Discuss hot spots and trends, what are the research results of primary Sjogren’s syndrome in 2021?

Only for medical professionals to read for reference diagnosis, treatment and disease evaluation.
Sjogren’s syndrome (SS) is no longer an unfamiliar disease in the hotspot of pSS research in 2021.
It is a disease with dry symptoms, autoantibodies and exocrine glands.
Lymphocyte infiltration is a characteristic autoimmune disease
.

In recent years, many medical researchers have explored the field of diagnosis and treatment of primary SS (pSS).
The accumulation of research results has allowed us to have more and more in-depth knowledge and understanding of the disease
.

Baiju passed the gap and inadvertently passed halfway in 2021
.

In the past six months, what research results have been published in which areas, and what progress has been brought about in diagnosis and treatment? Today, let’s sort it out! Diagnosis frontier dynamics: redefine disease staging and pay attention to early diagnosis.
With the deepening of disease research and understanding, the diagnosis and classification criteria of pSS are constantly being adjusted and revised
.

The internationally recognized and recommended diagnostic and classification standards include the 2002 European and American Expert Consensus Group (AECG) classification standards and the 2016 American College of Rheumatology/European Alliance Against Rheumatism (ACR/EULAR) jointly developed classification standards [1 ]
.

The AECG standard is comprehensive, involving oral symptoms, ocular symptoms, ocular characteristics, pathological examinations of glands, and autoantibody detection, etc.
It is highly instructive [2]; while the ACR/EULAR classification standard has more With high specificity and sensitivity, it uses SS disease activity (ESSDAI) as the selection criteria, so that patients with unobvious dry symptoms and mainly systemic symptoms can be classified [3]
.

Currently, there is no gold standard for diagnosis, and more complete evaluation methods are still to be explored
.

In this year's EULAR annual meeting, an observational study conducted a pooled analysis of the onset time (ie the appearance of symptoms) to the time of diagnosis (in line with AECG or ACR/EULAR classification criteria) for patients with dry symptoms (Mexico) [4]
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The results showed that the median time from symptom onset to diagnosis was 36 months [interquartile range (IQR) 12-84], which lasted longer and may lead to more serious clinical, serological and histopathological features ( Figure 1), which suggests the importance and necessity of early diagnosis of pSS
.

Figure 1: The correlation between the duration of dryness symptoms and the clinical, serological and histopathological manifestations of patients.
To better realize the early diagnosis of pSS, we should carry out more detailed disease staging for pSS
.

Clinical and experimental research results show that the development process of pSS can be divided into 4 stages, including the initial stage, preclinical stage, asymptomatic stage and dominant stage (Figure 2) [5]
.

Figure 2: Redefined pSS disease staging.
However, due to the complexity and heterogeneity of the disease, the above staging cannot be generalized to all SS patients
.

We still need to find better methods can be effective early diagnosis of the disease, such as new biomarkers, diagnostic tools and other updates
.

Treatment frontiers at a glance: What is the prospect of targeted therapy? Traditional therapeutic drugs rushed out of the "dark horse"! At present, there are no effective drugs approved for pSS indications.
At this stage, most of the drugs used in clinical practice are empirical treatments or treatments based on similar lesions, and there are no satisfactory treatment measures [6]
.

With the progress of the research on the pathological mechanism of the disease, the potential treatments of pSS are constantly enriched, especially in the field of biological targeted drugs, and related exploration is in full swing
.

The key role of B cells in the pathogenesis of pSS and the efficacy of related targeted drugs have been research hotspots in recent years
.

A report in the 2021 EULAR annual meeting[7] pointed out that the distribution of B cell subsets in the peripheral blood of SS patients is disordered, and the percentage and absolute number of plasmablasts, plasma cells and transitional B cells are significantly higher than those of healthy donors (P< 0.
01), and the level of plasmablasts is positively correlated with the occurrence of ESSDAI and lymphoma
.

This further emphasizes the importance of B cells in the pathogenesis of pSS based on previous studies
.

Research on the efficacy of targeted B-cell biological therapy has made some progress in the first half of this year: A study on rituximab (RTX) in the treatment of pSS (TRACTISS) announced its 48-week results at the EULAR annual meeting[8]
.

The study did not meet the primary endpoint (the primary endpoint was a 30% reduction in fatigue or dry mouth measured with a visual analog scale), but after RTX treatment, the inflammatory infiltration of the labial glands and non-irritating saliva flow in pSS patients improved
.

Iliumab (VAY736) is a monoclonal antibody that targets B cell activating factor (BAFF), which can cause B cell depletion
.

A 2b study aimed at evaluating the clinical efficacy and safety of VAY736 and placebo (PBO) in the treatment of pSS was announced at this year’s EULAR conference and its latest 52-week results [9]
.

The results show that continuous administration of VAY736 300 mg can provide patients with sustained clinical benefit
.

In addition to studying the efficacy of targeted drugs in the treatment of pSS, many researchers also focus on traditional treatment drugs
.

Will there be "dark horses" in traditional medicines? Iramod (IGU) is a disease-improving anti-rheumatic drug (DMARD) independently developed by China
.

In view of its mechanism of action on B cell function, such as inhibiting the terminal differentiation of B cells [10-12], IGU is considered to have the potential to treat pSS and may be a very promising drug
.

In 2020, IGU was included in the latest version of the "Primary Sjogren’s Syndrome Guidelines for Diagnosis and Treatment" as a recommended immunomodulator for pSS system treatment [6], and was approved by the National Medical Products Administration (NMPA) for the treatment of pSS Clinical trials of new drugs
.

Recently, the first case of IGU treatment of active pSS clinical trial (registration number: CTR20202385) has been successfully enrolled
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In addition, in the first half of this year, the results of studies exploring the efficacy of IGU in the treatment of pSS have shown that IGU has good efficacy and safety in pSS treatment, and has broad development potential: a meta-analysis exploring IGU treatment of pSS included a total of 19 eligible items.
Standard randomized controlled studies (RCTs), a total of 1384 subjects [13]
.

The results showed that compared with hydroxychloroquine (HCQ) + glucocorticoid (GC), IGU + HCQ + GC combined treatment significantly improved the clinical symptoms of pSS patients, including inflammatory indicators [ESR (ESR), immunoglobulin G ( IgG), rheumatoid factor (RF) levels], platelet count (PLT), salivary gland and lacrimal gland secretion function, and disease activity scores (ESSPRI and ESSDAI) (Figure 3), the treatment efficiency is also higher (P<0.
01)
.

Safety analysis shows that IGU combination therapy does not increase the risk of adverse events (AEs)
.

Figure 3: Comparison of some efficacy indicators between the IGU+HCQ+GC group and the HCQ+GC group.
The results of a study exploring the effectiveness and safety of IGU monotherapy for early pSS showed that during the IGU treatment period (24 weeks), the early concomitant In 27 pSS patients with hyperglobulinemia (disease duration ≤ 5 years), ESSDAI scores, IgG and RF levels were significantly reduced, especially in joints, biology and hematology (Figure 4) [14]
.

Figure 4: During the period of pSS patients receiving IGU treatment, the changes of related efficacy indicators over time.
The optimization of the disease/effect evaluation tools During the diagnosis and treatment of pSS, the evaluation of the disease is very important
.

The 2020 Guidelines for Diagnosis and Treatment of Primary Sjogren’s Syndrome clearly states that after diagnosis, patients should undergo a comprehensive evaluation, including the evaluation of common dryness, fatigue, and pain symptoms, as well as the evaluation of the involvement of various system organs [6]
.

ESSDAI is currently the most widely used disease activity assessment system in the world
.

A study in 2021 EULAR explored the distribution of real-world ESSDAI scores and its relationship with patient prognosis [15]
.

The results show that higher ESSDAI scores are associated with worse outcomes for patients in the real world, suggesting that in addition to symptomatic treatment, systemic disease assessment and treatment are important for improving the prognosis of patients with pSS
.

However, in previous RCT studies, with ESSDAI as the primary endpoint, the treatment response rate of the active treatment group and the placebo group is often difficult to show a large difference.
Considering the heterogeneity of pSS, it is necessary to include a number of clinically relevant parameters.
The composite end point is used to distinguish the efficacy
.

Some researchers have explored a new type of research compound endpoint CRESS, which includes 5 evaluation areas, and its response is defined as ≥3 items in the above 5 areas that meet the response criteria (Table 1) [16]
.

Table 1: The areas covered by CRESS and the definition of response OSS: Eye stain scoring method; UWS: Unstimulated whole saliva flow; SGUS: Salivary gland ultrasound compared with the smallest clinically important improvement (ESSDAI MCII) defined by ESSDAI, CRESS has a lower response rate in the placebo group, in RCTs with previous negative primary endpoints [TRACTISS study [17], multicenter abatacept study [18], and ETAP study (tocilizumab related) [19] If CRESS is used as the study endpoint, abatacept and RTX have a higher response rate for pSS than the placebo group, but there is no significant difference between tocilizumab and placebo
.

Therefore, CRESS has a good degree of discrimination and is a tool for efficacy evaluation in clinical trials of pSS
.

Summary: Since 2021 (as of June 2021), a number of research results related to pSS diagnosis and treatment have been reported and published
.

These research results will further promote the development of the field
.

The pace of exploration will not stop at the present.
There are still many unknowns and difficulties waiting for us to overcome.
We look forward to the emergence of more favorable results and the transformation of clinical applications! Reference materials: [1] Tao Qian, Liang Peisheng.
The evolution of diagnostic criteria for Sjogren’s syndrome[J].
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Classification criteria for Sjogren's syndrome: a revised version of European criteria proposed by the American European Consensus Group[J].
Ann Rheum Dis,2002,61:554-558.
[3]，.
2016 American Rheumatism Chinese Society/European Anti-Rheumatism Alliance Primary Sjogren’s Syndrome Classification Standard[J].
Chinese Journal of Rheumatology,2017,21(3):213-213.
[4]Gamboa-Alonso CM, Vega-Morale D, Riegatorres JC,et al.
CRITERIA FULLFILLMENT OF PRIMARY SJÖGREN's SYNDROME ACCORDING TO TIME OF EVOLUTION OF SICCA SYMPTOMS[J].
EULAR Abstract, 2021,80:1177.
Abstract number:AB0301.
[5]Wang B,Chen S,Zheng Q,et al.
Early diagnosis and treatment for Sjögren's syndrome:current challenges,redefined disease stages and future prospects[J].
J Autoimmun, 2021,117:102590.
[6]Sjögren's Syndrome Group, Chinese Medical Doctor Association Rheumatology and Immunology Physician Branch.
The original Standards for diagnosis and treatment of primary Sjogren’s syndrome[J].
Chinese Journal of Internal Medicine,2020,