Infection with a common cold virus may prime some people to develop the syndrome
At a glance:
Analysis of samples from patients with rheumatic diseases suggests prior infection with a common cold coronavirus may prime people for developing long COVID.
The study points to a potential marker of long COVID, a mystifying disorder estimated to affect 65 million people worldwide, and whose mechanisms remain unclear.
The findings can inform further clinical trials and help explain why some patients develop long COVID.
People with autoimmune rheumatoid disease who develop long COVID are more likely to have altered levels of inflammation-fueling antibodies specific to a coronavirus that causes the common cold, according to research led by HMS researchers at Brigham and Women’s Hospital, Massachusetts General Hospital, and the Ragon Institute of Mass General, MIT, and Harvard.
Specifically, the analysis indicates that prior infection with a common cold coronavirus and elevated antibodies against it may prime the immune system and make certain individuals more likely to develop long COVID.
The researchers caution that this mechanism is not likely to account for all cases of long COVID, which may be fueled by different mechanisms that vary widely across individuals.
The authors also note that their study was restricted to individuals with rheumatic diseases, and further research is needed to determine whether these findings apply more widely to patients without autoimmune disorders. Nonetheless, the scientists say, the findings serve as an important indicator that a person’s pre-pandemic viral history could modulate one’s risk for long COVID.
“Our study offers evidence and explanation for why some of our patients may be experiencing the persistent and wide-ranging symptoms of long COVID,” said study co-corresponding author Zachary Wallace, HMS assistant professor of medicine in the Division of Rheumatology, Allergy, and Immunology at Mass General. “Identifying a biomarker that helps us better understand current and previous infections could shed light on an inappropriate immune response that leads to some cases of long COVID.”
Starting with patients with rheumatic diseases, Wallace added, may allow researchers to develop biomarkers to understand who is at high risk for developing long COVID and strategically enroll individuals into clinical trials to either prevent long COVID or develop therapies to treat it.
“This study represents an important step in that direction,” Wallace said.
Up to 45 percent of individuals with rheumatic diseases, which include rheumatoid arthritis and other chronic autoimmune disorders that cause inflammation, experience persistent symptoms associated with long COVID 28 days after acute infection with SARS-CoV-2. Patients with rheumatic disease are also at risk for more severe disease and complications from acute infection.
Since the beginning of the pandemic, Wallace and his colleagues at Brigham and Women’s and Mass General have paid special attention to this group of patients to find insights that could help inform their treatment as well as the care of broader patient populations experiencing long COVID.
“At the very beginning of the pandemic, we joined forces to identify every rheumatic disease patient with COVID seen at our institutions so that we could follow their clinical course and collect survey and blood data,” said co-corresponding author Jeffrey Sparks, HMS associate professor of medicine in the Division of Rheumatology, Inflammation, and Immunity at Brigham and Women’s. “At first, we thought we might be doing this for a month or two, but the work continues today, and we are gaining important insights about a potential immune mechanism that may lead to long COVID, especially among patients with rheumatic disease.”
Wallace, Sparks, and colleagues analyzed immunologic changes in patients with rheumatic disease who recovered from COVID-19. The investigators measured antibody responses against various parts of SARS-CoV-2, comparing patients who developed long COVID with those who did not. They looked for differences in the immunologic fingerprints left behind by previous infections. The team found an unexpected signal tied to OC43, a coronavirus that causes common cold-like symptoms. Individuals with long COVID were more likely to have antibody responses specific to this form of coronavirus.
“When it comes to viruses, first exposure can shape lifelong immunity,” said co-corresponding author Galit Alter, who contributed to this work while at HMS and the Ragon Institute before joining Moderna Therapeutics in October 2022. “We know that, in the setting of influenza, previous exposure to a viral strain can influence a person’s immune response to subsequent strains. This concept — which we call ‘original antigenic sin,’ may be at play for coronaviruses too and may influence risk of long COVID, especially among individuals with rheumatic disease.”
The researchers plan to further pursue biomarkers of long COVID, including the OC43 signature, which may be useful for developing diagnostics, therapeutics, and more targeted clinical trials to test interventions.
Approximately 27% of patients with a rheumatic disease experienced a change in employment status during the early months of the COVID-19 pandemic, according to survey results published in The Lancet Rheumatology.
“People with rheumatic disease are at increased risk of infection due to immune dysregulation and the use of immunosuppressive medications,” Jonathan S. Hausmann, MD, of Beth Israel Deaconess Medical Center, in Boston, and colleagues wrote. “However, at the beginning of the COVID-19 pandemic, little was known to inform discussions about the risks of COVID-19 in people with these rheumatic diseases. As a result, people with rheumatic diseases faced substantial challenges in deciding how to modify their behavior to reduce their risk of infection with the SARS-CoV-2 virus.”
Nearly 30% of patients with a rheumatic disease experienced a change in employment status during the early months of the COVID-19 pandemic, according to survey results. Data derived from Hausmann JS, et al. Lancet Rheumatol. 2021;doi:10.1016/S2665-9913(21)00175-2.
“These challenges also greatly affected employment and education, and consequently, access to health insurance and the ability to obtain health care,” they added. “Understanding the effect of the pandemic on people with rheumatic disease might help rheumatologists better address their patients’ needs and inform policies to protect this potentially vulnerable population.”
To examine how the COVID-19 pandemic has affected patients with rheumatic disease across the world, Hausmann and colleagues, in partnership with the American College of Rheumatology and its COVID-19 Global Rheumatology Alliance, created a survey. Developed through the help of key stakeholder groups, the COVID-19 Global Rheumatology Alliance Survey was administered to adults with inflammatory or autoimmune rheumatic diseases around the world through social media, websites and patient support organizations.
Jonathan S. Hausmann
Questions covered demographics, rheumatic diagnosis, COVID-19 diagnosis, adoption of protective behaviors against coronavirus infection, medication access and changes, health care access and communication with rheumatologists, and changes in employment or schooling status. A total of 12,117 participants responded to the survey between April 3, 2020, and May 8, 2020. Among these respondents, 10,407 included the appropriate age data. The researchers included data from participants with and without COVID-19, but excluded those who reported only noninflammatory rheumatic diseases.
In all, the researchers included complete responses from 9,300 respondents in their analysis, of whom 90.1% were women, 9.6% were men and 0.3% were nonbinary. In addition, 67.5% of the included participants reported they were white, while 16.8% identified as Latin American, 2.1% were Black, 2% were Asian and 0.5% were Native American, Aboriginal or First Nation. The most common rheumatic diagnoses were rheumatoid arthritis, with 39.1%; systematic lupus erythematosus, at 31%; and Sjögren’s syndrome, at 13.9%.
According to the researchers, 82% of the included respondents had continued their antirheumatic medications as prescribed, while 99.7% reported they had been following the suggested protective behaviors to prevent or limit COVID-19 spread. A total of 2,524 respondents, or 27.1%, reported a change in employment status. In all, the number of respondents who reported working full time decreased 13.6%, from 4,066 to 3,514.
“Understanding the early behaviors of people with inflammatory and autoimmune conditions is necessary to assess the effects of the pandemic on this population, and not only those who became infected with SARS-CoV-2,” Hausmann and colleagues wrote. “A far-reaching consequence of the pandemic at the time of data collection was the abrupt change to employment, and many people with rheumatic disease were faced with delayed or reduced income. Unique within the field of rheumatology, our study illustrates the direction and magnitude of employment change from Jan 1, 2020, to May 8, 2020.”
“Further work should address the consequences of employment status changes for health care access, medication affordability, mental health and rheumatic disease activity,” they added. “With an improved understanding of COVID-19 and the existence of patient recommendations from professional organizations, future studies should address changes in behaviors, perceptions and concerns in this population, including COVID-19 vaccination, COVID-19 sequelae and the long-term effect of the pandemic on patient outcomes.”
As the COVID-19 pandemic continues, research emerges on the effects of the physical and emotional health and financial impact of individuals worldwide. The pandemic has shaped the way people interact with one another and this includes the way people prioritize and receive health care services.
This study highlights the behaviors worldwide of patients with rheumatic diseases and how that has changed during the pandemic. The researchers illustrate the importance of the health professional in identifying barriers to care, such as the loss of insurance coverage due to job loss/changes, as well as having conversations about patient perceptions and attitudes toward their medication regimen. Asking questions pertaining to how the pandemic has affected their lives personally as well as professionally can encourage conversations that may identify areas for intervention to improve overall health.
The study also indicated that many patients adopted what is described as “protective behaviors,” such as social distancing and masking. These positive behaviors can be encouraged, and health care providers can provide patients with the necessary resources that give them the most current up-to-date information in a time where things are rapidly changing. We can also provide reassurance or changes if needed to treatment regimens in order to optimize adherence and preventing disease flares.
Patients who are immunosuppressed may also need help from their health care team in the way of documentation for schools and places of employment to ensure that they have accommodations in place to help keep them safe from infection. As the patients and families that we care for continue to adapt to how their lives have been changed during this pandemic, health care professionals are in a prime position to engage in shared decision-making with our patients as a way to support them and optimize their health.
There is tired, and there is fatigue. Then there is fatigue associated with a rheumatic or autoimmune disease, which is multifactorial and debilitating and has confounded physicians and patients for decades.
“Time and again, I hear my patients say that at some point in the day, they hit the wall, or they feel like they are in quicksand,” Philip J. Mease, MD, of the Swedish Medical Center in Seattle and the University of Washington, told Healio Rheumatology. “They have to stop and rest because they simply cannot function at all, period. It is a bone-crushing weariness.”
It would follow that such a pervasive and significant problem should be addressed routinely in the clinic, if not in research. But data have consistently shown that patients still feel as though their fatigue is not acknowledged sufficiently by their rheumatologist. Or, worse, many patients feel as though their fatigue is ignored or not taken seriously.
One issue is the source. “The reality is that lots of things probably drive fatigue in rheumatic diseases,” Katie Druce, PhD, MSc, BSc, of the Centre for Epidemiology Versus Arthritis at the University of Manchester in the U.K., said in an interview. “There may be differences in the things that initially cause the fatigue — such as inflammation through sickness behavior — and the things that perpetuate it, such as chronic pain and low mood.”
With so many potential etiologies, treating or even managing this comorbidity can be difficult. This could partially explain why patients have felt like their physicians have been unable or unwilling to tackle the problem for so long.
Biologic therapies have helped, regularly demonstrating the capacity to mitigate fatigue to a certain extent. But getting cytokines in order is only part of a successful management regimen. A growing body of data is showing that exercise and wellness behaviors like mindfulness and meditation can improve associated factors such as sleep, pain, anxiety and depression.
However, understanding that wellness can help and actually putting such a regimen into action are two different things, according to Patricia Katz, PhD, professor of medicine and health policy at the University of California, San Francisco. “You can’t just tell a patient they should exercise,” she said. “They need a specific exercise prescription that is tailored to their needs, and that is just not part of training for most rheumatologists.”
Exercise and wellness paradigms are, in fact, evolving. Accordingly, rheumatologists have grown more comfortable discussing them as potential mitigators of fatigue.
In addition, COVID-19 put a spotlight on how mental health comorbidities can induce that ‘bone-crushing’ weariness. When the effectiveness of biologics is factored into the equation, it is possible that patients with rheumatic diseases may finally have hope that the disease comorbidity that is so important to them may be addressed in a meaningful and structured way.
But considerable work needs to be done to iron out the details. It starts with simply understanding why fatigue happens in the first place.
Although exercise routines adopting wellness behaviors can help mitigate the effects of fatigue, implementing these routines among patients is another animal altogether. “You can’t just tell a patient they should exercise,” Patricia Katz, PhD, told Healio Rheumatology. “They need a specific exercise prescription that is tailored to their needs, and that is just not part of training for most rheumatologists.”
Source: University of California, San Francisco.
Down to the Roots
Philip J. Mease
While Mease would not claim to fully understand fatigue as it pertains to the specialty, he offered a starting point for rheumatologists to consider. “I often acknowledge to my patients that having a rheumatic disease is like having a full-time job,” he said, noting the endless stream of doctor visits, medication or injection schedules, lab tests and imaging analyses that can keep patients away from their work, family and support systems. All of this, of course, sits on top of and exacerbates the routine stresses of life.
But it takes more than simply acknowledging fatigue to understand it, according to Leonard H. Calabrese, DO, director of the RJ Fasenmyer Center for Clinical Immunology at the Cleveland Clinic. He offered a reason why so many rheumatologists are loath to even open the dialogue. “We as rheumatologists are so well trained to identify, sort out and treat chief complaints in our patients,” he said. “But we are not nearly as good at evaluating a patient’s chief concerns.”
Desiree Azizoddin, PsyD, of the research faculty in the department of emergency medicine at Brigham and Women’s Hospital and clinical instructor at Harvard Medical School, urged rheumatologists to keep it simple. “Sleep is a big one,” she said. “Patients need to understand sleep hygiene, and that too much sleep or too little sleep can be a signal or a cause of fatigue.”
Azizoddin, who has conducted research in systemic lupus erythematosus, also highlighted stress as a critical component of fatigue. But this is where the etiologic challenges arise. The impact of stress on individuals without a chronic rheumatic disease can be difficult enough to parse out. When a condition like SLE is involved, it can be nearly impossible to understand where the stress of life ends and the stresses associated with the disease begin.
“There are neurological manifestations of lupus disease that can lead to psychiatric disorders and fatigue,” Azizoddin added. “However, they may be underlying conditions, or they may be completely unrelated or they may be genetically driven. Lupus can lead to depression and anxiety, but many patients may have had depression and anxiety before their lupus diagnosis.”
Turning to more clinical explanations, Mease noted that excessive proinflammatory cytokines in the central nervous system can affect various parts of the brain that may be related to the experience of fatigue. He said that TNF may be implicated, along with interleukin-1, IL-17 and IL-23.
Katie Druce
Understanding the exact nature and impact of these cytokines has proven challenging, according to Druce. “We consistently see that symptoms like pain, mood and disability are important, while the relationship with inflammation and disease activity can be less clear,” she said.
Further complicating the picture is that there may be “important subtypes” of fatigue within any disease group, according to Druce. “These subtypes may highlight differing symptom etiologies,” she said. “Some patients have high levels of inflammation but good mental health, while others have high inflammation and poor mental health. While we might be comfortable recommending only immunomodulation for the first group, we might want to try a hybrid immunomodulation and cognitive behavior therapy approach in the second.”
Katz added another layer to the problem. “When a patient has high disease activity, getting that activity under control is always the first target,” she said. Treatment to the target of controlled disease with disease-modifying antirheumatic drugs and, to a greater extent, biologic therapies, often yields benefits in fatigue, as well.
But patients with severe disease are not the only ones who are chronically fatigued. “The harder nut to crack is people who have their disease under control but still experience fatigue that affects their daily lives,” Katz said.
Desiree Azizoddin
“Fatigue does not always correlate with disease activity,” Azizoddin added.
Conventional wisdom would suggest that understanding the root causes of a comorbidity is a good place to start. After that, having a number of tools at hand to assess it would be the next step. Such tools proliferate, along with data investigating their utility, but making sense of that information has also proven challenging.
Missing the Mark
In 2019, Barbacki and colleagues conducted a database review in the Journal of Rheumatology outlining the instruments used to assess fatigue in SLE since 2007, which yielded 37 studies using eight different measures of fatigue. Results showed that the visual analog scale (VAS), Fatigue Severity Scale (FSS) and Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT) fatigue scale were most frequent. Two studies used the Multidimensional Assessment of Fatigue, while one used the Brief Fatigue Index (BFI).
“The FACIT score is a multidimensional questionnaire that gets at different qualities or aspects of fatigue,” Mease said. “It respects the fact that it is not a single item.”
In a paper published in Rheumatology Advances in Practice, Pearson and colleagues conducted a review of published articles to determine the quality and acceptability of PRO measures used to evaluate fatigue in axial spondyloarthritis. While 23 articles yielded evidence for nine fatigue-specific measures, they were unable to identify a fatigue measure specifically targeting the axial spondyloarthritis patient population. “Most measures provide a limited reflection of fatigue,” they wrote.
That said, the Multi-dimensional Assessment of Fatigue, Multi-dimensional Fatigue Inventory-20, FACIT and FSS were the “most comprehensive,” according to their findings. “The limited content and often poor quality of the reviewed measures limit any clear recommendation for fatigue assessment in this population,” they wrote.
Leonard H. Calabrese
Calabrese noted that the Cleveland Clinic uses the Patient-Reported Outcomes Measurement Information System (PROMIS) global fatigue score. “At a glance, I can see how severe fatigue is, and how much interference it is causing,” he said.
Katz acknowledged the utility of many of these parameters. However, she brought it back to basics. “If you are in a clinical setting, the best thing you can do is ask about fatigue,” she said.
A companion point is that as long as a rheumatologist is, in fact, addressing fatigue with their patients, any of these measures could have utility. “It depends on how you want to use it and what you are trying to achieve,” Katz said.
It is also important to understand the difference between measures used in a clinical setting and those used for research, according to Katz. “I understand that doctors have a small amount of time to discuss fatigue, so a simple rating scale, tracked over time from visit to visit, can be effective in learning whether a patient is feeling more or less fatigue,” she said. “In a research setting, we can use a longer questionnaire that has more precision. We can hit our targets a little better and hopefully extrapolate that information to the clinic.”
Rheumatologists have been hitting their targets with greater frequency in recent years, thanks to an evolving therapeutic armamentarium. But truly life-altering improvements in fatigue have continued to be elusive.
Treating to Target
“It is important to give credit where it is due by saying that rheumatologists were, rightly, for a very long time focused on targeting the aspects of rheumatic diseases which were most destructive, such as joint erosions, or most likely to lead to mortality,” Druce said. “It is only now that biologics, biosimilars and treat-to-target paradigms have revolutionized the impact and progression of many rheumatic diseases that there is space to consider some of the previously less urgent symptoms experienced by patients, like fatigue.”
Mease has hope for the capacity of biologics and other DMARDs to play a key role in helping patients combat their fatigue. “We are starting to see that fatigue may even improve before pain relief comes or joint swelling improves,” he said. “We know there is likely a centrally acting mechanism by which various drugs will do this. It is one of the things we are very interested in, how the drugs we use may impact central nervous system function.”
That said, it is still unclear how those mechanisms work. In the meantime, it is important for rheumatologists to manage expectations, according to Mease. “When I speak to patients about reaching targets for improvement in any clinical domain, including fatigue, I tell them that if we get 50% or 70% improvement, we have accomplished something,” he said.
While it can be difficult, Mease also tries to impress upon his patients the limits of therapeutic interventions. “We may not be able to remove the stress from your work or your family, but we can improve inflammation or certain parameters of immune-mediated fatigue,” he said.
If there is one other reason for optimism in hitting fatigue-based targets, it is that the FDA is finally beginning to recognize this comorbidity as a relevant entity, according to Mease. “Over the years, even though fatigue is always measured in trials, it did not make it to the label of our drugs,” he said. “This resistance was not bullheadedness on the part of the FDA; they were not ignoring the phenomenon. They wanted to be careful and note that fatigue can be present for many reasons.”
That changed recently when treatment of fatigue was added as a component to the label of guselkumab (Tremfya, Janssen). Several other drugs are applying to include fatigue on their labels, as well. This may allow clinicians to address the subject in a more structured way and induce a broader conversation about multipronged efforts to deal with fatigue. All of this may help achieve a goal that is so important to patients: breaking the cycle of disease activity, pain, depression and exhaustion that can lead to the most significant fatigue.
Breaking the Cycles
In a review published in Current Opinions in Rheumatology, Katz noted that while disease activity such as inflammation, pain and joint symptoms can yield greater fatigue in patients, this type of disease activity only accounts for “a small portion” of what patients actually feel.
“Instead, factors outside the direct effects of rheumatoid arthritis, such as obesity, physical inactivity, sleep disturbance and depression explain the majority of variation in fatigue,” she wrote.
A growing body of data is validating this conclusion. In a paper published in Lupus, Azizoddin and colleagues reported on a cohort of 116 patients with SLE. Multivariate analysis and stepwise regression analysis results showed significant and independent effects of depression, stress and pain on fatigue.
“Investigators are shooting themselves in the foot when including fatigue as an outcome but not including stress and depression in their models,” Azizoddin said. “We know they are related. This is why fatigue continues to be unsolved.”
In a paper published in the Pakistan Journal of Medical Sciences, Fertelli and colleagues investigated associations between fatigue and sleep quality, pain and depression in 151 patients with knee osteoarthritis and 147 healthy controls. Results showed that the knee OA group showed significantly higher fatigue scores and higher Pittsburgh Sleep Quality Index (PSQI) and Beck Depression Inventory (BDI) total scores compared with controls (P < .05). Moreover, a positive correlation was observed for fatigue score and PSQI, VAS and BDI scores (P < .05). “This fatigue suffered by them affected their sleep quality, pain and depression negatively,” the researchers concluded.
“Fatigue and depression are intertwined so closely that, sometimes, it may be difficult to disentangle them,” Katz said. “The descriptions are pretty similar across diseases.”
Azizoddin believes that rheumatologists can play a critical role in mitigating the synergistic effects of these disease comorbidities. “What physicians say carries weight,” she said. “So, when a physician says, ‘Your sleep and your stress are going to impact your disease and cause you to have more fatigue,’ they are inclined to listen.”
At that point, the physician may have more leverage in motivating the patient to engage in some sort of self-management regimen, whether it is exercise, meditation or a dedicated sleep hygiene routine.
Azizoddin added: “It can be helpful to remind patients that they can and should practice stress-relieving behavioral techniques, such as relaxation, breathing, yoga, and exercise, that can make a big difference.”
Get Well Soon
It does not take a physician with years of training and experience to understand that exercise is beneficial for healthy individuals and those with chronic diseases alike. Nor is it a significant logical leap to assume that wellness behaviors such as meditation or mindfulness can help with the stress, depression or anxiety that come with a chronic disease and may be driving fatigue.
The issue, for many rheumatologists, is that understanding these basic principles of general health and actually prescribing programs to target the specific fatigue experienced by an individual patient are two different animals altogether. In a paper published in Rheumatic and Musculoskeletal Diseases Open, Pope wrote that “specific programs for exercise and behavioral interventions are not standardized.”
But attempts are being made to figure out how to design such interventions to target fatigue.
Sveaas and colleagues wrote a paper in Physical Therapy investigating exercise as a treatment for axSpA. They noted that most programs for this patient population target flexibility rather than high-intensity exercise.
The study included 50 patients assigned a 3-month high-intensity exercise regimen and 50 controls. Results showed that 38 participants in the exercise group followed at least 80% of the program. Initial results showed a significant benefit of exercise on fatigue (mean group differences = –0.4; 95% CI, –0.7 – –0.1), vitality (5.0; 95% CI, 1.1-10.5), mood (–2; 95% CI, –3.7 – –0.04) and general health (9.0; 95% CI, 3.3-14.7).
“When we have completed needs assessments among rheumatologists and patients, we see that rheumatologists are very interested in wellness interventions,” Calabrese said. “The issue is that they do not have the time, expertise or confidence to engage with this kind of therapy.”
Calabrese added that many DOs and MDs are loath to refer their patients to “alternative therapies,” for fear that they may default on immune-based treatment. “We believe that wellness behavioral modification must complement targeted and aggressive therapy,” he said. “We believe it can provide an empowering message to improve not only self-efficacy among patients, but, ultimately, medication adherence.”
This message is starting to gain validation. Further conclusions from the Katz paper showed that the most effective approaches to reducing RA fatigue appear to be behavioral — such as increasing physical activity — or cognitive — such as cognitive behavioral interventions.
Katz suggested that the simple approach may be the best approach. “People just need to move more and sit less,” she said.
Until the mechanism of fatigue is completely understood — and, admittedly, it is entirely possible that it will never be understood — Calabrese encouraged rheumatologists to continue to talk to their patients about it. If they lack the confidence or know-how to follow-up on a wellness regimen, he noted that a wealth of materials is available online, including from the Cleveland Clinic.
But Calabrese believes that the current moment is a “new era in wellness,” with robust data being reported in “high impact” publications. This is not to mention the notion that COVID-19 “taught us that wellness behavior is critical to survival,” he said. “This is all incredibly validating for those of us who have been interested in fatigue for a long time.”
References:
Azizoddin DR, et al. Lupus. 2019;doi:10.1177/0961203318817826.
Barbacki A, et al. J Rheumatol. 2019;doi:10.3899/jrheum.180831.
Fertelli TK, et al. Pak J Med Sci. 2019;doi:10.12669/pjms.35.4.383.
Lack of antibody response following COVID-19 vaccination is the strongest predictor of breakthrough infection in patients with autoimmune rheumatic disease, according to data published in Annals of the Rheumatic Diseases.
“Patients with autoimmune rheumatic diseases (AIRD) have reduced responses to COVID-19 vaccination,” Padmanabha Shenoy, MD, DM, of the Center for Arthritis and Rheumatism Excellence (CARE), in Cochin, India, told Healio. “There is no biomarker to predict successful vaccination, and current recommendations do not support the use of antibody titers to measure protection from COVID-19.”
Lack of antibody response following COVID-19 vaccination is the strongest predictor of breakthrough infection in patients with autoimmune rheumatic disease, according to data.
To analyze the incidence and risk factors for breakthrough COVID-19 infection in patients with autoimmune rheumatic disease, Shenoy and colleagues prospectively followed 630 fully vaccinated patients from the Center for Arthritis and Rheumatism Excellence, in southern India. All participants had been diagnosed with an autoimmune rheumatic disease and completed two doses of a SARS-CoV2 vaccine. Individuals with prior COVID-19 infection were excluded. Enrollment began in March 2021, with follow-up ending in October 2021.
The researchers assessed antibodies to receptor binding domain of spike protein (anti-RBD) in all participants 4 to 6 weeks after the second vaccine dose. Participants were then stratified based on antibody response, with “good responders” demonstrating greater than 212 IU, “inadequate responders” having a range of 0.8 to 212 IU, and those with less than 0.8 IU identified as “non-responders.” After a minimum of 8 weeks post-vaccination, patients were followed up with every 2 months to identify breakthrough COVID-19 infection. In addition, all sero-converted participants who had contact with COVID-19 were examined for neutralizing antibodies.
Padmanabha Shenoy
Among the 630 participants, 78.6% received the AstraZeneca AZD1222 vaccine, while the remaining received the BBV152 vaccine, developed by Bharat Biotech International in India. The mean age of the participants was 55.2 years.
According to the researchers, the mean post-vaccination antibody titer was 854.1, with 60.3% identified as “good responders,” 22.7% as “inadequate responders” and 16.9% deemed “non-responders.”
In all, breakthrough COVID-19 infection occurred in 7.4% of participants, at a mean follow-up of 147.3 days. Breakthrough cases were proportionately highest among non-responders, at 17.75%, followed by inadequate responders, at 9.09%. Only 3.95% of good responders experienced breakthrough COVID-19. In a log-rank analysis, the researchers found that antibody response (P < .00001), vaccine type (P = .003) and mycophenolate mofetil use (P = .007) were significant predictors of breakthrough infection. However, in the multivariate Cox regression, only vaccine non-response was significantly associated with breakthrough COVID-19 infection (HR = 3.6; 95% CI, 1.58-8).
Among patients who were sero-converted and had contact with COVID-19, neutralization levels varied between those who did and did not develop infection.
“We showed that patients with AIRD having low anti-spike antibody titers are having higher risk of breakthrough infections,” Shenoy said. “The study provides a cheap and commonly available biomarker for estimating vaccination success. We do not need complicated T-cell assays — only antibody levels are sufficient as a predictor. Patients with inadequate anti-spike antibody titers should be shielded from infection and prioritized for booster doses.”
Rheumatic diseases can be divided in two groups, autoinflammatory and autoimmune disorders. The clinical presentation of both types of diseases overlap, but the pathological pathways underlying rheumatic autoinflammation and autoimmunity are distinct and are the subject of ongoing research. There are a number of ways in which these groups of diseases differ in terms of disease mechanisms and therapeutic responses. First, autoinflammatory diseases are driven by endogenous danger signals, metabolic mediators and cytokines, whereas autoimmunity involves the activation of T and B cells, the latter requiring V-(D)-J recombination of receptor-chain gene segments for maturation. Second, the efficacy of biologic agents directed against proinflammatory cytokines (for example IL-1β and TNF) also highlights differences between autoinflammatory and autoimmune processes. Finally, whereas autoinflammatory diseases are mostly driven by inflammasome-induced IL-1β and IL-18 production, autoimmune diseases are associated with type I interferon (IFN) signatures in blood. In this Review, we provide an overview of the monocyte intracellular pathways that drive autoinflammation and autoimmunity. We convey recent findings on how the type I IFN pathway can modulate IL-1β signalling (and vice versa), and discuss why IL-1β-mediated autoinflammatory diseases do not perpetuate into autoimmunity. The origins of intracellular autoantigens in autoimmune disorders are also discussed. Finally, we suggest how new mechanistic knowledge of autoinflammatory and autoimmune diseases might help improve treatment strategies to benefit patient care.
ARYAN'S BLOG 