Disease Activity Affects Fatigue Level

Anemia versus disease activity as a cause of fatigue in rheumatoid arthritis, Escobar et al, 2010

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What did they study?

Approximately 50% of RA patients are anemic, which is thought to be the result of inflammatory processes associated with the disease. Microbes require iron to grow, so it may be part of the natural immune system to actively reduce the amount of iron in the blood in response to infection.

This study evaluated 130 RA patients by measuring the level of fatigue using a 40 question survey in which patients rank on a scale of 0-4 their responses to questions about their physical, social, emotional and functional status. The lower the score, the more fatigued the patient is.

Patient fatigue was compared to hemoglobin levels and DAS-28 score (using number of painful and swollen joints, erythrocyte sedimentation rate (ESR) and a patient assessment of health on a scale of 0-10).

What were the results?

Fatigue score was not associated with hemoglobin levels, but was highly correlated with increases in DAS-28 score. The researchers further analyzed the data to look at whether ESR, joint pain/swelling, or global health score were the aspect of the score that correlated with increased fatigue and found that while ESR was not related to fatigue score, increases in the number of painful and swollen joints or global health scale were associated with higher levels of fatigue. 

What does this mean?

I discount the correlation of patient's reported global health score, since that will naturally be correlated with increased levels of fatigue--if the patient is fatigued they are more likely to feel depressed and thus subjectively score their disease as more severe. However, it is interesting that higher disease activity is more associated with fatigue than low blood iron levels. It indicates that while increasing iron levels is important for overall health, the key to reducing fatigue is managing inflammation. While DMARDs may have some anti-inflammatory effects, especially in the long term, it is clear that patients may need multiple therapies to maintain quality of life.

Differences in Interferon-gamma gene may predict severity of RA

Association between dinucleotide repeat in non-coding region of interferon-gamma gene and susceptibility to, and severity of, rheumatoid arthritis, Khani-Hanjani et al, 2000

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Definitions

Interferon-gamma (IFN-y) is an immunostimulating cytokine that is secreted by certain types of immune cells, called natural killer cells and T-lymphocytes. It stimulates many actions of immunity (e.g., increases the activity of macrophages and antibody production from B-cells) and is associated with many autoimmune diseases, including rheumatoid arthritis. IFN-y is produced by T-lymphocytes in inflamed synovial tissue in RA patients.

Polymorphisms, at least as used in this article, are basically different versions of the same gene in a certain region, meaning they have a different sequence. They can also be of varying lengths, as is the case in this paper. These polymorphisms can loosely be referred to as alleles, as is done in this paper. If a person has the same allele on both chromosomes (we have a pair of each, excluding the X/Y chromosomes), they are homozygous. If they have a different allele, they are heterozygous.

The genetic sequence of a gene is made up of introns and exons. Exons are the coding region, or the part of the gene that actually codes for the protein. Introns are the "rest" of the sequence. This article explains it well.

What did they study?

The researchers selected patients with mild or severe rheumatoid arthritis and compared the genetic make-up of the first intron on the gene that codes for IFN-y to normal (non-RA) patients. Severe RA was defined as patients who had failed to respond to treatment with three DMARDs and were taking cyclosporin. Mild RA was defined as patients who had well-controlled RA for three years on antimalarials, took no other DMARDs, and had fewer than 4 swollen and 0 deformed joints. A total of 60 severe, 39 mild, and 65 normal people were examined.

They looked at a range of six alleles of different lengths within the first intron, on both chromosomes (the gene is found on number 12): 120 base pairs (bp), 122 bp, 124 bp, 126 bp, 128 bp, and 130 bp.

What were the results?

The 120, 124, 128, and 130 bp alleles were present in approximately the same proportion of normal, mild, and severe patients. The 122 bp allele was much more common in normal or mild RA patients (80% and 64%, respectively) compared to severe RA patients (7%). Meanwhile, the 126 bp allele was more common in severe RA patients (73%) compared to normal or mild RA patients (12% and 21%, respectively). Furthermore, patients with severe RA were more likely to be homozygous for the 126 bp allele, while only 3% of mild patients and 0 normal patients were. Conversely, no severe RA patients were homozygous for the 122 bp allele, while 8% of mild RA patients and 17% of normal patients were.

What does this mean?

While this paper did not get into the significance of these genotypes with regards to IFN-y expression; however, in another paper (Dabora et al, 2002) they mention that the 126 bp allele described in this paper is associated with increased IFN-y production in vitro. Thus, from this study we not only learn that perhaps there is a detectable genotype that can predict potential severity of disease, but that the severity may be related to increased IFN-y production. This makes sense, as IFN-y increases immune activity and thus joint damage in RA patients.

Reading these articles, I think it is very notable that there is not a clear path or mechanism or really just one disease going on here. Rheumatoid arthritis is really a syndrome that has many causes: genetic or environmental.