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Rituximab in the treatment of systemic sclerosis-associated interstitial lung disease: Comment on the article by Yoo

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Abstract

Several lines of evidence from basic research indicate that B cells may contribute to the pathogenesis of systemic sclerosis. Clinical studies as well have provided preliminary data pointing to the direction that B-cell depletion with rituximab might be a therapeutic option for patients with this debilitating disease.
1
Rituximab in the treatment of systemic sclerosis-associated
interstitial lung disease. Comment on the article by Yoo
Dimitrios Daoussis, M.D. and Andrew P. Andonopoulos, M.D., FACP.
Division of Rheumatology, Department of Internal Medicine, Patras University
Hospital, University of Patras Medical School , Patras, Greece.
Address correspondence and reprint requests to: Dr. D. Daoussis, Department of
Internal Medicine, Division of Rheumatology, Patras University Hospital, 26504
Rion, Patras, Greece. Tel: +30-2610-999 693, FAX: +30-2610-993 982.
E-mail: jimdaoussis@hotmail.com
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Abstract
Several lines of evidence from basic research indicate that B cells may contribute to
the pathogenesis of systemic sclerosis. Clinical studies as well, have provided
preliminary data pointing to the direction that B cell depletion with rituximab might
be a therapeutic option for patients with this debilitating disease.
Key words: systemic sclerosis; scleroderma; rituximab; interstitial lung disease; B
cells; fibrosis; skin thickening; rheumatic diseases
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Dear Sir
We read with interest the article by Yoo which reported a case of successful treatment
of systemic sclerosis (SSc)-associated interstitial lung disease (ILD) with rituximab
(RTX) in a patient resistant to steroid and cyclophosphamide (CYC) therapy. The
author mentions that there is only one case report of improvement of SSc-associated
ILD with RTX so far. This is incorrect. We have previously shown that RTX may
improve lung function in patients with SSc-associated ILD, in a randomized,
controlled, proof of principle study, of one year duration. (1) This study was
available online (Epub ahead of print) since May 2009, six months prior of the date
this article was submitted. This is why we were surprised to notice that our study was
not included in the references even though the author has performed an exhaustive
literature search and has included all the articles regarding the use of rituximab in
SSc, including two in abstract form.
Three studies so far have explored the potential clinical efficacy of RTX in SSc. (1-3)
Our study, however, was the only one specifically designed to test the effect of RTX
on SSc-associated ILD, since the presence of ILD was an inclusion criterion and most
patients had severe ILD. On the contrary the other two studies excluded patients with
severe ILD and only a fraction of patients had evidence of mild ILD. We evaluated
14 patients with SSc. Eight patients were randomized to receive 2 courses of RTX at
baseline and 24 weeks, whereas 6 patients (control group) received standard treatment
alone. The median percentage of improvement of FVC in the RTX group was
10.25% whereas that of deterioration in the controls was 5.04% (p=0.002). The
median percentage of improvement of DLco in the RTX group was 19.46% whereas
that of deterioration in the control group was 7.5% (p=0.023). We also found
evidence of skin remodelling with reduction of collagen deposition in most patients
4
treated with RTX which correlated with skin B cell depletion. We have also
published a case report describing dramatic improvement of lung function and skin
fibrosis in a patient with severe, diffuse scleroderma following long term treatment
with RTX. (4) Our data indicate a possible disease modifying role of RTX in SSc,
particularly in SSc-associated lung disease. (5)
The case report by Yoo is in agreement with our data and suggests that RTX may
have beneficial effects on SSc-associated ILD. It is worth mentioning that this
particular patient showed a dramatic improvement in HRCT findings something that
was not observed in our cohort, probably due to the longer disease duration of our
patients which had more established fibrosis.
SSc is a multisystem disease with poor prognosis since no disease modifying drugs
exist so far. Cyclophosphamide has shown modest results, however its toxicity
restricts its long term use. Clinical, as well as basic research data indicate that
targeting B cells with RTX may be a promising therapeutic approach in SSc. We
propose that further exploration of the clinical efficacy of RTX in SSc-associated ILD
is highly needed. A direct comparison of RTX versus cyclophosphamide, the gold
standard of care so far, in a large, multicentre, randomized, double blind study, would
seem a reasonable approach.
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Reference List
(1) Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A,
Sirinian C et al. Experience with rituximab in scleroderma: results from a 1-
year, proof-of-principle study. (2010) Rheumatology (Oxford); 49:271-280.
(2) Lafyatis R, Kissin E, York M, Farina G, Viger K, Fritzler MJ et al. (2009) B cell
depletion with rituximab in patients with diffuse cutaneous systemic sclerosis.
Arthritis Rheum; 60:578-583.
(3) Smith V, Van Praet JT, Vandooren B, Van der CB, Naeyaert JM, Decuman S et
al. (2010) Rituximab in diffuse cutaneous systemic sclerosis: an open-label
clinical and histopathological study. Ann Rheum Dis; 69:193-197.
(4) Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A,
Korfiatis P et al. Is There a Role for B-cell Depletion as Therapy for
Scleroderma? A Case Report and Review of the Literature. Semin Arthritis
Rheum 2009. Epub ahead of print
(5) Simms RW, Lafyatis R. (2010) Rituximab: a potential therapeutic advance in
scleroderma: what is the evidence? Rheumatology (Oxford); 49:201-202.
... Daoussis and Andonopoulos [60] investigated the effect of rituximab therapy. Administration of rituximab signifi- cantly reduced the number of B cells in three patients (who had clinical responses) but had no effect on the re- maining three patients of the rituximab group (who did not respond) [60]. ...
... Daoussis and Andonopoulos [60] investigated the effect of rituximab therapy. Administration of rituximab signifi- cantly reduced the number of B cells in three patients (who had clinical responses) but had no effect on the re- maining three patients of the rituximab group (who did not respond) [60]. ...
Article
Skin involvement in SSc is an important marker of disease activity, severity and prognosis, making the assessment of skin a key issue in SSc clinical research. We reviewed the published data assessing skin involvement in clinical trials and summarized the major conclusions important in SSc clinical research. A systematic literature review identified randomized controlled trials using skin outcomes in SSc. Analysis examined the validity of the different skin measures based on literature findings. Twenty-two randomized controlled trials were found. The average study duration was 10.2 (s.d. 4.5) months, mean (s.d.) sample size 32.4 (32.6) and 26.7 (27.8) in intervention and control arms, respectively. The 17-site modified Rodnan skin score is a fully validated primary outcome measure in diffuse cutaneous SSc. Skin histology seems to be an appropriate method for evaluation of skin thickness. These findings have important implications for clinical trial design targeting skin involvement in SSc. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
... Although only infliximab reduced density of collagen, clinically it was only associated with stabilisation, and no clear benefit to skin. Rituximab was associated with both improvement in the skin score, and significant improvements in the dermal hyalinised collagen and dermal myofibroblast numbers (287,288). It demonstrated that three responders had a marked reduction in B cells, and these findings were associated with a clinical response, not found in the nonresponders to therapy. ...
Thesis
Clinical heterogeneity is a cardinal feature of systemic sclerosis (SSc). Hallmark SSc autoantibodies are central to diagnosis and associate with distinct patterns of skin and organ-based complications. Understanding molecular differences between patients, which reflect clinical outcomes in a meaningful way, have the potential to benefit clinical practice and research and give insight into pathogenesis of disease. The BIOPSY (BIOlogical Phenotyping in SYstemic sclerosis) dataset provided a platform for the integrated analysis of skin and blood samples, along with detailed clinical phenotyping. Through this I was able to explore key molecular differences in early dcSSc, in the context of the full scleroderma spectrum of patients (established dcSSc and lcSSc). The work presented in this thesis demonstrates that there were molecular differences between autoantibody state in the early dcSSc cohort, in skin and blood in serum protein analytes, histological analysis and skin gene expression. These differences are not appreciated when analysed by skin trajectory over a 12-month period. This could explain the clinical heterogeneity seen in SSc, and emphasized the importance of incorporating known autoantibody states in any clinical trial analysis. This work helps move SSc therapeutic strategies towards a more personalized medicine approach, as autoantibody differences may also explain differing response to therapeutics. The BIOPSY dataset also provided an opportunity to utilise blister fluid as an anchor for identifying plasma proteins that reflect skin severity. Blister fluid provides a unique insight int the local environment of the skin. Integrating skin biopsy transcriptomics and blister fluid allowed for the development of a surrogate skin score, using these modalities to identify key analytes in the plasma, and ensuring the plasma analytes reflected skin severity in a multisystem disease. The findings from this thesis are relevant to understanding disease behaviour and potentially impact future clinical trial design and interpretation.
... Studies in experimental animals and in humans with SSc have implicated the semantic role of B cells in the pathogenesis of the disease [5,13,14]. Apart from the peripheral blood, B cell infiltrates are apparent in lung tissue from SSc patients as well [15]. ...
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AbstractSystemic sclerosis (SSc) is a rare, aggressive, systemic, autoimmune disease especially because of internal (vital) organ involvement, most commonly over the last decades of the lungs. Therefore, there is an increasing need for the rheumatologist to select an effective treatment in order to improve patients’ prognosis. Recent experimental data have established a role of the B cell in pathogenesis of the disease. B cell depletion, although not usually chosen as first-line treatment, has been investigated over the past decade in controlled and uncontrolled trials with satisfactory results mainly in skin involvement, but trials of B cell depletion in improving lung function do not lag behind in effectiveness compared to respective results in the skin. This review is referring to trials that have attributed B cell depletion an optimistic view of halting progression of interstitial lung disease in scleroderm (PDF) Treating scleroderma lung disease with B-cell depletion. Available from: https://www.researchgate.net/publication/348522560_Treating_scleroderma_lung_disease_with_B-cell_depletion [accessed May 21 2021].
... The importance of these roles is supported by the therapeutic benefit gained from depleting B cells in patients with a range of autoimmune diseases. For example, patients with diseases such rheumatoid arthritis (RA) [71], type 1 diabetes (T1D) [72], anti-neutrophil cytoplasmic antibody (ANCA) vasculitis [73], multiple sclerosis (MS) [74], systemic sclerosis (SSc) [75,76], primary Sjögren's syndrome [77][78][79][80] and systemic lupus erythematosus (SLE) [81][82][83] benefit from therapeutic depletion of B cells. Of note in this respect is that B cell-depleting therapy has a clinical benefit without significantly affecting autoantibody levels, suggesting that, perhaps, other B cell functions, including antigen presentation and cytokine production could be critical aspects of B cell involvement in the pathogenesis of the autoimmune diseases. ...
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Objective. To assess the efficacy of rituximab (RTX) in SSc. Methods. Fourteen patients with SSc were evaluated. Eight patients were randomized to receive two cycles of RTX at baseline and 24 weeks [each cycle consisted of four weekly RTX infusions (375 mg/m²)] in addition to standard treatment, whereas six patients (control group) received standard treatment alone. Lung involvement was assessed by pulmonary function tests (PFTs) and chest high-resolution CT (HRCT). Skin involvement was assessed both clinically and histologically. Results. There was a significant increase of forced vital capacity (FVC) in the RTX group compared with baseline (mean ± s.d.: 68.13 ± 19.69 vs 75.63 ± 19.73, at baseline vs 1-year, respectively, P = 0.0018). The median percentage of improvement of FVC in the RTX group was 10.25%, whereas that of deterioration in the controls was 5.04% (P = 0.002). Similarly, diffusing capacity of carbon monoxide (DLCO) increased significantly in the RTX group compared with baseline (mean ± s.d.: 52.25 ± 20.71 vs 62 ± 23.21, at baseline vs 1-year respectively, P = 0.017). The median percentage of improvement of DLCO in the RTX group was 19.46%, whereas that of deterioration in the control group was 7.5% (P = 0.023). Skin thickening, assessed with the Modified Rodnan Skin Score (MRSS), improved significantly in the RTX group compared with the baseline score (mean ± s.d.: 13.5 ± 6.84 vs 8.37 ± 6.45 at baseline vs 1-year, respectively, P < 0.001). Conclusion. Our results indicate that RTX may improve lung function in patients with SSc. To confirm our encouraging results we propose that larger scale, multicentre studies with longer evaluation periods are needed.
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Full-text available
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Full-text available
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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. We performed an internet search using the keywords systemic sclerosis, scleroderma, rituximab, B-cells, fibrosis, interstitial lung disease (ILD), and therapy. 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. 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.
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The safety and potential efficacy of rituximab was examined in diffuse cutaneous systemic sclerosis (dc-SSc). A 24 week open-label study in which eight patients with dc-SSc received an infusion of 1000 mg rituximab administered at baseline and day 15, together with 100 mg methylprednisolone at each infusion. Assessment included CD19+ peripheral blood lymphocyte number, skin sclerosis score, indices of internal organ functioning, the health assessment questionnaire disability index, the 36-item Short Form health survey and histopathological evaluation of the skin. Ritixumab induced effective B-cell depletion in all patients (<5 CD19+ cells/microl blood). There was a significant change in skin score at week 24 (p<0.001). Also, significant improvements were measured in the dermal hyalinised collagen content (p = 0.014) and dermal myofibroblast numbers (p = 0.011). Two serious adverse events occurred, which were thought to be unrelated to the rituximab treatment. Rituximab appears to be well tolerated and may have potential efficacy for skin disease in dc-SSc.
Is there a role for B-cell depletion as therapy for scleroderma? A case report and review of the literature Epub ahead of print
  • Daoussis D Sn
  • Ac
  • C Kalogeropoulou
  • A Kazantzi
Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A, Korfiatis P et al. (2009) Is there a role for B-cell depletion as therapy for scleroderma? A case report and review of the literature. Semin Arthritis Rheum 2009. Epub ahead of print
Is There a Role for B-cell Depletion as Therapy for Scleroderma? A Case Report and Review of the Literature Epub ahead of print (5) Simms RW Rituximab: a potential therapeutic advance in scleroderma: what is the evidence?
  • D Daoussis
  • Sn Liossis
  • Ac Tsamandas
  • C Kalogeropoulou
  • A Kazantzi
  • P Korfiatis
Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A, Korfiatis P et al. Is There a Role for B-cell Depletion as Therapy for Scleroderma? A Case Report and Review of the Literature. Semin Arthritis Rheum 2009. Epub ahead of print (5) Simms RW, Lafyatis R. (2010) Rituximab: a potential therapeutic advance in scleroderma: what is the evidence? Rheumatology (Oxford); 49:201-202.