Systemic sclerosis (SSc) is a systemic rheumatic disease with poor prognosis since therapeutic options are limited. Recent evidence from animal models suggests that B-cells may be actively involved in the fibrotic process. B-cells from tight skin mice, an animal model of scleroderma, display a “hyperresponsive” phenotype; treatment with rituximab (RTX) significantly attenuates skin fibrosis in this animal model. In humans, B-cell infiltration is a prominent finding in most lung biopsies obtained from patients with SSc-associated interstitial lung disease. Several open label studies have assessed the clinical efficacy of RTX in SSc. In most patients skin fibrosis improved; lung function either improved or remained stable. Definite conclusions regarding the clinical efficacy of RTX in SSc cannot be drawn but further exploration with a multicenter, randomized study is warranted.
Systemic sclerosis (SSc) is a systemic rheumatic disease characterized by vasculopathy, autoimmunity, and fibrosis. The available therapeutic options are extremely limited and prognosis is variable. Cyclophosphamide (CYC) has shown modest efficacy in the treatment of SSc-associated interstitial lung disease (ILD) [
We performed a literature search in PubMed from 1995 and onwards. We used the following key words: systemic sclerosis, scleroderma, rituximab, B-cells, fibrosis, ILD, and therapy in various combinations.
Research in SSc has been problematic due to the low prevalence of the disease and the lack of an animal model that possesses all features of the human disease. Nevertheless, the tight skin mouse (TSK) and the bleomycin (BLM) induced mouse model of SSc have been extensively used as animal models of the disease. TSK mice are characterized by extensive skin fibrosis and immunological abnormalities including the presence of autoantibodies to topoisomerase-1, both reminiscent of those observed in the human disease [
In another study by Asano et al., the effect of enforced CD19 overexpression on B-cells in the TSK mouse model was assessed [
Recently it was reported that TSK mice have autoantibodies agaist CD22 which were found to be functional and able to attenuate CD22 activation [
Once the link between B-cell hyperactivity and fibrosis had been established in the TSK mouse, the next logical step would be to assess the effect of B-cell depletion in this animal model. RTX administration to newborn TSK mice led to a significant attenuation of skin fibrosis by 43% compared to control TSK mice accompanied by a significant reduction in autoantibody production [
The role of B-cells in fibrosis has also been explored in the BLM-induced mouse model of SSc. Besides skin involvement, lung fibrosis is a prominent feature of this animal model, making it suitable for the assessment of a given treatment on ILD. The investigators reported that BLM administration to CD19 knockout mice led to diminished skin thickening compared to BLM-treated WT littermates [
Recently, the role of CD19 during the development of pulmonary fibrosis in the BLM-induced model has been extensively assessed [
Research on animal models of scleroderma has provided evidence indicating a potential link between B-cell hyperactivity and fibrosis. However, we should note that SSc is a far more complex disease and therefore these data cannot be directly extrapolated to humans.
Only a few studies have addressed the potential contribution of B-cells in the pathogenesis of SSc. In one such study, it was reported that B-cells from patients with SSc had 20% higher CD19 expression compared to B-cells from healthy subjects [
Since patients with SSc express higher levels of CD19 on B-cells and since CD19 is a key molecule in the regulation of signaling thresholds in these cells, something that may relate to break of tolerance and induction of autoimmunity, investigators explored the mechanisms involved in CD19 overexpression in SSc B-cells. Tsuchiya et al. explored the potential association of CD19 polymorphisms with SSc and the level of CD19 expression on B-cells [
It is not clear why SSc B-cells exhibit such an “overactivated” phenotype; B-cell survival factors may be implicated. It has been reported that BAFF serum levels are higher in patients with SSc compared to healthy controls (
In a recent study it was found that peripheral blood mononuclear cells (PBMCs) from SSc patients produced significantly more APRIL (a proliferation inducing ligand), a B-cell survival factor, compared to PBMCs from healthy subjects (
An interesting study, performed by Whitfield et al. examined gene expression profile, using microarrays in scleroderma skin compared to normal [
The potential role of B-cells in SSc-associated ILD has been inadequately investigated. It has been reported that B-cells are present in lung biopsies from patients with SSc-associated ILD [
The above studies have documented the presence of B-cells in both skin and lung of patients with SSc. However direct evidence of a pathogenetic role is lacking.
There are 4 small-scale, open-label clinical studies exploring the potential clinical efficacy of RTX in SSc, including one from our research group and a few case reports. In the first study by Smith et al., eight patients with early (defined by disease duration of <4 years from the first non-Raynaud’s disease manifestation) diffuse SSc received a single course of RTX (consisting of 2 infusions, 1000 mg each, at day 1 and 15) [
Another study reported the effects of a single course of RTX treatment in 15 patients with early (as defined by disease duration of <18 months from the first non-Raynaud’s disease manifestation) diffuse SSc [
Our research group has performed an open label, randomized controlled, 1-year pilot study, assessing the effect of RTX in SSc [
Skin thickening, assessed with the MRSS, was similar in the two treatment groups at baseline (
Even though this is the first and only so far, randomized, controlled study assessing the efficacy of RTX in SSc, several limitations exist. Firstly, the small number of patients recruited does not provide the study with sufficient statistical power to prove efficacy. Additionally, most patients had long-standing disease since no disease duration restriction was applied and was heterogeneous in terms of disease duration, severity, and previous treatments.
Recently, one more study assessing the clinical efficacy of RTX in SSc was published [
Three case reports have also appeared in the literature regarding the use of RTX in SSc. The first case describing the beneficial effect of RTX on SSc-associated ILD was reported by McGonagle et al. [
The beneficial effect of RTX on SSc-associated ILD has also been documented in a case report by our group [
Studies assessing the efficacy of RTX in SSc.
Outcomes | |||||||||
Skin | Lung function tests | Functional status | |||||||
Study | Number of participants | Study type | Evaluation time point(months) | Number of RTX courses | |||||
Clinical assessment | histologic improvement (yes/no) | Skin B-cell depletion | |||||||
Smith et al. | 8 | Open label, uncontrolled | 6 | 1 | Improved | Yes | In 4 patients | Stable | Stable |
Lafyatis et al. | 15 | Open label, uncontrolled | 6/12 | 1 | Stable | Yes | Yes | Stable | Stable |
Daoussis et al. | 8 | Open label, randomized controlled | 12 | 2 | Improved | Yes | Yes | Improved | Improved |
Boselo et al. | 9 | Open label, uncontrolled | 6–36 | 1 (3 patients receive a second cycle) | Improved | Not reported | No | Stable | Improved |
McGonagle et al. | 1 | Case report | — | 2 | Not reported | Not reported | — | Improved | Improved |
Daoussis et al. | 1 | Case report | 24 | 4 | Improved | Improved | Yes | Improved | Improved |
Yu | 1 | Case report | — | 1 | Not reported | Not reported | — | Improved | Improved |
SSc is perhaps the most challenging disease for rheumatologists. So far treatment is based on nonspecific immunosuppression, with agents such as CYC [
The most fearful manifestation of SSc is lung disease which is nowadays the leading cause of mortality. The clinical evidence on the efficacy of RTX in SSc-associated ILD is limited, since most patients recruited either did not have ILD or had only very mild ILD. With the exception of our study, the other 3 studies were not designed to test the potential clinical efficacy of RTX in SSc-associated ILD. Nevertheless, in these three studies PFTs remained stable, even though most patients had early disease and therefore were most likely to exhibit declining PFTs during their followup. In our study, a significant improvement of lung function was reported in contrast to other studies where PFTs remained stable at 6 months compared to baseline. We should note, however, several differences in the design of the studies that could potentially explain these diverse findings. In the other studies most patients did not have ILD in contrast to our study where the presence of ILD was an inclusion criterion. Furthermore, the higher dose of RTX used (4 × 375 mg/m2 instead of 2 × 1000 mg), consecutive treatments, and the longer evaluation period could also be potential explanations. The significant improvement in lung function tests observed in our study indicates that RTX may favourably affect SSc-associated ILD. Long-term treatment with RTX may either improve or stabilize lung function over time in patients with SSc. All 8 patients recruited in the treatment arm group of our study remained on RTX treatment and received two additional courses; their PFTs continued to improve during the second year of followup [
If RTX turns out to be an effective treatment for SSc, which could be the potential mechanisms of action? Several possibilities exist. First, B-cells appear to be actively involved in the fibrotic process, as indicated by data derived from both animal models and humans. Elimination of skin infiltrating B-cells by RTX has been documented, albeit not consistently. Taking into account that B-cell infiltration is a prominent finding in lung biopsies from patients with SSc-associated ILD, depletion of this population may be a potential explanation for the clinical improvement. It would therefore be of great interest to study the effect of RTX on lung disease at a histological level, but this may be inherently difficult and challenging. We have also recently shown that RTX-induced improvement of skin fibrosis associates with a decrease in PDGFR phosphorylation (which corresponds to activation) in scleroderma skin [
Both experimental and clinical evidence regarding B-cell depletion in SSc is encouraging and certainly points to the direction that further exploration of its clinical efficacy is warranted. The best way forward would be a multicenter, randomized, double blind, placebo-controlled study. If such a study is performed we propose that it should focus on ILD rather than skin disease and that it should be designed in such a way, that patients are treated for at least one year and evaluated thereafter; in this way, a treatment effect on ILD (if any) would be more easily depicted. To our knowledge, up until now, no such study has been registered. Interestingly, however, a phase II study assessing the clinical efficacy of RTX in SSc-associated pulmonary arterial hypertension has already been launched (