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Immunosuppression for Connective Tissue Disease–Related Pulmonary Disease Toby M. Maher, MB, MSc, PhD, FRCP1,2,3

Street, London, United Kingdom 2 Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom 3 Centre for Inflammation and Tissue Repair, University College London, Rayne Institute, London, United Kingdom

Address for correspondence Toby M. Maher, MB, MSc, PhD, FRCP, NIHR Biological Research Unit, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, United Kingdom (e-mail: [email protected]).

Semin Respir Crit Care Med 2014;35:265–273.

Abstract

Keywords

► interstitial lung disease ► rituximab ► cyclophosphamide ► systemic sclerosis ► therapy ► polymyositis ► pulmonary vasculitis

With improvements in the systemic treatment of the various connective tissue diseases (CTDs) the pulmonary complications of these conditions are now, for many patients, the major cause of morbidity and impaired quality of life. Furthermore, at least in scleroderma, pulmonary disease has become the leading cause of death for this patient group. Although, the pathogenesis of CTD-related pulmonary disease is poorly understood there is an assumption that it arises as a sequelae of immune-mediated injury to the lung. As a result, immunosuppressant agents form the mainstay of treatment for pulmonary disease occurring in the context of CTD. There is, however, a paucity of clinical trial data available to inform treatment decisions across the spectrum of CTDrelated pulmonary disease. The best available evidence has been generated in scleroderma-associated interstitial lung disease. Therefore, treatment decisions are informed by registry data, case series, and individual case reports. With this in mind, corticosteroids together with azathioprine and mycophenolate mofetil are widely used for the management of mild disease or as a maintenance therapy, while cyclophosphamide and rituximab have emerged as treatments for refractory or rapidly progressive disease. This article examines the data underpinning the use of different immunosuppressants in CTD-associated pulmonary disease while highlighting limitations in the existing knowledge base and identifying questions for future clinical study.

As has been described elsewhere, a range of pulmonary complications are encountered across the different connective tissue diseases (CTDs). The nature of these pulmonary manifestations frequently differs according to the underlying CTD but they are, in general, driven by the same immunemediated processes, which occur in other disease-affected organs. As such, with a few exceptions, immunosuppressant drugs form the mainstay of treatment for pulmonary disease arising in individuals with CTD. This review will explore the current knowledge base concerning immunosuppressant therapy for pulmonary-related CTD manifestations including;

Issue Theme Pulmonary Complications of Connective Tissue Disease; Guest Editors, Danielle Antin-Ozerkis, MD, and Jeffrey Swigris, DO, MS

specific choice of immunosuppressant, timing of treatment, and the anticipated benefits of therapy.

Treatment Principles and Evidence Base Despite pulmonary complications being one of the most important causes of morbidity and mortality in individuals with CTD there have been a very few clinical trials conducted in this area.1–4 To date, only two appropriately powered, randomized controlled trials of treatment have been conducted in this patient group; with both of these assessing the

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DOI http://dx.doi.org/ 10.1055/s-0034-1371531. ISSN 1069-3424.

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1 NIHR Biological Research Unit, Royal Brompton Hospital, Sydney

CTD-ILD Treatment

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benefit of cyclophosphamide compared with placebo for the treatment of scleroderma-related interstitial lung disease (ILD).5,6 Thus, there is much that is unknown regarding optimal treatment of CTD-related pulmonary disease with decisions resting on the results of open label studies, registry data, and expert opinion. Important lacunae in the knowledge base includes the following: (1) the optimal time for initiating treatment and whether this should be at the time of discovery of pulmonary complications or only in those with extensive or progressive disease, (2) whether early and aggressive treatment alters disease outcomes in a manner akin to that seen in rheumatoid arthritis (RA) joint disease, (3) the relative beneficial effects of individual immunosuppressants and whether combination therapy is better than single agent treatment, (4) whether in some circumstances, for example, RA-associated ILD, immunosuppressant drugs may contribute to the development and progression of pulmonary disease, (5) whether treatments targeted at one organ system, for example, joint disease are effective in the treatment of other organ disease manifestations, and (6) the optimal duration of treatment or which measures should be used to guide treatment withdrawal. Answering these questions, although far from easy (due to the relative rarity of the diseases involved, the varied pulmonary presentations of disease and a lack of validated trial endpoints) will require carefully designed, multicenter studies of sufficient duration.7 The studies should be a priority for both the respiratory and rheumatology clinical communities and the relevant patient advocacy groups and charities. While individual CTDs give rise to a reasonably predictable range of pulmonary complications, autoimmune disease in general can affect any compartment of the lung giving rise to a variety of disease presentations. These include: airways disease (e.g., obliterative bronchiolitis in RA), ILD (with the observed histological lesions covering the full spectrum of those encountered in the idiopathic interstitial pneumonias, ranging from usual interstitial pneumonia (UIP) through to desquamative interstitial pneumonitis and even diffuse alveolar damage), pulmonary vascular disease (both pulmonary hypertension and vasculitis), and pleural disease (with

involvement extending from acute serositis through to chronic progressive pleural thickening). While the details of the patterns of pulmonary involvement in individual CTDs are discussed in other articles in this issue, ►Table 1 provides a summary of the characteristic pulmonary complications seen in the different CTDs with an indication of their relative frequency. The majority of evidence supporting the use of immunosuppressants in the treatment of CTD-related pulmonary disease relates to the management of ILD and, to a lesser extent, vasculitis. In certain CTDs where pulmonary hypertension appears to arise as a consequence of vasculitic inflammation, for example, systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), treatment with immunosuppressants can be effective. However, in scleroderma, a disease in which pulmonary hypertension occurs in up to 20% of cases, immunosuppression has no effect on either pulmonary pressures or subsequent disease progression and is therefore avoided unless indicated for other disease manifestations.8–10 Airways disease, especially obliterative bronchiolitis (OB), is another pulmonary complication that appears to respond poorly to immunosuppressant therapy and for which aggressive immunosuppression may even be deleterious.11 There is some evidence to suggest that repeated airway infection may be a cofactor for the development of OB, in particular in the lung transplant literature, where OB is the most common manifestation of chronic graft rejection.12,13 In lung transplant recipients protection against airway injury (through antibiotic prophylaxis14 and the prevention of microaspiration15) reduces the incidence and severity of OB. Anecdotally, the same may well be true in RArelated OB. The role of immunosuppression in the management of pleural disease complications is unclear and may vary between diseases being seemingly more effective in the acute plural manifestations of SLE than in the chronic pleural thickening occasionally seen in rheumatoid disease. In the context of CTD-ILD there are very little high-quality clinical trial data to guide the decision to initiate treatment. There is reasonable evidence across the CTDs to suggest that both the histological pattern of interstitial involvement and

Table 1 Connective tissue diseases and common pulmonary manifestations ILD UIP

NSIP

Airways

Pleural

Vascular

DAH

OP

Systemic sclerosis




þþþ








þþþ



Rheumatoid disease

þþ

þ

þ

þþ

þþ

þ




Primary Sjogren syndrome



þ




þþ

þ

þ



Mixed CTD

þ

þþ

þ

þ

þ

þþ



Idiopathic inflammatory myositis




þþ

þþþ





þ



Systemic lupus erythematosus



þ

þ

þ

þþþ

þ

þþ

Abbreviations: CTD, connective tissue disease; DAH, diffuse alveolar hemorrhage; ILD, interstitial lung disease; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; UIP, usual interstitial pneumonia. Note: Symbols represent relative frequency of each complication (, not seen;
, very low prevalence; þ, low prevalence; þþ, medium prevalence; and þþþ, high prevalence). Seminars in Respiratory and Critical Care Medicine

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severity of lung function impairment are both prognostic determinants (with UIP conferring a worse prognosis than nonspecific interstitial pneumonia [NSIP]3,16). Nonetheless, there is insufficient evidence to use these factors as a guide for therapy. Given an absence of evidence supporting diseasemodifying effects of either early and/or aggressive treatment of CTD-ILD combined with knowledge of the potential toxic effects of immunosuppressant treatment, the majority of clinicians tend to base their therapeutic decisions on disease severity and the level of functional impairment experienced by the affected patient. For individuals with CTD-ILD, the underlying histological lesion, as well as predicting prognosis, does, to a certain extent, predicts response to treatment. As demonstrated in ►Fig. 1, both organizing pneumonia and cellular NSIP can be expected to regress with therapy resulting in functional and lung function improvement. UIP, by contrast, is characterized by fixed fibrosis and architectural destruction (see ►Fig. 2) and the best that can be hoped for with treatment is stabilization of disease and prevention of further decline. With all the caveats concerning the current evidence base in mind, the remainder of this article will focus on individual immunosuppressants and the evidence supporting their use across the different CTDs and for the variety of pulmonary complications observed in these diseases.

Corticosteroids Although, corticosteroids are very widely used in the management of CTD-associated pulmonary disease, there are surprisingly little data to guide their use. The dose and route of corticosteroid administration is driven predominantly by local practice, expert opinion, and by reference to data generated from nonpulmonary disease. For patients with

Fig. 1 High-resolution computed tomography (CT) scans from a 52year-old man with scleroderma-related interstitial lung disease before (A) and 6 months after (B) treatment with six intravenous doses of cyclophosphamide (600 mg/m 2 body surface area) given at monthly intervals together with 10 mg oral prednisolone daily. The initial CT shows diffuse ground glass attenuation with some reticular change and associated traction bronchiectasis. Surgical lung biopsy confirmed mixed cellular and fibrotic nonspecific interstitial pneumonitis. Following therapy there has been a marked improvement in the CT appearances and this corresponded with a 30% improvement in lung function indices.

Fig. 2 Low-power photomicrograph (A) and high-resolution computed tomography (CT) scan (B) from a 54-year-old man with endstage rheumatoid-associated interstitial lung disease. The histological image demonstrates the characteristic appearance of usual interstitial pneumonia, with marked architectural destruction of the lung with loss of alveolar spaces, dense extracellular matrix deposition, fibroblastic foci, and bronchiolized honeycomb cysts. The CT scan shows the corresponding radiological changes of honeycomb destruction of the lung. The architectural destruction, characterized by the honeycomb change, exemplifies why this form of interstitial lung disease is poorly treatment responsive and conveys a grave prognosis.

scleroderma prednisolone doses are usually limited to 20 mg on alternate days or 10 mg daily so as to minimize the risk of steroid-induced renal crises.17 A recent singlecenter retrospective review of scleroderma cases suggested that, over 12 months, single agent corticosteroid treatment is associated with improved lung function (increase in forced vital capacity [FVC] of 158 mL) compared with no therapy (which resulted in a loss of 61 mL of FVC).18 Organizing pneumonia in the context of the idiopathic inflammatory myopathies is the pulmonary complication of CTD most sensitive to corticosteroid treatment. For this reason high-dose corticosteroids (either pulsed intravenous methyl prednisolone or an initial dose of 0.75–1 mg/kg/d of prednisolone) are typically used as first-line therapy in this disorder. This approach to management is supported by data from case reports and outcome observed in cryptogenic organizing pneumonia but has not been subject to assessment in clinical trials.19–22 Seminars in Respiratory and Critical Care Medicine

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Cyclophosphamide The alkylating agent cyclophosphamide is the best studied of all the immunosuppressants used for CTD-related pulmonary disease. It has been assessed as a treatment for scleroderma ILD in two multicenter randomized, placebo controlled trials. The first of these studies, by Tashkin et al compared oral cyclophosphamide (at a dose of 2 mg/kg body weight per day) to matching placebo for 1 year in 158 patients with scleroderma-associated ILD.6 The primary study endpoint was change in FVC at 1 year. Cyclophosphamide treatment was associated with a small (2.53%) but statistically significant (p ¼ 0.03) improvement in FVC when compared with placebo. There were no differences in serious adverse events between placebo and cyclophosphamide although there were more episodes of leucopoenia and hematuria in the active treatment arm. In the second study by Hoyles et al, 45 patients were randomized to receive a combination of lowdose prednisolone, six infusions of cyclophosphamide (given at monthly intervals at a dose of 600 mg/m2 body surface area), followed by azathioprine (2.5 mg/kg/d to a maximum of 200 mg daily) or triple placebo.5 Primary outcome was change in percent predicted FVC and single-breath diffusing capacity for carbon monoxide (DLco) at 1 year. There was a trend (p ¼ 0.08) toward improved FVC in the active treatment arm. As has been argued cogently by Wells et al, both of these studies were hampered in their recruitment of patients because they were conducted at a time when cyclophosphamide was already judged by most clinicians to be the standard of care for patients with progressive scleroderma-associated ILD.23 As such there was a reluctance by investigators to enroll individuals with progressive disease. Instead such individuals were, in the most part, treated outside the study with open label therapy. This view is borne out by the lack of disease progression observed in the placebo arms in both studies. Given that these studies were therefore conducted in individuals with relatively stable fibrotic disease it is perhaps unsurprising that relatively little treatment effect was observed. Several open-label retrospective studies of cyclophosphamide given for scleroderma-associated ILD have been reported in the literature.24–31 Overall these favor cyclophosphamide and tend to suggest a significant improvement in FVC. In most cases, pulsed intravenous cyclophosphamide and daily oral cyclophosphamide appear to have similar efficacy albeit that intravenous dosing appears to be better tolerated. Longitudinal follow-up of the study by Tashkin et al suggests that the beneficial effect of cyclophosphamide treatment wanes over time.6,32,33 Optimal duration of treatment therefore remains to be defined. As in the study by Hoyles et al many centers follow pulsed cyclophosphamide with either azathioprine or mycophenolate mofetil (MMF).5 The efficacy of this approach and appropriate length of treatment regimen remain to be defined.27,34 Cyclophosphamide has not been subjected to clinical trial assessment in any other CTDassociated pulmonary complication. Retrospective case series suggest that it has a similar efficacy to that seen in scleroderma ILD when used as a treatment for ILD associated with Seminars in Respiratory and Critical Care Medicine

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polymyositis, dermatomyositis or MCTD.35–37 It is unknown whether early treatment of CTD-ILD with cyclophosphamide has a disease-modifying effect and for this reason most centers only treat individuals with either extensive or progressive disease. In scleroderma the classification of ILD into limited or extensive, as described by Goh et al,38 provides a useful method for identifying patients requiring early aggressive treatment of their ILD. Ultimately, these questions require carefully designed and appropriately powered studies to provide the necessary answers for clinicians dealing with the practical issue of how best to treat scleroderma and other CTD-ILDs. The other disease area for which cyclophosphamide is considered first- or second-line treatment is in the management of CTD-related vasculitis and acute alveolar hemorrhage.39–41 In such cases the choice of treatment is analogous to that used in the management of other systemic vasculitidies.40,42–44

Azathioprine The purine analogue azathioprine exerts an immunosuppressant effect through inhibition of T- and B-lymphocyte proliferation. Although, widely used in combination with oral corticosteroids in the treatment of CTD-ILD, azathioprine has not been studied alone in any prospective randomized trials. In the study by Hoyles et al of intravenous cyclophosphamide, azathioprine (at a dose of 2.5 mg/kg/d) was used as maintenance therapy for 6 months following initial treatment with intravenous cyclophosphamide.5 As noted earlier, the active treatment arm was associated with a trend toward improved FVC at 12 months. In a prospective open-label study of 13 patients, Paone et al reported that 100 mg daily of azathioprine for 12 months maintained improvements achieved after 1 year’s treatment with intravenous cyclophosphamide in patients with scleroderma-associated ILD.45 In an observational cohort study, Bérezné et al reported similar stability in 23 patients treated with azathioprine following cyclophosphamide for scleroderma ILD.27 A retrospective review of 11 scleroderma patients treated with combined oral corticosteroids and azathioprine, suggested that for patients tolerating treatment, therapy was associated with stabilization or improvement in FVC compared with pretreatment baseline values.27 In idiopathic inflammatory myopathy (IIM), a retrospective analysis of a Taiwanese disease registry reported that use of azathioprine was associated with improved survival.46 The effect of azathioprine in rheumatoid-associated ILD, SLE, or Sjogren-related ILD has not been reported. For patients with pulmonary hypertension in the context of SLE, MCTD, and RA azathioprine is the most frequently used immunosuppressive therapy albeit with limited evidence to support its use or define efficacy.47

Methotrexate The antifolate drug methotrexate is thought to exert its immunosuppressant effect through inhibition of purine metabolism and consequent suppression of T-cell activation and intercellular adhesion molecule expression.48 Despite

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Mycophenolate Mofetil MMF is an inosine monophosphate dehydrogenase inhibitor, which reduces T- and B-cell proliferation through reduction in purine synthesis. MMF has been shown to be well tolerated in systemic sclerosis with retrospective studies suggesting that the drug has favorable effects on systemic manifestations of disease.55–59 In another retrospective study, Fischer et al looked at MMF use in 125 individuals with CTD-ILD, the largest proportion (44) of whom had scleroderma, and were able to demonstrate that MMF was associated with reduced steroid requirement and sustained improvement in FVC.60 An analysis of 69 patients across seven published case series suggests that MMF may stabilize disease in sclerodermaassociated ILD.61 In a consensus statement by the scleroderma clinical trials consortium and the Canadian Scleroderma Research Group, MMF was recommended by three-quarters of the 117 experts surveyed as maintenance therapy for scleroderma ILD.8 The scleroderma lung study (SLS) II is currently evaluating the effect of MMF as first-line therapy compared with cyclophosphamide in scleroderma ILD in a 2year randomized controlled trial (NCT00883129).

Calcineurin Inhibitors The calcineurin inhibitors ciclosporin and tacrolimus inhibit T-cell activation and signal transduction and are typically used to prevent rejection following solid organ transplant. Both drugs have been reported in case studies and small case series to be effective in the treatment of ILD associated with either polymyositis or dermatomyosistis.62–69 The largest of these studies reports 15 cases (identified from a registry of 179 patients with myositis) of IIM-associated ILD treated with calcineurin inhibitors for a median of 24 months. The majority (11 cases) were being treated for refractory disease.62 Overall, 13 of the 15 treated individuals had an improvement in lung function following initiation of a calcineurin inhibitor with an overall mean increase in FVC of 10% occurring over the course of active treatment. The available evidence suggests that calcineurin inhibitors should be considered for use as a therapy in individuals with treatment-resistant IIM-ILD or for those patients who relapse following standard first- and second-line therapy.

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Rituximab Rituximab, a chimeric (human/mouse) monoclonal antibody with a high affinity for the CD20 surface antigen expressed on pre-B and B-lymphocytes, results in rapid depletion of B cells from the peripheral circulation for 6 to 9 months.70 Evidence for the effectiveness of B-cell depletion exists in several immune-mediated conditions, including RA,71–73 antineutrophil cytoplasmic antibody-associated vasculitis44,74 and immune thrombocytopenic purpura.75 In a small open label, randomized proof of principle study of rituximab in scleroderma ILD (given at a dose of 375 mg/m2 weekly for 4 weeks at baseline and again at 24 weeks), Daoussis et al reported a significant improvement in FVC, compared with baseline, at 1 year in the rituximab group. In the active treatment group FVC increased from 68.1
19.7% predicted to 75.6
19.7% predicted (p ¼ 0.0018).76 In the cohort receiving best standard care there was an overall reduction in FVC over the 12 months of the study. Rituximab has been reported as an effective rescue therapy for patients with scleroderma ILD unresponsive to treatment with corticosteroid.77 In individuals with IIM-ILD for whom cyclophosphamide is contraindicated or else fails to induce a therapeutic response, rituximab may be an effective alternative. In a retrospective cohort study, Keir et al reported outcomes in nine individuals (six of whom had either polymyositis or dermatomyositis) with CTD-ILD. Overall rituximab, even though used as rescue therapy, was associated with clinically important improvements in lung function, gas exchange, and radiological disease extent.78 A larger follow-up cohort of 50 patients with fibrotic ILD (including 10 with IIM, 8 with scleroderma, 2 with RA, and 2 with MCTD) treated with rituximab reports similar results, with an average 8.9% improvement in FVC after 6 to 12 months in patients with CTD-ILD.79 An ongoing clinical trial, the RECITAL study (NCT01862926), is assessing, in a double dummy, randomized controlled trial, the efficacy of rituximab compared with intravenous cyclophosphamide when given as first-line therapy in progressive CTD-ILD (including scleroderma, IIM, and MCTD). Like cyclophosphamide, rituximab has been reported to have efficacy in the treatment of pulmonary vasculitis and diffuse alveolar hemorrhage occurring in the context of preexisting connective tissue disease.79–81

Imatanib The tyrosine kinase inhibitor, imatinib, prevents protein phosphorylation through inhibition of the specific tyrosine kinase, BCR-Abl. The drug was originally developed as a therapy for chronic myeloid leukemia. In vitro studies in human lung fibroblasts and in vivo studies utilizing the murine bleomycin model, albeit with the use of prophylactic dosing (i.e., at the time of bleomycin administration) of imatinib, suggest that imatinib may have antifibrotic actions.82 Sabnani et al reported the use of imatinib (200 mg daily) in combination with intravenous cyclophosphamide (500 mg every 3 weeks) in five patients with sclerodermaassociated ILD.83 The combination was well tolerated but Seminars in Respiratory and Critical Care Medicine

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methotrexate being the established first-line therapy for rheumatoid-related joint disease49 and having proven efficacy in preventing relapse of the vasculitidies,43 its role in the management of CTD-ILD is unclear. Mainly this is because of methotrexate’s perceived capacity to induce pulmonary complications.50,51 While methotrexate is undoubtedly capable of causing ILD, this appears to occur almost exclusively in individuals with RA and the incidence of this complication has probably been historically overestimated.52 Methotrexate is occasionally used for scleroderma ILD in individuals intolerant of azathioprine or MMF.8 There are reports of methotrexate being an effective second-line agent for ILD associated with MCTD and the idiopathic inflammatory myopathies.53,54

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efficacy was not determined. In a phase IIa open-label, single arm study, Spiera et al reported the use of imatinib (400 mg daily) for 1 year in 24 patients with diffuse cutaneous systemic sclerosis. In this group FVC improved, on average, by 6.4% compared with baseline over 12 months (p ¼ 0.008).84 More recently Khanna et al have reported a study of imatinib 600 mg/daily in 20 patients with scleroderma-associated ILD.85 At this dose imatinib was poorly tolerated with common adverse effects including fatigue, edema, diarrhea, nausea, and vomiting, generalized rash and new onset proteinuria. Only 60% of subjects completed the study. No beneficial effect of imatinib on FVC was observed. The use of imatinib for other CTD-ILDs is limited to a single case report in which 400 mg daily of imatinib for 20 weeks was apparently effective in improving symptoms due to MCTD-associated ILD.86 These mixed results preclude the routine use of imatinib in scleroderma ILD but are sufficient to merit further randomized, placebo-controlled studies.

of the CTDs respiratory disease is the leading cause of both morbidity and mortality. Despite an increasing repertoire of available therapies for the treatment of immune-mediated disease, there have been few significant advances in the management of the pulmonary complications of CTD. Corticosteroids together with azathioprine or MMF form the mainstay of treatment in milder cases while cyclophosphamide and, increasingly, rituximab represent the major treatment options for refractory or rapidly progressive disease. There is however, a desperate need for high-quality clinical trials in patients with CTD-related pulmonary disease so as to define both the best therapies and also the optimal management approach for this debilitating group of disorders.

Note T.M. is in receipt of unrestricted academic industry grants from GSK and Novartis. In the last 3 years T.M. or his institution have received advisory board or consultancy fees from; Actelion, Boehringer Ingelheim, GSK, InterMune, Novartis, Lanthio, Takeda, Sanofi-Aventis, and UCB. T.M. has received speaker’s fees from UCB, Boehringer Ingelheim, InterMune, and AstraZeneca. T.M. has participated as an investigator in industry sponsored clinical trials run by Boehringer Ingelheim, GSK, InterMune, Novartis, Roche, and Celgene.

Other Immunomodulatory Treatments A range of monoclonal antibody therapies have emerged in the fields of rheumatology and oncology in the last decade. While many of these drugs have an established role in the management of the systemic manifestations of CTD, their efficacy as potential treatments for CTD-ILD is largely unknown. The proinflammatory cytokine interleukin (IL)-6 has been implicated in the pathogenesis of pulmonary fibrosis and has been shown to be elevated in the serum of individuals with scleroderma ILD.87–90 Tocilizumab, an anti-IL-6 monoclonal antibody, has been reported to improve lung function in an individual with RA-ILD and in a 15-year-old girl with biopsy proven desquamative interstitial pneumonitis on a background of undefined autoimmune disease.91,92 Other monoclonal approaches that may have a potential future role in the management of CTD-ILD include, the anticomplement 5 antibody eculizumab19 and the anti CD-52 antibody alemtuzumab.93 By contrast the antitumor necrosis factor (TNF)-α antibodies, particularly infliximab and etanarcept, have been associated with an increased risk of developing ILD in individuals with rheumatoid disease.94–96 Although, TNF-α inhibition has been reported to be an effective treatment for the ILD associated with dermatomyositis,97 these drugs should be used with caution in individuals with preexisting lung disease in the context of CTD. In addition to the monoclonal antibodies, other immunomodulatory drugs that may be beneficial in the treatment of the pulmonary complications of CTD are the anti-IL-1Rα antibody, anakinra98,99 and hydroxychloroquine.100 Intravenous immunoglobulin therapy has also been reported to arrest the progression of ILD in several case reports and series of individuals with polymyositis or dermatomyositis.19,101,102

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2 3

4

5

6

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Conclusion As the systemic management of the CTDs has improved the pulmonary complications associated with these disorders have become an increasingly important problem. In many Seminars in Respiratory and Critical Care Medicine

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death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 2010; 69(10):1809–1815 Fischer A, du Bois R. Interstitial lung disease in connective tissue disorders. Lancet 2012;380(9842):689–698 Kim EJ, Collard HR, King TE Jr. Rheumatoid arthritis-associated interstitial lung disease: the relevance of histopathologic and radiographic pattern. Chest 2009;136(5):1397–1405 Fischer A, Swigris JJ, du Bois RM, et al. Anti-synthetase syndrome in ANA and anti-Jo-1 negative patients presenting with idiopathic interstitial pneumonia. Respir Med 2009;103(11):1719–1724 Hoyles RK, Ellis RW, Wellsbury J, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 2006;54(12):3962–3970 Tashkin DP, Elashoff R, Clements PJ, et al; Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354(25):2655–2666 Khanna D, Brown KK, Clements PJ, et al. Systemic sclerosisassociated interstitial lung disease-proposed recommendations for future randomized clinical trials. Clin Exp Rheumatol 2010; 28(2, Suppl 58):S55–S62 Walker KM, Pope J; participating members of the Scleroderma Clinical Trials Consortium (SCTC); Canadian Scleroderma Research Group (CSRG). Treatment of systemic sclerosis complications: what to use when first-line treatment fails—a consensus of systemic sclerosis experts. Semin Arthritis Rheum 2012;42(1):42–55 Launay D, Humbert M, Berezne A, et al. Clinical characteristics and survival in systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease. Chest 2011;140(4): 1016–1024

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