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Peripheral vasculopathy is a characteristic feature of systemic sclerosis (SSc).1 It is frequently associated with early onset of Raynaud’s phenomenon and can cause digital ischemia.2,3 A recent report of two cases4 showed the potential reversibility of SSc-related micro-vascular changes at 1 or 5 month after high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT). The effect of HDIT and autologous HCT on the SSc-related vascular changes of the digital arteries, however, has not been reported. A micro magnetic resonance angiography (MRA) technique was recently developed for the non-invasive visualization and assessment of the digital arteries and veins in vivo.5 In this case report, we present quantitative observations of the digital vasculature status using micro MRA before and after HDIT and autologous HCT.
The subject was a 49-year-old Caucasian male, with diffuse cutaneous SSc of 8 months’ duration. At the time of diagnosis, the patient presented with Raynaud’s syndrome, scleroderma, interstitial lung disease with ground-glass appearance on high-resolution computed tomography of the chest, numbness and pain in both hands, joint contractures in fingers, wrists and elbows, gastroesophageal reflux disease and telangiectasias. No digital ulcers or calcinosis were found. The modified Rodnan skin score was 28. The patient consented to participate in the SCOT trial (Scleroderma: CY or Transplantation) and was randomized to HDIT and autologous HCT.6 HDIT consisted of high-dose CY (120 mg/kg), fractionated TBI (800 cGy with lung and kidney shielding) and equine anti-thymocyte globulin (90 mg/kg) followed by transplantation of CD34 selected autologous hematopoietic progenitor cells (≥2.5×106 CD34 cells/kg).
The clinical evaluation at 1 year showed that the patient was clinically stable with resolution of joint contractures at the wrist and elbow. The modified Rodnan skin score was reduced to 24. The patient also reported a decreased frequency and severity of the Raynaud’s episodes. Other physical symptoms and signs were stable.
The micro MRA examinations were conducted before and 12 months after HDIT and autologous HCT, respectively. The subject was positioned in the exact same position for both scans as described earlier.5 Imaging plane planning and imaging parameters were all kept the same as reported before.5 No evidence of Raynaud’s syndrome was evident during either micro MRA examinations on the basis of clinical evaluation and verbal communication with the subject after each procedure.
In micro MRA, better visibility of the vessels was associated with higher blood flow in the blood vessels. Quantitative measurements of pre- and post-treatment vasculatures were obtained in this patient using earlier established methods.5
Images and results of image analysis are presented in Figure 1 and Table 1. The images shown in Figure 1 are presented with the same image contrast (window and level settings) between the baseline and post-transplant studies. The measurements of the eight healthy volunteers obtained earlier5 are also included in Table 1 for reference.
The baseline micro MRA identified a highly stenotic proper palmar digital artery, no visible dorsal digital veins (Figure 1a), and overall poorly visualized digital vessels (Figure 1b) in the right index finger. At the one-year follow-up, micro MRA showed that the degree of stenosis in the digital vasculature had dramatically decreased. As a result, the digital artery lumen cross-sectional size had increased from 0.13 to 0.37mm2 (~200% increase). The number of visible dorsal digital veins increased from 0 to 3 (Figure 1c). The overall vasculature was well visualized with a corresponding increase in the semi-quantitative vascular score5 (Figure 1d and Table 1).
We had shown earlier that micro MRA detected significant differences in the digital vasculature between SSc patients and healthy volunteers. The SSc patients had a significantly decreased digital artery lumen area, reduced number of digital veins and lowered overall vascular score compared with the healthy volunteers.5 It was also determined that both the digital artery lumen area and vascular scores of the SSc patients were inversely correlated with the duration of the patients’ disease. However in a single case report, the micro MRA after HDIT and HCT showed marked improvements in the digital vasculature. The improvement in the digital vasculature after HDIT and autologous HCT by micro MRA was also consistent with our earlier observations of improvements in the dermal blood vessels by histopathology.7 We therefore hypothesize that the sustained immunomodulatory effect of HDIT was the primary event resulting in the recovery from the SSc-related vasculopathy.8
When compared with the other approaches, quantitative micro MRA is a sensitive tool for detecting both early subtle changes and long-term morphological changes of the vasculature after treatment because of its deep penetration depth and high resolution. This capability, along with its non-invasiveness, makes micro MRA an ideal tool for serial monitoring after study treatments in clinical trials.
A potential limitation of the MRA technique is reproducibility, especially because of the potential for vasospasm caused by variations in the environmental factors, including temperature. However, we had earlier demonstrated highly significant differences in the digital vasculature between patients with SSc and normal individuals.5 The case presented here had comparable levels of abnormalities of the digital vasculature at baseline as was observed in the previous group of SSc patients. Our earlier data showed that all quantitative measurements made by micro MRA imaging were highly reproducible in healthy volunteers and SSc patients. Finally there were no clinical manifestations of Raynaud’s syndrome during the procedure.
In summary, there was a dramatic improvement in the digital vasculature of an SSc patient by micro MRA at 1 year after HDIT and autologous HCT. This is consistent with the improvement in the SSc vasculopathy, which was observed earlier in dermal blood vessels.7 Further studies are required to confirm that digital vasculature and blood flow is improved after HDIT and autologous HCT.
This work was supported by awards N01-AI-05419 from the National Institute of Allergy and Infectious Diseases and research funding from Scleroderma Research Foundation. The authors thank Zach Miller for his help in editing the paper.