International Journal of Rheumatic Diseases 2014
APLAR GRAND ROUND CASE
Two-year experience with mycophenolate mofetil in patients with scleroderma lung disease: a case series Neslihan YILMAZ,1,2 Meryem CAN,1 Derya KOCAKAYA,3 Sait KARAKURT3 and Sule YAVUZ1,2 1
Rheumatology Department, Faculty of Medicine, Marmara University, 2Rheumatology Department, Faculty of Medicine, Istanbul Science University, and 3Chest Medicine, Faculty of Medicine, Marmara University, Istanbul, Turkey
Abstract To assess the effect of mycophenolate mofetil (MMF) on pulmonary functions in patients with systemic sclerosisassociated lung disease (SSc-ILD) who experienced an inadequate response to first line cyclophosphamide (CYC) therapy. Twelve consecutive SSc-ILD patients who received MMF due to inadequate response to CYC as a first line agent, were retrospectively reviewed. Over the course of 2 years, pulmonary function tests (PFT) and high-resolution computed tomography (HRCT) scans were performed. Following initial baseline tests, PFTs were continued at a frequency of every 6 months and HRCT scans were performed every 12 months. After MMF treatment, values of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) improved in three (25%) and two (16.6%) patients, respectively. It is also noted that the evaluation of serial HCRT scans showed no change in 54.5% of patients. Our case series suggested that PFT and imaging scores seemed to be stabilized by MMF in SSc-ILD patients who were inadequate responders to CYC. Key words: interstitial lung disease, mycophenolate mofetil, scleroderma.
INTRODUCTION Pulmonary diseases in systemic sclerosis (SSc), including interstitial disease (ILD) and pulmonary hypertension, are the leading causes of morbidity and mortality.1,2 So far, no therapy has been proven to control scleroderma disease progress successfully; however, several immunosuppressive agents have been assessed for the treatment of SSc-ILD.3–9 Cyclophosphamide (CYC) is one of the agents that has been shown as useful in lung fibrosis therapy. In two prospective randomized controlled trials, pulmonary function tests (PFTs) have been shown to stabilize at 12 months; however,
Correspondence: Dr. Neslihan Yilmaz, Associate Professor, Istanbul Science University Rheumatology Department. Topkapi Mah. Tatlipinar Cad. No:6/2 Sehremini- Istanbul/ Turkey. E-mail: [email protected]
this effect has not been maintained with either oral or intravenous CYC therapy.10,11 Moreover, lung functions have been shown to continually decrease in more than 35% of patients at 4 years of treatment.12 So far, there are no specific recommendations for patients with progressive lung disease in SSc after failure of CYC therapy. Mycophenolate mofetil (MMF) is an inhibitor of lymphocyte proliferation that produces a reversible blockade of the purine synthesis pathway enzyme: inosine monophosphate dehydrogenase.13 MMF has demonstrated anti-inflammatory and antiproliferative properties and is, therefore, commonly used to prevent rejection following solid organ transplantation, as well as autoimmune and renal disorders.14–16 To date, a randomized controlled trial has not been done to assess the efficacy of MMF treatment in SSc-ILD; however, several retrospective studies have demonstrated a modest beneficial effect in pulmonary function.17–20 Our intention was to evaluate the effect of MMF in pulmonary
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
N. Yilmaz et al.
functions of patients with SSc-ILD, who have experienced an inadequate response or progressive lung disease with first-line CYC therapy.
10% in FVC and/or less than 15% at DLCO. Progressive disease was defined as progression on HRCT scan (> 20% on fibrosis) or an absolute decrease from baseline in the FVC of at least 10% and/or DLCO of 15%.
PATIENTS AND METHODS
Outcome measures
Subjects
The primary outcome of interest was the change in the pulmonary function tests, including percent of the predicted FVC, DLCO and DLCO/VA. The secondary outcome included ILD extension in HRCT scans within 2 years of the first MMF application.
The medical records from 2009 to 2012 of SSc-ILD patients at Marmara University Rheumatology Outpatient Clinic, were carefully reviewed retrospectively. Twelve SSc-ILD patients met the criteria to participate in this analysis due to either progressive lung disease or inadequate response with CYC therapy. Details of demographic and clinical features along with laboratory parameters, PFTs, imaging studies and management were noted. Interstitial disease was determined with findings of restrictive pattern on PFTs (including spirometry and measurement of gas diffusion), evidence of pulmonary fibrosis and/or ground-glass opacity on high-resolution computed tomography (HRCT) and/or findings of alveolitis in bronchoalveolar lavage fluid. Spirometric variables included the forced vital capacity (FVC) and the forced expiratory volume in 1 s (FEV1). PFT results were expressed as a percentage of normal predicted values based on age, sex and height. Single-breath diffusing capacity for carbon monoxide (DLCO) was tested using a conventional carbon monoxide/helium gas mixture and corrected for the simultaneously measured total lung capacity (DLCO/VA). The HRCT images were reviewed by an experienced chest medicine specialist blinded to clinical information by using the ‘Warrick semiquantitative scoring system’.21,22 The Warrick scoring system is used to evaluate severity and extent of SSc lung disease. Briefly, Warrick score is composed of: (i) a severity score, ranging from 0 (normal) to 15 (severe); and (ii) an extension score, ranging from 0 (normal) to 3 (severe). The two scores are calculated to find a total score (ranging from 0 to 30). The distribution of changes is evaluated in four zones: (i) above the aortic arch; (ii) between the aortic arch and the level of carina; (iii) between the level of carina and the level of the inferior pulmonary veins; and (iv) below the inferior pulmonary veins. The scores in the four localizations (a–d) are summed and divided by four, in order to calculate an extent/severity score. A global score of 7 is predictive of PFT abnormalities with a positive predictive value of 0.82, a sensitivity of 0.6 and specificity of 0.83.23 Good response was defined as improvement of more than 10% in FVC and/or more than 15% at DLCO. Inadequate response was defined as improvement less than
2
RESULTS As a standard approach for SSc-ILD patients in our clinic, all subjects were treated with CYC (monthly intravenous injections of 750 mg/m² or oral equivalent dose daily, for 6–12 months) and low-dose prednisolone (≤ 10 mg/day or equivalent) at the beginning. When a good response was revealed at the 6-month mark, oral azathiopurine (AZA) (2 mg/kg/day) was started for maintenance therapy. If there was an inadequate response or progressive disease as described above, treatment was switched to the MMF (Cellcept). Initially, patients received MMF 500 mg twice daily for 1 month. Titration up to 1500–2000 mg/day was carried out based on tolerance and response. In our 12 SSc-ILD patients the mean CYC dose was 15.6 8.5 g. At the 6 or 12 month evaluation of CYC therapy, nine of 12 patients had inadequate response or progressive disease and had to switch to MMF. Three patients (cases 2, 3 and 6) had a good response to CYC therapy at 12 months, and then were switched to AZA (2 mg/kg/day) as preferred. Follow-up results of these three patients showed a decline in their PFTs observed at 24 (12–28) months; then AZA therapy was switched to MMF. Patient 4 was prescribed AZA therapy despite progressive lung disease for 24 months before MMF initiation because of social problems. Nine were followed for a period of 24 months and the remaining three were followed for at least 12 months on MMF. The mean length of follow-up with MMF therapy was 19.9 5.8 months. Patients tolerated MMF therapy well, and no patient developed clinically significant infection and/or leucopenia during MMF treatment. Characteristics of patients before the MMF therapy are shown in Table 1. After MMF treatment, improvement greater than 10% in FVC values and respiratory symptoms were revealed in three patients (cases 5, 9 and 11). Only patient 4, experienced declined FVC levels, although her DLCO
International Journal of Rheumatic Diseases 2014
International Journal of Rheumatic Diseases 2014
46
51
62
40
45
41
44
40
54
56
68
64
1
2
3
4
5
6
7
8
9
10
11
12
F
F
F
F
F
F
F
F
F
F
M
F
Sex
4.5
9 6
– – Ex-smoker – Ex- smoker
– –
–
–
–
HT
–
–
HT
3
–
–
7
5.5
5.5
4
13
Smoker
8
8
–
–
–
4
Ex-smoker
–
–
Disease duration (years)
HT
Smoking
Comorbidities
Limited
Diffuse
Limited
Limited
Limited
Limited
Diffuse
Limited
Diffuse
Limited
Limited
Limited
Disease subset
ANA, Scl-70 ANA
ANA, Scl-70 ANA, Scl-70 ANA, Scl-70, Ro ANA, Scl-70 ANA
ANA, Ro
ANA
ANA, Scl-70 ANA, Scl-70, Ro ANA
Antibody profile
–
PAH
PAH
PAH
–
–
–
–
–
PAH
–
–
Heart disease
36
20
24
6
6
13
11
9
20
15
16
12
Total CYC dose (g)
Primer unresponsiveness Primer unresponsiveness
Primer unresponsiveness For switching maintenance For switching maintenance Primer unresponsiveness Primer unresponsiveness For switching maintenance Primer unresponsiveness Primer unresponsiveness Primer unresponsiveness Primer unresponsiveness
Reason for CYC withdrawal
–
–
–
–
–
–
12
–
24
30
30
–
Total AZA duration (months)
64
84
48
24
12
36
66
18
120
65
66
24
Follow-up prior to MMF (months)
12
18
26
24
20
22
26
9
22
24
24
12
Follow-up after MMF (months)
HRCT abnormalities
Ground-glass opacities and interseptal thickening Ground-glass opacities Total Warrick score: 18 Ground-glass opacities Total Warrick score: 7 Reticular opacities Total Warrick score: 3 Ground-glass opacities Total Warrick score: 21 Reticular opacities Total Warrick score: 21 Ground-glass opacities Total Warrick score: 18 Ground-glass opacities Total Warrick score: 17 Ground-glass opacities Total Warrick score: 4 Ground-glass opacities and interseptal thickening Total Warrick score: 25 Ground-glass opacities Total Warrick score: 16 Interseptal thickening Total Warrick score: 13
PAH, pulmonary arterial hypertension; HT, Hypertension; CYC, cyclophosphamide; AZA, azathioprine; MMF, mycophenolate mofetil; ANA, antinuclear antibodies.
Age
No.
Table 1 Demographic characteristics of SSc patients
Mycophenolate mofetil in interstitial lung fibrosis
3
4
CYC, cyclophosphamide; MMF, mycophenolate mofetil; FVC, forced vital capacity; DLCO/VA, diffusing capacity for carbon monoxide/total lung capacity; NA, not available; †improvement at FVC% pred ≥10% pre- versus post-MMF; ‡improvement at DLCO% pred ≥15% pre- versus post-MMF. Values in bold indicate patients with meaningful changes in their pulmonary function tests.
32 (58) 49 (87) 63 (62) 55 (65) 40 (61) 65 (91) 44 (56) 47 (77) 37 (71) 38 (64) 55 (73) 84 (105) 44 (68) 37 (71) 59 (54) 46 (46) 51 (86) 55 (85) 59 (43) 73 (79) 69 (100) 41 (59) 64 (59) 86 (109) 41 (64) 42 (69) 46 (45) 60 (67) 55 (93) 62 (79) 37 (48) 63 (88) 57 (92) 37 (50) 84 (69) NA 57 (1.70) 70 (2.82) 108 (3.11) 101 (3.12) 65 (1.86) 62 (1.94) 97 (2.71) 70 (1.9) 84 (2.19) 83 (2.5) 93 (2.07) 71 (1.89) 59 (1.81) 66 (2.80) 116 (3.22) 113 (3.38) 55 (1.55) 65 (2.17) 101 (2.72) 72 (1.89) 64 (1.98) 85 (2.58) 79 (1.83) 72 (1.93) 62 (2.01) 63 (2.67) 107 (3.01) 101 (3.12) 65 (1.95) 81 (2.74) 80 (2.34) 71 (1.88) 83 (2.21) 96 (2.58) 99 (2.43) NA 1 2‡ 3 4‡ 5† 6‡ 7 8 9† 10 11† 12
4 8 8 13 4 5.5 5.5 3 4.5 7 9 6
12 16 15 20 9 11 13 6 6 24 20 36
12 24 24 22 12 26 22 20 24 26 18 12
Before MMF treatment Before CYC treatment After MMF treatment Before MMF treatment
Total CYC dosage (g) Disease duration (years) Patient no.
Table 2 Follow-up data
In our SSc-ILD patients with inadequate response to CYC, pulmonary function tests improved in 41.6% of patients after MMF therapy. The treatment options for SSc-ILD have been rather limited. CYC is the only drug that has demonstrated a small but significant benefit in SSc-ILD in randomized controlled trials. However, this effect is only prominent when the drug is orally administered for 1 year and this effect diminishes at 24 months.10,11 Moreover, a recent meta-analysis by Nannini et al.24 has revealed that the improvement in PFT caused by CYC compared to placebo is modest, and changes in FVC and DLCO did not reach clinical significance. Again, this improvement has not remained in the long-run and about one-third of patients treated with CYC have shown a worsening in their PFT at 4 years.12 Predictors of lung fibrosis in SSc are scarce, and close monitoring of lung function is needed, especially in the early stage of the disease. The rate of decline of FVC and DLCO are important predictors of prognosis. In our groups, significant improvement at FVC or DLCO levels was observed in 41.6% of subjects and stabilization of the Warrick score was revealed in 54.5% of patients. Most of our patients (11/12) have reported that their respiratory symptoms improved with MMF therapy.
Total MMF treatment duration (months)
DISCUSSION
Before CYC treatment
FVC% of normal predicted values (L)
DLCO% of normal predicted values (DLCO/ VA)
values increased. FVC values were unchanged in the remaining eight patients. In these, three (cases 1, 7 and 8) revealed significant reduction in DLCO (more than 15%), but patients 7 and 8 reported that their respiratory symptoms had markedly improved. DLCO values increased by more than 15% in patients 2 and 6, with their breathlessness significantly decreased during MMF therapy (Table 2, Fig. 1a,b). Patients 2, 3, 4 and 6 had used AZA therapy for a period of at least 12 months before MMF. After MMF therapy, none of these patients had an increase in FVC results, but DLCO values increased more than 15% only in patients 2 and 6. Eleven patients had serial HRCT scans available during the follow-up period. According to the Warrick scoring system, we did not reveal significant changes in alveolitis score. On the other hand, there was a decreasing trend in fibrosis score in two patients (case 2, pre-treatment, 15, post-treatment, 12; case 11, pre-treatment, 14, posttreatment, 9) and an increasing trend in two patients (case 7, pre-treatment, 14, post-treatment, 18; case 8, pre-treatment, 14, post-treatment, 17) and there was no meaningful change in seven patients (Fig. 1c).
After MMF treatment
N. Yilmaz et al.
International Journal of Rheumatic Diseases 2014
Mycophenolate mofetil in interstitial lung fibrosis
(a)
140
Case 1 Case 2
120
Case 3
FVC %
100
Case 4 Case 5
80
Case 6 Case 7
60
Case 8 40
Case 9 Case 10
20 0
Case 11 Case 12 Pre-CYC
Post CYC/pre MMF
Post MMF
(b) 100
Case 1
90
Case 2
80
Case 3
DLCO %
70
Case 4
60
Case 5
50
Case 6 Case 7
40
Case 8
30
Case 9
20
Case 10
10 0
(c)
Case 11 Pre-CYC
Post-CYC/Pre-MMF
Post MMF
30
Case 1 Case 2
25
Total Warrick score
Case 12
Case 3
20
Case 4
15
Case 6
Case 5 Case 7
10
Case 8 Case 9
5 0
Case 10 Case 11
Pre MMF
Post MMF
Case 12
Figure 1 Changes of the forced vital capacity (a) and diffusing lung capacity for carbon monoxide/total lung capacity (b) measurements on cyclophosphamide and mycophenolate mofetil (MMF). (c) Changes of the total Warrick score on MMF.
When we compare our cohort with other available studies for MMF in SSc-ILD, Liossis et al.25 reported better results for DLCO and FVC. In their study all five patients demonstrated improvements in their DLCO and four of them showed enhanced FVC as well as complete resolution of their lung imaging. However, in the other three studies, including a meta analysis, we did not find a significant difference from our results.26–28 In a recently published study, Fischer et al.29 has evaluated the effectiveness of MMF, in a large cohort of connective tissue-related ILD, and have reported stable or
International Journal of Rheumatic Diseases 2014
improved lung parameters. Based on this, we cannot deny the possibility that MMF exhibits a disease-modifying effect, especially in the early course of the disease. Several scoring systems for HRCT abnormalities have been used in SSc-ILD. The Warrick scoring system is a semiquantitative method which is used to determine the grade and extent of the lung disease. According to the Warrick system, fibrosis score is correlated with low FVC and DLCO, but alveolitis score represented by pure ground-glass opacities, is not correlated with PFTs.30 Similarly, we observed that fibrosis scores were inversely correlated with FVC or DLCO in our patients (cases 2, 7, 8 and 11). Small observational studies like ours may have numerous limitations. Briefly, we cannot rule out in any uncontrolled study, that our results may reflect a regression to the mean. Our group consisted of rather severe patients indicated by higher Warrick score even after remarkable cumulative dose of CYC therapy (mean 16 g), therefore the pattern of some improvement in PFTs and Warrick scores suggested that the drug would be more beneficial in the early stages of ILD. Second, there is the heterogeneity of the previous CYC administration. Patients treated with oral CYC may have better improvement in their PFT results, as indicated in recent reports. This may also mask the real beneficial effect of MMF. Finally, as CT scoring was done by only one experienced pneumologist, this could present a weakness of this retrospective analysis. Other potential weakness of this scoring system may be that it can be less sensitive in detecting small changes during follow-up evaluations. Cyclophosphamide has potential for short and longterm toxicities. Even though the mean cumulative dose of CYC was 16 g in our cohort, we did not see any particular event that needed to be reported. During the 24 months of the study, none of our patients reported or needed to leave the study because of serious adverse events; however, mild abdominal pain occurred with MMF. In conclusion, from our results we cannot draw any definitive conclusion, but MMF seemed to stabilize PFTs and imaging scores. On the other hand, prospective, long-term studies in early SSc-ILD are required to evaluate certain issues. All authors declare there are no conflicts of interest.
REFERENCES 1 Harris ED, Budd RC, Firestein GS et al. (2005) Kelley’s Textbook of Rheumatology. Vol. II, pp 1279–303. Elsevier, Philadelphia.
5
N. Yilmaz et al.
2 Silver RM, Clements PJ (2003) Interstitial lung disease in systemic sclerosis: optimizing evaluation and management. Scleroderma Care Res 1, 1–20. 3 Silver RM, Warrick JH, Kinsella MB, Staudt LS, Baumann MH, Strange C (1993) Cyclophosphamide and low-dose prednisolone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease. J Rheumatol 20, 838–44. 4 Akesson A, Scheja A, Lundin A, Wollheim FA (1994) Improved pulmonary function in systemic sclerosis after treatment with cyclophosphamide. Arthritis Rheum 37, 729–35. 5 Steen VD, Lanz JK, Conte C, Ownes GR, Medsger TA (1994) Therapy for severe interstitial lung disease in systemic sclerosis: a retrospective study. Arthritis Rheum 37, 1290–6. 6 Giacomelli R, Valentini G, Salsano F et al. (2002) Cyclophosphamide pulse regimen in the treatment of alveolitis in systemic sclerosis. J Rheumatol 29, 731–6. 7 Pakas I, Ioannidis JP, Malagari K, Skopouli FN, Moutsopoulos HM, Vlachoviannopoulos PG (2002) Cyclophosphamide with low or high dose prednisolone for systemic sclerosis lung disease. J Rheumatol 29, 298–304. 8 Davas EM, Peppas C, Maragou M, Alvanou E, Hondros D, Dantis PC (1999) Intravenous cyclophosphamide pulse therapy for the treatment of lung disease associated with scleroderma. Clin Rheumatol 18, 455–61. 9 Griffiths B, Miles S, Moss H, Robertson R, Veale D, Emery P (2002) Systemic sclerosis and interstitial lung disease: a pilot study using pulsed intravenous methylprednisolone and cyclophosphamide to assess the effect on high resolution computed tomography scan and lung function. J Rheumatol 29, 2371–8. 10 Tashkin DP, Elashoff R, Clements PJ et al., for the Scleroderma Lung Study Research Group (2006) Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 354, 2655–66. 11 Tashkin DP, Elashoff R, Clements PJ et al. (2007) Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med 176, 1026–34. 12 Mittoo S, Wigley FM, Wise RA, Woods A, Xiao H, Hummers LK (2011) Long term effects of cyclophosphamide treatment on lung function and survival in scleroderma patients with interstitial lung disease. Open Rheumatol J 5, 1–6. 13 Villarroel MC, Hidalgo M, Jimeno A (2009) Mycophenolate mofetil: an update. Drugs Today 45, 521–32. 14 Allison AC, Eugui EM (2005) Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection. Transplantation 80 (Suppl. 2), 181–90. 15 Dooley MA, Jayne D, Ginzler EM et al. (2011) Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 365, 1886–95. 16 Majithia V, Harisdangkul V (2005) Mycophenolate mofetil (CellCept): an alternative therapy for autoimmune
6
17
18
19
20
21
22
23
24
25
26
27
28
29
30
inflammatory myopathy. Rheumatology (Oxford) 44 (3), 386–9. Gerbino AJ, Goss CH, Molitor JA (2008) Effect of mycophenolate mofetil on pulmonary function in sclerodermaassociated interstitial lung disease. Chest 133 (2), 455–60. Koutroumpas A, Ziogas A, Alexiou I, Barouta G, Sakkas LI (2010) Mycophenolate mofetil in systemic sclerosis-associated interstitial lung disease. Clin Rheumatol 29 (10), 1167–8. Liossis SNC, Bounas A, Andonopoulos AP (2006) Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology 45 (8), 1005–8. Zamora AC, Wolters PJ, Collard HR et al. (2008) Use of mycophenolate mofetil to treat scleroderma-associated interstitial lung disease. Respirat Med 102 (1), 150–5. Warrick JH, Bhalla M, Schabel SI, Silver RM (1991) High resolution computed tomography in early scleroderma lung disease. J Rheumatol 18, 1520–8. Bellia M, Cannizzaro F, Scichilone N et al. (2009) HRCT and scleroderma: semi quantitative evaluation of lung damage and functional abnormalities. Radiol Med 114, 190–203. Diot E, Boissinot E, Asquier E et al. (1998) Relationship between abnormalities on high-resolution CT and pulmonary function in systemic sclerosis. Chest 114, 1623–9. Nannini C, West CP, Erwin PJ, Matteson EL (2008) Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: a systematic review and meta-analysis of randomized controlled trials and observational prospective cohort studies. Arthritis Res Ther 10, 1–9. Liossis SNC, Bounas A, Andonopoulos AP (2006) Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology 45, 1005–8. Plastiras SC, Vlachoyiannopoulos PG, Tzelepis GE (2006) Letters to the Editor: Mycophenolate mofetil for interstitial lung disease in Scleroderma. Rheumatology 45, 1572–82. Tzouvelekis A, Galanopoulos N, Bouros E et al. (2012) Effect and safety of Mycophenolate mofetil or sodium in Systemic Sclerosis-Associated Interstitial Lung Disease: a meta-analysis. Pulm Med 2012, 1–7. Simeon-Aznar CP, Fonollosa-Pla V, Tolosa-Vilella C, SelvaO’Callaghan A, Solans-Laqu0 e R, Vilardell-Tarres M (2011) Effect of mycophenolate sodium in scleroderma-related interstitial lung disease. Clin Rheumatol 30 (11), 1393–8. Fischer A, Brown KK, Du Bois RM et al. (2013) Mycophenolate mofetil improves lung function in connective tissue disease associated interstitial lung disease. J Rheumatol 40 (5), 640–6. Goldin JG, Lynch DA, Strollo DC et al. (2008) High resolution CT scan findings in patients with symptomatic scleroderma-related interstitial lung disease. Chest 134, 358–67.
International Journal of Rheumatic Diseases 2014
APLAR GRAND ROUND CASE
Two-year experience with mycophenolate mofetil in patients with scleroderma lung disease: a case series Neslihan YILMAZ,1,2 Meryem CAN,1 Derya KOCAKAYA,3 Sait KARAKURT3 and Sule YAVUZ1,2 1
Rheumatology Department, Faculty of Medicine, Marmara University, 2Rheumatology Department, Faculty of Medicine, Istanbul Science University, and 3Chest Medicine, Faculty of Medicine, Marmara University, Istanbul, Turkey
Abstract To assess the effect of mycophenolate mofetil (MMF) on pulmonary functions in patients with systemic sclerosisassociated lung disease (SSc-ILD) who experienced an inadequate response to first line cyclophosphamide (CYC) therapy. Twelve consecutive SSc-ILD patients who received MMF due to inadequate response to CYC as a first line agent, were retrospectively reviewed. Over the course of 2 years, pulmonary function tests (PFT) and high-resolution computed tomography (HRCT) scans were performed. Following initial baseline tests, PFTs were continued at a frequency of every 6 months and HRCT scans were performed every 12 months. After MMF treatment, values of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) improved in three (25%) and two (16.6%) patients, respectively. It is also noted that the evaluation of serial HCRT scans showed no change in 54.5% of patients. Our case series suggested that PFT and imaging scores seemed to be stabilized by MMF in SSc-ILD patients who were inadequate responders to CYC. Key words: interstitial lung disease, mycophenolate mofetil, scleroderma.
INTRODUCTION Pulmonary diseases in systemic sclerosis (SSc), including interstitial disease (ILD) and pulmonary hypertension, are the leading causes of morbidity and mortality.1,2 So far, no therapy has been proven to control scleroderma disease progress successfully; however, several immunosuppressive agents have been assessed for the treatment of SSc-ILD.3–9 Cyclophosphamide (CYC) is one of the agents that has been shown as useful in lung fibrosis therapy. In two prospective randomized controlled trials, pulmonary function tests (PFTs) have been shown to stabilize at 12 months; however,
Correspondence: Dr. Neslihan Yilmaz, Associate Professor, Istanbul Science University Rheumatology Department. Topkapi Mah. Tatlipinar Cad. No:6/2 Sehremini- Istanbul/ Turkey. E-mail: [email protected]
this effect has not been maintained with either oral or intravenous CYC therapy.10,11 Moreover, lung functions have been shown to continually decrease in more than 35% of patients at 4 years of treatment.12 So far, there are no specific recommendations for patients with progressive lung disease in SSc after failure of CYC therapy. Mycophenolate mofetil (MMF) is an inhibitor of lymphocyte proliferation that produces a reversible blockade of the purine synthesis pathway enzyme: inosine monophosphate dehydrogenase.13 MMF has demonstrated anti-inflammatory and antiproliferative properties and is, therefore, commonly used to prevent rejection following solid organ transplantation, as well as autoimmune and renal disorders.14–16 To date, a randomized controlled trial has not been done to assess the efficacy of MMF treatment in SSc-ILD; however, several retrospective studies have demonstrated a modest beneficial effect in pulmonary function.17–20 Our intention was to evaluate the effect of MMF in pulmonary
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
N. Yilmaz et al.
functions of patients with SSc-ILD, who have experienced an inadequate response or progressive lung disease with first-line CYC therapy.
10% in FVC and/or less than 15% at DLCO. Progressive disease was defined as progression on HRCT scan (> 20% on fibrosis) or an absolute decrease from baseline in the FVC of at least 10% and/or DLCO of 15%.
PATIENTS AND METHODS
Outcome measures
Subjects
The primary outcome of interest was the change in the pulmonary function tests, including percent of the predicted FVC, DLCO and DLCO/VA. The secondary outcome included ILD extension in HRCT scans within 2 years of the first MMF application.
The medical records from 2009 to 2012 of SSc-ILD patients at Marmara University Rheumatology Outpatient Clinic, were carefully reviewed retrospectively. Twelve SSc-ILD patients met the criteria to participate in this analysis due to either progressive lung disease or inadequate response with CYC therapy. Details of demographic and clinical features along with laboratory parameters, PFTs, imaging studies and management were noted. Interstitial disease was determined with findings of restrictive pattern on PFTs (including spirometry and measurement of gas diffusion), evidence of pulmonary fibrosis and/or ground-glass opacity on high-resolution computed tomography (HRCT) and/or findings of alveolitis in bronchoalveolar lavage fluid. Spirometric variables included the forced vital capacity (FVC) and the forced expiratory volume in 1 s (FEV1). PFT results were expressed as a percentage of normal predicted values based on age, sex and height. Single-breath diffusing capacity for carbon monoxide (DLCO) was tested using a conventional carbon monoxide/helium gas mixture and corrected for the simultaneously measured total lung capacity (DLCO/VA). The HRCT images were reviewed by an experienced chest medicine specialist blinded to clinical information by using the ‘Warrick semiquantitative scoring system’.21,22 The Warrick scoring system is used to evaluate severity and extent of SSc lung disease. Briefly, Warrick score is composed of: (i) a severity score, ranging from 0 (normal) to 15 (severe); and (ii) an extension score, ranging from 0 (normal) to 3 (severe). The two scores are calculated to find a total score (ranging from 0 to 30). The distribution of changes is evaluated in four zones: (i) above the aortic arch; (ii) between the aortic arch and the level of carina; (iii) between the level of carina and the level of the inferior pulmonary veins; and (iv) below the inferior pulmonary veins. The scores in the four localizations (a–d) are summed and divided by four, in order to calculate an extent/severity score. A global score of 7 is predictive of PFT abnormalities with a positive predictive value of 0.82, a sensitivity of 0.6 and specificity of 0.83.23 Good response was defined as improvement of more than 10% in FVC and/or more than 15% at DLCO. Inadequate response was defined as improvement less than
2
RESULTS As a standard approach for SSc-ILD patients in our clinic, all subjects were treated with CYC (monthly intravenous injections of 750 mg/m² or oral equivalent dose daily, for 6–12 months) and low-dose prednisolone (≤ 10 mg/day or equivalent) at the beginning. When a good response was revealed at the 6-month mark, oral azathiopurine (AZA) (2 mg/kg/day) was started for maintenance therapy. If there was an inadequate response or progressive disease as described above, treatment was switched to the MMF (Cellcept). Initially, patients received MMF 500 mg twice daily for 1 month. Titration up to 1500–2000 mg/day was carried out based on tolerance and response. In our 12 SSc-ILD patients the mean CYC dose was 15.6 8.5 g. At the 6 or 12 month evaluation of CYC therapy, nine of 12 patients had inadequate response or progressive disease and had to switch to MMF. Three patients (cases 2, 3 and 6) had a good response to CYC therapy at 12 months, and then were switched to AZA (2 mg/kg/day) as preferred. Follow-up results of these three patients showed a decline in their PFTs observed at 24 (12–28) months; then AZA therapy was switched to MMF. Patient 4 was prescribed AZA therapy despite progressive lung disease for 24 months before MMF initiation because of social problems. Nine were followed for a period of 24 months and the remaining three were followed for at least 12 months on MMF. The mean length of follow-up with MMF therapy was 19.9 5.8 months. Patients tolerated MMF therapy well, and no patient developed clinically significant infection and/or leucopenia during MMF treatment. Characteristics of patients before the MMF therapy are shown in Table 1. After MMF treatment, improvement greater than 10% in FVC values and respiratory symptoms were revealed in three patients (cases 5, 9 and 11). Only patient 4, experienced declined FVC levels, although her DLCO
International Journal of Rheumatic Diseases 2014
International Journal of Rheumatic Diseases 2014
46
51
62
40
45
41
44
40
54
56
68
64
1
2
3
4
5
6
7
8
9
10
11
12
F
F
F
F
F
F
F
F
F
F
M
F
Sex
4.5
9 6
– – Ex-smoker – Ex- smoker
– –
–
–
–
HT
–
–
HT
3
–
–
7
5.5
5.5
4
13
Smoker
8
8
–
–
–
4
Ex-smoker
–
–
Disease duration (years)
HT
Smoking
Comorbidities
Limited
Diffuse
Limited
Limited
Limited
Limited
Diffuse
Limited
Diffuse
Limited
Limited
Limited
Disease subset
ANA, Scl-70 ANA
ANA, Scl-70 ANA, Scl-70 ANA, Scl-70, Ro ANA, Scl-70 ANA
ANA, Ro
ANA
ANA, Scl-70 ANA, Scl-70, Ro ANA
Antibody profile
–
PAH
PAH
PAH
–
–
–
–
–
PAH
–
–
Heart disease
36
20
24
6
6
13
11
9
20
15
16
12
Total CYC dose (g)
Primer unresponsiveness Primer unresponsiveness
Primer unresponsiveness For switching maintenance For switching maintenance Primer unresponsiveness Primer unresponsiveness For switching maintenance Primer unresponsiveness Primer unresponsiveness Primer unresponsiveness Primer unresponsiveness
Reason for CYC withdrawal
–
–
–
–
–
–
12
–
24
30
30
–
Total AZA duration (months)
64
84
48
24
12
36
66
18
120
65
66
24
Follow-up prior to MMF (months)
12
18
26
24
20
22
26
9
22
24
24
12
Follow-up after MMF (months)
HRCT abnormalities
Ground-glass opacities and interseptal thickening Ground-glass opacities Total Warrick score: 18 Ground-glass opacities Total Warrick score: 7 Reticular opacities Total Warrick score: 3 Ground-glass opacities Total Warrick score: 21 Reticular opacities Total Warrick score: 21 Ground-glass opacities Total Warrick score: 18 Ground-glass opacities Total Warrick score: 17 Ground-glass opacities Total Warrick score: 4 Ground-glass opacities and interseptal thickening Total Warrick score: 25 Ground-glass opacities Total Warrick score: 16 Interseptal thickening Total Warrick score: 13
PAH, pulmonary arterial hypertension; HT, Hypertension; CYC, cyclophosphamide; AZA, azathioprine; MMF, mycophenolate mofetil; ANA, antinuclear antibodies.
Age
No.
Table 1 Demographic characteristics of SSc patients
Mycophenolate mofetil in interstitial lung fibrosis
3
4
CYC, cyclophosphamide; MMF, mycophenolate mofetil; FVC, forced vital capacity; DLCO/VA, diffusing capacity for carbon monoxide/total lung capacity; NA, not available; †improvement at FVC% pred ≥10% pre- versus post-MMF; ‡improvement at DLCO% pred ≥15% pre- versus post-MMF. Values in bold indicate patients with meaningful changes in their pulmonary function tests.
32 (58) 49 (87) 63 (62) 55 (65) 40 (61) 65 (91) 44 (56) 47 (77) 37 (71) 38 (64) 55 (73) 84 (105) 44 (68) 37 (71) 59 (54) 46 (46) 51 (86) 55 (85) 59 (43) 73 (79) 69 (100) 41 (59) 64 (59) 86 (109) 41 (64) 42 (69) 46 (45) 60 (67) 55 (93) 62 (79) 37 (48) 63 (88) 57 (92) 37 (50) 84 (69) NA 57 (1.70) 70 (2.82) 108 (3.11) 101 (3.12) 65 (1.86) 62 (1.94) 97 (2.71) 70 (1.9) 84 (2.19) 83 (2.5) 93 (2.07) 71 (1.89) 59 (1.81) 66 (2.80) 116 (3.22) 113 (3.38) 55 (1.55) 65 (2.17) 101 (2.72) 72 (1.89) 64 (1.98) 85 (2.58) 79 (1.83) 72 (1.93) 62 (2.01) 63 (2.67) 107 (3.01) 101 (3.12) 65 (1.95) 81 (2.74) 80 (2.34) 71 (1.88) 83 (2.21) 96 (2.58) 99 (2.43) NA 1 2‡ 3 4‡ 5† 6‡ 7 8 9† 10 11† 12
4 8 8 13 4 5.5 5.5 3 4.5 7 9 6
12 16 15 20 9 11 13 6 6 24 20 36
12 24 24 22 12 26 22 20 24 26 18 12
Before MMF treatment Before CYC treatment After MMF treatment Before MMF treatment
Total CYC dosage (g) Disease duration (years) Patient no.
Table 2 Follow-up data
In our SSc-ILD patients with inadequate response to CYC, pulmonary function tests improved in 41.6% of patients after MMF therapy. The treatment options for SSc-ILD have been rather limited. CYC is the only drug that has demonstrated a small but significant benefit in SSc-ILD in randomized controlled trials. However, this effect is only prominent when the drug is orally administered for 1 year and this effect diminishes at 24 months.10,11 Moreover, a recent meta-analysis by Nannini et al.24 has revealed that the improvement in PFT caused by CYC compared to placebo is modest, and changes in FVC and DLCO did not reach clinical significance. Again, this improvement has not remained in the long-run and about one-third of patients treated with CYC have shown a worsening in their PFT at 4 years.12 Predictors of lung fibrosis in SSc are scarce, and close monitoring of lung function is needed, especially in the early stage of the disease. The rate of decline of FVC and DLCO are important predictors of prognosis. In our groups, significant improvement at FVC or DLCO levels was observed in 41.6% of subjects and stabilization of the Warrick score was revealed in 54.5% of patients. Most of our patients (11/12) have reported that their respiratory symptoms improved with MMF therapy.
Total MMF treatment duration (months)
DISCUSSION
Before CYC treatment
FVC% of normal predicted values (L)
DLCO% of normal predicted values (DLCO/ VA)
values increased. FVC values were unchanged in the remaining eight patients. In these, three (cases 1, 7 and 8) revealed significant reduction in DLCO (more than 15%), but patients 7 and 8 reported that their respiratory symptoms had markedly improved. DLCO values increased by more than 15% in patients 2 and 6, with their breathlessness significantly decreased during MMF therapy (Table 2, Fig. 1a,b). Patients 2, 3, 4 and 6 had used AZA therapy for a period of at least 12 months before MMF. After MMF therapy, none of these patients had an increase in FVC results, but DLCO values increased more than 15% only in patients 2 and 6. Eleven patients had serial HRCT scans available during the follow-up period. According to the Warrick scoring system, we did not reveal significant changes in alveolitis score. On the other hand, there was a decreasing trend in fibrosis score in two patients (case 2, pre-treatment, 15, post-treatment, 12; case 11, pre-treatment, 14, posttreatment, 9) and an increasing trend in two patients (case 7, pre-treatment, 14, post-treatment, 18; case 8, pre-treatment, 14, post-treatment, 17) and there was no meaningful change in seven patients (Fig. 1c).
After MMF treatment
N. Yilmaz et al.
International Journal of Rheumatic Diseases 2014
Mycophenolate mofetil in interstitial lung fibrosis
(a)
140
Case 1 Case 2
120
Case 3
FVC %
100
Case 4 Case 5
80
Case 6 Case 7
60
Case 8 40
Case 9 Case 10
20 0
Case 11 Case 12 Pre-CYC
Post CYC/pre MMF
Post MMF
(b) 100
Case 1
90
Case 2
80
Case 3
DLCO %
70
Case 4
60
Case 5
50
Case 6 Case 7
40
Case 8
30
Case 9
20
Case 10
10 0
(c)
Case 11 Pre-CYC
Post-CYC/Pre-MMF
Post MMF
30
Case 1 Case 2
25
Total Warrick score
Case 12
Case 3
20
Case 4
15
Case 6
Case 5 Case 7
10
Case 8 Case 9
5 0
Case 10 Case 11
Pre MMF
Post MMF
Case 12
Figure 1 Changes of the forced vital capacity (a) and diffusing lung capacity for carbon monoxide/total lung capacity (b) measurements on cyclophosphamide and mycophenolate mofetil (MMF). (c) Changes of the total Warrick score on MMF.
When we compare our cohort with other available studies for MMF in SSc-ILD, Liossis et al.25 reported better results for DLCO and FVC. In their study all five patients demonstrated improvements in their DLCO and four of them showed enhanced FVC as well as complete resolution of their lung imaging. However, in the other three studies, including a meta analysis, we did not find a significant difference from our results.26–28 In a recently published study, Fischer et al.29 has evaluated the effectiveness of MMF, in a large cohort of connective tissue-related ILD, and have reported stable or
International Journal of Rheumatic Diseases 2014
improved lung parameters. Based on this, we cannot deny the possibility that MMF exhibits a disease-modifying effect, especially in the early course of the disease. Several scoring systems for HRCT abnormalities have been used in SSc-ILD. The Warrick scoring system is a semiquantitative method which is used to determine the grade and extent of the lung disease. According to the Warrick system, fibrosis score is correlated with low FVC and DLCO, but alveolitis score represented by pure ground-glass opacities, is not correlated with PFTs.30 Similarly, we observed that fibrosis scores were inversely correlated with FVC or DLCO in our patients (cases 2, 7, 8 and 11). Small observational studies like ours may have numerous limitations. Briefly, we cannot rule out in any uncontrolled study, that our results may reflect a regression to the mean. Our group consisted of rather severe patients indicated by higher Warrick score even after remarkable cumulative dose of CYC therapy (mean 16 g), therefore the pattern of some improvement in PFTs and Warrick scores suggested that the drug would be more beneficial in the early stages of ILD. Second, there is the heterogeneity of the previous CYC administration. Patients treated with oral CYC may have better improvement in their PFT results, as indicated in recent reports. This may also mask the real beneficial effect of MMF. Finally, as CT scoring was done by only one experienced pneumologist, this could present a weakness of this retrospective analysis. Other potential weakness of this scoring system may be that it can be less sensitive in detecting small changes during follow-up evaluations. Cyclophosphamide has potential for short and longterm toxicities. Even though the mean cumulative dose of CYC was 16 g in our cohort, we did not see any particular event that needed to be reported. During the 24 months of the study, none of our patients reported or needed to leave the study because of serious adverse events; however, mild abdominal pain occurred with MMF. In conclusion, from our results we cannot draw any definitive conclusion, but MMF seemed to stabilize PFTs and imaging scores. On the other hand, prospective, long-term studies in early SSc-ILD are required to evaluate certain issues. All authors declare there are no conflicts of interest.
REFERENCES 1 Harris ED, Budd RC, Firestein GS et al. (2005) Kelley’s Textbook of Rheumatology. Vol. II, pp 1279–303. Elsevier, Philadelphia.
5
N. Yilmaz et al.
2 Silver RM, Clements PJ (2003) Interstitial lung disease in systemic sclerosis: optimizing evaluation and management. Scleroderma Care Res 1, 1–20. 3 Silver RM, Warrick JH, Kinsella MB, Staudt LS, Baumann MH, Strange C (1993) Cyclophosphamide and low-dose prednisolone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease. J Rheumatol 20, 838–44. 4 Akesson A, Scheja A, Lundin A, Wollheim FA (1994) Improved pulmonary function in systemic sclerosis after treatment with cyclophosphamide. Arthritis Rheum 37, 729–35. 5 Steen VD, Lanz JK, Conte C, Ownes GR, Medsger TA (1994) Therapy for severe interstitial lung disease in systemic sclerosis: a retrospective study. Arthritis Rheum 37, 1290–6. 6 Giacomelli R, Valentini G, Salsano F et al. (2002) Cyclophosphamide pulse regimen in the treatment of alveolitis in systemic sclerosis. J Rheumatol 29, 731–6. 7 Pakas I, Ioannidis JP, Malagari K, Skopouli FN, Moutsopoulos HM, Vlachoviannopoulos PG (2002) Cyclophosphamide with low or high dose prednisolone for systemic sclerosis lung disease. J Rheumatol 29, 298–304. 8 Davas EM, Peppas C, Maragou M, Alvanou E, Hondros D, Dantis PC (1999) Intravenous cyclophosphamide pulse therapy for the treatment of lung disease associated with scleroderma. Clin Rheumatol 18, 455–61. 9 Griffiths B, Miles S, Moss H, Robertson R, Veale D, Emery P (2002) Systemic sclerosis and interstitial lung disease: a pilot study using pulsed intravenous methylprednisolone and cyclophosphamide to assess the effect on high resolution computed tomography scan and lung function. J Rheumatol 29, 2371–8. 10 Tashkin DP, Elashoff R, Clements PJ et al., for the Scleroderma Lung Study Research Group (2006) Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 354, 2655–66. 11 Tashkin DP, Elashoff R, Clements PJ et al. (2007) Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med 176, 1026–34. 12 Mittoo S, Wigley FM, Wise RA, Woods A, Xiao H, Hummers LK (2011) Long term effects of cyclophosphamide treatment on lung function and survival in scleroderma patients with interstitial lung disease. Open Rheumatol J 5, 1–6. 13 Villarroel MC, Hidalgo M, Jimeno A (2009) Mycophenolate mofetil: an update. Drugs Today 45, 521–32. 14 Allison AC, Eugui EM (2005) Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection. Transplantation 80 (Suppl. 2), 181–90. 15 Dooley MA, Jayne D, Ginzler EM et al. (2011) Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 365, 1886–95. 16 Majithia V, Harisdangkul V (2005) Mycophenolate mofetil (CellCept): an alternative therapy for autoimmune
6
17
18
19
20
21
22
23
24
25
26
27
28
29
30
inflammatory myopathy. Rheumatology (Oxford) 44 (3), 386–9. Gerbino AJ, Goss CH, Molitor JA (2008) Effect of mycophenolate mofetil on pulmonary function in sclerodermaassociated interstitial lung disease. Chest 133 (2), 455–60. Koutroumpas A, Ziogas A, Alexiou I, Barouta G, Sakkas LI (2010) Mycophenolate mofetil in systemic sclerosis-associated interstitial lung disease. Clin Rheumatol 29 (10), 1167–8. Liossis SNC, Bounas A, Andonopoulos AP (2006) Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology 45 (8), 1005–8. Zamora AC, Wolters PJ, Collard HR et al. (2008) Use of mycophenolate mofetil to treat scleroderma-associated interstitial lung disease. Respirat Med 102 (1), 150–5. Warrick JH, Bhalla M, Schabel SI, Silver RM (1991) High resolution computed tomography in early scleroderma lung disease. J Rheumatol 18, 1520–8. Bellia M, Cannizzaro F, Scichilone N et al. (2009) HRCT and scleroderma: semi quantitative evaluation of lung damage and functional abnormalities. Radiol Med 114, 190–203. Diot E, Boissinot E, Asquier E et al. (1998) Relationship between abnormalities on high-resolution CT and pulmonary function in systemic sclerosis. Chest 114, 1623–9. Nannini C, West CP, Erwin PJ, Matteson EL (2008) Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: a systematic review and meta-analysis of randomized controlled trials and observational prospective cohort studies. Arthritis Res Ther 10, 1–9. Liossis SNC, Bounas A, Andonopoulos AP (2006) Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology 45, 1005–8. Plastiras SC, Vlachoyiannopoulos PG, Tzelepis GE (2006) Letters to the Editor: Mycophenolate mofetil for interstitial lung disease in Scleroderma. Rheumatology 45, 1572–82. Tzouvelekis A, Galanopoulos N, Bouros E et al. (2012) Effect and safety of Mycophenolate mofetil or sodium in Systemic Sclerosis-Associated Interstitial Lung Disease: a meta-analysis. Pulm Med 2012, 1–7. Simeon-Aznar CP, Fonollosa-Pla V, Tolosa-Vilella C, SelvaO’Callaghan A, Solans-Laqu0 e R, Vilardell-Tarres M (2011) Effect of mycophenolate sodium in scleroderma-related interstitial lung disease. Clin Rheumatol 30 (11), 1393–8. Fischer A, Brown KK, Du Bois RM et al. (2013) Mycophenolate mofetil improves lung function in connective tissue disease associated interstitial lung disease. J Rheumatol 40 (5), 640–6. Goldin JG, Lynch DA, Strollo DC et al. (2008) High resolution CT scan findings in patients with symptomatic scleroderma-related interstitial lung disease. Chest 134, 358–67.
International Journal of Rheumatic Diseases 2014
