Pain experience in children with juvenile idiopathic arthritis treated with anti-TNF agents compared to non-biologic standard treatment

Lomholt, Johanne Jeppesen; Thastum, Mikael; Herlin, Troels

doi:10.1186/1546-0096-11-21

Cited by 61 publications

(53 citation statements)

References 52 publications

(64 reference statements)

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“…Data represent mean ± SEM. *P < 0.05, **P < 0.01, # P < 0.001. ment (63,64). Preclinical studies should be performed to further examine these possibilities.…”

Section: Figurementioning

confidence: 99%

Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain

Heijnen²,

et al. 2013

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Chronic pain is a major clinical problem, yet the mechanisms underlying the transition from acute to chronic pain remain poorly understood. In mice, reduced expression of GPCR kinase 2 (GRK2) in nociceptors promotes cAMP signaling to the guanine nucleotide exchange factor EPAC1 and prolongs the PGE 2 -induced increase in pain sensitivity (hyperalgesia). Here we hypothesized that reduction of GRK2 or increased EPAC1 in dorsal root ganglion (DRG) neurons would promote the transition to chronic pain. We used 2 mouse models of hyperalgesic priming in which the transition from acute to chronic PGE 2 -induced hyperalgesia occurs. Hyperalgesic priming with carrageenan induced a sustained decrease in nociceptor GRK2, whereas priming with the PKCε agonist ΨεRACK increased DRG EPAC1. When either GRK2 was increased in vivo by viral-based gene transfer or EPAC1 was decreased in vivo, as was the case for mice heterozygous for Epac1 or mice treated with Epac1 antisense oligodeoxynucleotides, chronic PGE 2 -induced hyperalgesia development was prevented in the 2 priming models. Using the CFA model of chronic inflammatory pain, we found that increasing GRK2 or decreasing EPAC1 inhibited chronic hyperalgesia. Our data suggest that therapies targeted at balancing nociceptor GRK2 and EPAC1 levels have promise for the prevention and treatment of chronic pain.

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“…Data represent mean ± SEM. *P < 0.05, **P < 0.01, # P < 0.001. ment (63,64). Preclinical studies should be performed to further examine these possibilities.…”

Section: Figurementioning

confidence: 99%

Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain

Heijnen²,

et al. 2013

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“…Activated glial cells in the dorsal horn of the spinal cord and infiltrating macrophages or activated satellite glial cells in the DRGs produce proinflammatory cytokines that sensitize the sensory system (Ren and Dubner, 2010). Therefore, these neuroinflammatory pathways, including spinal cord and DRG cytokine production and glial cell activation, represent potential therapeutic targets for treating persistent pain states (Ren and Dubner, 2010;Graeber and Christie, 2012;Ji et al, , 2014.…”

Section: Introductionmentioning

confidence: 99%

“…Chronic pain is a major complaint of many patients suffering from chronic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. In these conditions, pain may even persist after successful treatment of the inflammation (Bielefeldt et al, 2009;Lee et al, 2011;Lomholt et al, 2013). Current treatments provide modest pain relief at best, due to lack of effectiveness or because treatment has to be suspended due to severe side effects (Borsook et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Nonetheless, the therapeutic potential of the native unmodified anti-inflammatory cytokines as stand-alone drugs is limited. First, the optimal function of these cytokines requires them to act in concert with other immunoregulatory cytokines (van Roon et al, 1996(van Roon et al, , 2001Joosten et al, 1997). Second, their relatively small size causes rapid clearance, thereby reducing their bioavailability.…”

Section: Introductionmentioning

confidence: 99%

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IL4-10 Fusion Protein Is a Novel Drug to Treat Persistent Inflammatory Pain

Eijkelkamp

Steen-Louws²,

Hartgring³

et al. 2016

Journal of Neuroscience

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Chronic pain is a major clinical problem that is difficult to treat and requires novel therapies. Although most pain therapies primarily target neurons, neuroinflammatory processes characterized by spinal cord and dorsal root ganglion production of proinflammatory cytokines play an important role in persistent pain states and represent potential therapeutic targets. Anti-inflammatory cytokines are attractive candidates to regulate aberrant neuroinflammatory processes, but the therapeutic potential of these cytokines as stand-alone drugs is limited. Their optimal function requires concerted actions with other regulatory cytokines, and their relatively small size causes rapid clearance. To overcome these limitations, we developed a fusion protein of the anti-inflammatory cytokines interleukin 4 (IL4) and IL10. The IL4-10 fusion protein is a 70 kDa glycosylated dimeric protein that retains the functional activity of both cytokine moieties. Intrathecal administration of IL4-10 dose-dependently inhibited persistent inflammatory pain in mice: three IL4-10 injections induced full resolution of inflammatory pain in two different mouse models of persistent inflammatory pain. Both cytokine moieties were required for optimal effects. The IL4-10 fusion protein was more effective than the individual cytokines or IL4 plus IL10 combination therapy and also inhibited allodynia in a mouse model of neuropathic pain. Mechanistically, IL4-10 inhibited the activity of glial cells and reduced spinal cord and dorsal root ganglion cytokine levels without affecting paw inflammation. In conclusion, we developed a novel fusion protein with improved efficacy to treat pain, compared with wild-type anti-inflammatory cytokines. The IL4-10 fusion protein has potential as a treatment for persistent inflammatory pain.

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“…The mechanism behind the alteration from acute inflammatory pain to chronic noninflammatory pain is not fully understood, though animal models have shown TNF-α to play a role in the sensitization of the central nervous system [33,34]. Studies evaluating the effect of anti-TNF-α treatment on pain in humans have reported divergent results [29,35]. The incidence rate of developing chronic non-inflammatory pain is reported to be highest the first 12 months after diagnosis of RA [36], also described in acute back pain [37,38].…”

Section: Das28 Over 5 Years Esr Over Timementioning

confidence: 99%

Comparing Five Year Out-Come in Two Cohorts of Patients with Early Rheumatoid Arthritis – A BARFOT Study

Andersson¹,

Forslind²,

Hafström³

2015

TORJ

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Abstract:The objective of the study was to compare disease characteristics over the first 5 years of disease in patients with RA, with disease onset in 1990s and 2000s, respectively.Methods: All 2235 patients with early RA (disease duration ≤12 months) were recruited from the BARFOT prospective observational study. These patients were divided into group 1 included 1992 to 1999 (N=1084, 66% women) and group 2 included 2000 to 2006 (N=1151, 69% women). Disease Activity Score (DAS28), VAS pain and Health Assessment Questionnaire (HAQ) were assessed during 5 years. Remission was defined as DAS28 <2.6.Results: At inclusion, both women and men in group 2 had higher mean DAS28 (SD) than group 1, 5.42 (1.22) vs 5.26 (1.19), p=0.004 and 5.28 (1.22) vs 5.00 (1.27), p=0.004, respectively, mainly dependant on pain and not on inflammatory related measures. Over time DAS28 decreased and was in both genders, from 6 months to the 5-year follow-up, significantly lower in group 2. At 5-year, both women and men in group 2 had higher rate of remission than women and men in group 1. However, despite reduction of VAS pain and HAQ there were no differences in pain and HAQ between groups at any time point. Conclusion:Patients included in the 2000s achieved higher frequency of remission at the 5 year follow-up compared with those included in the 1990s, suggested to reflect the more active medical treatment. Interestingly, however, improvement in pain and HAQ did not differ between the two patient cohorts.

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Pain experience in children with juvenile idiopathic arthritis treated with anti-TNF agents compared to non-biologic standard treatment

Cited by 61 publications

References 52 publications

Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain

Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain

IL4-10 Fusion Protein Is a Novel Drug to Treat Persistent Inflammatory Pain

Comparing Five Year Out-Come in Two Cohorts of Patients with Early Rheumatoid Arthritis – A BARFOT Study

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