M Güler-Yüksel

Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis

Objectives: To compare the occurrence of drug-free remission, functional ability and radiological damage after 4 years of response-driven treatment according to four different treatment strategies for rheumatoid arthritis (RA). Methods: Patients with recent-onset, active RA (n  =  508) were randomly assigned to four different treatment strategies: (1) sequential monotherapy; (2) step-up combination therapy; (3) initial combination therapy with prednisone and (4) initial combination therapy with infliximab. Treatment was adjusted based on 3-monthly disease activity score (DAS) assessments, aiming at a DAS ⩽2.4. From the third year, patients with a sustained DAS <1.6 discontinued treatment. Results: In total, 43% of patients were in remission (DAS <1.6) at 4 years and 13% were in drug-free remission: 14%, 12%, 8% and 18% of patients in groups 1–4, respectively. The absence of anti-cyclic citrullinated peptide antibodies, male gender and short symptom duration were independently associated with drug-free remission. Functional ability and remission were maintained in all four groups with the continuation of DAS-driven treatment, without significant differences between the groups. Significant progression of joint damage was observed in 38% and 31% of patients in groups 3 and 4 versus 51% and 54% of patients in groups 1 and 2 (p<0.05, group 4 versus groups 1 and 2, group 3 versus group 2). Conclusions: In patients with recent-onset active RA, drug-free remission was achieved in up to 18% of patients. DAS-driven treatment maintained clinical and functional improvement, independent of the treatment strategy. Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy.

The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study

Objective To compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis (RA) after 5 years follow-up. Methods 508 patients with recent-onset RA were randomly assigned into four treatment strategies: sequential monotherapy; step-up combination therapy; initial combination with prednisone; initial combination with infliximab. Treatment adjustments were made based on 3-monthly disease activity score (DAS) measurements (if DAS >2.4 next treatment step; if DAS ≤2.4 during ≥6 months taper to maintenance dose; if DAS <1.6 during ≥6 months stop antirheumatic treatment). Primary and secondary outcomes were functional ability, joint damage progression, health-related quality of life and (drug-free) remission percentages. Results After 5 years, 48% of patients were in clinical remission (DAS <1.6) and 14% in drug-free remission, irrespective of initial treatment. After an earlier improvement in functional ability and quality of life with initial combination therapy, from 1 year onwards clinical outcomes were comparable across the groups and stable during 5 years. The initial combination groups showed less joint damage in year 1. In years 2–5 annual progression was comparable across the groups. After 5 years, initial combination therapy resulted in significantly less joint damage progression, reflecting the earlier clinical response. Conclusion Irrespective of initial treatment, an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aimed at reducing disease activity, leading to 48% remission, 14% drug-free remission and sustained functional improvement. Starting with combination therapy resulted in earlier clinical improvement and less joint damage without more toxicity.

Changes in hand and generalised bone mineral density in patients with recent-onset rheumatoid arthritis

Objectives: To evaluate changes in bone mineral density (BMD) in the hands, hip and spine after 1 and 2 years of follow-up, in relation to antirheumatic and antiresorptive therapies and disease and demographic variables in patients with recent-onset rheumatoid arthritis (RA). Methods: Changes in BMD measured in metacarpals 2–4 by digital x-ray radiogrammetry and in the hip and spine by dual energy x-ray absorptiometry were assessed at baseline and after 1 and 2 years of follow-up in 218 patients with recent-onset RA from the BeSt study, who received one of four treatment strategies: sequential monotherapy (group 1); step-up combination therapy (group 2); initial combination therapy with tapered high-dose prednisone (group 3); or initial combination therapy with infliximab (group 4). Results: After 1 and 2 years, there was significant BMD loss in all locations, with significantly greater BMD loss in the hands than generalised BMD loss in the hip and spine. Initial combination therapy with prednisone or infliximab were associated with less hand BMD loss compared with initial monotherapy after 1 and 2 years (−0.9 and −1.6%, −0.6 and −1.4%, −1.7 and −3.3%, and −2.6 and −3.6% for group 4–1 after 1 and 2 years, overall p = 0.001 and p = 0.014, respectively). Progression in erosions was independently associated with increased BMD loss both in the hands and hip after 1 year. The use of bisphosphonates protected only against generalised BMD loss in the hip and spine. Conclusions: The association between joint damage progression and both hand and generalised BMD loss in RA suggests common pathways between these processes, with hand BMD loss occurring earlier in the disease course than generalised BMD loss.

Discontinuing treatment in patients with rheumatoid arthritis in sustained clinical remission: exploratory analyses from the BeSt study

Objectives To determine the relapse rate after discontinuing treatment in patients with rheumatoid arthritis (RA) in sustained clinical remission, to identify predictors of a relapse and to evaluate treatment response after restarting treatment. Methods Five-year data from the BeSt study were used, in which 508 patients with recent-onset RA were randomised into four dynamic treatment strategies, aiming at a disease activity score (DAS) ≤2.4. When DAS was <1.6 for ≥6 months, the last disease-modifying antirheumatic drug (DMARD) was tapered and discontinued. If DAS increased to ≥1.6, the last DMARD was immediately reintroduced. Results During a 5-year period, 115/508 patients (23%) achieved drug-free remission. Of these, 53 patients (46%) restarted treatment because the DAS was ≥1.6 after a median of 5 months, 59 patients (51%) remained in drug-free remission for a median duration of 23 months and 3 (3%) were lost to follow-up. In those who restarted treatment, mean (SD) DAS increased from 1.13 (0.73) at remission before tapering to 2.18 (0.65) at restart, reflecting an increase in all four components of DAS. Multivariable predictors for restarting treatment were anti-cyclic citrullinated peptide (anti-CCP), last DMARD sulfasalazine, low baseline Health Assessment Questionnaire score and high mean DAS until remission. Of the 53 patients who restarted treatment, 39 (74%) again achieved remission 3–6 months after the restart. The median (IQR) damage progression in those who restarted treatment during the year of DAS increase was 0 (0–1) Sharp-van der Heijde units. Conclusion During 5 years DAS steered treatment, nearly 25% of patients with RA achieved drug-free remission; 46% restarted DMARD monotherapy because of a relapse, the majority of whom again achieved clinical remission within 3–6 months without showing radiological progression during the relapse.

Changes in bone mineral density in patients with recent onset, active rheumatoid arthritis

Objectives: We examined the effects of four different treatment strategies on bone mineral density (BMD) in patients with recently diagnosed, active rheumatoid arthritis (RA) and the influence of disease-related and demographic factors on BMD loss after 1 year of follow-up in the BeSt trial. Methods: BMD measurements of the lumbar spine and total hip were performed in 342 patients with recent onset RA at baseline and after 1 year. Multivariable regression analyses were performed to determine independent associations between disease and demographic parameters and BMD loss after 1 year. Results: Median BMD loss after 1 year was 0.8% and 1.0% of baseline in the spine and the hip, respectively. No significant differences between the treatment groups, including corticosteroids and the anti-tumour necrosis factor-α infliximab, were observed with regard to BMD loss after 1 year of treatment. Joint damage at baseline and joint damage progression according to the Sharp–van der Heijde score were independently associated with more BMD loss after 1 year. The use of bisphosphonates independently protected against BMD loss. Conclusions: After 1 year of follow-up in the BeSt study, we did not find differences in BMD loss between the four treatment strategies, including high doses of corticosteroids and anti-tumour necrosis factor-α. Joint damage and joint damage progression are associated with high BMD loss, which emphasises that BMD loss and erosive RA have common pathways in their pathogenesis.

Can bone loss in rheumatoid arthritis be prevented

Rheumatoid arthritis (RA) is a systemic inflammatory disease that can lead to local joint deformations (bone erosions and joint space narrowing) and to extra-articular phenomena, including generalized osteoporosis. In addition, in patients with RA, the risk of vertebral and nonvertebral fractures is doubled. High disease activity (inflammation), immobility, and glucocorticoid use are common factors that substantially increase fracture risk in these patients, on top of the background fracture risk based on classical risk factors such as high age, low body mass, and female gender. New insights on the links between the immune system and the bone system, the field of osteoimmunology, have shown that local and generalized bone loss share common pathways. The receptor activator of nuclear factor κB ligand/osteoprotegerin pathway (RANKl/OPG) is one of the most important pathways, as it is (strongly) upregulated by inflammation. In modern treatment of RA with biologics, for example, TNFα-blocking agents and combination therapy of conventional disease-modifying antirheumatic drugs (DMARDs), clinical remission is a realistic treatment goal. As a consequence, in recent studies, it has been documented that both local and generalized bone loss is absent or minimal in those patients who are in clinical remission.

Treatment with TNF-α inhibitor infliximab might reduce hand osteoarthritis in patients with rheumatoid arthritis

OBJECTIVES To investigate the association between systemic and local inflammation and incident and progressive radiographic secondary osteoarthritis (OA) in interphalangeal joints (IPJs) over 3 years in rheumatoid arthritis (RA) patients and the effect of tumor necrosis factor alpha (TNF-α) inhibitor infliximab on secondary OA in IPJs. METHODS In the present observational longitudinal study baseline and 3-year hand X-rays of 416 recent-onset RA patients were scored for osteophytes and erosions in IPJs, blinded for time, using Osteoarthritis Research Society International atlas and Sharp-van der Heijde score. The associations between inflammatory factors and incident and progressive secondary OA in distal IPJs (DIPJs) and proximal IPJs (PIPJs) and the effect of infliximab compared to disease-modifying anti-rheumatic drug treatment on secondary OA were analyzed by multivariable regression and generalised estimating equations analyses. RESULTS Sixty-seven percent of the patients were female with, at baseline, a mean age of 54 years and OA present in DIPJs and PIPJs in 37% and 13%. Three years later, new secondary OA in DIPJs and PIPJs was seen in 11% and 10%, and progressive secondary OA in 36% and 35%. High erythrocyte sedimentation rate over 3 years and progressive erosive damage were risk factors for incident secondary OA in DIPJs, but not in PIPJs. At joint level, progression of erosions was associated with both incident and progressive secondary OA, only in DIPJs. Infliximab treatment was associated with lower incident secondary OA in PIPJs [relative risk 0.5 (95% confidence interval 0.2, 1.0)], independent of decrease in inflammation. CONCLUSION Incident and progressive secondary OA in DIPJs over 3 years was associated with high inflammatory activity in RA. Infliximab treatment reduced incident secondary OA in PIPJs independent of decrease in inflammation, suggesting that anti-TNF-α therapy might be effective against secondary hand OA via other pathways than suppression of inflammation. Further studies in populations of primary hand OA are necessary to determine the role of anti-TNF-α in treatment of primary hand OA.

Bone mineral density in patients with recently diagnosed, active rheumatoid arthritis

Objectives: Osteoporosis is a well-known extra-articular phenomenon in patients with uncontrolled, long-standing rheumatoid arthritis (RA). In the present study, the extent of osteoporosis and reduced bone mineral density (BMD) and the disease-related and demographic factors that are associated with osteoporosis and reduced BMD were examined in patients with recently diagnosed, active RA. Methods: BMD of the total hip and the lumbar spine was measured using dual-energy x ray absorptiometry in 381 patients with recently diagnosed active RA, who had never been treated with DMARDs or corticosteroids. Osteoporosis was defined as a T score ⩽−2.5 SD and reduced BMD as Z score ⩽−1 SD. Multivariate logistic regression analyses were performed to detect associations of osteoporosis and reduced BMD with disease activity, functional disability, joint damage (Sharp–van der Heijde score) and demographic factors. Results: Osteoporosis and reduced BMD were found in the spine and/or the hip in 11% and 25%, respectively, of the patients. Longer symptom duration and presence of rheumatoid factor (RF) were the only RA-specific markers for osteoporosis and reduced BMD. Further, postmenopausal status in women, a low body mass index, familial osteoporosis, and, remarkably, male gender, were independently associated with osteoporosis and reduced BMD. Conclusion: In patients with recently diagnosed active RA who had never been treated with DMARDs or corticosteroids, BMD seems to be well-preserved and predominantly related to demographic factors. Longer symptom duration and a positive RF, but not higher disease activity or more joint damage, were related to osteoporosis and reduced BMD.

Accelerated hand bone mineral density loss is associated with progressive joint damage in hands and feet in recent-onset rheumatoid arthritis

IntroductionTo investigate whether accelerated hand bone mineral density (BMD) loss is associated with progressive joint damage in hands and feet in the first year of rheumatoid arthritis (RA) and whether it is an independent predictor of subsequent progressive total joint damage after 4 years.MethodsIn 256 recent-onset RA patients, baseline and 1-year hand BMD was measured in metacarpals 2-4 by digital X-ray radiogrammetry. Joint damage in hands and feet were scored in random order according to the Sharp-van der Heijde method at baseline and yearly up to 4 years.Results68% of the patients had accelerated hand BMD loss (>-0.003 g/cm2) in the first year of RA. Hand BMD loss was associated with progressive joint damage after 1 year both in hands and feet with odds ratios (OR) (95% confidence intervals [CI]) of 5.3 (1.3-20.9) and 3.1 (1.0-9.7). In univariate analysis, hand BMD loss in the first year was a predictor of subsequent progressive total joint damage after 4 years with an OR (95% CI) of 3.1 (1.3-7.6). Multivariate analysis showed that only progressive joint damage in the first year and anti-citrullinated protein antibody positivity were independent predictors of long-term progressive joint damage.ConclusionsIn the first year of RA, accelerated hand BMD loss is associated with progressive joint damage in both hands and feet. Hand BMD loss in the first year of recent-onset RA predicts subsequent progressive total joint damage, however not independent of progressive joint damage in the first year.

Clinical synovitis in a particular joint is associated with progression of erosions and joint space narrowing in that same joint, but not in patients initially treated with infliximab

Objectives To assess the relationship between joint tenderness, swelling and joint damage progression in individual joints and to evaluate the influence of treatment on these relationships. Methods First-year data of the Behandel Strategieën (BeSt) study were used, in which patients recently diagnosed as having rheumatoid arthritis (RA) were randomly assigned into four different treatment strategies. Baseline and 1-year x-rays of the hands and feet were assessed using the Sharp–van der Heijde score (SHS). With generalised estimating equations, 3-monthly assessments of tender and swollen joints of year 1 were related to erosion progression, joint space narrowing (JSN) progression and total SHS progression at the individual joint level (definition >0.5 SHS units) in year 1, corrected for potential confounders and within-patient correlation for multiple joints per patient. Results During year 1, 59% of all 13 959 joints analysed were ever tender and 45% ever swollen, 2.1% showed erosion progression, 1.9% JSN progression and 3.6% SHS progression. Swelling and tenderness were both independently associated with erosion and JSN progression with comparable OR, although with higher OR in the hands than in the feet. Local swelling and tenderness were not associated with local damage progression in patients initially treated with infliximab. Conclusion Clinical signs of synovitis are associated with erosion and JSN progression in individual joints after 1 year in RA. A disconnect between synovitis and joint damage progression was observed at joint level in patients who were treated with methotrexate and infliximab as initial treatment, confirming the disconnect between synovitis and the development of joint damage in tumour necrosis factor blockers seen at patient level.