Anaemia May Predict Radiographic Damage in RA
Baseline characteristics of all included patients are listed in Table 1. More than 80% of subsequent consultations were scheduled after approval of TNF-α blocking agents in Switzerland for patients after failure of at least one conventional DMARD. Anti-TNF-α and other DMARD therapies were often intensified after inclusion, and the prevalence of TNF-α inhibitors and second-line biologics progressively reached 35% and 2% of patients, respectively. Use of methotrexate or other conventional DMARDs was registered at least once in 64% and 60% of the patients, respectively, over time.
Patients had a mean of 4.4 haemoglobin assessments over a mean follow-up period of 2.8 years. The mean baseline haemoglobin concentration was 12.7 (SD±1.4 g/dl) in women and 14.0±1.6 g/dl in men. Haemoglobin levels increased by 0.08±0.04 g/dl (p=0.04) after the first year, by 0.14±0.07 g/dl (p=0.06) after the second year, and by 0.16±0.09 g/dl (p=0.077) after the third year. Individual haemoglobin fluctuations in either direction (mean 1.6±1.2 g/dl) were more substantial. Higher haemoglobin concentrations were significantly associated with higher haemoglobin concentrations at baseline (0.04, 95% CI 0.03 to 0.05, p<0.001) and male gender (1.11, 95% CI 1.03 to 1.19, p<0.001), but negatively associated with higher DAS28ESR (−0.20 g/dl, 95% CI −0.23 to −0.18, p<0.001), higher erosion scores (−0.005, 95% CI −0.007 to −0.003, p<0.001), and treatment with non-selective NSAIDs (−0.16, 95% CI −0.20 to −0.12, p<0.001), with or without PPI cotherapy. Haemoglobin levels were not associated with baseline renal or gastrointestinal comorbidity.
Anemia occurred with similar frequency in men and women, oscillating around 24%, before a continuous negative time trend started in 2001 to reach 14.7% in 2007. No anaemia at any visit was found in 69.2% of patients, and persistent anaemia at all visits occurred in 10% of patients.
The annual anaemia incidence rate was 7.6% in 2531 initially non-anaemic patients. Patients with higher baseline DAS28ESR (HR 1.14, 95% CI 1.07 to 1.22, p<0.001), RF positivity (HR 1.49, 95% CI 1.16 to 1.92, p=0.002), registered haematological comorbidity (HR 1.76, 95% CI 1.23 to 2.53, p=0.002) or corticosteroid therapy (HR 1.31, 95% CI 1.03 to 1.67, p=0.028) became significantly more often anaemic. PPI comedication was often used in incident anaemia (HR 2.63, 95% CI 0.97 to 7.14, p=0.057) among patients with non-selective NSAID therapy (HR 1.29, 95% CI 1.06 to 1.57, p=0.013). By contrast, coxibs, gastrointestinal comorbidities or renal comorbidities were not associated with different anaemia incidence. Gastrointestinal toxicities were attributed to NSAIDs in 12 cases, but only one clinically manifest bleeding was reported. Haemoglobin concentrations normalised after a median of 1.3 (IQR: 0.9–3.2) years in 800 initially anaemic patients. Anaemia correction was slower in patients with reported haematological disorder (HR 0.60, 95% CI 0.48 to 0.75, p<0.001) or under non-selective NSAIDs (HR 0.73, 95% CI 0.60 to 0.89, p=0.002), but was accelerated after anti-TNF-α (HR 1.22, 95% CI 1.02 to 1.45, p=0.028) or PPI therapy (HR 7.77, 95% CI 1.86 to 32.39, p=0.005).
Treating rheumatologists reported baseline haematological comorbidity in only 19% of anaemic patients. Indicators of bone marrow insufficiency or other relevant blood cell abnormalities (white blood cell count below 3 g/l and thrombocytopenia below 50 g/l were reported in less than 0.4% or less than 0.2% of all cases, respectively. Reactive elevations in these blood cell counts, platelets ≥400 g/l (3.6%), or leukocytes ≥10 g/l (13.8%) were more frequent. Patient`s treatment with iron, vitamin B12, or erythropoietin was reported in nine, 15 and 14 cases, respectively. Malignancies were reported in 1.3% of all patients.
This relationship was studied in 9731 sets of radiographs from hands and forefeet in 2681 patients, of whom 627 individuals were anaemic at baseline according to WHO definition. The less stringent anaemia definition was fulfilled in 1487 individuals, and 506 patients complied with the definition of 'more severe anaemia'. In crude analyses and after statistical adjustments for potential confounding baseline parameters and the time-dependent DAS28ESR or cDAI, anaemic patients experienced significantly faster radiographic progression (p<0.001) than their non-anaemic counterparts, irrespective of the employed anaemia definition (figure 1). A 'dose-response effect' was suggested by the average 2.0% annual damage progression of the maximal score in WHO-defined anaemic patients versus 1.2% in non-anaemic patients; these values were 1.4% vs 1.1% according to the higher threshold of normal haemoglobin concentrations, but 2.4% vs 1.2% according to the definition of 'more severe anaemia'. Significant baseline determinants of radiographic progression in all these statistical models were baseline erosion scores (mean ~1.0 in all models, p<0.001), gender to the advantage of the male (mean 0.3–0.4%, dependent on the model, p=0.024–0.038), methotrexate therapy (mean 0.2–0.3% p=0.012–0.043), and non-selective NSAID therapy (mean ~0.3% in all models, p=0.013–0.024).
(Enlarge Image)
Figure 1.
Erosive progression over time in all 2681 evaluable rheumatoid arthritis (RA) patients. Progression trajectories were adjusted for differences in patient characteristics at their first x-ray (table 1), (A,C) DAS including the 28-joint count for tender and swollen joints and erythrocyte sedimentation rate (DAS28ESR) or (B,D) clinical disease activity index where indicated, plus anti-inflammatory therapies and covariates of RA severity. Values are mean and 95% CI. Erosion scores progressed significantly faster in patients with anaemia than in non-anaemic RA patients. The kinetics of damage progression accelerated with the grade of anaemia severity. (A and C) For comparison, the lower margin of the shaded area represents mean damage progression in clinical remission (DAS28ESR<2.6), and the upper margin disease progression in patients with high clinical disease activity (DAS28ESR>5.1). Patient numbers at given time points are the same in left (A,C) and right hand figures (B,D).
We obtained similar results as in the total patient population after exclusion of patients with non-selective NSAID therapy (figure 2A,B). Anaemia effects on erosive progression were reproduced in another independently selected patient population with anti-TNF therapy (figure 2C,D). By contrast with mild anaemia, WHO defined and 'more severe anaemia' exhibited similarly significant effects on x-ray progression (p<0.001) in these subgroups. Anaemia effects on radiographic outcome went insignificant after exclusion of all patients with steroid registration, but remained significant in the complementary population (p<0.001, data not shown). Finally, mean joint damage progression was faster in anaemia after selection of patients with DAS28ESR defined remission at their last observation (p=0.026, data not shown).
(Enlarge Image)
Figure 2.
Erosive progression over time was analysed in patients with and without anaemia, (A,B) without NSAID and (C,D) with antitumour necrosis factor-α therapy. Values are mean and 95% CI. The progression of erosions (mean±95% CI) was adjusted for potential confounders (figure 1, table 1). Patient numbers at given time points are the same in left (A,C) and right hand figures (B,D).
Results
Baseline characteristics of all included patients are listed in Table 1. More than 80% of subsequent consultations were scheduled after approval of TNF-α blocking agents in Switzerland for patients after failure of at least one conventional DMARD. Anti-TNF-α and other DMARD therapies were often intensified after inclusion, and the prevalence of TNF-α inhibitors and second-line biologics progressively reached 35% and 2% of patients, respectively. Use of methotrexate or other conventional DMARDs was registered at least once in 64% and 60% of the patients, respectively, over time.
Haemoglobin Concentrations
Patients had a mean of 4.4 haemoglobin assessments over a mean follow-up period of 2.8 years. The mean baseline haemoglobin concentration was 12.7 (SD±1.4 g/dl) in women and 14.0±1.6 g/dl in men. Haemoglobin levels increased by 0.08±0.04 g/dl (p=0.04) after the first year, by 0.14±0.07 g/dl (p=0.06) after the second year, and by 0.16±0.09 g/dl (p=0.077) after the third year. Individual haemoglobin fluctuations in either direction (mean 1.6±1.2 g/dl) were more substantial. Higher haemoglobin concentrations were significantly associated with higher haemoglobin concentrations at baseline (0.04, 95% CI 0.03 to 0.05, p<0.001) and male gender (1.11, 95% CI 1.03 to 1.19, p<0.001), but negatively associated with higher DAS28ESR (−0.20 g/dl, 95% CI −0.23 to −0.18, p<0.001), higher erosion scores (−0.005, 95% CI −0.007 to −0.003, p<0.001), and treatment with non-selective NSAIDs (−0.16, 95% CI −0.20 to −0.12, p<0.001), with or without PPI cotherapy. Haemoglobin levels were not associated with baseline renal or gastrointestinal comorbidity.
Prevalence of Anaemia
Anemia occurred with similar frequency in men and women, oscillating around 24%, before a continuous negative time trend started in 2001 to reach 14.7% in 2007. No anaemia at any visit was found in 69.2% of patients, and persistent anaemia at all visits occurred in 10% of patients.
Incidence and Correction of Anaemia
The annual anaemia incidence rate was 7.6% in 2531 initially non-anaemic patients. Patients with higher baseline DAS28ESR (HR 1.14, 95% CI 1.07 to 1.22, p<0.001), RF positivity (HR 1.49, 95% CI 1.16 to 1.92, p=0.002), registered haematological comorbidity (HR 1.76, 95% CI 1.23 to 2.53, p=0.002) or corticosteroid therapy (HR 1.31, 95% CI 1.03 to 1.67, p=0.028) became significantly more often anaemic. PPI comedication was often used in incident anaemia (HR 2.63, 95% CI 0.97 to 7.14, p=0.057) among patients with non-selective NSAID therapy (HR 1.29, 95% CI 1.06 to 1.57, p=0.013). By contrast, coxibs, gastrointestinal comorbidities or renal comorbidities were not associated with different anaemia incidence. Gastrointestinal toxicities were attributed to NSAIDs in 12 cases, but only one clinically manifest bleeding was reported. Haemoglobin concentrations normalised after a median of 1.3 (IQR: 0.9–3.2) years in 800 initially anaemic patients. Anaemia correction was slower in patients with reported haematological disorder (HR 0.60, 95% CI 0.48 to 0.75, p<0.001) or under non-selective NSAIDs (HR 0.73, 95% CI 0.60 to 0.89, p=0.002), but was accelerated after anti-TNF-α (HR 1.22, 95% CI 1.02 to 1.45, p=0.028) or PPI therapy (HR 7.77, 95% CI 1.86 to 32.39, p=0.005).
Reporting of Anaemia and Haematological Comorbidities
Treating rheumatologists reported baseline haematological comorbidity in only 19% of anaemic patients. Indicators of bone marrow insufficiency or other relevant blood cell abnormalities (white blood cell count below 3 g/l and thrombocytopenia below 50 g/l were reported in less than 0.4% or less than 0.2% of all cases, respectively. Reactive elevations in these blood cell counts, platelets ≥400 g/l (3.6%), or leukocytes ≥10 g/l (13.8%) were more frequent. Patient`s treatment with iron, vitamin B12, or erythropoietin was reported in nine, 15 and 14 cases, respectively. Malignancies were reported in 1.3% of all patients.
Anaemia and Erosions
This relationship was studied in 9731 sets of radiographs from hands and forefeet in 2681 patients, of whom 627 individuals were anaemic at baseline according to WHO definition. The less stringent anaemia definition was fulfilled in 1487 individuals, and 506 patients complied with the definition of 'more severe anaemia'. In crude analyses and after statistical adjustments for potential confounding baseline parameters and the time-dependent DAS28ESR or cDAI, anaemic patients experienced significantly faster radiographic progression (p<0.001) than their non-anaemic counterparts, irrespective of the employed anaemia definition (figure 1). A 'dose-response effect' was suggested by the average 2.0% annual damage progression of the maximal score in WHO-defined anaemic patients versus 1.2% in non-anaemic patients; these values were 1.4% vs 1.1% according to the higher threshold of normal haemoglobin concentrations, but 2.4% vs 1.2% according to the definition of 'more severe anaemia'. Significant baseline determinants of radiographic progression in all these statistical models were baseline erosion scores (mean ~1.0 in all models, p<0.001), gender to the advantage of the male (mean 0.3–0.4%, dependent on the model, p=0.024–0.038), methotrexate therapy (mean 0.2–0.3% p=0.012–0.043), and non-selective NSAID therapy (mean ~0.3% in all models, p=0.013–0.024).
(Enlarge Image)
Figure 1.
Erosive progression over time in all 2681 evaluable rheumatoid arthritis (RA) patients. Progression trajectories were adjusted for differences in patient characteristics at their first x-ray (table 1), (A,C) DAS including the 28-joint count for tender and swollen joints and erythrocyte sedimentation rate (DAS28ESR) or (B,D) clinical disease activity index where indicated, plus anti-inflammatory therapies and covariates of RA severity. Values are mean and 95% CI. Erosion scores progressed significantly faster in patients with anaemia than in non-anaemic RA patients. The kinetics of damage progression accelerated with the grade of anaemia severity. (A and C) For comparison, the lower margin of the shaded area represents mean damage progression in clinical remission (DAS28ESR<2.6), and the upper margin disease progression in patients with high clinical disease activity (DAS28ESR>5.1). Patient numbers at given time points are the same in left (A,C) and right hand figures (B,D).
Subgroup Analyses
We obtained similar results as in the total patient population after exclusion of patients with non-selective NSAID therapy (figure 2A,B). Anaemia effects on erosive progression were reproduced in another independently selected patient population with anti-TNF therapy (figure 2C,D). By contrast with mild anaemia, WHO defined and 'more severe anaemia' exhibited similarly significant effects on x-ray progression (p<0.001) in these subgroups. Anaemia effects on radiographic outcome went insignificant after exclusion of all patients with steroid registration, but remained significant in the complementary population (p<0.001, data not shown). Finally, mean joint damage progression was faster in anaemia after selection of patients with DAS28ESR defined remission at their last observation (p=0.026, data not shown).
(Enlarge Image)
Figure 2.
Erosive progression over time was analysed in patients with and without anaemia, (A,B) without NSAID and (C,D) with antitumour necrosis factor-α therapy. Values are mean and 95% CI. The progression of erosions (mean±95% CI) was adjusted for potential confounders (figure 1, table 1). Patient numbers at given time points are the same in left (A,C) and right hand figures (B,D).