Infection Risk During Targeted and Biologic Therapies in Rheumatoid Arthritis and Psoriatic Arthritis

Although biologic therapies have revolutionized the treatment for many patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA), they carry a well-known risk for infection. A meta-analysis indicated an increased risk for serious infection in patients with RA receiving a standard or high dose of biologics, but not a low dose.¹ The presence of comorbidities, such as an additional autoimmune disease or diabetes, further augments the risk for infection associated with biologics and targeted therapies.²

According to a review published in September 2020 by a multidisciplinary group of international experts, most biologic-induced infections occur within the first year of use.² The “major concerns are severe bacterial infections, mycobacterial and fungal diseases, herpes zoster and hepatitis B virus (HBV) reactivation and finally travel-associated infections,” the authors wrote. “The surveillance and prevention of the infectious risks [for] targeted therapies must be adapted to each mechanism of action and to specific populations.”

In their paper, Lortholary and colleagues² discussed the prevention and management of infection risk in RA and PsA.

Predicting Risk

Although it is difficult to predict the infection risk associated with biologics, partly due to a lack of validated biomarkers, several approaches have demonstrated promise and may be useful on a case-by-case basis.

Studies have shown that a total lymphocyte count less than 500 cells/mm³ was linked to an increased risk for serious infection in patients with RA receiving tofacitinib,³ and a baseline CD8+ T cell count of 211 cells/µL or less was predictive of clinically significant infection in this population.⁴

Among patients with autoimmune diseases receiving rituximab, those with baseline immunoglobulin (Ig)G levels of less than 6 to 7 g/L demonstrated significantly higher risk for severe infection in 2 different studies with a hazard ratio of 2.36 (P =.01) and an odds ratio of 4.9 (P =.005), respectively.^5,6

The RA Observation of Biologic Therapy (RABBIT) Risk Score was designed to estimate the risk of developing serious infection during the following 12 months.⁷ The tool was validated in 2 cohorts that included thousands of patients and a range of factors including age, recent history of infection, certain comorbidities, and current and previous medication history.

Other notable findings have shown significantly lower adenosine triphosphate (ATP) levels in patients with RA with infection receiving infliximab. Higher scores on the multibiomarker disease activity test were closely linked to higher rates of serious infection.² However, these predictive measures have not yet been validated in clinical practice.

Preventing Infection

Much of the data on strategies to prevent biologic-induced infection are derived from case series and observational cohort studies, and most recommendations are not supported by high-quality evidence.

“Besides the use of antiviral prophylaxis for patients with hepatitis B during rituximab therapy and the need for therapy for [latent tuberculosis infection (LTBI)] in patients receiving [tumor necrosis factor inhibitors], most recommendations are of low evidence, and therefore risk and benefits of these measures need to be taken into consideration,” Lortholary and colleagues wrote.²

According to the recent European League Against Rheumatism (EULAR) recommendations for vaccination in adults with autoimmune inflammatory rheumatic diseases,⁸ patients are recommended to receive an infectious disease consultation and any vaccinations that may be needed before initiation of therapy, depending on risk factors, vaccination and exposure history, and expected or completed travel to or from endemic areas.

According to study authors, when LTBI treatment is indicated, rifampin-based regimens are preferred due to the shorter course of treatment and better tolerability. Immunosuppressants may be initiated before LTBI treatment is completed.² 

Although universal co-trimoxazole prophylaxis to prevent opportunistic infection may not be recommended in these patients, a “simple rule of using co-trimoxazole prophylaxis in patients with high-dose steroids (>30 mg for >1 month) or those with combination immunosuppressive therapy, particularly in patients with low CD4+ T-cell counts, may target those patients at higher risk for opportunistic infections.”²

In a study of more than 700 patients with RA, co-trimoxazole prophylaxis significantly decreased the incidence of pneumocystis pneumonia (PCP) in those with at least 2 risk factors for PCP, including age at least 65 years, comorbid pulmonary disease, and glucocorticoid use.⁹

Patients who are HBsAg-positive or anti-HBc-positive receiving rituximab have the highest risk for hepatitis B reactivation. According to study authors, antiviral prophylaxis with entecavir or tenofovir may be recommended in these cases and should continue for at least 12 to18 months after rituximab is completed to avoid late reactivation. For patients with anti-HBc-positivity receiving other immunosuppressive therapies and with no evidence of active disease, monitoring with HBV DNAemia can be recommended at 1- to3-month intervals.²

We interviewed Jasvinder Singh, MD, MPH, rheumatologist, researcher, and professor of medicine and epidemiology at the University of Alabama in Birmingham, regarding the clinical implications of biologics treatment and infection risk in RA and PsA.

What is known about the infection risk associated with biologics in RA and PsA?

Jasvinder Singh, MD: It is very well-known that biologics used with RA and PsA are associated with a risk for infection, especially during the first year of initiating treatment. The risk for infection is lower after 1 to 2 years, though the reasons are unclear due to various factors, for example, patients often discontinuing or changing therapies.

The infection risk is even higher in patients with certain comorbidities. Registries in the United States and other countries reflect the real-world risk of these drugs beyond 1 to 2 years, and these [data] will provide more information on using them in patients with comorbidities.

What are some ways to prevent or reduce the risk for infection in these patient populations?

Dr Singh: All patients should be up to date on age-appropriate vaccinations, ideally before the start of therapy. This should occur without delay, especially for live vaccines – the optimal timing is 2 to 4 weeks before starting biologics to allow the body enough time to mount a response.

Patients can be advised to quit or cut down on smoking because of the increased risk for pulmonary infection, and studies have shown that biologics are not as effective in smokers.¹⁰ Physicians can discuss ways to treat and stop alcohol abuse, as heavy alcohol use puts these patients at higher risk for immunosuppression as well as liver damage, which is also increased with biologic use. It is also important to treat and control diabetes and other comorbid conditions that can influence infection risk.

What tips would you offer to clinicians about improving communication with patients regarding therapeutic options and risks? 

Dr Singh: The language we use sometimes doesn’t make sense to patients, including words such as “percent” and “risk.” [Physicians are recommended] to use language [that patients] can fully understand, and use tools to help them understand if needed.

It is important to ask patients for feedback to ensure effective communication and that they understand the true risks and benefits before choosing and starting therapies. You might say, “I gave you a lot of information. Tell me what you understand about how you will take this drug.” You may be surprised that the message was not conveyed as intended.

When discussing therapeutic options, [clinicians may] use patient preferences as the driving force in a shared decision making model. For example, [patients] might prefer to consider newer vs older drugs, or they might have a strong preference for self-injection vs infusion, and that further narrows down the options for discussion.

What else can clinicians consider while treating these patients?

Dr Singh: One important point – which people often forget when talking about the risk for infection with biologics – is that long-term use of glucocorticoids carries the highest risk for infection among the drugs used in patients with RA and PsA, along with the risk of osteoporosis, bone fractures, short-term effects on sleep and mood, and other effects. The concern pertains to durations of more than 6 months. It is important to limit the duration and dose of these drugs, and there should be a plan to taper the patient off.

What should be the focus of additional research in this area?

Dr Singh: There are a lot of important research needs remaining, including head-to-head trials to compare the harms and benefits of these drugs in lots of different patients at different timepoints in the disease.

We also need to understand why certain risk factors such as obesity and smoking make the drugs less effective, and we need long-term data – 2 and 5 years – regarding the effects of these drugs on disease course, infection risk, and more.

There is also a need for qualitative studies with nurses and patients to explore how they choose these drugs and factors that influence adherence.

References

1. Singh JA, Cameron C, Noorbaloochi S, et al. Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet. 2015;386(9990):258-265.
2. Lortholary O, Fernandez-Ruiz M, Baddley JW, Manuel O, Mariette X, Winthrop KL. Infectious complications of rheumatoid arthritis and psoriatic arthritis during targeted and biological therapies: a viewpoint in 2020. Ann Rheum Dis. Published online September 22, 2020. doi:10.1136/annrheumdis-2020-217092
3. van Vollenhoven R, Lee EB, Strengholt S, et al. Evaluation of the short-, mid-, and long-term effects of tofacitinib on lymphocytes in patients with rheumatoid arthritis. Arthritis Rheumatol. 2019;71(5):685-695.
4. Sonomoto K, Yamaoka K, Kubo S, et al. Effects of tofacitinib on lymphocytes in rheumatoid arthritis: relation to efficacy and infectious adverse events. Rheumatology (Oxford). 2014;53(5):914-8.
5. Lazarou I, Finckh A, Fischer L, et al. Low pre-treatment B-cell counts are not a risk factor of infection in patients treated with rituximab for autoimmune diseases: an observational study. Joint Bone Spine. 2016;83(2):191-197. doi:10.1016/j.jbspin.2015.05.012
6. Gottenberg J-E, Ravaud P, Bardin T, et al. Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum. 2010;62(9):2625-2632.
7. Biologika. RABBIT Risk Score of Infections. Accessed on October 20, 2020. https://biologika-register.de/en/rabbit/rabbit-risk-score-of-infections/
8. Furer V, Rondaan C, Heijstek MW, et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2020;79(1):39-52.
9. Katsuyama T, Saito K, Kubo S, Nawata M, Tanaka Y. Prophylaxis for Pneumocystis pneumonia in patients with rheumatoid arthritis treated with biologics, based on risk factors found in a retrospective study. Arthritis Res Ther. 2014;16(1):R43.
10. Rolon Campuzano R, Coronel Ale AL, Cerda OL, et al. Smoking signicantly reduces effectiveness and long-term survival of biologic treatment in patients with rheumatoid arthritis [abstract]. Arthritis Rheumatol. 2017;69(10).