Disease Information

General Information of the Disease (ID: DIS00332)

• Name: Rheumatoid arthritis
• ICD: ICD-11: FA20

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 13 drug(s) in total

Azathioprine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C5 (ABCC5) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Azathioprine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Betamethasone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Betamethasone
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Celecoxib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Celecoxib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Chloroquine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Chloroquine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Dexamethasone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dexamethasone
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Hydrocortisone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Hydrocortisone
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Indomethacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Indomethacin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Leflunomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Leflunomide
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Mutation; p.P151S+p.R175H+p.G245C+p.R282W
• Resistant Drug: Leflunomide
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The wild-type p53 tumor suppressor (p53) is overexpressed in response to DNA damage and inflammation in RA fibroblast-like synoviocytes (FLS), which are highly specialized mesenchymal cells located in the internal lining of the synovium and are involved in the pathogenesis and progression of RA. In line with the effects of p53 gain-of-function mutation in tumor progression, mutation-mediated gain-of-function of p53 may contribute to the invasiveness and apoptosis-resistant feature of FLS in RA and the increased expression of cartilage degradative proteases, leading to degeneration of cartilage and bone. Gene knockout or gene transfer studies using a collagen-II-induced arthritis (CIA) model have established the crucial role of p53 in RA that provides a basis for additional research to fully characterize the clinical implications of p53 somatic mutations in drug-resistant RA.

Methotrexate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Methotrexate
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Mutation; p.P151S+p.R175H+p.G245C+p.R282W
• Resistant Drug: Methotrexate
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The wild-type p53 tumor suppressor (p53) is overexpressed in response to DNA damage and inflammation in RA fibroblast-like synoviocytes (FLS), which are highly specialized mesenchymal cells located in the internal lining of the synovium and are involved in the pathogenesis and progression of RA. In line with the effects of p53 gain-of-function mutation in tumor progression, mutation-mediated gain-of-function of p53 may contribute to the invasiveness and apoptosis-resistant feature of FLS in RA and the increased expression of cartilage degradative proteases, leading to degeneration of cartilage and bone. Gene knockout or gene transfer studies using a collagen-II-induced arthritis (CIA) model have established the crucial role of p53 in RA that provides a basis for additional research to fully characterize the clinical implications of p53 somatic mutations in drug-resistant RA.

Methylprednisolone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Methylprednisolone
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Prednisone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Prednisone
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Sulfasalazine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sulfasalazine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Valdecoxib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Prostaglandin G/H synthase 2 (Cox-2) [2]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Function; Inhibition
• Resistant Drug: Valdecoxib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vivo Model: Standard diet fed male C57BL/6J (B6) mouse model; HFD fed male C57BL/6J (B6) mouse model; Mus musculus
• Experiment for Molecule Alteration: Enzyme linked immunosorbent assay; Western blotting analysis
• Mechanism Description: Valdecoxib improves lipid-induced skeletal muscle insulin resistance via simultaneous suppression of inflammation and endoplasmic reticulum stress.

Investigative Drug(s) 2 drug(s) in total

Bucillamine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Bucillamine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Lipopolysaccharide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Maternally expressed 3 (MEG3) [3]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Down-regulation; Interaction
• Resistant Drug: Lipopolysaccharide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Regulation; hsa04150
• In Vitro Model: Rat chondrocyte isolates; N.A.; .; N.A.
• In Vivo Model: Male SD rat model; Rattus norvegicus
• Experiment for Molecule Alteration: Overexpression assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA MEG3 inhibits rheumatoid arthritis through miR-141 and inactivation of AKT/mTOR signalling pathway.

References

• Ref 1: Drug-resistance in rheumatoid arthritis: the role of p53 gene mutations, ABC family transporters and personal factors .Curr Opin Pharmacol. 2020 Oct;54:59-71. doi: 10.1016/j.coph.2020.08.002. Epub 2020 Sep 14. 10.1016/j.coph.2020.08.002
• Ref 2: Valdecoxib improves lipid-induced skeletal muscle insulin resistance via simultaneous suppression of inflammation and endoplasmic reticulum stress .Biochem Pharmacol. 2021 Jun;188:114557. doi: 10.1016/j.bcp.2021.114557. Epub 2021 Apr 18. 10.1016/j.bcp.2021.114557
• Ref 3: LncRNA MEG3 contributes to adenosine-induced cytotoxicity in hepatoma HepG2 cells by downregulated ILF3 and autophagy inhibition via regulation PI3K-AKT-mTOR and beclin-1 signaling pathwayJ Cell Biochem. 2019 Oct;120(10):18172-18185. doi: 10.1002/jcb.29123. Epub 2019 May 29.