Autoimmune blistering diseases are painful and debilitating dermatoses. Their treatment is based on steroids, often for extended periods of time, leading patients to suffer the consequences of steroid-toxicity. Dedee Murrell. MD, DSc, Head of the Department of Dermatology at St George Hospital, University of New South Wales and Professorial Fellow at The George Institute for Global Health, is leading the way. Professor Murrell’s work has helped establish the importance of the Steritas  Glucocorticoid Toxicity Index (GTI) in dermatology, to elucidate the effects of steroid-toxicity in patients with autoimmune blistering diseases.

Still the gold standard: steroid treatment in autoimmune blistering disease

Autoimmune blistering diseases refer to a group of immunoglobulin G4-related skin diseases that manifest themselves as blister-like lesions of the skin and mucous membranes [1-3]. The lesions caused by autoimmune blistering diseases impact patients’ quality of life drastically, causing symptoms ranging from soreness and itching to debilitating pain, lethal infections, bleeding, denuding of the skin and mucous membranes, and difficulties swallowing because of oral blisters [4-6].  The mortality of autoimmune blistering disease patients is up to six times higher than that of the general population [7]. 

To control the symptoms and potentially fatal consequences of autoimmune blistering diseases, steroids play a central role, so much so that 75% of physicians use prednisone as the sole initial treatment for these conditions [8-11]. Topical steroids are often used in treating autoimmune blistering diseases such as bullous pemphigoid, pemphigus foliaceus, and pemphigus erythematosus. But the tedious, twice daily, whole body application of a steroid cream often leads to skin atrophy, redness, rashes, stretch marks, and infections [8]. 

When topical steroids are not sufficient, systemic steroids are the main treatment option for autoimmune blistering diseases [8-9].  The adverse effects of systemic steroids can be severe and debilitating, leading to weight gain, muscle weakness, changes of the skin, osteopenia, osteoporosis, and fractures. In addition, insulin resistance and type 2 diabetes mellitus, glaucoma and cataract formation, dyslipidemia, hypertension, and serious cardiovascular sequelae are also common consequences of steroid treatment. Finally, Cushing syndrome, infection, cognitive changes, insomnia, depression, anxiety, panic disorder, psychosis, and death may ensue [8,9,12-16]. 

Despite their grueling side effects, the potent anti-inflammatory and immunosuppressive action of steroids provide only temporary relief to patients suffering from complex autoimmune diseases if other treatments are not employed or are unavailable [17].  Intravenous immunoglobulins (IVIG), for example, have been shown to be safe and effective for treating autoimmune blistering diseases, but their widespread application is hampered by the high cost of this therapy [18,19].

Owing to the autoimmune etiology and heterogeneous nature of autoimmune blistering diseases, steroids continue to prevail in autoimmune blistering disease treatment, despite their severe side effects [9,17,18].

Decoding steroid-toxicity in autoimmune blistering diseases

While steroids continue to be a mainstay treatment for autoimmune blistering diseases, physicians and scientists are working on reducing the burden of steroid-toxicity. In these efforts, the GTI is proving to be a valuable and comprehensive clinical outcome assessment to systematically evaluate the toxic effects of steroids in these patients [9,18-22]. 

Professor Dedee Murrell and her team recently assessed the GTI in a study published in the Journal of the American Academy of Dermatology (JAAD). Utilization of the GTI allowed researchers to demonstrate the changes in steroid-toxicity over time by quantifying and comparing clinical outcomes of autoimmune blistering disease in both patients who were steroid naive, as well as in those who were previously treated with steroids. Professor Murrell’s team used the GTI to show not only how GTI scores differed between those patient groups, but also to demonstrate that GTI scores in patients receiving steroids showed progressive worsening, correlating highly with the cumulative doses of steroids [21]. 

Steroid-sparing is an approach that is particularly relevant when the use of steroids cannot be avoided, as is most commonly the case in autoimmune blistering diseases [20].  A combination of rituximab and prednisone, for example, was recently shown to be more effective and safer for the treatment of pemphigus than prednisone alone [9,10]. This line of investigation earned an international consensus recommendation for the combination of rituximab and prednisone as the first-line treatment for pemphigus. 

The steroid-sparing effects of rituximab in pemphigus patients were investigated  further by Elham Mazaherpour and colleagues. Utilizing the GTI to quantify the steroid-sparing ability of rituximab, the team showed that patients treated with only prednisolone had a significantly higher GTI score compared to patients treated with a combination of rituximab and prednisolone [12]. 

Efgartigimod (Vyvgart™), a novel medication developed by Argenx, is a first-in-class neonatal Fc receptor antagonist for the treatment of autoimmune diseases. To assess and quantify the steroid-sparing ability of efgartigimod in combination with prednisone for the treatment of bullous pemphigoid and pemphigus vulgaris or pemphigus foliaceus, Argenx is currently using the GTI in two phase 3 clinical trials (NCT05681481 and NCT04598477) [23]. 

These recent and ongoing studies demonstrate important applications of the GTI in autoimmune blistering diseases, offering a definitive outcome measure for the toxic effects of steroids in these complex diseases. The GTI, tailored to the design of individual clinical trials in academia and industry, provides a systematic way of assessing steroid-toxicity as an additional endpoint, enabling physicians to evaluate the side effects of steroids in real time, shedding light on steroid-toxicity in dermatology.

References 

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