BACKGROUND AND PURPOSEExcess morbidity/mortality in rheumatoid arthritis (RA) is associated with increased incidence of cardiovascular disease. In this ‘proof-of-concept’ study, vascular function was characterized in the murine collagen-induced arthritis (mCIA) model, the benchmark choice for evaluation of the pathological processes and assessment of new therapies.EXPERIMENTAL APPROACHMice in the very early stages of arthritis development [and appropriate naïve (non-immunized) age-matched controls] were used in the study. Blood pressure was measured using tail cuff plethysmography. Vascular function in rings of isolated aorta was studied with isometric tension myography. Levels of NO metabolites (NOx), MMP-9 protein and IL-1β in plasma and MMP-9 protein in aortic homogenates were quantified.KEY RESULTSImpaired vascular contractile responses in arthritis were unaffected by ex vivo inhibition of NOS (endothelial/neuronal and inducible) or COX activities. Endothelium-dependent and -independent relaxation, plasma NOx and blood pressure were unaffected by arthritis. Plasma and aortic homogenate MMP-9 protein levels were increased significantly in arthritis. Incubation of aortic tissues from naïve control animals with exogenous MMP-9 impaired subsequent contractile responses, mirroring that observed in arthritis. A role for IL-1β in perpetuating contractile dysfunction and increasing aortic MMP-9 was excluded.CONCLUSIONS AND IMPLICATIONSThese data identify for the first time a relationship between early arthritis and contractile dysfunction and a possible role for MMP-9 therein, in the absence of overt endothelial dysfunction or increased NO production. As such, MMP-9 may constitute a significant target for early intervention in RA patients with a view to decreasing risk of cardiovascular disease.

IntroductionThe first few months after symptom onset represents a pathologically distinct phase in rheumatoid arthritis (RA). We used relevant experimental models to define the pathological role of interferon-γ (IFN-γ) during early inflammatory arthritis.MethodsWe studied IFN-γ's capacity to modulate interleukin-1β (IL-1β) induced degenerative responses using RA fibroblast-like synoviocytes (FLS), a bovine articular cartilage explant (BACE)/RA-FLS co-culture model and an experimental inflammatory arthritis model (murine antigen-induced arthritis (AIA)).ResultsIFN-γ modulated IL-1β driven matrix metalloproteinases (MMP) synthesis resulting in the down-regulation of MMP-1 and MMP-3 production in vitro. IFN-γ did not affect IL-1β induced tissue inhibitor of metalloproteinase-1 (TIMP-1) production by RA FLS but skewed the MMP/TIMP-1 balance sufficiently to attenuate glycosaminoglycan-depletion in our BACE model. IFN-γ reduced IL-1β expression in the arthritic joint and prevented cartilage degeneration on Day 3 of AIA.ConclusionsEarly therapeutic intervention with IFN-γ may be critical to orchestrate tissue-protective responses during inflammatory arthritis.

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Fig 2: Immunohistological pictures:(a) Dense diffuse dermal infiltrate consisting of large histiocytes and multinucleated giant cells showing eosinophilic 'ground glass appearance';(b) diastase resistant granules in the cytoplasm (c) Positive CD68 immunohistochemical stain (brown colour) in the macrophages (d) Positive CD45 immunohistochemical stain (brown colour) in the macrophages Author contributionsAuthor 1-Omowunmi Ashaolu-Writing-original draft preparation, review and editing.

A 47-year-old printer presented in December 2004 with a 1-month history of progressive swelling of the left hand, forearm, and elbow associated with rash. This began with a single pustular lesion at the tip of the 5th finger, later evolving to several similar, closely related lesions (Fig 1) After 2 weeks, he developed 2 well-demarcated erythematous plaques with overlying desquamation on the left forearm. Diffuse swelling of the left hand began around that time, predominantly over the metacarpo-phalangeal joints and extensor tendons, associated with mild desquamation and tenderness. He also had olecranon bursitis and 2 0.5 ϫ 0.5 cm nodular swellings in a linear distribution in the medial upper arm (Figs. 2 and 3). His predominant symptom was unrelenting stiffness, and he was unable to grip or make a fist. Treatment in the community with erythromycin and diclofenac for 2 weeks had not produced any benefit. He had a paternal history of ankylosing spondylitis but had never experienced peripheral joint symptoms previously, and he did not have any history of psoriasis or gastrointestinal disease. Initial investigation revealed mild normocytic anemia ͓Hb 11.5 g/dL (12-17.5)͔ and elevated inflammatory markers ͓CRP 31.6 mg/L, (5-10) ESR 30 mm/h (1-9)͔ but no leukocytosis. Blood cultures were negative on repeated sampling and X-rays of the affected limb were normal. After closer questioning, it transpired that he kept tropical fish, one of which had died 2 months before his symptoms commenced, and that he had cleaned the fish tank around this time. A small amount of straw-colored fluid was aspirated from the olecranon bursa, but pus was obtained from the distal forearm lesion and acid-fast bacilli demonstrated on Ziehl Nielsen (ZN) staining, later classified as Mycobacterium marinum.