Rheumatoid arthritis (RA) treatment and management guidelines [7, 8] recommend starting treatment with conventional synthetic disease-modifying anti-rheumatic monotherapy (csDMARD) such as hydroxychloroquine, leflunomide, methotrexate or sulfasalazine.

Today, methotrexate (MTX) is the most widely used disease-modifying antirheumatic drug (DMARD) and the first to be “chosen” [1,2] for its efficacy, safety and cost [3.6] in the therapeutic management of Rheumatoid Arthritis (RA).

The European League Against Rheumatism (EULAR) [8] and their current guidelines for the treatment of RA define as a therapeutic goal the achievement of remission or, if remission is not possible, the achievement of low disease activity (LDA).

Unfortunately, from the DREAM register, only 6% of patients have obtained remission as defined by the criteria of the American College of Rheumatology (ACR) and EULAR; while 27% of patients instead achieved a Disease Activity Score (DAS28) of less than 2.6, a less rigorous goal of complete remission as it still allows for the existence of some residual disease activity [9].

If the treatment goal is not achieved through monotherapy, guidelines recommend switching to combination therapy with multiple conventional drugs or biologic targeted therapies – such as anti-TNF or Janus kinase inhibitors (JAK) – associated with methotrexate, where possible [7, 8].

Following these recommendations, it appears that approximately 25% of patients manage to achieve remission with initial monotherapy with methotrexate or glucocorticoids within 6 months, while another 25% only achieve the LDA. [1]

In total, therefore, only 1 in 2 patients respond correctly to methotrexate. The other half of the patient is forced to interrupt treatment due to ineffectiveness or adverse events and therefore switch to the use of biological drugs, generally with equally heterogeneous responses [5].

This is the case with anti-TNF drugs which, although they represent the main reserve treatment (96% of patients who fail methotrexate therapy are treated with an anti-TNF drug), in 65% of cases they do not produce the desired effects. [47]

Comprehensive classification of patient populations unresponsive to anti-TNF therapy is important for a better understanding of the disease mechanism and is critical to finding the most effective therapies for such individuals. Patients who do not respond to anti-TNFs (non-responders) can be classified into two groups of patients: those who are primary non-responders and those who initially respond but then show a loss of efficacy in response.

Primary non-responders may or may not show an initial response, but never reach their anti-TNF treatment goal. If these patients do not respond correctly to anti-TNF therapy, this is unlikely to happen for other anti-TNFs as well: this is due to the fact that the chronic inflammation caused by their disease is not sufficiently driven by TNF-α dependent biological processes.

Conversely, after an initial loss of response to one anti-TNF, switching to another anti-TNF may restore progress toward the treatment goal [1, 60]. Therefore, even if two drugs are both anti-TNF or have the same active ingredient, they do not necessarily have the same effect on the patient.

The RA population is very heterogeneous and the development of symptoms of the disease depends on a variety of genetic factors (particular susceptibility genes such as HLA-DRB1) and environmental factors (smoking, obesity, alterations in the microbiome of the mouth and intestine).

Being able to predict the initial response to medications has been a major challenge in managing rheumatoid arthritis for over twenty years [12] and is a good example of the increasingly interesting concept of personalized therapy, namely the choice of the most beneficial drug (tailored) for a particular patient.

This would be of enormous advantage, because identifying the patients least prone to the response of a given drug (e.g. methotrexate) would avoid unnecessary exposure to potentially toxic therapies, constituting a turning point to prevent and / or reduce the development of structural damage in years [13].

In recent times, we are seeing more and more the possibility of generating a turnaround. For example, by analyzing the transcriptome (RNA) of the synovium tissue – the main site of inflammation – it was possible to observe how the synovial membrane is different from patient to patient in terms of cells and molecules contained within it.

Taking into account that each drug acts on a different cell or molecule, such an analysis would make it possible to predict in advance the patient’s reaction to a specific drug. Through an in-depth study of the transcriptomic profile of the individual patient, it would therefore be possible to determine an ad hoc drug therapy, patient by patient and case by case.


7.   Kremer JM, Genovese MC, Cannon GW, Caldwell JR, Cush JJ, Furst DE, Luggen ME, Keystone E,            Weisman MH, Bensen WM, Kaine JL, Ruderman EM, Coleman P, Curtis DL, Kopp EJ, Kantor SM,            Waltuck J, Lindsley HB, Markenson JA, Strand V, Crawford B, Fernando I, Simpson K, Bathon JM:          concomitant therapy with leflunomide in patients with active rheumatoid arthritis despite stable                doses of methotrexate. A randomized, double-blind, placebo-controlled study. Ann Intern Med.                  2002, 137: 726-733.
8.   Mourao AF, Fonseca JE, Canhao H, Santos MJ, Bernardo A, Cordeiro A, Cravo AR, Ribeiro A,                     Teixeira A, Barcelos A, Malcata A, Faustino A, Duarte C, Ribeiro C, Nour D, Araujo D, Sousa E,                   Ramos F, Vinagre F, Ventura FS, Sequeira G, Santos H, Branco JC, Gomes JA, Silva JA, Ramos J,               Santo JE, Costa JA, Silva JA, et al
3. Kinder AJ, Hassell AB, Brand J, Brownfield A, Grove M, Shadforth MF: Treatment of inflammatory          arthritis with methotrexate in clinical practice: duration of treatment and incidence of adverse drug          reactions. Rheumatology (Oxford). 2005, 44: 61-66. 10.1093 / rheumatology / keh512.
6. Fonseca JE, Viana Queiroz M: Study of the efficacy, tolerance and acceptability of the treatment of            rheumatoid arthritis with methotrexate – experience of the last 10 years. CIAR Bulletin. 1997, 83-88.
5. Maetzel A, Wong A, Strand V, Tugwell P, Wells G, Bombardier C: Meta-analysis of treatment                      discontinuation rates among rheumatoid arthritis patients receiving disease-modifying anti-                        rheumatic   drugs. Rheumatology (Oxford). 2000, 39: 975-981. 10.1093 / rheumatology / 39.9.975.

1. Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, Kavanaugh A, McInnes IB,           Solomon DH, Strand V, Yamamoto K (2018) rheumatoid arthritis. Nat Rev Dis Primers 4: 18001
13.Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS,                       Weisman Emery P, Feldmann M, Harriman GR, Maini RN, Trial Anti-Tumor Necrosis Factor in                 rheumatoid arthritis with concomitant Therapy Study Group (2000) Infliximab and methotrexate in         the treatment of rheumatoid arthritis. Study of the anticancer necrosis factor in rheumatoid arthritis        with concomitant therapy study group. N Engl J Med 343 (22): 1594-1602
47.Curtis JR, Zhang J, Xie F, Beukelman T, Chen L, Fernandes J, Ginsberg S, Spettell C, Yun H, Saag             KG, Schiff M (2014) Use of oral and subcutaneous methotrexate in patients with rheumatoid arthritis       in the United States United. Arthritis Care Res 66 (11): 1604-1611
60. Wei W, Knapp K, Wang L, Chen CI, Craig GL, Ferguson K, Schwartzman S (2017) Persistence of                 treatment and clinical outcomes of tumor necrosis factor inhibitor cycling or switching to a new                 therapy mechanism d action: real-world observational study of rheumatoid arthritis patients in the          United States with prior therapy with tumor necrosis factor inhibitors. Adv Ther 34 (8): 1936–1952

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