Chihiro Nishijima

Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis

Systemic sclerosis (SSc) is characterized by multi‐organ fibrosis with an autoimmune background. Although autoantibodies are detected frequently in SSc patients, the role of autoantibody in the development of fibrosis remains unknown. Connective tissue homeostasis is a balance between the synthesis and degradation of the extracellular matrix (ECM); ECM degradation is regulated mainly by matrix metalloproteinases (MMPs). Anti‐MMP‐1 antibody is suggested to inhibit MMP‐1 and be involved in the development of the fibrosis in SSc. However, the accumulation of various ECM components in the tissue of SSc cannot be explained by the anti‐MMP‐1 antibody alone. In this study, we examined the presence  or  levels of antibody to MMP‐3, a protein which degrades various ECM components relevant to SSc fibrosis. Enzyme‐linked immunosorbent assay (ELISA) using human recombinant MMP‐3 revealed that IgG anti‐MMP‐3 autoantibody levels were elevated significantly in the sera from SSc patients, but not in patients with active systemic lupus erythematosus or dermatomyositis. IgG and IgM anti‐MMP‐3 antibody levels were significantly higher in diffuse cutaneous SSc, a severe form, than those in limited cutaneous SSc. Consistently, IgG anti‐MMP‐3 antibody levels correlated significantly with fibrosis of the skin, lung and renal blood vessels. The presence of IgG anti‐MMP‐3 autoantibody in sera from SSc patients was confirmed by immunoblotting analysis. Remarkably, MMP‐3 activity was inhibited by IgG anti‐MMP‐3 antibody. These results suggest that anti‐MMP‐3 antibody is a serological marker that reflects the severity of SSc and also suggest that it may contribute to the development of fibrosis by inhibiting MMP‐3 activity and reducing the ECM turnover.

Elevated Serum KL-6 Levels in Patients with Systemic Sclerosis: Association with the Severity of Pulmonary Fibrosis

Background: Serum KL-6 has been suggested to be a useful marker for the evaluation of interstitial lung disease activity. Objective: To determine the correlation between serum KL-6 levels and pulmonary fibrosis in patients with systemic sclerosis (SSc). Methods: Serum samples from patients with limited cutaneous SSc (lSSc; n = 19), diffuse cutaneous SSc (dSSc; n = 26) and normal individuals (n = 15) were examined by ELISA. Results: Serum KL-6 levels in SSc patients were significantly higher than those in normal controls. KL-6 levels in dSSc patients were significantly elevated compared with those in lSSc patients. Elevated KL-6 levels were associated with the presence of pulmonary fibrosis in SSc patients or dSSc patients. Furthermore, KL-6 levels inversely correlated with percentages of diffusion capacity of carbon monoxide and vital capacity in SSc patients or dSSc patients. Conclusion: KL-6 may be a simple, serologic indicator for the severity of pulmonary fibrosis in SSc.

Case of dermatophyte abscess caused by Trichophyton rubrum: a case report and review of the literature

A 54‐year‐old Japanese man without apparent immunosuppression presented with nodules with purulent drainage on the right lower leg. He had ringworm of the right leg and tinea unguium. A biopsy specimen of the nodule showed intradermal abscesses with fungal elements, and Trichophyton rubrum was cultured from both the pus and the biopsy specimen. Treatment with oral terbinafine resolved the nodules. Dermatophyte abscess is a rare, deep and invasive dermatophytosis, which is often associated with immunocompromised conditions. We provide a review of the literature including Japanese cases.

Successful treatment of cutaneous Mycobacterium chelonae infection with roxithromycin

Dear Editor, Mycobacterium chelonae is a rapidly growing mycobacterium that causes illnesses ranging from disseminated cutaneous infection, localized cellulitis, abscess, osteomyelitis, to catheter infection in immunocompetent or immunosuppressed patients. Recent studies have shown that isolates of M. chelonae are usually susceptible to clarithromycin, and thus it has been the drug of choice for cutaneous M. chelonae infection. However, there have been case reports of clarithromycin resistance in patients with M. chelonae infection. We report a case of cutaneous M. chelonae infection which exhibited resistance to clarithromycin and was successfully treated with roxithromycin. A 36-year-old, previously healthy, Japanese woman presented in April 2006 with a 4-week history of a painful subcutaneous nodule on the right upper arm. She had no previous history of trauma. Physical examination revealed a firm subcutaneous nodule 3 cm in diameter on the outside of her right upper arm. There was no discoloration of the overlying skin. Magnetic resonance imaging (MRI) of the nodule demonstrated a subcutaneous mass with similar signal intensity to muscle on T1-weighted images (Fig. 1), and a high signal on T2-weighted images. Postcontrast T1-weighted images demonstrated intense enhancement of the subcutaneous nodule, suggesting a hypervascular tumor. A presumptive clinical diagnosis of a subcutaneous tumor such as angioleiomyoma was made, and the tumor was excised. Histological examination of the tumor revealed a dense infiltrate of neutrophils, monocytes and lymphocytes (Fig. 2a). A few granulomas with multinuclear giant cells were also seen (Fig. 2b). A diagnosis of an abscess with an infectious granuloma was suggested, but Ziehl–Neelsen, Gram, and periodic acid-Schiff staining did not reveal any microorganisms. Two months later, a subcutaneous nodule recurred beside the excision site. A biopsy specimen of the nodule revealed the same histological findings. A culture of the nodule revealed a rapidly-growing Mycobacterium, which was identified as M. chelonae by DNA–DNA hybridization. Susceptibility testing of the organism was not performed. Oral minocycline, 100 mg twice daily, was started and subsequently discontinued due to gastrointestinal symptoms. After identification of the organism, she was treated with oral clarithromycin, 200 mg twice daily, for 5 weeks but the subcutaneous nodule enlarged. The treatment was changed to oral roxithromycin, 150 mg twice daily, which resolved the nodule within the first 4 weeks.

Case of bleomycin-induced scleroderma

MRSS-3 in three patients. Four patients had ulcers on their feet, and the other six patients had no ulcers. The relationship between the total skin score and SPP, ABI and PWV is shown in Figure 1(a). The patients with MRSS-2 and MRSS-3 scores had significantly lower SPP than healthy controls (P < 0.01). Similarly, MRSS-2 and MRSS-3 patients had significantly higher PWV than healthy controls (P < 0.05). These scores were not significantly different between the MRSS-2 and MRSS-3 groups. ABI was not significantly related to the total skin score. The relationship between skin ulcer and SPP, ABI and PWV is shown in Figure 1(b). The patients with ulcers on their feet had significantly lower SPP and ABI values than those without ulcers (P < 0.05). The PWV value was not significantly related to the presence of skin ulcers. The relationship among SPP, ABI and PWV is shown in Figure 1(c) for the healthy controls and SSc patient groups. In the healthy controls, ABI, PWV and SPP were highly correlated with each other (r = 0.896, r = 0.896, r = 0.836). In the SSc patient group, ABI PWV and SPP were not correlated with each other (r = 0.173, r = 0.069, r = 0.395). Various sizes of vessels are affected in systemic sclerosis. This might cause the differences among healthy controls and SSc patients. However, the study was limited because of the age difference between controls and patients. Compared with ASO, SSc involves smaller peripheral vessels. Therefore, ABI, which is calculated between the upper extremities and under the lower extremities, is not sufficient for evaluating SSc, even though it is useful for evaluating ASO. The total skin score was not related to ABI. The presence of skin ulcers was related to ABI, probably because patients who have digital ulcers might have macrovascular involvement. PWV, which checks the pulse wave of a peripheral artery, was effective for evaluating the advancement of SSc. SPP, which directly measures skin perfusion, is effective for evaluating SSc because direct skin perfusion has few biases and accurately measures skin ischemia. Kanetaka et al. reported SPP decreases when Raynaud’s phenomenon occurs. The present report provides evidence that SPP is useful for evaluating SSc-related ischemia. Generally, surgical therapy is not applied for SSc ischemic digital ulcer due to the risk of ulcer magnification. In ASO, low SPP leads to a low healing rate. It is thought that low SPP would also lead to a low healing rate in SSc. Moreover, SSc causes vasospasm, and is usually treated conservatively with vasodilators and antiplatelet drugs. Recently, endothelin receptor antagonists such as bosentan were shown to be effective for ischemic ulcers caused by SSc. It is not yet clear, however, when treatment with these drugs should be started. There are no guidelines for pharmacological treatment of ischemic ulcer caused by SSc. SPP might provide a standard measure to indicate when to initiate drug therapy, similar to how blood pressure is used for monitoring hypertension.

Spitz nevus on the sole of the foot presenting with transepidermal elimination

A 10-year-old Japanese girl presented with a rhomboid-shaped brown macule, 4x3 mm in size, on the sole of the right foot. Dermoscopic examination revealed a number of black dots and globules on the ridges of the skin, marking an area of symmetrical brown pigmentation. On the periphery, a streak-like arrangement of black dots/globules on the brown pigmentation was observed along the ridges, simulating a “starburst” pattern. The lesion was excised and histological examination showed a symmetrical wedge-shaped compound melanocytic lesion that consisted of junctional and intradermal nests of a mixture of large spindle and epithelioid cells. None of the cells were atypical, and maturation of the cells with increasing depth was observed. From these findings, a diagnosis of Spitz nevus was made. Transepidermal elimination of nevus cell nests was observed and there were small groups of degenerated melanin-laden cells in the cornified layer. Masson Fontana stain revealed fine melanin deposits in the nevus cells of the junctional and intradermal nests, as well as heavy melanin deposits in the small groups of degenerated cells in the cornified layer. The distribution of melanin may contribute to a unique dermoscopic finding in this case.

Digital ulcer in systemic sclerosis successfully treated with Waon therapy

Dear Editor, Systemic sclerosis (SSc) is a connective tissue disorder that is characterized by fibrosis and vascular abnormalities in the skin and visceral organs. SSc patients occasionally develop digital ulcers that cause local pain and functional impairment. Potential treatments for digital ulcers include calcium channel blockers, prostacyclin analogues and endothelin receptor antagonists. However, digital ulcers are often resistant to these conventional treatments and may be complicated with infection and eventually progress to necrosis of fingers and toes. Recently, a type of thermotherapy for chronic heart failure that uses a dry sauna maintained at 60°C (Waon therapy) has been reported to be effective for leg or toe ulcers in patients with peripheral arterial disease. Here, we present a case of SSc with a digital ulcer successfully treated with Waon therapy. A 76-year-old Japanese woman with SSc presented to our department in November 2008 with a 2-week history of a painful ulcer in the toe. She was diagnosed with primary biliary cirrhosis 17 years ago and underwent surgery for early gastric cancer 13 years ago. She had Raynaud’s phenomenon, sclerodactyly with absence of sclerosis of hands and forearms, reflux esophagitis, and positive anti-centromere antibody and she was diagnosed as SSc 4 years ago. She had been treated with oral ursodeoxycholic acid and rabeprazole sodium. Examination showed a cutaneous ulcer sized 1.5 9 1 cm that involved the periosteum of the digital bone on the fourth toe of the left foot (Fig. 1a). Chest roentgenogram and computed tomography were unremarkable. Echocardiography did not show pulmonary hypertension. Lupus anticoagulant and b2-anticardiolipin GP-I antibody were positive but further examination did not show thrombosis. A resting ankle-brachial pressure index (ABI) was normal. Skin perfusion pressure (SPP), which indicates the blood flow of the capillary artery, was 13 mmHg at the dorsum of the left foot. One-month treatment with oral aspirin and intravenous alprostadil and topical alprostadil alfadex was ineffective. She was then admitted to our hospital, and treatment with foot soaks in a carbon dioxide bath was added. One-week treatment did not change the ulcer, and severe toe pain could not be relieved by analgesics. We then started soothing warmth therapy (Waon therapy). In brief, the patient was placed in a far infrared ray dry sauna (Onda Co., Kagoshima, Japan), in which the temperature was evenly maintained at 60°C for 15 min, and then was placed on a bed outside the sauna for an additional 30 min with sufficient warmth provided by blankets. This treatment was approved by

Vascular-type Ehlers-Danlos syndrome presenting as recurrent compartment syndrome.

ejd.2011.1542 Auteur(s) : Yukari Yoshimura1, Chihiro Nishijima1, Kazuo Ikeda2, Keiko Ikeda3, Yo Niida4, Makoto Inaoki1 inaoki-m@kinbyou.hosp.go.jp 1 Department of Dermatology 2 Department of Orthopedic Surgery 3 Department of Cardiology, National Hospital Organization Kanazawa, Medical Center, Kanazawa, 1-1 Shimoishibiki-machi, Ishikawa 920-8650, Japan 4 Medical Genetics Center, Kanazawa Medical University Hospital, Ishikawa, Japan The vascular type of Ehlers-Danlos syndrome (EDS type IV, EDS-IV) [...]

Development of bullous pemphigoid after change of dialysis membrane

A 75‐year‐old Japanese man presented with pruritic blisters and macules on his trunk and extremities. He had been on hemodialysis for 4 years because of chronic renal failure, and in recent months, a polymethylmethacrylate membrane had been used for dialysis. After a change in dialysis membrane to a cellulose triacetate membrane, pruritic tense blisters developed on the extremities in combination with marked blood eosinophilia. Physical examination showed erythematous macules and tense blisters on the trunk and extremities. A biopsy specimen of an erythematous macule showed subepidermal vesicles and eosinophils that attached to the dermal–epidermal junction. Serum level of eosinophilic cationic protein was elevated. From clinical, histological, and immunological findings, a diagnosis of bullous pemphigoid was made. New blisters continued to erupt during the period in which the patient used the cellulose triacetate membrane dialyzer, and even after the use of clobetasol propionate. It resolved only after the patient came back to the use of a synthetic membrane dialyzer. We discontinued the use of clobetasol propionate, and neither bullous eruptions nor blood eosinophilia recurred. These observations suggest that cellulose membrane may be involved in the development of bullous pemphigoid through activation of eosinophils in the blood and the skin lesion, as in the present case.

Two cases of pemphigus vulgaris in remission showing high titer of anti-desmoglein 3 antibodies

1 Kwon CW, Land AS, Smoller BR, Scott G, Beck LA, Mercurio MG. Bullous pemphigoid associated with nivolumab, a programmed cell death 1 protein inhibitor. J Eur Acad Dermatol Venereol 2017; 31: e349–e350. 2 Bandino JP, Perry DM, Clarke CE, Marchell RM, Elston DM. Two cases of anti-programmed cell death 1-associated bullous pemphigoid-like disease and eruptive keratoacanthomas featuring combined histopathology. J Eur Acad Dermatol Venereol 2017; 31: e378–e380. 3 Ishii N, Teye K, Fukuda S et al. Anti-desmocollin autoantibodies in nonclassical pemphigus. Br J Dermatol 2015; 173: 59–68. 4 Gallo E, Garcia-Martin P, Fraga J et al. Paraneoplastic pemphigus with eosinophilic spongiosis and autoantibodies against desmocollins 2 and 3. Clin Exp Dermatol 2014; 39: 323–326. 5 Tanaka M, Hoashi T, Ichiyama S et al. Eczematous reactions mimicking psoriasiform dermatitis induced by nivolumab for advanced lung cancer. Australas J Dermatol 2018; https://doi.org/10. 1111/ajd.12868