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{{Wegener's granulomatosis}}
{{Wegener's granulomatosis}}
 
{{CMG}}{{APM}}{{AE}}{{KW}}{{CZ}}{{ADS}}
{{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}}


==Overview==
==Overview==
In most cases, treatment consists of a combination of a glucocorticoid (a steroid) and a cytotoxic medicine. Although these medicines are helpful in treating Wegener's granulomatosis, people and their doctors should be aware that they potentially have serious side effects. In many instances these can be minimized or prevented by careful monitoring by both the doctor and patient.
In most cases, treatment consists of a combination of a glucocorticoid (a steroid) and a cytotoxic medicine. It includes [[Glucocorticoid|glucocorticoids]], [[cyclophosphamide]], [[Rituximab]], [[Methotrexate]], [[Azathioprine]] and when needed with [[plasmapheresis]].


==Medical Therapy==
==Medical Therapy==
Before steroid treatment became available, mortality within one year was over 90%, with average survival being 5 months. Steroids prolonged average survival to 8 months. The introduction of [[cyclophosphamide]] (CYC) in the 1970s was a major breakthrough.<ref name=Bosch>{{cite journal |author=Bosch X, Guilabert A, Espinosa G, Mirapeix E |title=Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review |journal=JAMA |volume=298 |issue=6 |pages=655–69 |year=2007 |pmid=17684188 |doi=10.1001/jama.298.6.655}}</ref>
Before steroid treatment became available, mortality within one year was over 90%, with average survival being 5 months. Steroids prolonged average survival to 8 months. The introduction of [[cyclophosphamide]] (CYC) in the 1970s was a major breakthrough.<ref name="Bosch">{{cite journal |author=Bosch X, Guilabert A, Espinosa G, Mirapeix E |title=Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review |journal=JAMA |volume=298 |issue=6 |pages=655–69 |year=2007 |pmid=17684188 |doi=10.1001/jama.298.6.655}}</ref><ref name="pmid21109517">{{cite journal |vauthors=Flossmann O, Berden A, de Groot K, Hagen C, Harper L, Heijl C, Höglund P, Jayne D, Luqmani R, Mahr A, Mukhtyar C, Pusey C, Rasmussen N, Stegeman C, Walsh M, Westman K |title=Long-term patient survival in ANCA-associated vasculitis |journal=Ann. Rheum. Dis. |volume=70 |issue=3 |pages=488–94 |date=March 2011 |pmid=21109517 |doi=10.1136/ard.2010.137778 |url=}}</ref>


Initial treatment is generally with [[corticosteroids]] and oral [[cyclophosphamide]] (CYC), 1 mg/kg/day and 2 mg/kg/day, respectively. Occasionally CYC is given in monthly intravenous (IV) doses. Monitoring of the [[white blood cell|white blood count]] is essential during CYC therapy.  Once remission is attained (normally 3 to 6 months), treatment is frequently changed to [[azathioprine]] or [[methotrexate]], which are less toxic drugs.  Total duration of therapy should be at least one year, or longer in high risk patients.  Corticosteroids are tapered to a low maintenance dose, 5-10 mg/day. [[Plasmapheresis]] may be beneficial in severe disease or [[pulmonary hemorrhage]]. Experience with other treatment agents is very limited.
=== Initial treatment ===


A [[systematic review]] of 84 trials examined the evidence for various treatments in Wegener's granulomatosis. Many trials include data on pooled groups of patients with Wegener's and microscopic polyangiitis. In this review, cases are divided between localized disease, non-organ threatening, generalized organ-threatening disease and severe renal vasculitis and immediately life-threatening disease.<ref name=Bosch/>
==== 1. Immunosuppressants ====
* In localized disease, treatment with the antibiotic [[co-trimoxazole]] is recommended, with steroids in case of treatment failure.<ref name="pmid8637536">{{cite journal |author=Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG |title=Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. Dutch Co-Trimoxazole Wegener Study Group |journal=N. Engl. J. Med. |volume=335 |issue=1 |pages=16–20 |year=1996 |pmid=8637536 |doi= |url=http://content.nejm.org/cgi/content/abstract/335/1/16}}</ref>
 
* In generalized non-organ threatening disease, remission can be induced with [[methotrexate]] and steroids, where the steroid dose is reduced after a remission has been achieved and methotrexate used as maintenance.
====== 1.1 Glucocorticoids ======
* In case of organ-threatening disease, pulsed [[intravenous]] cyclophosphamide with steroids is recommended. Once remission has been achieved, [[azathioprine]] and steroids can be used to maintain remission.
* Parenteral regimen (pulse therapy)
* In severe renal vasculitis, the same regimen is used but with the addition of plasma exchange.
**Preferred regimen (1):[[Methylprednisolone]] 7-15 mg/kg IV q24h for 3 days (maximum, 500-1000 mg/kg/day)
* In [[pulmonary hemorrhage]], high doses of cyclophosphamide with pulsed [[methylprednisolone]] may be used, or alternatively CYC, steroids, and plasma exchange.


In severe disease not responsive to previously mentioned treatment, the review is positive about [[mycophenolate mofetil]], 15-deoxyspergualin, [[anti-thymocyte globulin]], [[rituximab]] and [[infliximab]]; data was less favourable for [[intravenous immunoglobulin]] (IVIG) and [[etanercept]].<ref name=Bosch/>
* Oral regimen (follows [[parenteral]] pulse therapy)
===Prednisone===
**Preferred regimen (1): [[Prednisone]] 1 mg/kg/day PO from Day 1 (maximum, 60-80 mg/day) tapered over 14 days with maximum of 20 mg/day
Prednisone is the most common glucocorticoid that doctors use. Prednisone is similar to cortisol, the natural glucocorticoid hormone produced by the body. It is chemically different from the anabolic steroids that have been used by athletes and is given in doses much higher than the body normally produces. Doctors usually give prednisone as a single morning dose to try to imitate how the body normally secretes cortisol.


When the person's illness improves, the prednisone dose is gradually decreased and converted to an every other day dosing schedule, usually over a period of 3 to 4 months. With further improvement in the disease, prednisone is gradually decreased and discontinued completely after approximately 6 to 12 months.
====== 1.2 Cyclophosphamide ======
* Oral regimen
** Preferred regimen (1):[[Cyclophosphamide]] 1.5-2 mg/kg PO q24h for 3-6 months or till remission is achieved (Check CBC for [[Neutropenia]] and administer [[Mesna]] for [[hemorrhagic cystitis]])
* Parenteral regimen (pulse therapy)
**Preferred regimen (1): [[Cyclophosphamide]] 15 mg/kg IV q2weekly for 3 doses and then q3weekly for 3-6 months (Check CBC for [[Neutropenia]] and administer [[Mesna]] for [[hemorrhagic cystitis]])


When prednisone is taken by mouth, the body stops making its own natural cortisol. As the prednisone dose is gradually reduced, the body will resume making cortisol again. It is extremely important that prednisone never be stopped suddenly because the body requires prednisone (or cortisol) to function and may not be able to immediately make what it needs.
* Patients using [[cyclophosphamide]] should also receive glucocorticoids.


Prednisone can affect the body's ability to fight off infection. People taking this medicine should report immediately any symptoms of infection and specifically, any fever to their doctors. Prednisone can also cause weight gain, cataracts, brittle bones, diabetes, and changes in mood and personality.
====== 1.3 Rituximab ======
* Parenteral regimen
**Preferred regimen (1): [[Rituximab]] 375 mg/m<sup>2</sup> IV q1week for 4 doses
**Alternative regimen (1): [[Rituximab]] 1g IV q2weekly for 2 doses


===Cyclophosphamide===
====== 1.4 Methotrexate ======
Cyclophosphamide (Cytoxan) is the most commonly used cytotoxic drug used to treat Wegener's granulomatosis. People take cyclophosphamide once a day by mouth and must take the drug all at once in the morning followed by drinking a large amount of liquid. Although the first dose of cyclophosphamide is based on the person's weight and kidney function, the doctor may adjust the dosage based on blood counts, which are monitored closely to be sure that the white blood cell count is maintained at a safe level.
* Parenteral regimen<ref name="pmid16052540">{{cite journal |vauthors=Specks U |title=Methotrexate for Wegener's granulomatosis: what is the evidence? |journal=Arthritis Rheum. |volume=52 |issue=8 |pages=2237–42 |date=August 2005 |pmid=16052540 |doi=10.1002/art.21146 |url=}}</ref>
**Preferred regimen (1): [[Methotrexate]] 7.5 mg IM/SQ q1weekly till 1 year or remission.


In the original regimen, cyclophosphamide was continued for a full year beyond that point at which the disease was in remission. The dose of cyclophosphamide was then decreased gradually and eventually stopped. In more recent treatment approaches, however, cyclophosphamide is given until remission and then switched to another medicine such as methotrexate or azathioprine (discussed below).
* Oral regimen
** Preferred regimen (1): [[Methotrexate]] 7.5 mg PO q1weekly till 1 year or remission.
* It is used in patients without any end organ damage and no life threatening disease.<ref name="pmid10943874">{{cite journal |vauthors=Langford CA, Talar-Williams C, Sneller MC |title=Use of methotrexate and glucocorticoids in the treatment of Wegener's granulomatosis. Long-term renal outcome in patients with glomerulonephritis |journal=Arthritis Rheum. |volume=43 |issue=8 |pages=1836–40 |date=August 2000 |pmid=10943874 |doi=10.1002/1529-0131(200008)43:8<1836::AID-ANR20>3.0.CO;2-R |url=}}</ref>
* Relapse rate are higher with Methotrexate.<ref name="pmid16052573">{{cite journal |vauthors=De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, Gross WL, Luqmani R, Jayne DR |title=Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis |journal=Arthritis Rheum. |volume=52 |issue=8 |pages=2461–9 |date=August 2005 |pmid=16052573 |doi=10.1002/art.21142 |url=}}</ref>


Cyclophosphamide is a powerful medicine that keeps the immune system from working normally. Doctors must monitor their patients carefully and perform blood tests frequently. Cyclophosphamide can cause an increased risk of infection, bone marrow suppression (lowering of blood counts), sterility, hemorrhagic cystitis (bleeding from the bladder), bladder cancer, as well as other serious side effects.
* Patients using [[methotrexate]] should also receive glucocorticoids.


===Methotrexate===
====== 1.4 Azathioprine ======
Methotrexate has been studied at NIH for the treatment of Wegener's granulomatosis since 1990. In people with active, but not immediately life threatening, Wegener's granulomatosis, methotrexate has been used in combination with prednisone to bring about remission. It also is used to maintain remission after a person has initially received cyclophosphamide. Methotrexate is usually given for 1 to 2 years, after which time if people stay in remission, it is decreased and stopped.
* Oral regimen
** Preferred regimen (1): [[Azathioprine]] 2 mg/kg/day PO for 6 months


Methotrexate is given once a week usually by mouth, but occasionally as an injection under the skin or in the muscle. People taking methotrexate need to have regular blood work to monitor their response and to watch for side effects.
==== 2. Plasma exchange ====
* Indications
** Renal dysfunction due to [[glomerulonephritis]]
** Positive [[Anti-glomerular basement membrane antibody]]
** [[Pulmonary hemorrhage]]


The side effects of methotrexate include infection, lowering of the blood counts, nausea, soreness and ulceration of the mouth lining, irritation of the lungs (pneumonitis), and inflammation and scarring of the liver. People taking methotrexate cannot drink alcoholic beverages. Methotrexate cannot be given to people who have poor kidney function or who have underlying liver disease such as hepatitis.
* Plasma exchange accompanies the pharmacological treatment


===Azathioprine===
Some guidelines for which drug to choose.<ref name="Bosch" />
Azathioprine (also called Imuran) is used primarily to maintain remission in people who have initially been treated and gone into remission with cyclophosphamide. It is taken once a day by mouth. Similar to methotrexate, it is usually given for 1 to 2 years after which time the dosage is lowered until it is stopped.
* In localized disease, treatment with the antibiotic [[co-trimoxazole]] is recommended, with steroids in case of treatment failure.<ref name="pmid8637536">{{cite journal |author=Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG |title=Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. Dutch Co-Trimoxazole Wegener Study Group |journal=N. Engl. J. Med. |volume=335 |issue=1 |pages=16–20 |year=1996 |pmid=8637536 |doi= |url=http://content.nejm.org/cgi/content/abstract/335/1/16}}</ref>
* In generalized non-organ threatening disease, remission can be induced with [[methotrexate]] and steroids, where the steroid dose is reduced after a remission has been achieved and methotrexate used as maintenance.
* In case of organ-threatening disease, pulsed [[intravenous]] cyclophosphamide with steroids is recommended. Once remission has been achieved, [[azathioprine]] and steroids can be used to maintain remission.
* In severe renal vasculitis, the same regimen is used but with the addition of plasma exchange.
* In [[pulmonary hemorrhage]], high doses of cyclophosphamide with pulsed [[methylprednisolone]] may be used, or alternatively CYC, steroids, and plasma exchange.


The side effects of azathioprine include infection, lowering of the blood counts, and rarely an allergic type reaction. In people who receive azathioprine to prevent rejection of a transplanted organ, there has been a suggestion of an increased risk of blood cancers (leukemia and lymphoma) but it is not clear whether this risk exists in other situations. People with poor kidney function or liver disease can take azathioprine.
In severe disease not responsive to previously mentioned treatment, [[mycophenolate mofetil]], 15-deoxyspergualin, [[anti-thymocyte globulin]], [[rituximab]] and [[infliximab]]; [[intravenous immunoglobulin]] (IVIG) and [[etanercept]].<ref name="Bosch" />


===Other medicines===
===Other medicines===

Latest revision as of 17:29, 11 April 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2]Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [3]Cafer Zorkun, M.D., Ph.D. [4]Amandeep Singh M.D.[5]

Overview

In most cases, treatment consists of a combination of a glucocorticoid (a steroid) and a cytotoxic medicine. It includes glucocorticoids, cyclophosphamide, Rituximab, Methotrexate, Azathioprine and when needed with plasmapheresis.

Medical Therapy

Before steroid treatment became available, mortality within one year was over 90%, with average survival being 5 months. Steroids prolonged average survival to 8 months. The introduction of cyclophosphamide (CYC) in the 1970s was a major breakthrough.[1][2]

Initial treatment

1. Immunosuppressants

1.1 Glucocorticoids
  • Parenteral regimen (pulse therapy)
    • Preferred regimen (1):Methylprednisolone 7-15 mg/kg IV q24h for 3 days (maximum, 500-1000 mg/kg/day)
  • Oral regimen (follows parenteral pulse therapy)
    • Preferred regimen (1): Prednisone 1 mg/kg/day PO from Day 1 (maximum, 60-80 mg/day) tapered over 14 days with maximum of 20 mg/day
1.2 Cyclophosphamide
1.3 Rituximab
  • Parenteral regimen
    • Preferred regimen (1): Rituximab 375 mg/m2 IV q1week for 4 doses
    • Alternative regimen (1): Rituximab 1g IV q2weekly for 2 doses
1.4 Methotrexate
  • Parenteral regimen[3]
    • Preferred regimen (1): Methotrexate 7.5 mg IM/SQ q1weekly till 1 year or remission.
  • Oral regimen
    • Preferred regimen (1): Methotrexate 7.5 mg PO q1weekly till 1 year or remission.
  • It is used in patients without any end organ damage and no life threatening disease.[4]
  • Relapse rate are higher with Methotrexate.[5]
  • Patients using methotrexate should also receive glucocorticoids.
1.4 Azathioprine
  • Oral regimen
    • Preferred regimen (1): Azathioprine 2 mg/kg/day PO for 6 months

2. Plasma exchange

  • Plasma exchange accompanies the pharmacological treatment

Some guidelines for which drug to choose.[1]

  • In localized disease, treatment with the antibiotic co-trimoxazole is recommended, with steroids in case of treatment failure.[6]
  • In generalized non-organ threatening disease, remission can be induced with methotrexate and steroids, where the steroid dose is reduced after a remission has been achieved and methotrexate used as maintenance.
  • In case of organ-threatening disease, pulsed intravenous cyclophosphamide with steroids is recommended. Once remission has been achieved, azathioprine and steroids can be used to maintain remission.
  • In severe renal vasculitis, the same regimen is used but with the addition of plasma exchange.
  • In pulmonary hemorrhage, high doses of cyclophosphamide with pulsed methylprednisolone may be used, or alternatively CYC, steroids, and plasma exchange.

In severe disease not responsive to previously mentioned treatment, mycophenolate mofetil, 15-deoxyspergualin, anti-thymocyte globulin, rituximab and infliximab; intravenous immunoglobulin (IVIG) and etanercept.[1]

Other medicines

During the course of treating Wegener's granulomatosis, doctors often give their patients other medicines to prevent medicine-related side effects. These include

  • Trimethoprim/sulfamethoxazole (also called bactrim or septra) is given three times a week to prevent Pneumocystis carinii infection (a lung infection)
  • A medicine regimen is often given to prevent prednisone-related bone loss (osteoporosis)
  • Folic acid or folinic acid (also called leucovorin) are often given to people taking methotrexate

References

  1. ↑ 1.0 1.1 1.2 Bosch X, Guilabert A, Espinosa G, Mirapeix E (2007). "Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review". JAMA. 298 (6): 655–69. doi:10.1001/jama.298.6.655. PMID 17684188.
  2. ↑ Flossmann O, Berden A, de Groot K, Hagen C, Harper L, Heijl C, Höglund P, Jayne D, Luqmani R, Mahr A, Mukhtyar C, Pusey C, Rasmussen N, Stegeman C, Walsh M, Westman K (March 2011). "Long-term patient survival in ANCA-associated vasculitis". Ann. Rheum. Dis. 70 (3): 488–94. doi:10.1136/ard.2010.137778. PMID 21109517.
  3. ↑ Specks U (August 2005). "Methotrexate for Wegener's granulomatosis: what is the evidence?". Arthritis Rheum. 52 (8): 2237–42. doi:10.1002/art.21146. PMID 16052540.
  4. ↑ Langford CA, Talar-Williams C, Sneller MC (August 2000). "Use of methotrexate and glucocorticoids in the treatment of Wegener's granulomatosis. Long-term renal outcome in patients with glomerulonephritis". Arthritis Rheum. 43 (8): 1836–40. doi:10.1002/1529-0131(200008)43:8<1836::AID-ANR20>3.0.CO;2-R. PMID 10943874.
  5. ↑ De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, Gross WL, Luqmani R, Jayne DR (August 2005). "Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis". Arthritis Rheum. 52 (8): 2461–9. doi:10.1002/art.21142. PMID 16052573.
  6. ↑ Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG (1996). "Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. Dutch Co-Trimoxazole Wegener Study Group". N. Engl. J. Med. 335 (1): 16–20. PMID 8637536.

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