Network-Based In Silico Analysis of New Combinations of Modern Drug Targets with Methotrexate for Response-Based Treatment of Rheumatoid Arthritis

Abstract

Background: Methotrexate (MTX), sulfonamides, hydroxychloroquine, and leflunomide have consistently resulted in remission with relatively mild to moderate adverse effects in patients with rheumatoid arthritis (RA). Modern medications outperform traditional treatments in that they target the pathological processes that underlie the development of RA.

Methods: Following PRISMA guidelines, the authors accomplished a systematic review of the clinical efficacy of RA drugs, including the biologics such as Tumor Necrosis Factor-alpha inhibitors (TNF-α i) like Etanercept, Infliximab, Golimumab, and Adalimumab, kinase inhibitors (JAK inhibitors including Baricitinib and Tofacitanib), SyK inhibitors like Fos-tamatinib, MAPK inhibitors such as Talmapimod, T-cell inhibitors (Abatacept), IL6 blockers (Tocilizumab), and B cells depleters (Rituximab). These drugs have been found to increase remission rates when combined with MTX. A bioinformatics-based network was designed applying STRING-MODEL and the DrugBank database for the aforementioned drugs and MTX and, finally, employed for this systematic review.

Results: Current research demonstrates that non-TNF-α inhibitor biologicals are particularly helpful in treating patients who did not respond well to conventional medications and TNF-α inhibitors. Despite being effective, these innovative drugs have a higher chance of producing hazardous side effects. The in silico investigations suggested an uncovered molecular interaction in combining MTX with other biological drugs. The STRING-MODEL showed that DHFR, TYMS, and ATIC, as the receptors of MTX, interact with each other but are not connected to the major interacted receptors.

Conclusions: New game-changing drugs including Mavrilimumab, Iguratimod, Upadacitinib, Fenebrutinib, and nanoparticles may be crucial in controlling symptoms in poorly managed RA patients. Emerging therapeutic targets like Toll-like 4 receptors, NLRP3 inflammasome complexes, and mesenchymal stem cells can further transform RA therapy.

Keywords: DMARDS; Inflammatory arthritis; JAK inhibitors; Rheumatoid arthritis; TLR4 receptor inhibition; new targeted therapy.

Figure 1

The PRISMA diagram of Rheumatoid Arthritis (RA) treatment in the current systematic study that represents the final included 236 related papers. Reason 1 was due to the lack of covering MTX in combination with other drugs; Reason 2 was the repeated reports; and Reason 3 was the papers with unclear results.

Figure 2

Rheumatoid Arthritis (RA) treatment strategies including first-line treatment Methotrexate (MTX) and Nonsteroidal anti-inflammatory drugs (NSAIDs) such as acetylsalicylate (Aspirin), naproxen (Naprosyn), ibuprofen (Advil and Motrin), and etodolac which are instances of fast-acting medications; the second-line treatment disease-modifying anti-rheumatic drugs (DMARDs) such as hydroxychloroquine, and sulfasalazine; biologic medications in combination with MTX like etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol, anakinra, and rituximab; new drugs such as mavrilimumab, iguratimod, upadacitinib, and fenebrutinib; Toll-like receptors (TLRs); nucleotide-binding domain and leucine-rich repeat pyrin containing protein-3 (NLRP3) inflammasome; and finally, mesenchymal stem cells (MSCs).

Figure 3

Shown are second-line treatments of Rheumatoid Arthritis (RA) by administrating MTX (MTX) in combination with other medications such as etanercept, infliximab, golimumab, adalimumab, bariceritinib, tofacitanib, fostamatinib, talmapimod, abatacept, tocilizumab, rituximab, certolizumab, and upadacitinib.

Figure 4

The new network was found by bioinformatics analyses based on DrugBank data and STRING-MODEL. The network illustrates the protein-coding targets of all MTX and other drugs in combination with MTX, including TYMS, ATIC, DHFR, TNF, LTA, FCGR1A, FCGR2A, FCGR2B, FCGR2C, FCGR3A, FCGR3B, JAK1, JAK2, JAK3, TYK2, SYK, MAPK14, CD80, CD86, IL6R, and MS4A1 genes. The question mark in the arrow refers to the unknown relationship of MTX with a combination of other drugs in this network.