Devis Benfaremo

Biologics in Inflammatory and Immunomediated Arthritis

BACKGROUND Biologic drugs, introduced in clinical practice almost twenty years ago, represent nowadays a prominent treatment option in patients with chronic inflammatory arthritis, such as Rheumatoid Arthritis, Psoriatic Arthritis and Spondyloarthritis, that include ankylosing spondylitis and non-radiographic axial spondyloarthritis. METHODS Several compounds targeting different pathways have been marketed and approved for the treatment of inflammatory arthritis, with a significant impact on the clinical outcomes and the natural history of the diseases. RESULTS There are currently seven classes of biologics that are available for the treatment of inflammatory arthritis, each inhibiting a different aspect of the immune-driven inflammatory pathway. They include: • Tumor Necrosis Factor (TNF) inhibitors (infliximab, adalimumab, etanercept, golimumab and certolizumab pegol); • Interleukin-1 (IL-1) receptor antagonists (anakinra); • Interleukin-6 (IL-6) inhibition (tocilizumab); • Interleukin-12/23 (IL23) inhibition (ustekinumab); • Interleukin-17 (IL-17) inhibition (secukinumab); • B-cell inhibition (anti-CD20, rituximab); • T-cell costimulation inhibition (anti-CTLA-4, abatacept). CONCLUSION In this review, we will focus on the role of biologic drugs in the treatment strategies for inflammatory arthritis.

Adalimumab efficacy in enteropathic spondyloarthritis: A 12-mo observational multidisciplinary study

AIM To report adalimumab (Ada) efficacy on articular-gastrointestinal disease and health-related quality of life (HRQoL) in patients with enteropathic spondyloarthritis (ES). METHODS A cohort of 52 patients with ES was evaluated in the departments of gastroenterology and internal medicine. At baseline, all patients underwent assessment by an integrated gastro-rheumatologic evaluation of articular and gastrointestinal activity, as well patient reported outcomes (PROs) of the HRQoL questionnaires. After this integrated evaluation and following a specific working flowchart, the Ada anti-tumor necrosis factor (TNF)-inhibitor was assigned to a cohort of 30 patients and its clinical efficacy was evaluated at baseline and after 6-mo and 12-mo treatment by the following tests: (1) Ankylosing Spondylitis Disease Activity Score-C-Reactive Protein (ASDAS-CRP); Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI) for articular activity; (2) Inflammatory Bowel Disease Questionnaire (IBDQ), Crohn’s Disease Activity Index (CDAI) and partial Mayo (pMayo) score for gastrointestinal symptoms and activity; and (3) Health Assessment Questionnaire (HAQ), Patient Global Assessment (PGA) and Short Form-36 health survey (SF-36) questionnaires for PROs of the HRQoL. RESULTS Integrated evaluation and management of the patients affected by ES, carried out simultaneously by a gastroenterologist and a rheumatologist, allowed clinicians to choose the optimal therapeutic strategy. In a cohort of 30 ES patients affected by active articular and gastrointestinal disease, or axial active articular inflammation, Ada led to fast and sustained improvement of both articular and gastrointestinal disease activities. In fact, all the clinimetric evaluation tests exploring articular or gastrointestinal activity, as well as all the HRQoL scores, showed a significant improvement having been achieved at the earliest (6-mo) assessment. This important clinical improvement was maintained at the 12-mo follow-up. Importantly, global and gastrointestinal quality of life significantly correlated with articular disease activity, providing evidence to support that the integrated evaluation is the best option to manage patients with ES. CONCLUSION Ada treatment, upon multidisciplinary (gastro-rheumatologic) evaluation, significantly improves both articular and gastrointestinal inflammation, thereby improving the HRQoL in patients affected by ES.

The DETection of Arthritis in Inflammatory boweL diseases (DETAIL) questionnaire: development and preliminary testing of a new tool to screen patients with inflammatory bowel disease for the presence of spondyloarthritis

To develop and to test in a preliminary way a new self-administered screening tool, called DETection of Arthritis in Inflammatory boweL diseases (DETAIL) questionnaire, in patients suffering from inflammatory bowel disease (IBD) not previously diagnosed as having a spondyloarthritis (SpA). DETAIL questionnaire was realized through the interrogation of 95 experts. They were asked to rate the importance of a list of items, derived from a review of the referral models of SpA, to detect the SpA manifestations in IBD patients. The six top-rated items composed the questionnaire, tested in IBD patients not already diagnosed having a SpA. One-hundred and twenty-eight patients were tested with the DETAIL questionnaire in the gastroenterology setting. After the rheumatologic assessment, in 21 (16.4%) subjects was diagnosed a SpA according to the Assessment of SpondyloArthritis international Society (ASAS) classification criteria. Of the six items of the DETAIL questionnaire, the best positive likelihood ratio (LR+) was found in item 2 (LR+ 3.82), exploring dactylitis, and in item 6 (LR+ 3.82) and item 5 (LR+ 3.40), two questions exploring inflammatory low back pain. Enthesitis (item 3—LR+ 2.87) and peripheral synovitis (item 1 – LR+ 2.81) gave similar results, while item 4, exploring the duration of low back pain, resulted in the worst performance (LR+ 1.99). Three of the six items answered in affirmative way gave a post-test probability ≥ 75%. The presence of a fibromyalgia represents a major confounder. The DETAIL questionnaire showed good screening properties that need to be confirmed in broader cohorts.

Mycophenolate mofetil-induced colitis in a patient with systemic sclerosis

We present the case of a 44-year-old woman affected by systemic sclerosis (SSc) who was admitted to our department for abdominal pain, nausea, vomiting and fever. Imaging studies showed the presence of a thickened colon wall involving the descending colon and the sigma, while a subsequent endoscopy revealed multiple serpiginous ulcers covered with fibrin and exudates. Under the hypothesis of drug-induced colitis, mycophenolate mofetil (MMF), which she was taking for SSc-related interstitial lung disease (ILD), was readily suspended, with a rapid recovery without further treatment. A follow-up colonoscopy showed the complete resolution of the ulcers. This is the first case of MMF-induced colitis in a patient being treated for SSc-ILD.

Biologics in Inflammatory Immune-mediated Systemic Diseases

BACKGROUND The use of biologic agents in systemic immune-mediated diseases has dramatically increased in recent years, replacing conventional immunosuppressive strategies that are characterized by unspecific mechanisms of action and burdened with serious adverse effects. Biologic drugs have selective action towards specific targets, with considerable steroid-sparing effect. They are used nowadays to induce remission or treat specific organ involvements in systemic autoimmune diseases. CONCLUSION In this review, we will discuss the scientific evidence supporting the use of biologics in these diseases, with a particular emphasis on their efficacy and safety profile compared to the conventional drugs.

THU0454 The Multidisciplinary Approach Is The Best Option To Achieve The Improvement of Disease Activity and Quality of Life in Patients Affected by Psoriatic Arthritis: Preliminary Results of A Monocentric Study

Background Psoriatic arthritis (PsA) is a chronic arthritis, included in the spondyloarthritis group, characterized by the coexistence of skin and joint inflammation. The delayed diagnosis and therapy may result in an increased rate of progression of clinical damage, affecting significantly the quality of life (QoL) (1). An integrated clinical examination of PsA patients, carried out by the dermatologist and rheumatologist, is actually considered the optimal approach to manage the PsA disease. Objectives Evaluation of the effect of the multidisciplinary integrated approach, performed by dermatologist and rheumatologist, in: a) the early diagnosis of PsA, and b) the quality of life before and after therapeutic integrated approach. Methods Since January 2015, we examined 145 consecutive patients complaining articular symptoms and/or psoriasis in the outpatient clinics and in the clinical ward of the dermatology and internal medicine departments. Among them, 53 patients were diagnosed as PsA and 21 by psoriasis (Pso). At baseline, after collegial evaluation, the treatment strategy was planned depending on articular activity-involvement (peripheral or axial), systemic inflammation (C-reactive protein, CRP, and erythrocyte-sedimentation rate, ESR, levels), and skin involvement. Moreover, at baseline and after 12-weeks, articular disease was assessed by Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), following ASAS (Assessment of SpondyloArthritis international Society) indications, and skin disease by the Psoriasis Area Severity Index (PASI). QoL was assessed using the Short Form-36 questionnaire (SF-36). Results At baseline, QoL was significantly worse in PsA than Pso patients, as assessed by mean SF-36 (physical component score, PCS, and mental component score, MCS) (Fig.1A). Female patients had significantly worse SF-36 MCS than male patients globally considered (37.4±8.4 vs 46.1±12.3, p=0.03), also in the PsA patients group alone (35.8±8.1 vs 44±13.7, p=0.01). After the integrated evaluation in: a) 33 PsA naïve patients a biological drug was prescribed; b) 3 patients switched to another biological drug; c) 11 patients assuming already a biological drug a synthetic DMARD was added; d) 6 a synthetic DMARD alone was prescribed (Fig. 1, Table I). At 12 weeks, 33 patients had been evaluated at follow-up. It was observed a significant improvement in articular disease as well as skin disease activity (Fig. 1). Consistently, a significant improvement was obtained also in QoL (Fig. 1) and a significant statistical correlation resulted between articular activity and QoL. In fact, a significant correlation between ASDAS-CRP and BASDAI with SF-36 PCS was observed (Fig. 1). Conclusions In our work, we demonstrate that the multidisciplinary treatment and follow-up approach in patients with PsA has achieved a significant and, most importantly, fast improvement in disease activity and patient reported QoL after 12 weeks. Thus this reinforces the importance of a shared choice of the therapy and it encourages further studies to assess the long-term outcomes and feasibility. References Betteridge N. et al. JEADV, 16 Sep2015. Disclosure of Interest None declared

Musculoskeletal and Rheumatic Diseases Induced by Immune Checkpoint Inhibitors: A Review of the Literature

Background: Immune checkpoint inhibitors are a new promising class of antitumor drugs that have been associated with a number of immune-related Adverse Events (AEs), including musculoskeletal and rheumatic disease. Methods: We searched Medline reviewing reports of musculoskeletal and rheumatic AEs induced by immune checkpoint inhibitors. Results: Several musculoskeletal and rheumatic AEs associated with immune checkpoint inhibitors treatment are reported in the literature. In particular, arthralgia and myalgia were the most common reported AEs, whereas the prevalence of arthritis, myositis and vasculitis is less characterized and mainly reported in case series and case reports. Other occasionally described AEs are sicca syndrome, polymyalgia rheumatica, systemic lupus erythematosus and sarcoidosis. Conclusion: Newly induced musculoskeletal and rheumatic diseases are a frequent adverse event associated with immune checkpoint inhibitors treatment

OP0271 Gastrointestinal damage and microbial translocation are involved in the development of immune system activation in inflammatory bowel disease-associated spondyloarthritis

Background The altered composition of the gastrointestinal (GI) microbiota, known as dysbiosis, can induce and modulate the systemic inflammation, through microbial translocation and T-cell activation, in several immuno-mediated diseases, such as inflammatory bowel disease (IBD), HIV infection, and ankylosing spondylitis. Objectives In a cohort of 85 patients with inflammatory bowel disease-associated spondyloarthritis (SpA/IBD), we assessed gut bacterial infiltration and intestinal damage. In systemic circulation, GI epithelial damage, microbial translocation and immune system activation were assessed with intestinal-fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), soluble CD14 (sCD14), respectively. Moreover, the in vitro activity of the latter two was evaluated on osteoblast cells. Methods I-FABP, LPS, sCD14, sclerostin (SOST) and anti-SOST antibodies (anti-SOST-IgG) were assayed with ELISAs. LPS and sCD14 were used in vitro to stimulate the MG63 human osteoblast-like cell line. Occludin, claudin-1, claudin-4, and the presence of bacteria were assessed, respectively, by real-time-PCR analysis and immunohystochemical staining of the ileum. Results Bacteria were detectable in the ileal epithelium of IBD patients, but only in SpA/IBD they were associated with epithelial damage and downregulation of occludin, claudin-1 and claudin-4 (figure 1A-B). The serum levels of I-FABP, LPS and sCD14 resulted significantly higher in axial (187.9, 14.03, and 26.97, respectively) and peripheral SpA/IBD (130.3, 11.55, and 18, respectively) than in IBD patients (IFABP 43.65, p<0.0001 for both patients’ groups; LPS 9.625, p<0.0001 vs Ax-SpA/IBD and=0.007 vs Per-SpA/IBD; sCD14 12.34, p<0.0001 for both patients’ groups) (figure 1C). In the SpA/IBD cohort, SOST was weakly correlated with I-FABP (r=-0.2683), LPS (r=-0.3063) and sCD14 (r=-0.3075), and anti-SOST-IgG with LPS (r=- 0.3959) and sCD14 (r=-0.3414). Moreover, sCD14 showed significant correlation with I-FABP (r=0.3316) and LPS (r=0.5649). In vitro, LPS, but not sCD14, significantly induced SOST expression through the upregulation of both Wnt3a and Wnt5a and the downregulation of the b-catenin proteins (figure 1D). On the opposite, the combination of LPS and sCD14 downregulated SOST expression through the upregulation of ERK1/2 and b-catenin protein (figure 1D).Abstract OP0271 – Figure 1 A. immunoistochemical staining of ileal bacteria. Ten ileal samples of patients affected by SpA/IBD or IBD were stained for bacteria infiltration (upper panel). Lower (from left to right): Gram and LPS staining of the same samples. B. Analysis of ¡leal tight-junctions proteins expression. From the left to the right: Ten ileal samples of patients affected by SpA/IBD or IBD were stained for occludin (and claudin-1 and -4, data not shown); count of occludin positive cells and quantitative real-time-PCR of occludin (and claudin-1 and -4, data not shown) expression in the same ¡leal samples. C. analysls of I-FABP, LPS and sCD14 serum levels in SpA/IBD and IBD patients. ELISAs assays were carried out in 45 patients with axial and 40 patients with peripheral SpA/IBD, and compared with IBD or HC. D. Western-blot analysis of MG-63 osteoblast-cells. The MG-63 osteoblast-like cell line was stimulated with LPS ± sCD14 in vitro and then cells were harvested for western blot analisys. Semi-quantitative densitometric analysis of the protein bands was carried out on the blot (data not shown). Statistical analysis: Kruskal-Wallis analysis. ••p<0.01; ••••p<0.0001; if not reported: p non significant. Abbreviations. SpA/IBD: inflammatory bowel disease-associated spondyloarthritis; ax-SpA/IBD: axial SpA/IBD: peripheral SpA/IBD; IBD: Inflammatory bowel disease; HC: healthy controls; I-FABP: intestinal fatty acid binding protein; LPS: bacterial lypopolysaccaride; sCD14: solubie CD14; ERK 1/2: extracellular Signal-regulated Kinase-1/2. Wnt: wingless protein family: SOST: sclerostin. Conclusions The role of gut inflammation and microbial translocation in the onset of arthritis in IBD patients are still under investigation. We have demonstrated that in SpA/IBD there is a significant bacterial infiltration of the ileal tract, associated with the downregulation of tight-junctions’ proteins (occludin, claudin-1 and claudin-4) and epithelial damage, that cause microbial translocation and higher plasma levels of I-FABP, LPS, and sCD14. LPS and sCD14, thus, could trigger a complex systemic inflammatory response acting on several biochemical pathways, linking the immune system (anti-SOST-IgG) and the bone (SOST). Disclosure of Interest None declared

A painful diagnosis

Dr. Fraticelli: A 53-year-old man was admitted to our department for a 10-day history of widespread limb pain, worsening in the evening and sometimes so excruciating to make him feel faint. These symptoms were not triggered by particular events or behaviors, and not relieved by rest or particular positions. He did not report fever, weight loss, night sweats, joint pain or any other systemic symptom. The patient’s history was of notable complexity. He had been suffering from allergic asthma during his youth. Twenty years before the current evaluation, hypertrophic cardiomyopathy was reported on a routine echocardiography. In the recent years, he also developed a mild arterial hypertension. Two years before admission, the patient had an acute coronary syndrome secondary to a noteworthy three-vessel coronary disease. At that time he was treated only with medical therapy. Later on he had a syncope, consequent with third grade atrio-ventricular blockade, that required the implantation of a pacemaker with ICD. During the stay in the cardiac surgery ward, he developed progressive weakness of lower limbs, with reduction of the tendon reflexes and sensitivity. Basing on the results of electromyography and cerebrospinal fluid analysis, a diagnosis of Guillain–Barrè syndrome was made and a subsequent trial with intravenous immunoglobulin (Ig) infusion (0.4 g/kg/day for 5 days) was successful. One year before presentation, the patient was admitted to our ward for the acute onset of hemoptysis. The physical examination revealed the presence of mild respiratory crackles on auscultation of both lung bases and a mild sensitivity reduction in the lower limbs. The main laboratory findings were an increase in the serum creatinine levels (1.77 mg/dL) and mild hemoglobinuria and proteinuria (1 g/day) on urinalysis. A high-resolution computed tomography (HRCT) of the chest revealed the presence of a ground-glass pattern, suggestive of alveolitis, and the subsequent bronchoscopy with bronchoalveolar lavage showed the presence of hemosiderin-containing macrophages. Globally considered, the findings were suggestive of a systemic vasculitis with multisystem involvement. The presence of high titers of perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) and the pauci-immune glomerulonephritis found on lightmicroscopy examination of the renal biopsy lead to the diagnosis of microscopic polyangiitis (MPA) (Fig. 1). The patient was treated with daily prednisone (starting from 50 mg/day) and one cycle of rituximab (375 mg/m g every week for 4 weeks [1]), followed by mycophenolate mofetil as steroid-sparing long-term treatment, achieving a consistent tapering of the prednisone dose. At the last follow-up, the disease appeared in remission. Ten months before our evaluation, the patient was admitted to the emergency department for a typical chest pain associated with cold sweating. After retrieval of abnormal ECG findings and elevation of cardiac enzymes, the patient underwent a coronary arteriography, which showed worsening of the known three-vessel stenosis. The & Paolo Fraticelli paolo.fraticelli@ospedaliriuniti.marche.it

Widespread painful nodules in a patient with rheumatoid arthritis

A 60-year-old woman affected by rheumatoid arthritis (RA) reported a 12-month history of progressive growth of multiple, painful and symmetrically distributed subcutaneous nodules affecting forearms, thighs and lower back. In the last months the size and the number of nodularities markedly increased, most recently with the appearance of a new lump every other week. These painful swellings had first appeared in the left forearm, with a single lesion progressively increasing in size, but later on similar lesions occurred in the other arm. On examination, multiple, tender and movable subcutaneous nodules with an increased consistency of sizes varying from 0.5–1.8 cm were present on both forearms, thighs and lower back (Fig. 1). The overlying skin did not show any abnormality but pain was evoked upon palpation with light pressure. The patient described the pain as burning, dull and persistent, slightly reduced during the night, ranging from5 to 8/10 on a numeric rating scale in the last week. The histologic examination of a nodule of the left forearm showed only adipose tissue.