Neuropathic-like pain symptoms in inflammatory hand osteoarthritis lower quality of life and may not decrease under prednisolone treatment.

BACKGROUND: Pain is common in hand osteoarthritis (OA) and multiple types may occur. We investigated the prevalence, associated patient characteristics, influence on health-related quality of life (HR-QoL) and response to anti-inflammatory treatment of neuropathic-like pain in inflammatory hand OA. METHODS: Data were analysed from a 6-week, randomized, double-blind, placebo-controlled trial investigating prednisolone treatment in 92 patients with painful inflammatory hand OA. Neuropathic-like pain was measured with the painDETECT questionnaire. Associations between baseline characteristics and baseline neuropathic-like pain were analysed with ordinal logistic regression, association of baseline neuropathic-like pain symptoms with baseline HR-QoL with linear regression, painDETECT and visual analogue scale (VAS) change from baseline to week 6 and interaction of painDETECT with prednisolone efficacy on VAS pain change from baseline to week 6 with generalized estimating equations (GEE). RESULTS: Of 91 patients (79% female, mean age 64) with complete painDETECT data at baseline, 53% were unlikely to have neuropathic-like pain, 31% were indeterminate and 16% were likely to have neuropathic-like pain. Neuropathic-like pain was associated with female sex, less radiographic damage and more comorbidities. Patients with neuropathic-like pain had lower HR-QoL (PCS-6.5 [95% CI -10.4 to -2.6]) than those without. Neuropathic-like pain symptoms remained under prednisolone treatment and no interaction was seen between painDETECT and prednisolone efficacy on VAS pain. CONCLUSIONS: In this study, 16% of inflammatory hand OA patients had neuropathic-like pain. They were more often female, had more comorbidities and had lower QoL than those without. Neuropathic-like pain symptoms remained despite prednisolone treatment and did not seem to affect the outcome of prednisolone treatment. SIGNIFICANCE: Pain is the dominant symptom in hand OA, with an unclear aetiology. In this study, we found that neuropathic-like pain may play a role in hand OA, that it showed associations with female sex, younger age and more comorbidities and that it lowered health-related quality of life in hand OA. Neuropathic-like pain in hand OA seems resistant to prednisolone therapy but did not seem to interfere with the treatment of inflammatory pain with prednisolone.

Real-time vs static scoring in musculoskeletal ultrasonography in patients with inflammatory hand osteoarthritis.

OBJECTIVES: Agreement between real-time and static ultrasonography has not been studied in musculoskeletal diseases. We studied this agreement in inflammatory hand OA. METHODS: Ultrasonography was performed blinded to clinical information of 30 joints of 75 patients with hand OA, treated with prednisolone in a randomized placebo-controlled double-blind trial. Images were scored real-time at acquisition and stored images were scored static (paired in known chronological order) for inflammatory features and osteophytes (score 0-3). Agreement between methods was studied at joint level with quadratic weighted kappa. At patient level intra-class correlations (ICC) of sum scores and change in sum-scores (delta baseline-week 6) were calculated. Responsiveness of scoring methods was analysed with generalized estimating equations (GEE) with treatment as independent and ultrasonography findings as dependent variable. RESULTS: Agreement at baseline was good to excellent at joint level (kappa 0.72-0.88) and moderate to excellent at patient level (ICC 0.58-0.91). Agreement for change in sum scores was poor to fair for synovial thickening and effusion (ICC 0.18 and 0.34, respectively), while excellent for Doppler signal (ICC 0.80). Real-time ultrasonography discriminated between prednisolone and placebo with a mean between-group difference of synovial thickening of -2.5 (95% CI: -4.7, -0.3). Static ultrasonography did not show a decrease in synovial thickening. CONCLUSION: While cross-sectional agreement between real-time and static ultrasonography is good, static ultrasonography measurement of synovial thickening did not show responsiveness to prednisone therapy while real-time ultrasonography did. Therefore, when ultrasonography is used in clinical trials, real-time dynamic scoring should remain the standard for now.

Earlier is better when treating rheumatoid arthritis: but can we detect a window of opportunity?

OBJECTIVES: The window of opportunity (WOO) hypothesis suggests a limited time frame to stop rheumatoid arthritis (RA). We hypothesised that a WOO could either be represented by a hyperbolic ('curved') decline in the chance to achieve the outcome sustained drug-free remission (sDFR) over time, after which achieving sDFR is not possible anymore, or by a more gradual linear decline approaching zero chance to achieve sDFR. METHODS: Patients with RA (symptom duration <2 years) were included from two randomised trials: BehandelStrategieën (BeSt), n=508 and Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED), n=479. Cox-regression was performed to assess the shape of the association between symptom duration and sDFR (Disease Activity Score<1.6, no disease-modifying anti-rheumatic drugs for ≥1 year) for patients starting slow-acting monotherapy (IMPROVED, BeSt) or fast-acting combination therapy (BeSt). Likelihood ratio tests were used to compare the fit of linear and non-linear models in both databases separately. Predictions from the best fitting models were used to assess whether the absolute risk to achieve sDFR approaches zero with increasing symptom duration. RESULTS: In BeSt and IMPROVED, 54/226 and 110/421 patients achieved sDFR with fast-acting treatment, and 53/243 (BeSt) with slow-acting treatment. Non-linear models did not fit better than linear models (fast-acting treatment BeSt p=0.743, IMPROVED p=0.337; slow-acting treatment BeSt p=0.609). After slow-acting monotherapy, linear models declined steeper. None of the models approached zero chance to achieve sDFR over time. CONCLUSIONS: The chance to achieve sDFR decreased gradually over time, and decreased fastest in patients starting slow-acting monotherapy. In both treatment groups, we found no evidence for a WOO within 2 years symptom duration.

Results of a 6-week treatment with 10 mg prednisolone in patients with hand osteoarthritis (HOPE): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Hand osteoarthritis is a prevalent joint condition that has a high burden of disease and an unmet medical need for effective therapeutic options. Since local inflammation is recognised as contributing to osteoarthritic complaints, the Hand Osteoarthritis Prednisolone Efficacy (HOPE) study aimed to investigate the efficacy and safety of short-term prednisolone in patients with painful hand osteoarthritis and synovial inflammation. METHODS: The HOPE study is a double-blind, randomised, placebo-controlled trial. We recruited eligible adults from rheumatology outpatient clinics at two sites in the Netherlands. Patients were considered eligible if they had symptomatic hand osteoarthritis and signs of inflammation in their distal and proximal interphalangeal (DIP/PIP) joints. For inclusion, patients were required to have four or more DIP/PIP joints with osteoarthritic nodes; at least one DIP/PIP joint with soft swelling or erythema; at least one DIP/PIP joint with a positive power Doppler signal or synovial thickening of at least grade 2 on ultrasound; and finger pain of at least 30 mm on a 100-mm visual analogue scale (VAS) that flared up during a 48-h non-steroidal anti-inflammatory drug (NSAID) washout (defined as worsening of finger pain by at least 20 mm on the VAS). Eligible patients were randomly assigned (1:1) to receive 10 mg prednisolone or placebo orally once daily for 6 weeks, followed by a 2-week tapering scheme, and a 6-week follow-up without study medication. The patients and study team were masked to treatment assignment. The primary endpoint was finger pain, assessed on a VAS, at 6 weeks in participants who had been randomly assigned to groups and attended the baseline visit. This study is registered with the Netherlands Trial Registry, number NTR5263. FINDINGS: We screened patients for enrolment between Dec 3, 2015, and May 31, 2018. Patients completed baseline visits and started treatment between Dec 14, 2015, and July 2, 2018, and the last study visit of the last patient was Oct 4, 2018. Of 149 patients assessed for eligibility, 57 (38%) patients were excluded (predominantly because they did not meet one or several inclusion criteria, most often because of an absence of synovial inflammation or of flare-ups after NSAID washout) and 92 (62%) patients were eligible for inclusion. We randomly assigned 46 (50%) patients to receive prednisolone and 46 (50%) patients to receive placebo, all of whom were included in the modified intention-to-treat analysis of the primary endpoint. 42 (91%) patients in the prednisolone group and 42 (91%) in the placebo group completed the 14-week study. The mean change between baseline and week 6 on VAS-reported finger pain was -21·5 (SD 21·7) in the prednisolone group and -5·2 (24·3) in the placebo group, with a mean between-group difference (of prednisolone vs placebo) of -16·5 (95% CI -26·1 to -6·9; p=0·0007). The number of non-serious adverse events was similar between the groups. Five serious adverse events were reported during our study: one serious adverse event in the prednisolone group (a myocardial infarction) and four serious adverse events in the placebo group (an infected traumatic leg haematoma that required surgery, bowel surgery, atrial fibrillation that required a pacemaker implantation, and symptomatic uterine myomas that required a hysterectomy). Four (4%) patients discontinued the study because of an adverse event: one (2%) patient receiving prednisolone (for a myocardial infarction) and three (7%) patients receiving placebo (for surgery of the bowel and for an infected leg haematoma and for Lyme disease arthritis of the knee). INTERPRETATION: Treatment with 10 mg prednisolone for 6 weeks is efficacious and safe for the treatment of patients with painful hand osteoarthritis and signs of inflammation. The results of our study provide clinicians with a new short-term treatment option for patients with hand osteoarthritis who report a flare-up of their disease. FUNDING: Dutch Arthritis Society.

Further Treatment Intensification in Undifferentiated and Rheumatoid Arthritis Patients Already in Low Disease Activity has Limited Benefit towards Physical Functioning.

BACKGROUND: It is recommended to optimise treatment as long as a predefined treatment target is not met, but should the aim be remission if patients are in low disease activity (LDA)? The aim of this study was to assess if, in patients with rheumatoid arthritis (RA) or patients with undifferentiated arthritis (UA) with Disease Activity Score (DAS) ≤ 2.4 (LDA), treatment intensification results in better functional ability. METHODS: In the IMPROVED study 610 patients with early RA or UA were treated with methotrexate + tapered high-dose prednisone. After 4 months, patients with DAS ≥ 1.6 were randomised to either of two treatment strategies. Patients with DAS < 1.6 tapered treatment. Over 5 years, patients with DAS ≥ 1.6 required treatment intensification, but protocol violations occurred, which allowed us to test the effect of treatment intensification regardless of subsequent DAS. A linear mixed model was used to test, in patients in LDA, the relationship between treatment intensification and functional ability (Health Assessment Questionnaire [HAQ]) over time. RESULTS: The number of patients in LDA per visit ranged from 88 to 146. Per visit, 27-74% of the patients in LDA had treatment intensification. We found a statistically significant effect of treatment intensification on ΔHAQ, corrected for baseline HAQ, age, sex and treatment strategy (ß = -0.085, 95% CI -0.13 to -0.044). When ΔDAS was added, the effect of treatment intensification was partly explained by ΔDAS, and the association with HAQ was no longer statistically significant (ß = -0.022, 95% CI -0.060 to 0.016). When the interaction between treatment intensification and time in follow-up was added, a statistically significant interaction was found (ß = 0.0098, 95% CI 0.0010 to 0.019), indicating lesser improvement in HAQ after treatment intensification if follow-up time increased. CONCLUSIONS: For patients with early RA and patients with UA already in LDA, further treatment intensification aimed at DAS remission does not result in meaningful functional improvement. TRIAL REGISTRATION: ISRCTN, 11916566 . Registered on 28 December 2006. EudraCT, 2006-006186-16 . Registered on 16 July 2007.

Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis.

Osteoarthritis [MIM 165720] is a common late-onset articular joint disease for which no pharmaceutical intervention is available to attenuate the cartilage degeneration. To identify a new osteoarthritis susceptibility locus, a genome-wide linkage scan and combined linkage association analysis were applied to 179 affected siblings and four trios with generalized osteoarthritis (The GARP study). We tested, for confirmation by association, 1478 subjects who required joint replacement and 734 controls in a UK population. Additional replication was tested in 1582 population-based females from the Rotterdam study that contained 94 cases with defined hip osteoarthritis and in 267 Japanese females with symptomatic hip osteoarthritis and 465 controls. Suggested evidence for linkage in the GARP study was observed on chromosome 14q32.11 (log of odds = 3.03, P = 1.9 x 10(-4)). Genotyping tagging single-nucleotide polymorphisms covering three important candidate genes revealed a common coding variant (rs225014; Thr92Ala) in the iodothyronine-deiodinase enzyme type 2 (D2) gene (DIO2 [MIM 601413]) which significantly explained the linkage signal (P = 0.006). Confirmation and replication by association in the additional osteoarthritis studies indicated a common DIO2 haplotype, exclusively containing the minor allele of rs225014 and common allele of rs12885300, with a combined recessive odds ratio of 1.79, 95% confidence interval (CI) 1.37-2.34 with P = 2.02 x 10(-5) in female cases with advanced/symptomatic hip osteoarthritis. The gene product of this DIO2 converts intracellular pro-hormone-3,3',5,5'-tetraiodothyronine (T4) into the active thyroid hormone 3,3',5-triiodothyronine (T3) thereby regulating intracellular levels of active T3 in target tissues such as the growth plate. Our results indicate a new susceptibility gene (DIO2) conferring risk to osteoarthritis.

Osteoarthritis of the knee: association between clinical features and MR imaging findings.

PURPOSE: To prospectively evaluate the association between clinical features and structural abnormalities found at magnetic resonance (MR) imaging in patients with osteoarthritis (OA) of the knee. MATERIALS AND METHODS: The study was approved by the institutional medical ethics review board. Written informed consent was obtained from each patient. MR images of the knee were obtained from 205 (42 [20%] men, 163 [80%] women; median age, 60 years; range, 43-77 years) patients in whom symptomatic OA at multiple joint sites was diagnosed. MR images were analyzed for various abnormalities of OA. All patients were interviewed concerning pain and stiffness in the knee that was imaged. Odds ratios (ORs) with 99% confidence intervals (CIs) were used to determine the association between the imaging findings and clinical features of OA. RESULTS: A large joint effusion was associated with pain (OR, 9.99; 99% CI: 1.28, 149) and stiffness (OR, 4.67; 99% CI: 1.26, 26.1). The presence of an osteophyte in the patellofemoral compartment (OR, 2.25; 99% CI: 1.06, 4.77) was associated with pain. All other imaging findings, including focal or diffuse cartilaginous abnormalities, subchondral cysts, bone marrow edema, subluxation of the meniscus, meniscal tears, or Baker cysts, were not associated with symptoms. CONCLUSION: Findings of this study indicate that only two associations exist between clinical symptoms and structural findings found on MR images in patients with OA of the knee.

The role of interleukin 10 promoter polymorphisms in the susceptibility of distal interphalangeal osteoarthritis.

OBJECTIVE: The interleukin (IL)-10 single nucleotide promoter polymorphism (SNP) -2849A is associated with decreased IL-10 production as measured by lipopolysaccharide (LPS) stimulated whole blood cultures. A low innate production of IL-10 using the same assay is associated with an increased risk of familial osteoarthritis (OA). We investigated the association of 7 novel SNP located downstream of the IL-10 transcription start site: -2849,-2763, -1330, -1082, -819, and -592, constituting the 4 ancient haplotypes, with distal interphalangeal (DIP) OA. METHODS: The study population comprised consecutive patients with and without radiological DIP OA (Kellgren-Lawrence score of > or = 2 in one joint) aged 40-70 years from a cohort of subjects with different types of arthritis in an early stage referred to an Early Arthritis Clinic (EAC). DNA typing for IL-10 SNP as well as radiographs of the hands were performed at clinic enrolment. Patients with rheumatoid arthritis, systemic lupus erythematosus, spondyloarthropathies, and psoriatic arthritis were excluded. RESULTS: The distribution of DIP OA and IL-10 SNP were comparable to representative samples of the Dutch population. In the cohort of 172 subjects, 57 had DIP OA (33%) and 115 (67%) had no DIP OA. No significant association was found between DIP OA and IL-10 SNP and the 4 common haplotypes IL10.1, IL10.2, IL10.3, and IL10.4. CONCLUSION: Our data suggest that IL-10 SNP, including -2849, which is associated with differential production, do not play a major role in the susceptibility of DIP OA.

Association of the risk of osteoarthritis with high innate production of interleukin-1beta and low innate production of interleukin-10 ex vivo, upon lipopolysaccharide stimulation.

OBJECTIVE: In a sibpair study of osteoarthritis (OA) patients, we investigated whether, upon stimulation with lipopolysaccharide (LPS), variations in the innate ex vivo production of interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), IL-10, and tumor necrosis factor alpha (TNFalpha) in whole-blood assays contribute to the risk of OA. METHODS: Data from 305 patients with OA at multiple sites (hand, knee, hip, and spine), whose median age was 60 years (range 43-79 years), were compared with those from 137 controls. OA was defined in accordance with the American College of Rheumatology criteria. Whole-blood samples were stimulated with LPS (10 ng/ml). In the supernatants, cytokines were measured by enzyme-linked immunosorbent assay. Odds ratios (ORs) were used as measures of the relative risk of OA in relation to quartiles of IL-1beta, IL-1Ra, TNFalpha, and IL-10 production. The ORs were adjusted for sex and age, and 95% confidence intervals (95% CIs) were computed using robust standard errors to take into account the intrafamily effect. RESULTS: Subjects in the highest quartile of IL-1beta and IL-1Ra had an increased risk of OA (OR 3.3, 95% CI 1.4-7.9 and OR 8.0, 95% CI 3.7-17.4, respectively), while subjects in the lowest quartile of IL-10 had a 3-fold increased risk of OA (OR 3.1, 95% CI 1.5-6.5). High innate ex vivo production of TNFalpha was not associated with an increased risk of OA. CONCLUSION: Subjects with a high innate ex vivo production of IL-1beta and IL-1Ra and low innate ex vivo production of IL-10 have an increased risk of OA. These results suggest that a proportion of the genetic susceptibility to OA may be encoded for by variations in innate cytokine activity.

The relationship between the MRI features of mild osteoarthritis in the patellofemoral and tibiofemoral compartments of the knee.

The aim of this work was to demonstrate the relationship between osteoarthritic changes seen on magnetic resonance (MR) images of the patellofemoral (PF) or tibiofemoral (TF) compartments in patients with mild osteoarthritis (OA) of the knee. MR images of the knee were obtained in 105 sib pairs (210 patients) who had been diagnosed with OA at multiple joints. Entry criteria included that the degree of OA in the knee examined should be between a Kellgren and Lawrence score of 2 or 3. MR images were analyzed for the presence of cartilaginous lesions, bone marrow edema (BME) and meniscal tears. The relationship between findings in the medial and lateral aspects of the PF and TF compartments was examined. The number of cartilaginous defects on either side of the PF compartment correlated positively with number of cartilaginous defects in the ipsilateral TF compartment (odds ratio, OR, 55, confidence interval, CI, 7.8-382). The number of cartilaginous defects in the PF compartment correlated positively with ipsilateral meniscal tears (OR 3.7, CI 1.0-14) and ipsilateral PF BME (OR 17, CI 3.8-72). Cartilaginous defects in the TF compartment correlated positively with ipsilateral meniscal tears (OR 9.8, CI 2.5-38) and ipsilateral TF BME (OR 120, CI 6.5-2,221). Osteoarthritic defects lateralize or medialize in the PF and TF compartments of the knee in patients with mild OA.

MRI assessment of knee osteoarthritis: Knee Osteoarthritis Scoring System (KOSS)--inter-observer and intra-observer reproducibility of a compartment-based scoring system.

OBJECTIVE: To develop a scoring system for quantifying osteoarthritic changes of the knee as identified by magnetic resonance (MR) imaging, and to determine its inter- and intra-observer reproducibility, in order to monitor medical therapy in research studies. DESIGN AND PATIENTS: Two independent observers evaluated 25 consecutive MR examinations of the knee in patients with previously defined clinical symptoms and radiological signs of osteoarthritis. We acquired on a 1.5 T system: coronal and sagittal proton density- and T2-weighted dual spin echo (SE) images, sagittal three-dimensional T1-weighted gradient echo (GE) images with fat suppression, and axial dual turbo SE images with fat suppression. Images were scored for the presence of cartilaginous lesions, osteophytes, subchondral cysts, bone marrow edema, and for meniscal abnormalities. Presence and size of effusion, synovitis and Baker's cyst were recorded. All parameters were ranked on a previously defined, semiquantitative scale, reflecting increasing severity of findings. Kappa, weighted kappa and intraclass correlation coefficient (ICC) were used to determine inter- and intra-observer variability. RESULTS: Inter-observer reproducibility was good (ICC value 0.77). Inter- and intra-observer reproducibility for individual parameters was good to very good (inter-observer ICC value 0.63-0.91; intra-observer ICC value 0.76-0.96). CONCLUSION: The presented comprehensive MR scoring system for osteoarthritic changes of the knee has a good to very good inter-observer and intra-observer reproducibility. Thus the score form with its definitions can be used for standardized assessment of osteoarthritic changes to monitor medical therapy in research studies.