A Cross-Sectional and Longitudinal Study to Define Alarmins and A-SAA Variants as Companion Markers in Early Rheumatoid Arthritis

Abstract

Nowadays, in the study of rheumatoid arthritis (RA), more and more interest is directed towards an earlier effective therapeutic intervention and the determination of companion markers for predicting response to therapy with the goal to prevent progressive joint damage, deformities, and functional disability. With the present work, we aimed at quantifying in a cohort of early RA (ERA) patients naïve to DMARD therapy, proteins whose increase was previously found associated with RA: serum amyloid A (A-SAA) and alarmins. Five A-SAA variants (SAA1α, SAA1β, SAA1γ, SAA2α, and SAA2β) but also S100A8 and S100A9 proteins were simultaneously quantified in plasma applying a method based on single targeted bottom-up proteomics LC-MS/MS. First, we compared their expression between ERA (n = 100) and healthy subjects (n = 100), then we focused on their trend by monitoring ERA patients naïve to DMARD treatment, 1 year after starting therapy. Only SAA1α and SAA2α levels were increased in ERA patients, and SAA2α appears to mostly mediate the pathological role of A-SAA. Levels of these variants, together with SAA1β, only decreased under biologic DMARD treatment but not under methotrexate monotherapy. This study highlights the importance to better understand the modulation of expression of these variants in ERA in order to subsequently better characterize their biological function. On the other hand, alarmin expression increased in ERA compared to controls but remained elevated after 12 months of methotrexate or biologic treatment. The work overcomes the concept of considering these proteins as biomarkers for diagnosis, demonstrating that SAA1α, SAA1β, and SAA2α variants but also S100A8 and S100A9 do not respond to all early treatment in ERA and should be rather considered as companion markers useful to improve the follow-up of treatment response and remission state. Moreover, it suggests that earlier use of biologics in addition to methotrexate may be worth considering.

The potential role of serum amyloid A as biomarker of rheumatic diseases: a systematic review and meta-analysis

“…Eighteen studies were conducted in Asia [ 41 , 42 , 44 – 46 , 48 , 50 , 55 , 57 , 59 – 61 , 65 – 69 , 72 ], six in Europe [ 52 – 54 , 58 , 62 , 64 ], five in America [ 47 , 49 , 51 , 56 , 70 ], two in Africa [ 63 , 71 ], and one in Oceania [ 43 ]. Thirteen study comparators included patients with RA [ 42 , 43 , 47 , 49 , 52 , 55 , 56 , 63 , 65 , 67 , 71 ], five with SLE [ 45 , 46 , 55 , 58 ], five with FMF [ 53 , 57 , 59 , 60 , 66 ], three with Takayasu arteritis (TA) [ 48 , 61 , 69 ], two with AS [ 44 , 68 ], two with SSc [ 54 , 62 ], two with osteoarthritis (OA) [ 52 , 55 ], one with BD [ 41 ], one with Henoch–Schönlein purpura (HSP) [ 50 ], one with spondylarthritis (SpA) [ 51 ], one with polymyalgia rheumatica (PMR) [ 64 ], one with PsA [ 70 ], and one with gout [ 72 ]. Mean RD duration was reported in 14 studies and ranged between 2.7 and 21.7 years [ 43 ...…”

“…The risk of bias was considered low in 25 studies [ 42 – 50 , 52 , 56 – 63 , 65 , 66 , 68 – 72 ] and moderate in the remaining seven [ 41 , 51 , 53 – 55 , 64 , 67 ] (Supplementary Table 2).…”

“…Five studies reported the ROC analysis of the diagnostic accuracy of SAA concentrations for RDs [ 57 , 59 , 65 , 67 , 68 ]. A de novo ROC analysis was conducted using data from two additional studies [ 54 , 63 ].…”

“…Sensitivity and specificity were extracted from these seven studies (nine comparator groups) which investigated a total of 910 participants (649 RD patients and 308 healthy controls, 68% females, mean age 41 years) (Table 2 ). Five studies were conducted in Asia [ 57 , 59 , 65 , 67 , 68 ], one in Europe [ 54 ], and one in Africa [ 63 ]. Five comparator groups included individuals with RA [ 63 , 65 , 67 ], two with FMF [ 57 , 59 ], one with SSc [ 54 ], and one with AS [ 68 ].…”

Association between Serum Amyloid A Level and White Matter Hyperintensity Burden: a Cross-Sectional Analysis in Patients with Acute Ischemic Stroke

“…In a recently published study, SAA was revealed as a novel independent predictor of infection after stroke [12]. Epidemiologic studies have demonstrated robust associations of elevated SAA with increased risk of atherosclerosis, rheumatoid arthritis, chronic obstructive pulmonary disease, and tumor [13][14][15][16]. Studies have further linked higher SAA levels to Alzheimer's dementia and cardiovascular disease, implying that endothelial dysfunction is a primary cause of disease [17][18][19][20].…”