Predictive risk factors before the onset of familial rheumatoid arthritis: the Tatarstan cohort study

Abstract

Background: A familial history of rheumatoid arthritis (RA) predisposes an individual to develop RA. This study aimed at investigating factors associated with this conversion from the Tatarstan cohort.

Methods: A total of 144 individuals, referred to as pre-RA and at risk for familial RA, were selected 2 years (range: 2-21 years) before conversion to RA and compared to non-converted 328 first-degree relatives (FDR) from RA as assessed after ≥2 years follow-up, and 355 healthy controls were also selected (HC). Preclinical parameters and socio-demographic/individual/HLA genetic factors were analyzed when data were available at the time of enrollment.

Results: As compared to FDR and HC groups, pre-RA individuals were characterized before conversion to RA by the presence of arthralgia, severe morning symptoms, a lower educational level, and rural location. An association with the HLA-DRB1 SE risk factor was also retrieved with symmetrical arthralgia and passive smoking. On the contrary, alcohol consumption and childlessness in women were protective and associated with the HLA-DRB1^*07:01 locus.

Conclusion: Before RA onset, a combination of individual and genetic factors characterized those who are at risk of progressing to RA among those with familial RA relatives.

Keywords: childless; familial rheumatoid arthritis; low education; risk factors; shared epitope; symmetrical arthralgia.

Figure 1

Clinical spectrum at the inclusion visit in the Tatarstan cohort of healthy controls (HC, n = 355) and rheumatoid arthritis (RA) relatives. Later being dichotomized according to their progression into RA (pre-RA, n = 144) or as FDR when no evolution was reported during the ≥2 years follow-up. (A) Prevalence of the 11 RA-associated clinical criteria, see Section 2 for details. FDR individuals were further subdivided according to their clinically suspected arthralgia (CSA) score. (B, C) odds ratio (OR) and significant p-values (in blue when 0.01 < p < 0.05, and in red p < 0.01 corresponding to the post-hoc adapted threshold) for the occurrence of the clinical criteria when pre-RA individuals were compared to HC (B) or compared to FDR (C). (D) Radar plot comparing clinical criteria between pre-RA individuals and FDR according to their CSA status.

Figure 2

Socio-demographic and individual behavioral factors to compare healthy controls (HC) and relatives from rheumatoid arthritis (RA) patients having evolved (pre-RA) or not (FDR) to RA. (A) Prevalence of the eight factors in the subgroups, see Section 2 for details. FDR was further subdivided according to their clinically suspected arthralgia (CSA) score. (B, C) Odds ratio (OR) and significant p-values (in blue when 0.01 < p < 0.05, and in red p < 0.01 corresponding to the post-hoc adapted threshold) for the occurrence of the individual criteria when pre-RA individuals were tested against HC (B) or against FDR (C). (D) Radar plot comparing individual criteria between pre-RA relatives and FDR according to their CSA status.

Figure 3

HLA A/B/C/DQB1 and DRB1 allele distribution among relatives from rheumatoid arthritis (RA) patients having evolved to RA (pre-RA) or not (FDR), and from healthy controls (HC). (A) Manhattan plot for the log10 (p-value) for each HLA allele and HLA-DQRB1 shared epitope (SE) between pre-RA and controls (red), FDR and controls (blue), and pre-RA and FDR (green). The dotted lines represent the significant p-values using an adapted threshold with a post-hoc false discovery rate approach (p = 0.01) or not (p = 0.05). (B) Allele frequency of HLA-B*35:01, HLA-DRB1 SE, and HLA-DRB1*07:01 among HC, FDR, and pre-RA individuals. (C) Odds ratio (OR) showing the genetic effect of HLA-B*35:01, HLA-DRB1 SE, and HLA-DRB1*07:01 between HC and pre-RA (red) or FDR (blue). The p-values are indicated when significant.

Figure 4

Interplay between the HLA-DRB1 shared epitope (SE) and HLA-DRB1*07:01 genetic factors and rheumatoid arthritis (RA)-associated factors in relatives from RA patients according to their evolution to RA (pre-RA) or not (FDR). (A) Prevalence of the 11 RA-associated clinical criteria according to their HLA-DRB1 shared epitope (SE) and HLA-DRB1*07:01 status in pre-RA and FDR. (B) HLA-DRB1 SE (red) and HLA-DRB1*07:01 (blue) influenced eight RA-associated risk factors to discriminate pre-RA from FDR. Data are represented as log10 (p-value) with a significant threshold fixed at p = 0.05. (C) Prevalence of the RA-associated individual factors. (D) HLA-DRB1 SE (red) and HLA-DRB1*07:01 (blue) influenced RA-associated individual factors to discriminate pre-RA from FDR.