Pseudoporphyria

INTRODUCTION — Pseudoporphyria is a bullous photodermatosis with the clinical and histologic features of porphyria cutanea tarda (PCT), in the absence of abnormalities in porphyrin metabolism [1]. Pseudoporphyria has been associated with medications, chronic renal failure and hemodialysis, and tanning beds. Patients typically present with skin fragility, bullae, milia, and scarring on the dorsum of the hands and other sun-exposed areas (picture 1A-B). Histologically, there is a noninflammatory subepidermal blister.

This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and treatment of pseudoporphyria. PCT and other types of porphyrias associated with photosensitivity are discussed separately. Other photosensitivity disorders are also discussed separately.

●(See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

●(See "Erythropoietic protoporphyria and X-linked protoporphyria".)

●(See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment".)

EPIDEMIOLOGY — Pseudoporphyria is a rare condition; its exact incidence is unknown. It occurs at any age and more frequently in women than in men. Pseudoporphyria has been reported in approximately 10 percent of children taking naproxen, a nonsteroidal anti-inflammatory drug (NSAID) routinely used in the therapy of juvenile idiopathic arthritis [2]. Among children treated with naproxen, risk factors for the development of pseudoporphyria include skin phototypes I or II (table 1), blue/gray eyes, and the concurrent use of chloroquine [2-4]. Naproxen and other propionic acid derivative NSAIDs are also the most common cause of pseudoporphyria in adults [5,6]. Pseudoporphyria has been reported in approximately 1 to 16 percent of hemodialysis patients [7-10].

ETIOLOGY AND PATHOGENESIS — Four factors have been implicated in the etiology of pseudoporphyria: ultraviolet (UV) radiation, medications, chronic renal failure and hemodialysis, and tanning beds.

Ultraviolet radiation — Although the exact pathogenetic mechanism is unknown, drug-induced pseudoporphyria is considered a photodynamic phototoxic drug reaction. In this type of reaction, the photosensitizing compound, upon absorption of the appropriate wavelength radiation, changes to an excited state and reacts with oxygen to form reactive oxygen species (ROS), such as singlet oxygen, hydrogen peroxide, or superoxide anion. ROS can damage cell components, such as nucleic acids, membranes, lipids, and proteins. Mediators of inflammation and inflammatory cells participate in tissue injury, including products of complement activation, proinflammatory cytokines, arachidonic acid metabolites, proteases, and polymorphonuclear leukocytes.

Medications — Pseudoporphyria was first identified among individuals taking the quinolone antibiotic nalidixic acid [11-13]. Subsequently, a variety of other medications have been associated with pseudoporphyria, including nonsteroidal anti-inflammatory drugs (NSAIDs), other types of antibiotics, diuretics, retinoids, and antineoplastic agents (table 2) [1,6,14-19]. Tyrosine kinase inhibitors imatinib and sunitinib, used in the treatment of several cancers, and voriconazole have also been associated with pseudoporphyria [15,16,20-24].

Naproxen, an NSAID derived from propionic acid, is responsible for most cases of pseudoporphyria [3,4,25-32]. Propionic acid derivative NSAIDs (eg, naproxen, oxaprozin, ketoprofen, and ibuprofen) are more likely to cause pseudoporphyria than other classes of NSAIDs [5,33-42]. However, several nonpropionic acid NSAIDs (eg, diflunisal, celecoxib, mefenamic acid, and nabumetone) have also been associated with pseudoporphyria [33-36,42,43].

It is unknown why pseudoporphyria manifests with vesicles and bullae, whereas drug-induced phototoxic reactions usually appear as exaggerated sunburns [13,31,44]. It is also unknown why pseudoporphyria usually continues for months after the drug has been discontinued. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.)

Hemodialysis and peritoneal dialysis — Pseudoporphyria occurs in patients with end-stage kidney disease who are receiving chronic hemodialysis or peritoneal dialysis [45-47]. In case series, 0.6 to 16 percent of patients on hemodialysis developed the disease [7-10]. Aluminum hydroxide in dialysis solutions or chemicals in polyvinyl chloride dialysis tubing are suspected to be the photosensitizing agents in these patients [48,49]. Other theories include an inability to handle oxidative stress due to reduced levels of the endogenous antioxidant glutathione [50]. Patients with end-stage kidney disease may also have elevated plasma porphyrins due to impaired excretion and decreased porphyrin clearance by hemodialysis or peritoneal dialysis [51,52].

Tanning beds and other artificial ultraviolet A sources — Pseudoporphyria was reported in a small number of women with frequent exposure to high doses of ultraviolet A (UVA) radiation from tanning beds [53-57]. In some cases, the patients were using medications (eg, naproxen, antibiotics, or oral contraceptives) that are known inducers of pseudoporphyria. There is a case report of UV radiation from nail hardening lamps aggravating pseudoporphyria [58].

HISTOPATHOLOGY — The histologic features of pseudoporphyria closely resemble those of porphyria cutanea tarda (PCT) and other types of porphyria that cause blistering. Histologic examination of a bullous lesion typically shows a noninflammatory subepidermal blister with a scant perivascular lymphocytic infiltrate (picture 2). Festooning (ie, the preservation of the dermal papillae in the floor of the lesion) may be seen [1,44,53,59].

Cytoid or "caterpillar" bodies, which are considered a specific histopathologic finding of porphyrias, are also seen in pseudoporphyria (picture 3) [59,60]. Caterpillar bodies are segmented and elongated structures containing laminin and type IV collagen that are positioned parallel to the epidermis [60,61]. Endothelial wall thickening from periodic acid-Schiff-positive, diastase-resistant material may be seen in the upper dermal microvasculature.

Direct immunofluorescence of lesional and perilesional skin reveals changes similar to those seen in PCT. Immunoglobulin G (IgG), immunoglobulin M (IgM), C3, and fibrinogen are frequently found at the dermoepidermal junction and in the vessel walls of lesional and perilesional skin (picture 4) [59]. Deposits of immunoglobulin and complement may be seen in the dermal vasculature in a doughnut-shaped pattern [59,62]. However, the absence of immunoreactants in dermal vessels and at the basement membrane zone does not exclude the diagnosis of pseudoporphyria.

Immunofluorescent antigen mapping has been performed to determine the level of skin splitting in pseudoporphyria. Using this technique, type IV collagen, laminin, and bullous pemphigoid antigen have been observed at the base of the blister, with no characteristic cleavage level [63]. However, ultrastructural studies have shown a split in the superficial dermis, with the basal lamina, hemidesmosomes, anchoring fibrils, and collagen fibers in the roof of the blister [31,53].

CLINICAL MANIFESTATIONS — Patients with pseudoporphyria present with bullae and vesicles typically localized to the dorsum of the hands, forearms, and face (picture 1A-B). Lesions may also occur on the lower legs and feet. Skin fragility and easy bruising after minor trauma are common complaints (picture 5) [28,29,64]. Bullae heal with scarring and milia in most patients [4,25,31,62,65].

In contrast to porphyria cutanea tarda (PCT), hypertrichosis, hyperpigmentation, and sclerodermoid changes are rarely reported in pseudoporphyria (table 3). (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical features'.)

CLINICAL COURSE — In most cases, drug-induced pseudoporphyria has a protracted course. Cutaneous lesions continue to develop even after the offending drug has been discontinued. In one series of 16 patients, the symptoms resolved within six months of discontinuation of the medication in 5 patients but persisted for an average of 2.5 years after discontinuation in 11 [62].

DIAGNOSIS — The diagnosis of pseudoporphyria is based upon the combination of the following:

●Cutaneous manifestations similar to those found in porphyria cutanea tarda (PCT) (eg, skin fragility, vesicles and bullae involving sun-exposed skin, particularly the face and the dorsum of the hands) (picture 1A-B).

●Histologic finding of subepidermal blister with scant perivascular lymphocytic infiltrate (picture 2). On direct immunofluorescence, detection of IgG, IgM, C3, and fibrinogen at the dermoepidermal junction and in the vessel walls (picture 4).

●Normal porphyrin levels in plasma, erythrocytes, urine, and stool. (See "Porphyrias: An overview", section on 'Diagnostic testing (blistering cutaneous porphyria suspected)'.)

●Reported use of potentially phototoxic medications (table 2), history of chronic renal failure and dialysis, or ultraviolet A (UVA) exposure.

●Because the clinical and histologic features of pseudoporphyria closely resemble those of PCT, pseudoporphyria is often only considered after evaluation for PCT has revealed normal porphyrin levels. This is an essential diagnostic criterion of pseudoporphyria.

In some instances, it may be necessary to obtain serology for antinuclear antibodies, antitype VII collagen antibodies, and anti-Ro/SSA and anti-La/SSB antibodies to exclude bullous lupus or epidermolysis bullosa acquisita. (See 'Differential diagnosis' below.)

Phototesting is not helpful in the evaluation of patients suspected of having pseudoporphyria. Although some individuals will exhibit a reduced minimal erythema dose (MED) to UVA, neither phototesting nor photoprovocation testing has been successful in reproducing the subepidermal blisters characteristic of the disease.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of pseudoporphyria includes porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP), other less common cutaneous porphyrias (ie, variegate porphyria, hereditary coproporphyria, congenital erythropoietic porphyria), and other bullous disorders presenting with similar clinical manifestations, including epidermolysis bullosa acquisita, bullous pemphigoid, bullous lupus erythematosus, and hydroa vacciniforme.

Porphyria cutanea tarda — Porphyria cutanea tarda (PCT) is a defect of porphyrin metabolism due to an inherited or acquired deficiency of hepatic uroporphyrinogen decarboxylase (UROD) and precipitated by several cofactors, including alcohol abuse, iron overload, hepatitis C, HIV infection, drugs (table 3), and end-stage kidney disease [66,67]. PCT usually presents in adulthood with blisters, bullae, increased fragility, scarring, and hyper- and hypopigmentation affecting sun-exposed areas of the body, such as the backs of the hands, forearms, face, ears, neck, and feet (picture 6A-C).

Measurement of total porphyrins in plasma, serum, or urine can differentiate PCT and the other less common cutaneous porphyrias from pseudoporphyria. However, distinguishing pseudoporphyria from PCT in the setting of end-stage kidney disease may be difficult.

In patients on hemodialysis or peritoneal dialysis, plasma porphyrins may be elevated in the absence of UROD deficiency due to impaired excretion and inefficient porphyrin clearance by the renal replacement therapy [51,52,68]. However, in these patients, the plasma porphyrin levels are lower than those seen in patients with PCT, and there is no predominance of the heptacarboxylic fraction typically seen in PCT [51]. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

Epidermolysis bullosa acquisita — Epidermolysis bullosa acquisita is a rare autoimmune bullous disease caused by autoantibodies against type VII collagen (picture 7A). Serous or hemorrhagic blisters are localized to areas of trauma, especially on the dorsum of the hands and feet and elbows. They heal with scarring, milia, and hyperpigmentation. On direct immunofluorescence, there is a linear deposit of IgG at the basement membrane zone. Circulating autoantibodies against collagen VII can be demonstrated by enzyme-linked immunosorbent assay (ELISA) techniques. (See "Epidermolysis bullosa acquisita".)

Bullous pemphigoid — Bullous pemphigoid is an autoimmune bullous disease occurring most commonly in older individuals. Urticarial plaques and tense bullae may occur in all body areas (picture 8). Direct immunofluorescence of perilesional skin shows IgG and C3, or C3 alone along the basement membrane zone. Circulating antibodies against the bullous pemphigoid antigen BP 180 can be detected by ELISA techniques. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

Pemphigus — Pemphigus is an autoimmune bullous disease caused by the development of autoantibodies to intercellular adhesion molecules desmoglein 1 and 3. Patients develop flaccid blisters and erosions, both on sun-exposed and sun-protected skin (picture 9). There are reports of pemphigus induced or aggravated by exposure to ultraviolet (UV) light [69-72]. Direct immunofluorescence staining showing intercellular deposition of IgG as well as the detection of circulating autoantibodies against cell surface antigens in serum are diagnostic. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)

Bullous lupus erythematosus — Bullous lupus erythematosus is an uncommon form of systemic lupus erythematosus caused by autoantibodies against type VII collagen [73]. Vesicles and tense bullae are most often localized to the neck and upper trunk but also may develop on unexposed skin (picture 10). Direct immunofluorescence demonstrates linear deposition of IgG, immunoglobulin A (IgA), IgM, and C3 along the dermoepidermal junction. Salt-split skin is positive for IgG, IgA, and IgM on the floor of the blister. (See "Overview of cutaneous lupus erythematosus", section on 'Bullous cutaneous lupus erythematosus'.)

Hydroa vacciniforme — In children with facial blistering, hydroa vacciniforme (picture 11A-B) can mimic pseudoporphyria. Hydroa vacciniforme is a rare photodermatosis of childhood characterized by vesicular lesions on sun-exposed skin that heal leaving depressed scars. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Hydroa vacciniforme'.)

Erythropoietic protoporphyria — Erythropoietic protoporphyria (EPP) is an autosomal recessive or pseudodominant disease of porphyrin metabolism due to ferrochelatase deficiency and characterized by painful, nonblistering photosensitivity usually manifesting in early childhood (table 4) [66,67]. Soon after or even during sun exposure, patients develop a severe burning or stinging pain that may be followed by redness, swelling, and petechiae formation (picture 12). Petechiae may last several days. The face and dorsum of the hands are most commonly affected. Repeated exposures may result in shallow vacciniforme scarring, perioral furrows, and waxy skin thickening (picture 13). The diagnosis of EPP is based upon the demonstration of a markedly increased free erythrocyte protoporphyrin. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

TREATMENT — Discontinuation of the offending agent and photoprotection are the most important aspects of the management of patients with pseudoporphyria. Evidence of efficacy of pharmacologic agents, such as N-acetylcysteine, is limited to a few case reports:

●Discontinuation of the offending agent – For patients with drug-induced pseudoporphyria, discontinuation of the offending agent (if possible) is a crucial aspect of management. The resolution of the clinical manifestations is slow. Patients can expect gradual improvement with a decrease in blistering and skin fragility over a period of months to years [62].

●Discontinuation of tanning bed use – For patients with pseudoporphyria associated with excessive exposure to artificial ultraviolet A (UVA) sources from tanning beds, discontinuation of the practice is essential for the control of disease.

●Photoprotection – Photoprotection is essential for all patients with pseudoporphyria. Photoprotection should continue at least until resolution of symptoms. Photoprotection measures include sun avoidance, use of protective clothing (long-sleeved shirts, blouses, pants, wide-brimmed hats), and broad-spectrum sunscreens (table 5). (See "Selection of sunscreen and sun-protective measures".)

●N-acetylcysteine – A beneficial effect of N-acetylcysteine has been reported in a few patients with chronic renal failure and hemodialysis-associated pseudoporphyria [74-80]. N-acetylcysteine is a precursor of glutathione, an endogenous antioxidant, the levels of which are reduced in hemodialysis patients.

●Other – There is a single report of a patient with hemodialysis-associated pseudoporphyria successfully treated with oral glutathione [78]. In another single case report, hemodialysis-associated pseudoporphyria was successfully treated with oral glutamine [81]. Two patients on hemodialysis responded to photoprotection and vitamin D supplementation [82].

SUMMARY AND RECOMMENDATIONS

●Definition and epidemiology – Pseudoporphyria is a bullous photodermatosis with the clinical and histologic features of porphyria cutanea tarda (PCT), in the absence of abnormalities in porphyrin metabolism. Pseudoporphyria has been reported in approximately 10 percent of children taking naproxen for juvenile idiopathic arthritis. (See 'Introduction' above and 'Epidemiology' above.)

●Pathogenesis – Although the exact pathogenetic mechanism is unknown, pseudoporphyria is considered a photodynamic phototoxic drug reaction. It is most often caused by medications, including nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, diuretics, and antineoplastic agents (table 2). (See 'Etiology and pathogenesis' above.)

●Clinical presentation – The clinical manifestations of pseudoporphyria closely resemble those of PCT and include skin fragility, bullae, and vesicles involving sun-exposed areas of the body, such as the face and dorsum of the hands (picture 1A-B). (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of pseudoporphyria is made in a patient with clinical and histologic features of PCT; normal porphyrin levels in red blood cells, plasma, urine, and stool; and reported use of phototoxic medications, hemodialysis, or tanning beds. (See 'Diagnosis' above.)

●Differential diagnosis – Pseudoporphyria should be differentiated from PCT (picture 6A-C), erythropoietic protoporphyria (picture 12), other less common photocutaneous porphyrias, and bullous disorders presenting with similar clinical manifestations, including epidermolysis bullosa acquisita (picture 7A-B), bullous pemphigoid (picture 8), pemphigus (picture 9), bullous lupus erythematosus (picture 10), and hydroa vacciniforme (picture 11A-B). (See 'Differential diagnosis' above.)

●Treatment – Discontinuation of the offending agent and photoprotection are the most important aspects of the management of patients with pseudoporphyria. N-acetylcysteine may be helpful for hemodialysis-associated pseudoporphyria. (See 'Treatment' above.)