SPIB-project - SIGR · consisting in abdominal pain and more than 12 liquid soft stool/day, and subjected to entero-MRI. Rheumatologic consultation requested for “arthralgia”

SPIB-project SPondyloarthropaties in Inflammatory Bowel diseases

Dott. Michele M. Luchetti

Clinica Medica Dipartimento di Scienze Cliniche e Molecolari

Enteropathic spondyloarthritis: new topic of interest or a forgotten one ?

A relationship between bowel and joints was reported for the first time by Smith in 1922, who described in patients with rheumatoid arthritis (RA) underwent surgery for colectomy an improvement of articular symptoms (R. Smith. Ann

Surg, 76, 515–578, 1922).

Only in 1964, the American Rheumatism Association classified arthritis associated with IBD as independent clinical form (Blumberg B.S. Arthritis Rheum 7, 93–97, 1964).

And, later, in 1976 Wright and Moll included enteroarthritis definitively among SpA group (V. Wright and J. H. M. Moll, Seronegative

Polyarthritis, North Holland Publishing Company, Amsterdam, The Netherlands, 1976). Luchetti MM Clin Medica, UNIVPM, I l

…This apparent lack of interest is reflected also by the fact that guidelines on IBD up to 2005 did not mention IBD-associated arthritis. Only in 2006 with the publication of the European Crohn’s and Colitis Organization (ECCO) evidence-based consensus on “special situations in Crohn’s disease”, articular manifestations are briefly discussed (Caprilli et al., Gut 2006; 55 Suppl 1: i36-i58)”.

Enteropathic spondyloarthritis: new topic of interest or a forgotten one ?

Luchetti MM Clin Medica, UNIVPM,

Possibile interessamento delle articolazioni assiali (sacroiliache e il rachide, condrosternali)…

…e in questo caso la sintomatologia tipica è costituita dall’ Inflammatory Back Pain (IBP)

Possibile interessamento delle articolazioni periferiche, generalmente in modo asimmetrico e con una maggiore prevalenza le grandi articolazioni…

….ed anche le zone iuxta ed extra-articolari, quali le entesi e i tendini (entesiti-dattilite)

presentano aggregazione familiare importante (background genetico comune HLA-B27 per la Spondilite Anchilosante)

Gruppo di affezioni infiammatorie croniche che condividono alcune caratteristiche comuni:

SpAs

Rudwaleit M. Int J Adv Rheumathol 2010

Diagnostic clues for the rheumatologist

Diagnostic clues for the gastroenterologist

• Family history of IBD • Chronic diarrhea • Chronic abdominal pain • Rectal bleeding • Weight loss • Persistent fever • History or evidence of

perianal fistula/abscess • Anemia

• Chronic back pain (>3 months)

• Peripheral joint pain/swelling

• Presence of signs of enthesitis

• History or evidence of dactylitis

Diagnostic clues for the rheumatologist or for the gastroenterologist to be evaluated in each single patient before considering referral to the gastroenterologist or to the rheumatologist. Adapted from Olivieri I. et al., Autoimmunity Reviews, 2014.

Luchetti MM Clin Medica, UNIVPM, I l

SPIB 2015

I should perhaps declare a personal, as well as a professional, interest in the field: I entered medical school 50 years ago, while suffering from AS that had gone undiagnosed for the previous 4 years. It took another 2 years…for the disease to be finally diagnosed. (Khan M.A., Rheumatology 2011).

Luchetti MM, Clin Medica, UNIVPM

Khan M. Arthritis Rheum 2000


The Journal of Rheumatology 2013; 40:10

“There is an UNACCEPTABLE DELAY in the diagnosis of axial spondyloarthritis (axSpA) in its early stages among patients at high risk, in particular those with inflammatory bowel disease (IBD)”

precedes IBD symptoms in 31% to 50% of patients

IBD and axSpA can occur simultaneously in 15% to

40% of patients

SPIB 2015

Ovvero: Pazienti affetti da IBD e LOMBALGIA INFIAMMATORIA: 1- HLA-27+

oppure 2- Sacroileite Rx e/o RMN

Diagnosi: SpA-IBD ASSIALE

Ovvero: Pazienti affetti da IBD e artrite periferica 1- HLA-27+

oppure 2- + entesite o dattilite

oppure 3- LOMBALGIA INFIAMMATORIA

Diagnosi: SpA-IBD PERIFERICA

Sacroileite, Sindesmofiti

< 40 anni

Cronico

Migliora i sintomi

>1 ora al risveglio Sciatica “TRONCA” (ginocchio-pube)

INFIAMMATORIO

Restringimento spazio discale, scoliosi, osteofitosi

RX-RMN

> 40 anni Esordio

Acuto o cronico Durata

Peggiora i sintomi Attività fisica

< 45’ al risveglio Sciatica CLASSICA

(schiena-piede)

Dolore/Rigidità

MECCANICO Caratteri

Inflammatory Back Pain Diagnostic Criteria


First recommendation

IBD patient • Active • Anamnestic

Enthesitis Dactilitis

Back pain Arthralgia-arthritis

Early Referral to the Rheumatologist

SPIB 2015

A.S., age 42, affected by CD and admitted in the hospital for a flare of the disease, consisting in abdominal pain and more than 12 liquid soft stool/day, and subjected to entero-MRI. Rheumatologic consultation requested for “arthralgia”

Entero-MRI

R L

Bone marrow oedema = ACTIVE sacroiiletis


Medical Problem: Arthralgia in patients affected by Inflammatory Bowel Diseases (IBD)

SPIB 2015

Divisione di Gastroenterologia

SPIB START: 2013

Consulenza Clinica Medica

INTRO


General issues and specific problems from the start

Symptoms present for years Underestimated, in particular in young patients

Treated with symptomatic drugs

Often considered consequent to the IBD Often “mitigated” by the treatment for IBD (anti-TNF-alfa!)

Never considered the option of a “specific” treatment for both the articular and the gastrointestinal inflammation

Need for an early diagnosis of Enteropatic Spondiloarthritis

(ES)

SPIB 2015 INTRO


I. (Early) Diagnosis of Enteropatic SpA (ES): not easy

ES: diagnosed by ASAS criteria

① Treatment ? ① Clinical Outcomes ? ① Quality of life of ES

patients ?

? Few lines in the ASAS/EULAR recomendations for

the management of AS (ARD 2014) Indipendent Clinical Outcomes of SpA and of IBD

Significantly worsened by articular symptoms

SPIB 2015


SPIB-project (SPondyloarthropaties in Inflammatory Bowel diseases )

2013-2014

2015 (ENDED follow up at 12 months)

Schematic Overview

A. Integration of the Gastroenterology and Rheumatologic Examination

B. Screening of pts affected by articular symptoms C. Diagnosis of ES D. Integrated Therapy E. Follow up and integrated evaluation of patient-reported

and clinical outcomes

SPIB 2015


Patient Studied:

n. 220 IBD pts In the outpatient clinics and clinical wards

(Gastroenterology and Internal Medicine)

Gastro

INTEGRATED EVALUATION

Rheuma

SPIB 2015


Patient Studied:

n. 220 IBD pts

Cohort of the Study: n. 178 IBD pts

Compliant

SCREENING for articular symptoms

PROs: HAQ VAS SF-36

Project Plan Scheme – T zero

PROs Gastro-Activity: CDAI IBDQ

Reuma-Activity: ASDAS BASDAI BASMI BASFI

II Rheumatologic Examination

No SpA SpA?

ES Cohort (n. 52)

IBD-def Cohort (n. 126)

III Evaluation: HLA-B27 Rx RMN

Venous sampling for Biomarkers Evaluation

INTEGRATED EVALUATION OF THE TREATMENT

TEST

SPIB 2015


SCREENING Time = 5-10 min Made by the MD In the

GASTROENTEROLOGY: • outpatient clinic • In DH • in the clinical ward

METHODS- Screening

II phase: Rheumatologic Evaluation Time = 30-45 min Made by the MD In the INTERNAL MEDICINE

outpatient clinic or in the clinical ward

SPIB 2015


SCREENING vs.The Toronto Questionary, Alnaqbi KA, J Rheumatol 2013, 40:10.

SPIB 2015 METHODS- Screening


METHODS - TESTs

Patient Reported Outcomes (PROs) “qualsiasi informazione riferita direttamente dai pazienti (report), senza interpretazione di medici o altri, sul proprio essere, il proprio agire e le proprie sensazioni in relazione alle condizioni di salute e agli interventi che ne sono connessi” Patrick DL, Burke LB, Powers JH, et al. Patient-reported outcomes to support medical product labelling claims: FDA perspective. Value in Health 2007;10(suppl.2):125-37 Dawson J, Doll H, Fitzpatrick R, Jenkinson C, et al. The routine use of patient reported outcome measures in healthcare settings, BMJ 2010; 340:c186

SPIB 2015

QUALITY OF LIFE

SF-36 HealthAssessement Questionary (HAQ)

Patient Global Assessment (PtGA)

Function explored General health status General health status Pain Items 36 22 Visual Analogue

Scale Peculiarity 8-scale profile of functional health and well-being

scores, as well as psychometrically-based physical /mental health summary measures

Assessment of the ability to perform normal daily duties

Normal score >80 (The higher the score the less disability) <20 <10

Gastroenterologic ACTIVITY

Crohn’s Disease Activity Index (CDAI) Inflammatory Bowel Disease Questionary (IBDQ)

Function explored Clinical and laboratory disease activity Social, systemic and emotional symptoms, as well as bowel related symptoms

Items 8 32 Peculiarity Item 4 (score value = 20): arthritis ? Normal score <150 >190 (The higher the score the less disability)

Rheumatologic ACTIVITY

ASDAS-CRP Ankylosing Spondylitis Disease

Activity Score

BASDAI Bath Ankylosing Spondylitis

Disease Activity Index

BASFI Bath Ankylosing Spondylitis

Functional Index

BASM Bath Ankylosing Spondylitis Metrology Index

Function explored Disease activity Disease activity Functional activity Functional activity Items 5 6 10 5 Peculiarity 1 laboratory item: CRP Visual scale Visual scale Measurement of

anatomical parameters

Normal score <1,3 <4 <4 <1

METHODS - TESTs SPIB 2015


SF-36

HAQ

VAS

CDAI

IBDQ

ASDAS BASDAI

BASMI

BASFI

TEST administration time: 30 min/each pt

entered in a specific database based on the Epi-Info platform

METHODS - TESTs SPIB 2015

STATISTICS Softwares: • GraphPad InStat • GraphPad Prism Clinical Data: Wilcoxon and Mann-Whitney non-parametric test Laboratory Data: Wilcoxon non-parametric test; Correlation by Spearman’s test; Deming (method II) linear regression


Project Plan – Follow Up

ES Cohort

IBD-def

Cohort Venous sampling for Biomarkers Evaluation

INTEGRATED EVALUATION OF THE TREATMENT

2014 2015 3

months 6

months 12

Months (JUNE)

SCREENING for articular symptoms

Gastro-Activity Evaluation: CDAI, IBDQ PROs Evaluation: HAQ, VAS, SF-36

Reuma-Activity Evaluation: ASDAS, BASDAI, BASMI, BASFI

In progress

SPIB 2015


Integration of the Gastroenterology and Rheumatologic Examination Screening of pts affected by articular symptoms

END POINTs SPIB Schematic Overview

1. DIAGNOSIS OF ENTEROPATIC SpA (ES)

2. EVALUATION OF THE QUALITY OF LIFE IN THE ES PTS

3. INTEGRATED ACTION (GASTRO-RHEUMA) FOR THE CHOICE

OF THE OPTIMAL TREATMENT-BASED ON ARTICULAR-

INTESTINAL INFLAMMATION

4. INTEGRATED EVALUATION (GASTRO-RHEUMA) OF THE

QUALITY OF LIFE, DISEASE ACTIVITY AND CLINICAL

REMISSION AFTER ACTION 3.

Diagnosis of ES Integrated Therapy Follow up and integrated evaluation of

patient-reported and clinical outcomes

SPIB 2015

RESULTS

I.Patients: screening for articular symptoms and constitution of the ES cohort

SPIB 2015

Luchetti MM et al. ARD June 2015

RESULTS - Patients

IBD: n. 220 pts affering into the study

80 pts (36%)

ENTEROPATHIC SpA (ES) n. 52 pts • 24 % of IBD pts • 65 % of the “Articular Symptoms Cohort”

IBD-def

COHORT: n. 126 pts

SCREENING

Articular symptoms

YES

NO

Osteoarthritis and/or other condition: n. 28 pts (16 % of IBD pts)

According to ASAS criteria

SPIB 2015


Articular Symptoms Cohort


IBD-def COHORT n=126 CD (Crohn’s Disease):UC (Ulcerative Colitis) 117 (67,5%) : 61 (32,5%)

M:F 98:80

Age (mean ± SD) 46,6 ± 14,44

Disease duration, in years (mean ± SD) 10,68 ± 9,23

Extra-intestinal symptoms (rheumatologic excluded), pts number 8 (4.5%)

Erythema nodosum, pts number 9 (5%)

Uveitis, pts number 3 (1,7%)

Therapy • Mesalazine • NSAID • DMARD • Corticosteroids • Anti-TNF-alfa drugs (infliximab:adalimumab)

38 (24,7%)

0 22 (14,3%) 28 (18,2%) 33 (28:5)

Oral contraceptives, pts number 8 (5,2%)

Smokers Ex-smokers

45 (29,2%) 35 (22,7%)

CD-Gastrointestinal Activity (assessed by CDAI) 76 REMISSION (65%) 25 MODERATE (21%) 16 MODERATE-TO-SEVERE (14%)

UC-Gastrointestinal Activity (assessed by Truelove and Witt’s)

• 41 MILD (67%) • 14 MODERATE (23%) • 6 SEVERE (10%)

SPIB 2015 RESULTS – Patients at the baseline

ES COHORT N=52 CD (Crohn’s Disease):UC (Ulcerative Colitis) 33(63%) :19 (37%)

M:F 22:29

Age (mean ± SD) 48,4 ± 12,34

Disease duration of IBD, in years (mean ± SD) 12,16 10,66 yrs

Erythema nodosum, pts number 1 (2%)

Uveitis, pts number 2 (3,9%)

Therapy • Mesalazine • NSAID • DMARD • Corticosteroids • Anti-TNF-alfa drugs (infliximab:adalimumab)

20 (39,2%)

1 (2%) 11 (21,6%) 8 (15,7%) 11 (7:7)

Oral contraceptives, pts number 3 (5,2%)

Smokers Ex-smokers

9 (17,6%) 12 (23,5%)

CD- Gastrointestinal Activity 13 inactive (40,6%) 12 mild (37,4) 8 moderate-to-severe (22%)

UC -Gastrointestinal Activity

• 10 mild (52,6%) • 6 moderate (31,5%) • 3 severe (15,9%)

CD - Gastrointestinal Activity

13 inactive (40,6%) 12 mild (37,4) 8 moderate-to-severe(22%)

76 remission (65%) 25 moderate (21%) 16 moderate-to-severe (14%)

UC - Gastrointestinal Activity

• 10 mild (52,6%) • 6 moderate (31,5%) • 3 severe (15,9%)

•41 mild (67%) •14 moderate (23%) •6 severe (10%)

RESULTS – Patients at the baseline SPIB 2015


ES IBD-def

ES COHORT - Rheumatologic features N=52 HLA-B27 positive, pts number 5 (10 %) Axial SpA: Peripheral SpA 28(54 %) : 24(46 %) Type of Axial Involvement, pts number Syndesmophytosis Bamboo Spine Sacroiliitis (MRI imaging)

2 (3,9%) 1 (1,9%) 25 (49%

of the cohort, 100% of the Axial-ES))

CD Articular Involvement, pts number • Axial • Peripheral • Enthesis

18 (35,3%) 14 (27,5%) 14 (27,5%)

UC Articular Involvement, pts number • Axial • Peripheral • Enthesis

10 (19,6%) 7 (13,7%) 8 (14 %)

Articular Disease Activity (global evaluation, score number) ASDAS-CRP BASDAI BASFI BASMI

3,2 ± 0,72 5,6 ± 1,98 3,1 ± 3,42 1,2 ± 1,35

SPIB 2015


RESULTS – Patients at the baseline

RESULTS

II. Analysis of the Quality of Life: the impact of articular disease on the quality of life of IBD pts

SPIB 2015


SPIB 2015 RESULTS – Quality of life at the baseline

SF-36 The quality of life in ES pts is significantly worsened by articular symptoms...

IBD

ES

PF PF SF SF BP BP RP RP

MH MH VT VT

*** *** *** *** *** *** *** ***

GH GH RE RE Luchetti MM et al. ARD June 2015

well-being

***p<0.001


well-being

***p<0.001


The quality of life in ES pts is significantly worsened by articular symptoms...

IBD ES

*** HAQ PtGA

IBD ES


…and it is significantly worsened by the persistence of gastrointestinal symptoms

CDAI

IBD ES

**

IBDQ

IBD ES

***

Active IBD **p<0.01; ***p<0.001 Luchetti MM et al. ARD June 2015

RESULTS

III. Analysis of the Quality of Life: the impact of the optimal therapeutic strategy on the quality of life of IBD pts

SPIB 2015


RESULTS – The integrated options of treatment SPIB 2015

ENTEROPATIC SpA (ES) Naive, n. 39 pts

Active IBD

IBD in remission

Peripheral SpA

Axial SpA

IBD refractory to conventional therapy at least for 3 months

+ Anti-TNF-alfa (used as recommended

for IBD treatment)

Axial SpA

Peripheral SpA

Salazopyrinor

Mtx

Salazopyrinor

Mtx

Dashed line: refractory

• PERIPHERAL-SpA = 14 pts (10 + MTX ; 4 + SZP) • AXIAL-SpA = 22 pts : + ADA; • PERIPHERAL-SpA, active-IBD and refractory to DMARDs = 3 pts : + ADA


RESULTS – The integrated options of treatment SPIB 2015

ENTEROPATIC SpA (ES) in-treatment with anti-TNF-alfa, n. 13 pts

Active IBD

IBD in remission

Peripheral SpA

Axial SpA

IBD refractory to therapy and posology variations at least for 5 months

SWITCH to another anti-TNF-alfa

(used as recommended for IBD treatment)

Axial SpA

Peripheral SpA

Salazopyrinor

Mtx

Dashed line: refractory

PERIPHERAL-SpA, 10 pts : 8 + MTX ; 2 + SZP AXIAL-SpA, 3 pts switched : + ADA

SpA-Refractory


+

SPIB 2015 RESULTS- PATIENTS AND TREATMENT ENTEROPATIC SpA (ES)

n. 52 pts

PERIPHERAL SpA n. 24 pts: • MTX, n. 18 • SZP, n. 6

AXIAL SpA n. 22 naive pts

AXIAL SpA n. 3 pts switched from IFX for inefficacy

PERIPHERAL SpA, Refractory, n. 3 naive pts

CD 33 (63%), UC 19 (37%) IBD active in 29 (56%) pts

DMARDs ADA, n. 28 pts

• MTX, 15-20 mg/week

• SZP, 1 gr x 2/daily

Dose: 160 mg the Ist week; 80 mg the IInd week; then, 40 mg every other week

Baseline

12 months Luchetti MM et al. ARD June 2015

N.B. THERAPY CHOICE STRICTLY BASED ON: 1. IBD activity + 2. IBD therapy at the baseline + 3. Articular involvement N.B. THERAPY DOSAGE BASED ON: 1. IBD activity

SPIB 2015 RESULTS – Quality of life after 12-months of treatment

IBD

ES

90% of the ES upon the start of the therapy pts reported a significant improvement in some indicators of the quality of life

well-being


SF-36

SPIB 2015 RESULTS – Quality of life after 12-months of treatment

CDAI

IBD ES

IBDQ

IBD ES

Active IBD or SpA *p<0.05; **p<0.01; ***p<0.001

This therapeutic effect has played a crucial role in improving the quality of life of ES pts

88% of ES pts receiving anti-TNF-alfa drugs has achieved a significant improvement of both gastrointestinal

T0= ES pts at baseline evaluation and after 12-months (T12) of treatment with anti-TNF-alfa drugs


*

T0 T12

BASDAI

***

T0 T12

ASDAS-CRP

***

and articular disease

SPIB 2015 RESULTS – COMPLIANCE AND SAFETY AT 12-MONTHS

ADHERENCE TO THERAPY


• 30 pts under BIOLOGIC THERAPY n. 24 ADA (4 switch from IFX) n. 6 IFX (1 switch from ADA)

• 8 pts under DMARDs n. 8 MTX n. 2 SZP

• 14 pts --> NO THERAPY FOR SPA 9 refused (safety concern) 1 stop ADA for surgery 1 stop ADA for pregnancy 1 stop ADA for psoriatic eruption 1 stop IFX for psoriatic eruption 1 stop IFX for infusion reaction

Reaction reported (n. 13, 33 %) IFX Psoriatic Eruption 2

Anaphylaxis 1 Leukopenia 1 Infusion Reactions 2

ADA Hair Loss 1 Serious Infection 3 Psoriatic Eruption 1 Recurrent Upper Respiratory

Tract Infection 2 Fatigue 2 Headache 1 Itching 1

SAFETY

SPIB 2015 CONCLUSIONS - 1

1) The QUALITY OF LIFE in ES pts is dramatically worsened by the occurrence of articular symptoms

2) The early diagnosis of ES and… 3) ….the choice of the optimal therapeutic strategy lead to a

consistent clinical remission of both the gastrointestinal (IBD) and articular disease (SpA).

4) Thus, the integrated clinical evaluation of these pts, carried out by the gastroenterologist and rheumatologist, should be strongly encouraged and supported in clinical practice

Patient reported outcomes and quality of life in a cohort of patients affected by entheropathic spondyloarthritis (ES): results at one-year of a monocentric prospective observational study


RESULTS

IV. Effect of adalimumab in ES: What’s about the impact of anti-TNF-alfa therapy, compared to DMARDs, on both the articular and the gastrointestinal inflammation?

SPIB 2015


SPIB 2015 RESULTS- ADA vs Sinth-DMARDs IN ES ADA, but not methotrexate or salazopyrine, consistently decreases articular inflammation…

Active SpA T0= ES pts at baseline evaluation and after 12-months (T12) of treatment with anti-TNF-alfa drugs

*

T0 Sinth-DMARDs

T0 ADA

T12 T12 T0 Sinth-DMARDs

T0 ADA

T12 T12

*p<0.05; ***p<0.001.

BASDAI ASDAS-CRP


***

* *

SPIB 2015 RESULTS- ADA vs Sinth-DMARDs IN ES

…and ADA, but not methotrexate or salazopyrine, significantly improves the quality of life globally considered in ES pts


PF PF SF SF BP BP RP RP MH MH VT VT GH GH RE RE

*** *** *** *** *** *** *** ***

SF-36 PtGA

T0 T12+ ADA

***

T0

T12+ADA well-being

***p<0.001

SPIB 2015 RESULTS- ARTICULAR VS. GASTROINTESTINAL ACTIVITY in ES

BASDAI

ASD

AS-

CR

P

ASD

AS-

CR

P

IBDQ

p<0.01* p<0.05*

*Spearman’s Correlation Stat-Test

In Axial-ES, but not in Peripheral-ES, articular inflammation is significantly correlated to gastrointestinal symptoms (and likely inflammation)


SPIB 2015 RESULTS- ADA vs Sinth-DMARDs IN ES

T0 ADA

naive T12

mg/

dl

** CRP

CDAI

T0 T12 + ADA

*

Active IBD *p<0.05; **p<0.01; ***p<0.001.

T0= ES pts at baseline evaluation and after 12-months (T12) of treatment with anti-TNF-alfa drugs

IBDQ

T0 T12+ ADA

***

Only ADA, but not methotrexate or salazopyrine, has been effective in reducing: systemic (CRP) and gastrointestinal inflammation


SPIB 2015 CONCLUSIONS - 2

1)The choice of the optimal therapeutic strategy in ES should consider drugs that are effective in inducing the disease remission of both SpA and IBD…

2)…thus reinforcing the importance of the integrated clinical evaluation of these pts.

3)ADA, but not synthetic DMARDs, is effective in reducing both the articular and the intestinal inflammation (88% of ES pts)…

4)…also in those refractory to DMARDs or IFX (n. 5 pts, 9,8%) 5)In Axial-ES (but not in Peripheral-ES) articular and

gastrointestinal inflammation seem to be correlated (implications in the pathogenesis of ES?)

Effect of adalimumab therapy on both gastrointestinal and articular inflammation at 12 months in patients affected by enteropathic spondyloarthritis: results from a monocentric prospective observational study


SPIB 2015 The SPIB Study Group

Dipartimento di Gastroenterologia Dott. Lorenzini I. Mosca P. Bolognini L. Fava G.

Clinica Medica Prof. Gabrielli A. Luchetti M.M. Balloni A. Benfaremo D. Capeci W. Rossini M.

Cedraro S. Ciferri M. Farinelli A. Gambacorta G.

Manfredi L. Pomponio G. Postacchini L. Tedesco S.

Lab. Med.Mol Avellini C. Spadoni T. Svegliati S.

Biomedico di Medicina Interna e Specialistica Prof. Triolo G. Ciccia F. Guggino G.

Luchetti MM, Clin Medica

email to: [email protected]

How could we increase the adherence to a study ?

Documents

SPIB-project - SIGR · consisting in abdominal pain and more than 12 liquid soft stool/day, and subjected to entero-MRI. Rheumatologic consultation requested for “arthralgia”