Matucci Cerinic, Marco

Miniati, Irene

Valentini, G

English

Florence Research

Available online http://arthritis-research.com/content/11/1/103Page 1 of 3(page number not for citation purposes)AbstractIn systemic sclerosis (SSc), there is no proven treatment to preventdisease progression. In a recent meta-analysis of three randomisedcontrolled trials (RCTs) and six open prospective studies oncyclophosphamide (CYC), no significant changes in lung functionwere observed. However, CYC is associated with an improvementof Mahler’s dyspnea index, short form-36 (physical and mentaldomains), and health-related quality of life, contributing to theamelioration of patients’ functional status. Further RCTs on earlySSc are needed to assess the real efficacy of CYC in inducingremission and increasing survival.In a previous issue of Arthritis Research & Therapy, Nanniniand colleagues [1] addressed the topic by a well-conductedmeta-analysis and concluded that cyclophosphamide (CYC)treatment does not induce a statistically significant improve-ment in lung function in systemic sclerosis (SSc) interstitiallung disease (ILD). This meta-analysis pooled the data fromthree randomised controlled trials (RCTs) and six obser-vational studies and focused on the changes in pulmonaryfunctional parameters (forced vital capacity [FVC] and diffus-ing lung capacity for carbon monoxide [DLCO]) of SScpatients treated with CYC for at least 1 year [1]. Such aconclusion sets a negative scenario in which CYC should notbe considered as an ‘anchor’ drug for the treatment of SScand ILD.In SSc, no drug or combination of drugs has been demon-strated to modify disease progression. In both RCTs versusplacebo, the trend toward improvement in FVC suggests thatthe efficacy of CYC on lung function is limited, as alsocorroborated by a mild effect size (Table 1) [2,3]. Thisnegative opinion may not reflect what is going on in a ‘reallife’ scenario, when other efficacy parameters are considered.Actually, the scleroderma lung study group reported, after12 months, a significant reduction of Mahler’s dyspnea indexin CYC-treated patients when compared with placebo(P <0.0001) and a statistically significant amelioration ofshort form-36 (SF-36) in each domain: mental (P = 0.006),emotional (P = 0.005), general health status (P = 0.003), andvitality (P = 0.009) [4]. Despite the negligible value of effectsize for all of these scale domains, minimum clinicallyimportant difference (which represents the smallest improve-ment in the score of a health-related quality of life measure-ment instrument which patients perceive as beneficial) wassignificantly higher for all measures in CYC-treated patients[5]. The improvement of dyspnea and reduction of skinthickness may have a favourable effect not only on functionalstatus but also on psychological aspects, as demonstrated bythe analysis of each SF-36 domain.In SSc, the efficacy of CYC is an important issue andtherefore attention needs to be focused on some clinicalfacts that are observed in ‘real life’ in everyday practice. Thefirst fact is that, when ILD is treated in an advanced phase, nodrug has been able to ‘clean’ the lung, reverting fibrosis into anormal parenchyma. Actually, in most studies carried out inpatients with long-lasting disease, CYC has been able to‘freeze’ the disease process. For a disease such as SSc, inwhich ‘everything (or nothing) seems to work’ [6], this may beconsidered a positive result that should encourage physiciansto move the use of CYC to the earliest phase of SSc, beforefibrosis does consistent damage in the interstitialcompartment. The second fact is that the identification ofearly pulmonary disease remains a problem because the toolsused so far may be inadequate. On high-resolution computedtomography, a ground-glass appearance of lower lobes canreflect the presence of a thin yet irreversible fibrosis [7].EditorialCyclophosphamide in systemic sclerosis: still in search of a ‘real life’ scenarioIrene Miniati1, Gabriele Valentini2 and Marco Matucci Cerinic11Department of Biomedicine, Division of Rheumatology AOUC, Denothe Center, University of Florence, Viale Pieraccini 18, 50139 Florence, Italy2Department of Internal Medicine, Rheumatology Unit, Second University of Naples, Via Pacifici 5, 80131 Napoli, ItalyCorresponding author: Marco Matucci Cerinic, cerinic@unifi.itPublished: 23 January 2009 Arthritis Research & Therapy 2009, 11:103 (doi:10.1186/ar2576)This article is online at http://arthritis-research.com/content/11/1/103© 2009 BioMed Central LtdSee related research by Nannini et al., http://arthritis-research.com/content/10/5/R124CYC = cyclophosphamide; DLCO = diffusing lung capacity for carbon monoxide; FVC = forced vital capacity; ILD = interstitial lung disease; QALY =quality-adjusted life year; RCT = randomised controlled trial; SF-36 = short form-36; SSc = systemic sclerosis.Arthritis Research & Therapy    Vol 11 No 1 Miniati et al.Page 2 of 3(page number not for citation purposes)Moreover, neither bronchoalveolar lavage findings nor theirchanges after CYC treatment may predict the response toCYC [8]. In this condition, the best available way to identifyactive and reversible disease seems to be the identification ofTable 1Primary and secondary outcomes in three randomised controlled trials and corresponding effect sizesReference Outcomes Effect size Safety1. Hoyles, et al. [3], Follow-up after 1 year 3 withdrawals in the active group due 2006 Primary endpoints: to side effects (1 patient had FVC: no change P = 0.08 versus placebo ES = 0.35 (CI –0.24, 0.94) intolerable nausea and 1 patient had DLCO: no change P = 0.64 versus placebo ES = –0.01 (CI –0.59, 0.58) abnormal findings on liver function TLC: no change P = 0.61 ES = 0.06 (CI –0.53, 0.64) tests during treatment with AZA) and FEV1: no change P = 0.16 ES = 0.28 (CI –0.31, 0.86) no withdrawals in the placebo group Kco: no change ES = 0.3 (CI –0.29, 0.88) (NNH = 11)Secondary endpoint:HRCT: trends toward to improve P = 0.39 NNT = 52. Tashkin, et al. [2], Skin score: decreased ES = –0.24 (CI 0.09, – 0.56) 20 patients withdrew in the active 2006 Diffuse ES = –0.06 (CI 0.27, – 0.38) group and 13 patients in the placebo Limited ES = –0.04 (CI 0.28, –0.37) group, mostly due to adverse events or serious adverse events within Primary outcome: 12 months.FVC: increased (P <0.03) favouring Cyc ES = 0.14 (CI –0.18, 0.47) (NNH = 11.2)Secondary outcomes:TLC: increased (P = 0.026) favouring Cyc ES = 0.19 (CI –0.13, 0.52)DLCO: no change ES = –0.06 (CI –0.38, 0.27)SF-36 score:Physical: no change versus placebo ES = 0.24 (CI –0.09, 0.56)Mental: no change versus placebo ES = 0.27 (CI –0.06, 0.6)HAQ-DI: decreased ES = –0.37 (CI –0.04, – 0.69)Transitional dyspnea score: improvement Not possible to calculateP <0.0013. Nadashkevich, MRSS: decreased after 12 (P <0.001) ES = –1.31 (CI –0.74, –1.85) No withdrawalset al. [11], 2006 and 18 months (P <0.01) of therapy in after 6 months Adverse events on Cyc included hair Cyc group versus baseline; P <0.001 ES = –5.94 (CI –4.7, –7.03) loss, nausea, dyspepsia, and versus controlled patients after 12 months leucopenia.ES = –9.21 (CI –7.39, –10.79) after 18 monthsAttack frequency of Raynaud: decreased ES = –1.99 (CI –1.34, – 2.58) after 12 (P <0.001) and 18 months after 6 months(P <0.01) of therapy in Cyc group versus ES = –8.35 (CI –6.69, –9.81) baseline; P <0.001 versus controlled after 12 monthspatients ES = –11.68 (CI –9.41, –13.66) after 18 months NNT = 1.3FVC: no change in Cyc group (P = NS), ES = 3.38 (CI 2.56, 4.12) worsening in AZA group (P <0.01) after after 6 months6, 12, and 18 months of therapy versus ES = 4.92 (CI 3.85, 5.86) baseline; P <0.001 versus controlled after 12 monthspatients ES = 7.38 (CI 5.89, 8.68) after 18 monthsDLCO: no change in Cyc group (P = NS), ES = 2.46 (CI 1.76, 3.1) worsening in AZA group (P <0.01) after after 6 months6, 12, and 18 months of change in Cyc ES = 5.12 (CI 4.02, 6.09) group (P = NS), worsening in AZA group after 12 months(P <0.001) after 12 and 18 months of ES = 7.72 (CI 6.16, 9.07) therapy versus baseline; P <0.001 versus after 18 monthscontrolled patientsAZA, azathioprine; CI, confidence interval; Cyc, cyclophosphamide; DLCO, diffusing lung capacity for carbon monoxide; ES, effect size; FEV1,forced expiratory volume in 1 second; FVC, forced vital capacity; HAQ-DI, Health Assessment Questionnaire-Disability Index; HRCT, high-resolution computed tomography; Kco, monoxide transfer coefficient; MRSS, modified Rodnan skin score; NNH, number needed to harm; NNT,number needed to treat; NS, not significant; SF-36, short form-36; TLC, total lung capacity.patients in whom a recent decrease of more than 10% inFVC and/or DLCO has occurred either with or without thedevelopment of new symptoms, mainly dyspnoea on exertion.The third fact is that the studies have focused their attentionon diffuse SSc patients only, whereas limited SSc patientswith ILD are not usually targeted in trials.Besides efficacy, there is still concern about the use of CYCfor the occurrence of adverse events. In fact, according to thescleroderma lung study group, basing the analysis on a casewith a history of SSc ILD of 1.5 years, the treatment-relatedtoxicity seems to be higher than the beneficial effect. How-ever, when the authors performed a sensitive analysis thatalso considered a treatment initiation after 0.7 and 3 yearsfrom the diagnosis, they demonstrated that an early initiationof the treatment was associated with a greater preservationof lung function and that it allowed a gain of 0.20 quality-adjusted life years (QALYs) versus a loss of 0.21 QALYs ofthe case base (disease duration of 1.5 years) and 0.44QALYs if started after 3 years from the diagnosis [9]. Thesedata clearly demonstrate that an early diagnosis of ILD in SScis fundamental for starting a treatment that may amelioratequality of life and increase survival.We know that the gold standard to assess the efficacy of adrug is an RCT and therefore the only way to lift the curtainon the role of CYC in ILD will derive from a trial on patientswith properly defined early and active SSc. The absence ofguidelines derived from RCT leaves the treatment in thehands of physicians who almost bare-handedly are stillconfronted with the challenge of blocking the evolution ofSSc and of ILD [10]. The increasing awareness andknowledge of SSc pathogenesis, the development ofinternational networks (European League AgainstRheumatism Scleroderma Trials And Research [EUSTAR]group), and the fact that new promising drugs(mycophenolate and kinase inhibitors) and treatmentstrategies (hematopoietic stem cell transplantation) are nowunder scrutiny in RCTs indicate that we are just at the dawnof a new era that likely will lead to the identification oftherapies able to consistently slow the eventual evolution ofSSc to fibrosis and atrophy.Competing interestsThe authors declare that they have no competing interests.References1. Nannini C, West CP, Erwin PJ, Matteson EL: Effects of cyclo-phosphamide on pulmonary function in patients with sclero-derma and interstitial lung disease: a systematic review andmeta-analysis of randomized controlled trials and observationalprospective cohort studies. Arthritis Res Ther 2008, 10:R124.2. Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, FurstDE, Arriola E, Silver R, Strange C, Bolster M, Seibold JR, Riley DJ,Hsu VM, Varga J, Schraufnagel DE, Theodore A, Simms R, WiseR, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E,Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Roth-field N, et al.: Cyclophosphamide versus placebo in sclero-derma lung disease. N Engl J Med 2006, 354:2655-2666.3. Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS,Roberts C, Desai S, Herrick AL, McHugh NJ, Foley NM, PearsonSB, Emery P, Veale DJ, Denton CP, Wells AU, Black CM, du BoisRM: A multicenter, prospective, randomized, double-blind,placebo-controlled trial of corticosteroids and intravenouscyclophosphamide followed by oral azathioprine for the treat-ment of pulmonary fibrosis in scleroderma. Arthritis Rheum2006, 54:3962-3970.4. Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, FurstDE, Silver RM, Goldin J, Arriola E, Strange C, Bolster MB, SeiboldJR, Riley DJ, Hsu VM, Varga J, Schraufnagel D, Theodore A,Simms R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M,Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, FesslerB, et al.: Effects of 1-year treatment with cyclophosphamideon outcomes at 2 years in scleroderma lung disease. Am JRespir Crit Care Med 2007, 176:1026-1034.5. Khanna D, Yan X, Tashkin DP, Furst DE, Elashoff R, Roth MD,Silver R, Strange C, Bolster M, Seibold JR, Riley DJ, Hsu VM,Varga J, Schraufnagel DE, Theodore A, Simms R, Wise R, WigleyF, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak K,Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Meter-sky M, et al.: Impact of oral cyclophosphamide on health-related quality of life in patients with active scleroderma lungdisease: results from the scleroderma lung study. ArthritisRheum 2007, 56:1676-1684.6. Furst DE, Clements PJ, Wong WK, Mayes MD, Wigley F, WhiteB, Weisman M, Barr W, Moreland L, Martin R, Medsger TA Jr.,Steen V, Collier D, Weinstein A, Lally E, Varga J, Weiner SR,Andrews B, Abeles M, Peter JB, Seibold JR: Effects of theAmerican College of Rheumatology systemic sclerosis trialguidelines on the nature of systemic sclerosis patients enter-ing a clinical trial. Rheumatology 2001, 40:615-622.7. Wells AU: High-resolution computed tomography and sclero-derma lung disease. Rheumatology (Oxford) 2008, 47 Suppl5:v59-61.8. Mittoo S, Wigley FM, Wise R, Xiao H, Hummers L: Persistenceof abnormal bronchoalveolar lavage findings after cyclophos-phamide treatment in scleroderma patients with interstitiallung disease. Arthritis Rheum 2007, 56:4195-4202.9. Khanna D, Furst DE, Clements PJ, Tashkin DP, Eckman MH: Oralcyclophosphamide for active scleroderma lung disease: adecision analysis. Med Decis Making 2008, 28:926-937.10. Miniati I, Conforti ML, Guiducci S, Matucci Cerinic M: Davidagainst Goliath: may we target and defeat interstitial lungdisease in systemic sclerosis? Clin Exp Rheumatol 2007,25:169-171.11. Nadashkevich O, Davis P, Fritzler M, Kovalenko W: A random-ized unblinded trial of cyclophosphamide versus azathioprinein the treatment of systemic sclerosis. Clin Rheumatol 2006,25:205-212.Available online http://arthritis-research.com/content/11/1/103Page 3 of 3(page number not for citation purposes)

Cyclophosphamide in systemic sclerosis: still in search of a &apos;real life&apos; scenario.

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Cyclophosphamide in systemic sclerosis: still in search of a 'real life' scenario.

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Cyclophosphamide in systemic sclerosis: still in search of a &apos;real life&apos; scenario.

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Cyclophosphamide in systemic sclerosis: still in search of a 'real life' scenario.