Is There a Role for B-cell Depletion as Therapy for Scleroderma? A Case Report and Review of the Literature

doi:10.1016/j.semarthrit.2009.09.003

Seminars in Arthritis and Rheumatism

Volume 40, Issue 2, October 2010, Pages 127-136

https://doi.org/10.1016/j.semarthrit.2009.09.003 Get rights and content

Objectives

Rituximab (RTX) has been successfully used in the treatment of several rheumatic diseases with an acceptable safety profile. We present herein a patient with systemic sclerosis (SSc) who exhibited significant improvement of his lung function and skin fibrosis following RTX administration, and review the literature regarding the role of B-cells in SSc and the potential efficacy of RTX in its treatment.

Methods

We performed an internet search using the keywords systemic sclerosis, scleroderma, rituximab, B-cells, fibrosis, interstitial lung disease (ILD), and therapy.

Results

Our patient, a 40-year old man with severe SSc-associated ILD, received 4 courses of RTX. The patient's lung function improved; forced vital capacity and diffusing capacity of carbon monoxide reached values of 35% and 33%, respectively, compared with 30% and 14% of pretreatment values. Skin thickening assessed clinically and histologically improved as well. Several lines of evidence suggest that B-cells may have a pathogenic role in SSc. B-cells from tight skin mice—an animal model of SSc—exhibit chronic hyperactivity; likewise, B-cells from patients with SSc overexpress CD19 and are chronically activated. Furthermore, studies have revealed that B-cell genes were specifically transcribed in SSc skin and that B-cell infiltration was a prominent feature of SSc-associated ILD. The potential clinical efficacy of RTX in SSc has been explored in a limited number of patients with encouraging results. Preliminary data suggest that RTX may favorably affect skin as well as lung disease in SSc.

Conclusions

Several basic research data underscore the potential pathogenic role of B-cells in SSc and clinical evidence suggests that RTX might be a therapeutic option in SSc. Large-scale multicenter studies are needed to evaluate the potential clinical efficacy of RTX in SSc.

Section snippets

Methods

PubMed, EMBASE, and congress conference proceedings were used for the literature search from 1995 onward. The search was limited to publications in English and the keywords used were as follows: systemic sclerosis, scleroderma, rituximab, B-cells, fibrosis, interstitial lung disease, and therapy in various combinations. The computerized search was completed with a manual search of reference lists from the articles retrieved.

Case Report

The patient, a 40-year old man, was diagnosed with diffuse SSc in 1993; interstitial lung disease (ILD) was evident with reduced forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco) values (60% and 70% of predicted, respectively). He gradually developed dyspnea on exertion (New York Heart Association [NYHA] class II) and his lung function tests declined (55% and 41% for FVC and DLco, 3 years after presentation). He received cyclophosphomide (CYC) pulse therapy for 2

Discussion

This is the first report on the effect of 6-monthly RTX courses over a 2-year period in a patient with SSc. The significant improvement of lung function, as indicated by multiple sequential lung function tests, oxygen saturation, 6MWD, and functional status in this patient, is promising. The improvement of skin fibrosis, as assessed both clinically and histologically, is also encouraging and may suggest a disease-modifying role of RTX in SSc.

Data from basic research studies indicate that

Acknowledgments

We thank C. Sirinian for kindly performing the immunohistochemistry and L. Costaridou for valuable contributions in developing the CAD system for volumetric quantification of lung patterns of ILD.

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Safety and efficacy of rituximab in connective tissue disease-associated interstitial lung disease: A systematic review and meta-analysis
2021, International Immunopharmacology
Rituximab (RTX) is widely used in the treatment of connective tissue disease (CTD) because it can target and eliminate pathogenic B cells. Interstitial lung disease (ILD) is one of the common complications of CTD; however, the clinical benefits of RTX in connective tissue disease-associated interstitial lung disease (CTD-ILD) are still controversial. This meta-analysis was performed to systematically evaluate the efficacy and safety of RTX in CTD-ILD patients.
We performed a systematic online query in PubMed, Cochrane, and Embase up to February 2020. Randomized controlled trials and observational studies on the use of RTX and conventional treatment in CTD-ILD patients were comprehensively reviewed and investigated.
In total, 6 studies, including 242 participants, were analysed. The pooled results showed that RTX is superior to conventional treatment methods in improving forced vital capacity and modified Rodnan skin scores (MRSS) in patients with systemic sclerosis (P＜0. 05), but there was no statistically significant difference between RTX and conventional treatment method in the improvement of lung diffusion function. The risk of adverse effects declined in the RTX therapy groups compared with the conventional therapy groups in terms of infection and the blood system.
The pooled results of this meta-analysis indicated that RTX is well tolerated, and RTX is able to improve or stabilize pulmonary function in CTD-ILD patients.
A novel bispecific antibody alleviates bleomycin-induced systemic sclerosis injury
2020, International Immunopharmacology
Systemic sclerosis (SSc) is induced by variety of factors and eventually causes multiple organ damage. In recent years, biological agents targeting cytokines and cell surface molecules have gradually come to market. Here, the anti-inflammatory and antifibrotic effects of a novel bispecific antibody (FL-BsAb1/17) targeting interleukin-17A (IL-17A) and interleukin-1β (IL-1β) were detected. Bleomycin (BLM) was subcutaneously injected for 21 consecutive days to establish the SSc mouse model, and mice were subsequently treated with etanercept or different doses (1, 5, 10 mg/kg) of FL-BsAb1/17. The results showed that FL-BsAb1/17 treatment (10 mg/kg, 5 mg/kg) significantly attenuated BLM-induced SSc-like inflammation by inhibiting the expression of inflammatory factors (IL-17A, IL-1β, IL-8, IL-22, IL-23, IL-6) and fibrosis, with specific outcomes of dermis thickening and lung fibrosis, by inhibiting the expression of fibrotic factors (TGF-β, α-sma, Col-1, Col-3) in the serum, skin and lungs. In addition, FL-BsAb1/17 (10 mg/kg, 5 mg/kg) downregulated protein levels of TGF-β and phosphorylated Smad2/3 in the skin and lungs and reduced collagen 1 protein levels. This indicated that FL-BsAb1/17 can inhibit the development of fibrosis by inhibiting the TGF-β/Smad2/3 signaling pathway. FL-BsAb1/17 (10 mg/kg, 5 mg/kg) could also effectively reduce the content of MDA, increase the activity of SOD and CAT, and improve the total antioxidant capacity (T-AOC). In conclusion, FL-BsAb1/17 alleviated BLM-induced SSc by downregulating inflammatory cascades, relieving oxidative stress and inhibiting TGF-β/Smad2/3 signaling. These data suggest that FL-BsAb1/17 has potential as a novel therapeutic candidate for SSc.
A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease
2017, Seminars in Arthritis and Rheumatism
Rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). We aimed to assess long-term efficacy and safety of RTX in SSc compared to standard treatment.
A total of 51 patients with SSc-associated interstitial lung disease were recruited and treated with RTX (n = 33) or conventional treatment (n = 18). Median follow-up was 4 years (range: 1–7). Conventional treatment consisted of azathioprine (n = 2), methotrexate (n = 6), and mycophenolate mofetil (n = 10).
Patients in the RTX group showed an increase in FVC at 2 years (mean ± SD of FVC: 80.60 ± 21.21 vs 86.90 ± 20.56 at baseline vs 2 years, respectively, p = 0.041 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow-up. At the 7 year time point the remaining patients in the RTX group (n = 5) had higher FVC compared to baseline (mean ± SD of FVC: 91.60 ± 14.81, p = 0.158 compared to baseline) in contrast to patients in the control group (n = 9) where FVC deteriorated (p < 0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group in FVC (p = 0.013). Improvement of skin thickening was found in both the RTX and the standard treatment group; however, direct comparison between groups strongly favored RTX at all-time points. Adverse events were comparable between groups.
Our data indicate that RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Randomized controlled studies are highly needed.
The role of Dickkopf-1 in joint remodeling and fibrosis: A link connecting spondyloarthropathies and scleroderma?
2017, Seminars in Arthritis and Rheumatism
Dickkopf-1 (Dkk-1) is a soluble inhibitor of the canonical Wnt pathway, which plays critical roles in embryonic development. Evidence suggests that this molecule regulates several aspects of both bone biology and fibrosis.
To provide an overview of our current knowledge of the role of Dkk-1 in joint remodeling and fibrosis.
We performed an electronic search (Medline) using the following key words: Dickkopf-1 (or Dkk-1), new bone formation, joint remodeling, ankylosing spondylitis, systemic sclerosis (or scleroderma), and fibrosis, supplemented by a manual search of references from retrieved articles.
Dkk-1 is a master regulator of joint remodeling in animal models of arthritis shifting the balance toward new bone formation when its expression is decreased and toward erosion/joint destruction when its expression is increased. In humans, evidence suggests that Dkk-1 may be dysfunctional in patients with ankylosing spondylitis, a prototype bone forming disease. Moreover, data from animal models indicate that Dkk-1 has a protective role against fibrosis in several organs. Recent data suggest that inhibiting the canonical Wnt pathway by overexpression of Dkk-1 could be a way to target TGF-β signaling in fibrotic diseases. Finally, B-cell depletion therapy in systemic sclerosis may exert its effects through TGF-β dependent upregulation of Dkk-1.
Dkk-1 appears to play a crucial role in both joint remodeling/ectopic ossification and fibrosis, and may be a prospective therapeutic modality for fibrotic diseases or diseases characterized by pathologic joint remodeling.
Rituximab in the treatment of patients with systemic sclerosis. Our experience and review of the literature
2015, Autoimmunity Reviews
Citation Excerpt :
In particular, the EUSTAR multicentre study analyzed the efficacy and safety of RTX in a relatively large series of patients, showing that the drug was able to significantly improve the extent of skin sclerosis in patients with diffuse SSc subset; moreover, in individuals with interstitial lung disease RTX was able to prevent a further decline of FVC compared to controls [31]. The clinical usefulness was associated with elevated patients' compliance and safety of RTX treatment as previously observed in other autoimmune rheumatic disorders [7–13,17,18,20–32]. Comparable results have been demonstrated in another recent trial [32] reporting a significant improvement of both skin sclerosis and other SSc activity/severity indexes after RTX cycles in patients unresponsive to recent treatment with cyclophosphamide.
The treatment of systemic sclerosis (SSc) represents a great clinical challenge because of the complex disease pathogenesis including vascular, fibrotic, and immune T- and B-lymphocyte-mediated alterations. Therefore, SSc should be treated by combined or sequential therapies according to prevalent clinico-pathogenetic phenotypes. Some preliminary data suggest that rituximab (RTX) may downregulate the B-cell over expression and correlated immunological abnormalities.
Here, we describe a series of 10 SSc patients (4 M and 6 F, mean age 46 ± 13.5SD years, mean disease duration 6.3 ± 2.7SD years; 5 pts had limited and 5 diffuse SSc cutaneous subset) treated with one or more cycles of RTX (4 weekly infusions of 375 mg/m²). The main indications to RTX were interstitial lung fibrosis, cutaneous, and/or articular manifestations unresponsive to previous therapies; ongoing treatments remained unchanged in all cases. The effects of RTX were evaluated after 6 months of the first cycle and at the end of long-term follow-up period (37 ± 21SD months, range 18–72 months). An updated review of the world literature was also done.
RTX significantly improved the extent of skin sclerosis in patients with diffuse SSc at 6 months evaluation (modified Rodnan skin score from 25 ± 4.3 to 17.2 ± 4.6; p = .022). A clinical improvement of other cutaneous manifestations, namely hypermelanosis (7/7), pruritus (6/8), and calcinosis (3/6) was observed. Moreover, arthritis revealed particularly responsive to RTX showing a clear-cut reduction of swollen and tender joints in 7/8 patients; while lung fibrosis detected in 8/10 remained stable in 6/8 and worsened in 2/8 at the end of follow-up. Pro-inflammatory cytokines, namely IL6, IL15, IL17, and IL23, evaluated in 3 patients with diffuse cutaneous SSc, showed a more or less pronounced reduction after the first RTX cycle.
These observations are in keeping with the majority of previous studies including 6 single case reports and 10 SSc series (from 5 to 43 pts), which frequently reported the beneficial effects of RTX on some SSc manifestations, particularly cutaneous sclerosis, along with the improvement/stabilization of lung fibrosis. Possible discrepancies among different clinical studies can be related to the etiopathogenetic complexity of SSc and not secondarily to the patients' selection and disease duration at the time of the study.
The present study and previous clinical trials suggest a possible therapeutical role of RTX in SSc, along with its good safety profile. The specific activity of RTX on B-cell-driven autoimmunity might explain its beneficial effects on some particular SSc clinical symptoms, namely the improvement of skin and articular involvement, and possibly the attenuation of lung fibrosis.
Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis
2015, Seminars in Arthritis and Rheumatism
To assess the long-term efficacy and safety of single and multiple courses of rituximab therapy in systemic sclerosis (SSc) patients with and without lung disease.
A total of 20 SSc patients with a diffuse disease were treated with rituximab. At baseline and during follow-up the lung involvement was evaluated with pulmonary function tests (FVC and DLCO) and with lung high-resolution computed tomography (HRCT).
The skin score, activity, and severity indices improved significantly after 12 months and at final follow-up compared to baseline.
After 12 months, there was a significant increase of FVC and TLC compared to baseline (p = 0.024 and p = 0.005, respectively), while the mean DLCO value remained stable.
Considering the last available follow-up in six patients with restrictive lung disease at baseline, two patients (33.3%) experienced an increase of more than 10% of FVC, one patient had a decrease of FVC >10%, while in three patients FVC remained stable (50%). After the mean follow-up of 48.5 ± 20.4 months, among the patients with normal lung parameters at baseline, FVC remained stable in 12 (85.7%) and in one patient (14.3%) it increased by more than 10%. At the final follow-up, the alveolar and interstitial HRCT scores remained stable in more than 80% of patients, both in patients with and without restrictive lung disease at baseline.
Anti-CD20 B cell depletion therapy is effective on skin involvement but seems also to preserve the pulmonary function, as supported by a stable or improved FVC and stable interstitial score, suggesting a possible role of rituximab as a modifying therapy overall in early diffuse SSc.

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: The authors have no conflicts of interest to disclose.

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Systemic sclerosisIs There a Role for B-cell Depletion as Therapy for Scleroderma? A Case Report and Review of the Literature

Objectives

Methods

Results

Conclusions

Section snippets

Methods

Case Report

Discussion

Acknowledgments

Mol Immunol

Am J Pathol

Am J Pathol

J Invest Dermatol

Am J Pathol

J Invest Dermatol

Cytokine Growth Factor Rev

Amplification of ROS and Ras in systemic sclerosis fibroblasts J Biol Chem

Blood

Best Pract Res Clin Haematol

Blood

Lancet

Lancet

Blood

Blood

Biol Blood Marrow Transplant

B lymphocytes and systemic sclerosis

Curr Opin Rheumatol

Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study

Rheumatology (Oxford)

B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis

Arthritis Rheum

Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study

Ann Rheum Dis

Towards quantification of interstitial pneumonia patterns in lung multidetector CTBioInformatics and BioEngineering

BIBE 20088th IEEE International Conference, Athens, Greece, October 8-10

A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation

Genome Res

Genetic and immunologic features associated with scleroderma-like syndrome of TSK mice

Curr Rheumatol Rep

CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse

J Clin Invest

Quantitative genetic variation in CD19 expression correlates with autoimmunity

J Immunol

Systemic sclerosis
Is There a Role for B-cell Depletion as Therapy for Scleroderma? A Case Report and Review of the Literature