Efficacy of alpha1-antitrypsin augmentation therapy in conditions other than pulmonary emphysema

Abstract

Up to now alpha 1-antitrypsin (AAT) augmentation therapy has been approved only for commercial use in selected adults with severe AAT deficiency-related pulmonary emphysema (i.e. PI*ZZ genotypes as well as combinations of Z, rare and null alleles expressing AAT serum concentrations <11 μmol/L). However, the compassionate use of augmentation therapy in recent years has proven outstanding efficacy in small cohorts of patients suffering from uncommon AAT deficiency-related diseases other than pulmonary emphysema, such as fibromyalgia, systemic vasculitis, relapsing panniculitis and bronchial asthma. Moreover, a series of preclinical studies provide evidence of the efficacy of AAT augmentation therapy in several infectious diseases, diabetes mellitus and organ transplant rejection. These facts have generated an expanding number of medical applications and patents with claims for other indications of AAT besides pulmonary emphysema. The aim of the present study is to compile and analyze both clinical and histological features of the aforementioned published case studies and reports where AAT augmentation therapy was used for conditions other than pulmonary emphysema. Particularly, our research refers to ten case reports and two clinical trials on AAT augmentation therapy in patients with both AAT deficiency and, at least, one of the following diseases: fibromyalgia, vasculitis, panniculitis and bronchial asthma. In all the cases, AAT was successfully applied whereas previous maximal conventional therapies had failed. In conclusion, laboratory studies in animals and humans as well as larger clinical trials should be, thus, performed in order to determine both the strong clinical efficacy and security of AAT in the treatment of conditions other than pulmonary emphysema.

Expanding the Clinical Indications for α1-Antitrypsin Therapy

“…Efficacy of AAT augmentation therapy in conditions other than pulmonary emphysema recently was addressed in an evidence-based analysis (156). Its use in conditions such as type 1 and type 2 diabetes; acute myocardial infarction and postinfarction remodeling; and GVHD, cystic fibrosis and IBD is currently being evaluated worldwide in controlled trials.…”

Recent Advances in the Research and Development of Alpha-1 Proteinase Inhibitor for Therapeutic Use

“…As evident from the available literature, due to the multiple biological activities of 1 -PI, it has been associated with other lung diseases (first of all, cystic fibrosis) and many non-pulmonary diseases (Table 3). Some of these conditions may possibly benefit from 1 -PI augmentation therapy (see recent reviewes by Blanco et al, 2011 andJanciauskiene et al, 2011). According to Blanco et al (2011), 1 -PI therapy has proven remarkable efficacy in small cohorts of 1 -PI-deficient patients who also suffer from fibromyalgia, systemic vasculitis, relapsing panniculitis and bronchial asthma.…”

“…Some of these conditions may possibly benefit from 1 -PI augmentation therapy (see recent reviewes by Blanco et al, 2011 andJanciauskiene et al, 2011). According to Blanco et al (2011), 1 -PI therapy has proven remarkable efficacy in small cohorts of 1 -PI-deficient patients who also suffer from fibromyalgia, systemic vasculitis, relapsing panniculitis and bronchial asthma. Although the putative benefits of 1 -PI therapy for treatment of additional rare diseases (some are listed in Table 3) requires much more clinical data than are currently available to support clinical efficacy and safety of 1 -PI treatment, in general it indicates a clear potential for additional 1 -PI supply to satisfy the anticipated clinical demand in near future.…”

“…If further clinical studies support the safety and efficacy of an aerosolized 1 -PI, and it is approved for treatment of cystic fibrosis, the demand for therapeutic  1 -PI preparations could be significantly increased. Dowd et al, 1995;Esnault, 1997;Griffith et al, 1996Panniculitis Chowdhury et al, 2002Gross et al, 2009;Kjus et al, 2002;Smith et al, 1987;Valverde et al, 2008Fibromyalgia Ablin et al, 2009Blanco et al, 2004;Blanco et al, 2010Asthma Blanco et al, 2008Blanco et al, 2011;Eden et al, 1997Pancreatitis Rabassa et al, 1995Needlham & Stockley, 2004Renal Szönyi et al, 2006Ting et., 2008Diabetes Kalis et al, 2010Lisowska-Myjak et al, 2006;Cancer Li et al, 2011;Lindor et al, 2010;Topic et al, 2011Rheumatoid arthritis Grimstein et al, 2010Grimstein et al, 2011Atherosclerosis Stakisaitis et al, 2001Talmud et al, 2003; Acute anterior uveitis Fearnley et al, 1988;Saari et al, 1986 Chronic rhinosinusitis Kilty et al, 2008Kilty et al, , 2010Maune et al, 1995 (Cantin et al, 2002b). According to their data, the site-specific conjugation with either 20 or 40 kD PEG at Cys 232 of nonglycosylated r- 1 -PI (human) results in an active inhibitor with extended in vivo stability.…”

Pulmonary Langerhans Cell Histiocytosis—Insight into the Incidence of Alfa-1-Antitrypsin Deficiency (A1ATD) Alleles

“…Cystic lung lesions are observed as an associated feature of this deficiency [1][2][3][4]. It has also been well documented that A1ATD deficient subjects exposed to cigarette smoke and/or occupational hazard are particularly prone to develop lung pathology relatively early in their lifetime [5,6].…”