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Inflammopharmacology

, Volume 26, Issue 5, pp 1175–1182 | Cite as

Efficacy analysis of hydroxychloroquine therapy in systemic lupus erythematosus: a study on disease activity and immunological biomarkers

  • Seyed Mostafa Monzavi
  • Aida Alirezaei
  • Zhaleh Shariati-Sarabi
  • Jalil Tavakol Afshari
  • Mahmoud Mahmoudi
  • Banafsheh Dormanesh
  • Faezeh Jahandoost
  • Ali Reza Khoshdel
  • Ali Etemad Rezaie
Original Article

Abstract

Background

Hydroxychloroquine (HCQ) is a widely prescribed medication to patients with systemic lupus erythematosus (SLE), with potential anti-inflammatory effects. This study was performed to investigate the efficacy of HCQ therapy by serial assessment of disease activity and serum levels of proinflammatory cytokines in SLE patients.

Methods

In this prospective cohort study, 41 newly diagnosed SLE patients receiving 400 mg HCQ per day were included. Patients requiring statins and immunosuppressive drugs except prednisolone at doses lower than 10 mg/day were excluded. Outcome measures were assessed before commencement of HCQ therapy (baseline visit) as well as in two follow-up visits (1 and 2 months after beginning the HCQ therapy). Serum samples of 41 age-matched healthy donors were used as controls.

Results

Median levels of IL-1β (p < 0.001), IL-6 (p = 0.001), and TNF-α (p < 0.001) were significantly higher, whereas, median CH50 level was significantly lower (p < 0.001) in SLE patients compared with controls. Two-month treatment with HCQ resulted in significant decrease in SLEDAI-2K (p < 0.001), anti-dsDNA (p < 0.001), IL-1β (p = 0.003), IL-6 (p < 0.001) and TNF-α (p < 0.001) and a significant increase in CH50 levels (p = 0.012). The reductions in SLEDAI-2K and serum levels of IL-1β and TNF-α were significantly greater in the first month compared with the reductions in the second month.

Conclusion

HCQ therapy is effective on clinical improvement of SLE patients through interfering with inflammatory signaling pathways, reducing anti-DNA autoantibodies and normalizing the complement activity.

Keywords

Complement system proteins Cytokines Hydroxychloroquine Systemic lupus erythematosus Treatment outcome 

Notes

Acknowledgements

The authors would like to thank vice chancellor for research of Mashhad University of Medical Sciences who kindly supported this study. The authors would also like to acknowledge Dr. K. Hashemzadeh and the staff of the department of internal medicine, Imam Reza Hospital, for their kind assistance during this study.

Compliance with ethical standards

Conflict of interest

All authors declared that they have no conflict of interest.

References

  1. Akhavan PS, Su J, Lou W, Gladman DD, Urowitz MB, Fortin PR (2013) The early protective effect of hydroxychloroquine on the risk of cumulative damage in patients with systemic lupus erythematosus. J Rheumatol 40:831–841CrossRefPubMedCentralPubMedGoogle Scholar
  2. Aringer M, Smolen J (2008) The role of tumor necrosis factor-alpha in systemic lupus erythematosus. Arthritis Res Ther 10:202CrossRefPubMedCentralPubMedGoogle Scholar
  3. Arora V, Verma J, Marwah V, Kumar A, Anand D, Das N (2012) Cytokine imbalance in systemic lupus erythematosus: a study on northern Indian subjects. Lupus 21:596–603CrossRefPubMedCentralPubMedGoogle Scholar
  4. Aviña-Zubieta JA, Esdaile JM (2012) Antimalarial Medications. In: Wallace DJ, Hahn BH (eds) Dubois’ lupus erythematosus and related syndromes, 8th edn. Saunders, Elsevier, Philadelphia, pp 601–608Google Scholar
  5. Cairoli E, Rebella M, Danese N, Garra V, Borba EF (2012) Hydroxychloroquine reduces low-density lipoprotein cholesterol levels in systemic lupus erythematosus: a longitudinal evaluation of the lipid-lowering effect. Lupus 21:1178–1182CrossRefPubMedCentralGoogle Scholar
  6. Cheng Q, Mumtaz IM, Khodadadi L, Radbruch A, Hoyer BF, Hiepe F (2013) Autoantibodies from long-lived ‘memory’ plasma cells of NZB/W mice drive immune complex nephritis. Ann Rheum Dis 72:2011–2017CrossRefPubMedCentralPubMedGoogle Scholar
  7. Costabile M (2010) Measuring the 50% haemolytic complement (CH50) activity of serum. J Vis Exp.  https://doi.org/10.3791/1923 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Danis VA, Rathjen DA, Brooks PM (1992) The effect of slow acting antirheumatic drugs on the production of cytokines by human monocytes. Inflammopharmacology 1:315–327CrossRefGoogle Scholar
  9. Dörner T, Giesecke C, Lipsky PE (2011) Mechanisms of B cell autoimmunity in SLE. Arthritis Res Ther 13:243CrossRefPubMedCentralPubMedGoogle Scholar
  10. Durcan L, Petri M (2016) Immunomodulators in SLE: clinical evidence and immunologic actions. J Autoimmun 74:73–84CrossRefPubMedCentralPubMedGoogle Scholar
  11. Eilertsen GØ, Nikolaisen C, Becker-Merok A, Nossent JC (2011) Interleukin-6 promotes arthritis and joint deformation in patients with systemic lupus erythematosus. Lupus 20:607–613CrossRefPubMedCentralPubMedGoogle Scholar
  12. Ferraccioli G, Houssiau FA (2013) Which B-cell subset should we target in lupus? Ann Rheum Dis 72:1891–1892CrossRefPubMedCentralPubMedGoogle Scholar
  13. Fox RI, Kang HI (1993) Mechanism of action of antimalarial drugs: inhibition of antigen processing and presentation. Lupus 2(Suppl 1):S9–S12PubMedPubMedCentralGoogle Scholar
  14. Gabay C, Cakir N, Moral F, Roux-Lombard P, Meyer O, Dayer JM, Vischer T, Yazici H, Guerne PA (1997) Circulating levels of tumor necrosis factor soluble receptors in systemic lupus erythematosus are significantly higher than in other rheumatic diseases and correlate with disease activity. J Rheumatol 24:303–308PubMedPubMedCentralGoogle Scholar
  15. Gladman DD, Ibañez D, Urowitz MB (2002) Systemic lupus erythematosus disease activity index 2000. J Rheumatol 29:288–291PubMedPubMedCentralGoogle Scholar
  16. Hsieh SC, Sun KH, Tsai CY, Tsai YY, Tsai ST, Huang DF, Han SH, Yu HS, Yu CL (2001) Monoclonal anti-double stranded DNA antibody is a leucocyte-binding protein to up-regulate interleukin-8 gene expression and elicit apoptosis of normal human polymorphonuclear neutrophils. Rheumatology (Oxford) 40:851–858CrossRefGoogle Scholar
  17. Illei GG, Tackey E, Lapteva L, Lipsky PE (2004) Biomarkers in systemic lupus erythematosus: II. Markers of disease activity. Arthritis Rheum 50:2048–2065CrossRefPubMedCentralPubMedGoogle Scholar
  18. Jung H, Bobba R, Su J, Shariati-Sarabi Z, Gladman DD, Urowitz M, Lou W, Fortin PR (2010) The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum 62:863–868CrossRefPubMedCentralPubMedGoogle Scholar
  19. Koenig KF, Groeschl I, Pesickova SS, Tesar V, Eisenberger U, Trendelenburg M (2012) Serum cytokine profile in patients with active lupus nephritis. Cytokine 60:410–416CrossRefPubMedCentralPubMedGoogle Scholar
  20. Leffler J, Bengtsson AA, Blom AM (2014) The complement system in systemic lupus erythematosus: an update. Ann Rheum Dis 73:1601–1606CrossRefPubMedCentralPubMedGoogle Scholar
  21. Lenert PS (2006) Targeting Toll-like receptor signaling in plasmacytoid dendritic cells and autoreactive B cells as a therapy for lupus. Arthritis Res Ther 8:203CrossRefPubMedCentralPubMedGoogle Scholar
  22. Manukyan G, Ghazaryan K, Ktsoyan Z, Khachatryan Z, Kelly D, Tatyan M, Agababova M, Aminov R (2010) Comparative analysis of cytokine profiles in autoinflammatory and autoimmune conditions. Cytokine 50:146–151CrossRefPubMedCentralPubMedGoogle Scholar
  23. Monteith AJ, Kang S, Scott E, Hillman K, Rajfur Z, Jacobson K, Costello MJ, Vilen BJ (2016) Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus. Proc Natl Acad Sci USA 113:E2142–E2151CrossRefPubMedCentralPubMedGoogle Scholar
  24. Müller-Calleja N, Manukyan D, Canisius A, Strand D, Lackner KJ (2017) Hydroxychloroquine inhibits proinflammatory signalling pathways by targeting endosomal NADPH oxidase. Ann Rheum Dis 76:891–897CrossRefPubMedCentralPubMedGoogle Scholar
  25. Pacheco Y, Barahona-Correa J, Monsalve DM, Acosta-Ampudia Y, Rojas M, Rodríguez Y, Saavedra J, Rodríguez-Jiménez M, Mantilla RD, Ramírez-Santana C, Molano-González N, Anaya JM (2017) Cytokine and autoantibody clusters interaction in systemic lupus erythematosus. J Transl Med 15:239CrossRefPubMedCentralPubMedGoogle Scholar
  26. Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, Bruce IN, Isenberg D, Wallace DJ, Nived O, Sturfelt G, Ramsey-Goldman R, Bae SC, Hanly JG, Sánchez-Guerrero J, Clarke A, Aranow C, Manzi S, Urowitz M, Gladman D, Kalunian K, Costner M, Werth VP, Zoma A, Bernatsky S, Ruiz-Irastorza G, Khamashta MA, Jacobsen S, Buyon JP, Maddison P, Dooley MA, van Vollenhoven RF, Ginzler E, Stoll T, Peschken C, Jorizzo JL, Callen JP, Lim SS, Fessler BJ, Inanc M, Kamen DL, Rahman A, Steinsson K, Franks AG Jr, Sigler L, Hameed S, Fang H, Pham N, Brey R, Weisman MH, McGwin G Jr, Magder LS (2012) Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 64:2677–2686CrossRefPubMedCentralPubMedGoogle Scholar
  27. Ponticelli C, Moroni G (2017) Hydroxychloroquine in systemic lupus erythematosus (SLE). Expert Opin Drug Saf 16:411–419CrossRefPubMedCentralPubMedGoogle Scholar
  28. Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF (2015) Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology 23:231–269CrossRefGoogle Scholar
  29. Raley MJ, Schwacha MG, Loegering DJ (1997) Lysosomotropic agents ameliorate macrophage dysfunction following the phagocytosis of IgG-coated erythrocytes: a role for lipid peroxidation. Inflammation 21:619–628CrossRefPubMedCentralPubMedGoogle Scholar
  30. Ripley BJ, Goncalves B, Isenberg DA, Latchman DS, Rahman A (2005) Raised levels of interleukin 6 in systemic lupus erythematosus correlate with anaemia. Ann Rheum Dis 64:849–853CrossRefPubMedCentralPubMedGoogle Scholar
  31. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA (2010) Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 69:20–28CrossRefPubMedCentralGoogle Scholar
  32. Sabry A, Sheashaa H, El-Husseini A, Mahmoud K, Eldahshan KF, George SK, Abdel-Khalek E, El-Shafey EM, Abo-Zenah H (2006) Proinflammatory cytokines (TNF-alpha and IL-6) in Egyptian patients with SLE: its correlation with disease activity. Cytokine 35:148–153CrossRefPubMedCentralPubMedGoogle Scholar
  33. Segal R, Dayan M, Zinger H, Mozes E (2001) Suppression of experimental systemic lupus erythematosus (SLE) in mice via TNF inhibition by an anti-TNFalpha monoclonal antibody and by pentoxiphylline. Lupus 10:23–31CrossRefPubMedCentralPubMedGoogle Scholar
  34. Shariati-Sarabi Z, Monzavi SM, Ranjbar A, Esmaily H, Etemadrezaie H (2013a) High disease activity is associated with high disease damage in an Iranian inception cohort of patients with lupus nephritis. Clin Exp Rheumatol 31:69–75PubMedGoogle Scholar
  35. Shariati-Sarabi Z, Ranjbar A, Monzavi SM, Esmaily H, Farzadnia M, Zeraati AA (2013b) Analysis of clinicopathologic correlations in Iranian patients with lupus nephritis. Int J Rheum Dis 16:731–738CrossRefPubMedGoogle Scholar
  36. Silva JC, Mariz HA, Rocha LF Jr, Oliveira PS, Dantas AT, Duarte AL, Pitta Ida R, Galdino SL, Pitta MG (2013) Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients. Clinics (Sao Paulo) 68:766–771CrossRefGoogle Scholar
  37. Spronk PE, Limburg PC, Kallenberg CG (1995) Serological markers of disease activity in systemic lupus erythematosus. Lupus 4:86–94CrossRefPubMedGoogle Scholar
  38. Studnicka-Benke A, Steiner G, Petera P, Smolen J (1996) Tumour necrosis factor alpha and its soluble receptors parallel clinical disease and autoimmune activity in systemic lupus erythematosus. Br J Rheumatol 35:1067–1074CrossRefPubMedGoogle Scholar
  39. Su X, Zhou T, Yang P, Edwards CK, Mountz JD (1998) Reduction of arthritis and pneumonitis in motheaten mice by soluble tumor necrosis factor receptor. Arthritis Rheum 41:139–149CrossRefPubMedGoogle Scholar
  40. Sun KH, Yu CL, Tang SJ, Sun GH (2000) Monoclonal anti-double-stranded DNA autoantibody stimulates the expression and release of IL-1beta, IL-6, IL-8, IL-10 and TNF-alpha from normal human mononuclear cells involving in the lupus pathogenesis. Immunology 99:352–360CrossRefPubMedCentralPubMedGoogle Scholar
  41. Tackey E, Lipsky PE, Illei GG (2004) Rationale for interleukin-6 blockade in systemic lupus erythematosus. Lupus 13:339–343CrossRefPubMedCentralPubMedGoogle Scholar
  42. Talaat RM, Mohamed SF, Bassyouni IH, Raouf AA (2015) Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: correlation with disease activity. Cytokine 72:146–153CrossRefPubMedCentralGoogle Scholar
  43. Tunnicliffe DJ, Singh-Grewal D, Kim S, Craig JC, Tong A (2015) Diagnosis, monitoring, and treatment of systemic lupus erythematosus: a systematic review of clinical practice guidelines. Arthritis Care Res (Hoboken) 67:1440–1452CrossRefGoogle Scholar
  44. Umare V, Pradhan V, Nadkar M, Rajadhyaksha A, Patwardhan M, Ghosh KK, Nadkarni AH (2014) Effect of proinflammatory cytokines (IL-6, TNF-α, and IL-1β) on clinical manifestations in Indian SLE patients. Mediators Inflamm 2014:385297CrossRefPubMedCentralPubMedGoogle Scholar
  45. van den Borne BE, Dijkmans BA, de Rooij HH, le Cessie S, Verweij CL (1997) Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells. J Rheumatol 24:55–60PubMedPubMedCentralGoogle Scholar
  46. van Loosdregt J, Spreafico R, Rossetti M, Prakken BJ, Lotz M, Albani S (2013) Hydroxychloroquine preferentially induces apoptosis of CD45RO + effector T cells by inhibiting autophagy: a possible mechanism for therapeutic modulation of T cells. J Allergy Clin Immunol 131:1443–1446CrossRefPubMedCentralPubMedGoogle Scholar
  47. Willis R, Seif AM, McGwin G Jr, Martinez-Martinez LA, González EB, Dang N, Papalardo E, Liu J, Vilá LM, Reveille JD, Alarcón GS, Pierangeli SS (2012) Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort. Lupus 21:830–835CrossRefPubMedCentralPubMedGoogle Scholar
  48. Willis R, Smikle M, DeCeulaer K, Romay-Penabad Z, Papalardo E, Jajoria P, Harper B, Murthy V, Petri M, Gonzalez EB (2017) Clinical associations of proinflammatory cytokines, oxidative biomarkers and vitamin D levels in systemic lupus erythematosus. Lupus 26:1517–1527CrossRefPubMedCentralPubMedGoogle Scholar
  49. Wozniacka A, Carter A, McCauliffe DP (2002) Antimalarials in cutaneous lupus erythematosus: mechanisms of therapeutic benefit. Lupus 11:71–81CrossRefPubMedCentralPubMedGoogle Scholar
  50. Wozniacka A, Lesiak A, Narbutt J, McCauliffe DP, Sysa-Jedrzejowska A (2006) Chloroquine treatment influences proinflammatory cytokine levels in systemic lupus erythematosus patients. Lupus 15:268–275CrossRefPubMedCentralPubMedGoogle Scholar
  51. Zharkova O, Celhar T, Cravens PD, Satterthwaite AB, Fairhurst AM, Davis LS (2017) Pathways leading to an immunological disease: systemic lupus erythematosus. Rheumatology (Oxford) 56(suppl_1):i55–i66CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Rheumatic Diseases Research CenterMashhad University of Medical SciencesMashhadIran
  2. 2.Department of Internal Medicine, Imam Reza HospitalMashhad University of Medical SciencesMashhadIran
  3. 3.Immunology Research Center, Buali Research InstituteMashhad University of Medical SciencesMashhadIran
  4. 4.AJA University of Medical SciencesTehranIran
  5. 5.Rosalind Franklin University of Medicine and ScienceNorth ChicagoUSA

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