Abstract
We would like to report our experience of using rituximab in cyclophosphamide refractory, rapidly progressive interstitial lung disease (ILD) in a patient with limited scleroderma. A 40-year-old man presented with 10-week history of inflammatory polyarthritis, which responded to a short course of oral corticosteroids. However, 3 weeks later, he developed new onset of exertional dyspnoea. High-resolution CT of the thorax was suggestive of early ILD. Surgical lung biopsy showed features of fibrotic non-specific interstitial pneumonia. He was diagnosed with scleroderma on the basis of: presence of anticentromere antibodies, Raynaud’s phenomenon, pulmonary fibrosis, digital oedema and hypomotility along with a dilated oesophagus. He was treated aggressively with pulse doses of corticosteroids and cyclophosphamide; however, his ILD continued to deteriorate. At this stage, he received rituximab (two pulses of 1 g each), which led to a gradual clinical improvement. Now, 12 months since his rituximab infusion, he walks 2 miles daily without any exertional dyspnoea.
Introduction
Scleroderma or systemic sclerosis (SSc) is a heterogeneous systemic disorder that is characterized by massive deposition of collagen and other matrix substances in connective tissue; moreover, there is also a small-vessel vasculopathy and an autoimmune response associated with autoantibodies. SSc-associated lung disease remains the lead cause of morbidity and mortality in SSc patients [Steen and Medsger, 2007], and is the second most frequent organ system involved. The treatment options for SSc have lagged behind those of rheumatoid arthritis, where therapeutic options have increased tremendously in the past decade with the introduction of biological agents. The traditional treatment approach to SSc revolves around an old phrase ‘no drug has been proven totally ineffective until it has been tried in scleroderma’. No treatment has proved to prevent disease progression, and cyclophosphamide remains the gold standard for severe skin and lung involvement. This clearly emphasizes the clinical need for more effective novel therapies. B cells may play a pivotal role in the pathophysiology of scleroderma [Kraaij and van Laar, 2008; Wollheim, 2004], and reports have claimed that targeting B cells is a viable treatment option in SSc patients with different organ involvements. We would like to share our experience of managing cyclophosphamide-refractory SSc-associated interstitial lung disease, where one course of rituximab led to almost complete clinical and radiological resolution of interstitial lung disease (ILD).
Case report
Serial 6-minute walk test results, which shows its sustained improvement with one course of rituximab.
Serial pulmonary function tests (PFTs) trends. This shows a gradual sustained improvement in PFTs. These were not measured between May 2009 (the time of first presentation with dyspnoea) and January 2010 (3 months post-rituximab course) as the patient’s condition rapidly deteriorated during this time, and he was undergoing treatments with cyclophosphamide or rituximab.
FVC, forced vital capacity; FEV1, forced expiratory volume in one second; DLCO, carbon monoxide diffusing capacity of the lung.
Axial high-resolution chest CT images from (A) September 2009, (B) October 2009 and (C) May 2010. Images from (A) show thickening of the interlobular and intralobular septae, ground glass opacification and traction bronchiolectasis. These changes were more severe in the lower lung zones. Subsequent imaging (B, C) showed successive improvement with only subtle residual interstitial reticulation and ground glass change evident on (C).
Discussion
The pathogenesis of SSc is poorly understood. However, few observations which indicate a potential role for B cells in the development of SSc are noteworthy. B-cell abnormalities are commonly noted in SSc, such as the production of disease-specific autoantibodies, polyclonal B-cell activation and hypergammaglobulinemia [Famularo et al. 1989]. Moreover, significantly increased expression of CD19 cells has been noted in memory and naive B cells [Sato et al. 2004, 2000], and the presence of CD20+ B cells have been observed in SSc skin biopsies [Whitfield et al. 2003]. Similarly, chronic B-cell activation through enhanced CD19 signalling has been linked to skin sclerosis in a murine model, suggesting that B cells are possible targets in the therapy for SSc [Saito et al. 2002]. Although, autoantibodies have not been shown to be pathogenic, they are present in the majority of patients with SSc and they define clinical subgroups. Similar to the other components of SSc, immunologic abnormalities have been a target of therapy, and depleting peripheral B cells by rituximab has been successfully tried so far. For SSc skin disease, two small, uncontrolled trials and a number of case reports have shown an improvement of skin involvement with rituximab [Smith et al. 2010; Bosello et al. 2010, 2007; Lombardi et al. 2008]; however, another open-labelled trial had failed to show any significant beneficial effect of rituximab on skin disease [Lafyatis et al. 2009]. It is worth mentioning that a recently published report described a single treatment course of rituximab that was shown to induce a consistent and sustained improvement of skin thickening, disease activity and functional ability, notably in patients with early disease [Bosello et al. 2010]. For scleroderma lung disease, one open-labelled study (randomized, controlled), and three case reports claim good clinical improvement of ILD with rituximab [Yoo, 2010; Daoussis et al. 2010a, 2010b; McGonagle et al. 2008]. Our results are in agreement with the majority of reports for SSc lung disease. However, the significant resolution of HRCT changes observed in our case was reported in only one other patient [Yoo, 2010] and the common feature noted between these two cases was the shorter disease duration. This suggests a better response with earlier intervention with rituximab before lung fibrosis is established.
We acknowledge that although there appears to be a very striking temporal relationship to the improved symptoms, PFTs and HRCT changes with the administration of rituximab, one cannot conclude based on this single case, and long-term prospective studies are needed to confirm these findings. We do not believe that resolution of his ILD is simply due to corticosteroids, as he received three doses of 1 g methylprednisolone in June 2009, which was followed by high doses of oral corticosteroids (reducing dose of 1 mg/kg/day); however, his ILD continued to deteriorate quite markedly until September 2009. However, it is possible that rituximab without prednisone would have failed despite the fact that prednisolone alone was ineffective. Similarly, this resolution of ILD is probably not attributable to the use of cyclophosphamide. Although, some studies of cyclophosphamide therapy for SSc–ILD have shown some continued improvement even after the drug was discontinued [Tashkin et al. 2007]; however, in contrast with their data, our patient continued to have significant clinical and radiological worsening of his ILD for up to 5 months of cyclophosphamide treatment. Thus, it is conceivable that the reported clinical improvement in our patient can be ascribed to rituximab therapy. While progressive ILD is felt to be more common among patients with diffuse skin disease, it is important to highlight that limited cutaneous SSc is also associated with severe, progressive ILD [Fischer et al. 2008]. Similarly, severe ILD can accompany SSc sine scleroderma, which is a rare form of SSc whereby patients acquire visceral disease in the absence of the characteristic cutaneous involvement [Fischer et al. 2006; Lomeo et al. 1989]. Fibrotic NSIP has been noted to be the predominant histopathologic pattern in lcSSc and has been related with significant survival benefit [Fischer et al. 2008; Park et al. 2007; Bouros et al. 2002; Kim et al. 2002].
It is also important to highlight that high doses of corticosteroids have been regarded as a risk factor for developing SSc renal crisis, as was also shown in a recent systematic review [Trang et al. 2010]; however, the renal functions in our patient remained normal after more than 1 year of treatment with moderate to high doses of corticosteroids. We acknowledge that research has shown that outcome in SSc lung disease is not linked to the histopathologic pattern, rather on the disease severity at presentation and serial carbon monoxide diffusing capacity of the lung (DLCO) trends [Bouros et al. 2002]. However, lung biopsy was obtained in our patient due to the diagnostic uncertainty, as he had no skin involvement apart from mild digital oedema, and he developed a rapidly progressive ILD pattern within few weeks of his initial presentation with inflammatory arthritis. Finally, what are the risks associated with rituximab therapy? Rituximab, a monoclonal anti-B-cell antibody, was originally used mainly in the management of patients with B-cell malignancies; however, in recent years, rituximab has emerged as a novel therapeutic alternative for patients with various autoimmune disorders. Since the use of these agents has increased worldwide, we are learning more about the occurrence of different adverse events, particularly the late-onset effects. In the short to medium term, some of the more common adverse events with rituximab infusions include the following: infusion reactions, infections, cytopenias (lymphopenia, neutropenia, thrombocytopenia, anaemia), activation of viruses, especially HBV, the development of antihuman chimeric antibodies and rare cardiac toxicity [Biogen Idec and Genentech, 2010]. Also worth mentioning are the reports of progressive multifocal leukoencephalopathy as a rare but devastating event after rituximab administration [Kranick et al. 2007], and currently rituximab carries a US FDA-mandated ‘black-box’ warning [FDA, 2007]. However, this risk is difficult to assess given the multiple confounders [Calabrese and Molloy, 2008]. Moreover, there are a few late-onset adverse events which cannot be overlooked. For example, the development of late-onset of neutropenia with a median interval of 77 days [Wolach et al. 2010] and the occurrence of iridocyclitis 1 year posttreatment of rituximab [El Fassi et al. 2010].
In conclusion, our report demonstrates the efficacy of rituximab in a patient with rapidly progressive SSc who had not responded to cyclophosphamide. Rituximab (one course) had a marked effect on lung involvement, leading to a dramatic clinical and radiological improvement. We suggest that rituximab appears to be worthy of consideration as an additional therapeutic modality for SSc patients with progressive lung involvement, where disease is recalcitrant to traditional treatment. There is supportive evidence suggesting a better response rate when introduced earlier in the disease course. For management of SSc-associated lung disease, rituximab seems an important welcome addition to a limited armamentarium.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors have no conflicts of interest to declare.