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     

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.     

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.     

Intersticiopatía pulmonar subclínica en pacientes con esclerosis sistémica. Estudio piloto sobre el papel del ultrasonido

IntroductionInterstitial lung disease (ILD) is a common comorbidity present in patients with systemic sclerosis (SSc). Employment of high-resolution computed tomography (HRCT) is very limited and lung ultrasound (LUS) can be an alternative tool for the early evaluation of ILD.ObjectiveTo determine the validity of LUS in the early detection of ILD in patients with SSc.MethodsSixty-eight patients with SSc ≥18 years without respiratory symptoms were included. A rheumatologist rated the subclinical respiratory condition, another rheumatologist blinded to the clinical assessment performed the LUS. To determine validity HRCT was performed as well.ResultsPrevalence of ILD in SSc patients was 41.2% in contrast to the 4.8% healthy controls (P = .0001). Variables associated with LUS and HRCT findings were anti-centromere antibodies (P = .005) and the Rodnan skin score (P = .004). A positive correlation was present between the findings of HRCT and LUS (P = .001). Sensitivity and specificity were 91.2% and 88.6% respectively. Good reliability in the LUS findings was found between observers (k = .72).ConclusionsBy proving to be a valid, trustworthy and feasible alternative tool, we consider that LUS can be implemented for the early detection of ILD in SSc.     

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.     

Short-term add-on tocilizumab and intravenous cyclophosphamide exhibited a remission-inducing effect in a patient with systemic lupus erythematosus with refractory multiorgan involvements including massive pericarditis and glomerulonephritis

We report on a 41-year-old woman with refractory systemic lupus erythematosus with massive pericarditis, macrophage activation syndrome, and glomerulonephritis despite high-dose glucocorticoids and tacrolimus. Tocilizumab dramatically improved pericarditis, and glomerulonephritis was controlled after adding cyclophosphamide. We had to halt tocilizumab and cyclophosphamide due to possible pneumocystis infection after five and three infusions of tocilizumab and intravenous cyclophosphamide, respectively. Nevertheless, no lupus flare had been observed on glucocorticoid monotherapy and enabled further rapid tapering prednisolone.     

Interstitial Lung Disease in Systemic Sclerosis

We reviewed the literature concerning pathogenesis, clinical features, diagnosis and treatment of interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). ILD is detectable in approximately 70% of patients at autopsy. Nonspecific interstitial pneumonia (NSIP) is the most common pathologic finding. The earliest phase of ILD in SSc is characterized by microvascular injury and alveolitis. Endothelial lesions, activation of coagulation proteases, especially thrombin, fibroblast proliferation, and differentiation of normal lung fibroblasts to a myofibroblasts phenotype are hallmarks of ILD in SSc. Diagnostic procedures used to detect ILD are chest X-ray, high-resolution computed tomography, bronchoalveolar lavage, lung function tests, and sometimes thoracoscopic lung biopsy. Novel and potentially useful methods to diagnose ILD in SSc are induced sputum and technetium-labeled diethylenetriamine pentaacetate (^99mTC-DTPA) clearance time. Cyclophosphamide seems to be relatively effective to treat ILD in the earliest phase, but the effects of other immunosuppressive drugs on the lungs are less convincing.     

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.     

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.