Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are regarded as the cornerstone of conventional treatment for AS. However little is known about concomitant NSAID use during treatment (with TNF-α inhibitors) in daily clinical practice. Methods and findings: Consecutive patients from the GLAS cohort were included. NSAID use and ASAS-NSAID index were evaluated at group level and at individual patient level during 52 weeks of follow-up. Analyses were stratified for treatment regimen. Generalized estimating equations (GEE) was used to evaluate NSAID use in relation to assessments of disease activity over time. In patients starting TNF-α inhibitors (n = 254), 79% used NSAIDs at baseline and this proportion decreased significantly to 38% at 52 weeks. ASAS-NSAID index also decreased significantly from median 65 to 0. In patients on conventional treatment (n = 139), 74% used NSAIDs at baseline with median ASAS-NSAID index of 50 and this remained stable during follow-up. At each follow-up visit, approximately half of the patients changed their type or dose of NSAIDs. GEE analysis over time showed that NSAID use was associated with AS disease activity score (p<0.05). This relation was more pronounced in patients treated with TNF-α inhibitors compared to conventional treatment (B = 0.825 vs. B = 0.250). Conclusions: In this observational cohort of established AS patients, there was no difference in baseline NSAID use between patients with and without indication for TNF-α inhibitors. NSAID use decreased significantly after starting TNF-α inhibitors. During conventional treatment, NSAID use remained stable at group level. However, NSAID use changed frequently at individual patient level and was significantly associated with disease activity.
Research Article; Medicine and health sciences; Pharmacology; Drugs; Analgesics; NSAIDs; Pain management; Clinical medicine; Clinical immunology; Autoimmune diseases; Ankylosing spondylitis; Biology and life sciences; Immunology; Pharmaceutics; Drug therapy; Physiology; Immune physiology; Cytokines; Immune system; Innate immune system; Developmental biology; Molecular development; Research and analysis methods; Research design; Cohort studies; Diagnostic medicine; Diagnostic radiology; Magnetic resonance imaging; Imaging techniques; Radiology and imaging; Gastroenterology and hepatology; Inflammatory bowel disease; Inflammatory diseases
Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that primarily affects the axial skeleton. Non-steroidal anti-inflammatory drugs (NSAIDs) are regarded as the cornerstone of conventional treatment for AS.[[
In AS, there is only limited data available comparing the efficacy of continued use of NSAIDs with on demand use. A single RCT studied symptom control and safety of continued versus on demand use of celecoxib and ketoprofen during 2 years of follow-up as a secondary outcome. No differences were found between the groups.[[
For over a decade, tumor necrosis factor-alpha (TNF-α) inhibitors are available for AS patients with active disease who have insufficient response to conventional treatment including NSAIDs. TNF-α inhibitors have shown to reduce the clinical signs and symptoms as well as serum levels of CRP and axial inflammation detected on MRI in AS patients with active disease.[[
So far, studies on concomitant NSAID use to the treatment of biologicals were only performed in patients with early active axiale SpA.[[
The aim of the present study was to evaluate NSAID use over time and to investigate if NSAID use was related to disease activity in patients with established AS from a large observational cohort study starting TNF-α inhibitors or receiving conventional treatment during a follow-up period of 52 weeks.
The GLAS cohort was approved by the local ethics committees of the MCL and UMCG and all patients provided written informed consent according to the Declaration of Helsinki. The present analysis was performed in the Groningen Leeuwarden Ankylosing Spondylitis (GLAS) cohort. The GLAS cohort is an ongoing prospective longitudinal observational cohort study with standardized follow-up. Since November 2004, consecutive AS outpatients who started TNF-α inhibitors from the University Medical Center Groningen (UMCG) and the Medical Center Leeuwarden (MCL) were included.[[
NSAIDs were prescribed based on expert opinion. TNF-α inhibitors were started according to the ASAS consensus statement.[[
Visits were scheduled at baseline (before start of TNF-α inhibitors) and after 6, 12, 24 and 52 weeks for the TNF-α inhibitor group. The conventional treatment group had scheduled visits at baseline, 24 and 52 weeks. At every visit, disease activity was assessed using the AS Disease Activity Score (ASDAS), Bath AS Disease Activity Index (BASDAI), and serum CRP level. [[
At every visit, NSAID use (yes/no) and type of NSAID was recorded. Dosage and frequency were assessed retrospectively from clinical records to calculate the ASAS-NSAID index. This index takes the specific NSAID and dosage into account as well as the percentage of days of NSAID intake during a period of interest.[[
Results were expressed as number of patients (%) and mean ± SD or median (interquartile range; IQR), for categorical and normally or non-normally distributed data, respectively. Analyses were stratified for treatment regimen: patients starting TNF-α inhibitors and patients on conventional treatment. Chi-square or Fisher’s Exact tests, Independent Samples t-tests, and Mann-Whitney U-tests were used to compare baseline characteristics. Linear and logistic generalized estimating equations (GEE) were used to analyze NSAID use over time. GEE is a technique for longitudinal data analysis, which makes use of all available data and allows unequal numbers of repeated measurements.[[
GEE was also applied to analyze the relation between NSAID use and disease activity over time, where disease activity was defined as the dependent variable. NSAID use was analyzed using 4 parameters: NSAID use (yes versus no), ASAS-NSAID index (continuous scale), low (index ≥10 versus <10), and high use (index ≥90 versus <90). To exclude potential bias due to TNF-α inhibitors discontinuation, analyses were also performed in patients using TNF-α inhibitors ≥80% of the follow up time. To exclude the influence of the initial positive effect of TNF-α inhibitors on the association between NSAID use and disease activity, analyses were also performed for 12 to 52 weeks of follow-up. P-values <0.05 were considered statistically significant. Statistical analysis was performed with IBM SPSS Statistics 22 (SPSS, Chicago, IL, USA).
Of the 393 included AS patients, 67% were male, mean age was 44 ± 13 years, median symptom duration 15 years (IQR 8–24), and 79% were HLA-B27 positive. Additionally, 254 (66%) patients started TNF-α inhibitors due to active disease (etanercept (58%), adalimumab (26%), or infliximab (15%)). Of the 254 patients who started TNF-α inhibitors, 217 (85%) used this treatment more than 80% of the follow-up time. The remaining 139 (34%) patients received conventional treatment. Patient characteristics were comparable between both groups, except higher disease activity, more often peripheral arthritis, and worse physical functioning in patients starting TNF-α inhibitors.(Table 1)
null: Baseline characteristics of the AS study population.
Total TNF-α inhibitors Conventional treatment P-value* n = 393 n = 254 n = 139 Patient characteristics Age (yrs) 44 ± 13 43 ± 12 44 ± 14 0.451 Male gender 261 (66%) 173 (68%) 88 (64%) 0.253 HLA-B27+ 294 (79%) 197 (81%) 97 (75%) 0.094 Duration of symptoms (yrs) 15 (8–24) 15 (9–24) 14 (7–24) 0.393 Time since diagnosis (yrs) 6 (1–16) 7 (1–24) 5 (1–16) 0.693 History of extra-spinal manifestations Peripheral arthritis 102 (27%) 76 (31%) 26 (20%) 0.015 IBD 36 (10%) 23 (9%) 13 (10%) 0.495 Uveitis 108 (28%) 73 (29%) 35 (27%) 0.334 Psoriasis 28 (7%) 15 (6%) 13 (10%) 0.125 Disease status BASDAI (range 0 to 10) 5.3 ± 2.2 6.1 ± 1.7 3.9 ± 2.2 <0.001 ASDAS 3.3 ± 1.1 3.8 ± 0.8 2.4 ± 0.9 <0.001 CRP (mg/l) 8 (8–17) 13 (5–22) 3 (2–7) <0.001 ESR (mm/h) 14 (7–28) 21 (10–35) 9 (4–13) <0.001 Peripheral arthritis 50 (13%) 43 (17%) 7 (5%) <0.001 BASFI (range 0 to 10) 4.8 ± 2.5 5.7 ± 2.1 3.2 ± 2.3 <0.001 Concomitant medication use Current NSAID use 289 (77%) 194 (79%) 95 (74%) 0.131 Current DMARD use 57 (15%) 47 (19%) 10 (7%) 0.002
1 *p-value: TNF-α inhibitors vs. conventional treatment. Values are number of patients (percentage), mean ± SD or median (IQR). HLA-B27+, human leukocyte antigen B27 positive; IBD, inflammatory bowel disease; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; ASDAS, Ankylosing Spondylitis Disease Activity Score; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; BASFI, Bath Ankylosing Spondylitis Functional Index; DMARD, disease-modifying antirheumatic drug
At baseline, 77% of patients used 12 different NSAIDs, mostly diclofenac (16%), naproxen (16%) and piroxicam (7%).(S1 Table) Baseline NSAID use was comparable between patients who started TNF-α inhibitors and patients on conventional treatment (79% vs. 74%). In patients who started TNF-α inhibitors, this proportion decreased significantly during follow-up to 38% at 52 weeks. When analyzing 2 different subgroups, low on demand and high NSAID use (defined by ASAS-NSAID as index resp. <10 and ≥90), the largest decrease in NSAID use was found during the first 6 weeks, followed by a slower gradual decrease up to 52 weeks.(Table 2) In the conventional treatment group, the proportion of patients using NSAIDs remained stable over time (82% at 52 weeks).(Table 2)
null: Changes in NSAID use at group level.
Baseline 6 weeks 12 weeks 24 weeks 52 weeks p- value TNF-α inhibitors n = 245 n = 214 n = 223 n = 223 n = 217 NSAID use (Y/N) 79% 57% 47% 41% 38% <0.001 ASAS-NSAID index 65 (23–100) 25 (0–60) 0 (0–50) 0 (0–50) 0 (0–50) <0.001 NSAID use low 24% 47% 56% 76% 77% <0.001 NSAID use high 44% 21% 15% 16% 14% <0.001 Conventional treatment n = 129 n = 109 n = 112 NSAID use (Y/N) 74% 80% 82% 0.183 ASAS-NSAID index 50 (0–100) 50 (5–100) 50 (7–100) 0.382 NSAID use low 44% 31% 28% 0.448 NSAID use high 36% 37% 38% 0.721
2 Values are percentage of patients or median (IQR).
Patients starting TNF-α inhibitors also showed a rapid and significant decrease in ASAS-NSAID index during the first 6 to 12 weeks and this reduction remained stable during all follow-up visits. In patients on conventional treatment, the total ASAS-NSAID index and subgroups did not change over time.(Table 2) These patterns were found in both males and females (data not shown). GEE analysis showed no significant interaction between gender and ASAS-NSAID index over time.
In total, 22 patients (6%) never used NSAIDs, of which 18 patients in the TNF-α inhibitor group and 4 patients in the conventional treatment group. In the TNF-α inhibitor group, 9 patients had known contraindications for NSAID use (gastrointestinal (n = 4), renal (n = 4) and a proven allergy (n = 1)). In the conventional treatment group, there were no known contraindications.
Assessing the variability in NSAID use at individual patient level revealed that 46 to 67% of the patients treated with TNF-α inhibitors remained on a stable dose at each follow-up visit. Furthermore, 20 to 46% of the patients reduced their dose or stopped NSAIDs at a follow-up visit. Additionally, only 8 to 15% of the patients increased their dose, started or switched NSAIDs at a follow-up visit.(Table 3) Of the patients using NSAIDs at baseline, 48% had stopped their NSAIDs 52 weeks after starting TNF-α inhibitors.
null: Changes in NSAID use at individual patient level.
Baseline 6 weeks 12 weeks 24 weeks 52 weeks TNF-α Inhibitors NSAID use at baseline 79% Dose escalation, start or switch 8% 11% 13% 15% Stable dose 46% 59% 67% 61% Dose reduction or stop 46% 30% 20% 24% Conventional treatment NSAID use at baseline 74% Dose escalation, start or switch 34% 26% Stable dose 46% 49% Dose reduction or stop 21% 26%
3 Patients who used no NSAIDs during follow-up were excluded from this table: 11% in TNF-α Inhibitor group and 6% in the conventional treatment group.
Although NSAID use at group level was stable over time in the conventional treatment group, there were many changes at individual patient level. At each follow-up visit, approximately half of the patients changed their NSAID use: 26 to 34% of the patients showed dose escalation, start or switch of NSAIDs and 21 to 26% dose reduction or stop of NSAIDs.(Table 3) Only 7% used NSAIDs at baseline and not at 52 weeks, where 13% did not use NSAIDs at baseline but had started at 52 weeks of follow up.
Disease activity reduced significantly after starting TNF-α inhibitors and remained low and stable during follow-up. In the conventional treatment group, disease activity was low and stable at all visits.(Fig 2) At 52 weeks, disease activity was comparable between both groups, BASDAI mean 3.4 vs. 3.7, ASDAS mean 2.2 vs. 2.3, and CRP median 3 vs. 3 respectively.
GEE analysis over time showed that NSAID use was significantly associated with disease activity. In the TNF-α inhibitor group, a significant association of all 4 NSAID parameters (NSAID use (yes/no), ASAS-NSAID index, low on demand use and high use) with ASDAS was found. GEE revealed that higher NSAID use was related to higher ASDAS and vice versa.(Table 4) Comparable results were found for BASDAI and CRP.(S2 and S3 Tables)
null: Association between ASDAS and NSAID use over time in AS patients.
B (95% CI) P-value Interval n TNF-α Inhibitors NSAID use Yes 0.825 (0.664–0.985) <0.001 1074 251 ASAS-NSAID index 0.009 (0.007–0.012) <0.001 1073 251 NSAID use low -0.831 (-0.672- -0.990) <0.001 1073 251 NSAID use high 0.855 (0.682–1.028) <0.001 1073 251 Conventional treatment NSAID use Yes 0.250 (0.006–0.493) 0.045 315 131 ASAS-NSAID index 0.002 (0.000–0.005) 0.059 314 131 NSAID use low - 0.223 (-0.425–0.022) 0.030 314 131 NSAID use high 0.269 (0.038–0.501) 0.023 314 131
The association between NSAID use and ASDAS remained significant in patients who used TNF-α inhibitors more than 80% of the follow-up time and when analyzing only 12 to 52 weeks of follow-up to exclude the initial effect of TNF-α inhibitors, although the regression coefficients were lower in these last analyses. (S4 Table)
In the conventional treatment group, a significant but less prominent association of 3 NSAID parameters NSAID use (yes/no), low on demand use and high use) with ASDAS was found. (Table 4) BASDAI was only significantly associated with low on demand NSAID use. For CRP, no significant associations with NSAID use were found.
In the present prospective observational cohort study, we evaluated NSAID use in relation to disease activity during 52 weeks of follow-up in established AS patients treated with and without TNF-α inhibitors in daily clinical practice. This is the first study assessing the difference in NSAID use at group level and at individual patient level in established AS.
In the TNF-α inhibitor group, a rapid and significant decrease of concomitant NSAID use was seen. NSAID use at group level remained low during the entire follow-up period. Although patients in our cohort were advised to take their NSAID on demand after 3 months of TNF-α inhibitor treatment, many patients reduced or stopped NSAIDs on their own initiative even earlier. The reason for this is most likely the positive effect on symptoms of TNF-α inhibitors. Our finding of rapid NSAID reduction after 6–12 weeks of TNF-α inhibitor treatment is in line with a previous RCT in early axial SpA which showed the NSAID sparing effect of 8 weeks etanercept treatment.[[
In our conventional treatment group, NSAID use remained stable over 52 weeks of follow-up, whereas in the conventional care group of the DESIR cohort a significant decrease in NSAID use over 2 years was shown.[[
In our GLAS cohort, frequent inter-individual changes in NSAID use were observed at each follow-up visit in both treatment groups. Interestingly, GEE analysis over time showed that NSAID use was significantly associated with disease activity. In the TNF-α inhibitor group, this relation was most pronounced and significant for all disease activity measures (i.e. ASDAS, BASDAI and CRP). Results remained significant when including patients who used TNF-α inhibitors more than 80% of the follow-up time and when analyzing 12 to 52 weeks of follow-up to exclude the influence of the initial positive effect of TNF-α inhibitors on the GEE analyses.
In the conventional treatment group, the association between NSAID use and disease activity was less pronounced and only found for ASDAS. This can be explained by less variation in disease activity in this treatment group, e.g. the large majority of patients had normal CRP levels, but it can also be related to lower power in GEE analysis because of the lower number of included patients and less frequent follow-up visits.
Since this is an observational cohort study in AS patients, it reflects NSAID use in daily clinical practice. No sub-analyses were performed on specific NSAIDs, e.g. traditional and COX-2 NSAIDs, due to small numbers. However, a recent meta-analysis showed no clear superiority in efficacy of any specific NSAID.[[
In summary, this is the first study investigating NSAID use in an established AS cohort on TNF-α inhibitors or conventional treatment. At baseline, we found no differences in NSAID use between AS patients with and without indication for TNF-α inhibitors. After starting TNF-α inhibitors, NSAID use decreased rapidly and remained low during follow-up. In patients receiving conventional treatment, NSAID use remained stable at group level over time. Conversely, at individual patient level, both the type and dose of NSAIDs changed frequently irrespective of treatment regimen. Therefore, stable NSAID use at group level does not necessarily reflect stable NSAID use at individual patient level. This should be taken into account in future evaluations and research on NSAID use in axial SpA. Most importantly, this is the first prospective cohort study of established AS patients that showed NSAID use was significantly associated with assessments of disease activity, which was most pronounced for patients treated with TNF-α inhibitors.
null. Specific NSAIDs used at baseline.(DOCX)
null. Association between BASDAI and NSAID use over time in AS patients.*Subgroup analysis of patients who used TNF-α inhibitors ≥80% of the follow up time. ** Analysis for 12 to 52 weeks of follow-up (excluding baseline and 6 weeks).(DOCX)
null. Association between CRP and NSAID use over time in AS patients.*Subgroup analysis of patients who used TNF-α inhibitors ≥80% of the follow up time. **Analysis for 12 to 52 weeks of follow-up (excluding baseline and 6 weeks).(DOCX)
null. Association between ASDAS and NSAID use over time in AS patients.*Subgroup analysis of patients who used TNF-α inhibitors ≥80% of the follow up time. ** Analysis for 12 to 52 weeks of follow-up (excluding baseline and 6 weeks).(DOCX)
The authors would like to thank all patients who participated in the GLAS cohort. Furthermore, the authors wish to acknowledge Dr. P.M. Houtman, Mrs. W. Gerlofs, Mrs. S. Katerbarg, Mrs. A. Krol, Mrs. R. Rumph, and Mrs. B. Burmania for their contribution to clinical data collection.
DIAGRAM: Fig 1: Flowchart of inclusion.
DIAGRAM: Fig 2: Disease activity over time in AS patients. ASDAS over time in patients starting TNF-α inhibitors (A) and receiving conventional treatment (B); BASDAI over time in patients starting TNF-α inhibitors (C) and receiving conventional treatment (D); CRP over time in patients starting TNF-α inhibitors (E) and receiving conventional treatment (F). *p<0.05 compared to baseline. Box-and-whisker plots: boxes indicate medians with interquartile ranges; + indicate means; whiskers indicate 5–95 percentile; • indicate outliers.
By Marlies J. G. Carbo, Writing – review & editing; Anneke Spoorenberg, Writing – review & editing; Fiona Maas, Writing – review & editing; Elisabeth Brouwer, Writing – review & editing; Reinhard Bos, Writing – review & editing; Hendrika Bootsma, Writing – review & editing; Eveline van der Veer, Writing – review & editing; Freke Wink, Writing – review & editing and Suzanne Arends, Writing – review & editing