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. 2018 Mar 1;20:39. doi: 10.1186/s13075-018-1537-8

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© The Author(s). 2018

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Fig. 9 — Histological data related to arthritic mice treated with CR6086, methotrexate (MTX), and their combination. Collagen-induced arthritis (CIA) mice, recruited upon arthritis onset, were treated with test drugs for 16 days. CR6086 was administered orally once daily, whereas MTX was administered intraperitoneally every third day. a Multiple histological scores of the paws after repeated administration of CR6086, MTX, and their combination. Scores were calculated as summed scores of all the paws under the protocol described in the Methods section of the main text. Data were plotted as box-and-whisker plots. ^bP < 0.001, ^cP < 0.01, ^dP < 0.05 vs vehicle-treated mice by Kruskal-Wallis test followed by two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli. b Representative photomicrographs of the paws after repeated administration of CR6086, MTX, and their combination in arthritic mice. Only some representative features are pointed out in the following images. Arrowhead: pannus; arrow: damaged cartilage; asterisk: diffuse inflammation. Elliptic marker (0): osteolysis. (1) Hind paw of vehicle control shows all signs of rheumatoid arthritis (RA): cartilage degeneration (arrows); pannus formation (arrowhead); osteolysis (0) and inflammatory infiltrate (asterisk). (2) Hind paw from an arthritic animal treated with MTX 1 mg/kg displays all the signs of RA, such as cartilage degeneration (arrows), pannus formation (arrowhead), osteolysis (0) and inflammatory infiltrate (asterisk). Some features, such as woven bone formation and synovial thickening, are not clearly visible at this order of magnification. (3) Hind paw from an arthritic animal treated with MTX 3 mg/kg still displays pannus formation (arrowhead) and cartilage damage (arrows). Moderate inflammation (asterisk) and osteolysis (0) can also be observed. (4) Hind paw from an arthritic animal treated with CR6086 30 mg/kg. Only few articular joints display minor degeneration (not visible at this magnification); few sites of moderate inflammation (asterisk) are present, and moderate pannus formation sites (arrowhead) can be seen. (5) Hind paw from an arthritic animal treated with CR6086 30 mg/kg + MTX 1 mg/kg displays only minor cartilage degeneration. Very sporadic cases of pannus formation (arrowhead) can be observed. (6) Hind paw from an arthritic animal treated with CR6086 30 mg/kg + MTX 3 mg/kg shows almost no visible RA features at this magnification