Latest Data: COVID Vaccine Safety, Protection, and Breakthrough Infections in Inflammatory, Autoimmune Diseases

Massimo Sandal

June 15, 2023

MILAN — The impact of the COVID-19 pandemic on patients with rheumatic and nonrheumatic autoimmune diseases is ongoing and not yet fully comprehended. New data presented at the European Alliance of Associations for Rheumatology (EULAR) 2023 Annual Meeting, primarily derived from the global COVID-19 in Autoimmune Diseases (COVAD) survey but not limited to it, provide reassurance regarding the protection and safety of COVID-19 vaccines for older and younger adults, as well as for pregnant and breastfeeding women. These data also explore the influence of underlying diseases and medications on breakthrough SARS-CoV-2 infections and infection outcomes.

Safety of Vaccines in Patients With Autoimmune or Immune-Mediated Diseases

Following vaccination, even with low levels of antibodies, the risk of severe COVID-19 remains relatively low for patients who receive immunosuppressive therapy for various immune-mediated inflammatory diseases (IMIDs). This encouraging finding comes from the Nor-vaC study, presented by Hilde Ørbo, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases, Diakonhjemmet Hospital, Oslo, Norway. During the presentation, Ørbo stated: "We did not find any specific diagnosis or medication associated with a significantly higher risk of hospitalization." Receiving booster doses of the vaccine, having high levels of anti-spike antibodies after vaccination, and achieving hybrid immunity are correlated with further reductions in the risk of breakthrough SARS-CoV-2 infections.

Dr Hilde Ørbo

Between February 15, 2021, and February 15, 2023, COVID-19 affected a similar proportion among the 729 patients and 350 healthy control persons (67% and 68%, respectively). Among the patients, 22 reported severe COVID-19, whereas none of the healthy control persons did. However, there were no fatalities among the patients. The study cohort consisted of patients with various IMIDs; 70% had an inflammatory joint disease. The use of immunosuppressive medications also varied, with 63% of patients using tumor necrosis factor inhibitors, either as monotherapy or in combination with other treatments, and other patients taking medications such as methotrexate, interleukin inhibitors, Janus kinase inhibitors, vedolizumab (Entyvio), and others.

While being older than 70 years and the presence of comorbidities were identified as risk factors for severe COVID-19, there was a significant reduction in risk with each additional vaccine dose. These results support the protective role of repeated COVID-19 vaccination for patients with IMIDs who are receiving immunosuppressive therapies; they yield a favorable prognosis even with the Omicron variant.

The study further compared the risk of severe COVID-19 between a group with hybrid immunity (having received three vaccine doses and experiencing breakthrough infection with the Omicron variant) and a group that received a fourth vaccine dose within the same time frame. The difference was striking: Hybrid immunity was associated with a 5.8-fold decrease in risk, compared with four-dose vaccination (P < .0001).

The level of antibodies, measured 2–4 weeks after the last vaccination, was predictive of the risk of breakthrough COVID-19. An antibody level above 6000 binding antibody units/mL after vaccination was significantlyassociated with a reduction in risk. "We can conclude that patients who receive multiple vaccine doses have a lower risk of COVID-19," Ørbo said. "In patients who recently experienced breakthrough infections, the administration of a booster vaccine dose might be delayed."

Dr Hendrik Schulze-Koops

"The virus has undergone changes throughout the pandemic, while the vaccines have remained relatively stable. Are we anticipating more infections over time?" asked Hendrik Schulze-Koops, MD, PhD, of Ludwig-Maximilians University in Munich, Germany, the session moderator. In response, Ørbo stated that 85% of the recorded infections in the study occurred after the emergence of the Omicron variant, and time was considered a covariable in the analysis.

Dr Pedro Machado

These data shed light on a topic discussed by Pedro Machado, MD, PhD, professor and consultant in rheumatology and neuromuscular diseases at University College London, England, during his scientific session talk entitled, "Unsolved Issues of COVID Vaccination and Re-vaccination." Machado referred to the VROOM study published in 2022, which examined the interruption of methotrexate for 2 weeks following booster administration. Both groups demonstrated a significant antibody response, but the group that stopped taking methotrexate showed double the antibody titers. However, he emphasized, "What remains unknown is the clinical relevance of these differences in terms of severe infection, hospitalization, or even death. The potential benefit of increased immunogenicity by interrupting conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate before or after vaccination needs to be balanced against the potential risk of disease flare. Ultimately, decision-making should be individualized based on factors such as comorbidities, disease activity, and other considerations." The results presented by Ørbo suggest that while there may be a clinical difference in terms of severe infection, the overall prognosis for vaccinated patients is reasonably good.

Regarding other DMARDs, such as biologics, the approach may differ. Machado suggested, "In patients using rituximab or other B cell–depleting therapies, SARS-CoV-2 vaccination should be scheduled in a way that optimizes vaccine immunogenicity. A minimum of 10 B cells/μL of blood is likely a relevant threshold above which a sufficient cellular and immune response is established."

COVID Vaccines Are Safe for Pregnant and Breastfeeding Women

According to data from the COVAD study, which comprised two global cross-sectional surveys conducted in 2021 and 2022, the COVID-19 vaccine appeared safe for pregnant and breastfeeding women with autoimmune diseases (AID).

Presenter Laura Andreoli, MD, PhD, of the University of Brescia, Italy, said that although pregnant patients with AID reported more adverse events related to vaccination, these rates were not significantly higher than those among pregnant, healthy control persons who were without AID. No difference in adverse events was observed between breastfeeding women and healthy control persons, and the incidence of disease flares did not significantly differ among all groups.

"In summary, this study provides initial insights into the safety of COVID-19 vaccination during the gestational and postpartum periods in women with autoimmune diseases. These reassuring observations will hopefully improve clinician-patient communication and address hesitancy towards COVID-19 vaccination, as the benefits for the mother and fetus through passive immunization appear to outweigh potential risks," Andreoli told Medscape Medical News.

"The large number of participants and the global geographical spread of the COVAD survey were very beneficial in gaining access to this important subset of patients," added Andreoli. However, she acknowledged that patients with low socioeconomic status and/or high disability were likely underrepresented. While no data on pregnancy outcomes have been collected thus far, Andreoli expressed the desire to include them in the study's follow-up.

The COVAD survey data also indicate that, in general, vaccine hesitancy among patients with AID is decreasing; from 2021 to 2022, it declined from 16.5% to 5.1%, as Machado indicated in his presentation.

Multiple Factors Contribute to Breakthrough Infections

The risk of breakthrough SARS-CoV-2 infections after vaccination varies among patients with rheumatoid arthritis (RA) and rheumatic or nonrheumatic autoimmune diseases, primarily depending on the underlying condition rather than the immunosuppressive medication. Environmental factors also appear to play a role. This complex landscape emerges from a further analysis of the COVAD survey dataset.

Dr Alessia Alunno

Alessia Alunno, MD, PhD, of the University of L'Aquila, Italy, presented a detailed and occasionally counterintuitive picture of similarities and differences among young adult patients (aged 18–35 years), mostly women, with various rheumatic and nonrheumatic diseases in relation to COVID-19. Most notably, the type of disease seemed to have more significance than the immunosuppression resulting from the treatment regimen. This held true for vaccine safety as well as for the risk of breakthrough COVID-19 and symptom profiles.

Patients with rheumatic disease (RMD) and nonrheumatic autoimmune disease (nr-AD) had significantly different therapeutic profiles on average. Before vaccination, 45% of patients with RMD used glucocorticoids (GC), and 91% used immunosuppressants (IS). In contrast, only 9.5% of nr-AD patients used GC, and 21% were taking IS.

Interestingly, the overall prevalence of reported SARS-CoV-2 infections was not influenced by medication and was practically identical (25% to 28%) across all groups. However, there were intriguing differences in the occurrence of infections before and after vaccination between disease groups. Prevaccine infections were less frequent among patients with RMD compared with healthy control persons (adjusted odds ratio [OR], 0.6), while the rates were similar among patients with nr-AD and healthy control persons. On the other hand, breakthrough infections were more frequent in patients with RMD (adjusted OR, 2.7), whereas the rate was similar between healthy control persons and patients with nr-AD.

Despite a much lower rate of GC/IS use, patients with nr-AD experienced repeated infections more frequently. In contrast, patients with RMD were less prone to multiple infections, even compared with healthy control persons (adjusted OR, 0.5).

Regarding the disease profile, fewer than 5% of all infected patients required advanced therapies for SARS-CoV-2 infection. Notably, all SARS-CoV-2 infections in patients with nr-AD were symptomatic, whereas among patients with RMD and healthy control persons, the incidence of asymptomatic infections was 3%. The rate of hospital admissions was 4% for patients with RMD, compared with 2% for patients with nr-AD and 1% for control persons. The RMD group exhibited some differences between prevaccine infections and breakthrough infections, including a significantly lower frequency of loss of smell and taste during breakthrough infections. Overall, patients with RMD and COVID-19 experienced cough, runny nose, throat pain, nausea, and vomiting more frequently. In contrast, patients with nr-AD had a much higher risk of skin rashes during breakthrough infections (adjusted OR, 8.7).

Vaccine adverse events (AEs) were also influenced by the underlying disease. Patients with RMD and those with nr-AD were more likely to experience mild AEs after the first or second dose compared with healthy control persons (adjusted OR, 2.4 and 2.0, respectively). The most common early, mild AEs across all groups were injection site pain, headache, and fatigue, but they occurred more frequently in the nr-AD group than in the RMD or healthy control group. Additionally, fever and chills occurred more frequently among the nr-AD group. Late, mild AEs and severe AEs were rare and affected all groups equally.

"The overall incidence of AEs was very low. Our results certainly do not undermine the safety of vaccines," Alunno said.

Disease flares were more common after vaccination (10% with RMD and 7% with nr-AD) than after infection (5% with RMD and 1.5% with nr-AD). Furthermore, in many cases, after vaccination, flares required a change of medications, particularly for patients with RMD.

Dr Naveen Ravichandran

Additional results from the COVAD survey from January to July 2022, presented by Naveen Ravichandran, MD, DM, of Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, revealed a higher prevalence (OR, 1.2; P = .001) of breakthrough infections among patients with RA. A total of 22.6% of patients with RA experienced breakthrough infections, compared with 20.6% for patients with other autoimmune rheumatic diseases and 18.4% of healthy control persons. Hospitalizations and the need for advanced treatment were also more common among patients with RA (30.9%) than among healthy control persons (13.9%). Patients with RA who had breakthrough infections tended to be older (closer to 50 years of age on average) and female, and they were more likely to have comorbidities and mental disorders. The human development index of the patient's country of residence also played a role. Further research is necessary to understand how breakthrough infection outcomes are affected by a patient's socioeconomic situation.

According to Ravichandran, medication was not a significant factor, except for the use of steroids and rituximab, which were associated with a higher risk of severe COVID-19 and hospitalization. Patients using rituximab, in particular, faced significantly increased odds for hospitalization (OR, 3.4) and severe breakthrough COVID-19 (OR, 3.0).

Dr Kim Lauper

Session moderator Kim Lauper, MD, of the University of Geneva, Switzerland, cautioned, "The roles of disease and medication are challenging to separate. Some diseases require a more aggressive immunosuppressive regimen. It's possible that different diseases affect the immune system differently, but it is not easy to demonstrate."

The complications observed in the data warrant further study, as mentioned by Schulze-Koops: "We have a problem tied to the timeline of the pandemic, where we had different viruses, different population behaviors, different treatments, and different standards of care over time. We also have differences between ethnic communities and regions of the world. But most importantly, we have different viruses: From the original strain to Delta to Omicron, we know they have very different clinical outcomes. I believe we need more scientific research to unravel these factors."

Ørbo, Ravichandran, Andreoli, and Alunno report no relevant financial relationships. Machado has received grants and/or honoraria from AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Janssen, Merck Sharp & Dohme, Novartis, Orphazyme, Pfizer, Roche, and UCB.

European Alliance of Associations for Rheumatology (EULAR) 2023 Annual Meeting: Abstracts OP0080, OP0081, OP0082, Presented May 31, 2023; Abstract LB0006, Presented June 3, 2023.

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