systemic sclerosis ( ssc ) is a multiorgan disorder , and progressive interstitial lung disease ( ild ) and scleroderma renal crisis ( src ) are serious complications in ssc patients .
cyclophosphamide ( cyc ) is the recommended therapy for ssc - associated ild ( ssc - ild ) , but its effectiveness is not sufficient .
we report a src patient who underwent treatment with cyc for progressive ild and whose src was successfully treated with angiotensin - converting - enzyme inhibitor ( ace - i ) and plasma exchange ( pe ) .
a 67-year - old female was referred to our hospital for stiffness in her hands and a high titer of antinuclear antibody ( ana ) of 1:640 .
the patient had a history of hypertension , and her blood pressure ( bp ) at first consultation was 110/66 mmhg with a medication of 5 mg amlodipine besylate a day .
physical examination revealed scleroderma extending bilaterally to the upper arms , nailfold bleeding , and fine crackles on her back .
her ana titer was positive at 1:1280 with homogeneous and nucleolar patterns , and anti - topoisomerase i antibody titer examined by immunodiffusion was positive at 1:2 .
serum krebs von den lungen-6 ( kl-6 ) level was 331 u / ml , which was within the normal range .
in addition to blood cell counts and urinalysis , other clinical data were unremarkable ( table 1 ) .
electrocardiogram demonstrated no arrhythmia , and ventricular dysfunction and pulmonary arterial hypertension were not revealed by echocardiography .
chest computed tomography ( ct ) presented bilateral slight ground - glass opacity ( ggo ) predominantly around the dorsal area ( figure .
1a ) , and gastroduodenal endoscopy showed atrophic gastritis and mild reflux esophagitis . from her clinical findings
, the diagnosis of diffuse - type ssc was made , and 20 mg / day of prednisolone ( psl ) was initiated for the newly onset edematous scleroderma .
laboratory data on first examination chest ct presented ggo shadow around dorsal area at first examination(a ) , got worse before ivcy(b ) , persisted before pe(c ) , improved right after pe(d ) , and still stabilized 2 years after pe(e ) .
seven months after psl therapy initiation ( 4 months before pe ) , she was aware of dyspnea on effort and worsening of hand stiffness .
the ggo shadow in her lung field in the chest ct had deteriorated ( figure .
1b ) , and arterial oxygen pressure under room air was decreased to 67.1 mmhg .
percentages of forced vital capacity ( fvc ) for the predicted values also decreased to 52.4% ( table 2 ) .
progressive ild was suspected , and therefore , 13.7 mg / kg body weight intravenous cyc ( ivcy ) pulse therapy was initiated for every 4 weeks .
however , after four courses of ivcy therapy , clinical improvement could not be obtained , and she began to complain of appetite loss , nausea , and general fatigue . on second admission
( 19 days before pe ) , her bp was 106/70 mmhg and body temperature ( bt ) was 36.8c .
laboratory data revealed that total bilirubin ( t - bil ) and lactate dehydrogenase ( ldh ) levels had increased to 1.8 mg / dl and 345 u / l , respectively .
c - reactive protein ( crp ) level was 0.73 mg / dl , which slightly exceeded the normal upper limit of 0.5 mg / dl .
the serum kl-6 level had progressively increased to 767 u / ml . urinalysis revealed mild proteinuria , but no hematuria .
the ggo shadow of her lung field in a chest ct , which presented a nonspecific interstitial pneumonia ( nsip ) pattern , had become slightly worse after four courses of ivcy therapy ( figure .
1c ) . cardiac dysfunction and pulmonary arterial hypertension were not observed again by echocardiography . by a few weeks ( 5 days before pe ) , the serum t - bil , ldh , and creatinine ( cr ) levels
the patient s hemoglobin levels had decreased to 10.5 g / dl , and her haptoglobin level was below 10 mg / dl with a negative coombs test , and schistocytes were observed under the microscope .
further examination of the blood revealed an international normalized ratio prothrombin time of 0.88 , an activated partial thromboplastin time of 30.8 s , and fibrinogen / fibrin degradation products ( fdp ) was 7.1 g / ml . the fdp level was slightly elevated , and her fibrinogen level was 388 mg / dl , which was within the normal range .
the plasma renin activity ( pra ) and aldosterone ( ald ) levels were elevated to 18.8 ng / ml / hr and 289 pg / ml , respectively .
her blood pressure was 123/65 mmhg , which was within the normal range , but slightly elevated over her usual level .
a disintegrin - like and metalloproteinase with thrombospondin type-1 motifs 13 ( adamts13 ) level was 32.4% , which was below the lower limit , but still detectable .
tests for the perinuclear and cytoplasmic antineutrophil cytoplasmic antibodies ( anca ) and anti - rna polymerase iii antibody were negative . taking these clinical findings into consideration , we diagnosed the patient with src with thrombotic microangiopathy ( tma ) and hemolytic anemia . although we did not get the result of adamts13 level when serum cr levels progressively elevated , we could not deny the involvement of thrombotic thrombocytopenic purpura ( ttp ) .
therefore , we initiated enalapril treatment accompanied by pe with 73.4 ml / kg body weight frozen fresh plasma for nine courses .
renal biopsy was not performed because of the need for immediate therapeutic induction and avoiding progressive renal damage . upon pe completion
her blood pressure returned to the normal level of 110/70 mmhg , and abnormal laboratory data had improved ( figure .
1d and e ) , and the worsening of pulmonary function had stopped and improved at 2 years after pe ( table 2 ) .
change in pulmonary function before and after pe clinical course of serum creatinine , lactate dehydrogenase , and platelet .
after ace - i accompanied with pe therapy , the abnormal laboratory data suggesting tma and renal damage had improved .
src is a severe complication , which mainly occurs in approximately 5% of diffuse - type ssc patients .
typical manifestations of src are progressive bp elevation and renal damage , which sometimes lead to poor prognoses .
our case did not present severe hypertension or renal damage , but her bp and serum cr were elevated above normal levels .
tma , which occurred in half of the src patients , was identified in our case .
in addition , the highest risk group for src are patients with early diffuse - type ssc and rapidly progressive skin sclerosis , but majority of ttp associated with ssc was reported to be of the limited type . src results from endothelial injury and intimal proliferation in the renal arteries , followed by activation of the renin - aldosterone system .
the pra and ald levels in our patient s case were high , which possibly indicated src .
although our patient should be diagnosed with src , it is difficult to rule out ttp at an acute phase of src because of the similarity between these two disorders and absence of adamts13 . to avoid therapeutic delay for the suspected disorder , initiation of pe
one of the reasons for a normal bp was the patient s long - term use of antihypertensives , and the other was slowly elevation rate of bp . considering the clinical course , the serum cr and ldh levels rapidly elevated from 5 days before pe ( figure 2 ) . at this time
pra had elevated because of the decrease in renal blood flow , followed by progressive hypertension .
we supposed that early initiation of ace - i and pe interrupted the elevation of bp .
if we had not started the therapy for src immediately , hypertension would have become apparent in our case .
this idea is based on the hypercoagulative state of the blood brought about by the corticosteroid . on the other hand ,
some reports have mentioned that corticosteroid administration is not a risk factor of src , but rather is the result of therapy for severe ssc .
steen et al . reported that a significantly greater proportion of src patients than ssc control patients received high - dose ( > 15 mg / day ) corticosteroid for 6 months prior to src onset , but there was no difference in the patients who had been taking corticosteroid continuously for more than 6 months . in our case , 11 months had passed from initiation of steroid therapy to src onset , which was a long interval for the development of steroid - induced src .
therefore , the contribution of corticosteroid to the development of src is unclear in this case .
typical renovascular histopathological findings of src include so - called  onion skin  lesions in the arteries ranging from the arcuate to cortical radiate arteries and fibrinoid thrombosis of the small vessels .
these changes are caused by endothelial damage to the small vessels , leading to an increase in vascular permeability , endothelial cell proliferation , and stenotic change because of platelet aggregation .
the increased production of th2 cytokines , such as interleukin-4 , -13 , and transforming growth factor- ( tgf- ) in ssc patients cause angiofibrosis and intimal stenosis by the activation of fibroblasts .
other mechanisms of vascular damage in ssc are antibody - dependent cell - mediated cytotoxicity by anti - endothelial autoantibody and hyper - excretion of endothelin-1 ( et-1 ) . although the only recommended therapy for src is ace - i , the efficacy of pe combined with ace - i has also been reported .
the therapeutic mechanism of pe is considered to be via the removal of cytokines that induce tissue fibrosis ; vasoconstrictive factors , such as et-1 ; and autoantibodies .
ssc - ild is also suspected to be caused by vascular stenosis and interstitial fibrosis due to advanced cytokine production . currently , the only recommended therapy for progressive ssc - ild is cyc ; however , the therapeutic efficacy of cyc is not sufficient . in our case
, the progressive interstitial shadow of pulmonary fibrosis stopped after pe , and stable radiographic findings had been maintained and pulmonary function had improved .
renovascular stenosis by endothelial injury , observed in the pathology of ssc patients , is also observed in the pulmonary arteries .
therefore , we speculate that pe has contributed to the clinical improvement of ssc - ild to some extent . the serum cr level at diagnosis is reported to be the prognostic indicator for src .
. immediate initiation of ace - i and pe combination therapy is thought to be effective for the amelioration of renal function and treatment of progressive ild .
 abstractsystemic sclerosis ( ssc ) is a multiorgan disorder involving the skin , heart , lungs , kidneys , and intestines . 
 progressive interstitial lung disease ( ild ) is a serious complication in ssc patients , and cyclophosphamide ( cyc ) is the only recommended therapy for this condition;1 ) however , its clinical effectiveness is not sufficient 
 . scleroderma renal crisis ( src ) is a rare complication , characterized by acute renal failure and progressive hypertension . 
 angiotensin - converting - enzyme inhibitor ( ace - i ) is a widely accepted therapy for src . 
 we report an ssc patient with src and progressive ild who underwent treatment with cyc and successful treatment with ace - i and plasma exchange ( pe ) . 
 src and ild are significant contributors to morbidity and mortality among ssc patients , and the therapy for these disorders is of great interest to rheumatologists . 
 this study presents the possibility of favorable effects of pe for ssc - associated ild and src . 
INTRODUCTION
A CASE REPORT
DISCUSSION