Severe hypoglycemia in propranolol treatment for infantile hemangiomas.

BACKGROUND: Infantile hemangioma (IH), formerly termed strawberry hemangioma, is a benign vascular tumor caused by capillary endothelial cell proliferation. The tumor regresses after 1 year of age, but sequelae occur in approximately half of the patients without systemic treatment. Propranolol (PPL) is currently the first-line therapeutic agent in Japan as well as in Western countries. It is not commonly known that PPL may induce severe hypoglycemia, in addition to cardiovascular and respiratory side effects. METHODS: We retrospectively analyzed patients with severe PPL-induced hypoglycemia in the 3 years since the launch of Hemangiol®, a PPL preparation specific for IH, in Japan in 2016. RESULTS: The incidence of severe hypoglycemia and of hypoglycemic convulsions following PPL treatment was estimated to be 0.54% and 0.35%, respectively. The incidence of hypoglycemic convulsions appeared to be higher in Japan than in Western countries. Severe hypoglycemia was common in infants aged >1 year, when PPL was used for ≥6 months. Severe hypoglycemia often develops from 05:00 a.m. to 09:00 a.m. and is frequently associated with prolonged periods of fasting, poor feeding, or poor physical conditions. CONCLUSION: To avoid the risk of hypoglycemia, the treatment should be initiated by 6 months of age during the proliferative phase at the latest, and should not be extended indiscriminately beyond 1 year of age. Guardians should be advised not to administer PPL on an empty stomach, in the presence of poor feeding, or who are in poor physical condition, not to prolong fasting after PPL administration, and to monitor the child's condition immediately after he or she wakes up.

Subcutaneous abscess in the shoulder caused by Prevotella bivia infection.

Prevotella bivia (P. bivia) is an anaerobic Gram-negative rod usually inhabiting in the urogenital system, and sometimes in the intra-oral space, whose infection to other parts of body is extremely rare. In this report, we describe a rare case of a recurrent infectious abscess due to P. bivia in the right shoulder of a middle-aged female.

Treatment Outcome with Fosravuconazole for Onychomycosis.

Fosravuconazole L-lysine ethanolate (F-RVCZ), a ravuconazole prodrug, is a newly available agent with high expectations for efficacy in the treatment of onychomycosis. However, clinical data regarding the efficacy of F-RVCZ are limited because the drug was launched only in Japan in 2018. Therefore, we analyzed the outcome of F-RVCZ therapy in the treatment of onychomycosis at outpatient dermatology clinics in Japan. We examined data for 109 patients (68 male, 41 female) with varying clinical type, including total dystrophic onychomycosis and dermatophytoma, and a wide range of age groups, including the elderly. The complete cure rate at 12 weeks was 6.4% (7/109) and 67.9% (74/109) at the last visit (mean time to last visit: 32 ± 14.2 weeks). Mean rate of improvement in the affected nail area was 49.1 ± 23.3% at 12 weeks and 86.8 ± 22.4% at the last visit. Efficacy at 12 weeks and the last visit, respectively, was as follows: none, 4 cases and 1 case; slight, 35 cases and 4 cases; moderate, 51 cases and 21 cases; significant, 12 cases and 9 cases; complete cure, 7 cases and 74 cases. There were no serious adverse events. This retrospective survey was the first large-scale analysis of actual clinical practice outcomes and had minimal exclusions. Compared to previous reports, our results demonstrated excellent efficacy of F-RVCZ therapy in a variety of patients. Considering our results and the ease of oral administration (1 capsule/day for 12 weeks) and few adverse events, F-RVCZ therapy appears to be a useful option for the treatment of onychomycosis.

A Case of Tinea faciei Due to Nannizzia gypsea: Inflammatory Eruption on the Medial Angle of the Eyelid.

Nannizzia gypsea is a geophilic dermatophyte, previously known as Microsporum gypseum before renaming under the new taxonomy. This organism is distributed all over the world and is considered to be involved in keratin degradation in the soil. Generally, human infection involves direct contact with fertile soil. Tinea caused by geophilic dermatophytes is much rarer than that caused by anthropophilic dermatophytes. According to the latest survey in Japan, dermatophytosis due to N. gypsea accounted for only 0.4% of cases. Clinical presentations vary and may mimic other inflammatory dermatitis, leading to incorrect diagnosis and delayed treatment. According to that past report, distal parts of the upper and lower extremities were more commonly affected, followed by the trunk, face and scalp, and rarely the nail plate. A 38-year-old woman presented with an approximately 3-week history of an itchy, solitary erythematous lesion on the left medial angle of the eyelid. Direct microscopic examination of scales revealed fungal elements, and the causative agents was identified as N. gypsea by morphological and molecular biological diagnoses. The eruption improved with systemic itraconazole treatment at 100 mg/day for 8 weeks. No recurrence has been seen for a year. However, she had no history of contact with any infectious source. Herein, we report a case of tinea faciei due to N. gypsea with an uncommon site and route of infection.

Gαi2 and Gαi3 Differentially Regulate Arrest from Flow and Chemotaxis in Mouse Neutrophils.

Leukocyte recruitment to inflammation sites progresses in a multistep cascade. Chemokines regulate multiple steps of the cascade, including arrest, transmigration, and chemotaxis. The most important chemokine receptor in mouse neutrophils is CXCR2, which couples through Gαi2- and Gαi3-containing heterotrimeric G proteins. Neutrophils arrest in response to CXCR2 stimulation. This is defective in Gαi2-deficient neutrophils. In this study, we show that Gαi3-deficient neutrophils showed reduced transmigration but normal arrest in mice. We also tested Gαi2- or Gαi3-deficient neutrophils in a CXCL1 gradient generated by a microfluidic device. Gαi3-, but not Gαi2-, deficient neutrophils showed significantly reduced migration and directionality. This was confirmed in a model of sterile inflammation in vivo. Gαi2-, but not Gαi3-, deficient neutrophils showed decreased Ca(2+) flux in response to CXCR2 stimulation. Conversely, Gαi3-, but not Gαi2-, deficient neutrophils exhibited reduced AKT phosphorylation upon CXCR2 stimulation. We conclude that Gαi2 controls arrest and Gαi3 controls transmigration and chemotaxis in response to chemokine stimulation of neutrophils.

'Slings' enable neutrophil rolling at high shear.

Most leukocytes can roll along the walls of venules at low shear stress (1 dyn cm−2), but neutrophils have the ability to roll at tenfold higher shear stress in microvessels in vivo. The mechanisms involved in this shear-resistant rolling are known to involve cell flattening and pulling of long membrane tethers at the rear. Here we show that these long tethers do not retract as postulated, but instead persist and appear as 'slings' at the front of rolling cells. We demonstrate slings in a model of acute inflammation in vivo and on P-selectin in vitro, where P-selectin-glycoprotein-ligand-1 (PSGL-1) is found in discrete sticky patches whereas LFA-1 is expressed over the entire length on slings. As neutrophils roll forward, slings wrap around the rolling cells and undergo a step-wise peeling from the P-selectin substrate enabled by the failure of PSGL-1 patches under hydrodynamic forces. The 'step-wise peeling of slings' is distinct from the 'pulling of tethers' reported previously. Each sling effectively lays out a cell-autonomous adhesive substrate in front of neutrophils rolling at high shear stress during inflammation.

Efficacy and safety of oral propranolol for infantile hemangioma in Japan.

BACKGROUND: There have been few reports on the efficacy and safety of oral propranolol at 3 mg/kg/day for infantile hemangioma (IH) in Japanese patients. METHODS: A multicenter, open-label phase III study was conducted to evaluate the efficacy and safety of oral propranolol solution in Japanese infants aged 35-150 days with proliferating IH. Thirty-two patients were enrolled in the study, received propranolol solution for 24 weeks at 3 mg/kg/day, and completed the study. RESULTS: The success rate (complete or nearly complete resolution) at week 24 (primary endpoint) was 78% (95%CI: 60-91%). The improvement rate since the previous visit was 100% (32/32) after week 5. Overall, the IH surface area, maximum diameter, and color intensity all decreased over time. Consistency in assessment between the centralized and the investigator on-site assessments was observed in 26 patients. Of the 32 patients, 11 needed further treatment other than the study drug. The incidence of adverse events (AE) and drug-related AE was 97% and 31%, respectively. AE that occurred in ≥two patients were either typical of propranolol use (such as blood pressure decrease) or common events in infants. AE that resulted in dose reduction were observed in two patients, but no serious AE or AE that led to study drug discontinuation were observed. CONCLUSION: Oral propranolol solution at 3 mg/kg/day is effective and safe in Japanese IH patients.

Effect of ambrisentan on peripheral circulation in patients with systemic sclerosis.

Systemic sclerosis (SSc) is characterized by disturbed blood circulation. The effect of ambrisentan, an endothelin-A receptor-selective antagonist, on impaired peripheral circulation in SSc remains largely elusive. Here we show SSc patients, whose clinical symptoms such as cyanosis and Raynaud's phenomenon, were ameliorated by the treatment with ambrisentan. Additionally, objective evaluations with thermography showed improvement of hand coldness in steady-state and cold challenge tests. Ambrisentan might have a potential to improve peripheral circulation in SSc.

Serum resistin levels: a possible correlation with pulmonary vascular involvement in patients with systemic sclerosis.

Our latest studies demonstrated the potential role of adipocytokines, including adiponectin, visfatin, retinol binding protein-4, and apelin, in the pathogenesis of systemic sclerosis (SSc). Given that resistin is another member of adipocytokines with pro-inflammatory and pro-angiogenic properties, we measured serum resistin levels by enzyme-linked immunosorbent assay in 52 SSc and 19 control subjects and evaluated their clinical correlation. Since serum resistin levels greatly and inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction [r = -0.78, p < 0.05 (n = 9)], we evaluated the clinical correlation of serum resistin levels in SSc patients with normal renal function (n = 43). Although serum resistin levels were comparable between diffuse cutaneous SSc (n = 22), limited cutaneous SSc (n = 21), and control subjects (n = 19) [median (25-75 percentiles); 18.7 ng/ml (13.3-48.0), 23.3 ng/ml (12.9-54.1), and 22.9 ng/ml (9.4-36.7), respectively], the prevalence of elevated right ventricular systolic pressure (RVSP) was significantly higher in SSc patients with elevated serum resistin levels than in those with normal levels [67 % (4/6) vs. 16 % (6/37), p < 0.05], and serum resistin levels were significantly increased in SSc patients with elevated RVSP (n = 10) as compared to those with normal RVSP (n = 33) [52.1 ng/ml (20.8-117.5) vs. 18.5 ng/ml (12.2-46.2), p < 0.05]. Thus, serum resistin levels may serve as a useful marker for pulmonary vascular involvement in SSc, suggesting a possible contribution of resistin to the pathogenesis of pulmonary arterial hypertension associated with SSc.

Decreased cathepsin V expression due to Fli1 deficiency contributes to the development of dermal fibrosis and proliferative vasculopathy in systemic sclerosis.

OBJECTIVES: Cathepsin V (CTSV) is a proteolytic enzyme potentially modulating angiogenic processes, collagen degradation and keratinocyte differentiation. We aimed to investigate the clinical association of serum CTSV levels and the mechanism by which CTSV expression is altered in SSc. METHODS: Serum CTSV levels were determined by ELISA in 51 SSc and 18 healthy subjects. CTSV expression was evaluated by immunostaining in SSc and normal skin and by RT-real-time PCR in normal and SSc dermal fibroblasts, normal dermal fibroblasts treated with TGF-ß1 or Fli1 siRNA and human dermal microvascular endothelial cells (ECs) treated with Fli1 siRNA. RESULTS: Serum CTSV levels were significantly lower in dcSSc and lcSSc patients than in healthy controls. In early-stage dcSSc, serum CTSV levels were remarkably and uniformly decreased compared with healthy controls. The decrease in serum CTSV levels in mid- and late-stage dcSSc and in lcSSc was linked to the development of proliferative vasculopathy. CTSV expression was decreased in microvascular ECs, pericytes/vascular smooth muscle cells and keratinocytes of dcSSc and lcSSc skin and in dermal fibroblasts of dcSSc skin compared with control skin. Consistently, CTSV expression was decreased in cultured dermal fibroblasts from early-stage dcSSc. Furthermore, mRNA levels of the CTSV gene were significantly decreased in normal fibroblasts treated with TGF-ß1 or Fli1 siRNA and in human dermal microvascular ECs treated with Fli1 siRNA. CONCLUSION: Loss of CTSV expression may contribute to the development of fibrosis, vasculopathy and the altered phenotype of keratinocytes in SSc.

Propranolol is more effective than pulsed dye laser and cryosurgery for infantile hemangiomas.

UNLABELLED: Propranolol hydrochloride is a nonselective ß-blocker that is used for the treatment of hypertension, arrhythmia, and angina pectoris. In Japan, it was recently approved for the treatment of childhood arrhythmia. It has been observed to produce drastic involution of infantile hemangiomas. The aim of this prospective study was to examine propranolol's superiority to classical therapy with pulsed dye laser and/or cryosurgery in treating proliferating infantile hemangiomas. Fifteen patients between the ages of 1 and 4 months with proliferating infantile hemangiomas received grinded propranolol tablets 2 mg/kg per day divided in three doses. Twelve patients with proliferating infantile hemangiomas receiving pulsed dye laser and/or cryosurgery were enrolled as controls. Baseline electrocardiogram, echocardiogram, and chest x-ray were performed. Monitoring of heart rate, blood pressure, and blood glucose was performed every 2 weeks. Efficacy was assessed by performing blinded volume measurements and taking photographs at every visit. Propranolol induced significantly earlier involution and redness reduction of infantile hemangiomas, compared to pulsed dye laser and cryosurgery. Adverse effects such as hypoglycemia, hypotension, or bradycardia did not occur. CONCLUSION: The dramatic response of infantile hemangiomas to propranolol and few side effects suggest that early treatment of infantile hemangiomas could result in decreased disfigurement. Propranolol should be considered as a first-line treatment of infantile hemangiomas.

Kerion Celsi due to Microsporum canis in an Adult Woman, Treated Successfully with Fosravuconazole.

A 64-year-old woman presented with a fist-sized, severely painful lesion with scales, crusts, pustules, erythema with subcutaneous abscess, and hair loss on the left temporal region. Direct microscopic examination revealed a large number of spores around the hair, which indicated ectothrix hair invasion, and some hyphae were also found. Histopathological examination showed significant inflammatory cell infiltration from the dermis to the subcutaneous tissues and into the hair follicles, destruction of the hair follicles with granulomatous reactions, and fungal masses along the hair within the hair follicles. Microsporum canis was identified based on morphological features via culture method and molecular biological analysis of the internal transcribed spacer region DNA sequence. The patient was diagnosed with kerion celsi caused by M. canis. For treatment of kerion celsi, we chose an oral antifungal agent, fosravuconazole (FRVCZ), which has been available since 2018 only in Japan. Clinical symptoms were cured in 12 weeks without scarring. No side effects were observed during oral administration of FRVCZ. The results of our case and several previous reports suggest that FRVCZ is effective in treating various types of dermatomycoses.

Rolling on E- or P-selectin induces the extended but not high-affinity conformation of LFA-1 in neutrophils.

Human blood neutrophils rolling on E- or P-selectin reduced their rolling velocity when intercellular adhesion molecule (ICAM)-1 was available. Similar to mouse neutrophils, this was dependent on P-selectin glycoprotein ligand 1 (PSGL1), alpha(L)beta(2) integrin, the Src family tyrosine kinase FGR and spleen tyrosine kinase SYK. Blocking phospholipase C or p38 MAP kinase attenuated, but did not abolish the velocity reduction. To test expression of integrin activation epitopes, we adapted an immobilized reporter assay and developed a new homogeneous microfluidics-based reporter antibody binding assay. Rolling on E- or P-selectin induced the extension reporter epitopes KIM127 and NKI-L16, but not the high affinity reporter epitope monoclonal antibody (mAb) 24. This enabled rolling neutrophils to bind to immobilized extension reporter, but not activation reporter antibodies and allowed binding of soluble KIM127 during rolling. We conclude that human neutrophil rolling on E- or P-selectin induces the extended alpha(L)beta(2) integrin conformation through signaling triggered by PSGL-1 engagement.

CD22 expression mediates the regulatory functions of peritoneal B-1a cells during the remission phase of contact hypersensitivity reactions.

Although contact hypersensitivity (CHS) has been considered a prototype of T cell-mediated immune reactions, recently a significant contribution of regulatory B cell subsets in the suppression of CHS has been demonstrated. CD22, one of the sialic acid-binding immunoglobulin-like lectins, is a B cell-specific molecule that negatively regulates BCR signaling. To clarify the roles of B cells in CHS, CHS in CD22(-/-) mice was investigated. CD22(-/-) mice showed delayed recovery from CHS reactions compared with that of wild-type mice. Transfer of wild-type peritoneal B-1a cells reversed the prolonged CHS reaction seen in CD22(-/-) mice, and this was blocked by the simultaneous injection with IL-10 receptor Ab. Although CD22(-/-) peritoneal B-1a cells were capable of producing IL-10 at wild-type levels, i.p. injection of differentially labeled wild-type/CD22(-/-) B cells demonstrated that a smaller number of CD22(-/-) B cells resided in lymphoid organs 5 d after CHS elicitation, suggesting a defect in survival or retention in activated CD22(-/-) peritoneal B-1 cells. Thus, our study reveals a regulatory role for peritoneal B-1a cells in CHS. Two distinct regulatory B cell subsets cooperatively inhibit CHS responses. Although splenic CD1d(hi)CD5(+) B cells have a crucial role in suppressing the acute exacerbating phase of CHS, peritoneal B-1a cells are likely to suppress the late remission phase as "regulatory B cells." CD22 deficiency results in disturbed CHS remission by impaired retention or survival of peritoneal B-1a cells that migrate into lymphoid organs.

Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity.

B cells play critical roles in the pathogenesis of lupus. To examine the influence of B cells on disease pathogenesis in a murine lupus model, New Zealand Black and New Zealand White F(1) hybrid (NZB/W) mice were generated that were deficient for CD19 (CD19(-/-) NZB/W mice), a B cell-specific cell surface molecule that is essential for optimal B cell signal transduction. The emergence of anti-nuclear Abs was significantly delayed in CD19(-/-) NZB/W mice compared with wild type NZB/W mice. However, the pathologic manifestations of nephritis appeared significantly earlier, and survival was significantly reduced in CD19(-/-) NZB/W mice compared with wild type mice. These results demonstrate both disease-promoting and protective roles for B cells in lupus pathogenesis. Recent studies have identified a potent regulatory B cell subset (B10 cells) within the rare CD1d(hi)CD5(+) B cell subset of the spleen that regulates acute inflammation and autoimmunity through the production of IL-10. In wild type NZB/W mice, the CD1d(hi)CD5(+)B220(+) B cell subset that includes B10 cells was increased by 2.5-fold during the disease course, whereas CD19(-/-) NZB/W mice lacked this CD1d(hi)CD5(+) regulatory B cell subset. However, the transfer of splenic CD1d(hi)CD5(+) B cells from wild type NZB/W mice into CD19(-/-) NZB/W recipients significantly prolonged their survival. Furthermore, regulatory T cells were significantly decreased in CD19(-/-) NZB/W mice, but the transfer of wild type CD1d(hi)CD5(+) B cells induced T regulatory cell expansion in CD19(-/-) NZB/W mice. These results demonstrate an important protective role for regulatory B10 cells in this systemic autoimmune disease.

Differential phosphorylation of functional tyrosines in CD19 modulates B-lymphocyte activation.

CD19 is a B-cell transmembrane molecule that is critical for B-cell activation. CD19 serves as a scaffold protein for key signal transduction molecules including Lyn, PI3K, and Vav, by providing docking sites for these molecules via phosphorylation of CD19-Y(513), CD19-Y(482), and CD19-Y(391). We investigated the process of CD19 tyrosine phophorylation during B-cell activation using Ab specific for each of these phosphorylated tyrosines. BCR engagement induced differential tyrosine phosphorylation, as CD19-Y(513) phophorylation occurred first, and CD19-Y(482) phosphorylation was delayed and transient. Different BCR isotypes exhibited distinct patterns of CD19 phosphorylation: IgG-BCR ligation resulted in faster phosphorylation of CD19-Y(513) and more intense phosphorylation of CD19-Y(391) than IgM-BCR ligation. This affected CD19-mediated downstream pathways involving Vav, PI3K, and Akt. Additionally, the phosphorylation profile of CD19 differed distinctly according to its plasma membrane location. CD19 phosphorylated at Y(513) was almost exclusively located within lipid rafts, whereas phosphorylated Y(482) and Y(391) were found both inside and outside of the rafts. Furthermore, the phosphorylation of all three tyrosines was remarkably enhanced and prolonged following the simultaneous stimulation of BCR and CD40. Thus, variations in phosphorylation patterns may contribute to the complexity of CD19-regulated signal transduction.

Retrospective Survey of Treatment Outcomes of Efinaconazole 10% Solution and Luliconazole 5% Solution for Onychomycosis in Our Facility.

Many clinicians prefer to treat onychomycosis systemically. However, systemic therapy may not be suitable for all onychomycosis patients due to drug interactions, side effects of oral medications, or comorbidities. Two topical agents (efinaconazole 10% in 2014 and luliconazole 5% in 2016) have recently been approved for treatment of onychomycosis in Japan. We investigated the efficacy of these topical agents at Teikyo University Mizonokuchi Hospital, Kanagawa, Japan. We conducted a retrospective survey among patients diagnosed with onychomycosis at our outpatient clinic and had been treated with either efinaconazole 10% solution or luliconazole 5% solution. Prior to commencement of treatment, the disease severity was evaluated using the Scoring Clinical Index for Onychomycosis (SCIO). Furthermore, the efficacies of these agents were evaluated using turbidity scoring at each visit to our outpatient clinic. Sixty-two patients (33 men, 29 women) applied efinaconazole 10% solution, and 72 patients (35 men, 37 women) applied luliconazole 5% solution. The mean SCIO scores were 18.1 and 17.4, respectively, and the mean 5-grade evaluation scores were 3.5 and 3.4, respectively. Complete cure rates were 40.3% (25/62) and 33.3% (24/72), respectively. The mean durations of treatment were 15.4 months and 11.9 months, respectively. There were no serious side effects in either treatment group. There were no significant differences between the two agents in improvement scores as assessed by the Tukey's test. Thus, efinaconazole 10% and luliconazole 5% topical solutions were effective for the treatment of onychomycosis. These topical agents may become important treatment options for this indication.

Serum levels of IgE anti-BP180 and anti-BP230 autoantibodies in patients with bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the hemidesmosomal proteins, BP180 and BP230. NC16A, a non-collagenous stretch of the BP180 ectodomain is the primary target of pathogenic IgG antibodies. Whereas IgG anti-BP180 autoantibodies play a primary role in the pathogenesis, there is a growing number of data regarding the potential pathogenic roles of IgE class autoantibodies in BP. OBJECTIVES: To examine the levels of IgG and IgE autoantibodies against BP180 and BP230, and to investigate mutual association and clinical relevance. METHODS: Sera obtained from 67BP patients and 36 healthy donors were subjected to ELISA assays to measure serum IgG and IgE levels of anti-BP180 and anti-BP230 antibodies. RESULTS: IgG anti-BP180 antibodies were positive in 63 (94%) of 67BP patients. IgG anti-BP230, IgE anti-BP180, and IgE anti-BP230 antibodies were found in 48 (72%), 20 (30%) and 45 (67%), respectively. IgG anti-BP180 levels were correlated with the affected areas. IgG anti-BP230 antibodies tended to increase in proportion to elongation of disease duration. IgE anti-BP230 levels showed a strong association with local eosinophil accumulation, while the levels were reversely related with the affected areas in BP. CONCLUSIONS: IgE autoantibodies to BP180 and BP230 are detected at high frequencies in BP. IgE anti-BP230 antibodies may have a role in attracting eosinophils to the skin lesions.

Prediction of therapeutic response before and during i.v. cyclophosphamide pulse therapy for interstitial lung disease in systemic sclerosis: A longitudinal observational study.

There have been no established parameters to predict responsiveness to i.v. cyclophosphamide (IVCY) pulse therapy in combination with corticosteroids in patients with interstitial lung disease (ILD) related to systemic sclerosis (SSc). This retrospective study was conducted to determine predictive factors for efficacy of IVCY at the time of before and during the treatment. Thirty-two Japanese SSc patients, ever treated for ILD with IVCY in combination with prednisolone, were analyzed retrospectively. We performed detailed time-course analyses of parameters derived from blood samples and pulmonary function tests. With the exclusion of eight unclassified patients, 24 patients were classified into 14 good responders (GR) or 10 poor responders (PR) on the basis of changes in percent predicted diffusing capacity for carbon monoxide (DLco). Pretreatment percent predicted DLco was significantly reduced in PR compared with GR. In addition, serum parameters such as Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D) and C-reactive protein were significantly higher in PR than in GR. Furthermore, our time-course analyses revealed a transient increase in serum KL-6 levels with a peak at 3 months after the first infusion of cyclophosphamide, which showed no relation to therapeutic efficacy. Moreover, continuously high serum KL-6 levels (>2000 U/mL) and rapid decrease in SP-D levels (<200 ng/mL) during IVCY were remarkably characteristic of PR and GR, respectively. ILD severity/activity before treatment and variability of serum KL-6 and SP-D levels during treatment may be useful to predict therapeutic effects of IVCY on SSc-ILD.