It is very challenging to do research on treatments for scleroderma, as is the case with most rare disorders. The small number of patients means that it is difficult to locate enough patients in a single geographical area to do appropriate, well controlled research. This usually means that multi-center research is required, which is costly and difficult to coordinate.
An additional complication for doing scleroderma research is the fact that scleroderma is a general term for a cluster of related diseases. It is quite possible that some treatments may be effective for some forms of scleroderma, but ineffective or less effective in other forms. And, since each subset of scleroderma affects an even smaller population than the total scleroderma patient population, research on subsets is even harder to do. Historically, most scleroderma research performed over the past 20 years has not been done on specific disease subsets, but usually on a heterogeneous population that includes both diffuse and limited scleroderma patients. Even the research that breaks down results into diffuse and limited scleroderma subsets does not address the fact that each of these broader categories includes patients with different specific antibodies.
By conducting research on an overall population of scleroderma patients without considering antibody subtypes, results may appear to be negative overall, yet still might be positive for a subset of the patients. For example, since limited forms of scleroderma typically progress much more slowly than the diffuse forms of the disease, it is quite conceivable that certain treatments which show minimal results for diffuse patients may be much more effective for limited scleroderma patients. Also, the slower progression means that it may take much longer to show positive results for experimental therapies than might be the case for the more rapidly progressing diffuse form. Unfortunately, little research has been done that takes this into consideration.
When considering investigational or alternative therapies, it is important to keep these limitations in mind. Since there are no generally accepted systemic treatments for scleroderma (although specific treatments for various symptoms may be quite effective), some physicians may decide to try alternative or experimental treatment approaches on an individual basis even though there is no clear research support for these treatments. When positive results follow such treatments, it is very easy to believe that these treatments caused the improvements. In some cases, this conclusion may be valid, however, it is important to realize that it is difficult to establish a cause and effect relationship between a treatment and a result with a single patient. In some cases, it may be desirable to withdraw an experimental treatment from a patient to see if improved symptoms worsen. If this occurs and the symptoms again improve when the treatment is resumed, this makes it much more likely that the treatment may be causing the improvement. Nevertheless, without well-controlled, double-blind research, cause and effect cannot be clearly established.
A Note About “Significant” Results in Research Studies
Several times a year, we see headlines in the popular press or in online discussion boards with titles like “New Drug Significantly Improves Lifespan of Late Stage Colon Cancer Patients!”. If you locate and read the original article (often very difficult to do), you might find that the article abstract says something like “in a pool of 87 stage V colon cancer patients, xiziphinate hexachloride increased average survival time from 4 months to 5 months”.
The article headline is correct but confusing. In the world of research, the word “significant” is a statistical term with a precise meaning. Typically, it means that there was only a 5% chance that the results of the study were not due to chance. To make it a bit clearer, if this same study was done a group of 10 patients, then it is much more likely that the one-month extension of survival time is just from chance and if you picked another group of 10 patients, then you might not seem the same results. On the other hand, if the study was done on 1000 patients, then it is extremely unlikely that this one-month increase in survival time was just from the chance makeup of the subject group.
Basically, the word “significant” in many research studies has nothing to do with clinical significance, but rather statistical significance. Is the one-month extension of lifespan “significant” to a stage V colon cancer patient? It may well be, but that is a judgment on the part of the patient and has little to do with the usage of the word “significant” in the research article. It is important to keep this in mind when you hear about research that talks about “significant” improvement from a treatment or medication.
To illustrate, if we look at the world of scleroderma research, a typical, well-designed research study on the effects of cyclophosphamide (Cytoxan) on lung function and other health-related symptoms (Tashkin et al. 2006) showed significant improvement in two measures of lung functioning at 12 months vs. a placebo group, although a third measure did not show significant improvement. On one of the measures (total lung capacity – % of predicted), in the Cytoxan group the value stayed the same as baseline at 12 months (around 70% of normal). In contrast, the placebo group dropped from 68% to 65%. Believe it or not, that difference is statistically significant! However, it really isn’t clinically significant. The only other significant change on another measure was even closer between the treatment and control group but still reached the less than 5% significance criteria.
Also, the researchers didn’t look a potential long-term harm to the patient from suppressing their immune system for a year. While the article abstract talked about the “significant but modest beneficial effect on lung function…” and mentioned that the effects “were maintained through the 24 months of the study”, it was only in the last sentence of the article itself that the authors noted that “Caution regarding the use of cyclophosphamide is still warranted, since potential long-term consequences were not evaluated.” Unfortunately, this is very typical in scholarly articles like this and virtually no clinicians ever look beyond the article abstract to see the cautionary note at the end of the actual article. Patients need to be aware of this problem when they are working with their physicians in devising treatment options. It is always important to understand about the potential for long-term problems with treatments that are being considered, especially when a treatment might provide modest real-world benefits, even if statistically “significant”.
Additional Learnings on Scleroderma Research
For more information on Scleroderma research, you can review our article, Understanding Medical Resaerch — Part 1. You can also visit our Resources page for additional insights into Scleroderma research, clinical trials and more.