Granulomatosis with polyangiitis medical therapy
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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]
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.
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]
Initial treatment
Immunosuppressants
- Preferred regimen (1):Methylprednisolone 7-15 mg/kg IV q24h for 14 3 days (maximum, 500-1000mg/kg)
- Preferred regimen (1): Prednisone mg PO q12h for 10-21 days (Contraindications/specific instructions)
- 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 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.
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.[1]
- In localized disease, treatment with the antibiotic co-trimoxazole is recommended, with steroids in case of treatment failure.[2]
- 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, 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.[1]
Cyclophosphamide
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.
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).
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.
Methotrexate
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.
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.
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.
Azathioprine
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.
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.
Rituximab
A trial (RITUXVAS)was conducted on 44 patients with ANCA-associated vasculitis. The trial showed that rituximab along with a corticosteroid was not superior to conventional therapy (Cyclophosphamide with corticosteroid). Patients who were given conventional therapy and those who were given rituximab had similar outcomes of remission (90%). However, there were less adverse affects seen in patients who took rituximab, such as leukopenia. The efficacy of rituximab when compared to cyclophosphamide was similar in comparison. However, the safety and the long term use of rituximab needs to be assessed.
Rituximab given as a maintenance therapy was conducted by MAINRITSAN on 115 patients. The trial showed that rituximab given at 500mg infusions every 6 months for a total of 18 months showed less relapse then the conventional therapy (azathioprine). The remission of relapse was 5% for rituximab and 29% for azathioprine. However, both treatments showed similar adverse effects. A further follow up study needs to conducted in order to determine adverse effects associated with long term rituximab use.
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
- ↑ 1.0 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.
- ↑ 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.