Hideki Maejima

Evaluation of nail disease in psoriatic arthritis by using a modified nail psoriasis severity score index

Background  The Classification of Psoriatic Arthritis Study Group published new criteria for classifying psoriatic arthritis (PsA) which included nail psoriasis. Our aim was to clarify the clinical importance of nail disease in PsA patients.

Antibodies against cyclic citrullinated peptide in Japanese psoriatic arthritis patients

Anti‐cyclic citrullinated peptide antibodies (anti‐CCP) are highly considered to indicate disease severity and be predictive markers in rheumatoid arthritis (RA). RA patients who are positive for anti‐CCP tend to progress more frequently to joint deformity and functionally deteriorate more than negative patients. A study concerning the presence of anti‐CCP in Japanese patients with psoriatic arthritis (PsA) has been published. Our aim was to clarify that anti‐CCP could be a potentially useful marker in PsA patients. We herein describe a PsA patient with presence of anti‐CCP. We examined anti‐CCP in 15 patients with PsA, and compared with 18 controls who had other types of psoriasis. Three PsA patients were positive for anti‐CCP, but no controls showed positive. The anti‐CCP‐positive patients had higher counts of radiographic erosion, higher prevalence rates of polyarticular disease, use of disease‐modifying anti‐rheumatic drugs, and the human leukocyte antigen DRB1*04 shared epitope than negative patients. Our study demonstrated that anti‐CCP was potentially both predictive and a severity marker of joint involvement in PsA, the same as in RA.

Case of Linear IgA Bullous Dermatosis-involved Ulcerative Colitis

To the Editor: There are a number of reports of linear IgA bullous dermatosis (LABD) associated with preexisting inflammatory bowel disease (IBD), in particular ulcerative colitis (UC).1 We report the case of a patient who developed LABD while receiving treatment for UC. A 28year-old female. UC was diagnosed 1 year ago by colonoscopy (Fig. 1a) and biopsy specimen (Fig. 1b). She was receiving oral mesalazine at 2250 mg daily and prednisolone at 5 mg daily, and her disease activity was well controlled. However, within a few days after she developed a disease relapse, with severe diarrhea and bloody stool, the patient also developed bullae with pruritus on her trunk, gluteal region, and axillary fossa. She was therefore referred to our department. She had noticed clear and tender vesicles and bullae on erosion not associated with erythematous plaques on her trunk and limbs (Fig. 1c). There were no mucosal lesions. Routine laboratory examinations revealed evidence of an acute inflammatory reaction (white blood cell count, 11,000/ L, serum and an elevated erythrocyte sedimentation rate [ESR] of 77 mm/h). An immunological study was performed, including serological tests to determine the presence of autoantibodies, complement levels, rheumatologic markers and immunoglobulin levels, and thyroid tests; however, no significant abnormalities were detected. The skin biopsy specimen showed subepidermal neutrophilrich bullae. Direct immunofluorescence studies showed linear deposition of only IgA on the basement membrane. An indirect immunofluorescence test revealed the presence of circulating anti-basement membrane zone IgA antibodies at a titer of 1:80. Based on these studies, we diagnosed her disease as LABD. She did not receive systemic medications such as vancomycin with subsequent bowel flares, which are sometimes associated with drug-induced linear IgA disease. The intestinal disease activity entered remission spontaneously without any treatments and then, within a few weeks, the eruptions also cleared. No further therapies were required. The patient presented with several episodes of the bullae appearing synchronously with deterioration of the gastrointestinal symptoms and then disappearing within a short time after improvement of the gastrointestinal symptoms. We considered it important to evaluate the pattern of appearance of the skin lesions in relation to the activity of UC as assessed objectively. These usually incorporate the frequency of bowel movements and rectal bleeding, as well as the serum hemoglobin, albumin, and ESR values. The present study used the UC Activity Index (UCAI).2 In our case, the bullae cleared when the UCAI values were below 180, and relapsed when the values exceeded 190 (Fig. 2). Cutaneous diseases have been reported in 10% of patients with UC. Nonspecific eruptions are seen, including urticaria, angioedema, erythema, and purpura.3 In a study of 70 LABD patients selected from a British population, 5 (7.1%) had UC, even though the prevalence of UC in the UK in the general population is only 0.05%, while very few case reports with dermatitis herpetiformis (DH) and UC have been published in the literature.1,4,5 The exact reason for the association between UC and LABD remains unclear. IBDs may induce nonspecific immunoglobulin activation, triggering IgA crossreactive idiotype production against dermoepidermal or epidermal antigens, to produce specific bullous disorders.4,5 Antibodies enter the circulation and are deposited in the skin and mucous membranes because they crossreact with specific peptides in the lamina lucida and sublamina densa regions of the basement membrane. Antibody deposition is thought to stimulate an inflammatory response that damages the basement membrane, leading to mucocutaneous disease.6 Using previously described parameters of activity, we determined the UCAI3 in our patient; the bullae appeared with an increase of the UCAI, and disappeared with a decrease of the UCAI. These findings suggest that the appearance of LABD was related to the activity of UC, with antibodies being produced as the UC activity increased. To the best of our knowledge, this is the first case in which a clear relationship has been documented between LABD and the activity of UC.

Moesin and stress-induced phosphoprotein-1 are possible sero-diagnostic markers of psoriasis.

To identify diagnostic markers for psoriasis vulgaris and psoriatic arthritis, autoantibodies in sera from psoriasis vulgaris and psoriatic arthritis patients were screened by two-dimensional immunoblotting (2D-IB). Based on 2D-IB and MADLI TOF/TOF-MS analyses, eleven proteins each in psoriasis vulgaris and psoriatic arthritis were identified as autoantigens. Furthermore, serum levels of moesin, keratin 17 (K17), annexin A1 (ANXA1), and stress-induced phophoprotein-1 (STIP1), which were detected as autoantigens, were studied by dot blot analysis with psoriasis patients and healthy controls. The levels of moesin and STIP1 were significantly higher in sera from patients with psoriasis vulgaris than in the controls (moesin: P<0.05, STIP1: P<0.005). The area under the curve (AUC) for moesin and STIP1 between patients with psoraisis vulgaris and controls was 0.747 and 0.792, respectively. STIP1 and K17 levels were significantly higher in sera from patients with psoriatic arthritis than in those with psoriasis vulgaris (P<0.05 each). The AUC for STIP1 and K17 between patients with psoriatic arthritis and psoriasis vulgaris was 0.69 and 0.72, respectively. The STIP1 or moesin, CK17 serum level was not correlated with disease activity of psoriasis patients. These data suggest that STIP1 and moesin may be novel and differential sero-diagnostic markers for psoriasis vulgaris and psoriatic arthritis.

Expression of bleomycin hydrolase in keratinization disorders

A neutral cysteine protease, bleomycin hydrolase (BH), is widely expressed in mammalian tissues, with the skin seeming to contain the highest level. Our previous study revealed that BH transcription is modulated both during differentiation and by cytokines. However, BH involvement in keratinization disorder is not well known. In the present study, we performed immunohistochemical studies of BH and other serine/cysteine proteases in human normal skin and lesional skin with keratinization disorders. BH-positive cells were detected in granular layers of orthokeratotic and hyperkeratotic skin diseases, such as erythrokeratoderma and lichen planus. In parakeratotic skin diseases with porokeratosis, pityriasis rubra pilaris and psoriasis, BH staining was decreased in lesional skins compared to that in normal skin. Similar results were obtained for cysteine proteases, caspase-14 and calpain I. On the other hand, cells positive for serine proteases kallikrein 5 and 7 were increased in parakeratotic and inflammatory skin diseases, such as psoriasis. Semi-quantification analysis revealed that BH- and caspase-14-positive staining had higher intensity than those of the other proteases in normal epidermis. As BH is the major citrulline aminopeptidase in normal granular layer, the alternation would have a significant effect on terminal differentiation processes, such as aberrant processing of deiminated peptides. Therefore, BH may play an important role during the late stage of epidermal differentiation.

Nestin expression is increased in the suprabasal epidermal layer in psoriasis vulgaris.

We investigated the expression of both epidermal fatty acid-binding protein (FABP5), a marker of transit amplifying cells, and nestin, a putative marker of epidermal stem cells, in psoriatic epidermis and in normal human cultured keratinocytes. In lesional psoriatic epidermis, immunostaining showed that the suprabasal layer was positive for nestin, with some cells co-expressing FABP5. Flow cytometric analysis revealed that the expression of both nestin and FABP5 were increased in keratinocytes cultured in a low concentration of calcium relative to those cultured in a high concentration of calcium. These results suggest that nestin and FABP5 are expressed in actively proliferating keratinocytes in vitro and in the suprabasal layer in lesional psoriatic epidermis, and that double-positive cells may identify transit amplifying cells in the epidermis.

Nestin is expressed in HMB-45 negative melanoma cells in dermal parts of nodular melanoma

Nestin, a marker of neural stem cells, is expressed in the stem cells of the mouse hair follicle. The nestin‐expressing hair follicle stem cells can differentiate into neurons, glia, keratocytes, smooth muscle cells and melanocytes in vitro. These pluripotent nestin‐expressing stem cells are keratin 15 (K15)‐negative, suggesting that they are in a relatively undifferentiated state. Recent studies suggest that the epithelial stem cells are important in tumorigenesis, and nestin expression is thought to be important in tumorigenesis. In the present study, we examined the expression of the hair follicle and neural stem cell marker nestin, as well as S‐100 and HMB‐45, in melanoma. Nestin immunoreactivity was observed in the HMB‐45‐negative melanoma cells in all five cases of amelanotic nodular melanomas. Moreover, nestin immunoreactivity was observed in the dermal parts in seven of 10 cases of melanotic nodular melanomas. Especially, nestin immunoreactivity was observed in the HMB‐45‐negative melanoma cells in the dermal parts of all 10 cases of HMB‐45‐negative amelanotic and melanotic nodular melanomas. On the other hand, nestin expression was negative in 10 of 12 cases of superficial spreading melanoma. These results suggest that nestin is an important marker of HMB‐45‐negative melanoma cells in the dermal parts of patients with nodular melanoma.

Microscopic polyangiitis presenting urticarial erythema and Henoch-Schönlein purpura: Two case reports

Microscopic polyangiitis (MPA) is well known as a life‐threatening member of a group of systemic vasculitis diseases. We report two cases of MPA. Case 1 was a 79‐year‐old‐man who had been diagnosed with anti‐neutrophil‐cytoplasmic‐antibody associated vasculitis (ANCA associated vasculitis) with alveolar hemorrhage and crescentric glomerulonephritis (CrGN). He presented with urticarial erythema in the abdomen, legs and back. The skin biopsy specimens showed leukocytoclastic vasculitis on the upper dermis. Case 2 was a 74‐year‐old‐man, who presented with purpura on the abdomen, buttocks and legs that were similar to Henoch‐Schönlein purpura (HSP). He also suffered from interstinal pneumonia. His renal biopsy specimens showed glomerulosclerosis and the peripheral pattern anti‐neutrophil cytoplasmic antibody (P‐ANCA) was positive. We reviewed the skin eruptions that had been reported with MPA, including our cases.

Analysis of clinical, radiological and laboratory variables in psoriatic arthritis with 25 Japanese patients

Psoriatic arthritis (PsA) has many clinical and radiological manifestations but lacks a specific laboratory marker. The aim of the present study was to identify noteworthy features in PsA patients on routine clinical examinations. The subjects were 25 PsA patients who were classified based on the Classification of Psoriatic Arthritis (CASPAR) criteria. The clinical and radiological findings and laboratory parameters were analyzed by retrospective chart review. On clinical examination, dactylitis was present in 13 (52%) of 25 patients, swollen and/or tender Achilles tendons were present in nine (36%), and sacroiliitis was present in eight (32%). Of the radiological features, juxta‐articular new bone formation (JANF) was seen in 12 (48%), extra‐articular new bone formation was seen in nine (36%) and sacroiliitis was seen in six (24%). Dactylitis and JANF had the highest prevalence rates. The Psoriasis Area and Severity Index score, swollen and/or tender joint count, erythrocyte sedimentation rate, C‐reactive protein, and matrix metalloproteinase‐3 were higher in patients with sacroiliitis than in those without sacroiliitis (P < 0.05). Dactylitis, JANF and sacroiliitis may be noteworthy manifestations in Japanese patients with PsA.

Adverse effects of methotrexate in three psoriatic arthritis patients

Methotrexate, a folic acid analogue with anti-proliferative and anti-inflammatory effects, is commonly used to treat patients with severe destructive psoriatic arthritis and has considerable efficacy. Combined anti-tumor necrosis factor and MTX therapy result in less treatment discontinuation due to adverse events. Despite its efficacy, MTX may result in adverse effects including hepatic, pulmonary, and renal toxicity as well as lymphoproliferative disorders and predisposition to infection. We herein report rare adverse effects of MTX treatment, specifically asymptomatic pulmonary tuberculosis, renal cell carcinoma, and lateral uveitis, in three psoriatic arthritis patients treated with MTX. MTX is an important drug for the treatment for psoriatic arthritis patient, but an awareness of the possible adverse effects is needed.