Joint destruction in rheumatoid arthritis : experimental, clinical and epidemiological studies

Background: Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic polyarticular synovial inflammation. Erosive joint destruction represents a major unsolved complication of RA.

Objectives: The aim of this thesis was to obtain increased knowledge of joint destruction by using a multidisciplinary approach. Firstly, the pathophysiological background of joint destruction was investigated at a cellular level in experimental arthritis. Secondly, consequences of joint destruction on locomotor changes in RA patients and the effect of orthopaedic surgery on RA patients mobility and locomotion were studied. Thirdly, epidemiological studies were performed to elucidate the overall use and application of orthopaedic surgery in Swedish RA patients.

Methodology and Results: 1) Collagen-induced arthritis (CIA) is a well-established animal model of arthritis with differential susceptibility in various rat strains. CIA in the arthritis-prone DA rat was used to study potent joint destructive cytokines (RANKL and IL-1â) in evolving arthritis, as assessed by immunohistochemistry. A concommitant expression of RANKL and IL-1beta was detected at sites of bone erosion, supporting the hypothesis that they are central contributors to joint destruction. To elucidate potential phenotypical differences, the expression of IL-1beta and TNF were documented in the DA rat compared with that of two arthritis-resistant rat strains. The DA rat expressed IL-1beta in articular cartilage, while the arthritis-resistant rat strains did not. This might explain why erosive arthritides are so easily induced in the DA rat and supports the hypothesis that articular chondrocytes may themselves play a major role in cartilage destruction.

2) Gait parameters of a large RA cohort were compared with healthy controls assessed by three-dimensional gait analysis. In addition, gait patterns were documented before and after ankle/hindfoot arthrodesis, which is an effective intervention to reduce pain due to joint destruction in RA patients. Joint motion, moments and work in the lower limbs were significantly decreased in RA patients compared with controls. Intervention with ankle/hindfoot arthrodesis proved beneficial to functional ability with improvement of joint movement, moments and work in both the knee and hip.

3) Data from the Swedish inpatient registry were analyzed to assess the use and temporal trends of orthopaedic surgery due to RA joint destruction. Rates of hospitalisation for Swedish RA patients as well as the total number of RA-related surgical procedures of the lower limbs decreased during 1987-2001. In addition, the rates of upper limb surgical interventions decreased during 1998-2004. This suggests that new treatments may have improved long-term health outcomes and/or that changes in clinical practice have reduced the likelihood of admission for Swedish RA patients.

Conclusions. Increased knowledge of the cellular pathophysiology leading to joint destruction may contribute to the development of new targeted therapies. Better understanding of the clinical characteristics of RA patients and epidemiological trends is valuable in evaluating changes in therapies and interventions. A multidisciplinary approach is helpful and might contribute to improved strategies and influence the future care of RA patients.

List of scientific papers

I. Weiss RJ, Erlandsson Harris H, Wick MC, Wretenberg P, Stark A, Palmblad K (2005). "Morphological characterization of receptor activator of NFkappaB ligand (RANKL) and IL-1beta expression in rodent collagen-induced arthritis." Scand J Immunol 62(1): 55-62.
https://pubmed.ncbi.nlm.nih.gov/16092922

II. Weiss RJ, Erlandsson Harris H, Palmblad K (2007). "Highly arthritis-susceptible DA rats express IL-1beta in the articular cartilage." [Submitted]

III. Weiss RJ, Wretenberg P, Stark A, Palmblad K, Larsson P, Gröndal L, Broström E (2007). "Gait pattern in rheumatoid arthritis." [Submitted]

IV. Weiss RJ, Broström E, Stark A, Wick MC, Wretenberg P (2007). "Ankle/hindfoot arthrodesis in rheumatoid arthritis improves kinematics and kinetics of the knee and hip: a prospective gait analysis study." Rheumatology 46(6): 1024-8.
https://pubmed.ncbi.nlm.nih.gov/17409135

V. Weiss RJ, Stark A, Wick MC, Ehlin A, Palmblad K, Wretenberg P (2006). "Orthopaedic surgery of the lower limbs in 49,802 rheumatoid arthritis patients: results from the Swedish National Inpatient Registry during 1987 to 2001." Ann Rheum Dis 65(3): 335-41.
https://pubmed.ncbi.nlm.nih.gov/16079168

VI. Weiss RJ, Ehlin A, Montgomery S, Wick MC, Stark A, Wretenberg P (2007). "Decrease of rheumatoid arthritis-related orthopaedic surgery of the upper-limbs between 1998 and 2004: data from 54,579 Swedish RA inpatients." Rheumatology. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/18296481