Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
Review
The clinical implications of thalidomide in inflammatory bowel diseases Expert Rev. Clin. Immunol. Early online, 1–10 (2015)
Antonella Diamanti*1, Teresa Capriati1, Bronislava Papadatou1, Daniela Knafelz1, Fiammetta Bracci1, Tiziana Corsetti2, Domenica Elia1 and Giuliano Torre1 1 Hepatology, Gastroenterology and Nutrition Unit, Bambino Gesu` Children’s Hospital, Piazza S. Onofrio 4, 00165 Rome, Italy 2 Pharmacy Service, Bambino Gesu` Children’s Hospital, Piazza S. Onofrio 4, 00165 Rome, Italy *Author for correspondence: Tel.: +39 668 592 339 Fax: +39 668 593 889 [email protected]
informahealthcare.com
Thalidomide has anti-inflammatory and anti-angiogenetic activity that makes it suitable for treating inflammatory bowel diseases (IBD). The recent guidelines from the European Crohn’s and Colitis Organization/European Society for Pediatric Gastroenterology Hepatology and Nutrition conclude that thalidomide cannot be recommended in refractory pediatric Crohn’s disease but that it may be considered in selected cohorts of patients who are not anti-TNFa agent responders. The main adverse effect is the potential teratogenicity that renders the long-term use of thalidomide problematic in young adults due to the strict need for contraceptive use. In short-term use it is relatively safe; the most likely adverse effect is the neuropathy, which is highly reversible in children. So far the use of thalidomide is reported in 223 adult and pediatric IBD patients (206 with Crohn’s disease). In the following sections, the authors will discuss efficacy and safety of thalidomide, in the short-term treatment of IBD. KEYWORDS: child . Crohn’s disease . inflammatory bowel disease . thalidomide . ulcerative colitis
Over the past decades, the incidence of inflammatory bowel diseases (IBD) in children is increasing particularly in North America and in Europe [1–3]. IBD have more common resistance or intolerance to treatments and higher recurrence of relapse in children than in adults [4–6]. Thus, pediatric IBD management could be so hard to suggest the use of thalidomide in selected cases despite the potential adverse events [7–34]. Thalidomide is an old drug but pathophysiological aspects make it still attractive in IBD [35]. It is easy to administer and rather cheaper than biologics. The recent guidelines from European Crohn’s and Colitis Organization/European Society for Pediatric Gastroenterology Hepatology and Nutrition (ECCO/ESPGHAN) conclude that thalidomide cannot be recommended in refractory pediatric Crohn’s disease (CD), but that it may be considered in selected patients who do not tolerate or are not responding to anti-TNFa agents [36]. Thalidomide was also successfully employed in some children with ulcerative colitis (UC) [11,12,17,31,32] not responding to conventional treatments [37]. Main adverse event is the potential teratogenicity [35,38] that impedes the long-term use in
10.1586/1744666X.2015.1027687
young adult patients because of the strict need for contraceptive use [35,38]. Thalidomide analogs, overall reported as immunomodulatory drugs are available and they have greater immune-modulatory and antiangiogenic potency than thalidomide but not its side effects [39–42]. They have even been employed in inflammatory, autoimmune and neoplastic diseases [39–41]. Lenalidomide was employed in one clinical trial, including 89 CD adults, at 5 mg as well as at 25 mg/day but it was not more effective than placebo [42]. In the following sections, the authors will discuss the key studies pertaining efficacy and safety of thalidomide in IBD. In CD, efficacy will be assessed according to the disease phenotype (luminal, fistulizing and intestinal bleeding CD). Safety concerns will be explored to evaluate their impact on the successful accomplishment of planned therapeutic programs. Thalidomide: history, pharmacological issues & mechanism of action History
Thalidomide was employed in clinical practice to treat morning sickness since 1956 in Europe, Australia, Canada and South America. It was withdrawn from the market because it
2015 Informa UK Ltd
ISSN 1744-666X
1
Review
Diamanti, Capriati, Papdatou, et al.
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
Table 1. Clinical applications of thalidomide and underlying pathophysiological mechanisms. Diseases conditions
Pathophysiological mechanisms
Rheumatological disorders: rheumatoid arthritis, ankylosing spondylitis, Still’s disease, Sjo¨gren’s syndrome, lupus Mucocutaneous diseases: pyoderma granulosum, prurigo nodularis, porphyria cutanea tarda and lichen planus Respiratory tract diseases: sarcoidosis, tuberculosis
Actions on cytokines†
Cancer: Kaposi’s sarcoma, renal-cell carcinoma, mantle cell lymphoma, glioma, metastatic melanoma, prostate cancer, pancreatic cancer. Breast, ovarian, head and neck, and various solid-organ cancers, cancer anorexia and cachexia
Actions on cytokines† Stimulation of Th1 immunity and associated increased IL-2 e IFN g secretion [12,78] Anti-angiogenic properties [81,96] Anti-proliferative (by inhibition of IL-6) and pro-apoptotic activity in tumor cells (by activation of caspase 8, down-regulation of NF-kB and decreased expression of apoptosis-inhibitory protein) [11,43,44] Cyclooxygenase-2 (COX-2) inhibition subsequent prostaglandin-E2
HIV
Co-stimulation of primary human T cells number and activity. Increased population of cytotoxic T cells and plasma levels of IL-2 receptor, a marker of T-cell activation [91,92]
Erythema nodosum leprosum
Actions on cytokines† Modification of surface cell adhesion molecules [94]
Multiple myeloma
Modification of surface cell adhesion molecules [94] Anti-angiogenic properties [81,96] Inhibition of cell surface adhesion molecules and of proliferation and induction of apoptosis and anti-angiogenic activities [41]
Systemic sclerosis
Actions on cytokines† Stimulation of Th1 immunity and associated increased IL-2 e IFN gamma secretion [12,78]
†
Inhibition of TNF-a, IL-1b, IL6, Il-12, GM-CSF and stimulation of IL-10 in peripheral blood mononuclear cells [78,89].
caused congenital birth defects, such as phocomelia or amelia [43]. Immune-modulatory and anti-angiogenic effects allowed to re-consider thalidomide as a therapeutic option in oncology and in several chronic inflammatory diseases [23–25,28,36,43–72]. Currently, the surveillance system known as the Pharmion Risk Management Program strictly controls thalidomide management to minimize its teratogenic risk. According to Pharmion Risk Management Program, it is mandatory for clinicians to acquire informed consent before thalidomide beginning and pregnancy test before and monthly after beginning treatment from women at childbearing age [73,74].
Why & how thalidomide works in IBD?
The therapeutic effect of thalidomide in IBD is based on: .
Pharmacological issues
Thalidomide (a-N-phthalimidoglutarimide) is an analog of glutamic acid formed by a ring of phthalimide and by a ring of glutarimide. It is a racemic mixture in 1:1 ratio of two enantiomers S ( ) and R (+) which interconvert because they have a chiral center. S ( ) determines anti-TNFa properties while to R (+) sedative effects by direct and selective action on diencephalic sleep centers receptors. Thalidomide is given orally mainly in the evening to reduce sedative effects. Blood peak is reached in 2–6 h. It is widely distributed in tissues and in body fluids due to low affinity with plasma proteins. Half-life is 5–7 h. Liver metabolizes thalidomide by cytochrome P450; less than 1% is eliminated unchanged by urine where it is no longer detectable after 48 h [43,44]. doi: 10.1586/1744666X.2015.1027687
.
Immunomodulatory and anti-inflammatory activity. It is related mainly to the inhibition of TNFa produced by monocytes, T-lymphocytes, alveolar macrophages, mononuclear cells in the lamina propria and microglia [75,76]. Thalidomide also interferes with the nuclear transcription of factor NF-kB which blocks the proteins synthesis involved in cell proliferation, inflammation, angiogenesis and apoptosis [11]. Furthermore, it inhibits IL-6 and IL-12 more selectively than steroids [77,78]. Thalidomide also decreases interferon gamma synthesis and induces enhanced IL-4 production [79,80]. Anti-angiogenetic property. Thalidomide reduces the production of VEGF and basic fibroblastic growth factor [81] which are involved in control of mucosal inflammation [82]. VEGF strongly expressed within vessel walls also determines neoangiogenesis in colonic angiodysplasias [83]. VEGF in CD is responsible for increased vascular permeability and neoangiogenesis, therefore it can contribute to intestinal bleeding [84–87]. Thus, anti-angiogenetic properties of thalidomide are mediated by the effects on VEGF [81,88]. VEGF levels are also related with disease activity in CD [85,86]. Thus, VEGF suppression may also support anti-inflammatory effects of thalidomide. Expert Rev. Clin. Immunol.
The clinical implications of thalidomide in IBD
Why & how the thalidomide works in others disease?
Review
0.5% 1979–1990
Several diseases have been favorably treated with thalidomide [11,12,43,44,47,78,81,89–96]; pathophysiological information according to each disease is summarized in TABLE 1.
1991–2000
16.5%
2001–2010
33%
2011–2014
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
Thalidomide & IBD: clinical efficacy & safety
Thalidomide was firstly employed in 1979 in a young UC woman, 28-years aged, with sacroiliac joints pain and unresponsive to oral steroids and sulfasalazine [7]. In FIGURE 1, we summarize the number of IBD cases treated with thalidomide and reported by decades. The literature trend shows growing interest on this drug over the years, with 33% of overall cases described in the past 4 years.
50%
Clinical efficacy Thalidomide & CD Thalidomide & luminal CD series
Vasiliauskas et al. [9] assessed safety, tolerance and efficacy of 50 mg/day and of 100 mg/day steroid-dependent CD patients; 70% of patients responded and 20% achieved remission. Side effects were mild and mostly transient. Bariol et al. [11] performed an open prospective clinical trial which included six CD and four UC patients, all symptomatic despite standard medical therapy. Five CD patients were considered responders, as indicated by the trend of stool frequency, stool consistency and Crohn’s Disease Activity Index (CDAI), all significantly improved within 3–5 weeks. At cessation of the trial, four patients showed complete mucosal healing and three reduced inflammation Bauditz et al. [12] in an open prospective study evaluated the effects of thalidomide on cytokines production in nine refractory
Figure 1. Trend of the reports on the clinical use of thalidomide in inflammatory bowel diseases since the first report (1979). The values are referred to the amount of overall published papers according to each period.
CD patients. Three patients discontinued the treatment due to sedative side effects; four had disease remission. Production of TNFa and IL-12 significantly decreased over treatment. Facchini et al. [15] report their retrospective experience with thalidomide in five patients with luminal CD, refractory to conventional treatments. One patient suspended treatment early (after 5 days) because of severe distal paresthesia. All patients achieved clinical and endoscopic remission. Lazzerini et al. [17] performed a retrospective study that included refractory 19 CD patients of which 17 achieved the remission in 8 weeks. In patients in remission, thalidomide was
Table 2. Thalidomide and luminal Crohn’s disease series. Patients (n) Dose Age (years) range (mg/day)
Remission (%) FU length Steroid length (months) tapering (months) (%)
Withdrawn
Review
The clinical implications of thalidomide in inflammatory bowel diseases Expert Rev. Clin. Immunol. Early online, 1–10 (2015)
Antonella Diamanti*1, Teresa Capriati1, Bronislava Papadatou1, Daniela Knafelz1, Fiammetta Bracci1, Tiziana Corsetti2, Domenica Elia1 and Giuliano Torre1 1 Hepatology, Gastroenterology and Nutrition Unit, Bambino Gesu` Children’s Hospital, Piazza S. Onofrio 4, 00165 Rome, Italy 2 Pharmacy Service, Bambino Gesu` Children’s Hospital, Piazza S. Onofrio 4, 00165 Rome, Italy *Author for correspondence: Tel.: +39 668 592 339 Fax: +39 668 593 889 [email protected]
informahealthcare.com
Thalidomide has anti-inflammatory and anti-angiogenetic activity that makes it suitable for treating inflammatory bowel diseases (IBD). The recent guidelines from the European Crohn’s and Colitis Organization/European Society for Pediatric Gastroenterology Hepatology and Nutrition conclude that thalidomide cannot be recommended in refractory pediatric Crohn’s disease but that it may be considered in selected cohorts of patients who are not anti-TNFa agent responders. The main adverse effect is the potential teratogenicity that renders the long-term use of thalidomide problematic in young adults due to the strict need for contraceptive use. In short-term use it is relatively safe; the most likely adverse effect is the neuropathy, which is highly reversible in children. So far the use of thalidomide is reported in 223 adult and pediatric IBD patients (206 with Crohn’s disease). In the following sections, the authors will discuss efficacy and safety of thalidomide, in the short-term treatment of IBD. KEYWORDS: child . Crohn’s disease . inflammatory bowel disease . thalidomide . ulcerative colitis
Over the past decades, the incidence of inflammatory bowel diseases (IBD) in children is increasing particularly in North America and in Europe [1–3]. IBD have more common resistance or intolerance to treatments and higher recurrence of relapse in children than in adults [4–6]. Thus, pediatric IBD management could be so hard to suggest the use of thalidomide in selected cases despite the potential adverse events [7–34]. Thalidomide is an old drug but pathophysiological aspects make it still attractive in IBD [35]. It is easy to administer and rather cheaper than biologics. The recent guidelines from European Crohn’s and Colitis Organization/European Society for Pediatric Gastroenterology Hepatology and Nutrition (ECCO/ESPGHAN) conclude that thalidomide cannot be recommended in refractory pediatric Crohn’s disease (CD), but that it may be considered in selected patients who do not tolerate or are not responding to anti-TNFa agents [36]. Thalidomide was also successfully employed in some children with ulcerative colitis (UC) [11,12,17,31,32] not responding to conventional treatments [37]. Main adverse event is the potential teratogenicity [35,38] that impedes the long-term use in
10.1586/1744666X.2015.1027687
young adult patients because of the strict need for contraceptive use [35,38]. Thalidomide analogs, overall reported as immunomodulatory drugs are available and they have greater immune-modulatory and antiangiogenic potency than thalidomide but not its side effects [39–42]. They have even been employed in inflammatory, autoimmune and neoplastic diseases [39–41]. Lenalidomide was employed in one clinical trial, including 89 CD adults, at 5 mg as well as at 25 mg/day but it was not more effective than placebo [42]. In the following sections, the authors will discuss the key studies pertaining efficacy and safety of thalidomide in IBD. In CD, efficacy will be assessed according to the disease phenotype (luminal, fistulizing and intestinal bleeding CD). Safety concerns will be explored to evaluate their impact on the successful accomplishment of planned therapeutic programs. Thalidomide: history, pharmacological issues & mechanism of action History
Thalidomide was employed in clinical practice to treat morning sickness since 1956 in Europe, Australia, Canada and South America. It was withdrawn from the market because it
2015 Informa UK Ltd
ISSN 1744-666X
1
Review
Diamanti, Capriati, Papdatou, et al.
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
Table 1. Clinical applications of thalidomide and underlying pathophysiological mechanisms. Diseases conditions
Pathophysiological mechanisms
Rheumatological disorders: rheumatoid arthritis, ankylosing spondylitis, Still’s disease, Sjo¨gren’s syndrome, lupus Mucocutaneous diseases: pyoderma granulosum, prurigo nodularis, porphyria cutanea tarda and lichen planus Respiratory tract diseases: sarcoidosis, tuberculosis
Actions on cytokines†
Cancer: Kaposi’s sarcoma, renal-cell carcinoma, mantle cell lymphoma, glioma, metastatic melanoma, prostate cancer, pancreatic cancer. Breast, ovarian, head and neck, and various solid-organ cancers, cancer anorexia and cachexia
Actions on cytokines† Stimulation of Th1 immunity and associated increased IL-2 e IFN g secretion [12,78] Anti-angiogenic properties [81,96] Anti-proliferative (by inhibition of IL-6) and pro-apoptotic activity in tumor cells (by activation of caspase 8, down-regulation of NF-kB and decreased expression of apoptosis-inhibitory protein) [11,43,44] Cyclooxygenase-2 (COX-2) inhibition subsequent prostaglandin-E2
HIV
Co-stimulation of primary human T cells number and activity. Increased population of cytotoxic T cells and plasma levels of IL-2 receptor, a marker of T-cell activation [91,92]
Erythema nodosum leprosum
Actions on cytokines† Modification of surface cell adhesion molecules [94]
Multiple myeloma
Modification of surface cell adhesion molecules [94] Anti-angiogenic properties [81,96] Inhibition of cell surface adhesion molecules and of proliferation and induction of apoptosis and anti-angiogenic activities [41]
Systemic sclerosis
Actions on cytokines† Stimulation of Th1 immunity and associated increased IL-2 e IFN gamma secretion [12,78]
†
Inhibition of TNF-a, IL-1b, IL6, Il-12, GM-CSF and stimulation of IL-10 in peripheral blood mononuclear cells [78,89].
caused congenital birth defects, such as phocomelia or amelia [43]. Immune-modulatory and anti-angiogenic effects allowed to re-consider thalidomide as a therapeutic option in oncology and in several chronic inflammatory diseases [23–25,28,36,43–72]. Currently, the surveillance system known as the Pharmion Risk Management Program strictly controls thalidomide management to minimize its teratogenic risk. According to Pharmion Risk Management Program, it is mandatory for clinicians to acquire informed consent before thalidomide beginning and pregnancy test before and monthly after beginning treatment from women at childbearing age [73,74].
Why & how thalidomide works in IBD?
The therapeutic effect of thalidomide in IBD is based on: .
Pharmacological issues
Thalidomide (a-N-phthalimidoglutarimide) is an analog of glutamic acid formed by a ring of phthalimide and by a ring of glutarimide. It is a racemic mixture in 1:1 ratio of two enantiomers S ( ) and R (+) which interconvert because they have a chiral center. S ( ) determines anti-TNFa properties while to R (+) sedative effects by direct and selective action on diencephalic sleep centers receptors. Thalidomide is given orally mainly in the evening to reduce sedative effects. Blood peak is reached in 2–6 h. It is widely distributed in tissues and in body fluids due to low affinity with plasma proteins. Half-life is 5–7 h. Liver metabolizes thalidomide by cytochrome P450; less than 1% is eliminated unchanged by urine where it is no longer detectable after 48 h [43,44]. doi: 10.1586/1744666X.2015.1027687
.
Immunomodulatory and anti-inflammatory activity. It is related mainly to the inhibition of TNFa produced by monocytes, T-lymphocytes, alveolar macrophages, mononuclear cells in the lamina propria and microglia [75,76]. Thalidomide also interferes with the nuclear transcription of factor NF-kB which blocks the proteins synthesis involved in cell proliferation, inflammation, angiogenesis and apoptosis [11]. Furthermore, it inhibits IL-6 and IL-12 more selectively than steroids [77,78]. Thalidomide also decreases interferon gamma synthesis and induces enhanced IL-4 production [79,80]. Anti-angiogenetic property. Thalidomide reduces the production of VEGF and basic fibroblastic growth factor [81] which are involved in control of mucosal inflammation [82]. VEGF strongly expressed within vessel walls also determines neoangiogenesis in colonic angiodysplasias [83]. VEGF in CD is responsible for increased vascular permeability and neoangiogenesis, therefore it can contribute to intestinal bleeding [84–87]. Thus, anti-angiogenetic properties of thalidomide are mediated by the effects on VEGF [81,88]. VEGF levels are also related with disease activity in CD [85,86]. Thus, VEGF suppression may also support anti-inflammatory effects of thalidomide. Expert Rev. Clin. Immunol.
The clinical implications of thalidomide in IBD
Why & how the thalidomide works in others disease?
Review
0.5% 1979–1990
Several diseases have been favorably treated with thalidomide [11,12,43,44,47,78,81,89–96]; pathophysiological information according to each disease is summarized in TABLE 1.
1991–2000
16.5%
2001–2010
33%
2011–2014
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nanyang Technological University on 04/28/15 For personal use only.
Thalidomide & IBD: clinical efficacy & safety
Thalidomide was firstly employed in 1979 in a young UC woman, 28-years aged, with sacroiliac joints pain and unresponsive to oral steroids and sulfasalazine [7]. In FIGURE 1, we summarize the number of IBD cases treated with thalidomide and reported by decades. The literature trend shows growing interest on this drug over the years, with 33% of overall cases described in the past 4 years.
50%
Clinical efficacy Thalidomide & CD Thalidomide & luminal CD series
Vasiliauskas et al. [9] assessed safety, tolerance and efficacy of 50 mg/day and of 100 mg/day steroid-dependent CD patients; 70% of patients responded and 20% achieved remission. Side effects were mild and mostly transient. Bariol et al. [11] performed an open prospective clinical trial which included six CD and four UC patients, all symptomatic despite standard medical therapy. Five CD patients were considered responders, as indicated by the trend of stool frequency, stool consistency and Crohn’s Disease Activity Index (CDAI), all significantly improved within 3–5 weeks. At cessation of the trial, four patients showed complete mucosal healing and three reduced inflammation Bauditz et al. [12] in an open prospective study evaluated the effects of thalidomide on cytokines production in nine refractory
Figure 1. Trend of the reports on the clinical use of thalidomide in inflammatory bowel diseases since the first report (1979). The values are referred to the amount of overall published papers according to each period.
CD patients. Three patients discontinued the treatment due to sedative side effects; four had disease remission. Production of TNFa and IL-12 significantly decreased over treatment. Facchini et al. [15] report their retrospective experience with thalidomide in five patients with luminal CD, refractory to conventional treatments. One patient suspended treatment early (after 5 days) because of severe distal paresthesia. All patients achieved clinical and endoscopic remission. Lazzerini et al. [17] performed a retrospective study that included refractory 19 CD patients of which 17 achieved the remission in 8 weeks. In patients in remission, thalidomide was
Table 2. Thalidomide and luminal Crohn’s disease series. Patients (n) Dose Age (years) range (mg/day)
Remission (%) FU length Steroid length (months) tapering (months) (%)
Withdrawn
