacteriosis. Differential diagnosis also includes fungal and atypical mycobacterial infections, histoplasmosis, aspergillosis, Tropheryma whipplei infection, leishmaniasis, drug reactions, immunodeficiencies, and Melkersson-Rosenthal syndrome [7, 10, 14].
The first-line treatment of cutaneous sarcoidosis typically involves glucocorticosteroids. For limited lesions, potent topical medications or intralesional administration are most often used, while disseminated lesions are an indication for systemic corticosteroids. If these methods are ineffective, it is suggested to start treatment with methotrexate or antimalarial drugs [8, 25]. TNF-a and JAK/STAT inhibitors have also become the focus of research in recent years and may be useful as the third-line therapy [26]. Paradoxically, they also have the potential to induce and exacerbate skin lesions in sarcoidosis [26].
Phototherapy is also one of the therapeutic options for cutaneous sarcoidosis. Long-wave ultraviolet radiation demonstrates multidirectional immunosuppressive and immunomodulatory effects, including inducing apoptosis of T helper lymphocytes and increasing the production of certain anti-inflammatory cytokines, such as IL-10 [25, 27]. It also stimulates collagenase synthesis in the dermis. In a retrospective analysis of the efficacy of UVA1 (340–400 nm) for various dermatological indications, 86.3% of patients with sarcoidosis achieved significant improvement or complete remission of lesions [28]. The mean UVA1 dose in the study was 67.6 ±20.6 J/cm², with 36.7 ±14.6 irradiations per cycle, achieving a total dose of 2611 ±1600 J/cm² [28]. The therapy was well tolerated. Mahnke et al. achieved almost complete remission of cutaneous lesions in an 82-year-old female patient with medium-dose UVA1 therapy 4 times a week, using 15 initiating sessions at doses of 20–40 J/cm² and 35 sessions with a target dose of 60 J/cm² (total dose of 2640 J/cm²) [29].
Psoralens used in UVA-induced photochemotherapy cross-link with DNA, inhibiting the cell cycle and consequently cell division [30]. The most commonly described form of PUVA therapy in the literature involves topical psoralen (gel, 0.005%). A systematic review by Lima et al. showed complete efficacy with this method in 3/6 patients and a 50% improvement in the remaining patients [31]. The initial dose was 0.2 J/cm² and was increased by 0.1–0.2 J/cm² to a maximum dose of 3.7 J/cm². On average, 50 irradiations were applied to patients and the therapy was combined with systemic treatment using either prednisolone or hydroxychloroquine. PUVA therapy with oral psoralen is widely used in other granulomatous diseases. In a systematic review by Mukovozov et al., the overall efficacy of PUVA in granuloma annulare was 59% (n = 77/131), while partial improvement was achieved in 25% of patients (n = 33/131) with a mean duration of treatment lasting 2.2 months [32].
The efficacy of NB UVB has also been described in a 69-year-old female patient with cutaneous sarcoidosis of the tibial region, whose lesions resembled fat necrosis [33]. In this case, irradiation with a dose of 0.3 J/cm² once a week was applied. After 8 months of treatment, a significant reduction in skin lesions was achieved, but inflammatory infiltration was still evident on histopathological examination. Given that the majority of sarcoidosis lesions involve the reticular layer of the dermis and that UV 311 nm radiation has a lower penetration depth and a weaker immunosuppressive effect relative to radiation in the 320–400 nm range, UVA phototherapy may be more effective treatment option than NB UVB in this more. However, it should be noted that UVA phototherapy is associated with a higher risk of cutaneous carcinogenesis.
Photodynamic therapy (PDT) with a photosensitizer is also increasingly used light treatment modality in dermatology. This involves the topical application of a photosensitizer, usually 5-aminolevulinic acid (ALA) or its derivative 5-aminolevulinic acid methyl ester (MAL), which is absorbed to a much greater extent by pathological cells than normal cells [34]. Under the influence of red light, the production of reactive oxygen species and consequently cellular apoptosis occurs. In addition to its cytotoxic effects, PDT also shows vascular destruction and immunomodulatory properties [25, 35]. A systematic review by Lima et al. found significant local improvement after implementing this method in 7/7 patients [31]. Local side effects such as burning sensation, erythema, edema, hyperpigmentation, and superficial peeling were reported. The local control of the disease in a 65-year-old female patient with recurrent head sarcoidosis after 10 PDT series and six daylight-PDT series was also described [36].
Laser therapy may also be applied in the treatment of limited skin lesions. The greatest number of case reports relate to the use of pulsed dye laser (PDL, 585–595 nm) in lupus pernio [31]. This is an emphysematous form of cutaneous sarcoidosis located mainly in the facial region and characterized by reddish-purple lesions in the form of papules, nodules, or plaques and dilated dermal blood vessels. The mechanism of PDL is based on selective damage to superficial and intermediate-depth dermal blood vessels, which justifies its reported efficacy in this variant of sarcoidosis [37]. The therapy is well tolerated, but may potentially be associated with erythema, skin atrophy, scarring, or dyspigmentation [25]. A case of the successful use of a fractional CO₂ laser in a patient with symmetric plaques of the cheek region was also documented [38]. This method is based on using the fractional photothermolysis and inducing tissue remodeling. There are single reports on the use of other types of lasers: Q-switched ruby laser, neodymium-YAG laser (Nd:YAG), potassium-titanium-phosphate laser (KTP), and intense pulsed light (IPL) [25, 31, 39].

Conclusions

Cutaneous sarcoidosis poses diagnostic and therapeutic challenges for physicians. PUVA phototherapy with psoralen may be an effective treatment option in cutaneous sarcoidosis.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References