More on Intralymphatic Injection of Autoantigen in Type 1 Diabetes REPLY

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Correspondence

n engl j med 377;4 nejm.org July 27, 2017

403

More on Intralymphatic Injection of Autoantigen

in Type 1 Diabetes

To the Editor:

Ludvigsson et al. (Feb. 16 issue)

1

report the results of the DIAGNODE-1 (GAD-Alum

[Diamyd] Administered into Lymph Nodes in

Combination with Vitamin D in Type 1 Diabetes)

trial. They found that injection of

alum-formulat-ed glutamic acid decarboxylase (GAD-alum) into

the inguinal lymph node plus administration of

oral vitamin D was “associated with preservation

of residual beta-cell function” and changes to

immunologic markers in patients with type 1

diabetes. Although the authors introduce an

in-teresting new approach, their data, as presented,

do not support their conclusions adequately.

In brief, the authors do not provide statistical

data to support assertions regarding the stable

C-peptide level in the patients. They also do not

provide raw data to support their accounts of

changes in immunologic markers, and they do

not adequately discuss how the “historical

age-matched patients” from specific trials

2-4

_were

chosen as a comparison group. Finally, they do not

show the standard-error bars that are necessary

to understand this small descriptive data set (see

Fig. 1 of their article, available at NEJM.org).

Con-clusive statements based on the results of small

pilot studies are inherently tenuous, but they are

particularly problematic when inadequate

infor-mation is provided to support the findings.

Michael Haller, M.D.

Mark Atkinson, Ph.D.

Desmond Schatz, M.D.

University of Florida Gainesville, FL hallemj@ peds . ufl . edu

No potential conflict of interest relevant to this letter was re-ported.

1. Ludvigsson J, Wahlberg J, Casas R. Intralymphatic injection

of autoantigen in type 1 diabetes. N Engl J Med 2017; 376: 697-9.

2. Wherrett DK, Bundy B, Becker DJ, et al. Antigen-based

ther-apy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet 2011; 378: 319-27.

3. Bizzarri C, Pitocco D, Napoli N, et al. No protective effect of

calcitriol on beta-cell function in recent-onset type 1 diabetes: the IMDIAB XIII trial. Diabetes Care 2010; 33: 1962-3.

4. Herold KC, Gitelman SE, Masharani U, et al. A single course

of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) re-sults in improvement in C-peptide responses and clinical pa-rameters for at least 2 years after onset of type 1 diabetes. Dia-betes 2005; 54: 1763-9.

DOI: 10.1056/NEJMc1703468

The authors and a colleague reply:

Several

years may be required to conduct well-powered,

randomized, placebo-controlled trials with long

follow-up in patients with type 1 diabetes. Thus,

although conclusive statements based on pilot

studies are inherently tenuous, small pilot trials,

even without controls, can speed up the process

and are needed to test new approaches before the

initiation of full-scale, randomized, controlled

trials.

In this early trial, autoantigen was injected

into each patient’s lymph nodes after ethics

ap-proval and written informed consent were

ob-tained. There are data from only six patients,

and standard errors are now shown in the

cor-rected Figure 1; inherently, such data do not

have strong statistical power. In addition, the

placebo group in our original Figure 1D should

have been labeled as the TrialNet

1

_placebo

group, not the DIAGNODE-1 placebo group.

This error has been corrected.

Our open-label trial had no controls, but

when we compare the results regarding

C-pep-tide levels with data from other trials

2,3

_{and with}

a control group from a GAD-alum trial in which

autoantigen was administered subcutaneously in

patients of a similar age,

1

_{the results appear to}

be promising (Fig. 1D). Additional data in Figure

1E show in vitro type 2 helper T-cell cytokine

secretion that is more pronounced than that

observed after subcutaneous administration of

higher doses of GAD-alum.

4

_Furthermore,

al-though most cytokine levels decreased to very

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T h e

ne w e ngl a nd jou r na l

o f

m e dicine

404

DIAGNODE-1 <6 mo, phase 1 (6 patients 20–24 yr) GAD-alum trial <3 mo, phase 2, 2 doses (5 patients 10–18 yr) GAD-alum trial <18 mo, phase 2, 2 doses (35 patients 10–18 yr) Anti-CD3 trial <6 mo, phase 2 (21 patients 8–30 yr)

GAD-alum TrialNet trial <3.3 mo, placebo group (6 patients 20–24 yr) GAD-alum trial <3 mo, phase 2, placebo group (7 patients 10–18 yr) GAD-alum trial <18 mo, phase 2, placebo group (34 patients 10–18 yr) Anti-CD3 trial <6 mo, phase 2, placebo group (21 patients 8–30 yr)

E

Insulin Dose (IU/kg/24 hr)

0.6 0.4 0.3 0.1 0.5 0.2 0.0

A

C-Peptide Level (% of baseline)

200 80 60 40 20 0 180 160 140 120 100 Day 1 6 15 Months Fasting C-peptide level AUC

Glycated Hemoglobin Level (%)

80 60 40 20 0 100 Day 1 1 2 3 6 15 Months Day 1 1 2 3 6 15 Months P=0.02 P=0.01 P=0.02 P=0.03 P=0.06 P<0.01 P<0.01

B

C

D

C-Peptide AUC (% of baseline)

140 80 100 120 60 40 20 0 0 Day 1 3 6 9 12 15 18 21 24 30 Months

Tumor necrosis factor Interferon-gamma Interleukin-17 Interleukin-5 Interleukin-13 Interleukin-2 Interleukin-10

GAD65 Cytokine Secretion Level

(pg/ml) 2000 60 25 10 95 130 165 200 300 20 0 Day 1 1 2 3 6 15 GAD-alum injection Months GAD-alum

injection GAD-aluminjection

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405

Notices

low levels at 15 months, levels of interleukin-10

and interleukin-2 increased.

Johnny Ludvigsson, M.D., Ph.D.

Beatriz Tavira, Ph.D.

Rosaura Casas, Ph.D.

Linköping University Linköping, Sweden johnny . ludvigsson@ liu . se

Dr. Tavira reports no potential conflict of interest relevant to this letter. Since publication of their letter, the authors report no further potential conflict of interest.

1. Wherrett DK, Bundy B, Becker DJ, et al. Antigen-based

ther-apy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet 2011; 378: 319-27.

2. Herold KC, Gitelman SE, Masharani U, et al. A single course

of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) re-sults in improvement in C-peptide responses and clinical pa-rameters for at least 2 years after onset of type 1 diabetes. Dia-betes 2005; 54: 1763-9.

3. Ludvigsson J, Faresjö M, Hjorth M, et al. GAD treatment and

insulin secretion in recent-onset type 1 diabetes. N Engl J Med 2008; 359: 1909-20.

4. Axelsson S, Chéramy M, Akerman L, Pihl M, Ludvigsson J,

Casas R. Cellular and humoral immune responses in type 1 dia-betic patients participating in a phase III GAD-alum interven-tion trial. Diabetes Care 2013; 36: 3418-24.

DOI: 10.1056/NEJMc1703468

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correction

Intralymphatic Injection of Autoantigen in Type 1 Diabetes (February 16, 2017;376:697-9). In the lower portion of Figure 1D (page 698), “DIAGNODE-1” should have been “TrialNet.” The article is correct at NEJM.org.

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UPDATE IN INTERNAL MEDICINE 2017

The course will be offered in Boston, Dec. 3–9. It is joitly presented by Harvard Medical School and Beth Israel Deacon-ess Medical Center.

Contact the Department of Continuing Education, Harvard Medical School, P.O. Box 825, Boston, MA 02117-0825; or call 617-384-8600; or e-mail ceprograms@hms.harvard.edu; or see http://www.updateinternalmedicine.com.

26TH WORLD CONGRESS OF LYMPHOLOGY

The biennial congress of the International Society of Lym-phology will be held in Barcelona, Sept. 25–29.

Contact the Congress Secretariat, Arantxa Events, Urban Busi-ness Center, Urgell 143, 2°, despacho A, 08036 Barcelona, Spain; or call (34) 935565505; or e-mail info@lymphologycongress2017 .com; or see http://www.lymphologycongress2017.com. Figure 1 (facing page). Changes in Insulin Doses

and C-Peptide, Glycated Hemoglobin, and Cytokine Levels over Time.

Panel A shows fasting C‑peptide levels and the mean area under the curve (AUC) of the serum C‑peptide level in the six patients after a mixed‑meal tolerance test. Panel B shows that the glycated hemoglobin level decreased with time. Panel C shows that the insulin re‑ quirement decreased with time. Panel D shows the nor‑ malized C‑peptide AUC in patients in the DIAGNODE‑1 trial as compared with some similar populations of pa‑ tients in other studies who had received placebo or active immune intervention with subcutaneous GAD‑alum (alum‑formulated glutamic acid decarboxylase [GAD65]) or anti‑CD3 monoclonal antibodies. I bars denote standard errors. Panel E shows the mean levels of GAD‑induced cytokine secretion in supernatants from peripheral‑blood mononuclear cells from baseline to 15 months.