Antimalarial resistance in lupus: a lesser-explored terrain

Abstract

Sir, Antimalarial agents have multifaceted immunomodulatory actions. These drugs reduce the frequency of flares and impede the overall progression of lupus erythematosus (LE). Although routinely employed in the management of LE, the response to antimalarials is not uniform. Studies have reported adequate response to hydroxychloroquine in fewer than 50% of cutaneous LE patients. Antimalarial switching has been attempted in non-response, and only 56% (that includes 37% partial responders) of the patients responded at 3 months, which decreased further to 22% at 48 months. Loss of efficacy was seen at a median of 9 months after switching. This suggests that some lupus patients do not respond adequately to antimalarials (primary resistance) or lose their response subsequently (secondary resistance). Some clinical pointers of non-response to antimalarials have been proposed including obesity, younger age, low socioeconomic status and absence of concomitant immunosuppressive treatments. Overall, the consensus remains that a low blood concentration of hydroxychloroquine is significantly associated with active and refractory disease. Non-adherence to prescription typically leads to a ‘very low’ blood hydroxychloroquine concentration and can be ascertained by unscheduled chromatography analysis in suspected patients. A recent study found non-adherence rates of approximately 18.4% in patients having systemic lupus erythematosus (SLE) flares, addressing non-compliance as an important factor that should be taken into account before a lupus patient is labeled ‘non-responder’. But, even after exclusion of non-compliant patients, the blood levels of hydroxychloroquine vary widely in patients who are being prescribed a similar dosage of the drug and might account for the variable clinical response. Although traditionally known for antibiotics, the concept of resistance has been extended to describe non-responsiveness to methotrexate, antihistamines, corticosteroids and aspirin. Resistance can exist at the level of drug entry, metabolism, efflux and target enzyme modification. In addition, cross-resistance could potentially exist between structurally similar antimalarials and could explain the only transient efficacy seen after switching. Many in-vitro studies attribute drug resistance to P-glycoprotein, an efflux protein that is induced on the membranes of peripheral CD4þ T lymphocytes. P-glycoprotein homologues have been described as a plausible explanation for chloroquine resistance in Plasmodium species. In addition, the mediators of active inflammation in LE including tumour necrosis factor-alpha, interleukin (IL)-2 and IL-4, might enhance the expression of P-glycoprotein (decreased hydroxychloroquine levels are observed significantly more often in disseminated and active LE). Increased blood levels of hydroxychloroquine in SLE patients on concomitant immunosuppression can be explained by the plausible inhibition of inflammation and P-glycoprotein by these agents. It will be of significance if the expression of P-glycoprotein could be studied in antimalarial non-responders, because the institution of specific P-glycoprotein inhibitors (cyclosporine, verapamil, tacrolimus) has been demonstrated to reverse the resistance mediated by this efflux protein. Of multiple microsomal enzymes (CYP2D6, CYP3A4, CYP3A5), polymorphism in CYP2D6 has been proposed to explain the variable interindividual pharmacokinetics of hydroxychloroquine. Decreased response to antimalarials seen in smokers has been attributed to microsomal enzyme upregulation, although the relationship between smoking and antimalarials is controversial at best, and some studies have found no differences in the blood levels of antimalarials or their efficiency between smokers and non-smokers. Analogous to anti-neoplastic drugs, enhanced signal transducers and activators of transcription (STAT-1) signaling has also recently been proposed to explain treatment resistance in SLE. Therefore, a possible antimalarial resistance in LE, its mechanisms, strategies to overcome it and the extent of cross-resistance is of significance and needs to be explored further, in order to gain Correspondence to: Keshavamurthy Vinay, Department of Dermatology, Venereology and Leprology Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India. Email: [email protected] Received 31 January 2018; accepted 18 October 2018