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Background:MTX is the first line treatment in early RA. There is robust evidence from cohort studies, but less from RCTs, that a “window of opportunity” exists over 12-16 weeks symptom duration. CR6086 is a selective prostaglandin EP4 receptor antagonist, with an immunomodulatory profile.Objectives:To test efficacy and safety of CR6086 added to MTX in early RA, DMARD-naïve patients.Methods:Patients with RA (ACR/EULAR 2010 criteria), < 1 year from symptom onset and naïve to DMARDs were randomized to oral CR6086 30, 90, 180mg, or placebo bid and oral MTX (20mg weekly) for 13 weeks (NCT03163966). Primary endpoint was the ACR20 response rate: 240 patients were needed to detect a difference among groups, with 50% responders on placebo and 70% on the 90mg CR6086 target dose. Pairwise comparisons of proportions were performed, with nonresponder imputation for withdrawals. A subgroup of patients underwent dynamic contrast-enhanced (DCE) MRI for quantification of synovitis at MCP and wrist joints, evaluated as DEMRIQ-ME and DEMRIQ-vol.Results:The ITT population included all 244 randomized patients receiving at least one dose of study drugs (59 CR6086 30mg/MTX, 60 CR6086 90mg/MTX, 63 CR6086 180mg/MTX, 62 placebo/MTX). Safety was good with no increased rate of infections or other disorders; however, there were more minor upper GI adverse events (AEs) with CR6086, and increased dropouts due to AEs with the 180mg dose (9/63, 14.3% vs 1.7-3.4% in other groups). There were more ACR20 responders with MTX monotherapy than predicted (59.7%) and thus the 10.3% difference with the 90mg target dose (70.0%) was not significant. The low 30mg dose was no better than placebo (55.9%), while the high 180mg dose did not provide additional benefit compared with 90mg (74.0% net of dropouts). CR6086 90mg and 180mg induced a significant improvement in MRI, compared with placebo (Fig. 1). In a post-hoc analysis in patients < 6 months from symptom onset (ACR definition of early RA: 98/244, 40.2%), MTX monotherapy exerted a large 76% ACR20 response rate that precluded potentiation. Conversely, in patients of 6-12 months disease duration (146/244, 59.8%) ACR20 responders were 48.6% with MTX monotherapy vs 68.4% with 90mg, i.e. a 19.8% difference as postulated, with proportional differences in secondary endpoints (Tab. 1).Conclusion:There was no benefit demonstrated for CR6086 added to MTX in the study cohort as a whole. However, in a post-hoc analysis, enhanced responses were observed with CR6086 90mg bid added to MTX in patients >6 months disease duration. This generated the hypothesis that addition of CR6086 90mg bid may benefit in RA patients initiating MTX after the window of opportunity, to be tested in further studies.Table 1.Patient characteristics & pregnancy outcomesSymptom onset (principal analysis)Symptom onset 6-12 months(post-hoc analysis)*Placebo+MTX(N=62)CR6086 90mg+MTX(N=60)Placebo+MTX(N=37)CR6086 90mg+MTX(N=38)ACR20, %59.7%70.0%48.6%68.4%ACR50, %33.9%38.3%29.7%39.5%ACR70, %17.7%23.3%10.8%28.9%DAS28 (CRP) 12.9%20.0%8.1%18.4%CDAI ≤2.8, %8.1%11.7%5.4%15.8%SDAI ≤3.3, %6.5%10.0%2.7%15.8%Boolean-based remission, %6.5%6.7%2.7%10.5%*In patients with symptom onset Figure 1.Change in MRI (DEMRIQ-ME#) after 13 weeksDisclosure of Interests:Karel Pavelka Consultant of: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Speakers bureau: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Ivanova Delina2 Delina: None declared, Minodora Mazur: None declared, Massimo D’Amato Employee of: Rottapharm Biotech, GIAMPAOLO GIACOVELLI Employee of: Rottapharm Biotech, Federica Girolami Employee of: Rottapharm Biotech, Marek Krogulec: None declared, René Østgård: None declared, Asger Reinstrup Bihlet Shareholder of: Nordic Bioscience A/S., Olga Kubassova Shareholder of: IAG, Image Analysis Group, Consultant of: Novartis, Takeda, Lilly, Employee of: IAG, Image Analysis Group, Lucio Rovati Shareholder of: Rottapharm Biotech, Employee of: Rottapharm Biotech, Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB

Multifocal motor neuropathy (MMN) usually progresses insidiously with lower motor neuron-type weakness, minimal or no sensory symptoms. Diagnostic criteria include motor conduction block (CB) at sites not exposed to compression or entrapment. CBs may persist or reverse irrespective of clinical outcome. Acute onset with generalized weakness is uncommon. We report four patients who presented acutely areflexia, pure motor deficits without sensory disturbances, multifocal CBs persisting at the same motor nerves on serial electrophysiological studies. Three patients had preceding infections; two showed IgM reactivity against the ganglioside GM1. Intravenous immuneglobulin (IVIg) improved or stabilized symptoms. Patients 2,3,4 receive maintenance therapy with IVIg for years. Acute-onset MMN (AMMN) should be differentiated from other immune-mediated neuropathies such as acute inflammatory polyneuropathy either demyelinating (AIDP) or axonal (AMAN), acute motor conduction block neuropathy (AMCBN), acute-onset chronic inflammatory demyelinating polyneuropathy (CIDP). The correct diagnosis deserves implications for patient long-term treatment and prognosis. Moreover, the authors address the problem of defining the spectrum of MMN particularly in the acute setting.

A previously healthy 49-year-old woman was admitted with dysarthria, right facio-brachial paresis, and hypesthesia. Brain CT and MRI showed left frontal opercular infarction (figure 1A). Transcranial color-coded duplex sonography did not detect vessel abnormalities but revealed right-to-left shunt (RLSh) (figure 1B). Transesophageal echocardiogram (figure 1C) identified a patent foramen …

A 40-year-old male developed swallowing difficulties, loss of strength, and imbalance. On admission, the patient exhibited bifacial, extremity weakness, ataxia, impaired sensation, and areflexia. Electrophysiology and nerve biopsy suggested demyelination. Spinal fluid revealed increased protein content. Plasmapheresis showed benefit, but neuropathy relapsed. At second recurrence, urine analysis showed heavy proteinuria. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS). Methylprednisolone and oral cyclophosphamide were given. Long-term steroids and immunoglobulin showed steady benefit. Concurrence of chronic inflammatory demyelinating polyneuropathy and FSGS suggests synergistic cellular and humoral autoimmune mechanisms related to either cross-reactivity within antigenic targets or mimicry between neural and renal epitopes.

Dear Editor: Inflammatory bowel diseases (IBD) are chronic disorders encompassing Crohn’s disease (CD) and ulcerative colitis (UC) characterized by abnormal mucosal immune response. Early pathology coincides with intestinal, mesenteric T-cell infiltration, cytokine production, bowel inflammation, and vasculitis. There is evidence that CD4 and CD8 T-cells can trigger autoimmunity when peripherally activated by antigens in a proinflammatory setting. Chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) are caused by immune responses mounted against uncharacterized epitopes. Polyneuropathies associated with IBD exhibit different phenotypes. We studied two patients with CIDP associated with IBD supporting the view of common causality. A 63-year-old woman experienced rectal hemorrhage, acral numbness, and unsteady gait during acute hepatitis. Intestinal biopsy diagnosed CD. Neurologic examination showed absent jerks and distal loss of all sensory modalities. Muscle strength was minimally affected. Normal laboratory results included B12, E vitamin serum level, tumor markers, microbial, and immunological screenings. Sural-evoked responses were either absent or diminished in amplitude with slowed velocity. There were prolonged F wave and distal latencies of median, tibial, and peroneal muscle action potentials. Sural biopsy showed fiber loss and demyelination in 30% of fibers teased. Onion bulbs and mononuclear inflammatory cells were absent. Patient was treated with long-term steroids. On clinical follow-up, her neurological disability progressed in the absence of CD recurrence. Sixteen years after onset, distal strength was graded 3/5, whereas ataxia was marked and distal sensation was severely impaired. Electrophysiology confirmed demyelination. The second patient when aged 33 was diagnosed having UC. Twelve months later, he developed acral paresthesias and extremity weakness graded 3/5 on examination. Deep jerks were unevokable; Romberg sign was positive, and touch and deep sensation was distally impaired. In nerve conduction, there were partial motor conduction block, abnormal temporal dispersion, and diminished velocity along median, ulnar, peroneal, and tibial nerves. Patient refused spinal tap. Treatment with metronidazole was not given. Repeated courses of intravenous immuneglobulins had benefit. Our patients presented common features of moderate distal rather than proximal weakness and ataxia due to proprioceptive sensory loss. Electrophysiology suggested in both ongoing multifocal demyelination, which was histologically proven in case 1. Neurological illness began acutely in patient 1 at CD onset, raising the question of a sensory variant of acute inflammatory demyelinating polyradiculoneuropathy or of CIDP with acute onset. UC of case 2 predated by 12 months his neuropathy, which improved with immunemodulating therapy and ultimately relapsed. Gondim et al. reported seven CIDP cases associated in three with CD and in four with UC: The three CD had more proximal than distal Int J Colorectal Dis (2009) 24:603–604 DOI 10.1007/s00384-009-0646-x