Complement activation in hidradenitis suppurativa: a new pathway of pathogenesis?

BACKGROUND: Despite the heavy purulence observed in hidradenitis suppurativa (HS), the kinetics of complement anaphylatoxins acting to prime chemotaxis of neutrophils has not been studied. OBJECTIVES: To explore complement activation in HS. METHODS: Circulating concentrations of complement factor C5a, as well as of membrane attack complex C5b-9, were determined in the plasma of 54 treatment-naïve patients and of 14 healthy controls, as well as in the pus of seven patients. Results were correlated with Hurley stage and International Hidradenitis Suppurativa Severity Score. Peripheral blood mononuclear cells (PBMCs) were isolated from seven patients with Hurley stage III HS and seven healthy volunteers and stimulated in the presence of 25% of plasma for the production of tumour necrosis factor-α (TNF-α). RESULTS: Circulating C5a and C5b-9 were significantly greater in patient than in control plasma; however, concentrations in pus were very low. Circulating C5a levels exceeding 28 ng mL-1 were associated with a specificity > 90% with the occurrence of HS. Circulating levels of C5a and C5b-9 were greater in patients with more severe HS. PBMCs of patients produced high concentrations of TNF-α only when growth medium was enriched with patient plasma; this was reversed with the addition of the C5a blocker IFX-1. CONCLUSIONS: Systemic complement activation occurs in HS and may be used as a surrogate biomarker of HS. C5a stimulates overproduction of TNF-α and may be a future therapeutic target.

Effect of mitoxantrone on MRI in progressive MS: results of the MIMS trial.

OBJECTIVE: To evaluate the effects of mitoxantrone (Mx) in progressive multiple sclerosis (MS) on MRI. METHODS: A total of 194 patients with worsening relapsing-remitting or secondary progressive MS were treated with Mx 12 mg/m2 (n = 34), Mx 5 mg/m2 (n = 40), or placebo (n = 36) at 3-month intervals IV over a 2-year period. In preselected MRI centers unenhanced and Gd-enhanced MRI scans were performed at month (M) 0, 12, and 24 in a non-randomized subset of 110 patients and non-selected for MRI criteria. The primary MRI outcome measure was the total number of MRI scans with positive Gd enhancement per group. RESULTS: Twelve mg/m2 Mx failed to reach a significant difference from placebo as measured by the primary MRI outcome at month 12 (p = 0.431) and 24 (p = 0.065). Secondary MRI outcome measures: 5 mg/m2 Mx influenced favorably the number of Gd-enhancing lesions only at month 24 (p = 0.004), but not at month 12 (p = 0.095). Twelve mg/m2 Mx reduced the number of T2-weighted lesions at month 24 (p = 0.027) and showed a positive trend at month 12 (p = 0.069), but not 5 mg/m2 Mx. The number of active MR lesions showed a strong trend toward reduction in the 12 mg/m2 Mx group only at month 24 (p = 0.054). All comparisons are vs placebo, and unadjusted for baseline incidence. CONCLUSIONS: In the MIMS trial 12 mg/m2 Mx does not reduce the number of MRI scans with positive Gd enhancement at month 12 and 24 vs placebo. Results of secondary MRI outcome measures are suggestive of a positive impact of 12 and 5 mg/m2 Mx on some of the Gd enhanced and unenhanced MRI measures as expected from other Mx MRI studies in the past.