Correlation Between Pain, Disease Activity, and Rheumatoid Factor Positivity in Patients with Chikungunya Arthritis

Abstract

Chikungunya fever (CHIKF) is an acute viral disease caused by the chikungunya virus (CHIKV) transmitted by Aedes mosquitoes. The acute phase presents with limited symptoms and low mortality, but approximately half of cases progress to more chronic illness with persistent and disabling joint symptoms. To better characterize the burden of chronic disease, we analyzed the relationship between pain intensity, the Disease Activity Index by DAS28-ESR, rheumatoid factor (RF) positivity, sex, and age in a retrospective cohort of 133 patients with chikungunya arthritis (CHIKA). We assessed all subjects by clinical evaluations, and laboratory testing, including the Pain Visual Analog Scale (VAS), the Disease Activity Score (DAS28-ESR), and RF measurement. We observed that pain intensity increased significantly with disease activity (ρ = 0.416 and p-value < 0.05) and with age (ρ = 0.259 and p-value = 0.003). Despite a predominance of women in our cohort, sex/gender was not associated with increased pain risk. Our study demonstrated a strong correlation between pain and disease activity, but assessment of these variables in a larger, prospective cohort should be undertaken to further characterize risk variables and improve therapy for patients with CHIKA.

Introduction

Chikungunya (CHIK) is caused by a single-stranded RNA (ribonucleic acid) virus of the genus Alphavirus of the Togaviridae family, called chikungunya virus (CHIKV). CHIK is often a biphasic illness. The acute phase, “chikungunya fever” (CHIKF) begins 3-7 days after CHIKV infection by an Aedes mosquito [1]. CHIKF is characterized by the abrupt onset of high fever, disabling polyarthralgia/polyarthritis, maculopapular skin rash, headache, myalgia, nausea, and diarrhea. This acute phase is generally limited to 10-14 days and has a low mortality rate [2]. However, it is estimated that 51% of infected individuals progress to a chronic phase characterized by persistent arthralgia, disabling chronic arthritis, and myalgia [3].

Since it was first isolated in Tanzania in 1952, CHIKV has caused recurrent epidemics during the second half of the 20th century throughout Asia and sub-Saharan Africa [4]. Beginning in 2004, CHIKV spread to several islands in the Indian Ocean, Southeast Asia, and India. In 2013 CHIK was introduced to the Americas, where more than 3.6 million cases have been reported in 50 countries [5].

During the chronic phase of CHIK, painful musculoskeletal symptoms predominate, varying in intensity [2]. Among patients with chikungunya arthritis (CHIKA), many have nonspecific arthralgia and myalgias, but some develop frank inflammatory arthritis [6,7]. These individuals may meet the American College of Rheumatology (ACR) 2010 criteria for rheumatoid arthritis (RA), with increased inflammatory markers, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), in addition to joint effusions, bone erosions, and synovial thickening on imaging studies [6].

Due to the similarities between CHIKA and RA, CHIKA patients have been assessed with outcome measures developed for RA [7-10], such as the Pain Visual Analog Scale (VAS) [11], the Disease Activity Score (DAS28-ESR) [12] and rheumatoid factor (RF) measurement. Using these measurement tools, there is increasing evidence that CHIKA follows a variable clinical course. In some individuals, the illness is self-limited and non-destructive, but others develop a chronic inflammatory course that mimics RA, with irreversible joint damage. For these more chronic patients, a treatment approach similar to RA, including Disease Modifying Antirheumatic Drugs (DMARDs) may be necessary [13].

CHIKA causes a spectrum of pain, disease severity, and patient outcomes. Our study contributes to the existing literature by exploring the correlation between pain intensity, disease activity, and RF positivity in a cohort of Brazilian patients with CHIKA, using Spearman’s correlation coefficient and hypothesis tests (Student’s t-test, Wilcoxon test) [14]. This study also assesses the influence of variables such as age and gender on these outcomes, expanding the understanding of factors that may influence disease progression and severity.

Materials and Methods

Among CHIK cases treated at a rheumatology outpatient clinic in Brazil in 2022, we retrospectively reviewed the medical records of a cohort of 133 individuals with CHIKA, based on data from 196 consecutive patients seen and who provided the necessary information. Cases were confirmed by CHIKV-specific IgM serology by immunochromatography or enzyme-linked immunosorbent assay (ELISA) (VIRCLIA® IgM MONOTEST VCM063).

Data for this study were collected using a standardized clinical and laboratory assessment form, which captured key patient details, including demographic information, laboratory results, and clinical evaluations pertinent to the study’s objectives. The clinical assessments included the Visual VAS for pain and the count of tender and swollen joints, both of which were used to calculate the DAS28-ESR score. In addition, laboratory measures such as complete blood count, CRP, RF, and ESR were obtained to assess the patients’ inflammatory status. All participants met the inclusion criteria, which required confirmed laboratory evidence of CHIKV infection and the presence of new-onset arthritis, as outlined in the methodology. These methods ensured consistent and accurate data collection, enabling a comprehensive analysis of disease activity and pain intensity.

Pain intensity was classified based on patients’ responses to the VAS as follows: 0 = “no pain,” >0 and ≤ 30 = “mild pain,” >30 and ≤ 60 = “moderate pain,” >60 and ≤100 = “severe pain” [11]. Disease activity was classified according to the European League Against Rheumatism: with DAS28-ESR < 2.6 = “remission,” DAS28-ESR ≥ 2.6 and ≤ 3.2 = “low disease activity,” DAS28-ESR > 3.2 and ≤ 5.1 = “moderate disease activity,” DAS28-ESR > 5.1 = “high disease activity.” The RF test was performed using the latex agglutination method and recorded as reactive (positive) when the result was ≥ 8 IU/ml.

This study was approved by the Human Research Ethics Committee of the Universidade Regional do Cariri - Ceará, Brazil (Opinion nº 5,562,805).

Statistical Analysis

Data were analyzed using descriptive and inferential statistics. To describe the demographic and clinical characteristics, means and standard deviations (SD) were calculated for continuous variables, and absolute and relative frequencies for categorical variables. The correlations between continuous variables were evaluated using Spearman’s correlation coefficient, as for all combinations of variables the distribution was not normal in the Shapiro-Wilk normality test [13]. The comparison between sex in relation to the means of the variables “pain” and “DAS28-ESR” was performed using the Student’s t-test for independent samples, and the Wilcoxon test was used for RF positivity [14]. All statistical tests were considered significant for p values ​​< 0.05. Data were analyzed using RStudio (version R-4.3.3 Windows, RStudio Team, Boston, MA) [15].

Results

Of the 133 patients in the cohort, 119 were women (89%). RF was positive for 22 patients (16.5%). Age ranged from 26 to 82 years (mean = 58.6 ± 13 years). The median age of the participants was 58 years (IQR: 49–70). The means ± SD for VAS and DAS28-ESR were 81.8 ± 19.2 and 5.9 ± 1.1, respectively. Most patients (83%) reported pain as severe, with only 2% classified as mild. Only one patient was classified as having low disease activity by DAS28-ESR, while 80% had high disease activity (Table 1).

Table 1. Demographic Profile and Clinical Characteristics of Patients with Chikungunya Arthritis.

Characteristics	Mean ± SD	n	%
Sex/Gender
Female		119	89.5
Male		14	10.5
Age	58.6 ± 13
Tender joint count	17.1 ± 7.3
Swollen joint count	5.0 ± 6.5
Patient global assessment	81.5 ± 19.2
Erythrocyte sedimentation rate	27.1 ± 17.2
Rheumatoid factor
<8		111	83.5
≥8		22	16.5
Disease Activity (DAS28-ESR)
Remission		0	0
Low		1	0.7
Moderate		26	19
High		106	80
Pain intensity (VAS)
Mild		3	2
Moderate		19	14
Severe		111	83.5

Table 2 presents the comparison of the means of the variables analyzed by sex. Men were younger (55.9 ± 12 years) and none had positive RF.

Table 2. Comparison of Means of Variables Analyzed by Sex in Patients with Chikungunya Arthritis.

Characteristics	Mean ± SD		p-value
	Men	Women
Age (years)	55.9 ± 12	58.9 ± 14	0.363
Time between first symptoms and first visit (days)	35.4 ± 18	43 ± 21	0.160
Rheumatoid factor	0	10 ± 33.5	0.081
Disease activity (DAS28-ESR)	5.6 ± 1.1	6.0 ± 1.2	0.161
Pain intensity (VAS)	74.2 ± 16.7	82.6 ± 19.2	0.109

Figure 1 presents the Spearman correlation coefficients for the variables analyzed in a heat diagram. The darker the color, the stronger the correlation between the variables. The results suggest a moderate positive correlation between pain intensity and disease activity by DAS28-ESR (ρ = 0.416 and p-value < 0.05). We also observed that this correlation increased significantly with increasing age (ρ = 0.259 and p-value < 0.05). However, there was no correlation between DAS28-ESR and RF (ρ = 0.142 and p-value = 0.102) nor between pain intensity and RF (ρ = 0.167 and p-value = 0.054). Age did not show a significant correlation with these last two variables.

Figure 1.

Spearman correlation coefficients of the relationship between the variables pain intensity, DAS-28, Rheumatoid factor, and age in 133 patients with Chikungunya arthritis.

The t-test and Wilcoxon tests did not indicate statistically significant differences in the means stratified by sex/gender, as observed: VAS (t = 1.68 and p-value 0.109); DAS28-ESR (t = 1.46 and p-value = 0.161); RF (Wilcoxon test = 987 and p-value = 0.081).

Discussion

In this study, we assessed whether there is correlation between the variables of pain, disease activity, age, sex/gender, and RF positivity in patients with CHIKA. We chose these variables to evaluate patients with CHIKA since they are established in RA, and assessment tools such as DAS28-ESR, VAS and RF test have also been used in CHIKA [16-21]. However, no previous study has verified the correlation between these variables in patients with CHIKA.

The average age in our cohort was similar to other CHIKA reports that range in age from 48 to 58 years [16,18,21-25]. Although RA can begin at any age, the age range in our CHIKA patients is similar to the age of onset of RA, typically around 40-50 years [26].

As in previous CHIKA reports, our CHIKA patients had high pain scores with a few weeks of illness similar to those persisting up to 40 months [24]. Most of our patients were classified as having moderate or severe pain.

Similarly, as in previous studies, our patients reported high rates of moderate and severe disease activity with high DAS28-ESR scores [16,18,21,25]. These high disease activity scores developed rapidly. In our study, the mean time between symptom onset and first office visit was only 35.4 ± 18 days. Our patients had similar disease activity to reported CHIKA patients with longer-standing illness [17].

Among our cohort of 133 CHIKA patients, RF positivity was found in 16.5%. In previous CHIKA studies, there is wide variation in RF positivity, ranging 3% to 100% [16,21,23].

We did not determine a correlation between RF positivity and pain intensity.

In our cohort, no men tested positive for RF, while 16.5% of the female participants were RF positive. This difference likely reflects the higher prevalence of RF positivity in women, as reported in various rheumatic diseases, including RA. Hormonal and immunological factors are thought to contribute to this increased predisposition in women, particularly in chronic inflammatory conditions such as CHIKA [27]. The relatively small percentage of male participants in this study (10.5%) may have also limited our ability to detect RF positivity in men.

It is possible that with a larger and more gender-balanced sample, RF positivity in men would become evident, or the observed sex/gender differences could be further clarified. Future studies with larger male cohorts are needed to investigate the relationship between gender and RF positivity in CHIKA patients.

In addition, studies have shown that women tend to experience more intense pain and higher disease activity across a range of chronic pain conditions, including RA and osteoarthritis [28,29]. This heightened sensitivity is believed to be influenced by biological factors, such as hormonal effects on nociceptor sensitization, with hormones like prolactin selectively sensitizing nociceptors in females [28,29].

Although our study did not assess seasonal variations, research has demonstrated that seasonal factors can influence disease activity in chronic inflammatory conditions such as RA. For example, studies like those by Mori et al. have shown that RA activity tends to peak in spring and winter, with higher remission rates observed in the fall [30]. Environmental factors, including changes in atmospheric pressure and colder temperatures, are believed to exacerbate musculoskeletal symptoms.

Our study was based on data collected from a single referral center, which limited our ability to include a broader population or conduct multicenter comparisons. While the findings are valid for the CHIK patients evaluated at this center, collaborations with other institutions, particularly in regions with a high prevalence of CHIK, could provide a more diverse and representative sample, improving the generalizability of the results.

Another limitation of this study is the lack of anti-citrullinated peptide antibody (ACPA) testing, primarily due to the cost, as many patients would need to pay for this test out of pocket, making it financially prohibitive for some. Additionally, the retrospective nature of the study and the relatively small cohort size are further limitations. Prospective studies with larger patient samples are needed to better understand the relationships between these variables and improve treatment for CHIKA.

Conclusion

Our study provides insights into the relationship between pain intensity, disease activity, age, and RF positivity in patients with CHIKA. We determined that pain intensity increases significantly with disease activity and with age.

Our results are consistent with previous studies on CHIKA, which have assessed pain intensity and disease activity using VAS and DAS28-VHS, respectively. However, RF positivity has varied widely between studies.

From a public health perspective, better understanding of the determinants of CHIKA severity can help to mitigate the impact of this disease within the community by identifying appropriate testing and treatment algorithms and optimize healthcare resources.

Glossary

CHIK

Chikungunya

CHIKA

Chikungunya arthritis

CHIKF

Chikungunya fever

CHIKV

Chikungunya virus

CRP

C-reactive protein

DAS28-ESR

Disease Activity Score in 28 joints using erythrocyte sedimentation rate

DMARDs

Disease Modifying Antirheumatic Drugs

ELISA

Enzyme-Linked Immunosorbent Assay

ESR

erythrocyte sedimentation rate

RA

rheumatoid arthritis

RF

rheumatoid factor

SD

standard deviation

VAS

Visual Analog Pain Scale

Financial support or Funding

None.