To the Editor,
The treatment of vasculitis associated with ANCA is still a topic of interest. Corticosteroids and cyclophosphamide are still the cornerstone in the treatment of vasculitis associated with ANCA. We must also point out the use of rituximab, a chimeric anti-CD20 antibody which has already been studied in several series of patients and which seems to have a beneficial effect on refractory patients or those with intolerance to the first-line therapy. It has also been used with other types of primary glomerulonephritis.
Several outbreaks seem to appear during the course of vasculitis associated with ANCA. In patients with an established chronic disease on dialysis or kidney transplant recipients, relapse from the baseline disease is usually unlikely, but not impossible.
We present the case of a patient diagnosed with vasculitis associated with ANCA with lung and kidney disease being treated with renal replacement therapy with haemodialysis. He suffered multiple outbreaks despite treatment with cyclophosphamide, corticosteroids and mycophenalate sodium. However, on beginning treatment with rituximab, he achieved full remission from the disease and ANCA levels returned to normal.
A male of 65 years of age, ex-smoker, diabetic was admitted to hospital in 2005 due to minor haemoptysis, oedemas on lower limbs, polyneuropathy, deterioration in renal function, and creatinine levels of 6 mg/dl. He was found to have severe anaemia together with impaired renal function, proteinuria of 1.5 g/day, haematuria with dysmorphic red blood cells; he was positive for mpo-ANCA with a titre of 68.34 U/ml. A kidney biopsy was performed showing extracapillary glomerulonephritis with fibrinoid necrosis and crescent formations with negative immunofluorescence. In view of the diagnosis of pauci-immune extracapillary glomerulonephritis with pulmonary involvement, treatment was begun with 3 bolus of methylprednisolone at 1 g/day and monthly cyclophosphamide bolus. The patient was discharged with creatinine level of 2.9 mg/dl, and continued the treatment with monthly bolus cyclophosphamide and corticosteroids.
A year after the diagnosis, in 2006, still in treatment with cyclophosphamide and corticosteroids, he had a new outbreak of vasculitis with a deterioration in renal function (Cr of 10.4 mg/dl), an increase in proteinuria and p-ANCA levels (188 U/l), with no evidence of alveolar bleeding. He was treated with methylprednisolone bolus. In view of the severity of the outbreak and the lack of renal function improvement, he was given renal replacement therapy with haemodialysis.
During the follow-up, the patient was diagnosed with bronchiectasis, and was admitted on several occasions with superinfections of the lung.
In 2007, a year after the onset of haemodialysis and in remission from the disease, he was re-admitted with a new outbreak of vasculitis with an episode of haemoptysis, muscle pain, asthenia, and worsening of the anaemia. ANCA levels were 100 U/l. He was treated with corticosteroids and i.v. cyclophosphamide, with a remission in the outbreak. Six months later, still in treatment with cyclophosphamide, he had a new outbreak characterized by fever, asthenia, haemoptysis and ANCA of 193 U/l. Treatment was begun with corticosteroids and cyclophosphamide, and mycophenolate was added as a maintenance therapy but was badly tolerated due to a digestive disorder and was abandoned.
In view of the patient’s history of outbreaks of vasculitis despite the standard immunosuppressor treatment with cyclophosphamide, and the fact that he was undergoing renal replacement therapy with haemodialysis, it was decided to begin treatment with 4 doses (375 mg/m2) of rituximab.
Later, the patient continued treatment with 4 bolus of cyclophosphamide per month, remaining in remission and with ANCA negativisation 21 months after beginning treatment with rituximab, without any secondary complications to date.
The pathogenesis of glomerulonephritis associated with ANCA is not totally clear. ANCA have been related with the pathogenesis of vasculitis, although the levels of ANCA in circulation do not always correlate with the level of activity of the disease. The generation of ANCA is determined by the activation of autoreactive B lymphocytes through the chronic stimulation of T lymphocytes, which explains the relapsing nature of the disease. Furthermore, ANCA produce the liberation of free radicals and proteolytic enzymes which leads to damage of the vascular endothelium in adjacent tissues.1
Immunosuppressor treatment of the outbreaks in patients on dialysis does not differ from the normal treatment for patients with a generalised disease. Regarding the maintenance therapy, various options have been attempted to reduce the toxicity associated with cyclophosphamide, such as azathioprine, mycophenolate mofetil, and leflunomide.2
In refractory cases, rituximab has been shown to be effective in achieveing remission from the disease in several series of patients. Rituximab is a chimeric anti-CD20 antibody which depletes B lymphocytes, so it has been proposed as a rescue therapy in refractory disease, as the aetiopathogenetic importance of B cells in the generation of ANCA is well known.3
As we have mentioned above, relapse of vasculitis is relatively uncommon in patients on haemodialysis, and it is even rarer to find patients such as ours with multiple relapses in spite receiving standard immunosuppressor therapy and haemodialysis.
Little experience has been acquired into the use of rituximab as a rescue therapy in haemodialysis patients. However, reviewing the bibliography, rituximab treatment was assayed in a patient with a history of terminal chronic disease on haemodialysis as a lymphoma B cell treatment, showing that therapeutic levels of the drug remain in the blood despite haemodialysis, so it is not necessary to adjust the treatment doses.4 Another patient with non-Hodgkin lymphoma requiring haemodialysis was treated with rituximab with no evidence of an increase in side effects.5
In our case, treatment began with 4 doses of rituximab accompanied with a monthly bolus of cyclophosphamide, with which remission from the vasculitis outbreaks was achieved together with the reduction and later negativisation of the levels of ANCA. This suggests that rituximab may be an effective drug as a rescue therapy in patients on chronic haemodialysis with a vasculitis relapse.
