Clinical Review

Insights and Implications of the VA Rheumatoid Arthritis Registry

Fed Pract. 2015 May;32(5):24-29

References

1. Banerjee S, Compton AP, Hooker RS, et al. Cardiovascular outcomes in male veterans with rheumatoid arthritis. Am J Cardiol. 2008;101(8):1201-1205.

2. Weyand CM, Schmidt D, Wagner U, Goronzy JJ. The influence of sex on the phenotype of rheumatoid arthritis. Arthritis Rheum. 1998;41(5):817-822.

3. Mikuls TR, Fay BT, Michaud K, et al. Associations of disease activity and treatments with mortality in men with rheumatoid arthritis: results from the VARA registry. Rheumatol (Oxford). 2011;50(1):101-109.

4. Baker JF, Billig E, Cannon GW, Caplan L, Majithia V, Mikuls TR. Weight loss and risk of death in rheumatoid arthritis [abstract 1391]. Arthritis Rheumatol. 2014;66(suppl 10):S613-S614.

5. Choi HK, Hernán MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002;359(9313):1173-1177.

6. Kerr G, Aujero M, Richards J, et al. Associations of hydroxychloroquine use with lipid profiles in rheumatoid arthritis: pharmacologic implications. Arthritis Care Res (Hoboken). 2014;66(11):1619-1626.

7. Wasko MC, Hubert HB, Lingala VB, et al. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA. 2007;298(2):187-193.

8. Saag KG, Teng GG, Patkar NM, et al; American College of Rheumatology. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59(6):762-784.

9. Michaud K, Mikuls TR, Call SE, et al. Poor to modest agreement between rheumatoid arthritis response measures in clinical practice. Clin Exp Rheumatol. 2009;27(4):633-640.

10. Shahouri SH, Michaud K, Mikuls TR, et al. Remission of rheumatoid arthritis in clinical practice: application of the American College of Rheumatology/European League Against Rheumatism 2011 remission criteria. Arthritis Rheum. 2011;63(11):3204-3215.

11. Shaver TS, Anderson JD, Weidensaul DN, et al. The problem of rheumatoid arthritis disease activity and remission in clinical practice. J Rheumatol. 2008;35(6):1015-1022.

12. Masri KR, Shaver TS, Shahouri SH, et al. Validity and reliability problems with patient global as a component of the ACR/EULAR remission criteria as used in clinical practice. J Rheumatol. 2012;39(6):1139-1145.

13. Aletaha D, Landewe R, Karonitsch T, et al. Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations. Ann Rheum Dis. 2008;67(10):1360-1364.

14. Gregersen PK, Amos CI, Lee AT, et al. REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis. Nat Genet. 2009;41(7):820-823.

15. Briggs FB, Ramsay PP, Madden E, et al. Supervised machine learning and logistic regression identifies novel epistatic risk factors with PTPN22 for rheumatoid arthritis. Genes Immun. 2010;11(3):199-208.

16. Mikuls TR, Gould KA, Bynoté KK, et al. Anticitrullinated protein antibody (ACPA) in rheumatoid arthritis: influence of an interaction between HLA-DRB1 shared epitope and a deletion polymorphism in glutathione S-transferase in a cross-sectional study. Arthritis Res Ther. 2010;12(6):R213.

17. Sokolove J, Johnson DS, Lahey LJ, et al. Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis. Arthritis Rheumatol. 2014;66(4):813-821.

18. Kerr GS, Sabahi I, Richards JS, et al. Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J Rheumatol. 2011;38(1):53-59.

19. Mikuls TR, LeVan TD, Sayles H, et al. Soluble CD14 and CD14 polymorphisms in rheumatoid arthritis. J Rheumatol. 2011;38(12):2509-2516.

20. Dwivedi N, Upadhyay J, Neeli I, et al. Felty’s syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps. Arthritis Rheum. 2012;64(4):982-992.

21. Harlow L, Rosas IO, Gochuico BR, et al. Identification of citrullinated hsp90 isoforms as novel autoantigens in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheum. 2013;65(4):869-879.

22. Cannon GW, Mikuls TR, Hayden CL, et al. Merging Veterans Affairs rheumatoid arthritis registry and pharmacy data to assess methotrexate adherence and disease activity in clinical practice. Arthritis Care Res (Hoboken). 2011;63(12):1680-1690.

23. Mikuls TR, Padala PR, Sayles HR, et al. Prospective study of posttraumatic stress disorder and disease activity outcomes in US veterans with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2013;65(2):227-234.

24. Sokolove J, Sayles H, Wagner CA, et al. Smoking status is associated with inflammatory cytokine profile and disease activity: decreased inflammation and disease improvement with smoking cessation? [abstract 348]. Arthritis Rheumatol. 2014;66(suppl 10):S146.

25. Criswell LA, Merlino LA, Cerhan JR, et al. Cigarette smoking and the risk of rheumatoid arthritis among postmenopausal women: results from the Iowa Women’s Health Study. Am J Med. 2002;112(6):465-471.

26. Hecht C, Englbrecht M, Rech J, et al. Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA [published online ahead of print August 12, 2014]. Ann Rheum Dis. doi: 10.1136/annrheumdis -2014-205428.

27. Cannon GW, DuVall SL, Haroldsen CL, et al. Persistence and dose escalation of tumor necrosis factor inhibitors in US veterans with rheumatoid arthritis. J Rheumatol. 2014;41(10):1935-1943.

28. Curtis JR, Baddley JW, Yang S, et al. Derivation and preliminary validation of an administrative claims-based algorithm for the effectiveness of medications for rheumatoid arthritis. Arthritis Res Ther. 2011;13(5):R155.

29. Caplan L, Davis LA, Bright CM, et al. Body mass index and the rheumatoid arthritis swollen joint count: an observational study. Arthritis Care Res (Hoboken). 2013;65(1):101-106.

30. Davis LA, Whitfield E, Cannon GW, et al. Association of rheumatoid arthritis susceptibility gene with lipid profiles in patients with rheumatoid arthritis. Rheumatology (Oxford). 2014;53(6):1014-1021.

31. Mikuls TR, Kazi S, Cipher D, et al. The association of race and ethnicity with disease expression in male US veterans with rheumatoid arthritis. J Rheumatol. 2007;34(7):1480-1484.

32. Miriovsky BJ, Michaud K, Thiele GM, et al. Anti-CCP antibody and rheumatoid factor concentrations predict greater disease activity in men with rheumatoid arthritis. Ann Rheum Dis. 2010;69(7):1292-1297.

33. Oei HB, Hooker RS, Cipher DJ, Reimold A. High rates of stopping or switching biological medications in veterans with rheumatoid arthritis. Clin Exp Rheumatol. 2009;27(6):926-934.

34. Richards JS, Peng J, Amdur RL, et al. Dual-energy X-ray absorptiometry and evaluation of the osteoporosis self-assessment tool in men with rheumatoid arthritis. J Clin Densitom. 2009;12(4):434-440.

35. Richards JS, Cannon GW, Hayden CL, et al. Adherence with bisphosphonate therapy in US veterans with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(12):1864-1870.

In contrast to oral prednisone use, which is associated with increased mortality risk, the use of methotrexate (MTX), the most commonly prescribed disease-modifying drug in RA, was associated with about a 40% reduction in all-cause mortality.³ This finding was consistent with data from other groups demonstrating that MTX use, alone or in combination with other treatments, is associated with substantial reductions in RA-related mortality, a benefit that seems to result from a robust cardioprotective effect in this population.⁵ Indeed, prior examinations of a VARA subpopulation revealed high rates of major acute coronary events during observation, a risk that was higher with increased disease activity.¹ Studies are now underway in non-RA patients to examine the effectiveness of MTX in secondary cardiovascular disease prevention.

Although not associated with a reduced mortality risk in a previous study, hydroxychloroquine (HCQ) seems to be associated with favorable changes in lipid profiles.³The VARA participants using HCQ were far more likely to achieve target lipid goals than were participants not using HCQ, including total cholesterol to high-density lipoprotein cholesterol (HDL-C) ratio and HDL-C to low-density lipoprotein cholesterol ratio.⁶ Importantly, these lipid changes appeared soon after HCQ initiation but were lost within 1 year of discontinuation. These results, coupled with data from separate groups suggesting that HCQ may also improve insulin resistance and even prevent the onset of diabetes, suggest that HCQ could play an important adjuvant treatment role by reducing cardiovascular morbidity in RA.⁷

Measurement Pitfalls

Proposed best practices in RA management increasingly call for the adoption of a “treat-to-target” approach, with the goal of achieving and maintaining patients in a state of low disease activity or remission.⁸ Although this strategy receives broad endorsement, its routine implementation is limited in the absence of a single universally accepted method for quantifying disease activity or assessing treatment response in the clinical setting. Indeed, several different measures of RA disease activity have been proposed, including at least 1 that was developed by VARA investigators.⁹

In a prior study, only poor to modest agreement was found among various proposed measures of treatment response and similar differences among the many proposed definitions of clinical remission.^9-11 Moreover, important limitations with the validity and reliability of the patient global health assessment in clinical practice was observed. This reflected, at least in part, the contributions of many non-RA factors to its value.¹² This is important, because the patient global health assessment is common to several composite disease activity measures, including remission criteria published by both the ACR and European League Against Rheumatism.¹³

RA Risk Factors

As part of a large collaborative consortium, VARA has been instrumental in studies examining risk factors for developing RA. These efforts have included reports of novel genetic risk factors in addition to others highlighting the importance of both gene-gene and gene-environment interactions in disease susceptibility.^14-16Among existing literature, these reports inform future efforts to further the understanding of RA pathogenesis in addition to those working to identify methods of risk stratification and disease prevention.

Disease Activity and Severity

The VARA has served as an important resource for studies examining biomarkers and other predictive factors in RA. In addition to serving as important diagnostic tools in the clinic, a recent report highlighted the potential synergistic role of RF and anti-CCP antibody in promoting disease inflammation.¹⁷ In this study, patients who were positive for both autoantibodies had much higher disease activity compared with sero-negative patients or individuals with just 1 positive autoantibody. Likewise, patients who were positive for both RF and anti-CCP had higher serum concentrations of CRP and several proinflammatory cytokines than did patients who were sero-negative or who had only 1 positive autoantibody.

In vitro studies done in parallel corroborated these observations, demonstrating for the first time that anticitrullinated protein antibody (ACPA)-containing immune complexes stimulated macrophage production of cytokines, which was further enhanced in the presence of RF. Other biomarkers investigated have included 25-hydroxy vitamin D, soluble forms of CD14 and autoantibodies to deiminated histones, neutrophil extracellular traps, and citrullinated heat shock protein.^18-21

Of high relevance to the VA, VARA has demonstrated robust associations of treatment noncompliance, posttraumatic stress disorder (PTSD), and cigarette smoking with worse RA outcomes.^22-24 In a longitudinal study of about 1,500 VARA enrollees, PTSD was independently associated with higher pain levels, tender joint counts, and self-reported disability in addition to worse patient global well-being.²³ In contrast, PTSD demonstrated no associations with measures more commonly attributed to ongoing inflammation, including swollen joint counts, ESR, or DAS-28 scores. In addition to demonstrating associations of PTSD with a more severe RA course, these findings suggest that the higher disease burden observed in patients with comorbid PTSD may be attributable to noninflammatory factors that may call for management strategies beyond disease-modifying therapies.