Juan-Manuel Anaya, MD, PhDCenter for Autoimmune Diseases Research (CREA)

Universidad del RosarioMéderi Hospital Universitario Mayor

Bogota, Colombia

www.urosario.edu.co/crea

Trends in the Treatment of Rheumatoid Arthritis in Latin America

Trends in the Treatment of Rheumatoid Arthritis in Latin America

What Latin America & the Caribbean (LAC) are like and what we can learn about rheumatoid arthritis from LAC.

Treatment of rheumatoid arthritis in LAC.

The Americas were first inhabited by people crossing the Bering Land Bridge from northeastern Asia into Alaska well over 10,000 years ago.

Europeans arrived after 1492 following Christopher Columbus´ voyages.

African people were captured and taken to America by the transatlantic slave trade from the 16th to the 19th centuries.

Latin America & the Caribbean have millions of tri-racial people of European, African and Amerindian ancestry.

Latin America & the Caribbean is a region of the Americas where Romance languages (i.e., those derived from Latin) – particularly Spanish, Portuguese, and French – are primarily spoken.

Area: 21,069,501 km² (7,880,000 sq mi), almost 3.9% of the Earth's surface or 14.1% of its land surface area.

Population: ~ 600 million and an economic growth rate of ~4%.

• Autoimmune diseases, such as rheumatoid arthritis, are complex traits in which both genetic and environmental factors are incriminated in their etiopathogenesis.

• The expression of these diseases varies depending on ethnicity and geography.

• The large and diverse population of Latin America & the Caribbean is a powerful resource for elucidating the genetic basis of these complex traits due to its high admixture.

Admixture in Latin America

Sans M. Hum Biol 2000;72:155. 503711Cuba

80<10<10Peru

80<10<10Ecuador

>80<10>10Bolivia

<4010>50Venezuela

266.567.5Argentina

43~057Chile

201565Brasil

1-207-15>80Uruguay

56341Mexico

>15>15<60Colombia

Amerindian (%)

African (%)

European (%)

Country

Amerindian Ancestry Influences Rheumatoid Arthritis

• The prevalence of RA is higher than expected among some Amerindian groups (Tlingit, Yakima, Pima, and Chippewa Indians).Del Puente A, et al. Am J Epidemiol. 1989;129:1170-8.Ferucci ED, et al. Semin Arthritis Rheum. 2005;34:662-7.

• Compared to Caucasians, RA in Latin America has an earlier age at onset and affects more women than men (5.2:1) with some clinical characteristics that differ from RA presentation in men. Barragán-Martínez C, et al. Gend Med 2012; 9:490-510.

• Loci associated with Amerindian ancestry in Latin American patients with RA were found in the “Genómica de artritis reumatoide” (GENAR) projectLópez Herráez D, et al. Arthritis Rheum 2013;65:1457-67.

PolyautoimmunityFamilial Autoimmunity

Familial Autoimmunity and Polyautoimmunity are frequent in Latin Americans

Clustering of autoimmune diseases is not random

Anaya JM. Autoimmun Rev 2014;13:423-6.Cárdenas-Roldán J, et al. BMC Med 2013;11:73.

Anaya JM. Arthritis Res Ther 2010;12:147.Anaya JM, et al. Expert Rev Clin Immunol 2007;3:623-35

Disease in first-degree relatives Parents Offspring Siblings

Systemic lupus erythematosus 25 (2,1%) 7 (0,6%) 39 (3,3%)

Rheumatoid arthritis 19 (1,6%) 0 13 (1,1%)

Autoimmune thyroid disease 12 (1%) 0 4 (0,3%)

Systemic sclerosis 0 0 1 (0,08%)

Polymyositis 1 (0,08%) 0 0

Familial Autoimmunity is frequent in Latin American patients with SLE GLADEL cohort (N =1,177)

Alarcón-Segovia D, et al. Arthritis Rheum 2005;52:1138-47.

High familial aggregation of RA in Latin American families with SLE (ls: 3.3, lp: 5.3).

A higher percentage of Mestizo SLE patients had relatives with autoimmune disease (54.9%) compared with non-Mestizo patients (41.1%) (p=0.001).

Factors Influencing Polyautoimmunity in Systemic Lupus Erythematosus

Variable AOR 95% CI p

Gender (female) 2.30 1.03 5.15 0.043

Articular involvement 2.02 1.26 3.23 0.003

Familial autoimmunity 1.61 1.14 2.28 0.007

Anti-Ro Ab 1.54 1.10 2.16 0.013

Origin (Colombia vs Spain) 1.78 1.40 2.27 < 0.0001

Rojas-Villarraga A, et al. Autoimmun Rev. 2010;9:229-32.

Ameridian Ancestry Influences Polyautoimmunity in Colombians

Amerindian ancestry European ancestry

p: 0.001 p: 0.003

Molano-González N et al. Submitted

HLA-DRB1*04 Influences the Risk of Rheumatoid Arthritis

in Latin Americans

Delgado-Vega & Anaya. Autoimmun Rev 2007;6:402.

Delgado-Vega & Anaya. Autoimmun Rev 2007;6:402.

Shared Epitope is a risk factor for Rheumatoid Arthritis in Latin Americans

Lee et al. J Rheumatol 2007;34:43

TNF -308 A is a Risk Factor for Rheumatoid Arthritis

in Latin Americans

Anaya et al. 2005 [298:308]

Combined [Fixed]

Ramirez et al. 2012 [394:434]

PTPN22 (1858 T) is a Risk Factor for Rheumatoid Arthritis in Colombians

Anaya JM, Gomez LM, et al. Genes Immun. 2005;6:628-31.Ramirez et al. Exp Rheumatol 2012;30:520-4.

Rheumatoid ArthritisColombiansRamírez et al. Clin Exp Rheumatol 2012

Systemic Lupus Erithematosus ColombiansAnaya et al. Genes Immun. 2005;6:628.Ramírez et al. Clin Exp Rheumatol 2012ArgentiniansOrrú et al. Hum Mol Genet 2009;18:569.

PTPN22 (1858 T) is a Pleiotropic Autoimmune Allelein Latin Americans

Sjögren´s SyndromeColombiansAnaya et al. Genes Immun. 2005;6:628.

Type 1 DiabetesColombiansAnaya et al. Genes Immun. 2005;6:628-31.BraziliansChagastelles et al .Tissue Antigens 2010;76:144.Rassi et al. Ann N Y Acad Sci. 2008;1150:282.

Brazilian Guidelines for the Diagnosis of Rheumatoid Arthritis

• Diagnosis of early RA (< 12 months) is of a summit importance because early diagnosis exerts beneficial effects on radiological and functional prognosis compared to later diagnosis.

• The 2010 ACR/EULAR criteria identify more patients with early RA than does the 1987 ACR criteria. However, the rate of false-positive cases is higher with the newer criteria.

• For established RA discriminatory powers of the 2010 ACR/EULAR and the 1987 ACR criteria are similar.

• Smoking increases the disease activity of RA and reduces clinical and functional responses over time. However, there is no sufficient evidence regarding its influence on radiological disease progression.

Mota LM, et al. Rev Bras Reumatol 2013;53:141-57.

Brazilian Guidelines for the Diagnosis of Rheumatoid Arthritis

• Rheumatoid factor (RF) measurement is related to prognosis (i.e., radiological progression and mortality).

• The sensitivity of anti-CCP is similar to that of RF, but its specificity is higher, particularly in the early disease stages.

• Anti-CCP evaluation is recommended in patients with a clinical suspicion of RA and negative for RF.

• RA progression is more severe in patients with extra-articular manifestations.

• Conventional radiography must be used in diagnostic and prognostic assessments. When needed and available, US and MRI should also be used.

Mota LM, et al. Rev Bras Reumatol 2013;53:141-57.

Brazilian Guidelines for the Diagnosis of Rheumatoid Arthritis

• The PTPN22 gene polymorphism is associated with RA. Although it is not predictive of specific therapeutic responses to biological therapy, it is predictive of remission when associated with anti-CCP. Alone or in combination with HLA- DRB1 (SE), the PTPN22 polymorphism allows estimations of radiological progression.

• The HLA-DRB1 gene seems to play a more important role in the prediction of poor prognosis relative to the progression, activity, severity, and mortality of RA.

Mota LM, et al. Rev Bras Reumatol 2013;53:141-57.

• GLADAR, a prospective, observational, multicenter, multinational inception cohort of 1093 adult patients with early RA (1 year from the first RA symptoms), from 46 centers in 14 Latin American countries, followed for 24 months.

• Female: 85% • Rheumatoid factor (+): 76% • Mean age at diagnosis: 46.5 (SD, 14.2) years, • Mean disease duration at the first visit: 5.8 (SD, 3.8) months.• Women had earlier onset than men (median 44.6 vs. 49.7

years, p<0.001)Cardiel MH, et al. J Clin Rheumatol 2012;18:327-35. Massardo L, et al. J Clin Rheumatol 2009;15:203-10.

Soriano ER, et al. Rheumatology (Oxford). 2008;47:1097-9. Cardiel MH, et al. Rheumatology (Oxford) 2006;45 Suppl 2:ii7-ii22.

Pons-Estel BA et al. Ann Rheum Dis 2008;67(Suppl II):336

Rheumatoid Arthritis in Latin America

Rheumatoid Arthritis in Latin America

In Early RA, extra-articular manifestations are present in 10%, and erosive disease is observed in 27.5% of patients. Joint erosions are observed more frequently in RF-positive patients and in those with no, or partial medical insurance coverage. Pons-Estel BA et al. Ann Rheum Dis 2008;67(Suppl II):336

Low/low-middle socioeconomic status influences disease activity in early RA.Massardo L, et al. Arthritis Care Res (Hoboken). 2012;64:1135-43.

Patients have a low understanding of their disease.Werner AM, et al. Rev Méd Chile 2006; 134: 1500-6Cadena J & Anaya JM. Arthritis Rheum 2003;49:738-40.

Characteristic AOR 95% CIAge at onset 1.04 1.02-1.06Polyautoimmunity 3.22 1.20-8.75Abdominal obesity 9.8 5.42-17.69House duties 23.17 7.8-68.82

Sarmiento-Monroy JC, et al. Arthritis 2012;2012:371909.

Cardiovascular Disease in Latin American Patients with Rheumatoid Arthritis

Trends in the Treatment of Rheumatoid Arthritis in Latin America

What Latin America & the Caribbean (LAC) are like and what we can learn about rheumatoid arthritis from LAC.

Treatment of rheumatoid arthritis in LAC.

• DMARD as initial treatment: 75% • MTX alone or in combination: 60.5%• Antimalarials: 32.1%• Sulfasalazine: 7.1%• LEF: 4%. • Combination therapy as initial treatment: 26%.

MTX + Antimalarials: 70% • Biologics: 1%.• Corticosteroids: 64%

Cardiel MH, et al. J Clin Rheumatol 2012;18:327-35.

2006

2009

2008

Treatment of Rheumatoid Arthritis in Latin America

Burgos-Vargas R, et al. Reumatol Clin 2013;9:106-12.

• There are differences between the various recommendations, especially regarding the criteria for beginning biological therapies, hierarchic sequence for using available biological drugs, and for suspending or switching them.

• Systematic review of the literature vs. opinion of experts and consultants.

• The recommendations for treatment of RA should be updated more frequently.

Fernandes et al. Rev Bras Reumatol 2011;51:220-30.

Rheumatology Biological Registries in Latin America

Titton DC, et al. Rev Bras Reumatol. 2011;51:152-60De la Vega M, et al Rev Arg Reumatol. 2013;24:08-14

Registries have been established for studying the long-term effects of treatment for RA, especially with respect to safety.

BIOBADASAR (Argentina)BIOBADABRASIL (Brazil)BIOBADAMEX (Mexico)BIOBADAURUGUAY (Uruguay)

Biological Therapy in Rheumatoid Arthritis in Argentina

Chaparro del Moral R et al. Rev Arg Reumatol. 2013;24:18-26

b S.E. P-value AORLack of efficacy 1.39 0.52 0.008 4.0Drug omission (forgetfulness) 1.03 0.31 0.001 2.8Hope for a quick response 0.71 0.28 0.01 2.0Public vs. Private insurance 1.55 0.47 0.001 4.7

Factors Associated with Noncompliance with Biological Therapy in Argentine Patients with Rheumatoid Arthritis

Chaparro del Moral R, et al. Rev Arg Reumatol 2013;24:18-26

Anti-TNF therapy Survival

Ventura-Ríos L, et al. Reumatol Clin 2012;8:189-94.

Reason BIOBADAMEXN= 1,481

BIOBADASERN= 5,493

BSRBRN= 10,391

Adverse effect 19,1% 41% 21%Inefficacy 33.6% 39% 22%Remission 17,0% 3% NA

De la Vega M, et al. Rheumatol Int 2013;33:827-35.

Reasons for Suspending Biological Therapy

1. Early diagnosis and proper treatment of comorbidities are recommended.

2. The specific treatment of RA should be adapted to the presence of comorbidities.

3. Angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers are preferred to treat systemic arterial hypertension.

4. In patients diagnosed with RA and diabetes mellitus, the continuous use of a high cumulative dose of corticoids should be avoided.

Management of Comorbidities in Patients with Rheumatoid Arthritis

Pereira IA, et al. Rev Bras Reumatol 2012;52:474-95.

5. Statins should be used to maintain LDL cholesterol levels under 100 mg/dL and the atherosclerotic index lower than 3.5 in patients with RA who have other comorbidities.

6. Metabolic syndrome should be treated.

7. Performing non-invasive tests to investigate subclinical atherosclerosis is recommended.

8. Greater surveillance for the early diagnosis of occult malignancy is recommended.

9. Preventive measures of venous thrombosis are suggested.

Pereira IA, et al. Rev Bras Reumatol 2012;52:474-95.

Management of Comorbidities in Patients with Rheumatoid Arthritis

10. Bone densitometry is recommended in RA patients over the age of 50 years and in younger patients on corticoid therapy at a dose greater than 7.5 mg for over three months.

11. Patients with RA and osteoporosis should be instructed to avoid falls, to increase their dietary calcium intake and sun exposure, and to exercise.

12. Calcium and vitamin D supplementation is suggested. Bisphosphonates are suggested for patients with T score < –2.5 on bone densitometry.

13. A multidisciplinary team, with the active participation of a rheumatologist, is recommended to treat comorbidities.

Pereira IA, et al. Rev Bras Reumatol 2012;52:474-95.

Management of Comorbidities in Patients with Rheumatoid Arthritis

Biosimilars

A molecule that is “highly similar” to a reference biotherapeutic product confirmed by a comparability exercise and showing similar quality, safety, and efficacy.

They promote cost containment and favor the sustainability of modern health systems in a panorama of aging population, demographic transition towards chronic diseases like RA, costly health technologies, and limited resources.

Desanvicente-Celis Z, et al. Immunotherapy. 2012;4:1841-57.Desanvicente-Celis Z, et al. Biosimilars 2013;3:1-17.

Biosimilars are available in Mexico, Brazil, Chile, Ecuador, Bolivia, Peru, Argentina, Panama, Guatemala, Costa Rica, and Colombia.

Similar Biotherapeutic ProductsDifferent Parties Affected by the Regulation and Marketing

Conclusions and Challenges

• RA in Latin America and the Caribean differs from other regions in the world.

• Make RA a public health priority, knowing its socioeconomic impact in terms of its high cost and burden on the health-care system.

• Burgos-Vargas R, et al. Reumatol Clin 2013;9:106-12.

• Building own evidence-based practice through research.

• Education!

• « Traiter vite et fort! »– Early Arthritis Clinics

• Marcos J, et al. General characteristics of an early arthritis cohort in Argentina. Rheumatology 2011;50:110-6.

• Arbeláez-Cortés A, et al. The Cali early arthritis clinic. Biomed Res Int 2014;2014: in press.

• Provide access to medications. Low cost - Price regulation.

Gracias! “How can we not hope that someday, when neighborliness, cooperation and respect have fulfilled their mission, the whole American continent will be a vast alliance of dignity and civilization brought about by languages and traditions?”

“¿Como no desear que algún día, cuando la vecindad , la colaboración y el respeto hayan cumplido su misión, todo el continente americano sea una vasta alianza de dignidad y de civilización propiciada por las lenguas y por las tradiciones?”