Proinflammatory Cytokines May Predict RA Risk

Elevated concentrations of proinflammatory cytokines, cytokine-related factors, and chemokines, indicating activation of the immune system, have been found in the blood of people years before they developed symptoms of rheumatoid arthritis that involved the joints, according to a report by Heidi Kokkonen and coinvestigators at Umeå (Sweden) University. The study was published in the February 2010 issue of Arthritis and Rheumatism.

By comparing blood samples of people diagnosed with RA to normal controls and “prepatients” (those who go on to develop RA), investigators said that they hope the results will help predict an individual's risk of developing RA.

The investigators analyzed samples from the Medical Biobank of Northern Sweden, which invites all adult individuals from the county of Västerbotten to contribute blood samples. Within this population-based cohort, there were 86 individuals who went on develop inflammatory joint disease that fulfilled American College of Rheumatology classification criteria for RA after their donation of blood. For these prepatients, the median time predating the onset of symptoms was 3.3 years (range, 1.1-5 years). Of the 86 prepatients, 69 also provided blood samples at the time of RA diagnosis. For every prepatient, three control subjects were randomly selected from the Biobank register and matched for sex, age, and area of residence.

Several cytokines, cytokine-related factors, and chemokines were upregulated in prepatients, compared with controls. The greatest increases were noted for the Th2-related cytokines, eotaxin, and interleukin-4, with elevated levels also observed for Th1 cytokines, IL-12, interferon-gamma, and IL-10.

A multivariate classification algorithm known as the random forest method, similar to decision trees, was used to estimate which groups of cytokines, cytokine-related factors, or chemokines could best distinguish a particular group of patients. For prepatients, characteristic changes were related to both the Th1 and Th2 lineage, and to Treg cells, representing the adaptive immune system, the authors wrote. Elevation of IL-17 levels did not reach statistical significance.

Levels of at least two-thirds of the cytokines or cytokine-related factors were above the median values for control subjects in 50 of 85 prepatients.

Of the chemokines, MCP-1 and MIP-1 alpha levels were significantly increased in prepatients, compared with controls, as were the levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte–colony stimulating factor (G-CSF).

When the authors calculated the sensitivity and specificity of different factors for the development of RA in prepatients, they found that after anti-CCP antibodies and IgM rheumatoid factor (IgM-RF), eotaxin had the highest sensitivity (22.4%) and specificity (95.3%), with an odds ratio of 5.8. About one-half of the cytokines and cytokine-related factors that had significant predicative value for the development of RA in prepatients were related to Th1, Th2, and Treg cells. When all analyzed factors and anti-CCP antibodies were included, the sensitivity level rose to 51.2%, with a specificity of 91.9% for predicting the development of RA among prepatients and control subjects.

The factors distinguishing individuals before and after the onset of RA represented a more general immunologic response, as well as stromal cells and angiogenic factors. After RA diagnosis, significant increases were seen for most of the factors that were measured. IL-17 concentrations actually decreased after RA diagnosis. “This observation endorses the role of IL-17 in the initiating phase [of RA], and, as the pathogenesis progresses, other factors are subsequently brought into action,” wrote the authors (Arthritis Rheum. 2010;62:383-91).

Although the authors were unable to conclude which agent initiates RA pathogenesis, they suggested that their findings present an opportunity for better predicting the risk of developing RA and intervening at an early stage to possibly prevent disease progression.

Elevated concentrations of proinflammatory cytokines, cytokine-related factors, and chemokines, indicating activation of the immune system, have been found in the blood of people years before they developed symptoms of rheumatoid arthritis that involved the joints, according to a report by Heidi Kokkonen and coinvestigators at Umeå (Sweden) University. The study was published in the February 2010 issue of Arthritis and Rheumatism.

By comparing blood samples of people diagnosed with RA to normal controls and “prepatients” (those who go on to develop RA), investigators said that they hope the results will help predict an individual's risk of developing RA.

The investigators analyzed samples from the Medical Biobank of Northern Sweden, which invites all adult individuals from the county of Västerbotten to contribute blood samples. Within this population-based cohort, there were 86 individuals who went on develop inflammatory joint disease that fulfilled American College of Rheumatology classification criteria for RA after their donation of blood. For these prepatients, the median time predating the onset of symptoms was 3.3 years (range, 1.1-5 years). Of the 86 prepatients, 69 also provided blood samples at the time of RA diagnosis. For every prepatient, three control subjects were randomly selected from the Biobank register and matched for sex, age, and area of residence.

Several cytokines, cytokine-related factors, and chemokines were upregulated in prepatients, compared with controls. The greatest increases were noted for the Th2-related cytokines, eotaxin, and interleukin-4, with elevated levels also observed for Th1 cytokines, IL-12, interferon-gamma, and IL-10.

A multivariate classification algorithm known as the random forest method, similar to decision trees, was used to estimate which groups of cytokines, cytokine-related factors, or chemokines could best distinguish a particular group of patients. For prepatients, characteristic changes were related to both the Th1 and Th2 lineage, and to Treg cells, representing the adaptive immune system, the authors wrote. Elevation of IL-17 levels did not reach statistical significance.

Levels of at least two-thirds of the cytokines or cytokine-related factors were above the median values for control subjects in 50 of 85 prepatients.

Of the chemokines, MCP-1 and MIP-1 alpha levels were significantly increased in prepatients, compared with controls, as were the levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte–colony stimulating factor (G-CSF).

When the authors calculated the sensitivity and specificity of different factors for the development of RA in prepatients, they found that after anti-CCP antibodies and IgM rheumatoid factor (IgM-RF), eotaxin had the highest sensitivity (22.4%) and specificity (95.3%), with an odds ratio of 5.8. About one-half of the cytokines and cytokine-related factors that had significant predicative value for the development of RA in prepatients were related to Th1, Th2, and Treg cells. When all analyzed factors and anti-CCP antibodies were included, the sensitivity level rose to 51.2%, with a specificity of 91.9% for predicting the development of RA among prepatients and control subjects.

The factors distinguishing individuals before and after the onset of RA represented a more general immunologic response, as well as stromal cells and angiogenic factors. After RA diagnosis, significant increases were seen for most of the factors that were measured. IL-17 concentrations actually decreased after RA diagnosis. “This observation endorses the role of IL-17 in the initiating phase [of RA], and, as the pathogenesis progresses, other factors are subsequently brought into action,” wrote the authors (Arthritis Rheum. 2010;62:383-91).

Although the authors were unable to conclude which agent initiates RA pathogenesis, they suggested that their findings present an opportunity for better predicting the risk of developing RA and intervening at an early stage to possibly prevent disease progression.

Elevated concentrations of proinflammatory cytokines, cytokine-related factors, and chemokines, indicating activation of the immune system, have been found in the blood of people years before they developed symptoms of rheumatoid arthritis that involved the joints, according to a report by Heidi Kokkonen and coinvestigators at Umeå (Sweden) University. The study was published in the February 2010 issue of Arthritis and Rheumatism.

By comparing blood samples of people diagnosed with RA to normal controls and “prepatients” (those who go on to develop RA), investigators said that they hope the results will help predict an individual's risk of developing RA.

The investigators analyzed samples from the Medical Biobank of Northern Sweden, which invites all adult individuals from the county of Västerbotten to contribute blood samples. Within this population-based cohort, there were 86 individuals who went on develop inflammatory joint disease that fulfilled American College of Rheumatology classification criteria for RA after their donation of blood. For these prepatients, the median time predating the onset of symptoms was 3.3 years (range, 1.1-5 years). Of the 86 prepatients, 69 also provided blood samples at the time of RA diagnosis. For every prepatient, three control subjects were randomly selected from the Biobank register and matched for sex, age, and area of residence.

Several cytokines, cytokine-related factors, and chemokines were upregulated in prepatients, compared with controls. The greatest increases were noted for the Th2-related cytokines, eotaxin, and interleukin-4, with elevated levels also observed for Th1 cytokines, IL-12, interferon-gamma, and IL-10.

A multivariate classification algorithm known as the random forest method, similar to decision trees, was used to estimate which groups of cytokines, cytokine-related factors, or chemokines could best distinguish a particular group of patients. For prepatients, characteristic changes were related to both the Th1 and Th2 lineage, and to Treg cells, representing the adaptive immune system, the authors wrote. Elevation of IL-17 levels did not reach statistical significance.

Levels of at least two-thirds of the cytokines or cytokine-related factors were above the median values for control subjects in 50 of 85 prepatients.

Of the chemokines, MCP-1 and MIP-1 alpha levels were significantly increased in prepatients, compared with controls, as were the levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte–colony stimulating factor (G-CSF).

When the authors calculated the sensitivity and specificity of different factors for the development of RA in prepatients, they found that after anti-CCP antibodies and IgM rheumatoid factor (IgM-RF), eotaxin had the highest sensitivity (22.4%) and specificity (95.3%), with an odds ratio of 5.8. About one-half of the cytokines and cytokine-related factors that had significant predicative value for the development of RA in prepatients were related to Th1, Th2, and Treg cells. When all analyzed factors and anti-CCP antibodies were included, the sensitivity level rose to 51.2%, with a specificity of 91.9% for predicting the development of RA among prepatients and control subjects.

The factors distinguishing individuals before and after the onset of RA represented a more general immunologic response, as well as stromal cells and angiogenic factors. After RA diagnosis, significant increases were seen for most of the factors that were measured. IL-17 concentrations actually decreased after RA diagnosis. “This observation endorses the role of IL-17 in the initiating phase [of RA], and, as the pathogenesis progresses, other factors are subsequently brought into action,” wrote the authors (Arthritis Rheum. 2010;62:383-91).

Although the authors were unable to conclude which agent initiates RA pathogenesis, they suggested that their findings present an opportunity for better predicting the risk of developing RA and intervening at an early stage to possibly prevent disease progression.