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Abstract
Objective To investigate the predictive value of discordance between (1) tender and swollen joint count and (2) patient's and evaluator's global assessment on remission in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA).
Methods From the prospective, multicentre Norwegian-Disease-Modifying Antirheumatic Drug study, we included patients with RA and PsA starting first-time tumour necrosis factor inhibitors and DMARD-naïve patients starting methotrexate between 2000 and 2012. The predictive value of ΔTSJ (tender minus swollen joint counts) and ΔPEG (patient's minus evaluator's global assessment) on remission was explored in prespecified logistic regression models adjusted for age, sex, disease duration and smoking.
Results A total of 2735 patients with RA and 1236 patients with PsA were included (mean (SD) age 55.0 (13.5)/48.3 (12.4) years, median(range) disease duration 0.7 (0.0–58.0)/1.3 (0.0–48.3) years, 69.7/48.4% females). Baseline ΔTSJ/ΔPEG reduced the likelihood of achieving DAS28<2.6, SDAI≤3.3, CDAI≤2.8, ACR/EULAR Boolean and DAPSA<4 remission after 3 and 6 months in RA (OR 0.95–0.97, p<0.001/OR 0.96–0.99, p≤0.01) and PsA (OR 0.91–0.94, p≤0.004/OR 0.89–0.99, p≤0.002), except for ΔPEG and 6-month DAS28 remission in PsA.
Conclusions Discordance between patient's and physician's evaluation of disease activity reflected through ΔTSJ and partly ΔPEG may reduce likelihood of remission in RA and PsA. The findings are relevant for use of the treat-to-target strategy in individual patients.
- Rheumatoid Arthritis
- Psoriatic Arthritis
- Disease Activity
- Treatment
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Introduction
Pain may be challenging to treat in inflammatory arthritides and has been emphasised as a core domain by the Outcome Measures in Rheumatology initiative (OMERACT) and the Group for Research and Assessment of Psoriasis and Psoriatic arthritis (GRAPPA).1 ,2
From the patient perspective, pain is reported to be the area of health in which patients have their highest priorities for improvement.3 ,4 Several studies have reported low association between pain and objective measures of inflammation.5 Chronification of pain and development of central sensitisation and conditioned pain modulation can lead to disconnection between tender and swollen joint count, which may be challenging for disease evaluation and treatment.5 ,6 Psychosocial factors and adverse life events may play a role in triggering sensitisation and chronic multisite musculoskeletal pain.7 Personality characteristics such as dispositional optimism, on the other hand, are found to modulate pain outcomes by abatement of endogenous pain facilitation and less use of catastrophising.8
Studies exploring the relationship between tender and swollen joints or patient's and evaluator's global assessment as predictors of remission in inflammatory arthritides are lacking in the current literature. However in a recent study in RA, swollen-to-tender joint count ratio was found to be predictive of ACR50 response to tumour necrosis factor inhibitors (TNFi).9
In this study, we aimed to investigate the predictive value of baseline tender and swollen joint count difference (ΔTSJ) as well as patient's and evaluator's global assessment difference (ΔPEG) on the likelihood of achieving remission by different criteria—ie, the agreed treatment targets—in patients with RA and PsA.
Methods
Patients
We included patients with RA and PsA from the Norwegian-Disease-Modifying Antirheumatic Drug (NOR-DMARD) register,10 who started their first TNFi with or without co-medication with methotrexate or started methotrexate as their first DMARD (see online supplementary figure S1). The NOR-DMARD register is a prospective, longitudinal, observational multicentre study initiated in December 2000, which until 2012 included patients >18 years with inflammatory arthropathies starting synthetic or biologic DMARDs, covering about one-third of the Norwegian population. Assessments were made at baseline, and after 3, 6 and 12 months and then yearly. The patients in the current analyses started the respective treatments between 1 December 2000 and 6 November 2012 and were followed until the 1 May 2013. Written informed consent was obtained from each patient. The study was approved by the National Data Inspectorate and by the Regional Committee for Medical and Health Research Ethics in Eastern Norway.
Assessments
Assessments included 32 tender/swollen joint count (28 joint count with assessment of ankles (0–2) and metatarsophalangeal joints (0–2)), visual analogue scales (VAS, 0–100) for joint pain, patient's and evaluator's global assessments, modified Health Assessment Questionnaire,11 erythrocyte sedimentation rate (mm/hour), C reactive protein (CRP, mg/L), baseline disease duration, current smoking status (yes/no). The numeric difference between 32 tender and 32 swollen joint count (ΔTSJ) and between patient's and evaluator's global assessment (ΔPEG) were calculated. Disease activity score for 28 joints (DAS28),12 Simplified Disease Activity Index (SDAI)13 and Clinical Disease Activity Index (CDAI)13 were computed, as well as a modified version of Disease Activity Index for Psoriatic Arthritis (DAPSA)14 including 32 joint count instead of the original 66/68 joint count.
The following remission criteria were explored: (1) DAS28<2.6,15 (2) SDAI≤3.3,16 ,17 (3) CDAI≤2.8,16 (4) American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean (28 tender joint count, 28 swollen joint count, patient's global assessment (0–10 scale), CRP (mg/dL), all ≤1),16 (5) modified DAPSA<4.18
Statistics
For the patients' demographic and baseline characteristics medians with 25th–75th percentiles were calculated for non-normally and means with SDs for normally distributed data. Quantitative results were compared using Mann-Whitney U test or independent t-test as appropriate. Proportions were analysed using χ2 test. The predictive value of ΔTSJ and ΔPEG for DAS28, SDAI, CDAI, ACR/EULAR Boolean and DAPSA remission was explored in prespecified logistic regression models adjusted for age, sex, baseline disease duration and smoking status. Hosmer-Lemeshow statistics was performed for testing of goodness of fit. Statistical tests were performed using SPSS V.21.0 for Windows.
Results
Demographics and baseline disease activity measures of patients with RA and PsA are displayed in table 1. Composite disease activity measures (DAS) were significantly higher in RA. ΔTSJ and ΔPEG were significantly higher in PsA.
Baseline demographics of patients with RA and PsA
Logistic regression analyses
Baseline ΔTSJ as well as ΔPEG were independent predictors of lower likelihood of achieving remission after 3 and 6 months, both in patients with RA and PsA (table 2).
The predictive value of baseline ∆TSJ and ∆PEG for achievement of remission (logistic regression analyses)
The predictive value of ΔTSJ for achievement of remission was consistent also in subgroup analyses of TNFi and methotrexate-treated patients (see online supplementary table S1). Corresponding subgroup analyses for ΔPEG were less consistent (see online supplementary table S2).
supplementary tables
The predictive value of dichotomised ΔTSJ and ΔPEG on remission
Positive values of ΔTSJ/ΔPEG were observed in 54.9%/61.2% of the patients with RA and 58.8%/69.9% of the patients with PsA, respectively. Patients with positive values of ΔTSJ and ΔPEG were less likely to achieve remission (see online supplementary table S3).
Achievement of remission according to categorisation of ΔTSJ and ΔPEG into quartiles
Bar charts of percentages of patients in remission at 6 months according to categorisation of ΔTSJ into quartiles are displayed in figure 1. This figure visualises how the likelihood of achieving remission diminishes with an increasing difference between number of tender and swollen joints. Corresponding bar charts for ΔPEG are displayed in online supplementary figure S2. The results are in principle similar, but less evident compared with ΔTSJ.
Bar chart of percentages of patients in remission at 6 months according to categorisation of ΔTSJ (tender minus swollen joint counts) into quartiles (A) rheumatoid arthritis, (B) psoriatic arthritis. ACR, American College of Rheumatology; CDAI, Clinical Disease Activity Index; DAPSA, Disease Activity Index for PsA; DAS28, 28 joint disease activity score; EULAR, European League Against Rheumatism; SDAI, Simplified Disease Activity Index; ΔTSJ, baseline tender and swollen joint count difference.
supplementary figure
Bar chart of percentages of patients in remission at 6 months according to categorization of Δ PEG into quartiles
Discussion
In this prospective, multicentre study, ΔTSJ and ΔPEG were found to be negative predictors of remission both in RA and PsA. The findings were consistent across DAS28, SDAI, CDAI, ACR/EULAR Boolean and DAPSA remission criteria as well as in subgroup analyses of TNFi and methotrexate-treated patients, although for the latter the findings were less consistent for ΔPEG compared with ΔTSJ.
We found significantly higher baseline composite scores of disease activity in RA compared with PsA, but significantly higher baseline ΔTSJ and ΔPEG in PsA. Still, the predictive value of ΔTSJ and ΔPEG was found to be similar in RA and PsA. We think the similarity of the findings across the two diseases supports that a treat-to-target strategy with a composite disease activity index that includes tender joint count as well as patient’s global assessment may perform as well in PsA as in RA.
This study underlines the influence of patient's perspective on disease evaluation. Tender joint count and patient's global assessment may both be influenced by pain.5 Level of pain is found to be multifactorial and may be influenced by adverse life events, psychosocial factors, sleep disturbances, dispositional optimism and other personality traits.7 ,8
Discordance between subjectively and objectively influenced measures of inflammation may reflect non-inflammatory factors that impact pain, which in turn may lead to misinterpretation of disease activity.5 According to Pollard et al,19 elevated ΔTSJ may identify patients with fibromyalgic RA, for whom evaluation of disease activity only with DAS28 may cause misclassification. Wolfe et al,20 on the other hand, report polysymptomatic distress rather than fibromyalgia to explain discrepancies between patient and physician measures of disease activity.
ΔTSJ and ΔPEG constitute important predictors of remission and may be considered in the shared decision making on treatment targets between the patient and healthcare provider in a treat-to-target strategy, for example, taking into consideration the predictive value of dichotomised ΔTSJ and ΔPEG (see online supplementary table S3) as well as the associations between the quartiles of ΔTSJ and ΔPEG and remission (figure 1, see online supplementary figure S2). The realistic treatment goals using DAS28, SDAI, CDAI and DAPSA scores for patients with positive ΔTSJ and ΔPEG may be higher numeric levels than for other patients, or alternative targets could be considered according to recommendation number 5 (RA) and 6 (PsA) in the updated treat-to-target recommendations.21 ,22
Studies are warranted to assess if alternative management strategies other than DMARDs may improve remission rates for patients with elevated ΔTSJ/ΔPEG and sustained disease activity, for example, taking into account a possible chronification of pain/insufficient pain management.
The main strength of this study is the prospective, multicentre design and the inclusion of a large cohort of both patients with RA and PsA. This is the first study to explore ΔTSJ and ΔPEG as predictors of remission in inflammatory arthritides. One recent study by Kristensen et al9 described swollen-to-tender joint count ratio as predictive of ACR50 response to TNFi in RA. In the real-life setting as in our study, some patients may have zero swollen or tender joints making the use of joint count ratio unfeasible. The same may be true for the global measures on VAS. We therefore chose to use the numeric differences as predictor variables.
Limitations of the study include assessment bias through examination by various physicians at various time points. Furthermore, the assessment of 32 and not 66/68 joint count may have led to overestimation of remission rates, particularly in PsA. Finally, the modification of DAPSA including 32 instead of the original 66/68 joint count is not validated for PsA and DAPSA is primarily developed as remission criteria for PsA and not RA. Still, the outcomes were similar for the different remission criteria explored.
In conclusion, discordance between patient's and evaluator's assessment of disease activity reflected through ΔTSJ, and partly through ΔPEG, may reduce likelihood of remission across the RA and PsA diagnoses as well as across different treatment regimens. The findings are relevant for the shared decision making between the patient and the healthcare provider when deciding on the treatment target within a treat-to-target strategy.
Acknowledgments
The authors thank the patients for participating in this study and the local rheumatology staff for data collection.
References
Supplementary materials
Lay summary
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Footnotes
Handling editor Hans WJ Bijlsma
Contributors BM, EKK, HBH, KMF, EL, GH and TKK were responsible for study design. AW, SK, ER, FK and TKK were responsible for data acquisition. BM analysed the data and wrote the manuscript. All authors critically revised the manuscript and approved the final version.
Funding The study was funded through a clinical research fellowship from Diakonhjemmet Hospital, originating from a network grant from South-Eastern Health Authority. Data collection in NOR-DMARD was partly funded through unrestricted grants from AbbVie, BMS, MSD, Pfizer (Wyeth), Roche and UCB.
Competing interests HBH has received fees for speaking and/or consulting from AbbVie, BMS, Pfizer, UCB, Roche, MSD and Novartis. GH has received fees for speaking and/or consulting from AbbVie, BMS, AMGEN, GSK, Mundifarma, Takeda, Eli Lilly, Pfizer, MSD, Novartis, Roche and UCB and received research funding to Martina Hansens Hospital and The Hospital of Southern Norway Trust from Pfizer. TKK has received fees for speaking and/or consulting from AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Epirus, Hospira-Pfizer, Merck-Serono, MSD, Novartis, Orion Pharma, Pfizer, Roche, Sandoz and UCB and received research funding to Diakonhjemmet Hospital from AbbVie, BMS, MSD, Pfizer, Roche and UCB.
Ethics approval Regional Committee for Medical and Health Research Ethics in Eastern Norway.
Provenance and peer review Not commissioned; externally peer reviewed.