By Don L. Goldenberg, MD
Any person with a chronic medical condition may be considered at increased risk for developing complications from the novel coronavirus, SARS-CoV-2, or subsequentCOVID-19 illness. Although the elderly and immunocompromised patients are considered to be at greatest risk for complications, there is no data to know what that risk is and whether it is primarily related to disease activity and current medications, or more affected by age, comorbid conditions, or other factors, such as smoking.
We do know that immune suppression, either from a systemic rheumatic disease or from immunosuppressive medications, increases the risk and severity of bacterial and opportunistic infections. The risk of any infection can be two- to four-fold higher in those with rheumatoid arthritis (RA), for instance, compared to the general population.1 There is some evidence that immune suppression results in more active viral replication. However, the medical community does not know whether rheumatic disease or immunosuppression increases the initial risk of COVID-19 infection. In an Italian study during the 2009-2010 influenza season, 160 patients diagnosed with RA and taking biologic drugs had a higher infection rate than controls but no increased complications or hospitalizations.2
The risk of infectious complications varies with rheumatic disease severity and activity as well as with the individual’s current medication.3 Every systemic immune disease increases the risk of infection.1 Certain diseases, such as systemic vasculitis, may be especially dangerous, but it is the current disease activity that may be more important than which rheumatic disease is present. In a study of more than 16,000 RA patients, there was a direct correlation of infection rate and complications with disease activity.4 Each 0.6 unit increase in RA disease activity resulted in a 25% increased rate of infections requiring hospitalization.
If a systemic immune disease has affected the lungs, such as that which occurs with systemic lupus erythematosus (SLE), vasculitis, or progressive systemic sclerosis, there is often great concern for respiratory complications. There is no evidence that non-systemic painful rheumatic conditions, including osteoarthritis, gout, or pseudogout, cause significant immune suppression.
There is no conclusive evidence that the current COVID-19 pandemic will result in more new cases of autoimmune diseases. (Image: iStock)
Biologic medications (infliximab, etanercept, adalimumab), small molecules (tofacitinib), or high doses of corticosteroids, may be considered especially likely to promote complications, such as secondary bacterial infection, following any viral infection.5 However, one study demonstrated a beneficial, rather than a deleterious effect, of biologic therapy in patients with RA who developed serious infections.6 In that study, conducted in Germany among 947 RA patients, those taking biologics had less sepsis or fatal outcome after a serious infection that those patients not taking the biologic drugs. Methotrexate has minimal risk of increased infections and there is no evidence that the antimalarial drugs, such as hydroxychloroquine, or sulfasalazine increase the risk of infection.
At the time of this writing (March 30, 2020), there have been no general guidelines released in the United States for managing patients with rheumatic/immune diseases during the current COVID-19 pandemic. However, the American College of Rheumatology (ACR) and the British Society for Rheumatology have suggested some steps, updated as of March 25, 2012.7,8 These recommendations have been incorporated into the following sections of this paper, along with input from the author’s rheumatology colleagues and experts across the US. Please note that these are not official clinical guidelines and that providers should always manage patient care on a case-by-case basis.
Clinical Approaches for Managing Rheumatic/Immune Diseases Amidst COVID-19
Patients with rheumatic/immune diseases should be encouraged to alert their primary care provider and specialist immediately if a question of COVID-19 infection is entertained. Depending on the patient’s disease status and current medications, individuals with rheumatic/immune disease should be considered to be a high-risk category for medical evaluation and appropriate testing.
Urgent and infection-related visits should take precedence over routine visits or elective surgery or procedures, such as soft-tissue or joint injections. Rehabilitative care, such as most physical or occupational therapy, should occur by telephone or with virtual technology. It is crucial to follow the CDC guidelines in regard to protecting patients and medical personnel during all office and hospital visits. (More on how providers are using telemedicine and chronic pain during the coronavirus pandemic.)
1. Continue Immunosuppressive Medications Unless Infection is Present
Ongoing medications, including immunosuppressive drugs, should be continued at the patient’s current dose, unless there is evidence of an active infection. Such drugs, including corticosteroids, should never be stopped abruptly. Stopping or switching medications may precipitate an exacerbation of the systemic disease, which is a risk factor for any infection and its complications. As noted, there is no data regarding the potential impact of specific immunosuppressive medications on COVID-19 infection.
If a patient is stable or in a disease remission, it may be prudent to consider a slow taper of immune suppressant medications on a case-by-case basis. Medications that primarily affect T cells might be a good candidate to consider stopping or lowering the dose. However, if the disease flares, that medication should be restarted.
During an infection, particularly in a hospitalized patient, immunosuppressive therapy should be paused. The exact timeframe for stopping the medication is unknown and needs to be assessed on an individual patient basis.
2. Corticosteroid and Steroid Injections Should Be Reserved for Severe Cases
In general, corticosteroids inhibit immune response and high doses should be avoided in any infection, in line with the general recommendations above. There is evidence that corticosteroids may increase the rate of certain viral infections, notably Herpes Zoster infection.5 During the COVID-19 pandemic, most groups recommend that corticosteroids NOT be injected into joints or soft-tissues.5,10
In contrast, high-dose corticosteroids may suppress the inflammatory response and be helpful to prevent lung damage, such as in acute respiratory distress syndrome (ARDS). Therefore, these drugs have been used in patients with COVID-19 infection and severe lung disease. Uncontrolled reports have demonstrated no clear efficacy.9
3. Continue with Intravenous Biologic Infusions
Those patients with rheumatic/immune diseases who are already receiving infusions of any biologic medication should continue on those regular infusions. Special attention should be made to inquire about recent fever, cough or exposure, and staff/equipment set-up, such as at least 6 feet separating infusion chairs. There may be situations wherein, because of repurposing of infusion space or equipment, that infusion treatment must be temporarily discontinued and other bridge medication initiated.
4. NSAIDs: Use Only with Caution
There has been conflicting data regarding the safety of NSAIDs, such as ibuprofen, naproxen, and prescription NSAIDs, during COVID-19 infection. On March 19, 2020, the World Health Organization (WHO) recommended that people with COVID-19 symptoms avoid taking the anti-inflammatory drug ibuprofen. However, most US physicians disagreed and a few days later the WHO reversed its decision. Daniel Solomon, MD, MPH, a rheumatologist from Brigham and Women’s Hospital in Boston and an expert in the use of these medications, has noted that there is no evidence that NSAIDs are unsafe to use during COVID-19 infection.11 However, use of NSAIDs or acetaminophen could mask fever potentially leading to a subsequent delay in a diagnosis of COVID-19.
5. Antimalarial Medications: The Jury is Still Out
Antimalarial medications, particularly hydroxychloroquine, has been used to treat RA, SLE, and other rheumatic disease for more than 40 years. In addition to their anti-inflammatory effect, antimalarials have been shown to interfere with viral attachment in laboratory studies.5 These drugs have been considered to be potentially useful in the treatment of COVID-19 infection and had been used in some patients at the peak of the China epidemic. There has been some evidence that chloroquine was effective, particularly in avoiding exacerbation of pneumonia, in COVID-19 infected patients.12
In early March 2020, President Trump announced that antimalarial drugs may be effective, safe, and relatively cheap; he touted their use in COVID-19 patients in the United States.13Despite this optimistic announcement, Anthony Fauci, MD, director of the US National Institute of Allergy and Infectious Disease, and other medical experts have repeatedly noted that any benefit so far is anecdotal.
One of the author’s colleagues, Michael Lockshin, MD, from the Hospital for Special Surgery in New York, stated in the media: “Rheumatologists are furious about the hype going on over this drug. There is a run on it and we’re getting calls every few minutes, literally, from patients who are trying to stay on the drug and finding it in short supply. If there were justification for everyone taking it, that would be one thing. It’s not hard to do the studies even in the midst of this crisis. We could have answers in a few weeks. But it’s being prescribed right and left.”13
Furthermore, a nationwide shortage of these antimalarials has developed, apparently in part because healthcare professionals have been prescribing them for themselves and their family.13 This drug stockpiling has already made it difficult for patients with rheumatic/immune diseases to refill their antimalarial medication. Some people have taken other products, not meant for human consumption, that contain chloroquine, with serious side effects and in one instance, death. Editor’s Note: See the American College of Rheumatology’s March 31, 2020 letter to governors across the US about HCQ and chloroquine, which are under investigation as potential treatments for the novel coronavirus and which have been successfully used to treat SLE and rheumatoid arthritis for decades. See a related article on HCQ use and retinopathy risk in treating patients with lupus.
Currently, the antimalarials, often combined with an antiviral drug or an antibiotic, are being used in hospitalized patients with COVID-19 infection in several countries, including the US. Controlled studies may soon shed light on their utility. The ACR has stated: “We hope that pragmatic clinical trials of these drugs can be done quickly to determine how well they work, who should get them, and at what point in the illness. If the demand for these drugs increases rapidly, we urge pharmaceutical companies to continue to provide these medications to mitigate drug shortages.”10) In response, pharmaceutical companies are donating hundreds of millions of doses of their branded hydroxychloroquine products.14-16
Patients with rheumatic disease tend to experience disease flares during times of excess stress. Any patient living with chronic pain, be that related to a systemic illness, a structural condition such as osteoarthritis or spinal stenosis, or a centralized pain disorder such as fibromyalgia, are likely to experience increased symptoms with the individual and societal stress of COVID-19. It may be especially difficult in the short-term to determine whether a patient’s worsening pain is related to disease exacerbation. Nevertheless, the following recommendations make sense for any patient experiencing increased symptoms.
1. Emotional and Mental Health
This is a time of highly unusual stress, with resultant persistent anxiety. Depression and suicidal ideation may also occur. Thus, there is an urgent need for clinicians to find innovative ways to offset such emotional and mental states in patients who are already struggling with chronic pain or illness.
Providers can reassure patients that such anxiety is normal. They should assess levels of despair and help patients guard against panic and hopelessness. While social distancing has limited wellness visits as well as quick referrals to mental health professionals, the use of telemedicine is gaining traction and is increasingly providing a means of communication for patient education and reassurance, symptom-checking, referral, and follow-up. Some of the author’s colleagues have implemented virtual mental health classes with excellent patient and family response.
The disruption of work and daily activities, along with constant worry, has made normal sleep habits unsettled. Clinicians should always remember to provide patients with sleep hygiene advice. In light of the pandemic, updated recommendations might include avoidance of reading or watching any news during the evening. Further, individuals may not be following their usual schedule or may be inclined to “sleep-in,” disrupting their usual circadian rhythm and perpetuating sleep disturbance. They should be encouraged to stick to their regular sleep routines as much as possible.
Exercise promotes mental and physical well-being in all of us. It is especially important in patients with rheumatic disease. The author’s patients with RA and OA often do best with water exercise. However, when health clubs and swimming pools are closed due to forced lockdowns, some form of replacement exercise is necessary, such as online yoga or tai-chi. Walking outside twice a day can also be helpful. The ACR and Arthritis Foundation have posted free online exercise programs, at rheumatology.org and arthritis.org, respectively.
Even in this pandemic, now is a good time to reinforce healthy lifestyle habits with our patients. Smoking and obesity are risk factors for RA and other rheumatic diseases.17 There is preliminary evidence that smokers have greater pulmonary complications from COVID-19 infection.9 Inactivity and lack of exercise increase can chronic pain and depression. Those patients who have not followed lifestyle recommendations regarding smoking cessation, nutrition, and weight management may be better motivated with the added danger of complications from the current pandemic.
More Guidance Is On the Way
Rheumatology COVID-19 Registry
The only way the medical and scientific community are going to determine the exact risk of COVID-19 in patients with rheumatic/immune diseases is to capture all the necessary data in national and international registries. This is already underway, co-sponsored by the ACR and the European League Against Rheumatism (EULAR). A similar registry is available for patients with inflammatory bowel disease at https://covidibd.org/ .
The stated mission of the Rheumatology COVID-19 Registry is to: “create a secure, de-identified, international case reporting registry and curate and disseminate the outputs from that registry. It is our hope that the information collected will help guide rheumatology clinicians in assessing and treating patients with rheumatologic disease and in evaluating the risk of infection in patients on immunosuppression.”18
Other Anti-Rheumatic Medications Being Tried
In addition to the antimalarial drugs, other anti-rheumatic drugs eventually may prove to be helpful, rather than harmful, in the treatment of COVID-19 infection. The antiviral drugs, lopinavir-ritonavir and remdesevir, have been used in China and throughout the world in patients with COVID-19, although it is uncertain whether they have been effective. Monoclonal antibodies that bind the coronavirus spike receptor and immunoglobulin derived from recovered patients’ plasma are being tested in the US and elsewhere.
Despite the concern that immunosuppressive drugs may increase infected patients at risk for complications, there is some hope that these medications’ anti-inflammatory properties can blunt lung injury. COVID-19 infection may result in what has been dubbed “a cytokine storm” as seen in rare diseases such as macrophage activation syndrome. In such situations, there is massive release of various cytokines, particularly interleukins. Therefore, some of the biologic, immunosuppressive drugs used by rheumatologists may turn out to be effective in treating severe COVID-19 infections.
For example, interleukin (IL-1 and IL-6) blockers have been effective in ARDS and the IL-6 blocker, tocilizumab, is being used in COVID-19 clinical trials in China and in Italy.5 There is also evidence that tumor necrosis factor (TNF) inhibitors may be effective and a study using adalimumab for COVID-19 infection is ongoing in China. A double-blind trial launched in the US in March 2020 on the IL-6 inhibitor sarilumab in patients with severe COVID-19 infection.19,20
On April 29, 2020, the American College of Rheumatology's COVID-19 Clinical Guidance Task Force released updated guidance for the care of patients with rheumatic diseases during the COVID-19 pandemic. A summary of key points:
Patients with rheumatic disease appear to be at risk for poor outcomes from SARS-CoV-2 (the virus that causes COVID-19) primarily because of general risk factors such as age and comorbidity. There is no evidence that rheumatic diseases are an independent risk factor for poor outcome from COVID-19 infection.
Patients with rheumatic disease should follow all general COVID-19 preventive measures, but in addition, rheumatology patients and providers may discuss ways to reduce the number of healthcare encounters and potential exposure to SARS-CoV-2, (e.g., monitoring blood work less frequently, using telehealth, and increasing the time between doses of intravenous medications).
The task force recommended continued use of ACE inhibitors and ARBs as well as NSAIDs unless there is evidence of kidney, gastrointestinal or cardiac complications.
The task force endorsed continued standard of care glucocorticoid administration, using the lowest dose possible to control the rheumatic disease and avoiding abrupt treatment withdrawal.
For ongoing treatment of stable patients with no SARS-CoV-2 exposure or infection: Hydroxychloroquine or chloroquine, sulfasalazine, methotrexate, leflunomide, immunosuppressants (e.g., tacrolimus, cyclosporine, mycophenolate mofetil, azathioprine), biologics, Janus kinase (JAK) inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, naproxen) may be continued. Denosumab, an injectable medication used for osteoporosis, may still be given, but the time between doses may be extended to as long as 8 months, to minimize healthcare encounters and if necessary due to limited access to infusions.
In patients with stable disease who have been exposed to SARS-CoV-2 (without known infection): Hydroxychloroquine, sulfasalazine and NSAIDs may be continued, but immunosuppressants (including tacrolimus, cyclosporine, mycophenolate ofetil and azathioprine), non-IL-6 biologics, and JAK inhibitors should be stopped temporarily, pending a negative test result for SARS-CoV-2 or after 2 weeks without COVID-19 infection symptoms. IL-6 inhibitors may also be continued in this situation, in select circumstances.
In rheumatic disease patients with a confirmed SARS-CoV-2 infection, anti-malarial therapies (hydroxychloroquine, chloroquine) may be continued, but sulfasalazine, methotrexate, leflunomide, immunosuppressants, non-IL-6 biologics, and JAK inhibitors should be stopped temporarily. For patients with severe respiratory symptoms, NSAIDs should be stopped. In select circumstances, IL-6 inhibitors may be continued.
Also on April 11, 2020, the Infectious Diseases Society of America released its recommendations for treating patients diagnosed with COVID-19 in the context of a clinical trial.
Discussion and Conclusion
The impact of COVID-19 on patients with rheumatic/immune diseases is just starting to be evaluated. Preliminary recommendations (summarized in the Clinical Takeaways section below) suggest that patients should be kept on their current medical regimen unless they become infected. At that point, especially if that person is hospitalized, any immunosuppressive medication should be stopped until all signs of infection have abated. Despite the concern that immunosuppressive medications increase the risk of complications from COVID-19, medications such as the antimalarials and certain biologic agents may prove to be effective in treating certain patients.
All patients should be monitored for exacerbations of mood disturbances and receive instruction in innovative ways to ensure adequate sleep and exercise during these difficult times.
At the time of this writing, there were no published recommendations for other immune disorders, such as multiple sclerosis or inflammatory bowel disease, and COVID-19 infection (Update: Part 2 of this article addresses MS, IBD, Psoriasis and Type 2 Diabetes in the context of COVID-19). Any advice at this early stage is preliminary and treatment is obviously a moving target. Hopefully, the medical and scientific community will be able to update and better target these statements quickly as well as get more insight on the impact of COVID-19 on a range of autoimmune diseases.
*This piece was additionally reviewed by clinical pharmacist and pain management expert Jeffrey Fudin , PharmD, DAIPM, FCCP, FASHP.
**This piece was updated April 13, 2020, and May 5, 2020 to address newly released ACR and IDSA recommendations.