The risk of anti-osteoporotic agent-induced severe cutaneous adverse drug reactions and their association with HLA.

BACKGROUND: There is increasing use of anti-osteoporotic agents (AOA) worldwide for prevention or management of patients with osteoporosis. However, there have been reports of severe cutaneous adverse reactions (SCAR) induced by AOA. A recent study showed weak association between HLA and strontium ranelate (SR)-SCAR. OBJECTIVE: To characterize patients with AOA-SCAR and investigate the HLA association and utility of in vitro diagnostic methods. METHODS: We enrolled 16 cases with AOA-cutaneous adverse drug reactions (cADR), including SCAR (n = 10: 8 with Stevens-Johnson syndrome [SJS] and 2 with drug rash with eosinophilia and systemic symptoms [DRESS]) and maculopapular exanthema (MPE) (n = 6) from Taiwan and Hong Kong. We analysed the clinical characteristics, outcomes, HLA alleles and in vitro testing of AOA-SCAR, and tolerability to alternative drugs. We further performed literature review and meta-analysis on the HLA association of AOA-SCAR. RESULTS: Our data showed strontium ranelate is the most common causality of AOA-SCAR in Asian populations. There was no cross-hypersensitivity of SR-SCAR with other AOA. HLA genotyping showed that SR-SJS was most significantly associated with HLA-A*33:03 (Pc = 5.17 × 10-3 , OR: 25.97, 95% CI: 3.08-219.33). Meta-analysis showed that HLA-A*33:03 was associated with SR-SJS (P = 5.01 × 10-5 ; sensitivity: 85.7%) in Asians. The sensitivity of lymphocyte activation test (LAT) for identifying the culprit drug of SR-SJS was 83.3%. CONCLUSIONS: Strontium ranelate is identified as the most notorious AOA associated with SCAR. The HLA-A*33:03 genetic allele and LAT testing may add benefits to the diagnosis of SR-SCAR in patients whose reaction developed while taking multiple drugs.

Comparison of indirubin concentrations in indigo naturalis ointment for psoriasis treatment: a randomized, double-blind, dosage-controlled trial.

BACKGROUND: Indigo naturalis and its refined formulation, Lindioil, are effective in treating psoriatic symptoms topically. Indirubin is the active ingredient in indigo naturalis. OBJECTIVES: To determine the efficacy and safety of different concentrations of indirubin in Lindioil ointment for treating psoriasis. METHODS: In this randomized, double-blind trial, adult patients presenting with chronic plaque psoriasis for > 1 year and with < 20% of the body surface area (BSA) affected were randomized to apply Lindioil ointment containing 200, 100, 50 or 10 µg g-1 of indirubin twice daily for 8 weeks followed by an additional 12-week safety/extension period. The primary end point was the mean percentage change in Psoriasis Area and Severity Index (PASI) score along with the proportion of participants achieving 75% and 90% reductions in PASI scores (PASI 75 and PASI 90, respectively) from baseline to week 8. RESULTS: The results from week 8 revealed that the 200 µg g-1 group had the greatest reduction in PASI score [69·2%, 95% confidence interval (CI) 55·5-82·8], followed by the 100 µg g-1 group (63·1%, 95% CI 52·8-73·5), the 10 µg g-1 group (53·4%, 95% CI 42·8-64·0) and the 50 µg g-1 group (50·3%, 95% CI 37·4-63·2), with a between-group comparison of P = 0·0445. The group with the highest proportion of the patients achieving PASI 75 (57%, P = 0·0474) and PASI 90 (30%, P = 0·0098) was the 200 µg g-1 group. No severe treatment-related adverse events were reported during the 20-week evaluation. CONCLUSIONS: An amount of 200 µg g-1 of indirubin in Lindioil ointment is the most effective concentration studied so far for treating psoriasis topically, and is safe.

Histopathological analysis and clinical correlation of drug reaction with eosinophilia and systemic symptoms (DRESS).

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse drug reaction. However, its histopathological features have not been well defined. OBJECTIVES: To identify the clinicohistopathological findings of DRESS, and analyse the cutaneous histopathological changes observed in DRESS compared with those observed in maculopapular exanthema (MPE). METHODS: In a retrospective study, conducted at Chang Gung Memorial Hospital (Taiwan) between 2001 and 2011, we compared the clinicohistopathological features of 32 patients with probable/definite DRESS (defined by the RegiSCAR scoring system) with those of 17 patients with MPE. RESULTS: The major pathological changes observed in patients with DRESS included dyskeratosis (97%), epidermal spongiosis (78%), interface vacuolization (91%), perivascular lymphocytic infiltration (97%) and eosinophilic infiltration (72%). Many pathological features were common to both MPE and DRESS. However, severe dyskeratosis, epidermal spongiosis and severe interface vacuolization were significantly more prominent in cases of DRESS (P < 0·05). The presence of severe dyskeratosis was significantly associated with the clinical severity of renal impairment (P = 0·01). CONCLUSIONS: The severe dyskeratosis detected in patients with DRESS may correlate with a greater extent of systemic involvement compared with that noted in MPE. However, the histopathological changes associated with DRESS are not entirely specific.

A patch testing and cross-sensitivity study of carbamazepine-induced severe cutaneous adverse drug reactions.

BACKGROUND: The usefulness of the drug patch testing for Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is still controversial. Recent studies have shown that HLA-B*1502 is strongly associated with CBZ-SJS/TEN in Chinese and Southeast Asian populations. OBJECTIVE: To evaluate the usefulness of patch tests for patients with carbamazepine (CBZ)-induced SJS, TEN and drug reaction with eosinophilia and systemic symptoms (DRESS) and the cross-reactivity in patch tests among the aromatic antiepileptic drugs. METHODS: We measure the frequency of positive patch test reactions and cross-sensitivity to structure-related aromatic anti-epileptic drugs (AEDs) for patients after SJS/TEN or DRESS episodes caused by CBZ. CBZ and other structure-related AEDs used for patch testing were prepared in 10% and 30% petrolatum. Secondary measures included the association of HLA-B*1502 genotype and frequency of possible side effects from the patch tests. RESULTS: Positive patch test reactions to 30% CBZ in the CBZ-SJS/TEN were 62.5% (10/16), and 70% (7/10) in the CBZ-DRESS. None of the 10 healthy controls displayed a positive reaction to tested agents. Cross-sensitivity to other aromatic AEDs was observed in both the CBZ-SJS/TEN and the CBZ-DRESS. Only the HLA-B*1502 genotype was present and strongly associated with the CBZ-SJS/TEN, but not with the CBZ-DRESS. CONCLUSION: Drug patch testing is a safe and useful method for the identification of CBZ as the culprit drug of SJS/TEN as well as DRESS. Testing of chemically or pharmacologically related AEDs may provide information on cross-reactivity for these patients.