Common Factors Of Alzheimer’s Disease And Rheumatoid Arthritis—Pathomechanism And Treatment Part 2

Appropriate biomarkers appear in the serum in RA patients, such as rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), C-reactive protein (CRP), amyloid A protein, and calgranulin [76]. 

In recent years, more and more studies have shown that rheumatoid factor (RF) is associated with memory to a certain extent. RF is a marker of autoimmune response and is often used to diagnose rheumatic diseases such as rheumatoid arthritis. However, studies have found that high levels of RF can affect a person's memory function, and this effect is not entirely negative.

First, some studies have shown that people with high RF levels retain and recall memories of emotional experiences better than others. This may be because RF is related to emotional regulation, and emotional experience is often an important component of memory. Therefore, even if RF levels are high, emotional memories may be strengthened.

Second, another study found that people with high RF levels perform better when performing some memory tasks. This is because RF can promote the growth and migration of neurons, thereby enhancing the formation and storage of memories. In this way, even if RF affects the formation and cognition of other memories, it will make people perform better in some specific areas or tasks.

In short, there is a certain association between RF and memory, but this association is not entirely negative. In some specific cases, high levels of RF may even enhance memory ability and bring unexpected benefits. Therefore, the test results of RF should be taken seriously, but there is no need to be too worried and anxious. We should actively face the different challenges in life and discover and utilize the opportunities therein. It can be seen that we need to improve memory. Cistanche can significantly improve memory because it has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

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The presence of amyloid structures is of particular interest since the amyloidosis of the light chains of transthyretin and immunoglobulins contributes to amyloid deposition in soft tissues. The accumulation process is, in effect, a direct cause of orthopedic diseases [77]. 

One of the studies indicated the presence of amyloid deposits detected during orthopedic procedures, especially in people over 70 years of age [78]. Moreover, a study by Donelly et al. [79] indicates that 10% of men over 50 and women over 60 after a biopsy have tendon sheath-positive markers of amyloid tissue [79]. 

Protein amyloid A (SAA, serum amyloid A), which is produced by liver cells, deserves additional attention. Hepatocytes that are stimulated by the presence of pro-inflammatory cytokines (including TNF-α, IL-1, and IL-6) produce SAA in increased amounts. One study determined that the overproduction of SAA can occur in several diseases related to inflammatory pathology. 

Such diseases include long-term inflammation, including chronic infections, such as tuberculosis, osteomyelitis, rheumatoid arthritis, inflammatory bowel disease, hereditary diseases, and hematological and solid neoplasms [80]. 

It is worth noting that the overproduction of pro-inflammatory cytokines promotes increased angiogenesis, the processes of connective-tissue binder degradation in RA, and increased amyloid activity, which characterize cytokines as pleiotropic mediators [81].

3. The Activity of the Immune System in AD and RA

Chronic systemic peripheral inflammation influences the neurodegenerative processes that are characteristic of AD. 

The activity of inflammatory cytokines such as TNF-α, IL-6, IL-1β, transforming growth factor beta (TGF-β), IL-12, and IL-18 is noticeable in AD patients compared to healthy controls [82]. The above-mentioned cytokines and their influence are being studied both in the pathogenesis of AD and in RA because the over-reactivity of the immune system is a common feature of these disorders. 

When determining the positive correlation between AD and RA, it should be noted that the incidence of AD is much higher in RA patients than in healthy people [83]. In a separate study, cognitive decline was observed later in life in people struggling with arthritic diseases, especially RA [84]. 

Work on the effects of systemic inflammation has been studied through the activity of anti-inflammatory drugs. Methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs), which are common pharmaceuticals used in RA, reduce the risk of AD-related dementia, especially when these drugs are administered early in the disease [85,86]. 

It is known that overactivity of the immune system is the bridge between these diseases; however, further research is needed to determine the exact correlation between RA and AD. A common feature between RA and AD is the dysregulation of cell cycle suppression genes, which in turn contributes to the incidence of systemic inflammation. 

Studies show that inflammatory changes affect the appearance of pathological changes in both disorders and cell cycle modifications are significantly age-regulated [87]. 

In the context of Alzheimer's disease, it is claimed that systemic inflammation influences the appearance of neurodegenerative changes [82]. Activation of the immune system contributes to the development of dysfunction in the central nervous system. Imaging tests show a reduced brain volume and pathological changes in white matter [88]. 

Systemic inflammation also affects the limited distribution of blood in the blood vessels, which contributes to brain dysfunction due to restricted oxygen supply. Therefore, it can be assumed that changes in circulating blood flow increase the risk of developing dementia [89]. 

In patients with depression and AD, raised levels of pro-inflammatory cytokines, acute phase proteins (APPs), interferon-gamma (IFN-γ), interleukin 1 (IL-1), IL-6, and TNF-α were observed [90]. Based on the literature, it is suggested that NSAIDs (non-steroidal anti-inflammatory drugs) inhibit the formation of fibrous Aβ by stimulating α-secretase. 

As a result of such activity, APP is transformed by a non-amyloidogenic path, which leads to a reduction in the formation of amyloidogenic forms [91]. The legitimacy of the use of NSAIDs in AD has been determined in several studies. A meta-analysis was performed, which included 16 cohort studies, conducted between 1995 and 2016 and involving 236,022 participants [92]. 

It showed that the current or previous use of NSAIDs was significantly associated with a reduced risk of AD compared to those who did not use NSAIDs. The study also shows correlations related to where the patients live (eight studies looked at populations from North America, six studies were from European countries, and two studies focused on Asian populations). 

Noteworthy, in this study, the researchers have studied the influence of the environmental factor. The authors showed that NSAID exposure was associated with a reduced risk of AD in population-based studies. Such correlations were not noted in the study on the importance of environmental factors. The study pointed to a significant impact of NSAID exposure in Europe. 

The borderline effect of NSAID exposure was observed in studies conducted in North America, and NSAID exposure was not associated with the reduced risk of AD in studies conducted in Asia. 

Current evidence suggests an effect of NSAIDs on a reduced risk of AD especially in large population-based cohort studies. The authors suggest that there is a need for a much larger study to justify the dose of the drug and the duration of NSAID exposure [92]. Among the similar meta-analyses cited by the authors of the study is a meta-analysis performed by Etminan et al. 

The authors of this study report a positive correlation between the use of NSAIDs and the onset of AD. Even though it includes nine observational studies, it is necessary to point out some limitations related, among other things, to the use of a specific NSAID and the reduction of the risk of AD [93]. 

One study evaluated the safety and efficacy of low doses of naproxen in preventing the progression of pre-asymptomatic AD among at-risk individuals with cognitive impairment. This two-year study involved 195 elderly people (mean age 63 years) who had a positive family history of AD. Patients underwent an imaging examination to exclude cognitive impairment. 

The researchers have divided the study participants into two groups. One of them received a placebo, while the second group was administrated with naproxen sodium at a dose of 220 mg twice daily. 

Multimodal, neurosensory, cognitive imaging and evaluation of cerebrospinal fluid biomarkers were performed at the start of the study, 3, 12, and 24 months. People who took naproxen sodium experienced side effects. 

Naproxen did not reduce the progression of AD. Moreover, secondary analyses did not show any significant effect of treatment on individual biomarker indicators of cerebrospinal fluid nor cognitive or neurosensory progressive pre-symptomatic AD [94]. 

The effectiveness of NSAIDs in AD was studied on the example of naproxen and celecoxib. This was a large, multi-year randomized, placebo-controlled clinical trial. The researchers concluded that not every drug can delay the onset of AD in adults with a family history of dementia [95]. The implementation of appropriate treatment for the patient often depends on their economic status. 

Particularly noteworthy is the study conducted by Moilna et al [96]. The study aimed to determine the relationship between socioeconomic status (SES) and delays in treatment with disease-modifying antirheumatic drugs (DMARDs) in RA patients. 

A total of 1209 RA patients were recruited for the study, of whom 1159 received DMARD treatment. Researchers have assessed SES based on education, occupation, and income. After a preliminary analysis, they divided the patients into terciles. 

The researchers assessed the severity of the disease, which was determined by the rate of disease activity in 28 joints. They determined joint damage based on manual radiographs according to the Sharp scale and physical disability based on a modified Health Assessment Questionnaire (M-HAQ). 

The researchers conclude that patients with lower SES experience longer delays in starting DMARD treatment. Additionally, patients who experience a greater delay in initiating DMARD treatment do experience a clinically significant increase in joint damage [96]. 

The relationship between AD and RA was investigated by Chou et al. [97]. The authors of the study analyzed medical and pharmaceutical claims. The analysis took into account data from adults who were commercially insured between 2000 and 2007. After analyzing the data, 325 people showed symptoms of AD and were diagnosed with RA. 

The study took into account the presence of concomitant diseases in patients such as coronary artery disease, diabetes, hyperlipidemia, hypertension, and peripheral vascular disease. It was determined that the overall incidence of AD among people with RA was 0.79%, while the incidence of AD among those without RA was 0.11%. 

In addition, it was shown that chronic conditions such as coronary artery disease, diabetes, and vascular disease significantly increased the relative risk of AD among patients with RA. The authors of the study additionally analyzed patients suffering from RA. For this purpose, the prevalence of AD among patients with RA after exposure to various RA therapies was determined. 

The drugs used in RA were methotrexate, prednisone, sulfasalazine, three anti-TNF drugs (adalimumab, etanercept, and infliximab), and an anti-CD20 drug (rituximab). The researchers concluded that anti-TNF therapy in RA lowered the risk of AD among these patients. 

Although the researchers have shown that inflammation is probably important in the pathology of AD, more research should be carried out in this direction [97]. Ungprasert et al. [98] drew similar conclusions and indicated an increased risk of dementia in patients suffering from RA [98]. The authors of the study suggest that the correlation between AD and RA should be linked to blood vessel disease. 

In the above monograph, the authors indicate that atherosclerosis caused by RA is a possible explanation for such a correlation. Atherosclerotic cardiovascular disease is a well-known risk factor for dementia [99]. 

In addition, the predisposition to the occurrence of atherosclerosis in patients with RA results from the negative impact of interacting cytokines on vascular endothelial cells [100]. It is worth noting that the occurrence of cardiovascular diseases is more common among patients with autoimmune inflammatory diseases [101].

Mendel's randomized controlled trials assessing the potential relationship between AD and RA are of particular interest. 

The authors of the study used publicly available collections of studies consisting of three-stage trans-ethnic, European-specific, and Asianspecific genome-wide association study (GWAS) meta-analyses, which evaluated 10 million single nucleotide polymorphisms (SNPs) in 29,880 RA cases and 73,758 controls assigned as exposures. 

The researchers used Mendelian randomization (MR), which uses genetic variants as instrumental variables. Its use assesses the relationship between the risk factor or exposure and whether the outcome is consistent with the causal effect. The analysis is dedicated to studies in which it is difficult to measure exposure and outcome in the same group of people. 

The study aimed to determine whether RA is causally related to AD using MR analysis of two trials. In this study, Bae and Lee [102] indicated a significant causal relationship between RA and AD. The researchers suggest that the study has some limitations. 

First of all, genetic variants have little effect on RA, and there is a need to experiment on a large population of people. In addition, the work was carried out on the European population. This is an inaccurate fact, as the relationship between AD and RA may be related to ethnicity. Therefore, the authors suggest that there is a need to conduct a study on a diverse study group. [102]. 

Other researchers have noted that drug therapy with anti-rheumatic drugs reduces the risk of dementia [103]. Researchers observed a reduced risk of dementia in cDMARD users compared with those not taking such medications. In addition, after the use of drugs, there was a reduction in the risk of dementia in those using cDMARD. The strongest effect was achieved with the use of MTX (methotrexate). 

The risk of dementia was 0.5% compared to 1.6% at 5 years and 1.5% at 3.0% at 15 years. The results obtained by the researchers are consistent with the estimated incidence of dementia in the UK in 2013, which was 1.3%. 

Despite the results, the authors of the study point to some limitations. The study involved people who suffered from comorbidities, including cardiovascular disease, myocardial infarction, congeal heart failure, peripheral vascular disease, interstitial lung disease, anemia, and osteoporosis. Before starting RA therapy, patients took antihypertensive drugs, analgesics, statins, or proton pump inhibitors. [103]. 

One of the newest studies conducted in 2020 confirms the above-mentioned findings and additionally indicates the potential protective effect of anti-TNF drugs in patients with RA [104]. This study was conducted on 56 million adults in the United States and showed a positive correlation between AD and RA and a lower risk of AD in patients taking etanercept, adalimumab, or infliximab. 

The authors of the study indicate that the above-mentioned biological drugs have poor distribution to the brain, and by acting systemically, they prevent TNF-α from entering the brain and thus prevent the risk of dementia. 

Thanks to this research, it is estimated that treatment of RA with TNF inhibitors can help prevent about 4.0% of AD cases (0.21 million) [104]. The correlations between AD and RA were investigated by McGeer and others [105]. 

Seventeen epidemiological studies from nine countries were used for the review. All these studies concluded that arthritis is a predisposing factor to the appearance of AD. 

The analysis also included studies that concluded about the positive importance of antiinflammatory drug therapy in AD. Using statistical meta-analysis methods, the researchers estimated the risk of developing AD in RA patients and anti-inflammatories compared to the general population. 

Seven case-control studies with arthritis as a risk factor yielded a total odds ratio of 0.556 (p < 0001), while four case-control studies with steroids yielded an odds ratio of 0.656 (p = 0.049). Three case-control studies with NSAIDs gave an odds ratio of 0.496 (p = 0.0002). 

When NSAIDs and steroids were combined into one category of anti-inflammatory drugs, the odds ratio was 0.556 (p < 0.0001). Therefore, the study confirmed the validity of the hypothesis of the protective effect of anti-inflammatory drugs in AD. Still, the researchers suggest that there is a need for clinical trials to thoroughly verify this hypothesis [105].

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