An Economic Evaluation of Stopping Versus Continuing Tumor Necrosis Factor Inhibitor Treatment in Rheumatoid Arthritis Patients With Disease Remission or Low Disease Activity: Results From a Pragmatic Open-Label Trial.

OBJECTIVE: To evaluate, from a societal perspective, the incremental cost-effectiveness of withdrawing tumor necrosis factor inhibitor (TNFi) treatment compared to continuation of these drugs within a 1-year, randomized trial among rheumatoid arthritis patients with longstanding, stable disease activity or remission. METHODS: Data were collected from a pragmatic, open-label trial. Cost-utility analysis was performed using the nonparametric bootstrapping method, and a cost-effectiveness acceptability curve was constructed using the net-monetary benefit framework, where a willingness-to-accept threshold (WTA) was defined as the minimal cost saved that a patient accepted for each quality-adjusted life year (QALY) lost. RESULTS: A total of 531 patients were randomized to the stop group and 286 patients to the continuation group. Withdrawal of TNFi treatment resulted in a >60% reduction of the total drug cost, but led to an increase of ∼30% in other health care expenditures. Compared to continuation, stopping TNFi resulted in a mean yearly cost saving of €7,133 (95% confidence interval [95% CI] €6,071, €8,234]) and was associated with a mean loss of QALYs of 0.02 (95% CI 0.002, 0.040). Mean saved cost per QALY lost and per extra flare incurred in the stop group compared to the continuation group was €368,269 (95% CI €155,132, €1,675,909) and €17,670 (95% CI €13,650, €22,721), respectively. At a WTA of €98,438 per QALY lost, the probability that stopping TNFi treatment is cost-effective was 100%. CONCLUSION: Although an official WTA is not defined, the mean saved cost of €368,269 per QALY lost seems acceptable in The Netherlands, given existing data on willingness to pay.

Age affects joint space narrowing in patients with early active rheumatoid arthritis.

BACKGROUND: Joint space narrowing (JSN) in rheumatoid arthritis (RA) may be a manifestation of (primary) osteoarthritis becoming more prominent with age. We investigated the severity and predictors of JSN progression among different age groups. METHODS: 10-year follow-up data of the BeSt study, a randomised controlled treat-to-target trial in early RA were used. Annual X-rays of hands and feet were scored using the Sharp/van der Heijde score (SHS). Subgroups were defined by age at baseline: ≥55, ≥40<55 and <40 years. JSN progression predictors were assessed by Poisson regression. RESULTS: Baseline JSN scores (median (IQR)) were higher in patients ≥55 (2.0 (0.0-6.0)) compared with the other age groups: 1.0 (0.0-3.0) ≥40<55 and 0.3 (0.0-3.0) <40, p<0.001. After 10 years, total JSN and SHS were similar in all age groups. In patients ≥55 the mean erythrocyte sedimentation rate (ESR) over time (relative risk 1.02 (95% CI 1.00 to 1.03)) and the combined presence of rheumatoid factor and anticitrullinated protein antibodies (RF+/ACPA+) (3.27 (1.25-8.53)) were significantly correlated with JSN progression. In patients <40 the baseline swollen joint count (SJC; 1.09 (1.01-1.18)) and ESR over time (1.04 (1.02-1.06)) were significantly associated. CONCLUSIONS: At baseline, patients with RA ≥55 years had more JSN than younger patients but after 10 years JSN scores were similar between age groups. Independent risk factors for JSN progression were baseline SJC and ESR over time in patients <40, RF+/ACPA+ and ESR over time in patients ≥55 years. This suggests that mechanisms leading to JSN progression are related to (residual) rheumatoid inflammation and vary between age groups. These mechanisms remain to be elucidated. TRIAL REGISTRATION NUMBERS: NTR262, NTR265.

Effectiveness of four dynamic treatment strategies in patients with anticitrullinated protein antibody-negative rheumatoid arthritis: a randomised trial.

OBJECTIVE: To determine the most effective treatment strategy among anticitrullinated protein antibodies (ACPA)-negative patients with early rheumatoid arthritis. METHODS: In the BeSt study, 184 ACPA-negative patients were randomised to: (1) sequential monotherapy, (2) step-up therapy, (3) initial combination including prednisone, (4) initial combination including infliximab. Treatment was targeted at the disease activity score (DAS) ≤2.4. Early response and 10-year outcomes were compared between the four strategy-arms in ACPA-negative patients. RESULTS: ACPA-negative patients achieved more short-term functional improvement from initial combination therapy than when on monotherapy (at month 3, mean Health Assessment Questionnaire (HAQ) 0.71 vs 0.98, p=0.006; at month 6, 0.59 vs 0.87, p=0.004). Functional ability over time was comparable between the strategy-arms (p=0.551) with a mean HAQ of 0.6 at year 10 (p=0.580 for comparison across the strategy-arms). 10-year radiographic progression was negligible (median 0.5) and comparable between the 4 strategy-arms (p=0.082). At year 10, remission was achieved by 11/40 (28%), 9/45 (20%), 17/56 (30%) and 17/43 patients (40%) in strategy-arms 1-4, respectively (p=0.434). Over time, similar remission percentages were achieved in all strategy-arms (p=0.815). 18%, 16%, 20% and 21% in strategy-arms 1 to 4 (p=0.742) were in drug-free remission at year 10, with a median duration of 60 months across the arms. CONCLUSIONS: Initial combination therapy with methotrexate, sulfasalazine and prednisone, or methotrexate and infliximab, is the most effective treatment strategy for ACPA-negative patients, resulting in earlier functional improvement than when on initial methotrexate monotherapy. After 10 years of targeted treatment, in all strategy-arms favourable clinical outcomes were achieved and radiographic progression was limited. TRIAL REGISTRATION NUMBER: NTR262, NTR265.

Association of high body mass index with decreased treatment response to combination therapy in recent-onset rheumatoid arthritis patients.

OBJECTIVE: To assess the association between high body mass index (BMI) and treatment response in recent-onset rheumatoid arthritis. METHODS: In the Behandelstrategieën voor Reumatoide Artritis (Treatment Strategies for Rheumatoid Arthritis) study, 508 patients were randomized to initial monotherapy or combination therapy with prednisone or infliximab (IFX). The response to Disease Activity Score (DAS) ≤2.4-steered treatment (first dose and after 1 year) was compared between patients with a BMI <25 kg/m(2) and ≥25 kg/m(2) , using relative risk (RR) regression analyses. DAS, components of DAS, and functional ability during the first year were compared using linear mixed models. RESULTS: High BMI was independently associated with failure to achieve a DAS ≤2.4 on initial therapy (RR 1.20 [95% confidence interval (95% CI) 1.05, 1.37]). The effect for combination therapy with prednisone was RR 1.55 (95% CI 1.06, 2.28) and for combination therapy with IFX 1.42 (95% CI 0.98, 2.06). The RRs for failure after 1 year were 1.46 (95% CI 0.75, 2.83) and 2.20 (95% CI 0.99, 4.92), respectively. High BMI was also associated with failure on delayed combination therapy with IFX, after adjustment for selection bias related to previous failure on disease-modifying antirheumatic drugs. No significant association was observed in the initial monotherapy groups. In the first year, patients with a high BMI had higher DAS and worse functional ability, with more tender joints and a higher visual analog scale global health, but not more swollen joints and similar systemic inflammation. CONCLUSION: High BMI was independently associated with failure to achieve low DAS on initial combination therapy with prednisone and on initial and delayed treatment with IFX. Patients with a high BMI experienced more pain, but not more swelling or systemic inflammation.

Progression of hand osteoarthritis over 2 years: a clinical and radiological follow-up study.

OBJECTIVES: To investigate the course of hand osteoarthritis over 2 years by currently available outcome measures. METHODS: 189 participants of the Genetics, Arthrosis and Progression (GARP) study with hand osteoarthritis were followed for 2 years. Self-reported hand pain and functional limitations were assessed with the Australian/Canadian osteoarthritis hand index (AUSCAN LK 3.0). Pain intensity upon lateral pressure in the interphalangeal and thumb base joints was graded on a four-point scale. Osteophytes (0-3) and joint space narrowing (JSN) (0-3) was scored at baseline and after 2 years in interphalangeal and thumb base joints. Standardised response means (SRM) were calculated. RESULTS: 172 (91%) patients completed the 2-year follow-up (mean age 60.5 years, 78.5% women). Statistically significant increases in self-reported pain and function scores, in pain intensity scores as well as in osteophyte and JSN total scores were seen over 2 years. SRM were 0.25, 0.23, 0.67, 0.34 and 0.35, respectively, for self-reported pain and function scores, pain intensity scores, osteophyte and JSN total scores. Radiological progression was not associated with changes in self-reported pain and function. Women in an early post-menopausal stage were especially at risk of progressing radiologically. CONCLUSIONS: Currently available outcome measures were able to assess progression over the relatively short time period of 2 years. Radiographic outcomes were more responsive than self-reported outcomes. Pain intensity upon lateral pressure seems to be a responsive measure but needs validation.

Risk factors in familial osteoarthritis: the GARP sibling study.

PURPOSE: To investigate the association between systemic and local risk factors and familial osteoarthritis (OA) at multiple sites. METHODS: Patients and their siblings had primary OA at multiple sites at middle age. OA diagnosis followed the American College of Rheumatology criteria. We recruited 345 controls (mean age 57 years (range 40-76), 64% women) by random sampling from the population by telephone and collected all data by questionnaires. Odds ratios (ORs) were adjusted for sex, age and body mass index (BMI) (kg/m(2)), 95% confidence intervals (CIs95) were computed using robust standard errors with the intra-family effect taken into account. RESULTS: Three hundred and eighty-two patients (mean age 60 years [range 43-79]), 82% women had OA in the spine (80%), hands (72%), knees (34%) and hips (24%). In women, an association of familial OA with a young age at natural menopause (<45 years), OR=2.6 (CI95 1.5-4.5) was found. Physically demanding jobs led to an increased risk of familial OA in men: OR=2.6 (CI95 1.3-5.3). Familial OA was more prevalent in individuals with a BMI>30, OR=2.0 (CI95 1.3-3.2) compared to a BMI of <25. Taller persons had a lower risk of familial OA, OR=0.33 (0.1-0.8) in the height category >180 cm relative to a height of <160 cm. A history of meniscectomy, increased the risk of familial OA at multiple sites with knee involvement, OR=6.2 (CI95 3.0-12.7). CONCLUSIONS: Systemic and local risk factors play a role in the etiology of familial OA at multiple sites.

Activity limitations in the lower extremities in patients with osteoarthritis: the modifying effects of illness perceptions and mental health.

OBJECTIVES: Using the International Classification of Functioning, Disability and Health as framework, we evaluated modifying effects of illness perceptions and mental health on the association between impairments in body structures and functions due to osteoarthritis (OA) and limitation in activities in the lower extremities. METHODS: Self-reported limitation in activities was assessed by the Western Ontario and McMaster Universities OA index (WOMAC) function subscale in 316 patients with knee or hip pain or evidence of OA on knee or hip radiographs. Body structures and functions were evaluated during clinical and radiological assessments. Illness perceptions and mental health were assessed with the revised Illness Perception Questionnaire (IPQ-R) and the mental component summary score of the RAND 36-item Health Survey, respectively. For each patient an expected WOMAC function score was calculated, using an equation based on a multivariate model of the association of body structures and functions with limitation in activities. RESULTS: The median (interquartile) self-reported WOMAC function score was 22.2 (9.6-43.5). Ninety-one patients reported more and 120 patients reported less limitation in activities than expected. Patients with lumbar spine degeneration, physical or exercise therapy and high IPQ-R identity, consequences and chronic timeline scores had an increased risk to report more limitation in activities than the expected range. Low IPQ-R identity, consequences and emotional representation scores and better mental health were associated with reporting less limitation in activities than the expected range. CONCLUSION: Illness perceptions and mental health modify the association between self-reported limitation in activities and calculated limitation in activities based on impairments in body structures and functions due to OA.

Association of matrilin-3 polymorphisms with spinal disc degeneration and osteoarthritis of the first carpometacarpal joint of the hand.

BACKGROUND: Seven polymorphisms in the matrilin-3(MATN3) gene were previously tested for genetic association with hand osteoarthritis in an Icelandic cohort. One of the variants, involving a conserved amino acid substitution (T303M; SNP5), was related to idiopathic hand osteoarthritis. OBJECTIVES: To investigate SNP5 and two other promising polymorphisms (rs2242190; SNP3, rs8176070; SNP6) for association with radiographic and symptomatic hand osteoarthritis phenotypes, as well as other heritable phenotypes. METHODS: Polymorphisms were examined in two distinct cohorts of subjects: a population based sample from the Rotterdam study (n = 809), and affected siblings from the genetics, osteoarthrosis and progression (GARP) study (n = 382). RESULTS: The originally described association of T303M with the hand osteoarthritis phenotype was not observed in the populations studied. In the Rotterdam sample, however, carrying the T allele of T303M conferred an odds ratio of 2.9 (95% confidence interval (CI), 1.2 to 7.3; p = 0.02) for spinal disc degeneration. In the GARP study, carriers of the A allele of SNP6 had an odds ratio of 2.0 (95% CI, 1.3 to 3.1, p = 0.004) for osteoarthritis of the first carpometacarpal joint (CMC1) as compared with the Rotterdam sample as a control group. Subsequent haplotype analysis showed that a common haplotype, containing the risk allele of SNP6, conferred a significant risk in sibling pairs with CMC1 osteoarthritis (odds ratio = 1.7 (95% CI, 1.1 to 2.7, p = 0.02)). CONCLUSIONS: These associations suggest that the MATN3 region also determines susceptibility to spinal disc degeneration and CMC1 osteoarthritis.

Association of the Frizzled-related protein gene with symptomatic osteoarthritis at multiple sites.

OBJECTIVE: To confirm the association of 2 variants of the Frizzled-related protein gene (FRZB) with osteoarthritis (OA) of the hip, and to investigate whether these variants also associate with other heritable generalized OA phenotypes. METHODS: An association analysis of 2 variants (R200W and R324G) of FRZB was performed in a random sample of 1,369 subjects (ages 55-70 years) from a population-based cohort (the Rotterdam Study) scored for radiographic characteristics of OA in the hip, hand, spine, and knee and in a patient population of Caucasian probands (ages 40-70 years) and their siblings selected for the presence of primary symptomatic OA at multiple sites. RESULTS: The allele frequency of the 2 variants was not significantly different between subjects with hip radiographic OA (ROA) and controls. The frequency of the G allele of the R324G variant was significantly increased in subjects with generalized ROA from the Rotterdam Study (0.10) and in subjects from the Genetics, osteoARthritis and Progression study (0.11) compared with that in controls from the Rotterdam Study (0.08). Carriers of this G allele had increased susceptibility for generalized ROA (odds ratio [OR] 1.4, 95% confidence interval [95% CI] 0.9-1.9, P = 0.10) or familial symptomatic OA at multiple sites (OR 1.6, 95% CI 1.1-2.3, P = 0.02). CONCLUSION: Our results confirm that the R324G variant of the FRZB gene is involved in OA and indicate a role of this variant in several generalized OA phenotypes. A more extended OA phenotype may indeed be expected from genetic variation in an essential pathway of skeletal development such as Wnt signaling.

Evidence for familial aggregation of hand, hip, and spine but not knee osteoarthritis in siblings with multiple joint involvement: the GARP study.

OBJECTIVE: To evaluate whether familial aggregation of osteoarthritis differs by joint site in a sibling pair study (GARP) of patients with osteoarthritis at multiple sites. SUBJECTS: White Dutch probands aged 40 to 70 years and their siblings with primary osteoarthritis at multiple sites. METHODS: The diagnosis of knee, hip, and spine osteoarthritis was based on a combination of pain or stiffness on most days of the previous month and osteophytes or joint space narrowing on x ray. Hand osteoarthritis was defined by ACR criteria. Odds ratios (OR) were calculated for siblings and probands sharing disease in the same joints. RESULTS: 191 sibling pairs were included (85% women; mean age 60 years). In the probands, osteoarthritis was present in spine (76%), hands (77%), knees (37%), and hips (26%). The most common combinations in probands were spine-hand (59%), spine-knee (27%), and hand-knee (25%). The OR adjusted for age, sex, and body mass index for siblings to be affected in the same joint sites as the proband were increased in osteoarthritis of the hand (OR = 4.4 (95% confidence interval, 2.0 to 9.5)), hip (OR = 3.9 (1.8 to 8.4)), spine (OR = 2.2 (1.0 to 5.1)), hip-spine (OR = 4.7 (2.1 to 10.4)), and hand-hip (OR = 3.4 (1.1 to 10.4)). Siblings of probands with osteoarthritis in the knee did not have an increased likelihood of knee osteoarthritis. CONCLUSIONS: In middle aged patients with familial osteoarthritis at multiple sites, familial aggregation of osteoarthritis was most striking for hand and hip but remarkably absent for the knee.

HLA class II is associated with distal interphalangeal osteoarthritis.

OBJECTIVE: To investigate whether there is an association between HLA class II and distal interphalangeal osteoarthritis (DIP OA). METHODS: The study group consisted of consecutive patients with and without DIP OA aged between 40 and 70 years. DIP OA was diagnosed by radiology. These patients were referred to an "Early Arthritis Clinic" (EAC) with different types of arthritis at an early stage. Patients with rheumatoid arthritis, systemic lupus erythematosus, spondyloarthropathies, and psoriatic arthritis were excluded for the purpose of this study. DNA typing for HLA-DR and x ray examination of the hands were performed at enrollment in the EAC. To establish whether the study group was representative of the Dutch population, a population based study in Zoetermeer (n=3243) for the prevalence of DIP OA and blood donors in the Leiden area (n=2400) for the HLA-DR antigen frequencies were used as references. RESULTS: Fifty five patients (33%) of the total study group (n=166) had DIP OA. The prevalence of DIP OA and frequency of the HLA-DR alleles were similar to those of the two reference groups. Within the study group an association between DIP OA and HLA-DR2 and DR4 with respectively odds ratios of 2.4 (95% confidence interval (CI) 1.1 to 5.0) and 0.3 (95% CI 0.1 to 0.7) was found. No association was found between other HLA-DR alleles and DIP OA. CONCLUSION: The study group is a representative sample of the Dutch population. The HLA-DR2 allele was more common in patients with DIP OA. Furthermore, an inverse relation was observed between DIP OA and HLA-DR4. The results confirm findings from other investigations implicating HLA-DR2 as a risk factor in the development of DIP OA.

Low-molecular-weight heparin combined with aspirin in pregnant women with thrombophilia and a history of preeclampsia or fetal growth restriction: a preliminary study.

OBJECTIVE: To assess the prevalence of haemostatic abnormalities in patients with an obstetric history of preeclampsia and/or fetal growth restriction and documented thrombophilia, and to evaluate the effects of low-molecular-weight heparin (LMWH) and aspirin on pregnancy outcome. METHOD: A total of 276 patients with a history of preeclampsia and/or fetal growth restriction were tested for the presence of coagulation abnormalities and anticardiolipin antibodies (ACA). Ninety patients with preeclampsia and 15 patients with isolated fetal growth restriction had haemostatic abnormalities. Twenty-six patients with coagulation abnormalities: protein S-deficiency, activated protein C (APC) resistance and/or > or =15 ACA GPL and/or MPL had a subsequent pregnancy and were treated with aspirin in combination with LMWH. Their pregnancy outcome was compared with all patients having a subsequent pregnancy from the same cohort without abnormalities, or <15 ACA GPL and/or MPL who received aspirin (n=19). RESULTS: In subsequent pregnancies birth weight of babies born to patients with an unequivocal coagulation abnormality (i.e., protein S-deficiency, APC resistance, or ACA titres > or =15 GPL and/or MPL), were higher than in the group with no disorders or <15 ACA GPL and/or MPL (P=0.019). CONCLUSIONS: In this preliminary study, LMWH appears to have a favourable effect on the pregnancy outcome of women with a history of preeclampsia and/or fetal growth restriction and documented thrombophilia. Randomised trials are required.

Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction.

OBJECTIVE: Our purpose was to assess the incidence of hyperhomocysteinemia in patients with a history of preeclampsia or fetal growth restriction, to evaluate the effects of vitamin supplementation on the methionine loading test, and to study the course of subsequent pregnancies in women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. STUDY DESIGN: A total of 207 consecutive patients with a history of preeclampsia or fetal growth restriction was tested for hyperhomocysteinemia. Thirty-seven were found to be positive and were treated with folic acid and vitamin B6, and 27 had a second methionine loading test after vitamin supplementation. Fourteen patients became pregnant again while receiving vitamins and aspirin. RESULTS: All patients who underwent a methionine loading test after vitamin supplementation had a completely normalized methionine loading test. Of the 14 pregnancies in women receiving vitamins and aspirin, 7 were complicated by preeclampsia. Birth weights were 2867 +/- 648 g compared with 1088 +/- 570 g in the previous pregnancies. CONCLUSIONS: Vitamin B6 and folic acid correct the methionine loading test in patients with hyperhomocysteinemia. Perinatal outcome in patients with a history of preeclampsia or fetal growth restriction and hyperhomocysteinemia appears to be favorable.