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 Autoimmunity2. Traditional mechanism of action

I. Antimicrobial

3. New mechanisms of actionI. ImmunomodulatoryII. Metabolic/CardiovascularIII. AntithromboticIV. Others

4. Autoimmune Diseases5. Polyautoimmunity6. 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

1955Synthetic form

of HCQ

1959Hobbs,

retinopathy

1943The alkaloids from the bark were extracted;Extensive cooperative

program of AMs research in USA.

1894Payne, quinine

effective in cutaneous lupus

During the WWII millions of soldiers took AM prophylaxis; improved the soldier’s rashes

and inflammatory arthritis

SLE, RAOthers

AntimalarialsAntimalarials

Images available on line: http://www.google.com/imgres?hl=es&biw=1024&bih=677&tbm

Synthetic forms

CQHCQ: 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 EffectsOcular

Retinopathy, blurred vision, corneal

changes/deposits

CVCardiomyopathy

Neuromuscular and skeletal

Myopathy, palsy, or neuromyopathy

CutaneousAlopecia, angioedema,

bleaching of hair, changes in pigmentation (black-blue

discoloration)

CNSAtaxia, dizziness, emotional changes,

headache, irritability, lassitude, nervousness, nightmares, psychosis,

seizure, vertigo

RespiratoryBronchospasm,

respiratory failure

GIAbdominal cramping,

anorexia, nausea, vomiting, diarrhea,

abnormal liver functionBen-Zvi I. Clinic Rev Allerg Immunol (2012) 42:145-153.

HematologicalAgranulocytosis, 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.

Ben-Zvi I. Clinic Rev Allerg Immunol (2012) 42:145-153.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.

Ben-Zvi I. Clinic Rev Allerg Immunol (2012) 42:145-153.Katz SJ and Russell AS. Curr Opin Rheumatol (2011) 23:278-281.

HCQ

Inhibition of T and B-cells receptors Ca Signaling ↓ Auto-Ab production

TLRs Signaling

↓ NK activity

Binding andStabilization DNA

↓ Mo Cytokine Productionх Phospholipase A2

х MMP

Antigen presentation

Impairment of phago/lysosomal function

Ben-Zvi I. Clinic Rev Allerg Immunol (2012) 42:145-153.

Absorption and blocking of UV light cutaneous reactions

Sifuentes-Giraldo, et al. Reumatol Clin. 2012, in press.

AMs and TLRsAMs and TLRsIntracellular 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 ErythematosusSara 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 ErythematosusSara Kaprove Penn, Amy H. Kao, Laura L. Schott, Jennifer R. Elliott, Frederico G.S. Toledo, Lewis Kuller,

Susasn Manzi, and Mary Chester M. Wasko

• Cross-sectional study.• 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 ofHydroxychloroquine or Methotrexate in Diabetic Patients

with Rheumatologic DiseasesLaura 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

12m12wHCQ/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 0.35Most proximal post-drug HbA1c 7.28±1.63 7.47±1.40 0.58Lowest post-drug HbA1c within 12 mo. 7.05±1.54 7.27±1.34 0.49ΔHbA1c (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 ofHydroxychloroquine or Methotrexate in Diabetic Patients

with Rheumatologic DiseasesLaura 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 ofDiabetes 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 T2DMHCQ 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.

Bili A et al. J Clin Rheumatol. 2011;17: 115-120.

Incident Rates of Type 2 Diabetes by Hydroxychloroquine Use Among Rheumatoid Arthritis Patients

Hydroxychloroquine UsePa

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) 0.28Drug 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 0.03IR, 95% CI 2.0-19.2 16.5-29.5

aFor 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 Adjustedfor 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 ofDiabetes 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 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.

Katz SJ and Russell AS. Curr Opin Rheumatol (2011) 23:278-281.Ben-Zvi I. Clinic Rev Allerg Immunol (2012) 42:145-153.

• Cross-sectional study.• 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 WithImprovement in Lipid Profiles in Rheumatoid Arthritis Patients

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 ProfileIn 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 in Antimalarials in Autoimmune DiseasesAutoimmune Diseases

Systemic Lupus Systemic 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 convencionalGC, ASA, AINEs, IECA, ARA II

Antimaláricos (CQ, HCQ)Inmunomoduladores

(AZA, MMF, CFM, MTX, CysA)

Terapia Biológica(RTX, Belimumab, IGIV)

PerspectivasAlteraciones inmunológicas= producción de autoanticuerpos

Factores endógenos:Perfil hormonal favorable.

Factores genéticos:Alelos de susceptibilidad

Factores ambientales:Sustancias químicas, silicona, infecciones, vacunas, LUV, ACO.

Compromiso sistémicoEndofenotipos

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.

Katz SJ and Russell AS. Curr Opin Rheumatol (2011) 23:278-281.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 insystemic 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 gradedaccording 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/HCQCQ/HCQ

HCQCQ/HCQ

HCQ

HCQHCQ

CQ/HCQHCQHCQ

CQ/HCQ

HCQCQ/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 insystemic 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 onThrombovascular Events in Systemic Lupus ErythematosusHyejung 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 analysisRisk 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) <0.01Age > 50 years 22(41) 25(23) 0.31(0.13–0.71) <0.01Age, mean ± SD years 45.6±14.6 40.2±14.2 1.04(1.01–1.07) 0.01Female sex 43(80) 93(86) 0.62(0.26–1.49) 0.28aCL titer ever ≥ 40 PL units 15(35) 22(24) 1.52(0.64–3.63) 0.34Ever smoked 16(30) 19(18) 1.97(0.91–4.28) 0.09Ever had diabetes mellitus 4(7) 5(5) 1.71(0.42–7.05) 0.46Ever had hypertension 27(50) 38(35) 2.45(1.04–5.75) 0.04Cholesterol level at start of followup, 5.4±1.4 5.2±1.5 1.10(0.87–1.38) 0.44Mean ± SD mmoles/literEver user of prednisone 39(72) 72(67) 1.41(0.62–3.21) 0.42Ever 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 ratioVariable (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.




Antiphospholipid Antiphospholipid 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.

Katz SJ and Russell AS. Curr Opin Rheumatol (2011) 23:278-281.

Sjögren’s SyndromeSjögren’s SyndromeAntimalarials in

Autoimmune Diseases

AMs in SSAMs in SS

Potential benefit for• Arthralgias• Myalgias• Sicca symptoms?

Katz SJ and Russell AS. Curr Opin Rheumatol (2011) 23:278-281.

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.

Thank you

antimalarials in autoimmunity. jcs

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