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【medical-news】硬皮病的未解之谜

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The Unfolding Mystery of Scleroderma

In Brief:

Scleroderma, an autoimmune disease, tends to afflict middle-age women and can affect many parts of the body, inside and out.

Lung disease, the biggest killer of scleroderma patients, is the main focus of research today..

Doctors have a growing arsenal of proven and potential treatments, some of which are risky and the subjects of current research, including stem cell transplants and powerful but toxic cancer drugs.

Like many autoimmune ailments, scleroderma remains a great unknown. Despite decades of research, the cause of this rare and complicated disease has yet to be discovered. But the good news is that doctors have a pretty clear understanding of how scleroderma progresses — a natural history, they call it — and are better than ever at extending and easing their patients’ lives.

“Lots of patients and lots of doctors used to consider it a ‘black box’ disease, a complete mystery, with little that could be done,” said Dr. Philip J. Clements of the University of California, Los Angeles, who is a scleroderma specialist. “Now there’s a body of evidence that tells us what to watch out for, and when.”

Experts now know, for example, that the gradual hardening of tissues and blood vessels that is a hallmark of scleroderma usually starts on the hands and face, with skin thickening, pitted scars and cool, pale fingertips among the earliest symptoms. Damage can then progress inward to internal organs, though the course varies widely from patient to patient. Of the 10,000 cases diagnosed among Americans each year, mainly women, a small subset will die quickly. But many others are able to manage their condition with a variety of treatments and have normal life expectancies.

Doctors also now know that if a patient’s internal organs are going to be affected as well as the skin, that is likely to happen in the first four or five years of the disease. So early diagnosis and close monitoring of the heart, lungs and kidneys are vitally important.

They have also learned that steroids, once viewed as a cure-all for immune disorders, can worsen the effects of scleroderma, especially in the kidneys, and should be used with caution.

“Learning which drugs to avoid was itself a big step,” said Dr. John Varga, the Gallagher Professor of Medicine at Northwestern University and chairman of the Medical Advisory Board for the Scleroderma Foundation, a nonprofit group that sponsors research and support for patients and families.

Kidney disease used to cause 90 percent of scleroderma-related deaths until the advent of a class of blood pressure drugs called angiotensin-converting enzyme, or ACE, inhibitors in the 1980s. ACE inhibitors prevent kidney damage by slowing down the chemicals that cause the muscles surrounding blood vessels to contract. Complications in the kidneys now account for only 14 percent of scleroderma deaths, Dr. Steen said.

The lungs are still a challenge. About 80 percent of scleroderma patients develop some form of lung problem — either pulmonary hypertension, due to hardening of the veins and arteries in the lung, or pulmonary fibrosis, in which the lung tissue becomes inflamed and then thickened with scarring. Some patients develop both. Either way, breathing becomes more difficult as the lungs become less pliable.

“If you die of a scleroderma-related problem, half of those deaths are from lung disease,” said Dr. Virginia Steen, a professor at Georgetown University and director of the Rheumatology Fellowship Program there. She wrote a seminal 2007 article that documented the shift from kidney disease to pulmonary disease as the biggest cause of death among scleroderma patients.

One successful remedy called Revatio, routinely prescribed since 2005, came from an unexpected source: Viagra. Repackaged from a little blue diamond to a round white tablet and renamed for marketing, dosage and insurance purposes, the drug works by relaxing the blood vessels and improving blood flow, whether for erectile or lung dysfunction.

“No one could understand why all these women were taking it four times a day,” said Frannie Waldron, chief executive of the Scleroderma Foundation.

Doctors also have a growing arsenal of experimental treatments and potential cures, some of which are risky.

Among them is cyclophosphamide, or Cytoxan, a powerful but highly toxic cancer drug that acts on the immune system. The drug decreases the inflammation that causes pulmonary fibrosis and has been used on scleroderma patients for the last 10 years.

But cytoxan has dangerous side effects, including an increased risk of bladder cancer, and usually is not given for more than a year. Moreover, the fibrosis seems to start again once drug treatments stop. Several studies involving the medication are under way, as well as efforts to find alternative treatments, many of them sponsored by drug companies.

Another big push involves stem cell transplant, an extremely risky process in which doctors try to reset the patient’s immune system and bypass the glitch that causes scleroderma. The procedure is the subject of a National Institutes of Health study called the SCOT trial, for Scleroderma: Cyclophosphamides or Transplantation?

Similar to a bone marrow transplant, doctors first draw the patient’s blood and extract the stem cells, the highly malleable building blocks that are thought to be free of the seeds of scleroderma. The patient is then subjected to high doses of radiation or chemotherapy with Cytoxan to kill the bone marrow. The last step is to reinfuse the stem cells, in the hopes that they replicate themselves in a healthy form free of disease.

The study will compare the benefits of the stem cell transplant with giving patients just monthly doses, but high ones, of Cytoxan. Preliminary results have been promising, several experts said.

“You’d think you’d have trouble recruiting for this,” said Dr. Arthur C. Theodore of Boston University, one of the investigators in the project. “But scleroderma patients are desperate.”

http://health.nytimes.com/ref/health/healthguide/esn-scleroderma-ess.html?ref=health

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2008-09-13 23:37 浏览 : 987 回复 : 3

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2008-09-16 09:47

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The Unfolding Mystery of Scleroderma
硬皮病的未解之谜

In Brief:
摘要：
Scleroderma, an autoimmune disease, tends to afflict middle-age women and can affect many parts of the body, inside and out.
硬皮病，一种自身免疫疾病，多发于中年妇女，可以影响到躯体内外的多个部位。

Lung disease, the biggest killer of scleroderma patients, is the main focus of research today..
肺病——硬皮病患者的最大杀手——成为近年的主要研究焦点。

Doctors have a growing arsenal of proven and potential treatments, some of which are risky and the subjects of current research, including stem cell transplants and powerful but toxic cancer drugs.
对于硬皮病，医生拥有了越来越多确诊和有潜在治疗作用的手段，其中部分具有一定的风险性，近期的研究对象包括干细胞移植和强效但有毒性的肿瘤药物。

Like many autoimmune ailments, scleroderma remains a great unknown. Despite decades of research, the cause of this rare and complicated disease has yet to be discovered. But the good news is that doctors have a pretty clear understanding of how scleroderma progresses — a natural history, they call it — and are better than ever at extending and easing their patients’ lives.
和许多自身免疫性疾病一样，硬皮病还是一个很大的谜团。尽管经过了数十年的研究，这种罕见的复杂疾病病因仍不清楚。但好在医生对于硬皮病的发展过程——被称为自然过程——了解比较充分，而且在延长患者生命并提高生存质量的方法上有了长足的发展。

“Lots of patients and lots of doctors used to consider it a ‘black box’ disease, a complete mystery, with little that could be done,” said Dr. Philip J. Clements of the University of California, Los Angeles, who is a scleroderma specialist. “Now there’s a body of evidence that tells us what to watch out for, and when.”
“许多的患者和医生曾将其看作是一个神秘的疾病，完全是个未解之谜，而且对它束手无策，”洛杉矶加州大学的Dr. Philip J. Clements说，他是一位硬皮病专家。“而现在有大量的证据可以告诉我们在什么阶段我们需要提防哪些问题。”

Experts now know, for example, that the gradual hardening of tissues and blood vessels that is a hallmark of scleroderma usually starts on the hands and face, with skin thickening, pitted scars and cool, pale fingertips among the earliest symptoms. Damage can then progress inward to internal organs, though the course varies widely from patient to patient. Of the 10,000 cases diagnosed among Americans each year, mainly women, a small subset will die quickly. But many others are able to manage their condition with a variety of treatments and have normal life expectancies.
例如，专家们现在知道，逐渐硬化的组织和血管作为硬皮病的特征，常常在手部和面部开始发生，伴随着皮肤变厚、出现凹痕和变凉、指端苍白等早期症状。损害过程随后逐渐向深部器官发展，但该过程在不同病人表现出较大差异。美国每年有10000例左右确诊患者，多数为女性，其中一小部分会迅速死亡。但是其他多数人可以通过多种治疗手段控制病程并享有通常的预期寿命。

Doctors also now know that if a patient’s internal organs are going to be affected as well as the skin, that is likely to happen in the first four or five years of the disease. So early diagnosis and close monitoring of the heart, lungs and kidneys are vitally important.
医生现在也知道了如果患者的内脏器官将象皮肤一样受到侵袭，这一过程一般会在疾病的前4到5年发生。因此早期确诊和对心脏、肺和肾脏的密切监测是性命攸关的。

They have also learned that steroids, once viewed as a cure-all for immune disorders, can worsen the effects of scleroderma, especially in the kidneys, and should be used with caution.
他们也了解了曾一度被认为是免疫疾病万灵丹的类固醇类可能是硬皮病的症状更加恶化，特别是对肾脏，因此应该慎用。

“Learning which drugs to avoid was itself a big step,” said Dr. John Varga, the Gallagher Professor of Medicine at Northwestern University and chairman of the Medical Advisory Board for the Scleroderma Foundation, a nonprofit group that sponsors research and support for patients and families.
“了解应该避免使用何种药物本身即是一大进步，” Dr. John Varga说，他是西北大学的医学Gallagher Professor，也是硬皮病基金医学顾问委员会主席，该非赢利组织向研究者和患者家庭提供资助。

Kidney disease used to cause 90 percent of scleroderma-related deaths until the advent of a class of blood pressure drugs called angiotensin-converting enzyme, or ACE, inhibitors in the 1980s. ACE inhibitors prevent kidney damage by slowing down the chemicals that cause the muscles surrounding blood vessels to contract. Complications in the kidneys now account for only 14 percent of scleroderma deaths, Dr. Steen said.
肾脏疾病曾经是90%硬皮病相关死亡的致死因素，直到上世纪八十年代一种被称为血管紧张素转化酶（ACE）抑制剂的降压药物问世。ACE抑制剂通过延缓化学物质导致的血管周围平滑肌收缩来防止肾脏损伤。现在肾脏并发症在硬皮病相关死亡中仅占约14%，Dr. Steen说。

The lungs are still a challenge. About 80 percent of scleroderma patients develop some form of lung problem — either pulmonary hypertension, due to hardening of the veins and arteries in the lung, or pulmonary fibrosis, in which the lung tissue becomes inflamed and then thickened with scarring. Some patients develop both. Either way, breathing becomes more difficult as the lungs become less pliable.
肺病仍是一大挑战，约有80%的硬皮病患者有某种形式的肺部疾病——可能是肺动脉高压，由肺部动静脉硬化引起；或者是肺纤维化，患者的肺部组织发生炎症，随即增厚并瘢痕化。部分患者同时患有这两种疾病。无论哪种病，肺部顺应性下降都造成呼吸困难。

“If you die of a scleroderma-related problem, half of those deaths are from lung disease,” said Dr. Virginia Steen, a professor at Georgetown University and director of the Rheumatology Fellowship Program there. She wrote a seminal 2007 article that documented the shift from kidney disease to pulmonary disease as the biggest cause of death among scleroderma patients.
“如果是死于硬皮病相关疾病，那么一半的死因是肺部并发症，” Dr. Virginia Steen说，她是Georgetown大学的教授，同时担任该校风湿病培训计划主任。她2007年所著的开创性文章将肾脏疾病向肺病转化列为了硬皮病患者最主要的死因。

One successful remedy called Revatio, routinely prescribed since 2005, came from an unexpected source: Viagra. Repackaged from a little blue diamond to a round white tablet and renamed for marketing, dosage and insurance purposes, the drug works by relaxing the blood vessels and improving blood flow, whether for erectile or lung dysfunction.
一个成功的药物，称为Revatio，从2005年开始成为常规处方药，它来自一个完全意想不到的地方：万艾可。从蓝色菱形小药丸重新包装成白色圆形药片并改用新的商品名、剂量和保险目的，该药通过舒张血管和改善血流起作用，不管是对于勃起障碍或肺功能异常。

“No one could understand why all these women were taking it four times a day,” said Frannie Waldron, chief executive of the Scleroderma Foundation.
“没有人知道为什么这些妇女每天服药四次，” 硬皮病基金会首席执行官Frannie Waldron说。

Doctors also have a growing arsenal of experimental treatments and potential cures, some of which are risky.
医生在经验性治疗和潜在治疗方面也有了越来越多的选择，其中部分具有一定的风险性。

Among them is cyclophosphamide, or Cytoxan, a powerful but highly toxic cancer drug that acts on the immune system. The drug decreases the inflammation that causes pulmonary fibrosis and has been used on scleroderma patients for the last 10 years.
其中之一就是环磷酰胺，即Cytoxan，一种强效但毒性较大的肿瘤用药，作用于免疫系统。该药能使导致肺纤维化的炎症得以减轻，在过去10年里被应用于硬皮病患者。

But cytoxan has dangerous side effects, including an increased risk of bladder cancer, and usually is not given for more than a year. Moreover, the fibrosis seems to start again once drug treatments stop. Several studies involving the medication are under way, as well as efforts to find alternative treatments, many of them sponsored by drug companies.
但是环磷酰胺具有危险的副作用，包括增加罹患膀胱癌的风险，一般用药时间不得超过一年。而且，在停药后肺纤维化过程似乎又开始进行。除了关于补充疗法疗效的研究外，数项关于药物治疗的研究正在进行中，多数由医药公司资助。

Another big push involves stem cell transplant, an extremely risky process in which doctors try to reset the patient’s immune system and bypass the glitch that causes scleroderma. The procedure is the subject of a National Institutes of Health study called the SCOT trial, for Scleroderma: Cyclophosphamides or Transplantation?
另一项努力就是干细胞抑制，这是一个相当危险的过程，医生尝试将患者的免疫系统复位，以绕过引发硬皮病的干扰因素。国立卫生研究所正在进行一个称为SCOT的试验项目——对于硬皮病：环磷酰胺还是移植？

Similar to a bone marrow transplant, doctors first draw the patient’s blood and extract the stem cells, the highly malleable building blocks that are thought to be free of the seeds of scleroderma. The patient is then subjected to high doses of radiation or chemotherapy with Cytoxan to kill the bone marrow. The last step is to reinfuse the stem cells, in the hopes that they replicate themselves in a healthy form free of disease.
与骨髓移植类似，医生首先抽出患者的血液并分离干细胞，这就是不含硬皮病致病因素的可大量扩增的建筑原料。随后患者接受高剂量的放疗或环磷酰胺化疗以杀死骨髓。最后一步就是重新输注干细胞，希望它们以健康的形式进行增殖。

The study will compare the benefits of the stem cell transplant with giving patients just monthly doses, but high ones, of Cytoxan. Preliminary results have been promising, several experts said.
研究将对干细胞移植以及每月一次给予患者高剂量环磷酰胺两种疗法的利益进行比较。多个专家称，初步结果显示还是有希望的。

“You’d think you’d have trouble recruiting for this,” said Dr. Arthur C. Theodore of Boston University, one of the investigators in the project. “But scleroderma patients are desperate.”
“你会认为你这样做是在惹麻烦，”该项目研究人员之一，来自波士顿大学的Dr. Arthur C. Theodore说，“但是硬皮病患者愿意铤而走险。”

2008-09-18 10:15

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编译：

硬皮病的未解之谜

摘要：

硬皮病，一种自身免疫疾病，多发于中年妇女，可以影响到躯体内外的多个部位。肺病——硬皮病患者的最大杀手——成为近年的主要研究焦点。对于硬皮病，医生拥有了越来越多确诊和有潜在治疗作用的手段，其中部分具有一定的风险性，近期的研究对象包括干细胞移植和强效但有毒性的肿瘤药物。

和许多自身免疫性疾病一样，硬皮病还是一个很大的谜团。尽管经过了数十年的研究，这种罕见的复杂疾病病因仍不清楚。但好在医生对于硬皮病的发展过程——被称为自然过程——了解比较充分，而且在延长患者生命并提高生存质量的方法上有了长足的发展。

“许多的患者和医生曾将其看作是一个神秘的疾病，完全是个未解之谜，而且对它束手无策，”洛杉矶加州大学的Dr. Philip J. Clements说，他是一位硬皮病专家。“而现在有大量的证据可以告诉我们在什么阶段我们需要提防哪些问题。”

例如，专家们现在知道，逐渐硬化的组织和血管作为硬皮病的特征，常常在手部和面部开始发生，伴随着皮肤变厚、出现凹痕和变凉、指端苍白等早期症状。损害过程随后逐渐向深部器官发展，但该过程在不同病人表现出较大差异。美国每年有10000例左右确诊患者，多数为女性，其中一小部分会迅速死亡。但是其他多数人可以通过多种治疗手段控制病程并享有通常的预期寿命。

医生现在也知道了如果患者的内脏器官将象皮肤一样受到侵袭，这一过程一般会在疾病的前4到5年发生。因此早期确诊和对心脏、肺和肾脏的密切监测是性命攸关的。

他们也了解了曾一度被认为是免疫疾病万灵丹的类固醇类可能是硬皮病的症状更加恶化，特别是对肾脏，因此应该慎用。

“了解应该避免使用何种药物本身即是一大进步，” Dr. John Varga说，他是西北大学的医学Gallagher Professor，也是硬皮病基金医学顾问委员会主席，该非赢利组织向研究者和患者家庭提供资助。

肾脏疾病曾经是90%硬皮病相关死亡的致死因素，直到上世纪八十年代一种被称为血管紧张素转化酶（ACE）抑制剂的降压药物问世。ACE抑制剂通过延缓化学物质导致的血管周围平滑肌收缩来防止肾脏损伤。现在肾脏并发症在硬皮病相关死亡中仅占约14%，Dr. Steen说。

肺病仍是一大挑战，约有80%的硬皮病患者有某种形式的肺部疾病——可能是肺动脉高压，由肺部动静脉硬化引起；或者是肺纤维化，患者的肺部组织发生炎症，随即增厚并瘢痕化。部分患者同时患有这两种疾病。无论哪种病，肺部顺应性下降都造成呼吸困难。

“如果是死于硬皮病相关疾病，那么一半的死因是肺部并发症，” Dr. Virginia Steen说，她是Georgetown大学的教授，同时担任该校风湿病培训计划主任。她2007年所著的开创性文章将肾脏疾病向肺病转化列为了硬皮病患者最主要的死因。

一个成功的药物，称为Revatio，从2005年开始成为常规处方药，它来自一个完全意想不到的地方：万艾可。从蓝色菱形小药丸重新包装成白色圆形药片并改用新的商品名、剂量和保险目的，该药通过舒张血管和改善血流起作用，不管是对于勃起障碍或肺功能异常。

“没有人知道为什么这些妇女每天服药四次，” 硬皮病基金会首席执行官Frannie Waldron说。

医生在经验性治疗和潜在治疗方面也有了越来越多的选择，其中部分具有一定的风险性。

其中之一就是环磷酰胺，即Cytoxan，一种强效但毒性较大的肿瘤用药，作用于免疫系统。该药能使导致肺纤维化的炎症得以减轻，在过去10年里被应用于硬皮病患者。

但是环磷酰胺具有危险的副作用，包括增加罹患膀胱癌的风险，一般用药时间不得超过一年。而且，在停药后肺纤维化过程似乎又开始进行。除了关于补充疗法疗效的研究外，数项关于药物治疗的研究正在进行中，多数由医药公司资助。

另一项努力就是干细胞抑制，这是一个相当危险的过程，医生尝试将患者的免疫系统复位，以绕过引发硬皮病的干扰因素。国立卫生研究所正在进行一个称为SCOT的试验项目——对于硬皮病：环磷酰胺还是移植？

与骨髓移植类似，医生首先抽出患者的血液并分离干细胞，这就是不含硬皮病致病因素的可大量扩增的建筑原料。随后患者接受高剂量的放疗或环磷酰胺化疗以杀死骨髓。最后一步就是重新输注干细胞，希望它们以健康的形式进行增殖。

研究将对干细胞移植以及每月一次给予患者高剂量环磷酰胺两种疗法的利益进行比较。多个专家称，初步结果显示还是有希望的。

“你会认为你这样做是在惹麻烦，”该项目研究人员之一，来自波士顿大学的Dr. Arthur C. Theodore说，“但是硬皮病患者愿意铤而走险。”

2008-09-18 10:18

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