ARTHRITIS & RHEUMATISM Vol. 56, No. 3, March 2007, pp 753–764 DOI 10.1002/art.22410 © 2007, American College of Rheumatology Serum Macrophage Inhibitory Cytokine 1 in Rheumatoid Arthritis A Potential Marker of Erosive Joint Destruction David A. Brown, 1 John Moore, 1 Heiko Johnen, 1 Tom J. Smeets, 2 Asne R. Bauskin, 1 Tamara Kuffner, 1 Helen Weedon, 3 Samuel T. Milliken, 1 Paul P. Tak, 2 Malcolm D. Smith, 3 and Samuel N. Breit 1 Objective. The transforming growth factor  su- perfamily member macrophage inhibitory cytokine 1 (MIC-1) is expressed upon macrophage activation, reg- ulated by the p53 pathway, and linked to clinical events in atherosclerosis and cancer. Since rheumatoid ar- thritis (RA) shares similar etiopathologic mechanisms with the above diseases, we sought to determine the clinical utility of determining MIC-1 serum levels and MIC-1 genotype in the management of RA. Methods. Ninety-one RA patients were recruited. Serum was collected from 83 of these patients and synovial biopsy samples were collected from the remain- ing 8 patients. Of the 83 patients from whom serum was collected, 61 were treated on an outpatient basis (de- fined as having nonsevere disease), and 22 patients went on to undergo hemopoietic stem cell transplantation (HSCT) (defined as having severe disease). Results. Serum levels of MIC-1 were higher in RA patients and reflected disease severity independently of classic disease markers. MIC-1 was detected in rheu- matoid synovial specimens, and allelic variation of MIC-1 was associated with earlier erosive disease and severe treatment-resistant chronic RA. Additionally, algorithms including serum and/or allelic variation in MIC-1 predicted response to HSCT, the presence of severe disease, and joint erosions. Conclusion. Determination of serum levels of MIC-1 and MIC-1 genotype may be clinically useful in the management of RA as well as in selection of patients for HSCT, since they predict disease course and re- sponse to therapy. The data indicate a potential role for MIC-1 in RA pathogenesis. These results warrant larger prospective studies to fully delineate and confirm a role for MIC-1 genotyping and serum estimation in patient selection for HSCT and in the management of RA. Rheumatoid arthritis (RA) is a debilitating illness (1) usually presenting with progressive multisystem in- flammatory involvement and having significant morbid- ity and mortality (2). Current therapy aims to curtail joint inflammation and destruction, the latter of which is heralded by the development of joint erosions. However, long-term treatment responses and disease outcomes have been variable, prompting investigation of disease- associated genetic factors. While genetic markers asso- ciate with various disease aspects and serum markers are used to follow disease course, none is capable of pre- dicting the rapidity of onset or progression of joint Supported in part by grants from the National Health and Medical Research Council, Australia, and St. Vincent’s Hospital, Sydney, and by a New South Wales Health Research and Development Infrastructure grant. Dr. Brown is recipient of a National Health and Medical Research Council Neil Hamilton Fairley Fellowship and the SpinalCure Australia Senior Research Fellowship; his work was also funded, in part, by the National Multiple Sclerosis Society (US). 1 David A. Brown, PhD, FRACP, John Moore, MD, FRACP, Heiko Johnen, PhD, Asne R. Bauskin, PhD, Tamara Kuffner, BSc, Samuel T. Milliken, FRACP, Samuel N. Breit, MD, FRACP: St. Vincent’s Hospital and University of New South Wales, Sydney, New South Wales, Australia; 2 Tom J. Smeets, PhD, Paul P. Tak, MD, PhD: University of Amsterdam, Amsterdam, The Netherlands; 3 Helen Weedon, BSc, Malcolm D. Smith, PhD, FRACP: Repatriation Gen- eral Hospital, Adelaide, South Australia, Australia. Drs. Smith and Breit contributed equally to this work. St. Vincent’s Hospital has obtained a patent for an MIC-1 immunoassay, from which royalties might accrue to Drs. Brown and Breit in the future. Address correspondence and reprint requests to Samuel N. Breit, MD, FRACP, Centre for Immunology, St. Vincent’s Hospital and University of New South Wales, Victoria Street, Sydney, New South Wales 2010, Australia. E-mail: S.Breit@cfi.unsw.edu.au. Submitted for publication October 2, 2006; accepted in re- vised form November 9, 2006. 753