Adverse effects of topical photodynamic therapy: a consensus review and approach to management.

BACKGROUND: Topical photodynamic therapy (PDT) is widely used to treat superficial nonmelanoma skin cancer and dysplasia, and is generally well tolerated. However, as with all treatments, adverse effects may occur and awareness may facilitate approaches to prevention and management. OBJECTIVES: To review the available evidence relating to the adverse effects of topical PDT, to help inform recommendations in updated clinical guidelines produced by the British Association of Dermatologists and British Photodermatology Group, and the efficacy of preventative and therapeutic approaches. METHODS: This review summarizes the published evidence related to the adverse effects of topical PDT and attempts to interpret this evidence in the context of patient risk and management. RESULTS: Pain and discomfort during PDT are acute adverse effects, which can be minimized through the use of modified and low-irradiance PDT regimens and do not therefore usually limit successful treatment delivery. Other adverse effects include the risk of contact allergy to photosensitizer prodrugs, although this is rare but should be kept in mind, particularly for patients who have received multiple PDT treatments to larger areas. There are no other significant documented longer-term risks and, to date, no evidence of cumulative toxicity or photocarcinogenic risk. CONCLUSIONS: Topical PDT is usually well tolerated, reinforcing the utility of this important therapeutic option in dermatology practice. The main acute adverse effect of pain can typically be minimized through preventative approaches of modified PDT regimens. Other adverse effects are uncommon and generally do not limit treatment delivery.

Conventional and combination topical photodynamic therapy for basal cell carcinoma: systematic review and meta-analysis.

BACKGROUND: Topical photodynamic therapy (PDT) is an established treatment option for low-risk basal cell carcinoma (BCC). OBJECTIVES: To compare efficacy, cosmesis and tolerability of PDT for BCC with alternative treatments. METHODS: MEDLINE, PubMed, Embase and CENTRAL databases were searched from inception until 1 September 2017. Included studies were randomized controlled trials (RCTs) of PDT for nodular (n) and superficial (s) BCC reporting at least one of the following outcomes: clearance at 3 months and sustained at 1 or 5 years; recurrence at ≥ 1 year; cosmesis; adverse events; tolerability. RESULTS: From 2331 search results, 15 RCTs (2327 patients; 3509 BCCs) were included. PDT efficacy (5-year sustained clearance) was high but inferior to excisional surgery [nBCC pooled risk ratio (RR) 0·76; 95% confidence interval (CI) 0·63-0·91], and without re-treatment of partially responding lesions, was modestly inferior to imiquimod (sBCC: RR 0·81; 95% CI 0·70-0·95) and similar to fluorouracil (sBCC: RR 0·88; 95% CI 0·75-1·04). Five-year sustained clearance was inferior with conventional vs. fractionated PDT (sBCC: RR 0·76; 95% CI 0·68-0·84). PDT cosmesis was superior to surgery (sBCC: RR 1·68, 95% CI 1·32-2·14; nBCC: RR 1·82, 95% CI 1·19-2·80) and cryosurgery (BCC: RR 3·73, 95% CI 1·96-7·07), and without re-treatment of partially responding lesions was similar to imiquimod (sBCC: RR 1·01, 95% CI 0·85-1·19) and fluorouracil (sBCC: RR 1·04, 95% CI 0·88-1·24). Peak pain was higher but of shorter duration with PDT than topical treatments. Serious adverse reactions were rarer with PDT than imiquimod (sBCC: RR 0·05, 95% CI 0·00-0·84) and fluorouracil (sBCC: RR 0·11, 95% CI 0·01-2·04). Combination PDT regimens demonstrated reduced recurrence and improved cosmesis; however, results from these small studies were often nonsignificant. CONCLUSIONS: PDT is an effective treatment for low-risk BCC, with excellent cosmesis and safety. Imiquimod has higher efficacy than single-cycle PDT but more adverse effects. Highest efficacy is with excisional surgery. Fractionated and combination PDT options warrant further study.

Evaluation of the clinical efficacy of the 1,450 nm laser in acne vulgaris: a randomized split-face, investigator-blinded clinical trial.

BACKGROUND: The 1450 nm laser shrinks sebaceous glands histologically, reduces seborrhoea and has been shown in numerous small uncontrolled studies to improve inflammatory acne. OBJECTIVES: To assess objectively the clinical efficacy and long-term outcome of the 1450 nm laser for inflammatory acne vulgaris. METHODS: Participants over 16 years of age with moderate to severe acne vulgaris were recruited from a secondary care dermatology department. A split-face format was used: the side of the face to be treated was randomized with the other side serving as a within-patient control. Treatment was delivered with the Candela 1450 nm Smoothbeam laser (Candela, Cwmbran, U.K.) using a double-pass technique, 6 mm spot size, 210 ms pulse duration and fluence of 8 or 9 J cm(-2) . Three treatments were performed monthly. The primary outcome was the change in inflammatory lesion count and grading (using the Leeds Revised Acne Grading Scale) between baseline and 4 weeks after the third treatment on the treated side as compared with the change in the control side. Participants were followed up every 3 months for 12 months after the last treatment. The single assessor was blinded as to the side treated. RESULTS: Thirty-eight participants entered the study and 32 completed the study at the primary outcome measure. Within participants, on average, the lesion count reduced by the same amount on both sides of the face [median 0, 95% confidence interval (CI) -4 to 2]. On average, acne grade reduced by the same amount on both sides (median 0, 95% CI -1 to 0). Twelve months after the last treatment (n = 23) the change in lesion count and grade between the treated and control sides of the face remained similar. Treatment was well tolerated. CONCLUSIONS: Treatment with the 1450 nm laser does not reduce inflammatory lesion count or acne grade when compared with a control side, using a split-face format in participants recruited from secondary care. Both sides of the face improved and a systemic effect of the laser is possible.

Compliance of renal transplant recipients with advice about sun protection measures: completing the audit cycle.

Renal transplant recipients are at increased risk for development of nonmelanoma skin carcinoma, owing to a number of causes, including ultraviolet exposure. It has been shown that, despite education, there is poor compliance by these patients with the advice given for protecting their skin from the sun. This repeat study was conducted to determine whether there had been an improvement in compliance over the last 6 years. Two hundred twenty-seven patients were invited to complete the questionnaire used in the previous study. This questionnaire was designed to establish whether patients understood the need for extra care, whether they recalled any education about protective measures, and what actual measures were taken. There was a significant increase in the proportion of patients taking appropriate precautions. Hence there has been a significant improvement in the compliance of renal transplant recipients in Yorkshire with skin protection measures since this was originally audited in 1998.

Laser resurfacing for facial acne scars.

BACKGROUND: Most people have acne at some stage during their life, with about one per cent being left with permanent acne scars. Recent laser techniques are thought to be more effective than chemical peels and dermabrasion. OBJECTIVES: To assess the effects of laser resurfacing for treating facial acne scars. SEARCH STRATEGY: We searched MEDLINE (1966 to April 1999), EMBASE (1980 to April 1999), Science Citation Index (1981 to April 1999), the Cochrane Controlled Trials Register (April 1999), DARE (April 1999), INAHTA (April 1999), NHS HTA Internet site (April 1999). Dermatological Surgery (1995 to March 1999) and the British Journal of Dermatology (1995 to September 1999) were handsearched. We searched the reference lists of relevant articles and contacted experts and commercial laser manufacturers. SELECTION CRITERIA: Randomised controlled trials which compare different laser resurfacing techniques for treating patients with facial acne scars, or compare laser resurfacing with other resurfacing techniques or no treatment. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected studies, assessed the quality of studies and extracted data. MAIN RESULTS: No randomised controlled trials where laser treatment was compared to either placebo or a different type of laser were found. Most of the 27 studies uncovered were poor quality case series with small numbers of acne-scarred patients. REVIEWER'S CONCLUSIONS: The lack of good quality evidence does not enable any conclusions to be drawn about the effectiveness of lasers for treating atrophic or ice-pick acne scars. Well designed randomised controlled comparisons of carbon dioxide versus Erbium:YAG laser are urgently needed.

The treatment of acne fulminans: a review of 25 cases.

The treatment of acne fulminans has been difficult. It is difficult to perform a controlled treatment trial due to the rarity of the complication. However, it is possible to compare four different therapeutic regimens which have evolved with time in the management of 25 patients over a period of 25 years. Oral antibiotics produced a slow response in the resolution of acne and systemic symptoms. The addition of a systemic steroid produced a quick resolution of systemic features, but the time until resolution of the acne was longer than when it was used in combination with oral isotretinoin. The protocols which used a combination of prednisolone and isotretinoin led to faster control of systemic features as well as clearance of acne when compared with other protocols. This was particularly so if the oral steroid was used sooner rather than later. We conclude that the preferred treatment of acne fulminans is oral prednisolone 0.5-1 mg/kg daily for 4-6 weeks (thereafter slowly reduced to zero) with oral isotretinoin being added to the regimen at the fourth week, initially at 0.5 mg/kg daily and gradually increased to achieve complete clearance.

The use of topical glycopyrrolate in the treatment of hyperhidrosis.

The use of an aqueous solution of 0.5% topical glycopyrollate was effective in the treatment of hyperhidrosis of the scalp and forehead after other treatments had proved ineffective; this appears to be the first report of its use in this condition.

Acne vulgaris in the elderly: the response to low-dose isotretinoin.

There is a very small number of patients who suffer from acne even in the sixth and seventh decades of life. These patients have suffered from acne for most of their lives, 30-60 years, and have often received multiple courses of antibiotics over many years. We saw 10 such patients over 4 years. One received oral isotretinoin 1 mg/kg per day, but was unable to tolerate the adverse effects of cheilitis and developed hyperlipidaemia. We subsequently treated nine others with oral isotretinoin, 0.25 mg/kg per day, for 6 months; in six the acne had virtually cleared by 3-4 months while the other three cleared by 6 months. Up to 36 months after therapy these patients have remained clear of acne except for one who relapsed after 11 months. Therefore, as these patients respond well with few side-effects both in the long- and short-term to low-dose isotretinoin, they should be treated with isotretinoin, although at the lower starting dose of 0.25 mg/kg per day compared with younger patients who are treated with 0.5-1 mg/kg per day, and the treatment maintained for 6 months.

Efficacy of pulsed dye laser treatment of port wine stain malformations of the lower limb.

BACKGROUND: There is relatively little information about treatment of port wine stains (PWS) of the lower limb. Few studies have specifically addressed the efficacy of pulsed dye laser (PDL) treatment of a PWS on the lower limb and there is no information on the relative efficacy at different sites on the lower limb. It has been suggested that treatment is not as successful when compared with the face and postinflammatory hyperpigmentation has been reported to be a significant problem. OBJECTIVES: To review retrospectively patients who attended for PDL treatment of PWS affecting the lower limb and assess the efficacy and adverse effects with particular reference to skin site. METHODS: A retrospective review was carried out of patients attending the Leeds Dermatology Laser Centre for treatment of a PWS on the lower limb with a 585-nm PDL. RESULTS: A total of 52 sites in 39 patients were treated: 17 on the thigh, 31 on the lower leg and four on the foot. The mean number of sessions per patient was 14, with an excellent outcome in seven treatment sites (13.5%), good in 13 (25%), moderate in 21 (40.4%) and poor outcome in 11 (21.1%). Patients were generally pleased with their results with a mean improvement of 7 on a scale of 0-10. Perifollicular persistence of the PWS was observed in six sites (11.5%). Adverse effects occurred in 36 patients (92.3%), most commonly hyperpigmentation (87%). Six patients (15.4%) developed atrophic scarring and four (10.3%) hypopigmentation. Atrophie blanche-like changes were seen in four patients on the lower leg. Hypertrophic scarring was not seen. CONCLUSIONS: Although physician-assessed good or excellent responses of 38.5% are lower than frequently reported for other skin sites and adverse effects may be more frequent, patient satisfaction with treatment was generally high. Patients with PWS on the lower limb merit a trial of PDL treatment.

Adverse reactions following pulsed tunable dye laser treatment of port wine stains in 701 patients.

The pulsed tunable dye laser (PTDL) is generally considered to have a very low incidence of adverse effects, allowing it to become the treatment of choice for the majority of port wine stains (PWS). The low incidence of adverse effects has led to difficulties in determining the true incidence and type of adverse effect seen with this laser. We therefore undertook a retrospective study of 701 patients with PWS, who received 3877 full treatments to determine the incidence and type of adverse effects seen following treatment with the PTDL. Blistering and crusting were seen in 5.9% an 0.7% of patients, respectively, but were transient events which usually healed without permanent sequelae. Hyper-pigmentation was the most frequently observed adverse effect seen in 9.1% of patients but generally showed gradual resolution over 6-12 months. Hypopigmentation was infrequent, seen in 1.4% of patients. The most significant adverse effects were atrophic and hypertrophic scarring seen in 4.3% and 0.7% of patients, respectively. Our observations show that there is a small but definite risk of atrophic scarring with a predisposition for younger patients. Hypertrophic scarring can occur albeit rarely and there may be predisposition towards the neck. In most cases test areas were not predictive of scarring. This underlines the need for a full discussion of scarring risk in patients with PWS undergoing treatment with the PTDL.

Scarred for life?

Acne vulgaris is a common inflammatory dermatosis capable of producing significant psychological and physical scarring. The following work describes the benefit of using a questionnaire as a clinical tool to identify acne patients who have developed psychological sequelae as a result of the disease process. In addition, the benefit of isotretinoin on psychological impact has also been highlighted by this work. A prospective clinical study examines the early use of isotretinoin in acne and demonstrates the beneficial effect of early therapy in minimising acne scarring. In summary, oral isotretinoin (Roaccutane/Accutane) provides a very effective therapy to prevent acne patients being 'scarred for life'!

Sudden deepening of pigmentation during haemodialysis due to severe haemolysis.

A 37-year-old woman with chronic renal failure developed pain in the right flank during haemodialysis followed by rapid and dramatic deepening of pigmentation. Investigation indicated that the cause was severe haemolysis most probably due to mechanical damage to red blood cells passing through a stenosis in a dialysis blood line. Severe haemolysis should be suspected in subjects who suffer rapidly increasing pigmentation during dialysis. Such severe haemolysis should be recognized and treated rapidly since it may produce life-threatening systemic problems.

The compliance of renal transplant recipients with advice about sun protection measures.

Renal transplant recipients have an increased risk of developing non-melanoma skin cancer. Ultraviolet radiation is one of the major cofactors in the development of skin cancer in the immunosuppressed. In view of this, we undertook this study to determine the advice given to renal transplant recipients and their compliance with that advice. Two hundred and two renal transplant recipients were interviewed using a questionnaire. Their knowledge about the risk of non-melanoma skin cancer and preventive measures was not good, despite advice and literature given to newly transplanted patients at the time of discharge from hospital. Only 54% remembered receiving advice. Renal physicians and nurses gave advice to the majority, with dermatologists providing advice only in 17% of cases. The use of sun-protective measures such as sun avoidance and protective clothing was poor and the use of sun barrier creams was inappropriate. Only 30% of patients knew why extra precautions against sunlight were necessary. Health professionals and dermatologists in particular need to take a more active role in raising the awareness of renal transplant recipients to their increased risk of non-melanoma skin cancer.

Patch testing to detect corticosteroid allergy: is it adequate?

Whilst patch testing with corticosteroids in ethanol is more sensitive than either petrolatum or the cream formulation, the frequency of false-negative reactions is not known. We have compared patch testing with corticosteroid at 1% in ethanol with intradermal (i.d.) tests using 1 mg corticosteroid suspended in normal saline. Patch tests with tixocortol pivalate and budesonide detected all patients allergic to hydrocortisone and budesonide, respectively. For other corticosteroids, the use of ethanol as a vehicle resulted in both false-positive and false-negative reactions. In particular, patch tests with hydrocortisone-17-butyrate missed 30% of all positive reactions detected by i.d. testing. There may be a case for advising the avoidance of this steroid in all patients who are positive on patch testing to tixocortol pivalate and budesonide.

Inflammation in acne scarring: a comparison of the responses in lesions from patients prone and not prone to scar.

BACKGROUND: Many patients with inflammatory acne suffer from significant scarring, which is disfiguring and difficult to treat. A cell-mediated immune response is considered to be involved in the pathogenesis of acne, although the extent of this response has been found to differ among patients. OBJECTIVE: To assess whether there were differences in the cell-mediated immune responses at different time points in inflamed lesion development and resolution in patients who were prone (S patients) and those with the same degree of inflamed acne who were not prone (NS patients) to develop scarring. METHODS: Cellular and vascular markers were investigated using standard immunohistochemical techniques on biopsies of inflamed lesions of known duration, i.e. < 6 h (n = 14), 24 h (n = 14), 48 h (n = 10), 72 h (n = 10) and 6-7 days (n = 11) from the backs of acne patients. RESULTS: In early lesions from NS patients there was a large influx of CD4+ T cells, macrophages and Langerhans cells with a high number of cells expressing HLA-DR. Also there was significant angiogenesis and vascular adhesion molecule expression. Cell recruitment peaked in 48 h lesions, after which leucocyte numbers decreased and vascular activity returned to normal. Of the T cells, only 50% were memory/effector (CD45RO+) and naive (CD45RA+) cells, while the remainder were unclassified (CD45RO-, CD45RA-). In early lesions from S patients, CD4+ T cell numbers were smaller, although a high proportion were skin homing memory/effector cells. Langerhans cell numbers and cellular HLA-DR expression were low, while numbers of macrophages, blood vessels and vascular adhesion molecules were high. In resolving lesions angiogenesis remained high, with a further influx of macrophages and skin homing memory/effector cells and increased cellular HLA-DR expression. CONCLUSIONS: The cellular infiltrate was large and active with a greater nonspecific response (few memory T cells) in early lesions of NS patients, which subsided in resolution. In contrast, a predominantly specific immune response was present in S patients, which was initially smaller and ineffective, but was increased and activated in resolving lesions. Such excessive inflammation in healing tissue is conducive to scarring and suggests that the use of topical anti-inflammatory treatments would be appropriate for these patients.

Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.

Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.