BRIEF REPORT. Denis Poddubnyy, 1 Hildrun Haibel, 1 J urgen Braun, 2 Martin Rudwaleit, 3 and Joachim Sieper 1

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1 ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 9, September 2015, pp DOI /art VC 2015, American College of Rheumatology BRIEF REPORT Clinical Course Over Two Years in Patients With Early Nonradiographic Axial Spondyloarthritis and Patients With Ankylosing Spondylitis Not Treated With Tumor Necrosis Factor Blockers: Results From the German Spondyloarthritis Inception Cohort Denis Poddubnyy, 1 Hildrun Haibel, 1 J urgen Braun, 2 Martin Rudwaleit, 3 and Joachim Sieper 1 Objective. To investigate the clinical course of disease over 2 years in patients with nonradiographic axial spondylarthritis (SpA) and patients with ankylosing spondylitis (AS). Methods. The study group comprised 303 patients with axial SpA (158 patients with AS and a symptom duration of 10 years and 145 patients with nonradiographic axial SpA and a symptom duration of 5 years) who did not receive tumor necrosis factor (TNF) blockers during 2 years of followup. Results. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) did not differ between patients with nonradiographic axial SpA and those with AS at any time point during followup. The Bath Ankylosing Spondylitis Functional Index was significantly higher in patients with AS at baseline only, but spinal mobility was generally better in patients with nonradiographic SpA compared with those with AS. At all time points, C-reactive protein (CRP) levels were significantly higher in patients with AS compared with patients with The German Spondyloarthritis Inception Cohort (GESPIC) has been supported by the German Federal Ministry of Education and Research (BMBF) (grant FKZ 01G19946), as part of the German Competence Network in Rheumatology. Because funding by BMBF was reduced according to schedule in 2005 and discontinued in 2007, complementary financial support was obtained from Abbott, Amgen, Centocor, Schering-Plough, and Wyeth. Since 2010, GESPIC has been supported by AbbVie, with additional support from the BMBF through the ANCYLOSS project (grant FZK 01EC1002D), the ArthroMark project (grants FKZ 01EC1009A and FKZ 01EC1401A), and the METARTHROS project (grant FKZ 01EC1407A). 1 Denis Poddubnyy, MD, Hildrun Haibel, MD, Joachim Sieper, MD: Charite Universit atsmedizin, Campus Benjamin Franklin, Berlin, Germany; 2 J urgen Braun, MD: Rheumazentrum Ruhrgebiet, Herne, Germany; 3 Martin Rudwaleit, MD: Klinikum Bielefeld Rosenh ohe, Bielefeld, Germany. Address correspondence to Denis Poddubnyy, MD, Charite Universit atsmedizin, Campus Benjamin Franklin, Rheumatology, Medical Department I, Hindenburgdamm 30, Berlin, Germany. denis.poddubnyy@charite.de. Submitted for publication January 9, 2015; accepted in revised form May 26, nonradiographic axial SpA. Accordingly, the Ankylosing Spondylitis Disease Activity Score (ASDAS) was significantly higher in the patients with AS at 2 of 4 time points. When patients with a BASDAI score of 4 plus an elevated CRP level at baseline were analyzed over time, there were no significant differences in the proportions of patients with nonradiographic axial SpA and those with AS who reached low disease activity status at 2 time points during 2 years of followup when a clinical definition of low disease activity was used (38% and 35%, respectively, achieved a BASDAI score of <4, and 13% and 15%, respectively, achieved a score of 2). When definitions that included the CRP level were used, however, a greater percentage of patients with nonradiographic axial SpA achieved low disease activity (25% of patients with nonradiographic axial SpA and 10% of patients with AS achieved a BASDAI score of <4 andanormalcrp level, and 13% of patients with nonradiographic axial SpA and 3% of those with AS achieved ASDAS-defined low disease activity). Conclusion. Patients with nonradiographic axial SpA and those with AS who were not treated with TNF blockers demonstrated a similar clinical disease course over 2 years. Patients with nonradiographic axial SpA achieved a status of low disease activity more frequently than those with AS if outcome parameters that included the CRP level were used. The frequencies of nonradiographic axial spondyloarthritis (SpA) and ankylosing spondylitis (AS), both of which are subtypes of axial SpA (1 3), are approximately equal among patients first diagnosed as having axial SpA (4,5). In general, patients in these 2 subgroups have similar clinical characteristics, especially those related to clinical signs of disease activity, as demonstrated in cross-sectional observational studies, including the German Spondyloarthritis Inception Cohort (GESPIC) (6), the Herne cohort (7), and the Swiss Clinical Quality 2369

2 2370 PODDUBNYY ET AL Management (SCQM) cohort (8). At the same time, nonradiographic axial SpA is characterized by a higher prevalence of female patients and a lower level of C- reactive protein (CRP) in comparison with AS. Nonetheless, similar rates of response to anti tumor necrosis factor (anti-tnf) therapy have been observed in patients with nonradiographic axial SpA and those with AS if clinical disease activity is accompanied by the presence of objective markers of inflammation, such as an elevated CRP level and/or active inflammation as noted on magnetic resonance imaging (MRI) (9,10). However, there is concern that the availability of anti-tnf agents as therapy for nonradiographic axial SpA might result in overtreatment, because a substantial proportion of these patients might achieve spontaneous remission over time without using anti-tnf agents (3). There are nearly no data from prospective trials comparing the clinical disease course in patients with nonradiographic axial SpA and those with AS, especially in the absence of treatment with anti-tnf agents. The purpose of the current study was to investigate the clinical disease course, including achievement of remission, in patients with nonradiographic axial SpA compared with those with AS in the absence of treatment with anti-tnf agents during 2 years of followup. To this end, we analyzed patients with nonradiographic axial SpA or AS of short duration; the patients were drawn from the prospective GESPIC cohort, which was started in 2000, when TNF blockers were not yet approved for axial SpA, including AS, and therefore were usually not available to treat these patients. PATIENTS AND METHODS The GESPIC cohort and the baseline characteristics of the patients were previously described in detail (6). Patients included in the GESPIC were required to have a definite clinical diagnosis of axial SpA according to the local treating rheumatologist. Patients with axial SpA were further classified, based on radiographic findings (11) and irrespective of the presence of concomitant psoriasis or inflammatory bowel disease, as having AS (radiographic axial SpA) or nonradiographic axial SpA. The classification of AS was based on fulfillment of the modified New York criteria (11), and an AS symptom duration of #10 was required for inclusion. The classification of nonradiographic axial SpA was based on fulfillment of the European Spondyloarthropathy Study Group criteria (12) with minor modifications (6), and the maximum allowable symptom duration for study inclusion was #5 years. Clinical assessment and patient selection. Study visits were scheduled every 6 months for 2 years and annually thereafter. At each visit, outcome assessments were performed. These included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (13), the Bath Ankylosing Spondylitis Functional Index (BASFI) (14), the patient s global assessment of disease activity as measured on a 0 10-point numerical rating scale (starting at the month 6 visit), and spinal mobility as assessed with the Bath Ankylosing Spondylitis Metrology Index (BASMI) based on the 2-step definition) (15). In addition, the presence of peripheral arthritis, enthesitis, or extraarticular manifestations as well as the type of therapy, including nonsteroidal antiinflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), systemic steroids, and TNF inhibitors, were documented. The Assessment of Spondylo- Arthritis international Society (ASAS) NSAID intake scores (16) were calculated for all time points. Laboratory tests included the CRP level and the erythrocyte sedimentation rate. Calculation of the ASAS-endorsed Ankylosing Spondylitis Disease Activity Score (ASDAS) (17), which includes 3 BASDAI questions, the patient s global assessment of disease activity, and the CRP level, was possible starting at the month 6 visit. Of the previously reported 462 patients with axial SpA (6), information from $1 time point during 2 years of followup was available in 334 patients (179 with AS and 155 with nonradiographic axial SpA). The great majority of these patients were enrolled and followed up in the GESPIC prior to authorization to market TNF inhibitors for the treatment of AS and nonradiographic axial SpA. However, 21 of the patients with AS and 10 of the patients with nonradiographic axial SpA received at least 1 dose of a TNF blocker over 2 years of followup and were excluded from further analysis. Therefore, the final analysis set in this study included 145 patients with nonradiographic axial SpA and 158 patients with AS. Patients with nonradiographic axial SpA were considered to be candidates for anti-tnf therapy at baseline if they had a BASDAI score of $4 and an elevated CRP level (.6 mg/ liter). Similar criteria were applied to patients with AS in order for the groups to be comparable. The following definitions of low disease activity were applied: a BASDAI score of,4, a BASDAI score of,4 and a normal CRP level, a BASDAI score of #2, and inactive disease as defined by an ASDAS of,1.3. The proportion of patients who were not treated with TNF blockers and achieved low disease activity at $2 time points during followup and the proportion achieving this level of response at the end of year 2 were calculated. Ethics committee approval. The study protocol was approved by the central ethics committee of the coordinating center (Charite Universit atsmedizin Berlin) and by the local ethics committees of all participating centers. Written informed consent was obtained from all patients. Statistical analysis. Methods for descriptive statistics, chi-square test, Fisher s exact test, and t-test were applied as appropriate. P values less than 0.05 were considered significant. RESULTS The baseline characteristics of the patients as a group and by subgroup are shown in Table 1. These characteristics were similar to those of patients in the previously described larger group (6). Taking into consideration only the 428 patients who were not treated with TNF blockers (214 with AS and 214 with nonradiographic axial SpA), the numbers of patients who were lost to followup were not significantly different between the group with AS (n 5 56; 26.2%) and the group with nonradiographic axial SpA (n 5 69; 32.2%) (P ).

3 CLINICAL DISEASE COURSE IN NONRADIOGRAPHIC AXIAL SpA AND AS 2371 Table 1. Baseline demographic and clinical characteristics of the patients with AS and the patients with nonradiographic axial SpA* Parameter All patients (n 5 303) AS (n 5 158) Nonradiographic axial SpA (n 5 145) P Age, mean 6 SD years Symptom duration, mean 6 SD years ,0.001 Male sex ,0.001 HLA B27 positive Peripheral arthritis Enthesitis Uveitis ever Psoriasis ever Inflammatory bowel disease ever Family history of SpA BASDAI, mean 6 SD (0 10 NRS) BASDAI $ CRP, mean 6 SD mg/liter Elevated CRP (.6 mg/liter) ,0.001 BASDAI $4 and elevated CRP ESR, mean 6 SD mm/hour ,0.001 BASFI, mean 6 SD (range 0 10) BASMI, mean 6 SD (range 0 10) ,0.001 Treatment with NSAIDs NSAID intake score, mean 6 SD Treatment with DMARDs Treatment with systemic steroids Current smokers * Except where indicated otherwise, values are the percent. BASDAI 5 Bath Ankylosing Spondylitis Disease Activity Index; NRS 5 numerical rating scale; CRP 5 C-reactive protein; ESR 5 erythrocyte sedimentation rate; BASFI 5 Bath Ankylosing Spondylitis Disease Functional Index; BASMI 5 Bath Ankylosing Spondylitis Metrology Index; NSAIDs 5 nonsteroidal antiinflammatory drugs; DMARDs 5 disease-modifying antirheumatic drugs. Ankylosing spondylitis (AS) versus nonradiographic axial spondyloarthritis (SpA). Based on the 12-point Berlin index (6). During the 6-month period prior to baseline. The baseline characteristics of the patients who were lost to followup (n 5 125) were not different from those of the patients who attended at least 1 followup visit and were included in the final analysis set (n 5 303), with the exception of symptom duration, which was slightly lower in the patients who were lost to followup (mean 6 SD years versus years; P ). In particular, there were no differences between these groups in the BASDAI score (mean 6 SD versus ; P ), the CRP level ( versus mg/liter; P ), and the NSAID intake score ( versus ; P ). In the final analysis set, besides the difference in symptom duration, which was related to the inclusion criteria of the GESPIC, the prevalence of male patients was lower, the levels of acute-phase reactants were lower, and function and spinal mobility at baseline were slightly better in patients with nonradiographic axial SpA compared with patients with AS. During followup, patients with nonradiographic axial SpA and those with AS had nearly equal BASDAI scores over time; the BASFI was slightly lower in patients with nonradiographic axial SpA, although this difference was statistically significant only at baseline (Figures 1A and B). NSAID intake as measured by the ASAS NSAID intake score (Figure 1D) was comparable between the subgroups. Patients with nonradiographic axial SpA had lower CRP levels at all time points compared with patients with AS (Figure 1C). However, the ASDAS was significantly lower in patients with nonradiographic axial SpA compared with patients with AS at 2 time points only (at month 6, 2.3 versus 2.6 [P ]; at month 12, 2.2 versus 2.6 [P ]; at month 18, 2.3 versus 2.4 [P ]; at month 24, 2.3 versus 2.4 [P ]). Spinal mobility (as measured by the BASMI) was generally better in patients with nonradiographic axial SpA than in those with AS (at month 6, 1.2 versus 2.0 [P, 0.001]; at month 12, 1.2 versus 2.1 [P, 0.001]; at month 18, 1.3 versus 2.0 [P ]; at month 24, 1.3 versus 2.0 [P ]). Among all patients who did not receive a TNF blocker during 2 years of followup, 18 patients with nonradiographic axial SpA (12.4%) and 42 patients with AS

4 2372 PODDUBNYY ET AL Figure 1. Disease activity (A), functional status (B), C-reactive protein (CRP) levels (C), and nonsteroidal antiinflammatory drug (NSAID) intake scores (D) over 24 months in patients with nonradiographic axial spondyloarthritis (nr-axspa) and patients with ankylosing spondylitis (AS) not treated with tumor necrosis factor blockers. BASDAI 5 Bath Ankylosing Spondylitis Disease Activity Index; BASFI 5 Bath Ankylosing Spondylitis Functional Index. * 5 P, 0.05 versus nonradiographic axial SpA, by 2-sided t-test. (26.8%) had a baseline BASDAI of $4 and an elevated (.6 mg/liter) CRP level (mean 6 SD mg/ liter and mg/liter, respectively; P ). Among the patients in whom high baseline disease activity at baseline was defined according to the BASDAI and CRP, 16 patients with nonradiographic axial SpA and 39 patients with AS had followup information at $2 time points during the 2-year followup. Followup information at the 2-year time point was available in 9 patients with nonradiographic axial SpA and in 22 patients with AS. The mean 6 SD NSAID intake score over 2 years was slightly higher in patients with nonradiographic axial SpA than in those with AS ( versus ; P ). The proportion of patients who achieved a low disease activity state without anti-tnf therapy at $2 time points during followup was numerically higher (although statistically not significant) among those with nonradiographic axial SpA if a definition that incorporated a normal CRP level was used (for BASDAI,4 and normal CRP, 25% of patients with nonradiographic axial SpA versus 10% of patients with AS; for ASDAS-defined inactive disease, 13% and 3%, respectively) (Figure 2A). If, however, a definition based on clinical symptoms only was applied, a low disease activity state was achieved by similar proportions of patients with nonradiographic axial SpA and patients with AS (i.e., for a BASDAI of,4, 38% and 36%, respectively; for a BASDAI of #2, 13% and 15%, respectively) (Figure 2A). Similar trends were observed for the proportions of patients who achieved low disease activity at year 2 (Figure 2B). Based on criteria that included the CRP level, the proportion of patients who achieved a low disease activity state at year 2 was greater among those with nonradiographic axial SpA than among those with AS. When a pure clinical definition of low disease activity was applied (BASDAI without CRP level), more patients with nonradiographic axial SpA had a BASDAI score of,4 at year 2 (56%, versus 36% of patients with AS; P not significant), but fewer patients with nonradiographic axial SpA had a BASDAI of #2 (11%, versus 18% of patients with AS; P not significant).

5 CLINICAL DISEASE COURSE IN NONRADIOGRAPHIC AXIAL SpA AND AS 2373 Figure 2. Proportions of patients with nonradiographic axial SpA and patients with AS who had high disease activity at baseline (BASDAI score $4 and CRP level.6 mg/liter) and achieved a low disease activity state without anti tumor necrosis factor (anti-tnf) therapy during 2 years of followup, according to the following definitions: BASDAI score,4, BASDAI score,4 and normal CRP, BASDAI score #2, and Ankylosing Spondylitis Disease Activity Score (ASDAS) defined inactive disease. A, Percentage of patients who achieved a low disease activity state at $2 time points. B, Percentage of patients who had achieved a low disease activity state at year 2. See Figure 1 for other definitions. DISCUSSION This report is the first to describe the disease course over a period of 2 years in a cohort of patients with axial SpA who were not treated with TNF blockers and received only conventional treatment with NSAIDs. A minor proportion of the patients were also treated with nonbiologic DMARDs and steroids. At baseline, the characteristics of the patients with AS and those with nonradiographic axial SpA were similar, except for the male:female ratio, the levels of acute-phase reactants, and spinal mobility/function, as reported previously (6) and confirmed in 2 independent observational studies, the German Herne cohort (7) and the Swiss SCQM cohort (8). The difference in the symptom duration was related to the differences in the inclusion criteria of the

6 2374 PODDUBNYY ET AL GESPIC cohort. Importantly, both subgroups demonstrated a similar disease course over time, as measured by disease activity (BASDAI), functional status (BASFI), and NSAID intake, without major variations at the group level (Figure 1). The CRP level remained higher in patients with AS than in patients with nonradiographic axial SpA at all time points during followup, and the CRPdriven mean ASDAS value was significantly higher in patients with AS at 2 time points during followup. These data indicate that although the level of symptoms is very similar in nonradiographic axial SpA, the burden of inflammation is higher in AS. Using a BASDAI of $4 plus an elevated CRP level as a definition of active disease at baseline, we showed that 12.4% of the patients with nonradiographic axial SpA and 26.8% of those with AS would have been candidates for TNF blocker therapy. Current approval for the treatment of nonradiographic axial SpA with TNF blockers in the European Union and several other countries (but not in the US, where TNF blockers currently are not approved for the treatment of nonradiographic axial SpA) requires a BASDAI score of $4 plus an elevated CRP level or the presence of active bony inflammation seen on MRI. MRI was not performed in the current study, and the number of patients suitable for anti-tnf therapy might have been slightly higher if patients with positive findings on MRI had been included. A previous study showed that both the median CRP level and the median number of spinal inflammatory lesions on MRI were significantly higher in patients with AS compared with patients with nonradiographic axial SpA (7). However, the majority of the patients in the current study had not been treated with the maximal dose of an NSAID, which is another essential prerequisite for the treatment of nonradiographic axial SpA with TNF blockers. Therefore, the percentage of patients with nonradiographic axial SpA suitable for treatment with a TNF blocker in daily clinical practice might come close to the percentage reported in this study. Using the definition of active disease at baseline described above, we next addressed the question of what percentage of these patients would spontaneously (i.e., without TNF blocker treatment) achieve low disease activity status during 2 years of followup. Only relatively small proportions of patients in both groups achieved low disease activity status without anti-tnf therapy, and the proportion was greater among patients with nonradiographic axial SpA when outcome measures that included the CRP were used. For instance, a BASDAI score of,4 and a normal CRP level at $2 time points after baseline were achieved by 25% of the patients with nonradiographic axial SpA and by 10% of patients with AS, while ASDAS-defined inactive disease was achieved by 13% and 3% of these patients, respectively, although none of the differences were significant. Interestingly, the mean baseline CRP level was not different in the 2 subgroups with active disease at baseline, indicating that other factors in addition to the CRP level might be responsible for a slightly more active disease course in patients with radiographic changes. When the pure clinical definitions of low disease activity (i.e., a BASDAI score of,4 and a BASDAI score of #2) were applied, there was nearly no difference in the proportions of patients with nonradiographic axial SpA and those with AS who achieved such a disease state at $2 time points during followup (Figure 1A). Interestingly, during the followup period, NSAID intake was higher in the subgroup of patients with nonradiographic axial SpA who had high disease activity at baseline, which might at least partially explain the observed trend toward higher proportions of patients with low disease activity among those with nonradiographic axial SpA. Thus, more patients with AS than patients with nonradiographic axial SpA would have been candidates for TNF blocker therapy, because of the higher proportion of patients with an elevated CRP level in the former group. Most importantly, however, similar and relatively small numbers of patients with nonradiographic axial SpA and patients with AS included in this study (;1% of each subgroup) would have achieved spontaneous remission over time after having active disease at baseline, indicating that the risk of overtreatment of patients with nonradiographic axial SpA with TNF blockers is small and not different from that in AS patients. The limitations of the study include its observational design, the natural heterogeneity of the groups, the relatively high proportion of withdrawals, and some differences related to the inclusion criteria of the cohort (different symptom durations at baseline). Although the baseline characteristics related to disease activity were not different between patients who were lost to followup and those who remained in the cohort, and although similar proportions of patients with nonradiographic axial SpA and patients with AS withdrew, a relationship between lost-to-followup status and achievement of low disease activity cannot absolutely be excluded. The small sample size of patients with high disease activity precludes a strong conclusion regarding the presence or absence of significant differences between the group with nonradiographic axial SpA and the AS group. Also, due to the real-life character of the cohort, it was not possible to confirm whether patients with high disease activity experienced NSAID failure (i.e., inefficacy of or intolerability to $2 NSAIDs at the highest recom-

7 CLINICAL DISEASE COURSE IN NONRADIOGRAPHIC AXIAL SpA AND AS 2375 mended doses). Although the majority of patients were enrolled in the GESPIC prior to authorization for marketing of TNF blockers as treatment for AS and nonradiographic axial SpA, the probability of being treated with TNF blockers during followup might have been higher in patients with AS than in those with nonradiographic axial SpA. Finally, the data presented in the current report were obtained in a population of patients with a short symptom duration and might not necessarily be generalizable to patients with long standing disease. In conclusion, nearly all of the similarities and differences between patients with nonradiographic axial SpA and those with AS that were observed at baseline were sustained during a 2-year followup period. Both subgroups demonstrated a similar clinical disease course over 2 years and a rather low rate of remission in the absence of TNF blocker treatment. Higher CRP levels in patients with AS might be indicative of a higher inflammation burden in this subgroup. ACKNOWLEDGMENTS We thank Prof. M. Leirisalo-Repo (Finland), Prof. D. van der Heijde (The Netherlands), and Prof. M. Dougados (France) for scientific advice on the design of the cohort. We are grateful to Beate Buss and Petra Tietz for monitoring the cohort, Johanna Callhoff, Anja Weiss, and Martina Niewerth for the data management support, Joachim Listing for statistics advice, Janis Vahldiek and Georg Heine for handling of the radiographic images and for developing the image scoring interface, and to all patients who voluntarily participate in this cohort. We also thank the following rheumatologists for the inclusion and followup of their patients: J. Brandt, H. Brandt, G.-R. Burmester, H. Deister, E. Edelmann, J. Emmerich, M. Enderlein, E. Feist, A. Gauliard, E. Gromnica-Ihle, F. Heldmann, S. Hermann, U. von Hin uber, U. H ubner, K. Karberg, C. Kedor, E. M arker-hermann, H. N usslein, R. Pelle-Lohfink, D. Pick, G. Reichmuth, E. Riehers, M. Rihl, R. Schmidt, S. Schnarr, U. Schneider, I.-H. Song, I. Spiller, U. Syrbe, V. Walz, S. Wassenberg, H. M. Wisseler, H. Zeidler, and S. Zinke. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Poddubnyy had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Poddubnyy, Haibel, Braun, Rudwaleit, Sieper. Acquisition of data. Poddubnyy, Haibel, Rudwaleit, Sieper. Analysis and interpretation of data. Poddubnyy, Haibel, Braun, Rudwaleit, Sieper. REFERENCES 1. Rudwaleit M, van der Heijde D, Landewe R, Listing J, Akkoc N, Brandt J, et al. 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