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Basic and translational research
Extended report
Progression to rheumatoid arthritis in early inflammatory arthritis is associated with low IL-7 serum levels
  1. Vincent Goëb1,2,
  2. Philippe Aegerter3,4,
  3. Rekha Parmar1,
  4. Patrice Fardellone2,
  5. Oliver Vittecoq5,6,
  6. Philip G Conaghan1,
  7. Paul Emery1,
  8. Xavier Le Loët5,6,
  9. Frédérique Ponchel1
  1. 1Division of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds & NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK
  2. 2Department of Rheumatology, Amiens University Hospital, Amiens, France
  3. 3Département de santé publique, AP-HP, Hôpital Ambroise Paré, Boulogne-Billancourt, France
  4. 4Université Versailles St-Quentin, UPRES EA 2506, Paris, France
  5. 5Department of Rheumatology, Rouen University Hospital, Rouen, France
  6. 6Inserm U905, Rouen University, Rouen, France
  1. Correspondence to Professor Paul Emery, Leeds Musculoskeletal Biomedical Research Unit, Chapel Allerton Hospital, Leeds LS7 4SA, UK; p.emery{at}leeds.ac.uk

Abstract

Objective Early diagnosis of rheumatoid arthritis (RA) remains a challenge. Interleukin (IL)-7 is a pleiotropic cytokine that plays a central role in the development and maintenance of T-cells and has been associated with T-cell dysfunction in RA. Serum levels of IL-7 are reduced in both early and established disease. The aim of this study was to determine whether serum IL-7 can identify patients with very early inflammatory joint symptoms who will progress to RA, and to examine whether IL-7 levels predict disease persistence and radiographic progression.

Methods Patients with inflammatory joint symptoms <6 months followed over 5 years for progression to RA and 80 healthy controls were studied. Baseline IL-7 levels were measured by ELISA.

Results Of 250 patients, 108 developed RA (ACR 1987- criteria). IL-7 at inclusion was reduced significantly in RA compared with non-RA patients (p=0.009). IL-7 was categorised using the lower limit of the healthy control distribution (10 pg/ml). In multivariate analysis, independent predictors of RA development were: antibodies against citrullinated peptides (ACPA) positivity (p=0.001), IL-7<10 pg/ml (p=0.003) and swollen joint count (p=0.050). In the ACPA-negative subgroup (n=199), the only predictors were: DAS-44 (p=0.001), IL-7<10 pg/ml (p=0.010) and radiographic erosions (p=0.050). At 1-year follow-up, remission (DAS<1.6) was only predicted by ACPA negativity (p=0.019) and IL-7>17 pg/ml at recruitment (p=0.013).

Conclusion These data demonstrate that low IL-7 levels in patients with recent onset of symptoms may have value as a diagnostic biomarker predicting the progression to RA, particularly in ACPA-negative disease, as well as being related to RA progression.

  • Early Rheumatoid Arthritis
  • Cytokines
  • Qualitative research

https://doi.org/10.1136/annrheumdis-2012-202377

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    Introduction

    Rheumatoid arthritis (RA) is a chronic inflammatory disease that could result in disabling joint destruction. Early diagnosis is essential for the prompt administration of treatments to enable optimum structural and functional outcomes,1 ideally remission. Clinical presentation is variable and not prognostic. Therefore, there is an unmet need for biomarkers of progression to RA which could be used as early as possible in the disease process. Autoantibodies are a hallmark of autoimmune disease and as such have been associated with RA. Rheumatoid factor (RF) has long been associated with RA; however, it lacks specificity and sensitivity is not particularly high.2 More recently, anti citrullinated peptides antibody (ACPA) have become clinically available and although they also lack sensitivity in the very early stages of the disease, their specificity is higher.2 Concomitant positivity of RF and ACPA has been shown to be highly predictive of RA but again with low sensitivity (<50%) in early disease.3

    Several genetic markers have been shown to be associated with RA.4 Genetic markers have the advantage of being present before the onset of disease. However, in a French Caucasian cohort of patients with Very Early inflammatory Arthritis symptoms (VErA) cohort,5 we previously reported that known genetic risk factors for RA (PTPN22 1858T, TNFRII 196R and HLA-shared epitope alleles) did not improve the predictive value of autoimmune markers such as RF and ACPA for the progression to subsequent RA.6 The discovery of specific biomarkers that would allow the diagnosis of RA at the very early onset of the disease process therefore remains a crucial goal for clinicians.

    Cytokines and other soluble factors in serum are prime candidates. Interleukin-7 (IL-7) is a pleiotropic cytokine that plays a major role in the regulation of peripheral T-cell homeostasis.7–9 IL-7 is part of the IL-2/IL-15 cytokine family that uses the common γ-chain (CD132) to signal from a membrane bound specific IL-7 receptor (CD127). Janus kinases (Jak-3) and STAT-5 pathways are then activated.10 IL-7 signalling also activates the SRC kinase pathways, potentially regulating T-cell recepter signal transduction11 and also the c-Jun N-terminal kinase and p38 kinase pathways involved in T-cell proliferation.12 Reduced levels of circulating IL-7 have been reported8 ,13 in both established RA and in patients with less than 24 months symptom duration. This relative deficiency may account for certain of the immune dysregulation associated with RA such as peripheral blood T-cells anergy, loss of responsiveness to recall antigen and defective signalling.14 However, IL-7 is highly expressed in the joints of RA patients,13 ,15 ,16 where it has an opposing role, enhancing T-cell functions17 and then potentially contributing to perpetuating inflammation. Such contrast between low systemic and high disease site expression of IL-7 has been observed in other autoimmune diseases including systemic sclerosis18 and colitis.19

    We hypothesised that a reduction in circulating IL-7 levels may have diagnostic value for RA. The aim of this study was to determine whether IL-7 titres in serum of patients with very early (less than 6 months of duration) inflammatory joint symptoms will identify patients who will progress to RA and to examine its prognostic value.

    Patients and methods

    Patient recruitment into the VErA cohort

    The VErA cohort comprises 310 patients (of which 250 had sera available) with very early arthritis who were prospectively recruited between 1998 and January 2002 from a community based recruitment.5 The protocol was approved by the Committee for Protection of Persons Participating in Biomedical Research of Rouen (French law 88–1138; 20 December 1988). Before entry into the protocol, each patient gave written consent after receiving verbal and written information regarding the nature, duration and purpose of the study and Institutional Review Board approval. Briefly, patients had swelling of at least two joints persisting for longer than 4 weeks but less than 6 months (median: 4.2 months, range: 0.9–6.0 months). They were all disease-modifying antirheumatic drug-naive at inclusion. The demographic and clinical data (joint counts, C reactive protein (CRP), disease activity score (DAS) 44, autoantibody status) are described in table 1. All were European Caucasians. RF and HLA-SE status were collected. Radiographs of hands/wrists and feet were performed at inclusion and every 12 months during the follow-up period. Radiographs were assessed by two independent rheumatologists to quantify progression of erosions. ACPA status was tested using inclusion sera when the anti-CCP2 test subsequently became available. Patients were followed for 5 years until fulfilling the American College of Rheumatology (ACR) 1987 criteria for RA or exited the study if diagnosed with a different, non-RA, type of arthritis (eg, reactive arthritis, gout). All patients with a diagnosis of RA were treated initially with hydroxychloroquine, followed by methotrexate if required according to best practice at the time.20

    View this table:
    Table 1

    Demographic and clinical factors associated with progression to RA

    IL-7 ELISA

    Serum samples were collected at baseline recruitment into the VErA cohort and 250 were available for this study. IL-7 was measured by direct high sensitivity sandwich ELISA (R&D Systems, Abingdon, UK) in accordance with the manufacturer's instructions. The sensitivities of the assay were <0.1 pg/ml for IL-7.

    80 healthy controls (HCs) without arthralgia were recruited to establish normal circulating IL-7 range (figure 1A, median 15.05 pg/ml, range 9.4–24.8 pg/ml). There was no influence of age (median 36, range 24–68 years) and sex (43 males and 37 female subjects) on IL-7 levels in this HC population.

    Figure 1
    Figure 1

    Interleukin (IL)-7 distribution in (A) healthy controls (n=80) and patients of the Very Early inflammatory Arthritis symptoms (VErA) cohort (n=250) and (B) patients evolving towards rheumatoid arthritis (RA) (n=108) or not (n=142).

    Statistics

    Mean, median and dispersion parameters—SD, range and IQR—were calculated for quantitative variables. Proportions were used to describe qualitative variables. Comparisons of qualitative, quantitative, variables between groups were performed by the χ2 test and the non-parametric Kruskal–Wallis test, respectively. Association between baseline factors and ultimate diagnosis of RA (yes/no) were assessed by multivariate logistic regression model. Linearity of relationship with continuous covariates was checked by general additive models. Competing models were compared by the Akaike Information Criterion. p Values <0.05 were considered significant. Statistical analysis was performed with R V.2.10 language (R Foundation for Statistical Computing, Vienna, Austria. http://www.R-project.org/).

    Results

    Of the 250 patients included, 108 developed RA (4.8±1.1 year follow-up duration), 20 remained unclassified arthritis (at 5 years), 96 were diagnosed with other arthritides (including spondyloarthropathies, osteoarthritis, connective tissue disease (CTD), reactive arthritis and gout; mean 1.9±1.5 years follow-up) and 26 had no persistence of joint symptoms.

    IL-7 serum levels in the VErA cohort

    In the 250 serum samples available from the VErA cohort, the distributions of IL-7 values showed a similar median (13.55 pg/ml) in patients compared with HC (15.05 pg/ml); however, the range of the distribution tended to shift towards lower values with a similar maximum (25.8 pg/ml for VErA) but very different minimum value (2.65 pg/ml, p=0.095).

    The range of IL-7 levels in the patients developing RA was shifted towards lower value (figure 1B, median 12.6 pg/ml, range 2.65–23.50 pg/ml) compared with the non-RA patients (table 1, median 15.06 pg/ml, range 6.68–25.8 pg/ml, p=0.009).

    Prediction of developing RA

    Bivariate analysis of clinical parameters showed the expected association of RA diagnostic with the presence of shared epitope (table 1, p=0.003), RF (p=0.001) and ACPA (p=0.001). Higher swollen joint count and CRP were also associated with development of RA (p=0.001 and p=0.014, respectively) and as a consequence the DAS44 (Ritchie) was also higher (p=0.001).

    We then explored factors that may influence IL-7 levels in patients who developed RA (n=108). Gender and age did not influence IL-7 levels. Presence of autoantibody (RF and ACPA) or shared epitope (SE) was not associated with a change in IL-7 distribution; however, as expected strong association was detected among the presence of ACPA, RF and SE (p<0.001). Patients with longer symptom duration, higher swollen joint count and Health Assessment Questionnaire (HAQ) also appeared to be associated with lower levels of IL-7; however, all associations were weak (R<0.350).

    Univariate logistic analysis for prediction of RA development was performed. A model with CRP and joint counts performed better than the model with DAS44 alone. IL-7 levels were coded as reduced or not using two thresholds: first the median of the IL-7 distribution in the VErA cohort (below or above 13.55 pg/ml) and second using the fifth percentile of the HC controls distribution (below or above 10 pg/ml). Using the more stringent IL-7 criteria (IL-7<10 pg/ml), ACPA positivity was found to be the best predictor of progression to RA (table 2, p=0.003), followed by low level of IL-7 (p=0.012) and then by HAQ, joint count, CRP and SE (as well as RF though non-significantly).

    View this table:
    Table 2

    Univariate and multivariate analysis of diagnostic factors in VErA

    The variables significantly associated with RA diagnosis in univariate analysis (ACPA (accounting for RF and SE)), IL-7, HAQ, joint count and CRP, were further examined in multivariate logistic regression. The development of RA was predicted by three variables (table 2): ACPA (p=0.001), IL-7 (p=0.003) and swollen joint count (p=0.010).

    Diagnostic ability

    Sensitivity and specificity of these biomarkers were then calculated (table 3). Individually, the presence of ACPA demonstrated a relatively low sensitivity (35%) in very early disease but high specificity (94%). Reduction of IL-7 levels was less sensitive (28%) but showed good specificity (84.5%). Combining these two biomarkers increased greatly specificity but at the expense of sensitivity.

    View this table:
    Table 3

    Sensitivity and specificity of predictors of RA diagnostic

    The loss of sensitivity in combining ACPA with IL-7 and the lack of difference of IL-7 distribution according to ACPA status suggested non-overlapping biomarkers. We therefore repeated the logistic regression analysis in all patients who were ACPA-negative (table 2, n=199, of whom 67 progressed to RA). In this model, the use of DAS44 performed better than its individual components. Predictors of the development of RA were high DAS (p=0.001) and low IL-7 levels (p=0.010). Low IL-7 level was the most specific biomarker (table 3, 83%) with no loss of sensitivity (27.5%) compared with the sensitivity in the overall VErA cohort (28%). Combining DAS and IL-7 showed increased specificity (95%) over the use of DAS alone (65%).

    Disease progression

    In those patients diagnosed with RA (n=108), disease evolution was monitored at 1 year postbaseline visit using DAS44-Ritchie and erosion counts at 2 years. Persistent disease at 1 year (DAS≥1.6) was associated with longer symptom duration at baseline (table 4, p=0.003) and with the presence of autoantibodies or SE (p=0.008) in univariate analysis. Higher IL-7 levels were also associated with absence of disease activity (DAS<1.6) (p=0.008). Using multivariate logistic regression, DAS<1.6 at 1 year was best predicted by absence of ACPA (p=0.019) and higher IL-7 at inclusion (coding IL-7 using the upper quartile of the distribution: IL-7>17.0 pg/ml, p=0.013). In the 67 ACPA-negative RA patients, only high IL-7>17 pg/ml at baseline was predictive of DAS<1.6 at 1 year (p=0.001). When investigating predictors of the development of new erosions at 2 years of follow-up, new erosions were associated only with reduced levels of IL-7<10 pg/ml at baseline (p=0.033).

    View this table:
    Table 4

    Demographic and clinical factors associated with DAS<1.6 at 1 year in patients progressing towards RA (n=108)

    Discussion

    The current study demonstrated that in patients with short duration arthritis, low circulating levels of IL-7 at presentation is predictive of progression to RA. The sensitivity (28%) and specificity (85%) of IL-7 reduction does not improve diagnosis in the presence of ACPA; however, the two biomarkers appear independent and therefore allow additional diagnostic value for patients with no ACPA autoantibodies. With respect to disease persistence, high circulating levels of IL-7 (>17 pg/ml) at baseline in RA patients was associated with lack of disease activity at 1 year. Importantly, in this very early cohort, low IL-7 level (<10 pg/ml) was the only predictor of structural damage (progression of erosion at 2 years).

    There is an unfulfilled clinical need for a novel diagnostic biomarker predictive of RA particularly for autoantibody-negative patients. Recently, new antibody specificities have been reported notably for other post-translational protein modifications such as carbomylation21 or oxidation22 ,23 with promising results due to the absence of overlap with the presence of ACPA. Cytokine candidates have been extensively studied but, to our knowledge, with extremely limited success. Increases in circulating levels of several cytokines (tumour necrosis factor α, IL-1β and IL-13) were observed in patients with <6 months RA compared with HC.24 This is less valuable in clinical practice where the need is to differentiate individuals progressing to RA from those who will not. Furthermore, increase in such cytokines was closely associated with ACPA-positive patients and was therefore not improving diagnosis. A multiplex biomarker platform (combining IL-6, bone turnover markers, metalloproteinase, inflammatory markers and several citrullinated epitopes) has recently been tested with respect to RA diagnosis, again in <6 months symptom duration patients.25 ,26 Some discriminant diagnostic ability was reported; however, this was tested using other established arthritides as disease controls (ankylosing spondylitis and psoriatic arthritis). Pending replication of our data in new cohorts with early symptoms suggesting a risk of developing RA, measuring circulating levels of IL-7 offers an novel diagnostic biomarker test that could guide clinical decision making, particularly in sero-negative patients.

    There are currently several predictors of the risk for severe articular damage (radiographic progression) at disease diagnosis. These include the presence of autoantibodies (ACPA, IgA-RF)27 ,28 as well as particular haplotype of the SE,28 high CRP and the presence bone turnover biomarker (notably pyridinoline in the VErA cohort).29 Serum levels of IL-6, tumour necrosis factor α, visfatin and adiponectin in patients with early RA were also associated with structural damage progression.26 ,30 IL-7 is, however, directly involved in bone physiology31 with a significant increase in bone mass observed in IL-7-KO mice due to the loss of IL-7-dependent expression of RANKL32 whereas mice fed IL-7 developed bone loss.33 ,34 IL-7 is elevated in active RA synovitis but not in remission.13 Conversely, IL-7 is reduced in the blood of active RA but normal levels are recovered in remission.8 ,35 We would propose that progression to RA in patients with low blood levels of IL-7 is associated with the development of synovitis with high joint IL-7 levels affecting bone remodelling locally, hence favouring the development of erosions.

    Lower levels of IL-7 were weakly associated with longer symptom duration, higher swollen joint count and HAQ which are all poor prognostic factors.36 However, in multivariate analysis none of these factors were predictive suggesting that IL-7 may have higher discriminating value. Recovery of normal levels of IL-7 have also been observed in 50% of patients with chronic RA achieving remission8 associated with improved T-cell functions (unpublished observation). The relationship between IL-7 levels and the status of the immune system need further investigation in RA knowing that immune-senescence for example is quite closely related with loss of IL-7.37 The ability to predict increase in disease activity may permit choice of more aggressive therapy allowing tailoring of patient management.

    There are several factors that can influence IL-7 measurements in addition to donor variability in both health and disease, notably assay performance. Reports of the presence of soluble form of the IL-7-receptor responsible for reduced levels of IL-7 in HIV-infected patients have recently been published.38 ,39 A similar role for the sIL-2R has long been recognised in RA40 ,41 and similar investigations need to be performed in RA as it was reported at annual meeting of the ACR in 2011 that levels of sIL-7R are high systemic erythematosus lupus,42 and furthermore, inflammation appears to trigger the expression of the sIL-7R by fibroblasts.43 IL-7 is not one of known cytokines to need particular collection precautions (related to stress, cachexia, diurnal rhythm or diet) that may influence the measurement of cytokines; however, there are several IL-7 ELISAs and other types of assay (cytometric beads assay or Luminex assay) commercially available. Importantly, levels of IL-7 reported in over 17 publications for HC using five different kits were similar (reviewed in13) in contrast to multiplex Luminex beads assays that were sensitive to interference from heterophilic antibodies such as RF44 and generated false-positive results.45

    In summary, IL-7 may have diagnostic and prognostic value in early arthritis. Replication of our data in similar cohorts of patients at risk of RA would permit adoption of this biomarker in routine clinical practice notably for sero-negative patients. ACPA-positive individuals with no clinical synovitis could also benefit from monitoring IL-7 levels. The fact that levels of IL-7 were partially recovered in disease-modifying antirheumatic drug-induced remission8 ,35 also suggests that IL-7 levels could be a viable option for monitoring the need for escalation or change of therapy.

    Acknowledgments

    This work has been partly supported by a European Union funded FP7-integrated project Masterswitch No. 223404 and the IMI funded project BeTheCure. VG received a travel fellowship from the French society of Rheumatology (SFR).

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    Footnotes

    • Contributors VG, PF, OV, XLL: designed VErA cohort and recruited patients. VG, RP, PA, FP: performed the statistical analysis. FP: performed the analysis of sample. VG, PC, FP, PE: interpreted results and wrote the paper. All the authors reviewed the manuscript.

    • Funding FP7 Health Programme.

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval Committee for the protection of person participating in biomedical research Rouen France.

    • Provenance and peer review Not commissioned; externally peer reviewed.