Skin and ophthalmic complications of chloroquine and hydroxychloroquine in patients with rheumatoid arthritis and systemic lupus erythematous

ABSTRACT Immunosuppressive agents are routinely used to control autoimmunity. However, some adverse events are correlated to their clinical applications. The aim of this study was to study the clinical findings and ocular and cutaneous side effects of chloroquine (CQ) and hydroxychloroquine (HCQ), as current immunomodulators, in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This descriptive study was performed on 360 individuals referred to the Rheumatology clinic during 2003–2020. Demographic characteristics and other information were collected from patients with RA and SLE. Skin and ocular complications were evaluated in patients who were on treatment with CQ and HCQ. Study populations consisted of 199 subjects with RA and 161 cases with SLE. The frequencies of skin and ocular complications in all patients treated with CQ and HCQ were 32 (17.65%) and 94 (51.9%), respectively. The prevalence of skin complications in patients with RA and SLE was 20 (10.05%) and 22 (13.66%), respectively. The frequencies of ocular complications in patients with RA and SLE were, respectively, 58 (29.4%) and 36 (22.5%). Multiple logistic regression analysis revealed that ophthalmic complications of CQ and HCQ in all patients were dependent on the effects of the duration of drug uses, disease duration, and cumulative doses (p < 0.05), unlike skin complications. Disease types had no effect on ocular complications. Based on these findings, treatment with CQ and HCQ participates in some skin and ocular complications in patients with RA and SLE which are largely associated with the duration of disease and treatment.


Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the breakdown of tolerance to self-antigens, production of autoantibodies against self-antigens, formation of immune complex, and its deposition in different tissues which lead to inflammation and tissue damage.It affects approximately 1% of the general population.This disorder contributes to swelling, inflammation, and destruction of joints, which may lead to severe disability and early death. [1]ystemic lupus erythematosus (SLE) is mentioned as a heterogeneous autoimmune disease with defect(s) in tolerance to self-antigens leads to autoantibody production against self-antigens.Autoantibodies bind to circulating antigens.[4] The prevalence of SLE is estimated from 50 to 150 cases per 100,000 individuals. [5]Although, the etiology of autoimmune disorders is not yet well reported, it is revealed that hormonal, environmental, and genetic factors are responsible for their development.
Until now, several therapeutic approaches have been proposed for the treatment of autoimmunity.Immunosuppressive agents are considered as the most treatment to control these diseases. [6]Among immunoregulatory drugs, chloroquine (CQ) is mostly employed to treat RA and SLE.Despite the appropriate therapeutic effect of these drugs, some side effects have been reported upon their clinical applications.The itching is mentioned as a major skin side effects of CQ among Africans (up to 70%). [7]Long-term use of CQ in patients suffering from RA and SLE may have toxic effects on the eye, such as keratopathy and maculopathy.Animal studies have revealed that treatment with CQ leads to damage the inner and outer retina of the eye.In line with toxic effects of this drug, it is reported that CQ can participate in enhancing the rate of allergic dermatitis, skin rash, brown pigmentation in the mucous membranes and skin, photosensitivity, separation of the nail from the bed, and whitening of the hair on the head and eyebrows. [8,9]Although some reports have pointed to adverse events of CQ in patients with autoimmunity, others have shown that these impacts are largely related to the duration and dose of the drug so that they are mostly observed in patients who are treated with high doses of CQ for a long-term period. [10,11]ydroxychloroquine (HCQ) is one of the most frequently used drugs in the treatment of RA, SLE, and other autoimmune diseases due to its immunomodulatory, anti-inflammatory, photoprotective, and metabolic actions and low side effect profile.Previous reports have pointed that the use of HCQ can result in some ophthalmic complications in patients suffering from autoimmunity. [12]Retinopathy is mentioned as a potential side effect of longterm treatment with HCQ.Other ocular complications related to HCQ are photopsia, sensitivity to light, metamorphopsia, paracentral scotoma. [13]The daily dose, long-term prescription, and drug administration in patients with kidney diseases are considered as risk factors for enhancing adverse events of HCQ. [14]In line with this notion, Youssef et al. revealed that the frequencies of vision loss in patients treated with HCQ for more than 5 years and CQfor more than 20 years were 7.5% and 20%, respectively. [15]In another study by Jaumouillé et al., it was shown that 6.5% of patients treated with HCQ suffered from maculopathy and the major risk factor was the cumulative dose of the drug. [16]Melles et al. reported that the prevalence of retinopathy was 7.5% in autoimmune patients treated with HCQ.In this study, several risk factors have been proposed to be responsible for increasing retinopathy including the daily dose, duration of drug use, kidney diseases, and simultaneous treatment with tamoxifen. [17]Tangtavorn et al. showed that age and sex along with cumulative dose may be considered as other predisposing factors for inducing retinopathy in patients treated with HCQ and CQ. [18]Another study showed that the race could act as a risk factor for increasing retinopathy associated with HCQ. [9]In contrast to the previous studies, some reports have indicated that HCQ induced retinopathy in only 2.9% of patients. [19]aving considered that CQ and HCQ are mostly prescribed to treat RA, SLE, and other autoimmune disorders and there is a discrepancy in adverse events of these drugs in different populations, the aim of the current study was to investigate the clinical findings and ocular and cutaneous complications of CQ and HCQ in patients with RA and SLE.

Materials and methods
The study population consisted of 360 individuals with RA and SLE who were chosen from Iranian Rheumatology Registry System.The patients were referred to the rheumatology clinic of Shahid Beheshti hospital, Kashan, Iran from February 2003 to May 2020.The disease diagnosis was performed by a rheumatologist according to Systemic Lupus International Collaborating Clinics classification criteria for SLE [20] and ACR/EULAR criteria for RA. [21,22]All patients were on remission phase of disease and had no other health problems at the last visit.Patients were on treatment with CQ and HCQ at least 10 months after the study initiation.During the treatment of SLE, approximately 20% of patients received cyclophosphamide pulse therapy for six months and then mycophenolate mofetil for 18 months, due to severe renal involvement.Skin and ophthalmic complications were assessed after CQ and HCQ administrations and confirmed by the dermatologist and ophthalmologist, respectively.Ophthalmology visit, including anterior segment examination and fundoscopy using a slit lamp device, was performed before the treatment and then annually by an ophthalmologist.Perimetry was also performed on each ophthalmology visit.Patients were tested on conventional automated perimetry, with the central 10-2 SITA-Standard program.A field perimeter (Humphrey Field Analyzer II, HFA; Carl Zeiss Meditec, Dublin, CA) was used to provide a standard evaluation of the central visual field (±10°) of patients.The treatment with CQ or HCQ was stopped for patients with new pigmentary changes in the macula or a scotoma in the visual field and those with severe skin rash and diffuse hyperpigmentation.Inclusion criteria was patients with the conclusive diagnosis of RA and SLE.Exclusion criteria included: 1)individuals with a history of eye diseases such as ocular toxoplasmosis and degenerative retinal disease; 2) diabetic patients with ocular involvement; and 3) subjects with skin disorders.

Statistical analysis
Data were analyzed by SPSS (V. 19, IBM, Chicago, IL.) and are represented as the mean ± standard deviation (SD).The normal distributions of data was evaluated by Kolmogorov -Smirnov test.The groups with the normal distributions were analyzed using unpaired t-tests, while those with nonnormal distributions were compared by Mann -Whitney tests.Fishers exact and Chisquare tests were employed to compare the ratios.p values less than or equal to 0.05 were considered statistically significant.

Patient descriptions
Among 360 individuals participated in the study, 161 cases (44.7%) had SLE and 199 subjects (55.3%) had RA.Of 360 patients, 323 (89.7%) were women.The mean age of the patients was 51.7 years.The mean age of disease onset was 42.6 years, while the mean of disease duration was approximately 8.9 years.Of 161 subjects with RA, 5 cases had subcutaneous nodule and one case had vasculitis.Other demographic and clinical characteristics of patients are shown in Table 1.
There was a significant difference in the gender, age, disease duration, and mean age of disease onset between RA and SLE patients (p = 0.001).However, no significant difference was observed in terms of the nationality, duration of drug uses, cumulative doses, and daily doses of CQ and HCQ between RA and SLE groups(Table 1).

Skin and ophthalmic complications of CQ and HCQ in patients with RA and SLE
As shown in Table 2,10.05% of patients with RA suffered from skin complications related to CQ and HCQ, while it was 13.66% for patients with SLE.The most frequent ocular complication in patients with RA and SLE was retinopathy(Table 2).The most common skin complications in patients were hyperpigmentation and Rash (Table 2).Other data revealed a significant difference in corneal deposition between RA and SLE groups (p = 0.048).Other skin and ocular complications of CQ and HCQ are shown in Table 2.
In the next step, multiple logistic regression analysis was used to remove possible impacts of effective factors on the occurrence of ocular and skin complications.Our data revealed that ophthalmic complications of HCQ, unlike to CQ, in patients with RA and SLE were dependent on the effects of the use of drug, age of patients, and age of disease onset (p < 0.01, Table 3).The values of adds ratio (O.R:1.09)revealed that patient age had a positive impacts on the occurrence of ocular complications of patients with SLE and RA, while the use of HCQ and age of disease onset showed protective effects on these complications in those suffering from SLE and RA (Table 3).
Other results indicated that skin complications observed in patients with SLE and RA were dependent on the impacts of the administration of CQ and HCQ and their cumulative doses (Table 3).We observed that the use of HCQ had a protective effect on skin complications in patients (O.R:0.146,Table 3).

Discussion
Despite suitable therapeutic impacts of CQ and HCQ, some reports have pointed to adverse events upon their clinical applications.It is indicated that the use of CQ and HCQ is related to some skin and ophthalmic complications in patients with RA and SLE.Furthermore, there are some studies showing the enhancements of skin and ocular complications in patients treated with HCQ and CQ are largely associated with age, sex, cumulative dose, daily dose, and drug use in patients with kidney diseases.Therefore, this study was conducted to investigate the clinical findings, ocular and skin side effects of CQ and HCQ in patients with RA and SLE.
The results of the current study revealed that the use of CQ and HCQ could result in some skin and ocular complications in patients with autoimmunity.This finding is consistent with other reports indicating ocular complications of HCQ in patients with RA and SLE.The most common ocular complications in our patients were retinopathy and corneal deposition.Jaumouillé et al. showed that 6.5% of patients on long-term HCQ had maculopathy. [16]It is indicated that HCQ may be considered as a predisposing factor for enhancing retinopathy in autoimmune patients. [23]In a study conducted by Melles et al. theprevalence of HCQ-induced retinopathy was reported as 7.5%. [17]In addition, it is indicated that treatment with HCQ for more than 5 years and CQ for more than 20 years could lead to reduce up to 7.5% and 20% in vision, respectively. [15]Therefore, SLE patients treated with these drugs should be closely monitored for retinopathy and other ocular complications, especially patients with renal failures. [24]ome reports have mentioned that ocular complications of CQ and HCQ are related to the duration of drug uses, duration of the disease, and cumulative doses, [25] the impacts of these parameters on clinical complications in patients with SLE and RA were evaluated.Our data revealed that ophthalmic complications of CQ and HCQ in patients with RA and SLE were significantly associated with the duration of drug uses, disease duration, and cumulative doses, unlike the daily dose of CQ and HCQ.This finding was in contrast with the result of a few studies pointing to no relationship between disease duration and ocular toxicity of HCQ in patients with RA. [26] However, there are numerous researches showing ocular complications in patients with SLE and RA were directly correlated to the duration of the disease and duration of HCQ use. [27]urthermore, previous studies incriminated the cumulative dose of HCQ as the main risk factor for maculopathy. [16,18]This discrepancy may be due to the incompatibility between the duration of drug use and duration of the disease.With the increase in the duration of the disease, the duration of using the drug increases and can increase number of eye complications caused by the drug.
Having considered that the daily dose of HCQ and CQ is mentioned as one of the main risk factors for ocular complications, the correlation of the daily dose with ocular complications of HCQ and CQ were studied.We observed that the daily doses of the drugs had no significant relationship with ocular complications, which is in contrast with previous studies. [17,28,29]This inconsistency may be attributed to differences in the daily doses of HCQ and CQ used in the present study and previous reports. [28,29]lthough there is some evidence showing low side effect profile of CQ and HCQ, several studies reported multiple skin complications in patients treated with these drugs. [30]Several skin complications have been reported in regard to treatment with these drugs, including pruritus, rash, urticaria, bullous eruptions, photosensitivity and pigmentation. [30]n line with this notion, our data revealed that patients treated with CQ and HCQ had some skin complications which hyperpigmentation was the most common reported complication.Moreover, multiple logistic regression analysis indicated that cutaneous complications were independent of the effects of the nationality, duration of drug uses, disease duration, cumulative doses, and disease types.2][33]

Conclusion
The findings of the current study along with previous reports provide evidence to show that HCQ and CQ drugs result in some skin and ocular complications which are associated with the impacts of the duration of drug uses, disease duration, and cumulative doses.Althoughthese observations suggest that patients on treatment with these drugs should be closely monitored for some skin and ocular complications, especially patients with renal failures, a limitation of the study was lack of the control groups with SLE and RA received other immunosuppressive agents but no HCQ and CQ treatments.Therefore, further studies with larger sample size are required to clarify the possible skin and ocular complications of immunosuppressive drugs along with HCQ and CQ.

Table . 1
Demographic, laboratory, and clinical characteristics of patients with SLE and RA.

Table 2
Ocular and skin complications related to CQ and HCQ in patients with RA and SLE.

Table 3 .
Multiple logistic regression analysis of effective factors on the occurrence of ocular and skin complications in patients with SLE and RA.Standard error of B; 3 Adjusted odds ratio (O.R); 4 95% confidence interval for adjusted O.R.