Biologics-Based Therapy for the Treatment of Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) remains a major clinical problem, but treatments involving biologics have revolutionized its management. They target pathogenically relevant cytokines such as tumor necrosis factor and immune cells such as B cells. In RA, biologics reduce joint inflammation, limit erosive damage, decrease disability, and improve quality of life. Infections are the main risk associated with their use. Because of the high prices of biologics, their cost-effectiveness is a matter of debate. They are mainly coadministered with disease-modifying drugs such as methotrexate when the latter are found to achieve insufficient disease control on their own.

Designing Anti-inflammatory Drugs from Parasitic Worms: A Synthetic Small Molecule Analogue of the Acanthocheilonema viteae Product ES-62 Prevents Development of Collagen-Induced Arthritis

“…11a (see Figure A) and 12b both mimicked ES-62 in targeting IL-12p40 production via each of TLR2, 4, and 9, and this cytokine is pathogenic in CIA due to it being a component of both IL-12p70 and IL-23, which promote Th1 and Th17 responses, respectively, and hence a therapeutic target (ustekinumab) in inflammatory autoimmune diseases. , By contrast, sulfonamide 21l and carboxamide 24b did not target LPS- and BLP-mediated IL-12p40 responses, respectively. Sulfone 11a additionally targeted IL-6 production (see also Figure B) in response to all three TLRs (although this did not reach statistical significance for TLR2 in all experiments), and this cytokine has also been shown to be pathogenic and thus a therapeutic target (tocilizumab) in RA . Although sulfone 12b could suppress CpG-mediated IL-6 responses, it was less effective at inhibiting such TLR2- or TLR4-coupled responses (decreases not reaching statistical significance), which have been shown to be important in the development of inflammatory Th17 responses, including those in arthritis. − Moreover, as observed with ES-62, , ( 11a (Figure C), but not 21l (results not shown), was able to inhibit TLR-mediated p65 NF-κB activation in response to all three PAMPs.…”

“…Sulfone 11a additionally targeted IL-6 production (see also Figure 3B) in response to all three TLRs (although this did not reach statistical significance for TLR2 in all experiments), and this cytokine has also been shown to be pathogenic 44 and thus a therapeutic target (tocilizumab) in RA. 45 Although sulfone 12b could suppress CpG-mediated IL-6 responses, it was less effective at inhibiting such TLR2- or TLR4-coupled responses (decreases not reaching statistical significance), which have been shown to be important in the development of inflammatory Th17 responses, including those in arthritis. 46−48 Moreover, as observed with ES-62, 40,49 ( 11a (Figure 3C), but not 21l (results not shown), was able to inhibit TLR-mediated p65 NF-κB activation in response to all three PAMPs.…”

Designing Anti-inflammatory Drugs from Parasitic Worms: A Synthetic Small Molecule Analogue of the Acanthocheilonema viteae Product ES-62 Prevents Development of Collagen-Induced Arthritis

“…11a (see Figure A) and 12b both mimicked ES-62 in targeting IL-12p40 production via each of TLR2, 4, and 9, and this cytokine is pathogenic in CIA due to it being a component of both IL-12p70 and IL-23, which promote Th1 and Th17 responses, respectively, and hence a therapeutic target (ustekinumab) in inflammatory autoimmune diseases. , By contrast, sulfonamide 21l and carboxamide 24b did not target LPS- and BLP-mediated IL-12p40 responses, respectively. Sulfone 11a additionally targeted IL-6 production (see also Figure B) in response to all three TLRs (although this did not reach statistical significance for TLR2 in all experiments), and this cytokine has also been shown to be pathogenic and thus a therapeutic target (tocilizumab) in RA . Although sulfone 12b could suppress CpG-mediated IL-6 responses, it was less effective at inhibiting such TLR2- or TLR4-coupled responses (decreases not reaching statistical significance), which have been shown to be important in the development of inflammatory Th17 responses, including those in arthritis. − Moreover, as observed with ES-62, , ( 11a (Figure C), but not 21l (results not shown), was able to inhibit TLR-mediated p65 NF-κB activation in response to all three PAMPs.…”

“…Sulfone 11a additionally targeted IL-6 production (see also Figure 3B) in response to all three TLRs (although this did not reach statistical significance for TLR2 in all experiments), and this cytokine has also been shown to be pathogenic 44 and thus a therapeutic target (tocilizumab) in RA. 45 Although sulfone 12b could suppress CpG-mediated IL-6 responses, it was less effective at inhibiting such TLR2- or TLR4-coupled responses (decreases not reaching statistical significance), which have been shown to be important in the development of inflammatory Th17 responses, including those in arthritis. 46−48 Moreover, as observed with ES-62, 40,49 ( 11a (Figure 3C), but not 21l (results not shown), was able to inhibit TLR-mediated p65 NF-κB activation in response to all three PAMPs.…”

Impact of TNF inhibitor therapy on joint replacement rates in rheumatoid arthritis: a matched cohort analysis of BSRBR-RA UK registry data

“…Many of these studies have inferred a possible role of biologics in this decline. Indeed, a reduction in need for joint replacement associated with TNFi use would be an expected finding given previous evidence of TNFi use reducing joint damage as measured radiographically [15]. A previous meta-analysis of 70 RCT studies reported that annual radiographic progression was 0.6% less in patients treated with biologics compared with those on a single DMARD [40].…”

Multitiered Proteome Analysis Displays the Hyperpermeability of the Rheumatoid Synovial Compartment for Plasma Proteins

“…Such a bias of proteins moving from blood to SF is of great relevance, especially with respect to the biodistribution of systemically delivered therapeutics. The availability of mAb treatments for the therapy of RA has transformed the treatment of RA within the past decades ( 37 , 38 ). However, with the recent advent of multispecific antibodies, antibody derivatives, and larger polymer scaffolds ( 39 , 40 , 41 ), even more complex therapeutics are conceivable.…”

Designing Anti-inflammatory Drugs from Parasitic Worms: A Synthetic Small Molecule Analogue of the Acanthocheilonema viteae Product ES-62 Prevents Development of Collagen-Induced Arthritis

“…11a (see Figure A) and 12b both mimicked ES-62 in targeting IL-12p40 production via each of TLR2, 4, and 9, and this cytokine is pathogenic in CIA due to it being a component of both IL-12p70 and IL-23, which promote Th1 and Th17 responses, respectively, and hence a therapeutic target (ustekinumab) in inflammatory autoimmune diseases. , By contrast, sulfonamide 21l and carboxamide 24b did not target LPS- and BLP-mediated IL-12p40 responses, respectively. Sulfone 11a additionally targeted IL-6 production (see also Figure B) in response to all three TLRs (although this did not reach statistical significance for TLR2 in all experiments), and this cytokine has also been shown to be pathogenic and thus a therapeutic target (tocilizumab) in RA . Although sulfone 12b could suppress CpG-mediated IL-6 responses, it was less effective at inhibiting such TLR2- or TLR4-coupled responses (decreases not reaching statistical significance), which have been shown to be important in the development of inflammatory Th17 responses, including those in arthritis. − Moreover, as observed with ES-62, , ( 11a (Figure C), but not 21l (results not shown), was able to inhibit TLR-mediated p65 NF-κB activation in response to all three PAMPs.…”

“…Sulfone 11a additionally targeted IL-6 production (see also Figure 3B) in response to all three TLRs (although this did not reach statistical significance for TLR2 in all experiments), and this cytokine has also been shown to be pathogenic 44 and thus a therapeutic target (tocilizumab) in RA. 45 Although sulfone 12b could suppress CpG-mediated IL-6 responses, it was less effective at inhibiting such TLR2- or TLR4-coupled responses (decreases not reaching statistical significance), which have been shown to be important in the development of inflammatory Th17 responses, including those in arthritis. 46−48 Moreover, as observed with ES-62, 40,49 ( 11a (Figure 3C), but not 21l (results not shown), was able to inhibit TLR-mediated p65 NF-κB activation in response to all three PAMPs.…”

Impact of TNF inhibitor therapy on joint replacement rates in rheumatoid arthritis: a matched cohort analysis of BSRBR-RA UK registry data

“…Many of these studies have inferred a possible role of biologics in this decline. Indeed, a reduction in need for joint replacement associated with TNFi use would be an expected finding given previous evidence of TNFi use reducing joint damage as measured radiographically [15]. A previous meta-analysis of 70 RCT studies reported that annual radiographic progression was 0.6% less in patients treated with biologics compared with those on a single DMARD [40].…”

Multitiered Proteome Analysis Displays the Hyperpermeability of the Rheumatoid Synovial Compartment for Plasma Proteins

“…Such a bias of proteins moving from blood to SF is of great relevance, especially with respect to the biodistribution of systemically delivered therapeutics. The availability of mAb treatments for the therapy of RA has transformed the treatment of RA within the past decades ( 37 , 38 ). However, with the recent advent of multispecific antibodies, antibody derivatives, and larger polymer scaffolds ( 39 , 40 , 41 ), even more complex therapeutics are conceivable.…”

Designing Anti-inflammatory Drugs from Parasitic Worms: A Synthetic Small Molecule Analogue of the Acanthocheilonema viteae Product ES-62 Prevents Development of Collagen-Induced Arthritis

“…11a (see Figure A) and 12b both mimicked ES-62 in targeting IL-12p40 production via each of TLR2, 4, and 9, and this cytokine is pathogenic in CIA due to it being a component of both IL-12p70 and IL-23, which promote Th1 and Th17 responses, respectively, and hence a therapeutic target (ustekinumab) in inflammatory autoimmune diseases. , By contrast, sulfonamide 21l and carboxamide 24b did not target LPS- and BLP-mediated IL-12p40 responses, respectively. Sulfone 11a additionally targeted IL-6 production (see also Figure B) in response to all three TLRs (although this did not reach statistical significance for TLR2 in all experiments), and this cytokine has also been shown to be pathogenic and thus a therapeutic target (tocilizumab) in RA . Although sulfone 12b could suppress CpG-mediated IL-6 responses, it was less effective at inhibiting such TLR2- or TLR4-coupled responses (decreases not reaching statistical significance), which have been shown to be important in the development of inflammatory Th17 responses, including those in arthritis. − Moreover, as observed with ES-62, , ( 11a (Figure C), but not 21l (results not shown), was able to inhibit TLR-mediated p65 NF-κB activation in response to all three PAMPs.…”

“…Sulfone 11a additionally targeted IL-6 production (see also Figure 3B) in response to all three TLRs (although this did not reach statistical significance for TLR2 in all experiments), and this cytokine has also been shown to be pathogenic 44 and thus a therapeutic target (tocilizumab) in RA. 45 Although sulfone 12b could suppress CpG-mediated IL-6 responses, it was less effective at inhibiting such TLR2- or TLR4-coupled responses (decreases not reaching statistical significance), which have been shown to be important in the development of inflammatory Th17 responses, including those in arthritis. 46−48 Moreover, as observed with ES-62, 40,49 ( 11a (Figure 3C), but not 21l (results not shown), was able to inhibit TLR-mediated p65 NF-κB activation in response to all three PAMPs.…”

Impact of TNF inhibitor therapy on joint replacement rates in rheumatoid arthritis: a matched cohort analysis of BSRBR-RA UK registry data

“…Many of these studies have inferred a possible role of biologics in this decline. Indeed, a reduction in need for joint replacement associated with TNFi use would be an expected finding given previous evidence of TNFi use reducing joint damage as measured radiographically [15]. A previous meta-analysis of 70 RCT studies reported that annual radiographic progression was 0.6% less in patients treated with biologics compared with those on a single DMARD [40].…”

Multitiered Proteome Analysis Displays the Hyperpermeability of the Rheumatoid Synovial Compartment for Plasma Proteins

“…Such a bias of proteins moving from blood to SF is of great relevance, especially with respect to the biodistribution of systemically delivered therapeutics. The availability of mAb treatments for the therapy of RA has transformed the treatment of RA within the past decades ( 37 , 38 ). However, with the recent advent of multispecific antibodies, antibody derivatives, and larger polymer scaffolds ( 39 , 40 , 41 ), even more complex therapeutics are conceivable.…”