Autoimmune diseases are a group of disorders in which the primary cause is an inflammatory reaction resulting from the body’s own immune system attacking normal tissues. They may affect one of more organs or tissue types, which often include skin, blood vessels, connective tissues, endocrine glands, joint and muscles. Well-known examples of the nearly 100 different autoimmune or related disorders include multiple sclerosis, rheumatoid arthritis, Sjögren’s syndrome, systemic lupus erythematosus, and type 1 diabetes.
Scleroderma, derived from the Greek words “sklerosis,” meaning hardness, and “derma,” meaning skin, is another autoimmune disorder. While the cause is unknown, this chronic disease stems from the over-production of collagen, which results in the hardening of the skin and internal organs such as the lungs, kidneys, heart, and gastrointestinal tract. In terms of outward appearance, one of the most common and recognizable symptoms of the disease is the formation of thick scar tissue (fibrosis) and hardening of the skin.
Because the disease is relatively rare, the exact incidence and prevalence of scleroderma is unknown. It is estimated that approximately 250 persons per million American adults are affected by scleroderma, which usually develops between the ages of 35 and 55.
Due to the low incidence, some generalists may not have extensive patient experience with scleroderma. Accordingly, education and awareness of the disease in addition to groups such as the Scleroderma Foundation, a national nonprofit health organization, can be the greatest resources for managing scleroderma and helping patients reduce the risk of further complications.
“The rheumatologist is the physician that coordinates the care of scleroderma patients and seeing a specialist who knows about this disease is important,” said Christine Gaydos, Executive Director of the Scleroderma Foundation’s Delaware Valley Chapter, in an interview with Life Science Digest. “We get calls in the office from people outside of the major cities where physicians see less scleroderma patients and may not be as up-to-date on the current research and clinical studies that are available. In these cases, we help the patient find experts familiar with the hallmarks of the disease in the Philadelphia region.”
As just one example of the nuances associated with the disease, many scleroderma patients have some sort of functional heart problem and echocardiograms are among the most cost-effective and least invasive methods available for screening cardiac anatomy. While generalists most commonly request an echocardiogram to assess left ventricular dysfunction and determine if high blood pressure has damaged the heart or blood vessels, scleroderma patients often experience pulmonary arterial hypertension (PAH), where the arteries from the heart to the lungs narrow down and generate high pressure on the right side of the heart. In addition, results from an echocardiogram can be very different from a more comprehensive right heart catheterization (RHC), which is more accurate in diagnosing PAH.
Heterogeneous Clinical Presentation and Outcomes
There are two main forms of scleroderma: systemic and localized. More common in children, the localized form or scleroderma affects a local area of skin in patches (morphea), in a line down an arm or leg (linear scleroderma), or in a line down the forehead (scleroderma en coup de sabre). Systemic sclerosis (SSc), which usually affects internal organs and systems as well as the skin, is more common in adults – especially women. Systemic sclerosis can be further divided into two subtypes based on the extent of skin involvement: limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc). In lcSSc, skin thickening only involves the hands and forearms, lower legs, and feet. In dcSSc, the upper arms, thighs, or trunk are affected.
Raynaud’s phenomenon, which manifests as recurrent vasospasm of the fingers and toes usually in response to stress or cold exposures, occurs in the majority of patients with SSc and may be the first sign of the scleroderma disease process. Raynaud’s phenomenon is more common in adults than SSc and only a fraction of patients diagnosed with Raynaud’s phenomenon will have or develop SSc.
For patients with either localized scleroderma or lcSSc, scleroderma may be a mild condition. In contrast, SSc has high mortality and morbidity. Due to a better understanding of the condition, and more treatments available for specific organ-based complications, outcomes have improved in SSc.
For example, in a retrospective cohort analysis of 520 SSc patients, 5-year survival among dcSSc patients has improved from 69% in the historical cohort (1990–1993) to 84% in the contemporary cohort (2000–2003). Five-year survival among lcSSc patients was relatively unchanged at greater than 91% for both the historical and contemporary cohorts. Ten-year survival data from time of SSc disease diagnosis ranges from 66% to 82% based on data from other cohort studies.
Renal, cardiac, and pulmonary involvement, however, remain the major complications that limit survival. Interstitial lung disease (ILD), a condition in which the lung tissue has become scarred or inflamed, develops in up to 75% of patients with SSc and represents one of the two main causes of death. High blood pressure in the blood vessels of the lungs is another highly lethal condition that affects SSc patients. However, there are now many medications to treat PAH and the earlier it is detected and treated, the better the result will be. In the past, kidney disease was the leading cause of death, but early detection and treatment have brought this largely under control.
Although there are medications to slow down disease progression and help with symptoms, including pain, dry eyes and mouth, stomach irritation, etc. there is as yet no cure for scleroderma.
Traditional immunosuppressive medications, primarily available for cancer chemotherapy (cyclophosphamide) or to prevent rejection after organ transplantation, have been used for decades to treat autoimmune disorders, including many rheumatologic conditions such as systemic lupus erythematosus and rheumatoid arthritis. While they have demonstrated some efficacy during early skin involvement and active lung inflammation, they do not appear to provide benefits during the later phases of the disease.
In a previous study, the Scleroderma Lung Study I (SLS I), investigators evaluated a 1-year cyclophosphamide (CYC) treatment for people with scleroderma-related ILD. The study results demonstrated statistically significant improvements in forced vital capacity, total lung capacity, dyspnea, Rodnan skin scores, and several measures of quality of life. However, when patients were followed for another year after completing their CYC therapy, the beneficial effects of CYC waned and were no longer significant by the 24-month follow-up. Preliminary information suggests that an alternative immunosuppressive medication, CellCept® (mycophenolate mofetil, or MMF, by the Roche Group), may be effective in treating this disease, be given for longer periods, and result in fewer side effects.
An ongoing study with a targeted enrollment of 150 patients, the Scleroderma Lung Study II (SLS II), will compare the safety and efficacy of a 2-year treatment with MMF versus a 1-year treatment with CYC. Specifically, investigators will determine whether MMF produces similar or better improvements in lung capacity and fewer side effects throughout the entire 2-year period (ClinicalTrials.gov identifier: NCT00883129). Study completion for SLS II is targeted for 2014.
Non-randomized studies of haemopoietic stem-cell transplantation (HSCT) in SSc have shown improvements in lung function and skin flexibility, but with high treatment-related mortality. In 2011, preliminary results from an open-label, randomized, controlled phase 2 trial by investigators at Northwestern Memorial Hospital were published. The study enrolled 19 patients who were aged younger than 60 years with dcSSc (ClinicalTrials.gov identifier NCT00278525). All ten patients randomly allocated to receive HSCT improved at or before 12 months’ follow-up, compared with none of nine allocated to cyclophosphamide. Eight of nine control patients had disease progression compared with no patients treated by HSCT, and seven patients switched to HSCT. Compared with baseline, data for 11 patients with follow-up to 2 years after HSCT suggested that improvements in modified Rodnan skin scores and forced vital capacity persisted. Longer follow-up is needed and the study’s estimated completion date is September 2012.
In 2010, the first study to provide evidence of clinical benefit (improved lung function) for rituximab (Rituxan®, Genentech, Inc. and Biogen Idec, Inc.) in SSc patients with interstitial lung disease was published. According to the study results, patients randomized to receive rituximab had a median 10.25% increase in forced vital capacity (FVC) compared with baseline, while those who received standard treatment had a deterioration of 5.04% (P=0.002), at 1-year. There also was a significant 19.46% increase in diffusing capacity of carbon monoxide (DLco) in the rituximab-treated patients, while the controls showed deterioration of 7.5% (P=0.023). Skin fibrosis, assessed with the Modified Rodnan Skin Score, also improved by a median of 38.33%, while it worsened by 5.23% in controls. Due to the study’s small size and the fact that most patients had longstanding disease, had been treated with multiple immunosuppressive agents in the past, and were receiving concurrent therapies during the study, the results need to be replicated in a multicenter randomized trial.
The rarity of scleroderma and the heterogeneity of its clinical presentation hamper efforts to develop new treatments for the disease. In fact, according to a search of ClinicalTrials.gov, there are only 36 clinical studies currently open to investigate new treatment options for scleroderma. More investment in research, education, and awareness for scleroderma is clearly needed, as evidenced by the introduction of S. 649, the Scleroderma Research and Awareness Act, by Senator Kristen Gillibrand (D-NY) on March 17, 2011. The bill is a companion to H.R. 1672 and both bills would increase funding for expanded scleroderma research at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). You can help make a difference through participation in various events and activities being held in connection with Scleroderma Awareness Month during the month of June and by contacting public officials to support passage of the Scleroderma Research and Awareness Act.
 Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study. Nihtyanova SI, Tang EC, Coghlan JG, Wells AU, Black CM, Denton CP. QJM. 2010 Feb;103(2):109-15. Epub 2009 Dec 4.
 Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J, Craig R, Hirano I, Marshall K, Ruderman E, Jovanovic B, Milanetti F, Jain S, Boyce K, Morgan A, Carr J, Barr W. Lancet. 2011 Aug 6;378(9790):498-506. Epub 2011 Jul 21.