COVID-19: Care of adult patients with systemic rheumatic disease

INTRODUCTION — At the end of 2019, a novel coronavirus that was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei Province of China. By 2020, infection with this virus led to a pandemic that has spread throughout most countries of the world. The illness caused by this virus, which has been termed coronavirus disease 2019 (COVID-19), primarily manifests as a lung infection with symptoms ranging from those of a mild upper respiratory infection to severe pneumonia, acute respiratory distress syndrome, and death.

Severe illness can occur in previously healthy individuals, but also in patients with underlying medical conditions, including patients with systemic rheumatic diseases. This topic will discuss the care of patients with systemic rheumatic diseases during the COVID-19 pandemic. Other important aspects of COVID-19 infection are reviewed in detail separately; please refer to our COVID-19 homepage to view the complete list of UpToDate COVID-19 topics.

RISK OF COVID-19 INFECTION

Disease- and comorbidity-related risks — The presence of a rheumatologic disease alone may be associated with an increased risk for developing COVID-19 with more adverse outcomes, although the evidence is mixed and likely related to the heterogeneity of these disorders and their therapies [1-12]. One cohort study found that the risk of severe COVID-19 was similar among patients with rheumatologic diseases compared with matched controls, although there was a trend towards more severe COVID-19 among the subset of patients with connective tissue disease (1.82, 95% CI 1.00-3.30), unlike those with inflammatory arthritis [1].

There are limited data specifically regarding patients with systemic lupus erythematosus (SLE) and COVID-19. It is uncertain whether patients with SLE are at any increased risk of COVID-19. In one large cohort of unvaccinated patients with SLE in New York City, 4 percent developed symptomatic COVID-19, while the estimated general population prevalence of infection was 2 percent [13]. Baseline use of immunosuppressive drugs did not appear to affect the severity of infection. In a registry study of 1606 patients with SLE, worse outcomes were associated with older age, male sex, prednisone use, comorbidities such as kidney and cardiovascular disease, and increased lupus disease activity [14]. Compared with White individuals who have SLE, Black and Hispanic patients with SLE have been shown to experience more severe outcomes, similar to what is observed in the general population [15].

Gout may be associated with a higher risk of COVID-19. In a study of 1,390,953 patients who have received a SARS-CoV-2 vaccine, gout was associated with an increased risk of breakthrough infections (partially adjusted HR 1.24, 95% CI 1.19-1.30) and hospitalization (adjusted hazard ratio [HR] 1.30, 95% CI 1.10-1.53) [16].

Patients with various rheumatologic diseases have a higher prevalence of several comorbidities such as advanced age, chronic pulmonary and kidney disease, heart disease, hypertension, obesity, and diabetes [17-25], which in turn are risk factors for severe illness with COVID-19. Findings from observational studies (prior to the availability of vaccines) suggest that comorbidities in patients with rheumatologic diseases contribute to an increased risk of more severe COVID-19 [1,3-7,10]. In a case series of 600 patients with rheumatologic diseases and COVID-19, a multivariable-adjusted analysis showed hospitalized cases in comparison with nonhospitalized cases had more comorbidities, including hypertension (45 versus 23 percent), lung disease (30 versus 14 percent), diabetes (17 versus 7 percent), cardiovascular disease (14 versus 7 percent), and chronic renal insufficiency/end-stage kidney disease (12 versus 2 percent) [3]. (See "COVID-19: Clinical features", section on 'Risk factors for severe illness' and "COVID-19: Clinical features", section on 'Increasing age'.)

There is limited high-quality evidence regarding the incremental risk for hospitalization due to COVID-19 infection attributable to an established rheumatologic disease [8,10,26-30]. In a large cohort study of United States veterans conducted prior to the availability of COVID-19 vaccines, a diagnosis of rheumatoid arthritis was associated with an increased risk of COVID-19 and COVID-19-related hospitalization or death compared with patients without rheumatoid arthritis (HR 1.25, 95% CI 1.13-1.39, and HR 1.35, 95% CI 1.10-1.66, respectively) [8]. Factors associated with these adverse outcomes included disease-modifying antirheumatic drug (DMARD) and prednisone use, being a Black or Hispanic American, and several chronic conditions. In addition, a nationwide cohort study from Demark including over 58,000 patients with systemic rheumatic diseases, also prior to the availability of COVID-19 vaccines, found that patients with systemic rheumatic diseases were more likely to be hospitalized compared with the general population (HR 1.46, 95% CI 1.15-1.86) [30].

Certain laboratory abnormalities have been associated with poor outcomes in patients with COVID-19, such as lymphopenia (particularly low CD4+ T cells) and elevated levels of C-reactive protein, interleukin (IL) 6, and creatine kinase (see "COVID-19: Clinical features", section on 'Risk factors for severe illness'); these abnormalities result from the infection and the immune response to the infection. It is unknown whether such abnormalities, if pre-existing due to another disorder (eg, a systemic rheumatic disease), have any impact on disease outcome.

Risks associated with rheumatologic disease therapies — Treatments for rheumatologic disease impact the risk of COVID-19 infection by impairing the immunologic response to the virus as well as to protective vaccines [31-37]. Both methotrexate (MTX) and rituximab have been associated with increased risk of repeat COVID-19 infection in patients with rheumatic diseases [38]. Treatment with B cell-depleting agents such as rituximab are a particular concern because they impair humoral responses to vaccination. (See 'Coordinating vaccine administration with immunosuppressive therapy' below.)

Therapies for rheumatologic disease may also lead to worse outcomes for patients once infected with SARS-CoV-2. Although the data are mixed, available large cohort studies suggest that B-cell depletion with agents such as rituximab and certain other immunosuppressive agents, particularly cyclophosphamide (CYC) and mycophenolate, appear to be associated with higher risk of worse outcomes for COVID-19 [3,25-27,39-52]. Studies on specific agents include the following:

●Rituximab – Several studies have suggested that patients who develop COVID-19 infection and are treated with rituximab, including patients with rheumatoid arthritis, are at increased risk of a more prolonged disease course, severe disease, and/or worse outcomes [11,25,47,53-56]. Therefore, administration of a subsequent dose of rituximab should be delayed, or the patient should be transitioned to another immunosuppressive agent, whenever possible [57].

●Systemic glucocorticoids – Although glucocorticoids may be a useful intervention for severe COVID-19 (see "COVID-19: Management in hospitalized adults", section on 'Dexamethasone and other glucocorticoids'), limited observational data have raised the question of whether glucocorticoid therapy may also be associated with increased susceptibility to more severe disease in both rheumatologic [3,25,58] and inflammatory bowel disease. (See "COVID-19: Issues related to gastrointestinal disease in adults", section on 'Adjusting IBD medications'.)

The lack of benefit of HCQ therapy for treatment of COVID-19 infection is described separately. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Therapies that we do not recommend'.)

CLINICAL MANIFESTATIONS AND DIAGNOSTIC CONSIDERATIONS

Clinical presentation of the infection in patients with rheumatologic disease — The clinical features of COVID-19 among patients with systemic rheumatic diseases are variable and are not known to be different than patients without these underlying diseases. There are insufficient data from reported cases to determine whether the type of rheumatologic disease or the intensity of immunosuppressive therapy influences the clinical presentation of COVID-19 in this population (see 'Disease registries' below). However, it is possible that some features of rheumatologic disease may be difficult to distinguish from those of COVID-19. (See 'Features of rheumatologic disease that can mimic or be mimicked by COVID-19' below.)

Features of rheumatologic disease that can mimic or be mimicked by COVID-19 — A variety of rheumatologic diseases may have clinical features that can mimic or be mimicked by COVID-19, such as fever, malaise, myalgias, and fatigue. For patients who carry an existing diagnosis of a rheumatologic disease, the clinician may need to distinguish a disease flare from possible COVID-19 infection, and a high level of suspicion for this infection should be maintained when and where COVID-19 may be prevalent. The approach to testing for COVID-19 is discussed separately. (See "COVID-19: Diagnosis", section on 'Diagnostic approach'.)

Specific examples of such conditions include diseases that can manifest with fever (eg, systemic lupus erythematosus [SLE]); headache (eg, giant cell arteritis [GCA] [59]); gastrointestinal symptoms (eg, spondyloarthritis, systemic sclerosis [SSc], SLE, and Behçet syndrome); dyspnea (eg, interstitial pulmonary disease due to rheumatoid arthritis, SSc, or SLE); stroke (eg, antiphospholipid syndrome [APS]); pernio- or chilblain-like lesions, sometimes called "COVID toes" (eg, chilblain lupus erythematosus); and a Kawasaki-like multisystem inflammatory syndrome in children (MIS-C, also referred to as pediatric multisystem inflammatory syndrome [PMIS]). Patients with severe COVID-19 can also develop cutaneous vasculitis-like lesions and systemic arterial and venous thromboemboli, including cryptogenic strokes and other vasculopathy features [60,61]. Additionally, some patients experience a more prolonged recovery from COVID-19 infection, with persistent symptoms including fatigue and dyspnea. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis" and "COVID-19: Hypercoagulability", section on 'Clinical features' and "COVID-19: Clinical features", section on 'Clinical manifestations' and "COVID-19: Cutaneous manifestations and issues related to dermatologic care", section on 'Cutaneous manifestations of COVID-19' and "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")", section on 'Persistent symptoms'.)

In addition, laboratory abnormalities such as an elevated erythrocyte sedimentation rate, C-reactive protein levels, ferritin, interleukin (IL) 6, and creatine kinase levels can be seen in both COVID-19 and in association with various rheumatologic diseases.

Medications used to treat rheumatologic disease may also cause adverse effects that can mimic clinical manifestations of COVID-19 (eg, sulfasalazine [SSZ], which may cause gastrointestinal symptoms, and methotrexate [MTX], which may cause pulmonary abnormalities).

Referral for rheumatologic evaluation may be appropriate in patients with known or suspected COVID-19 who do not have an established rheumatologic disease diagnosis yet have additional clinical features concerning for rheumatologic disease (eg, findings suggestive of synovitis or serologies characteristic of autoimmune rheumatic disease).

COVID-19 as a risk factor for rheumatologic disease — New-onset rheumatologic disease appears to be uncommon following COVID-19, but cases of incident systemic rheumatic disease are increasingly described; among them are inflammatory arthritis, GCA, inflammatory myopathy, APS, and Sjögren's disease [62,63]. However, it remains uncertain whether reported cases are causally related to the viral infection.

Other case reports of possible virus-associated new-onset systemic rheumatic diseases include reactive arthritis [64,65]; crystal-induced arthritis [66]; SSc [67], antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis [68,69]; adult-onset Still's disease [70]; small vessel cardiac vasculitis and endotheliitis [71]; and immunoglobulin (Ig) A vasculitis [72].

Multisystem inflammatory syndrome in adults — Rarely, a multisystem inflammatory syndrome (MIS) similar to Kawasaki disease has been seen that occurs almost exclusively in children (see "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis"); though cases have also been reported in adults (MIS-A) [73-79]. A case definition for MIS-A from the Centers for Disease Control and Prevention (CDC) has been established [80].

An analysis from the CDC of 27 reported cases of MIS-A noted that it is characterized by markedly elevated inflammatory markers and multiorgan dysfunction, particularly cardiac dysfunction, but without severe respiratory illness [74]. Other features have included gastrointestinal, dermatologic, and neurologic symptoms. Exposure to SARS-CoV-2 was documented by either concurrent positive polymerase chain reaction (PCR) test results (approximately two-thirds of patients) or antibody assays indicating recent infection. Antibody testing to confirm previous SARS-CoV-2 infection can be important in identifying MIS-A among those with compatible signs and symptoms, as these patients might not have positive SARS-CoV-2 PCR or antigen test results at the time of presentation with this illness. Optimal treatment strategies have not been determined, but these patients have generally been managed very similarly to children with MIS-C. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome".)

In a subsequent systematic review of reported cases of MIS-A involving 221 patients, the median onset of disease was approximately 4 weeks after acute COVID-19 infection [79]. The major disease manifestations included fever, hypotension, cardiac dysfunction, shortness of breath, and diarrhea. The majority of patients were admitted to the intensive care unit (57 percent), and 7 percent died.

MIS-A/MIS-C may be difficult to distinguish from biphasic acute COVID-19 and sequelae of acute SARS-CoV-2 infection; however, there are some clinical characteristics that may help distinguish acute severe COVID-19 and MIS-C/MIS-A. As an example, children with MIS-C are commonly between the ages of 6 and 12, are non-Hispanic Black, and have severe cardiovascular or mucocutaneous involvement and severe inflammation [81]. It is uncertain whether these distinctions also apply to MIS-A. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis", section on 'Differentiating MIS-C and acute COVID-19'.)

Notably, the incidence of MIS-C correlates with the main circulating variant of SARS-CoV-2. In the Paediatric Active Enhanced Disease Surveillance (PAEDS) network from Australia, the pre-Delta rate was 13 cases per 10,000, which decreased to 5 per 10,000 during Delta and 0.8 per 10,000 during Omicron [82]. Similar reductions in incidence have been observed in Israel [83] and Denmark [84]. It remains unclear whether this represents an attenuation of certain variants to trigger hyperinflammation or reflects increased acquired immunity (whether through infection or vaccination), although vaccination has been associated with reductions in MIS-C incidence [85-87].

For individuals who had SARS-CoV-2 infection complicated by MIS, there are theoretical concerns regarding immune dysregulation that could potentially be triggered by the SARS-CoV-2 vaccine that are discussed separately. (See "COVID-19: Vaccines", section on 'History of SARS-CoV-2 infection'.)

MANAGEMENT OF PATIENTS WITH KNOWN OR SUSPECTED SARS-CoV-2 EXPOSURE OR INFECTION

Medication management in patients following exposure

●Rheumatologic disease medications – Adjustments to medication regimens in patients thought to be recently exposed to the SARS-CoV-2 virus should be individualized, with considerations regarding vaccination status, suspected or known individual's vaccine response, patient's immunosuppressive regimen (eg, rituximab use) and other risk factors, and access to COVID-19-specific therapies.

•Vaccinated individuals – Although the assessment should be individualized, patients effectively vaccinated may generally be able to continue immunosuppressive therapy following exposure. By contrast, a patient who is due for a subsequent dose of rituximab but lacks evidence of an antibody response to vaccination may benefit from a delay in the scheduled infusion.

•Unvaccinated individuals – Our approach to medication management following exposure in unvaccinated individuals is largely based upon expert opinion and extrapolation from the management of patients taking these medications who have developed other infections and is consistent with the management practices recommended by the American College of Rheumatology (ACR) [88], as well as being generally similar to other guidelines [57,89-91]. High-quality evidence regarding the effects of stopping or maintaining medications for systemic rheumatic diseases in the setting of SARS-CoV-2 exposure is lacking.

Our general approach to medication management of unvaccinated individuals after a significant exposure is as follows [88]:

-Sulfasalazine (SSZ), nonsteroidal antiinflammatory drugs (NSAIDs), and hydroxychloroquine (HCQ)/chloroquine (CQ) may be continued. NSAID use would not differ from patients without exposure to SARS-CoV-2, consistent with most international and specialty guidelines [88,92-94]. There is a lack of scientific evidence for any novel increased risk associated with NSAID use in patients with COVID-19, and several reports support their safety [95,96]. SSZ can be continued given the relatively low risk of serious infection associated with it [97,98]. However, there are data suggesting uncertainty regarding the safety of SSZ among patients with COVID-19 [25].

-Whether methotrexate (MTX) or leflunomide (LEF) should be discontinued must be assessed on a case-by-case basis weighing the potential risks of infection and its sequelae against the possible risk of rheumatologic disease flare during the period the drug is held. If the medications have been temporarily held, they can generally be resumed pending a negative test result for COVID-19 or after two weeks of symptom-free observation. Treatment with MTX and LEF is also associated with a relatively low risk of serious infection [99,100], particularly when given as monotherapy.

-For most patients who are asymptomatic and recently exposed to SARS-CoV-2, we typically stop cyclophosphamide (CYC), mycophenolate, azathioprine (AZA), tacrolimus, anti-tumor necrosis factor (TNF) agents, abatacept, interleukin (IL) 6 receptor inhibitors, and Janus kinase (JAK) inhibitors (eg, tofacitinib), pending a negative test result for COVID-19 or after two weeks of symptom-free observation (see 'Postinfection management/resumption of therapy' below). However, these agents may be continued in individual cases, particularly in those for whom an increased risk of disease flare is a substantial concern. In addition, in selected patients, it may be appropriate to continue IL-6 receptor inhibitors as suggested by the ACR guidance [88]. High-quality evidence regarding continuation of the use of IL-6 receptor inhibitors in this setting is lacking. The use of IL-6 inhibitors for the treatment of severe COVID-19 is discussed separately. (See "COVID-19: Management in hospitalized adults", section on 'IL-6 pathway inhibitors (eg, tocilizumab)'.)

Although HCQ is also associated with a low risk of serious infection, reports highlight the potential for cardiotoxicity (particularly QT prolongation and arrhythmias) that could be exacerbated in the setting of COVID-19, during which patients may require use of other QT-prolonging medications [101], which is the rationale for temporarily holding HCQ therapy in patients with known or suspected COVID-19. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Cardiotoxicity' and "COVID-19: Arrhythmias and conduction system disease", section on 'Patients receiving therapies that prolong the QT interval'.)

The rationale for temporarily discontinuing the other immunosuppressive drugs, biologic agents, and JAK inhibitors is based upon their associated increased risk of serious infection compared with conventional disease-modifying antirheumatic drugs (DMARDs) [102,103] and the theoretically low likelihood that such a change would trigger a disease flare. However, IL-6 pathway inhibitors, such as tocilizumab and sarilumab, or a JAK inhibitor may be effective in hospitalized patients with severe COVID-19 infection for management of an intense inflammatory state similar to a cytokine release syndrome. (See "COVID-19: Management in hospitalized adults", section on 'IL-6 pathway inhibitors (eg, tocilizumab)'.)

●Post-exposure prophylaxis – The role of post-exposure prophylaxis with monoclonal antibody therapy in individuals at high risk for severe COVID-19 is discussed separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'No role for post-exposure prophylaxis'.)

Medication management with documented or presumptive COVID-19 — Adjustments to medication regimens in patients with documented or presumptive COVID-19 should be individualized with specific attention to the severity of the infection. Our approach is largely based upon expert opinion and extrapolation from the management of patients on these medications who have developed other infections, and is consistent with the management practices recommended by the ACR [88], as well as being generally similar to other guidelines [57,89-91].

Our overall approach to both unvaccinated and vaccinated individuals is as follows:

●For most patients with documented or presumptive COVID-19, we suggest temporarily discontinuing HCQ/CQ, SSZ, MTX, LEF, immunosuppressants (eg, mycophenolate, AZA), biologic agents (eg, anti-TNF inhibitors, IL-6 receptor inhibitors), and JAK inhibitors during the period of active infection. However, in cases where patients have active or organ-threating rheumatologic disease, continuation of immunosuppressive therapy may be required based upon an individualized assessment. The decision to continue these agents should be made in close consultation with specialists in rheumatology, infectious disease, and critical care who are involved in the management of the patient's acute illnesses. A particular agent may be continued in certain cases when it has proven value for the treatment of certain features of COVID-19 associated with a heightened inflammatory response (eg, tocilizumab, sarilumab, and baricitinib). (See "COVID-19: Management in hospitalized adults", section on 'IL-6 pathway inhibitors (eg, tocilizumab)' and "COVID-19: Management in hospitalized adults", section on 'Baricitinib and JAK inhibitors'.)

The rationale for holding HCQ/CQ is related to its potential for cardiotoxicity, particularly in the context of COVID-19, and is discussed above (see 'Medication management in patients following exposure' above). For SSZ, the reasoning is mainly related to concerns about potential adverse effects from this agent (eg, gastrointestinal upset, diarrhea, hepatitis, cytopenias, and, rarely, pneumonitis) that could be confused with clinical and laboratory manifestations of COVID-19. Additionally, temporarily holding SSZ for up to two to three weeks would be unlikely to result in significant rheumatologic disease flares.

We discontinue MTX, LEF, immunosuppressants, biologic agents, and JAK inhibitors given our concern for impairing the host defense against COVID-19 and the risk of causing additional infections, although there are no data to confirm or convincingly refute such risk. In addition, the risk of rheumatologic disease flare is likely to be relatively low during a limited period of several weeks. Most infections associated with these medications are bacterial and opportunistic in origin; these risks remain relevant, as a substantial proportion of patients with COVID-19 develop the complication of bacterial pneumonia [104]. Additional risks of treatment with certain biologics and JAK inhibitors include reactivation of viral infections, including herpes zoster [105].

●For patients with severe respiratory, cardiac, or kidney involvement, NSAIDs should be discontinued as they would be in patients without COVID-19.

●Patients treated with glucocorticoids should maintain the same dose to avoid acute rheumatologic disease flare and the complications of adrenal insufficiency associated with abrupt discontinuation. The use of glucocorticoids, including both systemic (eg, oral) and intraarticular glucocorticoids, should be consistent with best practices employed in patients without COVID-19. As in usual practice, in the setting of a critically ill patient with a swollen joint, the possibility of other infection should be excluded before joint injection, and this approach should be used as sparingly as possible. (See "Joint aspiration or injection in adults: Technique and indications", section on 'Indications for aspiration or injection'.)

Although glucocorticoid therapy increases the risk of infections, abrupt discontinuation of these medications is not feasible or safe in seriously ill patients. To minimize adverse reactions, we treat patients who require glucocorticoids for systemic rheumatic disease with the lowest necessary dose for the shortest period of time. (See "Major adverse effects of systemic glucocorticoids".)

Hospitalized patients with severe COVID-19 infection may receive dexamethasone therapy for cytokine storm. Following cessation of dexamethasone therapy for this indication, patients with rheumatic disease receiving glucocorticoid therapy prior to their hospitalization for COVID-19 infection should generally resume the pre-COVID-19 dose of glucocorticoids. The use of dexamethasone for the treatment of severe COVID-19 is discussed separately. (See "COVID-19: Management in hospitalized adults", section on 'Dexamethasone and other glucocorticoids' and "COVID-19: Management of the intubated adult", section on 'Use of glucocorticoids for non-COVID-19 reasons' and "COVID-19: Management in hospitalized adults", section on 'Patients with oxygen requirement/severe disease'.)

Postinfection management/resumption of therapy — The optimal time to resume immunosuppressive medications after infection with COVID-19 is unknown and has not been subject to empirical study. We base the timing for resumption of antirheumatic drug therapy (including conventional synthetic, biologic, and targeted DMARDs and other immunosuppressive drugs) largely upon the severity and characteristics of the infection in a given patient and the time since exposure to the infection or onset of symptoms. The rheumatologic disease indications and urgency of reinstitution of therapy may also influence timing:

●Asymptomatic patients without documented infection following suspected exposure – For asymptomatic patients without documented infection following suspected exposure, we resume antirheumatic medications once a negative test result has been documented at an appropriate timepoint following the suspected exposure to SARS-CoV-2 or in untested patients, after two weeks of symptom-free observation. (See "COVID-19: Diagnosis", section on 'For post-exposure testing' and 'Medication management in patients following exposure' above.)

●Asymptomatic patients with positive testing – For patients who are and remain asymptomatic but have had a positive reverse transcription polymerase chain reaction (PCR) or antigen test for SARS-CoV-2, we typically resume antirheumatic drug therapy approximately 10 to 17 days after the last date of positive testing. However, the date to resume treatment should be individualized according to vaccination status and/or previous receipt of monoclonal antibodies and other COVID-19-specific therapies. Also, patients with more urgent rheumatologic disease-related indications for therapy might resume therapy earlier in some cases. (See 'Medication management with documented or presumptive COVID-19' above.)

●Symptomatic but uncomplicated COVID-19 – For patients with uncomplicated symptomatic COVID-19, we typically restart antirheumatic medications within 7 to 14 days of symptom resolution. As examples, such patients include those with mild or no pulmonary symptoms who have been treated in the ambulatory setting or by self-quarantine. For patients who remain asymptomatic after infection but have a positive PCR or antigen test result for SARS-CoV-2, we may delay restarting antirheumatic medications 10 to 17 days after the test result. As above, the timing should be individualized according to vaccination status, previous receipt of monoclonal antibodies and other COVID-19-specific therapies, and rheumatologic disease management considerations. Patients with cancer who have been treated with B cell-depleting agents and develop COVID-19 infection show prolonged PCR positivity that correlates with culturable virus [106], and therefore the window of holding antirheumatic agents may need to be longer in that group with impaired humoral immunity to avoid viral persistence.

●Severe COVID-19 – Decisions regarding the timing of reinitiating rheumatologic disease therapies in patients recovering from more severe COVID-19-related illness should be individualized based upon the severity and organ systems affected, the clinical urgency of resuming antirheumatic drug therapy, and shared decision-making that considers the relative risks and benefits of the relevant treatments in the context of the patient's infection and its related complications.

Our approach is consistent with the guidelines of the ACR [88], the limited data that relate to this issue, and observations regarding the course of the infection (see "COVID-19: Clinical features" and "COVID-19: Diagnosis"). In a small observational study of nine patients, seroconversion was detected in all patients after two weeks and viral loads progressively decreased; despite detection of virus by PCR, live virus was unable to be isolated after eight days [107]. Further information regarding how long patients with rheumatologic disease harbor live virus and remain infectious is needed.

The role for either direct detection of SARS-CoV-2 (eg, by PCR) or for antiviral antibody testing for deciding when medications can be resumed following infection is uncertain. Virus has been detected in selected patients by PCR for periods approaching 30 days [107]. As alluded to above, some reports suggest prolonged SARS-CoV-2 shedding may be more common among immunosuppressed hosts.

The management of COVID-19 is discussed in detail separately. (See "COVID-19: Evaluation of adults with acute illness in the outpatient setting" and "COVID-19: Management in hospitalized adults".)

MANAGEMENT CONSIDERATIONS FOR PATIENTS IN THE ABSENCE OF INFECTION OR KNOWN EXPOSURE

General principles

●Patients with rheumatologic diseases should be practicing the widely recommended prevention strategies that are focused on mitigating infection risk. This includes adopting practices such as optimal hand hygiene, physical distancing, and wearing a mask in public when adequate physical distancing is not possible. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)

●For most patients with newly diagnosed, stable, or active disease, management generally does not differ from usual treatment approaches in the absence of COVID-19. Modifications of the treatment regimen (eg, use of rituximab) should be individualized and influenced by disease severity and the presumed effectiveness and safety of available treatment alternatives.

Modifications to routine rheumatologic care — Modifications to routine rheumatologic care that minimize risk of exposure to COVID-19 when necessary (eg, during periods of increased prevalence and risk) include:

●Optimal use of telehealth visits, ideally with video. Descriptions of approaches to examination of the musculoskeletal system during a telemedicine visit have been reported for the shoulder, hips, and knees [108,109]; the cervical and lumbar spine [108]; the elbows [109]; the ankles [108,110]; and the feet [110]. Additionally, strategies for assessment of disease activity have also been described [111].

Some rheumatologists and patients have found telehealth to be useful and effective [112]. However, there are some disadvantages to depending upon this approach. While some clinicians have used telehealth to facilitate ongoing care, many patients lack access to the required technology [113,114]. Less than half of rheumatologists in one survey felt they were able to provide efficient care with telehealth, and it often required more time than an in-person visit [115].

COVID-19 vaccination while on immunosuppressive therapy

Indications for vaccination — For nearly all eligible individuals with systemic rheumatic diseases, we recommend COVID-19 vaccination, consistent with age restrictions of local regulatory authorities. The safety of COVID-19 vaccination in patients with inflammatory rheumatic diseases appears to be similar to that in patients with noninflammatory rheumatic diseases [116,117]. When possible, vaccinations should be administered prior to the initiation of immunosuppression [57]. Patients with systemic rheumatic diseases who are receiving any immunosuppressive or immunomodulatory therapy are also generally considered to be among those immunosuppressed patients who are appropriate candidates for additional vaccine doses (extra primary series dose and boosters) following the usual primary series (figure 1). In a large population-based study, vaccine effectiveness against severe outcomes (hospitalization or death due to COVID-19) after two doses was between 92 and 97 percent for patients with rheumatoid arthritis, ankylosing spondylitis, psoriasis, or inflammatory bowel disease [118]. The COVID-19 vaccine schedule for immunocompromised patients is discussed in detail separately. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

These immunosuppressive or immunomodulatory therapies include sulfasalazine (SSZ), leflunomide (LEF), azathioprine (AZA), CYC, tumor necrosis factor (TNF) inhibitors, interleukin (IL) 6 inhibitors, IL-1 inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, IL-23 inhibitors, belimumab, oral calcineurin inhibitors, intravenous immune globulin (IVIG), methotrexate (MTX), mycophenolate, glucocorticoids, abatacept, rituximab, and apremilast. Nonsteroidal antiinflammatory drugs (NSAIDs) and hydroxychloroquine (HCQ) are not considered to be immunosuppressive and therefore are not indications for additional vaccine doses.

The use of one or more additional vaccine doses following the primary series in immunocompromised individuals is discussed in detail separately. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

Following COVID-19 vaccination, patients should continue to follow all public health guidelines regarding physical distancing and other preventive measures.

We do not routinely order any laboratory testing (eg, antibody tests for IgM and/or IgG to spike or nucleocapsid proteins) to assess immunity to SARS-CoV-2 post-vaccination or to assess the need for vaccination in a yet-unvaccinated person. We do not know the levels of anti-SARS-CoV-2 spike antibodies that protect against COVID-19 infection, hospitalization due to severe COVID-19 infection, and death from COVID-19 infection (ie, that convey seroprotection); therefore, the clinical utility of these test results has not been established in this setting.

Coordinating vaccine administration with immunosuppressive therapy — For some patients taking specific immunomodulatory therapies, we suggest modifications to either the immunomodulatory medication or vaccine timing. Adjustments to medication regimens should be individualized with specific attention to the severity of the disease activity, as some patients with poorly controlled or severe disease may not tolerate a temporary medication interruption.

Although most patients with systemic rheumatic diseases are able to develop adequate protection in response to vaccinations, the immune response may be blunted in patients receiving certain immunomodulatory therapies [31-37] (see "COVID-19: Vaccines", section on 'Immunocompromised individuals'). In particular, B lymphocyte-depleting agents (eg, rituximab) and other medications that affect lymphocytes (eg, mycophenolate, CYC, AZA, and MTX) may impair an appropriate antibody response to the messenger ribonucleic acid (mRNA) vaccines [31-34,55,119-122]. However, antigen-specific CD4 and CD8 cellular responses may be induced by mRNA vaccines despite reduced antibody responses [123-126].

Our approach to vaccine dosing and timing in patients requiring immunomodulatory therapy is consistent with that of the American College of Rheumatology (ACR) COVID-19 Vaccine Clinical Guidance Task Force and is as follows [127-132]:

●Abatacept (intravenous) – We suggest timing the vaccine administration so that it occurs one week prior to the next dose of intravenous abatacept.

●Abatacept (subcutaneous) – We suggest holding subcutaneous abatacept for one to two weeks (as disease activity allows) after each vaccine dose.

●Acetaminophen, NSAIDs – We suggest holding acetaminophen and NSAIDs for 24 hours prior to each vaccine dose, assuming that the disease is stable. There are no restrictions on use after vaccination once symptoms develop.

●Belimumab (subcutaneous) – We suggest holding belimumab for one to two weeks (as disease activity allows) after each vaccine dose.

●TNF inhibitors, anti-IL-6 receptor inhibitor, IL-1 inhibitors, IL-17 inhibitors, IL-12/23, and other cytokine inhibitors – These medications may be continued without modifications to therapy. However, some experts prefer to hold these medications (as disease activity allows) for one to two weeks after each vaccine dose.

●Cyclophosphamide (intravenous) – We suggest administering intravenous CYC so that it will occur approximately one week after each vaccine dose, when feasible.

●Hydroxychloroquine, glucocorticoids, and IVIG – These medications may be continued without modifications to therapy.

●Rituximab or other anti-CD20 B cell-depleting agents – We suggest initiating the vaccine series approximately four weeks prior to the next scheduled rituximab cycle, assuming the patient's COVID-19 exposure risk can be reasonably mitigated by preventive health measures. We also suggest delaying rituximab two to four weeks after the second vaccine dose. Subsequent vaccine doses may be given two to four weeks before the next anticipated rituximab dose. Some clinicians use CD19 B cell counts as a guide for vaccine timing and subsequent rituximab dosing.

An observational study including 123 patients with systemic rheumatic diseases found that patients receiving rituximab were less likely to develop an antibody response after the first dose of SARS-CoV-2 mRNA vaccine compared with other immunomodulatory agents [32]. A second dose of a SARS-CoV-2 vaccine had little impact on the seroconversion rate in patients receiving rituximab [31].

In a prospective cohort study comparing the serologic response to the mRNA vaccine of 87 patients on rituximab with that of 1096 healthy controls, 22 percent of patients versus 98 percent of healthy controls demonstrated a serologic response after two doses [122]. The time since the last rituximab infusion was associated with serologic response (median 267 days in responders versus 107 days in nonresponders). After 2 vaccine doses, 53 percent of patients on rituximab had a CD4 T cell response and 74 percent had a CD8 T cell response. Among the patients on rituximab who received a third vaccine dose, 16 percent had a serologic response and 100 percent demonstrated T cell responses.

●Other conventional and targeted immunosuppressive medications (eg, apremilast; AZA; calcineurin inhibitors; CYC [oral]; LEF; MTX; Janus kinase [JAK] inhibitors [baricitinib, tofacitinib, upadacitinib]; mycophenolate; SSZ) – We suggest holding each medication for one to two weeks after vaccine dose. If possible, mycophenolate should also be held the week before the vaccine is administered.

An observational study including 123 patients with systemic rheumatic diseases found that patients receiving mycophenolate were less likely to develop an antibody response after the first dose of SARS-CoV-2 mRNA vaccine compared with other immunomodulatory agents [32]. A second dose of a SARS-CoV-2 vaccine improved the seroconversion rate in patients treated with mycophenolate [31]. Another observational study of patients with systemic lupus erythematosus (SLE) receiving an mRNA COVID-19 vaccine found that holding mycophenolate for a week after vaccination increased SARS-CoV-2 antibody IgG levels without an increase in SLE flares compared with continuing mycophenolate [133].

In one series involving two cohorts (from the United States and Germany) with a total of 82 patients with immune-mediated inflammatory diseases who received two doses of an mRNA vaccine, humoral responses were judged as inadequate more often in patients receiving background MTX compared with those not taking MTX and healthy controls (62 versus 92 and 98 percent, respectively) [34].

Several randomized trials have suggested patients who temporarily hold MTX have a better antibody response compared with those who continue therapy [134,135]. As an example, in a randomized trial of 178 patients with either rheumatoid arthritis or psoriatic arthritis, holding one dose of MTX following the second dose of the vaccine in the initial series was associated with an increase in the median post-vaccination antibody titers when compared with giving MTX as scheduled (2553 versus 990 international units) and did not increase the risk of disease flare [134]. In a post-hoc analysis, holding MTX following each vaccination in the initial series did not further augment the antibody response.

This approach is largely based on expert opinion, evidence extrapolated from the immunologic effects of the individual medications as they relate to other vaccines and vaccine types, and observational data among patients who have received a SARS-CoV-2 mRNA vaccine. The efficacy of this approach remains to be established.

Additional considerations — It has been hypothesized that patients who have had SARS-CoV-2 infection complicated by multisystem inflammatory syndrome (MIS) may be at risk for a dysregulated response after vaccination. Considerations regarding vaccination in patients with a history of MIS are discussed in detail separately. (See "COVID-19: Vaccines", section on 'History of SARS-CoV-2 infection'.)

It remains uncertain whether the vaccines for COVID-19 may provoke a flare of an underlying systemic rheumatic disease as a result of immune activation or secondary to nonspecific adjuvant effect. Limited data have suggested a low incidence rate of a possible disease flare following vaccination [116,136-138]. In a large cohort including patients with inflammatory systemic rheumatic diseases, approximately 4 percent of patients experienced a disease flare [116]. The mean time to flare following vaccination was six days. Adverse effects associated with COVID-19 vaccines are discussed separately. (See "COVID-19: Vaccines", section on 'Expected adverse effects and their management' and "COVID-19: Vaccines", section on 'Rare but serious associated events'.)

Pre-exposure prophylaxis — Patients with rheumatologic diseases who are moderately to severely immunocompromised and who may not have mounted an adequate immune response to the COVID-19 vaccine may be appropriate candidates for pre-exposure prophylaxis monoclonal antibody therapy. However, there are currently no options approved by the US Food and Drug Administration (FDA) for pre-exposure prophylaxis because most circulating variants are resistant or have reduced susceptibility to these therapies. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Monoclonal antibodies ineffective for pre-exposure prophylaxis'.)

PROGNOSIS — There is limited evidence identifying risk factors for poor outcomes with COVID-19 infection unique to patients with rheumatologic disease. There is also limited evidence of adverse rheumatologic disease outcomes following infection other than the short-term risk of increased disease activity due to temporary drug discontinuation. The use of vaccination, pre-exposure prophylaxis, and COVID-19-specific therapies are likely to benefit patients with rheumatologic diseases, but available data are limited. (See 'Disease- and comorbidity-related risks' above and 'Risks associated with rheumatologic disease therapies' above.)

DISEASE REGISTRIES — Several registries have enrolled patients with systemic rheumatic diseases to improve the understanding of the impact of SARS-CoV-2 virus infection on this patient population. More information can be found on the following websites:

●COVID-19 Global Rheumatology Alliance registry

●The EULAR – COVID-19 registry for rheumatologists and other clinicians

RESOURCES FOR PATIENTS — Links to resources with information about COVID-19 for patients with rheumatologic diseases from select rheumatology society and government-sponsored guidelines are presented separately. (See "Society guideline links: COVID-19 – Rheumatology care", section on 'Resources for patients'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics" and "Society guideline links: COVID-19 – Rheumatology care".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 vaccines (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Risk of COVID-19 infection – The presence of a rheumatologic disease alone may be associated with an increased risk for developing COVID-19 with more adverse outcomes, although the evidence is mixed. Additionally, patients with various rheumatologic diseases have a higher prevalence of several comorbidities such as advanced age, chronic pulmonary and kidney disease, heart disease, hypertension, obesity, and diabetes, which, in turn, are risk factors for severe illness with COVID-19. (See 'Disease- and comorbidity-related risks' above.)

Some observational data suggest that rituximab use is associated with an increased risk of more severe COVID-19 infection. (See 'Risks associated with rheumatologic disease therapies' above.)

●Clinical features – The clinical features of COVID-19 among patients with systemic rheumatic diseases are variable and are not known to be different from those of patients without these underlying diseases. However, a variety of rheumatologic diseases may have clinical features that can mimic or be mimicked by COVID-19, such as malaise, myalgias, and fatigue. For patients with an existing diagnosis of a rheumatologic disease, the clinician may need to distinguish signs and symptoms of a disease flare from those of possible COVID-19 infection; therefore, a high level of suspicion of COVID-19 should be maintained where it is prevalent. (See 'Clinical presentation of the infection in patients with rheumatologic disease' above and 'Features of rheumatologic disease that can mimic or be mimicked by COVID-19' above.)

●Medication management following exposure – Adjustments to medication regimens in patients thought to be recently exposed to the SARS-CoV-2 virus should be individualized, with considerations regarding vaccination status, suspected or known individual's vaccine response, patient's immunosuppressive regimen (eg, rituximab use) and other risk factors, and access to COVID-19-specific therapies. (See 'Medication management in patients following exposure' above.)

●Medication management with infection – Adjustments to medication regimens in patients with documented or presumptive COVID-19 should be individualized with specific attention to the severity of the infection. Our general approach is as follows (see 'Medication management with documented or presumptive COVID-19' above):

•For most patients with documented or presumptive COVID-19, we suggest temporarily holding hydroxychloroquine (HCQ)/chloroquine (CQ), sulfasalazine (SSZ), methotrexate (MTX), leflunomide (LEF), immunosuppressants (eg, mycophenolate, azathioprine [AZA], cyclophosphamide [CYC]), biologic agents (eg, anti-tumor necrosis factor [TNF] inhibitors, interleukin [IL] 6 receptor inhibitors), and Janus kinase (JAK) inhibitors during the period of active infection (Grade 2C). However, in cases where patients have active or organ-threating rheumatologic disease, continuation of their immunosuppressive therapy may be required based upon an individualized assessment. The decision to continue these agents should be made in close consultation with the experts in rheumatology, infectious disease, and critical care involved in the management of the patient's acute illnesses. Another exception to discontinuation of a particular agent may be for selected patients in whom an antirheumatic therapeutic also has value for the treatment of features of COVID-19. (See "COVID-19: Management in hospitalized adults", section on 'Specific treatments'.)

•Patients receiving glucocorticoids should maintain the prescribed dose to avoid acute rheumatologic disease flare and the complications of adrenal insufficiency associated with abrupt discontinuation of this medication. The use of dexamethasone for the treatment of severe COVID-19 is discussed separately. (See "COVID-19: Management in hospitalized adults", section on 'Dexamethasone and other glucocorticoids' and "COVID-19: Management of the intubated adult", section on 'Use of glucocorticoids for non-COVID-19 reasons' and "COVID-19: Management in hospitalized adults", section on 'Patients with oxygen requirement/severe disease'.)

●Postinfection rheumatologic disease management – The timing for resumption of antirheumatic drug therapy depends largely upon the severity and characteristics of the infection in a given patient and the time since exposure to the infection or onset of symptoms. The rheumatologic disease indications and urgency of reinstitution of therapy may also influence timing. For asymptomatic patients with positive testing for the virus, we usually resume therapy 10 to 17 days after positive testing; for patients with symptomatic but uncomplicated disease, we wait until 7 to 14 days after symptom resolution; however, the specific date to resume treatment should be individualized according to vaccination status and/or previous receipt of monoclonal antibodies and other COVID-19-specific therapies. For patients with more severe disease, an individualized approach is required. (See 'Postinfection management/resumption of therapy' above.)

●Patients without known exposure – The medication management of patients with newly diagnosed, stable, or active rheumatologic disease who are not known to have infection with or without exposure to SARS-CoV-2 generally does not differ from usual treatment approaches in the absence of COVID-19. We initiate or continue all medications indicated for the management of the patient's systemic rheumatic disease. (See 'General principles' above.)

Modifications to routine rheumatologic care that minimize risk of exposure to COVID-19 when possible include optimal use of telehealth visits, decreased frequency of routine laboratory surveillance when associated risk is deemed to be low, and the use of lower-volume laboratories offsite from larger health care facilities. (See 'Modifications to routine rheumatologic care' above.)

●COVID-19 vaccination – For eligible individuals with systemic rheumatic diseases, we recommend COVID-19 vaccination to reduce the risk of serious illness, hospitalization, and death (Grade 1B). Patients with systemic rheumatic diseases who are receiving any immunosuppressive or immunomodulatory therapy are also generally considered to be among those immunosuppressed patients who are appropriate candidates for additional vaccine doses following the primary series (figure 1). The COVID-19 vaccine schedule for immunocompromised patients is discussed in detail separately. (See 'Indications for vaccination' above and "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

●Timing of vaccination – For patients taking certain immunomodulatory therapies, we suggest holding such agents (typically for one week) after vaccination if disease activity is adequately controlled (Grade 2C). The immune response to the SARS-CoV-2 vaccines in patients receiving immunomodulatory therapies may be blunted compared with the general population. However, adjustments to medication regimens should be individualized with specific attention to the severity of the disease activity. This general approach applies to any dose of vaccine, whether part of the primary series or a booster dose. Details regarding the specific immunomodulatory therapies are presented above. (See 'Coordinating vaccine administration with immunosuppressive therapy' above.)

●Pre-exposure prophylaxis – Patients with rheumatologic diseases who are moderately to severely immunocompromised and who may not have mounted an adequate immune response to the COVID-19 vaccine may be appropriate candidates for pre-exposure prophylaxis monoclonal antibody therapy. However, there are currently no options approved by the US Food and Drug Administration (FDA) for pre-exposure prophylaxis because most circulating variants are resistant or have reduced susceptibility to these therapies. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Monoclonal antibodies ineffective for pre-exposure prophylaxis'.)

●Prognosis – There is limited evidence identifying risk factors for poor outcomes with COVID-19 infection unique to patients with rheumatologic disease and limited evidence of adverse rheumatologic disease outcomes following infection itself. The use of vaccination, pre-exposure prophylaxis, and COVID-19-specific therapies is likely to benefit patients with rheumatologic diseases, but further studies are needed. (See 'Prognosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Ted R Mikuls, MD, MSPH and Ellen M Gravallese, MD, who contributed to earlier versions of this topic review.