New highlights from NEJM 2017

Anchalee Senavonge. MD.

1 September 2017

Division of Allergy & Immunology

Department of Pediatrics, Faculty of Medicine

Chulalongkorn University

Publish 22 June 2017 Publish 30 June 2017

ZONDA trial

Asthma phenotype

Sally E Wenzel et al. Nature Medicine. May 2012. Vol 18 No 5.

J.B. Bice et al. / Ann Allergy Asthma Immunol 112 (2014) 108e115.

GINA 2017

• “Add-on anti-IgE (omalizumab): patients aged ≥6 years with moderate or severe allergic asthma that is uncontrolled on Step 4 (Evidence A)”

• “Add-on anti-IL-5 treatment (SC mepolizumab, IV reslizumab): patients aged ≥12 years with severe eosinophilic asthma that is uncontrolled on Step 4 treatment (Evidence B)”

Pavord ID et al.DREAM study. Lancet 2012;380:651-9Castro M et al. Lancet Respir Med 2015;3:355-66.

Anti IL-5

1. Mepolizumab (Nucala, GSK) : humanized IgG1 mAb against IL-5

2. Reslizumab (Cinqair,Teva) : humanized IgG4 mAb against IL-5

3. Benralizumab (Astra) : humanized Ab targeting the alpha-chain of IL-5 receptor

Benralizumab

• A humanized, afucosylated IgG1 monoclonal antibody

• engineered to eliminate fucose sugars from the oligosaccharides in the Fc region

• directed against the alpha subunit of the IL-5 receptor

• Mechanism: induces direct, rapid, nearly complete depletion of eosinophils by means of NK cell–mediated Ab-dependent cellular cytotoxic effects

N Engl J Med 2017;376:2448-58

Presenter

Presentation Notes

Afucosylation enhances the interaction of benralizumab with its binding site

G Pelaia et al. Role of biologics in severe eosinophilic asthma. Ther Clin Risk Manag 2016:12: 1075-1082

Anti IL-5 vs Anti-IL5R

Tan LD et al. Benralizumab: a unique IL-5 inhibitor for severe asthma.

J Asthma Allergy 2016 Apr 4;9:71-81

Benralizumab targets the effector cells themselves that are circulating and lung-tissue/resident tissue eosinophils and basophils

Mepolizumab and Reslizumab act by neutralizing the effects and block the activation of eosinophils by IL-5

Presenter

Presentation Notes

Afucosylation enhances the interaction of benralizumab with its binding site and thus heightens antibody-dependent cell-mediated cytotoxicity (ADCC) functions by > 1,000-fold over the parental antibody.31,41,57–59Afucosylated IgG 1 mAbs have a high-binding affinity to the FcgRIIIa region, and they can overcome the inhibitory effects exhibited by serum IgG เทียบกับ other anti-IL-5 mAbs (eg, mepolizumab and reslizumab) act by neutralizing the effects of IL-5 and block the activation of eosinophils by IL-5. benralizumab targets the effector cells themselves that are circulating and lung-tissue resident tissue eosinophils and basophils คือ not only blocks all recruitment, activation, and mobilization of eosinophils but it also allows the depletion of eosinophils in the circulation, bone marrow, and target tissues, particularly airways and lungs in asthmatics. Therefore, benralizumab might provide a more complete depletion of airway eosinophils and basophils through enhanced ADCC and subsequently effect in greater reductions of asthma exacerbations

Before ZONDA trial…

SIROCCO

CALIMA

Bleecker ER, et al.Lancet; October 2016; 388: 2115–27

FitzGerald JM et al. Lancet; October 2016; 388: 2128–41

• Randomized, double-blind, parallel-group, placebo-controlled phase 3 study at 374 sites in 17 countries

• P: 1,205 severe uncontrolled asthmatics (age 12-75 years) • diagnosis of asthma for at least 1 year and at least 2

exacerbations while on high-dosage ICS plus LABA in previous year

Bleecker ER, et al.Lancet 2016; 388: 2115–27

SIROCCO

Presenter

Presentation Notes

Australia, Brazil, Bulgaria, Czech Republic, France, Italy, Mexico, Peru, Poland, Russia, South Africa, South Korea, Spain, Turkey, the UK, the USA, and Vietnam

SIROCCO Intervention

• Randomly assigned (1:1:1) 1. Benralizumab 30 mg SC q 4 weeks

2. Benralizumab 30 mg SC q 4 weeks for 3 doses then q 8 weeks

3. Placebo

For 48 weeks- stratified patients (2:1) for eosinophil counts of >=300/μL and <300/μL

Outcome

• Primary endpoint: annual exacerbation rate ratio “add-on effect”

• Secondary endpoint: prebronchodilator FEV 1 and total asthma symptom score at week 48, for patients with blood eosinophil counts of at least 300 cells/µL



51% 45% Primaryendpoint

exacerbation

Presenter

Presentation Notes

ลด annual exa เฉพาะกลุ่มที่มี eosino>300 ถ้าน้อยกว่าจะคร่อม1 For the primary endpoint, both dosing regimens of benralizumab signifi cantly decreased the annual asthma exacerbation rate compared with placebo at week 48. For the Q4W cohort, the rate ratio versus placebo was 0·55 (95% CI 0·42–0·71; p<0·0001), and for the Q8W cohort, it was 0·49 (0·37–0·64; p<0·0001).


Secondary Endpoint

FEV1

Presenter

Presentation Notes

The diff erence in least-squares mean change from baseline between the benralizumab Q4W and placebo cohorts was 0·106 L (95% CI 0·016–0·196; p=0·0215) and between the benralizumab Q8W and placebo cohorts it was 0·159 L (0·068–0·249; p=0·0006).

SIROCCO study conclusion

• The study confirmed the efficacy and safety of benralizumab for severe asthma and elevated eosinophils, which are uncontrolled by high-dosage ICS plus LABA (additional option)

• Clinical efficacy related to baseline blood eosinophil counts, similar in mepolizumab and reslizumab studies

• Q8W dosage was efficacious: potential to lower disease burden and reduce costs


CALIMA

• Randomized, double-blind, parallel-group, placebo-controlled phase 3 study at 303 sites in 11 countries

• P: 1,306 severe uncontrolled asthmatics (age 12-75 yr) • by medium-dosage to high-dosage ICS plus LABA and a

history of two or more exacerbations in the previous year

FitzGerald JM et al. Lancet 2016; 388: 2128–41

Presenter

Presentation Notes

USA, Canada, Germany, Sweden, Poland, Romania, Ukraine, Argentina, Chile, Japan, and the Philippines

Intervention

• Randomly assigned (1:1:1) 1. Benralizumab 30 mg SC q 4 weeks

2. Benralizumab 30 mg SC q 4 weeks for 3 doses then q 8 weeks

3. Placebo

For 56 weeks - stratified patients (2:1) for eosinophil counts of >=300/μL and <300/μL

Outcome

• Primary endpoint: annual rate ratio of asthma exacerbations for patients receiving high-dosage ICS+ LABA with baseline blood eosinophils ≥300/μL

• Secondary endpoint: pre-bronchodilator FEV1 and total asthma symptom score for patients receiving high-dosage ICS+ LABA with baseline blood eosinophils ≥300/μL


CALIMA

Primary outcome

Exacerbation


36% 28%

Presenter

Presentation Notes

Benralizumab resulted in signifi cantly lower annual exacerbation rates with the Q4W regimen (rate 0·60 [95% CI 0·48–0·74], rate ratio 0·64 [95% CI 0·49–0·85], p=0·0018, n=241) and Q8W regimen (rate 0·66 [95% CI 0·54–0·82], rate ratio 0·72 [95% CI 0·54–0·95], p=0·0188, n=239) compared with placebo (rate 0·93 [95% CI 0·77–1·12], n=248)


Secondary Endpoint

FEV1

Presenter

Presentation Notes

Improvements in pre-bronchodilator FEV1 were present within 4 weeks of treatment start and were maintained throughout the entire treatment period 120 ml

• The study showed that 56 weeks of add-on therapy with benralizumab 30 mg Q4W and Q8W significantly reduced the annual rate of asthma exacerbations by up to 36% for patients with severe asthma and elevated blood eosinophils

• Confirm and support SIROCCO study, but efficacy less than SIROCCO- possible regional heterogeneity

CALIMA study conclusion


Presenter

Presentation Notes

patients from the eastern Europe and rest of world (ie, South America) regions who had fewer exacerbations in the year before study entry

FitzGerald JM et al. Lancet;Oct 2016; 388: 2128–41Bleecker ER, et al.Lancet; Oct 2016; 388: 2115–27

Presenter

Presentation Notes

Allergy

ZONDA trial

Assessed the effect of benralizumab on the steroid sparing effect

In adult patients who had severe asthma with persistent blood eosinophilia despite high-dose ICS+LABAs and oral glucocorticoids

Presenter

Presentation Notes

Zonda แปลว่า dry wind often carrying dust in Argentina

Inclusion criteria

• 369 patients, age 18-75 years• Severe asthma treated with

• medium to high-dose ICS (>250 mcg fluticasone DPI) and LABA ≥ 12 months

• high-dose ICS (>500 mcg fluticasone DPI) and LABA therapy for ≥ 6 months

• Blood eosinophil> 150 cells/ul• Receiving oral glucocorticoid (GC) therapy for ≥ 6 continuous

months (equivalent to 7.5 to 40 mg/day of prednisolone)

P Nair et al. N Engl J Med 2017;376:2448-58

Exclusion criteria

• Significant asthma exacerbation requiring systemic GC, or ↑dose of oral GC

• History of life-threatening asthma• Asthma control reached at an oral GC dose of ≤5 mg/day• Use Omalizumab, on immunotherapy


Intervention

Randomly assigned (1:1:1) 1. Benralizumab 30 mg SC q 4 weeks 2. Benralizumab 30 mg SC q 4 weeks for 3 doses then q 8 weeks 3. PlaceboFor 28 weeks

• stratified according to eosinophil count (150 -300, ≥300 cells/ul)



Presenter

Presentation Notes

The oral glucocorticoid dose was further reduced, every 4 weeks, in the intervention period from weeks 4 to 24. The oral glucocorticoid dose that was reached at week 24, or the complete discontinuation of oral glucocorticoid therapy, was maintained until week 28. The last dose of benralizumab or placebo was administered at the week 24 visit. The oral glucocorticoid dose was further reduced, every 4 weeks, in the intervention period from weeks 4 to 24.

Assessment

• Asthma exacerbation defined as • temporary increase in systemic GC dose for at least 3

days to • an emergency department visit

• ACQ score• Blood and induced sputum for the analysis of

eosinophils


Presenter

Presentation Notes

The ACQ-6 is scored on a scale from 0 to 6, with lower numbers indicating better control of asthma), and the AQLQ(S)+12 is scored on a scale from 1 to 7, with higher scores indicating better asthma-related quality of life

Endpoints

• Primary : percentage change in oral GC dose from baseline to week 28

• Secondary: • percentages of patients who had a reduction in the

average daily oral GC dose of ≥ 25%, ≥ 50%, or 100% (discontinuation)

• percentage of patients with an average final oral GC dose of ≤ 5.0 mg/day


Primary Outcome

Mean reduction 75% from baseline Vs Placebo 25%

Odd ratio 4 times



Presenter

Presentation Notes

Error bars represent 95% confidence intervals. Values are slightly offset from each other at each time point for clarity.

Secondary outcome50% in Benralizumab group

stop OCS

Reduce OCS ≤5.0 mg/day Odd ratio =3


Benralizumab was associated with a longer time to the first exacerbation Every 4 weeks: hazard ratio = 0.39; (95% CI 0.22 to 0.66)Every 8 weeks: hazard ratio = 0.32; (95% CI, 0.17 to 0.57)


Presenter

Presentation Notes

the median percentage change from baseline to week 28 in the oral glucocorticoid dose in patients who received benralizumab or placebo. Error bars represent 95% confidence intervals. Values are slightly offset from each other at each time point for clarity. Panel B is a Kaplan–Meier cumulative incidence curve for the time to the first exacerbation in patients who received benralizumab as compared with those who received placebo. Benralizumab administered every 4 weeks was associated with a longer time to the first exacerbation than was placebo (hazard ratio, 0.39; 95% confidence interval [CI], 0.22 to 0.66; P<0.001), and benralizumab administered every 8 weeks was also associated with a longer time to the first exacerbation than was placebo (hazard ratio, 0.32; 95% CI, 0.17 to 0.57; P<0.001)

Secondary outcome: Annual asthma exacerbation rate• Placebo = 1.83• Benralizumab Q4W= 0.83

• 55% lower than placebo

• benralizumab Q8W=0.54• 70% lower than placebo


Presenter

Presentation Notes

1.83-0.83/1.83=55%


At week 20, higher than placebo by 256 ml (Q4W),

222 ml (Q8W)

By 28 weeks, no longer significant

difference

Secondary outcome: FEV1

Presenter

Presentation Notes

Mean changes in pre-bronchodilator FEV1 0.126 L, 0.232 L, and 0.239 L for patients who received placebo, benralizumab Q4W, or benralizumab Q8W, respectively

Side effects

Nasopharyngitis 17%Worsening asthma 13%

Bronchitis 10%


ZONDA trial conclusion

• Benralizumab significantly reduced the oral GC dose, while asthma control was maintained, in patients who had severe asthma an elevated blood eosinophil count

• The likelihood was more than 4 times • One half the patients who were receiving benralizumab

stopped oral GC therapy completely

• Targeting of the alpha subunit of the IL-5 receptor has potential advantages over existing anti–IL-5 therapies


Limitation

• Not address long-term efficacy and safety• 20% not respond to Benralizumab- unclear why

• Perhaps the presence of blood eosinophilia may not identify the eosinophil as a key effector cell in some patients


Muraro et al. J Allergy Clin Immunol 2016;137:1347-58.

30 June 2017

O Zen et al. NEJM 2017 Jul 6;377(1):52-61.

What is CD55

• “Decay accelerating factor” (DAF)• One of complement regulatory proteins• A globular glycoprotein anchored to the cell

membrane by glycosylphosphatidylinositol (GPI)

Middleton textbook 8th edition

Presenter

Presentation Notes

Paroxysmal nocturnal hemoglobinuria: genetic mutation leading to the inability to synthesize the glycosyl-phosphatidylinositol (GPI) anchor that binds these proteins to cell membranes.The corresponding gene PIGA (phosphatidylinositol glycan class A) in the X chromosome The triad of hemolytic anemia, pancytopenia, and thrombosis. acking in all hematopoietic cells are called complement-regulating surface proteins, including the decay-accelerating factor (DAF), or CD55 [8] ; homologous restriction factor (HRF), or C8 binding protein; and membrane inhibitor of reactive lysis (MIRL), or CD59.

What is CD55?

Middleton textbook 8th edition

Presenter

Presentation Notes

CD55 is attached to the surface by a glycosylphos-phatidylinositol moiety and inhibits complement activation by destabilizing and preventing the formation of C3 and C5 convertases, which pre-vents complement damage.

Amanda Kirchner Piccoli et al. Rev Bras Reumatol 2011;51(5):497-510

CD55 inhibits formation of new C3 and C5 convertases and accelerate the degradation of these pre-formed enzymes

Presenter

Presentation Notes

Cd55: Inhibits C3 and C5 cleavage by inhibiting the formation of new C3 and C5 convertases, in addition to accelerating the degradation of these pre-formed enzymes. คือมันจะไป c4b ใน classical กับ lecitin pathway ไม่ให้รวมกับ c2a และ recognize c3b ใน alter pathway ไม่ให้รวมกับ Bb เป็นC3 convertase และก็กันC5 convertase ด้วย คล้ายกัน CD59 Interferes directly with the structuration of MAC through its physical incorporation in the complex being formed, preventing C9 units from binding to the C5b-8 complex. CD46 Binds to the opsonins C3b and C4b, acting as a cofactor in their proteolytic degradation by the serine protease factor I CD35 Interacts with C3b and C4b to promote neutrophil-mediated phagocytosis. Acts as a cofactor to inactivate C3b and C4b to iC3b and iC4b through factor

Monogenic IBD diseases

• At least 64 genes identified in early-onset or very-early-onset inflammatory bowel disease

• Mutations affect intestinal epithelial barrier, phagocytosis processes, immune regulation, and inflammation


• loss-of-function variant in PLVAP (encoding plasmalemma vesicle associated protein)

• biallelic loss-of-function variants in CCBE1 or FAT4 (Hennekam syndrome)

• Previous studies: CD55 deficiency associated with PLE


Monogenic IBD diseases

Uhlig et al. Gastroenterology Nov 2014. Vol. 147, No. 5

Method

• 11 patients from 8 consanguineous families with unaffected parents (AR pattern)

• Moroccan, Syrian, or Turkish• Age 3-23 years• Diagnosis of early-onset protein-losing enteropathy

• primary intestinal lymphangiectasia, edema due to hypo-proteinemia, malabsorption, bowel inflammation, recurrent infections, angiopathic thromboembolic disease

• Whole-exome sequencing was performed • Evaluate the function of CD55 in patients' cells


Presenter

Presentation Notes

PLE characterized by early-onset gastroin-testinal symptoms, edema, malnutrition, hypo-albuminemia, and hypogammaglobulinemia, from eight consanguineous families with unaffected parents


Presenter

Presentation Notes

Affected persons who were homozygous for the mu-tant allele are indicated by solid symbols, heterozy-gous persons by half solid symbols, unaffected per-sons by open symbols, and an affected person with an unknown genotype by an open red symbol. Circles indicate female persons, and squares male persons; the triangle in Family 1 represents a miscarriage, and the slash in Family 5 indicates a person who had died. Patient 6.1 died during the course of the study (indi-cated by a slash)

Results

• identified 5 distinct homozygous, novel, loss-of-function CD55 variants mutations in 9 patients


Presenter

Presentation Notes

1.1, 7.1 homozygous for a dinucleotide deletion and a 4-nucleotide insertion at nucleotide positions 149 and 150 Glutamic acid> alanine, frameshift 2.1, 3.1, 5.1, 5.2 homozygous for a single-nucleotide deletion at position 109. Glycine > alanine, frameshift Threonine>asparagine, frameshift 8.1 homozygous for a single-nucleotide insertion at position 267. All three variants resulted in a frameshift and cause premature termination of CD55 mRNA translation. 4 a novel homozygous missense mutation in CD55 encodes a cysteine-to-serine substitution in the fourth short consensus repeat domain , cysteine>serine In Patient 6.1, a variant disrupting an exon 3 splice acceptor site probably caused alternative splicing. In all the patients, CD55 protein expression was lost, with only Patient 6.1 having minor residual expression การอ่านคือ C coding DNA G genomic M mitochondrial R RNA P protein


Loss of CD55 and Increased complement deposition

Panel B shows the pooled analysis of C3d staining with or without IgG1 precoating with an anti-CD28 antibody to activate the classical pathway

Panel A shows pooled analyses of C3d staining on T cells obtained from healthy controls and from five patients with CD55 deficiency. The middle lines of the I bars indicate mean values, and the I bars ±1 SD

Presenter

Presentation Notes

After incubation with human serum, we observed increased C3 fragment deposition on patients' CD4+ T-cell blasts by staining for an epitope common to C3, C3b, and C3d Panel A shows pooled analyses of C3d staining on T cells obtained from healthy controls and from five patients with CD55 deficiency. The middle lines of the I bars indicate mean values, and the I bars ±1 SD. Panel B shows the pooled analysis of C3d staining with or without IgG1 precoating with an anti-CD28 antibody to activate the classical pathway (coating the cells with mouse IgG1) CD28.2 as an activator of the classical complement pathway For complement deposition, cells were stained with a 1:300 dilution of anti-C3d antibody for 30 minutes Cells were washed 3X and resuspended in FACS buffer (PBS, 1%FBS) and analyzed for C3d deposition by flow cytometry

Excessive Production of Inflammatory Cytokines by CD55-Deficient T Cells

• Cd55−/− mice producing more interferon-γ and less interleukin-10

• TNF and interferon-γ induced procoagulatory decreases in thrombomodulin and increases in tissue factor

• Thus instigate the severe thrombophilia

• CD55 can convey a costimulatory signal for T-cell activation and production of IL-10, inhibitory cytokine to intestinal inflammation



CHAPLECD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy

Presenter

Presentation Notes

Pro-inflammatory and pro-coagulant changes produce excessive complement effectors potentially during immune responses to the gut microbiome. This leads to endothelial and epithelial damage and lymph vessel distortion and compromised lymphatic flow causing lymphangiectasia, GI protein loss, and malabsorption of fat and micronutrients. This is associated with mucosal edema due to hypoproteinemia, pathological inflammation and lymphocyte infiltration due to cytokine changes, and intraluminal complement activation thus compromising intestinal epithelial barrier function. This, combined with hypercoagulability within blood vessels impairs normal circulatory dynamics, thus exacerbating PLE.


Presenter

Presentation Notes

Panel A: shows a schematic of the complement cascade with the key cell surface regulators, CD46, Factor H, Factor I, CD55, and CD59 (boxed) coded for the known complement regulatory disorders. **PNH เกิดจาก somatic mutations that disable the glycosylphosphati-dylinositol anchor that tethers CD55 and CD59 to the cell surface, leading to complement-mediated hemolysis and thrombosis. **Atypical HUS เกิดจากHeterozygous germline loss-of-function variants affecting C3, factor H, factor I, or CD46 **Unlike PNH or the atypi-cal hemolytic–uremic syndrome, isolated CD55 deficiency causes early-onset protein-losing enter-opathy owing to primary intestinal lymphangi-ectasia and bowel inflammation ***CHAPLE syndrome comprises CD55 (decay-acclerating factor) deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (PLE)

In Vitro Inhibition of Complement by EculizumabFormulation

Eculizumab is a humanized monoclonal antibody that was derived from the murine antihuman C5 antibody m5G1.1.


Presenter

Presentation Notes

We observed that C5a production, which was elevated on incubation with patients' cells, was abrogated by coincubation with an experimental formulation of eculizumab, a complement-inhib-itory therapeutic agent that is used to treat parox-ysmal nocturnal hemoglobinuria (PNH) and the atypical hemolytic–uremic syndrome

Potential treatment

• “Eculizumab”• suppressed C5a production on patients' cells• warrants further investigation as a potential

treatment of the CHAPLE syndrome


Eculizumab

• recombinant, fully humanized hybrid IgG2/IgG4 monoclonal antibody directed against human complement component C5

• derived from the murine antihuman C5 antibody m5G1.1

• Role: atypical HUS, C3 glomerulopathies, PNH

Zuber, J. et al. Nat. Rev. Nephrol. 8, 643–657 (2012)

Presenter

Presentation Notes

carries the complementary-determining regions of the mouse anti-human C5 IgG, inserted into a germline framework region, including the hinge region from human IgG2, which does not bind Fc receptors, and the CH2–CH3 domains from human IgG4, which are unable to activate complement

Zuber, J. et al. Nat. Rev. Nephrol. 8, 643–657 (2012)

Presenter

Presentation Notes

Eculizumab carries the complementary-determining regions of the mouse anti-human C5 IgG, inserted into a germline framework region, including the hinge region from human IgG2, which does not bind Fc receptors, and the CH2–CH3 domains from human IgG4, which are unable to activate complement. These modifications minimize immunogenicity and prevent pro-inflammatory responses mediated by the IgG Fc portion . b | A molecular model of the C5 convertase portion C3bBb (in cyan and beige, respectively) in a complex with a substrate molecule C5 (green). The second C3b molecule of the C3bBbC3b complex is depicted as a dashed line because its location is still unknown. Mapping the 21-residue-long peptide, in the middle of which is the m5G1.1 epitope KSSKC (red), on this structure reveals the molecular mechanism of action of eculizumab. Because the C5 convertases of the classical and the alternative pathway are very similar, we suggest that eculizumab prevents the entry of the substrate molecule C5 into the C5 convertases. c | A schematic representation of the molecular mechanism of action of eculizumab. Upper part: in the absence of the drug, the substrate C5 enters into the C5 convertase and is cleaved to C5a and C5b. C5b binds C6, C7, C8 and several molecules of C9 to form the membrane attack complex C5b–9. Lower part: eculizumab binds to C5 with a very high affinity, preventing its entry into the C5 convertase. This effect prevents C5 cleavage and the formation of C5a and C5b–9.

Kurolap A, Eshach-Adiv O, Hershkovitz T, et al. N Engl J Med. July 2017.

Kurolap A, Eshach-Adiv O, Hershkovitz T, et al. Loss of CD55 in eculizumab-responsive protein-losing enteropathy. N Engl J Med 2017;377:87-9. DOI: 10.1056/NEJMc1707173

• Off-label compassionate therapy initially obtained for 2.5-year-old boy (V-7) in a critical deteriorating condition (Cheyne–Stokes respiration, hypotension, hypothermia, acidosis)

• Following therapeutic success, compassionate care approval a 10-year-old girl (V-3) and a 20-year-old man (IV-11)


Presenter

Presentation Notes

extended consanguineous family of Muslim-Arab origin (Fig.S1A). The kindred comprises six patients across several generations in four nuclear families that are affected with congenital protein losing enteropathy (PLE) associated with primary intestinal lymphangiectasia (PIL) and hypercoagulability All available affected individuals (n=5) were found to harbor a homozygous truncating mutation in CD55, while 27 additional healthy family members (including parents and siblings) were either heterozygous for the mutation or wild-type Onset เริ่ม 10 เดือนถึงสามขวบ โดยมี 2 คนที่ deadจาก complications คือ III3, V4 thrombotic events in three of the patients, including recurrent central-line thrombosis (Patients IV-11 and V-4), Budd-Chiari syndrome (Patient V-4), superior vena cava syndrome (Patients IV-11, V-4 and V-7), and sinus-vein thrombosis (Patient V-7)

Results• The positive effect within 12 hours

• V-7 stabilized and a reduction in bowel movements, discharged after 17 days of treatment. His albumin and protein normalized within a month and remain stable.

• V-3: hospitalized with severe hypoalbuminemia, significant ascites and bowel obstruction

• After 1st dose, an alleviation of abdominal pain, taken off analgesics, enable corrective intestinal resection surgery in 2 months

• IV-11: constant uncontrolled diarrhea• After 1st dose, reduction in frequency and consistency of bowel

movements, albumin and total protein normalized in 2 weeks


Presenter

Presentation Notes

V-3 was hospitalized with severe hypoalbuminemia, significant ascites and bowel obstruction requiring surgery. IV-11 had constant uncontrolled diarrhea greatly restricting his quality of life, although his albumin level was 3.2 g/dL, not as low as the other patients


Presenter

Presentation Notes

Decrease complement activation, a con-tinuous increase in serum albumin and total protein concentrations, and a decrease in the number of stools

Conclusion

• Although the exact mechanism that causes intestinal protein loss is currently unclear

• The response to eculizumab in these patients suggests that high levels of MAC, possibly precipitating intestinal-tissue damage are involved


Take home messages

• Currently, biologic personalized medicine is widely studied.• New anti-IL5 alpha receptor, Benralizumab, showed efficacy in

decrease asthma exacerbation and steroid-sparing effect.• Patients 12 years or older with moderate to severe asthma and

blood eosinophil more than 300 mm3/ul are likely to benefit from Benralizumab.

• Protein-losing enteropathy can be monogenic diseases. CD55, a complement regulator protein, defect can cause inflammatory bowel and PLE.

• CD55 deficiency have shown relation to hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE syndrome).

• Identification the CD55 deficiency is clinical significant due to the possible treatment with Eculizumab.

New highlights from NEJM 2017

Health & Medicine

Transcript of New highlights from NEJM 2017