Yuko Kanno

Acute urticaria with elevated circulating interleukin-6 is resistant to anti-histamine treatment.

Histamine released from dermal mast cells plays a central role in the increased vascular permeability in acute urticaria, and administration of anti‐histamines usually suppresses development of wheals. Acute idiopathic urticaria, particularly a severe case, occasionally presents with acute inflammatory reactions such as low‐grade fever and leukocytosis and is resistant to anti‐histamines. Considering the wide spectrum of proinflammatory cytokines and chemokines that can be released from activated mast cells, some of them might be involved in the pathogenesis of urticaria. We measured plasma levels of interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), and tumor necrosis factor‐α (TNF‐α) in 16 cases of severe acute urticaria. None of them showed elevated plasma levels of IL‐8 or TNF‐α. Nine out of 16 acute urticaria patients showed elevated circulating IL‐6 with concomitant increases in serum CRP levels. All such patients were resistant to conventional anti‐histamine treatment and required systemic steroids for complete suppression of wheal development. After subsidence of the urticaria, their elevated IL‐6 and CRP levels dropped to their normal ranges. In contrast, all but one patient without elevated circulating IL‐6 was successfully treated with a H1 receptor antagonist, cetirizine. The data suggest involvement of IL‐6 in the pathogenesis of severe acute urticaria that is resistant to anti‐histamines.

Elevation of circulating thrombin–antithrombin III complex and fibrin degradation products in urticaria: A laboratory finding unrelated to intravascular coagulopathy

Dear Editor, Voluminous exudation of plasma components into the dermis through the hyperpermeable cutaneous vasculature marks a pathophysiological feature of urticaria. When skin mast cells are stimulated to degranulate by injection of recombinant human stem cell factor, fibrin is shown to be deposited in the perivascular area at the injected sites. Fibrin formation, therefore, originating from extravasated plasma fibrinogen could likewise occur in urticarial skin lesion. Massive fibrin formation in the dermis may well affect the plasma levels of coagulation/ fibrinolysis parameters. As shown in Table 1, a large proportion of urticaria patients showed elevated circulating thrombin–antithrombin III complex (TAT) and/or D-dimer. Nobody showed a drop in plasma antithrombin III (AT III) activity, or a detectable level of plasma soluble fibrin monomer complex (SFMC). All the patients showed normal levels or ranges of platelet counts, prothrombin time (PT), activated partial thromboplastin time (APTT), plasma protein C and S activities, serum compliment C3 and C4,

Eosinophilic cellulitis as a cutaneous manifestation of idiopathic hypereosinophilic syndrome

Three patients with eosinophilic cellulitis associated with sustained peripheral blood eosinophilia of unidentified cause are reported. They also presented with diversities of extracutaneous symptoms such as bronchospasm, sensory polyneuropathies, epigastralgia, and gangrenous eosinophilic enteritis. These cases suggest that eosinophilic cellulitis can develop as a cutaneous manifestation of idiopathic hypereosinophilic syndrome.

Subungual hyperkeratosis due to sarcoidosis

A 30‐year‐old Japanese woman presented to our clinic for evaluation and treatment of subungual hyperkeratotic lesions of the toenails. Five years previously the bilateral parotid glands and hilar lymph nodes became enlarged, and tender subcutaneous nodules developed in the lower extremities. Transbronchial lung biopsies showed epithelioid granulomas and systemic sarcoidosis was diagnosed. A skin biopsy showed nonspecific septal panniculitis, a finding compatible with erythema nodosum. Since then the patient had experienced intermittent episodes of low grade fever, general malaise, dyspnea, diarrhea, and superficial lymphadenopathy, and systemic steroid was administered when the disease was aggravated. The initial erythema nodosum subsided in a couple of months and was replaced by a large number of slightly scaly, erythematous papules and nodules in the lower extremities and in the face. The biopsy specimens of these lesions showed noncaseating epithelioid granulomas in the dermls. These cutaneous lesions waxed and waned along with the systemic symptoms. The patient had never had uveitis or lupus pernio. A few months previously new erythematous papules and nodules had developed in the face and in the lower extremities. Hyperkeratotic verrucous lesions also developed at the hyponychium and beneath the distal portion of the nail plates in all the toenails (Fig. 1a). The proximal and lateral nail folds and the nail plates appeared normal. Repeated potassium hydroxide stain and culture of the subungual hyperkeratotic materials were negative for fungus. Roentgenogram of the toe phalanges was normal. Interestingly, none of the fingernails were affected. A biopsy specimen of the nail bed showed orthokeratotic hyperkeratosis and acanthosis of the epidermis, but no papillomatosis or vacuolated keratinocytes (not shown). There were discrete epithelioid granulomas in the superficial dermis (Fig. 2). Systemic steroid, 30 mg/day, was administered because the patients lung parenchymal lesions were aggravated. The subungual hyperkeratosis rapidly improved after administrating steroid for 2 weeks (Fig. 1b).

A Specific Thrombin Inhibitor, Argatroban, Alleviates Herpes Zoster‐associated Pain

We report the result of a randomized, controlled, open trial of anti‐thrombin therapy for herpes zoster‐associated pain. Fifty‐five herpes zoster patients within 8 days after the onset of skin lesion were enrolled in the trial. Patients were treated with an optimal dose of oral acyclovir (4000 mg/day for 7 days) with or without intravenous administration of a specific anti‐thrombin agent, argatroban (10 mg/day, three times a week). Administration of argatroban reduced pain intensity at the 4th through 21st day after the initiation of treatment as determined by visual analogue scale (Mann‐Whitney U test, p<0.05). It also shortened the median time to cessation of analgesic use (14 days vs. 24 days, p=0.02, logrank test), although it did not significantly reduce the median time to cessation of pain (21 days vs. 43 days, p=0.07, logrank test). None of the enrolled patients showed evidence of adverse effects including hemorrhagic diathesis. The results suggested that relatively low doses of argatroban are effective in reducing herpes zoster‐associated pain. Up‐regulation of prothrombin expression by the vascular endothelial and sweat gland epithelial cells in the active skin lesion and transient elevation of plasma thrombin‐antithrombin III complex levels in a proportion of patients suggest a lesional generation of thrombin in herpes zoster. This may be relevant to the beneficial effects of the anti‐thrombin treatment on the resolution of herpes zoster‐associated pain.

Tsutsugamushi Disease in the Central Part of Japan

Two cases of tsutsugamushi disease misdiagnosed initially as drug eruption were reported. Clinical symptoms of both cases disappeared dramatically after starting minocycline. Statistical examinations were performed on 29 cases of tsutsugamushi disease, including those observed in Mie Prefecture since 1982. Half of them were seen in the last 2 years. The onset was predominantly recorded in November (59%). Presumptive sites of infection were forests (63%) and fields (21%). No patients were infected along river‐banks.

Short-term etretinate therapy for prurigo chronica multiformis

Prurigo chronica multiformis is an intensely pruritic, chronic cutaneous disorder of unknown etiology without any effective treatment. This is a report on the results of using etretinate therapy to treat prurigo chronica multiformis. Thirty‐seven patients (average age; 69.1 ± 11.5 year‐old) were treated with 30 mg/day etretinate along with topical steroids (very strong classes) and oral antihistamines. Etretinate was discontinued as soon as remission was achieved. Thirty‐six patients were followed up for at least four weeks. The number of patients who achieved remission increased progressively after the initiation of etretinate therapy; 18 patients were totally and 14 were partially free of active skin lesions within four weeks. Eventually, 27 patients achieved remission with an average duration of 4.4 ± 3.1 weeks etretinate treatment (range; 1–14 weeks), and five achieved partial remission. Four patients discontinued etretinate within two weeks because of the absence of clinical response (two cases) or exacerbation of the skin lesion (two cases). Among the 27 patients who had achieved remission, 23 had recurrence after the cessation of etretinate. The remission period ranged from 1 to 32 weeks with an average duration of 5.7 ± 6.7 weeks. Combined treatment with topical steroids and oral antihistamines did not achieve remission in the recurrent cases but re‐administration of 30 mg/day etretinate did. Our observation suggests that a moderate dose of etretinate is a safe and effective therapy for prurigo chronica multiformis, which is often resistant to conventional treatment using topical steroids and oral antihistamines.