Best Paper from Ophthalmological Society of West Bengal (6´) : Progression of Hydroxychloroquine Toxicity After its Discontinuation

Dr. Subhrangshu Sengupta (S14452 )

 

 

Introduction :

Hydroxychloroquine (HCQ) and Chloroquine (CQ) are widely used for the treatment of autoimmune diseases like Systemic Lupus Erythematosus(SLE), Rheumatoid Arthritis (RA) and other related inflammatory and dermatological conditions. Newer applications of this drug in diabetes mellitus, heart disease and adjunct cancer therapy are also being evaluated.^[1] The retino-toxic effects of CQ and HCQ have been recognised for quite a few years now, with “Bull’s Eye Maculopathy”, ophthalmoscopically evident as a ring of parafoveal Retinal Pigment Epithelium (RPE) depigmentation with sparing of the central fovea, representing severe toxicity. However, this distribution is infrequent in Asians, who typically show early damage in a more peripheral pattern. ^[2,3] CQ/HCQ toxicity is however not treatable, so earliest detection of HCQ toxicity and subsequent replacement of the drug by treating physician is the only way to preserve loss of central vision.

The current study included subjects who had been on HCQ/CQ for atleast two years but had discontinued the same on medical advice and had no clinically evident funduscopic abnormality (on examination with a +78D lens) at enumeration. The study aimed to assess the retinal status at inclusion, along with progression of any morphological retinal alterations over the next two years.

Materials and Methods :

This prospective study was initiated after approval from Institutional Review Board. Subjects who had been on HCQ/CQ for atleast two years, but at the time of enumeration had been medically advised to discontinue the same, were considered for inclusion. However, subjects with a history of prolonged (>1 year) daily usage of HCQ/CQ at >7mg/kg body weight were not enumerated. Subjects with any corneal disease and media opacities preventing adequate view of the posterior pole, subjects with history of ocular trauma, one eyed and bilaterally blind patients and those with any histories of ocular surgery in either eye were not enumerated. Subjects were also excluded if they had ophthalmoscopically evident Bull’s Eye Maculopathy, any evident macular pathology or any other previously diagnosed ocular or systemic disease that could affect the optic nerve, visual field or retinal health or were on other medications affecting the retina (eg, tamoxifen, ethambutol). Included subjects were made to sign informed consent form before enumeration.

The subjects were examined at inclusion and subsequently were followed up every six months for the next 2 years. At each visit, all subjects underwent complete ophthalmological check up including assessment of visual acuity, color vision(by Ishihara Chart), slit lamp examination and dilated fundoscopy including +78D biomicroscopy. Prior to dilation, all subjects underwent Central 10-2 Automated Perimetry (Carl Zeiss Inc, USA) using the SITA algorithm. Included subjects also underwent Spectral Domain – OCT (RT Vue SD OCT, Optovue), wherein 6mm macular scans and line scans were recorded. Special note was taken of the status of the ellipsoid zone(EZ).

Results :

Nine subjects fulfilling the laid down inclusion/exclusion criteria were included in the current study. All the subjects were females with an average age of 62 years at the time of inclusion (Range : 44-69 years). All of those included had ceased intake of CQ/HCQ 5-12 months prior, on advice of treating physician. The average treatment duration of the included subjects was about 8.5 years(Range: 3-16 years). None of the included subjects had any ophthalmoscopically detectable fundal lesion at the time of inclusion, as per inclusion criteria.

Table 1 shows the change in best corrected visual acuity of the included subjects over two years(in ETDR letters). The subjects lost between zero and twelve ETDRS letters during the study period.

Table 1: Change in Best Corrected Visual Acuity (ETDRS letters) over two years of study

 

Subject	Age	Eye	BCVA	BCVA	BCVA	BCVA	BCVA	BCVA M24-
	(yrs)		M0	M6	M12	M18	M24	BCVA M0
1	44	RE	66	64	64	64	62	4
		LE	64	64	64	62	60	4
2	54	RE	58	58	58	58	58	0
		LE	57	57	56	56	54	3
3	59	RE	68	66	66	64	64	4
		LE	66	63	62	60	60	6
4	63	RE	66	62	62	62	61	5
		LE	66	66	65	64	65	1
5	64	RE	60	60	58	58	58	2
		LE	62	62	61	61	61	1
6	66	RE	54	54	54	52	50	4
		LE	53	51	49	50	50	3
7	68	RE	57	57	56	54	56	1
		LE	54	54	52	51	50	4
8	68	RE	51	49	47	44	42	9

 

		LE	56	50	44	44	44	12
9	69	RE	53	51	51	49	48	5
		LE	55	51	51	50	50	5

 

At the time of inclusion, only one eye of a single subject had a small area of disruption of ellipsoid zone on SD OCT (maximum linear dimension = 82 microns) with no subject demonstrating any significant defect in the 10-2 field reports (based on age and sex matched Pattern Standard Deviation(PSD) values from the database of Humphrey Field Analyser, Carl Zeiss, USA). At the end of the study period, twelve eyes of eight subjects developed new disruptions of the ellipsoid zone(EZ) and one eye showed progression of EZ disruption on SD OCT. Four eyes did not show any significant change in foveal contour or architecture and one eye showed appearance of cystic spaces in the neuroretinal layers on OCT. Eleven eyes of seven subjects showed a significant progression on AP, based on change in PSD Values at p<0.05, as shown in Table 2. None of the subjects however had any color vision abnormality (as detected by Ishihara Chart) or “bull’s eye maculopathy” at the end of the study period.

Table 2: Changes in Ellipsoid Zone(EZ) disruption by SD-OCT and Pattern Standard Deviation (PSD) by Humphrey Field Analyser (10-2, SITA Standard) of the included subjects over 24 months of study

 

Subject	Age	Eye	EZ	EZ	PSD by 10-2	PSD by 10-2
	(yrs)		Disruption	Disruption	HFA (dB)	HFA (dB) at
			(µ) at M0	(µ) at M24	at M0	M24
1	44	RE	0	0	1.62	2.98
		LE	0	78	1.88	7.89
2	54	RE	0	0	1.12	2.43
		LE	0	0, MCC	1.26	2.41
3	59	RE	0	104	1.87	9.11
		LE	0	124	2.11	8.45
4	63	RE	0	92	1.99	7.12
		LE	0	49	1.42	2.27

 

5	64	RE	0	58	1.84	2.26
		LE	0	0	1.32	2.13
6	66	RE	0	146	2.11	11.02
		LE	0	109	1.92	9.94
7	68	RE	0	0	1.26	2.19
		LE	0	122	1.86	7.24
8	68	RE	0	157	2.41	10.1
		LE	82	194	2.66	11.49
9	69	RE	0	202	2.12	10.62
		LE	0	160	2.44	14.14

 

Legend : EZ Disruption = Ellipsoid Zone Disruption as determined by SD-OCT (RTVue)

 

	PSD = Pattern Standard Deviation;					HFA = Humphrey Field Analyser
	M0 = Initiation of study/Month 0;					M24 = End of Study period/Month 24
Table 3 summarises the various parameters analyzed during the course of the study over
twenty four months.
Table 3: Various analysed parameters in the included subjects over 24 months
Subject		Age	Eye	Months	Years of	BCVA	EZ	PSD
				since	Exposure	Change	Disruption	decrease 10-
				Cessation at			(µ) at M24	2 HFA (dB)
				Exit (24mts)				at M24 (Avg
								= 5.03dB)
1		44	RE	29	4	4	0	1.36
			LE			4	78	6.01
2		54	RE	29	3	0	0	1.31
			LE			3	0, MCC	1.15
3		59	RE	34	10	4	104	7.24

 

		LE			6	124	6.34
4	63	RE	33	8	5	92	5.13
		LE			1	49	0.85
5	64	RE	30	6	2	58	0.42
		LE			1	0	0.81
6	66	RE	35	11	4	146	8.91
		LE			3	109	8.02
7	68	RE	36	7	1	0	0.93
		LE			4	122	5.38
8	68	RE	36	16	9	157	7.69
		LE			12	194	8.83
9	69	RE	33	12	5	202	8.5
		LE			5	160	11.7

 

Legend : EZ Disruption = Ellipsoid Zone Disruption as determined by SD-OCT (RTVue)

PSD = Pattern Standard Deviation;HFA = Humphrey Field Analyser

M0 = Initiation of study/Month 0;M24 = End of Study period/Month 24

Discussions and Conclusion :

Data on long-term follow-up after cessation of CQ/HCQ therapy are limited. The current study was prospective and examined patients over a duration of two years and provides follow up data of 36 months post cessation of CQ/HCQS in two subjects.

Older studies using visual acuity or visual fields as parameter concluded that retinal function either remained stable, sometimes improved and only occasionally deteriorated after cessation of CQ or HCQ intake.^[4,5] A later study reported a decrease of retinal function during follow-up in 63% of patients over a period of 8 years. ^[6] Few recent studies have also described progressive loss of retinal function have also been described. ^[7,8,9] In a recent study, Kellner et al concluded that CQ retinopathy can progress over a long period of time after drug cessation and may be complicated by cystoid macular oedema, epiretinal membrane formation and peripheral involvement. ^[10]

The present study showed a deterioration in BCVA progressing even three years after stopping HCQ/CQ (p<0.05) with an average decrease of 2.55 ETDRS letters at 12 months and 4.05 ETDRS letters(p<0.001) at 24 months in the included subjects. Only one eye(5.56%) had EZ disruption on SD-OCT at initiation of the study whereas 13 EYES (72.2 %) had EZ disruption at end of study period. None of the included subjects had PSD<1% on 10-2 SITA Standard by HFA at initiation whereas 11 eyes (61.1 %) had PSD<1% at end of study period. The current study also established a positive correlation between EZ Disruption/AP deterioration and duration of exposure to HCQ/CQ, as shown in Table 4.

Table 4 : Correlation of the various factors analyzed over 24 months of study

 

Variables Analyzed	Pearson’s Correlation	P
	Coefficient [r]	value
Years of Exposure and PSD at Month 24	0.61	0.007
Years of Exposure and EZ disruption at	0.699	0.0012
Month 24
Visual Acuity Decrease and Decrease in PSD	0.53	0.02
at Month 24
Visual Acuity and EZ Disruption at Month 24	0.53	0.024

 

Legend : EZ Disruption = Ellipsoid Zone Disruption as determined by SD-OCT (RTVue)

PSD = Pattern Standard Deviation as measured by Humphrey Field Analyser(p<0.05 was considered statistically significant; hence all the analyzed values were statistically significant)The study thereby concludes that subjects who are initiated on HCQ/CQ need to be counselled accordingly. Once definitive signs of retinopathy are recognized, the decision to stop medication should be made in conjunction with the patient and the prescribing physician. Early recognition of ocular toxic effects of CQ/HCQ, even before any fundus changes are clinically visible, using visual fields (Central 10-2) and SD-OCT, will greatly minimize late progression and the risk of visual loss. Our dataset therefore substantiates the recommendation that basic non invasive ocular tests like Automated Perimetry and Spectral Domain OCT should be carried out routinely (six monthly/yearly) in subjects taking chloroquine or hydroxychloroquine.

References :

1. Marmor MF, Kellner U, Lai TYY, Melles RB, Mieler WF, et al. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology 2016;123:1386-94.
2. Melles RB, Marmor MF. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity. Ophthalmology 2015;122:110–6.
3. Lee DH, Melles RB, Joe SG, et al. Pericentral hydroxychloroquine retinopathy in Korean patients. Ophthalmology 2015;122:1252–6.
4. Carr RE, Henkind P, Rothfield N, et al. Ocular toxicity of antimalarial drugs. Long-term follow-up. Am J Ophthalmol 1968;66:738–44.
5. Brinkley JR Jr, Dubois EL, Ryan SJ. Long-term course of chloroquine retinopathy after cessation of medication. Am J Ophthalmol 1979;88:1–11.
6. Easterbrook M. Long-term course of antimalarial maculopathy after cessation of treatment. Can J Ophthalmol 1992;27:237–9.
7. Salu P, Uvijls A, van den Brande P, et al. Normalization of generalized retinal function and progression of maculopathy after cessation of therapy in a case of severe hydroxychloroquine retinopathy with 19 years follow-up. Doc Ophthalmol 2010;120:251–64.
8. Michaelides M, Stover NB, Francis PJ, et al. Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy. Arch Ophthalmol 2011;129:30–9.
9. Kazi MS, Saurabh K, Rishi P, et al. Delayed onset chloroquine retinopathy presenting 10 years after long-term usage of chloroquine. Middle East Afr J Ophthalmol 2013;20:89–91.
10. Kellner S, Weinitz S, Farmand G, Kellner U. Cystoid macular oedema and epiretinal membrane formation during progression of chloroquine retinopathy after drug cessation. Br J Ophthalmol 2014;98:200–206.