Naotomo Kambe

Serum soluble interleukin-2 receptor level is more sensitive than angiotensin-converting enzyme or lysozyme for diagnosis of sarcoidosis and may be a marker of multiple organ involvement

Skin lesions in sarcoidosis are often the initial symptoms that enable the dermatologist to be the first to diagnose this granulomatosis. However, diagnosis is sometimes very problematic. In 2015, the diagnostic criteria for sarcoidosis were updated in Japan, with elevated serum soluble interleukin‐2 receptor (sIL‐2R) replacing negative tuberculin reaction. Therefore, we assessed the clinical utility of sIL‐2R compared with two other common markers, angiotensin‐converting enzyme (ACE) and lysozyme, in patients who visited the dermatology clinic. Data from 72 patients showed that sIL‐2R was more sensitive than both ACE and lysozyme in supporting a diagnosis of sarcoidosis (52.8%) compared with ACE (29%) and lysozyme (26.4%). Additionally, the sIL‐2R level was significantly higher in patients with multiple organ involvement and parenchymal infiltration. Patients with elevated sIL‐2R levels had higher serum ACE and lysozyme levels, a higher incidence of pulmonary involvement, more severe chest radiographic stage and a high incidence of expression‐specific signs by imaging analysis. Receiver–operator curve analysis showed that sIL‐2R was a better marker at the threshold cut‐off point compared with ACE and lysozyme for identifying patients with multiple organ involvement, detecting patients with pulmonary disease and parenchymal infiltration as well as predicting the presence of specific signs in the diagnosis of sarcoidosis. Moreover, the kinetics of sIL‐2R levels correlated closely with clinical manifestations, in contrast to the modest changes of ACE and lysozyme levels during the follow‐up period. In conclusion, sIL‐2R may be considered a good marker for diagnosis and a potential indicator of disease activity.

Pluripotent stem cell models of Blau syndrome reveal an IFN-γ–dependent inflammatory response in macrophages

&NA; Figure. No caption available. Background: Blau syndrome, or early‐onset sarcoidosis, is a juvenile‐onset systemic granulomatosis associated with a mutation in nucleotide‐binding oligomerization domain 2 (NOD2). The underlying mechanisms of Blau syndrome leading to autoinflammation are still unclear, and there is currently no effective specific treatment for Blau syndrome. Objectives: To elucidate the mechanisms of autoinflammation in patients with Blau syndrome, we sought to clarify the relation between disease‐associated mutant NOD2 and the inflammatory response in human samples. Methods: Blau syndrome–specific induced pluripotent stem cell (iPSC) lines were established. The disease‐associated NOD2 mutation of iPSCs was corrected by using a CRISPR‐Cas9 system to precisely evaluate the in vitro phenotype of iPSC‐derived cells. We also introduced the same NOD2 mutation into a control iPSC line. These isogenic iPSCs were then differentiated into monocytic cell lineages, and the statuses of nuclear factor &kgr;B pathway and proinflammatory cytokine secretion were investigated. Results: IFN‐&ggr; acted as a priming signal through upregulation of NOD2. In iPSC‐derived macrophages with mutant NOD2, IFN‐&ggr; treatment induced ligand‐independent nuclear factor &kgr;B activation and proinflammatory cytokine production. RNA sequencing analysis revealed distinct transcriptional profiles of mutant macrophages both before and after IFN‐&ggr; treatment. Patient‐derived macrophages demonstrated a similar IFN‐&ggr;–dependent inflammatory response. Conclusions: Our data support the significance of ligand‐independent autoinflammation in the pathophysiology of Blau syndrome. Our comprehensive isogenic disease‐specific iPSC panel provides a useful platform for probing therapeutic and diagnostic clues for the treatment of patients with Blau syndrome.

Early cutaneous eruptions after oral hydroxychloroquine in a lupus erythematosus patient: A case report and review of the published work

Hydroxychloroquine (HCQ) is an effective treatment of lupus erythematosus. Although adverse effects, mainly gastrointestinal and cutaneous manifestations, are rare, they may result in the cessation of medication in some patients with severe reactions. Therefore, the evaluation of a patients condition is important for a dermatologist to decide whether to cease or continue HCQ. We herein report a case of a 36‐year‐old Japanese woman with systemic lupus erythematosus and cutaneous eruptions caused by the p.o. administration of HCQ. Because she wanted to continue the medication and had only mild cutaneous eruptions without any adverse effects in other organs, we continued HCQ with careful monitoring. All cutaneous eruptions disappeared within 1 week. We also reviewed published case reports on skin lesions that developed after HCQ treatments, and propose strategies for early cutaneous eruptions after HCQ treatments. When the cutaneous reactions are mild without any reactions in other organs, withdrawal of the drug is not required. However, when cutaneous eruptions are accompanied by some common reactions, HCQ needs to be stopped for a period of time and may subsequently be carefully re‐administrated.

The role of mast cells in autoinflammation

The concept of autoinflammation was proposed to define a new class of immune disorders categorized by self‐directed inflammation that is driven via activation of innate immune pathways. Within innate immunity, inflammasomes serve as intracellular signaling platforms to endogenous danger molecules and pathogens. Their key function is the cleavage of pro‐interleukin‐1β (pro‐IL‐1β) into its active form to promote inflammation and programmed cell death. A growing number of inflammasome sensors were described, among which NLR family pyrin domain containing 3 (NLRP3) is the best‐studied sensor. Besides macrophages, monocytes, and other innate immune cells, mast cells (MCs) were shown to express functional inflammasomes too. Also, MCs are both, a source and target of IL‐1β. Here we review the functional relevance and role of MC inflammasomes and MC‐derived IL‐1β in contributing to the inflammation at the skin, joints, and central nervous system in rare monogenic autoinflammatory conditions and also common inflammatory and degenerative diseases.

Four cases of anti‐Mi‐2 antibody‐positive dermatomyositis: relationship between anti‐Mi‐2 antibody titre and disease severity and activity

Editor Anti-Mi-2 antibody was found to be a specific marker for dermatomyositis (DM). Patients with anti-Mi-2 antibody generally have a more favourable prognosis, such as milder muscle involvement and a lower risk of interstitial lung disease (ILD) and malignancy. However, it currently remains unclear whether the anti-Mi-2 antibody titre correlates with disease severity and activity, or if repeated testing for disease monitoring is beneficial. Therefore, we evaluated the relationship between clinical severity or activity and anti-Mi-2 antibody levels or ANA titres of four patients with anti-Mi-2 antibody-positive DM. Case 1: A 56-year-old man noted erythema on the face 2 years ago, and skin eruptions gradually expanded to the trunk. Diffuse purplish erythema from the forehead to the cheeks, flagellate erythema on the upper back, periungual erythema, punctate haemorrhage on the perionychium and Gottron’s sign were observed. Case 2: A 62-year-old man had skin rash on his face and hands for 6 years. He was referred to our hospital due to an increase in serum CK levels. Mild oedematous erythema on both eyelids and erythema on the forehead and around the nose were observed. Periungual erythema, punctate haemorrhage and Gottron’s sign were noted. Case 3: A 36-year-old man was admitted to our hospital with a 3-year history of erythema on the face and both hands. Slight erythema around the nose and neck, periungual erythema, Gottron’s sign on both hands and punctate haemorrhage were observed. Case 4: A 69-year-old woman had erythema on her face and back and developed muscle weakness 3 years ago. Erythema around the nose, eyebrows and forehead, periungual erythema, punctate haemorrhage and Gottron’s sign were observed. We performed an immunoprecipitation (IP) assay with S-labelled K562 cell extracts as previously reported and identified the anti-Mi-2 antibody in all patients. Other circulating antibodies were not detected, except for anti-SS-A antibody in case 4. The clinical features of the four patients are summarized in Table 1. We diagnosed all four cases as DM from skin eruptions and myositis. Muscle weakness was observed in all cases, whereas none had ILD or malignancy. All patients showed Gottron’s sign, periungual erythema, punctate haemorrhage on the perionychium and facial erythema. Truncal erythema was observed in two of the four patients, but was very mild. The patients in this study showed similar clinical manifestations with characteristic DM skin lesions as previously reported. After treatment initiation with 1 mg/kg/day prednisolone, skin eruptions and muscle weakness improved in all cases. Table 2 shows serial ANA and anti-Mi-2 antibody titres in these patients. We did not measure the titre before treatment initiation in case 4; however, the other 3 cases showed a decrease in their titres with the treatment. Cases 1 and 2 had higher CK levels and more severe muscle weakness than case 3. Correlated with the disease severity, ANA titres were higher in cases 1 and 2 and anti-Mi-2 titres were higher in case 2 than in case 3. Moreover, ANA titre showed decreases during treatments in cases 1, 2

Up-regulated expression of CD86 on circulating intermediate monocytes correlated with disease severity in psoriasis

BACKGROUND The number of intermediate monocytes (CD14++CD16+) increases in many inflammatory conditions. However, it is not yet known which functional markers expressed by these populations are linked to the pathogenesis of psoriasis. OBJECTIVES We evaluated the expression of functional markers on circulating intermediate monocytes. Our goal was to correlate specific populations and their markers with the clinical severity of psoriasis. METHODS A cohort of 43 psoriatic patients was subjected to analysis. The proportion of intermediate monocytes with CD86 expression was evaluated by flow cytometry. Serum beta defensin-2 levels were measured by ELISA. Immunofluorescent staining was performed in order to identify the presence of CD14+CD16+ cells that co-expressed CD86 in affected skin tissues. RESULTS Upregulated expression of CD86 on the intermediate subset (but not the number of intermediate monocytes) correlated with clinical severity as measured by PASI scores and serum beta defensin-2 levels. Immunostaining also showed the presence of CD86+CD14+CD16+ cells in the epidermis and dermis of psoriatic plaques, which was associated with increased epidermal proliferation. CONCLUSION These results suggest that the expression of CD86 on circulating intermediate monocytes could be used as an index in clinical practice and provide novel insights into how these cells join a complex immune network under the pathological conditions of psoriasis.

Protein contact dermatitis induced by cabbage with recurrent symptoms after oral intake

Dear Editor, Protein contact dermatitis (PCD), a particular form of contact dermatitis, was first reported in 1976 by Hjorth and RoedPetersen. The most frequent symptom is a chronic or recurrent eczema affecting the fingertips or extending to the wrists and arms. For diagnosing PCD, a skin prick test with fresh or commercial materials is the gold standard, while patch tests are usually negative. Therefore, PCD is considered a type I hypersensitivity reaction. A 43-year-old female experienced painful redness, swelling, and cracks involving her fingers (Fig. 1a) 2 months after she started cutting vegetables in a supermarket. Her symptoms persisted despite wearing gloves and applying topical steroids. Patch tests were positive only for nickel, while tests for gloves and other allergens were negative. She had an elevated non-specific immunoglobulin E in the serum at 1174 IU/mL (normal threshold is 320 IU/mL), but the immunoglobulin E test of 33 common allergens using the MAST33 (Hitachi Chemical, Tokyo, Japan) was negative. Immunoglobulin E tests for potatoes, celery, or pumpkin, which she had a chance to contact during her work, were also negative. When she shredded cabbage with her bare hands, swelling and painful lesions appeared on her hands after about 5 h and persisted during the next day. A skin prick test was performed with “prick-to-prick” method using fresh vegetables and the result was positive for cabbage as well as other vegetables belonging to the same species (Japanese mustard spinach and broccoli) after 15 minutes (Fig. 1b). She used gloves strictly and avoided eating raw cabbage. Then, the lesions resolved within 1 week; however, her symptoms appeared again 2 days after she ate white radish and on other days after she ate a Japanese-style savory pancake, okonomiyaki, in which the main ingredient is heat-cooked cabbage, even though she did not cook it by herself. Her symptoms resolved only when she stopped eating heat-cooked cabbage. In food handlers, cooks, housewives and caterers, the common allergens that cause PCD are fruits, vegetables and spices. The reduced integrity of the stratum corneum barrier facilitates penetration of the high-molecular-weight protein into the skin. Many kinds of vegetables have been reported as the allergens of PCD, but to the best of our knowledge, no data related to cabbage have been found. In the Japanese literature, 8 cases of PCD caused by wheat, rice, or shrimp had no symptoms after consumption of boiled food. However, the present patient still showed symptoms after the oral intake of (a)

Psoriatic skin lesions induced by abatacept: Case report and review of the published work.

Dear Editor, Abatacept is a soluble chimeric protein consisting of the extracellular domain of human CD152 linked to the modified Fc portion of human immunoglobulin G1. Here, we present a case of a patient with rheumatoid arthritis (RA) who developed psoriatic skin lesions after treatment with abatacept. A 76-year-old woman had suffered from RA for 24 years. She was seropositive for rheumatoid factor and had antibodies to cyclic citrullinated peptides. She had no clinical evidence of psoriasiform skin lesions either before or at the time of initiation of abatacept, and there was no family history of psoriasis. Therapy with an s.c. injection of abatacept concomitant with prednisone 5 mg daily was initiated at a dose of 125 mg/week. After the sixth dose of abatacept, she noticed skin eruptions on her hands. Physical examination revealed thick, well-demarcated psoriasiform plaques on the forehead, postauricular area and the dorsal surface of both hands (Fig. 1). A biopsy specimen obtained from the left hand showed elongated rete ridges, parakeratosis and mononuclear cell infiltration around the vessels in the dermis, which were consistent with psoriasis. After topical treatment with calcipotriol hydrate/betamethasone dipropionate, her skin lesions improved. Although the patient noted that her joint pain had improved during the 3 months of abatacept treatment, her rheumatologist discontinued her treatment because of dizziness, a reported side-effect of abatacept. A complete and immediate resolution of the cutaneous eruptions occurred after discontinuation of abatacept. The case described herein suggests a clear link between abatacept administration and the development of cutaneous lesions. We reviewed the published work and found 11 cases of RA with psoriasiform lesions induced by abatacept. Table 1 summarizes the characteristics of the psoriasis in these 11 patients. Plaque psoriasis was the predominant type of psoriasis (8/11, 73%). One case was the guttate type. Both cases with pustular psoriasis were reported to be restricted to the palms or soles. Our collective data revealed that more than half of the cases with skin lesions limited to the extremities (6/11) were able to continue abatacept therapy. Abatacept therapy was discontinued in four cases with skin lesions observed on the entire body or trunk. Because our patient’s eruptions were observed in relatively limited areas and showed a good response to topical treatment, we suggest that she could have continued abatacept therapy without any other side-effects. In a systematic review, 10 of 1955 patients treated with abatacept presented with psoriasis (0.51%). Most events were mild or moderate in severity except for two cases with severe psoriasis. The mechanism underlying this phenomenon remains elusive. Psoriasiform eruptions after abatacept therapy may be related to an imbalance in the T-helper (Th)17/Th1 ratio; in some circumstances, this may aggravate autoimmunity by a paradoxical influx of inflammatory mediators induced by abatacept. In summary, patients with confirmed psoriasis should be evaluated based on the extent and tolerability of their skin lesions. The important point for clinical practice is that the majority of patients with RA could continue abatacept therapy despite the development of mild to moderate psoriasiform skin lesions.