Relationship between Lymph Node Volume and Pain following Certolizumab Therapy for Rheumatoid Arthritis Flare: A Pilot Study

Rahimi, Homaira; Dieudonne, Gregory; Kheyfits, Valeriy; Bouta, Echoe M.; Wood, Ronald W.; Barrett, Rick; Moorehead, Sharon; Schwarz, Edward M.; Ritchlin, Christopher T.

doi:10.4137/cmamd.s40237

Cited by 11 publications

(13 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pro-inflammatory cytokines, in addition to their roles in disease progression in inflamed joints, have been implicated in arthritic pain development, but also generally in pain progression [ 1 , 2 ]. For example, inhibition of the action of tumour necrosis factor (TNF) [ 3 , 4 ] or granulocyte macrophage-colony stimulating factor (GM-CSF) [ 5 ] ameliorates joint pain in animal models of inflammatory arthritis and also clinically in RA patients [ 6 , 7 ]. We recently described a new GM-CSF➔CCL17 pathway in monocytes/macrophages in vitro, which we found to be important in vivo not only for inflammatory arthritic pain and disease development [ 8 – 10 ], but also for osteoarthritic pain and disease [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…macrophage-colony stimulating factor (GM-CSF) [5] ameliorates joint pain in animal models of inflammatory arthritis and also clinically in RA patients [6,7]. We recently described a new GM-CSF➔CCL17 pathway in monocytes/macrophages in vitro, which we found to be important in vivo not only for inflammatory arthritic pain and disease development [8][9][10], but also for osteoarthritic pain and disease [10].…”

mentioning

confidence: 99%

See 1 more Smart Citation

IL-23 in arthritic and inflammatory pain development in mice

et al. 2020

View full text Add to dashboard Cite

Background: The cytokine, interleukin-23 (IL-23), can be critical for the progression of inflammatory diseases, including arthritis, and is often associated with T lymphocyte biology. We previously showed that certain lymphocyte-independent, inflammatory arthritis and pain models have a similar requirement for tumour necrosis factor (TNF), granulocyte macrophage-colony stimulating factor (GM-CSF), and CC motif ligand 17 (CCL17). Given this correlation in cytokine requirements, we explored whether IL-23 might interact with this cytokine cluster in the control of arthritic and inflammatory pain. Methods: The role of IL-23 in the development of pain-like behaviour was investigated using mouse arthritis models (zymosan-induced arthritis and GM-CSF-, TNF-, and CCL17-driven monoarticular arthritis) and inflammatory pain models (intraplantar zymosan, GM-CSF, TNF, and CCL17). Additionally, IL-23-induced inflammatory pain was measured in GM-CSF −/− , Tnf −/− , and Ccl17 E/E mice and in the presence of indomethacin. Pain-like behaviour and arthritis were assessed by relative weight distribution in hindlimbs and histology, respectively. Cytokine mRNA expression in knees and paw skin was analysed by quantitative PCR. Blood and synovial cell populations were analysed by flow cytometry. Results: We report, using Il23p19 −/− mice, that innate immune (zymosan)-driven arthritic pain-like behaviour (herein referred to as pain) was completely dependent upon IL-23; optimal arthritic disease development required IL-23 (P < 0.05). Zymosan-induced inflammatory pain was also completely dependent on IL-23. In addition, we found that exogenous TNF-, GM-CSF-, and CCL17-driven arthritic pain, as well as inflammatory pain driven by each of these cytokines, were absent in Il23p19 −/− mice; optimal disease in these mBSA-primed models was dependent on IL-23 (P < 0.05). Supporting this cytokine connection, it was found conversely that IL-23 (200 ng) can induce inflammatory pain at 4 h (P < 0.0001) with a requirement for each of the other cytokines as well as cyclooxygenase activity. Conclusions: These findings indicate a role for IL-23 in innate immune-mediated arthritic and inflammatory pain with potential links to TNF, GM-CSF, CCL17, and eicosanoid function.

show abstract

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

IL-23 in arthritic and inflammatory pain development in mice

et al. 2020

View full text Add to dashboard Cite

show abstract

“…We have focused on the synovial lymphatic system during arthritic progression and flare (10,12,16,20,25,26,35,43,44), and the effects of interventions that specifically target lymphatic contractions, whose physiologic importance in supporting lymphatic drainage and subsequent onset of lymphedema have been established in preclinical and clinical studies (7,29,45,46). We have also performed transmission electron microscopy studies on WT, Expanding and Collapsed PLVs (42).…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, we used CE-MRI to show that RA patients with the smallest change in lymph node volume during anti-TNF therapy experienced the greatest pain relief in symptomatic knee joints with a remarkably linear inverse correlation (28). Most recently, we utilized NIR-ICG imaging (10) to show that lymphatic drainage in the hands of RA patients with active disease is decreased compared to healthy controls (29).…”

Section: Introductionmentioning

confidence: 99%

Ex vivo Demonstration of Functional Deficiencies in Popliteal Lymphatic Vessels from TNF-Tg Mice with Inflammatory Arthritis

Scallan

Bouta

Rahimi

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Rheumatoid arthritis (RA) is a progressive immune-mediated inflammatory disease characterized by intermittent episodes of pain and inflammation in affected joints, or flares. Recent studies demonstrated lymphangiogenesis and expansion of draining lymph nodes during chronic inflammatory arthritis, and lymphatic dysfunction associated with collapse of draining lymph nodes in RA patients and TNF-transgenic (TNF-Tg) mice experiencing arthritic flare. As the intrinsic differences between lymphatic vessels afferent to healthy, expanding, and collapsed draining lymph nodes are unknown, we characterized the ex vivo behavior of popliteal lymphatic vessels (PLVs) from WT and TNF-Tg mice. We also interrogated the mechanisms of lymphatic dysfunction through inhibition of nitric oxide synthase (NOS). Methods: Popliteal lymph nodes (PLNs) in TNF-Tg mice were phenotyped as Expanding or Collapsed by in vivo ultrasound and age-matched to WT littermate controls. The PLVs were harvested and cannulated for ex vivo functional analysis over a relatively wide range of hydrostatic pressures (0.5 to 10 cmH2O) to quantify the end diastolic diameter (EDD), tone, amplitude (AMP), ejection fraction (EF), contraction frequency (FREQ) and fractional pump flow (FPF) with or without NOS inhibitors Data was analyzed using repeated measures two-way ANOVA with Bonferroni's post hoc test. Results: Real time videos of the cannulated PLVs demonstrated the predicted phenotypes of robust versus weak contractions of the WT versus TNF-Tg PLV, respectively. Quantitative analyses confirmed that TNF-Tg PLVs had significantly decreased AMP, EF and FPF versus WT (p<0.05). EF and FPF were recovered by NOS inhibition, while the reduction in AMP was NOS independent. No differences in EDD, tone, or FREQ were observed between WT and TNF-Tg PLVs, nor between Expanding versus Collapsed PLVs. Conclusion: These findings support the concept that chronic inflammatory arthritis leads to NOS dependent and independent draining lymphatic vessel dysfunction that exacerbates disease, and may trigger arthritic flare due to decreased egress of inflammatory cells and soluble factors from affected joints.

show abstract

“…Imaging studies of lymphadenopathy in RA patients have shown significant alterations in the size and morphology of draining lymph nodes. In a small cohort of RA patients experiencing flares, contrast-enhanced magnetic resonance imaging of draining lymph nodes displayed a reduction of lymph node volume after treatment (18). Manzo and colleagues used power Doppler ultrasound (PDUS) imaging of the axillary lymph nodes in RA patients with active hand disease to demonstrate hypertrophy of the node cortex without clinical lymphadenopathy, along with a strong PDUS signal in the cortical and hilar regions (19).…”

Section: Introductionmentioning

confidence: 99%

Altered Lymphatic Vessel Anatomy and Markedly Diminished Lymph Clearance in Affected Hands of Patients With Active Rheumatoid Arthritis

Bell

Rahimi

Kenney

et al. 2020

Arthritis & Rheumatology

Self Cite

View full text Add to dashboard Cite

Objective To assess differences between lymphatic function in the affected hands of rheumatoid arthritis (RA) patients with active synovitis and that of healthy controls, using indocyanine green (ICG) dye and near‐infrared (NIR) imaging. Methods NIR imaging of the hands of 8 patients with active RA and 13 healthy controls was performed following web space injection of 0.1 ml of 100 μM ICG. The percentage of ICG retention in the web spaces was determined by NIR imaging at baseline and at 7 days (±1 day) after the initial injections; image analysis provided contraction frequency. ICG+ lymphatic vessel (LV) length and branching architecture were assessed. Results Retention of ICG in RA hands was higher compared to controls (P < 0.01). The average contraction frequency of ICG+ LVs in RA patients and in controls did not differ (mean ± SD 0.53 ± 0.39 contractions/minute versus 0.51 ± 0.35 contractions/minute). Total ICG+ LV length in RA hands was lower compared to healthy controls (58.3 ± 15.0 cm versus 71.4 ± 16.1 cm; P < 0.001), concomitant with a decrease in the number of ICG+ basilic LVs in the hands of RA patients (P < 0.05). Conclusion Lymphatic drainage in the hands of RA patients with active disease was reduced compared to controls. This reduction was associated with a decrease in total length of ICG+ LVs on the dorsal surface of the hands, which continued to contract at a similar rate to that observed in controls. These findings provide a plausible mechanism for exacerbation of synovitis and joint damage, specifically the accumulation and retention of inflammatory cells and catabolic factors in RA joints due to impaired efferent lymphatic flow. NIR/ICG imaging of RA hands is feasible and warrants formal investigation as a primary outcome measure for arthritis disease severity and/or persistence in future clinical trials.

show abstract

Relationship between Lymph Node Volume and Pain following Certolizumab Therapy for Rheumatoid Arthritis Flare: A Pilot Study

Cited by 11 publications

References 34 publications

IL-23 in arthritic and inflammatory pain development in mice

IL-23 in arthritic and inflammatory pain development in mice

Ex vivo Demonstration of Functional Deficiencies in Popliteal Lymphatic Vessels from TNF-Tg Mice with Inflammatory Arthritis

Altered Lymphatic Vessel Anatomy and Markedly Diminished Lymph Clearance in Affected Hands of Patients With Active Rheumatoid Arthritis

Contact Info

Product

Resources

About