Anaemia to predict radiographic progression in Rheumatoid Arthritis
The severity of rheumatoid arthritis (RA) is highly variable between patients and currently known risk factors explain only part of this variance.(1) Much research is dedicated to identify additional new risk factors. Such factors may shed light on the processes underlying progression of RA and many risk factors together may enable risk stratification and individualized treatment of RA.
With interest we read the study by Moller et al, showing that RA- patients with anaemia have more severe radiological progression.(2) Although anaemia in RA is generally considered to be a consequence of chronic inflammation, this recent study -based on RA patients included in the Swiss SCQM-database- observed that the association between anaemia and joint damage was independent of the association between disease activity (measured with the DAS28ESR and cDAI) and joint damage. This led to the presumptions that anaemia in RA captures disease processes that are unmeasured by established disease activity markers (e.g. subclinical inflammation) and that evaluation of the haemoglobin level may help to identify patients with rapid radiological progression.
Since in science replication of findings is relevant to ascertain the validity, we evaluated the association between anaemia at first presentation and disease severity over 7 years in 676 early RA patients included in the Leiden Early Arthritis Clinic.(1) Two outcome measures were studied. First, radiological progression; 3502 sets of hand and feet radiographs were made with yearly intervals and scored according to the Sharp-van-der-Heijde method by one reader (ICC 0.91).(3) Second, disease persistency was assessed by evaluating its counterpart, achieving DMARD- free sustained remission.(4) Analyses were done using multivariate normal regression analysis and cox regression.(5) All analyses were adjusted for age, gender and treatment strategy.(1) The haemoglobin level was determined at first presentation. The WHO definitions for the presence and severity of anaemia were used.(6)
24.1% of the RA-patients had anaemia at first presentation. These patients were older and had a higher swollen joint count (SJC), ESR and CRP (Table 1). Patients with anaemia had more severe joint damage progression (beta 1.03, p 0.012, indicating a 1.03 higher rate of joint destruction per year, which equals 1.037= 23% more joint damage after 7 years). Similar to M?ller et al, we also adjusted for ESR, SJC and RF; this did not affect the association (beta 1.03, p 0.040) (Figure 1A). When evaluating the three haemoglobin categories a "dose-dependent" effect was observed (beta 1.03, p 0.002). Also this association was significant after adjusting for ESR, SJC and RF (beta 1.02, p 0.032) (Figure 1B). All analyses remained significant when the CRP was included as covariate instead of the ESR (data not shown).(7) Patients with anaemia tended to achieve DMARD-free remission less often than patients without anaemia (HR 0.57, 95% CI 0.34-0.95, p 0.031), also after adjusting for ESR, SJC and RF (HR 0.59, 95% CI 0.34-1.02, p 0.056) (Figure 1C).
Analysis on this population-based inception cohort revealed that within RA anaemia is independently associated with radiographic progression. As clinical inflammation in RA may predominantly affect the feet,(8) we evaluated a 66-SJC that -in contrast tot the DAS28ESR and cDAI used by Moller et al- included the MTP-joints. Nonetheless, also we observed that anaemia independently predicted disease severity. This may indicate that anaemia indeed reflects subclinical inflammation. Future studies are required to unravel this association.
Table 1 Characteristics of RA patients per haemoglobin category. Table available on the monthly Epage.
Figure 1. Joint destruction (Sharp-van der Heijde scores) and DMARD- free sustained remission curves over 7 years follow-up in RA patients, categorized according to the presence (A, C) or severity (B) of anaemia. Figure available on the monthly Epage.
(1) de Rooy DP, van der Linden MP, Knevel R, et al. Predicting arthritis outcomes--what can be learned from the Leiden Early Arthritis Clinic? Rheumatology (Oxford) 2011;50:93-100.
(2) Möller B, Scherer A, Forger F, et al. Anaemia may add information to standardised disease activity assessment to predict radiographic damage in rheumatoid arthritis: a prospective cohort study. Ann Rheum Dis Published Online First: 16 March 2013. doi:10.1136/annrheumdis-2012-202709
(3) Knevel R, Krabben A, Brouwer E, et al. Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study. Ann Rheum Dis 2012;71:1651-7.
(4) van der Woude D, Young A, Jayakumar K, et al. Prevalence of and predictive factors for sustained disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: results from two large early arthritis cohorts. Arthritis Rheum 2009;60:2262-71.
(5) Knevel R, Tsonaka R, Cessie SL, et al. Comparison of methodologies for analysing the progression of joint destruction in rheumatoid arthritis. Scand J Rheumatol Published Online First: 20 February 2013. doi:10.3109/03009742.2012.7286182013
(6) WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. Geneva, World Health Organization, 2011 (WHO/NMH/NHD/MNM/11.1) (http://www/who.int/vmnis/indicators/haemoglobin.pdf, accessed [March 2013]).
(7) Wells G, Becker JC, Teng J, et al. Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis 2009;68:954-60.
(8) Knevel R, Kwok KY, de Rooy DP, et al. Evaluating joint destruction in rheumatoid arthritis: is it necessary to radiograph both hands and feet? Ann Rheum Dis 2013;72:345-9.
Conflict of Interest: