**Core tip:** Enteropathic spondyloarthritis (ES) is characterized by articular inflammation in patients with inflammatory bowel diseases, such as Crohn's disease or ulcerative colitis. Correct management, especially covering both of the two clinical manifestations (gastro-rheumatologic), remains a challenge. In this study, we demonstrated that the integrated gastroenterological and rheumatologic evaluation of ES patients achieved the best therapeutic approach. In particular, we demonstrated that in a real-life cohort of ES patients, the tumor necrosis factor-inhibitor, adalimumab, led to fast and sustained improvement of articular and gastrointestinal inflammation, with a consequent improvement in the global and gastrointestinal quality of life.

INTRODUCTION
============

Enteropathic spondyloarthritis (ES) is a seronegative spondyloarthropathy (SpA) characterized by the presence of articular inflammation in patients affected by inflammatory bowel diseases (IBDs), such as Crohn's disease (CD) or ulcerative colitis (UC)\[[@B1],[@B2]\]. Arthritis is the most frequent extra-intestinal manifestation in patients with IBDs\[[@B1]\] and it may primarily involve the axial joints, presenting with definite ankylosing spondylitis (AS) and/or isolated sacroiliitis, or peripheral joints and/or peri-articular structures, such as tendons and entheses\[[@B3]\]. The articular manifestations significantly affect health-related quality of life (HRQoL) of ES patients\[[@B4]\].

Although a link between inflammation of the joints and gut has been demonstrated\[[@B5],[@B6]\], only half of ES patients are actually evaluated by a rheumatologist for proper diagnosis and, thus, for an integrated therapeutic approach through a coordinated action with the treating gastroenterologist\[[@B7]\]. Thus, an integrated clinical evaluation and therapeutic approach encompassing both the intestinal and articular features in ES patients, will likely be beneficial, particularly for the clinical outcomes. It has been demonstrated by recent studies that tumor necrosis factor (TNF)-alpha inhibitors could be effective therapeutic agents against ES\[[@B8]\], but few to date have reported on their real-life efficacy in this disease.

Herein, we have investigated the role of a gastro-rheumatologic multidisciplinary management and therapeutic approach in ES patients through evaluation of the efficacy of the TNF-alpha inhibitor adalimumab (Ada), assessing the efficacy on both gastrointestinal and rheumatologic disease activities and on the patient-reported HRQoL.

MATERIALS AND METHODS
=====================

Patients and study design
-------------------------

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\[[@B9]\]. The patients' clinical and laboratory data are shown in Table [1](#T1){ref-type="table"}, and the patient group is henceforth defined as the "ES-AN" cohort (Enteropathic spondyloarthritis from Ancona, Italy).

###### 

Enteropathic spondyloarthritis patient features

                                                                   **ES-AN, *n* = 52**   **ES-AN/Ada, *n* = 30**
  ---------------------------------------------------------------- --------------------- -------------------------
  Crohn's disease:Ulcerative colitis                               31 (60):21 (40)       19 (63):11 (37)
  Males:Females                                                    22 (42):30 (58)       17 (57):13 (43)
  Age in years                                                     47.2 ± 14.2           46.2 ± 14.4
  Disease duration of IBD in years                                 11.3 ± 10.1           8.8 ± 7.9
  Smokers:Ex-smokers                                               9 (17):20 (38)        
  HLA-B27 positivity                                               5 (10)                4 (13)
  Prior surgical intervention for IBD                              13 (25)               5 (17)
  Previous extra-intestinal disease                                6 (11)                5 (17)
  Eritema nodosum                                                  2                     1
  Uveitis                                                          3                     3
  Pioderma gangrenosum                                             1                     1
  Crohn's disease activity by CDAI                                                       
  Inactive                                                         14 (45)               7 (37)
  Moderate                                                         10 (32)               8 (42)
  Moderate-to-Severe                                               7 (23)                4 (21)
  Ulcerative colitis activity by partial Mayo                                            
  Mild                                                             18 (86)               8 (73)
  Moderate                                                         3 (14)                3 (27)
  Severe                                                           0                     0
  Current medication at baseline                                                         
  Non-steroids anti-inflammatory drugs                             3                     0
  Sulfasalazine                                                    3                     2
  Mesalazine                                                       25                    12
  Cyclosporine                                                     1                     1
  Azathioprine                                                     9                     5
  Oral steroids                                                    12                    7
  Topical steroids                                                 3                     2
  Metotrexate                                                      2                     1
  Infliximab                                                       6                     4
  Adalimumab                                                       2                     0
  Spondyloarthritis features                                                             
  Ankylosing spondylitis according to Modified New York Criteria   16 (31)               10 (33)
  Non-radiographic Axial-Spondyloarthritis by ASAS Criteria        13 (25)               10 (33)
  Peripheral- Spondyloarthritis                                    23 (44)               10 (33)
  Type of axial involvement                                        *n* = 29              *n* = 20
  Syndesmophytosis                                                 8 (28)                6 (30)
  Bamboo spine                                                     2 (7)                 2 (10)
  Sacroiliitis by MRI and/or X-ray                                 29 (100)              20 (100)
  Type of articular involvement in Crohn's disease                 *n* = 31              *n* = 19
  Axial                                                            16 (52)               11 (58)
  Axial and peripheral                                             4                     3
  Peripheral only                                                  15 (48)               8 (42)
  Enthesitis                                                       9 (29)                5 (26)
  Type of articular involvement in ulcerative colitis              *n* = 21              *n* = 11
  Axial                                                            13 (62)               9 (82)
  Axial and peripheral                                             9                     5
  Peripheral only                                                  8 (38)                2 (18)
  Enthesitis                                                       4 (19)                2 (18)

Data are presented as *n*, *n* (%) or mean ± SD. CDAI: Crohn's Disease Activity Index; ES-AN: Patient cohort with enteropathic spondyloarthritis from the SPIB Program, Ancona, Italy; ES-AN/Ada: Patients of the ES-AN cohort treated with adalimumab; IBD: Inflammatory bowel disease; NSAID: Non-steroidal anti-inflammatory drug.

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](#F1){ref-type="fig"}) 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:

![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.](WJG-23-7139-g001){#F1}

**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.

Study measures and evaluation
-----------------------------

All patients of the ES-AN cohort were assessed for clinical disease activity and HRQoL (Table [2](#T2){ref-type="table"}). Briefly, articular (SpA) disease activity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)\[[@B10]\] and the Ankylosing Spondylitis Disease Activity Score-C-Reactive Protein (ASDAS-CRP) calculation\[[@B11]\]; gastrointestinal (IBD) disease activity was assessed with the Crohn's Disease Activity Index (CDAI) for CD\[[@B12]\] and the partial Mayo (pMAYO) score for UC\[[@B13]\].

###### 

Clinimetric test for articular-gastrointestinal activity and patient reported outcomes of health-related quality of life

  **Test**                                                                                                                                          **Items and interpretation**
  ------------------------------------------------------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  Bath Ankylosing Spondylitis Disease Index\[[@B10]\]                                                                                               6 items: (1) fatigue, (2) back pain, (3) peripheral pain/swelling, (4) discomfort at pressure, (5) morning discomfort, and (6) duration of morning stiffness;
                                                                                                                                                    Range from 0 to 10, with lower number representing less severe disease activity;
                                                                                                                                                    Score \> 4 = active disease.
  Ankylosing Spondylitis Disease Activity Score-C-Reactive Protein\[[@B11]\]                                                                        5 items: (1) back pain, (2) morning stiffness, (3) patient global, (4) peripheral pain/swelling, and (5) C-reactive protein;
                                                                                                                                                    Score \< 1.3 = inactive disease; Score 1.3 to \< 2.1 = moderate activity; Score 2.1 to ≤ 3.5 = high activity; Score \> 3.5 = very high activit; Change ≥ 1.1 = clinically important improvement; Change ≥ 2.0 = major improvement.
  Crohn's Disease Activity Index\[[@B12]\]                                                                                                          8 items: (1) liquid stools, (2) abdominal pain, (3) general well-being, (4) extra-intestinal manifestations (including arthralgia), (5) use of anti-diarrheals, (6) abdominal masses, and (7) hematocrit, 8) weight;
                                                                                                                                                    Final score is the sum of items, weighted by different factors;
                                                                                                                                                    Score \< 150 = non-active disease; Score \> 150 = active disease; Score \> 450 = extremely severe disease.
  Partial MAYO score\[[@B13]\]                                                                                                                      3 items: (1) stool frequency, (2) rectal bleeding, and (3) physician global assessment;
  Range from 0 to 9;                                                                                                                                
  Score \< 2 = disease remission; Score 2-4 = mild disease activity; Score 5-7 = moderate disease activity; Score \> 7 = severe disease activity.   
  Bath Ankylosing Spondylitis Functional Index\[[@B14]\]                                                                                            10 questions designed to determine the degree of functional limitation;
  Final score ranges from 0 to 10, with lower score indicating less functional limitation.                                                          
  Inflammatory Bowel Disease Questionnaire\[[@B15]\]                                                                                                32 questions divided into 4 subscales: (1) bowel symptoms (10 questions); (2) systemic symptoms, including sleep disorders and fatigue (5 questions); (3) emotional function, such as depression, aggression and irritation (12 questions); and (4) social function, meaning the ability to participate in social activities and to work (5 questions);
  The patient is invited to choose from 1 to 7 for every question;                                                                                  
  Total score ranges from 32 to 224 points, with lower scores reflecting worse quality of life.                                                     
  Patient Global Assessment (PtGA)                                                                                                                  Collected on a numeric rating scale ranging from 0 to 10 for the question asking the patient: "Considering all the ways your disease affects you, how much do you think is active today?"
  Short Form-36 health survey\[[@B16]\]                                                                                                             Generic health status instrument with 8 domains: (1) physical function, (2) body pain, (3) role limitations--physical, (4) general health, (5) vitality, (6) social function, (7) role limitations--emotional, and (8) mental health;
  Greater scores reflect better health status;                                                                                                      
  Summarized in two summary scores defined as the (1) physical component score (Sf-36/PCS) and (2) mental component score (Sf-36/MCS).              

Patient-reported outcomes (PROs) were assessed with tests specific for articular-related symptoms \[*i.e*. the Bath Ankylosing Spondylitis Functional Index (BASFI)\]\[[@B14]\] and gastrointestinal-related symptoms \[*i.e*. the Inflammatory Bowel Disease Questionnaire (IBDQ)\]\[[@B15]\]. 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)\[[@B16]\].

Statistical analysis
--------------------

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).

RESULTS
=======

Baseline assessment of the patients
-----------------------------------

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](#T1){ref-type="table"}). 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\[[@B2]\]. 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](#F1){ref-type="fig"}, 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](#T1){ref-type="table"}).

Evaluation of articular and gastrointestinal disease activity
-------------------------------------------------------------

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](#F2){ref-type="fig"}). 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](#F2){ref-type="fig"}).

![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). ^a^*P* \< 0.05, ^b^*P* \< 0.01, ^e^*P* \< 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.](WJG-23-7139-g002){#F2}

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](#F2){ref-type="fig"}), and maintained at 12 mo, when the clinical remission was observed in almost all patients (Figure [2A](#F2){ref-type="fig"}). 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](#F2){ref-type="fig"}). All the values and comparisons are detailed in Table [3](#T3){ref-type="table"}.

###### 

Scores of the clinimetric test for articular-gastrointestinal activity and patient reported outcomes of health-related quality of life

                    **Baseline**   **T6**                                         **T12**
  ----------------- -------------- ---------------------------------------------- ----------------------------------------------
  CDAI, *n* = 19    181.3 ± 93.2   112.3 ± 63.0[b](#T3FN2){ref-type="table-fn"}   82.7 ± 48.7[b](#T3FN2){ref-type="table-fn"}
  pMAYO, *n* = 11   3.27 ± 1.79    1.81 ± 1.07[a](#T3FN1){ref-type="table-fn"}    1.63 ± 1.43[a](#T3FN1){ref-type="table-fn"}
  IBDQ              145.3 ± 36.8   172.8 ± 36.7[e](#T3FN3){ref-type="table-fn"}   180.7 ± 33.0[e](#T3FN3){ref-type="table-fn"}
  BASDAI            5.5 ± 1.7      3.2 ± 1.8[e](#T3FN3){ref-type="table-fn"}      3.3 ± 1.7[e](#T3FN3){ref-type="table-fn"}
  BASFI             3.2 ± 2.4      1.8 ± 1.4[e](#T3FN3){ref-type="table-fn"}      2.0 ± 1.3[a](#T3FN1){ref-type="table-fn"}
  ASDAS-CRP         3.2 ± 0.8      1.9 ± 0.6[e](#T3FN3){ref-type="table-fn"}      1.9 ± 0.6[e](#T3FN3){ref-type="table-fn"}
  PtGA              61.1 ± 20.6    35.6 ± 19.1[b](#T3FN2){ref-type="table-fn"}    33.0 ± 19.1[b](#T3FN2){ref-type="table-fn"}
  HAQ               4.7 ± 8.5      2.0 ± 4.2[a](#T3FN1){ref-type="table-fn"}      1.6 ± 3.5[a](#T3FN1){ref-type="table-fn"}
  Sf-36/PCS         42.2 ± 9.7     48.4 ± 7.2[e](#T3FN3){ref-type="table-fn"}     48.5 ± 7.3[b](#T3FN2){ref-type="table-fn"}
  Sf-36/MCS         35.4 ± 10.9    39.4 ± 8.8[a](#T3FN1){ref-type="table-fn"}     41.4 ± 9.7[a](#T3FN1){ref-type="table-fn"}
  CRP in mg/dL      2.7 ± 3.7      0.8 ± 1.2[a](#T3FN1){ref-type="table-fn"}      0.5 ± 0.6[a](#T3FN1){ref-type="table-fn"}

*P* \< 0.05,

*P* \< 0.01,

*P* \< 0.001. ASDAS-CRP: Ankylosing Spondylitis Disease Activity Score-C-Reactive Protein; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis Functional Index; CDAI: Crohn's Disease Activity Index; CRP: C-Reactive Protein; pMAYO: partial Mayo score; HAQ: Health Assessment Questionnaire; IBDQ: Inflammatory Bowel Disease Questionnaire; PtGA: Patient Global Assessment; 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; T6 and T12: Results of the evaluation after 6 mo and 12 mo of treatment with adalimumab respectively.

Evaluation of the HRQoL
-----------------------

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](#F2){ref-type="fig"}) 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](#F2){ref-type="fig"}); 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](#T3){ref-type="table"}.

Correlations between variables
------------------------------

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](#F3){ref-type="fig"}), BASDAI, and with most of the PROs of the HRQoL, as assessed by Sf-36/MCS and CDAI (Table [4](#T4){ref-type="table"}). 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](#T4){ref-type="table"}). 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](#F4){ref-type="fig"}) 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](#F2){ref-type="fig"}), 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](#T4){ref-type="table"}.

![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.](WJG-23-7139-g003){#F3}

###### 

Correlations between the scores of clinimetric tests for articular-gastrointestinal activity and patient reported outcomes of health-related quality of life scores

                                                              **CDAI**                                **pMAYO**                               **IBDQ**                                **BASDAI**                              **BASFI**                               **ASDAS-CRP**                           **PtGA**                                **HAQ**                                 **Sf-36/ PCS**                          **Sf-36/ MCS**                          **CRP**
  ----------------------------------------------------------- --------------------------------------- --------------------------------------- --------------------------------------- --------------------------------------- --------------------------------------- --------------------------------------- --------------------------------------- --------------------------------------- --------------------------------------- --------------------------------------- ---------------------------------------
  At baseline                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
  CDAI                                                        1                                       1                                       -0.57[b](#T4FN2){ref-type="table-fn"}   0.19                                    0.29                                    0.21                                    0.14                                    0.12                                    -0.24                                   -0.33                                   0.35
  pMAYO                                                       1                                       1                                       -0.48[a](#T4FN1){ref-type="table-fn"}   0.34                                    0.38                                    0.37                                    0.15                                    0.18                                    -0.14                                   -0.11                                   0.28
  IBDQ                                                        -0.57[b](#T4FN2){ref-type="table-fn"}   -0.48[a](#T4FN1){ref-type="table-fn"}   1                                       -0.38[b](#T4FN2){ref-type="table-fn"}   -0.34[a](#T4FN1){ref-type="table-fn"}   -0.52[b](#T4FN2){ref-type="table-fn"}   -0.26                                   -0.19                                   0.27                                    0.67[b](#T4FN2){ref-type="table-fn"}    -0.26
  BASDAI                                                      0.19                                    0.34                                    -0.38[b](#T4FN2){ref-type="table-fn"}   1                                       0.64[b](#T4FN2){ref-type="table-fn"}    0.69[b](#T4FN2){ref-type="table-fn"}    0.24                                    0.26                                    -0.22                                   -0.31[a](#T4FN1){ref-type="table-fn"}   0.00
  BASFI                                                       0.29                                    0.38                                    -0.34[a](#T4FN1){ref-type="table-fn"}   0.64[b](#T4FN2){ref-type="table-fn"}    1                                       0.57[b](#T4FN2){ref-type="table-fn"}    0.37[b](#T4FN2){ref-type="table-fn"}    0.36[b](#T4FN2){ref-type="table-fn"}    -0.44[b](#T4FN2){ref-type="table-fn"}   -0.15                                   0.37[b](#T4FN2){ref-type="table-fn"}
  ASDAS-CRP                                                   0.21                                    0.37                                    -0.52[b](#T4FN2){ref-type="table-fn"}   0.69[b](#T4FN2){ref-type="table-fn"}    0.57[b](#T4FN2){ref-type="table-fn"}    1                                       0.37[b](#T4FN2){ref-type="table-fn"}    0.36[b](#T4FN2){ref-type="table-fn"}    -0.30[a](#T4FN1){ref-type="table-fn"}   -0.41[b](#T4FN2){ref-type="table-fn"}   0.32[a](#T4FN1){ref-type="table-fn"}
  PtGA                                                        0.14                                    0.15                                    -0.26                                   0.24                                    0.37[b](#T4FN2){ref-type="table-fn"}    0.37[b](#T4FN2){ref-type="table-fn"}    1                                       0.22                                    -0.14                                   -0.22                                   0.14
  HAQ                                                         0.12                                    0.18                                    -0.19                                   0.26                                    0.36[b](#T4FN2){ref-type="table-fn"}    0.36[b](#T4FN2){ref-type="table-fn"}    0.22                                    1                                       -0.46[b](#T4FN2){ref-type="table-fn"}   -0.03                                   0.07
  Sf-36/PCS                                                   -0.24                                   -0.14                                   0.27                                    -0.22                                   -0.44^e^                                -0.30[a](#T4FN1){ref-type="table-fn"}   -0.14                                   -0.46[b](#T4FN2){ref-type="table-fn"}   1                                       0.05                                    -0.13
  Sf-36/MCS                                                   -0.33                                   -0.11                                   0.67[b](#T4FN2){ref-type="table-fn"}    -0.31[a](#T4FN1){ref-type="table-fn"}   -0.15                                   -0.41[b](#T4FN2){ref-type="table-fn"}   -0.22                                   -0.03                                   0.05                                    1                                       -0.08
  After 12 mo of therapy with adalimumab (ES-AN/Ada cohort)                                                                                                                                                                                                                                                                                                                                                                                                                   
  CDAI                                                        1                                       1                                       -0.83[b](#T4FN2){ref-type="table-fn"}   0.16                                    0.56[a](#T4FN1){ref-type="table-fn"}    0.54[a](#T4FN1){ref-type="table-fn"}    0.53[a](#T4FN1){ref-type="table-fn"}    0.53[a](#T4FN1){ref-type="table-fn"}    -0.71[b](#T4FN2){ref-type="table-fn"}   -0.67[b](#T4FN2){ref-type="table-fn"}   0.75[b](#T4FN2){ref-type="table-fn"}
  pMAYO                                                       1                                       1                                       -0.51                                   0.18                                    0.49                                    0.17                                    0.56                                    -0.29                                   -0.14                                   -0.25                                   0.6
  IBDQ                                                        -0.83[b](#T4FN2){ref-type="table-fn"}   -0.51                                   1                                       -0.23                                   -0.56[b](#T4FN2){ref-type="table-fn"}   -0.55[b](#T4FN2){ref-type="table-fn"}   -0.61[b](#T4FN2){ref-type="table-fn"}   -0.36[a](#T4FN1){ref-type="table-fn"}   0.53[b](#T4FN2){ref-type="table-fn"}    0.66[b](#T4FN2){ref-type="table-fn"}    -0.52[b](#T4FN2){ref-type="table-fn"}
  BASDAI                                                      0.16                                    0.18                                    -0.23                                   1                                       0.58[b](#T4FN2){ref-type="table-fn"}    0.68[b](#T4FN2){ref-type="table-fn"}    0.51[b](#T4FN2){ref-type="table-fn"}    0.39[a](#T4FN1){ref-type="table-fn"}    -0.52[b](#T4FN2){ref-type="table-fn"}   -0.11                                   -0.14
  BASFI                                                       0.56[a](#T4FN1){ref-type="table-fn"}    0.49                                    -0.56[b](#T4FN2){ref-type="table-fn"}   0.58[b](#T4FN2){ref-type="table-fn"}    1                                       0.56[b](#T4FN2){ref-type="table-fn"}    0.64[b](#T4FN2){ref-type="table-fn"}    0.54[b](#T4FN2){ref-type="table-fn"}    -0.52[b](#T4FN2){ref-type="table-fn"}   -0.45[a](#T4FN1){ref-type="table-fn"}   0.16
  ASDAS-CRP                                                   0.54[a](#T4FN1){ref-type="table-fn"}    0.17                                    -0.55[b](#T4FN2){ref-type="table-fn"}   0.68[b](#T4FN2){ref-type="table-fn"}    0.56[b](#T4FN2){ref-type="table-fn"}    1                                       0.67[b](#T4FN2){ref-type="table-fn"}    0.38[a](#T4FN1){ref-type="table-fn"}    -0.62[b](#T4FN2){ref-type="table-fn"}   -0.41[a](#T4FN1){ref-type="table-fn"}   0.31
  PtGA                                                        0.53[a](#T4FN1){ref-type="table-fn"}    0.56                                    -0.61[b](#T4FN2){ref-type="table-fn"}   0.51[b](#T4FN2){ref-type="table-fn"}    0.64[b](#T4FN2){ref-type="table-fn"}    0.67[b](#T4FN2){ref-type="table-fn"}    1                                       0.51[b](#T4FN2){ref-type="table-fn"}    -0.37[a](#T4FN1){ref-type="table-fn"}   -0.59[b](#T4FN2){ref-type="table-fn"}   0.26
  HAQ                                                         0.53[a](#T4FN1){ref-type="table-fn"}    -0.29                                   -0.36[a](#T4FN1){ref-type="table-fn"}   0.39[a](#T4FN1){ref-type="table-fn"}    0.54[b](#T4FN2){ref-type="table-fn"}    0.38[a](#T4FN1){ref-type="table-fn"}    0.51[b](#T4FN2){ref-type="table-fn"}    1                                       -0.47[b](#T4FN2){ref-type="table-fn"}   -0.40[a](#T4FN1){ref-type="table-fn"}   0.10
  Sf-36/PCS                                                   1                                       1                                       -0.83[b](#T4FN2){ref-type="table-fn"}   0.16                                    0.56[a](#T4FN1){ref-type="table-fn"}    0.54[a](#T4FN1){ref-type="table-fn"}    0.53[a](#T4FN1){ref-type="table-fn"}    0.53[a](#T4FN1){ref-type="table-fn"}    -0.71[b](#T4FN2){ref-type="table-fn"}   -0.67[b](#T4FN2){ref-type="table-fn"}   0.75[b](#T4FN2){ref-type="table-fn"}
  Sf-36/MCS                                                   1                                       1                                       -0.51                                   0.18                                    0.49                                    0.17                                    0.56                                    -0.29                                   -0.14                                   -0.25                                   0.60
  CRP                                                         -0.83[b](#T4FN2){ref-type="table-fn"}   -0.51                                   1                                       -0.23                                   -0.56[b](#T4FN2){ref-type="table-fn"}   -0.55[b](#T4FN2){ref-type="table-fn"}   -0.61[b](#T4FN2){ref-type="table-fn"}   -0.36[a](#T4FN1){ref-type="table-fn"}   0.53[b](#T4FN2){ref-type="table-fn"}    0.66[b](#T4FN2){ref-type="table-fn"}    -0.52[b](#T4FN2){ref-type="table-fn"}

Correlations between variables were assessed in the 30 patients with enteropathic spondyloarthritis from Ancona, Italy, at baseline and after 6 mo (data not shown) and 12 mo of therapy with adalimumab (ES-AN/Ada), using Pearson's correlation coefficient;

*P* \< 0.05,

*P* \< 0.01. ASDAS-CRP: Ankylosing Spondylitis Disease Activity Score-C-Reactive Protein; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis Functional Index; CDAI: Crohn's Disease Activity Index; CRP: C-Reactive Protein; HAQ: Health Assessment Questionnaire; IBDQ: Inflammatory Bowel Disease Questionnaire; pMAYO: partial Mayo score; PtGA: Patient Global Assessment; 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.

![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.](WJG-23-7139-g004){#F4}

Tolerability
------------

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.

DISCUSSION
==========

The association between SpAs and IBDs has been known since the beginning of the last century\[[@B17]\]. However, gastroenterologists and rheumatologists continue to carry out their clinical evaluations and the therapeutic management of these diseases, now known collectively as ES, independently. In this regard, the different clinical guidelines employed by the two medical specialists may lead to different therapeutic decisions for the same clinical scenario, ultimately harboring potential for different clinical outcomes of the disease. A critical issue in the clinical management of ES is the correct therapeutic choice, and an important role has emerged recently for the TNF-alpha inhibitors in this regard. Infliximab was the first TNF-alpha inhibitor used in ES\[[@B18]\], but Ada has recently been applied to ES patients affected by CD and has achieved rates of clinical remission up to 50%\[[@B19]\].

To our knowledge, this is the first study demonstrating the efficacy of the integrated gastrorheumatologic approach for evaluation and therapeutic management of ES patients, with efficacy evidenced through assessments of disease activity and HRQoL over a 12-mo period. As dictated by our operative algorithm, both the gastroenterologist and the rheumatologist evaluated each of the patients in the study cohort, with both of the specialists collaborating to choose the optimal therapy. This integrated multidisciplinary approach, therefore, considered the gastrointestinal and articular disease activities simultaneously and, most importantly in the latter case, the site of articular inflammation (axial or peripheral). Thus, for example, in the case of axial spondyloarthritis, the therapy with anti-TNF-alpha inhibitors was mandatory, following the latest rheumatologic indications\[[@B20]\].

Since only few studies in the literature have so far evaluated the efficacy and safety of anti-TNF-alpha in ES, we employed the up and coming Ada treatment in our study. The results indicated that in ES patients, regardless of IBD type and/or site of articular involvement, Ada significantly improves the inflammation states of both the joints (assessed by ASDAS-CRP and BASDAI) and gut (assessed by CDAI or pMAYO score), as well as the HRQoL. Moreover, the benefits were already observable at 6 mo and the improvements were maintained at 12 mo. Ada also consistently improved not only the physical function in almost all ES patients (assessed by PtGA, BASFI, HAQ and Sf-36/PCS) but also their psychological function (assessed by Sf-36/MCS and IBDQ), from baseline to 6 mo.

It is noteworthy that in our study the strong linear relationship between articular-gastrointestinal disease activity and the PROs confirms the strong link between gut and joint inflammations. In fact, the IBDQ (specific for the gastrointestinal-related quality of life) strongly correlated with results of the clinimetric tests of articular activity (ASDAS-CRP, BASDAI and BASFI); additionally, the articular disease activity (assessed by ASDAS-CRP) strongly correlated with all of the PROs studied, even those specific for IBDs. To the contrary, however, at baseline the gastrointestinal disease activity scores (except for those of the IBDQ) did not correlate well with the other variables, but at 12 mo of therapy the CDAI correlated with most of the articular and PROs of HRQoL. This latter finding may be consequent to the different degrees of disease activities reported by the patients at baseline, which, after the treatment, tend to be globally ameliorated both at the gastrointestinal and articular levels.

Thus, since only the ASDAS-CRP test proved to be the most reliable in all patients in our study, we think that it should be necessary to develop composite scores and HRQoL questionnaires specific and suitable for ES patients at diagnosis, similar to those developed for other multidisciplinary diseases, such as psoriatic arthritis\[[@B21]\]. In conclusion, in our work that was carried out in a real-life cohort of a significant number of ES patients, we demonstrated that Ada produced a fast and significant improvement of both the gastrointestinal and articular scores of disease activity and, moreover, of the HRQoL. This clinical result was achieved by employing an integrated outpatient clinic specific for ES patients, as recently endorsed, particularly with regard to early diagnosis\[[@B22],[@B23]\]. The integrated approach provided the optimal management of both the multidisciplinary clinical evaluation and the therapy of these patients. Further studies are certainly warranted to assess the long-term outcomes, and tolerability, of Ada and other TNF-alpha inhibitors in patients affected by ES.

COMMENTS
========

Background
----------

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.

Research frontiers
------------------

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.

Innovations and breakthroughs
-----------------------------

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.

Applications
------------

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).

Terminology
-----------

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.

Peer-review
-----------

This is an interesting and well-conducted work.

ACKNOWLEDGMENTS
===============

We would like to acknowledge all the patients who enthusiastically participated in this study. We are also grateful with Miss Lucrezia Lombardi for her assistance in the writing and revision of the manuscript.

Manuscript source: Unsolicited manuscript

Specialty type: Gastroenterology and Hepatology

Country of origin: Italy

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): 0

Grade C (Good): C, C

Grade D (Fair): 0

Grade E (Poor): 0

Institutional review board statement: The study was reviewed and approved by the Comitato Etico, Polo Ospedaliero-Universitaria "Umberto I-G.M. Lancisi-G. Salesi", Ancona, Italy, according to the 2015 local and national procedural laws.

Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.

Conflict-of-interest statement: There are no conflicts of interest to report.

Data sharing statement: No additional data are available.

Peer-review started: April 1, 2017

First decision: June 5, 2017

Article in press: August 15, 2017

P- Reviewer: Garcia-Olmo D, Pellicano R S- Editor: Gong ZM L- Editor: A E- Editor: Huang Y

[^1]: Author contributions: Luchetti MM and Benfaremo D contributed equally to this work; Luchetti MM, Benfaremo D and Ciccia F contributed to study conception and design, data analysis and interpretation, and writing of the article; Benfaremo D, Bolognini L, Ciferri M, Farinelli A, Rossini M and Mosca P contributed to data acquisition; Luchetti MM, Benfaremo D, Ciccia F, Triolo G and Gabrielli A contributed to editing, reviewing and final approval of article.

    Correspondence to: Michele Maria Luchetti, MD, Dipartimento Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, Ancona 60126, Italy. <m.luchetti@univpm.it>

    Telephone: +39-71-2206101 Fax: +39-71-2206103
