Updates From the American College of Rheumatology 2020 Annual Scientific Meeting

How Sjogren Syndrome Intersects With COVID-19

Robert Fox, MD; Alan N. Baer, MD

Disclosures

December 24, 2020

In view of the pandemic, the American College of Rheumatology (ACR) annual scientific meeting (newly titled "ACR Convergence 2020") was held as a virtual event with its content, including symposia and research presentations, broadcast to registrants online. The meeting abstracts are posted online.

First, a Brief Detour

Before we review some highlights of the annual ACR meeting, we would like to share a few thoughts about what we may learn from the COVID-19 pandemic that will enhance our understanding of Sjogren syndrome (SS) and vice versa.

Autoimmune conditions like SS are generally thought to originate from the interaction of genetic and nongenetic (such as viral) factors. Because the onset of SS is sporadic, however, it has never been associated with a specific infectious agent, as was rheumatic fever after streptococcal infections or even the "epidemic" of reactive arthritis reported by Hans Reiter in cavalry soldiers with intestinal infections during World War I.

Indeed, in the United States we frequently do not see the onset of seronegative spondyloarthropathy as a postinfectious manifestation. But the initial association of reactive arthritis with well-characterized epidemics allowed the later recognition of specific factors, such as HLA-B27, as a common feature.

COVID-19 infection can become a complex autoimmune disorder in some patients, with the development of interstitial pneumonitis, myocarditis, elevation of acute phase reactants, and cytokine storm. Particular autoantibodies may influence the outcome of the COVID-19 infection. Thus, rheumatologists need to be alert to the postinfectious mechanisms leading to clinical features (including brain fog and fatigue in COVID "long haulers") as well as unexpected effects of COVID vaccination on our patients with SS.

SS is an autoimmune disease that is thought to be triggered by one or more viral infections, with those related to Epstein-Barr virus (EBV) and hepatitis C virus receiving particular scrutiny. Alternatively, endogenous microRNAs encoded in the genome may play a role in initiating and/or perpetuating the autoimmunity of SS. A problem with defining EBV as a causative agent in SS is its high seroprevalence rate in the human population, stemming from ubiquitous infections in childhood or as infectious mononucleosis in early adulthood. EBV remains in a latent state in the mesenchymal cells of the salivary glands of the nasopharynx and reactivates periodically with secretion of virus into saliva. The high prevalence of EBV infection in men has precluded the occurrence of EBV epidemics that might show a causal relationship with SS if a high number of cases arose post-infection.

Susceptibility to SS is strongly associated with the HLA-DR3 histocompatibility locus and other linked genes in the White population. These genes predispose to the formation of autoantibodies, such as anti-SS A (Ro). The SS-A antigen is a protein that binds to hYRNA. The resultant SSA/hYRNA complex is known to serve as a chaperone for a variety of viral RNAs. Indeed, the process of SS-A/hYRNA complex entry into phagocytic or epithelial cells involves its direction to cytoplasmic compartments where the single- and double-stranded regions of the hYRNA can activate Toll-like receptors (TLRs).

SS patients experience lacrimal and salivary gland dysfunction, resulting in dry eyes and mouth. They also frequently have disruption of taste and smell. Cognitive fog and fatigue are also common in SS patients and can significantly impair their quality of life.

COVID-19 is a single-stranded RNA virus that gains access to the cell cytoplasm after binding to an ACE2 receptor. The intracytoplasmic RNA can subsequently activate TLRs, leading to release of cytokines and activation of coagulation pathways. High titers of autoantibodies against type I interferons (type I, alpha 2, and omega) were found in 101 of 987 patients with life-threatening COVID-19 but were not found in patients who were not infected or patients who had mild or asymptomatic infection. Thus, an altered innate or acquired immune response may impact the clinical course of COVID-19.

Sporadic earlier reports have also noted autoantibodies against IFNs in patients after infection by members of the herpesvirus family, including EBV. In patients with systemic SS disease flares, we will need to search for novel neutralizing autoantibodies that may result from these altered immune responses following reactivation of endogenous viruses or exogenous infections.

Characteristic early symptoms in COVID-19 are altered taste and smell, as well as arthralgia and myalgia, symptoms common in SS. The SARS-CoV-2 virus that causes COVID-19 is not detected in the spinal fluid or central nervous system neurons in the vast majority of infected patients with neurologic symptoms, so involvement of neural supporting epithelial cells has been invoked as a cause of neurologic dysfunction.

A substantial proportion of young, previously healthy COVID-19 patients (including those who do not require hospital admission) have long-term fatigue, cognitive changes, and diminished quality of life. The mechanisms of this brain fog remain unclear, but involvement of the cholinergic pathways has been proposed. Other mutations (generally in loci encoding cytokines) have been reported to predispose patients to prolonged postinfectious fatigue. Chronic fatigue and brain fog are important symptoms in patients with SS, a disorder characterized by its cholinergic pathway involvement. The "epidemic" of these symptoms after COVID-19 may provide insight into their pathogenesis in SS.

From ACR 2020: What's New in Therapy?

The Sjogren's Foundation fall 2020 conference was held in conjunction with ACR Convergence 2020 as a live Zoom presentation. The results of the iscalimab (Novartis CFZ533) study were presented by Dr Athena Papas. Iscalimab is a monoclonal antibody that blocks CD40-CD154-mediated interactions between T cells and B cells, thereby inhibiting B-cell activation, immunoglobulin class-switching, and germinal center formation. Patients receiving the high dose of 10 mg/kg had a significant reduction in ESSDAI (a weighted score for organ and biological variables) relative to placebo at 12 weeks.

Papas also reviewed the results of ianalumab (Novartis VAY736), a dual–mode-of-action biologic that combines BAFF receptor inhibition with B-cell depletion. This double-blind, multicenter trial compared doses of 5 mg, 50 mg, and 300 mg at week 24 of treatment. A randomization of the 300 mg dose to placebo or 300 mg dose continuation was also performed. The primary endpoint of clinical improvement in ESSDAI was statistically significant at the 300 mg dose (P = .0019). ESSPRI (a patient-reported outcome measure of dryness, pain, and fatigue symptoms) and FACIT-F (a patient-reported measure of fatigue occurring in the context of chronic illness) showed no significant added benefits compared with placebo. The preliminary safety profile up to week 24 was good.

From ACR 2020: Monitoring Outcomes During Therapy

Although the ESSDAI has been the commonly used primary endpoint in recent clinical trials, large placebo response rates have led to a search for a composite endpoint with better performance than the ESSDAI. Toward this end, Arends and colleagues reported Composite of Relevant Endpoints for Sjogren's Syndrome (CRESS). Using a Delphi method of developing expert opinion consensus, five items were found to be the most relevant to assess the effect of treatment: patient-reported symptoms, ocular dryness measures, salivary gland function and structure measures, and serologic items.

For measurement of systemic disease activity, the modified score (termed ClinESSDAI) showed higher discrimination than the ESSDAI because the biologic domain is now treated as a separate entity. The CRESS can be used if ocular surface staining and/or salivary gland ultrasonography are not available for the evaluation. This leaves the more frequently obtained Schirmer test and unstimulated whole saliva as objective measurements of ocular and salivary function. The serologic item now includes serum levels of IgM-RF and IgG.

Pinto and colleagues reported a double-blind study of transcranial direct current stimulation (tDCS) on 36 participants, all women 18-65 years of age, who received five consecutive or sham tDCS treatment sessions with an intensity of 2 mA for 20 minutes/day. The active group experienced a significant reduction in fatigue as measured by a self-report scale. There were no between-group differences in secondary outcomes of sleep, mood, or anxiety.

Khatri and colleagues reported their identification of 10 new risk loci associated with SS in a genome-wide association study, which extends from 10 to 20 the number of loci already identified. The associated proteins modulate cytokines of type 1 IFN pathway, IFN-gamma, IL-10, and RET signaling pathways. Other proteins involve the T-cell receptor complex structure, apoptotic pathway enhancement, and ingestion of apoptotic products. Thus, these new genetic associations can influence the production of autoantigens, their presentation on the cell surface, and cytokine response by the immune system by influencing the enhancer/promoter regions.

Joachims and colleagues reported the dysregulation of a noncoding RNA (LINCO1871). They proposed that this noncoding RNA could lead to a dysregulated T-cell inflammatory response.

Conclusion

The COVID-19 pandemic has shown us how different individuals may have markedly different outcomes in response to the same virus. Also, preexisting autoantibodies and comorbid conditions influence the subsequent "autoimmune" phase of the postinfectious course. Some patients, termed "long haulers," have persistent fatigue, which remains one of the biggest challenges in our patients with autoimmune disorders.

At ACR Convergence, we learned about several new therapies, genetic associations, and outcome measures. Perhaps the most important outcome from this COVID-19 epidemic is that the whole world of immunologists, virologists, and neurologists is now focusing on the genetic mechanisms that underlie the transition from infection into chronic autoimmunity in a subset of infected patients. For the field of SS, this may be our "rheumatic fever" or "seronegative reactive spondyloarthropathy" moment. We need to look beyond our inconvenience of lockdowns to find keys to better treatment for our SS patients during infection or perhaps during the upcoming COVID-19 vaccinations.

Robert Fox, MD, specializes in the pathogenesis and treatment of Sjögren syndrome at the Scripps Memorial Hospital and Research Institute. He is also a member of several advisory boards, such as the ACR Advisory Board for Sjogren's Syndrome and the Advisory Board for the National Sjögren's Syndrome Foundation.

Alan N. Baer, MD, is a professor of medicine at Johns Hopkins University School of Medicine. He founded the Sjögren's Syndrome Clinic in the Rheumatology Division at Johns Hopkins shortly after joining the faculty there in 2007.

Dr Fox would like to acknowledge the stimulating contributions by Dr Eric Topol at the Scripps Memorial Hospital and Research Institute, who has been a tireless advocate for evaluation of COVID-19 etiology and therapy. Topol is also editor-in-chief of Medscape. Speculations and any errors in virology are entirely due to the authors of this article.

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