Experience with azathioprine in systemic sclerosis associated with interstitial lung disease

the aim of this study was to evaluate the safety and efficacy of azathioprine in the treatment of interstitial lung disease (ILD) associated with systemic sclerosis (SSc). The records of patients with SSc with ILD who were treated with azathoprine were reviewed. Patients were treated with azathioprine and low-dose prednisone if they had progressive pulmonary symptoms (deterioration in the dyspnea score) or poor or deteriorating lung function. Response was classified as improved if the FVC increased more than 10% from baseline, and stable if it remained within 10% of baseline. Serial dyspnea scores were recorded. Eleven patients were treated with azathioprine, three of whom received treatment for 6 months or less owing to adverse effects (nausea, leukopenia and pulmonary tuberculosis in one patient each). The remaining eight patients received at least 12 months treatment and the results suggested an improvement in the mean percent predicted FVC from a baseline value of 54.25±3.53 to 63.38±6.15 after 12 months (p=0.101). Overall, five patients improved and three remained stable. The mean dyspnea score (n=8) improved from a baseline of 1.55±0.19 to 0.50±0.19 at 12 months (p=0.011). This is the first case series of patients with SSc-associated ILD treated with azathioprine. Our results suggest that azathioprine may have a role in stabilizing lung function and improving symptoms in SSc, although this needs confirmation by a randomized controlled trial.Abbreviations ILD Interstitial lung disease - SSc Systemic sclerosis     

Interstitial lung disease in systemic sclerosis

Lung involvement frequently complicates systemic sclerosis (SSc), provoking loss of quality of life and a poor expectation of survival. For this reason an early diagnosis of lung involvement is warranted: high-resolution computed tomography (HRCT), pulmonary function tests (PFT), lung scintigraphy with DTPA and bronchoalveolar lavage (BAL) are mandatory to define and follow-up pulmonary interstitium. Coughing and a sensation of breathlessness on exertion are the earliest symptoms of lung involvement. Lung involvement may be investigated with PFTs, which are non-invasive and require breathing into a tube via a mouthpiece. Forced vital capacity, which measures the total amount of air capable of being blown forcefully, and the diffusion capacity for carbon monoxide, a measure of how well oxygen diffuses into blood, are the most important functional measures. A routine chest X-ray may demonstrate fibrosis, but it is not very sensitive for detecting early or mild disease. For this reason, a HRCT scan is required. This non-invasive investigation provides images of multiple slices through the lung, from top (apex) to bottom (base), and can even detect lung involvement in early phases when no symptoms are present. ^99mT-DTPA is recommended in those patients with isolated diffusion deficits on lung function tests and in addition to HRCT in confirming the suspicion of vascular disease rather than early fibrosing alveolitis. Bronchoscopy with BAL is an invasive test that also may provide information about the inflammatory status of the affected areas of the lung detected during HRCT. In order to detect alveolitis, it should be performed as early as possible, to start prompt immunosuppressive treatment.     

The natural course of progressive systemic sclerosis patients with interstitial lung involvement

Objective The aim of the study is to assess the natural course of systemic sclerosis (SSc) in patients with interstitial lung involvement and to evaluate the effects of treatment. Materials and methods Sixty SSc patients with interstitial lung involvement were included in the study and history and retrospective data records of the patients were reviewed. Results It was observed that 47 patients (78.3%) had Raynaud’s phenomenon, 7 patients (11.7%) had skin involvement, 5 patients (8.3%) had joint involvement, and 1 patient (1.7%) had gastrointestinal system involvement as the first manifestation of the disease. Lung involvement had developed on an average of 113±106 months after the first manifestation of the disease and was apparent within the first year in 10 patients (16.7%), between 1 and 2 years in 3 patients (5%), between 2 and 3 years in 2 patients (3.3%), between 3 and 4 years in 5 patients (8.3%), between 4 and 10 years in 21 patients (35%), and after 10 years in 19 patients (31.7%). When the symptoms of lung involvement appeared, 37 patients (61.7%) were not receiving treatment while 23 (38.3%) were using an immunosuppressive agent. The time interval of lung involvement for the treated patients was 131±95 months while it was 101±112 months in untreated patients (p>0.05). Conclusion In SSc patients with intersititial pulmonary involvement, the disease frequently starts with Raynaud’s phenomenon and pulmonary symptoms tend to appear at a mean of 7 years after the onset of disease. The first sign of the disease, the probability of interstitial pulmonary involvement, is highest during the first 15 years after. Although this probability decreases after 15 years, in up to 10% of the patients, interstitial pulmonary involvement can still occur even up to 40 years. Immunosuppressive treatment is not effective in preventing the development of pulmonary involvement. However, it delays the manifestation of pulmonary symptoms for nearly 4 years.     

Clinical significance of monitoring serum adiponectin levels during intravenous pulse cyclophosphamide therapy in interstitial lung disease associated with systemic sclerosis

Objective

To investigate the clinical significance of monitoring serum adiponectin levels during intravenous pulse cyclophosphamide (IVCY) in systemic sclerosis (SSc) patients with interstitial lung disease (ILD).

Methods

Serum adiponectin levels were determined by a specific enzyme-linked immunosorbent assay in eight SSc patients with active ILD who underwent IVCY and 27 healthy controls. In patients, serum samples were drawn the day before each IVCY.

Results

Serum adiponectin levels were significantly decreased in SSc patients with active ILD before the first IVCY compared with healthy controls [median (25–75 percentile): 3.21 (2.70–4.19) vs. 7.42 (6.06–10.82) μg/ml; P < 0.01). After the completion of whole IVCY, serum adiponectin levels were significantly increased [17.55 (6.47–39.45) μg/ml; P < 0.05] compared with the initial levels, and this increase significantly correlated with the decrease in ILD scores. Importantly, the dynamics of serum adiponectin levels during the IVCY therapy reflected its efficacy against SSc-ILD over the treatment and the follow-up period.

Conclusion

The monitoring of serum adiponectin levels during the IVCY treatment may be useful to identify SSc patients with ILD refractory to the treatment and at high risk for exacerbations during the follow-up period.     

Mycophenolate mofetil as a therapeutic agent for interstitial lung diseases in systemic sclerosis

Systemic sclerosis (SSc) is an intractable disease that causes fibrosis in all organs. Approximately 40% of patients with SSc have some degree of interstitial lung disease (ILD). One third of patients with SSc and ILD, approximately 15% of all patients, have pulmonary lesions, which slowly progress to respiratory failure resistant to corticosteroid and other treatments.A randomized controlled trial conducted in the United States indicated that one year of treatment with oral cyclophosphamide in patients with SSc-ILD had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and health-related quality of life. However, all the effects, except for a sustained impact on dyspnea, disappeared approximately one year after stopping oral administration of cyclophosphamide. A randomized controlled trial using cyclophosphamide and mycophenolate mofetil (MMF) was then held in the United States for 142 patients with SSc-ILD. Treatment of SSc-ILD with MMF for two years or cyclophosphamide for one year both resulted in significant improvements in lung function over the 2-year course of the study. Leukopenia and thrombocytopenia occurred less often in patients administered MMF than in those administered cyclophosphamide.MMF is currently not approved for the treatment of SSc-ILD in Japan. Both MMF and cyclophosphamide were effective against ILD associated with SSc and, in particular, MMF was useful in terms of tolerability. When MMF is approved, it should be positioned as one of the first treatment options for SSc-ILD, which will further enhance the treatment of this disease in Japan.     

Dynamics of serum angiopoietin-2 levels correlate with efficacy of intravenous pulse cyclophosphamide therapy for interstitial lung disease associated with systemic sclerosis

Objective

Angiopoietin-2 (Ang2) regulates the transition between vascular quiescence and angiogenesis in a context-dependent manner. In systemic sclerosis (SSc), serum Ang2 levels correlate with its disease activity. Therefore, we investigated the clinical significance of monitoring serum Ang2 levels during intravenous pulse cyclophosphamide (IVCY) therapy in SSc patients with interstitial lung disease (ILD).

Methods

Serum Ang2 levels were determined by a specific enzyme-linked immunosorbent assay in seven SSc patients treated with IVCY and 20 healthy controls. In the patient group, serum samples were drawn the day before each IVCY therapy.

Results

Serum Ang2 levels tended to be higher in SSc patients before IVCY than in healthy controls and significantly correlated with KL-6, surfactant protein D, erythrocyte sedimentation rate, and C-reactive protein in SSc patients with ILD. In sera drawn before the last IVCY, Ang2 levels were significantly decreased compared with initial levels. Notably, Δ serum Ang2 levels between baseline and after the first IVCY significantly correlated with Δ ILD score between before and after the entire IVCY therapy (r = 0.90, p < 0.01).

Conclusion

Monitoring Ang2 levels during IVCY treatment may be useful to evaluate and predict the efficacy of this treatment for SSc-ILD.     

Antifibrotics in systemic sclerosis

Systemic sclerosis (SSc) is a rare and complex disease, involving multiple organs, with high morbidity and mortality. Fibrosis is the hallmark of SSc, although vascular and inflammatory mechanisms are also implicated in its pathogenesis. Disease management is challenging, due to its heterogeneous presentation, and to the limited number of controlled clinical trials to guide treating clinicians. Immunosuppressive agents have been used to prevent progression, especially in the lung, before irreversible injury occurs, with some, although modest, benefit. Nintedanib, a tyrosine kinase inhibitor, has recently demonstrated safety and efficacy in interstitial lung disease (ILD) associated with SSc, and many other antifibrotics are being assessed as possible beneficial therapies, with promising results. An important unmet need remains, to clarify to which patients, when, and with which agent therapy should be initiated, to achieve optimal outcomes. This review summarizes available evidence for current and emerging antifibrotic therapies in SSc patients.     

Serum concentration of surfactant protein D in patients with systemic sclerosis: The potential marker of the interstitial lung disease severity

Pulmonary involvement is a severe manifestation of systemic sclerosis (SSc). The study was designed to determine the serum level of surfactant protein D (SP-D) in patients with SSc in relation to clinical and laboratory parameters as well as to analyze dynamics of changes of these indices within one year of observation.SP-D was assayed in 41 patients with SSc and 15 healthy controls. Additionally, pulmonary function tests, chest high-resolution computed tomography (HRCT), and inflammatory markers were assessed. All tests were performed twice: at entry and repeated after one year of observation.The serum level of SP-D was significantly higher in patients with SSc than in healthy controls. Serum concentration of SP-D was significantly higher in patients with systemic sclerosis-related interstitial lung disease (SSc-ILD) than in those without SSc-ILD. SP-D was found to correlate with lung involvement evaluated with the Medsger score (diffusing capacity of the lung for carbon monoxide (DLCO), forced vital capacity, radiological changes, and estimated pressure in the pulmonary artery in echocardiography). SP-D correlated with the honeycombing and/or reticular pattern in HRCT and ground glass opacification pattern. Serum concentration of SP-D was elevated in patients with a decreased DLCO. Furthermore, SP-D was higher in patients with diffuse cutaneous type (dcSSc) of the disease than in those with SSc limited type (lcSSc). Because of the small size of the group, it was not possible to perform a statistical analysis for patients who had different results in HRCT, VC, and Medsger score between the first and the second evaluation.SP-D seems to be an index for assessing lung involvement. It reflects the state of pulmonary fibrosis but not the dynamics of the pulmonary fibrosis progression. Further studies are needed to evaluate clinical application of the index, and currently, there is no evidence for the recommendation of the application of SP-D in routine evaluation of patients with SSc.     

Incidence and predictors of interstitial lung disease (ILD) in Thai patients with early systemic sclerosis: Inception cohort study

Objectives: To determine and compare the prevalence of interstitial lung disease (ILD), the severity of high-resolution computed tomography (HRCT) score and incidence rate (IR) of ILD between the two subsets of early-SSc (systemic sclerosis) patients. We also determined the factors associated with ILD.

Methods: We used an inception cohort of early-SSc patients seen between January 2010 and June 2014. All patients underwent HRCT at study entry and annually thereafter.

Results: One hundred and thirteen patients (66 females and 89 diffuse cutaneous SSc [dcSSc]) with a mean?±?SD age of 53.4?±?8.4 years and mean disease duration of 12.9?±?10.3 months at cohort entry were enrolled. At enrollment, patients with dcSSc had a higher prevalence of ILD (78.7% vs. 45.8%, p?=?0.002), and a higher total HRCT score (10.3?±?9.5 vs. 4.4?±?5.6, p?=?0.001) compared with limited cutaneous SSc (lcSSc). DcSSc patients had a higher IR of ILD than lcSSc patients (58.8 vs.17.3 per 100 person-years, p?<?0.001). Univariable analysis revealed that male gender, presence of anti-Scl 70 and absent anti-centromere antibody was significant predictors of ILD. In Cox-regression analysis, a positive anti-centromere [hazard ratio (HR) 0.09 95% confidence interval (95% CI 0.01–0.73)] was a protective factor.

Conclusions: DcSSc patients had more severe HRCT scores and higher IR of ILD compared with lcSSc patients. Male gender, presence of anti-Scl 70, and absent anti-centromere antibody predicted the future development of ILD in early-SSc patients.     

A randomized unblinded trial of cyclophosphamide versus azathioprine in the treatment of systemic sclerosis

Current therapeutic modalities for the treatment of systemic sclerosis (SSc) have significant limitations. The window of opportunity to prevent tissue fibrosis and irreversible damage occurs during the early inflammatory phase of this condition. A drug that we believe has promise to exert a desired effect in early SSc is cyclophosphamide (CYC). However, there are only a few published reports regarding the use of cytotoxic immunosuppressive medications at the onset of the illness. The goal of this study was to test the efficacy and toxicity of CYC in patients with early diffuse SSc. The study design was a randomized, unblinded, 18 months per patient trial with a comparison group that received azathioprine (AZ). Thirty patients were assigned to receive oral CYC (2 mg/kg daily for 12 months and then maintained on 1 mg/kg daily) and 30 patients were assigned to receive oral AZ (2.5 mg/kg daily for 12 months and then maintained on 2 mg/kg daily). During first 6 months of the trial, the patients also received prednisolone, which was started at a dosage of 15 mg daily and tapered to zero by the end of the sixth month. After treatment there was a statistically significant improvement in the modified Rodnan skin score (MRSS), attack frequency of Raynauds phenomenon (RP), and erythrocyte sedimentation rate (ESR) in the CYC-group, but not in the AZ-group. The forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCO) did not change after treatment in the CYC-group, but statistically significantly worsened in the AZ-group. No life-threatening or irreversible adverse reactions were observed in either group. This study showed that CYC is a promising disease modifying medication for SSc as it exhibited a positive influence on the evolution of disease.     

系统性硬化症相关间质性肺疾病的临床特点及危险因素分析

目的探讨系统性硬化症相关间质性肺疾病（SSc-ILD）的临床特点及危险因素。方法收集系统性硬化症（SSc）患者68例,根据有无间质性肺疾病（ILD）分为SSc-ILD组（44例）和单纯SSc组（24例）,分析SSc-ILD患者临床表现、自身抗体、胸部CT、肺功能及超声心动图特点,并与单纯SSc组比较。结果 SSc-ILD组中弥漫性皮肤损害型SSc（dcSSc）21例、局限性皮肤损害型SSc（lcSSc）23例,有呼吸系统表现者34例,其中活动后胸闷/气短30例、干咳18例。抗Scl-70抗体在SSc-ILD和dcSSc中的阳性率分别高于单纯SSc和lcSSc。SSc-ILD最常见的胸部CT表现为磨玻璃影（25例）,其次为网格状影（19例）。28例SSc-ILD行肺功能检测,其中弥散功能减退24例、限制性通气功能障碍13例。8例单纯SSc出现弥散功能减退,其中6例行超声心动图检查,5例有肺动脉高压（PAH）。SSc患者PAH发生率为58.93%（33/56）,ILD同时合并PAH者23例。结论 SSc-ILD以活动后胸闷/气短、磨玻璃影和弥散功能减退常见。单纯SSc若出现弥散功能减退,需警惕PAH可能。dcSSc及抗Scl-70抗体阳性是SSc发生ILD的危险因素。     

Operator-independent quantitative chest computed tomography versus standard assessment of interstitial lung disease related to systemic sclerosis: A multi-centric study

Abstract

Purpose. Interstitial lung disease (ILD) related to systemic sclerosis (SSc) is assessed with pulmonary functional tests (PFTs) and semi-quantitative scores based on extent of ILD detectable on chest computed tomography (CT). CT quantitative indexes (QCTIs) are promising tools to assess extent of ILD. This study's aim is to evaluate the validity of QCTI compared with that of chest CT standard evaluation and PFTs. Moreover, QCTI differences between patients’ subgroups according to prognostic stratifications were investigated.

Methods. ILD-SSc of patients from six rheumatological clinics was routinely assessed with chest CT and PFTs. Patients were clustered according to prognosis based on functional and/or radiological examinations. Finally, chest CTs were processed with OsiriX in order to obtain QCTI.

Results. Two hundred fifty-seven SSc patients were enrolled. QCTI correlation between extent of ILD and PFTs range from ? 0.60 to 0.58 and from ? 0.54 to 0.52, respectively. The majority of QCTI have a different distribution in patients’ subgroups based on prognosis. Most of QCTI discriminate patients with an ILD severity leading to a poor prognosis.

Conclusions. QCTI assessment of ILD-SSc is comparable to the evaluation based on chest CT and/or PFTs. QCTI values corresponding to severe ILD were identified. QCTIs are excellent candidates for a new and more reliable SSc-ILD assessment.     

Intravenous dexamethasone pulse therapy in diffuse systemic sclerosis

Thirty-five patients with diffuse systemic sclerosis were studied in a randomized, placebo-controlled, double-blind study. Seventeen patients received intravenous dexamethasone pulse therapy, while 18 patients received placebo. Each pulse consisted of 100 mg dexamethasone in 250 ml 5% dextrose infused intravenously over 1 h. Pulse therapy was repeated every month for 6 months. Assessment of disease status with various parameters was done at entry and at completion of trial, i.e. after 6 months. Significant improvement in skin involvement was seen in the study group, with the total skin score (TSS) decreasing from 28.5±12.2 to 25.8±12.8, while in the control group, TSS increased from 30.6±13.2 to 34.7±10. Similarly, significant improvement was noted in the flexion index. Other parametres that included extension index, maximum oral opening, range of movement of joints, functional disability score, Raynaud's phenomenon (frequency and duration), ESR, proteinuria, chest X-ray, ECG, lung function tests, barium swallow and antinuclear antibody were unchanged. Adverse effects of therapy were limited to an increased incidence of minor chest infections. It is concluded that intravenous pulse dexamethasone may be useful in the treatment of diffuse systemic sclerosis.     

Combination of intravenous pulses of cyclophosphamide and methylprednizolone in patients with systemic sclerosis and interstitial lung disease

The purpose of the study was to examine prospectively the efficacy and safety of the combination of intravenous pulses of cyclophosphamide and methylprednizolone, in the treatment of scleroderma lung disease. Thirteen patients were treated with the above combination for up to 24 months. Prior to this treatment, they underwent a pulmonary function evaluation and high resolution computed tomography (HRCT). Carbon monoxide diffusion lung capacity and forced vital capacity were repeated at 6, 12, 24 and 48 months. HRCT was repeated at the end of the treatment period, but in between and afterwards in some patients, as well. A significant percentage of patients (66.6%) showed stabilization or improvement of their pulmonary function. Patients with already seriously compromised function, before treatment, were the least likely to exhibit this evolution pattern. There was a tendency in some individuals to deteriorate on later evaluations, off treatment, although they had stabilized at the end of the treatment. There was rather a poor correlation between functional evolution and HRCT appearance. Finally, the regimen was well tolerated. Our results suggest that the employed combination is safe and effective, mainly in stabilizing the respiratory function of the patients. This goal is more realistic when treatment is given before significant functional compromise has ensued. The need for long-term immunosuppression to maintain the initial favorable response is suggested.     

Mycophenolate mofetil therapy for rapidly progressive interstitial lung disease in a patient with clinically amyopathic dermatomyositis

Abstract

Background Though concern of hepatitis B virus (HBV) reactivation by antirheumatic agents has limited therapeutic opportunities in HBV-infected rheumatoid arthritis (RA) patients, the relative risks (RR) among such agents have not been clarified.

Objective We compared the reporting of antirheumatic-agent-associated hepatitis B.

Patients We assessed 92 hepatitis B cases and 98,069 controls from a population of 98,161 RA patients registered into the US Food and Drug Administration’s (FDA’s) adverse event database between 2004 and 2010.

Measurements A reporting odds ratio (ROR), a signal suggesting a risk for hepatitis B among antirheumatic agents, was measured.

Results Treatment with corticosteroids [ROR 2.3 (95 % confidence interval 1.3–4.0)], methotrexate [4.9 (3.9–6.0)], rituximab [7.2 (5.3–9.9)], tacrolimus [4.2 (1.5–11.9)], or reporting from Japan [2.2 (1.1–4.2)] were associated with higher signal, whereas adalimumab had a lower ROR [0.2 (0.1–0.4)].

Limitations There are known limitations of spontaneous reporting, such as underreporting, the Weber effect, reporting bias, indication bias, and limited clinical information such as HBV status.

Conclusions Adalimumab’s low reporting rate is most likely be due to notoriety. However, the possibility that adalimumab might suppress reactivation of HBV cannot be denied. Until the possibility is clarified in well-designed clinical studies, physicians should use adalimumab cautiously in patients with HBV.     

Serum nitric oxide metabolites and disease activity in patients with systemic sclerosis

There is no surrogate marker in serum for defining disease activity in scleroderma (SSc). Nitric oxide (NO), which regulates vasodilation and possesses pro-inflammatory actions, has been implicated in the pathogenesis of SSc. We compared serum NO _x (total nitrate and nitrite) level in SSc patients to healthy controls and evaluated its correlation with detailed symptomatology and scoring systems for various organ involvement. Symptoms and physical findings that suggested disease activity in regard to various organs were documented. Lung function test, high-resolution computed tomographic (HRCT) scan of thorax and echocardiography were performed. Serum NO _x was measured by chemiluminescence. Serum NO _x levels in SSc (n = 43) were significantly higher (72.4 ± 47.8 μM) than age- and sex-matched controls (n = 41; 37.1 ± 13.5 μM; p < 0.001). Serum NO _x were not found to be associated with lung fibrosis defined by lung function parameters or inflammation and fibrosis scores on HRCT. Twenty-two patients were found to have elevated serum NO _x level defined as mean ± 2 SD of normal controls. Logistic regression analysis revealed that age (OR 1.12, p = 0.02) and elevated pulmonary arterial pressure (PAP) (n = 9; OR 145.3, p = 0.01) were predictive factors for elevated serum NO _x . Prednisolone use was associated with lower serum NO _x level (OR 0.06, p = 0.04). Elevated PAP of increasing severity was found to be associated with higher level of serum NO _x (p = 0.004 by trend). Serum NO _x in SSc patients were elevated compared to healthy controls. Serum NO _x level was determined by multiple factors including age, prednisolone use, and elevated PAP.