This study was carried out in a cohort of 52 patients with ES, including 31 affected by CD (59.6%) and 21 by UC (40.3%), collectively representing 23.6% of the 220 overall patient population with IBD in the Spondyloarthritis in IBD Project (commonly referred to as SPIB), described elsewhere[9]. The patients’ clinical and laboratory data are shown in Table 1, and the patient group is henceforth defined as the “ES-AN” cohort (Enteropathic spondyloarthritis from Ancona, Italy).

At each clinical observation, both the rheumatologist and the gastroenterologist collaborated in a shared session to develop the therapeutic strategy by applying a specifically designed algorithm (Figure 1) that was mainly based upon gastrointestinal-articular disease activity and the site of articular involvement at diagnosis (axial or peripheral arthritis). Briefly, the ES-AN patients were primarily separated into the following two groups for comparative analysis:

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Figure 1 Therapeutic algorithm of the ES-AN patient cohort at the time of entry into the study. A: ES patients biological drugs-naïve were treated depending on IBD activity and site of the articular involvement, as follows: a) Ax-ES-AN with Ada as the TNF-inhibitor in first-line therapy, due to the absolute contraindication for a long-course treatment with NSAIDs in cases of IBDs; b) Per-ES-AN in cases of active IBD and in those patients who were non-responders to short-course corticosteroid treatment (not > 3 mo) or NSAIDs (not > 2 wk), with DMARD (methotrexate or sulfasalazine), or in cases of ESR > 30 mm/h and/or CRP > 0.5 mg/dL, and polyarticular inflammatory involvement with Ada; c) Per-ES-AN in inactive IBD, with steroids or DMARDs, depending on the number of inflamed joints and systemic inflammation (evaluated by ESR and/or CRP); B: ES patients already in treatment with infliximab for the IBD. In the ES-AN patients already treated with IFX: a) Per-ES-AN with active IBD were switched to Ada; b) Per-ES-AN with IBD in remission received a DMARD in addition to the IFX already in use; c) Ax-ES-AS were switched to Ada, regardless of IBD activity. Dashed line: Patients refractory to therapy. Therapeutic doses: DMARDs were prescribed at the standard dose regimens (salazopyrine 2 gr bid; methotrexate 10-20 mg once a week); Ada was used following the therapeutic dosage and indications for IBDs (160 mg at d 1 and 80 mg after 2 wk, followed by 40 mg every 2 wk). Ada: Adalimumab; AX-ES-AN: Patients with axial spondyloarthritis in the ES-AN cohort; CRP: C-reactive protein; ES: Enteropathic spondyloarthritis; ES-AN: Patients affected by ES in the Ancona’s cohort; ESR: Erythrocyte sedimentation rate: DMARD: Disease modifying anti-rheumatic drug; IBD: Inflammatory bowel disease; NSAID: Non-steroidal anti-inflammatory drug; Per-ES-AN: Patients with peripheral spondyloarthritis in the ES-AN cohort.

Group I (biological drugs-naïve group): This group encompassed three treatment subgroups. In the axial-ES-AN (Ax-ES-AN) subgroup, patients were administered Ada as first-line therapy, due to the absolute contraindication for a long-course treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) in case of IBD. In the peripheral-ES-AN (Per-ES-AN) subgroup, patients with active IBD or who were non-responders to a short course of corticosteroids (not more than 3 mo) or NSAIDs (not more than 2 wk) were administered either a disease-modifying anti-rheumatic drug (DMARD), such as either methotrexate (MTX) or sulfasalazine (SSZ), or Ada if erythrocyte sedimentation rate (ESR) was > 30 mm/h and/or C-reactive protein (CRP) concentration was > 0.5 mg/dL and/or in the presence of polyarticular inflammatory involvement. In the Per-ES-AN in inactive IBDs subgroup, patients were administered steroids or DMARDs, depending on count number of inflamed joints and systemic inflammation (evaluated by ESR and/or CRP).

Group II (TNF inhibitor-treated group): This group also encompassed three treatment subgroups. For the first, the Per-ES-AN consisting of patients with still active IBD were switched to another TNF-inhibitor (Ada). For the second, the Per-ES-AN consisting of patients with IBD in remission were administered a DMARD in addition to the TNF-inhibitor already in use. For the third, the Ax-ES-AN patients were switched to Ada, regardless of IBD activity.

In all patients, the TNF-inhibitor Ada was used as recommended for IBD treatment: 160 mg in the first week, 80 mg for the next 2 wk, and thereafter 40 mg once every 2 wk.

All patients of the ES-AN cohort were assessed for clinical disease activity and HRQoL (Table 2). Briefly, articular (SpA) disease activity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)[10] and the Ankylosing Spondylitis Disease Activity Score-C-Reactive Protein (ASDAS-CRP) calculation[11]; gastrointestinal (IBD) disease activity was assessed with the Crohn’s Disease Activity Index (CDAI) for CD[12] and the partial Mayo (pMAYO) score for UC[13].

Patient-reported outcomes (PROs) were assessed with tests specific for articular-related symptoms [i.e. the Bath Ankylosing Spondylitis Functional Index (BASFI)][14] and gastrointestinal-related symptoms [i.e. the Inflammatory Bowel Disease Questionnaire (IBDQ)][15]. Global wellness was assessed by use of the Health Assessment Questionnaire (HAQ), Patient Global Assessment (PtGA), and the Short Form-36 health survey (SF-36)[16].

Endpoints of this study were the disease activity indexes at baseline and at 6-mo and 12-mo follow-ups. Variables are presented as mean ± standard deviation. Comparisons between groups at baseline and between baseline and subsequent assessments were performed, respectively, with unpaired and paired Student’s t-tests. Correlations between variables were assessed using Pearson’s correlation coefficient. Data were analyzed using the SPSS software (v22.0; IBM SPSS Statistics for Windows, Armonk, NY, United States).

In the ES-AN cohort, 29 (57.6%) patients were affected by predominant axial SpA (Ax-ES-AN) and 23 (42.3%) by peripheral SpA (Per-ES-AN) (Table 1). Only 5 patients showed positivity for human leukocyte antigen-B27 (9.6%), including 4 affected by Ax-ES-AN and 1 by Per-ES-AN. Sacroiliitis was found in all the Ax-ES-AN patients, but 17 (55%) patients fulfilled the Modified New York Criteria for AS, whereas 13 (45%) were affected by non-radiographic axial-SpA[2]. Syndesmophytosis was found in 8 (27.6%) of the Ax-ES-AN patients at different levels, but only 2 (6.9%) presented a bamboo spine radiologic feature at baseline. Concurrent peripheral arthritis and enthesitis were present in about half of the Ax-ES-AN patients (44.8%).

According to the established criteria, IBD was active in 63.2% of the CD patients and in 98% of the UC patients, although the degrees of activity varied. At baseline, no differences were observed between the axial and peripheral spondyloarthritis patients and between the CD and UC patients for the articular disease activity (BASDAI, ASDAS-CRP) and the PROs [IBDQ, BASFI, PtGA, HAQ, SF-36 Physical Component Score (PCS) and Mental Component Score (MCS)] (data not shown). Following findings from the integrated evaluation and according to the algorithm presented in Figure 1, the criteria employed in our study to guide the therapeutic choice were (1) the presence and/or absence of active IBD (evaluated by both the gastroenterologist and by the results of the gastrointestinal tests and PROs); and (2) the site of articular involvement (axial or peripheral joints). Thus, Ada was assigned to a cohort of 30 patients, henceforth defined as the ES-AN/Ada cohort. Among this cohort, 4 were switched from infliximab for inefficacy, and the total was comprised of 20 patients with Ax-ES-AN and 10 patients with Per-ES-AN (Table 1).

In most of the ES-AN/Ada patients, articular disease activity, as assessed by ASDAS-CRP and BASDAI, was significantly improved at 6-mo compared to baseline (ASDAS-CRP: 3.2 ± 0.8 vs 1.9 ± 0.6, P < 0.001; BASDAI: 5.5 ± 1.7 vs 3.2 ± 1.8, P < 0.001). A major clinical improvement (ASDAS change of ≥ 2) occurred in 21% and an important clinical improvement (ASDAS change of ≥ 1.1) occurred in 52% (Figure 2A). The improvement of articular disease was significant in both the axial and the peripheral subgroups of patients (P < 0.001 for both comparisons). The clinical improvement at the articular level was maintained at the 12-mo examination (Figure 2A).

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Figure 2 Evaluation of articular-gastrointestinal disease activity and HRQoL in the ES-AN patient cohort at baseline and after adalimumab therapy. All data of the ES-AN patients were collected at baseline (T0), and after 6 mo (T6) and 12 mo (T12) of therapy. A: Evaluation of the articular disease activity with BASDAI or ASDAS-CRP (Left), and of the gastrointestinal disease activity by CDAI for CD and pMAYO for UC (Right); B: Evaluation of PROs of gastrointestinal disease activity by IBDQ (Left), and of global wellness by the PtGA (Right). ^aP < 0.05, ^bP < 0.01, ^eP < 0.001. ASDAS-CRP: Ankylosing Spondylitis Disease Activity Score/C-Reactive Protein; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; CDAI: Crohn’s Disease Activity Index; ES: Enteropathic spondyloarthritis; ES-AN: Patients affected by ES in the Ancona’s cohort; HRQoL: Health-Related Quality of Life; IBDQ: Inflammatory Bowel Disease Questionnaire; pMAYO: Partial Mayo score; PROs: Patient reported outcomes.

Regarding the gastrointestinal disease activity, in the CD patients the treatment led to a fast, consistent and significant improvement of the gastrointestinal symptoms at 6 mo, as assessed by the CDAI score (181.3 ± 93.2 vs 112.3 ± 63.0, P < 0.01; Figure 2A), and maintained at 12 mo, when the clinical remission was observed in almost all patients (Figure 2A). In parallel, a significant clinical improvement was observed also in the UC patients, as shown by the decrease of the pMAYO score at the 6-mo and 12-mo examinations (Figure 2A). All the values and comparisons are detailed in Table 3.

ES-AN/Ada patients reported significant improvement, from baseline to 6 mo, in the IBDQ (145.3 ± 36.8 vs 172.8 ± 36.7, P < 0.01), PtGA (61.1 ± 20.6 vs 35.6 ± 19.1, P < 0.01; Figure 2B) and HAQ (4.8 ± 7.9 vs 2.0 ± 4.2, P < 0.05) scores, and this improvement was maintained at 12 mo. Moreover, regarding the PROs impacting articular function and global health wellness, significant improvements were observed from baseline to 6 mo in the BASFI (3.2 ± 2.4 vs 1.8 ± 1.4, P < 0.01), Sf-36/PCS (42.2 ± 9.7 vs 48.4 ± 7.3, P < 0.01) and Sf-36/MCS scores (35.4 ± 10.9 vs 39.4± 8.8, P < 0.05; Figure 2C); again, the improvements were maintained at 12 mo. The improvement of all the scores for PROs was similar in both the Ax-ES-AN/Ada and Per-ES-AN/Ada subgroups at each follow-up observation. All the values and comparisons are detailed in Table 3.

At baseline, it is noteworthy that a consistent significant correlation was observed between the IBDQ test (specific for the evaluation of the PROs related to the gastrointestinal disease activity) and the clinimetric scores of articular activity, as assessed by ASDAS-CRP (Figure 3A), BASDAI, and with most of the PROs of the HRQoL, as assessed by Sf-36/MCS and CDAI (Table 4). Moreover, articular disease activity at baseline was significantly correlated with worse results in the HRQoL tests, as shown by the Sf-36/PCS and Sf-36/MCS scores (Table 4). After 12 mo of Ada treatment, improvement of the articular activity (ASDAS-CRP) correlated significantly with decrease in the gastrointestinal disease activity scores, as assessed by CDAI in the CD patients (Figure 4A) and IBDQ in all of the patients, and with most of the PROs of the HRQoL, as shown by the Sf-36/PCS (r = -0.30, P < 0.05) and Sf-36/MCS (r = -0.41, P < 0.01) scores (Figure 2C), as well as the BASFI (r = 0.57, P < 0.001), PtGA (r = 0.37, P < 0.01) and HAQ (r = 0.28, P < 0.05) scores. All the correlations for the values at 12-mo examination are detailed in Table 4.

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Figure 3 Correlations between articular and gastrointestinal disease activity and HRQoL scores in the ES-AN patient cohort at baseline. A: Correlation between the PROs of gastrointestinal disease activity (assessed by IBQD) scores and SF-36 summary scores (assessed by PCS and MCS) with articular activity scores (assessed by ASDAS-CRP); B: Correlation of the articular function (assessed by BASFI with SF-36/PCS); C: Correlation of the IBDQ with crohn’s disease gastrointestinal disease activity (assessed by CDAI) and the SF-36/MCS. ASDAS-CRP: Ankylosing Spondylitis Disease Activity Score-C-Reactive Protein; CDAI: Crohn’s Disease Activity Index; ES: Enteropathic spondyloarthritis; ES-AN: Patients affected by ES in the ancona’s cohort; HRQoL: Health-Related Quality of Life; IBDQ: Inflammatory Bowel Disease Questionnaire; PROs: Patient reported outcomes; SF-36/MCS: Summary of “Mental Component Score” of the Short Form-36 health survey; SF-36/PCS: Summary of “Physical Component Score” of the Short Form-36 health survey.

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Figure 4 Correlations between articular and gastrointestinal disease activity and HRQoL scores in the ES-AN patient cohort after adalimumab therapy. A: Evaluation data collected for the 30 ES-AN/Ada patients after 12 mo of therapy, showing correlation between gastrointestinal and articular disease activity in Crohn’s disease patients (assessed by CDAI) and ASDAS-CRP respectively, and between ASDAS-CRP and SF-36 summary scores (PCS and MCS); B: Correlation between CDAI and articular function (assessed by BASFI); C: Correlation between the gastrointestinal quality of life (assessed by IBDQ) and CDAI and SF-36/MCS. ASDAS-CRP: Ankylosing Spondylitis Disease Activity Score-C-Reactive Protein; CDAI: Crohn’s Disease Activity Index; ES-AN: Patients affected by ES in the Ancona’s cohort; ES-AN/Ada: Patients of the ES-AN cohort treated with adalimumab; HRQoL: Health-Related Quality of Life; IBDQ: Inflammatory Bowel Disease Questionnaire; SF-36/MCS: Summary of “Mental Component Score” of the Short Form-36 health survey; SF-36/PCS: Summary of “Physical Component Score” of the Short Form-36 health survey; Sf-36/PCS: Summary of “Physical Component Score” of the short form-36 health survey; PROs: Patient reported outcomes.

Ada was well tolerated throughout the follow-up period. Side effects reported included recurrent upper respiratory tract infections (n = 2), bothersome hair loss (n = 1), and widespread itch (n = 2); but none necessitated suspension of the treatment. One patient suffered from a serious infection (axillary suppurative hidradenitis) that required prolonged antibiotic treatment. The other minor side effects reported were headache and fatigue.

Enteropathic spondyloarthritis (ES) is characterized by articular inflammation in patients with inflammatory bowel diseases (IBDs), such as Crohn’s disease or ulcerative colitis. Arthritis is the most frequent extra-intestinal manifestation found in IBD patients, yet only half of the ES patients are actually evaluated by a rheumatologist for a proper diagnosis and, thereafter, for receipt of an integrated therapeutic approach through a coordinated action between the two specialists.

Considering the multidisciplinary intrinsic “face” of IBDs and the novel therapeutic opportunities that comprise the biological drugs, as in the case of anti-tumor necrosis factor (TNF)-alpha inhibitors, an integrated approach and evaluation of all ES patients should be routinely employed and strongly encouraged to obtain the best therapeutic efficacy on all the clinical manifestations of this disease.

In this work, the authors have demonstrated that the integrated (simultaneous) evaluation of patients affected by ES, through the coordinated efforts of a gastroenterologist and rheumatologist, led to the best therapeutic approach, thereby allowing the patients to achieve a consistent clinical remission of both the articular and gastrointestinal inflammations.

Through this study authors have been able to generate a simple working flowchart of the multidisciplinary clinical care process applied during the patients’ integrated assessment. They suggest that in patients with ES and in consideration of the therapeutic choice, particular attention should be paid to the presence of active intestinal disease, presence of active articular (arthritis) and/or periarticular (enthesitis) disease and localization of the joints’ inflammation (peripheral or axial, as in the case of sacroiliitis).

ES belongs to the group of seronegative spondyloarthritis (SpA) and, as such, is characterized by the presence of arthritis in patients affected by IBDs; it is also known as SpA-IBD.

This is an interesting and well-conducted work.