B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial

Abstract

Introduction: An over-expression of CD19 has been shown in B cells of systemic sclerosis (SSc) and B cells are thought to contribute to the induction of skin fibrosis in the tight skin mouse model. The aim was to define the outcome on safety and the change in skin score after rituximab therapy in SSc patients and to correlate the clinical characteristics with the levels of interleukin (IL)-6 and with the immune cell infiltrate detected by immunohistochemistry.

Methods: Nine patients with SSc with mean age 40.9 +/- 11.1 years were treated with anti-CD20, 1 g at time 0 and after 14 days. Skin biopsy was performed at baseline and during the follow-up. B-cell activating factor (BAFF) and IL-6 levels were also determined at the follow-up times.

Results: After 6 months patients presented a median decrease of the skin score of 43.3% (range 21.1-64.0%), and a decrease in disease activity index and disease severity index. IL-6 levels decreased permanently during the follow up. After treatment, a complete depletion of peripheral blood B cells was observed in all but 2 patients. Only 3 patients presented CD20 positive cells in the biopsy of the involved skin at baseline.

Conclusions: Anti-CD20 treatment has been well tolerated and SSc patients experienced an improvement of the skin score and of clinical symptoms. The clear fall in IL-6 levels could contribute to the skin fibrosis improvement, while the presence of B cells in the skin seems to be irrelevant with respect to the outcome after B cell depletion.

Trial registration: ISRCTN77554566.

Figure 1

Clinical improvement during follow up in nine systemic sclerosis patients treated with anti-CD20. Clinical improvement in the nine patients treated with anti-CD20 during the follow-up times (3, 6, 12, 18, 24 and 36 months). Skin score, blood CD20 levels, severity index and activity index were assessed at baseline (0) and after 3, 6, 12, 18, 24 and 36 months. In the first graph precyclophosphamide (preCYP) skin score and skin score at time 0 (time of beginning of rituximab (RTX)) are reported. Each line represents the modification of different parameters in each patient during the follow up. Each symbol (on the left) represents one patient and corresponds to the number of the patient of Table 3.

Figure 2

(a) IL-6 and (b) BAFF levels at baseline and during follow up. IL-6 and B-cell activating factor (BAFF) levels evaluated in nine patients treated with anti-CD20 at baseline and during the follow up. (a and b) Each line represents the modification of IL-6 and BAFF parameters in each patient during the follow up. Each symbol (on the right) represents one patient and corresponds to the number of the patient of Table 3.

Figure 3

B and T cell staining in systemic sclerosis biopsies. In a forearm biopsy, immunohistochemistry revealed an expression of the B-cell marker CD20 in a limited number of (a) lymphocytes while a prominent expression of the T-cell marker CD3 was detected in the (b) perivascular lymphocytic infiltrate. Original magnification × 400.