Rituximab in Diffuse Cutaneous Systemic Sclerosis
Rituximab in Diffuse Cutaneous Systemic Sclerosis
B cells have been noted to be present in skin and lung biopsies from SSc patients in several studies. They are generally found in the perivascular region. The dermatology literature has focused on the T-cell component of this lymphocytic infiltrate, but a study published in 1977 noted that plasma cells were also present (Fig. 1). Lafyatis et al. investigated the effects of B-cell depletion with RTX in 15 patients with recent-onset dcSSC. As B cells were not present in skin biopsies taken from healthy controls, these authors concluded that perivascular B-cell infiltrates are clearly a pathological feature of SSc skin. However, despite the finding that RTX caused B-cell depletion in skin and peripheral blood, no beneficial effect on the skin score was documented in their group of patients ( Table 1 ).
(Enlarge Image)
Figure 1.
Skin biopsy from a patient with early SSc showing a lymphoplasmacytic infiltrate, especially in perivascular regions
(A) Haematoxylin and eosin staining × 40 magnification: low power view showing aggregates of lymphoid cells (circle) within the dermis, which is thickened by compacted collagen bundles; (B) ×100 magnification; (C) ×200 magnification showing that the infiltrate contains plasma cells (arrows), particularly in the perivascular region.
Nevertheless, others have noted efficacy of RTX therapy in modifying skin thickness in small, uncontrolled SSc trials ( Table 1 ). Daoussis et al. studied eight patients with SSc, who were treated with four cycles of RTX and followed up for 2 years. Skin thickening, measured using the mRSS, was improved at 2 years compared with baseline (mean levels fell from 13.5 to 4.9 U). Evidence of histological improvement was seen in six of the eight patients, with a reduction in collagen deposition in the papillary dermis and the myofibroblast score (which fell to <20% of baseline values), along with the expected B-cell depletion. Smith et al. conducted a 24-week open-label study in eight dcSSC patients who were followed after one cycle of RTX at standard doses with methylprednisolone (100 mg per infusion). B-cell depletion was demonstrated to have occurred. There was a significant reduction in the mRSS skin score from 24.8 U (S.D. 3.4) at baseline to 14.3 U (S.D. 3.5) at week 24 (P = 0.001), representing a 43% improvement. This cohort was then re-treated with a further pair of RTX infusions at 6 months and followed up for 2 years. The skin score had fallen slightly further to 13.6 U at 24 months. Skin histology confirmed a concomitant improvement in dermal hyalinized collagen content, which fell from a mean of 69.3 U at baseline (S.D. 22.8) to 33.1 U at 24 months (S.D. 27.0) (P = 0.009). Myofibroblast numbers were also reduced after RTX therapy. These observations are in accord with those of Lafyatis et al., who noted a close association between the myofibroblast score and the mRSS (n = 28, R = 0.54, P = 0.00001), consistent with the profibrotic role that myofibroblasts are likely to play in this condition.
However, open studies are confounded by the known spontaneous regression of skin thickening in dcSSC, which can be quite variable, especially in early disease. Data from the negative 2007 trial of the anti-TGF-β monoclonal, CAT-192, published by Denton et al., indicated that the skin score could fall in placebo-treated patients by up to 20% compared with baseline levels, depending on disease duration. Similarly, Steen et al. estimated that spontaneous regression could reduce dermal thickening by up to 50% of baseline levels in dcSSc of <3 years duration.
The effects of RTX on lung function have also been investigated in SSc patients, as recently reviewed by Cappelli et al.. Lafyatis et al. described B cells as ' … frequently found arranged in lymphoid aggregates but also seen in a more diffuse pattern' in SSc-associated interstitial lung disease (SSc-ILD). In their 2009 study, this group found evidence that ILD might respond to RTX, because there was an average increase of 3.5% in the percentage predicted FVC at 6 months compared with baseline in RTX-treated patients. That finding is consistent with the improvement in FVC noted in RTX-treated patients in the recent EUSTAR cohort and might suggest that the lung is more responsive to B-cell depletion therapy than the skin.
Daoussis et al. evaluated lung function after 1 year in their study of eight SSc patients treated with RTX and six controls. They reported a median percentage improvement in FVC in the RTX group of 10.3% compared with a deterioration in controls of 5.0% (P = 0.002). Similarly, the median percentage improvement in DLCO in the RTX group was 19.5% compared with a deterioration of 7.5% in the control group (P = 0.023). In a study from the Royal Brompton Hospital (London), Keir et al. retrospectively reviewed the progress of 50 patients with severe, progressive ILD who had been treated with RTX between 2010 and 2012. The CTD-ILD subgroup (n = 33) included eight SSc patients. Analysis revealed that the percentage predicted FVC fell by 13.3% in the 6–12 months before RTX administration but then increased by 8.9% post-RTX (P < 0.01). Similarly, the percentage predicted DLCO fell by 18.8% pre-RTX but then stabilized to 0.0% post-RTX (P < 0.01). The authors concluded that RTX may be of benefit in those CTD-ILD patients with aggressive lung disease that was not responsive to conventional immunosuppression, and RCTs are under way to formally test this hypothesis in various subgroups, including SSc.
What Is the Evidence That B Cells Play a Role in SSc Pathology?
Evidence of Effects of RTX on the Skin in SSc
B cells have been noted to be present in skin and lung biopsies from SSc patients in several studies. They are generally found in the perivascular region. The dermatology literature has focused on the T-cell component of this lymphocytic infiltrate, but a study published in 1977 noted that plasma cells were also present (Fig. 1). Lafyatis et al. investigated the effects of B-cell depletion with RTX in 15 patients with recent-onset dcSSC. As B cells were not present in skin biopsies taken from healthy controls, these authors concluded that perivascular B-cell infiltrates are clearly a pathological feature of SSc skin. However, despite the finding that RTX caused B-cell depletion in skin and peripheral blood, no beneficial effect on the skin score was documented in their group of patients ( Table 1 ).
(Enlarge Image)
Figure 1.
Skin biopsy from a patient with early SSc showing a lymphoplasmacytic infiltrate, especially in perivascular regions
(A) Haematoxylin and eosin staining × 40 magnification: low power view showing aggregates of lymphoid cells (circle) within the dermis, which is thickened by compacted collagen bundles; (B) ×100 magnification; (C) ×200 magnification showing that the infiltrate contains plasma cells (arrows), particularly in the perivascular region.
Nevertheless, others have noted efficacy of RTX therapy in modifying skin thickness in small, uncontrolled SSc trials ( Table 1 ). Daoussis et al. studied eight patients with SSc, who were treated with four cycles of RTX and followed up for 2 years. Skin thickening, measured using the mRSS, was improved at 2 years compared with baseline (mean levels fell from 13.5 to 4.9 U). Evidence of histological improvement was seen in six of the eight patients, with a reduction in collagen deposition in the papillary dermis and the myofibroblast score (which fell to <20% of baseline values), along with the expected B-cell depletion. Smith et al. conducted a 24-week open-label study in eight dcSSC patients who were followed after one cycle of RTX at standard doses with methylprednisolone (100 mg per infusion). B-cell depletion was demonstrated to have occurred. There was a significant reduction in the mRSS skin score from 24.8 U (S.D. 3.4) at baseline to 14.3 U (S.D. 3.5) at week 24 (P = 0.001), representing a 43% improvement. This cohort was then re-treated with a further pair of RTX infusions at 6 months and followed up for 2 years. The skin score had fallen slightly further to 13.6 U at 24 months. Skin histology confirmed a concomitant improvement in dermal hyalinized collagen content, which fell from a mean of 69.3 U at baseline (S.D. 22.8) to 33.1 U at 24 months (S.D. 27.0) (P = 0.009). Myofibroblast numbers were also reduced after RTX therapy. These observations are in accord with those of Lafyatis et al., who noted a close association between the myofibroblast score and the mRSS (n = 28, R = 0.54, P = 0.00001), consistent with the profibrotic role that myofibroblasts are likely to play in this condition.
However, open studies are confounded by the known spontaneous regression of skin thickening in dcSSC, which can be quite variable, especially in early disease. Data from the negative 2007 trial of the anti-TGF-β monoclonal, CAT-192, published by Denton et al., indicated that the skin score could fall in placebo-treated patients by up to 20% compared with baseline levels, depending on disease duration. Similarly, Steen et al. estimated that spontaneous regression could reduce dermal thickening by up to 50% of baseline levels in dcSSc of <3 years duration.
Evidence of Effects of RTX on the Lungs in SS
The effects of RTX on lung function have also been investigated in SSc patients, as recently reviewed by Cappelli et al.. Lafyatis et al. described B cells as ' … frequently found arranged in lymphoid aggregates but also seen in a more diffuse pattern' in SSc-associated interstitial lung disease (SSc-ILD). In their 2009 study, this group found evidence that ILD might respond to RTX, because there was an average increase of 3.5% in the percentage predicted FVC at 6 months compared with baseline in RTX-treated patients. That finding is consistent with the improvement in FVC noted in RTX-treated patients in the recent EUSTAR cohort and might suggest that the lung is more responsive to B-cell depletion therapy than the skin.
Daoussis et al. evaluated lung function after 1 year in their study of eight SSc patients treated with RTX and six controls. They reported a median percentage improvement in FVC in the RTX group of 10.3% compared with a deterioration in controls of 5.0% (P = 0.002). Similarly, the median percentage improvement in DLCO in the RTX group was 19.5% compared with a deterioration of 7.5% in the control group (P = 0.023). In a study from the Royal Brompton Hospital (London), Keir et al. retrospectively reviewed the progress of 50 patients with severe, progressive ILD who had been treated with RTX between 2010 and 2012. The CTD-ILD subgroup (n = 33) included eight SSc patients. Analysis revealed that the percentage predicted FVC fell by 13.3% in the 6–12 months before RTX administration but then increased by 8.9% post-RTX (P < 0.01). Similarly, the percentage predicted DLCO fell by 18.8% pre-RTX but then stabilized to 0.0% post-RTX (P < 0.01). The authors concluded that RTX may be of benefit in those CTD-ILD patients with aggressive lung disease that was not responsive to conventional immunosuppression, and RCTs are under way to formally test this hypothesis in various subgroups, including SSc.
