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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Types of lupus erythematosus
  5. Lupus erythematosus and cigarette smoking
  6. Association between smoking and increased disease activity in lupus erythematosus
  7. Association between antimalarials and smoking in lupus erythematosus
  8. Smoking and non-adherenence to medication
  9. Discussion
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

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.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Types of lupus erythematosus
  5. Lupus erythematosus and cigarette smoking
  6. Association between smoking and increased disease activity in lupus erythematosus
  7. Association between antimalarials and smoking in lupus erythematosus
  8. Smoking and non-adherenence to medication
  9. Discussion
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

Antimalarial therapy has been used to treat cutaneous and systemic lupus erythematosus (CLE, SLE) for decades. Payne is credited as the first physician to use antimalarial therapy in the form of quinine for CLE in 1894.1 Although gold was used for the treatment of CLE from the 1930s, it went out of favour with the advent of synthetic antimalarials in the 1950s.2 Systemic corticosteroids and other immunosuppressive agents did not come into use until the mid-20th century.2

Since antimalarials first became widely used for LE in the 1950s, they have remained the first-line therapeutic agents, with response rates as high as 75–95% in the treatment of CLE.3 Although controlled studies comparing the efficacy of antimalarials (such as chloroquine and hydroxychloroquine) vs. 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 LE-nonspecific skin lesions.

The most commonly chosen antimalarial agent is hydroxychloroquine sulfate, as it is usually well tolerated, with chloroquine and quinacrine as alternatives.2 Quinacrine 100 mg/day may be added to the regimen in patients who are not responsive to hydroxychloroquine alone, although it may turn the skin yellow at higher doses.4,5 Hydroxychloroquine is given at 200 mg once or twice per day, and should not induce ocular toxicity if the dose is < 6.5 mg/kg/day.6 However, doses higher than this are not contraindicated and may in fact be beneficial in some patients; they are generally used by rheumatology departments.2 Chloroquine is given at 250 mg/day, with levels up to 4 mg/kg/day showing no associated eye toxicity.2 Quinacrine is not thought to cause eye toxicity. Eye examinations should be considered approximately once every 6–12 months for patients on hydroxychloroquine or chloroquine.2

Types of lupus erythematosus

  1. Top of page
  2. Summary
  3. Introduction
  4. Types of lupus erythematosus
  5. Lupus erythematosus and cigarette smoking
  6. Association between smoking and increased disease activity in lupus erythematosus
  7. Association between antimalarials and smoking in lupus erythematosus
  8. Smoking and non-adherenence to medication
  9. Discussion
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

There are three major categories of LE-specific disease: acute (A)CLE, subacute (S)CLE and cutaneous (C)CLE.

ACLE is categorized as localized or generalized. Localized ACLE is characterized by erythema over the malar eminences of the face and bridge of the nose (butterfly rash), typically sparing the nasolabial folds.7 Generalized ACLE is a diffuse papular erythema of the face, limbs or upper trunk, which resembles a viral exanthem or drug eruption,8 and is present in 35% of patients with SLE.9 Lesions develop quickly, and last for hours to days.

SCLE is also subdivided into two morphological variants: annular and papulosquamous. Annular SCLE (also referred to as lupus marginatus, symmetrical erythema centrifugum, autoimmune annular erythema and LE gyratum repens) is characterized by erythematous macules and papules that subsequently develop into papulosquamous or annular plaques. Although most patients tend to develop one predominant type of lesion, some display elements of both simultaneously. A growing number of medications have been noted to induce SCLE, including naproxen sodium, phenytoin, diltiazem, thiazides, tumour necrosis factor inhibitors, terbinafine and antihistamines.8 Interestingly, the very medications used to treat SLE, including hydroxychloroquine and quinacrine, have also been implicated in the development or worsening of CLE lesions.10,11

CCLE is subdivided into classic discoid (D)LE, hypertrophic/verrucous DLE, mucosal DLE, lichen DLE, LE profundus/LE panniculitis, LE tumidus, chilblain LE, and other rare variants. Classic DLE is the commonest form of CCLE, occurring in 20% of patients with SLE.12–15

Lupus erythematosus and cigarette smoking

  1. Top of page
  2. Summary
  3. Introduction
  4. Types of lupus erythematosus
  5. Lupus erythematosus and cigarette smoking
  6. Association between smoking and increased disease activity in lupus erythematosus
  7. Association between antimalarials and smoking in lupus erythematosus
  8. Smoking and non-adherenence to medication
  9. Discussion
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

Cigarette smoking was first suggested in 1993 to interfere with antimalarial efficacy in treating patients with CLE.16 A closer look at antimalarial-treated patients with CLE who classified themselves as smokers vs. nonsmokers found reduced lesion-clearing rates in smokers.17 In addition, antimalarials have been associated with several potentially serious adverse effects, including irreversible loss of vision.18,19 In this review, we discuss the many facets of interaction between smoking and antimalarials with the aim of helping clinicians make the best use of these therapies when treating CLE.

Association between smoking and increased disease activity in lupus erythematosus

  1. Top of page
  2. Summary
  3. Introduction
  4. Types of lupus erythematosus
  5. Lupus erythematosus and cigarette smoking
  6. Association between smoking and increased disease activity in lupus erythematosus
  7. Association between antimalarials and smoking in lupus erythematosus
  8. Smoking and non-adherenence to medication
  9. Discussion
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

There have been reports of an association between cigarette smoking and autoimmune disease, including SLE and DLE.20–25 A review of 28 patients with DLE in a private dermatology practice found the prevalence of smoking to be 82% in patients with DLE, compared with 22% in age- and sex-matched controls.23 Interestingly, a meta-analysis of seven case–control studies and two cohort studies found a slightly increased risk of LE posed by current smoking, although no increased risk was associated with past smoking. Cigarette smoking has also been linked with increased disease activity in SLE.26

CLE, including DLE and SCLE, has been shown to be more prevalent among smokers.23,25,27,28 A case–control study of 57 patients diagnosed with DLE and 215 healthy controls found that 84.2% of the patients were smokers, significantly higher than the 33.5% of healthy controls who smoked. The association between smoking and SCLE seems to be especially pronounced in men, with one retrospective study reporting that all of the male patients with SCLE were smokers.28

Association between antimalarials and smoking in lupus erythematosus

  1. Top of page
  2. Summary
  3. Introduction
  4. Types of lupus erythematosus
  5. Lupus erythematosus and cigarette smoking
  6. Association between smoking and increased disease activity in lupus erythematosus
  7. Association between antimalarials and smoking in lupus erythematosus
  8. Smoking and non-adherenence to medication
  9. Discussion
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

Cigarette smoking remains one of the leading mortality risk factors, responsible for nearly one in five deaths in the USA.29 An estimated 443 000 Americans died prematurely between 2000 and 2004 from smoking or second-hand smoke, resulting in a total economic burden of approximately US$193 billion per year.30 Worldwide, over 5.4 million smoking-related deaths occur every year, more than tuberculosis, malaria, and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome combined.31

Cigarette smoking has been suspected to increase the risk and activity of SLE20,32 and CLE.17,33 In addition to being linked causally to CLE, smoking interferes with the efficacy of antimalarial therapies.17,33,33–36 In a recent study evaluating the effect of smoking on response to antimalarial treatment in LE tumidus, smokers had a significantly higher mean clinical score than nonsmokers on the Disease Area and Severity Index.34 Moreover, smokers had a significantly lower reduction in clinical score with antimalarial treatment compared with nonsmokers;34 88% of nonsmokers (7 of 8 patients) but only 57% of smokers (16 of 28 patients) had a clinical score of 1 or 0 (range, 0–6) after 3 months of treatment with antimalarial drugs.34

Jewell and McCauliffe33 examined the effects of cigarette smoking on the therapeutic response to antimalarial agents in patients with DLE and SCLE. In total, 61 patients (47 DLE, 14 SCLE) were classified as antimalarial responders or nonresponders on the basis of descriptions in their medical records, and a significant difference (< 0.0002) in the antimalarial response rate was seen for smokers (40%) compared with nonsmokers (90%).33 The response rate and the number of cigarettes reportedly smoked were found to be inversely related, with only one of six patients who smoked two packs per day responding to antimalarial therapy, suggesting that the effect of cigarette smoking on the efficacy of antimalarial medications may be dose-related.33 The authors concluded that patients with CLE who smoke are significantly less likely to respond to antimalarial therapy.33

There are reports of several patients with antimalarial-refractory CLE improving dramatically after cessation of cigarette smoking, without any other changes in treatment.16,33 There are also reports of the addition of quinacrine improving the therapeutic response in patients who have not responded to treatment with hydroxychloroquine or chloroquine alone.36–39 Cavazzana et al.40 found that the combination of hydroxychloroquine and quinacrine at 100 mg four times daily is well tolerated and rapidly effective in the treatment of LE skin lesions unresponsive to hydroxychloroquine alone.

Some data indicate that cigarette smoking might interfere in a direct manner with the effectiveness of hydroxychloroquine and chloroquine in CLE.17,33 Elimination of a single dose of quinine sulfate, an antimalarial medication structurally similar to chloroquine and hydroxychloroquine, was found to be enhanced with cigarette smoking.41 As these antimalarial agents are partly metabolized via the cytochrome P450 enzyme system and as the constituents of cigarette smoke are known potent inducers of cytochrome P450, it has been hypothesized that the resistance of CLE to antimalarials might be explained by a modification of the metabolism of these drugs.33,42

It is well established that low blood hydroxychloroquine concentrations are associated with SLE disease activity, are a strong predictor of exacerbations,43 and may help to diagnose poor adherence.44 However, the association between hydroxychloroquine concentration and smoking is less clear. A 2007 study quantified hydroxychloroquine levels by high performance liquid chromatography,45 and similar mean blood hydroxychloroquine concentrations were found in active smokers and nonsmokers.45 In the smoking group, no correlation was found between the number of cigarettes and the blood hydroxychloroquine concentrations.45 The study concluded that there is no significant relationship between cigarette smoking and hydroxychloroquine concentrations.45 This is a strong argument against a direct effect of smoking on hydroxychloroquine metabolism.46

Another mode of interaction has been described as a modification of the lysosomal accumulation of antimalarial agents.45 Antimalarials are thought to act via stabilization of lysosomal membranes, with both nicotine and antimalarial drugs sequestered in lysosomes, acting in a lysosomotrophic manner.47 Nicotine has been shown to strongly inhibit the uptake of chloroquine in cultured cells, and may inhibit the stabilizing effect of antimalarials by blocking their accumulation within lysosomes.48 The possibility of a direct deleterious effect of smoking on cutaneous lesions has also been suggested.45

Smoking and non-adherenence to medication

  1. Top of page
  2. Summary
  3. Introduction
  4. Types of lupus erythematosus
  5. Lupus erythematosus and cigarette smoking
  6. Association between smoking and increased disease activity in lupus erythematosus
  7. Association between antimalarials and smoking in lupus erythematosus
  8. Smoking and non-adherenence to medication
  9. Discussion
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

Smokers are different from nonsmokers in more ways than in the use of cigarettes.42 A cohort of smokers will tend to consume more caffeine, alcohol, analgesics, laxatives and hypnotics than will a similar cohort of nonsmokers.49,50 It is thus possible that some other factor associated with smoking affects antimalarial efficacy in patients with LE.

Adherence to medical regimens has been studied in detail since the 1960s,47,51 and a fairly high level (37%) of nonadherence to doctors’ advice was reported in one study.51 A more recent meta-analysis of over 500 studies on adherence to medical recommendations found the average nonadherence rate to be 24.8%.52

Cigarette smoking is associated with lifestyle and health risk behaviours that may influence medication adherence. Smokers are more likely to be risk takers and to engage in behaviour that involves negative consequences balanced by potential gain.53 For example, smokers are more likely than nonsmokers to avoid use of seat belts54 and to report risky sexual behaviour.55 Smokers are also less likely than nonsmokers to engage in healthy behaviours, such as healthy eating,56 physical activity,57 and cancer screening.58,59 Similarly, cigarette smoking is harmful to health, yet 50–70% of HIV-positive people smoke despite their compromised immune systems.60–63 There are no data on smoking and use of sunscreens or sun-protective clothing.

In a single study, smoking at the time of myocardial infarction appeared to be associated with an increased likelihood of discontinuing cardioprotective medications,64 but was shown to have no significant difference in continuation of cardioprotective medications in another study.65 In a trial evaluating lifestyle and psychosocial risk factors as predictors of nonadherence to medication, smoking was shown to be a significant predictor of nonadherence to blood-pressure medication.66 Lifestyle patterns including smoking were also assessed to be a factor when promoting adherence to medication in older people.67

The association between current smoking (which has a high prevalence among people living with HIV) and medication adherence was evaluated in a study of 168 patients with HIV who were prescribed highly active antiretroviral therapy (HAART). The study assessed viral load, CD4+ count, cigarette smoking, and the past week and 3-month medication adherence.68 The study found that 70% of participants smoked at least one cigarette per day, and smoking was associated with poorer past week and 3-month medication adherence.3 In a study of HIV-positive men and women (n = 64), current cigarette smoking, lower CD4 counts and lower educational status emerged as independent predictors of poorer adherence among patients on HAART.69

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Types of lupus erythematosus
  5. Lupus erythematosus and cigarette smoking
  6. Association between smoking and increased disease activity in lupus erythematosus
  7. Association between antimalarials and smoking in lupus erythematosus
  8. Smoking and non-adherenence to medication
  9. Discussion
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

The clinical belief that hydroxychloroquine has a long-term protective effect against major disease flares in SLE has been confirmed in the literature, with hydroxychloroquine shown to reduce major flares by 57%.70 In addition, there are data to support an association of hydroxychloroquine with a delay in integument damage development71 and with a protective effect in retarding the development of renal damage in patients with SLE.71 A recent study found that older age at onset, longer disease duration, history of smoking, antiphospholipid positivity, history of nephritis and use of immunomodulating medications are risk factors for thrombosis in SLE.72 This study was the first to confirm in a large and ethnically diverse SLE cohort that hydroxychloroquine use is protective against thrombosis. Many more studies have confirmed the clinical efficacy of antimalarials in the treatment of LE. Studies must also evaluate adherence to the use of sunscreen and sun-protective clothing in smokers vs. nonsmokers.

Although the exact pathophysiology of how cigarette smoking is associated with increased disease activity in LE is still unknown, several plausible hypotheses exist. Similarities and differences between the potential roles of cigarettes in the different subsets of lupus are reflected in Table 1. Cigarette smoke contains nicotine in addition to numerous toxins and free radicals, which can interact with DNA, leading to genetic mutations and inducing gene activation, which may result in autoimmune disease.73–75 Cigarette smoke, which is phototoxic, may trigger photosensitive disorders such as SLE and CLE.76 Smokers display increased epidermal surface molecules, such as intercellular adhesion molecule-1, which have been implicated in primary and ultraviolet-induced CLE lesions.77,78 In addition, cigarette smoke activates tissue-damaging matrix metalloproteinases and increases cytokines such as interleukin-6, an important marker of inflammation in lupus.77,79

Table 1.   Similarities and differences between the potential roles of cigarettes in the different subsets of lupus.
DiseaseSusceptibilitySeverityTherapeutic response
  1. ACLE, acute cutaneous lupus erythematosus; CCLE, chronic cutaneous lupus erythematosus; CLE, cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; LE, lupus erythematosus; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus.

ACLEThere is an association between cigarette smoking and autoimmune disease, including SLE.20–25Cigarette smoking has been linked with increased disease activity in SLE.26 Cigarette smoking has been suspected to increase the risk and the activity of SLE20,32 and CLE.17,33A significant difference in the antimalarial response rate was observed for smokers (40%) vs. nonsmokers (90%).33
SCLESCLE has been shown to be more prevalent among smokers.23,25,27,28 There is a slightly increased risk posed by current smoking, although no increased risk was associated with past smoking.26 The association between smoking and SCLE appears to be especially pronounced in men.28Cigarette smoking has been suspected to increase the risk and the activity of SLE20,32 and CLE.17,33A significant difference in the antimalarial response rate was observed for smokers (40%) vs. nonsmokers (90%).33 Response rate and the number of cigarettes reportedly smoked were found to be inversely related, suggesting that the effect of cigarette smoking on the efficacy of antimalarial medications may be dose-related.33
CCLEDLE has been shown to be more prevalent among smokers.25,27–29 There is an association between cigarette smoking and autoimmune disease, including DLE.20–25 The prevalence of smoking in patients with DLE was found to be 82%, vs. 22% in controls matched for age and gender.23 About 84.2% of discoid patients with DLE are smokers vs. 33.5% of healthy controls.28Cigarette smoking has been suspected to increase the risk and the activity of SLE20,32 and CLE.17,33 Smokers with LE tumidus had a significantly higher mean disease area and severity index clinical score than nonsmokers.34Smokers had a significantly lower reduction in clinical score with antimalarial treatment compared with nonsmokers.34 About 88% of nonsmokers (7 of 8 patients) but only 57% of smokers (16 of 28 patients) had a clinical score of 1 or 0 (range, 0–6) after 3 months of treatment with antimalarial drugs.33 A significant difference in the antimalarial response rate was observed for smokers (40%) vs. nonsmokers (90%).34 Response rate and the number of cigarettes reportedly smoked were found to be inversely related, suggesting that the effect of cigarette smoking on the efficacy of antimalarial medications may be dose-related.33

It is interesting to note the disproportionate number of smokers in lupus studies. Several possibilities may explain this finding. Studies tend to be conducted at large academic medical centres to which patients are referred by outside physicians. It is possible that patients who did not respond initially to antimalarial therapy were selected for referral, thus leading to bias. It may also be that smoking histories in current nonsmokers are more likely to be omitted from the medical records, leading to a disproportionate number of nonsmokers being excluded from the study due to lack of information on smoking status.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Types of lupus erythematosus
  5. Lupus erythematosus and cigarette smoking
  6. Association between smoking and increased disease activity in lupus erythematosus
  7. Association between antimalarials and smoking in lupus erythematosus
  8. Smoking and non-adherenence to medication
  9. Discussion
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

Although the major effect of smoking on disease onset, disease type or in treatment response is unclear, smoking seems to affect disease treatment most substantially. There is little direct evidence about how cigarette smoking interferes with antimalarial efficacy in the treatment of CLE. Nonadherence (including to sun-protection regimens) in smokers may be a possible reason. Smoking may also directly reduce the efficacy of antimalarials via one or more pathways, such as more rapid metabolization by induction of microsomal enzymes in the liver. Evidence-based data with long-term follow-up is needed to determine the aetiology of diminished antimalarial response and selection of the best treatment to maximize long-term remission in CLE.

Despite numerous public campaigns that attempt to address the dangers of smoking, many tobacco users are unwilling or unable to target their cigarette addiction. Despite knowledge of the well-known long-term complications of smoking, many smokers require additional reinforcements to quit the habit. Given that smoking negatively affects a number cutaneous conditions, dermatologists are de facto active participants in smoking prevention and cessation, and must provide their smoker patients with incentive, guidance and intervention to help them discontinue the habit.80

Learning points

  1. Top of page
  2. Summary
  3. Introduction
  4. Types of lupus erythematosus
  5. Lupus erythematosus and cigarette smoking
  6. Association between smoking and increased disease activity in lupus erythematosus
  7. Association between antimalarials and smoking in lupus erythematosus
  8. Smoking and non-adherenence to medication
  9. Discussion
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions
  • • 
    Antimalarials have remained the first-line therapeutic agents for the management of LE since the 1950s, with response rates as high as 75–95% in the treatment of CLE.
  • • 
    Smoking seems to inhibit the therapeutic efficacy of antimalarials when treating CLE.
  • • 
    Antimalarials have been associated with several potentially serious adverse effects, including irreversible loss of vision.
  • • 
    There have been reports of an association between cigarette smoking and autoimmune disease, including SLE and DLE.
  • • 
    There is little direct evidence about how cigarette smoking interferes with antimalarial efficacy in the treatment of CLE, but nonadherence to treatment by smokers may be one reason.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Types of lupus erythematosus
  5. Lupus erythematosus and cigarette smoking
  6. Association between smoking and increased disease activity in lupus erythematosus
  7. Association between antimalarials and smoking in lupus erythematosus
  8. Smoking and non-adherenence to medication
  9. Discussion
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

CPD questions

  1. Top of page
  2. Summary
  3. Introduction
  4. Types of lupus erythematosus
  5. Lupus erythematosus and cigarette smoking
  6. Association between smoking and increased disease activity in lupus erythematosus
  7. Association between antimalarials and smoking in lupus erythematosus
  8. Smoking and non-adherenence to medication
  9. Discussion
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

Question 1

What are first-line therapeutic agents for the management of LE?

a) Antimalarials

b) Systemic corticosteroids

c) Dapsone

d) Retinoids

e) Thalidomide

Question 2

The most commonly chosen antimalarial agent for the management of LE is:

a) Hydroxychloroquine sulfate

b) Chloroquine

c) Quinacrine

d) Mefloquine

e) Primaquine

Question 3

Which medication may turn the skin yellow at higher doses?

a) Hydroxychloroquine sulfate

b) Chloroquine

c) Quinacrine

d) Mefloquine

e) Primaquine

Question 4

How often should eye examinations be considered for patients on hydroxychloroquine or chloroquine?

a) Once a week

b) Once a month

c) Approximately once every 6–12 months

d) Once every 5 years

e) Once every 10 years

Question 5

Which of the following is not a subdivision of chronic cutaneous lupus erythematous?

a) Classic discoid (D)LE

b) Hypertrophic/verrucous DLE

c) LE profundus/LE panniculitis

d) Mucosal DLE

e) Lupus marginatus

Instructions for answering questions

  1. Top of page
  2. Summary
  3. Introduction
  4. Types of lupus erythematosus
  5. Lupus erythematosus and cigarette smoking
  6. Association between smoking and increased disease activity in lupus erythematosus
  7. Association between antimalarials and smoking in lupus erythematosus
  8. Smoking and non-adherenence to medication
  9. Discussion
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

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