Autoimmune disease after alemtuzumab

treatment for multiple sclerosis in a

multicenter cohort

M. Cossburn, MD, ABSTRACT

MRCP Objective: To define the rate, timing, and clinical risk factors for the development of autoimmune
A.A. Pace, MD disease (AID) after alemtuzumab treatment for multiple sclerosis (MS).
J. Jones, PhD
Methods: We analyzed prospective clinical and serologic data from 248 patients with MS treated
R. Ali, MRCP
with alemtuzumab, with median follow-up of 34.3 months (range 6.7107.3).
G. Ingram, MRCP
K. Baker, MRCP Results: Novel AID developed in 22.2%. Thyroid AID was most frequent (15.7%). A range of
C. Hirst, MD hematologic, renal, and dermatologic AID were also observed as was asymptomatic development
J. Zajicek, PhD of novel autoantibodies. AID was seen from 2 weeks after initial treatment and was most frequent
N. Scolding, PhD 1218 months after first treatment. No new cases of AID were identified 60 months or more
M. Boggild, MD after initial treatment and risk of AID was independent of total alemtuzumab dose or interval of
T. Pickersgill, MRCP dosage. While established risk factors for AID including sex and age had no impact on AID fre-
Y. Ben-Shlomo, PhD quency, both family history (odds ratio 7.31, 95% confidence interval 3.0217.68) of AID and
A. Coles, PhD a personal smoking history (odds ratio 3.05, 95% confidence interval 1.506.19) were predic-
N.P. Robertson, MD tive of AID expression.
Conclusions: Cumulative risk for AID in MS following alemtuzumab is 22.2%, most frequent be-
tween 12 and 18 months following first dose and evident for up to 5 years. Individual risk is
Address correspondence and reprint
requests to Prof. N. Robertson,
modified by smoking and family history, which should be incorporated within the counseling pro-
Department of Psychological cess prior to treatment.
Medicine and Neurology, Cardiff
University, University Hospital of Classification of evidence: This study provides Class IV evidence that the risk of AID after alemtu-
Wales, Heath Park, Cardiff, CF14 zumab treatment for MS is time-limited and modified by external factors. Neurology 2011;77:573579
4XN, UK

GLOSSARY
AID autoimmune disease; ANA antinuclear antibody; ANCA antinuclear cytoplasmic antibody; CBC complete blood
count; dsDNA double-stranded deoxyribonucleic antibody; GBM glomerular basement membrane; ITP immune throm-
bocytopenic purpura; MS multiple sclerosis; PPMS primary progressive MS; RRMS relapsing-remitting MS; SPMS
secondary progressive MS; TFT thyroid function test; TPO thyroid peroxidase antibody.

The humanized anti-CD52 monoclonal antibody alemtuzumab (Campath-1H, Genzyme

Supplemental data at
www.neurology.org
Inc., Cambridge, MA) induces an immune-mediated, rapid, and profound depletion of lym-
phocytes,1 followed by differential recovery of lymphocyte subsets with prolonged suppression
of CD4 T cells,2 making it an attractive treatment for prototypically T-cell driven diseases.3
Phase II evidence suggests alemtuzumab reduces relapse rates in multiple sclerosis (MS) by over
70% compared to interferon -1a, improves MRI parameters, and may also reduce disability.4
However, at least 20% of patients with MS treated with alemtuzumab develop de novo
antibody-mediated autoimmune diseases (AID) during follow-up.4,5 Graves disease is most
commonly reported, but potentially more serious conditions including immune thrombocyto-
penic purpura (ITP) in 3% of cases and anti-GBM disease at much lower frequency may
develop.6 Because of the relatively novel application of alemtuzumab in MS it is currently

Supplemental Data
From the Department of Psychological Medicine and Neurology (M.C., G.I., K.B., C.H., T.P., N.P.R.), Cardiff University, University Hospital of
Wales, Heath Park, Cardiff, UK; Department of Neurology (A.A.P., J.Z.), Penninsula Medical School, Tamar Science Park, Derriford, Plymouth;
Neurology Unit (J.J., A.C.), Department of Clinical Neurosciences, Cambridge University, Addenbrookes Hospital, Cambridge; Department of
Neurology (R.A., M.B.), The Walton Centre NHS Foundation Trust, Fazakerley, Liverpool; Institute of Clinical Neurology (N.S.), University of
Bristol, Frenchay Hospital, Bristol; and Department of Social and Community Medicine University of Bristol (Y.B.-S.), Canynge Hall, Bristol, UK.
Disclosure: Author disclosures are provided at the end of the article.

Copyright 2011 by AAN Enterprises, Inc. 573

 unclear whether AID risk is time-limited,
dose-dependent, or whether specific condi-
tions develop at predictable intervals from
drug exposure.
In this study, we describe the follow-up of
a large cohort of patients with MS treated
with alemtuzumab from the United King-
dom, aiming to define the proportion of pa-
tients developing AID, to define the nature
and extent of AID observed, and to perform
an analysis of time to onset. In order to refine
patient-specific risk, we correlated pretreat-
ment clinical and demographic information,
including established clinical risk factors,7,8 with
rate of AID expression. These data allow an in-
sight into the development of alemtuzumab-
associated AID in MS for neurologists, helping
inform provision of pretreatment counseling,
long-term follow-up, and AID surveillance.
METHODS Patients and data collection. Data were col-
lected prospectively on patients from 5 MS centers in the United
Kingdom (Bristol, Cambridge, Cardiff, Liverpool, and Plym-
outh) according to a standardized protocol. Patients were in-
cluded if they received their first alemtuzumab treatment in any
of the 5 centers between January 1, 2001, and December 31,
2009, and were not participants in CAMMS 223, CAMMS 323,
or CAMMS 324 studies. The sample size reflects the maximal
population identified through this process rather than a precal-
culated limit. Baseline demographic details collected included
gender, age, and type of MS at time of treatment (relapsing-
remitting MS [RRMS], secondary progressive MS [SPMS], pri-
mary progressive MS [PPMS]). The presence of abnormal serum
antibodies prior to treatment was documented. Details of treat-
ment regimens recorded included date and number of treat-
ments, individual treatment dose, and cumulative dose received.
Details on family history of autoimmunity and smoking status
(current/ever/never) were gathered as these are established risk
factors for AID. Environmental iodine exposure is another rec-
ognized risk factor for autoimmune thyroid disease, but informa-
tion on this was not collected because of difficulties in estimating
exposure retrospectively.
Standard protocols and procedures. Ethical review of this
study was undertaken and approval granted by a local ethical
review board. Consent to use of clinical data for research pur-
poses was obtained.
Treatment protocol. Prior to 2006, patients received an initi-
ation dose of 24 30 mg IV per day for 5 consecutive days, with
1 g IV methylprednisolone given as pretreatment on the first 3
days only. After 2006, the daily dose was reduced to 12 mg.
Routine top-up treatment after 12 months, consisting of 3 con-
secutive daily doses of alemtuzumab with concurrent steroid pre-
treatment, was provided unless contraindicated. Predefined
contraindications to repeat treatment included anaphylactic re-
actions, other significant adverse events, or the development of a
severe, life-threatening autoimmune disease in the interim. Ad-
ditional courses of alemtuzumab were given as needed after in-
574 Neurology 77 August 9, 2011
tervals of not less than 12 months, either because of emergent
clinical features suggesting recurrence of disease activity or the
development of new or enhancing lesions on MRI performed 12
months or more after second treatment.
Patients were reviewed at 4 6 weeks posttreatment and then
at 3-month intervals, during which patients were monitored for
signs and symptoms suggestive of renewed disease activity, in-
creasing disability, or emergent AID. Complete blood counts
(CBC) were monitored monthly, thyroid function tests (TFTs)
3-monthly, and an autoantibody panel at 6-month intervals in-
cluding TPO antibodies, TSH receptor antibodies, and ANA.
More detailed autoimmune screening undertaken where indi-
cated included antinuclear cytoplasmic antibodies (ANCA),
double-stranded deoxyribonucleic antibodies (dsDNA), cardioli-
pin antibodies, and antiglomerular basement membrane (GBM)
antibodies.
Outcomes. The primary outcome measure of the study was the
proportion of patients developing new autoimmunity. Develop-
ment of new autoimmunity was defined as either 1) the presence
of a previously undetected autoantibody at unequivocal titers
(varying according to type of antibody and local laboratory
norms), present on at least 2 occasions separated by at least 3
months; or 2) clinically detectable symptoms, signs, or biochem-
ical disturbance consistent with the diagnosis of an autoimmune
condition not present prior to treatment, confirmed by an inde-
pendent specialist unblinded to alemtuzumab treatment.
Details of the timing of onset of autoimmunity with re-
spect to treatment, condition type, and patient outcome were
recorded.
Statistical methods. Statistical analysis was carried out using
SPSS 16.1 (SPSS Inc., Chicago, IL). Baseline demographics were
calculated by numbers of treatments received. Time to develop-
ment of AID was categorized by dividing the follow-up period
into consecutive blocks of 6-months duration and calculating
the rates of new AID in each period as a proportion of those at
risk. Differences in mean time to onset from treatment between
types of AID were analyzed using one-way analysis of variance
with Bonferroni correction. The relationship between age and
risk of AID was assessed using the Mann-Whitney U test, and
the relationship between age and timing of AID assessed using
the ordinary least squares method. Risk factors for autoimmu-
nity were assessed using Fisher exact test. Variables seen to affect
risk of AID were subjected to further analysis with odds ratios
calculated using univariable and multivariable logistic regression
models. In addition, we tested for potential interactions for the
variables age, smoking, family history, and sex by using the like-
lihood ratio test to compare models with and without interac-
tions. A multiple imputation technique was used to enhance
sample size and avoid bias associated with missing data (assumed
to be missing at random). This was implemented using fully
conditional specification models (SPSS 17.0) and by generating
10 datasets to take into account the additional uncertainty
around the imputed parameters.
RESULTS Patient demographics and treatments. A
total of 248 patients met the inclusion criteria, of
which 77 (31.04%) were male. At treatment 215
(86.69%) had RRMS and the remainder SPMS with
the exception of 2 patients (0.81%) who had PPMS
with relapses. Demographic details for the patients
by number of courses received are shown in table 1.
 Table 1 Demographic characteristics of the cohort shown with respect to the number of treatment
courses received
Single course
Sex, M:F 9:25
Prior DMT usage, % 38.2
Age, y, median (range) 35.5 (1948)
EDSS, median (range) 3.0 (0.06.0)
ARR, median (range) 2.1 (1.13.6)
Disease duration, y, median (range) 3.4 (0.36.5)
Abbreviations: ARR annualized relapse rate prior to treatment (calculated for individual patients); DMT disease-
modifying treatment; EDSS Expanded Disability Status Scale at treatment commencement.
Treatment regimens were determined by the
treating center, adjusted over time to reflect current
practice in major clinical trials. Overall patients re-
ceived a median cumulative dose of 96 mg of alemtu-
zumab (range 36 228 mg) over a median of 2
courses (range 1 4) with a median first dose of 60
mg and 36 mg for subsequent courses. Mean dura-
tion of follow-up was 41.18 months (SD 24.51),
with median follow-up being 34.32 months (range
6.67107.30). Two patients were not retreated due
to adverse events (liver enzyme elevations in both
cases). Both patients were included in the overall
analysis, one of whom went on to develop AID.
Autoimmunity. Antibodies were present prior to
treatment in 10 patients (4.03%); the majority of
these were asymptomatic antinuclear antibodies
(ANA). Positive thyroid peroxidase antibodies
(TPO) were detected in 2 patients (0.81%). New
Figure 1 Rates of autoimmune disease (AID) by duration of follow-up
Patients having completed less than 1 full year of follow-up have the lowest rates of AID,
significantly lower than those having completed 3 years (Fisher exact test). There are no
other significant associations between duration of follow-up and AID rate and the trend is
nonsignificant (2 for trend).
Two courses Three or more Total
44:95 24:51 77:171
44.6 42.7 43.1
39 (1765) 38 (2055) 38 (1765)
2.5 (1.07.5) 3.5 (1.55.5) 2.5 (0.07.5)
2.9 (1.64.9) 2.1 (1.33.8) 2.3 (1.14.9)
3.7 (0.87.1) 3.8 (0.97.6) 3.7 (0.37.6)
autoimmunity was seen in 55 patients (22.17%) dur-
ing follow-up, with 16 (20.78%) males and 39
(22.81%) females affected. Rates of AID by duration
of follow-up are shown in figure 1. The majority of
AID were of thyroid origin (n 41, 77.36%) of
which Graves disease was the most frequent clinical
phenotype (n 29; 70.73% of thyroid disease cases;
54.72% of all AID). A transient thyroiditis was also
seen in 5 patients (12.20% of thyroid disease, 9.43%
of AID). In these cases the clinical phenotype was of
an initial thyrotoxic phase followed by either a return
to normal thyroid function (n 2) or development
of hypothyroidism (n 3). Overall, 37 cases of thy-
roid disease required medical treatment (Graves 29/
30, hypothyroidism 5/6, and thyroiditis 3/5), 8 of
the Graves cases requiring radioactive iodine. No pa-
tient in this series has developed significant thyroid
eye disease needing operative intervention.
Six patients (2.42%) developed potentially seri-
ous AID with 5 cases of ITP (2 male, 3 female) and
one of GBM disease (female). Of these, one case of
ITP and the case of GBM disease have been reported
elsewhere.9 Onset of illness was abrupt, preceded by
abnormalities in hematologic or biochemical screen-
ing in only 2 cases. All patients attended promptly
when symptomatic and were investigated appropri-
ately. All cases of ITP required steroid treatment to
which they responded well, without need for addi-
tional adjunctive medical or surgical treatment. The
case of anti-GBM disease (which has previously been
reported9) developed acute renal failure requiring di-
alysis; the patient has subsequently undergone renal
transplantation with no evidence of disease recur-
rence in the transplanted kidney.
Rates of serious AID, thyroid disease, the major
category of AID, and autoimmunity overall did not
differ between sexes. Types and frequencies of AID
are summarized in table 2. In addition, 2 patients
developed pulmonary illnesses at 59 and 72 months
after treatment. These were subsequently confirmed
as cases of hypersensitivity pneumonitis, a condition
Neurology 77 August 9, 2011 575
 months. In total, 50% of AID occurred within the
Table 2 Frequency of clinically manifest
AID post-alemtuzumaba
first 18 months after first treatment and 75% by 3
years. No cases of AID were identified beyond 60
AID type Subtype Frequency months despite longer follow-up in almost 32% of
Thyroid (n 42) Graves 31 patients. Cumulative dose, dosage interval, and dos-
Hypothyroidism 6 age frequency did not influence observed frequency
Thyroiditis 5 of AID. A table detailing rates of AID by treatment
Hematologic (n 6) ITP 5 course is included as table e-1 on the Neurology
Neutropenia 1 Web site at www.neurology.org.
Renal (n 1) GBMD 1 Effect of established risk factors. Age. Median age at
Other clinical (n 4) Vitiligo 2 treatment for those developing AID was 39.0 years
Bullous skin rash 1 and 38.0 for those without ( p 0.642). In addition,
Colitis 1 age did not influence time to AID (r2 0.04, p
0.431).
Abbreviations: AID autoimmune disease; GBMD glo-
merular basement membrane disease (previously report- Sex. AID occurred in 20.78% of male patients and
ed9); ITP immune thrombocytopenic purpura. 22.81% of female patients, respectively (n 55;
a
The results are displayed by functional system group.
M:F 16:39, p 0.868).
Family history. Data were obtainable from 231 pa-
which, while immune mediated, and likely to be part
of the spectrum of disorders emerging as a conse- tients, including all who developed AID posttreat-
quence of treatment, did not meet the definition of ment. In 26 (11.26%), a family history of
autoimmunity used in this study, and we elected not autoimmune disease was identified, and of these 16
to include these patients in the analysis. (61.54%) subsequently developed a treatment-
Mean time to AID was 23.43 months from initial related AID ( p 0.001; odds ratio [OR] 7.31, 95%
treatment (range 0.4354.25, SD 20.91). The short- confidence interval [CI] 3.0217.68).
est time to onset occurred in a female patient with Smoking. Smoking histories were obtained from
documented positive TPO antibody pretreatment, 196 patients, which included 49 of the 55 cases of
who developed hypothyroidism at 0.23 months post- de novo AID. The overall rate of ever smoking in
treatment, her thyroid function having been normal this sample was 38.3% with 19.3% being active
previously. The longest interval to AID was 54.25 smokers at the time of treatment. When compared
months in another female patient developing hypo- with never-smokers, ever-smokers had an in-
thyroidism. Figure 2 summarizes time to AID by creased risk of AID ( p 0.001; OR 3.05, 95% CI
subtype; there was no difference in time to autoim- 1.50 6.19).
munity between AID subtypes ( p 0.513). Distri- Effects of risk factor interactions. The logistic regres-
bution of AID by time to onset from treatment is sion model confirmed the significance of the effects
summarized in figure 3. This risk has an apparent of both family history (adjusted OR 9.42, 95% CI
bimodal distribution and is skewed toward early 3.59 24.71) and smoking (adjusted OR 3.91, 95%
follow-up with peaks at 1218 months and 30 36 CI 1.76 8.67) on AID risk. Furthermore, it revealed

Figure 2 Timing of autoimmune disease (AID) by disease subtype

Type of AID is represented on the x-axis. Each point on the scatterplot represents a single case; horizontal lines represent
the group median time to AID.

576 Neurology 77 August 9, 2011

 Figure 3 Rates of autoimmune disease (AID) with time
Each bar represents a 6-month block from initial treatment. Pale bars represent the proportion of total cohort remaining at
risk at the beginning of each time block. Dark bars represent the rate of new cases of AID occurring within the time block
with respect to the numbers at risk. The solid line represents the cumulative frequency of AID cases at a given timepoint.
no significant additional predictive value of the inter-
action between variables.
DISCUSSION In this, the largest reported study of
autoimmunity after alemtuzumab for MS to date,
treatment was associated with excess development of
posttreatment autoimmunity. The rates seen are sim-
ilar to those reported previously in smaller co-
horts.4,6,9,10 The most common AID observed was
thyroid disease although potentially more serious
AID were also apparent. Time periods associated
with increased risk were identified, with 50% of AID
emerging within 24 months of initial treatment
and the peak rate of AID seen between 12 and 18
months after first treatment and no AID develop-
ing after 60 months. Risk was not influenced by
cumulative dose or dosage interval. The propor-
tion of patients developing AID in this series is
similar to that reported in the CAMMS223 study
in which 23% of patients developed autoimmune
thyroid disease over a 36-month period with 3%
developing ITP4 despite the extended follow-up of
this patient series, suggesting that the risk of AID
after alemtuzumab may be time-limited.
Five patients (2%) developed ITP. All were strict
participants in CBC surveillance but 3 became symp-
tomatic within the intertest intervals. In the
CAMMS223 study, there was one fatality as a conse-
quence of ITP. A further death has been reported
related to a possible autoimmune hemolytic anemia
complicating alemtuzumab treatment for chronic
immune demyelinating polyneuropathy.11 In this
study, no fatalities were reported, possibly because all
cases of more serious AID were identified rapidly af-
ter symptom onset, reflecting increased awareness of
the need for vigilant patient and clinician monitoring
of symptomatic, clinical, and hematologic indices
predicting potentially serious AID.
The relationship between MS and AID has im-
portant potential implications when considering
mechanisms of autoimmunity and for care of pa-
tients receiving this treatment. Time periods of in-
creased risk appear to cluster between 12 and 18 and
30 36 months posttreatment, suggesting a differen-
tial effect relating to these time periods. Recognition
of periods of increased risk will benefit patients by
permitting enhanced vigilance and may help direct
research into the mechanisms of AID development
post-alemtuzumab. Furthermore, the distribution of
AID following initial treatment implies that risk for
AID is unrelated to total dose of alemtuzumab re-
ceived or the interval of dosage.
The limitation of AID expression to 22% of this
cohort despite all being exposed to the same agent
suggests that additional factors are likely to influence
predisposition to autoimmunity. One such factor
may be IL-21, a cytokine of the human gamma chain
family that has been shown to drive autoimmunity
in the nonobese diabetic mouse model via in-
creased T-cell cycling and reduced survival.12 In a
study of 94 unselected patients with MS, autoim-
Neurology 77 August 9, 2011 577
 munity following treatment with alemtuzumab
was related to genetically determined elevations in
serum concentration of IL-21, which could be de-
tected prior to treatment.13
An excess of autoimmune thyroid disease noted in
patients with MS and their first-degree relatives sug-
gests the presence of an etiologic link between these 2
diseases.14 This risk is higher in multiplex rather than
simplex families, implying that elements of this ex-
cess risk of AID in patients with MS and their rela-
tives are likely to be under genetic control and also
exhibits a genetic loading effect.15 The association of
family history with AID in this study supports this
hypothesis; nevertheless, the rates of thyroid disease
observed in this study are far greater than those prev-
alent in the general MS population. Evidence for a
link between MS and other AID is scarce; however,
an association between ITP and MS has also been
suggested, with a coexisting diagnosis of MS being
25 times more frequent than expected in American
adult patients with ITP,16 an observation that has
also been replicated in European populations.1719
This study identified smoking as a potential risk
factor for the development of autoimmunity post-
alemtuzumab with 42.7% of smokers developing
AID compared with 17.2% of nonsmokers, with OR
of AID in smokers of 3.05. Smoking has previously
been identified as a risk factor for the development
of thyroid disease,8 though the magnitude of effect
in studies of wild-type autoimmune thyroid dis-
ease is much less than that seen in this study.
Smoking has been shown to have wide-ranging
immunologic effects, altering B-cell20 and T-cell21,22
function, upregulating complement components,23
and modifying gene expression.24,25 Intriguingly, a
number of studies suggest that smoking may be an
independent risk factor for the development of MS.26
Any, or all, of these effects might be important in the
development of autoimmunity in the context of
alemtuzumab-treated MS. Further investigation is
warranted to study the mechanisms by which smok-
ing might influence the development of AID and
into whether a relationship exists between smoking
and previously identified immunologic risk factors
for AID post-alemtuzumab such as elevated IL-21
concentrations.
Conversely, gender and age (known risk factors
for autoimmune thyroid disease in population stud-
ies7) are not associated with AID in this cohort. This
suggests that the mechanisms by which AID arises
post-alemtuzumab may differ significantly from
wild-type disease. Evidence from studies of untreated
patients with MS provide some support for this,
since rates of autoimmune thyroid disease in males
578 Neurology 77 August 9, 2011
are much higher than expected from control popula-
tions whereas rates in females are similar.19
While this study is limited by its variable
follow-up we have demonstrated that the risk of de-
veloping AID is present from shortly after treatment
until up to 5 years after the first dose is received.
Within this time there are windows where the risks
are greater but clinicians should remain vigilant
throughout follow-up and act quickly to identify po-
tential AID. Treatment with alemtuzumab should
take place within a standardized framework to ensure
appropriate management and longitudinal follow-up
with regular and robust monitoring of hematologic,
immunologic, biochemical, and clinical indices re-
quired to ensure early detection of potentially serious
AID. While the risk of autoimmunity appears to pla-
teau with time, the identification of cases of hyper-
sensitivity to external antigen occurring late after
treatment suggests that the effects of alemtuzumab
on the immune system are long-lasting and that vigi-
lance for immune-mediated adverse effects of treat-
ment need to be enduring.
AUTHOR CONTRIBUTIONS
Dr. Cossburn co-conceived the study, collected data, wrote and reviewed
drafts of the manuscript, and contributed to statistical analysis. Dr. Pace col-
lected data, wrote and reviewed drafts of the manuscript. Dr. Jones collected
data, wrote and reviewed drafts of the manuscript. Dr. Ali collected data,
wrote and reviewed drafts of the manuscript. Dr. Ingram collected
data, wrote and reviewed drafts of the manuscript. Dr. Baker collected
data, wrote and reviewed drafts of the manuscript. Dr. Hirst collec-
ted data, wrote and reviewed drafts of the manuscript. Dr. Zajicek wrote
and reviewed drafts of the manuscript. Dr. Scolding wrote and reviewed
drafts of the manuscript. Dr. Boggild wrote and reviewed drafts of the
manuscript. Dr. Pickersgill wrote and reviewed drafts of the manuscript.
Dr. Ben-Shlomo wrote and reviewed drafts of the manuscript and assisted
in the statistical analysis. Dr. Coles wrote and reviewed drafts of the man-
uscript. Dr. Robertson co-conceived the study, collected data, wrote and
reviewed drafts of the manuscript.
DISCLOSURE
Dr. Cossburn and Dr. Pace report no disclosures. Dr. Jones has received
speaker honoraria from Genzyme Corporation and receives research sup-
port from the MS Society of the United Kingdom and the Academy of
Medical Sciences (UK). Dr. Ali, Dr. Ingram, Dr. Baker, and Dr. Hirst
report no disclosures. Dr. Zajicek serves on a scientific advisory board for
and has received funding for travel from Bayer Schering Pharma. Dr.
Scolding serves on the editorial boards of journals relating to neurosci-
ences and has received research support from Teva Pharmaceutical Indus-
tries Ltd., Merck Serono, Biogen Idec, Bayer Schering Pharma, the
Burden Trust, the Myelin Project, and the Silverman Foundation. Dr.
Boggild serves on scientific advisory boards for Teva Pharmaceuticals In-
dustries Ltd., Novartis, and Biogen Idec and has received funding for
travel from Merck Serono and Teva Pharmaceuticals Industries Ltd. Dr.
Pickersgill has served on scientific advisory boards for Teva Pharmaceuti-
cal Industries Ltd. and Biogen Idec; has received funding for travel from
Merck Serono and Biogen Idec; and owns stock in Genzyme Corporation.
Dr. Ben-Shlomo has received publishing royalties from books; is a mem-
ber of the Department of Health Scientific Advisory Group for the multi-
ple sclerosis risk sharing scheme; and receives research support from
Cancer Research UK, the Tourettes Syndrome Association USA, the Brit-
ish Heart Foundation, the Medical Research Council, the Wellcome
Trust, Economic and Social Research Council, and Bristol Research into
Alzheimers Care of the Elderly. Dr. Coles serves on scientific advisory
boards for Multiple Sclerosis Society of GB & NI, the International Soci-
ety for Neuroimmunology, and Genzyme Corporation; has received
funding for travel from Merck Serono and Genzyme Corporation; serves
as the Co-Editor of Advances in Clinical Neuroscience and Rehabilitation;
holds a patent for the use of IL-21 as a biomarker for autoimmunity after
alemtuzumab; serves as a consultant for Genzyme Corporation and Merck
Serono; and his department has received research support from Genzyme
Corporation. Dr. Robertsons department has received research support
from Genzyme Corporation.
Received June 4, 2010. Accepted in final form April 6, 2011.
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