The inconsistent reports regarding the effects of age on risk of 4AQR suggest that it is a weak factor. Some have reported no effect [18, 28, 30]. Many have reported that increasing age increases the risk of hydroxychloroquine and chloroquine retinopathy [14, 31]. In reports showing an association, the most commonly asserted threshold for increased risk is 60 years [15, 23], although some have posited ages 40 [17, 32], 50 [6, 31], 65 [33], or 70 [34] years as more appropriate.

There is no rational basis for any of these thresholds [35]. The evidence to support associations of increased susceptibility to 4AQR with age is indirect. For example, a documented case of hydroxychloroquine retinopathy occurred in a patient taking less than 6.5 mg/kg/d. The patient happened to be older than 60 years. Because dosing was appropriate and there were no other risk factors, age was hypothesized to be a relevant predisposing factor [35]. In other studies the age of patients with and without retinopathy has not been compared [36].

It is probable that risk increases incrementally and continuously with age rather than reaching a threshold at which risk suddenly increases. Evidence for this comes from articles in which the median age for patients developing hydroxychloroquine and chloroquine retinopathy is greater than that of patients without retinopathy taking these drugs [14, 37]. In a multivariable analysis of risk factors associated with hydroxychloroquine retinopathy, age was not a significant predictor after other variables were taken into account [15]. Although Elman suggested that age less than 50 implies no need to screen [31], enough patients under age 50 have been reported with retinopathy that younger age does not excuse screening in published guidelines.

There may be multiple mechanisms by which increased age adds to the risk of 4AQR. For example, renal function decreases with age. As decreased renal function is a risk factor for 4AQR, increased age may just be an indirect risk factor working through the proximate factor of diminished renal function [22]. Likewise, effectiveness of hepatic metabolism of 4AQs may decrease with age, although this has not been investigated.

More than 90 % of cases of 4AQR occur in females [1, 28, 38, 39], but the relevant factor for this preponderance is the lower heights and ideal body weights (IBWs) of females with no adjustment of dosing. That is, the risk factor is the overdosing and not the gender.

A calculation illustrates this point. The average height of women in the US population is 65 ± SD3.5 inches and that of men is 69 ± SD2.8 inches. The IBW at which a typical hydroxychloroquine (HC) dose of 400 mg/d becomes toxic based on a threshold of 6.5 mg/kg/d is 135 pounds, which corresponds to a height of 5 ft 3 inches using the National Heart Lung and Blood Institute Table of IBW (Table 7.2). If one assumes that the distribution of IBWs is normal, then the concept of a Z-score is applicable (see Chap. 8). The Z-score tells where, along the normal distribution, a value of the independent variable (in this case height) lies. It is calculated by the formula Z = (X − μ)/σ, where X is the value of the variable (in this case, 63 inches), μ is the mean value of the normal distribution (in this case, 65 inches), and σ is the standard deviation of the distribution (in this case, 3.5 inches). The Z-score for a height of 5 feet 3 inches (63 inches) would be Z = (X − μ)/σ = (63–65)/3.5 = −0.5714. Looking this score up in a standard table of Z-scores shows that 28.4 % of women will be overdosed with typical 400 mg/d dosing of hydroxychloroquine. The analogous calculation of a Z-score for men yields a score of −2.14 which implies that only 1.6 % of men will be overdosed with typical hydroxychloroquine dosing. Similar calculations for the other algorithms of IBW in common use yield height cut-points ranging from 62 to 68 inches at which typical dosing represents overdosing (Table 7.2) [40].

The importance of adjusted daily dose (ADD) is suggested by the rarity of retinopathy in patients who take 4AQs for malaria prophylaxis (a low-dose use, see Chap. 2) and the frequency of overdosing among patients with retinopathy who take the drugs for chronic autoimmune diseases (a higher-dose use) [6, 29, 50]. However, the evidence to support the role of ADD is not ironclad. Patients developing retinopathy do not always have higher mean daily doses than patients without retinopathy. For example, in one study involving both 4AQs, 18 patients with retinopathy had a mean daily dosage that was significantly higher than 84 patients without retinopathy. For patients on chloroquine, the mean daily doses were 5.35 ± 0.26 mg/kg (IBW)/d (n = 10) and 3.97 ± 1.2 mg/kg (IBW)/d (n = 34) for the cases with and without retinopathy, respectively. For those on hydroxychloroquine, the mean daily doses were 8.39 ± 0.42 mg/kg (IBW)/d (n = 8) and 6.90 ± 0.23 mg/kg (IBW)/d (n = 50) for the cases with and without retinopathy, respectively [2]. However, in a different study that involved both 4AQs, the mean ADDs were not different between patients with and without retinopathy [14].

There is considerable overlap in the daily dosing of patients with and without retinopathy. Many patients taking toxic doses never develop retinopathy, and rarely do patients taking subtoxic doses develop retinopathy. Levy and colleagues reported on 302 patients taking 6.5 mg/kg/d or more based on actual body weight (ABW). Only one of them developed retinopathy [51]. An example of such a patient is shown in Fig. 7.1. There have been between approximately 20 cases in which retinopathy developed despite adjusted daily dosing in the range less than 6.5 mg/kg (IBW)/d [1, 26, 52–59]. This implies considerable individual variability in sensitivity to retinopathy [60].

A range of maximal safe daily doses can be found in the literature ranging from 3 to 5.1 mg/kg/d for chloroquine and from 6 to 7.8 mg/kg/d for hydroxychloroquine (see Chaps. 2 and 3) [2, 61–63]. The most commonly cited toxic thresholds are 3.5 mg/kg(IBW)/d for chloroquine and 6.5 mg/kg (IBW)/d for hydroxychloroquine (see Table 3.​2).

It is important to normalize dosing by the lesser of IBW and ABW [29, 64, 65]. The importance of calculating daily dose based on IBW has been known for a long time although it is often not done and is often done inaccurately [66–70]. In the obese person, much of the body weight is fat, into which 4AQs do not distribute much (see Chap. 2), and a false sense of safe dosing may be engendered [14]. Less well known is adjusting the dose for ABW when ABW is less than IBW [25]. A flow chart (Fig. 7.2) will help the clinician who screens for hydroxychloroquine retinopathy. To reduce dosing, an easy method is to exclude dosing for 1 or 2 days of the week—typically the weekend. Because of the long half-life of hydroxychloroquine, no important fluctuations in plasma hydroxychloroquine concentrations are effected by this method. The average daily dose is calculated by adding the total weekly dose and dividing by seven.

In clinical practice, guidelines for regulating dosing based on IBW frequently get translated into guidelines based on height. These translations are based on an underlying assumption by the issuer as to which algorithm for IBW should be used. For example, Schwartz states that 400 mg/d of HC is safe unless a patient is shorter than 5 feet 2 inches [71]. This is equivalent to choosing the Metropolitan Life Insurance Table for Women of Medium Build, Top of Range algorithm relating height and IBW. Marmor makes an analogous statement that women of height less than 5 feet 7 inches are overdosed when taking hydroxychloroquine 400 mg/d. Implicit in his comment is a preference for a different algorithm relating height and IBW than the one favored by Schwartz [46, 47]. There is no evidence to guide the clinician in choosing an algorithm, but the choice has consequences. Choosing an algorithm associated with a lighter IBW (e.g., the one favored by Marmor) for a given height will lead to lower dosing, but will imply that the screening eye doctor will need to call prescribing physicians more often to adjust dosing downward. Choosing a “heavier” algorithm will allow higher doses for patients, but calls to change dosing downward will be fewer [47].

When the ADD is 6.5 mg/kg/d or less, the risk of development of retinopathy is extremely low [33, 72]. Mackenzie reported that he had never seen a case of 4AQR in a patient taking less than 6.5 mg/kg/d of hydroxychloroquine or 3.5 mg/kg/d of chloroquine [2]. His sample size for making this statement was 900 patients. Bernstein reported on 1,500 patients and noted that he had never seen a case of hydroxychloroquine retinopathy if the patient took less than 6.5 mg/kg/d and had been taking drug for less than 10 years [72, 73]. Levy reported that of 1,556 patients taking hydroxychloroquine, the only patient with definite toxicity was taking greater than 6.5 mg/kg/d [51]. In the only prospective study, 526 patients taking hydroxychloroquine at doses less than or equal to 6.5 mg/kg (ABW)/d were followed for 6 years with no cases of retinopathy. Subsequently two of these patients developed retinopathy after 6.5 and 8 years of retinopathy, respectively [74]. Had they been dosed based on IBW, presumably the incidence of retinopathy would have been even less. Since this report there have been at least 15 cases that violate his threshold [54–58, 75, 76], but this is as good a practical threshold for safety as has been found and has been widely adopted.

Among reports of retinopathy for which daily dosing by IBW has been reported, rates of overdosing range from 12.8 to 100 % (Fig. 7.1) [1, 20, 25, 30, 33, 39, 51, 63, 65, 66, 78]. The percentage of patients overdosed depends on the algorithm for IBW that is used [47]. The most common daily dosages prescribed are 400 mg/d for hydroxychloroquine and 250 mg/d for chloroquine [16, 25, 47, 69]. In the author’s series of 433 patients taking hydroxychloroquine screened for retinopathy for whom daily dosing was determined, 60 % were taking 400 mg/d. Grierson reported that 611 of 758 (81 %) of patients taking hydroxychloroquine were given 400 mg/d [69]. These commonly prescribed daily doses are in the toxic range for many women of small stature and low IBW and many taller women with an asthenic somatotype and lower ABW than IBW based on height. In the latter situation, it is the ABW that should be used for calculating daily dosing, and not the IBW [25].

In failure analyses of cases of 4AQR, overdosage is the most common problem and the most important problem, because it is remediable [1, 20, 33, 40, 79, 80]. Lowering daily dosage is a good response to data that suggest but do not prove retinopathy [23, 24, 62]. The general principle guiding clinical practice in prescribing 4AQs should be to find the smallest effective dose [31, 80, 81].