Top 12: Research in Systemic Lupus Erythematosus at a Glance

ACR CONVERGENCE 2021—More than 200 research abstracts related to lupus were accepted for presentation at ACR Convergence 2021 in November. Specific topics varied greatly. We don’t have the space to discuss many abstracts, but below, I have tried to touch on a number of different areas discussed at the meeting.

Abstract 1735—Glucocorticoid discontinuation in patients with systemic lupus erythematosus with prior severe organ manifestation¹

Research by Nakai T, et al.

Glucocorticoids, such as prednisone and prednisolone, are highly effective agents for the treatment of systemic lupus erythematosus (SLE), but they come with significant toxicity that can lead to organ damage. Tapering glucocorticoids is always a goal of therapy, but this goal is frequently not met because of concerns that disease will flare. However, the study by Nakai and colleagues demonstrates that glucocorticoids can be tapered and discontinued even in patients who have had prior severe organ manifestations. Indeed, the rate of flare after discontinuation of glucocorticoids was similar in patients with or without severe organ manifestations.

Among factors that could influence flare, the presence of antibodies to Sm/ribonucleoprotein (RNP) showed a negative influence on flare-free remission; in contrast, anti-DNA antibody on the day of discontinuation of glucocorticoids did not have an effect.

In addition to indicating the feasibility of glucocorticoid discontinuation, this study is important in highlighting the role of anti-Sm/RNP antibodies in promoting pathogenesis; this role likely relates to the formation of immune complexes that induce interferon and subsequent downstream effects of this cytokine. Future studies will hopefully identify biomarkers to better determine patients for whom glucocorticoid discontinuation is possible.

Abstract 1463—Use of telemedicine for follow-up of lupus nephritis in the COVID-19 outbreak: The 6-month results of a randomized controlled trial²

Research by So H, et al.

The COVID-19 pandemic has had an enormous impact on the healthcare delivery system, arising from the care of patients with the infection, as well as those patients with other conditions whose care is affected by access issues and a reluctance to enter facilities with infected patients. Recognizing the importance of social distancing to limit contact with the virus, many hospitals and practices instituted the use of telemedicine to keep patients safely at home for routine visits. This approach was rapidly adapted in the midst of a severe public health emergency, leaving many unknowns about telemedicine’s effectiveness and impact on patients.

A single-center, randomized, open-label study by So et al. shows that the use of telemedicine for patients with SLE can lead to better patient satisfaction, as well as improved short-term outcomes, although those patients using telemedicine had more hospitalizations.

The accumulated experience from this and other studies suggests that telemedicine can be useful even as the virus recedes. A hybrid system incorporating telemedicine may have value, however, because some patients may need in-person visits so rheumatologists can monitor their disease more closely; a higher physician global assessment score may identify such patients.

Abstract 0326—Apolipoprotein L1 (APOL1) in African-American SLE: Frequency and clinical associations³

Research by Petri M, et al.

Patients of African ancestry have worse outcomes from renal disease than patients of European ancestry, resulting in part from the influence of apolipoprotein L1 (APOL1) gene variants. These variants have presumably arisen as part of the host defense against trypanasomiasis in Africa. As now shown, two gene variants, called G1 and G2, increase the risk for a number of forms of renal disease, including lupus nephritis, as well as a greater likelihood of progression to chronic kidney disease (CKD) and end-stage renal disease (ESRD). In addition to the effects of the gene variants on the kidney, some studies have suggested an increase in the risk of cardiovascular disease.

This study by Petri et al. confirmed the high risk of renal disease in patients with at least one risk allele, but it did not find an association with avascular necrosis, cardiovascular disease or pulmonary fibrosis. A larger study may be needed to evaluate the risks for these complications more fully, but these findings are nevertheless important in indicating the vulnerability of the kidney to the presence of risk variants in patients with SLE.

In the future, more basic studies should clarify the intracellular role of APOL1; important issues to be elucidated concern its regulation by toll-like receptors and interferon and its role in processes such as autophagy.

Given the high burden of CKD among African Americans, these investigations are very important, with lupus providing a unique setting to delineate structure-function relationships of the gene variants and their role in pathophysiology.

Abstract 0323—Ro positivity is an under‐recognised poor prognostic marker in systemic lupus erythematosus patients⁴

Research by Liao K, et al.

Anti-nuclear antibodies (ANAs) in SLE come in two main types: those specific for SLE (i.e., anti-DNA antibody and anti-Sm antibody), and those that are not specific for SLE and have a wider expression in other rheumatic diseases (e.g., anti-Ro antibody, anti-RNP antibody). In general, studies on the pathogenesis of SLE have tended to focus on disease-specific ANAs rather than non-disease-specific ANAs.

Of non-specific ANAs, anti-Ro antibody clearly appears to be an important disease mediator. This study demonstrates that patients with SLE who were anti-Ro positive had notable clinical and immunological features: hypocomplementemia, overlapping features with Sjögren’s syndrome, more rash and more renal disease. Not surprisingly, anti-Ro-positive patients were more likely to be treated with immunosuppressive agents than those without this specificity.

These findings point to a role of anti-Ro antibody in important events in lupus; this role may result from the formation of immune complexes that induce interferon production and, therefore, drive more severe disease.

Despite its non-disease-specific nature, anti-Ro antibody may serve as a biomarker in SLE not just to identify an overlap with Sjögren’s syndrome, but also to denote a more severe phenotype that may need more intensive immunosuppression.

Abstract 1273—A 12-week aerobic exercise training program in women with systemic lupus erythematosus (SLE) improves fatigue, mitochondrial dysfunction and associated interferon gene signature⁵

Research by Hasni S, et al.

Fatigue is one of the most pervasive, persistent and disabling symptoms of SLE. Its origin is unclear, although fatigue may emerge during inflammatory responses as part of so-called sickness behavior. Fatigue does not appear related to disease activity in SLE, however, and there is no established treatment approach.

As shown in a small trial of patients with low disease activity but significant fatigue, an aerobic exercise program (i.e., treadmill exercise for 30 minutes three times a week for 12 weeks) can have significant benefits. These benefits include increases in the time to the anaerobic threshold and 10-minute walk time, along with decreased fatigue. Interestingly, blood from some patients in this trial exhibited reductions in interferon-stimulated gene (ISG) expression, a signature immunological feature of SLE.

Because these changes may reflect improvements in mitochondrial function, exercise may have an impact on patient symptoms as well as underlying disease mechanisms.

Given the powerful effect of fatigue on patient well-being and quality of life, further investigation into the role of exercise is clearly indicated. Correspondingly, as trials for pharmacological agents with new mechanisms of action advance, it will be important to assess more directly their effects on fatigue (and related symptoms), even if the link to measures of disease activity is uncertain.

Abstract 1460—Lupus nephritis renal responses in relation to treatment and demographics: Observations from a multi-racial/ethnic cohort of 159 patients in the NYU Lupus Registry⁶

Research by Haj-Ali M, et al.

Lupus nephritis is a heterogeneous disease that differs in course among racial and ethnic populations. In the U.S., African American and Hispanic patients have worse outcomes than Americans of European descent, while, in Asia, the response rates observed for certain agents (e.g., mycophenolate mofetil or MMF) appear better. Added to these differences is heterogeneity in the approach to therapy.

Until recently, no agents had received U.S. Food & Drug Administration (FDA) approval for the treatment of lupus nephritis. Thus, therapy has varied widely, although results reported in clinical trials have influenced the choice of agents in selected populations.

The paper by Haj-Ali et al. provides a retrospective picture of the treatment of lupus nephritis in an ethnically diverse population at an academic center experienced in the management of lupus. Although the number of patients in this study is limited, the data suggest that the responses to treatment with MMF and cyclophosphamide (CYC) at 104 weeks are better than responses to treatment with either MMF with tacrolimus, or rituximab with CYC.

The results of the study differed from those of previous studies with respect to outcomes in African American and Hispanic patients; these differences may relate to the use of MMF as a first-line therapy and the use of low-dose CYC and rituximab as rescue options.

Data from real-world experiences are valuable adjuncts to randomized clinical trials, despite the many uncertainties. Indeed, studies of this kind will provide necessary comparative data as new agents (i.e., belimumab and voclosporin) become part of the armamentarium of drugs used to treat one of the most serious manifestations of SLE.

Abstract 1744—Improvement of renal and non-renal SLE outcome measures on sirolimus therapy—a 21-year follow-up study of 73 patients⁷

Research by Piranavan P, Perl A

Until the recent approval of drugs with a specific indication for lupus nephritis, treatment of this serious complication involved a wide range of immunosuppressive agents essentially borrowed from other fields. Cyclophosphamide, azathioprine and mycophenolate mofetil (MMF) achieved the greatest use, with rituximab also used, depending on the clinical setting. Sirolimus has represented another alternative given its extensive use in the setting of organ transplantation.

Sirolimus inhibits the mechanistic target of rapamycin (mTOR), a serine-threonine kinase, that may be important in driving immune dysfunction in SLE. As the study of Piranavan et al. shows, sirolimus is well tolerated by patients and is effective in reducing serological, as well as clinical, manifestations of SLE, both renal and non-renal.

As the number of approved agents for SLE increases, studies will be needed to determine the best pharmacologic approaches for the various manifestations of lupus and the role of sirolimus among the other agents, especially for severe disease complications, such as nephritis.

Abstract 1423—Ability of soluble immune mediators and SLE-associated autoantibody specificities to forecast transition to classified SLE and inform a lupus classification risk immune index⁸

Research by Munroe M, et al.

Like other autoimmune diseases, SLE develops over time, and in the months to years prior to the clinical onset of disease, the immune systems of patients show distinctive changes heralding impending disease. The changes include expression of autoantibodies, as well as increases in levels of various cytokines and chemokines that together can represent a signature for a state of pre-autoimmunity that will transition to full-blown disease classifiable as SLE.

Munroe et al. used samples from the U.S. Department of Defense Serum Repository to measure multiple analytes reflective of immune activity and create a Lupus Classification Risk Immune Index (LCRII) for risk prediction. This index could prove valuable in evaluating patients with so-called incomplete lupus in which signs and symptoms, especially anti-nuclear antibody production, are present but are insufficient to allow classification by either ACR or Systemic Lupus Erythematosus International Collaborating Clinics Group (SLICC) criteria. Screening of family members at high risk of disease (e.g., sisters) is another setting in which the use of an index, such as the LCRII, can be explored.

Abstract 0857—Association of telomere length with phenotypic frailty in systemic lupus erythematosus⁹

Research by Lieber S, et al.

The course of SLE can be characterized in terms of measures, such as disease activity (e.g., SLEDAI) and damage (SLICC Damage Index), whether the damage arises from inflammatory disease activity or complications of therapy. Frailty is another measure of disease that can provide valuable information about the functional capacity of patients, their resilience and physiologic reserve.

Studied most extensively in the context of aging, frailty is a physical state that can be defined in five domains: weight loss, weakness, fatigue, slowness and low activity. Importantly, frailty is associated with increased mortality. The study by Lieber et al. examined telomere length in a cohort of patients with SLE assessed using objective and self-reported measures of frailty.

Telomere length, a molecular marker related to DNA sequences at the ends of chromosomes, can be conceptualized as a measure of accelerated aging. The study shows that about one-fourth of patients with SLE are frail by at least self-reporting and that frailty is associated with shorter telomere length.

Along with other studies on frailty, these data support telomere length as a molecular correlate of accelerated aging and suggest the value of frailty assessment as an adjunct to measures of disease activity and damage.

Abstract 1489—Identification of mitochondrial antigens targeted by autoantibodies in systemic lupus erythematosus (SLE)¹⁰

Research by Becker Y, et al.

The production of antibodies to components of the cell nucleus (i.e., ANAs) is the most characteristic immunologic feature of SLE, although autoantibodies to cytoplasmic antigens also occur. Recognition of autoantibodies to cytoplasmic antigens is important because antibodies to ribosomal P proteins, for example, are highly associated with SLE. Thus, the use of the term ANA can be misleading for serologic testing, especially if a laboratory calls a sample with cytoplasmic staining negative; the term anti-cellular antibody may be preferred to ANA to be more inclusive and call attention to autoreactivity against cytoplasmic targets.

Recently, investigators have identified antibodies to mitochondria in the sera of patients with SLE, an interesting finding because mitochondria, a cellular organelle, have intrinsic immunostimulatory properties due to molecular similarities to bacteria (e.g., DNA with unmethylated CpG motifs). The anti-mitochondrial antibodies in SLE differ, however, from those in primary biliary cholangitis.

As the study by Becker et al. demonstrates, the complement component 1Q subcomponent binding protein (C1qBP) and mitofusin 1 (Mfn1) are members of the mitochondrial proteasome that can serve as autoantigens in SLE and show associations with serological markers for the antiphospholipid antibody syndrome.

Studies like this are important to expand and clarify the serological profile of SLE, as well as focus attention on the mitochondria as a unique source of autoantigens that can drive SLE.

Abstract 0888—Disease flares in lupus are concordant with Ruminococcus blautia gnavus blooms within unstable gut microbiota communities¹¹

Research by Azzouz D, et al.

The study by Azzouz et al. provides new insights into the role of the microbiome in the pathogenesis of SLE. The microbiome represents the huge collection of bacteria, fungi and viruses that inhabit locales around the body, with the gut microbiome attracting the most investigative interest because of its size and role in metabolism and immune regulation. Dysbiosis is a disturbance in the usual composition of the microbiome, potentially contributing to disease susceptibility.

Among disturbances documented in this study, longitudinal instability of organisms in the gut in SLE is notable, with transient spikes of potentially pathogenic organisms, such as Ruminococcus blautia gnavus, occurring, especially in patients with renal disease. As the molecular analyses of the ribosomal genes of the bacteria indicated, blooms of Ruminococcus blautia gnavus can coincide with disease flares. This finding could suggest that blooms impair the gut barrier function allowing translocation of bacterial products into the circulation to drive inflammation.

Although the origin of the blooms is not clear, these findings, nevertheless, indicate that the gut microbiome may be a target of therapy, with the goal of restoring the stability of its composition and reducing the occurrence of more pathogenic species.

Abstract 0872—Lack of association between cognitive test performance and cognitive symptoms in systemic lupus erythematosus (SLE)¹²

Research by Raghunath S, et al.

Although inflammation (and consequent damage) is the cardinal feature of SLE, patients with SLE experience symptoms whose relationship to inflammation is less clear. These symptoms include pain, fatigue, mood disorders and cognitive dysfunction, all of which can affect patients’ quality of life. In general, these symptoms do not respond to conventional anti-inflammatory treatment and immunosuppressives. The assessment of these symptoms in the study of SLE usually involves instruments or measures imported from other fields, most notably neuropsychology.

As the findings of Raghunath et al. indicate—from the study of 87 patients with SLE—cognitive symptoms were strongly associated with depression, anxiety and fibromyalgia, but were not correlated with results of a battery of neuropsychiatric tests recommended by the ACR for this purpose.

These results are important in highlighting the limitations of current approaches for evaluating certain symptoms and suggest the need for developing tests of cognition specific for the setting of SLE to better assess functional capacity.

Dr. Pisetsky

David S. Pisetsky, MD, PhD, is a professor of medicine and immunology at Duke University School of Medicine in Durham, N.C., a staff rheumatologist at the Durham VA Medical Center and the first physician editor of The Rheumatologist.

Dr. Pisetsky received his BA from Harvard College, Cambridge, Mass., in 1967 and his PhD and MD from the Albert Einstein College of Medicine, The Bronx, N.Y., in 1972 and 1973. Following house staff training at the Yale-New Haven Hospital, Connecticut, he was a clinical associate at the National Cancer Institute, Bethesda, Md. He joined the faculty of the Duke University Medical Center in 1978, where he has remained since. He served as chief of rheumatology and immunology at Duke from 1996–2007 and chief of the rheumatology section at the Durham VAMC from 1978–2019.

Dr. Pisetsky has conducted basic and translational research on the pathogenesis of systemic lupus erythematosus (SLE) and the immunological properties of nuclear macromolecules. Most recently, he has investigated the immune activities of microparticles, as well as the immunochemical properties of anti-nuclear antibodies. In 2001, he was awarded the Howley Prize from the Arthritis Foundation for his work on the immune properties of DNA. In 2016, he received the Presidential Gold Medal from the ACR.

From 2000–05, Dr. Pisetsky served as editor of Arthritis & Rheumatism, and has been an associate editor of the Annals of the Rheumatic Diseases since 2012. He served as the president of the United States Bone and Joint Initiative from 2015–17.

References

1. Nakai T, Iwata F, Kidoguchi G, et al. Glucocorticoid discontinuation in patients with systemic lupus erythematosus with prior severe organ manifestation [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
2. So H, Chow E, Cheng I, et al. Use of telemedicine for follow-up of lupus nephritis in the COVID-19 outbreak: The 6-month results of a randomized controlled trial [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
3. Petri M, Kallas R, Li J, et al. Apolipoprotein L1 (APOL1) in African-American SLE: Frequency and clinical associations [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
4. Liao K, De Silva T, Bonin J. Ro positivity is an under‐recognised poor prognostic marker in systemic lupus erythematosus patients [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
5. Hasni S, Chapman M, Feng R, et al. A 12-week aerobic exercise training program in women with systemic lupus erythematosus (SLE) improves fatigue, mitochondrial dysfunction and associated interferon gene signature [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
6. Haj-Ali M, Deonaraine K, Engel A, et al. Lupus nephritis renal responses in relation to treatment and demographics: Observations from a multi-racial/ethnic cohort of 159 patients in the NYU Lupus Registry [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
7. Piranavan P, Perl A. Improvement of renal and non-renal SLE outcome measures on sirolimus therapy—a 21-year follow-up study of 73 patients [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
8. Munroe M, Lu R, Gross T, et al. Ability of soluble immune mediators and SLE-associated autoantibody specificities to forecast transition to classified SLE and inform a lupus classification risk immune index [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
9. Lieber S, Lipschultz R, Zahid S, et al. Association of telomere length with phenotypic frailty in systemic lupus erythematosus [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
10. Becker Y, Gagné J, Julien A, et al. Identification of mitochondrial antigens targeted by autoantibodies in systemic lupus erythematosus (SLE) [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
11. Azzouz D, Chen Z, Li Z, et al. Disease flares in lupus are concordant with Ruminococcus blautia gnavus blooms within unstable gut microbiota communities [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
12. Raghunath S, Glikmann-Johnston Y, Guymer E, et al. Lack of association between cognitive test performance and cognitive symptoms in systemic lupus erythematosus (SLE) [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).