***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The majority of patients with systemic sclerosis ( SSc ) have gastrointestinal ( GI ) tract involvement , but therapies using prokinetic agents are usually unsatisfactory . Ghrelin stimulates gastric motility in healthy human volunteers . In this study , we investigated whether ghrelin could improve gastric emptying in patients with gastrointestinal symptoms due to SSc . The study was performed in a r and omized , double-blind , placebo-controlled crossover fashion on two occasions . Ten SSc patients with GI tract involvement received an infusion of either ghrelin ( 5.0 μg/kg ) or saline , and gastric emptying rate was evaluated by ¹³C-acetic acid breath test . Gastric emptying was significantly accelerated by ghrelin infusion in patients with SSc ( ghrelin vs. saline : 43.3 ± 11.4 min vs. 53.4 ± 5.4 min , P=0.03 ) . No serious adverse effects were observed . Our results suggest that ghrelin might represent a new therapeutic approach for GI tract involvement in patients with SSc OBJECTIVES This paper aims to investigate the efficacy of intravenous immunoglobulin ( IVIG ) for  skin sclerosis in diffuse cutaneous systemic sclerosis ( dcSSc ) by a r and omised , double-blind , placebo-controlled , multicentre trial ( DBT ) with subsequent long-term observational and readministration studies . METHODS In DBT , IVIG ( 400mg/kg/day for 5 consecutive days : a single course ) or placebo ( P ) was intravenously administered to 63 dcSSc patients of 17 medical institutions in Japan , and changes in the modified Rodnan skin thickness score ( MRSS ) 12 weeks after administration or at discontinuation were compared as a primary endpoint . Patients with a 5-point or more improvement in the MRSS were continuously observed ( long-term observational study ) , whereas IVIG was administered to those with less than a 5-point improvement ( readministration study ) . RESULTS In DBT , changes in the MRSS ( mean±SD ) were -3.3±4.2 and -4.2±4.6 in IVIG and P groups , respectively , and were not significantly different . Non-responder patients were subsequently subjected to the readministration study , and the change in the MRSS ( LS-mean±SEM ) at 60 weeks after the first administration was -8.3±1.0 in the IVIG → IVIG ( GG ) group treated with two courses of IVIG administration and -4.1±1.1 in the P → IVIG ( PG ) group treated with a single course of IVIG administration . The GG group represented a significant improvement in the MRSS against the PG group ( p=0.0040 ) . CONCLUSIONS Although the primary endpoint was not achieved in DBT , repeated administration of IVIG for two courses may be effective for skin sclerosis in dcSSc . Further investigation by the administration of plural courses will be necessary Objective To assess the safety and effectiveness of imatinib mesylate in the treatment of diffuse cutaneous systemic sclerosis ( dcSSc ) . Methods In this phase IIa , open-label , single-arm clinical trial , 30 patients with dcSSc were treated with imatinib 400 mg daily . Patients were monitored monthly for safety assessment s. Modified Rodnan skin scores ( MRSS ) were assessed every 3 months . Pulmonary function testing , chest radiography , echocardiography and skin biopsies were performed at baseline and after 12 months of treatment . Results Twenty-four patients completed 12 months of therapy .  171 adverse events ( AE ) with possible relation to imatinib were identified ; 97.6 % were grade 1 or 2 . Twenty-four serious AE were identified , two of which were attributed to study medication . MRSS decreased by 6.6 points or 22.4 % at 12 months ( p=0.001 ) . This change was evident starting at the 6-month time point ( Δ=−4.5 ; p<0.001 ) and was seen in patients with both early and late-stage disease . Forced vital capacity ( FVC ) improved by 6.4 % predicted ( p=0.008 ) , and the diffusion capacity remained stable . The improvement in FVC was significantly greater in patients without interstitial lung disease . Health-related quality of life measures improved or remained stable . Blinded dermatopathological analysis confirmed a significant decrease in skin thickness and improvement in skin morphology . Conclusions Treatment with imatinib was tolerated by most patients in this cohort . Although AE were common , most were mild to moderate . In this open-label experience , improvements in skin thickening and FVC were observed . Further investigation of tyrosine kinase inhibition for dcSSc in a double-blind r and omised placebo controlled trial is warranted . Clinical Trials.gov , Objective . A prospect i ve observational study of mycophenolate mofetil ( MMF ) treatment in patients with diffuse progressive cutaneous systemic sclerosis ( SSc ) of recent onset . Methods . Twenty-five previously untreated consecutive patients with recent-onset ( < 24 mo ) diffuse progressive cutaneous SSc received MMF as the only disease-modifying therapy . Modified Rodnan skin score ( mRSS ) and affected body surface area ( BSA ) were compared from initiation of MMF to study end . Pulmonary function tests performed at the same institution before therapy and at study end were available in 15 patients .  Histopathology and real-time PCR assessment of fibrosis-related gene expression were performed before and after treatment in skin biopsies from 3 patients . Results . At 18.2 ± 8.73 months of MMF therapy ( median 2000 mg/day ) the mRSS decreased from 24.56 ± 8.62 to 14.52 ± 10.9 ( p = 0.0004 ) and the affected BSA from 36 % ± 16 % to 14 % ± 13.3 % ( p = 0.00001 ) . Pulmonary function tests remained stable from initiation of MMF to the end of the study . Skin histopathology showed a remarkable reduction in accumulation of fibrotic tissue . Real-time PCR of skin biopsies demonstrated a marked decrease in expression of fibrosis-related genes . Conclusion . Patients with diffuse progressive cutaneous SSc of recent onset treated with MMF experienced marked improvement in skin involvement and stabilization of pulmonary function . Skin biopsies from 3 patients demonstrated histopathological improvement and decreased expression of fibrosis-related genes The association of cyclophosphamide ( CYC ) and prednisone ( PRED ) for the treatment of lung fibrosis in systemic sclerosis ( SSc ) was only evaluated in uncontrolled studies , although in idiopathic interstitial lung disease ( ILD ) this association seems to be beneficial in patients with non-specific interstitial pneumonia ( NSIP ) . Objectives : To treat SSc-ILD in a prospect i ve open-label controlled study based on lung pattern during 12 months of treatment . Methods : A 3-year analysis was also performed . Twenty-four consecutive patients with SSc and ILD were su bmi tted to an open lung biopsy . Eighteen patients ( NSIP ) were r and omized in two groups : CYC versus CYC + PRED during 12 months . Lung function tests ( diffusion lung capacity of monoxide carbone corrected for hemoglobin concentration ( DLCO-Hb ) , forced vital capacity ( FVC ) , total lung capacity ) and Modified Rodnan Skin Score ( MRSS ) were performed before , after one of treatment and after 3 years from the end of the treatment . Results : Pulmonary function tests were similar in both groups on baseline . After 1 year of treatment , FVC% was comparable between CYC groups ( p = 0.72 ) and in CYC + PRED ( p = 0.40 ) . Three years after the end of treatment , FVC% values ( p = 0.39 in group CYC and p = 0.61 in CYC + PRED and p = 0.22 in CYC + PRED ) and DLCO-Hb ( p = 0.54 in CYC and p = 0.28 in CYC + PRED ) were similar compared to 1 year of treatment . We observed a reduction of the MRSS in the CYC + PRED group after 1 year of treatment ( p = 0.02 ) ; although after 3 years , MRSS values remained stable in both groups . Conclusions : CYC was effective to stabilize lung function parameters in NSIP lung pattern of SSc disease for 3 years after the end of a 1-year therapy Objective The primary objective of the study was to explore safety and tolerability of hyperimmune caprine serum ( AIMS PRO ) in established diffuse cutaneous systemic sclerosis ( SSc ) . Secondary objectives included assessment of potential efficacy and biological activity and exploration of c and i date biomarkers . Methods This was a double-blind parallel group r and omised placebo-controlled clinical trial . After informed consent 20 patients with established diffuse cutaneous SSc of greater than 3 years duration not receiving immunosuppressive therapy were r and omised to receive either active ( n=10 ) or placebo formulation ( n=10 ) by subcutaneous twice weekly injection over 26 weeks . Clinical assessment s were evaluated over 26 weeks . Results There were no safety concerns during this study . Frequency of adverse events was not different between active and placebo groups . Mean modified Rodnan Skin Score ( mRSS ) fell by 1.4±4.7 units with active treatment but increased by 2.1±6.4 units on placebo when baseline values were compared with 26 weeks and responder analysis showed clinical ly meaningful improvement in mRSS at 26 weeks in 5 ( 50 % ) of actively treated patients compared with 1 ( 10 % ) in the control group ( p=0.062 ) . PIIINP ( µg/L ) showed a comparatively larger increase in the treatment group compared with the placebo group , ( p=0.0118 ) . Conclusions These results confirm tolerability and safety of this novel biological agent in established diffuse SSc . The value of a placebo treated control group in small clinical trials evaluating skin disease in SSc is confirmed . Potential improvement in mRSS and changes in PIIINP in cases receiving active therapy suggest that this intervention may be of clinical benefit and warrants further evaluation OBJECTIVES To evaluate the effect of adaptive oral hygiene devices and orofacial exercise to improve gingival health among adults with systemic sclerosis ( SSc ) . METHODS Forty-eight patients with SSc were assigned r and omly to the multifaceted oral health intervention or usual dental care control group . Participants in the intervention group received a rechargeable , powered Oral-B ® oscillating-rotating-pulsating toothbrush and a Reach ® Access ™ Flosser that has a toothbrush-like h and le . For those with an oral aperture of less than 40 mm , orofacial exercises were taught . Participants in the control group were each given a manual toothbrush and dental floss . Participants in both groups received instructions and demonstration on the use of the devices , and were requested to perform the respective intervention twice a day for 6 months . Evaluations were at baseline , 3- , and 6-months . The main outcome was gingival index ( GI ) , an indicator of gingival inflammation . RESULTS Both groups showed significant reduction in GI scores at 6 months ( ps<0.005 ) . Reduction in GI scores of the intervention group at 6 months was 20.8 % which is considered to be clinical ly significant . Compared to the control group , the intervention group showed a significant and larger reduction in GI score by 8 % at 6 months ( p=0.0007 ) . CONCLUSIONS Results support the use of adaptive devices and orofacial exercise to improve gingival health in adults with SSc when compared to use of manual toothbrushing and finger-held flossing . Recommending and educating patients with SSc to use adaptive devices to clean the tooth surfaces looks promising for long-term oral health improvement Drug development for SSc has been hindered by the relative paucity of vali date d outcome measures and biomarkers for use in clinical trials . The Scleroderma Clinical Trials Consortium ( SCTC ) conducted an interactive session at the Scleroderma International Workshop in Cambridge , UK in July 2011 to discuss clinical trial design in SSc . The following issues were discussed : 1 ) primary outcome for trials of SSc - skin vs. lung vs. composite ; 2 ) ischaemic digital ulcers in SSc - healing vs. repair vs. composite ; 3 ) pulmonary arterial hypertension in SSc ; and 4 ) neglected aspects of SSc - opportunities for study or of lower priority and feasibility . R and omised controlled trials with collection of biospecimens are necessary to assess efficacy of therapeutic agents , vali date novel outcome measures , and discover and vali date potential biomarkers for each of these areas . Although SSc is a rare , heterogeneous disease , collaborative efforts led by the SCTC and other international networks will ultimately improve the design of clinical trials of promising therapies for SSc Introduction Pulmonary involvement represents a major cause of death of systemic sclerosis ( SSc ) patients . Recent data suggest that tyrosine kinase inhibitors , such as imatinib , may be a therapeutic option for SSc patients . However , preliminary published clinical trials were inconclusive about imatinib efficacy and showed side effects . The purpose of this study was to verify efficacy and tolerability of low-dose imatinib on interstitial lung disease in a cohort of SSc patients unresponsive to cyclophosphamide therapy . Methods Thirty consecutive SSc patients with active pulmonary involvement , unresponsive 
    Output:
    
Our systematic review of the last 4 years of treatment emphasizes known treatment strategies already in practice , but also identifies new therapeutic approaches with additional biologic agents and hematopoietic stem cell transplantation