Risk of Coronavirus Disease 2019 Among Patients with Rheumatic Musculoskeletal Diseases

At the onset of the COVID-19 pandemic, one of the earliest public health interventions was advising patients to avoid crowded areas, even before the transmission mechanisms of the SARS-CoV-2 virus were fully understood. Social distancing measures were encouraged, especially avoiding poorly ventilated spaces and crowded events. As it became clear that the virus spread through aerosolized particles, patients living with RMDs were urged to maintain social and physical distancing, practice appropriate hygiene, and wear masks, particularly for those who were immunosuppressed

Patients with RMDs were particularly concerned about their risk of contracting SARS-CoV-2. A US-based Veterans Administration study indicated that patients with rheumatoid arthritis (RA) had a 25% higher risk of being diagnosed with COVID-19 compared to those without RA. Similarly, data from the UK biobank demonstrated an increased risk of COVID-19 infection in patients with rheumatoid arthritis but no increased risk of infection for patients with gout. A meta-analysis demonstrated that patients with RMDs had a 52% higher relative risk of developing a SARS-CoV-2 infection compared to the general population.

Factors Associated with Severity of Disease

With the uncertainty of the risk of infection early in the COVID-19 pandemic, it was crucial to identify the spectrum of symptoms and their severity, as well as the factors that contributed to the risk of severe COVID-19 infection. Factors that were associated with a higher risk of mortality emerged, including older age, elevated body mass index, male sex, and pre-existing comorbidities such as cardiovascular disease, pulmonary diseases, diabetes mellitus, chronic kidney disease, and rheumatic diseases. Various cohort, registry, and case-controlled studies confirmed that patients with RMDs faced heightened risks of severe COVID-19, including hospitalization and intensive care unit admission, particularly in the presence of comorbid conditions and active disease.

One early study—OpenSAFELY—from the UK primary care database found that patients with RA, systemic lupus erythematosus, and psoriasis had a higher risk of COVID-19-associated death than the general population. Within this study, variation was observed in outcomes among patients with different rheumatic diseases. For instance, patients with rheumatoid arthritis had an increased risk of death from COVID-19, whereas patients with gout did not. Further analysis revealed that certain immunosuppressants were associated with particularly high risks of poor COVID-19 outcomes. For instance, glucocorticoid use (greater than 10 mg prednisone daily), rituximab use, and Janus kinase (JAK) inhibitor use have been associated with poor outcomes.

Interpreting these associations, however, has not been straightforward. The increased severity of COVID-19 infection among patients using certain disease-modifying antirheumatic drugs (DMARDs), such as JAK inhibitors, daily glucocorticoids, and combination DMARD regimens, may in part be related to the more severe underlying RMD activity at baseline. Indeed, patients with greater disease activity at the time of COVID-19 infection have worse outcomes than those with well-controlled disease activity. One notable exception is the risk of severe COVID-19 among rituximab users; rituximab has been consistently associated with an increased risk of hospitalization, mechanical ventilation, and death among rheumatic disease patients infected with COVID-19 ¹⁴ . In the United States, variation in outcomes was observed among patients of different racial groups. There appeared to be a higher rate of infection among African American, Latino/Hispanic, and Asian American patient populations compared with non-Hispanic White patients. Additionally, non-White groups were found to have poorer outcomes, likely due to social determinants impacting equitable access to care during and before the pandemic.

In contrast, other DMARDs, such as tumor necrosis factor (TNF) inhibitors and hydroxychloroquine, were not associated with more severe outcomes. A study analyzing pooled data from patients with inflammatory bowel disease or skin psoriasis receiving TNF inhibitors included over 6000 patients from 74 countries. Findings indicated that patients who received TNF inhibitors in combination with azathioprine or 6-mercaptopurine, or those who received azathioprine or 6-mercaptopurine as monotherapy, had higher risks of hospitalization or death compared to those receiving only TNF inhibitors. These results suggested that TNF inhibitor monotherapy may be beneficial in some ways for COVID-19 in individuals with various immune-mediated inflammatory diseases, such as RMDs and inflammatory bowel disease. In a large National Institutes of Health trial (ACTIV-1 IM), infliximab was tested as a treatment for COVID-19 pneumonia. There was no statistically significant improvement in recovery from pneumonia compared to the placebo but those randomized to infliximab had a lower risk of death.

In the post-vaccine era and with the emergence of new SARS-CoV-2 variants, most patients with rheumatic diseases who received vaccines did not develop severe COVID-19. However, patients receiving rituximab continued to experience more severe disease outcomes.

Vaccines

With the development of COVID-19 vaccines, patients with rheumatic diseases hoped for a promising end to the pandemic. However, they also worried about the vaccine’s efficacy and side effects, particularly for those on immunosuppressive therapies. ^{, ,} Due to the novel mechanism of action of mRNA vaccines, their impact on patients with rheumatic diseases was initially unknown. The mRNA vaccine enters cells and triggers them to create a spike protein displayed on the cell surface. This spike protein is recognized as foreign by the immune system, which then creates memory B cells to recognize this protein if encountered again, allowing for a quick immune response to the actual virus. Conversely, a protein subunit vaccine contains the spike protein itself, removing the need to create it within the cell. This protein is similarly recognized as foreign and triggers an immune response like the mRNA vaccine. Extensive analysis of the mRNA vaccines through the Vaccine Adverse Event Reporting System and cohort studies including people with RMDs did not demonstrate a higher risk for side effect or adverse events related to the vaccine. ^,

The American College of Rheumatology (ACR) has developed recommendations for COVID-19 vaccination among patients with rheumatic diseases, emphasizing shared decision-making and a personalized approach. The ACR Task Force advised continuing certain medications, such as hydroxychloroquine, leflunomide, sulfasalazine, apremilast, and intravenous immunoglobulin, without discontinuing them for the COVID vaccine. For other immunomodulatory therapies, there was moderate consensus for similar recommendations. Given the long effect of rituximab, it is recommended that vaccines be timed 4 weeks before the subsequent dose; if peripheral B cells are allowed to return (vs remaining undetected), then the response to vaccination is better. Early recommendations were based on limited data on vaccine efficacy in rheumatic disease patients and the effect of immunosuppression on vaccine response. If an individual is moderately or severely immunocompromised, as are most patients with RMDs, then they may benefit from additional doses of the vaccines based on data in some populations illustrating that additional doses improve the quantity of circulating antibody.

Our understanding of the benefits and risks of holding immunosuppression before and/or after the COVID-19 vaccine continues to evolve. A UK multicenter, open-label, parallel-group randomized trial found that a 2-week hold of methotrexate improved antibody response following vaccination. While there were some increased flares of disease activity, most were self-managed and resolved quickly with the re-initiation of methotrexate. The ACR advises that vaccination and medication decisions should be shared between the patient and provider. If a patient is actively flaring or their disease is not well-controlled, DMARDs should be continued during vaccination.

Vaccine uptake in rheumatic disease patients is influenced by physician recommendation. Studies show that patients with autoimmune, inflammatory, and rheumatic diseases (AIIRDs) are less likely to be vaccinated (44% vs 56%) and more likely to express vaccine hesitancy (14% vs 10%) compared to those without AIIRDs. The main reason for vaccine hesitancy was concern over safety and side effects. Hesitancy toward booster vaccines was primarily due to a lack of information or recommendation from medical professionals.

Telemedicine

In March 2020, the United States implemented a lockdown as a first line of defense against the COVID-19 pandemic. This situation was not unique to the United States; nearly every country globally went into lockdown during this period. ^, With all non-essential businesses shut down, clinics across all medical specialties, including rheumatology, were unable to see patients in person. However, the management of chronic diseases, disease exacerbations, and new disease presentations could not wait until the lockdown measures were lifted. This necessitated a rapid transition to telemedicine across medical specialties. Telehealth had been used before the pandemic, but its necessity during this period led to a rapid growth in its use, which continues today.

One study evaluated the impact of the pandemic on clinic visits in a community practice rheumatology network by looking at data from pre-COVID, during the COVID transition (6 weeks beginning March 23, 2020), and post-COVID (May to August 2020). Pre-COVID, this network averaged 7075 visits weekly. During the pandemic, visits decreased by 24.6% but returned to pre-pandemic levels post-COVID. Telehealth encounters increased from practically 0 pre-COVID to 41.4% of visits during the pandemic. Even after the COVID-19 health emergency restrictions were lifted, telehealth remained popular and about 27.7% of visits were conducted via telehealth.

Prior to the pandemic, one of the barriers to implementing telehealth in the United States was the lack of insurance reimbursement. During the pandemic, the US Centers for Medicare and Medicaid Services expanded reimbursement and coverage for telehealth encounters. It is unclear how coverage for telehealth services will evolve as we move further from the pandemic.

A challenge during the rapid rise of telehealth in rheumatology during the pandemic has been adapting the physical examination for telehealth. Suggested modifications to improve telehealth examinations include patient self-palpation of joints and range of motion testing as substitutes for the musculoskeletal examination. The ACR recommended using clinical disease activity index (CDAI) and disease activity score 28 (DAS-28) scores for telehealth encounters, with modifications such as using patient-reported swollen and tender joint counts instead of provider-evaluated counts, and scoring the DAS-28 without acute phase reactants. Patients typically require baseline training to perform their own joint counts effectively. Following training, patients’ and providers’ tender joint counts tend to correlate well, but swollen joint counts do not correlate as well.

Although a large portion of medical care transitioned to telemedicine during the pandemic, this shift posed challenges related to technology access, digital literacy, and the inability to perform certain aspects of the physical examination remotely. ^, Consequently, telemedicine may not have been accessible to many patients of lower socioeconomic status or those from marginalized populations. However, for patients with access to telemedicine, rheumatology providers leveraged platforms to deliver educational resources, self-care tips, and behavioral interventions tailored to individual needs. ^, By fostering patient engagement and autonomy with these methods, providers promoted adherence to treatment plans, early recognition of disease flares, and proactive communication with health care teams.

Patient satisfaction is crucial for the persistence of telehealth beyond the pandemic. One survey of patients who had telehealth appointments revealed that satisfaction was highly dependent on perceived benefits such as decreased financial burden, minimized time away from work, and reduced mobility or visual impairments. Despite this, over 70% of the individuals were satisfied with the telehealth specialist care they received in one study. ^, Another study, however, found that patients prefer face-to-face consultation because of concerns related to the accuracy of the examination and diagnosis.

Ultimately, not every individual or encounter is appropriate for telehealth. One retrospective review found that 79.9% to 85.0% of consultations in rheumatology could be evaluated via telehealth without the need for face-to-face encounters. The Encounter Appropriateness Score for You (EASY model) has been identified to help determine which visits are appropriate for telehealth. The EASY model assigns points based on a number of factors, including patient, provider, and encounter characteristics, to determine the most appropriate visit type. Implementing the EASY model or similar algorithms can help identify which patients need face-to-face visits and which are suitable for telehealth as we continue to transition out of the pandemic period.

Continuity of Care and Medication Interruptions

Patients with rheumatic diseases require routine monitoring and management of their chronic conditions, but the COVID-19 pandemic caused numerous disruptions in their continuity of care as described earlier. A primary challenge was the disruption of in-person medical consultations. Lockdowns, social distancing measures, and concerns about viral transmission led to the cancellation or postponement of routine clinic visits, infusion therapies, and elective procedures. These interruptions resulted in delays in disease monitoring and timely adjustments of treatment regimens, potentially impacting disease control and patient outcomes. ^, Some patients may have also become non-adherent to their treatment regimens due to the lack of routine continuity.

The COVID-19 pandemic also exacerbated existing health care disparities, disproportionately affecting patients with RMDs from marginalized communities. Socioeconomic factors such as limited access to technology for telemedicine visits, inadequate health insurance coverage, and disparities in vaccine distribution heightened the vulnerability of these populations. ^,

Patients with previously undiagnosed rheumatologic conditions faced delays in diagnosis and treatment, as many postponed seeking medical care due to fears of contracting COVID-19 or difficulties accessing health care services. The extent of these delays’ impact is currently unclear. However, as clinics shifted back to conducting face-to-face examinations and prioritizing existing patients, new patients frequently experienced further delays in receiving care. These diagnostic delays may have led to disease progression, irreversible joint damage, and poorer treatment outcomes. Additionally, delays in initiating or adjusting immunosuppressive therapies increased the risk of disease flares and complications among patients with rheumatic diseases. Additional studies in years to come will provide greater insights into these impacts.

Patients with RMD faced a unique adversity during the pandemic as many medications used for rheumatic diseases were repurposed for the treatment of COVID-19 and the subsequent cytokine storm. These medications included hydroxychloroquine (although this was ultimately found ineffective), interleukin-6 inhibitors, and JAK inhibitors. The repurposing of these drugs led to shortages and other challenges which often negatively impacted patients with rheumatic diseases. ^,

Mental Health and Quality of Life

The COVID-19 pandemic has had profound effects on patients with RMDs worldwide, with repercussions extending beyond physical health to encompass mental well-being. Contending with the day-to-day management of a chronic illness, patients with RMDs face unique challenges exacerbating existing stress, anxiety, depression, and other mental health concerns. Over the last decade, various studies have elucidated the intricate interplay between rheumatological disorders and mental health, shedding light on the amplified impact of the pandemic on this vulnerable population. ^,

Patients with rheumatic diseases experienced heightened levels of anxiety and stress during the pandemic due to various uncertainties. Concerns about the risk of severe illness from COVID-19, disruptions in accessing health care, and changes in treatment plans all contributed to psychological distress. Many patients struggled with fear of their condition worsening, especially with limited in-person medical visits and postponed elective procedures. The strict social distancing measures implemented during the pandemic also led to feelings of loneliness and isolation among patients with RMDs. ^, Patients cited limited interactions with health care providers, reduced access to support networks, and decreased participation in community activities. Additionally, pre-existing depression among these patients was exacerbated by pandemic-related stressors, such as heightened disease activity, financial strain, and disrupted routines. The inability to engage in preferred activities and exposure to negative news further contributed to feelings of hopelessness.

Coping mechanisms used by patients with RMD were significantly impacted by the pandemic, with restrictions on outdoor activities, closure of recreational facilities, and limitations on physical therapy services disrupting established strategies. Moreover, while telemedicine was essential for continuity of care, the shift away from in-person consultations may have hindered effective coping for patients accustomed to face-to-face interactions. Overall, the COVID-19 pandemic has had a profound impact on the mental health of patients with RMD, highlighting the importance of targeted interventions to address psychological distress and promote resilience in this vulnerable population.

Pediatric Considerations

There were widespread disruptions in pediatric rheumatology clinical practice, similar to in the adult population, due to the COVID-19 pandemic as well as rare complications from COVID-19 infection.

Multisystem Inflammatory Syndrome in Children (MIS-C) emerged as a concerning complication associated with COVID-19 in pediatric populations. MIS-C typically presents several weeks after a child has been infected with the SARS-CoV-2 virus and is characterized by inflammation affecting multiple organ systems. Symptoms often include fever, rash, abdominal pain, vomiting, diarrhea, and evidence of cardiac involvement, such as myocarditis or coronary artery abnormalities. Although the exact cause of MIS-C is not fully understood, it is believed to result from an exaggerated immune response triggered by the virus. Early recognition and prompt treatment are crucial for managing MIS-C and preventing serious complications, highlighting the importance of ongoing vigilance and monitoring of COVID-19-related health issues in children.

There were significant psychological ramifications for pediatric patients with RMDs, including increased levels of anxiety, depression, and stress due to concerns about their health, lack of continuity of care, and social isolation. Many schools faced temporary closures and consequent transitions to online learning, thereby depriving these patients from the typical social interactions with peers. Parents and/or caregivers of pediatric rheumatology patients also experienced heightened levels of stress and anxiety during the pandemic, and often children with heightened anxiety mirrored the anxiety of their caregiver. Concerns about their child’s health, disruptions in health care services, and uncertainty about the future contributed to caregiver burden and emotional distress. Parents faced challenges in balancing their caregiving responsibilities with work, household duties, and managing the impact of the pandemic on family dynamics. Adolescents were found to have a particular difficulty with sleeping through the height of the pandemic; this was associated with poor mental health and emotional difficulties. Providers could encourage families to look to coping and support methods, including telepsychiatry services, virtual support groups, and psychological interventions tailored to the needs of pediatric patients and their caregivers.