clinical science symposium : dmards - hcq and eye : a blind spot - dr s j gupta
TRANSCRIPT
S J Gupta,S J Gupta,New DelhiNew Delhi
Sant Parmanand Sant Parmanand HospitalHospital
D-110 Defence D-110 Defence ColonyColony
HCQ: A Blind Spot?HCQ: A Blind Spot?
IRACON 2016: IRACON 2016: Kochi: Kochi: 26/11/201626/11/2016
HCQ: A Blind Spot:HCQ: A Blind Spot:Outline..Outline..
Uses and Mechanism of Uses and Mechanism of anti-rheumatic action;anti-rheumatic action;
Side effects- Side effects- Retinal Retinal toxicitytoxicity
Screening tests & Screening tests & Guidelines for screeningGuidelines for screening
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Rheumatology: Rheumatology: Used ExtensivelyUsed Extensively
RA; CTDs- RA; CTDs- SLE, SLE, PSS, SSc, IIM…PSS, SSc, IIM…
Post Lyme IJDPost Lyme IJD11
Chikungunya Chikungunya (CK)(CK)22
APLA syndromeAPLA syndrome33
Other Uses:Other Uses: MALARIAMALARIA Lipid & Glucose Lipid & Glucose
metabolismmetabolism44
Inhibition of Inhibition of autophagyautophagy55
HCQ HCQ Uses Uses
1.1. Steere Steere AC et al. Arth and Rheum. 2006 Oct. 54 (10): 3079–86.AC et al. Arth and Rheum. 2006 Oct. 54 (10): 3079–86.2.2. Ravindran V. Clin Rheumatol. Oct 2016. DOI 10.1007/s10067-Ravindran V. Clin Rheumatol. Oct 2016. DOI 10.1007/s10067-016-016- 3429-03429-03.3.Giannakopoulos B et al. N Engl J Med 2013; 368:1033-44.Giannakopoulos B et al. N Engl J Med 2013; 368:1033-44.4.4. Mirella PH et al. Ther Adv Endocrinol Metab 2014; Vol 5 (4) 77–Mirella PH et al. Ther Adv Endocrinol Metab 2014; Vol 5 (4) 77–85855.5.Choi AMK et al. N Engl J Med 2013; 368: 651-62.Choi AMK et al. N Engl J Med 2013; 368: 651-62.
HCQ: HCQ: Anti-inflammatory Anti-inflammatory actionaction::
Fox R: Semin Arthr Rheum 1993: Oct 23 (2 Suppl1) 82-91Fox R: Semin Arthr Rheum 1993: Oct 23 (2 Suppl1) 82-91
i) Reduces i) Reduces formation of formation of
antigen peptide-antigen peptide-MHC complexMHC complex
ii) Inhibition of TLR ii) Inhibition of TLR
CD4CD4 II II MHCMHC
PeptidePeptide
Down regulation of immune Down regulation of immune responseresponse
T Cell activationT Cell activation
HCQ- Side Effects:HCQ- Side Effects:British National Formulary: BNF 2012: BNF.orgBritish National Formulary: BNF 2012: BNF.org
Non-Serious Non-Serious ((commoncommon))
.Hair loss; .Hair loss;
..skin skin discolorationdiscoloration
CautionCaution.CNS-epilepsy;.CNS-epilepsy;..G6PD; .Porphyria;G6PD; .Porphyria;.Psoriasis;.Psoriasis;.Myasthenia Gravis;.Myasthenia Gravis;
Serious (Serious (rarerare) ) .Thrombocytopeni.Thrombocytopeni
a;a;.Agranulocytosis;.Agranulocytosis;.Mental disorders;.Mental disorders;.Exfoliative .Exfoliative
dermatitis (SJ);dermatitis (SJ);.Myopathy;.Myopathy;
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GeneralGeneral
HCQ- Ocular Side HCQ- Ocular Side Effects:Effects:
‘‘The Blind Spot’The Blind Spot’
Cornea, Lens, Cornea, Lens, Ciliary BodyCiliary Body
Deposits reverse on Deposits reverse on discontinuation discontinuation and no significant and no significant visual impairmentvisual impairment
RETINARETINAPotentially serious Potentially serious
with permanent with permanent visual visual implicationsimplications
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Yam JC et al. Hong Kong Med J. 2007 Aug; 12 (4): 294-Yam JC et al. Hong Kong Med J. 2007 Aug; 12 (4): 294-304304
HCQ- Retinal ToxicityHCQ- Retinal Toxicity
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1.1. HCQ- HCQ- pH of RPE Lysozomes pH of RPE Lysozomes impairs impairs RPE cell function;RPE cell function;
2.2. Genetic- photoreceptor specific ATP-Genetic- photoreceptor specific ATP-binding cassette transporter ABCA4 binding cassette transporter ABCA4 (coded for by the ABCR gene).(coded for by the ABCR gene).
Weinlander E et al. Screening and Diagnosis of Hydroxychloroquine Weinlander E et al. Screening and Diagnosis of Hydroxychloroquine Toxicity: Advances and Controversies. J Clin Exp Ophthalmol 2016. 7: Toxicity: Advances and Controversies. J Clin Exp Ophthalmol 2016. 7:
e117. e117.
HCQ- Retinal ToxicityHCQ- Retinal Toxicity
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Bull’s Eye Bull’s Eye MaculopathyMaculopathy
1.1. HCQ- HCQ- pH of RPE Lysozomes pH of RPE Lysozomes impairs RPE cell function; impairs RPE cell function;2.2. Genetic- photoreceptor specific ATP-binding cassette Genetic- photoreceptor specific ATP-binding cassette
transporter ABCA4 (coded for by the ABCR genetransporter ABCA4 (coded for by the ABCR gene).).
Screening for Ocular Side Effects- Screening for Ocular Side Effects- The ‘Blind Spot’?The ‘Blind Spot’?
SYMPTOMSSYMPTOMS.Visual glare; .Visual glare; .Night blindness;.Night blindness;.Impaired color .Impaired color
vision;vision;.Visual field .Visual field
defectsdefects
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Many patients are Many patients are asymptomaticasymptomatic
Screening for Ocular Side Effects- Screening for Ocular Side Effects- The ‘Blind Spot’?The ‘Blind Spot’?
SYMPTOMSSYMPTOMS.Visual glare; .Visual glare; .Night blindness;.Night blindness;.Impaired color .Impaired color
vision;vision;.Visual field .Visual field
defectsdefects
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Many patients are Many patients are asymptomaticasymptomatic
SCREENINGSCREENING.Visual acuity;.Visual acuity;.Colour vision;.Colour vision;.Amsler’s Grid;.Amsler’s Grid;.Visual field .Visual field
(perimetry);(perimetry);.Fundoscopy).Fundoscopy)
2002 AAO Guidelines for Screening 2002 AAO Guidelines for Screening for Retinal Toxicity: for Retinal Toxicity:
Marmor et al. Ophthalmology 2002 Jul; 109 (7): Marmor et al. Ophthalmology 2002 Jul; 109 (7):
No routine testing No routine testing during the during the first 5 yrsfirst 5 yrs: : .No risk factors .No risk factors .Dose .Dose 6.5 mg/kg of HCQ & 6.5 mg/kg of HCQ & 3 mg/kg of 3 mg/kg of
CQ;CQ;.Baseline eye exam normal.Baseline eye exam normal
Exam- vision, overall eye condition, Exam- vision, overall eye condition, retinal lesions that may simulate HCQ retinal lesions that may simulate HCQ toxicity; toxicity;
Automated visual field testing, Amsler's Automated visual field testing, Amsler's grid and color vision can be helpful in grid and color vision can be helpful in making an early diagnosis.making an early diagnosis. 11
2002 AAO Guidelines for Screening 2002 AAO Guidelines for Screening for Retinal Toxicity: for Retinal Toxicity:
Marmor et al. Ophthalmology 2002 Jul; 109 (7): Marmor et al. Ophthalmology 2002 Jul; 109 (7): No routine testing No routine testing during the during the first 5 yrsfirst 5 yrs: :
.No .No risk factorsrisk factorsi)i) Dose based on Dose based on ideal body weightideal body weightii)ii) TD TD 1000mg HCQ & 460mg CQ1000mg HCQ & 460mg CQiii)iii) Therapy Therapy 5yrs; Age 5yrs; Age 60 yrs60 yrsiv)iv) Renal Disease; Existing Retinal Renal Disease; Existing Retinal
diseasediseasev)v) GeneticGenetic
.Dose .Dose 6.5 mg/kg of HCQ & 6.5 mg/kg of HCQ & 3 mg/kg of CQ;3 mg/kg of CQ;
.Baseline eye exam normal.Baseline eye exam normal12
2002 AAO Guidelines for Screening 2002 AAO Guidelines for Screening for Retinal Toxicity: for Retinal Toxicity:
Marmor et al. Ophthalmology 2002 Jul; 109 (7): Marmor et al. Ophthalmology 2002 Jul; 109 (7): No routine testing No routine testing during the during the first 5 yrsfirst 5 yrs: :
.No risk factors .No risk factors
.Dose .Dose 6.5 mg/kg of HCQ & 6.5 mg/kg of HCQ & 3 mg/kg of CQ;3 mg/kg of CQ;
.Baseline eye exam normal.Baseline eye exam normal Exam- vision, overall eye condition, retinal lesions that may Exam- vision, overall eye condition, retinal lesions that may
simulate HCQ toxicity; simulate HCQ toxicity; Automated visual field testing, Amsler's grid and color Automated visual field testing, Amsler's grid and color
vision can be helpful in making an early diagnosis.vision can be helpful in making an early diagnosis. Full field Full field electro-retinogramelectro-retinogram (ffERG) & (ffERG) &
electro-oculogramelectro-oculogram (EOG) (EOG) notnot reliable tests reliable tests of early toxicity. Multifocal ERG (mfERG) of early toxicity. Multifocal ERG (mfERG) could play a role in could play a role in early detectionearly detection of the of the toxicity toxicity remains to be establishedremains to be established..
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HCQ- Screening for Retinal HCQ- Screening for Retinal Toxicity: Toxicity: New developmentsNew developments
More sophisticated tests for More sophisticated tests for earlyearly retinal involvement:retinal involvement:
Multi-focal electro-retinogram Multi-focal electro-retinogram mfERGmfERG, ,
Fundus auto fluorescence Fundus auto fluorescence FAFFAF Spectral domain optical Spectral domain optical
coherence tomography coherence tomography SD OCTSD OCT
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Rahimy E. Multimodal Imaging in Plaquenil Toxicity. Review of Rahimy E. Multimodal Imaging in Plaquenil Toxicity. Review of Ophthalmology. June 2014Ophthalmology. June 2014
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OCT Scan of Normal EyeOCT Scan of Normal Eye
Staurenghi: OCT Consensus: Ophthalmology Staurenghi: OCT Consensus: Ophthalmology 20142014
OCT Scan of PatientOCT Scan of Patient
• SLESLE• HCQ ~ 8 yrs:HCQ ~ 8 yrs: TD~ 900mgTD~ 900mg• Normal FundusNormal Fundus• Normal VisualNormal Visual FieldsFields
Courtesy: Dept of Ophthalmology, Apollo Courtesy: Dept of Ophthalmology, Apollo Hospital, DelhiHospital, Delhi
1.1.Max 5 yrs between baseline test & Max 5 yrs between baseline test & regular annual FU- regular annual FU- unless risk factors unless risk factors 2.2.Dose (of HCQ/CQ) calculated on ideal Dose (of HCQ/CQ) calculated on ideal BW. BW. 3.3.Not recommended- Not recommended- FA, TD OCT, Amsler's FA, TD OCT, Amsler's grid & color vision.grid & color vision.4.4.10-2 automated visual field (AVF) should 10-2 automated visual field (AVF) should be included in baseline tests be included in baseline tests PLUS 1 ofPLUS 1 of:: i) SD-OCT, ii) FAF or iii) mfERGi) SD-OCT, ii) FAF or iii) mfERG. .
The sensitivity & specificity of the objective The sensitivity & specificity of the objective screening tests have not yet been determined.screening tests have not yet been determined.
2011 AAO Guidelines for Screening 2011 AAO Guidelines for Screening for Retinal Toxicity: for Retinal Toxicity:
Marmor et al. Ophthalmology 2011 Feb; 118 (2): 415-22Marmor et al. Ophthalmology 2011 Feb; 118 (2): 415-22
HCQ- Screening for Retinal HCQ- Screening for Retinal ToxicityToxicity
Melles RB. Risk of Toxic Retinopathy in Patients on Long-term HCQ Melles RB. Risk of Toxic Retinopathy in Patients on Long-term HCQ Therapy: JAMA Ophthalmol. 2014; Therapy: JAMA Ophthalmol. 2014;
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Risk of Toxic Retinopathy in Patients Risk of Toxic Retinopathy in Patients on Long-term HCQ Therapy:on Long-term HCQ Therapy:
RESULTSRESULTS::• Real BW better than ideal BW- riskReal BW better than ideal BW- risk predictor predictor • Prevalence of HCQ retinopathy- Prevalence of HCQ retinopathy- 7.5%7.5% varies- dose & durationvaries- dose & duration• 4.0 to 5.0mg/kg- prevalence 4.0 to 5.0mg/kg- prevalence 2% 2% forfor 11stst 10 yrs but 10 yrs but ~20% after 20 yrs ~20% after 20 yrs • Other risk factors include: Other risk factors include:
-kidney disease-kidney disease-concurrent tamoxifen therapy-concurrent tamoxifen therapy
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AAO Recommendations on Screening AAO Recommendations on Screening for HCQ Retinopathy- 2016 revision: for HCQ Retinopathy- 2016 revision:
Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94
1. 1. PatternPattern::2. 2. DoseDose::3. 3. RiskRisk::4. 4. RiskRisk factorsfactors::5. 5. ScheduleSchedule::6. 6. TestsTests::7. 7. CounselingCounseling::
AAO Recommendations on Screening AAO Recommendations on Screening for HCQ Retinopathy- 2016 revision: for HCQ Retinopathy- 2016 revision:
Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94
1. 1. PatternPattern:: Parafoveal: Asian- Parafoveal: Asian- Extra-Extra-macularmacular -Automated VF 30-2-Automated VF 30-2
2. 2. DoseDose::3. 3. RiskRisk::4. 4. RiskRisk factorsfactors::5. 5. ScheduleSchedule::6. 6. TestsTests::7. 7. CounselingCounseling::
AAO Recommendations on Screening AAO Recommendations on Screening for HCQ Retinopathy- 2016 revision: for HCQ Retinopathy- 2016 revision:
Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94
1. 1. PatternPattern:: Parafoveal: Asian- Parafoveal: Asian- Extra-Extra-macularmacular
2. 2. DoseDose:: 5mg/kg 5mg/kg realreal body weight: HCQ body weight: HCQ ( no guideline for CQ ( no guideline for CQ 2.3)2.3)
3. 3. RiskRisk::4. 4. RiskRisk factorsfactors::5. 5. ScheduleSchedule::6. 6. TestsTests::7. 7. CounselingCounseling::
AAO Recommendations on Screening AAO Recommendations on Screening for HCQ Retinopathy- 2016 revision: for HCQ Retinopathy- 2016 revision:
Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94
1. 1. PatternPattern:: Parafoveal: Asian- Parafoveal: Asian- Extra-Extra-macularmacular
2. 2. DoseDose:: 5mg/kg 5mg/kg realreal body weight: HCQ body weight: HCQ ((2.3 CQ)2.3 CQ)
3. 3. RiskRisk:: Upto 5 years Upto 5 years 1%, 10 yrs 1%, 10 yrs 2%; 2%; ~~20 yrs ~20%20 yrs ~20% (~4% next year) (~4% next year)
4. 4. RiskRisk factorsfactors::5. 5. ScheduleSchedule::6. 6. TestsTests::7. 7. CounselingCounseling::
AAO Recommendations on Screening AAO Recommendations on Screening for HCQ Retinopathy- 2016 revision: for HCQ Retinopathy- 2016 revision:
Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94
1. 1. PatternPattern:: Parafoveal: Asian- Parafoveal: Asian- Extra-Extra-macularmacular
2. 2. DoseDose:: 5mg/kg 5mg/kg realreal body weight: HCQ body weight: HCQ ((2.3 CQ)2.3 CQ)
3. 3. RiskRisk:: Upto 5 years Upto 5 years 1%, 10 yrs 1%, 10 yrs 2%; 2%; ~~20 yrs ~20%20 yrs ~20%
4. 4. RiskRisk factorsfactors::
Renal disease, Tamoxifen useRenal disease, Tamoxifen use
5. 5. ScheduleSchedule::6. 6. TestsTests::7. 7. CounselingCounseling::
AAO Recommendations on Screening AAO Recommendations on Screening for HCQ Retinopathy- 2016 revision: for HCQ Retinopathy- 2016 revision:
Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94
1. 1. PatternPattern:: Parafoveal: Asian- Parafoveal: Asian- Extra-Extra-macularmacular
2. 2. DoseDose:: 5mg/kg 5mg/kg realreal body weight: HCQ body weight: HCQ ((2.3 CQ)2.3 CQ)
3. 3. RiskRisk:: Upto 5 years Upto 5 years 1%, 10 yrs 1%, 10 yrs 2%; 2%; ~~20 yrs ~20%20 yrs ~20%
4. 4. RiskRisk factorsfactors::
Renal disease, Tamoxifen useRenal disease, Tamoxifen use
5. 5. ScheduleSchedule::
Baseline-fundus; Annual- 5 yrs+Baseline-fundus; Annual- 5 yrs+
6. 6. TestsTests::7. 7. CounselingCounseling::
AAO Recommendations on Screening AAO Recommendations on Screening for HCQ Retinopathy- 2016 revision: for HCQ Retinopathy- 2016 revision:
Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94
1. 1. PatternPattern:: Parafoveal: Asian- Parafoveal: Asian- Extra-Extra-macularmacular
2. 2. DoseDose:: 5mg/kg 5mg/kg realreal body weight: HCQ body weight: HCQ ((2.3 CQ)2.3 CQ)
3. 3. RiskRisk:: Upto 5 years Upto 5 years 1%, 10 yrs 1%, 10 yrs 2%; 2%; ~~20 yrs ~20%20 yrs ~20%
4. 4. RiskRisk factorsfactors::
Renal disease, Tamoxifen useRenal disease, Tamoxifen use
5. 5. ScheduleSchedule::
Baseline-fundus; Annual- 5 yrs+Baseline-fundus; Annual- 5 yrs+
6. 6. TestsTests:: Automated visual fields; SD-Automated visual fields; SD-OCT; OCT;
~ mfERG, FAF may be helpful~ mfERG, FAF may be helpful7. 7. CounselingCounseling::
AAO Recommendations on Screening AAO Recommendations on Screening for HCQ Retinopathy- 2016 revision: for HCQ Retinopathy- 2016 revision:
Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94
1. 1. PatternPattern:: Parafoveal: Asian- Parafoveal: Asian- Extra-Extra-macularmacular
2. 2. DoseDose:: 5mg/kg 5mg/kg realreal body weight: HCQ body weight: HCQ ((2.3 CQ)2.3 CQ)
3. 3. RiskRisk:: Upto 5 years Upto 5 years 1%, 10 yrs 1%, 10 yrs 2%; 2%; ~~20 yrs ~20%20 yrs ~20%
4. 4. RiskRisk factorsfactors::
Renal disease, Tamoxifen useRenal disease, Tamoxifen use
5. 5. ScheduleSchedule::
Baseline-fundus; Annual- 5 yrs+Baseline-fundus; Annual- 5 yrs+
6. 6. TestsTests:: Automated visual fields; SD-Automated visual fields; SD-OCT; OCT;
~ mfERG, FAF may be helpful~ mfERG, FAF may be helpful7. 7. CounselingCounseling::
Appropriate counselingAppropriate counseling
AAO Recommendations on Screening AAO Recommendations on Screening for HCQ Retinopathy- 2016 revision: for HCQ Retinopathy- 2016 revision:
Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94Marmor et al. Ophthalmology 2016 Feb; 123: 1386-94
HCQ: HCQ: The Blind Spot?The Blind Spot?SummarySummary
HCQ widely usedHCQ widely used Small but definite risk of Small but definite risk of
retinal toxicityretinal toxicity Dose, duration, risk factorsDose, duration, risk factors ScreeningScreening CounselingCounseling
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Dr Nikunj Dadhania,Dr Nikunj Dadhania,11stst Yr DNB Rheumatology, Yr DNB Rheumatology,
Apollo Indraprastha Apollo Indraprastha Hospital,Hospital,New DelhiNew Delhi
Acknowledgement:Acknowledgement:
Thank you Thank you
for your for your
attention!attention!
Automated VFT: 10-Automated VFT: 10-22
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‘‘Flying Saucer’ SignFlying Saucer’ Sign Chen: Clin Ophth: 2010: 4. Chen: Clin Ophth: 2010: 4. 1151-581151-58
Guidelines for Screening for Guidelines for Screening for Retinal Toxicity:Retinal Toxicity:
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1.1. Fundoscopy & Perimetry every 12 Fundoscopy & Perimetry every 12 mths;mths;
2.2. Baseline evaluation in patients > Baseline evaluation in patients > 60 yrs & with renal impairment60 yrs & with renal impairment
IRA IRA GuidelinesGuidelines::
Misra et al. Indian Jour Rheumatol. 2008 Nov; 3 (3):Misra et al. Indian Jour Rheumatol. 2008 Nov; 3 (3):
i) Reduces i) Reduces formation of formation of peptide-MHC peptide-MHC
complex complex pH- IV vacuoles:pH- IV vacuoles:
.protein degradation .protein degradation in lysozomesin lysozomes.post-translational .post-translational modification of modification of proteins in Golgi proteins in Golgi apparatusapparatus
ii) Inhibition of TLR ii) Inhibition of TLR
CD4CD4 II II MHCMHC
PeptidePeptide
HCQ: HCQ: Anti-inflammatory Anti-inflammatory actionaction::
Fox R: Semin Arthr Rheum 1993: Oct 23 (2 Suppl1) 82-91Fox R: Semin Arthr Rheum 1993: Oct 23 (2 Suppl1) 82-91
Down regulation of immune responseDown regulation of immune responseT Cell activationT Cell activation