EC Clinical and Medical Case Reports

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which affects multiple organs. Both innate and adaptive immune responses are involved. Complex interaction of environments, genetics, and hormones leads to immune dysregulation, tolerance disintegration to self-antigens, resulting in autoantibody production, inflammation, and end organs destruction. Aberrations in cellular metabolism, abnormal phenotype, subsets, function of T and B lymphocytes have been identified as important factors in the underlying pathophysiology.

Symptoms associated with the disease are arthritis (joint pains and swelling), hemolytic anemia (destruction of red blood cells), leucopenia (low levels of white blood cells), neurological manifestations (psychosis, seizures), oral ulcers, renal failure, skin rashes, and thrombocytopenia (low platelet numbers). All these will further increase morbidity and mortality. However, early and accurate diagnosis of systemic lupus erythematosus will be of great significant in the prevention of morbidity and mortality. Non-biologic (conventional) or biologic (monoclonal antibodies, mAbs) therapeutic agents used alone, in combination or sequentially have enhanced the achievement of both short-term and long-term treatment objectives namely prevention of flares and organ damage, optimization of health-related quality of life, and long-term patient survival. Although enzyme-linked immunosorbent assay (ELISA) is a reasonable method for monoclonal antibodies quantifications, however chromatographic analyses in particular hyphenated systems (for example LC/MS/MS), have become more valuable approaches for both non-biologic and biologic therapeutic agents in biological fluids.

 Keywords: Systemic Lupus Erythematosus; Non-Biologic and Biologic Therapeutic Agents; Quantification in Biological Fluids

1. de Larrinoa IR. “What is new in systemic lupus erythematosus”. Rheumatology Clinics1 (2015): 27-32.
2. Tsokos GC. “Systemic lupus erythematosus”. New England Journal of Medicine22 (2011): 2110-2121.
3. Ocampo-Piraquive V., et al. “Mortality in systemic lupus erythematosus: Causes, predictors and interventions”. Expert Review of Clinical Immunology12 (2018): 1043-1053.
4. Lisnevskaia L., et al. “Systemic lupus erythematosus”. Lancet 9957 (2014): 1878-1888.
5. Ma K., et al. “Multiple functions of B cells in the pathogenesis of systemic lupus erythematosus”. International Journal of Molecular Science 23 (2019): 6021.
6. Möckel T., et al. “B cell activating factor (BAFF): Structure, functions, autoimmunity and clinical implications in systemic lupus erythematosus (SLE)”. Autoimmunity Reviews2 (2021): 102736.
7. Orme J and Mohan C. “Macrophage subpopulations in systemic lupus erythematosus”. Discovery Medicine69 (2012): 151-158.
8. Bennett L et al. “Interferon and granulopoiesis signatures in systemic lupus erythematosus blood”. Journal of Experimental Medicine6 (2003): 711-723.
9. Son M et al. “SLE-associated risk factors affect DC function”. Immunology Reviews 1 (2016): 100-117.
10. Arandjelovic S and Ravichandran KS. “Phagocytosis of apoptotic cells in homeostasis”. Nature Immunology9 (2015): 907-917.
11. Fortuna G and Brennan MT. “Systemic lupus erythematosus: Epidemiology, pathophysiology, manifestations, and management”. Dental Clinics of North America4 (2013): 631-655.
12. Antonis F et al. “Update οn the diagnosis and management of systemic lupus erythematosus”. Annals of Rheumatic Diseases1 (2021): 14-25.
13. Panagiotis A and Lambros A. “Current treatment approach, emerging therapies and new horizons in systemic lupus erythematosus”. Life Journal7 (2023): 1496.
14. Hashii N et al. “Generic MS-based method for the bioanalysis of therapeutic monoclonal antibodies in nonclinical studies”. Bioanalysis4 (2020): 231-236.
15. Ruiz-Irastorza G and Khamashta MA. “Hydroxychloroquine: The cornerstone of lupus therapy”. Lupus 4 (2008): 271-273.
16. Schrezenmeier E and Dörner T. “Mechanisms of action of hydroxychloroquine and chloroquine: Implications for rheumatology”. Nature Reviews Rheumatology3 (2020): 155-166.
17. Fox R. “Anti-malarial drugs: Possible mechanisms of action in autoimmune disease and prospects for drug development”. Lupus S1 (1996): S4-S10.
18. Penn SK et al. “Hydroxychloroquine and glycemia in women with rheumatoid arthritis and systemic lupus erythematosus”. Journal of Rheumatology 6 (2010): 1136-1142.
19. Capone ML et al. “Human pharmacology of naproxen sodium”. Journal of Pharmacology and Experimental Therapeutics2 (2007): 453-460.
20. Tanaka Y. “State-of-the-art treatment of systemic lupus erythematosus”. International Journal of Rheumatology Diseases4 (2020): 465-471.
21. Porta S et al. “Glucocorticoids in systemic lupus erythematosus. Ten questions and some issues”. Journal of Clinical Medicine9 (2020): 2709-2714.
22. Jaryal A and Vikrant S. “Current status of lupus nephritis”. Indian Journal of Medical Research2 (2017): 167-178.
23. Fortin PR et al. “Steroid-sparing effects of methotrexate in systemic lupus erythematosus: A double-blind, randomized, placebo-controlled trial”. Arthritis and Rheumatology12 (2008): 1796-1804.
24. Islam MN et al. “Efficacy and safety of methotrexate in articular and cutaneous manifestations of systemic lupus erythematosus”. International Journal of Rheumatology Diseases1 (2012): 62-68.
25. Pego-Reigosa JM et al. “Efficacy and safety of nonbiologic immunosuppressants in the treatment of nonrenal systemic lupus erythematosus: A systematic review”. Arthritis Care and Research11 (2013): 1775-1785.
26. Sakthiswary R and D’Cruz D. “Intravenous immunoglobulin in the therapeutic armamentarium of systemic lupus erythematosus: A systematic review and meta-analysis”. Medicine 16 (2014): e86-e94.
27. Zandman-Goddard G et al. “Intravenous immunoglobulin therapy and systemic lupus erythematosus”. Clinical Reviews Allergy Immunology 3 (2005): 219-228.
28. Zandman-Goddard G et al. “Intravenous immunoglobulins in systemic lupus erythematosus: From the bench to the bedside”. Lupus10 (2009): 884-888.
29. Magro R. “Biological therapies and their clinical impact in the treatment of systemic lupus erythematosus”. Therapeutic Advances in Musculoskeletal Diseases 11 (2019):
30. Sabahi R and Anolik JH. “B-cell-targeted therapy for systemic lupus erythematosus”. Drugs 15 (2006): 1933-1948.
31. Liossis SN and Melissaropoulos K. “Molecular abnormalities of the B cell in systemic lupus erythematosus are candidates for functional inhibition treatments”. Expert Opinions on Pharmacotherapy6 (2014): 833-840.
32. García-Hernández., et al. “Tocilizumab for treating refractory haemolytic anaemia in a patient with systemic lupus erythematosus”. Rheumatology10 (2012): 1918-1919.
33. Sanz I. “Systemic lupus erythematosus: Extent and patterns of off-label use of rituximab for SLE”. Nature Reviews Rheumatology 12 (2016): 700-702.
34. van Vollenhoven RF et al. “Belimumab in the treatment of systemic lupus erythematosus: High disease activity predictors of response”. Annals of the Rheumatology Diseases8 (2012): 1343-1349.
35. Guerreiro CS and Isenberg DA. “Belimumab in systemic lupus erythematosus (SLE): Evidence-to-date and clinical usefulness”. Therapeutic Advances in Musculoskeletal Diseases 3 (2017): 75-85.
36. Lenert A et al. “Spotlight on blisibimod and its potential in the treatment of systemic lupus erythematosus: Evidence to date”. Drug Design Development and Therapy 11 (2017): 747-757.
37. Bag-Ozbek A and Hui-Yuen JS. “Emerging B-Cell therapies in systemic lupus erythematosus”. Therapeutics and Clinical Risk Management 17 (2021): 39-54.
38. Isenberg DA et al. “Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: Results from ILLUMINATE-1, a 52- week, phase III, multicentre, randomised, double-blind, placebo-controlled study”. Annals of the Rheumatology Diseases 2 (2016): 323-331.
39. Merrill JT et al. “Efficacy and safety of atacicept in patients with systemic lupus erythematosus: Results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled, Parallel-Arm, Phase IIb Study”. Arthritis and Rheumatology 2 (2018): 266-276.
40. Gottenberg JE et al. “Efficacy of epratuzumab, an anti-cd22 monoclonal igg antibody, in systemic lupus erythematosus patients with associated Sjögren’s syndrome: Post Hoc analyses from the EMBODY trials”. Arthritis and Rheumatology 5 (2018): 763-773.
41. Ostendorf L et al. “Targeting CD38 with daratumumab in refractory systemic lupus erythematosus”. New England Journal of Medicine 12 (2020): 1149-1155.
42. Lamb YN. “Ocrelizumab: A review in multiple sclerosis”. Drugs 3 (2022): 323-334.
43. Reddy V et al. “Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples”. Rheumatology7 (2017): 1227-1237.
44. Masoud S et al. “Ofatumumab for B cell depletion in patients with systemic lupus erythematosus who are allergic to rituximab”. Rheumatology 7 (2018): 1156-1161.
45. Satterthwaite AB. “Bruton’s tyrosine kinase, a component of B Cell signaling pathways, has multiple roles in the pathogenesis of lupus”. Frontiers in Immunology 8 (2017): 1986-1993.
46. Alexander T., et al. “The proteasome inhibitor bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus”. Annals of the Rheumatology Diseases 7 (2015): 1474-1478.
47. Walhelm T., et al. “Clinical experience of proteasome inhibitor bortezomib regarding efficacy and safety in severe systemic lupus erythematosus: a nationwide study”. Frontiers in Immunology 12 (2021): 756941-756945.
48. Moulton VR and Tsokos GC. “T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity”. Journal of Clinical Investigation6 (2015): 2220-2227.
49. Sakaguchi S. “Taking regulatory T cells into medicine”. Journal of Experimental Medicine 218 (2021): e20210831.
50. Rönnblom L. “The importance of the type I interferon system in autoimmunity”. Clinical and Experimental Rheumatology S98 (2016): 21-24.
51. Khamashta M et al. “Sifalimumab, an antiinterferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: A randomised, double-blind, placebo controlled study”. Annals of the Rheumatology Diseases11 (2016): 1909-1916.
52. Soichot M et al. “Development, validation and clinical application of a LC-MS/MS method for the simultaneous quantification of hydroxychloroquine and its active metabolites in human whole blood”. Journal of Pharmaceutical and Biomedical Analysis 100 (2014): 131-137.
53. Carlsson H et al. “Measurement of hydroxychloroquine in blood from SLE patients using LC-HRMS— evaluation of whole blood, plasma, and serum as sample matrices”. Arthritis Research and Therapy1 (2020): 125.
54. Mok CC et al. “Hydroxychloroquine serum concentrations and flares of systemic lupus erythematosus: a longitudinal cohort analysis”. Arthritis Care and Research9 (2016): 1295-1302.
55. María NG et al. “Determination of prednisolone and prednisone in plasma, whole blood, urine, and bound-to-plasma proteins by high-performance liquid chromatography”. Journal of Chromatographic Science4 (2005): 201-206.
56. Francesco RD et al. “Simultaneous determination of cortisol, dexamethasone, methylprednisolone, prednisone, prednisolone, mycophenolic acid and mycophenolic acid glucuronide in human plasma utilizing liquid chromatography- tandem mass spectrometry”. Journal of Chromatography B 1 (2007): 42-51.
57. Goyal RN and Bishnol S. “Simultaneous voltammetric determination of prednisone and prednisolone in human body fluids”. Talanta3 (2009): 768-774.
58. SA Döppenschmitt., et al. “Simultaneous determination of prednisolone, prednisolone acetate and hydrocortisone in human serum by high-performance liquid chromatography”. Journal of Chromatography B 2 (1995): 237-246.
59. Frerichs VA and Tornatore KM. “Determination of the glucocorticoids prednisone, prednisolone, dexamethasone, and cortisol in human serum using liquid chromatography coupled to tandem mass spectrometry”. Journal of Chromatography B 2 (2004): 329-338.
60. Garg V and Jusko WJ. “Simultaneous analysis of prednisone, prednisolone and their major hydroxylated metabolites in urine by high performance liquid chromatography”. Journal of Chromatography B1 (2014): 97-104.
61. Raja MJ et al. “Simultaneous determination of azathioprine and its metabolite 6-mercaptopurine in human plasma using solid phase extraction-evaporation and liquid chromatography-positive electrospray tandem mass spectrometry”. International Current Pharmaceutical Journal11 (2012): 342-352.
62. Maddocks JL. “Assay of azathioprine, 6-mercaptopurine and a novel thiopurine metabolite in human plasma”. British Journal of Clinical Pharmacy 3 (1979): 273-278.
63. Binscheck T et al. “HPLC assay for the measurement of azathioprine in human serum sample”. Journal Chromatography B Biomedical Sciences Applications 2 (1996): 287-294.
64. Marakova K et al. “Capillary electrophoresis hyphenated with mass spectrometry for determination of inflammatory bowel disease drugs in clinical urine samples”. Molecules11 (2017): 1973- 1979.
65. Szeitz A et al. “Assay for the determination of ibuprofen in human plasma using ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS)”. American Journal of Analytical Chemistry2 (2010): 47-58.
66. Ganesan M., et al. “Determination of ibuprofen in human plasma with minimal sample pretreatment”. International Journal of Pharmaceutical Sciences and Research 14 (2010): 120-127.
67. Tan SC., et al. “Enantiospecific analysis of ibuprofen by high performance liquid chromatography: Determination of free and total drug enantiomer concentrations in serum and urine”. Chromatographia 46 (1997): 23-32.
68. Yilmaz B and Erdem AF. “Determination of ibuprofen in human plasma and urine by gas chromatography/mass spectrometry”. Journal of AOAC International 2 (2014): 415-420.
69. deVeries JX., et al. “The analysis of ibuprofen enantiomers in human plasma and urine by high performance liquid chromatography on an α₁-acid glycoprotein chiral stationary phase”. Journal of Liquid Chromatography 10 (1994): 2127-2145.
70. Mulder MB., et al. “Therapeutic drug monitoring of methotrexate in plasma using ultra high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: necessary after administration of glucarpidase in methotrexate intoxications”. Therapeutic Drug Monitoring 4 (2018): 383-385.
71. Wu D., et al. “A simple, rapid and reliable liquid chromatography-mass spectrometry method for determination of methotrexate in human plasma and its application to therapeutic drug monitoring”. Biomedical Chromatography8 (2015): 1197-1202.
72. Naresh Kumar Tripathy NK., et al. “A rapid method for determination of serum methotrexate using ultra-high-performance liquid chromatography-tandem mass spectrometry and its application in therapeutic drug monitoring”. Journal of Laboratory Physicians 3 (2023): 345-353.
73. McTaggart MP and Keevil BG. “A rapid LC-MS/MS assay for the measurement of serum methotrexate in patients who have received high doses for chemotherapy”. Annals of Clinical Biochemistry 6 (2021): 599-604.
74. Zayed S and Bela F. “Determination of the monoclonal antibody tocilizumab by a validated micellar electrokinetic chromatography method”. Chromatographia5 (2022): 481-488.
75. Takada M., et al. “Simple and rapid analysis of tocilizumab using HPLC—fluorescence detection method”. Luminescence 3 (2019): 347-352.
76. Millet A., et al. “Development, validation, and comparison of two mass spectrometry methods (LC-MS/HRMS and LC-MS/MS) for the quantification of rituximab in human plasma”. Molecules 5 (2021): 1383-1389.
77. Truffot A et al. “Simultaneous quantification of rituximab and eculizumab in human plasma by liquid chromatography-tandem mass spectrometry and comparison with rituximab ELISA kits”. Clinical Biochemistry 87 (2021): 60-66.
78. Iwamoto N et al. “Validated LC/MS bioanalysis of rituximab CDR peptides using nano-surface and molecular-orientation limited (nsmol) proteolysis”. Biological and Pharmaceutical Bulletin 7 (2016): 1187-1194.
79. Verougstraete N., et al. “Quantification of eight hematological tyrosine kinase inhibitors in both plasma and whole blood by a validated LC-MS/MS method”. Talanta 226 (2021): 122140.
80. Croitoru DM., et al. “New approach in determining ibrutinib in human plasma by hplc-dad and application of the method in a preliminary pharmacokinetic study”. Farmacia4 (2020): 640-645.
81. Mukai Y., et al. “Novel high-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification of BCR-ABL and Bruton’s tyrosine kinase inhibitors and their three active metabolites in human plasma”. Journal of Chromatography B Analytical Technologies in the and Biomedical Life Science 1137 (2020): 121928.
82. Écsiová D., et al. “High-throughput salting-out assisted liquid-liquid extraction using a 3D printed device and its application in the quantification of ibrutinib and its metabolite PCI-45227 in human serum”. Journal of Pharmaceutical and Biomedical Analysis 219 (2022): 114923.
83. Guo Z., et al. “A simplified method for bortezomib determination using dried blood spots in combination with liquid chromatography/tandem mass spectrometry”. Journal Chromatography B 1181 (2021): 122905.
84. Chandramowli B and Rajkamal BB. “A validated LC-MS/MS Method for the estimation of bortezomib and bortezomib d3 (is) in human plasma with protein precipitation and special filter cartridges”. Journal of Applied Pharmaceutical Science 1 (2017): 35-41.
85. Ezan E and Bitsch F. “Critical comparison of MS and immunoassays for the bioanalysis of therapeutic antibodies”. Bioanalysis8 (2009): 1375-1388.
86. Iwamoto N., et al. “Validated LC/MS bioanalysis of rituximab CDR peptides using nano-surface and molecular-orientation limited (nsmol) proteolysis”. Biological and Pharmaceutical Bulletin7 (2016): 1187-1194.