Antimalarials in Autoimmunity. JCS

Antimalarials in autoimmunity:
insight into new mechanisms of
action
Juan Camilo Sarmiento-Monroy, MD., Esp.
Research Assistant
Center for Autoimmune Diseases Research
Universidad del Rosario
26.October.2012

BackgroundBackground
• Quinine was first recognized as a potent antimalarial (AM)
agent hundreds of years ago.
• Benefical effects of AMs have been increasingly recognized
in other diseases in addition to malaria.
• AMs were shown to have several immunomodulatory
effects.
• Currently, they have an established role in the
management of many ADs such as SLE and RA.
• Additional metabolic, CV, antithrombotic, and
antineoplastic effects.
Ben-Zvi I. Clinic Rev Allerg Immunol (2012) 42:145-153.
Katz SJ and Russell AS. Curr Opin Rheumatol (2011) 23:278-281.

AMs-CREAAMs-CREA
• SS Cohort (n = 412)
• 85/172 (49.4%)
• SLE Cohort (n = 302)
• 152/302 (50.3%)
• 57/152 LN (37.5%)
• RA Cohort (n = 1,128)
• 762/1040 (73.3%)

ContentContent
1. AMs: From Malaria to Autoimmunity
2. Traditional mechanism of action
I. Antimicrobial
3. New mechanisms of action
I. Immunomodulatory
II. Metabolic/Cardiovascular
III. Antithrombotic
IV. Others
4. Autoimmune Diseases
5. Polyautoimmunity
6. Take-home messages

From Malaria to AutoimmunityFrom Malaria to Autoimmunity
1630
Incan
descendents in
Peru; Countess of
Chinchon with a
mysterious bark
powder
1934
Synthesized
by Germans
1955
Synthetic form
of HCQ
1959
Hobbs,
retinopathy
1943
The alkaloids from the
bark were extracted;
Extensive cooperative
program of AMs
research in USA.
1894
Payne, quinine
effective in
cutaneous lupus
During the WWII millions of
soldiers took AM prophylaxis;
improved the soldier’s rashes
and inflammatory arthritis
SLE, RA
Others

AntimalarialsAntimalarials
Images available on line: http://www.google.com/imgres?hl=es&biw=1024&bih=677&tbm
Synthetic forms
CQ
HCQ: Decreasing its toxicity while
conserving its efficacy.
F/k
 Orally administered.
 Long half-life of 40 days.
 Slow onset of clinical action.
 Crosses the placenta.

AMs: Adverse EffectsAMs: Adverse Effects
Ocular
Retinopathy, blurred
vision, corneal
changes/deposits
CV
Cardiomyopathy
Neuromuscular and
skeletal
Myopathy, palsy, or
neuromyopathy
Cutaneous
Alopecia, angioedema,
bleaching of hair, changes in
pigmentation (black-blue
discoloration)
CNS
Ataxia, dizziness, emotional changes,
headache, irritability, lassitude,
nervousness, nightmares, psychosis,
seizure, vertigo
Respiratory
Bronchospasm,
respiratory failure
GI
Abdominal cramping,
anorexia, nausea,
vomiting, diarrhea,
abnormal liver function
Hematological
Agranulocytosis, aplastic anemia,
hemolysis, leukopenia,
thrombocytopenia

Antimicrobial EffectsAntimicrobial Effects

Antimicrobial EffectsAntimicrobial Effects
• HCQ was found to be effective
against bacterial and viral
infections.
• Alkalinization of intracellular acidic
organelles infected by bacteria.
• Chronic Q-fever endocarditis;
others.
• Inhibition of entry steps and
glycosylation of viral proteins.
• HIV; hCoV.
Dorner T. Nature (2010) 6;10-11.

AMs: Old drugs, new perspectivesAMs: Old drugs, new perspectives
HCQ has numerous known
immunomodulatory effects,
but its specific mechanism in
individual diseases is not
clear.
AM medications continue to
be widely used in the
treatment of rheumatic
diseases.

HCQ
Inhibition of T and B-cells receptors Ca Signaling
↓ Auto-Ab production
TLRs Signaling
↓ NK activity
Binding and
Stabilization DNA
↓ Mo Cytokine Production
х Phospholipase A2
х MMP
Antigen presentation
Impairment of
phago/lysosomal function
Absorption and blocking of UV
light cutaneous reactions

Sifuentes-Giraldo, et al. Reumatol Clin. 2012, in press.
AMs and TLRsAMs and TLRs
Intracellular TLRs recognize
self nucleic acid components,
including immune complexes.
This mechanism of action could
be responsible for a number of
effects of AMs agents.

AMs in AutoimmunityAMs in Autoimmunity

Pleiotropic mechanisms of actionPleiotropic mechanisms of action

Metabolic EffectsMetabolic Effects
“anti-diabetic”
• ↓ Fasting blood glucose.
• ↓ HbA1c.
• ↓ Insulin resistance.
• ↓ CV risk by improving
glycemic control in RA and SLE
patients.
• ↓ Risk of developing T2DM in
RA patients.
Blazar BR et al. Diabetes (1984) 33(12):1133–1137.
Shojania K et al. J Rheumatol (1999) 26(1):195–196.
Bili A et al. J Clin Rheumatol (2011);17: 115-120.

• Cross-sectional study.
• Objective– To determine the relationship between current HCQ use and glycemic
control, in nondiabetic women with SLE or RA.
• 326 Nondiabetic women, SLE (n = 149) and RA (n = 177), recruited between 2000 and
2005 for a cross-sectional evaluation of CV risk factors were characterized by HCQ
usage status.
• Unadjusted and multivariately adjusted mean fasting glucose, median insulin, and
insulin resistance were compared among HCQ users and nonusers for disease-specific
groups.
• More women with SLE were taking HCQ than those with RA (48% vs 18%; p < 0.0001).
Penn S et al. J Rheumatol 2010;37(6):1136-1142.
Hydroxychloroquine and Glycemia in Women with
Rheumatoid Arthritis and Systemic Lupus Erythematosus
Sara Kaprove Penn, Amy H. Kao, Laura L. Schott, Jennifer R. Elliott, Frederico G.S. Toledo, Lewis Kuller,
Susasn Manzi, and Mary Chester M. Wasko

• For women with SLE/RA, after adjustment for age, waist circumference, disease
duration, PDN dosage, CRP, menopausal status, NSAIDs, and disease-specific
indicators, serum glucose was lower in HCQ users than in nonusers (SLE: 85.9 VS 89.3
mg/dl, p = 0.04; RA: 82.5 vs 86.6 mg/dl, p = 0.05).
Conclusions
• HCQ use was associated with lower fasting glucose in women with SLE or RA.
• The use of HCQ may be beneficial for reducing CV risk by improving glycemic control in
these patients.
Penn S et al. J Rheumatol 2010;37(6):1136-1142.
Hydroxychloroquine and Glycemia in Women with
Rheumatoid Arthritis and Systemic Lupus Erythematosus
Sara Kaprove Penn, Amy H. Kao, Laura L. Schott, Jennifer R. Elliott, Frederico G.S. Toledo, Lewis Kuller,
Susasn Manzi, and Mary Chester M. Wasko

• Objective– To examine medical records of patients with DM and concomitant
rheumatic illness to measure changes in HbA1c after starting HCQ or MTX.
• Electronic medical records to identify patients initiating either HCQ or MTX, with a
diagnosis of DM or HbA1c ≥7%
• SLE and RA patients; 45 HCQ and 37 MTX users (n = 82).
Rekedal LR et al. Arthritis Rheuma. 2010. December ; 62(12): 3569-3573.
Changes in Glycated Hemoglobin after Initiation of
Hydroxychloroquine or Methotrexate in Diabetic Patients
with Rheumatologic Diseases
Laura R. Rekedal, BA, Elena Massarotti, MD, Rajesh Garg, MD, Radhika Bhatia, MD, MPH, Timothy
Gleeson, BS, Bing Lu, PhD, and Daniel H. Solomon, MD, MPH
RAHbA1c HbA1c’ HbA1c’’
T2DM
12m12w
HCQ/MTX

∆∆HbA1cHbA1c
• Adjusted linear regression models determined changes in HbA1c from pre-drug values
to the lowest post-drug values within twelve months.
• In fully adjusted analyses, the reduction in HbA1c among HCQ users was 0.54%
greater than the drop among MTX users (p = 0.041).
HCQ MTX
P value*
(n = 45) (n = 37)
Mean ± SD
Pre-drug HbA1c 7.71±1.46 7.38±1.66 0.35
Most proximal post-drug HbA1c 7.28±1.63 7.47±1.40 0.58
Lowest post-drug HbA1c within 12 mo. 7.05±1.54 7.27±1.34 0.49
ΔHbA1c (Pre-drug minus lowest post-drug) 0.66±1.31 0.11±0.87 0.04
* P-values from general linear regression adjusted for rheumatologic diagnosis, cumulative steroid use, duration (months) between drug initiation
and lowest HbA1c, a change in DM medication, body mass index, age, and gender.

Conclusions
• HCQ initiation was associated with a significantly greater reduction in HbA1c as
compared to MTX initiation among diabetic patients with RA/SLE.
• This study highlight HCQ’s potential ability to decrease HbA1c in diabetic persons with
systemic inflammatory disease.
Changes in Glycated Hemoglobin after Initiation of
Hydroxychloroquine or Methotrexate in Diabetic Patients
with Rheumatologic Diseases
Laura R. Rekedal, BA, Elena Massarotti, MD, Rajesh Garg, MD, Radhika Bhatia, MD, MPH, Timothy
Gleeson, BS, Bing Lu, PhD, and Daniel H. Solomon, MD, MPH

• Retrospective cohort.
• Objective– To replicate the protective relationship between HCQ use and decrease
risk of T2DM in RA patients.
• 1,127 adults with newly diagnosed RA and no diabetes within the Geisinger Health
System between January 1, 2003, and March 31, 2008.
• The median follow-up times for the ever and never HCQ users were 26 and 23
months.
• The median duration of HCQ exposure was 14 months.
Bili A et al. J Clin Rheumatol. 2011;17: 115-120.
Hydroxychloroquine Use and Decreased Risk of
Diabetes in Rheumatoid Arthritis Patients
Androniki Bili, MD, MPH, Jennifer A. Sartorius, MS, H. Lester Kirchner, PhD, Stephanie J. Morris, DO,
Lindsay J. Ledwich, DO, Jana L. Antohe, MD, Sorina Dancea, MD, Eric D. Newman, MD, and Mary Chester
M. Wasko, MD, MSc
RA Cohort T2DM
HCQ Ever users (n = 333)
HCQ Never users (n = 794)
ADA 2010

Of the 48 (4.3%) cases developing diabetes during observation, 3 were exposed to HCQ at
time of development and 45 were nonexposed, yielding incidence rates of 6.2 and 22.0
per 1000 per year (p = 0.03), respectively.
Incident Rates of Type 2 Diabetes by Hydroxychloroquine Use Among
Rheumatoid Arthritis Patients
Hydroxychloroquine Use
Pa
Ever (n = 333) Never (n = 794)
n 484 2041
No. incident cases of type 2 diabetes 3 45
Observation time, median (25th
75th
percentile), mo 26.0 (13.3-43.2) 23.0 (8.5-47.4) 0.28
Drug exposure time, median (25th
75th
percentile), mo 14.0 (5.4-25.2) NA
Time until type 2 diabetes diagnosis, median (25th
75th
percentile),b
mo
20.0 (14.0-36.3) 16.9 (4.6-24.1) 0.36
IR, x1000 6.2 22.0 0.03
IR, 95% CI 2.0-19.2 16.5-29.5
a
For median time comparisons calculated using Kruskal-Wallis test; for incidence diabetes rate calculated using Poisson regression model, relative risk = 0.28 (95% CI, 0.09-0.91; P = 0.03) for
hydroxychloroquine ever users compared with never users.
bOnly among those who developed diabetes.
IR, incidence rate; NA, not applicable.

Hydroxychloroquine Use
Unadjusted
Adjusted for Sex,
Age, and Race
Additionally Adjusted for BMI, RF, Anti-
CCP Ab, NSAIDs, GC, MTX, TNF-α Inhibitors
Additionally
Adjusted
for ESR
HR (95% CI) 0.28 (0.09-0.91) 0.31 (0.10-1.00) 0.27 (0.08-0.90) 0.29 (0.09-0.95)
P 0.034 0.049 0.033 0.041
BMI was calculated as weight in kilograms divided by height in meters squared.
RF, rheumatoid factor; anti-CCP Ab, anti-cyclic citrullinated peptide antibodies; NSAIDs, nonsteroidal anti-inflammatory drugs; ESR, erythrocyte
sedimentation rate (Westergren); HR, hazard ratio.
• Cox proportional hazard regression models for current HCQ use.
• Each model controlled for variables in the prior model.
• The unadjusted model yielded a HR of 0.28 (95% CI, 0.09-0.91; P = 0.03) for comparing
current to noncurrent HCQ use.
Risk of Developing Type 2 Diabetes in Rheumatoid
Arthritis Patients

Risk of Developing T2DM in RARisk of Developing T2DM in RA
• Time until diagnosis of diabetes
was modeled using the Cox
proportional hazards regression
model.
• Cumulative incidence of diabetes
for the RA patients by HCQ ever or
never use.

Conclusions
• Potential benefit of HCQ in attenuating the risk of diabetes in rheumatoid arthritis
patients.
• Further work is needed to determine its potential preventive role in other groups at
high risk for diabetes.
Hydroxychloroquine Use and Decreased Risk of
Diabetes in Rheumatoid Arthritis Patients
Androniki Bili, MD, MPH, Jennifer A. Sartorius, MS, H. Lester Kirchner, PhD, Stephanie J. Morris, DO,
Lindsay J. Ledwich, DO, Jana L. Antohe, MD, Sorina Dancea, MD, Eric D. Newman, MD, and Mary Chester
M. Wasko, MD, MSc

Metabolic EffectsMetabolic Effects
• ↑ C-peptide response,
improved β cell functioning.
• ↓ intracellular insulin
degradation.
• The mechanism(s) of action of
HCQ in regulating glycemia
are not well understood.
• Novel mechanism or
established antiinflammatory
effect?
• CD8 T cells, TLR-9?

CV EffectsCV Effects
• HCQ have a favorable effect on lipid
profile in patients with ADs.
• Wallace et al. Showed that in RA
and SLE patients, treatment with
HCQ lowered the levels of TC, TGL,
and LDL, irrespective of
concomitant GC administration,
diet, or weight.
• Improves endothelial function.
• Cholesterol synthesis, LDL receptor,
HMG CoA reductase, TLR-9?
Wallace DJ et al. Am J Med (1990);89(3):322–326.

• Objective– To determine if HCQ use was associated with an improvement in lipid
levels in an inceptin RA cohort (Geisinger Health System Information Technology
Department); Electronic health records.
• Only patients with a least one lipid level post-RA diagnosis were included.
• Patients were 69% women and 98% white, with a median age of 65 years and a
median BMI of 29.8 kg/m2
.
Hydroxychloroquine Use Associated With
Improvement in Lipid Profiles in
Stephanie J. Morris, Mary Chester M. Wasko, Jana L. Antohe, Jennifer A. Sartorius, H. Lester Kirchner,
Sorina Dancea, and Androniki Bili
Morris SJ et al. Arthritis Care & Research. 2011;63(4);530-534
RA Diagnosis
?
RA Cohort
(n = 1,539)
Lipid Profile
(n = 706)
HCQ

• Potential risk and protective factors for dyslipidemia were controlled for in linear
mixed-effects regression models for LDL, HDL, TC, TGL, LDL/HDL, and TC/HDL.
• Adjustment for demographic features, BMI, ESR, CRP level, RF, anti–CCP, DM,
hypertension, and use of GC, NSAIDs, anti–TNF α therapy, MTX, and lipid lowering
medications.

HCQ and Lipid ProfileHCQ and Lipid Profile
In the adjusted regression models, HCQ
use was associated with the following
average differences in lipids:
• LDL decrease of 7.55 mg/dl (p < 0.001)
• HDL increase of 1.02 mg/dl (p = 0.20)
• TC decrease of 7.70 mg/dl (p = 0.002)
• TGL decrease of 10.91 mg/dl (p = 0.06)

HCQ and Lipid ProfileHCQ and Lipid Profile
In the adjusted regression models, HCQ
use was associated with the following
average differences in lipids:
• LDL/HDL decrease of 0.136 (p = 0.008)
• TC/HDL decrease of 0.191 (p = 0.006),
which were stable over time

Conclusions
• This findings support the potential benefit of HCQ in attenuating the risk of diabetes in
rheumatoid arthritis patients.
• Further work is needed to determine its potential preventive role in other groups at
high risk for diabetes.
• Considering these results, its safety profile, and low cost, HCQ remains a valuable
initial or adjunct therapy in patients at high risk for CVD.

CV EffectsCV Effects
AMs
• Should be consider in
rheumatic patients with
significant CV risk factors.
• Could have a role in
ameliorating the adverse
effects of corticosteroid
therapy on lipid profile.

Antithrombotic EffectsAntithrombotic Effects
• HCQ inhibits platelet
aggregation and release of AA
from stimulated platelets.
• SLE_APS: protective against
thrombosis, reduce risk of
plaque formation.

Antithrombotic EffectsAntithrombotic Effects
HCQ: antithrombotic
mechanism in APS is not
completely understood.
Espinola et al. Showed that
HCQ inhibits platelet
activation by aPL antibodies.

Antineoplastic EffectsAntineoplastic Effects
Although preliminary studies
look promising, the potential
role for AMs in the treatment
of malignancies remains to be
established.
• Burkitt lymphoma (p53)
• CLL
(caspase-3, Bcl-2/bax ratio)
• Brest cancer
(MCF-7, Bcap-37)
• Other solid tumors (e.g. colon,
lung, and GM).
• CQ sensitizes cancer cells to
radiation and chemotherapy

Additional EffectsAdditional Effects
• GVHD in mice.
• Kikuchi-Fujimoto disease.
• Sarcoidosis.
• Subglottic stenosis.
• Sensory neuropathy syndrome.
• Hemoglobinopathies.
• Cardiac neonatal lupus.

New mechanisms of actionNew mechanisms of action

Antimalarials inAntimalarials in
Autoimmune DiseasesAutoimmune Diseases

Systemic LupusSystemic Lupus
ErythematosusErythematosus
Antimalarials
in
Autoimmune Diseases

LES-like
Outcomes
Full-blown SLE
phenotype
ACR Classification
Criteria
Clinical heterogeneity
• A retrospective nested cohort study
of 130 patients with SLE analysed
the effect of AMs in delaying the
completion of ACR classification
criteria in patients with lupus-like
disease.
• 102 Patients taking HCQ delayed the
time until diagnosis of full-blown
SLE (1.08 vs 0.29 years, p = 0.018),
being less likely to present with
proteinuria (p < 0.05), leucopenia (p
< 0.05) or lymphopenia (p < 0.001).
James J et al. Lupus 2007;16:401–9.

Tratamiento convencional
GC, ASA, AINEs, IECA, ARA II
Antimaláricos (CQ, HCQ)
Inmunomoduladores
(AZA, MMF, CFM, MTX, CysA)
Terapia Biológica
(RTX, Belimumab, IGIV)
Perspectivas
Alteraciones inmunológicas=
producción de autoanticuerpos
Factores
endógenos:
Perfil hormonal
favorable.
Factores genéticos:
Alelos de
susceptibilidad
Factores
ambientales:
Sustancias químicas,
silicona, infecciones,
vacunas, LUV, ACO.
Compromiso sistémico
Endofenotipos
Heterogeneidad clínica

AMs in SLEAMs in SLE
• Skin (malar rash, subacute lesions, discoid lupus).
• Joint involvement.
• Constitutional symptoms.
• Steroid sparing.
• Beneficial both therapeutically and preventatively.
• Maintain remission and reduce the risk for organ-
threatening flares.
• They should not be stopped, as their removal could
precipitate a flare of the disease.
• Offer protection from major infections.
Dorner T. Nature (2010) 6;10-11.

• SLR of the English literature between 1982 and 2007;
MEDLINE and EMBASE databases.
• RCTs and observational studies were selected.
• Case reports were excluded except for toxicity reports.
• The GRADE system was used to analyse the quality of
the evidence.
• A total of 95 articles were included in the systematic
review.
• Toxicity related to AMs is infrequent, mild and usually
reversible, with HCQ having a safer profile.
Clinical efficacy and side effects of antimalarials in
systemic lupus erythematosus: a systematic review
G Ruiz-Irastorza, M Ramos-Casals, P Brito-Zeron, M A Khamashta
Ruiz-Irastorza G et al. Ann Rheum Dis 2010;69:20-28

Effects of AMs in SLE patients gradedEffects of AMs in SLE patients graded
according to the quality of evidenceaccording to the quality of evidence
High
Reduction of SLE activity (also in pregnancy)
Reduction of mortality
Moderate
Increase in BMD
Protective effect on thrombotic events
Protective effect on irreversible organ damage
Low
Reduction of severe flares
Adjuvant effect for achieving LN remission
Beneficial effect on serum lipid levels
Protective effect on osteonecrosis
Delaying the evolution to SLE
Protective effect on cancer
Very low
Reduction of 1–25 (OH)2 vitamin D levels
Reduction of atherosclerosis
CQ/HCQ
CQ/HCQ
HCQ
CQ/HCQ
HCQ
HCQ
HCQ
CQ/HCQ
HCQ
HCQ
CQ/HCQ
HCQ
CQ/HCQ
AM, antimalarial; BMD, bone mineral density; CQ, chloroquine; HCQ, hydroxychloroquine; LN,
lupus nephritis.

Conclusions
• In pregnant women, high levels of evidence were found
that AMs, particularly HCQ, decrease lupus activity
without harming the baby.
• Given the broad spectrum of beneficial effects and the
safety profile, HCQ should be given to most patients
with SLE during the whole course of the disease,
irrespective of its severity, and be continued during
pregnancy.
Clinical efficacy and side effects of antimalarials in
systemic lupus erythematosus: a systematic review
G Ruiz-Irastorza, M Ramos-Casals, P Brito-Zeron, M A Khamashta

AMs in SLE CohortsAMs in SLE Cohorts
GLADEL
 AM use (OR 0.39, 95% CI 0.26, 0.58), older age at disease onset (OR
0.98, 95% CI 0.96, 0.99) and female gender (OR 0.56, 95% CI 0.32, 0.99)
were negatively associated with higher risk of renal disease.
LUMINA
 The protective effect of AMs in renal damage was demonstrated in 635
Lupus in Minorities patients.
 The use of HCQ was associated with a delay in the occurrence of renal
damage (HR 0.12, 95% CI 0.02-0.97, p = 0.0464).
Pons-Estel GJ et al. Rheumatology. 2012;51:1293 – 1298.
Pons-Estel et al. Arthritis Care & Research. 2009;61(6);830-839.

• Nested case–control study embedded in an inception cohort of patients with SLE.
• Objective– To assess whether exposure to AMs is associated with a decrease in TEs in
SLE patients.
• 54 cases of TE were identified, and these were matched with 108 control subjects
(lupus patients without TEs).
Jung H et al. Arthritis & Rheumatism. 2010;62(3);863-868
The Protective Effect of Antimalarial Drugs on
Thrombovascular Events in Systemic Lupus Erythematosus
Hyejung Jung, Raja Bobba, Jiandong Su, Zhaleh Shariati-Sarabi, Dafna D. Gladman,
Murray Urowitz, Wendy Lou, and Paul R. Fortin

• Adjustments for possible confounding by calendar year, duration of disease, duration
of observation, and severity of lupus.
• After controlling for the possible confounding variables in conditional logistic
regression models, the use of antimalarial drugs was assessed for its effects on the
development of TEs in lupus patients.

Univariate analysisUnivariate analysis
Risk factors associated with thrombovascular events during
the 2-year follow-up in patients with SLE*
Cases
(n = 54)
Controls
(n = 108)
Odds ratio
(95% CI)
P
Ever user of antimalarial drugs 17(32) 57(53) 0.31(0.13–0.71) <0.01
Age > 50 years 22(41) 25(23) 0.31(0.13–0.71) <0.01
Age, mean ± SD years 45.6±14.6 40.2±14.2 1.04(1.01–1.07) 0.01
Female sex 43(80) 93(86) 0.62(0.26–1.49) 0.28
aCL titer ever ≥ 40 PL units 15(35) 22(24) 1.52(0.64–3.63) 0.34
Ever smoked 16(30) 19(18) 1.97(0.91–4.28) 0.09
Ever had diabetes mellitus 4(7) 5(5) 1.71(0.42–7.05) 0.46
Ever had hypertension 27(50) 38(35) 2.45(1.04–5.75) 0.04
Cholesterol level at start of followup, 5.4±1.4 5.2±1.5 1.10(0.87–1.38) 0.44
Mean ± SD mmoles/liter
Ever user of prednisone 39(72) 72(67) 1.41(0.62–3.21) 0.42
Ever user of immunosuppressive drugs 21(39) 38(36) 1.21(0.58–2.50) 0.62
*Except where indicated otherwise, values are the number (%) of patients. 95% CI = 95% confidence interval; aCL = anticardiolipin antibody; PL units =
IgG or IgM phospholipid units.

Multivariate analysisMultivariate analysis
Odds ratio
Variable (95% CI) P
Ever use of antimalarial
drugs
0.32 (0.14-0.74) <0.01
Older age 1.04 (1.01-1.07) 0.02
*95% CI = 95% confidence interval
• Risk factors identified by multivariate analysis as showing a significant association with
trombovascular events during the 2-year followup in patients with SLE.
• Use of AMs drugs and older age remained significant, but the effect of hypertension
was lost.

Conclusion
The results from this nested case–control study demonstrate that, after accounting for
the effects of disease severity, disease duration, and calendar year, antimalarial drugs
were found to be thromboprotective, being associated with a 68% reduction in the
risk of all TEs.

AntiphospholipidAntiphospholipid
SyndromeSyndrome
Antimalarials
in
Autoimmune Diseases

aPL antibodies may exert their
thrombophilic effect by
interfering with Annexin A5.
AMs in APSAMs in APS
aPL impede AnxA5 binding to the
phospholipid surface.
AnxA5
Pro-thrombotic Anti-thrombotic

• Rand et al. HCQ significantly
reduces the binding of aPL-
B2GPI complexes to
phospholipid surfaces, and also
protects against the disruption
of the potent anticoagulant
Annexin A5 by aPL.
• AnxA5 have been found in
both platelets as well as
placental trophoblasts.
AMs in APSAMs in APS

Rheumatoid ArthritisRheumatoid ArthritisAntimalarials
in
Autoimmune Diseases

AMs in RAAMs in RA
• Mild disease.
• Combination with DMARD
treatment.
• Perhaps the great advantage of
AMs has been their safety
profile, especially when
compared to other options in
the DMARD family.

Sjögren’s SyndromeSjögren’s SyndromeAntimalarials
in
Autoimmune Diseases

AMs in SSAMs in SS
Potential benefit for
• Arthralgias
• Myalgias
• Sicca symptoms?

PolyautoimmunityPolyautoimmunityAntimalarials
in
Autoimmune Diseases

AMs in PoliautoimmunityAMs in Poliautoimmunity
• SLE_APS_RA
• CV Risk
 Traditional
 Non-traditional risk factors: GC
• Comorbidities
 T2DM
 Dyslipidemia
 Neoplasia?
• Pleiotropic effects

Take-home messagesTake-home messages
Antimalarials
• Have numerous known immunomodulatory
effects.
• Have been described on diseases in nearly all
major branches of medicine.
• Are safe and inexpensive medications used
frequently in SLE and RA patients.
• May also have a role in the treatment of APS.
Prospective studies are needed to confirm
these data.

Take-home messagesTake-home messages
• There are currently many ongoing clinical trials
studying the effects of AMs in other diseases.
• The effectiveness of HCQ in these diseases, and
in other potential conditions still remains to be
demostrated in the future
• Despite their established clinical utility, their
exact mechanism of action remains unclear.

Antimalarials in Autoimmunity. JCS

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