Download Supplementary Table 1 | Potential issues regarding prevention of

Supplementary Table 1 | Potential issues regarding prevention of ARDs
Issue
Discussion
Understanding of the natural history of
These issues could be evaluated through natural history studies of
ARDs must be sufficient to enable
preclinical ARDs that target high-risk populations, such as relatives
accurate prediction of future disease in
of patients with established disease or cohorts of high-risk
each individual (that is, personalized
individuals identified through broad population screening for genetic
medicine), and to identify therapeutic
factors or expression of biomarkers that are enriched in prevalent
targets for prevention of disease
and incident autoimmunity and clinically apparent diseaseS1,S2,S3
development
What should be included in prediction
In terms of clinical trial design, prediction models would probably
models for disease?
need to identify individuals who are likely to develop clinically
apparent disease in a relatively short period of time (or ‘imminent’
disease) to enable completion of studies within a defined time
period
What are appropriate public-health
Individuals who are at-risk of future ARDs could be identified
efforts to identify individuals at-risk of
through broad public-health efforts used in diseases such as cancer
ARDs in whom disease prevention would or heart disease, or by targeting high-risk populations, such as
be reasonable approach?
family members of patients with disease, individuals from
populations with increased risk of disease (for example, American
Indians), or individuals identified through screening mechanisms
who have high-risk genetic (for example, shared epitope) and/or
environmental exposures (for example, smokers or those with
certain infections)
The cost-effectiveness of preventing ARDs needs to be evaluated,
including analyses of the costs of identifying at-risk individuals, the
possibility of treating individuals who have markers of potentially
increased risk of ARDs, but never develop clinically apparent
disease, and the potential future benefits and adverse effects of
treatment
How high should the likelihood of future
Lifestyle intervention (for example, smoking cessation) might be an
ARD be before initiating preventive
acceptable approach in many individuals with even a relatively low
therapy?
risk of future ARD; however, high-risk pharmacologic therapy will
probably require a higher likelihood of disease development to be
justified
What will individuals who are at-risk of a Answering this question will require determination of what level of
future ARD be willing to undergo for
risk an individual would need to be presented with before they
prevention?
agree to undergo therapy
Published work suggests that relatives of patients with RA would be
willing to participate in a pharmacologic prevention trial if their risk
for RA was >30% within 5 yearsS4
Is intervention worthwhile in individuals
Autoimmunity might not be benign, even if classic manifestations of
with autoimmunity, even if they have
tissue injury, such as synovitis in RA, are not present; for example,
low risk of progression to a clinically
emerging data suggesting that autoantibodies might be associated
apparent ARD?
with an increased CVD riskS5
At what point in preclinical autoimmunity Attempts to halt autoimmunity might be more successful if
is it most reasonable to intervene?
intervention occurs very early in the disease process, before a
possible transition from ‘benign’ to ‘pathogenic’ autoimmunity;
however, the clinical benefit of early intervention could take years
to identify
Intervention in late preclinical disease might already be too late to
effectively halt/abrogate autoimmunity
What pharmacological agent or other
Deciding which pharmacological agent is appropriate requires an
intervention that will adequately
understanding of relevant biologic pathways for disease prevention,
abrogate disease in its preclinical phase
and balancing of the probably risks and benefits of the preventive
is appropriate to use in individuals
intervention/agent in each individual
without clinical disease?
What do we hope to achieve with
Whether resetting of the immune system and drug-free remission is
preventive interventions and are
possible in patients with ARD remains unknown
adequate measures in place to measure
The acceptability of early initiation of immunomodulation to prevent
such responses to a preventive
tissue damage, even if the immunomodulatory agent must be used
intervention?
indefinitely to maintain control of autoimmunity and prevention of
clinical manifestations of disease, must also be determined
Established measures of disease activity have not been well tested
Other considerations
in preclinical disease, thus, relevant outcomes measures must be
developed if preventive interventions are implemented in individuals
with minimal or absent symptoms; we must determine whether
changes in biomarkers alone can be used as outcomes, or whether
clinically defined end points be the gold standard for prevention
studies
Given effective treatments are available for most ARDs, withholding
treatment until clear disease is present might be more ethical than
risking over-treating an individual with autoimmunity who might
never develop clinically meaningful disease; however, this
standpoint must be justified based on the results of future studies
Strategies to identify individuals at high-risk of future disease might
also lead to more rigorous clinical follow-up and early treatment
that is beneficial, even if prevention strategies do not exist;
however, an important consideration is whether screening
programmes that identify individuals who are potentially susceptibly
to ARDs will affect their ability to purchase health insurance
coverage
Supplementary references:
S1. El-Gabalawy, H. S. et al. Familial clustering of the serum cytokine profile in the relatives of rheumatoid arthritis
patients. Arthritis Rheum. 64, 1720–1729 (2012).
S2. Bos, W. H. et al. Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated
protein antibody status: a prospective cohort study. Ann. Rheum. Dis. 69, 490–494 (2010).
S3. Kolfenbach, J. R. et al. A prospective approach to investigating the natural history of preclinical rheumatoid
arthritis (RA) using first-degree relatives of probands with RA. Arthritis Rheum. 61, 1735–1742 (2009).
S4. Novotny, F., Haeny, S., Hudelson, P., Escher, M. & Finckh, A. Primary prevention of rheumatoid arthritis: a
qualitative study in a high-risk population. Joint Bone Spine 80, 673–674 (2013).
S5. Agmon-Levin, N. & Selmi, C. The autoimmune side of heart and lung diseases. Clin. Rev. Allergy Immunol. 44,
1–5 (2013).