Serum H‐ficolin levels: Clinical association with interstitial lung disease in patients with systemic sclerosis

Ficolins, a group of oligomeric lectins consisting of three isoforms (H‐, L‐ and M‐ficolin), contribute to innate immunity via activating the complement pathway and/or acting directly as opsonins against pathogens and apoptotic cells. Because apoptotic cells likely drive the development of systemic sclerosis (SSc) partly through innate immunity, we assessed the clinical association of serum H‐ficolin levels in SSc patients. Despite no difference in serum H‐ficolin levels between SSc and control subjects, SSc patients with decreased serum H‐ficolin levels tended to have a higher prevalence of interstitial lung disease (ILD). More importantly, serum H‐ficolin levels inversely correlated with ground‐glass opacity score on chest computed tomography in SSc‐ILD patients. Therefore, H‐ficolin‐related innate immunity may be involved in SSc‐ILD development.     

Serum levels of interleukin‐18‐binding protein isoform a: Clinical association with inflammation and pulmonary hypertension in systemic sclerosis

Systemic sclerosis (SSc) is a chronic autoimmune inflammatory disease characterized by extensive tissue fibrosis and various vascular complications. A wealth of evidence suggests the substantial contribution of pro‐inflammatory cytokines to the development of SSc, but the role of interleukin (IL)‐18 signaling in this disease still remains elusive. To address this issue, we herein determined serum levels of IL‐18‐binding protein isoform a (IL‐18BPa), a soluble decoy receptor for IL‐18, by enzyme‐linked immunosorbent assay in 57 SSc patients and 20 healthy controls and evaluated their clinical correlation. Serum IL‐18BPa levels were higher in SSc patients than in healthy controls, while comparable between diffuse cutaneous SSc and limited cutaneous SSc patients. Although serum IL‐18BPa levels were not associated with dermal and pulmonary fibrotic parameters in SSc patients, there was a significant positive correlation between serum IL‐18BPa levels and right ventricular systolic pressure estimated by echocardiography. Furthermore, in 24 SSc patients who underwent right heart catheterization, serum IL‐18BPa levels positively correlated with mean pulmonary arterial pressure. As for systemic inflammatory markers, significant positive correlations of circulating IL‐18BPa levels with erythrocyte sedimentation rate and C‐reactive protein were noted. These results suggest that the inhibition of IL‐18 signaling by IL‐18BPa may be involved in the development of pulmonary vascular involvement leading to pulmonary hypertension and modulate the systemic inflammation in SSc.     

Rituximab therapy is more effective than cyclophosphamide therapy for Japanese patients with anti‐topoisomerase I‐positive systemic sclerosis‐associated interstitial lung disease

Systemic sclerosis‐associated interstitial lung disease (SSc‐ILD) is the most frequent cause of death for SSc but there is still no sufficient treatment available. Although cyclophosphamide (CYC) therapy is a common treatment which has shown statistical efficacy against SSc‐ILD to date, its effects are temporary and not enough. Rituximab (RTX), the anti‐CD20 monoclonal antibody, has recently shown efficacy in many autoimmune diseases. In SSc‐ILD, RTX is also considered to be one of the novel treatment candidates. However, studies of SSc‐ILD in Japanese treated with RTX have only a few case reports. Therefore, in this study, we retrospectively compared nine patients treated with RTX and 30 patients treated with CYC to investigate the efficacy of RTX treatment for Japanese anti‐topoisomerase I‐positive SSc‐ILD patients. At the 24‐month evaluation, the improvement rates of percent predicted of forced vital capacity and percent predicted of diffusing capacity of the lung carbon monoxide in the RTX‐treated group were significantly higher than those in the CYC‐treated group (20.6 ± 8.8% vs 1.1 ± 3.9%; P < 0.05 and 34.0 ± 6.0% vs ?1.5 ± 2.8%; P < 0.01, respectively). In addition, skin thickness scores also showed a marked improvement from 13.5 points before the start of treatment to 5.8 points after 24 months by RTX therapy (P < 0.05). These results suggest that RTX treatment is more effective for Japanese SSc‐ILD patients than CYC treatment. In the future, it is expected that large‐scale clinical trials will show the usefulness of RTX treatment for SSc‐ILD.     

Rapid alteration of serum interleukin‐6 levels may predict the reactivity of i.v. cyclophosphamide pulse therapy in systemic sclerosis‐associated interstitial lung disease

Systemic sclerosis (SSc) is an autoimmune disorder characterized by excessive extracellular matrix deposition. Although SSc‐associated interstitial lung disease (ILD) is one of the most important complications as a cause of death in SSc, prediction factors of treatment reactivity in SSc‐ILD are still unclear. To assess relationships between interleukin (IL)‐6 and reactivity to treatment, we measured serum IL‐6 levels in 23 of active SSc‐ILD patients under i.v. cyclophosphamide (IVCY) therapy and 20 of stabilized SSc‐ILD, using the high‐sensitivity enzyme‐linked immunoassay system. Serum IL‐6 levels in active SSc‐ILD patients were significantly higher than those in stabilized SSc‐ILD patients. Among active SSc‐ILD patients, baseline serum IL‐6 levels were not significantly different between IVCY responders and non‐responders. Meanwhile, serum IL‐6 levels after three IVCY doses out of a total of six were decreased in responders but not in non‐responders. Regarding changes of parameters by the three doses of a total of six of IVCY, change in serum IL‐6 levels correlated inversely with that in values of pulmonary function test. Thus, the rapid decrease in serum IL‐6 levels during a couple of doses may predict the efficacy of IVCY therapy against SSc‐ILD.     

Decreased serum cathepsin S levels in patients with systemic sclerosis-associated interstitial lung disease

Cathepsin S (CTSS) is a lysosomal proteolytic enzyme regulating intracellular and extracellular biological activities, including immunity/inflammation and remodeling of vasculature and extracellular matrix, which are the three cardinal pathological events associated with systemic sclerosis (SSc). To elucidate the potential role of CTSS in the development of SSc, we investigated the clinical correlation of serum CTSS levels. Because serum CTSS levels were inversely correlated with estimated glomerular filtration rate (eGFR) in SSc patients with renal dysfunction (eGFR, <60 min/mL per 1.73 m²), SSc patients with normal renal function (eGFR, ≥60 min/mL per 1.73 m²) were analyzed. Serum CTSS levels were significantly decreased in diffuse cutaneous SSc patients compared with limited cutaneous SSc patients and healthy controls. Among vascular and fibrotic clinical manifestations, Raynaud’s phenomenon and interstitial lung disease (ILD) were relevant to a significant decrease in serum CTSS levels. Importantly, serum CTSS levels negatively correlated with serum levels of Krebs von den Lungen-6 and surfactant protein D in total SSc patients, while not correlating with modified Rodnan total skin thickness score and the percentage of predicted diffusion lung capacity for carbon monoxide and showing a positive trend with the percentage of predicted vital capacity. These results suggest a potential contribution of decreased CTSS expression to the development of ILD in patients with SSc.     

Successful experience of rituximab therapy for systemic sclerosis‐associated interstitial lung disease with concomitant systemic lupus erythematosus

Previous studies have demonstrated that B cells play critical roles in autoimmune disorders including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). However, the effectiveness of rituximab (RTX), a chimeric anti‐CD20 antibody, for SSc‐associated interstitial lung disease (ILD) or SLE disease activity remains controversial. We herein report an SSc patient with severely progressed ILD and concomitant SLE treated by two cycles of RTX at baseline and half a year later. This treatment improved ILD and SLE activities, along with reduction of dermal sclerosis and serum anti‐topoisomerase I antibody levels. In addition, our detailed time‐course data indicate that half a year may be appropriate as an interval between each cycle of RTX therapy aimed at SSc‐associated ILD or SLE. Overall, the current report could pave the way to establish RTX as a disease‐modifying drug for patients with SSc and/or SLE showing resistance to other already approved medications.     

Possible association of decreased serum CXCL14 levels with digital ulcers in patients with systemic sclerosis

CXCL14 serves as a chemoattractant for activated macrophages, immature dendritic cells and natural killer cells, as well as an antiangiogenic factor by preventing the migration of endothelial cells. CXCL14 also exerts an inhibitory effect on the CXCL12/CXCR4 signaling pathway, which is involved in the maintenance of T‐helper (Th)2 bias, and promotes Th1 immune response under the physiological and pathological conditions. Because CXCL14‐mediated biological processes seem to be involved in the development of systemic sclerosis (SSc), which is characterized by Th2/Th17‐skewed immune polarization and impaired neovascularization, we investigated the clinical correlation of serum CXCL14 levels in patients with this disease. Serum CXCL14 levels were significantly decreased in SSc patients compared with healthy individuals and in diffuse cutaneous SSc patients relative to limited cutaneous SSc patients. SSc patients with digital ulcers had serum CXCL14 levels significantly lower than those without. Furthermore, i.v. cyclophosphamide pulse significantly increased serum CXCL14 levels as compared with the baseline in SSc patients with interstitial lung disease successfully treated with this therapy. These results indicate that decreased CXCL14 expression may contribute to the maintenance of Th2‐skewed immune polarization and dysregulated neovascularization, both of which underlie the developmental process of SSc.     

Plasma homocysteine levels are positively associated with interstitial lung disease in dermatomyositis patients with anti‐aminoacyl‐tRNA synthetase antibody

Homocysteine is a sulfhydryl‐containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of central and peripheral vascular disorders, including carotid, coronary and peripheral arterial diseases, and Raynaud’s phenomenon. Recently, associations of plasma homocysteine levels with autoimmune diseases such as systemic lupus erythematodes and systemic sclerosis have been reported. However, no study analyzed the association between plasma homocysteine levels and dermatomyositis (DM). The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with DM. Plasma homocysteine levels in 28 Japanese patients with DM and 22 healthy controls were examined. We found that the plasma homocysteine levels in DM patients were significantly higher than those in healthy individuals (15.8 ± 1.1 vs 8.5 ± 0.5 µmol/L, P < 0.01). Presence of mechanic’s hand, complication of interstitial lung disease (ILD), high serum Krebs von den Lungen‐6 (KL‐6), surfactant protein‐D and creatine kinase levels, and anti‐aminoacyl‐tRNA synthetase (ARS) antibody (Ab) positivity were significantly more prevalent among DM patients with elevated plasma homocysteine levels. The plasma homocysteine levels in DM patients with mechanic’s hand, ILD and anti‐ARS Ab were significantly higher than those in DM without those features. Furthermore, the plasma homocysteine levels were positively correlated with serum KL‐6 levels. These results suggest that the pathogenesis of elevated plasma homocysteine levels may be associated with ILD in DM patients, especially with anti‐ARS Ab, and further examination is required.     

Successful use of intravenous cyclophosphamide pulse therapy for interstitial lung disease in a patient with systemic sclerosis on hemodialysis

Interstitial lung disease and scleroderma renal crisis are major complications of systemic sclerosis, which occasionally coexist in patients with the diffuse cutaneous subtype. We herein report a case of diffuse cutaneous systemic sclerosis under hemodialysis due to a previous history of scleroderma renal crisis, whose interstitial lung disease was effectively and safely treated with a half dose of i.v. cyclophosphamide pulse. The dose of cyclophosphamide and the timing of hemodialysis leading to efficacy and low toxicity are discussed.     

Rapid decrease of serum surfactant protein-D levels predicts the reactivity of rituximab therapy in systemic sclerosis-associated interstitial lung disease

Systemic sclerosis (SSc) is an autoimmune disorder characterized by vascular damage and excessive fibrosis. SSc-associated interstitial lung disease (ILD) is a leading cause of death in SSc. Several studies have shown the efficacy of rituximab (RTX) in SSc-ILD, but no study has examined the relation between RTX reactivity and change of serum marker levels. In this study we examined the relation between change of serum surfactant protein-D (SP-D) levels and change of percentage forced vital capacity (FVC) in 11 SSc-ILD patients with anti-topoisomerase I antibody treated by RTX. Serum SP-D levels were significantly decreased compared with baseline at 2 weeks after first RTX infusion in good responders (P = 0.04), while not in poor responders (P = 0.77). Moreover, ΔSP-D at 2 weeks negatively correlated with Δ%FVC at 24 weeks (P = 0.001). In conclusion, we suggested that the rapid decrease of SP-D levels may be a predictive marker of RTX effect against SSc-ILD.     

Clinical significance of endothelial vasodilatory function evaluated by EndoPAT in patients with systemic sclerosis

Endothelial dysfunction is a hallmark of vasculopathy associated with systemic sclerosis (SSc). Reactive hyperemia peripheral arterial tonometry is a rapid and non-invasive technique to assess peripheral microvascular endothelial function by measuring changes in digital pulse volume during reactive hyperemia. Low scores of the reactive hyperemia index (RHI) imply an impaired vasodilatory response and, accordingly, impaired endothelial and vascular health. To investigate the clinical significance of the RHI in SSc patients, RHI values were measured in 43 SSc patients and 10 healthy controls. In diffuse cutaneous SSc (dcSSc) patients, RHI values were significantly decreased compared with healthy controls, and inversely correlated with disease duration. In total SSc patients, there was a significant inverse correlation between RHI values and skin score, and interstitial lung disease was associated with the decrease in RHI values. Among vascular symptoms, the current and past history of digital ulcers was seen more frequently in patients with decreased RHI values than in those with normal RHI values. Although no SSc patients had pulmonary arterial hypertension, an inverse correlation was evident between RHI values and mean pulmonary arterial pressure measured by right heart catheterization. These results indicate that the decrease in RHI values is associated with skin fibrosis, interstitial lung disease, digital ulcers and pulmonary vascular involvement leading to pulmonary arterial hypertension, supporting the canonical idea that endothelial dysfunction is a critical event underlying the development of tissue fibrosis and vascular complications in SSc.     

Pemphigus vulgaris‐associated interstitial lung disease

Autoimmune bullous diseases (AIBDs)‐associated interstitial lung disease (ILD) is extremely rare. Pemphigus vulgaris (PV) is an intraepidermal autoimmune blistering disease caused by circulating autoantibodies against desmoglein. To date, PV‐associated ILD has rarely been reported in English literature. We report a rare association of PV and ILD. A 53‐year‐old Chinese female with PV for 8 months developed ILD after a relapse of PV for 2 months due to discontinuation of oral prednisone by herself. She was successfully treated by systemic methylprednisolone. Taken previously reported bullous pemphigoid‐associated ILD and linear IgA/IgG bullous dermatosis‐associated ILD together, in general, AIBDs‐associated ILD occurs when AIBDs relapse or are not controlled, responds well to systemic corticosteroids, and has a relatively better prognosis when compared with rheumatoid arthritis‐ or dermatomyositis‐associated ILD.     

Late‐onset anaphylactic reactions following i.v. cyclophosphamide pulse in a patient with systemic sclerosis and systemic lupus erythematosus overlap syndrome

Late‐onset anaphylactic reaction is a rare adverse effect of i.v. cyclophosphamide pulse (IVCY), which is caused by cyclophosphamide metabolites. We herein report a case of scleroderma and lupus overlap syndrome who developed anaphylactic reactions 3 h to 4 days after IVCY. Long time lapses between IVCY and appearance of symptoms are compatible with type I hypersensitivity to cyclophosphamide metabolites, appearing as late‐onset anaphylactic reaction. Albeit unusual, this is an important anaphylactic reaction to be aware of following IVCY.     

Elevated MMP-7 levels in patients with systemic sclerosis: correlation with pulmonary involvement

Background: Fibrosis is characterized by an excessive accumulation of connective tissue because of an imbalance between synthesis and degradation of extracellular matrix proteins. Systemic sclerosis (SSc) is a prototypic chronic inflammatory disease leading to a severe fibrosis of the skin and many internal organs. Questions Addressed: We investigated whether serum MMP‐7 levels reflect the activity of the fibrotic reaction in systemic sclerosis. Experimental Design: Serum samples were obtained from 123 patients with systemic sclerosis. MMP‐serum levels of all patients with SSc were compared with age‐matched healthy controls. Results: Significantly increased median serum MMP‐7 levels were found in patients with SSc when compared with controls. The median MMP‐7 serum level of patients with lung fibrosis (LF) was significantly higher compared with those without LF. Accordingly, patients with dyspnea and DLCO (diffusion capacity of the lung for carbon monoxide) levels below 60% showed significantly higher median MMP‐7 levels. Conclusions: Elevated MMP‐7 levels are associated with an advanced stage of SSc and LF. These data suggest that in SSc MMP‐7 is involved in the process of fibrotic tissue remodelling.     

Percentage of residual B cells after 2 weeks of rituximab treatment predicts the improvement of systemic sclerosis-associated interstitial lung disease

The benefit of rituximab (RTX) for systemic sclerosis-associated interstitial lung disease (SSc-ILD) has been shown in previous clinical trials. However, predictors of RTX efficacy have not been clarified. We investigated whether B-cell responsiveness to RTX is related to therapeutic effect. Ten SSc-ILD patients treated with RTX in an independent clinical trial (Japan Registry of Clinical Trials, jRCTs031180373) were included in this analysis. Peripheral B-cell counts were examined retrospectively before RTX administration (baseline) and at 2, 4, 12, and 24 weeks after the first RTX administration, along with percent-predicted forced vital capacity (%FVC) before and 24 weeks after RTX treatment. Relative to baseline, the percentage of residual peripheral blood B cells at 2 weeks after RTX was negatively correlated with the %FVC improvement at the 24-week assessment (r = ?0.41, p = 0.04). In the subgroup with less than 5% B-cell persistence at week 2, %FVC at the 24-week assessment was significantly improved compared to baseline (p = 0.02). In another subgroup with more than 5% residual B cells, %FVC was not significantly different after 24 weeks compared to baseline (p = 0.41). In conclusion, the removal rate of B cells after 2 weeks of RTX treatment may be a useful surrogate marker of subsequent SSc-ILD improvement.     

Clinically amyopathic dermatomyositis with rapidly progressive interstitial pneumonia: The relation between the disease activity and the serum interleukin‐6 level

A 67‐year‐old woman exhibited chilblain‐like erythema on the bilateral auricles, erythema with hyperkeratosis on the sides of fingers and the bilateral elbows, and erythema on the extensor/flexor sides of the finger joints and the iliac regions. Fine crackles were audible on the dorsal side of the bilateral lower lung regions. We diagnosed clinically amyopathic dermatomyositis accompanied by rapidly progressive interstitial pneumonia. While we initiated immunosuppressive therapy, the respiratory failure showed no responses. We performed endotoxin adsorption therapy using polymyxin B‐immobilized fiber column direct hemoperfusion (PMX‐DHP). After the first PMX‐DHP session, the respiratory condition was slightly improved but it soon deteriorated. At the second PMX‐DHP session, subcutaneous and mediastinal emphysema was noted. The patient died, showing no improvement in the respiratory condition. We measured the levels of serum interleukin (IL)‐6, tumor necrosis factor (TNF)‐α and IL‐10 before and after PMX‐DHP and compared them with previously reported levels. The levels of TNF‐α and IL‐10 showed no or slight changes, but those of IL‐6 at the beginning of the treatment were higher compared with previous reports. After the first PMX‐DHP, the IL‐6 level decreased with slight improvement in respiratory condition. However, after the second PMX‐DHP, it increased markedly with exacerbation of the respiratory failure. The serum IL‐6 level is considered to be effective for the evaluation of the disease activity and prognosis under the treatment by PMX‐DHP.     

Serum interleukin-6 level is reflected in elevated high-sensitivity C-reactive protein level in patients with systemic sclerosis

Systemic sclerosis (SSc) is a systemic connective tissue disease of unknown etiology which presents immunological, vascular and connective tissue abnormalities. Serum interleukin (IL)-6 has been reported to be elevated in patients with SSc. Clinical and laboratory findings affecting the elevated level of high-sensitivity C-reactive protein (hs-CRP) were studied in patients with SSc. Clinical and laboratory findings also included serum IL-6 level. Thirty-nine SSc patients (male : female = 7:32, age 19-84 years, mean 62.6 years) were studied. hs-CRP was measured with a nephelometric assay. Serum IL-6 level was measured by enzyme-linked immunosorbent assay. The distributions of hs-CRP showed that 18 cases (46.2%) were not elevated (<0.07 mg/dL), but 21 cases (53.8%) were (≥0.07 mg/dL). Alkaline phosphatase and IL-6 in SSc patients with elevated hs-CRP (291 ± 95 U/L, 3.23 ± 2.74 pg/mL) were significantly more elevated than those in not elevated patients (221 ± 75 U/L, 1.53 ± 1.12 pg/mL) (P < 0.02, P < 0.01). The correlation between hs-CRP level and IL-6 level in SSc patients was 0.687 (P < 0.001). In conclusion, elevated serum IL-6 levels are reflected in elevated hs-CRP levels in SSc patients.     

Possible pro‐inflammatory role of heparin‐binding epidermal growth factor‐like growth factor in the active phase of systemic sclerosis

Heparin‐binding epidermal growth factor (EGF)‐like growth factor (HB‐EGF) is a member of the EGF family growth factors, which affects multiple aspects of the wound healing process such as epithelialization, wound contraction and angiogenesis. In our study, we measured the serum HB‐EGF levels of 51 systemic sclerosis (SSc) patients, which showed a significant increase compared with those of 20 normal subjects. Further analysis revealed a positive correlation between the HB‐EGF level and pulmonary ground‐glass score but no correlation between the former and pulmonary fibrosis score. Other findings include: a significant increase of serum sialylated carbohydrate antigen KL‐6 levels and significant shortness of disease duration in the diffuse cutaneous SSc patients with elevated HB‐EGF levels; and significantly higher HB‐EGF levels in the presence of Raynaud's phenomenon, in that of telangiectasia, and in the absence of contracture of phalanges in all SSc patients. We then evaluated HB‐EGF mRNA levels of fibroblasts harvested from skin samples of the SSc patients and those of foreskin‐derived fibroblasts treated with transforming growth factor‐β, both of which were significantly higher than each control. In conclusion, we speculate that HB‐EGF plays a pro‐inflammatory role in the active skin and lung lesions of SSc.