Recent Advances In Scleroderma
by Janet Pope MD MPH FRCPC
From her presentation to the SSO Symposium, October 1994
"There have been advances in treating some symptoms which commonly occur in scleroderma such as skin cracking, swallowing problems and Raynaud's. In addition, clinical research is moving at a rapid pace to try to determine possible treatments in this disease.
New skin creams
Newer topical skin creams are now available to lubricate the skin in patients with scleroderma. These include lotions with urea such as Uremol and Ulactin, and Dormer cream which contains another potent lubricant. These are helpful for preventing dryness and cracked skin.
Heartburn and swallowing problems
Many patients with scleroderma suffer from heartburn and swallowing problems. This occurs from decreased propulsion of food from the esophagus (gullet) and subsequent irritation and stricture from acid returning from the stomach into the esophagus. Losec (omeprazole) is indicated for esophagitis and is effective in decreasing stomach acid. This medication is expensive but has been extremely helpful in scleroderma. Some patients who previously required frequent dilations of their esophagus now need fewer procedures due to the use of this medication. Scleroderma patients are prone to poor propulsion of food leaving the stomach causing symptoms of bloating or early fullness. There are now several drugs which can enhance bowel motility including domperidone, cisapride and metaclopramide (maxeran). These medications are usually well tolerated. Although they cannot change the thickening and scarring of the gut, they can improve symptoms. Rarely scleroderma can cause bowel overgrowth where too much bacteria occurs in the bowel causing intermittent diarrhea and gas. This can be treated with antibiotics. Some people require frequent alternating courses of antibiotics to prevent weight loss from malabsorption due to the diarrhea. A hydrogen breath test can be used to diagnose bowel overgrowth, or antibiotics can be tried without testing if the history is suggestive of this problem. For the few people with scleroderma who have severe bowel involvement, total parenteral nutrition can be given through a large intravenous line. This is rarely needed, but many patients with weight loss or poor appetites can benefit from nutritional supplements such as high-calorie and protein drinks.
Treatment for Raynaud's
Raynaud's phenomenon is the name given to the reversible colour change in the hands and feet. The colour turns white, especially in the cold, and upon rewarming the digits often become blue or red. It is very common in scleroderma. Most patients try to avoid attacks of Raynaud's by staying warm, including wearing mittens, warm socks and hats. Over the previous decade, the standard treatment to relieve the symptoms of colour change and accompanying pain has been calcium channel blockers such as nifedipine (adalat). This group of drugs is often well tolerated, although in some people, it causes headaches, flushing, ankle swelling and worsening heartburn. There are newer calcium channel blockers, such as felodipine (renedit) which sometimes have fewer side effects. In the USA and Britain, studies have been done in patients with severe Raynaud's and show that iloprost (an intravenous drug) is helpful in healing fingertip ulcers and improving pain. The effects may last for several weeks after a single infusion. It is not currently available in Canada but rheumatologists have used an equivalent drug called prostagladin E1 with good results. In cases of severe Raynaud's sympathetic nerve block and occasionally surgery are tried to relieve symptoms. These treatments are not usually used except when conventional therapy has not helped and symptoms are severe.
Improved research
Recommendations have been made in order to improve research in scleroderma. Clinical research guidelines have been developed by the American College of Rheumatology to enhance the conduct of good clinical trials in this disease. These guidelines recommend certain outcome measurement which should be used. This includes skin scores and the presence of internal organ involvement (such as of the lung and kidney). Skin scores are measures of skin involvement over the body. The body is divided into areas and each area is given a score based on the degree of involvement. The higher the skin score, the more severe the scleroderma changes on the skin. The scores have been shown to be related to disease severity and those with more severe involvement of the internal organs have higher skin scores. There are several methods of performing skin scores and researchers in Canada, the USA and Great Britain have come together to determine which are more reliable and therefore better for use in clinical trials.
Trials underway to look for new treatments
There are currently four major randomized trials underway studying the effectiveness of various treatments for early severe scleroderma. The patients entered into these trials have had their symptoms for only a few years or less, and all have extensive skin involvement. The trials include patients with early disease only because the skin is less scarred compared to late disease and is more apt to improve with treatment. In addition, patients with more severe skin disease have a higher risk of having internal organ involvement (more severe iscleroderma) where experimental therapy may be justified. With regards to the natural history of scleroderma, one third of patients will improve with time irrespective of treatment. This occurrence needs to be considered when designing studies and avoids the conclusion that a treatment is effective when the patients treated may have improved anyway on no treatment.
(1) In Canada, several centres are involved in a trial comparing methotrexate to placebo. From early reports, methotrexate appears to be promising resulting in softening of the skin. It is commonly used in the treatment of rheumatoid arthritis and psoriasis.
(2) In the USA a large study comparing low dose D-penicillamine (cupramine) to conventional dose is being carried out. The object is to prove if D-penicillamine is effective in treating scleroderma. A small dose of penicillamine is used for comparison and is similar to the use of a placebo, but still gives the patients the metallic taste which is a side effect of the drug. This allows the patients and investigators to be blinded (unaware of the treatment allocation).
(3) In the USA and in one Canadian centre, there is a trial comparing photopheresis with placebo treatment to see if this expensive therapy can soften the skin in patients with systemic sclerosis.
(4) In England, researchers are studying the efficacy of a drug called alpha-interferon. Most trials currently underway are comparing active medication to a placebo (inactive substance) to try to determine first if the treatment is better than no treatment. We must demonstrate any drug to be superior to placebo before routinely recommending the treatment to patients. These studies also allow us to document the side effects of the drug under trial. Increased pigmentation of skin We have recently looked at why patients with scleroderma have increased pigmentation or darkening of their skin. This research grant was funded from the Scleroderma Society of Ontario (SSO). We found that the pigmentation was not due to a problem with the hormone cortisol. Low levels of cortisol can cause the skin to darken. Patients who had scleroderma were biopsied in areas where the skin felt normal, but was pigmented, and adjacent areas where the skin was not darkened. We found that both areas of skin often were abnormal under the microscope, having some degree of thickening present even though it was not felt to be involved by feeling the skin. In the areas where there was increased pigmentation, there was evidence of greater numbers of cells which contain pigment (melanocytes) and usually more severe skin thickening. It is difficult to interpret these results, however it is likely that the skin involvement in scleroderma is more extensive than it appears clinically.
Further research is needed to determine if there are local factors which cause the skin to be more severely affected in one area (such as the hands) compared to other areas, such as the abdomen and back. When reviewing the research that is currently underway in scleroderma, it appears that many different groups internationally are looking for better treatment and a more thorough understanding of this rare but important disease."
