[Dapsone-induced agranulocytosis. The role of xenobiotic-metabolizing enzymes demonstrated by a case report]. / Dapson-induzierte Agranulozytose. Die Rolle fremdstoffmetabolisierender Enzyme am Beispiel einer Kasuistik.

A 34-year-old female patient with a three year history of generalized granuloma annulare was treated systemically with dapsone (DADPS). Six weeks after the onset of treatment, the patient developed an extensive tonsillitis of the base of the tongue with fever and malaise. Routine laboratory work showed a leukocytopenia with agranulocytosis. Further investigation revealed a marked decrease of the enzyme activity of N-acetyltransferase 2, which plays an important role in dapsone metabolism. Treatment included the cessation of dapsone, antibiotic coverage, and G-CSF leading to the rapid improvement of symptoms and normalization of leukocyte counts. Dapsone-induced angina agranulocytotica is a rare event and is interpreted as an idiosyncratic reaction. Depending on genetic polymorphisms of various enzymes, dapsone can be metabolized to immunologically or toxicologically relevant intermediates. Because of the risk of severe hematologic reactions, dapsone should only be employed for solid indications and with appropriate monitoring.

[Treatment of therapy-resistant acral ulcers with iloprost]. / Behandlung therapieresistenter akraler Ulzera mit Iloprost.

Patients with systemic sclerosis (SSc) develop often acral ulcers which are resistant to therapy and may result in gangrene and amputation. We investigated the effects of iloprost infusion on the acral ulcers and necrosis in patients with five patients with SSc and one with mixed connective tissue disease who had been previously treated with various modalities without improvement. All patients had Raynaud phenomenon, acral ulcers and necrosis. Iloprost 25 microg per day was administered intravenously daily over six hours for ten consecutive days. Eight weeks later all patients were treated with a second iloprost therapy cycle for five days. Two patients with severe ulceration received a third cycle until remission occurred. In all cases acral ulcers healed completely and no patient relapsed during an observation period of 6 months.

Pyoderma gangrenosum after cesarean delivery.

In this reported case of pyoderma gangrenosum after cesarean delivery, deep ulceration involved the entire lower abdomen before immunosuppressive treatment was started. Initial high doses of prednisolone followed by low doses of cyclosporine A led to complete resolution of the skin lesions. This case report illustrates the importance of early diagnosis and effective systemic immunosuppressive therapy of pyoderma gangrenosum.

[Combination of antimalarial drugs mepacrine and chloroquine in therapy refractory cutaneous lupus erythematosus]. / Kombination der Antimalariamittel Mepacrin und Chloroquin bei therapieresistentem kutanem Lupus erythematodes.

Antimalarials represent the first line in treatment of cutaneous lupus erythematosus (LE). However, some patients show no improvement on monotherapy with chloroquine or hydroxychloroquine. A 30-year-old female patient had treatment-resistant cutaneous LE exhibiting features of both LE tumidus and subacute cutaneous LE. Previously, the patient had been unsuccessfully treated with chloroquine, hydroxychloroquine, dapsone, and azathioprine, each in combination with variable doses of prednisolone. However, the LE lesions increased during these therapeutic regimens. A combination of chloroquine and mepacrine therapy led to improvement and then total clearing after 4 months of treatment.

Polymorphisms of the xenobiotic-metabolizing enzymes CYP1A1 and NAT-2 in systemic sclerosis and lupus erythematosus.

The etiology of systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is still unknown. In several cases, however, xenobiotics (i.e. drugs and occupational agents) were identified as etiologic agents and associations with certain polymorphic alleles of xenobiotic-metabolizing enzymes have been reported. Cytochrome P4501A1 (CYP1A1) and N-acetyltransferase 2 (NAT-2) are xenobiotic-metabolizing enzymes of phase 1- and phase 2-metabolism, respectively. CYP1A1 may activate drugs and other chemicals to reactive metabolites. NAT-2 is the most important enzyme in acetylation of aromatic amines, and thus may be responsible for detoxification of many of these compounds. Two polymorphisms of the human CYP1A1 gene, a point mutation in the 3' flanking region of the gene (Msp1) and a mutation in exon 7 leading to an isoleucine-valine-exchange in the heme-binding region of the enzyme, have been described and may lead to a higher basal and inducible enzyme activity. With respect to NAT-2, several alleles which combine for the two phenotypes "fast" and "slow" acetylators have been described. We analyzed the gene frequencies of the CYP1A1 polymorphisms and the phenotypes of NAT-2 in patients suffering from idiopathic SLE or SSc. CYP1A1 polymorphisms were analyzed in genomic DNA by PCR, whereas NAT-2 phenotypes were measured by the caffeine method. For CYP1A1 polymorphisms, 106 patients have been typed until now. The SLE group (n = 68) exhibited a significant increase (p < 0.05) in the mutant Val-allele (OR = 2.59) when compared to controls (n = 184). However, no significant differences in allele frequencies for MspI in the SLE group and for both CYP1A1 polymorphisms in the SSc group could be observed. Regarding the NAT-2 phenotype, patients suffering from SLE (n = 88) 75% and SSc (n = 26) 80.2%, respectively, were slow acetylators compared to 55% slow acetylators in the healthy German population (p < 0.05). The observed increased frequencies of the CYP1A1 mutant Val-allele and the slow actylator phenotype in idiopathic autoimmune disease support our concept that in slow acetylators non-acetylated xenobiotics may accumulate and are subsequently metabolized by other enzymes into reactive intermediates. Thus, enhanced formation of reactive metabolites could alter self-proteins presented to the immune system thus stimulating autoreactive T cells which induce autoimmunity.

Multiple basal cell carcinomas associated with hairy cell leukaemia.

We report the case of a caucasian woman who, between the ages of 49 and 51 years, developed multiple (> 20) basal cell carcinomas (BCC). There was no family history of BCC. No abnormalities in the human homologue of the Drosophila segment polarity gene patched (PTCH), glutathione S-transferases T1 and M1, or cytochrome P450 1A1 were detected by polymerase chain reaction (PCR)-based molecular analysis. There was, however, actinic damage of the skin in sun-exposed areas. The patient was diagnosed as having hairy cell leukaemia (HCL) at the age of 51 years, based upon leucocyte morphology as assessed by light and electron microscopy, tartrate-resistant acid leucocyte phosphatase (TRAP) staining, fluorescence activated cell scanning of peripheral blood leucocytes and bone marrow histology. As the leukaemia slowly progressed over a 3-month period, the patient developed four further BCCs. Given that HCL is characterized by a profound defect in T-cell function, it is conceivable that T-cell immune dysregulation can contribute to the pathogenesis of BCC, possibly enhancing the aetiological effect of ultraviolet irradiation.

Porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) is the most frequent form of porphyria. The underlying enzymatic defect in PCT is a reduced activity of the enzyme uroporphyrinogen decarboxylase (Uro-D). Four different types of Uro-D disturbances are known. Pseudoporphyrias such as porphyria cutanea uraemica or drug-induced PCT-like skin symptoms are distinguished from PCT. Porphyrinogens such as estrogens or alcohol, or other inducers of P450 isoenzymes provoke PCT. Polymorphisms of P450 isoenzymes, iron overload and infection with hepatitis C virus play an important role in the etiopathogenesis of disease manifestation. Dominant clinical symptoms are bullae, increased cutaneous vulnerability, hypertrichosis and elastosis. Biochemically, total porphyrin levels in urine are increased with a predominance of uroporphyrin and heptacarboxylic porphyrin. Isocoproporphyrin is demonstrable in feces. Best therapeutic strategies are the oral administration of chloroquine 125 mg twice a week and repetitive bloodlettings or the combination of both.

Cutaneous adverse reaction to ciprofloxacin: demonstration of specific lymphocyte proliferation and cross-reactivity to ofloxacin in vitro.

Ciprofloxacin (CPFX) is a widely used fluoroquinolone antibiotic, inducing cutaneous adverse drug reactions in about 1 to 2% of the treated patients. Conclusive diagnosis of drug allergy, however, still remains a major problem in daily clinical practice. Here, we present 2 patients with drug allergy to CPFX. In both cases the clinical suspicion for CPFX as the causative agent was confirmed in vitro by means of the lymphocyte transformation test, whereas epicutaneous patch tests remained negative. In vivo, a small percentage of the drug is biotransformed to the three major metabolites desethylene-, sulfo- and oxociprofloxacin. Though structurally closely related to their mother compound, these metabolites failed to induce in vitro lymphocyte proliferation in both patients. On the other hand, in vitro crossreactivity to ofloxacin, another fluorinated quinolone, could be demonstrated, which to our knowledge has not previously been reported.

Lamotrigine-induced Stevens-Johnson syndrome: demonstration of specific lymphocyte reactivity in vitro.

The novel antiepileptic drug lamotrigine (LTG) is effective as an adjunctive medication in partial seizures. The main adverse effects of LTG are skin eruptions, occurring in 3-10% of the treated patients, but these are rarely severe. The risk of cutaneous side effects is increased in patients receiving sodium valproate comedication, probably by doubling the plasma half-life of LTG due to competition with hepatic glucuronidation. Conversely, the risk can be reduced by adding LTG in a lower dose. Here, we report a patient who developed Stevens-Johnson syndrome (SJS) 5 weeks after adding low-dose LTG comedication to sodium valproate. An LTG-induced pathogenesis of the SJS was considered likely by a positive lymphocyte transformation test to the drug. The patient showed maximal peripheral blood lymphocyte reactivity to 50 micrograms LTG/ml with a stimulation index of 4.7 but not to nontoxic concentrations of sodium valproate. Lymphocytes from untreated controls neither reacted to LTG nor to sodium valproate.

T cells ignore the parent drug propylthiouracil but are sensitized to a reactive metabolite generated in vivo.

The antithyroid drug propylthiouracil (PTU) is known to cause adverse immunological side effects, such as a lupus-like syndrome and vasculitic disorders. In vitro experiments have established that myeloperoxidase of activated neutrophils can oxidize PTU to the reactive intermediate propyluracil 2-sulfonate PTU-SO3-, and it has been proposed that PTU-SO3- might be responsible for the PTU-associated side effects. Here, using the direct popliteal lymph node assay (PLNA) in mice we found that PTU-SO3-, indeed, induced a T-cell-dependent primary PLN response, whereas the parent compound PTU failed to do so. As shown by adoptive transfer PLNA, splenic T cells of mice that had received four injections of PTU-SO3- mounted a specific secondary response to the reactive metabolite, but not to PTU. When homogenized peritoneal phagocytes, which had been incubated with PTU in vitro, were used as the antigen, a primary response in the direct PLNA was elicited, suggesting that the phagocytes contained the reactive metabolite. Moreover, T cells sensitized to the reactive metabolite PTU-SO3- were detected in mice that were undergoing long-term treatment with PTU plus an additional treatment with phorbol myristate acetate for stimulation of the oxidative metabolism of their phagocytic cells. Together, these findings support the concept that phagocytes oxidize PTU to its immunogenic metabolite, PTU-SO3-, which then, presumably via covalently binding to self-proteins, induces T cell sensitization.

Coagulation factor V gene mutation associated with activated protein C resistance leading to recurrent thrombosis, leg ulcers, and lymphedema: successful treatment with intermittent compression.

Activated protein C resistance is the most frequent cause of venous thrombosis. We describe a patient with extensive ulcerations and severe lymphedema of the legs after recurrent thrombosis. Laboratory tests revealed a pathologic activated protein C resistance and a reduced functional protein S. The underlying genetic defect was identified as a heterozygous coagulation factor V mutation. A combined therapeutic approach of intermittent compression, repeated debridements and systemic antibiotics resulted in marked improvement of both lymphedema and leg ulcers.