Sustained DMARD-free remission in rheumatoid arthritis – about concepts and moving towards practice

Sustained DMARD-free remission (SDFR) is the best possible outcome in RA. It is characterized by sustained absence of clinical arthritis, which is accompanied by resolution of symptoms and restoration of normal physical functioning. Therefore it's the best proxy for cure in RA. The mechanisms underlying SDFR-development are yet unidentified. Hypothetically, there are two possible scenarios. The first hypothesis is based on the concept of regaining immune-tolerance, which implies that RA-patients are similar at diagnosis and that disease-processes during the disease-course shift into a favorable direction, resulting in regaining a state in which arthritis is persistently absent. This could imply that SDFR is theoretically achievable for all RA-patients. The alternative hypothesis is that RA-patients who achieve SDFR are intrinsically different from those who cannot. This would imply that DMARD-cessation could be restricted to a subgroup of RA-patients. Since the 1990s, DMARD-discontinuation and SDFR have been increasingly studied as long-term-outcome in RA. In this review, we describe hitherto results of clinical, genetic, serological, histological and imaging studies and looked for arguments for the first or second hypothesis in both auto-antibody-positive and auto-antibody-negative RA. In auto-antibody-negative RA, SDFR is presumably restricted to a subgroup of patients with high serological-markers of inflammation at diagnosis and a rapid and sustained decrease in inflammation after treatment-start. Identifying these RA-patients could be helpful in realizing personalized-medicine. In auto-antibody-positive RA, only few patients achieve SDFR and no definite conclusions can be drawn, but data could suggest that SDFR-patients might be a subgroup with relatively low inflammation from disease-presentation onwards.</p

Association of Interosseous Tendon Inflammation in the Hand With Different Early Arthritides in a 10-Year Magnetic Resonance Imaging Study

Objective: Inflammation around the tendons of the hand interosseous muscles (interosseous tendon inflammation [ITI]) was recently identified on magnetic resonance imaging (MRI) in a set of patients with rheumatoid arthritis (RA) and arthralgia. We conducted a large MRI study to assess the prevalence of ITI at diagnosis of RA and of other arthritides, as well as its relationship with clinical signs. Methods: A total of 1,205 patients presenting with various types of early arthritis between 2010 and 2020 underwent contrast-enhanced hand MRI as part of the prospective Leiden Early Arthritis Cohort. MRI was evaluated with blinding for clinical data, for ITI lateral of metacarpophalangeal (MCP) joints 2–5, and for synovitis/tenosynovitis/osteitis. We assessed ITI presence at baseline per diagnosis and its relationship with clinical characteristics (ie, presence of hand arthritis, increased acute phase reactants, and local joint swelling and tenderness). Logistic regression and generalized estimating equations were used with adjustment for age and established local inflammation features (synovitis/tenosynovitis/osteitis). Results: A total of 36% of patients with early RA (n = 532) had ITI; this was similar in patients with anti–citrullinated protein antibody (ACPA)-negative RA (37%) and those with ACPA-positive RA (34%; P = 0.53). ITI occurred regularly in remitting seronegative symmetrical synovitis with pitting edema (60%) and connective tissue diseases (44%) and less frequently in undifferentiated arthritis (14%), psoriatic arthritis (14%), inflammatory osteoarthritis (8%), reactive arthritis (7%), crystal arthritis (7%), and peripheral spondylarthritis (4%). ITI occurred more often in diagnoses with frequent arthritis of the hands (P &lt; 0.001) and increased acute-phase reactants (P &lt; 0.001). Within RA, ITI occurred together with local MCP joint synovitis (odds ratio [OR] 2.4, 95% confidence interval [95% CI] 1.7–3.4), tenosynovitis (OR 2.4, 95% CI 1.8–3.3), and osteitis (OR 2.2, 95% CI 1.6–3.1) on MRI. Moreover, ITI presence was associated with local MCP joint tenderness (OR 1.6, 95% CI 1.2–2.1) and swelling (OR 1.8, 95% CI 1.3–2.6), independent of age and MRI-detected synovitis/tenosynovitis/osteitis. Conclusion:ITI occurs regularly in RA and other arthritides with preferential involvement of hand joints and increased acute-phase reactants. At the MCP joint level, ITI associates independently with joint tenderness and swelling. Hence, ITI is a newly identified inflamed tissue mainly found in arthritides with particularly extensive and symptomatic inflammation.</p

Improving our understanding of the paradoxical protective effect of obesity on radiographic damage:a large magnetic resonance imaging-study in early arthritis

Objective:Obesity conveys a risk for RA development, while paradoxically, associating with less radiographic progression after RA diagnosis. Using MRI we can study this surprising association in detail from MRI-detected synovitis and osteitis to MRI-detected erosive progression, which precedes radiographic progression. Previous research suggested obesity associates with less osteitis and synovitis. We therefore aimed to (i) validate the previously suggested association between BMI and MRI-detected osteitis/synovitis; (ii) study whether this is specific for ACPA-positive or ACPA-negative RA or also present in other arthritides; (iii) study whether MRI-detected osteitis associates with MRI-detected erosive progression; and (iv) study whether obesity associates with MRI-detected erosive progression. Methods:We studied 1029 early arthritis patients (454 RA, 575 other arthritides), consecutively included in Leiden Early Arthritis Clinic. At baseline patients underwent hand-and-foot MRI that were RAMRIS-scored, and 149 RA patients underwent follow-up MRIs. We studied associations between baseline BMI and MRI-detected osteitis/synovitis (using linear regression), and erosive progression (using Poisson mixed models). Results: In RA, higher BMI associated with less osteitis at disease onset (b ¼ 0.94; 95% CI: 0.93, 0.96) but not with synovitis. Higher BMI associated with less osteitis in ACPA-positive RA (b ¼ 0.95; 95% CI: 0.93, 0.97), ACPA-negative RA (b ¼ 0.97; 95% CI: 0.95, 0.99) and other arthritides (b ¼ 0.98; 95% CI: 0.96, 0.99). Over 2 years, overweight and obesity associated with less MRI-detected erosive progression (P ¼ 0.02 and 0.03, respectively). Osteitis also associated with erosive progression over 2 years (P &lt; 0.001). Conclusions: High BMI relates to less osteitis at disease onset, which is not confined to RA. Within RA, high BMI and less osteitis associated with less MRI-detected erosive progression. This suggests that the protective effect of obesity on radiographic progression is exerted via a path of less osteitis and subsequently fewer MRI-detected erosions.</p

Improving our understanding of the paradoxical protective effect of obesity on radiographic damage:a large magnetic resonance imaging-study in early arthritis

Objective:Obesity conveys a risk for RA development, while paradoxically, associating with less radiographic progression after RA diagnosis. Using MRI we can study this surprising association in detail from MRI-detected synovitis and osteitis to MRI-detected erosive progression, which precedes radiographic progression. Previous research suggested obesity associates with less osteitis and synovitis. We therefore aimed to (i) validate the previously suggested association between BMI and MRI-detected osteitis/synovitis; (ii) study whether this is specific for ACPA-positive or ACPA-negative RA or also present in other arthritides; (iii) study whether MRI-detected osteitis associates with MRI-detected erosive progression; and (iv) study whether obesity associates with MRI-detected erosive progression. Methods:We studied 1029 early arthritis patients (454 RA, 575 other arthritides), consecutively included in Leiden Early Arthritis Clinic. At baseline patients underwent hand-and-foot MRI that were RAMRIS-scored, and 149 RA patients underwent follow-up MRIs. We studied associations between baseline BMI and MRI-detected osteitis/synovitis (using linear regression), and erosive progression (using Poisson mixed models). Results: In RA, higher BMI associated with less osteitis at disease onset (b ¼ 0.94; 95% CI: 0.93, 0.96) but not with synovitis. Higher BMI associated with less osteitis in ACPA-positive RA (b ¼ 0.95; 95% CI: 0.93, 0.97), ACPA-negative RA (b ¼ 0.97; 95% CI: 0.95, 0.99) and other arthritides (b ¼ 0.98; 95% CI: 0.96, 0.99). Over 2 years, overweight and obesity associated with less MRI-detected erosive progression (P ¼ 0.02 and 0.03, respectively). Osteitis also associated with erosive progression over 2 years (P &lt; 0.001). Conclusions: High BMI relates to less osteitis at disease onset, which is not confined to RA. Within RA, high BMI and less osteitis associated with less MRI-detected erosive progression. This suggests that the protective effect of obesity on radiographic progression is exerted via a path of less osteitis and subsequently fewer MRI-detected erosions.</p

Patients with obesity have more inflamed joints and higher CRP levels during the disease course in ACPA-positive RA but not in ACPA-negative RA

BACKGROUND: Obese RA patients have higher disease activity scores (DAS). Previous research showed that obese RA patients have higher tender joint count (TJC) and VAS general health. However, it remains unclear whether DAS components measuring local and systemic inflammation (swollen joint count (SJC), CRP) are increased and if this is present in the total RA population or confined to an ACPA subgroup. As ACPA is suggested to enhance inflammatory responses, we hypothesized that the association of obesity with SJC and CRP is present especially in ACPA-positive RA. We therefore studied associations of obesity with courses of DAS components in ACPA subgroups. METHODS: We studied 649 RA patients (291 ACPA-positive), included in the Leiden Early Arthritis Clinic. Five-year courses of DAS44 and DAS44 components (SJC-44, TJC-53, CRP, VAS (0-100)) were compared between RA patients with normal weight (BMI 18.5-24.9), overweight (25.0-29.9), and obesity (≥ 30.0), stratified for ACPA. Linear/Poisson mixed models with a knot at 4 months were used. RESULTS: Obese RA patients had + 0.32 higher DAS compared to normal weight during the 5-year follow-up. In ACPA-positive RA, obese patients had + 0.43 (95% CI: 0.22, 0.64) higher DAS, whereas in ACPA-negative RA, this difference was smaller and not statistically significant: + 0.19 (95% CI: - 0.01, 0.38). In ACPA-positive RA, all DAS components were significantly higher in obese patients compared to normal weight: SJC + 60% (IRR1.60; 95% CI: 1.18, 2.16), CRP + 3.7 mg/L (95% CI:0.95, 6.53), TJC + 55% (IRR1.55; 95% CI:1.15, 2.10), and VAS + 9 (95% CI: 4.0, 14.2). ACPA-negative obese RA patients tended to have higher TJC (IRR1.22; 95% CI: 0.96, 1.55) and VAS (β4.3; 95% CI: - 0.4, 9.0), while SJC (IRR1.07; 95% CI:0.85, 1.33) and CRP (β0.24; 95% CI: - 1.29, 3.32) were unaffected. CONCLUSION: The association of obesity with a worse DAS course is mainly present in ACPA-positive RA; especially SJC and CRP levels remain higher in ACPA-positive RA patients with obesity but not ACPA-negative RA patients. This is the first demonstration that obesity influences the disease course of ACPA-positive and ACPA-negative RA differently.</p

Patients with obesity have more inflamed joints and higher CRP levels during the disease course in ACPA-positive RA but not in ACPA-negative RA

BACKGROUND: Obese RA patients have higher disease activity scores (DAS). Previous research showed that obese RA patients have higher tender joint count (TJC) and VAS general health. However, it remains unclear whether DAS components measuring local and systemic inflammation (swollen joint count (SJC), CRP) are increased and if this is present in the total RA population or confined to an ACPA subgroup. As ACPA is suggested to enhance inflammatory responses, we hypothesized that the association of obesity with SJC and CRP is present especially in ACPA-positive RA. We therefore studied associations of obesity with courses of DAS components in ACPA subgroups. METHODS: We studied 649 RA patients (291 ACPA-positive), included in the Leiden Early Arthritis Clinic. Five-year courses of DAS44 and DAS44 components (SJC-44, TJC-53, CRP, VAS (0-100)) were compared between RA patients with normal weight (BMI 18.5-24.9), overweight (25.0-29.9), and obesity (≥ 30.0), stratified for ACPA. Linear/Poisson mixed models with a knot at 4 months were used. RESULTS: Obese RA patients had + 0.32 higher DAS compared to normal weight during the 5-year follow-up. In ACPA-positive RA, obese patients had + 0.43 (95% CI: 0.22, 0.64) higher DAS, whereas in ACPA-negative RA, this difference was smaller and not statistically significant: + 0.19 (95% CI: - 0.01, 0.38). In ACPA-positive RA, all DAS components were significantly higher in obese patients compared to normal weight: SJC + 60% (IRR1.60; 95% CI: 1.18, 2.16), CRP + 3.7 mg/L (95% CI:0.95, 6.53), TJC + 55% (IRR1.55; 95% CI:1.15, 2.10), and VAS + 9 (95% CI: 4.0, 14.2). ACPA-negative obese RA patients tended to have higher TJC (IRR1.22; 95% CI: 0.96, 1.55) and VAS (β4.3; 95% CI: - 0.4, 9.0), while SJC (IRR1.07; 95% CI:0.85, 1.33) and CRP (β0.24; 95% CI: - 1.29, 3.32) were unaffected. CONCLUSION: The association of obesity with a worse DAS course is mainly present in ACPA-positive RA; especially SJC and CRP levels remain higher in ACPA-positive RA patients with obesity but not ACPA-negative RA patients. This is the first demonstration that obesity influences the disease course of ACPA-positive and ACPA-negative RA differently.</p

Forefoot inflammation in recent-onset ACPA-positive and ACPA-negative RA:clinically similar, but different in underlying inflamed tissues

OBJECTIVES: Although joint swelling is traditionally interpreted as synovitis, recent imaging studies showed that there is also inflammation of tenosynovium and intermetatarsal bursae in the forefoot. We aimed to increase our understanding of differences and similarities regarding forefoot involvement between ACPA-positive and ACPA-negative rheumatoid arthritis (RA) at diagnosis. Therefore, we (1) compared metatarsophalangeal (MTP) joint counts, walking disabilities and inflamed tissues between ACPA groups and (2) studied associations of joint swelling/tenderness and walking disabilities with underlying inflamed tissues within ACPA groups. METHODS: 171 ACPA-positive and 203 ACPA-negative consecutively diagnosed patients with RA had a physical joint examination (swollen joint count-66/tender joint count-68), filled a Health Assessment Questionnaire including the domain walking and underwent MRI of the MTP joints at diagnosis. Synovitis, tenosynovitis, osteitis and intermetatarsal bursitis (IMB) were assessed. Findings in age-matched healthy controls were applied to define abnormalities on MRI. RESULTS: While ACPA-negative RA patients had more swollen joints (mean SJC 8 vs 6 in ACPA-positives, p=0.003), the number of swollen MTP joints was similar (mean 1 in both groups); walking disabilities were also equally common (49% vs 53%). In contrast, inflamed tissues were all more prevalent in ACPA-positive compared with ACPA-negative RA. Within ACPA-positive RA, IMB was associated independently with MTP-joint swelling (OR 2.6, 95% CI 1.4 to 5.0) and tenderness (OR 3.0, 95% CI 1.8 to 5.0). While in ACPA-negatives, synovitis was associated independently with MTP-joint swelling (OR 2.8, 95% CI 1.4 to 5.8) and tenderness (OR 2.5, 95% CI 1.3 to 4.8). Tenosynovitis contributed most to walking disabilities. CONCLUSIONS: Although the forefoot of ACPA-positives and ACPA-negatives share clinical similarities at diagnosis, there are differences in underlying inflamed tissues. This reinforces that ACPA-positive and ACPA-negative RA are different entities.</p

Patients with rheumatoid arthritis presenting with mono- or oligo-arthritis and high VAS-ratings remain the most fatigued during 5 years of follow-up

Objectives: The severity of fatigue in RA has improved very little in recent decades, leaving a large unmet need. Fortunately, not all RA patients suffer from persistent fatigue, but the subgroup of patients who suffer the most is insufficiently recognizable at diagnosis. As disease activity is partly coupled to fatigue, DAS components may associate with the course of fatigue. We aimed to identify those RA patients who remain fatigued by studying DAS components at diagnosis in relation to the course of fatigue over a 5-year follow-up period in two independent early RA cohorts. Methods: In all, 1560 consecutive RA patients included in the Leiden Early Arthritis Cohort and 415 RA patients included in the tREACH trial were studied. Swollen joint count, tender joint count, ESR and Patient Global Assessment (PGA) [on a Visual Analogue Scale (VAS)] were studied in relation to fatigue (VAS, 0-100 mm) over a period of 5 years, using linear mixed models. Results: Higher tender joint count and higher PGA at diagnosis were associated with a more severe course of fatigue. Furthermore, patients with mono- or oligo-arthritis at diagnosis remained more fatigued. The swollen joint count, in contrast, showed an inverse association. An investigation of combinations of the aforementioned characteristics revealed that patients presenting with mono- or oligo-arthritis and PGA ≥ 50 remained the most fatigued over time (+20 mm vs polyarthritis with PGA &lt; 50), while the DAS course over time did not differ. This subgroup comprised 14% of the early RA population. Data from the tREACH trial showed similar findings. Conclusion: The RA patients who remain the most fatigued were those characterized by mono- or oligo-arthritis and high PGA (VAS ≥ 50) at diagnosis. This understanding may enable early-intervention with non-pharmacological approaches in dedicated patient groups.</p

Clinically suspect arthralgia and rheumatoid arthritis:patients’ perceptions of illness

Objectives: Clinically suspect arthralgia (CSA) is an at-risk stage of rheumatoid arthritis (RA), in which patients experience symptoms and physical limitations. Perceptions of CSA-patients have remained largely unknown. Therefore, we aimed to map perceptions of CSA-patients and compare these to RA-patients. Additionally, we studied changes in perceptions in CSA over time. Methods: Three hundred and ninety-nine consecutively included CSA-patients from the Leiden and Rotterdam CSA-cohorts and 100 recently diagnosed RA-patients from the Leiden Early Arthritis Clinic were included. Patients’ illness perceptions (IP) were assessed using the Brief Illness Perception Questionnaire (BIPQ), consisting of 8 questions (scale 0–10; higher score indicating more negative IP) covering cognitive, emotional and comprehensibility domains, and one open question about causes of disease. IP were measured at baseline in both populations and during 2 years follow-up in the CSA-cohorts. Results: Total BIPQ-scores were comparable at CSA-presentation and RA-diagnosis (40 ± 11 and 40 ± 10; range 0–80). Comparing dimensions separately revealed that CSA-patients were less worried about physical complaints compared to RA-patients. However, CSA-patients were more negative about expected treatment-effect on symptoms. IP over time in CSA improved in patients without development of clinical arthritis (from 38 ± 11 to 34 ± 14; P = 0.005) but remained similar in CSA-patients who progressed to arthritis/RA (mean 40 at both timepoints). CSA-patients mainly perceived physical strain and heredity as causes of their complaints. Conclusions: Although CSA-patients have not developed clinical arthritis, illness perceptions at CSA-presentation and RA-diagnosis are equally severe. Knowledge on worries and expectations may contribute to improving patient-contact and care in patients at risk of RA.</p