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AAV is a systemic necrotizing vasculitis involving multiple organs and systems.
Recently, a summary of clinical practice on the diagnosis and treatment of ANCA-associated vasculitis (AAV) was published in Rheumatology. Let’s take a look at what dry goods are available ~
Figure 1: Screenshot of this overview.
Performance of AAV
AAV is a group of systemic vasculitis characterized by the detection of ANCA in serum, which mainly involves small blood vessels. It is characterized by full-thickness inflammation, necrosis and granuloma formation in small blood vessels.
Common symptoms can be manifested as fever, joint pain, myalgia, fatigue, weight loss, etc. When lung, kidney, gastrointestinal tract, nervous system and five senses are involved, corresponding clinical manifestations will appear. Musculoskeletal symptoms of the whole body are not specific, but they are common; The following clinical manifestations can also occur alone or in combination: chronic recurrent sinusitis accompanied by nasal scab, hollow pulmonary nodules, rapidly progressive necrotizing oligoimmune complex glomerulonephritis, multiple mononeuropathy, pericarditis or myocarditis and obvious purpura, while respiratory and renal failure at the same time is called "pneumorenal syndrome", which is an acute and severe manifestation of AAV.
Generally speaking, multiple organs and systems involved at the same time and obvious inflammatory reaction are often the key clues to diagnose AAV.
How to diagnose?
1, patient evaluation and diagnostic evaluation
When the diagnosis of AAV is suspected, a comprehensive clinical evaluation should be conducted to assess whether all the organs that may be involved are involved (see Table 1).
Table 1: Patient Assessment and Diagnostic Assessment
Routine blood tests should be carried out, and alveolar hemorrhage should be highly suspected if there is a continuous decrease in hemoglobin level.
Urine analysis is essential in finding hematuria, proteinuria and urine culture to eliminate infection, and the detection of proteinuria needs to be evaluated by quantitative urine protein/creatinine ratio.
All patients underwent chest X-ray examination. When respiratory involvement (such as alveolitis, pulmonary infiltration or nodules) is suspected, chest CT examination should be conducted in time.
When ENT involvement is suspected, CT examination of paranasal sinuses must be performed and evaluated by ENT experts (including nasal and laryngeal fibroscopy, etc.).
Electromyography was performed when peripheral nerve involvement was suspected.
In a word, it is suggested to carry out multidisciplinary examination according to the organ system involved.
2. The value of ANCA screening
It is strongly recommended to screen ANCA, and the detection of protease 3(PR3)-ANCA and myeloperoxidase (MPO)-ANCA is highly specific.
In the meta-analysis of evaluating the value of ANCA, the sensitivity and specificity of anti-PR3 antibody were 80% and 93%, while the sensitivity and specificity of anti-MPO antibody were 58% and 96%. The specificity of ANCA was different between granulomatous vasculitis (GPA) and microscopic polyangiitis (MPA), with PR3-ANCA positive accounting for 78%-87% in GPA and MPO-ANCA in MPA.
ANCA was not detected in the blood of about 10% patients with GPA and MPA, reminding us that there may be other biomarkers that have not been found when considering the diagnosis of AAV.
Besides AAV, ANCA is occasionally found in some patients with infection, other autoimmune diseases and other vasculitis.
3. When will the biopsy be performed?
Biopsy of kidney, lung, nose, nerve and muscle tissue can provide reliable evidence for the diagnosis and differential diagnosis of diseases.
The diagnostic rate of pathology may vary significantly with different biopsy sites. For example, renal biopsy has a high diagnostic rate, while paranasal sinus biopsy often suggests nonspecific inflammation.
Although biopsy is the gold standard and strongly recommended, in clinical practice, when the clinical manifestations are consistent with ANCA detection, biopsy can be omitted. In the latest classification standards of American Rheumatology Association (ACR) and European Union Against Rheumatism (EULAR) in 2022, when other diseases simulating vasculitis are excluded and diagnosed as vasculitis, biopsy is not a mandatory standard.
In short, biopsy (especially renal biopsy) should always be considered for patients suspected of active disease to evaluate the condition.
4. Classification criteria of MPA and GPA
At present, there is no diagnostic standard for AAV, so clinical manifestations, histological and laboratory data are very important for diagnosis.
Figure 2: GPA classification standard updated by 2022 ACR/EULAR
Figure 3: MPA classification standard updated by 2022 ACR/EULAR
The total score ≥5 points can diagnose GPA or MPA.
Treatment
1. Glucocorticoid
When the diagnosis of AAV is suspected, GC should be started, and the initial measurement is 1mg/kg prednisone (or equivalent) per day, or 500-1000mg methylprednisolone intravenously for 3-5 days.
PEXIVAS research shows that for critically ill patients who initially received methylprednisolone shock therapy, the GC dosage is reduced faster than that of the traditional regimen, that is, prednisone is reduced to 20mg per day within 7 weeks after starting treatment and 5mg per day within 19 weeks, which is as safe and effective as the standard dosage. The research shows that the risk of serious infection is low within one year.
LOVAS study showed that the initial remission of AAV (inanimate/severe organ involvement) was induced by GC of 0.5mg/kg/ day. As RITAZAREM study showed, the incidence of hypogammaglobulinemia (IgG<5g/L) was halved during the follow-up period.
It is mentioned that GC should be gradually reduced after induction of remission, and may be stopped gradually within the first year after diagnosis. At present, there is no high-quality evidence to support the need to maintain the optimal dose and duration of GC for AAV remission, so GC treatment should be individualized.
2. Immunosuppressive drugs that induce remission
① severe AAV
GC combined with cyclophosphamide (CTX) or rituximab is the standard scheme to induce severe disease remission at present, although more and more evidence shows that in some subgroups of patients, such as PR3-ANCA positive patients and patients with disease recurrence, rituximab is better than CTX to maintain fertility.
CTX can be administered intravenously or orally, and the dosage should be reduced in elderly patients with renal insufficiency. The dosage of 15mg/kg is selected according to the most widely used CYCLOPS regimen in Europe. Compared with the daily oral regimen (2mg/kg/d), the cumulative dosage of CTX can be reduced by 50%, and the remission rate is similar, while the end-stage renal disease, adverse events or survival time have not increased, but the risk of disease recurrence has increased in the long run.
The two regimens usually stop taking drugs 3-6 months after remission, and then start maintenance treatment.
Rituximab (375mg/m2 per week, four times in total or 1000mg twice every two weeks) is not inferior to CTX in inducing remission, and it is more advantageous in PR3-ANCA positive or recurrent patients.
There is little evidence to compare CTX with rituximab in patients with low glomerular filtration rate (< 20 ml/min/1.73m2). According to the suggestion of KDIGO guidelines in 2021, in addition to the first and third intravenous use of 15mg/kg CTX, such patients can also choose to use 375mg/m2 of rituximab combined with CTX for four consecutive weeks. However, this combination may bring additional risk of infection, and a recent retrospective study showed that rituximab alone may be as effective as CTX in inducing remission in patients with eGFR<30ml/min/1.73m2.
In all patients, compound sulfamethoxazole should be taken orally for at least 3 months after the last use of CTX to prevent pneumocystis carinii pneumonia (atrovaquinone or pentamidine aerosol should be used in case of intolerance/allergy) until B cells are rebuilt after rituximab treatment.
② Non-severe AAV
For non-serious disease-induced remission, rituximab is more effective than conventional immunosuppressants, and MTX and MMF can be used as substitutes when rituximab or CTX cannot be used. Studies have shown that MTX and MMF are not inferior to CTX in the remission rate of 6 months, but the recurrence rate during follow-up is higher than CTX, especially in PR3-ANCA positive patients.
3. Immunosuppressive drugs to maintain remission
After CTX or rituximab combined with low-dose GC induction therapy, rituximab (500 mg every 6 months) is superior to azathioprine in the maintenance and remission of GPA and MPA. It has been proved that the maintenance treatment of rituximab (1000mg once every 4 months) is safe and effective in patients with recurrence. For patients with contraindications to rituximab, AZA or MTX can be considered as alternative therapy.
On the other hand, the use of rituximab may lead to hypogammaglobulinemia and increased risk of infection, so it is suggested to use low-dose rituximab to maintain remission. In clinical practice, not only drug safety but also the risk of disease recurrence should be considered.
AZA(2mg/kg/ day) and MTX(0.3mg/kg increased to the maximum of 25mg/ week) have similar effects on maintaining remission of AAV, and they are second-line drugs for maintaining remission. Patients with impaired renal function (eGFR<45ml/min) should avoid using MTX.
At present, EULAR recommends maintaining treatment for at least 2 years, and recent studies using rituximab or AZA regimen show that immunosuppressive treatment for more than 2 years can reduce the recurrence rate of the disease.
4, plasma exchange and complement C5 receptor inhibitors
PEXIVAS research shows that routine plasma exchange treatment for severe GPA/MPA patients with glomerulonephritis (eGFR<50ml/min/1.73m2) or alveolar hemorrhage has no benefit. This result is contrary to the previous MEPEX1 study, which may be due to the stricter inclusion criteria of the latter [creatinine (> 5.8mg/dl) and glomerulonephritis confirmed by biopsy are required]. The subgroup analysis of PEXIVAS study showed that plasma exchange did not benefit significantly in these subgroups.
Meta-analysis published recently shows that plasma exchange at the age of 12 months in patients with severe renal disease may be beneficial to the prognosis of kidney if the infection rate is high.
Therefore, even with severe renal disease, the use of plasma exchange is still controversial, and it is not recommended as a routine treatment.
It is worth noting that the position of international guidelines on plasma exchange of AAV is quite different. The KDIGO Alliance recommends plasma exchange for patients who need dialysis or whose creatinine increases rapidly > 500 mol/L (> 5.8 mg/DL), or for patients with severe hypoxemia and alveolar hemorrhage, while the 2021 ACR guidelines suggest that plasma exchange is not recommended for patients with active AAV glomerulonephritis or alveolar hemorrhage. EULAR 2022 suggested that plasma exchange should be considered in patients with rapid increase of creatinine > 300μmol/l, but there is no evidence that routine plasma exchange can treat alveolar hemorrhage.
Recently, in addition to CTX or rituximab, avacopan, an oral complement factor C5 receptor inhibitor, has been approved and licensed for the induced remission and maintenance treatment of severe AAV, in order to replace or limit the dosage of GC.
So which patients will benefit the most from this new treatment, especially considering the cost of the drug, is still worth discussing.
According to the study of its mechanism of action, avacopan seems to be the most useful for patients with severe kidney disease and alveolar hemorrhage, as well as patients with high risk of GC-induced comorbidity, including the elderly.
summary
When the patient is highly suspected of AAV, further ANCA detection is needed, and all organs are evaluated, and if necessary, tissue biopsy is performed to make a definite diagnosis.
Clinical treatment strategies should vary according to the severity, age, weight, complications and prognosis of AAV.
Recent studies support rituximab as the first choice to induce and maintain remission.
In addition, compared with the conventional scheme, a small amount of GC is equally effective and safer in inducing remission.
There is insufficient evidence to support the routine use of plasma exchange for treatment.
References:
Baptiste Chevet, Divi Cornec, Marta Casal Moura, Emilie Cornec-Le Gall, Diagnosing and treating ANCA-associated vasculitis: an updated review for clinical practice.[J] Rheumatology.
This article is the first channel of rheumatism immunity in medical field.
The author of this article is Socrates’ afternoon tea.
This article reviews Chen Xinpeng, Deputy Chief Physician.
Responsible editor, cassette tape
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