Anti-TNF therapy in ankylosing spondylitis: insights for the clinician

Coates, Laura C.; Marzo‐Ortega, Helena; Bennett, Alexander N.; Emery, Paul

doi:10.1177/1759720x09359728

Cited by 27 publications

(15 citation statements)

References 40 publications

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“…On the other hand, it has been shown that younger patients with short duration of disease and high functional status would benefit more from TNFi treatment because these patients present more acute inflammation but less irreversible structural damage has occurred . However, it has also been reported that TNFi are effective in controlling disease activity in advanced AS …”

Section: Discussionmentioning

confidence: 99%

Predictive clinical‐genetic model of long‐term non‐response to tumor necrosis factor‐alpha inhibitor therapy in spondyloarthritis

Borda

Campos²,

Sanz³

et al. 2019

Int J of Rheum Dis

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Aim: Tumor necrosis factor inhibitors (TNFi) are effective in controlling disease activity in spondyloarthritis (SpA). However, in a proportion of patients these treatments are ineffective or lead to adverse events. Recently, alternative therapies, such as interleukin (IL)-17 or IL-23 inhibitors, have emerged in the treatment of these pathologies. This study aimed to determine clinical and genetic predictors of non-response to TNFi treatment in 118 spondyloarthritis patients diagnosed according to Assessment in SpondyloArthritis International Society (ASAS) criteria.Method: From the literature, 41 single nucleotide polymorphisms (SNPs) were selected that had previously been associated with TNFi treatment response in spondyloarthropathies, rheumatoid arthritis and psoriasis. A clinical non-response was defined as a decrease of <50% of initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in axial involvement, or a reduction of less than 1.2 of initial Disease Activity Score of 28 joints-C-reactive protein (DAS28-CRP) in patients with only peripheral involvement. Univariate and multivariate hazard ratios (HR) were determined using Cox proportional hazard models to analyze the potential prognostic factors affecting non-response to TNFi treatment. Results:The clinical factors that significantly increased the non-response rate were: global visual analog scale (VAS), CRP, BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI), and the number of TNFi used. Only rs11591741 SNP showed an association with non-response. In the multivariate analysis, females had a non-response rate 4.46 times higher than males; each one-point increase in the BASFI index increased the non-response rate by 75%, and being a genotype GG vs GC or CC carrier was associated with an almost 4 times greater non-response rate. Conclusion:We developed a clinical-genetic model to identify SpA patients with a long-term non-response to TNFi therapy. K E Y W O R D Santi-TNF treatment, genetics, single nucleotide polymorphisms, spondyloarthritis

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Section: Discussionmentioning

confidence: 99%

Predictive clinical‐genetic model of long‐term non‐response to tumor necrosis factor‐alpha inhibitor therapy in spondyloarthritis

Borda

Campos²,

Sanz³

et al. 2019

Int J of Rheum Dis

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“…Whereas TNF-TNF-R engagement is known to induce apoptosis, under certain conditions caspase-8-mediated processing of IL-1β and IL-18 is more prominent (20). Moreover, anti-TNF therapy has also been implicated as a potential therapeutic against inflammatory bone diseases in clinics (23,24 …”

Section: Tnf-signaling Pathway Does Not Engage Inflammatory Caspase 8mentioning

confidence: 99%

NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β–mediated osteomyelitis

Gurung

Burton

Kanneganti

2016

Proc. Natl. Acad. Sci. U.S.A.

112

115

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Missense mutation in the proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) gene results in the development of spontaneous chronic bone disease characterized by bone deformity and inflammation that is reminiscent of patients with chronic multifocal osteomyelitis (cmo). Interestingly, this disease is specifically mediated by IL-1β but not IL-1α. The precise molecular pathways that promote pathogenic IL-1β production in Pstpip2cmo mice remain unidentified. Furthermore, how IL-1β provokes inflammatory bone disease in Pstpip2cmo mice is not known. Here, we demonstrate that double deficiency of Nod like receptor family, pyrin domain containing 3 (NLRP3) and caspase 8 in Pstpip2cmo mice provides similar protection as observed in caspase-1 and caspase-8–deficient Pstpip2cmo mice, demonstrating redundant roles for the NLRP3 inflammasome and caspase 8 in provoking osteomyelitic disease in Pstpip2cmo mice. Consistently, immunofluorescence studies exhibited distinct caspase-1 and caspase-8 puncta in diseased Ptpn6spin neutrophils. Data from our chimera studies demonstrated that IL-1β produced by hematopoietic cells is sensed by the radioresistant compartment to promote bone disease. Furthermore, our results showed that the IL-1β signaling is unidirectional and feedback signaling of IL-1β onto the hematopoietic compartment is not important for disease induction. In conclusion, our studies have uncovered the combined actions of the NLRP3 inflammasome and caspase 8 leading to IL-1β maturation and the directionality of IL-1β in driving disease in Pstpip2cmo mice.

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“…This suggests that cytokines produced by monocytes contribute to inflammation. An association between the serum levels of inflammatory mediators and disease activity in AS has been reported (32, 33) Moreover, therapeutic success of anti-TNF agents in both AS and ERA further supports the role of pro-inflammatory cytokines in SpA (34,35).…”

Section: Discussionmentioning

confidence: 85%

Patients with enthesitis related arthritis show similar monocyte function pattern as seen in adult axial spondyloarthropathy

2020

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Background: Axial SpA and Enthesitis related arthritis (ERA) patients show strong HLA-B27 association, gut dysbiosis, high toll like receptor (TLR)2 and 4 expression on monocytes, pro-inflammatory cytokine production and elevated levels of TLR4 endogenous ligands [tenascin-c (TNC) and myeloid related protein (MRP)8/14] in serum. Hence, we aimed to understand if these diseases have similar or different monocyte response. Methods: Fifty adult axial SpA, 52 ERA patients and 25 healthy controls (HC) were enrolled. Cytokine-producing monocyte frequency before and after stimulation with lipopolysaccharide (LPS), peptidoglycan (PG), TNC or MRP8 were measured in whole blood (WB) and synovial fluid mononuclear cells (SFMC) by flow cytometry. Also, IL-6, TNF, MMP3, TNC and MRP8/14 levels were measured in unstimulated and TLR ligand stimulated WB cultures supernatant by ELISA. Finally, the mRNA expression levels of TNF and IL-6 were measured post stimulation with LPS, TNC and MRP8. Results: At baseline, ERA and axial SpA patients showed similar TNF-α producing monocyte frequency which was higher than HC. MRP8 simulation led to increased TNF-α producing monocyte frequency in ERA than axial SpA. TNC and MRP8 stimulation led to similar IL-6 producing monocyte frequency in axial SpA and ERA patients. Baseline TNF and IL-6 producing monocyte frequency also modestly correlated with disease activity scores. TNF and IL-6 producing monocyte frequency increased in response to TLR stimulation in SFMC from both patients. In culture supernatants, axial SpA and ERA patients showed similar TNF production at baseline. MRP8 and TNC stimulation led to higher TNF production from ERA. Baseline IL-6 and MMP3 production was higher in ERA while TLR stimulation led to similar IL-6 and MMP3 production from axial SpA and ERA. TNC stimulation led to higher MMP3 production in ERA. mRNA expression in response to TLR stimulation was observed to be similar in axial SpA and ERA. TNC production was higher in ERA at baseline, while MRP8/14 production was higher in axial SpA than ERA post stimulation. Conclusion: ERA patients have similar monocyte response to exogenous and endogenous TLR ligands as patients with axial SpA. This suggests that differences between pediatric and adult-onset SpA are minimal and they may have a common pathogenesis.

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Anti-TNF therapy in ankylosing spondylitis: insights for the clinician

Cited by 27 publications

References 40 publications

Predictive clinical‐genetic model of long‐term non‐response to tumor necrosis factor‐alpha inhibitor therapy in spondyloarthritis

Predictive clinical‐genetic model of long‐term non‐response to tumor necrosis factor‐alpha inhibitor therapy in spondyloarthritis

NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β–mediated osteomyelitis

Patients with enthesitis related arthritis show similar monocyte function pattern as seen in adult axial spondyloarthropathy

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