Olli Mäkelä

Radiation Synovectomy with Holmium-­166 Ferric Hydroxide Macroaggregate -­ Experimental Study in Rabbits and

Horses

Opponent

Professor Sheila Laverty, University of Montreal, Canada

Reviewers

Docent Martti Hannelin, Central Hospital of Etelä-Saimaa, Finland

Professor Elwyn Firth, Massey University, New Zealand

Supervisors

Professor Riitta-Mari Tulamo, University of Helsinki, Finland

Professor Antti Sukura, University of Helsinki, Finland

Professor Heikki Helminen, University of Kuopio, Finlad

Assistant Professor Mikko Lammi, University of Kuopio, Finland

Articles of the thesis

Rheumatoid arthritis (RA) is an inflammatory disorder characterized by synovial cell proliferation and microvascular injury. RA often leads to permanent articular cartilage damage because the inflamed synovium is an abundant source of cytokines and enzymes harmful to the articular cartilage. If repeated intra-articular corticosteroid treatments fail to control synovial inflammation, surgical, chemical, and radiation synovectomy (RSYN) with different radioactive preparations have been used to arrest the inflammation and the progression of cartilage degeneration. In this experimental study, the normal joints of rabbits and horses were investigated to assess the effects of RSYN with a relatively new radiopharmaceutical, holmium-166 ferric hydroxide macroaggregate (166Ho FHMA), to determine whether it would be a suitable candidate for therapeutic use in humans, and possibly also in horses.

   The treated joints were injected with radioactive 166Ho FHMA and the control joints with nonradioactive 165Ho FHMA. Both in rabbits and horses, radioactive 166Ho FHMA markedly suppressed the synovial lining hyperplasia compared with control joints. In addition, multifocal necrosis of the synovial lining, neovascularization, and eventually subsynovial fibrosis were seen in the joints treated with 166Ho FHMA. In rabbits, the pattern of multifocal synovial necrosis as well as the intra-articular distribution of radioactivity in the autoradiography images suggested an uneven distribution of 166Ho FHMA within the joint. Autoradiography analysis of lapine knees showed some leakage of radioactivity 3 days postinjection. In horses,166Ho FHMA treatment caused reactive synovitis in fetlock joints. A large dose of strong beta-emitter 166Ho resulted in excessive radiation injury and local pain. Joint fluid analysis of horses showed very little residual radioactivity 5 days after RSYN; 166Ho FHMA had probably been effectively cleared from the synovial fluid by the synovium. Scintigraphic examination revealed no extra-articular leakage of radioactivity. Increased synovial fluid protein levels after RSYN indicated radiation-induced soft-tissue injury and leakage of plasma into the synovial fluid from the vasculature. Synovial restoration in rabbit knees was evident 2 months after 166Ho FHMA, whereas equine synovium had regenerated poorly.

   The composition and morphology of adult articular cartilage in both species were not markedly affected by 166Ho FHMA treatment. Young rabbit cartilage showed mild radiation-induced fibrillation of the cartilage surface after 166Ho FHMA treatment but no further breakdown of the collagen framework during the 1-year follow-up. Active

35S-sulfate incorporation indicated normal chondrocyte metabolism in all zones of the cartilage. Only transient irradiation-induced derangement of matrix production was seen in young rabbits, and transient downregulation of collagen synthesis in horses.

   Overall, suppression of synovial hyperplasia, little extra-articular leakage, and only minor effects on articular cartilage suggest that RSYN can be used in clinical management of arthritis in man and horses provided that untoward side-effects are avoided.

  1. Mäkelä O, Penttilä P, Kolehmainen E, Sukura A, Sankari S, Tulamo R-M. Experimental radiation synovectomy in rabbit knee with holmium-166 ferric hydroxide macroaggregate. Nucl Med Biol 29: 593-598, 2002 [Pubmed] [Full text]

  2. Mäkelä OT, Lammi MJ, Uusitalo H, Hyttinen MM, Vuorio E, Helminen HJ, Tulamo R-M. Analysis of lapine cartilage matrix after radiosynovectomy with holmium-166 ferric hydroxide macroaggregate. Ann Rheum Dis 62: 43-49, 2003 [Pubmed] [Full text]

  3. Mäkelä O, Sukura A, Penttilä P, Hiltunen J, Tulamo R-M. Radiation synovectomy with holmium-166 ferric hydroxide macroaggregate in equine metacarpophalangeal and metatarsophalangeal joints. Vet Surg 32: 402-409, 2003 [Pubmed] [Full text]

  4. Mäkelä OT, Lammi MJ, Uusitalo H, Viitanen M, Hyttinen MM, Jurvelin JS, Vuorio E, Helminen HJ, Tulamo R-M. Effect of radiosynovectomy with holmium-166 ferric hydroxide macroaggregate on adult equine cartilage. J Rheumatol 31: 321-328, 2004 [Pubmed] [Full text]

Last updated January 29, 2019