Rheumatoid arthritis (RA) is a multifactorial, inflammatory and progressive autoimmune disease, most commonly found in people between the ages of 45 and 55, which mainly affects the joints, although it can also affect other parts of the body. It begins with a destruction of the synovial membrane that covers the joints causing an inflammatory condition that can end up damaging nearby structures such as bones, ligaments and tendons. As a consequence of this degenerative process the patient presents a progressive deformity of the joints and a reduction of joint mobility, which in many cases leads to a limitation in the development of some tasks of daily life. Due to this degenerative process, the establishment of effective therapies as soon as possible is essential to control inflammation, prevent deterioration, functional disability and, as a whole, slow down the progression of the disease.

The preclinical period of RA is characterized by immune dysregulation and a diffuse inflammatory picture without typical disease manifestations. During this period, the classical laboratory tests; Rheumatoid Factor (RF), with a sensitivity of 65-80% and a specificity of 85%, and Antibodies to Citrullinated Peptides (ACPA), with a sensitivity of 60-80% and specificity of 95-98%, may be negative, which highlights the need to find new biomarkers that allow diagnosing the disease at the earliest possible stage.

Multiple studies have revealed that the genetic contribution in RA ranges from 30% to 60%. This high percentage indicates that genetic studies are essential in order to identify those at risk for RA, as well as to initiate appropriate preventive measures, including pharmacological, dietary and lifestyle modifications as necessary. For all those cases without genetic contribution, between 40-70% of patients, protein biomarkers are considered the most interesting option.

The understanding of the genetic susceptibility and pathogenic mechanisms underlying RA has greatly improved in recent years thanks to the development of Next-generation Sequencing (NGS) technologies and whole-genome whole genome studies. These studies have uncovered more than 100 genetic loci associated with increased RA risk, establishing 98 genes that could potentially contribute to RA onset. HLA and some non-HLA genes have been linked to the development of antibodies against citrullinated peptides, allowing differentiation between ACPA-seropositive and ACPA-seronegative patients. However, the study of ACPA-negative RA patients over the years has been challenging. In fact, it has been suggested that ACPA-seronegative RA may be heterogeneous with respect to genetics and related pathogenic mechanisms.

For all these reasons, RA currently needs the arrival of new biomarkers in clinical practice. new biomarkers into clinical practice. Classical diagnostic approaches based on single parameters have shown enormous limitations in most diseases. Only the specific characteristics of some disorders, such as diabetes, allow these approaches to remain valid. Most diseases are complex processes that, in order to understand them, require a more global and ambitious approach based on the study of differential expression at the gene level and at the protein level. In the specific case of RA, the analysis of gene and protein panels can be of great help in establishing an early diagnosis, as well as in providing a more complete picture of the disease and the pathways involved.