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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

It's well recognized that patients with rheumatoid arthritis (RA) are at increased risk for developing infections. "We don't know why for certain, but RA is a disease characterized by dysregulation of the immune system and so it's possible that this immune dysregulation predisposes these patients to infection," said Bryant R. England, MD, PhD, of the University of Nebraska Medical Center in Omaha.

"The other possibility is certainly that the medications we're using to treat RA which are immunosuppressive may be increasing the risk of developing COVID and severe COVID outcomes," England told 麻豆传媒. Common comorbidities such as of the heart and lung also likely contribute.

So what has this meant during the age of COVID-19?

The VA Study

A by England and co-authors offered some insights into this question. In the matched cohort study of 33,886 RA patients and an equivalent number of matched non-RA controls, patients had a 25% higher risk for developing COVID-19 and a 35% greater risk of hospitalization or death.

"COVID-19 appears to yield a disproportionate impact among vulnerable populations, particularly among the elderly and those with chronic diseases," the investigators wrote in Arthritis & Rheumatology.

Among the chronic diseases that have been recognized as predisposing to severe COVID are cancer, diabetes, cardiovascular disease, chronic kidney disease, and sickle cell disease. Few previous studies have evaluated risks among patients with rheumatic diseases, however, and what data are available on infection risks in general typically have focused on bacterial, rather than viral, etiologies.

So England's team conducted a retrospective study of patients enrolled in the VA Health Administration database from January through December 2020. Participants' mean age was 68, 85% were male, and three-quarters were white. Patients were more likely than controls to be smokers, to have a higher body mass index, and to have a greater Elixhauser Comorbidity Index.

During 31,552 person-years of follow-up among RA patients, there were 856 cases of COVID, for an incidence rate of 27.3 (95% CI 25.5-29.2) per 1,000 person years, while among controls there were 647 cases during 31,552 person-years of follow-up, for an incidence rate of 20.5 (95% CI 19-22.1) per 1,000.

After adjustment for demographics, comorbidities, local COVID rates, and healthcare utilization, the adjusted hazard ratio for COVID in patients with RA was 1.25 (95% CI 1.13-1.39). For the risk of hospitalization or death, the adjusted hazard ratio was 1.35 (95% CI 1.10-1.66).

Patients who received both prednisone and disease-modifying antirheumatic drugs (including conventional agents, biologics, and targeted synthetic drugs) were at increased risk for COVID (HR 1.66, 95% CI 1.36-2.03) and had a two-fold or higher risk for hospitalization or death (HR 2.12, 95% CI 1.48-3.03).

Among other factors that were associated with increased risks were Black race, higher comorbidity index, and obesity. Multiple chronic conditions were associated with increased risks for both COVID in general and severe outcomes, including heart failure, chronic lung disease, diabetes, and liver disease.

"Consideration should be given to the establishment of RA, and potentially other conditions that require treatment with similar immunosuppressive medications, as a chronic condition that should receive prioritization for COVID-19 prevention and management strategies," England and colleagues concluded.

Evolving Guidance

The American College of Rheumatology (ACR) initially responded to the urgency of the pandemic by convening a clinical task force in March 2020 to develop a "living document" that would provide guidance to caregivers and patients, being updated regularly to reflect the disease's rapidly changing knowledge and experience base.

The of the guidance document, published in April 2020, focused on "risk assessment and prevention, the use of rheumatic disease treatments in patients at risk for exposure, rheumatic disease treatment immediately following known SARS-CoV-2 exposure ... and management of rheumatic disease in the context of COVID-19."

At that point, however, data were sparse for many aspects of risks and management, and the task force authors acknowledged: "Evidence supporting the final recommendations was universally of very low quality, either indirect and/or limited to case series or retrospective cohort studies of COVID-19 patients with limited or no information on underlying rheumatic disease status."

But experience was gained rapidly, with made available in June 2021 and made available in August 2021, with the focus shifting primarily to vaccination. Among the recommendations in version 3 were that all patients with rheumatic and musculoskeletal disorders or autoimmune and inflammatory rheumatic diseases should be offered the vaccine consistent with age restrictions; that no specific vaccine was preferred over others; and that vaccinations should be done as soon as possible except for patients in the intensive care unit.

The vaccine was also recommended for household members and close contacts of patients with autoimmune and inflammatory rheumatic diseases, but laboratory tests for antibodies should not be done routinely.

The panel at that point also recommended that the timing of vaccination not be delayed among patients receiving various medications, including methotrexate, tumor necrosis factor (TNF) and other cytokine inhibitors, or patients receiving prednisone in dosages below 20 mg/day.

But consensus among task force members was not achieved for the circumstance of a patient on prednisone in higher doses: "Controversy stemmed as to whether vaccine response might be blunted in this circumstance, which may relate to the glucocorticoids themselves or to the presumably high disease activity and severity" associated with high prednisone use, the panel wrote. In the case of rituximab, which typically is given in cycles with 6-month intervals, the vaccine should be given approximately 4 weeks before the next scheduled cycle.

With regard to the use of immunotherapies around the time of vaccination, the task force suggested that there was no need to modify or withhold treatment with hydroxychloroquine, sulfasalazine, or prednisone, but that methotrexate should be withheld for a week after mRNA vaccines and for 2 weeks after the single-dose vaccine. The methotrexate guidance was based on experience with influenza and pneumococcal vaccines, the panel noted.

Brief interruptions also were recommended for JAK inhibitors and abatacept.

"However, the use of medications through the vaccination period is all balanced on discussions between the patient and provider. So, for example, if a patient's RA is really active and debilitating, holding their medicine around the time of the vaccine may not really be feasible because we would worry that their disease would be even further out of control," England told 麻豆传媒. "But for someone who has well controlled RA that's been stable for a long time, that is a patient who is more likely to do fine holding their medication for awhile."

Version 3 of the guidance document also set out a research agenda that recommended the following:

• Evaluate the risk of disease flares with vaccination
• Provide direct comparisons among the vaccines regarding efficacy and safety, as well as long-term durability in relation to antirheumatic therapies
• Assess the need for booster doses
• Undertake efficacy and immunogenicity studies following vaccination among patients receiving immunomodulatory therapies
• Establish a repository containing data to facilitate future vaccine-related research for COVID-19 and possibly other viruses
• Conduct large-scale epidemiologic studies of COVID-19 outcomes

Version 4 and More

of the document was published online in Arthritis & Rheumatology in May 2022. The authors cautioned that because information about COVID-19 has been changing so rapidly, more recent information than that presented in peer-reviewed published manuscripts may be available, and that readers should refer to the for the most up-to-date recommendations.

This iteration of the guidance document included changes such as the preference of the two-dose mRNA vaccines over the single-dose vaccine. In addition, for patients who have already received the primary two vaccine doses, a supplemental third dose was recommended after 28 days for any patients with autoimmune/inflammatory disease who were receiving any immunomodulatory treatment other than hydroxychloroquine monotherapy.

"We have seen with Omicron that protection from the vaccine (or probably, wild-type infection) only lasts about 6 months, and so some patients with rheumatic and musculoskeletal diseases are now recommended to get a total of five vaccine doses," the lead author of the guideline, Jeffrey R. Curtis, MD, of the University of Alabama at Birmingham, told 麻豆传媒.

"I suspect that concept will persist and we'll end up seeing vaccination boosters recommended to be repeated, like we do with flu," said Curtis, who is the Marguerite Jones Harbert-Gene Ball Endowed Professor of Medicine.

With regard to the use of immunosuppressive therapies around the time of vaccination, the panel recommended that agents such as abatacept, methotrexate, and JAK inhibitors be withheld for 1 or 2 weeks after each vaccine dose, if disease control allows. For cytokine inhibitors such as TNF blockers, the task force members were unable to reach consensus as to whether treatment should be halted temporarily.

The panel also emphasized that the recommendations regarding timing of immunomodulatory medications and vaccines was largely extrapolated from evidence obtained with other vaccines -- meaning that the recommendations should be considered conditional, and that providers should "avoid being overly dogmatic in following these recommendations."

A guidance summary of , which was posted by the ACR in February 2022 and will be submitted to Arthritis & Rheumatology for publication, emphasized -- as did the previous versions -- that the guidance offered was not intended to replace clinical judgment. "Modifications made to treatment plans, particularly in complex rheumatic patients, are highly disease-, patient-, geography-, and time-specific and, therefore, must be individualized as part of a shared decision-making process," the document stated.

The task force also emphasized that RA patients were at higher risk for hospitalization and poor outcomes compared with the general population, and that the expected response to vaccination in many patients on immunomodulatory therapies is "blunted in its magnitude and duration."

That concern was addressed in a presented at the 2021 virtual congress of the ACR, in which Alfred Kim, MD, PhD, of Washington University School of Medicine in St. Louis, described the results of the COVID-19 Vaccine Responses in Patients with Autoimmune Disease study, which prospectively evaluated the immunogenicity and reactogenicity of the mRNA vaccines in patients with chronic inflammatory diseases.

The study included 197 patients and 53 immunocompetent controls, and found that the patients had a threefold decrease in anti-S IgG titers, with the strongest effect observed for patients treated with B-cell depletion (such as rituximab) and glucocorticoids. The reductions in response in these two treated groups were 36-fold and 13-fold, respectively.

Antibody titers also were blunted in patients receiving methotrexate and JAK inhibitors, while treatment with other agents such as TNF inhibitors and IL-12/23 inhibitors showed only modest decreases in response.

In addition, there was a theoretical risk for disease flare following receipt of the vaccine. In a recent prospective study from Johns Hopkins University in Baltimore that included 1,377 patients with rheumatic and musculoskeletal diseases who had been inoculated against COVID-19, 11% of patients experienced disease flares requiring treatment, but none of the flares were serious. The authors, led by Julie J. Paik, MD, noted that few patients with these diseases had been included in the clinical trials of the vaccines, which led to hesitancy among patients. The results were "reassuring," according to the authors, and should help alleviate patients' anxiety about vaccination.

The possibility of breakthrough infections also has been a concern. Another presentation at the ACR 2021 virtual congress considered this risk. In a retrospective cohort analysis of the U.S. National COVID Cohort Collaborative presented by Jasvinder Singh, MD, of the University of Alabama at Birmingham, in a , 47,303 patients with an autoimmune or inflammatory rheumatic disease such as RA, spondyloarthritis, lupus, systemic sclerosis, or gout, were compared with individuals without these diseases with regard to breakthrough infections during the 14 days after COVID-19 vaccination.

The analysis found increased adjusted odds of breakthrough COVID-19 infections in several of these conditions. For RA, the odds ratio for breakthrough infection after adjustment for factors such as age, sex, and race/ethnicity was 1.54 (95% CI 1.40-1.69, P<0.001).

Version 5 also focused on more information about supplemental and booster doses. An important change in this version was that patients who have received the primary two doses but are not expected to have had an adequate response should be given a third dose as well as a subsequent booster. This was similar to CDC's recommendations for immunocompromised individuals.

At this point, the task force was again unable to reach consensus as to whether anti-cytokine therapies such as TNF inhibitors should be temporarily interrupted following doses of the COVID vaccine. However, for other conventional or targeted immunomodulatory agents such as JAK inhibitors, the advice was to hold for 1 or 2 weeks after the vaccine dose, as disease activity allowed.

As in earlier versions of the document, version 5 noted that routine lab testing for antibodies to IgM and/or IgG spike or nucleocapsid proteins was not recommended to assess post-vaccine immunity. Curtis, who was the guidance document's lead author, explained the rationale for this in an ACR podcast, stating, "This is a virus, and antibodies aren't the only way we fight off viruses. [Antibodies and immunity] are often correlated, but what we really care about is T cells and what cell-mediated immunity is doing. The interpretation [of antibody tests] is important, and we don't have a good correlate for protection. It's still murky."

The Question of Monoclonal Antibodies

A further recommendation in version 4 was that patients with autoimmune/inflammatory diseases who were at high risk for poor COVID outcomes should be given monoclonal antibodies, either as post-exposure prophylaxis or as treatment for new symptomatic infection. But recommendations regarding monoclonal antibody treatment have changed along with the shifting of prevalent viral strains.

For example, sotrovimab was available under emergency use authorization for the treatment of mild-to-moderate disease for outpatients who were at risk for progression to severe disease and was included in the ACR version 5 list of available monoclonal antibodies. However, in CDC reported that the proportion of cases associated with the Omicron BA.2 subvariant -- insufficiently responsive to sotrovimab -- exceeded 50% in all regions of the U.S. The FDA accordingly determined that sotrovimab was no longer authorized in the U.S. for the treatment of COVID-19.

An additional treatment, REGEN-COV, which is a combination of casirivimab and imdevimab, was granted emergency use authorization in 2021 and had been recommended in version 4, but use in the U.S. was because of the dominance of the Omicron variant and a "high unlikelihood" that this combination would be effective against that variant. The emergency use authorization for another combination, bamlanivimab/etesevimab, also was limited to cases in which exposure was to variants other than Omicron.

However, in February the FDA gave emergency use authorization to bebtelovimab as a treatment for mild-to-moderate COVID-19, noting that laboratory testing suggested that this agent was active against Omicron and the BA.2 subvariant.

Finally, while version 5 represents the latest advice from the ACR, the pandemic and its treatments continue to evolve rapidly. "One of the things about COVID is that when a study is published, a month or two later there's all sorts of new information out there already," said England. Updates on matters relating to treatment and vaccination for COVID-19 are available on the .

The COVID guidance document will continue to be updated as newer information and experience become available. "The ACR is committed to updating this guidance as a 'living document' as new evidence emerges," the document stated.

Nonetheless, said Curtis, "I think until we have a meaningful amount of new data, we probably won't make any big changes to the guidance past version 5, and so I don't expect a new version for a while."

Pre-exposure Prophylaxis

At present there is "overwhelming evidence" that RA patients most at risk for serious adverse outcomes from COVID-19 are those on B cell-depleting agents such as rituximab, noted Cassie Calabrese, DO, of the Cleveland Clinic. Such patients are also at the highest risk for poor vaccine responses.

She added that there is currently an emergency use authorization for pre-exposure prophylaxis (PreP) with a combination of the monoclonal antibodies tixagevimab co-packaged with cilgavimab and branded as Evusheld, which has been demonstrated to lower the risk for severe outcomes in such patients.

This combination of monoclonal antibodies has retained activity against Omicron and subvariants and has a long half-life of approximately 6 months, she explained. "Most major centers are making efforts to get the most severe immunocompromised patients, who are most likely to be vaccine nonresponders, on this agent, which should include all patients on rituximab."

"Unfortunately many clinicians outside of major medical centers may be unaware of care pathways to get their patients treated, and they advocate networking with local infectious disease colleagues who are well aware," Calabrese continued. "How effective this PreP treatment will be in these B cell-depleted patients is under active investigation, but based on preliminary data it offers significant hope to our most vulnerable patients of providing meaningful protection at a time when their own immune system is not able to."

Read previous installments in this series:

Part 1: RA Beginnings: Before the Painful Joints

Part 2: RA: Still a Clinical Diagnosis

Part 3: RA: Choosing Initial Treatment

Part 4: Case Study: Patient With RA Develops Dangerous Symptoms

Part 5: Second-Line Treatment of Rheumatoid Arthritis: What Are the Options?