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. 

Biologics or Methotrexate--What is the Safer and More Effective Therapy?

Systematic Review and Meta-Analysis of the Efficacy and Safety of Existing TNF Blocking Agents in Treatment of Rheumatoid Arthritis, Aaltonen et al, 2012

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What did they study?

This article is a meta review of 26 clinical trials that evaluated the safety and efficacy of TNF-alpha inhibitors, the most popular biologic therapy for RA patients. Five different therapies were evaluated in these studies:

• Adalimumab, (Humira®) – 8 studies
• Enteracept (Enbrel®) – 7 studies
• Infliximab (Remicade®) – 5 studies
• Golimumab (Simponi®) – 3 studies
• Certolizumab (Cimzia®) – 3 studies

To evaluate efficacy, the researchers evaluated each study to calculate the relative likelihood that study patients would achieve 20, 50, or 70% disease improvement, compared to patients in the control group (placebo or methotrexate), with 50% improvement being the primary goal to define the “risk ratio” of success. They also evaluated the efficacy of a TNF-alpha blocker combined with methotrexate compared to methotrexate alone. Finally, they evaluated whether higher doses of TNF-alpha blocker we associated with improved outcomes.

Safety was evaluated by comparing the risk of an adverse event that required withdrawal from the study for patients treated with the study drug versus patients in the control group (placebo or methotrexate). Combined (TNF-alpha blocker + methotrexate) was also evaluated as well as higher doses of TNF-alpha blocker.

What were the results?

In general, TNF-alpha blockers alone were only marginally (and not statistically significantly) better than methotrexate for achieving a 50% improvement for patients. When compared to control in general, enteracept, adalimumab, and certolizumab had substantially higher relative risk of achieving 50% improvement. Infliximab and golimumab had higher relative risk than controls, but were close. When TNF-alpha blockers were combined with methotrexate, the outcome was substantially better. Increasing the dose of TNF-alpha blocker did not appear to result in an improved outcome.

The primary adverse event observed with TNF-alpha blocker treatment was an injection site reaction, which is expected for biologic products. When compared to control, most of the TNF-alpha blockers had a higher relative risk of an adverse event, with the exception of enteracept. When administered alone, enteracept had a lower relative risk than control of an adverse event. However, when methotrexate was added to enteracept, this improved risk was eliminated. Higher doses of TNF-alpha blockers did not appear to increase the risk of an adverse event.

What does this mean?

From this study, it appears that enteracept is more efficacious and safe compared to other treatments, although not more efficacious that the substantially less expensive methotrexate. From a cost-benefit perspective, a patient would probably benefit more from starting with methotrexate and only adding or switching to enteracept if they don’t see an improvement in their symptoms under this traditional therapy.

There is likely a bias against golimumab and certlizumab in this review, given that there were many fewer studies represented. Furthermore, these are newer products, with both approved for use in RA patients in 2009, compared to enteracept , which was approved in 1998. A longer patient history and more trial data may even out the results.

On a further note, studies of drug efficacy are based on combination therapy with methotrexate. I would be interested in seeing studies evaluating biologic therapy in combination with other DMARD medications, such as hydroxychloroquine (Plaquenil) and especially with Sulfasalazine, which inhibits TNF-alpha on its own.

Why do ACPA-positive patients tend to have more bone damage?

Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin, Harre et al, 2012

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First, some definitions to help you understand this article:

Vimentin is a part of the skeleton of many connective tissue cells, including bone cells.


Citrullination is a chemical change in a protein that changes its amino acid makeup (check out this page  for more information about proteins and amino acids). Citrullination commonly occurs as a result of inflammation.

There are several types of bone cells. This article focuses on osteoclasts, which are responsible for resorbing (destructing) bone. Osteoclasts don't always exist, although they generally can be found somewhere in your body. You always have the stem cells that become osteoclasts in your body (called precursors, below). These cells are activated by a member of the tumor necrosis (TNF) family--I will talk about TNF in a future article. Bone resorption is not always a bad thing. It is a necessary process of life. When structural bone cells (osteocytes) are damaged by injury or inflammation, osteoclasts take away the damaged tissue so that is can be replaced with new, healthy bone. 
In rheumatoid arthritis, osteoclasts resorb bone but it is not able to be repaired at the pace that it is destroyed. This leads to joint damage and eventually complete joint destruction.


Anti-citrullinated protein antibody (ACPA) was discussed briefly in the previous article. These are antibodies found almost exclusively in people with RA and approximately 2/3 of RA patients have detectable ACPA in their blood. These are antibodies that attack bind to proteins that have undergone citrullination. An antibody titer is just a measure of the amount of antibody that is in a sample. For more about antibodies in general, see this article.

What did they study?

The researchers started by measuring levels of bone resorption biomarkers (levels of which indicate how much bone is being resorbed) in the blood of people with normal (non-RA), seronegative RA, ACPA-positive RA, and RF-positive RA. The RA patients were all newly diagnosed patients who had not been treated with drugs that affect the immune system.

They then collected blood from patients with high titers of ACPA and examined how these antibodies bind to certain proteins, to see if they have a binding preference for citrullinated vimentin and to see if they would bind to other citrullinated proteins.

To understand how ACPA promotes bone destruction, the researchers cultured precursor cells with ACPA-positive and negative serum (from RA patients) to see if the presence of ACPA encouraged the cells to differentiate into osteoclasts. They also tested to see if the osteoclasts that differentiated in the presence of ACPA were better at breaking down bone using slices of cow bones.

Finally, they isolated ACPA that specifically binds to citrullinated vimentin and administered these antibodies to mice with impaired immune systems (make fewer white blood cells). After four weeks, they measured the size and density of bones as well as bone resorptive, bone building markers, and TNF-alpha. They also measured the susceptibility of precursor cells to become osteoclasts.

What were the results?

In patients that were positive for ACPA, the researchers found significantly higher levels of bone resorption factors and the amount increased substantially depending on the titer of ACPA in the blood. Seronegative and RF-postive only patients did not have increased levels compared to non-RA patients. The antibodies from ACPA-positive patients bound to citrullinated vimentin, but not to vimentin in its normal state.

When precursor cells were cultured with ACPA-positive serum more cells differentiated into osteoclasts compared to cells treated with normal or negative RA serum. These results were confirmed in the mice. The animals that were administered ACPA had significantly lower bone density and high bone resorptive markers. Furthermore, there were more osteoclasts observed. The ACPA-dosed mice did not, however, have increased bone building factors compared to normal mice.

Precursor cells from these animals were also more susceptible to becoming osteoclasts as they appeared to be more sensitive to factors that induce this differentiation.  ACPA-administered mice had higher levels of TNF-alpha, which the researchers confirmed in cell culture has a sensitizing effect on precursor cells. Inflammation and cellular injury are key factors in increasing the amount of citrullinated vimentin that is expressed in these cells. The antibodies binding to the citrullinated vimentin in cells appears to further encourage the cells to differentiate into osteoclasts.

What does this mean?

I mentioned in the previous article that ACPA-positive patients tend to have more bone and joint destruction than seronegative patients. In this article, we come understand why.

TNF-alpha is a pro-inflammatory cytokine (chemical signal in the immune system), and is present in high levels in RA patients. In fact, there are many drugs now available that interfere with TNF-alpha to reduce severity of disease. It appears from this study that the presence of TNF-alpha makes precursor cells more likely to become osteoclasts.

These results may indicate that physicians should consider the earlier use of TNF-alpha inhibiting drugs in treated ACPA-positive patients. The results also further underline the importance of controlling inflammation in patients, regardless of ACPA status.

Early Diagnosis Linked to Likelihood of Remission in One Year

Very early rheumatoid arthritis as a predictor of remission: a multicentre real life prospective study, Gremese et al 2012

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What did they study?

This study, conducted in Italy, evaluated the percentage of patients that experienced remission of rheumatoid arthritis symptoms after one year of treatment. Patients referred to the study, which required the presence of two or more swollen joints, were broken down into two groups, depending on whether their symptoms were present for more or less than 12 weeks. Those patients with symptoms lasting less than 12 weeks were referred to as VERA, or very early rheumatoid arthritis.

All patients were started on 15 mg/week of methotrexate (or up to 25 mg/week) for three months. Following that three month period, patients were treated according to their individual doctor's plan, with the option of adding another non-biologic DMARD or a biologic TNF-alpha blocker like Enteracept (AKA, Enbrel).

After 12 months of treatment, patients were assessed for the number of swollen and tender joints, erythrocyte sedimentation rate, C-reactive protein levels in their blood, duration of morning stiffness, self-reported assessment of pain and health, and HAQ disability index.

What were the results?

After 12 months of treatment, 34.3% of patients achieved remission as defined by DAS-28 score of <2.6 and 15.2% achieved remission as defined by the American College of Rheumatology, which is a stricter standard.

Of those patients that achieved remission, statistical analyses showed that the most likely predictive factor was treatment with DMARD within three months of symptoms appearing. 

Interestingly, at the end of the 12 month period, patients with VERA were generally only on a non-biologic DMARD. Only 9.5% of those patients were on a TNF-alpha blocker. In comparison, 25.6% patients who enrolled on the study with symptoms lasting longer than three months were on a TNF-alpha blocker. Furthermore, of those patients in remission, only 10% of VERA patients received a TNF-alpha blocker, but 32% of non-VERA patients had.

What does this mean?

This study demonstrates the importance of early diagnosis and treatment in patients. In the paper, the investigators discussed educating the population about rheumatoid arthritis and its symptoms to encourage potential patients to seek medical attention early on. They also stressed education of primary care physicians in recognizing the symptoms and referring patients to the care of a rheumatology specialist early.

It is important to inform and educate the public about rheumatoid arthritis. It is easy to, as I did, talk yourself out of taking your pain and other symptoms seriously. As shown in this study, a delayed diagnosis is very much related to staying in pain and becoming disabled. Since this is a disease that first affects people in the prime of their lives, early treatment is especially vital to avoid losing productive years.