Description of the condition
Connective tissue disease (CTD) can affect any component of the respiratory tract, causing a diverse range of disorders. When it is associated with interstitial lung disease (ILD), CTD is classified within the current American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus statement as one of the forms of diffuse parenchymal lung disease of known cause (ATS/ERS Consensus Statement). Approximately 30% of individuals with ILD have associated CTD, which presents subsequent to the development of ILD in about 15% of sufferers (Mittoo 2009).
Various approaches have been used to define connective tissue disease–related interstitial lung disease (CTD-ILD). The most rigorous approach is to include only people with features that clearly meet published diagnostic criteria for systemic autoimmune disease. However, many sufferers of ILD display one or more features of CTD clinically or serologically, without meeting diagnostic criteria. Amongst the definitions that have so far been applied to this cohort, significant heterogeneity in disease behaviour has been displayed, suggesting that further refinement is required to distinguish persons in this group suffering from CTD-ILD from those with idiopathic interstitial pneumonia (Corte 2012).
The connective tissue disorders most commonly associated with ILD include scleroderma/systemic sclerosis, rheumatoid arthritis, polymyositis/dermatomyositis and Sjögren's syndrome. Each may be associated with progressive and fatal disease, but survival data in general are better than those seen for idiopathic forms of ILD (Fischer 2008; Park 2007). As an example, five-year survival for people with systemic sclerosis–related ILD has been reported to be approximately 85%, as opposed to 50% for idiopathic disease (Wells 1994). It remains to be elucidated what features are the principal determinants of progression among suffers of CTD-ILD. Histologically, non-specific interstitial pneumonia, usual interstitial pneumonia (UIP), organising pneumonia and lymphocytic interstitial pneumonia all may occur. Although for idiopathic interstitial pneumonia, UIP carries a significantly worse prognosis than other histological forms, with the exception of rheumatoid arthritis, a histological impact on prognosis is not seen in CTD-ILD (Bouros 2002; Kim 2010).
Despite resulting in better survival than its idiopathic counterparts, ILD is the major cause of death amongst individuals with scleroderma (Ferri 2002). When present, ILD contributes to reduced physical function and quality of life (Baron 2008). Correlation has been demonstrated between extent of ILD and degree of disability, and this correlation serves as a predictor of disease behaviour. Radiological and physiological extent of ILD in cohorts suffering from CTD and scleroderma has been demonstrated to adversely affect prognosis (Goh 2008; Park 2007). A greater rate of decline in physiological values such as forced vital capacity (FVC) is a predictor of mortality in people with scleroderma (Assassi 2010).
Description of the intervention
Cyclophosphamide is a highly potent immunosuppressant that has demonstrated efficacy in inducing and maintaining remission in a range of autoimmune and inflammatory illnesses (Gourley 1996; Hoffman 1992). Its immunosuppressant activity may occur in a number of ways. Through its action as an alkylating agent, cyclophosphamide causes cross-linkage of a variety of macromolecules, including DNA, producing cell death amongst resting and dividing lymphocytes. Additionally, it produces impaired humoral and cellular immune responses (Hall 1992).
Cyclophosphamide is associated with a range of important toxicities that make its usage problematic, limiting its prescription to a specialist setting. Most patients experience nausea and hair thinning. Haemorrhagic cystitis and bladder cancer are produced by exposure of the bladder to acrolein, a metabolite of cyclophosphamide. The risk of each is related to total cumulative dose, with a total dosage greater than 100 g most strongly associated with bladder cancer. To reduce total dosage, duration of cyclophosphamide usage is often limited to periods shorter than 12 months.
Cyclophosphamide causes bone marrow suppression with associated risks of bacterial and opportunistic infections, as well as reactivation of dormant infections such as tuberculosis. It is associated with gonadal toxicity with the potential to cause premature ovarian failure and oligospermia or azoospermia. It is teratogenic and should be avoided throughout pregnancy. The risk of haematological malignancy, skin cancer and solid organ malignancy is increased.
Cyclophosphamide is administered in daily oral and intermittent intravenous protocols, with intravenous regimens having gained a vogue because they allow a reduction by up to two-thirds of total cumulative dose, thereby reducing the risk of malignancy and bladder toxicity (Boumpas 1992). The standard oral dosage in patients with normal renal function is 2 mg/kg/d, and intravenous doses range between 500 and 1000 mg/m2 body surface area administered every four to six weeks. Therapy generally is provided for at least six months and is followed by treatment with a less toxic alternative immunosuppressant.
How the intervention might work
On radiological grounds, fibrotic lung disease associated with CTD is similar to that seen in idiopathic interstitial pneumonia (Hwang 2009). Similar pathways have been suggested in their causation with elevated levels of a range of similar pro-inflammatory and pro-fibrotic cytokines such as transforming growth factor (TGF)-beta signalling pathways, along with growth factors and chemokines involved in connective tissue deposition (Mathai 2010; Murray 2011; Peng 2011).
Despite these similarities, recent research has highlighted genetic differences in the MUC5-B promoter region between sufferers of idiopathic pulmonary fibrosis (IPF) and scleroderma-related ILD (Stock 2013). Histological differences are apparent, with CTD-ILD demonstrating an increase in germinal centre density and inflammation and reduced numbers of fibroblastic foci (Song 2009). These differences suggest an alternative "inflammatory" pathogenesis that is likely crucial in providing the basis for CTD-ILD’s improved natural history and responsiveness to immunosuppressant therapy. A number of immunosuppressant approaches have been used for the treatment of IPF, and each has demonstrated a disappointing lack of efficacy (Raghu 2012). Only limited data can be found for most of the immunosuppressant therapies used in CTD-ILD, but supportive case series data are available for a number of them, including prednisolone, methotrexate, azathioprine, cyclosporine and mycophenolate mofetil (Fischer 2013). Cyclophosphamide has a significantly greater literature exploring its use, including several placebo-controlled trials in CTD-ILD (Hoyles 2006; Tashkin 2006).
Why it is important to do this review
Decision making in the treatment of CTD-ILD is difficult, with the clinician having to balance a high level of need for therapy in a severely unwell patient population against the potential for adverse effects from highly toxic therapy for which only relatively limited data on efficacy can be found. Research in this field has been limited, with publications frequently representing case reports or case series. It is not clear whether evidence of efficacy in one CTD subtype can be extrapolated to all forms. Similarly, it is not clear whether histological subtype, disease duration or disease extent can be used to predict responsiveness. Although these issues cannot currently be answered in the absence of sufficient clinical studies, improved understanding of the strength of the treatment effect of cyclophosphamide in CTD-ILD, as well as the extent to which adverse effects can be expected, would be of great assistance in clinical decision making.