Arthritis

Arthritis is an inflammatory disease of the joints, causing pain, swelling, and stiffness. Inflammation affects not only the cartilage of the joints, but also surrounding tissues, including the connective tissue of the skin, bones, and muscle. Most of the rheumatic diseases are autoimmune diseases, where autoantibodies are produced targeting normal antigens, such as the Fc region of IgG.

Rheumatoid arthritis (RA) is the most common form of chronic inflammatory arthritis, affecting close to 1% of the adult population. RA is a debilitating disease, but current treatments may lead to life-threatening adverse effects. Treatment is usually started with glucocorticoids and methotrexate (MTX). Administration of alkaline phosphatase inhibits release of pro-inflammatory chemokines, and could find use as therapy in RA (Chandrupatla et al., 2018).

Patients with RA are at higher risk of acute cardiovascular events than the general population. Genetics, smoking and certain infectious agents, such as GI pathogens, are associated with increased risk for RA. Axial spondyloarthritis (axSpA) is a disease family where the axial skeleton (spine and sacroiliac joints) is mainly affected; ankylosing spondylitis (AS) belongs to this disease family and is almost as common as RA.

The joint damage begins as the inflammation of the synovial membrane (synovitis). Synovial membrane lines the joints with cavities (synovial joints). Local and infiltrating mononuclear cells are activated and concentrated in the synovial fluid, leading to the swelling of the joint, and formation of new blood vessels (angiogenesis). Synovitis may occur in association with osteoarthritis (OA) and other diseases than arthritis, such as lupus and gout, but is most common in RA. Normally, synovial fibroblasts take part in remodelling of extracellular matrix (ECM) by producing structural components such as collagen, lubricating molecules such as hyaluronic acid, and enzymes. Together, activated fibroblasts in the synovium, chondrocytes in the cartilage, osteoclasts in the bone, and inflammatory cells overproduce ECM degrading enzymes, and stimulate angiogenesis.

B cells play a central role in the pathogenesis of RA by production of autoantibodies and proinflammatory cytokines, and by their antigen-presenting function cause the production of wider array of autoantibodies. Targeted B cell therapies, such as anti-CD20 antibody rituximab, attenuate the B cell accumulation at the site of inflammation. In RA, macrophages are abundant in the inflamed synovial membrane and fluid (Bresnihan, 1999), and also contribute to the inflammation in both acute and chronic phases of the disease.

Inflammation sensitizes the nociceptors in the joints (Gatenholm & Brittberg, 2018). Prostaglandins, especially PGE2, are mediators for inflammation and pain in RA and OA. Substance P, acting via neurokinin-1 receptor, has anti-inflammatory and regenerative properties. VEGF has a role in bone repair, and VEGF receptors are found on osteoblasts and chondrocytes. CGRP and neuropeptide Y levels are increased in synovial fluid in RA (Gatenholm & Brittberg, 2018).

PET imaging

Activated macrophages are abundant in the arthritic tissues. While inflamed tissues are generally very well perfused, in the collagen-rich synovial fluid the tracer distribution can be limited by both perfusion and diffusion. Relatively long distribution time may therefore be required for good separation of healthy and affected joints.

[18F]FDG and several other inflammation markers have been used in monitoring the activity of RA and effect of therapeutics (Beckers et al., 2004; Goerres et al., 2006; Irmler et al., 2010; Gompels and Paleolog, 2011; Roivainen et al., 2013; Okamura et al., 2014; Buijnen et al., 2014; Yamashita et al., 2014; van der Geest et al., 2015; Nozaki et al., 2016; Terry et al., 2016; Kubota et al., 2017; Mitra et al., 2017; Narayan et al., 2017 and 2018; Fosse et al., 2018; Lee et al., 2019). A marker of cellular proliferation, [11C]choline has been used in RA imaging.

Folate receptor β is expressed in activated macrophages in the inflamed synovium, providing a specific target for PET imaging and therapy (Paulos et al., 2004; Chandrupatla et al., 2019; Steinz et al., 2022).

Fibroblast-like synoviocytes (FLSs) in inflamed joints overexpress FAP. FAP radioligands could be used for imaging RA (Ge et al., 2022; Zhang et al., 2023).

In animal models, VAP-1 radioligands have shown promise in detecting synovitis, including synovitis caused by Borrelia burgdorferi.

Fluoride uptake in the bone is increased during bone remodelling, which is a mechanism of osteoarthritis progression. High [18F]F- uptake is observed in early stage of osteoarthritis. Both [18F]F- and [18F]FDG uptake is increased in RA affected joints (Watanabe et al., 2016). [18F]F- PET-MRI can provide useful parameters of cartilage-bone interactions and bone morphology in osteoarthritis (Savic et al., 2016; Tibrewala et al., 2019).

Excessive bone formation is an hallmark of ankylosing spondylitis, which can be detected using [18F]F- PET, allowing also the assessment of treatment effect (Bruijnen et al., 2018).

Adenosine maintains the homeostasis in cartilage (Corciulo et al., 2017), and PET imaging of A2ARs might be useful in arthritis studies.

Mannan injection causes acute inflammation in rodents, and has been used to generate a psoriasis, psoriatic arthritis, and rheumatoid arthritis mouse model (Khmaladze et al, 2014; Hagert et al., 2018). Intraperitoneal administration of [18F]fluoromannan, co-administered with 2 or 10 mg mannan, leads to wide distribution of the radiopharmaceutical, including the joints, bone marrow, and skin (Hagert et al., 2019).


See also:


Literature

Grassi W, De Angelis R, Lamanna G, Cervini C. The clinical features of rheumatoid arthritis. Eur J Radiol. 1998; 27(Suppl 1): S18-24. 10.1016/S0720-048X(98)00038-2.

Kumar LD, Karthik R, Gayathri N, Sivasudha T. Advancement in contemporary diagnostic and therapeutic approaches for rheumatoid arthritis. Biomed Pharmacother. 2016; 79: 52-61. doi: 10.1016/j.biopha.2016.02.001.

Mathiessen A, Conaghan PG. Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis Res Ther. 2017; 19(1): 18. doi: 10.1186/s13075-017-1229-9.

Müller R, von Kempis J (eds.): Clinical Trials in Rheumatology. Springer, 2011. doi: 10.1007/978-1-84996-384-8.

Resnick D, Kransdorf MJ: Bone and Joint Imaging, 3rd ed., Elsevier, 2005. ISBN 0-7216-0270-3.



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Updated at: 2023-08-01
Created at: 2017-10-03
Written by: Vesa Oikonen