|Ahead of print publication
Infections associated with systemic lupus erythematosus: Tackling two devils in the deep blue sea
Katsunori Suzuki1, Yoshiya Tanaka2
1 Division of Infection Control and Prevention, Hospital, University of Occupational and Environmental Health, Kitakyushu, Japan
2 The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
|Date of Submission||11-Apr-2022|
|Date of Acceptance||25-May-2022|
|Date of Web Publication||26-Jul-2022|
1-1 Iseigaoka, Yahata-nishi, Kitakyushu 807-8555
Source of Support: None, Conflict of Interest: None
Systemic lupus erythematosus (SLE) is a quintessential systemic autoimmune disease with multiorgan involvement. Although its pathology has been elucidated and therapeutic advances are being made, infections remain the leading cause of death in SLE. In addition to immune abnormalities caused by SLE itself, the use of nonspecific glucocorticoids and immunosuppressants during treatment induces a state of immune suppression, increasing the risk of infection. Bacterial infections are the most common, but impaired cell-mediated immunity may also lead to the development of opportunistic infections, as well as viral and fungal infections. When treating SLE, caution is required for the development of infectious complications, such as latent tuberculosis, de novo hepatitis B, Pneumocystis jiroveci pneumonia (PJP), herpes zoster, and cytomegalovirus infection. Vaccination is recommended for vaccine-preventable diseases for appropriate management of infections. For other infectious diseases, such as tuberculosis, PJP, and disseminated herpes zoster, adequate treatment is necessary.
Keywords: Glucocorticoid, immunosuppressant, infection, management, opportunistic infection, systemic lupus erythematosus
| Introduction|| |
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease. Most patients diagnosed with SLE are in their 20s and 30s, with a male-to-female ratio of 1:9–10. The disease affects multiple organs, including the skin, joints, kidneys, serosa, lungs, central nervous system, and hematopoietic system. The 10-year survival rate is reported 70%–90%, which is not high, considering the age of onset, and infections are the leading cause of death in SLE., Molecular-targeted therapies for SLE are being developed, and nonspecific glucocorticoids (GC) and immunosuppressants are the mainstay for SLE treatment. However, in addition to the immune abnormalities caused by the disease itself, these drugs can trigger serious adverse events, including infections attributable to decreased immune function. Approximately 50% of SLE patients are hospitalized for infection during the course of the disease. This article focuses on infectious diseases associated with SLE. We first discuss the pathology, therapeutic agents, and immunosuppressive mechanisms in SLE and then describe the infectious diseases to watch for and their treatment, prevention, and management.
| Pathology and Diagnosis of Systemic Lupus Erythematosus|| |
SLE is a multifactorial disease involving genetic and environmental factors, immune and endocrine systems, epigenetic regulation, etc.,,,, Disease susceptibility genes identified by genome-wide association studies are related to intracellular signaling, apoptosis, and transcriptional regulation in the innate and adaptive immune systems. In addition to stimulation of the innate immune system, such as type I interferon (IFN) and soluble B-cell activating factor (BAFF) produced by dendritic cells, genetic predisposition, environmental, and other factors induce a breakdown of immunologic self-tolerance, leading to phenomena such as abnormal activation of T cells and differentiation of B cells into autoantibody-producing cells. Autoantibodies bind to antigens to form immune complexes, deposited in the tissue, and activate the complement system. This induces a type III hypersensitive reaction, causing tissue damage and impairment in the kidneys, joints, and other organs, presenting various clinical symptoms.
Since the prognosis of SLE is strongly influenced by initial treatment, a fast and accurate diagnosis is essential. The diagnosis is made according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for SLE. For each patient with antinuclear antibody ≥1:80, EULAR/ACR scores for clinical and immunological items are calculated, and if the total score is ≥10 points, a diagnosis of SLE can be established. If renal biopsy reveals Class III or IV lupus nephritis according to the International Society of Nephrology and the Renal Pathology Society 2003 classification of lupus nephritis, this alone counts as 10 points, and SLE can be diagnosed.
Treatment of Systemic Lupus Erythematosus and Challenges
The therapeutic goal for SLE is to achieve remission without systemic symptoms and organ damage. The focus is directed at avoiding relapse, minimizing complications and adverse drug reactions to prevent organ impairment, optimizing patients' quality of life, and aiming for long-term survival. The necessity for treatment and initial doses of GC and immunosuppressants are determined based on a comprehensive evaluation of disease activity, major organ damage, disease classification, complications, and other relevant information.
If a patient with high disease activity has a severe organ involvement, such as lupus nephritis or neuropsychiatric lupus, prompt initiation of combination therapy with antimalaria, high-dose GC and immunosuppressants is recommended [Figure 1].,,, Hydroxychloroquine, an antimalaria, is recommended as a cornerstone treatment for all SLE patients without contraindications. For immunosuppressive therapy, cyclophosphamide (CYC) pulse therapy and mycophenolate mofetil (MMF) are recommended. If no improvement is achieved by the initial treatment for 6 months, the immunosuppressant is switched, or belimumab (an anti-soluble BAFF antibody) or anifrolumab (a monoclonal antibody against the type I IFN receptor) is used. After remission induction, maintenance therapy is continued with minimum necessary doses of GC, combined with MMF or azathioprine for 3 years. Subsequently, the discontinuation of GC is considered.
|Figure 1: A postulated algorism of treatment of SLE. If a patient with high disease activity has a severe organ involvement, such as lupus nephritis or neuropsychiatric lupus, prompt initiation of combination therapy with antimalaria, high-dose GC and immunosuppressants is recommended. SLE: Systemic lupus erythematosus, GC: glucocorticoids|
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However, in SLE patients, immune abnormalities are also caused by the disease itself. The skin's barrier function may be disrupted, manifesting as cutaneous lesions, such as butterfly erythema and skin ulcers. This is due to the diminished function of polymorphonuclear leukocytes to produce interleukin-12, which connects the innate and adaptive immune systems, and is essential for defense against pathogens [Figure 2]. Moreover, impaired adaptive immunity can cause hypogammaglobulinemia in SLE patients, possibly increasing infection risk. Furthermore, GC and immunosuppressants markedly promote immunosuppression. These drugs are thought to suppress the functions of both the innate and adaptive immune systems, further elevating the risk of infection.
|Figure 2: Mechanisms on increased risk of infection by treatment of SLE. In SLE patients, immune abnormalities are caused by the disease itself as well as GC/immunosuppressants. This is due to the diminished function of polymorphonuclear leukocytes to produce IL-12, which connects the innate and adaptive immune systems, and is essential for defense against pathogens. SLE: Systemic lupus erythematosus, GC: glucocorticoids, IL: 12 Interleukin-12|
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| Systemic Lupus Erythematosus and Infections|| |
Infections are a series of syndromes caused by the abnormal proliferation of pathogens that have entered the body due to the disruption of biological barriers. Most infections in SLE patients are bacterial. The most common infections, regardless of the use of immunosuppressants, are the same as those found in the general population. These include respiratory infections caused by Streptococcus pneumoniae, urinary tract infections due to Escherichia coli, and skin and soft tissue infections due to Staphylococcus aureus.,
In addition to common bacterial infections, viral and fungal infections may occur concomitantly because of impaired cell-mediated immunity. We reported the incidence of common infections, such as hepatitis B virus (HBV), hepatitis C virus (HCV), tuberculosis, and Pneumocystis jiroveci pneumonia (PJP) in Asia-Pacific region. The prevalence of chronic HBV carriers among SLE patients in Japan, Israel, Taiwan, and mainland China were 0.8%, 0.9%, 3.5%–4.2%, and 2.3%–3.1%, respectively. HCV infection rates among SLE patients were reported as 1.1%–16.5%, significantly higher than those in the general population.
Herpes zoster occurs more frequently after the age of 50 years, but it is the most common viral pathogen in SLE patients. Compared to age-matched controls, the incidence of herpes zoster is higher in SLE patients, particularly those on CYC or azathioprine, or at least 60 mg/day of prednisone, who have an elevated risk for bacterial infection and superinfection. As for cytomegalovirus infection, those who were seropositive for cytomegalovirus accounted for >90% of the SLE patients and 60%–70% of the general population.
Tuberculosis occurs in 10.0%–11.4% of SLE patients in Asia. The annual incidence of tuberculosis among SLE patients in Asian countries ranges from 150 per 100,000 persons in Turkey to 2450 per 100,000 persons in India. In Asia, the incidence rate of PJP has been reported as 0.2%–1.9% among different cohorts, which is higher than that in the US. Because the signs and symptoms such as fever and fatigue are often very similar between a flare of SLE from acute onset of infectious diseases, there are not any established guideline and recommendation to differentiate these conditions. Careful differential diagnosis is strongly recommended when a flare of SLE is distinguished from acute onset of infections.
| Therapeutic Agents Used for Systemic Lupus Erythematosus|| |
Owing to its potent anti-inflammatory effects, GC plays a central role in the treatment of SLE. However, even at low doses, GC negatively regulates the innate immune system and increases the susceptibility to infection. At high doses, they suppress innate and adaptive immune systems, causing the development of opportunistic infections. Stuck et al. analyzed data from 4198 patients in 71 controlled clinical trials in 1989 and found that the overall incidence of infectious complications was 12.7% in 2111 patients in the GC group and 8% in 2087 patients in the control group, showing a high relative risk of 1.6. The relative risk was particularly high in patients with neurological disorders (2.8). The percentage did not increase in patients receiving prednisone at a daily dose of <10 mg or a cumulative dose of <700 mg. Long-term immunosuppression through lymphocytes begins approximately 21 days after the initiation of continuous GC use. In addition to the treatment duration, there is also a clear dose-response relationship. A nested case-control study within the prospective Lupus-Cruces cohort found that the risk of serious infections increases by 12% for each mg/day of prednisone. In other studies, infections with common bacteria, such as S. pneumoniae and S. aureus, were reported as the most frequent in SLE patients. The use of GC has also been linked to an increased risk of other infections, including tubercle bacillus, nontuberculous mycobacteriosis, pneumocystis, and varicella-zoster virus. Thus, higher daily doses of GC are associated with a higher risk of both common and opportunistic infections.
Hydroxychloroquine is the most commonly used therapeutic drug for SLE and is used as a first-line treatment for SLE without major organ damage and is positioned as a standard basic drug. Hydroxychloroquine was originally developed as an anti-malarial drug. It accumulates in the lysosomes of immunocompetent and other cells and inactivates acidic proteases or suppresses antigen processing to exert anti-inflammatory and immunomodulatory effects. It has multiple actions related to anti-inflammatory effects, including interference with MHC class II expression and antigen presentation, accumulation in lysosomes, and decreased production of inflammatory cytokines., Hydroxychloroquine does not increase the risk of infection, but reduces the doses of GC and immunosuppressants, thereby indirectly reducing the risk of infection.
MMF displays anti-inflammatory action by depleting guanosine nucleotides in T and B lymphocytes to inhibit their proliferation and antibody formation, and by suppressing the expression of adhesion molecules to inhibit the recruitment of lymphocytes and monocytes to sites of inflammation. The drug is used as part of induction or maintenance therapy in patients with lupus nephritis or those undergoing organ transplantation. A 2015 study analyzed 244 patients who started MMF therapy and found a significantly increased risk of bacterial (not viral) infection over a median follow-up period of 47 days. A previous study compared infectious complications in SLE patients induced by MMF with those induced by CYC and azathioprine over a period of 6–12 months. No difference was found in the rates of serious infections among these three immunosuppressants. In a randomized controlled trial of MMF versus azathioprine in patients with lupus nephritis conducted over a longer period, all patients received CYC plus GC 0.5 mg/kg/day before being assigned to azathioprine or MMF. After an average of 48 months, a slight increase was observed in the number of patients with infection, but this was not significant. Similar results were obtained in a study in which patients with lupus nephritis randomized to azathioprine or MMF after the initiation of CYC or MMF therapy were followed-up for 36 months. A small association was found between MMF and invasive fungal infections such as Aspergillus, Mucor, Cryptococcus, Histoplasma capsulatum, and Coccidioides immitis.
CYC binds nucleic acids to proteins, inhibiting nucleic acid metabolism, thereby regulating the lymphocyte cell cycle. CYC has been approved for the treatment of refractory rheumatic diseases, such as SLE, and is administered to patients with neuropsychiatric SLE and severe lupus nephritis. The drug is often administered by pulse therapy, which is a method of intermittent high-dose intravenous infusion.,, Significant adverse reactions to CYC therapy include susceptibility to opportunistic infections, hypogonadism, and hepatic disorders. Pryor et al. analyzed 100 SLE patients treated with CYC and presented data on 45 SLE patients treated with high-dose GC monotherapy. A difference was observed in the rate of infectious complications between high-dose GC monotherapy (12%) and high-dose GC combined with CYC (45%). However, the two groups could not be compared because of differences in patient characteristics, such as the rates of concomitant renal lesions and multiple organ lesions.
Thus, the cumulative CYC dose may play a role in the development of infectious complications. In another retrospective study conducted in 90 patients, 50% of the patients received low-dose CYC (cumulative dose ≤ 2.5 g) and had significantly fewer infectious complications than those who underwent comparative treatment (cumulative dose > 2.5 g). These studies were limited by the high possibility of selection bias; therefore, these results should be cautiously interpreted. The risk of infection appears to be the highest in patients with leukopenia treated with combined CYC and GC. Along with high-dose GC, the use of CYC has been linked to serious and atypical cytomegalovirus and respiratory infections caused by P. jiroveci.
Although cyclosporine A and tacrolimus (TAC) differ in their molecular structure and intracellular binding characteristics, they exert their immunosuppressive action mainly by controlling cytokine transcription via inhibition of calcineurin activation in T cells. There are data showing no significant difference in the incidence of infection when compared to MMF. The incidence of herpes zoster was lower in patients treated with TAC (TAC: 3% vs. MMF: 18%). However, these drugs have also been linked to a high incidence of cytomegalovirus and herpes zoster.
BAFF is a main costimulator of B cells expressed on the cell surfaces, such as dendritic cells and macrophages, or produced as soluble BAFF. It binds to the receptors BAFF-R, TACI, and BCMA on B-cells to support autoreactive B cells by suppressing apoptosis, enhancing class switching, and inducing their differentiation into antibody-producing cells. In SLE patients, serum soluble BAFF levels are reported to increase in correlation with disease activity and serum dsDNA antibody levels, and are strongly involved in SLE pathogenesis. In a large multicenter clinical trial, the incidence of serious infections was comparable between the belimumab (6%) and placebo (4%) groups, and the incidence of all infections was 74% and 69% in the belimumab and placebo groups, respectively, showing no significant difference. No increase in adverse events has been reported, including infections.,
In SLE, the expression of IFN-related genes is characteristically high and plays a central role in SLE pathogenesis. In the phase III TULIP-2 trial conducted in patients with moderate to severe SLE using anifrolumab, an antibody against the type I IFN receptor, the treatment group had a significantly higher percentage of patients achieving a BICLA response at week 52 than the placebo group. The drug showed a high efficacy in patients with high IFN-related gene expression, suggesting its potential in precision medicine. According to the integrated analysis of phase II and III studies on the safety profile, there were no significant differences between the anifrolumab and placebo groups in terms of adverse events, serious adverse events, adverse events leading to discontinuation, and serious infections. However, the anifrolumab group had an increased incidence of herpes zoster (6.1%) and respiratory infection with a low rate of SLE exacerbation.
B-cells play a key role in the pathogenesis of SLE and other autoimmune diseases. In Europe and the US, rituximab, a chimeric antibody targeting the CD20 molecule on the surface of B-cells, has been approved for use in rheumatoid arthritis and clinically applied in SLE treatment. However, phase II/III studies of rituximab in SLE failed to show any significant difference in efficacy between the rituximab and placebo groups. Furthermore, the death of two SLE patients using rituximab because of PML led to the suspension of the LUNAR phase III study in lupus nephritis. PML is a rare, often fatal disease caused by reactivation of the JC virus, and there are data showing that PML occurs more frequently in SLE patients than in those with other rheumatic diseases. Rheumatoid arthritis studies showed that patients receiving two doses of 1000 mg rituximab (2 weeks apart) had higher rates of serious infections than those receiving two doses of 500 mg rituximab. However, a meta-analysis showed that the risk of serious infections did not increase in the rituximab group compared to the placebo group. Data from a rheumatoid arthritis registry suggested that using GC and rituximab may increase the risk of infection in patients with an IgG level of <600 mg/dL at baseline. The most common infections are bacterial pneumonia, herpes zoster, and urinary tract infections.
| Infections to Watch for in the Management of Systemic Lupus Erythematosus|| |
Screening for latent tuberculosis is necessary prior to immunosuppressive therapy. Since the diagnosis of latent tuberculosis infection (LTBI) is not affected by the Bacillus Calmette–Guérin vaccination program, it is usually based on the results of IFN-gamma release assay or a combination of imaging findings, such as computed tomography scan of the chest. IFN-gamma release assay and chest CT are recommended when patients with SLE are treated with high dose of GC, immunosuppressants and/or biologicals, but careful screening by performing chest X-rays and tuberculin reactions should be more realistic in most of Asian countries. If LTBI is diagnosed, the initiation of monotherapy with isoniazid (INH; an anti-tuberculosis agent) is considered to prevent disease onset and progression [Figure 3].
|Figure 3: Screening for latent tuberculosis in SLE. Screening for latent tuberculosis is necessary prior to immunosuppressive therapy. The diagnosis of LTBI is based on the results of interferon-gamma release assay or a combination of imaging findings, such as computed tomography scan of the chest. SLE: Systemic lupus erythematosus, LTBI: Latent tuberculosis infection|
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INH has also been shown to decrease the onset of LTBI in patients with rheumatic diseases and connective tissue diseases., There have been no reports of increased adverse events caused by INH administration in these diseases. However, the initiation of oral INH therapy requires watching for hepatic dysfunction. In real-world settings, there may be cases of inconclusive IFN-gamma release assays. When this happens, the initiation of oral INH therapy needs to be determined based on imaging findings of the chest and the patient's clinical picture.
De novo hepatitis B
Before initiating immunosuppressant therapy for SLE, it is necessary to check whether the patient has been infected with HBV. Immunosuppressive therapy may lead to HBV reactivation in patients with a history of HBV infection. This is called de novo hepatitis B, in which severe hepatitis is triggered by HBV reactivation in the liver of chronic HBV patients. To check for past HBV infection, a negative result of the HBs antigen test alone is not sufficient, and measurements of HBs and HBc antibodies are also needed. For patients testing positive for either of these antibodies, the level of HBV DNA in the blood must be measured. If DNA is detected, nucleic acid analogue therapy should be initiated after consultation with a hepatologist. Even if the HBV DNA level in the blood is below the detection limit, careful follow-up should be conducted by measuring the level every 1–3 months.
Pneumocystis jiroveci pneumonia
PJP is a serious and potentially life-threatening condition. In 24,367 SLE patients identified from the database of the National Health Insurance Research conducted in Taiwan between 1997 and 2012, the risk of PJP in SLE patients was investigated and compared to the incidence rate of PJP in 243,670 age-and sex-matched individuals without SLE. The results revealed that the risk of PJP infection was substantially higher in SLE patients. Sulfamethoxazole/trimethoprim is highly effective for PJP prevention, and studies have shown that the combination drug is capable of bringing near-complete suppression of PJP onset when administered as prophylaxis., In our department, prophylactic administration of sulfamethoxazole/trimethoprim is recommended for patients who meet two of the following criteria: GC use, age ≥65 years, and concomitant lung disease.
However, adverse events, such as cytopenia and electrolyte abnormalities, are not uncommon in real-world settings, and continuous use of the drug is difficult in some patients. Depending on the adverse event, the use of sulfamethoxazole/trimethoprim may be considered because some cases may respond to desensitization therapy, which involves gradually increasing doses. Alternative treatments include pentamidine inhalation and oral administration of atovaquone. Because of possible adverse events, prophylactic use of the drug cannot be universally recommended to all patients, and factors such as the presence or absence of concomitant lung lesions and the degree of immunosuppression must be considered for patient selection.
SLE patients are more likely to develop herpes zoster, for which GC use is a risk factor. The use of CYC and MMF is also associated with an increased risk of herpes zoster. In hematopoietic stem cell transplantation, the efficacy of prophylactic administration of the antiviral drug acyclovir has been demonstrated. However, since the onset of herpes zoster in SLE patients varies among reports, the appropriate duration of acyclovir use remains unclear. Therefore, it is not viable to use the drug as a prophylaxis against herpes zoster in SLE. As for vaccination, recombinant vaccines have emerged to be highly effective.,
According to a report on an investigation of underlying diseases for cytomegalovirus infection in Japan, SLE was the most common among connective tissue diseases and rheumatic diseases. For the diagnosis of cytomegalovirus infection, antigenemia has become available as a test to detect viral antigens in leukocytes by immunostaining, and we have experienced cases where early diagnosis was possible in real-world settings.
| Infection Control|| |
In SLE patients, various immune functions are impaired by the disease itself and the immunosuppressants used, increasing the risk of infection. Therefore, patients on immunosuppressive therapy are especially encouraged to receive vaccination against vaccine-preventable diseases. Live vaccines are contraindicated in patients undergoing immunosuppressive therapy. The inactivated vaccines that may be administered are influenza and pneumococcal vaccines. Influenza vaccination in patients with connective tissue diseases and rheumatic diseases, including SLE, is strongly recommended. Regarding the exacerbation of connective tissue diseases by influenza vaccination, many studies have reported no worsening of disease activity, but some reports suggest decreased antibody production caused by influenza vaccination in SLE patients. Considering the overall benefits and safety, influenza vaccination is recommended as long as the patients have no history of vaccine hypersensitivity.
Regarding pneumococcal vaccination in SLE patients, some researchers say that the vaccine effects remain unchanged, while others say they are diminished. There has been no report on its influence on the primary disease. Similar to influenza vaccines, pneumococcal vaccination is recommended. As for general precautions against infection, preventing transmission via physical contact and respiratory droplets is usually sufficient even for the most difficult-to-treat, drug-resistant bacteria, such as carbapenem-resistant Enterobacteriaceae and extended-spectrum β-lactamase-producing Enterobacteriaceae. Since tuberculosis, PJP, and disseminated herpes zoster can be transmitted via the air, appropriate measures such as single-room isolation and use of N95 face masks are necessary [Figure 4].
|Figure 4: Importance of combating airborne infection. When we take airborne infection precautions, we should wear N95 masks as well as eye protection to prevent infectious aerosol transmission through the nasolacrimal duct. The picture is the author by himself|
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There are data showing human-to-human transmission of PJP. Because most infants had been exposed to P. jiroveci, it was inferred that P. jiroveci is ubiquitous and may be found in environmental sources, such as soil. The induced sputum from a healthcare professional who had been in contact with a PJP patient contained P. jiroveci with the same genotype. A 1-month-old infant born to a mother with AIDS-PJP developed PJP, and the genotype of P. jiroveci isolated from them matched. There have been reports of PJP clusters in transplant wards and outpatient settings, with identical genotype of P. jiroveci detected from each patient. P. jiroveci DNA was detected in 79% of the air samples collected at 1 m from infected patients and 33% of the samples collected at 8 m. Examination of the nasal swab or gargle samples collected from medical staff who had contact with PJP patients found P. jiroveci DNA in nine out of 102 staff members. It was also detected in the exhaled breath of two of nine staff members. A detailed investigation of the transmission routes of a PJP outbreak in postkidney transplant patients showed that three of the 10 patients who were sources of infection were asymptomatic carriers. Accordingly, measures against nosocomial infection are necessary for patients with PJP. Particularly, those in the acute phase are likely to spread infectious microorganisms by coughing. Therefore, it is desirable to avoid placing these patients in a room shared with patients at high risk of developing PJP until the final load is reduced by treatment and managed in single rooms if possible. In addition, in a place where immunodeficient patients gather (e.g., outpatient waiting room), it is necessary to ensure that PJP patients wear a surgical mask and follow other precautions to prevent transmission.
| Summary|| |
In the management of SLE, sufficient attention should be paid to the development of infection during the course of treatment. Immune abnormalities may be caused by therapeutic agents in addition to the disease itself. Most infections found in SLE are common bacterial infections. However, the drugs selected for treatment may increase the risk of opportunistic infections. Vaccination against vaccine-preventable infections is important. Before the initiation of immunosuppressive therapy, adequate screening should be implemented for certain infectious diseases, such as LTBI and de novo HBV. Appropriate control measures are needed for the occurrence of opportunistic infections during SLE treatment. Before starting treatment, it is recommended to share infection-related information with patients and determine treatment eligibility, content, and plan through shared decision-making.
The authors thank all the medical staff in all participating institutions for research and clinical works.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]