Takenobu Ohashi

Antifibrotic effect of lysophosphatidic acid receptors LPA1 and LPA3 antagonist on experimental murine scleroderma induced by bleomycin

The study of lysophosphatidic acid (LPA) receptor has recently focused on its involvement in the pathogenesis of systemic sclerosis (SSc). We examined the inhibitory effects of the antagonist for the LPA receptor, a selective LPA1 and LPA3 antagonist (Ki16425), on dermal and lung fibrosis in a mouse model of SSc. Ki16425 was administered intra‐dermally after 6 h on the same sites as bleomycin injection. Histopathological examination showed that skin lesions were markedly attenuated by treatment with Ki16425 at doses of 1 and 10 mg/kg, along with reduced dermal thickness. Hydroxyproline contents in the Ki16425‐treated skin showed a decrease of 35% (1 mg/kg) and 45% (10 mg/kg) compared with those in the oil‐injected skin of the controls. The number of mast cells and phospho‐Smad2/3‐positive spindle cells of the Ki16425‐treated skin was significantly decreased compared with that in the controls. Additionally, RT‐PCR analysis showed that the mRNA levels of TGF‐β1, CTGF, MIP‐1α, IFN‐γ and collagen α1(I) were significantly decreased in both the 1‐mg/kg and 10‐mg/kg groups of the Ki16425‐treated mice compared with those in the controls. Furthermore, treatment with bleomycin and Ki16425 showed reduction in lung fibrosis, and the hydroxyproline contents in the lungs of the Ki16425‐treated mice showed a decrease of 25% (1 mg/kg) and 32% (10 mg/kg) compared with those in the lungs of the controls. Taken together, Ki16425 was found to improve dermal and lung fibrosis in a mouse model of bleomycin‐induced murine scleroderma. These results suggest that Ki16425 has the potential to be an effective new treatment for scleroderma.

Cellulitis-like skin necrosis induced by postoperative local interferon-β injection for malignant melanoma on the buttock.

arthritis. IGD can be associated with autoimmune or rheumatologic diseases in 20–30% of patients. Etiology of IGD remains enigmatic, however; because of the frequent association with autoimmune diseases, some postulate that circulating autoantibodies may contribute to the pathogenesis. As circulating autoantibodies are not ubiquitous in patients with IGD, further studies are necessary. Interstitial granulomatous dermatitis is associated with internal malignancies. Cornejo et al. reported an IGD-like eruption in a myelodysplasia patient that ultimately progressed to leukemia, suggesting that IGD-like eruption may represent a paraneoplastic phenomenon in pre-leukemic patients. Moreover, Schreckenberg et al. reported a case of IGD with paraneoplastic rheumatoid arthritis, suggesting that IGD should be considered a paraneoplastic phenomenon in patients with malignancies. In conclusion, we report a first case of IGD with arthritis associated with anaplastic large cell lymphoma. IGD should remain a differential diagnosis for patients with rheumatologic condition that have concomitant skin lesions with histological features of interstitial infiltration with collagen degeneration. The association between IGD and malignancies indicates that further study is needed to determine whether IGD represents a paraneoplastic syndrome.

Unusual milia amyloidosis as initial signs of multiple myeloma‐associated systemic amyloidosis

A 77-year-old woman was admitted to our hospital for surgical treatment of facial lentigo maligna. She also complained of multiple whitish nodules and a number of petechiae on the digits and hands of a few years’ duration. Physical examination revealed whitish, firm, milialike small nodules with a diameter of approximately 2– 3 mm and purpura on the dorsal and ventral aspects of bilateral fingers and hands (Fig. 1). Also, there were yellowish, soft, elastic, flat-elevated plaques on the upper palpebras and around the anus. Trachyonychia and brittle nails were observed; however, oral lesions were not. Histopathological examination of the whitish nodule showed a cyst lined by a few layers of stratified epithelium, including concentric lamellae of keratin within the cyst in the dermis (Fig. 2a). Furthermore, deposition of amorphous materials was seen in the papillary dermis, which was positively stained by Congo red and Dylon stain (Fig. 2b). Immunohistologically, the dermal deposits reacted positively with antibody to k light chain of immunoglobulin but negative for j light chain and IgG. Laboratory examination showed 4.2 9 10/ll of leukocytes (27% of lymphocytes and none of atypical lymphocytes), 817 mg/dl of IgG, 118 mg/dl of IgA, and 61 mg/dl of IgM. Serum electrophoresis revealed M protein. In the urine, Bence-Jones proteins were detected for IgLk and IgLj. Bone marrow biopsy revealed a diffuse infiltration of predominantly small to middle-sized atypical plasma cells; most cells were immunoreactive for k light chain of immunoglobulin.

Eosinophilic fasciitis with severe joint contracture in a patient with bladder cancer and B-cell lymphoma

has been reported. Our patient further developed hematological malignancy during the course. Dichloromethane and 1,2dichloropropane were carcinogenic, ink-removal agents used in the printing industry, that can cause cholangiocarcinoma, and we suspect that they were contained in the organic solvents used by our patient. This might have played a role in the occurrence of hematological malignancy. Eosinophilic fasciitis is sometimes associated with several autoimmune conditions, among which morphea is the most frequent but association with generalized morphea is rare. Furthermore, association with vitiligo and eosinophilic fasciitis is also rare, and only a few cases have been reported including vitiligo-like hypopigmentation. Whether hematological malignancy is associated with eosinophilic fasciitis or environmental factors is uncertain, however, our rare case demonstrates that diverse hematological as well as immunological manifestations can occur in association with eosinophilic fasciitis.

Acquired reactive perforating collagenosis associated with systemic lupus erythematosus.

detected in the present case, whereas dermal cicatrization with recurrent EN may disturb local circulation. Although she noticed no apparent skin injury, her skin was dry and itchy and, therefore, scratching-induced microtrauma might have been a trigger for ulceration. In conclusion, we reported a rare familial case of BS with intractable leg ulcers. BS may cause intractable leg ulcers, in case recurrent EN results in disturbed local circulation.

Peristomal pyoderma gangrenosum: A report of three cases

1 Cohen PR. Neutrophilic dermatoses: a review of current treatment options. Am J Clin Dermatol 2009; 10: 301–312. 2 Ikeda S, Takahashi H, Suga Y et al. Therapeutic depletion of myeloid lineage leukocytes in patients with generalized pustular psoriasis indicates a major role for neutrophils in the immunopathogenesis of psoriasis. J Am Acad Dermatol 2013; 68: 609–617. 3 Kanekura T, Hiraishi K, Kawahara K, Maruyama I, Kanzaki T. Granulocyte and monocyte adsorption apheresis (GCAP) for refractory skin diseases caused by activated neutrophils and psoriatic arthritis: evidence that GCAP removes Mac-1-expressing neutrophils. Ther Apher Dial 2006; 10: 247–256. 4 Kato S, Hosomi E, Amano F et al. The efficacy of intensive granulocyte and monocyte adsorption apheresis in a patient with Crohn’s disease complicated by extensive subcutaneous aseptic neutrophilic abscesses. J Crohns Colitis 2012; 6: 787–791. 5 Sanchez-Garcia J, Serrano-L opez J, Garc ıa-Sanchez V et al. Tumor necrosis factor-a-secreting CD16 + antigen presenting cells are effectively removed by granulocytapheresis in ulcerative colitis patients. J Gastroenterol Hepatol 2010; 25: 1869–1875.

Lichen striatus following influenza infection

were absent in our patient. Patch tests are useful in identifying the culprit drug in SDRIFE, but the positive rate is reportedly low. A reliable examination to reach the diagnosis is the provocation test. The most common causative drugs in SDRIFE were beta-lactam antibiotics. However, corticosteroids, biologics and chemotherapeutic agents may also cause the eruption. Acetaminophen may induce urticaria, maculopapular eruption, fixed drug eruption, angioedema, and toxic epidermal necrolysis, but only one case of SDRIFE has been associated with acetaminophen. It is important to be aware of SDRIFE as an unusual drug reaction since the connection between the skin eruption and drug exposure may easily be overlooked and thus result in misdiagnosis.

Auricular pyoderma gangrenosum with penetration in a patient with rheumatoid arthritis

Dear Editor, Pyoderma gangrenosum (PG) is a disease characterized by refractory, sterile, deep ulcers, which frequently involve the lower extremities in women aged between 20 and 60 years. By contrast, PG involving other peripheral structures such as the ear is rare. PG is often associated with several systemic diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and hematological diseases. We herein describe a case of PG involving the ear with penetration in a patient with severe RA. An 83-year-old woman was admitted to our hospital, complaining of multiple ulcers on the head and neck and lower extremities. She had been suffering from RA and associated interstitial lung disease for 20 years, and had been treated with non-steroidal anti-inflammatory drugs and prednisolone (2.5 mg/ day) at the visit to our hospital. Physical examination showed multiple deep ulcers on the scalp, ear, knee, lower legs, toes and sole (Fig. 1a). The ulceration was undermined and the border was slightly elevated and edematous. The surface presented reddish granulation and was partially covered with necrotic tissues. Furthermore, an ulcer of the earlobe was penetrated (Fig. 1b). Disease Activity Score of 28 joints – C-reactive protein (DAS28-CRP) score was 5.26 and neither rheumatoid nodules nor splenomegaly were present. Laboratory examination showed increased white blood cell counts (17 700/lL, with 90% neutrophils and 1% lymphocytes), CRP (11.6 mg/dL), positive rheumatoid factor (93 IU/mL, normal < 20), anti-cyclic citrullinated peptide (CCP) antibody (370 U/mL, normal < 4.5) and matrix metalloproteinase-3 (MMP3) (139 ng/mL, normal; 17.3–59.7) levels. Further investigations for cryoglobulin, M-protein, myeloperoxidase–anti-neutrophil cytoplasmic antibody and proteinase-3–anti-neutrophil cytoplasmic antibody were all negative. Cultures for bacteria were sterile. A biopsy specimen from the lower leg revealed dense neutrophil and lymphocyte infiltration in the whole dermis. In the upper edematous dermis, a number of neutrophils and lymphocytes infiltrated, and in the midto lower dermis, a neutrophilic abscess was located with the basophilic collagen bundles surrounded by histiocytes and plasma cells (Fig. 2). There were no findings of vasculitis. Results of the direct immunofluorescence tests were negative for deposition of immunoglobulin A (IgA), IgM, IgG and C3. She was successfully treated with oral prednisolone (40 mg/day), and multiple ulcers on other sites than the ear resulted in epithelialization, but the auricular lesion healed, leaving penetration. PG is characterized by sterile neutrophilic infiltration in the skin, and sometimes associated with systemic diseases such as IBD and RA, in both of which the interleukin 23 T-helper 17 (IL-23/Th17) axis plays a crucial role. PG is occasionally seen in relation with severity and activity of RA. Neutrophils play an important role in the onset and perpetuation of RA, and activated neutrophils are suggested to be recruited to the skin sites, leading to various neutrophilic dermatosis. Our patient severely developed multiple ulcers on the head and neck, lower limbs and peripheral sites, in a close association with activity of RA. Ulceration on the shin presented with typical clinical features of PG, and histological examination also revealed the features of PG. Detailed examination denied other causes such as venous insufficiency, vasculitis, cryoglobulinemia and infection. Neoplasms were also denied because deep ulcers sufficiently improved by systemic prednisolone without recurrence. Of note, our case developed pyoderma lesions around the bilateral ear with penetration. PG infrequently involves the peripheral sites, such as fingers, ears and genital regions. Previously, several cases of auricular PG have been reported, a few of which were unassociated with systemic diseases. Our case developed typical PG on the common sites such as lower legs and knee, as well as rare peripheral regions such as toes and ears. Peripheral PG should be widely recognized.

Clinicopathological analysis of mechanic's hand associated with dermatomyositis.

Mechanics hand is often seen in the fingers of patients with dermatomyositis and is frequently associated with anti‐aminoacyl‐transfer RNA synthetase autoantibodies and interstitial lung disease. We analysed the clinical symptoms of 50 patients with dermatomyositis who had visited our department, 26 of whom also had mechanics hand. A histological examination was carried out in 16 of the 26 cases, which revealed hyperkeratosis in all cases and colloid bodies in the epidermis in 15 cases. The number of cases of interstitial lung disease in patients with mechanics hand (22/26, 85%) was significantly higher than that in those without mechanics hand (12/24, 50%) (P < 0.05). Mechanics hand is an important skin lesion of dermatomyositis, and increases the likelihood of interstitial lung disease

Eccrine poroma with calcification and metaplastic ossification

Dear Editor, Secondary calcification in eccrine poroma is rarely observed, and ossification has yet to be reported. In the present report, we describe a case of eccrine poroma on the chest, with concurrent histological calcification and metaplastic ossification. A 66-year-old man visited our hospital complaining of an asymptomatic nodule on the chest which had appeared 20 years previously. He had experienced occasional bleeding for a few years before presentation. Physical examination revealed a well-circumscribed reddish nodule on the chest with an erosive surface covered with necrotic tissues (Fig. 1a). The nodule was completely removed under local anesthesia. Histological features showed cords of tumor cells extending from the erosive epidermis into the mid-dermis (Fig. 1b). The tumor cells had basophilic cells with small, round nuclei. Of note, lamellar bony structures containing osteoblasts were found beneath the tumor islands (Fig. 1c). Further, calcification was observed within the tumor islands (Fig. 1d). Von Kossa staining revealed ossification and calcification. To date, secondary ossification has been reported in association with various benign as well as malignant tumors, such as melanocytic nevus (nevus of Nanta), blue nevus, organoid nevus, acne, mixed tumor, epidermal and dermoid cysts, trichoepithelioma, pilomatricoma, lipoma, dermatofibroma, keratoacanthoma, pyogenic granuloma, basal cell carcinoma, squamous cell carcinoma and melanoma. To the best of our knowledge, this is the first case of eccrine poroma with metaplastic ossification. Secondary ossification has been observed within the facial lesions in most of the cases. By contrast, eccrine poroma arose on the chest. Osteoblasts play a central role in bone formation, and secrete several inducing factors such as bone morphogenetic protein (BMP)-2, BMP-4, b-catenin, osteopontin, osteonectin and osteocalcin, which exert effects on precursor cells derived from mesenchymal or adipose-derived cells. BMP are members of transforming growth factor (TGF)-b, and transform fibroblasts, primitive mesenchymal cells or progenitor cells in the bone marrow into osteoblasts. In particular, BMP-2 has intense osteoinduction activity, and promotes the differentiation of immature undifferentiated mesenchymal cells into osteoblasts. TGF-b and connective tissue growth factor, which is regulated by TGF-b, may stimulate primitive mesenchymal cells or displaced embryonic cells in the stroma to differentiate into osteocytes.