What to do if serum IgG4 increases? China's first expert consensus on diagnosis and treatment of IgG4-related diseases is here

*Only for medical professionals to read and refer to the first Chinese expert consensus on IgG4-RD, a must-see! IgG4-related disease (IgG4-RD) is an immune-mediated chronic inflammation with fibrosis.
The main histopathological manifestations are lymphatic and plasma cell infiltration with IgG4+ plasma cells, accompanied by striated fibrosis.
, Phlebitis obliterans and eosinophil infiltration.

It can affect multiple organs and systems throughout the body, and the clinical manifestations are complex and diverse.

Due to the short time to understand the disease, the overall level of diagnosis and treatment of IgG4-RD in my country is uneven, and there is no relevant expert consensus or diagnosis and treatment guidelines in China.

Since the first international expert consensus was published in 2015 (the consensus references ended in February 2014), no new expert consensus or guidelines have been released.

Therefore, in order to further standardize and improve the level of diagnosis and treatment of IgG4-RD in my country, and provide clinicians with the latest reference opinions for the diagnosis and treatment of this disease, the China Rare Diseases Alliance and the Chinese Rheumatology Branch jointly organized domestic experts in this field and combined the latest literature.
Relevant evidence has formulated this consensus.

The classification of evidence and the strength of recommendation for treatment in this consensus refer to the classification of evidence and the strength of recommendation established by the Oxford Center for Evidence-Based Medicine in 2001 (Table 1).

Table 1 The classification of evidence and the strength of recommendations developed by the Oxford Center for Evidence-Based Medicine in 2001.
There are 12 recommendations in this consensus, including 1 general recommendation and 11 specific recommendations.

Recommendation 01 is led by the Department of Rheumatology and Immunology, and the diagnosis, evaluation, treatment and follow-up of IgG4-RD can be completed by multidisciplinary joint IgG4-RD is a systemic disease that can involve multiple organs and tissues throughout the body, including salivary glands, pancreas, lacrimal glands, and orbits Peripheral and orbital tissues, lymph nodes, biliary system, kidney, thyroid, nervous system, retroperitoneum, mesenteric, skin, liver, lung, pleura, mediastinum, pericardium, artery, breast, prostate, etc.

Patients may have multiple organ involvement successively or at the same time, and the onset symptoms and clinical manifestations are complicated and diverse due to the different organs involved.

The clinical characteristics of patients with different organs involved are quite different, which leads to patients to go to different specialties.

In view of the fact that IgG4-RD can affect almost all organs in the body, and the clinical manifestations are complex and diverse, it is recommended to be led by the Department of Gastroenterology, Hepatology, Stomatology, Ophthalmology, Nephrology, Respiratory, Cardiology, Hematology, and Endocrinology , Biliary and Pancreatic Surgery, Otorhinolaryngology, Neurology, Pathology, Imaging, Urology and Basic Surgery, etc.
, to complete the diagnosis, evaluation, treatment and follow-up of the disease.

Recommendation 02 It is recommended to diagnose according to the IgG4-RD comprehensive diagnostic criteria formulated by Japan in 2011 and the IgG4-RD classification criteria formulated by 2019ACR/EULAR.
The clinical manifestations of IgG4-RD are multi-organ involvement, complex and diverse.
At present, no single index can be effective for patients.
For accurate diagnosis and classification, clinical history, serology, imaging and histopathological characteristics must be combined.

In addition, the disease needs to be differentiated from the blood system and solid tumors, chronic infections, other rheumatic immune diseases, histiocytosis, etc.
Therefore, it is recommended to apply the IgG4-RD comprehensive diagnostic criteria developed by Japan in 2011 and the American College of Rheumatology (ACR) in 2019.
)/European Anti-Rheumatism Alliance (EULAR) developed the IgG4-RD classification criteria for diagnosis.
When specific organs are affected, the diagnostic criteria for specific organ involvements established by different specialties can also be referred to.

  Note that the IgG4-RD comprehensive diagnostic criteria formulated in Japan in 2011 mainly include three aspects: characteristic clinical manifestations, elevated serum IgG4, and typical pathological features.

However, in addition to clinically characteristic manifestations, this standard emphasizes elevated serum IgG4 levels and pathological characteristics, so its sensitivity and specificity are not very ideal.

The 2019 ACR/EULAR IgG4-RD international classification standard mainly includes the characteristic clinical manifestations of common organ involvement, and emphasizes the exclusion of multiple diseases that mimic IgG4-RD.

In addition, compared with the 2011 diagnostic criteria, its advantage is that patients can be classified as IgG4-RD even when there is a lack of pathological diagnosis or serum IgG4 is not elevated.

The specificity is 99.
2% and 97.
8%, and the sensitivity is 85.
5% and 82.
0%, respectively.

This standard is more suitable for clinical research of IgG4-RD.

Recommendation 03 Elevated serum IgG4 is an important indicator for IgG4-RD diagnosis and disease assessment, but its diagnostic specificity is not high.
Elevated serum IgG4 levels are not specific biological indicators for IgG4-RD, and can be seen in many other diseases, such as Tumors, systemic vasculitis, chronic infections, allergic diseases, etc.
; on the other hand, not all patients with IgG4-RD have elevated serum IgG4 levels, and some patients with IgG4-RD have normal serum IgG4 levels.

Therefore, this indicator can neither be used as a sufficient condition for the diagnosis of IgG4-RD, nor is it a necessary condition.

  Note that almost all patients have been controlled by glucocorticoids (hereinafter referred to as hormones) or other effective treatments, and serum IgG4 levels have dropped significantly.
However, a considerable proportion of patients have IgG4 levels that cannot fall to normal, especially when the baseline value is high.
Of patients are not easy to fall to normal levels.

Elevation of IgG4 during maintenance treatment does not indicate recurrence of the disease, but the risk of recurrence increases in patients who continue to increase, and close monitoring is required.

It is recommended that imaging examinations play an important role in the diagnosis and evaluation of organs involved in IgG4-RD.
Choose the appropriate examination method according to the affected part of the patient.
IgG4-RD can involve multiple organs and systems throughout the body.
Because the course of the disease is relatively insidious and early Part of the affected area has no corresponding symptoms and signs, so imaging is not only used to evaluate the characteristics, scope, and activity of the affected area, but also helps to find some asymptomatic internal organ involvement.

  Note that organ damage caused by IgG4-RD is often manifested as diffuse or focal swelling of the organ on CT, while the T2-weighted image of MRI is manifested as low signal.

18F-Deoxyglucose PET/CT (18F-FDG-PET/CT) showed the characteristic type of organ involvement, which is a good indicator of the diagnosis.
At the same time, the examination can assist in the differential diagnosis of IgG4-RD, especially in the difficulty of biopsy of the affected part.
Large and difficult to perform histopathological examination. In addition, 18F-FDG-PET/CT can help distinguish IgG4-related pancreatitis and pancreatic cancer, and is an effective inspection tool in the evaluation of the distribution of involvement of organs outside the pancreas, selection of biopsy sites, efficacy judgments, and recurrence monitoring.

Ultrasonography is safe and simple.
It is an important screening tool for IgG4-RD, especially the involvement of pancreas, lacrimal glands, salivary glands, lymph nodes and other organs.
However, it requires a high level of operator experience and knowledge.

Recommendation 05: Characteristic pathological changes are an important basis for the diagnosis of IgG4-RD.
Pathological examination is very important for the differential diagnosis and exclusion of simulated diseases.
Therefore, it is recommended that those with conditions should undergo tissue biopsy and histopathological examination is one of the main criteria for the diagnosis of IgG4-RD.
One.

In the pathological diagnosis expert consensus reached at the IgG4-RD International Symposium in 2011, characteristic pathological manifestations include: (1) Characteristic histological manifestations: massive lymphatic and plasma cell infiltration, striated fibrosis, and phlebitis obliterans (2) IgG4+ plasma cell infiltration: the number of IgG4+ plasma cells in the affected tissue increases, and the ratio of IgG4+ plasma cells/IgG+ plasma cells increases.

Other common histopathological features include unobstructed phlebitis and eosinophil infiltration.
In the IgG4-RD classification and diagnostic criteria developed by ACR/EULAR in 2019, the above pathological features and the degree of IgG4+ plasma cell infiltration are carried out according to the weight.
Scoring, with typical pathological characteristics is essential for the diagnosis of IgG4-RD.

The IgG4-RD classification standard established by ACR/EULAR in 2019 also proposed that the following pathological manifestations do not support IgG4-RD: massive tissue cell infiltration, massive neutrophil infiltration, atypical cells, giant cell infiltration, obvious tissue necrosis, epithelioid Granuloma, necrotizing vasculitis, etc.

  Note that in practical clinical applications, pathological examinations have many difficulties, such as deep organ involvement or difficulty in biopsy of certain affected parts, which restrict the acquisition of pathological specimens; tissue specimen collection methods such as fine needle aspiration may also cause technical deviations; Most importantly, the three characteristic manifestations in part of the affected tissues usually do not appear at the same time, and the performance of the three characteristics in different involved organs is also inconsistent.

The recommended value of the number of IgG4+ plasma cells/high power in different affected tissues has not been unified so far, and most recommend IgG4+ plasma cells/high power >30-40.

However, in retroperitoneal fibrosis or some kidney diseases, IgG4+ plasma cells/high power> 10 can be considered positive.

In addition, the ratio of IgG4+ plasma cells/IgG+ plasma cells>40% is also an important basis for diagnosing IgG4-RD.
Sometimes this ratio is more accurate than the count of IgG4+ plasma cells, especially in needle biopsy tissues, severe fibrotic tissues, or Castleman disease.
When waiting for phase identification.

It is recommended that patients diagnosed with IgG4-RD in 06 should be evaluated for disease activity and severity.
Evaluation of the patient's condition is recommended to refer to IgG4-RD RI.

IgG4-RD RI is to evaluate the disease condition of the past 28 days.
According to the different involvement of each organ, it is given 0 to 3 points, and the total is divided into the sum of the scores of each organ.

When the disease of an important organ involved is urgent and requires active treatment, the score of that organ needs to be doubled.

The latest version is revised in 2018.
The main change is to change the score of each organ's involvement from 0~4 to 0~3.

  Note that this standard also has certain shortcomings.
First, the evaluation of the patient’s clinical condition is greatly interfered by the clinician’s subjective factors; the second is that after treatment for patients with visceral involvement, if accurate scoring is required at each follow-up, imaging examinations must be repeated.
Therefore, in clinical practice, the time interval for re-examination of imaging should be determined according to the patient's condition.

It is recommended that patients with IgG4-RD who are symptomatic and active should receive treatment, and patients who are asymptomatic but with important organ involvement and progress should also be treated in time.
The treatment of IgG4-RD is divided into two stages: induction of remission and maintenance treatment.

Treatment indications: All symptomatic patients with active IgG4-RD require treatment, especially the pancreas, biliary tract, kidneys, lungs, central nervous system and other important organs.

Early treatment can prevent irreversible organ damage caused by inflammation and fibrosis.

Asymptomatic patients with important organ involvement, such as active and progressing disease, also need treatment.

For asymptomatic and slow-developing superficial organ involvement, such as IgG4-related lacrimal gland inflammation, submandibular gland inflammation, and lymphadenopathy, the treatment can be temporarily stopped, and the strategy of "watchful and waiting" can be adopted for close observation.

If there are obvious symptoms or the above treatment indications appear, treatment can be initiated.

For asymptomatic internal organ involvement, if the disease is stable and the probability of complications is low, temporary observation and follow-up can be performed, but it must be evaluated again in a short period of time; once laboratory or imaging tests indicate the progress of organ damage, prompt treatment is required.

  Note that when the rapid progress of the disease may cause irreversible organ damage, emergency treatment is required to prevent organ damage as soon as possible and improve the prognosis.

Conditions that require emergency treatment include: aortitis, retroperitoneal fibrosis, proximal bile duct stenosis, tubulointerstitial nephritis, dura meningitis, diffuse pancreatic enlargement, pericarditis, hypophysitis, etc.

Recommendation 08 Glucocorticoids are the first-line drugs for the treatment of IgG4-RD (level of evidence 2a, recommendation level B) So far, hormones are still the cornerstone of the treatment of IgG4-RD, and are also recognized first-line drugs that can be used to induce remission and maintain disease stage.

(1) Remission induction therapy: medium-dose hormone, equivalent to 30-40 mg/d of prednisone, is currently the most commonly recommended starting dosage, but the specific dosage of hormones for different patients should be based on age, weight, affected organs, and condition Severity and comorbidities should be adjusted appropriately, and the starting dose of hormones can be appropriately increased for patients with severe disease at baseline.

After 2~4 weeks of treatment, the initial dose can be reduced regularly after the disease is effectively controlled.
Reduce 5 mg every 1~2 weeks to the maintenance dose.

(2) Maintenance treatment: IgG4-RD recurrence is more common.
Many studies have shown that after induction of remission, low-dose hormone maintenance treatment can reduce the recurrence rate.
Maintenance treatment is recommended for 1 to 3 years.

(3) Hormone therapy for relapsed patients: Most relapsed patients can be relieved by using the initial treatment dose of hormones again, and if necessary, increase the hormone dose, or extend the course of treatment to better control the condition.

A number of studies on IgG4-RD, especially in patients with type I AIP, suggest that the effective rate of relapsed patients receiving hormone therapy is 95%-97.
1%. However, in some patients, if there are obvious hormonal side effects, other hormonal reducing agents, such as immunosuppressants and biological agents, need to be added.

  Note that the rate of hormone reduction should also be adjusted according to the improvement of clinical conditions, changes in serological indicators (such as liver and kidney function, IgG4 levels, etc.
), and imaging results.

In the process of hormone therapy, it is necessary to pay attention to adverse reactions such as infection, elevated blood sugar, and osteoporosis, and try to use the smallest dose as far as possible under the premise of maintaining the stability of the disease.

It is recommended that the combination of 09 immunosuppressive agents and glucocorticoids is more effective than glucocorticoids alone in controlling the disease and reducing the recurrence of IgG4-RD patients (evidence level 2b, recommendation level B).
When the patient has a single hormone therapy that cannot fully control the disease, Or when the hormones cannot be reduced due to the persistent disease, or the disease repeats during the reduction process, and the side effects of hormones are obvious, it is recommended to use hormone reduction drugs in combination, mainly including traditional immunosuppressants and biological agents.

Among the traditional immunosuppressants, mycophenolate mofetil and azathioprine are the most widely used in clinical practice.
These two drugs have been proven effective in patients with IgG4-related pancreatitis, cholangitis, and dural involvement.

  Note that the usage and dosage of immunosuppressive agents are not yet the best recommendations.
You can refer to other rheumatic immune diseases with organ damage.
However, considering that IgG4-RD patients are mainly middle-aged and elderly patients, and most of the disease progresses slowly, in order to reduce related adverse effects In response, the dose of immunosuppressive agents can be appropriately reduced.

Due to the slow onset of traditional immunosuppressive agents, immunosuppressive agents alone are not recommended for the treatment of patients with acutely active IgG4-RD.

In addition, whether immunosuppressants can replace hormones to maintain a stable condition after treatment remission still needs clinical research evidence.

During medication, the patient's blood routine, liver and kidney function, etc.
should be closely monitored, and the medication-induced leukopenia, thrombocytopenia, and liver function damage and other adverse reactions should be vigilant.

Recommendation 10 Biological agents can be used for refractory or relapsed IgG4-RD (evidence level 2b, recommendation level B).
The application of biological targeted therapy in IgG4-RD has gradually attracted attention.

Rituximab is an anti-CD20 monoclonal antibody, which is mainly used to eliminate B cells.
It has achieved good efficacy in both initial treatment and relapsed IgG4-RD. Rituximab can be used for IgG4-RD patients who have failed traditional treatment, relapsed during hormone reduction, and have hormone resistance or intolerance.

There are currently two recommended methods of using rituximab, intravenous infusion of 375 mg/m2 × 4 times a week; or intravenous infusion of 1000 mg/time × 2 times, once every 2 weeks; it can be given before medication Methylprednisolone 100 mg prevents infusion reactions, and the effects of the two methods are similar.

It is recommended that the treatment plan for patients with relapse of IgG4-RD should be re-formulated according to the patient’s relapsed organs and previous medications (evidence level 5, recommendation level D).
IgG4-RD is a disease that is prone to relapse, whether it is after stopping the drug or in small doses.
In the hormone maintenance stage, different foreign studies have reported that the recurrence rate of IgG4-RD patients during the follow-up process is as high as 24%~63%.

There are many risk factors for recurrence, including males, young patients, a history of allergic diseases, severe disease at onset, high eosinophil count at baseline, high serum IgG4 levels, upper bile duct obstruction, and small initial doses of hormones.
Maintenance therapy requires small doses of hormones, no maintenance therapy or delayed treatment, etc.
The history of past recurrence and imaging shows that the disease is heavier, which also indicates that the disease is prone to recurrence.

Therefore, low-dose hormone maintenance therapy is recommended for patients with IgG4-RD, especially those with high IgG4 levels, multiple organ involvement, a history of recurrence, or upper bile duct obstruction.

Whether the pure serum IgG4 level rises again requires active intervention is still inconclusive.

  Note that the treatment plan for relapsed patients depends on the patient's recurring organs, previous medications, whether hormones are stopped, and hormone maintenance doses.
For those who stop and relapse after remission, the previous effective drugs can be repeated, and the treatment can be maintained for a longer period of time; Hormone can also be combined with traditional disease-improving anti-rheumatic drugs (DMARDs) or biological agents (such as rituximab).

For patients who relapse during hormone maintenance therapy, it is recommended to increase the amount of hormones while combining traditional DMARDs or biological agents.

Surgery is recommended for special cases of IgG4-RD as one of the treatment options (evidence level 4, recommendation level C).
When a special part of the IgG4-RD patient is involved, it may cause compression and other emergency situations such as organ dysfunction, such as drug treatment When it cannot be resolved quickly, it is necessary to take rapid and effective surgical operation or interventional treatment to intervene to relieve symptoms as soon as possible, avoid further deterioration of the condition, and create conditions for subsequent drug treatment.

In addition, for long-term, serious, irreversible organ fibrosis, such as periorbital fibrous pseudotumor and sclerosing mesenteritis, surgery can be considered when the effect of hormone treatment is not good.

Some patients can obtain the effect of reducing complications and recurrence through surgical treatment.

In summary, with the gradual understanding of IgG4-RD in various fields, scholars believe that the disease may be an underestimated rare disease.

Although IgG4-RD is a benign inflammatory disease, a small number of patients have a tendency to heal on their own, but most patients show a gradual progress in the course of the disease, which may lead to important organ dysfunction and even life-threatening.

Therefore, the diagnosis, treatment and follow-up of IgG4-RD need to be carried out in a multi-disciplinary joint under the leadership of the Department of Rheumatology and Immunology.

Although hormones are still the first-line treatment drugs for most patients, there are many adverse reactions in long-term use.
Therefore, various alternative or combination therapy drugs with hormones are constantly being explored.

There are still many unknown areas for IgG4-RD.
With the progress of research and the deepening of cognition, the consensus group will update relevant content in time to provide clinicians with updated information with high-level evidence-based medical evidence to improve overall The level of diagnosis and treatment of IgG4-RD in my country.

References: [1] Zhang Wen, Dong Lingli, Zhu Jian, et al.
Chinese expert consensus on diagnosis and treatment of IgG4-related diseases[J].
Chinese Journal of Internal Medicine, 2021, 60(3):192-206.
DOI: 10.
3760/cma.
j .
cn112138-20200803-00726.