Sir, Churg–Strauss syndrome (CSS) is a necrotizing small-vessel vasculitis characterized by eosinophil recruitment and inflammation. IL-5 is a Th2 cytokine implicated in the pathogenesis of CSS by mediating eosinophil maturation, chemotaxis and adhesion to the vascular endothelium. Elevated levels of IL-5 are found in patients with active CSS, demonstrating that T-cell activation correlates with disease activity [1, 2]. Traditionally, treatment of CSS has consisted of immunosuppression with corticosteroids, and in more severe cases, the addition of agents such as AZA or cyclophosphamide [3–5].
Rituximab, the chimeric anti-CD20 monoclonal antibody, induces B-cell depletion and has been successfully used in numerous autoimmune diseases [6, 7]. There have been only a few reports of the use of rituximab as salvage therapy in the treatment of refractory CSS and its mechanism of action remains unclear [8, 9].
We describe two cases of CSS in whom rituximab was used as additional therapy. The first patient failed to enter sustained disease remission with conventional treatment while the second patient had a more protracted history of grumbling disease, and was not responding to conventional treatment. Rituximab resulted in a clinical, serological and biochemical improvement in both cases. In addition, we found that serum IL-5 was elevated in these patients during the active disease period despite conventional therapy, but reduced following rituximab treatment. This effect preceded the reduction in circulating eosinophils, suggesting that rituximab mediates its beneficial actions in CSS, at least in part, through the inhibition of T-cell IL-5 production.
A 40-yr-old asthmatic man was referred to our unit with a 6-week history of bilateral anterior uveitis and a week-long history of dyspnoea with recent onset haemoptysis, systemic malaise and small joint arthralgia. Blood tests demonstrated a normocytic anaemia, with haemoglobin 10.8 g/dl, eosinophilia (2.7 × 109/l), and an elevated CRP of 111 mg/l (0–10 mg/l). A chest radiograph demonstrated diffuse bilateral alveolar shadowing suggestive of pulmonary haemorrhage. Immunological testing revealed a C-ANCA, with a PR3-ANCA level of 593 IU/ml (0–25 IU/ml).
A diagnosis of CSS with pulmonary haemorrhage was made. Following treatment with intravenous methylprednisolone, pulsed intravenous cyclophosphamide and seven plasma exchanges, his systemic symptoms improved and chest radiograph cleared. However, 8 weeks after the initial diagnosis, and following four pulses of cyclophosphamide with high-dose steroids, disease recurred with arthralgia, nail-fold infarcts, skin nodules, red eyes and an active urinary sediment. PR3-ANCA remained elevated at 236 IU/ml. An increase in steroids resulted in no alleviation of symptoms. The patient was treated with rituximab, administered as 1 g doses, 2 weeks apart, while steroids and cyclophosphamide were continued. Subsequently, B cells were completely depleted and he rapidly entered disease remission. Serum IL-5, measured by ELISA (R and D systems, Abingdon, UK), was elevated at presentation (24.2 pg/ml), fell initially following treatment initiation, but rose again (to 59.7 pg/ml). Increasing steroids resulted in some decrease in IL-5 (39.7 pg/ml), but this stabilized and only following rituximab therapy, did the levels normalize (15.1 pg/ml 2 weeks later, and undetectable after 4 weeks). Circulating eosinophils subsequently fell (Fig. 1). Nine months post-rituximab he remains B-cell depleted, on low-dose steroids and AZA, with a negative PR3-ANCA and quiescent disease.
A 66-yr-old man, with a past history of asthma and nasal polyps, and a 6-month history of a necrotic leg ulcer, presented with progressive, upper limb numbness and weakness, a right foot drop, worsening of his asthma and a purpuric lower limb rash. Investigations demonstrated an eosinophilia (15.1 × 109/l), positive P-ANCA, anti-MPO Ab 100 U/ml (normal range, 0–6), CRP 142 mg/l and ESR 77 mm/h. Nerve conduction studies showed a sensory-motor peripheral neuropathy and a diagnosis of CSS was made. The patient received treatment with intravenous then high-dose oral corticosteroids, intravenous cyclophosphamide and a course of intravenous immunoglobulin (IVIG). He made a slow clinical improvement, associated with a decrease in peripheral eosinophilia (1.4 × 109/l) and MPO-ANCA (23 U/ml). Subsequently, he developed ‘grumbling’ disease, characterized by weakness, malaise and persistent eosinophilia (4.7–9.2 × 109/l), although P-ANCA remained negative. Despite continued treatment with pulsed cyclophosphamide, oral prednisolone, intermittent pulsed methylprednisolone and IVIG, significant deterioration in his neuropathy occurred along with uncontrolled atrial fibrillation. Rituximab was administered (4-weekly doses of 375 mg/m2) following which only low-dose oral corticosteroids were continued. His symptoms improved and eosinophil count dropped to 1.1 × 109/l. As with the first patient, serum IL-5 was elevated prior to rituximab, despite immunotherapy (9.8 pg/ml), but became undetectable 12 weeks following therapy, again preceding the decline in eosinophils.
In both cases, disease activity persisted while serum IL-5 and eosinophil numbers remained elevated, despite aggressive immunosuppression. Only following rituximab therapy was disease remission established with normalization of IL-5 and reduction in eosinophil numbers. Our data are the first to demonstrate that IL-5 levels fall following rituximab therapy and suggest that this T-cell function may underlie its beneficial effect in CSS.
Disclosure statement: D.J. has received a research grant from Roche in support of an investigator-initiated clinical trial. All other authors have declared no conflicts of interest.