The traditional treatment of systemic vasculitides with long‐term oral cyclophosphamide (CPM) and high‐dose corticosteroids has given way to more conservative approaches with shorter induction with CPM, followed by maintenance treatment with azathioprine or methotrexate.1 Despite this, 30–50% of patients relapse by 12 months. Endothelial dysfunction and tumour necrosis factor (TNF) α play a major part in pathogenesis.2 Raised TNF levels are associated with vascular damage and correlate with disease activity.
We describe an open‐label uncontrolled prospective study of anti‐TNFα (infliximab), in the management of patients with systemic vasculitides who failed to maintain remission on conventional immunosuppressive treatment.
We prospectively recruited nine patients with systemic vasculitides: three with Wegener's granulomatosis, two with Behçet's disease, and one each with Churg Strauss vasculitis, adult onset still's disease, Henoch Schonlein purpura and relapsing polychondritis. All failed to respond to one or more immunosuppressives (cyclophosphamide, methotrexate, azathioprine or mycophenolate mofetil) and required >15 mg/day prednisolone (range 15–80 mg).
All patients were scheduled to receive five infusions of infliximab (5 mg/kg) over a period of 6 months. The study was approved by the Guy's and St Thomas' Hospital Research Ethics Committee, and informed consent was obtained from patients before entering the study.
The median age of the patients was 46 years (range 34–62 years) and disease duration was 6 years (range 3–8 years).3,4,5,6,7,8 Only five patients completed five infusions of infliximab; in four, infliximab was discontinued because of adverse effects (table 1).
Table 1 Adverse effects/flares after infliximab infusions.
| Diagnosis | Number of infusions | New autoantibodies | Adverse events/flares | Hospital admission | Treatment for flares/adverse reaction | Deaths |
|---|---|---|---|---|---|---|
| Wegener's granulomatosis | 5 | Nil | Hearing and vision deterioration | No | CPM+M pred | No |
| Wegener's granulomatosis | 5 | ANA, DNA | Hearing loss and lupus‐like reaction | No | Prednisolone+CPM | No |
| Wegener's granulomatosis | 3 | Nil | Leucopenia and anaemia | No | Blood transfusion | No |
| Churg strauss disease | 2 | Nil | Brain stem event and lupus‐like reaction | Yes | M pred +IVIG | No |
| Behçet's disease | 5 | Nil | Severe lupus‐like syndrome and flare | Yes | M pred and IVIG | No |
| Behçet's disease | 5 | ANA, DNA | Scleritis, nodular vasculitis | No | Prednisolone 80 mg/day | No |
| Henoch Schonlein purpura | 1 | Nil | Severe lupus‐like reaction | Yes | M pred+IVIG | No |
| Relapsing polychondritis | 3 | ANA, DNA and lupus anticoagulant | Tired and progressive tracheal stenosis | No | Prednisolone 20 mg/day | No |
| Adult‐onset Still's disease | 5 | ANA, DNA and smooth muscle | Severe flare (serum ferritin >14 000, CRP >300 and ESR 110) | Yes | M pred+IVIG | Yes, after 6 months |
ANA, antinuclear antibodies; CPM, intravenous cyclophosphamide; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; IVIG, intravenous immunoglobulins; M pred, intravenous methyl prednisolone.
We found no improvement in the median Birmingham Vasculitis Activity Score, Vascular Damage Index and SF‐36 scores. Four patients developed new autoantibodies (table 1), which became negative 3 months after discontinuation of infliximab. Four patients required admission for a severe flare of symptoms and lupus‐like reaction, and rescue with methyl prednisolone (500 mg) pulses and intravenous immunoglobulins (table 1). One patient with adult‐onset still's disease died after 6 months secondary to cardiac failure. Her inflammatory markers remained grossly abnormal throughout (table 1). The relationship with the infliximab infusions was not clear, but a postmortem examination did not show coronary artery disease, thrombosis or valvular abnormality. The study was terminated prematurely on safety grounds, and relevant authorities were informed.
Previously, several reports have suggested that anti‐TNFα is effective in patients with systemic vasculitides.3,4 Booth et al5 described improvement in endothelial function after anti‐TNFα treatment in patients with systemic vasculitides. Our findings do not support previous observations that infliximab helps to achieve remission in patients with systemic vasculitides that is difficult to treat.
A recent study (Wegener's Granulomatosis Etanercept Trial) failed to show any additional advantage when etanercept was added to conventional treatment. Solid malignancies were noted in the etanercept arm, giving rise to serious safety concerns.6
In summary, the adverse effects and lack of benefit experienced in our series raises concerns about the role of anti‐TNFα in patients with systemic vasculitides. Other biological treatments such as B cell depletion7 and/or intravenous immunoglobulin in antineutrophil cytoplasmic antibodies associated vasculitides may be more fruitful.8
Abbreviations
CPM - cyclophosphamide
TNF - tumour necrosis factor
Footnotes
Competing interests: None declared.
References
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