Overview of Systemic Sclerosis
Scleroderma, also known as systemic sclerosis (SSc), is a multisystem disease affecting skin and, more variably, other tissues, commonly including joints, muscles, lungs, the gastrointestinal tract and kidneys. It is one of a group of diseases in which fibrosis is associated with organ dysfunction. Fibrosis can involve the liver (Lefton et al., 2009; Pinzani et al., 2005), lung(Frankel and Schwarz, 2009), kidneys (Schnaper, 2005), and less commonly other organs, representing a final common pathway to organ dysfunction. In SSc tissue fibrosis is widespread, variably involving skin, lungs and the gastrointestinal tract.
Although SSc can affect almost any part of the body, skin disease is the most consistent clinical manifestation. Skin disease typically starts in the hands with an edematous phase of hand swelling lasting one to several months. The skin then progressively thickens and tethers to underlying tissues. In diffuse cutaneous SSc (dcSSc), skin thickening, induration and tethering typically extend proximally up the arm and can involve the torso, abdomen, face and legs. Patients with limited cutaneous SSc (lcSSc) have skin disease limited to below the elbow and face and neck as well as other characteristic clinical features. SSc skin pathology (diffuse and limited cutaneous SSc) shows fibrosis and variable perivascular lymphocyte infiltration in the deep reticular dermis.
SSc affects multiple other body systems. Most severe complications are seen more frequently in dcSSc with considerable morbidity and mortality(Steen and Medsger, 2000). Lung disease manifests as interstitial fibrosis or pulmonary arterial hypertension (PAH, more common in lcSSc). Lung disease remains the leading cause of death among SSc patients. Gastrointestinal disease primarily results from dysmotility. In the esophagus and stomach this most commonly leads to esophagitis. In the small and large bowel this most commonly leads to constipation, bowel obstruction and/or malnutrition. Renal disease is primarily manifest as accelerated hypertension and renal insufficiency. Angiotension converting enzyme inhibitors are generally though not uniformly effective for treating this manifestation, which previously led to significant mortality.
Other important clinical manifestations include cold-induced vasospastic disease in extremities (Raynaud's phenomenon) and digital ulcers. SSc can also have cardiac manifestations. Pericarditis is the most frequent cardiac manifestation. Subclinical pericarditis is common with large effusions developing occasionally. Myocardial involvement with low-grade myocardial fibrosis is relatively common, but not frequently of clinical importance (Follansbee et al., 1985). Fibrosis most commonly manifests as the appearance of a septal infarction pattern on EKG in patients with normal coronary arteries, or as ventricular conduction delays. Occasionally myocardial fibrosis leads to heart failure. Cardiac arrhythmias are seen in \~5% of patients with SSc. Most common are atrial or ventricular ectopy, generally not associated with more serious rhythm disturbances. However, thallium perfusion defects are associated with sudden cardiac death (Steen et al., 1996).
Current treatment for SSc is limited (Steen, 2001). For most disease manifestations treatment is primarily symptomatic and generally inadequate. The exception is renal disease, scleroderma renal crisis, once a major cause of mortality in SSc patients, can often be treated successfully with angiotensin converting enzyme inhibitors. Pulmonary complications now represent the major cause of mortality. Cyclophosphamide provides some benefit in patients with interstitial lung disease (ILD), the most lethal complication of SSc. However, the effect of this agent on SSc-associated ILD is modest and transient (Tashkin et al., 2006; Tashkin et al., 2007). Pulmonary arterial hypertension (PAH) also leads to considerable mortality in SSc patients. PAH may respond to vasodilators such as epoprostanol and bosentan, but frequently responses are incomplete and mortality still high(Badesch et al., 2009) . Bowel hypomotility also leads to considerable morbidity and sometimes mortality. Esophageal hypomotility is treated, frequently without success, with pro-motility and acid-blocking agents. Dysmotility of the lower bowel and its complications are even more difficult to treat with pro-motility agents providing modest relief in some patients and antibiotics helping in cases of small bowel overgrowth. Thus there are limited therapeutic alternatives for SSc patients faced with progressive lung or bowel disease.
Skin fibrosis, the hallmark feature of SSc remains without effective treatment. Although skin changes in SSc are not a cause of mortality, they cause considerable morbidity, may reflect similar pathological processes to those that occur in the bowel and lungs, correlate highly with prognosis and disease progression in other organ systems, and can be reproducibly assessed by skin score testing. Skin disease is of particular interest for evaluation in clinical trials since it is easily biopsied and can thus be repeatedly assessed for pathological changes during clinical trials (Lafyatis et al., 2009).
Part of the difficulty in finding effective treatments for SSc has been a continuing uncertainty regarding what initiates pathogenesis. The cause of disease manifestations in SSc remains obscure, although three major pathophysiologic explanations have been advanced. Prominent pathologic changes in dermal and pulmonary tissues show fibrosis, suggesting abnormalities in matrix deposition. Vascular disease, resulting in scleroderma renal crisis, digital ischemia and pulmonary hypertension suggests dysfunction of the vascular endothelium. Autoantibodies in SSc patient sera suggest that immune dysfunction and autoimmunity may contribute to or cause disease. The different pathological features in different organs have provided support for each of these mechanisms, but not clarified which is most important in overall pathogenesis.
Background: IL-1 Rationale for blocking IL-1 in Systemic Sclerosis: The inflammasome and fibrosis Several observations have implicated IL-1 in fibrotic diseases and SSc. Environmental or occupational exposure to silica dust leads to fibrosis (Cohen et al., 2008) and has been associated with SSc (Rustin et al., 1990). Recently, several groups have shown in murine models that silica dust activates inflammation and fibrosis through the inflammasome (Cassel et al., 2008; Hornung et al., 2008) . Activation of the inflammasome also contributes to bleomycin-induced lung injury (Gasse et al., 2007).
Rilonacept blocks IL-1β signaling by acting as a soluble decoy receptor that binds IL-1β and prevents its interaction with cell surface receptors. Rilonacept also binds IL-1α and IL-1 receptor antagonist (IL-1ra) with reduced affinity.
Rationale for Rilonacept In This Study SSc presents special problems for developing therapies due to the heterogeneous clinical presentation, the variability of disease progression and the difficulty quantifying the extent of disease. The variability of disease progression presents particular challenges for deciding whom to treat, leading to overtreatment of patients as well as misinterpretation of open label trials. This heterogeneity of disease progression has also required recruitment of relatively large patient numbers into clinical trials, many with skin disease that is going to stabilize or improve spontaneously (Amjadi et al., 2009).
Purpose/Objectives
This study will utilize a 4-gene biomarker of skin disease as the primary efficacy outcome in a short duration, placebo-controlled clinical trial of rilonacept, designed to provide preliminary data for a larger trial. The change in 4-gene SSc biomarker skin score from day 0 to day 42 or last observation carried forward(LOCF) will be measured in both rilanocept-treated patients as well as placebo patients and the scores will be compared. These gene biomarkers should provide a strong surrogate for such trials in the future and, if IL-1 is indeed the cytokine leading to fibrosis in this disease, provide a highly significant start to finding a therapeutic for SSc that for the first time might dramatically affect fibrosis. A central hypothesis of this study is that IL-1 inhibition will downregulate the 4-gene biomarker over a relatively short period of time, much shorter than is historically thought necessary to see changes in the MRSS. Entry criteria will include the recent onset of dcSSc as this is the population most likely to show progressive skin disease and also the population examined in previous studies showing correlations between MRSS and the 4-gene biomarker.
Secondary outcomes will include other validated measures of SSc disease activity. MRSS, SSc health assessment questionnaire (SHAQ), which includes the health assessment questionnaire (HAQ) and a SSc specific, patient visual analogue scale (VAS) for organ specific involvement will be followed during the trial. Several studies suggest that the SHAQ accurately measures disease activity and may detect smaller changes in health status. This study will also test the effect of rilonacept on global skin gene expression using microarray analyses of skin biopsies. In addition, serum biomarkers of SSc disease activity (COMP, THS-1 and IFI44) and a biomarker of inflammasome activation (CRP) will be tested before and after treatment. The change in MRSS score, SHAQ score, skin myofibroblast score, gene expression, CRP and serum biomarkers from day 0 to day 52 will be compared between the rilanocept-treated patients and the placebo-treated patients.
