Wegner's Granulomatosis

General

• Male:female ratio of 2:1
• Peak in 40s
• Autoimmune disease characterized by necrotizing granulomas and angiitis
• Diagnosis is made by lung or kidney biopsy
• Death comes from renal failure or respiratory failure
• Treated with steroids and cytotoxic drugs

Respiratory Tract (100% involved)
Upper respiratory tract

• Mucosal thickening in paranasal sinuses
• Bone and cartilage destruction

Lung

• Multiple nodules of varying sizes, especially at bases
• Cavitate frequently (50%)
• Masses wax and wane
• Pleural effusion (25%)
• Alveolar infiltrate occasionally

Other Organs

• Urinary tract:focal glomerulonephritis (50%)
• Joints:migratory polyarthropathy (56%)
• Skin:inflammatory skin lesions (44%)
• Eyes and ears:proptosis and otitis media (29%)
• Heart and pericardium: myocardial infarction (28%)
• CNS: neuritis (22%)

Symptoms

• Rhinorrhea
• Sinusitis
• Epistaxis
• Cough with hemoptysis

Midline Lethal Granuloma

• Variant of Wegener’s consisting of mutilating granulomatosis and neoplastic lesions limited to nose and paranasal sinuses

INITIAL TREATMENT FOR WG:

 We recommend combination cyclophosphamide-glucocorticoid therapy in the initial treatment of most patients with WG or MPA.

- This is particularly indicated in those with life-threatening disease, including patients with a serum creatinine concentration greater than 2.0 mg/dL (177 µmol/L), pulmonary involvement resulting in hypoxemia, CNS disease, and/or bowel perforation/infarction.

  - Either daily oral or monthly intravenous cyclophosphamide is effective in inducing remissions in most patients with WG or MPA. The critical point in the management of patients on cyclophosphamide is close clinical follow-up and regular laboratory testing to avoid neutropenia.

a) Daily oral cyclophosphamide-glucocorticoid regimen

*Cyclophosphamide is given orally in a dose of 1.5 to 2 mg/kg per day. Therapy is continued until a stable remission is induced, which is usually achieved within three to six months. The white blood cell count (WBC) must be closely monitored and the cyclophosphamide dose adjusted to avoid severe leukopenia (WBC should remain above 3000/mm3 and absolute neutrophil count above 1500/mm3).

*When initiating glucocorticoid therapy, there is disagreement among experts and among the authors as to whether therapy should be begun with pulse methylprednisolone (7 to 15 mg/kg to a maximum dose of 500 to 1000 mg/day for three days) in all patients or only in those with necrotizing or crescentic glomerulonephritis or more severe respiratory disease.

Oral glucocorticoid therapy, either from day 1 or day 4 if pulse methylprednisolone is given, typically consists of 1 mg/kg per day (maximum of 60 to 80 mg/day) of oral prednisone (or its equivalent). A variety of prednisone tapering schemes have been employed. In general, the initial high dose should be continued for two to four weeks. If significant improvement is observed at this time, the dose of prednisone may be tapered slowly, with the goal of reaching 20 mg of prednisone per day by the end of two months and an overall glucocorticoid course of between six and nine months. Alternate day glucocorticoid regimens, once recommended in WG, are not generally employed now.

b) Monthly intravenous cyclophosphamide — An alternative to daily oral cyclophosphamide is intravenous monthly pulse cyclophosphamide therapy. Monthly cyclophosphamide is typically administered in doses of 0.5 to 1.0 g/m2 body surface area for three to six months, until a stable remission is induced. Prednisone is given concurrently with monthly intravenous cyclophosphamide, using similar regimens as with daily oral cyclophosphamide.

 - Prophylaxis — Given the toxicity of cyclophosphamide, prophylactic therapy should be provided for Pneumocystis pneumonia usually with trimethoprim sulfamethoxazole. Trimethoprim-sulfamethoxazole should not be used by patients also taking methotrexate.
Other prophylactic measures are directed at preventing bladder and gonadal toxicity.
Given the toxicities of prolonged glucocorticoid use, prophylactic treatments should be provided for oropharyngeal fungal infections (nystatin), gastritis (H2 blocker or proton pump inhibitor for patients at increased risk for gastrointestinal bleeding), and bone loss (calcium and vitamin D or bisphosphonate).

 Methotrexate — A methotrexate-based regimen, in conjunction with glucocorticoids, is an option in patients with mild disease . This primarily includes those with pulmonary nodules or infiltrates without respiratory compromise, and/or ocular disease. Although this regimen can be used to treat patients with glomerulonephritis and normal or near-normal serum creatinine, it is not recommended given the high rate of relapse. If the regimen is used, patients require close follow-up.
A methotrexate-based regimen may be particularly attractive in such patients who have limited bone marrow reserve from past cyclophosphamide use, a history of cyclophosphamide-induced bladder injury, or concerns relating to major cyclophosphamide toxicity. Methotrexate should not be administered to patients with a serum creatinine concentration above 2.0 mg/dL (177 µmol/L) given the increased risk of toxicity in those with renal dysfunction, and patients should not receive concurrent trimethoprim-sulfamethoxazole.
One regimen consists of oral methotrexate at an initial dose of 0.3 mg/kg (but not exceeding 15 mg) once per week, with increases of 2.5 mg each week to a maximum dose of 20 to 25 mg/week [27] . Since methotrexate is a structural analogue of folic acid that can competitively inhibit the binding of dihydrofolic acid (FH2) to the enzyme dihydrofolate reductase (DHFR), folic acid (1 to 2 mg/day) or folinic acid (2.5 to 5 mg per week, 24 hours after methotrexate) should be given concurrently to reduce potential toxicity.

 Glucocorticoids are administered concurrently with methotrexate. The dosing regimen for prednisone is the same as that previously described for prednisone when used with daily oral cyclophosphamide therapy.

 Plasma exchange — We suggest plasma exchange in selected groups of patients with WG or MPA, given the high morbidity and mortality associated with these specific clinical settings: Patients with anti-GBM antibodies as well as ANC Patients with severe pulmonary hemorrhage on presentation (as defined radiographically or by arterial oxygen saturation) or those with worsening pulmonary hemorrhage despite the combination of high-dose glucocorticoids and cyclophosphamide Patients who have advanced renal dysfunction at presentation, as defined by a serum creatinine level above 5.8 mg/dL (500 µmol/L) and/or dialysis dependence
 The potential morbidity associated with plasma exchange must be strongly considered before pursuing this modality given the uncertainty regarding its benefits.
 The method and duration of plasma exchange vary with the response to therapy and the clinical presentation.

Among patients with ANCA-associated vasculitis who present with advanced renal dysfunction, we suggest seven sessions of plasma exchange over two weeks (60 mL/kg at each session). A more prolonged regimen is used in patients with anti-GBM disease.
In general, albumin can be used as the replacement fluid. However, if the patient has had a recent renal biopsy or has pulmonary hemorrhage, then one to two liters of fresh frozen plasma should be substituted for albumin at the end of the procedure to reverse pheresis-induced depletion of coagulation factors.
If a severe infection develops in the setting of plasma exchange, a single infusion of intravenous immune globulin (100 to 400 mg/kg) can be given to partially replenish antibody levels.