Randomized, Double-Blind, Placebo-Controlled Trial if IL1-TRAP, Rilonacept, in Systemic Sclerosis -A Phase I/II Biomarker Trial

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).