Are You Confident of the Diagnosis?
The term pseudoporphyria refers to a photodistributed vesiculo-bullous disorder with clinical and histologic features resembling those of porphyria cutanea tarda (PCT), but without the accompanying biochemical porphyrin abnormalities. The disorder was initially described in 1975, referring to chronic renal failure patients with a PCT-like bullous disorder. Since then, pseudoporphyria has been attributed to various medications, ultraviolet (UV) A radiation, and excessive sun exposure.
What you should be alert for in the history
Making the diagnosis of pseudoporphyria requires taking a careful history, including UV light exposure, current or prior medications, medical history, and family history.
Characteristic features on physical examination
Physical examination should focus on differential findings, including the presence or abscence of hyperpigmentation, hypertrichosis, sclerodermoid features, dystrophic calcification, facial scarring, waxy thickening, milia, and skin fragility. The distribution of the lesions should be carefully noted.
The clinical findings of pseudoporphyria may be identical to or closely resemble those of PCT. Sun-exposed skin may present with vesicles, bullae, skin fragility, milia, and scarring. The most commonly affected sites are the dorsal hands and digits (Figure 1), but the extensor legs, upper chest, and face may also be involved. In contrast to PCT, hypertrichosis, hyperpigmentation, sclerodermoid changes, and dystrophic calcifications are not common. Children may present with facial scarring resembling erythropoietic protoporphyria.
Routine histologic examination, direct and indirect immunofluorescence, and serologic tests including blood, urine, and fecal porphyrins should be performed in order to rule out PCT, erythropoietic protoporphyria (EPP), epidermolysis bullosa acquisita, bullous pemphigoid, and bullous lupus erythematosus. By definition, porphyrin assays of red blood cells, plasma, urine, and feces are normal in pseudoporphyria. Biopsies for histologic evaluation with hematoxylin and eosin stains and direct immunofluorescence (DIF) should be performed. To exclude bullous pemphigoid, indirect serum samples for immunofluorescence evaluation and ELISA (enzyme-linked immunosorbent assay) testing for bullous pemphigoid antigens 1 and 2 can be requested.
Expected results of diagnostic studies
Histopathology and immunofluorescence show characteristics similar to PCT. Findings include subepidermal bullae with or without festooning of dermal papillae and mild lymphocytic perivascular infiltrate. PAS-positive thickening of blood vessel walls and sclerosis of collagen may also be noted and may be helpful in differentiating pseudoporphyria from PCT, as these occur less often in pseudoporphyria. DIF shows similar, nonspecific findings in both pseudoporphyria and PCT. These findings indicate granular deposits of IgG and C3 at the dermoepidermal junction and perivascular region. Postive DIF findings are suggestive, but not required in making the diagnosis of pseudoporphyria. IgM, IgA, and fibrinogen may be deposited in pseudoporphyria and PCT, but cytoid bodies are more common in PCT.
The differential diagnosis of pseudoporphyria includes, PCT, erythropoietic protoporphyria (EPP), hydroa vacciniforme, epidermolysis bullosa acquisita, bullous pemphigoid, and bullous lupus erythematosus. However, several features distinguish pseudoporphyria from “true” porphyria. Females predominate in tanning bed and pseudoporphyria induced by nonsteroidal antiinflammatory drugs (NSAIDS), whereas PCT predominantly afftects males. Additionally, physical findings such as hypertrichosis, hyperpigmentation, sclerodermoid changes, and dystrophic calcification are frequently evident in PCT but not in pseudoporphyria. In children taking NSAIDs who develop facial scarring, history of burning, routine histologic examination, and free porphyrin levels should exclude hydroa vacciniforme and EPP.
Who is at Risk for Developing this Disease?
The epidemiology of pseudoporphyria varies depending on the causative agent and certain predisposing conditions. There are, however, certain notable trends. In adults, naproxen-induced pseudoporphyria and tanning bed-induced pseudoporphyria has been observed primarily in females, the latter of which may be attributed to trends in gender use of sunless tanning beds.
All reports of tanning bed-induced pseudoporphyria involve patients aged younger than 50 years, with the majority being in their 20s and 30s. Fair skin appears to be a predisposing skin factor in both adults and children. Hepatic impairment has also been observed in some patients with pseudoporphyria, and this may play a concomittant role in the development of the disease.
Overall, most cases of NSAID-induced pseudoporphyria occur in children, with reports of incidences up to 11.4% in children taking NSAIDs for juvenile idiopathic arthritis (JIA). Naproxen is the most common culprit, and it is routinely used in the treatment of children with JIA and associated rheumatologic diseases due to its high tolerability and long-half life.
Pseudoporphyria has been found to occur, on average, 1.5 years after treatment with naproxen, The skin on the face is most commonly involved, and typically displays 10 or fewer vesicular lesions. Additionally, it has been found that JIA disease activity as indicated by low Hgb level, increased WBC count, and elevated ESR may be risk factors for development of pseudoporphyria.
What is the Cause of the Disease?
The following causative agents have all been linked with pseudoporphyria:
Ultraviolet (UV) A tanning beds
Psoralen plus UVA (PUVA) phototherapy
Excessive sun exposure
Nnonsteroidal antiinflammatory drugs (NSAIDs)
ampicilin-sulbactam combined vwith cefepime
oral contraceptive pills
Excessive Coca-Cola consumption
Chronic renal failure and hemodialysis
Hepatitis C virus
Just as in PCT, evidence indicates that UV light is a necessary factor in the development of pseudoporphyria, especially given the distribution of lesions in photoexposed areas. Because of the association with photosensitizing drugs, excessive sun exposure, tanning beds, and PUVA phototherapy, the action spectrum of UV light in pseudoporphyria appears to be in the UVA range. Even with normal porphyrin levels, a phototoxic reaction can occur in the presence of dermally penetrating UVA.
The lesions of tanning bed-induced pseudoporphyria occur most frequently on the dorsal hands, but other photodistributed areas such as the knees, pretibial surfaces, feet, and upper chest can also be involved. Although tanning bed exposure has independently been linked with pseudoporphyria, interestingly enough, many of the reported cases have involved patients who concurrently took medications that are known inducers of pseudoporphyria, such as NSAIDs, furosemide, tetracyclines, or oral contraceptives.
Medications may directly cause phototoxic reactions or may release oxygen free radicals. Additionally, medications such as retinoids, NSAIDs, and nalidixic acid may lower the threshold for UVA effects by being photosensitizers. Repeated endothelial damage may cause increased vascular permeability and result in blister formation.
Several cases of nabumetone (a structurally similar drug to naproxen)-induced pseudoporphyria have been reported, with some studies indicating that connective tissue disease may be a predisposing factor for pseudoporphyria in patients taking this drug. Other isolated cases of pseudoporphyria have also been reported with oxaprozin, ketoprofen, mefenamic acid, diflunisal, and carisoprodol/aspirin. Photosensitivity, but not pseudoporphyria, has been reported with piroxicam, tiaprofenic acid, and benoxaprofen.
Cross-reactions between causative drugs may also exist. One notable association has been that seen with the loop diuretics torsemide and furosemide. The persistence of lesions after switching from torsemide to furosemide treatment and the disappearance of these lesions after altogether stopping furosemide treatment suggests a cross-reaction between the two drugs. This may be due to the fact that both drugs belong to the sulfamide group of diuretics, sharing similar chemical structures. In children, however, the majority of cases of pseudoporphyria have been associated with naproxen.
Fluorinated quinolone antibiotics such as ofloxacin have been shown to affect screening for urinary porphyrins, resulting in a 20-fold increase in these levels. A 2-fold increase in urinary porphyrins has been observed with ciprofloxacin and norfloxacin. Additionally, since these agents can induce photosensitivity, this may lead to a false-positive diagnosis of PCT.
End-stage renal disease
Reports of successful treatment of hemodialysis (HD)-associated pseudoporphyria with N-acetylcysteine suggest that oxygen free radicals may be important mediators in this subset of patients. Due to reduced circulating levels of glutathione in patients with ESRD, they are especially prone to oxidative stress, a factor which may increase their suspecitbility to the adverse effects of UV light exposure even at low or normal porphyrin levels. In the setting of chornic renal failure, pseudoporphyria may also be due to the additive effect of UVA exposure and inadequate renal clearance of photosensitive drugs.
Additionally, ESRD patients may actually have abnormal porphyrin profiles due to impaired excretion (rather than uroporphyrinogen decarboxylase deficiency) of porphyrins, and this is likely to contribute to the increased photosensitivity and subsequent blistering. Estimates suggest that pseudoporphyria occurs in 1.2-1.8% of ESRD patients on HD, and very rarely in patients on peritoneal dialysis. Interestingly, patients on HD tend to have higher plasma uroporphyrin levels than those patients on peritoneal dialysis, which may account for the higher incidence of pseudoporphyria in HD patients.
Other proposed factors that can elicit pseudoporphyria in patients with ESRD on HD include diuretics, aluminum hydroxide, hemosiderosis, silicone particles, erythropoietin, and polyvinyl choloride dialysis tubing. It can be difficult to establish the diagnosis of pseudoporphyria distinct from PCT, because PCT concurrent with chronic renal failure can also occur. This is especially complicated by the known higher incidence of asymptomatic serum porphyrin abnormalities. Because of the difficulties encountered in the setting of HD, plasma porphyrins and fecal porphyrins should also be evaluated in patients with chronic renal failure.
Systemic Implications and Complications
There are no known systemic complications related to pseudoporphyria. There are no studies to suggest patients with pseudoporphyria have an independently higher risk for melanoma or non-melanoma skin cancer development. Scarring as the result of vesicle formation may be psychologically disturbing.
Treatment options are summarized in Table I.
|1. Discontinue suspected agents (including medications and UVA exposure, PUVA, etc.)||1. Sun protection, especially against UVA wavelengths|
|2. Switch to alternative regimens with less photosensitizing profiles (ex. in patients on NSAIDs, switch to diclofenac, indomethacin, sulindac)|
|3. N-acetylcysteine in HD-associated pseudoporphyria|
HD, hemodialysis; NSAIDS, nonsteroidal antiinflammatory drugs; PUVA, psoralen plus ultraviolet A
N-acetylcysteine is a metabolic precursor of glutathione, and its administration therefore increases the biosynthesis of glutathione in conditions of increased oxidative stress. Therefore, this is a viable options in end-stage renal disease (ESRD) patients who are more susceptible to the adverse effects of UV light exposure. Doses from 800-1200 mg/day in divided doses have been found to be effective.
Phlebotomy and antimalarial therapies such as hydroxychloroquine are useful in the treatment of PCT but play no significant role in the treatment of pseudoporphyria. In particular, hydroxychloroquine is thought to form complexes with porphyrins that are cleared by the kidneys, and thus it would not be expected to be useful in hemodialysis (HD) patients because the complexes would be of too high molecular weight to pass through a dialysis membrane. There is also currently no consensus on whether erythropoietin is a treatment or an inducer of pseudoporphyria.
Photoprotective clothing and sunscreens should be recommended. Sunscreens should have a sun protection factor of 30 and contain UVA blocking ingredients (eg, zinc oxide, titanium dioxide, avobenzone, or mexoryl).
Optimal Therapeutic Approach for this Disease
The optimal therapeutic approach for this disorder should follow the steps above, in order. All of these therapies pose little risk to the patient, and have an outstanding risk/benefit ratio. Treatment options in ESRD patients on HD may prove to be more challenging, as resistance to N-acetylcysteine has been found in isolated cases.
Despite the difficulty in treating renal failure patients, the therapeutic approach should begin with the discontinuation of suspected agents, switch to an alternate regimen, and administration of N-acetylcysteine when ESRD on or off HD is a known co-morbidity. Barrier protection against UVA wavelengths should be a lifelong physical intervention for patients with a history of pseudoporphyria.
Once the offending agent has been discontinued, the prognosis for pseudoporphyria is good. It may take several months for skin lesiosn to resolve, and some patients are left with permanent scarring. This is especially true in the setting of drug-induced porphyria. No further monitoring, follow-up, or maintenance therapy is necessary once the clinical symptoms have resolved. Future avoidance of precipitating drugs and UVA light is, however, critical.
Unusual Clinical Scenarios to Consider in Patient Management
A recent case report suggests an unusual presentation of this disorder, in which an ESRD patient with hemodialysis-induced pseudoporphyria did not respond to 3 months of treatment with oral N-acetylcysteine. However, the patient showed near-immediate resolution of blisters within 1 month of treatment with oral chloroquine.
Additionally, naproxen-induced pseudoporphyria, the majority of which cases occur in children, may persist in these patients despite discontinuation of the medication. Previous studies have shown that blister formation in this population may last up to 5 weeks, skin fragility up to 4-6 months, and scarring may persist for years.
What is the Evidence?
Green, JJ, Manders, SM. “Pseudoporphyria”. J Am Acad Dermatol. vol. 44. 2001. pp. 100-8. (A thorough review of the pathophysiology, suspected etiologies, and treatment options of pseudoporphyria. Includes detailed discussion of differential diagnosis and distinguising of pseudoporphyria from other bullous disorders.)
El Kabbaj, D, Laalou, A, Alouane, Z. “Hemodialysis-assciated pseudoporphyria resistant to N-acetylcysteine”. Saudi J Kidney Dis Transpl. vol. 22. 2011 Mar. pp. 311-4. (A case report of a 33-year-old female patient with HD-associated pseudoporphyria that did not repsond to treatment with oral N-acetylcysteine but did respond to treatment with oral chloroquine. The article also highlights the possible causes for difficulty in interpreting urinary porphyrin assays of patients in renal failure.)
Berghoff, AT, English, JC. “Imantinib mesylate-induced pseudoporphyria”. J Am Acad Dermatol. vol. 63. 2010 Jul. pp. e14-6. (A brief case report of a 63-year-old female with CML on Imantinib mesylate (IM), a tyrosine kinase inhibitor, as well as naproxen and estrogen supplements. Discontinuation of naproxen and estrogen therapies did not lead to resolution of primary blistering, favoring IM as the most likely cause of pseudoporphyria.)
Perez-Bustillo, A, Sanchez-Sambucety, P, Suarez-Amor, O. “Torsemide-induced pseudoporphyria”. Arch Dermatol. vol. 144. Jun. pp. 812-3. (A case report of a 64-year-old male with chronic renal failure who presented with blistering lesions 2 months after starting torsemide therapy. However, the persistence of lesions after substituting furosemide for torsemide suggests a cross-reaction between the two drugs, and warrants caution in using drugs belonging to the same family.)
Degiovanni, CV, Darley, CR. “Pseudoporphyria occuring during a course of ciprofloxacin”. Clin Exp Dermatol. vol. 33. 2008 Jan. pp. 109-10. (A case report of a 65-year-old male on ciprofloxacin treatment for a chest infection presenting with blistering and ulcerations on the dorsum of his hands. The patient reported a concomittant heavy use of alcohol and had elevated LFTs, suggesting that hepatic impairment may play a role in the development of pseudoporphyria. The article also includes a discussion of fluoroquinolones as photosensitizing drugs.)
Kwong, WT, Hsu, S. “Pseudoporphyria associated with voriconazole”. J Drugs Dermatol. vol. 6. 2007 Oct. pp. 1042-4. (A case report of a 50-year-old female, status-post lung transplant for end-stage emphysema and on voriconazole therapy for prophylaxis against invasive aspergillosis. The patient presented with blistering after commencing a 10-minute daily walking regimen. She was maintained on voriconazole therapy due to its clinical necessity, but her blistering was controlled with the use of a sunscreen with UVA/UVB protection.)
Cooke, NS, McKenna, K. “A case of haemodialysis-associated pseudoporphyria successfully treated with oral N-acetylcysteine”. Clin Exp Dermatol. vol. 32. 2007 Jan. pp. 64-6. (A case report of a 33-year-old female with HD-associated pseudoporphyria successfully responding to treatment with oral N-acetylcysteine. Includes a discussion of pseudoporphyria occuring in HD versus peritoneal dialysis, as well the clinical utility and mechanism of N-acetylcysteine treatment in HD-associated pseudoporphyria.)
Schad, SG, Kraus, A, Haubitz, I. “Early onset pauciarticular arthritis is the major risk factor for naproxen-induced pseudoporphyria in juvenile idiopathic arthritis”. Arthritis Res Ther. vol. 9. 2007. pp. R10(A prospective study of the incidence of pseudoporphyria in 196 patients with JIA treated with naproxen, and comparison of the data with that froma matched control group with JIA not treated with naproxen in order to identify potential risk factors for the development of pseudoporphyria. The study found an incidence of 11.4% in the occurrence of pseudoporphyria, and this was particularly frequent in children with early-onset pauciarticular type of JIA.)
Fevang, SA, Kroon, S, Skadberg, O. “Pseudoporphyria or porphyria cutanea tarda? Diagnostic and treatment difficulties”. Acta Derm Vernereol. vol. 88. 2008. pp. 426-7. (A case report of an 81-year -ld male with chronic renal failure on HD who did not respond to treatment with N-acetylcysteine or Plaquenil. The article includes a discussion of potential difficulties in treatment of pseudoporphyria in HD patients, as well as possible reasons for failure of treatment.)
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