We describe the impact of α4-β1/7 blockade with natalizumab, a recombinant humanised immunoglobulin (Ig) G4κ monoclonal antibody (mAb) targeted to the α4 subunit of the α4β1 and α4β7 integrins, on the gut and spine inflammation in a patient with ankylosing spondylitis (AS) who developed multiple sclerosis after treatment with tumour necrosis factor (TNF)-blocking agents. A 45-year-old man with human leucocyte antigen (HLA)-B27-positive AS was admitted in January 2007. He had been diagnosed with AS 4 years earlier based on the presence of inflammatory back pain, peripheral arthritis, radiographic bilateral grade 2 sacroiliitis, HLA-B27 positivity. At that time, he had evidence of chronic intestinal inflammation upon histological evaluation of the gut. He was treated with adalimumab for 2 years, achieving a good clinical response. In March 2009, MRI of the brain was performed for the occurrence of paresthesias affecting his left arm and intermittent diplopia, revealing multiple encephalic demyelinating lesions. A diagnosis of multiple sclerosis was made, adalimumab discontinued and treatment with interferon beta-1α and pulse intravenous steroid started. Because of the presence of acute relapses and progression of disability, in September 2009, natalizumab was initiated. At that time, inflammatory low back pain and peripheral arthritis (six swollen joints) were also present and the patient had a C-reactive protein (CRP) level of 26mg/L, with a disease activity evaluated by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 1 of 6.4. A complete remission of neurological symptoms with normalisation of CRP levels (2 mg/L), and a significant improvement of inflammatory lower back pain and the disappearance of peripheral arthritis (BASDAI 2) was obtained after 6 months of natalizumab therapy. Remission of neurological and rheumatological symptoms was persistently maintained over 6 years. During natalizumab therapy, the patient reported only the use of on-demand analgesics. In January 2016, radiographic re-evaluation of the spine and a new ileocolonoscopy were performed, showing complete remission of gut inflammation (figure 1A, B) without any significant progression of spinal disease on both conventional X-rays and MRI (figure 1C–F). α4β7 integrin heterodimer expressed by lymphoid cells and its cognate ligand MAdCAM1 expressed by gut epithelial cells have been shown to attract and immobilise cells coming from the systemic circulation to the gut. 2 α4β7+ and MAdCAM1 have been also demonstrated to be overexpressed in the gut and the inflamed bone marrow of AS patients and potentially involved in the re-circulation, from the gut to the AS inflamed extraintestinal sites, of pro-inflammatory interleukin (IL)-17-and IL-22-producing α4β7+ group 3 innate lymphoid cells. 3

Blockade of α4β1–7 integrins inhibits the ability of lymphocytes to bind to endothelial receptors, thus preventing their migration into the inflamed tissues4 5 and being effective in the treatment of human inflammatory disorders such as multiple sclerosis6 and Crohn’s disease. 7 Here we provide the first demonstration of the clinical efficacy of natalizumab in a patient with AS. Furthermore, although no histological resolution of gut inflammation has been demonstrated in AS patients over time, 8 a significant amelioration of intestinal inflammation was observed in our patient. In light of this information, α4β7 targeted agents may become an alternative option at least for AS patients for whom TNF blockers are not indicated.