How to reduce hormones to treat lupus?

*Only for medical professionals to read and refer to scientific research progress, drug trials, guide updates, a large inventory of the progress of lupus diagnosis and treatment in 2020! In line with the original intention of "spreading the strongest rheumatism and creating a new academic fashion", on the occasion of saying goodbye to the old and welcoming the new, the "medical industry" media teamed up with 4 top domestic rheumatism and immunology departments to invite 17+ famous rheumatism experts to cover 8 rheumatism hotspots.
Diseases start "riding the wind and breaking the waves-2020 annual inventory of rheumatism".

What I brought to my colleagues in the Department of Rheumatology and Immunology in front of the screen today is the "Progress in Diagnosis and Treatment of Systemic Lupus Erythematosus (SLE) in 2020" shared by Professor Hao Yanjie, Department of Rheumatology and Immunology, Peking University First Hospital.
What clinicians are most concerned about is the update of the guidelines, and Professor Hao Yanjie has brought extremely rich speech content! Look at the progress of lupus scientific research from the three key words! SLE is a classic autoimmune disease with strong disease heterogeneity and high requirements for individualized diagnosis and treatment.

Professor Hao Yanjie shared and interpreted the research published in 2020 from three aspects: the most cutting-edge biomarker-related research, the standard treatment status of lupus patients in my country, and the hormone reduction that clinicians are most concerned about.

Such patients may be more suitable to use biological agents! In the field of biomarkers, Professor Yanjie Hao selected a study from the United Kingdom.

The study selected two SLE cohorts-CONVAS (non-selective lupus cohort) and BILAG-BR (UK application of biological agents SLE patient registration), using the data of these two cohorts to explore the biomarkers of patients with refractory lupus.

According to the results of antibodies, IFN index, and flow cytometry, the researchers divided SLE patients into 3 categories (Figure 1): Figure 1 The study divided patients with refractory SLE into 3 categories.
Source: Professor Yanjie Hao's speech PPT research final findings , Anti-Sm/U1RNP antibody positive & high IFN Score A (high interferon score) This group of patients has more severe clinical manifestations (severe overall manifestations and severe multi-system involvement) and worse response to traditional drugs (hormones, immunosuppressive agents).
It may be more suitable to use biological agents for first-line treatment.

Looking back over the past 10 years, how is the compliance rate of SLE patients in China? Standard treatment is the focus of domestic and foreign guidelines in recent years.
In this sharing, Professor Hao Yanjie selected a 10-year follow-up cohort study of SLE in the Department of Rheumatology and Immunology of Peking University First Hospital.
The study included 218 newly-treated SLE patients and reviewed recent studies.
In the past 10 years, Chinese patients with SLE have reached the standard in the real world (Figure 2).

 Figure 2 The study was published in a sub-issue of the international journal BMJ/Picture Source BMJ Professor Hao Yanjie gave a detailed interpretation of the research results.
Overall, under the current treatment system, 5.
5% of newly treated SLE patients in my country reached the clinical level in the first year of treatment Remission, 18.
8% of patients with low disease activity, the effect of reaching the target is not satisfactory; but after 5 years of follow-up, the above two data climbed to 76.
6% and 92.
6% respectively, indicating that the treatment effect of SLE patients with long-term standardized treatment is predictable .

In addition, this study also conducted a detailed analysis of each SLE disease remission index, and found that among all the indexes, the serum index and the hormone dose are the two most difficult to achieve (Figure 3), which deserves the attention of clinicians.
.

 Figure 3 The specific compliance status of each standard/picture source Professor Yanjie Hao’s speech PPT The SLE-related diagnosis and treatment guidelines released in recent years emphasize that, when possible, the hormone dosage of SLE patients needs to be reduced to a minimum or even stopped.

However, based on the current research results, Professor Hao Yanjie believes that hormone reduction is the biggest challenge in the treatment of SLE.

How to reduce hormones? How to stop? Hormone reduction is a difficult point in the treatment of SLE.
Many doctors think that it is difficult to achieve the ideal state required by the guidelines in actual clinical scenarios.
Professor Yanjie Hao selected two latest studies to explore the possibility of gradual reduction of hormones. The first study was a single-center, prospective cohort, and retrospective analysis from Italy (Figure 4).
The study included 148 patients, of which 91 (61.
5%) patients had been tested with hormones (prednisone on reduced stop).
The average dose was 5 mg), of which 77 (84.
6%) patients achieved hormone discontinuation, and only 18 (23%) relapsed.

 Figure 4 Study published in RMD Open/Tuyuan Professor Hao Yanjie’s speech PPT Another single-center, prospective study from France enrolled patients with stable disease for at least one year and SLEDAI score <4, and randomized the patients to discontinue the drug In the experiment, the control group was treated with prednisone 5 mg/d.

The results showed that the recurrence rate of patients in the hormone discontinuation group was significantly higher than that of the maintenance treatment group (Figure 5).

 Figure 5 The recurrence rate of patients in the hormone discontinuation group was significantly higher than that of the maintenance treatment group/Tuyuan Professor Yanjie Hao’s presentation PPT.
In summary, Professor Yanjie Hao pointed out: “Disabling glucocorticoids is a possible goal for SLE patients; Or in patients with low disease activity, hormone reduction and stopping can be tried; but stopping hormones may increase the chance of recurrence, and more research is needed to guide the timing and plan of hormone reduction and stopping in SLE patients.

"From the mechanism to the clinical view.
The latest SLE drug clinical trial! Accuracy and targeting have been the focus of rheumatic immunotherapy in recent years, and SLE is no exception.
Professor Hao Yanjie selected 3 SLE drug-related clinical trials and briefly introduced the progress of SLE therapy drugs in 2020.

Targeting BLyS-the imbalance of beliyuumab cytokines plays an important role in the occurrence and development of SLE.
Among them, B cell activating factor (BLyS) can promote the maturation of autoreactive B cells, which is the key to SLE Pathogenic factor.

The biological agent Belyumab can target soluble BLyS to inhibit the maturation of autoreactive B cells, promote more autoreactive B cell apoptosis, and reduce the differentiation of autoreactive B cells into autoantibodies.
Plasma cells (Figure 6). Figure 6: Overview of the effects of Belyumumab/Source: Professor Yanjie Hao’s speech PPT 2020, the authoritative journal NEJM published a clinical study of belyumumab in the treatment of active lupus nephritis (LN)-BLISS-LN study, the study It is a 104-week global, multicenter, randomized, double-blind, placebo-controlled study, and it is also the largest LN study to date.

On the basis of the standard remission induction program, the study randomly divided the included LN patients into a belyumumab treatment group and a placebo group.

The results showed that the combination of belyumumab on the basis of the standard treatment plan, the patient's renal remission rate, remission time, clinical deterioration time and other aspects, the curative effect was significantly better than the standard treatment alone (Figure 7), and the safety was good.

Note: CRR=complete renal remission; PERR=renal curative effect response Figure 7 The proportion of patients in the beliyuumab group who achieved CRR and PERR was significantly higher than that in the placebo group/Tuyuan Professor Yanjie Hao’s speech PPT I interferon receptor antagonism Agent-Anifrolumab In the innate immune system, interferon plays an important role in the disease progression of SLE.

In 2020, a 52-week global, multicenter, randomized, double-blind, placebo-controlled study on the type I interferon receptor antagonist Anifrolumab was also published in NEJM.

The study included patients with moderate to severe active SLE who received standard treatment.
The response rate of the British Isles Comprehensive Lupus Assessment (BICLA) was used as the study endpoint (Figure 8), and the type I interferon receptor antagonist Anifrolumab was explored in moderate to severe cases.
Efficacy in patients with active SLE.

 Figure 8: The main endpoint of the study/Source: Professor Yanjie Hao’s presentation.
The PPT study results showed that at 52 weeks, Anifrolumab in each subgroup was shown to significantly increase the BICLA response rate.
At the same time, demographic characteristics, baseline disease activity, and baseline glucocorticoid use And the baseline serum type I interferon level did not affect the efficacy.

In the third study on the effectiveness and safety of low-dose IL-2 in the treatment of SLE, Professor Hao Yanjie selected a small-dose IL-2 (interleukin-2) for the treatment of SLE.

The study comes from the team of Professor Li Zhanguo from Peking University People's Hospital.
It is a 24-week randomized, double-blind, placebo-controlled clinical trial of drugs that included patients with active SLE who received standard treatment.

The results of the study showed that the IL-2 treatment group was significantly better than the placebo group in terms of the improvement of the SLEDAI score, the SRI-4 response rate, clinical remission, and hormone reduction (Figure 9, the IL-2 treatment group in red).
And there is no increase in the patient's adverse reactions, suggesting that the application of low-dose IL-2 in the treatment of SLE in patients with active SLE under the standard treatment regimen may be effective and well tolerated.

Figure 9 The main indicators of the IL-2 treatment group are superior to placebo/Tuyuan Professor Yanjie Hao’s speech PPT small molecule drugs and biological agents are the new favorites in the field of rheumatism.
In addition to the above drugs, Professor Yanjie Hao also briefly introduced other Research drugs (Figure 10), and expect more new drugs to be launched for SLE patients to choose from.

 Figure 10 Other new SLE drugs under development/Tuyuan Professor Yanjie Hao's speech PPT Traditional immunosuppressive multi-target treatment of LNSLE diagnosis and treatment rookies appear frequently, and traditional immunosuppressants are not far behind.

At the end of the drug clinical progress, Professor Yanjie Hao introduced a new calcineurin inhibitor (CNI)-Voclosporin.

Professor Hao Yanjie pointed out that the drug has obvious advantages, including: small impact on glomerular filtration rate, drug-related hypertension and hyperlipidemia are rare, and the relationship between blood drug concentration and efficacy is stable.

A global, randomized, double-blind, placebo-controlled study explored the clinical efficacy of Voclosporin combined with mycophenolate mofetil (MMF) in the treatment of LN.

The results showed that combined Voclosporin treatment of LN, the patient's remission rate was significantly better than that of standard treatment alone (especially in refractory Hispanic/Latino patients).

Professor Hao Yanjie said that multi-target treatment of LN is a treatment model proposed by Chinese scholars for SLE, especially LN.
Compared with traditional hormone combined with cyclophosphamide treatment, it has obvious curative advantages and deserves the attention of clinicians. The 2020 guide is updated, and integrity has become the strongest keyword! In the final part of the speech, Professor Hao Yanjie introduced the SLE management guidelines issued by the European Union of Rheumatology (EULAR) in 2019, the diagnosis and treatment guidelines for LN jointly issued by EULAR and the European Association of Nephrology (ERA-EDTA) in 2019, and the 2020 China Systematic Guidelines.
Guidelines for the diagnosis and treatment of lupus erythematosus.

The updates of the three major guides all have the same key word-integrity.

2019EULAR Management Guidelines Update This update of EULAR-SLE guidelines includes three modules: general principles, treatment goals, and drug selection.

In the general principle, Professor Yanjie Hao believes that the newly added "treatment goals include long-term survival rate of patients, prevention of organ damage and improvement of health-related quality of life" (Figure 11) are extremely important, reminding clinicians to manage patients in multiple dimensions.
While treating diseases, pay attention to the protection of organs and the improvement of quality of life.
Figure 11 EULAR-SLE guidelines update general principles / Tu Yuan Professor Hao Yanjie's presentation PPT In terms of treatment goals, EULAR-SLE guidelines clearly propose to maintain the lowest possible hormone dose Clinical remission or low disease activity (2b/B), while preventing the recurrence of all organ diseases (2b/B); if recurrence occurs, the current treatment plan can be adjusted to a higher dose, switch or add new treatments based on the severity of the organs involved Drugs (2b/C).

In traditional medicines, the guidelines have also been updated accordingly.
For example, the therapeutic dose of hydroxychloroquine sulfate (HCQ) has been reduced compared with the past, and more attention has been paid to the screening of adverse reactions during drug use (Figure 12).

 Figure 12 Update of traditional treatment drugs For the new favorite in the field of rheumatism-biologics, EULAR-SLE guidelines have also been updated.

It is proposed that patients who do not respond well to standard treatments (due to residual disease activity, hormones cannot be gradually reduced and/or frequent relapses) should be considered for additional treatment with belimumab (1a/A); in addition to standard immunosuppressive agents Patients with refractory or intolerant/contraindicated organ involvement may consider rituximab therapy (2b/C).

The EULAR/ERA-EDTA-LN guideline update is similar to the EULAR-SLE guideline.
The latest EULAR/ERA-EDTA-LN guideline also proposes a "holistic view" of LN treatment—protecting patients' long-term renal function and survival, preventing disease recurrence, and protecting Organ damage, manage complications, and improve disease-related quality of life (HRQOL).

In addition, this EULAR/ERA-EDTA-LN guideline update has clarified the time points and step-by-step goals for controlling urine protein, and proposed more stringent time points for proteinuria compliance (Figure 13) and broader quantitative goals for proteinuria.
——UPCR 500-700mg/g or 24h urine protein 500-700mg at 12 months of treatment.

 Figure 13: The latest proteinuria standard time point Professor Hao Yanjie pointed out that this EULAR/ERA-EDTA-LN guideline update has made it clear that the focus of LN management is not just kidney damage (to avoid blindly pursuing lower urine protein.
Dosage, long-term treatment of hormones and immunosuppressive agents) should be aligned with the management goals of SLE, and reduce the damage of various organs as the overall treatment goal.

It is worth mentioning that in 2020, the update of my country’s SLE guidelines is also synchronized with the international ones.
It puts forward the treatment goal of “delaying the progression of the disease to the greatest extent and reducing organ damage”, and combining the characteristics of the Chinese population, it gives different disease activity levels.
Specific treatment plan (Figure 14).

 Figure 14 2020 China SLE Diagnosis and Treatment Guidelines At the end of the speech, Professor Hao Yanjie said that although many advances have been made in the field of SLE diagnosis and treatment in 2020, there are still many clinical needs that have not been met.

In her view, there are many future research directions for SLE.
Whether it is treatment goals, current status, or the most cutting-edge biomarkers, new drug development and testing, all doctors in the field of rheumatism and immunity are required to explore together.  Figure 15: Introduction to experts in the future research direction of SLEProfessor Yanjie Hao, Chief Physician of the Department of Rheumatology and Immunology, Peking University First Hospital, Peking University Medical Doctor, Peking University Medical Doctor, Young Member of the Rheumatology and Immunology Branch of the Chinese Medical Doctor Association, Pulmonary Vascular and Interstitial Diseases Member of the academic group, member of the Rheumatology and Immunity Branch of the Beijing Medical Association, and member of the Asia Pacific Lupus Collaboration Group (APLC).
He was a visiting scholar at the University of Melbourne, Australia, mainly engaged in research on systemic lupus erythematosus and connective tissue disease-related pulmonary hypertension.
The author has published many SCI articles in Eur Respir J, Arthritis Rheumatol, Arthritis Res Ther, Lupus, Clinical Rheumatology and other journals.
Hosted or participated in a number of scientific research projects.
He is a reviewer of journals such as Lupus, Plos ONE, Peking University Journal (Medical Edition), etc.
He has delivered conference speeches at international conferences such as the World Scleroderma Conference, the Asia-Pacific Annual Rheumatism Conference, and the Australian Annual Rheumatism Conference, and won the Best Scientific Research Award at the 2014 Australian Rheumatism Annual Conference