Systemic sclerosis (SSc also known as scleroderma) is a devastating chronic immune-mediated inflammatory syndrome that is characterized by progressive organ dysfunction. The most common affected systems are the skin, the gastrointestinal tract, the lungs and the heart. Capillary endothelium is involved leading to ischemia and digital necrosis. Patients develop an interstitial lung disease (ILD) prototype dominated by pulmonary hypertension (PHA) and failed gad exchange. Almost all patients are also presenting with signs of intestinal dysmotility leading to gastrointestinal reflux and bloating1. Hallmarks of SSc are fibrosis of the skin and internal organs, production of autoantibodies and vasculopathy. SSc is the only rheumatic disorder accompanied by substantial lethality; so far no specific treatment targeting the mechanism of pathogenesis is available.

The major denominator in the pathogenesis of SSc is the activation of fibroblast proliferation for the production of pre-collagen and the deposition of collagen in tissues; this leads to organ fibrosis and organ dysfunction. Activation of fibroblasts may come from transforming growth factor-β (TGFβ) and from interleukin (IL)-1α3. Circulating IL- 1α was measured in 66 Japanese patients with SSc and compared to 19 well-matched for age and gender healthy comparators. IL-1α was significantly greater than comparators; levels were similar between patients with limited cutaneous SSc and diffuse cutaneous SSc4. Contrary to IL-1β, IL-1α localizes on cell membranes and it is transported to the nucleus where it acts as a transcription factor. Whereas fibroblasts of healthy subjects produce IL-1α only after activation, fibroblasts from patients with SSc produce IL-1α extensively through a vicious autocrine pathway. More precisely, the IL-1R1 receptor is over-activated on fibroblasts from patients with SSc; this receptor binds to constitutively over-produced IL-1α by the same fibroblasts and this leads to a vicious cycle of fibroblast activation and production of pre-collagen4. Moreover, excess release of preformed IL-1α from the cytosol of damaged or stressed- cells leads to the recruitment of hematopoietic cells to the site of the inflammation through endothelial activation and disruption of the vascular wall5 explaining, at least in part, the vasculopathy of SSc. It has recently been shown that platelet microparticles and danger-associated molecular patterns (DAMPs) like high mobility group box-1 (HMGB1) are increased in the circulation of patients with SSc5. DAMPs can also prime platelet activation through an IL-1 dependent mechanism in patients with SSc The above evidence suggests that targeting IL-1α may be a novel target for the management of SSc.

Bermekimab (MABp1) is a first-in-class true human monoclonal antibody cloned directly from human B lymphocytes that specifically targets and neutralizes IL-1α. The drug has been tested so far in three randomized clinical trials (RCTs) in disease areas; metastatic colon carcinoma and hidradenitis suppurativa (HS). HS is a chronic devastating skin disorder that affects skin areas rich in apocrine glands. Bermekimab was administered intravenously every other week at a dose of 7.5mg/kg for 12 weeks; efficacy was compared to placebo. A total of 20 patients with severe HS who have failed or who were not eligible for adalimumab treatment were enrolled in this RCT; 60% responded to bermekimab compared to 10% of placebo comparators (p: 0.035). The salient feature of this trial was the provision of a proof-of-concept for the mechanism of action of bermekimab involving the down-regulation of the production of human β-defensin-2 (hBD-2). More precisely, whole blood was stimulated at the end of the 12-week treatment period with heat-killed Staphylococcus aureus. The total blood capacity of placebo-treated comparators was negatively associated with the decrease of the involved skin depth as measured by ultrasound; this negative association ceased to exist among bermekimab-treated patients. In another large- scale RCT , bermekimab was intravenously administered in 207 patients with metastatic or unresectable colorectal cancer and compared with 102 patients treated with placebo. The study primary endpoint was composite involving stable or increased lean body mass and stability or improvement in at least two or three symptoms of pain, fatigue and anorexia. This was achieved in 33% of bermekimab-treated and 19% of placebo-treated patients respectively (p: 0.0045).