Systemic Lupus Erythematosus

Managing risk factors & New drugs in clinical trials

Introduction & Scope

​Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by the immune system's attack on the body's own tissues, leading to widespread inflammation and tissue damage. The exact cause remains multifactorial, involving genetic, hormonal, and environmental factors. This multi-systemic disorder affects women (9:1 ratio), especially those of childbearing age, and is more prevalent in certain ethnic groups, including African Americans, Hispanics, and Asians. The typical onset age is between 15-45.
 
Epidemiologically, SLE affects 20-150 individuals per 100,000 worldwide, with significant variation based on geographic and ethnic factors. The mortality rate for SLE patients has improved with advancements in treatment; however, it remains two to three-fold higher compared to the general population, primarily due to complications such as cardiovascular disease, infections, and renal involvement.
 
The burden of SLE on patients and the medical community is substantial. Patients often experience a range of debilitating symptoms including fatigue, joint pain, skin rashes, and organ dysfunction, which can significantly impact their quality of life. The medical community faces challenges in diagnosing and managing SLE due to its heterogeneous presentation and the need for long-term, multidisciplinary care. The economic burden is also considerable, encompassing direct medical costs, such as hospitalizations and medications, and indirect costs related to loss of productivity and disability.
 
Comprehensive coverage of this subject is beyond the scope of our efforts. The leading information sources on Lupus include:
The CDC-Lupus
National Resource Center on Lupus
The Lupus Initiative
The Lupus Foundation of America
 
Medscape also provides an excellent write-up on the subject: Systemic Lupus Erythematosus (SLE)
 
Here we will focus on preventive aspects, which consist of managing risk factors. We will also examine the latest clinical trials of new therapeutics reflecting potential advances benefiting patients.

Managing Risk Factors

​Since the cause of the disease is multifactorial with both genetic, viral, bacterial, and environmental components, potentially predisposed individuals should pay attention to all of them.
 
Genetic components
Contribution from genetics predates the advances in genotyping, whole genome sequencing and genome wide association studies. The disease is known for its high heritability, 66%. Twin studies showed concordance rates of 24-56% versus 2-5% in monozygotic (identical) and dizygotic twins, respectively. Sibling recurrence studies showed that the risk ratio is between 8 to 29 [1]. On that basis alone, the existence of a relative suffering from Lupus should be a warning about potential predispositions to the disease. Moreover, the predisposition risk is proportional to the degree of relatedness to the patient. The predisposed individual could work with a primary care doctor to establish a surveillance program to address the risk. From a scientific point of view, genotyping to identify the major SLE risk alleles and establish a polygenic risk score could be informative in determining a proper course of action. Engaging a genetic counselor to work in concert with the primary care doctor could be highly productive.
 
 
Viral infections
The link between virus infections and SLE is well established. Most notably were infections by Epstein-Barr (EBV) virus, Cytomegalovirus (CMV), Parvovirus B19 and the retroviruses [2]. Anecdotal reports have also linked Dengue virus, Hepatitis C and Covid 19 infections to SLE [3-5]. Monitoring for these infections and implementing vaccinations as recommended by the CDC or American College of Rheumatology (ACR) should be part of any surveillance program for predisposed individuals.
 
Gut microbiota:
Multiple studies have reported on the imbalance in the gut microbiota (dysbiosis) of SLE patients compared to healthy controls [6]. Despite marked geographical differences reflecting local diets and eating habits, at least two common denominators were associated with SLE dysbiosis: an decrease in overall biodiversity accompanied by a low ratio of Firmicutes to Bacteroidetes (Low F:B ratio). These conditions favor disruption of the intestinal barrier (leaky gut) and translocation of symbionts and pathobionts (notably Lachnospiraceae, Enterococcus gallinarum, Ruminococcus gnavus and Lactobacillus reuteri) into the lamina propria resulting in local inflammation and induction of autoantibodies via antigen mimicry. Considering that the current treatment regimen for SLE remains unsatisfactory, targeting the gut microbiota is attracting significant interest. Intervention through diet, probiotics, and fecal microbiota transplantations (FMT) are all under investigation to improve clinical outcome. Preliminary small single arm clinical trials have demonstrated the potential utility of FMT [7]. At the current stage of development determining the level of dysbiosis in predisposed patients could be useful for assessing the course of the disease before the appearance of symptoms. All attempts to correct the dysbiosis by diet, probiotics or FMT, remain at the experimental stage under strict medical supervision.
 
Environmental factors
A sound understanding of the risks discussed above sets the stage for managing known environmental triggers. It would be difficult to rank-order the most significant trigger for everyone since the clinical presentation of the disease is complex and varies depending on individuals. Nevertheless, individuals predisposed to SLE need to be on high alert for the most significant triggers including:
 
Exposure to occupational and non-occupational chemicals: Multiple studies have implicated exposure to certain chemicals to the development of SLE. Industrial and agricultural workers were most affected. These chemicals include silica & silicates, pesticides (especially polychlorinated biphenyls and dibenzofurans), industrial solvents, and heavy metals (especially lead and mercury) [8, 9, 12 &13].
 
Smoking: The effect of cigarette smoking on the development and exacerbation of Lupus fueled debates for years due to conflicting study results. Nevertheless, most recent reviews and meta-analyses of the data suggest that smoking exposure not only increases SLE disease risk but also affected progression and treatment [8-10, 14].
 
UV and sun exposure: There is ample clinical evidence demonstrating a clear relationship between excessive sun exposure, especially exposure to UV-B range, and the development of different variant forms of Lupus and subsequent flares. Moreover, photosensitivity is known as a key factor in the pathogenesis of the disease [8-11].
 
Medications: the fact that certain medications could induced a variant type of Lupus known as DIL (Drug-Induced Lupus) was known since 1945 [16]. Unlike other forms of Lupus, DIL tends to resolve upon discontinuation of the drug [17]. Over the years, the list of DIL medications grew longer. A recent study of the World Health Organization pharmacovigilance data base [18] identified 118 medications where procainamide, hydralazine and three TNF-alpha inhibitors (infliximab, adalimumab, etanercept) featured prominently as being most associated with DIL.
 
Sex hormone therapy: It is a special case of medications triggering the onset of SLE. A large 10-year cohort study showed dose dependent increased risk in susceptible women who just started combined oral contraceptives [19]. In transgender women receiving sex hormones before and after sex reassignment surgery the risk also increased [20-24]. Interestingly, the contraceptives did not affect the course of the disease in women who already had active but stable Lupus, except for those with medium or elevated level antiphospholipid (aPL) antibodies [9].

References
[1] Deng Y, Tsao BP. Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat Rev Rheumatol. 2010;6(12):683-692. doi: 10.1038/nrrheum.2010.176.
[2] Blank M, Schoenfeld Y & Perl A. Cross-talk of the environment with the host genome and the immune system through endogenous retroviruses in systemic lupus erythematosus. Lupus 2009; 18: 1136-1143.
[3] Rajadhyaksha A, Mehra S. Dengue fever evolving into systemic lupus erythematosus and lupus nephritis: a case report. Lupus. 2012;21: 999-1002. doi:10.1177/0961203312437807
[4] Sayiner ZA, Haque U, Malik MU, Gurakar A. Hepatitis C virus infection and its rheumatologic implications. Gastroenterol Hepatol (N Y). 2014;10: 287-93.
[5] Zamani, B., Moeini Taba, SM. & Shayestehpour, M. Systemic lupus erythematosus manifestation following COVID-19: a case report. J Med Case Reports. 2021;15,29. https://doi.org/10.1186/s13256-020-02582-8
[6] Toumi E, Mezouar S, Plauzolles A, et al. Gut microbiota in SLE: from animal models to clinical evidence and pharmacological perspectives. Lupus Science & Medicine. 2023;10: e000776.
doi: 10.1136/lupus-2022-000776
[7] Huang C and Yi P, Zhu M et al. Safety and efficacy of fecal microbiota transplantation for treatment of systemic lupus erythematosus: An EXPLORER trial. Journal of Autoimmunity. 2022; 130: 102844. doi.org/10.1016/j.jaut.2022.102844
[8] Refai RH, Hussein MF, Abdou MH & Abou‑Raya AN. Environmental risk factors of systemic lupus erythematosus: a case–control study. Nature Scientific Reports. 2023; 13:10219. https://doi.org/10.1038/s41598-023-36901-y
[9] Cardelli C, Zucchi D, Elefante E, Signorini V, Menchini M, Stagnaro C, Mosca M & Tani C. Environment and systemic lupus erythematosus. Clinical and Experimental Rheumatology. 2024; 42: 1104-1114.
[10] Bengtsson AA, Rylander L, Hagmar L, Nivet O & Sturfelt G. Risk factors for developing systemic lupus erythromatosus: a case-controlled study in southern Sweden. Rheumatology 2002; 41: 563-571.
[11] Kuhn A, Wenzel J & Weyd H. Photosensitivity, Apoptosis, and Cytokines in the Pathogenesis of Lupus Erythematosus: a Critical Review. Clinic Rev Allerg Immunol. 2014; 47:148–162. https://doi.org/10.1007/s12016-013-8403-x
[12] Tsai P-C, Ko Y-C, Huang W, Liu H-S & Guo L. Increased liver and lupus mortalities in 24-year follow-up of the Taiwanese people highly exposed to polychlorinated biphenyls and dibenzofurans. Science of the Total Environment. 2007; 374: 216–222.
[13] Parks CG & De Roos AJ. Pesticides, chemical and industrial exposures in relation to systemic lupus erythematosus. Lupus. 2014; 23: 527–536. doi:10.1177/0961203313511680.
[14] Mak A & Tay SH. Environmental Factors, Toxicants and Systemic Lupus Erythematosus. Int. J. Mol. Sci. 2014; 15: 16043-16056. https://doi.org/10.3390/ijms150916043
[15] Arnaud L, Mertz P, Gavand P, et al. Drug-induced systemic lupus: revisiting the ever-changing spectrum of the disease using the WHO pharmacovigilance database. Annals of the Rheumatic Diseases. 2019;78:504-508.
[16] Hoffman BJ. Sensitivity to sulfadiazine resembling acute disseminated lupus erythematosus. Arch Dermatol Syphilol 1945; 51:190–192.
[17] Kaufman CL & Quiroz EH. Drug-Induced Lupus Erythematosus. Medscape. 2020; 1065086. https://emedicine.medscape.com/article/1065086-overview
[18] Arnaud L, Mertz P, Gavand PE et al. Drug-induced systemic lupus: revisiting the ever-changing spectrum of the disease using the WHO pharmacovigilance database. Ann Rheum Dis 2019; 78: 504-8. https:// doi.org/10.1136/annrheumdis-2018-214598
[19] Bernier MO, Mikaeloff Y, Hudson M et al. Combined oral contraceptive use and the risk of systemic lupus erythematosus. Arthritis Rheum. 2009; 61: 476-81. https://doi.org/10.1002/art.24398
[20] Santos-Ocampo AS. New onset systemic lupus erythematosus in a transgender man: possible role of feminizing sex hormones. J Clin Rheumatol. 2007; 13: 29-30. https://doi. org/10.1097/01.rhu.0000256169.05087.ad
[21] Zandman-Goddard G, Solomon M, Barzilai A et al.: Lupus erythematosus tu midus induced by sex reassignment surgery. J Rheumatol 2007; 34: 1938-40.
[22] Chan KL, Mok CC: Development of sys temic lupus erythematosus in a male-to-fe male transsexual: the role of sex hormones revisited. Lupus 2013; 22: 1399-402. https://doi.org/10.1177/0961203313500550
[23] Pontes LT, Camilo DT, De Bortoli MR et al.: New-onset lupus nephritis after male to-female sex reassignment surgery. Lupus 2018; 27: 2166-69. https://doi.org/10.1177/0961203318800571
[24] Hill BG, Hodge B, Misischia R: Lupus nephritis in a transgender woman on cross sex hormone therapy: a case for the role of oestrogen in systemic lupus erythematosus. Lupus 2020; 29: 1807-10. https://doi.org/10.1177/0961203320946372

New drugs in clinical trials

​The current standard of care uses different drug classes including: antimalarials (hydroxychloroquine), nonsteroidal anti-inflammatory drugs (NSAIDs: ibuprofen, naproxen, and diclofenac), corticosteroids (prednisone, methylprednisolone) and other immunosuppressives (cyclophosphamide, methotrexate, azathioprine, mycophenolate, and immunoglobulin). Recent entities include biologics targeting the survival and development of B-lymphocytes (belimumab & rituximab), Type 1 interferon antagonist (anifrolumab) and two calcineurin inhibitors (tacrolimus & voclosporin). The current standard of care is inadequate since these drugs only mitigate the course of the disease and come with significant side effects, decreasing the quality of life of patients.
 
A review of novel therapeutics in the clinical trials database (clinicaltrials.gov) provides a glimpse of the future. The new drug in clinical trials falls into five categories including: cell therapy, biologics, small molecule, natural product, and probiotics.
 
Cell therapy is the newest promising approach since the preliminary report by Mackensen et al [1] showing the effectiveness of anti CD19 chimeric antigen receptor T cell treatment (CAR-T) in five patients. There are currently a total of 36 CAR-T trials targeting various cell surface antigens (CD3, CD19, CD20, BCMA or combinations thereof) driving T and B lymphocytes development and proliferation. Most notable among these trials is the one undertaken by Cartesian Therapeutics, which employs mRNA-based CAR-T (Descartes-08, trial NCT06038474) bypassing the need for isolating T cells from the blood of patients and ex vivo transfection. In addition, the chimeric antigen receptor technology also utilizes NK cells as two anti CD19 CAR-NK trials are recruiting patients. Cell therapy also features mesenchymal stem cell transplantations from either umbilical cord blood or bone marrow. Finally, there is a single trial employing NK cells from umbilical cord blood. The table shown below summarizes the cell therapy efforts.

Cell therapy	Number of clinical trials
	Enrollment completed (07/26/2024)	Enrolling
CAR-T therapy target
CD19	0	21
BCMA	0	3
CD19 & BCMA	0	8
CD19 & CD20	0	2
CD19 & CD3	0	1
BCMA & CD20	0	1
CAR-NK therapy target
CD19	0	2
Allogeneic umbilical cord blood NK therapy	0	1
Mesenchymal Stem Cell (MSC) therapy
Allogeneic umbilical cord blood derived	0	5
Allogeneic bone marrow derived	1	2
Autologous bone marrow derived	0	1

 

​Biologics include traditional mono and bispecific monoclonal antibodies, Fab fragments, bispecific diabody, fusion proteins and cytokines. Biologics aims at a broader set of targets. Besides the B and T cell surface antigens they also target other immune modulators implicated in the pathogenesis of Lupus including the plasmacytoid dendritic cell antigens BDCA2 and ILT7, the CD40/CD40L pair, cytokine, cytokine receptors, FcRn, protein tyrosine phosphatase receptor type S and the complement system. Clinical trials with different types of biologics are summarized in the table below.

Biologics	Number of clinical trials
	Enrollment completed (07/26/2024)	Enrolling
Monoclonal antibody target
BAFFR	1	5
BCMA	0	1
CD20	1	4
CD38	0	3
IFNAR-1	1	2
BDCA2	0	3
CD40 Ligand (CD40L)	0	1
CD40	1	0
IFN beta 1	0	1
IFN gamma	1	0
IL-6R	0	1
ILT7	0	1
PTPRS (Protein Tyrosine Phosphatase Receptor Type S)	0	1
Complement C5 protein	0	1
FcRn Ig binding site	1	0
Engineered bispecific antibody target
CD3 & CD19	0	1
CD20 & CD3	1	1
CD28 & ICOS	1	0
Fab fragment target
TNF	0	1
C1q	0	1
FcRn	0	1
Engineered bispecific diabody target
CD32B & CD79B	1	0
Engineered Fusion Proteins
TACI ECD fused to IgG1 Fc	0	8
IL-2-CD25(IL-2Ralpha) fusion	0	1
2 Tn3 CD40L binding domains-Human serum albumin fusion	0	1
Cytokines
Interleukin 2 (IL-2)	0	1
IL-2 mutein	1	2

 

​Small molecules targeted the kinases in signal transduction pathways that are downstream of T and B cell receptors (BTK, mTOR), cytokine receptors (JAKs & TYKs) and Toll like receptors (IRAKs) implicated in the pathogenesis of Lupus. Alternative strategies include the development of protease inhibitors to block the activities of the complement system (Factor B & D) and immunoproteasomes (LMP2&7). A modulator of Sphingosine-1-phosphate receptor-1 which could rectify the balance between Treg and TH17 cells, is also in trials for effectiveness in SLE. Finally, N-acetylcysteine is in clinical trials for SLE for its dual role as antioxidant and inhibitor of the mTOR signaling pathway. The table shown below summarizes all current small molecules trials.

Small Molecules target	Number of clinical trials
	Enrollment completed (07/26/2024)	Enrolling
TLR 7 and/or 8	0	3
Janus kinases (JAK 1 and/or 2)	3	5
Bruton tyrosine kinase (BTK)	1	1
Tyrosine kinase 2 (TYK-2)	0	2
IRAK-4	0	1
Mammalian Target of Rapamycin (mTOR)	0	1
KRAS G12C	0	1
Alternative Complement System (Factor B, D)	0	2
Immunoproteasome LMP 2&7	0	1
Sphingosine 1 Phosphate Receptor 1 (S1P1)	0	2
Lymphocyte glutathione depletion	0	1

 

​Natural product: A single trial uses curcumin for Lupus Nephritis (NCT05714670) based on promising results seen in Lupus mouse models. Infiltration of neutrophils and their release of inflammatory factors decreased in renal tissues of mouse models when treated with curcumin. The effect resulted from inhibition of the PI3K/AKT/NF-κB signaling pathway, which is upregulated by interleukin-8 to induce neutrophil migration and renal inflammation.
 
 Probiotics: A single trial (NCT05433857) addresses the use of Lacteol Forte in Systemic Lupus Erythematosus. Lacteol Forte is a probiotic containing Lactobacillus acidophilus LB strain.
 
The overall failure rate in clinical trials for novel entities in the autoimmune/inflammation therapeutic area could be as high as 85% according to statistical surveys done in 2018 [2]. Accordingly, there is hope that 4 to 5 of the entities listed above could soon reach patients. A breakthrough in CAR-T cell therapy providing more than just symptomatic alleviation would be most desirable. Moreover, delivery of the chimeric antigen receptor (CAR) to T cells or NK cells via mRNA technology would be most convenient for patients.

References
[1] Mackensen, A., Müller, F., Mougiakakos, D. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 28, 2124–2132 (2022). https://doi.org/10.1038/s41591-022-02017-5
[2] Chi Heem Wong, Kien Wei Siah, Andrew W Lo, Estimation of clinical trial success rates and related parameters. Biostatistics 20, 273–286 (2019). https://doi.org/10.1093/biostatistics/kxx069