Authors: Rita Baron-Faust,Jill Buyon
The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (19 page)
A diagnosis of scleroderma can often be made by a physical exam alone, but bloodwork and other diagnostic tests may be needed to assess the extent of the disease.
“Most of the symptoms, like swollen fingers or heartburn, are pretty common, and many women and their doctors may dismiss them. The skin thickening may also be very subtle in the beginning and is not easily detected,” says Dr. Mayes. “The difficulty we have is in determining when this constellation of symptoms points to scleroderma.”
While Raynaud’s phenomenon is often the first sign of scleroderma, it can also occur on its own, and it’s fairly common in otherwise healthy women. “In the beginning, it’s hard to distinguish between scleroderma and primary Raynaud’s phenomenon,” says Dr. Mayes. “One of the major indications of secondary Raynaud’s is the sores on the tips of the fingers. This does not occur in primary Raynaud’s disease.”
In 2013, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) issued new classification criteria for scleroderma to aid diagnosis. Each item on the list is assigned a points value. A total score of 9 points or above is required for a definite diagnosis. Your rheumatologist may use this list during your exam.
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The first item on the list is “skin thickening of the fingers of both hands extending
proximal
(near)
to the metacarpal phalangeal
joints.” The bones of the fingers are called
phalanges
, and the bones of the palm are the
metacarpals
. The finger joints closest to the palm are the
metacarpophalangeals (MCP)
. Skin thickening in those areas is an automatic 9 points and indicates scleroderma.
The other items on the list:
- Other skin thickening on the fingers, such as puffiness or sclerodactyly = 4 points.
- Fingertip lesions (fingertip ulcers and/or pitting scars) = 3 points.
- Telangiectasias = 2 points
- Abnormalities of the nailfold capillaries = 2 points
- Interstitial lung disease and/or pulmonary hypertension = 2 points
- Raynaud’s phenomenon = 3 points
- Autoantibodies (e.g., anticentromere antibodies, see below) = 3 points
Again, if your score adds up to 9, a physical exam alone may lead to a diagnosis. But other tests may be needed to confirm a diagnosis of scleroderma.
Antinuclear antibody (ANA) tests
using an indirect immunofluorescent method will be positive in 85 to 90 percent of scleroderma patients (and in 99 percent of women with lupus). However, with some of the newer ANA tests, using a different method, 40 percent of women with scleroderma may have a negative test depending on which method is used. A woman with Raynaud’s phenomenon and a positive ANA but no other symptoms needs to be followed closely for six-month intervals over a period of two to five years.
Other antibodies
, such as
anticentromere antibodies
(associated with limited scleroderma and esophageal problems and pulmonary arterial hypertension),
anti-Scl 70 antibodies (anti-topoisomerase I antibodies)
(associated with systemic sclerosis), and
anti-RNA polymerase III antibodies
(associated with severe diffuse skin disease and high risk of kidney involvement) can be helpful in making the diagnosis as well as giving prognostic information about the course of the disease, but they are not 100 percent specific.
A complete blood count (CBC)
will be needed to see whether there is a low red cell count due to anemia (which can be due to many causes) or a low white cell count. Serum creatinine will be tested to help assess kidney function.
Special x-ray tests
are performed if a woman is experiencing chronic heartburn to assess potential problems or damage to the gastrointestinal tract.
There are several types of tests: A
barium swallow
involves drinking a small amount of liquid containing barium (which shows up white on the x-ray) to see whether there is scarring or an ulcer in the esophagus.
An x-ray “movie” called a
cine esophagram
may be done to see if there’s decreased motion in the esophagus, an ulcer in the lower end of the esophagus, or a stricture. In an
upper GI series
, ingested barium is followed as it moves through the stomach to the small intestine. A small intestine transit study measures the amount of time this takes and can indicate impaired bowel function.
If you have chronic heartburn,
endoscopy
may also be done to check for inflammation or ulcers. This test uses a small tube (
endoscope
) with a fiberoptic device passed through the mouth down into the esophagus and stomach, allowing the doctor to examine the lining.
Pulmonary function tests (PFTs)
with diffusing capacity are usually done to assess potential damage to the lungs if a woman has shortness of breath or a dry cough but should also be done at the time of diagnosis of scleroderma as baseline. Pulmonary function testing involves breathing into a machine that measures lung volume and lung flow and the ability to exchange carbon dioxide for oxygen (diffusing capacity) to establish a baseline. “This way if a woman does develop shortness of breath or a dry cough, we can look back on that test and determine whether there’s been a change from that,” says Dr. Mayes. CAT scans can reveal scar tissue and inflammation in the lungs before it’s apparent on chest x-rays.
Based on the results of the skin exam, a diagnosis of limited or diffuse scleroderma can usually be made. A diagnosis of
undifferentiated connective tissue disease (UCTD)
or
undifferentiated autoimmune syndrome (UAS)
is given when a woman does not fully meet the criteria for scleroderma (or lupus or Sjögren’s syndrome).
There are a number of disorders that can resemble scleroderma but are actually quite distinct.
Sclered
e
ma
causes thickened skin on the upper body (the face, neck, head, and shoulders), sometimes spreading down to the arms or trunk. The disorder can occur in people with long-term diabetes. Women usually will not have Raynaud’s, ANAs, or organ involvement.
Eosinophilic fascitis (EF)
occurs when white blood cells (eosinophils and leukocytes) attack tissues called
fascia
, which separate muscle from fat. This thin sheet of tissue becomes inflamed, swollen, and tender. The skin overlying the area becomes dimpled (like the skin of an orange), and the underlying tissue will feel hard. EF affects the arms, trunk, and legs but not usually the hands or face (there’s little fascia in those areas). The onset of EF is rapid, with skin changes that may be followed in a few weeks by decreased range of motion in the central body, shoulders, and hips and contractures of the elbows and knees. Raynaud’s is usually not present, and ANAs will be negative, but there will be marked increases in eosinophils in the blood and fascial tissue (seen on biopsy).
Chronic graft-versus-host disease (GVHD)
can cause patches of thickened skin on the arms, trunk, and legs that look like localized scleroderma. GVHD can occur in bone marrow transplant patients but is not reported after organ transplantation. In marrow transplants, high-dose chemotherapy is first given to “kill” the host immune system by destroying the bone marrow, and then a patient is given an infusion of marrow from a matched donor to reconstitute the immune system. However, even with the best matches, the donor marrow cells can react against the recipient and set off a barrage of toxic cytokines; this acute GVHD is treated with immunosuppressants. The reaction can be chronic in some marrow transplant patients. Immunosuppressants can control chronic GVHD, but they may not cure it.
The vast majority (85 to 90 percent) of those diagnosed with localized and systemic scleroderma are women. But if female hormones play a role, it’s only slight, speculates Dr. Mayes. “Scleroderma is different from lupus or rheumatoid arthritis. Pregnancy usually makes symptoms of RA better, but in some cases lupus can worsen. In systemic sclerosis, pregnancy is considered a high-risk period because the disease itself, and not hormones, can cause problems for some women.”
One of the intriguing theories of why women are more prone to scleroderma (and other autoimmune diseases) has to do with
microchimerism
, the presence of fetal cells from a past pregnancy that remain in a woman’s
bloodstream for many years (see
page 13
). It may be that the combination of self and nonself antigens (some from the father, some from the mother) in fetal cells may contribute to a form of graft-versus-host disease.
Studies have found that women with scleroderma have 20 times the number of persistent fetal cells found in other women who’d had children but didn’t have scleroderma.
“However, there are many scleroderma patients who have never been pregnant (or are male) that are not explained by this theory. Microchimerism may just be an incidental finding, since it is seen in other diseases and not all scleroderma patients. It may be a risk factor, like genes,” remarks Dr. Steen. “We have no strong candidate for what causes scleroderma, whether it’s a virus or environmental toxin. In fact, scleroderma could be several diseases which occur differently in women, depending on their genetic makeup.”
Karen’s story continues:
At first I was put on penicillamine, but I started to develop kidney problems and still had the fatigue. So I was put on low-dose steroids. That calmed the disease down initially. But then my skin turned hard all over my body. It turned hard on my chest, and I couldn’t wear a bra. It turned hard on my stomach, my legs, my arms, and my face. When I tried to smile or raise my eyebrows my skin would pull and stretch—it was just terrible. You feel like
you’ve been put into this nightmare and you have to find the inner resources to pull yourself out of it, to try to cope with it. I had almost alligator skin. My doctor finally put me on this drug that’s used for transplant patients, cyclosporine. It helped dramatically. Within about three months, my skin was softening all over. I was on the drug for four or five years, when the disease was very active. I got really well on cyclosporine.I went back to work three days a week. The scarring in my esophagus didn’t go away, and the stomach acid backed up, so I took acid-blocking drugs. I also had some kidney damage and developed high blood pressure. I took medication for that and I’m still on steroids. The skin on my hands is still very tight, and they are very curved. But I feel much better and I have a pretty active life again and have plenty of energy for my children.
While there’s no cure for scleroderma, many of the problems created by the disease can be treated individually. We have used current treatment recommendations from EULAR and the EULAR Scleroderma Trials and Research group (EUSTAR).
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Medications used most often to ease symptoms of Raynaud’s are vasodilators, usually
calcium channel blockers
, which improve blood flow to the small blood vessels in the fingers (see
pages 339
to
140
). The first-line treatment is
nifedipine (Procardia)
or
amlodipine (Norvasc)
. Other drugs in this class are
diltiazem (Cardizem, Dilacor, and Tiazac)
,
felodipine (Plendil)
, and
nicardipine (Cardene)
.
“Frequently, scleroderma occurs in young women who are quite thin, and they will have blood pressures of 90/60 and you cannot lower their blood pressure any further. They are going to get dizzy and lightheaded,” says Dr. Mayes. “With most women you start at a low dose, and if they become lightheaded, dizzy, or develop headaches, you have to stop or lower the dose of the drugs.”
In such cases, alternatives include
pentoxifylline (Trental)
, which helps blood flow more easily through narrow blood vessels and can slightly lower
blood pressure, and
dipyridamole (pentoxifylline)
or
clopidogrel bisulfate (Plavix)
, which prevent platelets from forming clots. The latter two drugs do not lower blood pressure, but they can cause an increased risk of bleeding and cannot be used in pregnancy. Doctors generally advise against using pentoxifylline while breast-feeding. Nitroglycerin patches can be used to improve circulation and heal finger ulcers. The antihypertensive
losartan (Cozaar)
may help reduce the frequency and severity of Raynaud’s attacks.
Sildenafil (Revatio)
and
tadalafil (Adcirca)
, the
phosphodiesterase type V (PDE V) inhibitors
better known as the erectile dysfunction drugs
Viagra
and
Cialis
, also may help relieve Raynaud’s by dilating small blood vessels in the fingers.
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For healing digital ulcers related to Raynaud’s and scleroderma,
intravenous iloprost (Ventavis)
, a synthetic version of
prostacyclin
that inhibits platelets from clumping, dilates blood vessels, and increases blood flow to the fingers. It may also help heal endothelial cells and prevent fibrotic changes in the skin. Moisturizers and lubricants must be used regularly to prevent fissures and infections. If ulcers become infected, topical or systemic antibiotics are used.
Biofeedback training, in which people learn to increase blood flow to the fingers through electronic or thermal feedback, has been touted as an alternative approach to treating Raynaud’s. But most studies were small and uncontrolled, and there’s no strong evidence to show that it works.
Most important—if you smoke, quit immediately. Nicotine is a potent vasoconstrictor and can make your Raynaud’s worse.
In GERD, the esophagus is being affected by a weakening of the valve that keeps acid in the stomach, allowing the acid to “reflux” into the esophagus. Drugs called proton pump inhibitors such as
omeprazole (Prilosec)
,
pantoprazole (Protonix)
, or
lansoprazole (Prevacid)
decrease acid production.
Esomeprazole (Nexium)
can heal irritation and erosions caused by acid. It is available in prescription strength (40 mg) and over-the-counter (23.5 mg). Other drugs like
cimetidine (Zantac, Tagamet)
block formation of stomach acid. Prokinetic agents like
metoclopramide (Reglan)
may improve decreased motility of the esophagus or small intestine.
The diarrhea caused by bacterial overgrowth in the small intestine can sometimes be cleared up with a short course of antibiotics. Malabsorption may also be caused by bacterial overgrowth.
Also helpful: eating slowly, chewing food thoroughly, drinking plenty of water (alternating sips of water with bites of food can ease passage of food), not eating within two hours of going to bed, and sleeping with the head of your bed elevated.
Inflammation of the air sacs of the lungs, called
alveolitis
, often precedes
interstitial lung disease
, which affects the tissues and spaces around the air sacs. Cytoxan is used to treat interstitial lung disease, given orally or in “pulses” (monthly intravenous infusions), and more commonly now, another transplant drug,
mycophenolate mofetil (MMF, CellCept)
, is used.
Pulmonary fibrosis
, due to
interstitial lung fibrosis
, may also be aggravated by breathing microscopic particles of stomach acid during sleep, and treating GERD may improve symptoms. Other management includes prevention of infections and exercise, along with home oxygen therapy in some cases.
High blood pressure in the lungs (
pulmonary arterial hypertension, PAH
) occurs in about 15 percent of scleroderma patients, as small blood vessels in the lungs become thickened and resistant to blood flow.
Bosentan (Tracleer)
, an endothelin receptor antagonist (ERA), is used for treating pulmonary hypertension. The drug, given orally, relaxes the endothelial cells lining blood vessels by blocking a receptor for a protein that acts as a
vasoconstrictor
(
endothelin
). Clinical trials showed improved breathing, exercise potential, and quality of life. An inhaled form of
iloprost
may be used for PAH.
Patients with early diffuse scleroderma need to monitor their blood pressure regularly to be aware of any increase, which is the first sign of serious kidney problems. If blood pressure begins to rise, a physician must be consulted immediately so
angiotensin-converting enzyme (ACE) inhibitors
, a lifesaving treatment, can be given. These include
captopril (Capoten)
and
enalapril (Vasotec)
.
Sildenafil
and
tadalafil
can improve exercise capacity and blood flow and are also used to treat PAH. Pulmonary hypertension can also be treated with oxygen and blood thinners.
In severe cases, prostacyclins, including intravenous
epoprostenol (Flolan), and intravenous and subcutaneous treprostinil
may be given in continuous infusions, using a small portable pump. This drug is a form of prostaglandin, a substance that occurs naturally in the body and is involved in many biological functions. Prostacyclins relax blood vessels and increase the blood supply to the lungs. Studies are under way with oral and inhaled prostaglandin preparations to make therapy easier and less expensive.
Skin thickening sometimes improves by itself, but so far no drugs have been shown to soften skin. Methotrexate may improve skin in early diffuse disease and shows some positive effects on muscles, joints, and tendons. Physical and occupational therapy are extremely important for patients with diffuse skin thickening in order to maintain as much mobility as possible. Adequate pain control is also necessary so patients can do the difficult and aggressive exercise program.
High-dose chemotherapy with stem cell rescue involves harvesting stem cells (the cells that grow into different kinds of cells, including white blood cells), purifying and freezing them, then destroying a patients’ abnormal immune system with high doses of chemotherapy (usually cyclophosphamide). After chemotherapy, the stem cells are defrosted and infused back into the patient to reconstitute the immune system with lymphocytes that hopefully will not be autoreactive. Recent clinical trials are using
autologous peripheral blood hemapoietic stem cells
, stem cells taken from the patient’s bloodstream, rather than bone marrow.
Studies so far suggest these transplants pose a tough trade-off—the risk of serious side effects (such as organ failure), dying from the treatment, or the chance of living longer.
One major clinical trial, the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, found that
hemapoietic stem cell
transplant (HSCT)
was more effective than intravenous cyclophosphamide, despite causing more deaths in the first two months after treatment and more serious events in the first year.
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Compared to cyclophosphamide, HSCT led to better long-term survival among 156 people with early diffuse cutaneous disease. The ASTIS results, reported in 2014, also show improved lung function (most of the patients had interstitial lung disease) and skin softening after two years. Around 22 percent of patients relapsed before two years and needed more immunosuppressant therapy.
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A small 2011 clinical trial at Northwestern University also found that HSCT improved skin and pulmonary function in scleroderma patients for up to two years, compared to conventional treatment.
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Other trials are ongoing.
Overall, stem cell transplantation has a relatively high mortality rate (around 5 to 10 percent). So the procedure is usually reserved for people diagnosed within the last four to five years with diffuse cutaneous scleroderma and only mild-to-moderate organ involvement or limited cutaneous disease with progressive internal organ involvement after conventional treatment has failed. “But it’s very hard to predict who will do well,” comments Dr. Mayes.
There are several new studies looking at promising medications particularly for skin thickening and for lung fibrosis. Patients should strongly consider participating in such trials at scleroderma centers of excellence, which can be identified at the Scleroderma Foundation website or through
clinicaltrials.gov
.
An experimental oral drug,
selexipag
, has shown some promise for treating PAH. Selexipag is a
selective prostacyclin IP receptor agonist
and dilates blood vessels in the lung. In a recent clinical trial, the drug improved survival and breathing difficulties by 14 percent after four years.
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