Genotype-Phenotype Study of Patients With Plaquenil -Induced Retinal Toxicity, With Evaluation of the ABCA4 Gene

Official title

Genotype - Phenotype Study of Patients With Plaquenil-induced Retinal Toxicity

Overview

Background: \- Plaquenil (hydroxychloroquine) is an anti-inflammatory drug that is used to treat some autoimmune diseases such as lupus and rheumatoid arthritis. This drug can damage the retina by causing a condition called Plaquenil-induced retinal toxicity, which may lead to vision loss. However, most people taking Plaquenil do not develop this problem. Researchers are interested in studying whether differences in a person's genes explain why some people develop Plaquenil-induced retinal toxicity while others do not. Objectives: \- To investigate possible correlations between certain genes or genetic mutations and Plaquenil-induced retinal toxicity. Eligibility: * Individuals at least 18 years of age who have previously used Plaquenil. * History of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or Sjogren's syndrome. * Both individuals who have and have not developed Plaquenil-induced retinal toxicity will be eligible for this study. Design: * The study requires five annual outpatient visits to the NIH Clinical Center. * Participants will provide a personal and family medical history, and will have a full eye examination. * Participants will also provide blood samples for genetic analysis, including whole exome and whole genome sequencing. * No treatment will be provided as part of this protocol.

Detailed description

OBJECTIVE:

The objective of this study is to investigate whether there is a correlation between genetic mutations, beginning with an analysis of ABCA4, and Plaquenil(R)-induced retinal toxicity and to describe the phenotype of Plaquenil(R)-induced retinal toxicity.

STUDY POPULATION:

The study will enroll 100 patients, 18 years of age or older, found to have Plaquenil(R)-induced retinal toxicity. 200 volunteers with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or Sjogren's syndrome and history of Plaquenil(R) use, but without evidence of retinal toxicity, will also be recruited.

DESIGN:

The study is a longitudinal, observational study with five annual outpatient visits to the NEI clinic. All participants will provide a blood sample for genetic analysis, including whole exome or whole genome sequencing.

OUTCOME MEASURES:

Clinical examination and blood samples will be used for genetic testing and mutation identification. The primary outcome of this study is to identify genetic mutations, starting with those in ABCA4 gene, associated with retinal toxicity in participants with a history of Plaquenil(R) use. Secondary objectives include determining the utility of testing metrics in evaluating the presence of retinal toxicity.

Primary outcome measures

• The outcome of this study is to identify genetic mutations, starting with those in ABCA4 gene, associated with retinal toxicity in participants with a history of plaquenil use. [Time frame: annually for five years]

Secondary outcome measures (1)

• The secondary outcome of this study is to determine the utility of various testing metrics in evaluating the presence of retinal toxicity. [Time frame: annually for five years]

Eligibility criteria

• INCLUSION CRITERIA:

1\. Affected participants must be 18 years of age or older and have:

• History of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) or Sjogren's syndrome, and
• History of Plaquenil(R) use, and
• Evidence of Plaquenil(R)-induced retinal toxicity, based on clinical findings.

2\. Unaffected volunteers must be 18 years of age or older and have:

• History of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) or Sjogren's syndrome, and
• History of Plaquenil(R) use, and
• No retinal disease upon examination within the last six months.

3\. All participants must be able to:

• Provide their own consent, and
• Safely provide a blood sample.

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Exclusion criteria

Participants with other known (genetic) retinal disease including but not limited to: Stargardt's disease and cone or cone-rod dystrophy whose diagnosis preceded their Plaquenil(R) use. Participants with no known previous genetic diagnosis but with clinical findings associated with a genetic diagnosis, such as parafoveal or macular flecks which are associated with Stargardt's disease or fundus flavimaculatus, will also be excluded.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United States · 1 center

• National Institutes of Health Clinical Center — Bethesda

Publications

• Levy GD, Munz SJ, Paschal J, Cohen HB, Pince KJ, Peterson T. Incidence of hydroxychloroquine retinopathy in 1,207 patients in a large multicenter outpatient practice. Arthritis Rheum. 1997 Aug;40(8):1482-6. doi: 10.1002/art.1780400817. PMID 9259429
• HOBBS HE, SORSBY A, FREEDMAN A. Retinopathy following chloroquine therapy. Lancet. 1959 Oct 3;2(7101):478-80. doi: 10.1016/s0140-6736(59)90604-x. No abstract available. PMID 14402143
• Webster AR, Heon E, Lotery AJ, Vandenburgh K, Casavant TL, Oh KT, Beck G, Fishman GA, Lam BL, Levin A, Heckenlively JR, Jacobson SG, Weleber RG, Sheffield VC, Stone EM. An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89. PMID 11328725

Identifiers

NCT: NCT01145196 · 100140 · 10-EI-0140

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗