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Pathophysiology

Pathophysiology

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Epidemiology

     Definition-

     Causative Agent-

     Risk Factors-

     Exposures-

Time Course-

     Prodromal pattern-

     Duration-

PathophysiolOGY

 

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Rheumatoid Arthritis

Epidemiology

Definition

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that may involve several tissues and organs but particularly affects the joints (Hopkins et al., 2019). According to Nemtsova et al. (2019) RA is a chronic disease of the connective tissue with progressive damage to the joints and systemic disorders.

Causative Agent

Rheumatoid arthritis is a disorder that is most likely a result from a combination of genetic susceptibility and several environmental and lifestyle factors. In rheumatoid arthritis, the immune system recognizes autoantigens and releases inflammatory chemicals such as cytokines and produce autoantibodies such as rheumatoid factor and anti-citrullinated protein antibodies that attack the joints resulting to inflammation and bone destruction. Also, pathogens such as Porphyromonas gingivalis, Prevotella species, Mycoplasma pneumoniae, Escherichia coli, rubella virus, and Epstein-Barr virus (EBV) have been suggested as potential causes of RA (England & Mikuls, 2019).

Risk Factors

Rheumatoid arthritis can strike at any age but the risk of RA increases with age. There is a highest onset of RA among adults age 60s. Women are noted to be of higher risk to develop RA than men. Cigarette smoking is associated in developing RA. Other risk factors for RA include women who have never given birth, children of lower income parents, and obesity (Centers for Disease Control and Prevention, n.d.). Stress and individuals with post-traumatic stress disorder have been found to have an increased risk in developing rheumatoid arthritis (England & Mikuls, 2019).

A family history of rheumatoid arthritis is a known risk factor for RA. Early age  menopause has been reported to confer higher RA risk. Chronic inflammation of mucosal sites, including the oral mucosa and lung appears to be a risk factor for RA. Oral cavity pathogens which include Porphyromonas gingivalis, Prevotella species, and Aggregatibacter actinomycetemcomitans have been identified as risk factors in RA. Viral infections caused by Epstein-Barr virus, parvovirus B19, rubella, cytomegalovirus, and human T-lymphotropic virus type 1 have been implicated as risk factors for RA. Bacterial infections caused by Mycoplasma pneumoniae, Proteus mirabilis, and Escherichia coli have also been reported in RA (England & Mikuls, 2019).

Genetics play an important role in RA as variations in human leukocyte antigen (HLA) particularly HLA-DRB1 gene has been noted as the most significant genetic risk factor for RA (Hopkins et al., 2019). Epigenetics such as specific changes in DNA methylation and histone modifications have been identified to play an important role in developing RA (Nemtsova et al., 2019).

Individuals with autoantibodies like rheumatoid factor (RF) and proinflammatory response such as cytokine productions which are characteristics of RA can be detected in the blood prior to RA onset. These are considered risk factors are as they represent the early biologic processes that precede and subsequently lead to clinically apparent rheumatoid arthritis (England & Mikuls, 2019).

Exposures

A range of airborne inhalant exposures has been associated with increased risk for RA. Occupations with exposure to airborne inhalants, including silica, appear to confer greater risk of RA, especially in men. Farming and exposure to chemical fertilizers and solvents have also been associated with increased RA risk. Residential proximity to traffic has been associated with higher risk of RA (England & Mikuls, 2019). Some early life exposures such as children whose mothers smoked may have an increased risk of developing RA in adulthood (Centers for Disease Control and Prevention, n.d.).

Time Course

Prodromal Pattern

The disease onset is gradual in a typical RA with predominant symptoms of pain, swelling of many joints, and stiffness. In few patients, there is episodic onset of RA with one to several joints that are being affected for hours to days then followed by periods of being  symptom-free which may last from days to months (Venables & England, 2021). Symptoms of fatigue and low-grade fever are also noted during the early stage of RA. Certain joints in the hands and feet and small joints such as wrists are typically affected first and with symmetrical joints being affected in RA (Arthritis Foundation, n.d.).

Duration

The course of rheumatoid arthritis is variable. Approximately 15-20% of patients with RA have intermittent disease and with periods of exacerbation and good prognosis (Venables, 2019). Usually, rheumatoid arthritis presents as a polyarticular disease with a gradual onset. Acute onset can be found in some patients with monoarticular disease with intermittent or migratory joint involvement. Rheumatoid arthritis usually progresses from the periphery to the more proximal joints that result in a significant locomotor disability in a period of 10 -20 years among patients who do not respond to RA treatment (Venables & England, 2021).

Pathophysiology

Rheumatoid arthritis is an autoimmune chronic disease that is triggered by antigenic agents which can be environmental or infectious agent to a genetically susceptible host (Hopkins et al., 2019). Susceptibility of a person to RA depends upon a pattern of inherited genes especially those with human leukocyte antigen (HLA). Environmental stimuli such as smoking and other pathogenic agents such as bacteria called Porphyromonas gingivalis causing gingivitis and Epstein-Barr virus are important factors in the development of RA (Firestein & Guma, 2020).

Genetics and environmental interactions can cause modification of a person’s own antigens which can make it seem foreign to the immune cells leading to an immune response. In cigarette smoking, which is strongly associated with rheumatoid arthritis, it prompts the expression of peptidyl arginine deiminase in alveolar macrophages. The aforementioned enzymes then convert arginine to citrulline which is known as citrullination which then lead to the formation of neoantigens that is being recognized by the adaptive immune system. This period of genetics and environmental interactions can be regarded as pre-RA as immune abnormalities are detected before the development of clinical manifestations of RA (Firestein & Guma, 2020).

The synovial membrane which lines the joint capsule is the first joint tissue to be affected in RA. Rheumatoid arthritis involves inflammation of the synovium also known as synovitis, swelling of joints, ankylosis or joint stiffness, and articular cartilage destruction. The presence of antigens and genetic susceptibility in RA cause a chronic autoimmune reaction resulting to the activation of CD4+ helper T cells and perhaps B lymphocytes. There is also a local release of inflammatory cytokines and mediators which promote tissue injury. The important cytokines in RA include interferon-gamma (IFNγ) which activates synovial cells and macrophages, and interleukin (IL)-17 which stimulates monocytes and neutrophils. Also, tumor necrosis factor (TNF) and IL-1 together with other cytokines stimulate cells of the synovium to proliferate and produce other inflammatory mediators such as matrix metalloproteinases and prostaglandin E2 which contributes to cartilage destruction. The activated T cells and synovial fibroblasts produce receptor activator of nuclear factor kappa-Β ligand (RANKL) which then stimulates the activity of osteoclasts resulting to bone resorption and increased bone loss. Also, the inflammatory cytokines alter the synovial membrane converting it into a pannus which is a thick abnormal layer of granulation tissue that acts like a local invasive tumor which grows over the articular surface which can lead to the destruction of the joint in RA (Hopkins et al., 2019). Moreover, the synovial fibroblasts, which are the main cells of synovial membrane when activated can migrate and travel through blood vessels and attack other cartilage in the body which is being evident as there is symmetrical joint involvement in patients with RA (Ospelt, 2017).

The activation of CD4 T cell also activate the B cells and this can be through co-stimulation. The role of B cells in rheumatoid arthritis includes antibody or immunoglobulin production which become autoantibodies due to intensive exposure to the antigen. These antibodies include rheumatoid factor and anti-citrullinated protein antibodies (Firestein & Guma, 2020). Antibodies that target the Fc fragment of immunoglobulin (Ig) G are called rheumatoid factors. IgM RF is the commonly mentioned rheumatoid factor although IgG and IgA can also be found (Tiwari et al., 2020). The rheumatoid factor then forms autoimmune complexes that can deposit in the synovial fluid resulting to joint injury (Hopkins et al., 2019). The second antibody in RA which is the anti- citrullinated protein antibody (ACPA) target citrullinated proteins, such as vimentin and fibrin, which are proteins that have arginine residues and have been converted to citrullinate. The presence of RF and ACPA in a person with rheumatoid arthritis are likely to have more erosions of bones and joints and more extraarticular manifestations (Firestein & Guma, 2020).

The synovial membrane in RA undergoes hyperplastic thickening along with swelling and damage caused by leukocyte infiltration. As synovial inflammation progresses, the hypertrophied endothelial cells, inflammatory cells, platelets, and fibrin occlude small venules which decrease the vascular flow to the synovial tissue. The increased metabolic needs due to hypertrophy and hyperplasia together with compromised circulation leads to hypoxia in metabolic acidosis. This further leads to the release of hydrolytic enzymes from synovial cells to the surrounding tissue resulting to the inflammation of tendons and ligaments and also erosion of the articular cartilage in rheumatoid arthritis (Hopkins et al., 2019).

Meanwhile, in the synovial fluid, there are abundant neutrophils in RA synovial effusions with more prevalent CD8+ cells than CD4+ in the fluid. The neutrophils in the synovial fluid essentially produce proteases and reactive oxygen species that result to bone and cartilage degradation and erosion that is found in patients with rheumatoid arthritis (Firestein & Guma, 2020).

References

Arthritis Foundation. (n.d.). Rheumatoid arthritis: Causes, symptoms, treatments and more.

Retrieved May 1, 2021, from https://www.arthritis.org/diseases/rheumatoid-arthritis

Centers for Disease Control and Prevention. (n.d.). Rheumatoid arthritis (RA).

https://www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html#risk

England, B. R., & Mikuls, T. R. (2019). Epidemiology of, risk factors for, and possible causes of

rheumatoid arthritis. UpToDate. Retrieved April 26, 2021, from https://www-uptodate-com.ezproxy.stfrancis.edu/contents/epidemiology-of-risk-factors-for-and-possible-causes-of-rheumatoid-arthritis?search=rheumatoid%20arthritis&topicRef=7513&source=see_link

Firestein, G. S., & Guma, M. (2020). Pathogenesis of rheumatoid arthritis. UpToDate. Retrieved

May 1, 2021, from https://www-uptodate-com.ezproxy.stfrancis.edu/contents/pathogenesis-of-rheumatoid-arthritis?search=rheumatoid%20arthritis%20pathophysiology&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Gravallese, E. M., & Chopra, R. (2019). Synovial pathology in rheumatoid arthritis. UpToDate.

Retrieved April 30, 2021, from https://www-uptodate-com.ezproxy.stfrancis.edu/contents/synovial-pathology-in-rheumatoid-arthritis?search=rheumatoid%20arthritis%20&topicRef=7513&source=see_link

Hopkins, L. W., Smallheer, B. A., & McCance, K. L. (2019). Alterations of musculoskeletal

function. In K. L. McCance & S. E. Huether (Eds.), Pathophysiology: The biologic basis for disease in adults and children (8th ed., pp. 1423-1471). Elsevier.

Nemtsova, M. V., Zaletaev, D. V., Bure, I. V., Mikhaylenko, D. S., Kuznetsova, E. B.,

Alekseeva, E. A., Beloukhova, M. I., Deviatkin, A. A., Lukashev, A. N., & Zamyatnin Jr., A. A. (2019). Epigenetic changes in the pathogenesis of rheumatoid arthritis. Frontiers in Genetics, 10(570). https://doi.org/10.3389/fgene.2019.00570

Ospelt, C. (2017). Synovial fibroblasts in 2017. RMD Open, 3(2).

http://dx.doi.org/10.1136/rmdopen-2017-000471

Tiwari, V., Jandu, J. S., & Bergman, M. J. (2020). Rheumatoid factor. StatPearls.

https://www.ncbi.nlm.nih.gov/books/NBK532898/

Vandever, L. (2019). Rheumatoid arthritis by the numbers: Facts, statistics, and you. Healthline.

Retrieved April 26, 2021, from https://www.healthline.com/health/rheumatoid-arthritis/facts-statistics-infographic

Venables, P. J. W. (2019). Disease outcome and functional capacity in rheumatoid arthritis.

UpToDate. Retrieved May 1, 2021, from https://www-uptodate-com.ezproxy.stfrancis.edu/contents/disease-outcome-and-functional-capacity-in-rheumatoid-arthritis?search=rheumatoid%20arthritis%20pathophysiology&source=search_result&selectedTitle=11~150&usage_type=default&display_rank=11

Venables, P. J. W., & England, B. R. (2021). Clinical manifestations of rheumatoid arthritis.

UpToDate. Retrieved April 30, 2021, from https://www-uptodate-com.ezproxy.stfrancis.edu/contents/clinical-manifestations-of-rheumatoid-arthritis?search=rheumatoid%20arthritis%20&source=search_result&selectedTitle=4~150&usage_type=default&display_rank=4

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Ankylosing Spondylitis

Epidemiology

Definition

Ankylosing spondylitis is a chronic inflammatory autoimmune disease that mostly affects the spine joints leading to severe chronic pain and can also lead to spine fusion in advanced cases (Zhu et al., 2019). Tsao et al (2019) define ankylosing spondylitis as a chronic inflammatory disease that affects the axial spine and is characterized by chronic back pain, progressive spinal stiffness, peripheral arthritis, entheses, involvement of the peripheral joints and sacroiliac joints, hip pain, dactylitis, and postural abnormalities.

Causative Agent

Ankylosing spondylitis occurs from complex interactions between environmental factors and genetic background. Genetically, HLA-B27 which occurs in some people is thought to trigger an autoimmune reaction in the body that leads to the common bacteria in the body being attacked, causing the symptoms of ankylosing spondylitis (Zhu et al., 2019). Microorganisms such as Klebsiella pneumoniae and Porphyromonadaceae act as triggering factors of the innate immune system and thus they act as exacerbating agents in the autoimmune process of ankylosing spondylitis (Zhu et al., 2019).

Risk Factors

Risk factors for ankylosing spondylitis include gender, age, and genetics. For gender, men have a higher risk of developing ankylosing spondylitis (AS) as they are 2 to 3 times more likely to suffer from the disease when compared to women. (Chen et al., 2021). Men also have more severe symptoms. For the age, AS normally begins during adolescence and young adulthood. 95% of people have AS diagnosis before the age of 45 years. Genetics is a very important risk factor in AS. The majority of individuals with AS have the HLA-B gene. HLA-B gene produces a protein actively involved in the body’s immunity as it is a component of the human leukocyte antigen complex that produces cell-surface proteins that assist the immune system to distinguish between the foreign substances and the body’s molecules (Chimenti et al., 2021). HLA-B27 is a variation of HLA-B that is associated with an increased risk of ankylosing spondylitis. Other genes associated with an increased risk to AS include ERAP1, IL1A, and IL23R (Chimenti et al., 2021).

Exposures

Exposure to environmental pollutants and toxins such as uranium, trimethylarsine oxide, and tungsten is a trigger of ankylosing spondylitis (Shiue, 2016). Additionally, individuals residing in older households have higher rates of ankylosing spondylitis indicating that asbestos could be a possible trigger to AS. Exposure to tobacco smoke is also a trigger of ankylosing spondylitis (Shiue, 2016). Long-term exposure to particulate matter and a high intake of a high-fat diet are also associated with the development of AS (Soleimanifar et al., 2019).

Time Course

Prodromal Pattern

Ankylosing spondylitis normally starts at the site where the spine joins the pelvis and especially within the sacroiliac joints leading to pain and stiffness and may affect mobility and the shape of the spine (Farooque et al., 2021). The early onset of ankylosing spondylitis is characterized by signs and symptoms such as pain and stiffness of the hips and the lower back, particularly in the morning and after inactivity. Fatigue and neck are also early symptoms of ankylosing spondylitis (Farooque et al., 2021). Overtimes, these symptoms may deteriorate or stop/improve at irregular intervals. During the onset of the disease, the area that is most commonly affected include the vertebrae in the lower back, hips, and shoulder joints, joint between the base of the spine and pelvis, the cartilage between the ribs and breastbone, and the site where the ligaments and tendons attach to bones, mostly the spine. Other early symptoms of AS are mild fever, loss of appetite, night sweats, and malaise (Zhu et al., 2019). The symptoms gradually develop over weeks or months and are more pronounced at night and in the morning.

Duration

The course of ankylosing spondylitis variable. Ankylosing spondylitis starts with inflammatory back pain that persists for more than 3 months. Ankylosing spondylitis gradually moves from the base of the spine to the neck and imaging tests such as MRI can demonstrate the severity of the condition based on how much the spine is affected. The changes in the spine can be difficult to spot during the first few years but they become visible with time (Voruganti & Bowness, 2020). When the inflammation worsens, other body parts such as the entheses may be affected leading to pain in the hips, ribs, thighs, heels, and shoulders. Inflammatory conditions may also occur where approximately 1/3 of individuals with ankylosing spondylitis have eye inflammation.

During the second stage of the disease, the joints are involved especially the sacroiliac joint and this is visible during an x-ray. As a result, the diagnosis of AS is more likely during the second stage (Voruganti & Bowness, 2020). Diagnosis of ankylosing spondylitis is rarely early and the interval between the initial symptoms and the diagnosis may take about five to ten years. The third stage is characterized by irreversible damage. There is a chronic inflammation of the joints that leads to the loss of bone (Zhu et al., 2019). There is also syndesmophytes, which is the calcification of the spinal ligaments. As ankylosing spondylitis develops and the spine gets more immobilized when the bone forms within the joints, the shape of the spine changes and appears like bamboo which increases the risk of a fracture within the vertebrae. Symptoms in the final stage may take more than 10 years to manifest.

Pathophysiology

The pathophysiology of ankylosing spondylitis has a clear association with the HLA-B gene because 1-2 percent of people having HLA-B27 genotype develop AS and about 85 percent of individuals with ankylosing spondylitis express HLA-B27 genotype (Akassou & Bakri, 2018). There is no single agent allied to the causation of ankylosing spondylitis. The interaction of genetic, environmental, and immunological factors explains the development of AS. Interactions that occur between MHC-I molecule HLA-B27 with T cell response are key to the pathophysiology of AS.  According to Voruganti & Bowness (2020), there is a complex interaction between increased serum levels of IgA and acute stage reactants of inflammation, the HLA-B27, and the immune system of the body. The main target of the immune system and the inflammation in ankylosing spondylitis is entheseal fibrocartilage where there is inflammation of enthesis at the vertebrae (Watad et al., 2018). Therefore, the key pathology of AS is enthesitis coupled with chronic inflammation, and this includes macrophages, CD4+ and CD8+ T lymphocytes. Cytokines and especially transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) are also key in the inflammatory process as they trigger fibrosis, inflammation, and ossification at areas of enthesitis (Voruganti & Bowness, 2020). The processes that occur at the entheses include inflammation, the erosion of the bone as well as the formation of syndesmophyte.  The tumor necrosis factor is a key mediator during the inflammatory process. The release of systemic or local cytokine is associated with bone loss where bone loss is associated with a rise in the resorption of bone. TNF plays a significant role in osteoclast activity and bone development in AS. To trigger bone resorption, osteoclasts release hydrochloric acid that dissolves minerals in the bone and also releases metalloproteases which break down the collagenous matrix, leading to bone loss (Boyce et al., 2018). Inflammatory cytokines are associated with loss of bone mineral density (BMD). Impaired absorption of calcium and vitamin D is also associated with the development of AS. Lee et al (2021) explain that reduced physical activity and immobility play an important role in bone loss in ankylosing spondylitis. As ankylosing spondylitis progresses, the neighboring joint tissues or articular tissues are destroyed. The replacement of the new and original cartilages occurs through the fusion of the bone. This leads up to the joining up or fusion of the joint bones, stiffness as well as immobility. This is the most pronounced symptom within the spine in AS.

 

 

References

Akassou, A., & Bakri, Y. (2018). Does HLA-B27 Status Influence Ankylosing Spondylitis Phenotype?. Clinical medicine insights. Arthritis and musculoskeletal disorders, 11, 1179544117751627. https://doi.org/10.1177/1179544117751627

Boyce, B. F., Li, J., Xing, L., & Yao, Z. (2018). Bone remodeling and the role of TRAF3 in osteoclastic bone resorption. Frontiers in immunology, 9, 2263.

Chen, H. H., Chen, Y. M., Lai, K. L., Hsieh, T. Y., Hung, W. T., Lin, C. T., … & Chen, Y. H. (2020). Gender difference in ASAS HI among patients with ankylosing spondylitis. PloS one, 15(7), e0235678.

Chimenti, M. S., Perricone, C., D’Antonio, A., Ferraioli, M., Conigliaro, P., Triggianese, P., Ciccacci, C., Borgiani, P., & Perricone, R. (2021). Genetics, Epigenetics, and Gender Impact in Axial-Spondyloarthritis Susceptibility: An Update on Genetic Polymorphisms and Their Sex Related Associations. Frontiers in genetics, 12, 671976. https://doi.org/10.3389/fgene.2021.671976

Farooque, K., Kar, S., Siamwala, B. S., & Sharma, V. (2021). Retrospective Diagnosis of Ankylosing Spondylitis after Spinal Fractures: A Review of 3 Cases and Clinical Implication. Case Reports in Orthopedic Research, 4(2), 173-179.

Lee, S. Y., Song, R., Yang, H. I., Chung, S. W., Lee, Y. A., Hong, S. J., … & Lee, S. H. (2021). The bone bridge significantly affects the decrease in bone mineral density measured with quantitative computed tomography in ankylosing spondylitis. PloS one, 16(4), e0249578.

Shiue, I. (2016). Relationship of environmental exposures and ankylosing spondylitis and spinal mobility: US NHAENS, 2009–2010. International journal of environmental health research, 25(3), 322-329.

Soleimanifar, N., Nicknam, M. H., Bidad, K., Jamshidi, A. R., Mahmoudi, M., Mostafaei, S., … & Nikbin, B. (2019). Effect of food intake and ambient air pollution exposure on ankylosing spondylitis disease activity. Advances in Rheumatology, 59.

Tsao, C. H., Huang, J. Y., Huang, H. H., Hung, Y. M., Wei, J. C. C., & Hung, Y. T. (2019). Ankylosing Spondylitis Is Associated With Risk of New-Onset Obstructive Sleep Apnea: A Nationwide Population-Based Cohort Study. Frontiers in medicine, 6, 285.

Voruganti, A., & Bowness, P. (2020). New developments in our understanding of ankylosing spondylitis pathogenesis. Immunology, 161(2), 94–102. https://doi.org/10.1111/imm.13242

Watad, A., Cuthbert, R. J., Amital, H., & McGonagle, D. (2018). Enthesitis: Much More Than Focal Insertion Point Inflammation. Current rheumatology reports, 20(7), 41. https://doi.org/10.1007/s11926-018-0751-3

Zhu, W., He, X., Cheng, K., Zhang, L., Chen, D., Wang, X., Qiu, G., Cao, X., & Weng, X. (2019). Ankylosing spondylitis: etiology, pathogenesis, and treatments. Bone Research, 7, 22. https://doi.org/10.1038/s41413-019-0057-8

 

 

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