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Predictors of response to anti-TNF therapy in RA patients with moderate or high DAS28 scores
Joint Bone Spine 81 (2014) 37–40
Available online at www.sciencedirect.com
Original article
Predictors of response to anti-TNF therapy in RA patients with moderate or high DAS28 scores Fabiola Atzeni a,∗ , Sara Bongiovanni a , Antonio Marchesoni b , Matteo Filippini c , Roberto Caporali d , Roberto Gorla c , Lorenzo Cavagna d , Ennio Giulio Favalli b , Francesco Saccardo e , Piercarlo Sarzi-Puttini a a
Rheumatology Unit, L.Sacco University Hospital of Milan, Milan, Italy Day Hospital of Rheumatology, G. Pini Orthopedic Institute, Chair of Rheumatology in Milan, Milan, Italy c Rheumatology and Immunology Unit, Spedali Civili di Brescia, Brescia, Italy d Chair of Rheumatology, IRCCS Policlinico S. Matteo, Pavia, Italy e Internal Medicine, Ospedale di Saronno, A.O. Busto Arsizio, Saronno, Italy b
a r t i c l e
i n f o
Article history: Accepted 6 April 2013 Available online 2 June 2013 Keywords: High and moderate disease activity DAS28 scores Predictive factors Anti-TNF
a b s t r a c t Objectives: To identify the clinical factors predicting a good clinical response to anti-TNF therapy in rheumatoid arthritis (RA) patients entered in the LORHEN registry after 5 years of treatment with antiTNF agents and divided into two groups on the basis of their baseline DAS28 scores (moderate > 3.2–5.1 [MDA] and high > 5.1 [HDA]). Methods: Disease activity at baseline and after 12 months was assessed using the DAS28, and response was evaluated using the EULAR improvement criteria. Results: The study involved 1300 patients with established RA: 975 with HDA and 325 with MDA. After a mean 36-month, 29.6% of the patients had a DAS28 score of less or equal to 2.6 (HDA 25.8% vs. MDA 43.0%; P < 0.001) and were considered to be in remission. A higher probability of a good EULAR response in patients with HDA was associated with male gender (F vs. M – OR 0.45, 95% CI 0.26–0.78; P: 0.004), lower age at the start of treatment (OR 0.98, 95% CI 0.96–0.99; P: 0.002), the absence of comorbidities (OR 0.18, 95% CI 0.06–0.52; P: 0.002) or no previous use of corticosteroids (OR 1.92, 95% CI 1.14–3.22; P: 0.015) and the use of adalimumab vs. infliximab (OR 2.21, 95% CI 1.37–3.57; P 0.001); in patients with MDA, the probability of a good EULAR response was associated with male gender (F vs. M – OR 0.39, 95% CI 0.17–0.90; P: 0.027). Conclusions: With the exception of male gender, the factors predicting a good EULAR response are different in patients with MDA and those with HDA. © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction A number of studies [1–4] have found that patients who start anti-tumour necrosis factor (TNF) therapy with lower 28-joint disease activity scores (DAS28 scores) are more likely to achieve disease remission (defined as a DAS28 score of less than 2.6), but less likely to achieve a 50% or 70% improvement in disease activity as defined by the American College of Rheumatology (ACR) response criteria [5]. The British Society for Rheumatology Biologics Register (BSRBR) has shown that treatment with anti-TNF therapy is effective in patients with high (HDA) or moderate disease activity (MDA) [6], and that anti-TNF therapy may be similarly cost effective in both groups as assessed using health economic models based on changes in Health Assessment Questionnaire (HAQ) scores.
∗ Corresponding author. E-mail address: [email protected] (F. Atzeni).
Various studies have investigated the clinical predictors of response to traditional disease-modifying anti-rheumatic drugs (DMARDs) and anti-TNF agents [6,7], and a recent systematic review has identified a number of independent predictors of remission: i.e. baseline clinical and laboratory characteristics and genetic markers, including male gender, young age, late-onset RA, a short disease duration, being a non-smoker, low baseline disease activity, the absence of rheumatoid factor (RF) and anti-citrullinated peptide, and the concurrent use of DMARDs in anti-TNF-treated patients. However, the predictive value of these prognostic factors needs to be confirmed [7]. No previous study has compared predictors of response in RA patients with MDA (DAS28 scores of 3.2-5.1) or HDA (DAS28 scores of more than 5.1). The aim of this study was to identify the clinical factors predicting a good clinical response to anti-TNF in the RA patients with MDA or HDA entered in the Lombardy Rheumatology Network (LORHEN) registry after 5 years of treatment with antiTNF agents [8].
1297-319X/$ – see front matter © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2013.04.005
38
F. Atzeni et al. / Joint Bone Spine 81 (2014) 37–40
2. Methods
3. Results
This analysis was restricted to the LOHREN registry patients who had been diagnosed as having RA by a rheumatologist, had not been exposed to biological agents, were starting one of the three available anti-TNF agents (etanercept [ETN], infliximab [IFN] or adalimumab [ADA]) at that time, and had been followed up for a minimum of twelve months after the registry was started in 1999 [8]. All of the patients were treated in accordance with the Italian Society of Rheumatology (SIR) guidelines for the use of anti-TNF agents: a diagnosis of RA (ACR criteria); a failure to respond to at least one course of combined therapy with full-dose traditional DMARDs, one of which should always be methotrexate (MTX) unless contraindicated; and active disease as defined by a 28-joint disease activity score (DAS28 score) of greater than 3.5 [9]. The prospective protocol included information on demographics, the clinical characteristics of the patients, and response measures. Disease activity at baseline and after twelve months was assessed using the DAS28, and response was evaluated on the basis of the EULAR improvement criteria [10].
Table 1 shows the demographic and clinical characteristics of the 1300 patients with established RA included in the study (326 treated with ETN, 385 treated with ADA, and 589 treated with IFN); 975 with HDA and 325 with MDA were analysed in terms of clinical efficacy. At the start of therapy, the patients had a mean age of 54.66 ± 13.74 years, a disease duration of 7.5 ± 7.9 years, and a baseline DAS28 score of 5.77 ± 1.05 (HDA 6.23 ± 0.71; MDA 4.37 ± 0.51). After a mean of 36 months, complete clinical and laboratory data were available for 608 patients, 180 of whom (29.6%) had achieved a DAS28 of less than or equal to 2.6 (HDA 25.8%; MDA 43.0%; P < 0.001) and were considered to be in remission, and 282 (46.4%) had achieved a good EULAR response (HDA 43.5%; MDA 56.3; P < 0.001) (Table 2). A lack of response was more frequent in the patients with MDA (24.4% vs. 10.6%; P < 0.001). A higher probability of a good EULAR response in patients with HDA was associated with male gender (F vs. M – OR 0.45, 95% CI 0.26–0.78; P: 0.004), lower age at the start of treatment (OR 0.98, 95% CI 0.96–0.99; P: 0.002), the absence of comorbidities (OR 0.18, 95% CI 0.06–0.52; P: 0.002) or no previous use of corticosteroids (OR 1.92, 95% CI 1.14–3.23; P: 0.015) and the use of adalimumab vs. infliximab (OR 2.21, 95% CI 1.37–3.57; P: 0.001); in patients with MDA, the probability was associated with male gender (F vs. M – OR 0.39, 95% CI 0.17–0.90; P: 0.027) (Table 3). Predictive factors of no EULAR response in patients with HAD and MDA are reported in Table 4. Age, disease duration, the presence of RF and the previous use of DMARDs did not predict response in this cohort of patients, but the patients with HDA without concomitant comorbidities were more likely to achieve a good clinical response.
2.1. Statistical analysis The differences between patients with severe or moderate RA were analysed using the data relating to all of the patients entered in the LORHEN registry since 1999, and followed-up for a minimum of twelve months. The continuous variables (mean values and standard deviations) were analysed using the KruskalWallis non-parametric test, and the categorical variables (absolute numbers and percentages) were analysed using the chi-squared test. The potential predictors of response were identified using multivariate binary logistic regression models. All of the analyses were made using SAS version 9.2 (SAS Institute, Inc.; Cary, NC), and a P value ≤ 0.05 was considered statistically significant.
4. Discussion In line with those of the British registry study [6], our results confirm that anti-TNF therapy is effective in patients with HDA or
Table 1 Characteristics of 1300 rheumatoid arthritis (RA) patients by DAS28 scores. Overall
DAS28 (> 5.1)
DAS28 (3.2–5.1)
No. of patients (%)
1300
975 (75)
325 (25)
Mean age, years
54.6 ± 13.7
55.9 ± 13.4
50.9 ± 13.9
Females, n (%)
1064 (81.8)
824 (84.5)
240 (73.8)
Males, n (%)
236 (18.2)
151 (15.5)
85 (26.2)
Mean disease duration, years
7.5 ± 7.9
7.2 ± 7.9
8.3 ± 7.9
Presence of comorbidity, n (%)
851 (65.5)
668 (68.5)
183 (56.3)
Swollen joints, n (%)
9.57 ± 5.65
11.09 ± 5.20
5.01 ± 4.32
Tender joints, n (%)
10.82 ± 6.57
12.98 ± 5.89
4.34 ± 3.49
Mean DAS28 score
5.77 ± 1.05
6.23 ± 0.71
4.37 ± 0.51
Mean Health Assessment Questionnaire score
1.44 ± 0.62
1.54 ± 0.59
1.06 ± 0.58
Rheumatoid factor, n (%)
995 (76.5)
760 (77.9)
235 (72.3)
Anti-CCP, n (%)
1070 (82.3)
810 (83.1)
260 (80.0)
Smokers, n (%)
261 (20.1)
189 (19.4)
69 (21.1)
Mean erythrocyte sedimentation rate, mm/1st h
39.6 ± 21.6
43.9 ± 21
26.3 ± 17.3
Anti-TNF agents Etanercept, n (%) Adalimumab, n (%) Infliximab, n (%)
326 (25) 385 (29.6) 589 (45.3)
232 (23) 266 (27) 477 (48.9)
94 (28.9) 119 (36.6) 112 (34.4)
Concomitant medications Corticosteroids, n (%) DMARDs, n (%)
278 (21.4) 288 (22.2)
198 (20.3) 203 (20.8)
80 (24.6) 85 (26.2)
DMARDs: disease-modifying anti-rheumatic drugs; anti-CCP: anti-anti-citrullinated peptide.
F. Atzeni et al. / Joint Bone Spine 81 (2014) 37–40
39
Table 2 EULAR response in patients with high (HDA) or moderate levels of disease activity (MDA). EULAR response
Overall
Absent Moderate Good Remission
83 (13.6) 243 (40) 282 (46.4) 180/282 (29.6)
HDA
MDA
(DAS28 > 5.1) n = 473
(DAS28: 3.2–5.1) n = 135
50 (10.6) 217 (45.9) 206 (43.5) 122 (25.8)
33 (24.4) 26 (19.3) 76 (56.3) 58 (43.0)
P value
< 0.001 < 0.001 < 0.001 < 0.001
Table 3 Predictors of a good EULAR response using multivariate binary logistic regression models in patients with DAS28 scores > 5.1 or 3.2–5.1. Overall P Lower age at the start of anti-TNF Gender female vs. male Comorbidity vs. no comorbidity Tender joints count 28 Swollen joints count 28 High ESR vs. low Adalimumab vs. infliximab Etanercept vs. infliximab Adalimumab vs. etanercept MTX vs. other DMARDs Corticosteroids no vs. yes Smoke no vs. yes
0.001 < 0.001 0.002 0.011 0.903 0.355 0.001 0.179 0.093 0.418 0.005 0.138
OR (95 CI) 0.98 (0.96–0.99) 0.44 (0.28–0.69) 0.28 (0.13–0.64) 0.96 (0.94–0.99) 1.00 (0.96–1.05) 0.84 (0.57–1.22) 1.98 (1.31–2.99) 1.35 (0.87–2.08) 1.5 (0.93–2.40) 2.06 (0.36–11.87) 1.90 (1.22–2.98) 0.71 (0.46–1.12)
Patients with DAS28 > 5.1
Patients with DAS28 >3.2–<5.1
P
OR (95 CI)
P
OR (95 CI)
0.002 0.004 0.002 0.013 0.922 0.515 0.001 0.308 0.051 0.860 0.015 0.227
0.98 (0.96–0.99) 0.45 (0.26–0.78) 0.18 (0.06–0.52) 0.96 (0.92–0.99) 1.00 (0.96–1.05) 0.85 (0.51–1.40) 2.21 (1.37–3.57) 1.30 (0.79–2.13) 1.74 (0.99–3.04) 1.24 (0.12–12.82) 1.92 (1.14–3.23) 0.73 (0.44–1.21)
0.123 0.027 0.845 0.531 0.620 0.413 0.210 0.170 0.869 0.506 0.190 0.146
0.98 (0.95–1.01) 0.39 (0.17–0.90) 0.86 (0.19–3.83) 1.04 (0.90–1.22) 1.03 (0.92–1.15) 0.69 (0.28–1.68) 1.85 (0.71–4.87) 1.99 (0.75–5.32) 0.93 (0.35–2.39) 2.67 (0.15–48.34) 2.07 (0.70–6.13) 0.45 (0.16–1.32)
DMARDs: disease-modifying anti-rheumatic drugs; MTX: methotrexate; ESR: erythrocyte sedimentation rate.
MDA. However, as in the case of various other studies [1–4], the number of patients achieving disease remission was significantly higher in the MDA group, as was the number of non-responders. It is reasonable to think that the higher number of EULAR responders in the MDA group was related to their less aggressive disease. However, it is worth noting that the remission threshold is much more easily achieved starting from a low DAS28 score. The apparent contradiction of more non-responders in the MDA group than in the HDA group may be explained by a kind of “floor effect” in the former and the phenomenon of regression towards the mean in the latter. In other words, low DAS28 scores may be less likely to decrease by at least 0.6 because they are already quite low, and very high levels of disease activity may improve spontaneously as a result of natural disease fluctuations. In Italy (unlike in some other countries), as both the previous and current national guidelines permit the use of anti-TNF therapies in patients with a DAS28 score of less than 5.1 [9,11], many patients have received them and it is
therefore possible to evaluate the factors predicting response and non-response. The factors predicting a good EULAR response were different in our MDA and HDA patients. With the exception of male gender (which was predictive in both groups), none of the evaluated factors was associated with a EULAR response in the MDA patients, but a number were associated with a EULAR response in the HDA patients (Table 3). It is difficult to explain why age at the start of anti-TNF therapy, the absence of comorbidities were independently predictive of EULAR response only in the HDA patients, by why the use of ADA (but not ETN) compared with IFN only predicted a response in the HDA patients may be explained by the fact that the drugs were marketed at different times (IFN first, followed by ETN and then ADA) and used in patients with different disease characteristics. At the start of therapy, the patients treated with IFN had significantly greater disease activity (DAS28) and disability (DI-HAQ). The much smaller number of MDA patients (135 vs. 473)
Table 4 Predictors of no EULAR response using multivariate binary logistic regression models in patients with high levels of disease activity (HAD) versus those with moderate levels of disease activity (MDA). Overall
Age at the start of anti-TNF Gender female vs. male Major comorbidity vs. absence Minor comorbidity vs. absence Tender joints 28 Swollen joints 28 Higher ESR vs. lower Adalimumab vs. infliximab Etanercept vs. infliximab Adalimumab vs. etanercept DMARDs MTX vs. other Corticosteroids no vs. yes Smoke no vs. yes
Patients with DAS28 > 5.1
Patients with DAS28 >3.2–<5.1
P
OR (95 CI)
P
OR (95 CI)
P
OR (95 CI)
0.0007 0.0004 0.0022 0.3935 0.0108 0.8966 0.3439 0.0012 0.1787 0.0935 0.3818 0.0049 0.1282
1.024 (1.01–1.038) 2.301 (1.455–3.638) 3.519 (1.571–7.883) 1.184 (0.804–1.744) 1.039 (1.009–1.069) 0.997 (0.955–1.041) 1.203 (0.82–1.766) 0.506 (0.335–0.765) 0.743 (0.481–1.146) 0.667 (0.415–1.071) 0.455 (0.078–2.66) 0.525 (0.335–0.823) 1.416 (0.905–2.216)
0.0015 0.0043 0.0015 0.2439 0.0134 0.904 0.5152 0.0011 0.3079 0.0512 0.7295 0.0146 0.2124
1.026 (1.01–1.042) 2.234 (1.287–3.879) 5.545 (1.921–16) 1.302 (0.835–2.031) 1.048 (1.01–1.088) 0.997 (0.95–1.046) 1.182 (0.714–1.957) 0.452 (0.28–0.729) 0.772 (0.469–1.27) 0.574 (0.328–1.003) 0.648 (0.055–7.582) 0.522 (0.309–0.88) 1.382 (0.831–2.296)
0.0872 0.027 0.8277 0.6624 0.4934 0.5663 0.3689 0.17 0.1326 0.8697 0.5312 0.1398 0.104
1.028 (0.996–1.062) 2.548 (1.112–5.837) 1.184 (0.259–5.409) 0.833 (0.366–1.895) 0.949 (0.816–1.103) 0.968 (0.866–1.082) 1.517 (0.611–3.766) 0.503 (0.189–1.342) 0.465 (0.171–1.262) 1.083 (0.418–2.807) 0.383 (0.019–7.743) 0.432 (0142–1.317) 2.455 (0.831–7.252)
DMARDs: disease-modifying anti-rheumatic drugs; MTX: methotrexate.
40
F. Atzeni et al. / Joint Bone Spine 81 (2014) 37–40
may have contributed to this finding (type I error) and, as only 261 of the patients were smokers, this may also explain the absence of an association between smoking and a poor response to therapy. The relatively small MDA population was a limitation of this study. One recent systematic review has evaluated 18 papers describing a number of independent predictors of remission, including baseline clinical and laboratory characteristics and genetic markers, such as male gender, a young age, late-onset RA, etc. [7]. We have previously found that males are more likely to achieve remission after 36 months of therapy [12], and Straub et al. [13] have speculated that male patients should gain greater benefit from anti-TNF agents because of their effects on the neuroendocrine axis, which include higher levels of antiinflammatory androgens in the synovial tissue in comparison with females. It is interesting that male gender was the only factor independently associated with a response to therapy in both groups. In conclusion, within the limits of this observational design, the findings of this study show that anti-TNF agents are effective in the long-term in RA patients with MDA at the time they started the therapy, and that these patients more frequently achieved EULAR remission than the patients with HDA. With the exception of male gender, no factor was predictive of a response to therapy in the patients with MDA, but this finding needs to be confirmed by studies of larger populations. Contributors All of the authors collected and recorded the LORHEN registry data. F. Atzeni and P. Sarzi-Puttini suggested how to analyse the data and wrote the manuscript. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements The authors acknowledge the enthusiastic collaboration of all of the consultant rheumatologists in providing the data. The authors wish to thank Dr. R. Benini for his statistical support. References [1] Listing J, Strangfeld A, Rau R, et al. Clinical and functional remission: even though biologics are superior to conventional DMARDs overall success rates remain low – results from RABBIT, the German biologics register. Arthritis Res Ther 2006;8:R66. [2] Hyrich KL, Watson KD, Silman AJ, et al. Predictors of response to anti-TNFalpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology 2006;45:1558–65. [3] Burmester GR, Ferraccioli G, Flipo RM, et al. Clinical remission and/or minimal disease activity in patients receiving adalimumab treatment in a multinational, open-label, twelve-week study. Arthritis Rheum 2008;59:32–4. [4] Kristensen LE, Kapetanovic MC, Gulfe A, et al. Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients with established RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatology 2008;47:495–9. [5] Felson DT, Anderson JJ, Boers M, et al. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727–35. [6] Hyrich KL, Deighton C, Watson KD, et al. Benefit of anti-TNF therapy in rheumatoid arthritis patients with moderate disease activity. Rheumatology (Oxford) 2009;48:1323–7. [7] Katchamart W, Johnson S, Lin HJ, et al. Predictors for remission in rheumatoid arthritis patients: a systematic review. Arthritis Care Res (Hoboken) 2010;62:1128–43. [8] Sarzi-Puttini P, Antivalle M, Marchesoni A, et al. Efficacy and safety of anti-TNF agents in the Lombardy rheumatoid arthritis network (LORHEN). Reumatismo 2008;60:290–5. [9] Valesini G, Montecucco C, Cutolo M. Anti-TNF treatment for rheumatoid arthritis. Clin Exp Rheum 2006;4:414–23. [10] Makinen H, Kautiainen H, Hannonen P, et al. Is DAS28 an appropriate tool to assess remission in rheumatoid arthritis? Ann Rheum Dis 2005;64:1410–3. [11] Caporali R, Conti F, Alivernini S, et al. Recommendations for the use of biologic therapy in rheumatoid arthritis: update from the Italian Society for Rheumatology I. Efficacy. Clin Exp Rheumatol 2011;29:S7–14. [12] Atzeni F, Antivalle M, Pallavicini FB, et al. Predicting response to anti-TNF treatment in rheumatoid arthritis patients. Autoimmun Rev 2009;8:431–7. [13] Straub RH, Harle P, Sarzi-Puttini P, et al. Tumor necrosis factor-neutralizing therapies improve altered hormone axes: an alternative mode of antiinflammatory action. Arthritis Rheum 2006;54:2039–46.
Available online at www.sciencedirect.com
Original article
Predictors of response to anti-TNF therapy in RA patients with moderate or high DAS28 scores Fabiola Atzeni a,∗ , Sara Bongiovanni a , Antonio Marchesoni b , Matteo Filippini c , Roberto Caporali d , Roberto Gorla c , Lorenzo Cavagna d , Ennio Giulio Favalli b , Francesco Saccardo e , Piercarlo Sarzi-Puttini a a
Rheumatology Unit, L.Sacco University Hospital of Milan, Milan, Italy Day Hospital of Rheumatology, G. Pini Orthopedic Institute, Chair of Rheumatology in Milan, Milan, Italy c Rheumatology and Immunology Unit, Spedali Civili di Brescia, Brescia, Italy d Chair of Rheumatology, IRCCS Policlinico S. Matteo, Pavia, Italy e Internal Medicine, Ospedale di Saronno, A.O. Busto Arsizio, Saronno, Italy b
a r t i c l e
i n f o
Article history: Accepted 6 April 2013 Available online 2 June 2013 Keywords: High and moderate disease activity DAS28 scores Predictive factors Anti-TNF
a b s t r a c t Objectives: To identify the clinical factors predicting a good clinical response to anti-TNF therapy in rheumatoid arthritis (RA) patients entered in the LORHEN registry after 5 years of treatment with antiTNF agents and divided into two groups on the basis of their baseline DAS28 scores (moderate > 3.2–5.1 [MDA] and high > 5.1 [HDA]). Methods: Disease activity at baseline and after 12 months was assessed using the DAS28, and response was evaluated using the EULAR improvement criteria. Results: The study involved 1300 patients with established RA: 975 with HDA and 325 with MDA. After a mean 36-month, 29.6% of the patients had a DAS28 score of less or equal to 2.6 (HDA 25.8% vs. MDA 43.0%; P < 0.001) and were considered to be in remission. A higher probability of a good EULAR response in patients with HDA was associated with male gender (F vs. M – OR 0.45, 95% CI 0.26–0.78; P: 0.004), lower age at the start of treatment (OR 0.98, 95% CI 0.96–0.99; P: 0.002), the absence of comorbidities (OR 0.18, 95% CI 0.06–0.52; P: 0.002) or no previous use of corticosteroids (OR 1.92, 95% CI 1.14–3.22; P: 0.015) and the use of adalimumab vs. infliximab (OR 2.21, 95% CI 1.37–3.57; P 0.001); in patients with MDA, the probability of a good EULAR response was associated with male gender (F vs. M – OR 0.39, 95% CI 0.17–0.90; P: 0.027). Conclusions: With the exception of male gender, the factors predicting a good EULAR response are different in patients with MDA and those with HDA. © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction A number of studies [1–4] have found that patients who start anti-tumour necrosis factor (TNF) therapy with lower 28-joint disease activity scores (DAS28 scores) are more likely to achieve disease remission (defined as a DAS28 score of less than 2.6), but less likely to achieve a 50% or 70% improvement in disease activity as defined by the American College of Rheumatology (ACR) response criteria [5]. The British Society for Rheumatology Biologics Register (BSRBR) has shown that treatment with anti-TNF therapy is effective in patients with high (HDA) or moderate disease activity (MDA) [6], and that anti-TNF therapy may be similarly cost effective in both groups as assessed using health economic models based on changes in Health Assessment Questionnaire (HAQ) scores.
∗ Corresponding author. E-mail address: [email protected] (F. Atzeni).
Various studies have investigated the clinical predictors of response to traditional disease-modifying anti-rheumatic drugs (DMARDs) and anti-TNF agents [6,7], and a recent systematic review has identified a number of independent predictors of remission: i.e. baseline clinical and laboratory characteristics and genetic markers, including male gender, young age, late-onset RA, a short disease duration, being a non-smoker, low baseline disease activity, the absence of rheumatoid factor (RF) and anti-citrullinated peptide, and the concurrent use of DMARDs in anti-TNF-treated patients. However, the predictive value of these prognostic factors needs to be confirmed [7]. No previous study has compared predictors of response in RA patients with MDA (DAS28 scores of 3.2-5.1) or HDA (DAS28 scores of more than 5.1). The aim of this study was to identify the clinical factors predicting a good clinical response to anti-TNF in the RA patients with MDA or HDA entered in the Lombardy Rheumatology Network (LORHEN) registry after 5 years of treatment with antiTNF agents [8].
1297-319X/$ – see front matter © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2013.04.005
38
F. Atzeni et al. / Joint Bone Spine 81 (2014) 37–40
2. Methods
3. Results
This analysis was restricted to the LOHREN registry patients who had been diagnosed as having RA by a rheumatologist, had not been exposed to biological agents, were starting one of the three available anti-TNF agents (etanercept [ETN], infliximab [IFN] or adalimumab [ADA]) at that time, and had been followed up for a minimum of twelve months after the registry was started in 1999 [8]. All of the patients were treated in accordance with the Italian Society of Rheumatology (SIR) guidelines for the use of anti-TNF agents: a diagnosis of RA (ACR criteria); a failure to respond to at least one course of combined therapy with full-dose traditional DMARDs, one of which should always be methotrexate (MTX) unless contraindicated; and active disease as defined by a 28-joint disease activity score (DAS28 score) of greater than 3.5 [9]. The prospective protocol included information on demographics, the clinical characteristics of the patients, and response measures. Disease activity at baseline and after twelve months was assessed using the DAS28, and response was evaluated on the basis of the EULAR improvement criteria [10].
Table 1 shows the demographic and clinical characteristics of the 1300 patients with established RA included in the study (326 treated with ETN, 385 treated with ADA, and 589 treated with IFN); 975 with HDA and 325 with MDA were analysed in terms of clinical efficacy. At the start of therapy, the patients had a mean age of 54.66 ± 13.74 years, a disease duration of 7.5 ± 7.9 years, and a baseline DAS28 score of 5.77 ± 1.05 (HDA 6.23 ± 0.71; MDA 4.37 ± 0.51). After a mean of 36 months, complete clinical and laboratory data were available for 608 patients, 180 of whom (29.6%) had achieved a DAS28 of less than or equal to 2.6 (HDA 25.8%; MDA 43.0%; P < 0.001) and were considered to be in remission, and 282 (46.4%) had achieved a good EULAR response (HDA 43.5%; MDA 56.3; P < 0.001) (Table 2). A lack of response was more frequent in the patients with MDA (24.4% vs. 10.6%; P < 0.001). A higher probability of a good EULAR response in patients with HDA was associated with male gender (F vs. M – OR 0.45, 95% CI 0.26–0.78; P: 0.004), lower age at the start of treatment (OR 0.98, 95% CI 0.96–0.99; P: 0.002), the absence of comorbidities (OR 0.18, 95% CI 0.06–0.52; P: 0.002) or no previous use of corticosteroids (OR 1.92, 95% CI 1.14–3.23; P: 0.015) and the use of adalimumab vs. infliximab (OR 2.21, 95% CI 1.37–3.57; P: 0.001); in patients with MDA, the probability was associated with male gender (F vs. M – OR 0.39, 95% CI 0.17–0.90; P: 0.027) (Table 3). Predictive factors of no EULAR response in patients with HAD and MDA are reported in Table 4. Age, disease duration, the presence of RF and the previous use of DMARDs did not predict response in this cohort of patients, but the patients with HDA without concomitant comorbidities were more likely to achieve a good clinical response.
2.1. Statistical analysis The differences between patients with severe or moderate RA were analysed using the data relating to all of the patients entered in the LORHEN registry since 1999, and followed-up for a minimum of twelve months. The continuous variables (mean values and standard deviations) were analysed using the KruskalWallis non-parametric test, and the categorical variables (absolute numbers and percentages) were analysed using the chi-squared test. The potential predictors of response were identified using multivariate binary logistic regression models. All of the analyses were made using SAS version 9.2 (SAS Institute, Inc.; Cary, NC), and a P value ≤ 0.05 was considered statistically significant.
4. Discussion In line with those of the British registry study [6], our results confirm that anti-TNF therapy is effective in patients with HDA or
Table 1 Characteristics of 1300 rheumatoid arthritis (RA) patients by DAS28 scores. Overall
DAS28 (> 5.1)
DAS28 (3.2–5.1)
No. of patients (%)
1300
975 (75)
325 (25)
Mean age, years
54.6 ± 13.7
55.9 ± 13.4
50.9 ± 13.9
Females, n (%)
1064 (81.8)
824 (84.5)
240 (73.8)
Males, n (%)
236 (18.2)
151 (15.5)
85 (26.2)
Mean disease duration, years
7.5 ± 7.9
7.2 ± 7.9
8.3 ± 7.9
Presence of comorbidity, n (%)
851 (65.5)
668 (68.5)
183 (56.3)
Swollen joints, n (%)
9.57 ± 5.65
11.09 ± 5.20
5.01 ± 4.32
Tender joints, n (%)
10.82 ± 6.57
12.98 ± 5.89
4.34 ± 3.49
Mean DAS28 score
5.77 ± 1.05
6.23 ± 0.71
4.37 ± 0.51
Mean Health Assessment Questionnaire score
1.44 ± 0.62
1.54 ± 0.59
1.06 ± 0.58
Rheumatoid factor, n (%)
995 (76.5)
760 (77.9)
235 (72.3)
Anti-CCP, n (%)
1070 (82.3)
810 (83.1)
260 (80.0)
Smokers, n (%)
261 (20.1)
189 (19.4)
69 (21.1)
Mean erythrocyte sedimentation rate, mm/1st h
39.6 ± 21.6
43.9 ± 21
26.3 ± 17.3
Anti-TNF agents Etanercept, n (%) Adalimumab, n (%) Infliximab, n (%)
326 (25) 385 (29.6) 589 (45.3)
232 (23) 266 (27) 477 (48.9)
94 (28.9) 119 (36.6) 112 (34.4)
Concomitant medications Corticosteroids, n (%) DMARDs, n (%)
278 (21.4) 288 (22.2)
198 (20.3) 203 (20.8)
80 (24.6) 85 (26.2)
DMARDs: disease-modifying anti-rheumatic drugs; anti-CCP: anti-anti-citrullinated peptide.
F. Atzeni et al. / Joint Bone Spine 81 (2014) 37–40
39
Table 2 EULAR response in patients with high (HDA) or moderate levels of disease activity (MDA). EULAR response
Overall
Absent Moderate Good Remission
83 (13.6) 243 (40) 282 (46.4) 180/282 (29.6)
HDA
MDA
(DAS28 > 5.1) n = 473
(DAS28: 3.2–5.1) n = 135
50 (10.6) 217 (45.9) 206 (43.5) 122 (25.8)
33 (24.4) 26 (19.3) 76 (56.3) 58 (43.0)
P value
< 0.001 < 0.001 < 0.001 < 0.001
Table 3 Predictors of a good EULAR response using multivariate binary logistic regression models in patients with DAS28 scores > 5.1 or 3.2–5.1. Overall P Lower age at the start of anti-TNF Gender female vs. male Comorbidity vs. no comorbidity Tender joints count 28 Swollen joints count 28 High ESR vs. low Adalimumab vs. infliximab Etanercept vs. infliximab Adalimumab vs. etanercept MTX vs. other DMARDs Corticosteroids no vs. yes Smoke no vs. yes
0.001 < 0.001 0.002 0.011 0.903 0.355 0.001 0.179 0.093 0.418 0.005 0.138
OR (95 CI) 0.98 (0.96–0.99) 0.44 (0.28–0.69) 0.28 (0.13–0.64) 0.96 (0.94–0.99) 1.00 (0.96–1.05) 0.84 (0.57–1.22) 1.98 (1.31–2.99) 1.35 (0.87–2.08) 1.5 (0.93–2.40) 2.06 (0.36–11.87) 1.90 (1.22–2.98) 0.71 (0.46–1.12)
Patients with DAS28 > 5.1
Patients with DAS28 >3.2–<5.1
P
OR (95 CI)
P
OR (95 CI)
0.002 0.004 0.002 0.013 0.922 0.515 0.001 0.308 0.051 0.860 0.015 0.227
0.98 (0.96–0.99) 0.45 (0.26–0.78) 0.18 (0.06–0.52) 0.96 (0.92–0.99) 1.00 (0.96–1.05) 0.85 (0.51–1.40) 2.21 (1.37–3.57) 1.30 (0.79–2.13) 1.74 (0.99–3.04) 1.24 (0.12–12.82) 1.92 (1.14–3.23) 0.73 (0.44–1.21)
0.123 0.027 0.845 0.531 0.620 0.413 0.210 0.170 0.869 0.506 0.190 0.146
0.98 (0.95–1.01) 0.39 (0.17–0.90) 0.86 (0.19–3.83) 1.04 (0.90–1.22) 1.03 (0.92–1.15) 0.69 (0.28–1.68) 1.85 (0.71–4.87) 1.99 (0.75–5.32) 0.93 (0.35–2.39) 2.67 (0.15–48.34) 2.07 (0.70–6.13) 0.45 (0.16–1.32)
DMARDs: disease-modifying anti-rheumatic drugs; MTX: methotrexate; ESR: erythrocyte sedimentation rate.
MDA. However, as in the case of various other studies [1–4], the number of patients achieving disease remission was significantly higher in the MDA group, as was the number of non-responders. It is reasonable to think that the higher number of EULAR responders in the MDA group was related to their less aggressive disease. However, it is worth noting that the remission threshold is much more easily achieved starting from a low DAS28 score. The apparent contradiction of more non-responders in the MDA group than in the HDA group may be explained by a kind of “floor effect” in the former and the phenomenon of regression towards the mean in the latter. In other words, low DAS28 scores may be less likely to decrease by at least 0.6 because they are already quite low, and very high levels of disease activity may improve spontaneously as a result of natural disease fluctuations. In Italy (unlike in some other countries), as both the previous and current national guidelines permit the use of anti-TNF therapies in patients with a DAS28 score of less than 5.1 [9,11], many patients have received them and it is
therefore possible to evaluate the factors predicting response and non-response. The factors predicting a good EULAR response were different in our MDA and HDA patients. With the exception of male gender (which was predictive in both groups), none of the evaluated factors was associated with a EULAR response in the MDA patients, but a number were associated with a EULAR response in the HDA patients (Table 3). It is difficult to explain why age at the start of anti-TNF therapy, the absence of comorbidities were independently predictive of EULAR response only in the HDA patients, by why the use of ADA (but not ETN) compared with IFN only predicted a response in the HDA patients may be explained by the fact that the drugs were marketed at different times (IFN first, followed by ETN and then ADA) and used in patients with different disease characteristics. At the start of therapy, the patients treated with IFN had significantly greater disease activity (DAS28) and disability (DI-HAQ). The much smaller number of MDA patients (135 vs. 473)
Table 4 Predictors of no EULAR response using multivariate binary logistic regression models in patients with high levels of disease activity (HAD) versus those with moderate levels of disease activity (MDA). Overall
Age at the start of anti-TNF Gender female vs. male Major comorbidity vs. absence Minor comorbidity vs. absence Tender joints 28 Swollen joints 28 Higher ESR vs. lower Adalimumab vs. infliximab Etanercept vs. infliximab Adalimumab vs. etanercept DMARDs MTX vs. other Corticosteroids no vs. yes Smoke no vs. yes
Patients with DAS28 > 5.1
Patients with DAS28 >3.2–<5.1
P
OR (95 CI)
P
OR (95 CI)
P
OR (95 CI)
0.0007 0.0004 0.0022 0.3935 0.0108 0.8966 0.3439 0.0012 0.1787 0.0935 0.3818 0.0049 0.1282
1.024 (1.01–1.038) 2.301 (1.455–3.638) 3.519 (1.571–7.883) 1.184 (0.804–1.744) 1.039 (1.009–1.069) 0.997 (0.955–1.041) 1.203 (0.82–1.766) 0.506 (0.335–0.765) 0.743 (0.481–1.146) 0.667 (0.415–1.071) 0.455 (0.078–2.66) 0.525 (0.335–0.823) 1.416 (0.905–2.216)
0.0015 0.0043 0.0015 0.2439 0.0134 0.904 0.5152 0.0011 0.3079 0.0512 0.7295 0.0146 0.2124
1.026 (1.01–1.042) 2.234 (1.287–3.879) 5.545 (1.921–16) 1.302 (0.835–2.031) 1.048 (1.01–1.088) 0.997 (0.95–1.046) 1.182 (0.714–1.957) 0.452 (0.28–0.729) 0.772 (0.469–1.27) 0.574 (0.328–1.003) 0.648 (0.055–7.582) 0.522 (0.309–0.88) 1.382 (0.831–2.296)
0.0872 0.027 0.8277 0.6624 0.4934 0.5663 0.3689 0.17 0.1326 0.8697 0.5312 0.1398 0.104
1.028 (0.996–1.062) 2.548 (1.112–5.837) 1.184 (0.259–5.409) 0.833 (0.366–1.895) 0.949 (0.816–1.103) 0.968 (0.866–1.082) 1.517 (0.611–3.766) 0.503 (0.189–1.342) 0.465 (0.171–1.262) 1.083 (0.418–2.807) 0.383 (0.019–7.743) 0.432 (0142–1.317) 2.455 (0.831–7.252)
DMARDs: disease-modifying anti-rheumatic drugs; MTX: methotrexate.
40
F. Atzeni et al. / Joint Bone Spine 81 (2014) 37–40
may have contributed to this finding (type I error) and, as only 261 of the patients were smokers, this may also explain the absence of an association between smoking and a poor response to therapy. The relatively small MDA population was a limitation of this study. One recent systematic review has evaluated 18 papers describing a number of independent predictors of remission, including baseline clinical and laboratory characteristics and genetic markers, such as male gender, a young age, late-onset RA, etc. [7]. We have previously found that males are more likely to achieve remission after 36 months of therapy [12], and Straub et al. [13] have speculated that male patients should gain greater benefit from anti-TNF agents because of their effects on the neuroendocrine axis, which include higher levels of antiinflammatory androgens in the synovial tissue in comparison with females. It is interesting that male gender was the only factor independently associated with a response to therapy in both groups. In conclusion, within the limits of this observational design, the findings of this study show that anti-TNF agents are effective in the long-term in RA patients with MDA at the time they started the therapy, and that these patients more frequently achieved EULAR remission than the patients with HDA. With the exception of male gender, no factor was predictive of a response to therapy in the patients with MDA, but this finding needs to be confirmed by studies of larger populations. Contributors All of the authors collected and recorded the LORHEN registry data. F. Atzeni and P. Sarzi-Puttini suggested how to analyse the data and wrote the manuscript. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements The authors acknowledge the enthusiastic collaboration of all of the consultant rheumatologists in providing the data. The authors wish to thank Dr. R. Benini for his statistical support. References [1] Listing J, Strangfeld A, Rau R, et al. Clinical and functional remission: even though biologics are superior to conventional DMARDs overall success rates remain low – results from RABBIT, the German biologics register. Arthritis Res Ther 2006;8:R66. [2] Hyrich KL, Watson KD, Silman AJ, et al. Predictors of response to anti-TNFalpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology 2006;45:1558–65. [3] Burmester GR, Ferraccioli G, Flipo RM, et al. Clinical remission and/or minimal disease activity in patients receiving adalimumab treatment in a multinational, open-label, twelve-week study. Arthritis Rheum 2008;59:32–4. [4] Kristensen LE, Kapetanovic MC, Gulfe A, et al. Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients with established RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatology 2008;47:495–9. [5] Felson DT, Anderson JJ, Boers M, et al. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727–35. [6] Hyrich KL, Deighton C, Watson KD, et al. Benefit of anti-TNF therapy in rheumatoid arthritis patients with moderate disease activity. Rheumatology (Oxford) 2009;48:1323–7. [7] Katchamart W, Johnson S, Lin HJ, et al. Predictors for remission in rheumatoid arthritis patients: a systematic review. Arthritis Care Res (Hoboken) 2010;62:1128–43. [8] Sarzi-Puttini P, Antivalle M, Marchesoni A, et al. Efficacy and safety of anti-TNF agents in the Lombardy rheumatoid arthritis network (LORHEN). Reumatismo 2008;60:290–5. [9] Valesini G, Montecucco C, Cutolo M. Anti-TNF treatment for rheumatoid arthritis. Clin Exp Rheum 2006;4:414–23. [10] Makinen H, Kautiainen H, Hannonen P, et al. Is DAS28 an appropriate tool to assess remission in rheumatoid arthritis? Ann Rheum Dis 2005;64:1410–3. [11] Caporali R, Conti F, Alivernini S, et al. Recommendations for the use of biologic therapy in rheumatoid arthritis: update from the Italian Society for Rheumatology I. Efficacy. Clin Exp Rheumatol 2011;29:S7–14. [12] Atzeni F, Antivalle M, Pallavicini FB, et al. Predicting response to anti-TNF treatment in rheumatoid arthritis patients. Autoimmun Rev 2009;8:431–7. [13] Straub RH, Harle P, Sarzi-Puttini P, et al. Tumor necrosis factor-neutralizing therapies improve altered hormone axes: an alternative mode of antiinflammatory action. Arthritis Rheum 2006;54:2039–46.