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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 1  |  Page : 8-13

Clinical Characteristics of Antineutrophil Cytoplasmic Antibodies Associated Vasculitis in the Elderly


Department of Nephrology, People's Hospital of Zhejiang Province, Hangzhou 310014, Zhejiang Province, China

Date of Web Publication1-Feb-2016

Correspondence Address:
Qiang He
Department of Nephrology, People's Hospital of Zhejiang Province, Hangzhou 310014, Zhejiang Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2394-2916.175393

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  Abstract 

Antineutrophil cytoplasmic antibodies (ANCAs) associated vasculitis is a necrotizing vascular inflammation, usually involving multiple organs. It is one of the major diseases that cause deterioration of renal function rapidly in the elderly. The latest Chapel Hill Consensus Conference 2012 has updated the name of ANCA-associated vasculitis. Some high quality randomized clinical trials provide the evident basis for the treatment of vasculitis. However, elderly patients often suffer complex diseases, and are associated with underlying diseases, so it is difficult to be diagnosed and treated. It is very important to make optimized individual strategies of treatment for elderly patients with vasculitis.

Keywords: Antineutrophil cytoplasmic antibody, elderly, vasculitis


How to cite this article:
He Q, Shao L. Clinical Characteristics of Antineutrophil Cytoplasmic Antibodies Associated Vasculitis in the Elderly. J Integr Nephrol Androl 2016;3:8-13

How to cite this URL:
He Q, Shao L. Clinical Characteristics of Antineutrophil Cytoplasmic Antibodies Associated Vasculitis in the Elderly. J Integr Nephrol Androl [serial online] 2016 [cited 2020 Sep 29];3:8-13. Available from: http://www.journal-ina.com/text.asp?2016/3/1/8/175393


  Introduction Top


Antineutrophil cytoplasmic antibodies (ANCAs) associated vasculitis is a kind of necrotic small vessel inflammation with the characteristics of pauci immune complex deposition, small vein, arteriole, and small vessel involvement and often accompanied by myeloperoxidase (MPO) ANCA or proteinase 3 (PR3) ANCA positive. This disease often appears in elderly population. ANCA-associated vasculitis, as one of the important diseases to aggravate the deterioration of elderly renal function, needs to be paid attention immediately. In the past 50 years, although it has made great progress, including the establishment of ANCA detection methodology in the 1990s and the current prospective treatment plan, ANCA-associated vasculitis still has various problems to be resolved such as side effects, recurrence treatment, and effective infection prevention. This paper will analyze characteristics of the latest clinical classifications, elderly ANCA-associated vasculitis epidemiology, various treatment methods, and how to optimize treatment plan.


  Updated classification standard and clinical characteristics Top


The latest Chapel Hill Consensus Conference (CHCC) 2012 naming system specifically names ANCA-associated polyangiitis independently and puts it in polyangiitis classification. [1] Its clinical manifestation is vessel wall pauci immune complex deposition. Hence, it should be distinguished from other immune complex depositive vasculitis such as glomerular basement membrane, allergic purpura, and cryoglobulinemia. ANCA-associated polyangiitis includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic GPA (EGPA). The new naming system adopts opinions from American College of Rheumatism, American Society of Nephrology, and European League against Rheumatism, using GPA replacing Wegner's Granulomatosis. For the importance of EC in EGPA diagnosis, EGPA is recommended to replace Churg-Strauss. Moreover, some prefixes are also recommended, such as MPO positive ANCA-associated vasculitis and negative ANCA-associated vasculitis. Compared with CHCC naming system in 1994, the new system puts more focus on pathological characteristics and classifies it to make it easy to understand and apply.


  Epidemiological characteristics and predisposing factors of elderly antineutrophil cytoplasmic antibodies associated vasculitis Top


This disease has different incidences at home and abroad. More than 10 years ago, ANCA-associated vasculitis incidence was 20/1000,000 in Europe and North America. The total incidence was 180/1000,000 in Britain, and it became one of the common autoimmune diseases in Western countries. There is a comparative survey between Japan and the British Commonwealth. The incidences are, respectively, 22.6/1000,000 and 21.8/1000,000 with the age of 69.7 and 60.5. In Japan, 83% of the patients belong to MPA, and the British Commonwealth countries have 66% GPA patients. Recently, a multicenter cross-sectional survey reveals the average age is 63.5 in 486 cases. Among them, GPA takes up 64.6%, MPA is 23.2%, and EGPA accounts for 10.7%. [2] At home, in Beijing single-center survey, MPA is 79.1%, taking the highest proportion in ANCA-associated vasculitis. The second is GPA, taking up 20.4%, and the lowest is EGPA, accounting for 0.5%. In this survey, there is an inquiry aiming to the elderly more than 65 years old, and the average age is 68.2%. Among them, perinuclear ANCAs (P-ANCAs) positive takes up 90% (128/141), and MPO-ANCA positive is 10%. It is worth noting that only less than half of the patients are diagnosed within 3 months.

The current researches show the cause and pathogenesis of ANCA-associated vasculitis are not clear. The possible predisposing factors are genetic factor, environmental factor, infection, and drug. The familial current ANCA-associated vasculitis and the different incidence areas reflect genetic factor. Human leukocyte antigen, ANCA target antigen gene, and α1-gene polymorphism of trypsin have close relation with the incidence and recurrence of ANCA-associated vasculitis. For environmental factor, the relation between silicon and vasculitis causes people's attention. According to epidemiology materials, in ANCA-associated vasculitis or GPA, 22-46% patients have silicon contact history and more close relation to contact time. [3] As to environmental factor, it includes smoke, construction material, and pesticide. Infection will lead to inflammatory factor release, induce neutral granulocyte sensitization, and cause endothelial cell activation. It is the premise of ANCA-mediated endothelial cell injury. The incidence and recurrence of vasculitis have a close relation with Staphylococcus aureus and Pseudomonas aeruginosa. For drug factor, propylthiouracil and ANCA can induce ANCA and vasculitis under certain conditions.

Integrating surveys both at home and abroad, we find ANCA-associated vasculitis often appears in elderly population. GPA in foreign countries and MPA at home reveal genetic factor and the great race differences. In addition, predisposing factor mainly includes environment, infection, and drug. All these factors always interact with each other and make the cause and pathogenesis of ANCA-associated vasculitis complex.


  Application characteristics of various diagnosis and treatment methods on elderly antineutrophil cytoplasmic antibodies associated vasculitis Top


Multi-system involvement, easy to misdiagnose

ANCA-associated vasculitis often involves several organs and has different clinical manifestations. The commonly involved organs are lung, kidney, skin, bone, muscle, gastrointestinal tract, C. N. S., and the five sense organs. It is easy to misdiagnose, and it becomes one of the difficult problems in Internal Medicine Department for its diagnosis and treatment. If the following symptoms take place, the possibility of vasculitis should be concerned: Middle-aged people, severe systemic inflammatory response, fever with unknown reason, weak, weight loss, and multi-system involvement including lung, kidney, joint muscle, skin, eye, ear, nose, nervous system, untreated lung inflammation, unbalanced anemia with hemorrhage, and decreased renal function. Through tissue biopsy, the identified diagnoses include necrotic small vessel inflammation of immune complex deposition, P-ANCA and anti-MPO antibody or cytoplasmic ANCAs, and anti-PR3 antibody positive. According to the research, if P-ANCA and anti-PR3 antibodies all take on in positive form, the specificity of diagnosed MPA is more than 99%. In clinical practice, the Birmingham Vasculitis Activity Score (BVAS) is recommended to be used in vasculitis activity assessment.

Current treatment methods all based on evidence-based medicine

Fifty years ago, due to the shortage of treatment measures, the mean survival time of the diagnosed patients was 5 months. Later, although glucocorticoid therapy was added, the mean survival time was still 8 months. Since Fauci and Wolff creatively took cytoxan into usage in the 1970s, the treatment effect of ANCA-associated vasculitis had gotten great progress. There is no great controversy at present for the stage treatment plan. In induction period, the main goal is to control active lesion and prevent injury of important organs. Recurrence prevention is the treatment target in the maintenance period. The classic early period treatment method is take oral cyclophosphamide (CYC) every day, and the state of illness will be eased after 6-9 months. When it comes to maintenance period, change CYC into oral Imuran for more than 1 year. According to the severity of the disease, European Vasculitis Study Group (EUVAS) divides ANCA-associated vasculitis into five categories to make optimized treatment plan [Table 1] [4] .
Table 1: European Vasculitis Study categories of antineutrophil cytoplasmic antibodies-associated vasculitis

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CYCLOPS research has confirmed that CYC implosive and oral therapies are consistent in induction period. Moreover, they have less dose accumulation and obviously decreased side effects of leucopenia. Moreover, there is no statistical significance between serious adverse events and fatality rate. [5] In the later 4.3 years follow-up, we find CYC implosive treatment has a high recurrence. However, in general, there is no statistical significance between these two groups when it comes to survival rate, renal function, and serious adverse reactions. The further research focuses on patients with systemic disease and the elderly more than 80 years old are excluded. This research initially puts forward that the dose of CYC should be adjusted according to age, renal function, and leukocyte count. In CYC shock group, the basic impact dose is 15 mg/kg (weight). If the patient is 60-70-year-old, the dose should be reduced 2.5 mg/kg every time. Accordingly, the dose should be 5 mg/kg for patients more than 70-year-old. If the serum creatinine is between 300 and 500 μmol/L, every time, the impact dose should be reduced 2.5 mg/kg. After implosive therapy, if the white blood cell is from 2 × 10 9 /L to 3 × 10 9 /L, the dose should be reduced 20%. In oral CYC group, the basic dose is 2 mg/kg (weight) every day. Patients more than 60-year-old should reduce 25%, and patients more than 70-year-old should reduce 50%. In this research, although the elderly more than 80 years old are excluded, the dose of CYC has been adjusted according to age. Moreover, the later researches basically refer to this dose reduction plan and have important reference value to dose adjustment of elderly ANCA-associated vasculitis.

CYCAZAREM research indicates, in maintenance period, using Imuran replacing CYC will not increase recurrence rate. Meanwhile, it can reduce CYC dose and potential risks such as secondary tumor and infertility. [6] Hence, this method is recommended to patients in the maintenance period. The population in this research is consistent with CYCLOPS research, belonging to systemic category patients. In this research, for the patients more than 75-year-old and with serious condition are excluded, it is unknown whether it is suitable to patients more than 75-year-old. More elderly cases need to be taken in randomized controlled trial (RCT) research.

For severe ANCA-associated vasculitis, methylprednisolone implosive therapy can be used in initial treatment, with 0.5-1.0 g methylprednisolone for 3 days to control acute symptoms. Plasmapheresis is suitable to severe ANCA-associated vasculitis patients, pneumorrhagia patients, and renal failure patients who need hemodialysis therapy. Plasmapheresis should be conducted 1 time within a day until the pulmonary hemorrhage stops. After that, it can be conducted every other day. Moreover, the total number is 7-10 times. [7] Plasmapheresis combined with glucocorticoid and CYC therapy is helpful to the recovery of renal function failure. However, there is no obvious advantage if plasmapheresis is not combined with pneumorrhagia and renal function failure.

In recent 10 years, the most outstanding research is the application of a new therapy plan - rituximab in ANCA-associated vasculitis treatment. According to RAVE ITN group research, rituximab not only can be served as a new therapy to severe ANCA-associated vasculitis but also belongs to a newly discovery to ANCA-associated vasculitis and recurrent ANCA-associated vasculitis. [8] In EUVAS group, although the research is based on 44 cases newly discovered ANCA-associated vasculitis patients, the result has not shown the advantage of rituximab. [9] For the population is small in above research, other large-scale researches still confirm the same effect of rituximab with CYC, as the first-line therapy plan in induction period. Moreover, rituximab has similar adverse reactions with CYC and can be used as alternative treatment plan in ANCA-associated vasculitis treatment. This is also confirmed in the later researches. The research shows, in the side of recurrent disease treatment, rituximab has obvious advantage compared with CYC combined with Imuran therapy. In these two groups, the remission rates are, respectively, 67% and 42% in the 6 months follow-up. [10] In recent follow-up, the 18 months complete remission patients take up 39% and 33% in rituximab group and cytoxan therapy group, without statistical significance. In the analysis of recurrent subgroups, although rituximab takes on obvious advantage at 6 months and 12 months, it has no obvious advantage at 18 months. There is no statistical significance in the sides of side effect and serious adverse events. Hence, it is estimated that these two methods have a consistent treatment effect. For the age of these two groups, the average ages are respectively 54.0 ± 16.8 and 51.5 ± 14.1. Hence, the value among elderly population still needs to be verified. As the treatment method in induction period, mycophenolate is still in dispute. At home, General Hospital of Nanjing Military Region has conducted a single-center nonblind clinical trial to compare mycophenolate with CYC in induction treatment. The included 35 cases belong to systemic ANCA-associated vasculitis. The result shows the 6 months disease activity of BVAS value is obviously lower than CYC group. The complete remission rates are, respectively, 77.8% and 47.1%, and the recovery rates of renal function are, respectively, 41.7% and 16.7%. This research excludes patients more than 65-year-old, and the majority of the patients belong to MPA. This research indicates mycophenolate can be used as effective drug in MPA induction period. Moreover, the shortage of this research is it lacks long-term follow-up. [11] The purpose of improve research in EUVAS is to verify the function of mycophenolate in maintenance period. Through 39 months follow-up, we find mycophenolate mofetil (MMF) group has higher recurrent rate, and the risk ratio is 1.69. Hence, this is not recommended as the first-line treatment plan for mycophenolate has poorer effectiveness than Imuran in maintenance period. However, the average age of the included population is 55 years old. GPA takes up 59.2% in mycophenolate group, and GPA accounts for 68.7% in Imuran group. For these two researches at home and abroad, although the age of the included patients is relatively young, MPA takes up very different proportions in these two researches. Hence, it is still in dispute. Therefore, it is necessary to conduct RCT in the Asian population and take a certain number of elderly people in. [12]

From the comparison between methotrexate group and standard CYC therapy group in NORA research, the 6 months remission rate of methotrexate has no obvious advantage compared to CYC but has the higher recurrent rate at 18 months than CYC. Hence, it is not recommended currently. [13] Besides, there is the research reveals leflunomide has more advantages than methotrexate in preventing WD recurrence. [14]

In Wegener's Granulomatosis Etanercept Trial research, etanercept is evaluated in maintenance period of ANCA-associated vasculitis treatment. It has not shown more effective functions in maintenance period of GPA therapy but has potential risk to increase solid tumor. [15]

Immunoglobulin has not high-quality evidence-based medicine bases in ANCA-associated vasculitis application. A multicenter research from France vasculitis group indicates immunoglobulin can be served as adjunctive therapy to ANCA-associated vasculitis for the high safety and tolerability. [16]

Characteristics of elderly antineutrophil cytoplasmic antibodies-associated vasculitis

From the review of RCT researches about ANCA-associated vasculitis treatment, it is easy to be found the elderly patients are always excluded in clinical trials for various reasons such as too many complications, poor compliance, and serious state. Hence, it is inappropriate to directly bring this research result to elderly population. It should be screened in practical application. Elderly ANCA-associated vasculitis takes on complex manifestation, crypticity, and rapid progress. Hence, it has a poor prognosis and high risk. The elderly patients are inclined to take treatment resistance. [17]

According to multifactor analysis, serum creatinine >400 μmol/L, and the age more than 65 are independent risks of poor prognosis. Moreover, if the patient is more than 65-year-old, CYC dose should be reduced by 25%. Recently, there is a literature review retrospectively analyses 41 cases elderly ANCA-associated vasculitis and 52 cases nonaged patients to compare immunosuppressant reduction and the effectiveness of full dose immunosuppressant. The research result is the elderly group has higher mortality, and the cardiovascular death is increasing in elderly population. If the dose of immunosuppressant is reduced 20% in elderly population, the curative effect and complications will keep balance with full dose treatment in young population. The research also points out the high fatality rate in elderly population may result from the morbidity of cardiovascular disease. Hence, careful assessment of cardiovascular state and active measures are needed in elderly population.

In ANCA-associated vasculitis always has complex state, poor prognosis, and basic complication. Hence, in the process of diagnosis and treatment, it puts forward higher requirement to clinical doctors. In the author's opinion, it is necessary to make individual optimized treatment strategies.

Treatment strategies in induction period

In ANCA-associated vasculitis with the threat of combined organ function failure, glucocorticoid combined with CYC venous shock therapy should be taken. To control acute symptoms, in initial treatment, 0.5-1.0 g methylprednisolone shock therapy for 3 days is recommended. As to combined pulmonary hemorrhage and renal function failure, plasma exchange therapy should be conducted. Then, take 1 mg/kg (weight) prednisone orally and gradually reduce the dose within 3-4 months. Besides, combine CYC shock therapy 1 time every 3 weeks, totally 6 months. After 6 months, the prednisone should be reduced 10 mg and maintains 15 months. Then, reduce 7.5 mg and maintain 3 months. The elderly patients' CYC dose must be reduced. If patient takes shock therapy, the basic dose is 15 mg/kg (weight). Every time, the dose should be reduced 2.5 mg/kg for patients from 60 to 70-year-old. For patients more than 70-year-old, the dose should be reduced 5 mg/kg each time. If the serum creatinine is between 300 and 500 μmol/L, every time, the dose should be reduced 2.5 mg/kg (weight). After shock therapy, check white blood cell, if it is between 2 × 10 9 /L and 3 × 10 9 /L, the dose should be reduced 20%. In oral CYC therapy group, the basic dose is 2 mg/kg (weight). Moreover, the dose should be reduced 25% if the patient is more than 60-year-old, similarly, 50% reduction for patients more than 70-year-old. In recurrent and intractable ANCA-associated vasculitis cases, rituximab still remains the preferred treatment plan with sufficient evidences.

Treatment strategies in maintenance period

Small dose prednisone should be gradually reduced within 12-24 months. Immediately take Imuran 2 mg/(kg/day) after stopping CYC, 2 times every day. After 6 months, the dose should be reduced 1.5 mg/(kg/day), 2 times every day, totally more than 6 months. GPA should be maintained 2 years. According to improve research, mycophenolate has a poorer effect than Imuran in maintenance period, so it cannot become first line therapy. However, the average age of this research is 55 years old. In MMF therapy group, GPA takes up 59.2%. In Imuran group, GPA accounts for 68.7%. For the potential function of mycophenolate in MPA, MMF is recommended in maintenance period if the patient cannot tolerate Imuran. Meanwhile, more RCT researches aiming to domestic population are expected.

The purpose of supporting treatment is to reduce short-term and long-term complications. For the high morbidity and infections in elderly ANCA-associated vasculitis, infection prevention becomes very important in the whole process of treatment. At present, the commonly used infection prevention drug is trimethoprim sulfamethoxazole (0.5-1 mg, take it orally every day). It can be used to prevent Chi's lung and other respiratory infections. Monitor immunologic function, for example, T-cell bacteria count of CD4 + T-cell should be more than 200. The active assessment of cardiovascular complication at baseline may help reduce total mortality of this disease when it is treated appropriately and intervened actively. In early stage, supply calcium and Vitamin D. If osteoporosis occurs, add calcitonin and diphosphonate. Renal function failure patients need to control blood pressure strictly. When using CYC therapy, take mesna to prevent urinary tract's toxic action. In the course of follow-up, intensive education and overall assessment should be taken.


  Conclusion Top


Elderly ANCA-associated vasculitis has various clinical manifestations and poor prognosis. It is easy to be misdiagnosed and very hard to be diagnosed and treated. Immunosuppressant is recommended to control the activity of vasculitis except having uncontrollable infection. Based on current classic treatment plans, immunosuppressant should be reduced according to the patients' age, renal function, and numbers of white blood cell. At the same time, strengthening supporting treatment is the important part to prevent infection effectively. Some basic diseases, like cardiovascular disease, need to be assessed to reduce the risk of total death. And more large-sample RCT researches toward Chinese need to be conducted to accurately assess immunosuppressant application in MPA, GPA, and EGPA.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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