Use of antimalarials in dermatology

The antimalarials chloroquine and hydroxychloroquine have been used for the treatment of inflammatory diseases for more than 60 years. Even today new indications evolve due to the complex mode of action of these compounds. Due to the fear of side effects, especially irreversible retinopathy, their use is often limited. These side‐effects, however, are a consequence of excessive daily dosages. An effective, safe therapy needs correct dosing, i. e. adherence to maximal daily dosages of 3.5(–4) mg chloroquine or 6(–6.5) mg hydroxychloroquine per kilogram ideal body weight. If the actual body weight is lower than the ideal body weight, this actual weight is used for the calculation of the dosage. Observing these limits allows a rather safe therapy of the diseases like lupus erythematosus, REM syndrome, porphyria cutanea tarda (2 × 125 mg chloroquine/week), cutaneous sarcoidosis and dermatomyositis. If standard therapies fail, then antimalarials can be tried to treat Sjögren syndrome, granu‐loma annulare or erosive lichen planus. If therapy fails, either can be combined with quinacrine to increase their effectiveness. Chloroquine and hydroxychloroquine are indispensable and well‐tolerated essential drugs in dermatology and especially suited as part of a combination scheme, for example with corticosteroids, as they act synergistically and reduce side‐effects.     

Chloroquine retinopathy: preventable by monitoring the maximum daily dose

Decisive for the development of chloroquine retinopathy is not the total cumulative dose. Recent findings indicate that retinopathy develops if daily dosages are too high. Therefore, daily dosages of 4 mg chloroquine/kg ideal body weight and 6.5 mg hydroxychloroquine/kg body weight, respectively, should not be exceeded. If these maximum daily dosages are observed, long-term therapy over periods of months or even years seems to be safe.     

Synthetic antimalarials

The antimalarials, mainly chloroquine and hydroxychloroquine, derive from the quinoleine core of quinine. Their initial therapeutic indication was the treatment of malaria attacks but, because of anti-inflammatory and immuno-modulatory activities, they have been since used to treat many other pathologies, in particular dermatological ones. For some of these pathologies, lupus or porphyria cutanea tarda for example, the use of these molecules is based on obvious scientific evidence. For other pathologies (cutaneous sarcoidosis, polymyositis, polymorphous light eruption...), the data on the medical literature corroborating the daily clinical practice are extremely poor. Their toxicity is limited. Their most common toxic effects are gastrointestinal (mild nausea or diarrhea) or mucocutaneous (reversible skin or mucosal pigmentation). Their most serious and dreaded side effect, retinopathy, can be largely prevented by using amounts of APS adapted to the weight of the patients. The recommended "safe" daily dose for hydroxychloroquine is 6.5 mg per kilogramme of body weight and for chloroquine 4 mg per kilogramme of body weight. However, at 6- to 12 months intervals, follow-up eye examinations should be performed.     

Azithromycin and COVID‐19: Prompt early use at first signs of this infection in adults and children,an approach worthy of consideration

The devastating effects of the coronavirus designated severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) have led to urgent attempts to find effective therapeutic agents for inpatient and outpatient treatment of COVID‐19. Initial enthusiasm for the combination of hydroxychloroquine and azithromycin has abated. However, as a result of positive clinical experience with azithromycin used alone during the first few days of the flu‐like illness caused by this coronavirus, we recommend formal clinical trials using azithromycin early in the course of a COVID‐19 infection. There is one clinical trial initiated, the individually randomized, telemedicine‐based, “Azithromycin for COVID‐19 Treatment in Outpatients Nationwide” based at the University of California San Francisco. This placebo‐controlled trial is designed to determine the efficacy of a single 1.2‐g dose of oral azithromycin to prevent COVID‐19 patient progression to hospitalization. We recommend formal clinical trials of azithromycin in its prepackaged form at the first sign of COVID‐19 infection in adults and children, using an initial adult dose of 500 mg followed by 250 mg per day for 4 days, a total cumulative dose of 1.5 g, and for children 5 to 18 years of age, 10 mg/kg on the first day followed by 5 mg/kg for 4 days.     

Adverse cutaneous reactions to hydroxychloroquine are more common in patients with dermatomyositis than in patients with cutaneous lupus erythematosus

BACKGROUND: Hydroxychloroquine sulfate and other antimalarial drugs have been used successfully as adjunctive therapy for patients with cutaneous lesions of dermatomyositis over the past 20 years. An increased incidence of cutaneous reactions to hydroxychloroquine has been postulated to occur in patients with dermatomyositis. OBJECTIVE: To determine if adverse cutaneous eruptions due to hydroxychloroquine are more common in patients with dermatomyositis than in those with cutaneous lupus erythematosus. DESIGN: Retrospective, age-, sex-, and race-matched case-control study. SETTING: University-affiliated practice. PATIENTS: The study comprised 42 patients with dermatomyositis (39 adults) and 39 age-, sex-, and race-matched adult patients with lupus erythematosus. MAIN OUTCOME MEASURES: Presence or absence of documented drug eruption due to hydroxychloroquine exposure. RESULTS: Of 39 patients, 12 (31%) with dermatomyositis developed a cutaneous reaction to hydroxychloroquine. Among age-, sex-, and race-matched patients with cutaneous lupus erythematosus, only 1 developed a cutaneous reaction to hydroxychloroquine. None of the reactions observed in our patients resulted in serious morbidity or mortality. Additionally, 4 patients with dermatomyositis who reacted to hydroxychloroquine were treated with oral chloroquine phosphate, 2 of whom also reacted to chloroquine phosphate. CONCLUSIONS: When contemplating antimalarial therapy for dermatomyositis, both the physician and the patient should recognize that non-life-threatening cutaneous reactions may occur in approximately one third of patients and that perhaps one half of those who react to hydroxychloroquine will also react to chloroquine.     

Hydroxychloroquine-Induced Retinopathy

Dermatologists use antimalarials to treat conditions such as cutaneous lupus erythematosus. One potentially serious adverse effect of these agents is irreversible maculopathy. Although there is some evidence that hydroxychloroquine and chloroquine have similarly narrow therapeutic indices with regard to retinal toxicity, the former is thought to be less damaging to the retina and is thus more widely employed by dermatologists. The current recommended maximal dose for hydroxychloroquine is 6.5 mg/kg/day, with the weight in kilograms used for this calculation being the ideal bodyweight rather than actual bodyweight. Ophthalmologic follow-up is an important component of monitoring patients taking antimalarials. Recommendations for follow-up frequency have varied, and we present the recent guidelines from the American Academy of Ophthalmology. Despite dose limitations and ophthalmologic monitoring, irreversible retinal damage can occur. Among the reported cases, there does not seem to be any obvious predictor of the development of maculopathy. The idiosyncratic nature of this adverse effect may be related to interindividual differences in drug metabolism. To understand why only some patients develop retinopathy, better pharmacokinetic models need to be developed, and further elucidation of the precise mechanism of retinal damage is required.     

Kombination der Antimalariamittel Mepacrin und Chloroquin bei therapieresistentem kutanem Lupus erythematodes

Antimalarials represent the first line in treatment of cutaneous lupus erythematosus (LE). However, some patients show no improvement on monotherapy with chloroquine or hydroxychloroquine. A 30-year-old female patient had treatment-resistant cutaneous LE exhibiting features of both LE tumidus and subacute cutaneous LE. Previously, the patient had been unsuccessfully treated with chloroquine, hydroxychloroquine, dapsone, and azathioprine, each in combination with variable doses of prednisolone. However, the LE lesions increased during these therapeutic regimens. A combination of chloroquine and mepacrine therapy led to improvement and then total clearing after 4 months of treatment.     

Photodermatosis induced by hydroxychloroquine: 4 cases]

BACKGROUND: Hydroxychloroquine is an antimalarial drug often used in dermatology for its photo-protective effects. Four cases of photodermatosis induced by hydroxychloroquine are reported. CASE REPORTS: Four patients, aged from 21 to 68 years, developed a photolocalized eruption from 6 days to 10 weeks after starting hydroxychloroquine. The minimal erythemal dose was decreased in the total spectra and UVA at the onset of the eruption and became normal after stopping hydroxychloroquine in the 2 patients that were controlled. In 3 cases, hydroxychloroquine was the only single drug imputable; chronological imputability was plausible. In the last case, both hydroxychloroquine, carbamazepine and fluvoxamine had a common imputability which was plausible. In the 4 cases, a favourable outcome was observed after stopping hydroxychloroquine, and no recurrence occurred with a mean follow-up of 3.8 years (1-4 years). In one case, a photodistributed eruption occurred during treatment with a related molecule: chloroquine. DISCUSSION: Photodermatosis with hydroxychloroquine have rarely been described in the literature, while quinine from which hydroxychloroquine is derived, is well known for its risk of photosensibilization. The main differential diagnosis of these drug eruptions is an eruption caused by the photodermatosis that initially required treatment with hydroxychloroquine.     

Antimalarials—Are They Safe to Use in Children?

Abstract: From 963 to the present, many reviews of antimalarials for use in dermatology have mentioned the special sensitivity of children to these drugs. Fatal reactions have been limited to accidental or intentional overdosage and two instances of IM injection. While 1 gm of chloroquine can produce fatal reaction in very young children, analysis of published and unpublished cases show that adults exhibit a similar sensitivity when compared on a mg/kg basis. This information should encourage a physician to use antimalarials where appropriate, but special precaution should be taken to prevent poisoning.     

儿童头皮深在性红斑狼疮五例

目的 探讨儿童头皮深在性红斑狼疮（LEP）临床及病理学特征。 方法 回顾性分析5例LEP患儿临床、组织病理特点及治疗和预后情况。 结果 5例儿童头皮LEP,男2例,女3例;中位发病年龄5个月（范围2 ～ 38个月）;中位病程15个月（范围4 ～ 72个月）。皮损为头部弧形或环形紫红色萎缩性斑块伴脱发,枕部及颞部最常受累。1例患儿抗核抗体（ANA）1 ∶ 100,4例患儿ANA抗Ro/SSA、La/SSB抗体检查均为阴性。组织病理学改变主要为脂肪透明变性,黏蛋白沉积及脂肪小叶淋巴细胞灶状聚集。2例口服泼尼松（1.5 ~ 2） mg·kg-1·d-1, 1例口服羟氯喹5 mg·kg-1·d-1,1例口服泼尼松1.5 mg·kg-1·d-1并联合羟氯喹5 mg·kg-1·d-1;1例患儿仅外用卤米松乳膏及0.03%他克莫司软膏。患儿皮损于治疗后2 ~ 3月均获得缓解,6个月消退,新发生长,随访1.5年未见病情反复。 结论 头皮LEP对泼尼松及羟氯喹治疗反应良好,患儿可选用强效糖皮质激素及钙调磷酸酶抑制剂外用治疗。     

Effective treatment with hydroxychloroquine in a case of annular elastolytic giant cell granuloma

Annular elastolytic giant cell granuloma (AEGCG) is a rare granulomatous and elastolytic skin disease of unknown pathogenesis. Therapy for AEGCG is controversial. The data about the effectiveness of chloroquine in the treatment of AEGCG are also variable. Here, we report a case of AEGCG with significant improvement after a total treatment period of 22 weeks with hydroxychloroquine. Although a possibility of spontaneous remission cannot be ruled out, we think that chloroquine can be considered as an effective treatment of this chronic disorder.     

Sequential concentration of chloroquine in human hair correlates with ingested dose and duration of therapy.

Human scalp hair was analyzed for chloroquine using gas-chromatography. In 5 patients it was demonstrated that the amount of uptake of chloroquine into the hair varied proportionally with the dosage (from 500 mg/week to 10 g single dose) and with the time of administration. The chloroquine concentrations ranged from 8 to 1100 micrograms/g hair. Chloroquine could be determined quantitatively after a single toxic dosage used in a suicidal attempt and also after low therapeutic doses. The sequential examination of the hair shaft allows an assessment of the chloroquine amount taken over time, the individual dosage, the initiation and termination of therapy. As hairs can be collected easily, they are a unique specimen for investigation, and it is suggested that they can virtually be used as a "tachogram" of chloroquine drug-therapy or intoxication.     

Optimal Use of Antimalarials in Treating Cutaneous Lupus Erythematosus

Antimalarials have been used to treat cutaneous and systemic lupus erythematosus (LE) for decades. Although controlled studies comparing the efficacy of antimalarials versus placebo and other treatments are generally lacking, many case reports and series support the therapeutic efficacy of these agents in treating both LE-specific and -nonspecific skin lesions. Currently, the two most frequently used antimalarial agents are chloroquine and hydroxychloroquine. There may be a delay of weeks to months in the onset of therapeutic effects of antimalarials when treating LE. Smoking appears to inhibit the therapeutic efficacy of antimalarials when treating cutaneous LE. Antimalarials have been associated with a number of potentially serious adverse effects, including irreversible loss of vision. The aim of this review is to discuss the many facets of antimalarials that will help clinicians optimally utilize these agents when treating cutaneous LE.     

Hydroxychloroquine and smoking in patients with cutaneous lupus erythematosus

Antimalarials, such as chloroquine and hydroxychloroquine, have been used to treat cutaneous and systemic lupus erythematosus for decades with excellent therapeutic efficacy. Smoking seems to inhibit the therapeutic efficacy of antimalarials when treating cutaneous lupus erythematosus (CLE), but the reason behind this observation is unclear. In addition, antimalarials have been associated with several potentially serious adverse effects, including irreversible loss of vision. The aim of this literature review is to discuss the evidence for how cigarette smoking interferes with antimalarial efficacy in the treatment of CLE. Evidence-based data with long-term follow-up will allow determination of the aetiology for diminished antimalarial response, and enable selection of the best treatment to maximize long-term remission in CLE.     

Aspectos prácticos de la quinacrina como tratamiento del lupus eritematoso cutáneo: serie de casos

Hydroxychloroquine and chloroquine are antimalarials used as first-line treatment of cutaneous lupus. Quinacrine is not often employed by Spanish physicians due to a lack of information about its use and the fact that it is not marketed in Spain. It is effective in monotherapy or in combination therapy with other antimalarials. One of the advantages of quinacrine over chloroquine and hydroxychloroquine is that it does not appear to cause retinal toxicity.Quinacrine is used as second-line therapy in patients with pre-existing eye problems that contraindicate treatment with chloroquine or hydroxychloroquine (after evaluation of which drug has the better risk-benefit relationship), and in combination therapy with other antimalarials in patients with resistance or only a partial response to chloroquine or hydroxychloroquine.We report 8 cases of patients with cutaneous lupus who received treatment with quinacrine in monotherapy or in combination with others antimalarials. Lesions resolved in 5 patients and improved in 3. Therapy had to be withdrawn in 1 patient due to an exacerbation of his psoriasis.     

Hydroxychloroquine-induced hyperpigmentation: the staining pattern

We report two cases of hydroxychloroquine-induced hyperpigmentation presenting in a 50-year-old Caucasian female (case 1) and a 78-year-old female (case 2), both receiving 400 mg per day. Case 1 had an arthritis predominant undifferentiated connective tissue disease, which was treated with hydroxychloroquine for 4-5 years. She presented with a mottled, reticulated macular gray pigmentation involving the upper back and shoulders. Case 2 had a history of systemic lupus erythematosus and rheumatoid arthritis, treated with hydroxychloroquine for 1.5 years. She presented to the hospital for treatment of constrictive cardiomyopathy and was noted to have a blue macular pigmentation involving the right temple. The biopsies from both patients showed superficial dermal, yellow-brown, non-refractile and coarsely granular pigment deposition. A Fontana-Masson stain highlighted some of these granules, while the Perl's iron stain was negative. Rare, previous reports of hyperpigmentation indicate the presence of both melanin and hemosiderin in patients being treated with antimalarial medication. To our knowledge, this staining pattern for hydroxychloroquine has not been previously reported in the literature and supports that hydroxychloroquine, in addition to chloroquine, binds to melanin.     

Tinea Capitis: An Overview with Emphasis on Management

Tinea capitis is perhaps the most common mycotic infection in children. In North America the epidemiology of tinea capitis has changed so that Trichophyton tonsurans now predominates over Micro-sporum audouinii. With this transition the utility of the Wood's light for diagnosis has been reduced since T. tonsurans infection is Wood's light negative. Griseofulvin has been the mainstay of therapy for the last 40 years. The newer antifungal agents-itraconazole, terbinafine, and fluconazole-appear to be effective and safe for the treatment of tinea capitis. When tinea capitis is due to T. tonsurans or other endothrix species the following regimens have been used: itraconazole continuous regimen (5 mg/kg/day for 4 weeks), itraconazole pulse regimen with capsules (5 mg/kg/day for 1 week plus 1-3 pulses 3 weeks apart), and itraconazole pulse regimen with oral solution (3 mg/kg/day for 1 week plus 1-3 pulses 3 weeks apart). With terbinafine tablets the continuous regimen (>40 kg body weight, 250 mg/day; 20-40 kg, 125 mg/day; and <20 kg, 125 mg/day) is given for 2 to 4 weeks. Fluconazole tablets or oral suspension (6 mg/kg/day) were administered for 20 days in one trial. Another possibility may be 6 mg/kg/day for 2 weeks and evaluating the scalp 4 weeks later. An extra week of therapy (6 mg/kg/day) can be administered if clinically indicated at that time. A once-weekly regimen may also be effective. When ectothrix organisms (e.g., Microsporum canis) are present, a longer duration of therapy may be required. The data suggest that the newer agents are effective, safe with few adverse effects, and have a high benefit:risk ratio. It remains to be seen to what extent griseofulvin will be superseded for the treatment of tinea capitis. Adjunctive therapies may help decrease the risk of infection to other individuals. Appropriate measures should be taken to reduce the possibility of reinfection.     

外阴-阴道-牙龈综合征临床研究

目的 探讨外阴-阴道-牙龈综合征(VVGS)的临床特征及治疗策略.方法 收集11例VVGS患者的临床资料并进行分析.结果 11例VVGS确诊时的平均年龄和中位年龄均为46岁,平均病程4年.疼痛糜烂性红斑位于阴道前庭7例,齿龈10例,双侧颊黏膜5例;性交疼痛8例;阴道溢血4例.7例应用小剂量甲泼尼龙联合羟氯喹或秋水仙碱,4例仅口服羟氯喹,11例患者均外用0.1%他克莫司软膏,8例获痊愈或显效,未见明显不良反应.结论 VVGS多见于中年女性,痛性红斑好发于阴道前庭和齿龈,性交疼痛常见.甲泼尼龙联合羟氯喹片及单独应用羟氯喹治疗轻症患者疗效好.0.1%他克莫司软膏可作为局部维持治疗的药物之一.     

Cyclosporin A in the treatment of severe allergic contact dermatitis

Background Allergic contact dermatitis is sometimes difficult to treat because the patients are unable to effect prevention. Contact dermatitis can then become chronic and progressive, posing serious therapeutic problems. Patients and Method Fifteen patients with severe allergic contact dermatitis were treated with cyclosporin A (CyA). All patients were polysensitized and unable to avoid with haptens for socioeconomic reasons. The drug was given orally at a dose of 5 mg/kg/day for 4 weeks followed by 3 mg/kg/day for a further 2 months. In three patients the treatment was continued for a further period of 60 days at 2 mg/kg/day. Results All patients responded well to the therapy and no side effects were observed. The manifestations of acute inflammation improved rapidly, whereas the signs of chronic reaction took longer to regress. At the end of treatment some subjects remained without lesions for up 6 months while others relapsed with mild forms. The recurrent dermatitis responded to a further cycle of CyA. Patch test reactions were only slightly modified after 30 days of treatment. Conclusion Our results qualify CyA as a new drug for the treatment of allergic contact dermatitis. It cannot be regarded as the elective treatment but it can be extremely useful in chronic and severe cases.     

Lupus erythematosus. Part II: Clinical picture,diagnosis and treatment

Lupus erythematosus (LE) is an important dermatologic autoimmune disease. In many respects, it may be regarded as a model autoimmune disease due to its spectrum of autoimmune antibodies and involvement of different organ systems, as well as response to immunosuppressive agents which target B cells and T cells and their cytokines. A recently published article in this Journal summarized the most important knowledge about epidemiology, genetics, and immunology of LE. Here, the different clinical manifestations, diagnostic procedures and current therapeutic approaches will be described. Special emphasis is placed on different cutaneous manifestations of LE. In regard to treatment, the classic treatment approaches such as corticosteroids, methotrexate, chloroquine and hydroxychloroquine will be described. Lastly, new therapeutic approaches with specific monoclonal antibodies which are currently used in systemic LE, such as belimumab (Benlysta®), will be addressed. The most recent developments in this area could have implications even for purely cutaneous forms of LE.