PMR Pathophysiology: An Expert's Perspective

Transcript

ReachMDAnnouncer:
Welcome to ReachMD.  This medical industry feature, titled “Understanding PMR Pathophysiology: An Expert's Perspective” is sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals. This program is intended for US healthcare professionals.

Here’s Dr. Leonard Calabrese.

Dr. Calabrese:
I’m Dr. Len Calabrese. I’m a professor of medicine at the Cleveland Clinic Lerner College of Medicine.

ReachMD Announcer:
What are the patterns of inflammation commonly seen in patients with PMR?

Dr. Calabrese:
Polymyalgia rheumatica is one of the most common inflammatory syndromes seen in patients after the age of 50. It’s characterized by the acute or subacute onset of pain and stiffness in the neck and shoulders and hip girdle and low back.

This is also exquisitely sensitive to glucocorticoids which are highly effective therapy, but unfortunately are required for prolonged periods of time and mount attendant toxicity.

ReachMDAnnouncer:
Which immune pathways have been linked to PMR disease activity?

Dr. Calabrese:
The immunopathogenesis of polymyalgia rheumatica is incompletely understood. But there’s robust evidence that there are perturbations of both innate and adaptive immune responses. There is overexpression of an activation of certain T-cell subsets and at the same time it is mediated primarily by cytokines.

Many of the clinical expressions of PMR such as pain, fatigue, early morning stiffness are believed to be mediated by inflammatory cytokines. These cytokines generate the acute phase response, elevated sed rate and CRP and are also responsible for pain, early morning stiffness. Among these cytokines that have been incriminated in polymyalgia rheumatica include IL-6, IL-1, TNF, IL-17 and others.

ReachMD Announcer:
What makes the pathophysiology of PMR different from other rheumatic diseases?

Dr. Calabrese:
First of all, it is among if not the most common inflammatory disease associated with aging. It virtually doesn’t occur before the age of 50 and becomes increasingly common after that. We believe that this is linked in some way to immunosenescence of the immune system.

There’s a strong relationship between polymyalgia rheumatica and GCA. Epidemiologically they are tightly linked because many patients may have both conditions. Yet at the same time many patients have either one or the other. We know that cytokines are drivers of both conditions, and that IL-6 plays a prominent role in both of these disorders. Together the links are very strong, but we don’t understand at this time why they are separate and why they overlap.

ReachMD Announcer:
What evidence exists for the role of IL-6 in PMR pathophysiology?

Dr. Calabrese:
There’s a robust body of data supporting the role of IL-6 in the immunopathogenesis of polymyalgia rheumatica. First and foremost is its strong association with giant cell arteritis where we know that IL-6 is an important inflammatory cytokine. In polymyalgia rheumatica IL-6 can drive pain, early morning stiffness, is associated with intercurrent mood disorders and fatigability. Experimental evidence has demonstrated that IL-6 increases as disease activity increases in polymyalgia rheumatica and finally and most recently IL-6 has been found by in situ immunohistochemistry within the inflamed tissues of patients with PMR. Collectively, IL-6 is a very prominent part of the pathogenesis of polymyalgia rheumatica.

ReachMD Announcer:
How does IL-6 contribute to disease progression?

Dr. Calabrese:
The role of IL-6 in polymyalgia rheumatica has broad implications. Not only is it a driver of the acute phase response but it’s responsible for many of the attendant symptoms. We know that it is directly related to pain where IL-6 has nociceptive properties. We also know that IL-6 is a highly efficient biomarker for intercurrent mood disorders, which are often seen in patients with chronic inflammatory diseases. IL-6 is also probably the most reproducible circadian cytokine during sleep and disturbances of sleep and painful and inflammatory conditions cause intrusion of IL-6 in the early morning hours contributing to early morning stiffness. Finally, IL-6 has been directly linked to many fatigue-like states which are very common polymyalgia rheumatica.

ReachMD Announcer:

For More Information on PMR, Visit www.PMRandIL6.com

This program was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals. If you missed any part of this discussion, visit ReachMD.com/industry-feature. This is ReachMD. Be Part of the Knowledge.

References

Bartoloni E, Pucci G, Alunno A, Gerli R, Shchillaci G. Chapter 9: Polymyalgia Rheumatica. In: Nussinovitch U, ed. The Heart in Rheumatic, Autoimmune and Inflammatory Diseases. 1st edition. Elsevier; 2017:213-231.

Bauer ME, Teixeira AL. Neuroinflammation in mood disorders: role of regulatory immune cells. Neuroimmunomodulation. 2021;28(3):99-107. doi: 10.1159/0000515594

Camellino D, Soldano S, Cutolo M, Cimmino MA. Dissecting the inflammatory response in polymyalgia rheumatica: the relative role of IL-6 and its inhibition. Rheumatology Int. 2018;(38):1699-1704. doi:10.1007/s00296-018-4086-1

Carvajal-Alegria G, Boukhlal S, Divi Cornec D, Valérie Devauchelle-Pensec V. The pathophysiology of polymyalgia rheumatica, small pieces of a big puzzle. Autoimmun Rev.2020;19(11):102670. doi:10.1016/j.autrev.2020.102670

Crowson CS, Matteson EL, Myasoedova E, Michet CJ, Ernste FC, Warrington KJ, et al. The Lifetime Risk of Adult-Onset Rheumatoid Arthritis and Other Inflammatory Autoimmune Rheumatic Diseases. Arthritis Rheum. 2011;63(3)633-639. doi:10.1002/art.30155.

De Jongh RF, Vissers KC, Meert TF, Booij LHDJ, De Deyne CS, Heylen RJ. The role of interleukin-6 in nociception and pain. Anesth Analg. 2003;96(4):1096-1103. doi:10.1213/01.ANE.0000055362.56604.78

Dasgupta B, Panayi GS. Interleukin-6 in serum of patients with polymyalgia rheumatica and giant cell arteritis. Br J Rheumatol. 1990;29(6):456-458. doi:10.1093/rheumatology/29.6.456

Favalli E. Understanding the role of interleukin-6 (IL-6) in the joint and beyond: a comprehensive review of IL-6 inhibition for the management of rheumatoid arthritis. Rheumatol Ther. 2020;7(3):473-516. doi:10.1007/s40744-020-00219-2

Floris A, Piga M, Cauli A, Salvarani C, Mathieu A. Polymyalgia rheumatica: an autoinflammatory disorder? RMD Open.2018;4(1):e000694. doi:10.1136/rmdopen-2018-000694

Gabay C. Interleukin-6 and chronic inflammation. Arthritis Research & Therapy 2006, 8(Suppl 2):S3

Gabriel SE, Sunku J, Salvarani C, O’Fallon WM, Hunder GG. Adverse outcomes of antiinflammatory therapy among patients with polymyalgia rheumatica. Arthritis Rheum. 1997;40(10):1873-1878. doi:10.1002/art.1780401022

Gonzalez-Gay MA, Matteson EL, Castañeda S. Polymyalgia rheumatica. Lancet. 2017;390(10103):1700-1712. doi:10.1016/S0140-6736(17)31825-1

Grossberg AJ, Vichaya EG, Gross PS, Ford BG, Scott KA, Estrada D, et al. Interleukin 6-independent metabolic reprogramming as a driver of cancer-related fatigue. Brain Behav Immun. 2020;88:230-241. doi: 10.1016/j.bbi.2020.05.043

Grygiel-Górniak B, Puszczewicz M. Fatigue and interleukin-6 – a multi-faceted relationship. Reumatologia. 2015;53(4):207-212. doi:10.5114/reum.2015.53998

Guggino G, Ferrante A, Macaluso F, Triolo G, Ciccia F. Pathogenesis of polymyalgia rheumatica. Reumatismo. 2018;70(1):10-17. doi:10.4081/reumatismo.2018.1048

Hysa E, Gotelli E, Sammorì S, Cimmino MA, Paolino S, Pizzorni C, et al. Immune system activation in polymyalgia rheumatica: which balance between autoinflammation and autoimmunity? A systematic review. Autoimmunity Rev.2022;21(2):102995. doi:10.1016/j.autrev.2021.102995

Jiemy WF, Zhang A, Boots AMH, Heeringa P, Sandovici M, Diepstra A, et al. Expression of interleukin-6 in synovial tissue of patients with polymyalgia rheumatica. Ann Rheum Dis. 2022;annrheumdis-2022-222873. Online ahead of print. doi:10.1136/ard-2022-222873

Kappelmann N, Dantzer R, Khandaker GM. Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19. Psychoneuroendocrinology. 2021;131:105295. doi: 10.1016/j.psyneuen.2021.105295

Kreiner F, Langberg H, Galbo H. Increased muscle interstitial levels of inflammatory cytokines in polymyalgia rheumatica. Arthritis Rheum. 2010;62(12):3768-3775. doi:10.1002/art.27728

Meliconi R, Pulsatelli L, Uguccioni M, Salvarani C, Macchioni P, Melchiorri C, et al. Leukocyte infiltration in synovial tissue from the shoulder of patients with polymyalgia rheumatica. Quantitative analysis and influence of corticosteroid treatment. Arthritis Rheum. 1996;39(7):1199-1207. doi:10.1002/art.1780390719

Milchert M, Brzosko M. Diagnosis of polymyalgia rheumatica usually means a favourable outcome for your patient. Indian J Med Res. 2017;145(5):593-600. doi:10.4103/ijmr.IJMR_298_17

Mori S, Koga Y. Glucocorticoid-resistant polymyalgia rheumatica: pretreatment characteristics and tocilizumab therapy. Clin Rheumatol. 2016;35(5):1367-1375. doi:10.1007/s10067-014-2650-y

Muller S., Whittle R., Hider S.L., Belcher J., Helliwell T., Morton C., Hughes E., Lawton S.A., Mallen C.D. Longitudinal clusters of pain and stiffness in polymyalgia rheumatica: 2-year results from the PMR Cohort Study. Rheumatology 2019;0:1–10

Nesher G, Breuer G. Giant cell arteritis and polymyalgia rheumatica: 2016 update. Rambam Maimonides Med J. 2016;7(4):e0035. doi:10.5041/RMMJ.10262

Roche NE, Fulbright JW, Wagner AD, Hunder GG, Goronzy JJ, Weyand CM. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum. 1993;36(9):1286-1294. doi:10.1002/art.1780360913

Salvarani C, Barozzi L, Boiardi L, Pipitone N, Bajocchi GL, Macchioni PL, et al. Lumbar interspinous bursitis in active polymyalgia rheumatica. Clin Exp Rheumatol. 2013;31(4):526-531.

Sebba, A. Pain: A Review of Interleukin-6 and Its Roles in the Pain of Rheumatoid Arthritis. Open Access Rheumatol. 2021;13:31-43. doi: 10.2147/OARRR.S291388

Ting EY-C, Yang AC, Tsai S-J. Role of interleukin-6 in depressive disorder. Int J Mol Sci. 2020;21(6):2194. doi:10.3390/ijms21062194

Twohig H, Mitchell C, Mallen C, Adebajo A, Mathers N. “I suddenly felt I’d aged”: a qualitative study of patient experiences of polymyalgia rheumatica (PMR). Patient Educ Couns. 2015;98(5):645-650. doi:10.1016/j.pec.2014.12.013

Unwin B, Williams CM, Gilliland W. Polymyalgia rheumatica and giant cell arteritis. Am Fam Physician. 2006;74(9):1547-1554.

Vgontzas AN, Bixler EO, Lin H-M, Prolo P, Trakada G, Chrousos GP. IL-6 and its circadian secretion in humans. Neuroimmunomodulation. 2005;12(3):131-140. doi:10.1159/000084844

Zakout SA, Clarke LL, Jessop D, Rainer H, Straub RH, Kirwan JR. Circadian variation in plasma IL-6 and the role of modified-release prednisone in polymyalgia rheumatica. Int J Clin Rheumatol. 2014;9(5):431-439. doi:10.2217/IJR.14.29