The year was 1991. It was my first Tuesday as a rheumatology fellow at the University of Pittsburgh’s Presbyterian Hospital. Navigating a maze of buildings and hallways, I delivered myself to the entrance to the scleroderma clinic. Running late and not knowing whether there was a separate entrance for staff, I clicked open the door. The clinic space was eerily quiet. All business in my white lab coat and lobster necktie, I bustled through the waiting area. Looking neither to the right nor left, I focused on the gray carpet, aiming for a door adjacent to the check-in counter.
A cough caught my attention, and half-turning, I made eye contact with a young woman whose woody face shook me to the bone. She had a loose, afghan sweater draped over her boney shoulders. An intravenous line tunneled through her neck, delivering a creamy solution from a plastic bag hooked onto a stainless steel pole. She smiled, but her mouth opened awkwardly, doll-like. Her smile was all teeth, the hide-bound skin of her cheeks resisting the upward pull of her lips. I waved awkwardly back. She pulled a claw-like hand out from beneath the afghan and flexed the fingers in reply.
He pushed his glasses back from where they rested at the tip of his nose. “I know that, as a practicing internist for the past six years, you’ve amassed considerable clinical acumen. But as a new fellow, we don’t expect you to be knowledgeable regarding scleroderma. You might go an entire general internal medicine career without diagnosing a single case.”
“That’s true,” I answered.
“As a center for scleroderma, we take our time in these evaluations. There are scleroderma mimics: sclerodema, myxomatous granulomatosis, eosinophilia fasciitis, to name a few, and undoubtedly you’ve been reading about the eosinophilic myalgia syndrome,” he added, checking his watch. I hoped my face didn’t give away the fact that I had no idea what he was talking about. “Be thorough,” he added. “This is a multi-system disease. The skin changes can be heartbreaking, but the deeper involvement of the lungs, heart, bowels and kidneys, means they are where the most serious pathology may occur.”
My Patient No. 1: The History & Initial Exam
I pulled my first patient’s chart from the rack: 35 years old, female, married, two children, from—I flipped back to the information page—Albuquerque, N.M. Geophysicist. That’s interesting. There was a letter from her internist, a recent consult from the University of Arizona Arthritis Center, and reams of lab and radiographic studies. I scribbled down notes, intent on summarizing her case for my presentation to Dr. Medsger. Then I knocked lightly on the door and entered.
The woman I had waved to was my first patient, Jennifer Indura. She smiled again and introduced her husband, Michael. Up close, the skin involvement was even more disturbing and dramatic, her face waxy and taut, the fingers contracted, the forearms thickened and woody.
Together, we reviewed her recent history: “The Raynaud’s happened for the first time last winter when I went out to scrape ice off the windshield and forgot my mittens,” she began. “The fingers looked dead, like all the blood was drained out. A few months later, even putting my hand into the freezer to take out a package of frozen vegetables triggered an attack.” She turned her hands over. “That’s when I began to get these.”
The tips of the pointer finger and ring finger of the right hand were blackened and cool. She flinched, and her eyes welled up as I gently tried to pull the dressings off. Reflexively, her husband leaned forward and put his hand over mine. “Here, let me help you.” He reached into her handbag and pulled out a pint of sterile water to soak the gauze and applied a dab of Lidocaine gel to the base of the finger to numb the area. “There,” he exhaled, “that should make it easier to undress.”
“So the Raynaud’s came first? Any other problems begin at that time?” I asked, waiting for the anesthetic to take effect.
“It was strange, but I developed heartburn for the first time since I was pregnant with our two girls. That’s why I take the …”
“The Zantac,” her husband finished.
“Right. So that helped some. But then the fingers became puffy and swollen, and my hands itched. When the itching spread to my arms and chest, it drove me crazy, especially at night, couldn’t sleep, and the heartburn worsened, so …. Was that when we increased the Zantac to twice a day, Michael?” she asked.
“Right. And we made the appointment for the rheumatologist at the arthritis center.”
“They were very nice; they gave me doxepin for the itching and told me it looked like I had early scleroderma.” She reached up and scratched her forehead with her free hand, winced and shifted slightly. Her voice dropped off. “I think you can take that last roll of gauze off. I’m okay.”
I reached over and pulled at the end of the gauze. A sliver of scab and pink tissue came with it. “Sorry,” I mumbled, staring at the wound. It looked raw and painful. The edges were bluish black. My first impression was that the distal finger should be amputated and be done with it. It looked that bad. “Okay,” I exhaled, “let’s protect the finger, while I go through the rest of your history and exam,” I said as I lightly rewrapped the wound.
I looked down at my notes, “So when did the skin-tightening begin?” I felt awkward, intensely aware of her discomfort.
“Six, maybe eight months ago. The skin tightened wherever there was originally swelling; first the fingers and toes, then the back of my hands, forearms and ankles, more recently, the neck and face. I got depressed. I mean, I am depressed, can’t sleep, the fingers were painful. They’re still painful.”
“Cough? Shortness of breath?” I asked.
“No, but I really can’t do much.”
“And the weight loss? It looks like from your internist’s notes, that you’ve lost about 30 lbs. in the past six months?”
“That’s stabilized,” her husband interjected. “Anyway, her weight stabilized at about 105 lbs. when they admitted her at the University of Arizona and found the scleroderma had affected the bowel. When a feeding tube didn’t work out, they placed the central line about two months ago.
I ran my finger down the intake sheet. “Your blood pressure. 138/86. It’s a bit up. Is that new?”
“I think so,” Mr. Indura scratched the stubble on his cheek and checked back in his notes. “Let me see, we don’t check it very often at home. Four months ago, 112/74, three weeks ago, 130/82. Maybe it’s the pain. Jennifer, do you think it’s time for a Vicodin?” She nodded almost unperceptively. I looked at the loosely wrapped fingers and regretted removing the dressings.
I reached over and felt Dr. Indura’s forearms. I’d never felt scleroderma skin before. It was foreign, as if her skin belonged to another species of the animal kingdom. Cool and hide-bound, it resisted my attempts to gather a fleshy portion between my thumb and forefinger to pinch it together. Wherever the skin crossed over a joint, there was a contracture. This explained the claw-like appearance of her fingers, the lack of full extension at the elbows, and the milder contractures at the knees. The hips and shoulders were, thankfully, spared.
I asked her to open her mouth and clicked on my penlight to peer inside. I realized that while the tongue, teeth and gums appeared normal, the facial scleroderma limited her ability to open the mouth fully. The heart sounds were normal, as was the thyroid gland and lymph nodes along the side of the neck. Dry crackles, like crinkled cellophane, were present in the lower half of each lung. I went back to the heart and listened intently. Was she in heart failure? No, I didn’t hear the distinctive sounds of heart failure. But then again, the heart sounds were not quite right. Was the second pulmonic heart sound increased?
When I was finished, I excused myself, saying that I would review her case with Dr. Medsger and we’d return in a few minutes. The Induras were visibly relieved. They hadn’t come all the way to the University of Pittsburgh to see me; they were here to see Dr. Medsger and hoping against hope that he could help.
Reporting My Findings
When I walked back to the doctor’s station, Dr. Medsger looked up from an article he was reviewing. “What did you find out?” he asked.
I repeated Dr. Indura’s story, beginning with the Raynaud’s and the puffy fingers, followed by the fingertip ulcers, the progressive hide-bound skin, the weight loss, the placement of the central line for nutrition. I began my review of her physical exam with a description of the gangrenous fingertip and was about to …
“Blood pressure?” Dr. Medsger interjected. “We begin with the vital signs here.” He paused. “They’re important.”
I looked down at my notes. “BP 138/86, resting heart rate: 96/minute. They’re up a bit, but she’s anxious and in pain. The fingertip ulcers look horrendous.” Dr. Medsger raised an eyebrow. I went on. “Her husband recorded a few recent blood pressures. They were mostly normal, so today’s reading might be a red herring, a blip.”
“Or?” Dr. Medsger locked onto my eyes.
I blinked as I silently reviewed the differential diagnosis of hypertension, including rarer triggers, such as renal artery hypertension, pheochromocytoma, Conn’s syndrome and … “scleroderma renal crisis?” I asked.
“Could be.” Dr. Medsger replied.
“But it’s pretty borderline, isn’t it? In my practice I wouldn’t even consider treating her with meds unless it was consistently over 140/90.”
Dr. Medsger reached into his briefcase and pulled out an article from the Journal of Medicine titled “Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis: Review of a 25-year experience with 68 cases,” and plunked it on the table.1 I wondered if he was going to ask me to go home to Maine. He stood and buttoned his white coat. “Anything else?”
“Her lungs. Inspiratory crackles in both bases,” I said.
“Anything else?”
I hesitated. “Her heart sounds were unusual. The second heart sound at the left sternal border was increased. There might have been a soft diastolic murmur, same location.”
“And what do you think that means?”
“She could have pulmonary hypertension,” I replied. My mind was sifting through and retrieving information that had been lightly used. Even though I had never diagnosed a patient with pulmonary hypertension, I believed I was correct. It made sense. It was the right setting.
“Good. Let’s take a look.”
In the Exam Room
Dr. Medsger lightly shook hands with the Induras and asked Dr. Indura if he could see a picture of her two children. A crooked smile radiated into her cheeks. She opened up her purse with the better of her two hands and retrieved a photo of the girls in ice skates flanking their father.
“Beautiful girls. Ice skating in Albuquerque—who would guess?” Dr. Medsger handed back the picture and wrapped the blood pressure cuff around Dr. Indura’s upper arm. After pumping up the cuff, he slowly released the pressure and wrote down the BP on a scrap of paper. “138/90. We’ll take it one more time in a few minutes. Dr. Radis, can you ask Gail at the desk if she can have lab come down to draw some blood?”
When I returned, Dr. Medsger was performing a skin score, a grading system by which the skin of scleroderma patients can be objectively assessed and assigned a total score each visit rather than simply estimating whether the skin is better, worse or the same. He asked me to palpate Dr. Indura’s distal forearm as she repetitively flexed the fingers of her right hand.
Beneath my fingers, I felt a leathery creakiness to the tissues, a tendon friction rub.
“Physical diagnosis still matters; even before the more obvious skin thickening occurs, a tendon friction rub at the wrist or elbow is a distinctive feature of diffuse scleroderma,” Dr. Medsger said.
The lab drew six tubes of blood. In a low voice, Dr. Medsger pointed to a red top tube and asked the tech to run the chemistries STAT. Then he toggled back and forth between listening to the lungs and heart. He repeated the blood pressure and took out his pen and drew a graph with a single curved line on the yellow pad. It rose steeply, leveled out and gradually declined.
“This,” Dr. Medsger declared to the Induras, “is what we believe is the natural history of diffuse scleroderma. Over approximately seven years, even without treatment, most patients’ skin scores level off, and eventually, there is some degree of softening. The trunk, followed by the face and proximal limbs improve first, while the earliest skin changes in the hands are last, and they may not resolve completely. Now, of course our ultimate goal is to cure scleroderma, but if we can’t cure the disease today, our goal is to compress the curve, limit skin tightening and aggressively treat internal damage when it first arises.”
He looked up. The Induras hung on his every word.
“What they undoubtedly told you at the University of Arizona is that there is no medical treatment proved by double-blind, placebo-controlled studies that can predictably alter the natural history of the disease, and unfortunately, that’s true. My belief is that if you start a medication, such as penicillamine—and there are other candidate medications—relatively early in the disease, we can improve the outcome. In addition, we have several trials here at the University of Pittsburgh looking at other medications in early diffuse scleroderma.”
The lab tech knocked and handed Dr. Medsger the results of the blood chemistries. He tapped a finger on the desk, considering the results.
“Is there a problem? Mr. Indura asked.
“We’d like you to stay here at the hospital for a few days.” Dr. Medsger replied evenly. “Your elevated blood pressure is having an effect on the function of your kidneys. We need to aggressively …”
At this, Dr. Indura burst into tears. She’d managed the flight from New Mexico, the cramped seating and awkward transfers from the plane to a rental car to the hotel, a leaking connector to her intravenous line and the news that the University of Pittsburgh didn’t have a magic bullet for her scleroderma. Now, she was being told that her kidneys were damaged. She lay her head on the end table and sobbed.
Causes & Pathophysiology
The cause of progressive systemic sclerosis (diffuse scleroderma), like so many disorders in rheumatology, is unknown. Gerald P. Rodnan, MD, a mentor to Dr. Medsger at the University of Pittsburgh in the 1970s, devoted the majority of his professional life to the disease, and although he made a host of critical observations, was unable to consistently improve the crushing impact of the disease on his patients.
On the one hand, certain occupations that increase the exposure to chemicals, such as polyvinyl chloride, benzene or toluene, or the mining of coal or gold with chronic exposure to silica raise the risk in men for developing the disease.2 On the other hand, the majority of cases of diffuse scleroderma are in women with little or no industrial exposure.
Tryptophan supplementation in the early 1990s triggered a scleroderma-like disease: eosinophilic myalgia syndrome (EMS).3 The supplement, advertised as a sleep aid was linked to thickening of the skin, damage to peripheral nerves, lung inflammation and high levels of blood and tissue eosinophils. Although superficially, patients with the eosinophilic myalgia syndrome resembled patients with diffuse scleroderma, the disorder was clearly distinct. Mysteriously, the trigger for EMS was not felt to be the tryptophan itself, but a contaminant in the manufacturing process for the supplements.4 Except for rare, sporadic case of EMS in recent years, the epidemic resolved after the supplement was removed from the market.
Scleroderma may be a chronic immunologic reaction to ‘non-self’ cells—an unsuccessful attempt by the immune system to recognize & eliminate the cells of the previous generation.
Additional insights into the trigger(s) for diffuse scleroderma have been difficult to tease out. Genetic predisposition plays a role, but the rarity of the disorder, estimated at an annual incidence of only 19 cases per million, suggests that other risk factors may be in play beyond genetic risk alone.5
One discovery researchers are recently focusing on is the concept that at birth, small amounts of fetal cells pass through the placenta into the maternal circulation, and that these cells, in some women, may persist for decades in the maternal circulation. Conversely, there may be a mixing of maternal cells in the fetal circulation (perhaps explaining why males or nulliparous women develop scleroderma, albeit at a lower frequency). When skin biopsies are performed in scleroderma patients, these fetal cells (or in the case of men—maternal cells) are seen more frequently and in higher numbers than in patients without scleroderma.6 Potentially, then, scleroderma may be a chronic immunologic reaction to “non-self” cells—an unsuccessful attempt by the immune system to recognize and eliminate the cells of the previous generation.
Back to the Patient
After clinic hours, I located Dr. Indura in the Intensive Care Unit on the 12th floor of Presbyterian University Hospital. An arterial line had been inserted into the radial artery at the right wrist, and a monitor overhead gave a continuous reading of her blood pressures. The pressures were elevated even higher than the morning readings: 168/98, and I was surprised she was requiring oxygen. She was asleep, nestled in a matrix of IV lines, nasal oxygen and a Foley catheter draining from her bladder. Her primary nurse put her finger up to her mouth as I entered the room. She closed the drapes, and we moved outside the room.
“She’s had a difficult morning,” her nurse began. “The medical student, resident and medicine attending took a long time to settle her in, and she just dozed off. They had a horrendous time getting the arterial line in. Just couldn’t hit it. They finally had to call one of the anesthesia residents, and even she had some trouble threading it in. And you are?”
“Chuck Radis. I’m the new rheumatology fellow.”
“We don’t see you guys down here very often.” She glanced back at the curtain. “Her skin looks awful. Have you seen her fingers? They look like they’re going to fall off.”
“So did the primary service start her on captopril for the hypertension?” I asked.
“Let me see.” She scanned the med list. “Captopril. Captopril. Okay, here it is, 25 mg twice daily. I gave her the first dose about an hour ago. The med resident wants to take it slow. Did you see her creatinine of 2.5? Poor thing, she’s so young. Medicine is worried the captopril might bottom out her blood pressure.”
“Can you get me the beeper number of the resident? From our perspective, we need to push the captopril quickly up to whatever dose normalizes her BP, otherwise her kidneys are going to shut down. Has her blood pressure been running this high all day?” I asked.
“No, but creeping pretty steadily upward. So have her O2 needs. What’s going on there?”
“We think the scleroderma is involving the lungs.”
“Doesn’t she need a diuretic? She has crackles in both bases,” her nurse asked.
“No. The oxygenation won’t respond to that. It’s not like heart failure.”
At that moment, Dr. Medsger strode through the door and peeked through the curtain at Dr. Indura. He took one look at the monitor, turned on his heels and crossed his arms, “Dr. Radis, what’s going on with her captopril?”
“First dose an hour ago, 25 mg.” I knew this was not the answer he wanted to hear.
“That’s unacceptable. Have you called the primary service?” The ICU nurse quietly dialed the medicine service resident’s pager. A minute later I was on the phone with the resident and making our case for more aggressive management of Dr. Indura’s hypertension.
When I looked up, Dr. Medsger was sitting on the edge of Dr. Indura’s bed. The pharmacy drawer was open; he held the next dose of captopril in the palm of his hand.
“Dr. Indura, I want you to take an additional dose of the blood pressure medication captopril. Take your time. Here, why don’t you sit on the edge of the bed? Let’s make sure it goes all the way down. Dr. Radis, can you get us a cup of water?” He waited a minute as she swallowed the pill and brushed her hair back from her face with the back of her hand.
“Based on today’s blood work, we believe you have what we call scleroderma renal crisis. Captopril is the drug of choice for scleroderma hypertension, and we’ll be titrating up the dose until your blood pressure normalizes.” He paused and held her forearm lightly. “Your kidneys have already taken a significant hit.”
“And I’m sorry, but there’s more bad news.” He pulled out her chest X-ray from a folder and hung it on the view box on the far wall. “These patchy white areas are likely triggered by your scleroderma. I’ve consulted one of our pulmonary specialists. It may require a bronchoscopy, a test where they pass a flexible tube into your windpipe to biopsy the lung. We may need to start a medication called cyclophosphamide to treat the lung.
During the night, Dr. Indura’s blood pressure remained elevated. At one point it reached 210/118. When we reached the maximum recommended dose of captopril, a second medication was added, and still the pressures remained unacceptably high. Her urine output diminished. The pointer and ring finger of the right hand blackened and turned stone cold. A morphine drip was hung.
Early the next morning, her blood pressure finally normalized. We didn’t expect her creatinine to improve, but I was dismayed that it continued to climb. In between my visits, multiple specialists weighed in on the case. A GI consultant ordered several studies to assess whether bacterial overgrowth syndrome was present. When scleroderma slows down the motility of the small bowel, bacteria populate areas of the bowel that are usually sterile. This may result in weight loss due to nausea, vomiting and reduced absorption of nutrients. The treatment: a low dose of an antibiotic. Unfortunately, Dr. Indura vomited the first dose, then the second, before we switched to an intravenous formulation.
Surgery declared that the pointer finger would probably need to be amputated at the middle knuckle, but now was not the time to operate. She was too unstable. Dermatology performed a forearm skin biopsy for a research study. The immunology basic science department took one sample, the dermatopathology department another—both departments searching for clues in the pathogenesis of the disease.
The pulmonologist passed a bronchoscope into the lungs and performed a transbronchial biopsy. I heard that it was touch and go during the procedure; her oxygen levels plummeted, but recovered after the bronchoscope was removed from her airway. The results would lay to rest whether an unusual infection was inflaming the lungs or active scleroderma. Post-bronchoscopy, Dr. Indura’s oxygen needs never returned to baseline. She became increasingly short of breath and restless.
The next day, I called pathology and got a wet read on the lung biopsy. The result: Severe inflammation. After notifying Dr. Medsger, I wrote the order for cyclophosphamide. Cyclophosphamide has, as doctors say when talking about a particularly toxic drug, a narrow therapeutic window. I stood at the bedside as the cyclophosphamide infused, but I was uneasy; we’re giving this lady a lot of IV fluid and it has nowhere to go. Her urine output was minimal. I called the on-call kidney fellow and he recommended high-dose furosemide to help her kidneys flush out the extra fluid. Maybe that would work.
On the fourth hospitalization day, Dr. Indura’s kidneys essentially shut down. We doubled the dose of furosemide. No response. That afternoon, Dr. Medsger sat down with Dr. Indura and her husband and discussed dialysis. He explained that although it was critical to begin dialysis, over time the kidneys could recover some degree of function. The key was to get her over this crisis. The Induras readily agreed.
That night Dr. Indura crashed. Her lungs filled with fluid; her oxygen levels plummeted, and when I made my early morning rounds, I heard the oddly reassuring metronome of the ventilator before I pulled open the curtain to her room: shhk, shhtk, shhk. At the head of the bed, a surgical resident draped sterile towels over her neck and right shoulder in preparation for inserting a dialysis catheter. I went out to talk with her husband.
He was alone in the family room, his face in his hands, eyes puffy and bloodshot. I sat down, saying nothing.
“Medsger?” he asked finally. “Is he around yet this morning?”
“No. Not yet. It’s 6:00 a.m. He usually rounds by 7:00,” I replied.
Mr. Indura nodded almost imperceptibly. I offered him a Snickers bar. He waved me off, but the eccentricity of the offer appealed to him, and he sat up and unwrapped the bar. We ate our Snickers bars together in silence. It seemed to revive him. “I’ve been reading about scleroderma,” he said finally. “Why Michelle? We don’t use chemicals on our lawn. Our backyard backs up onto a national forest. She eats right, doesn’t smoke or do drugs, works like a dog, great mother,” his voice cracked. “Great wife, I mean not that people deserve a friggin’ deadly disease because they treat their body like a sewer pipe.”
“I know, it doesn’t make sense,” I agreed.
“She’s like Job. Just when she’s adjusted to a new challenge, there’s something new. Every inch of her body seems like it’s inflamed. And inside, her bowel, the lung, the kidneys, I feel like she’s rotting away. And for what? Is this some sort of cosmic punishment?”
Immunopathology of Scleroderma
This image shows the hand of a 34-year-old woman with scleroderma and skin hardening on her fingers. Source: SPL/Science Source
That morning, I attended our weekly rheumatology research conference. The topic: The immunopathology of diffuse scleroderma. Over the green expanse of three blackboards, arrows and lines connected the up-regulatory and down-regulatory pathways leading to excess production of collagen by fibroblasts and overgrowth of vascular endothelial cells. I noticed that the board was full of question marks linking the proposed pathways. Various cytokines were presented as a rogue’s gallery of potential triggers or perpetuators of the disease: transforming growth factor B (TGF-B), platelet-activating factor (PAF), endothelial growth factor 1 (EGF-1), fibroblast-activation factor (FAF), interleukin 1. It was suggested that several could be targeted for novel drug studies.
A member of the basic science faculty presented the preliminary results of a scleroderma study in which several of the key cytokines were down-regulated in a mouse model. I took out my notepad and copied the blackboard presentation for later review. After medical school, four years of an internal medicine residency and six years of primary care medical practice, I was back in school, learning a new language.
That night, a strange image came to mind as I dreamed about diffuse scleroderma and other complex immunologic disorders. I was in a glider cruising low over New York City, low enough to make out clusters of pedestrians waiting for the light to change. Trucks spewed smoke, taxis beeped, traffic police blew their whistles. Overhead, electrical wires surged with power. Beneath the streets, hidden from view, fluids coursed through water and septic lines, flushing the system. Somewhere, a social worker, policeman or construction worker was hard at work, endlessly at work, attempting to fix a broken life or a broken line.
Like a modern city, the human body’s immune system is held together by complex invisible threads. Regulators of behavior are not all or nothing; they exert their effect on the body by the ebb and flow of chemical messages. Helper T cells, suppressor T cells, killer T cells, dendritic cells—all allow the system to up-regulate and down-regulate with astounding precision. When researchers discover a new thread, they characterize it and seek to understand how this new variable fits into the larger system. One thread leads to another thread, another interconnected system. Over time, a clearer picture is emerging, but as yet, the picture is incomplete, and at times, paradoxical: You pull on one thread, and the seam closes. You pull on another thread, and a sleeve falls off.
Back to the Present
That was in 1991. Since that time, dramatically effective drugs—but no cures—have been developed for many immune-mediated diseases: rheumatoid arthritis and lupus, ankylosing spondylitis and vasculitis, the list grows yearly. But the enigma of diffuse scleroderma remains. Dr. Medsger at the University of Pittsburgh and others around the globe have devoted entire medical careers to chasing down leads, performing clinical trials, incrementally improving the care for this dreadful disease. They’ve made a difference, a critical difference in the lives of their scleroderma patients. But the answers have been slow in coming.
A recently published randomized controlled trial of tocilizumab in systemic sclerosis and the 48-week, open-label extension study may offer new hope for scleroderma patients.7,8 As myeloablative autologous stem cell transplantation is refined and toxicities are reduced, this approach may also offer additional treatment options for patients with severe disease.9 Perhaps, we are on the cusp of finally achieving consistent, effective management for this horrific disease.
I remember Dr. Indura. The answers can’t come soon enough.
Charles Radis, DO, is clinical professor of medicine at the University of New England, College of Osteopathic Medicine and employed part time at Maine Coast Memorial Hospital in Ellsworth, Maine.
References
- Traub YM, Shapiro AP, Rodnan GP, Medsger TA. Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Review of a 25-year experience with 68 cases. Medicine. 1983 Nov;62(6):335–352.
- Nietert PJ, Sutherland SE, Silver RM, et al. Is occupational organic solvent exposure a risk factor for scleroderma? Arthritis Rheum. 1998 Jun;41(6):1111–1118.
- Belongia EA, Hedberg CW, Gleich GJ, et al. An investigation of the cause of the eosinophilia–myalgia syndrome associated with tryptophan use. New Engl J Med. 1990 Aug 9;323(6):357–365.
- Hill RH Jr., Caudill SP, Philen RM, et al. Contaminants in L-tryptophan associated with eosinophilia myalgia syndrome. Arch Environ Contam Toxicol. 1993 Jul;25(1):134–142.
- Mayes MD, Lacey JV Jr., Beebe-Dimmer J, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003 Aug;48(8):2246–2255.
- Artlett CM, Smith JB, Jimenez SA. Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N Engl J Med. 1998 Apr 23;338(17):1186–1191.
- Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): A phase 2, randomised, controlled trial. Lancet. 2016 Jun 25;387(10038):2630–2640.
- Khanna D, Denton CP, Lin CJF, et al. Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: Results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis. 2018 Feb;77(2):212–220.
- Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. New Engl J Med. 2018 Jan 4;378(1):35–47.
