F. Alasti

Disease activity in psoriatic arthritis (PsA): defining remission and treatment success using the DAPSA score

Background The Disease Activity Index for Psoriatic Arthritis (DAPSA) is a valid and discriminative tool. Definitions of disease activity states and therapeutic response are still missing. We derived such criteria for the DAPSA. Methods We retrieved 30 patient profiles from an observational database including joint counts, patient pain and global activity ratings and C-reactive protein (CRP) and carried out a survey among experts to classify patients into remission (REM), low (LDA), moderate (MDA) or high (HDA) disease activity. Based on the distributions of DAPSA in each of these expert-assigned states we defined the cutpoints between groups. We performed similar analyses evaluating a clinical score (cDAPSA), omitting CRP. To define minor, moderate and major treatment response, we used Cohens Kappa statistics and analysed agreement of DAPSA percentage change with ACR20/50/70-response in three randomised controlled trials. Results Our survey yielded a response rate of 75% (n=33). Mean DAPSA differed significantly between patients classified as REM, LDA, MDA or HDA (p<0.001). Based on the distributions of DAPSA in these groups, we propose cut-off values of ≤4 for REM, >4 and ≤14 for LDA, >14 and ≤28 for MDA and >28 for HDA. We observed best agreement with ACR20/50/70-response at DAPSA changes of 50/75/85%, reflecting minor, moderate and major improvement. Conclusions The DAPSA constitutes a disease-specific, validated and feasible tool for PsA assessment. In this study, we provide criteria for disease activity states and treatment response. They are based on an international expert survey, and show good performance in clinical trials and observational data.

Rheumatoid factor determines structural progression of rheumatoid arthritis dependent and independent of disease activity

Background Rheumatoid factor (RF) is prototypic for rheumatoid arthritis (RA) and serves diagnostic and prognostic purposes. RF is associated with joint destruction, but the role of disease activity as a potential mediator of these effects has not been clearly elucidated yet. Objective To investigate if higher radiographic progression (Sharp score, ΔTSS) in RF+ patients is dependent or independent of disease activity. Methods The authors performed a cross-sectional multivariate analysis at baseline and a matched cohort study in patients from five RA clinical trials. The authors pooled methotrexate treatment arms and compared ΔTSS in RF+ and RF− patients before and after matching for other associated variables. Results Among 686 patients, 124 were RF− and 562 RF+, 343 having high (>160 U/ml) RF. ΔTSS was 1.03±5.83, 3.23±8.10 and 3.58±8.18 (p<0.0001), respectively, and similarly for erosions and joint space narrowing (JSN). After matching for other prognostically important variables, ΔTSS still was lower among 61 RF− versus 61 RF high+ patients (0.52±2.47 vs 3.09±8.28; p=0.028), mainly related to differences in erosion score (0.31±1.88 vs 2.07±5.62; p=0.035), but not JSN (0.21±1.26 vs 1.02±3.31; p=0.162). Conclusions The data reveal that damage progression in seropositive RA patients is related to higher levels of disease activity and to independent effects of RF, particularly on bone damage. This calls for consideration of RF status irrespective of disease activity.

Rheumatoid arthritis near remission: clinical rather than laboratory inflammation is associated with radiographic progression

Background Disease activity in rheumatoid arthritis (RA) can be measured clinically (eg, swollen joint count (SJC)) or systemically (eg, C reactive protein (CRP)). In general, both contribute to the progression of joint damage, but the relevance of residual inflammation in patients near remission is unclear. Objective To determine the independent contribution of SJC and CRP to progression of joint damage in patients near remission. Methods Data from methotrexate monotherapy arms of the ASPIRE, ERA, Leflunomide, PREMIER and TEMPO trials (n=1184) were pooled and the average SJC and CRP values from visits at 6, 9 and 12 months were determined. The two variables were then dichotomised into active and inactive, where inactive was defined as a mean. Radiographic outcomes were assessed according to these definitions. Results The greatest progression was seen in patients in whom both SJC and CRP were active and the smallest in those in whom both were inactive. If SJC was inactive, radiographic progression was not different between those with inactive or active CRP (0.7±4.3/year and 0.8±5.4/year, respectively, p=0.19). However, if CRP was inactive (<1 mg/dl), SJC status still determined radiographic progression (0.7±4.3/year and 1.8±5.6/year, for inactive and active SJC, respectively, p=0.004). The importance of SJC in patients with inactive CRP was also shown in a linear model (p=0.019), while CRP was not significantly different in patients with inactive SJC (p=0.40). Conclusion In patients with RA who are near remission, the amount of joint swelling appears to be more predictive of radiographic progression than the amount of CRP.

Optimisation of a treat-to-target approach in rheumatoid arthritis: strategies for the 3-month time point.

Background Treat-to-target (T2T) is a widely accepted management strategy for rheumatoid arthritis (RA) with a key decision point at 3 months after treatment initiation. At this time point, it remains unclear which patients will benefit from treatment adaptation or from continuation of existing treatment. Methods We performed a pooled analysis of patient-level clinical trial data of patients with RA. We used a diagnostic testing methodology and a probabilistic approach employing logistic regression to investigate which levels of response at 3 months can inform treatment decisions in regard to achieving the target at 6 months. Results To be at least 80% sensitive for achieving the low disease activity (LDA) target at 6 months, a change at 3 months in Simplified Disease Activity Index/Clinical Disease Activity Index (SDAI or CDAI) of 58% needs to be observed at 3 months. Higher changes are needed to sensitively predict remission (REM). Not reaching the (minor) SDAI 50% response level is afflicted with very low negative likelihood ratios (LRs) (0.28 for LDA and 0.07 for REM at 6 months). Experiencing (major) SDAI 85% response has substantial positive LRs of 9.2 for reaching LDA and 6.2 for reaching REM at 6 months. In logistic regression, the change at 3 months is significantly associated with reaching of the target at 6 months. Conclusions The 3-month time point is a critical decision point. Not achieving minor responses at 3 months makes reaching of the treatment target at 6 months highly unlikely, while reaching major responses is highly predictive of reaching the treatment target.

Rheumatoid factor, not antibodies against citrullinated proteins, is associated with baseline disease activity in rheumatoid arthritis clinical trials

IntroductionAlthough the prognostic value of rheumatoid factor (RF) and autoantibodies against citrullinated proteins (ACPAs) in patients with rheumatoid arthritis (RA) is well established, their association with RA disease activity remains unclear. Here, we investigate this association in a large study using data from clinical trials.MethodsWe used baseline data from four recent randomized controlled clinical trials of RA. We investigated individual and composite measures of disease activity. The relationship of RF and ACPAs with these measures was investigated by using stratified analysis (comparing four groups of patients according to the presence or absence of RF and ACPAs) and matched analysis (disease activity levels compared between patients negative and patients highly positive for one autoantibody who were matched for levels of the other autoantibody as well as for age, gender, and duration of RA).ResultsA total of 2118 patients were analysed in the different cohorts. In the stratified analysis, RF+ patients, regardless of ACPA status, had the highest levels of disease activity, whereas ACPA+ patients had disease activity that was similar to or lower than that of ACPA− patients, both in the presence and in the absence of RF. When matched for ACPA levels, patients with highly positive RF had significantly higher disease activity for all composite indices compared with patients who were RF− (P = 0.0067), whereas ACPA-highly-positive and ACPA-negative patients matched for RF levels had similar disease activity, again even with the tendency toward lower disease activity for ACPA+ patients (P = 0.054).ConclusionThe data presented suggest that the presence of RF has a clear association with higher levels of disease activity but that the presence of ACPAs has not and even appears to be associated with lower disease activity.

Rituximab dissociates the tight link between disease activity and joint damage in rheumatoid arthritis patients

Background/objective Progression of joint damage is linked to disease activity. This link is dissociated upon treatment with tumour necrosis factor (TNF)- or IL-6-inhibitors plus methotrexate (MTX). It is hitherto unknown if this may also be true for therapies targeting B-cells. We thus evaluated if rituximab (RTX) therapy inhibits joint damage irrespective of its effects on disease activity. Methods We used a random 90% sample of data from two arms of the IMAGE trial comprising patients with active early rheumatoid arthritis (RA) receiving MTX (n=188) or MTX+RTX 1000 mg (n=204). Patients were divided into low, moderate and high disease activity at one year of treatment by simplified disease activity index (low disease activity (LDA), moderate disease activity (MDA), high disease activity (HDA)), or by swollen joint count (SJC) or C reactive protein (CRP) tertiles. Progression of damage by the Genant modified total Sharp score (TGSS) was compared between therapies (Kruskal-Wallis, Wilcoxon tests) for each of these subgroups. Results In patients treated with MTX, 1-year progression of TGSS In LDA, MDA and HDA was 0.40±0.88, 1.04±1.73, and 1.31±3.02, respectively. In contrast, on RTX+MTX, TGSS progression was 0.38±1.07, 0.39±1.28, and −0.05±0.44, respectively (for MDA and HDA the progression of TGSS was significantly lower in the combined group than in the MTX group: p=0.003 and p=0.05, respectively). Additional analyses (tertiles of SJC, CRP, and matching for disease activity) confirmed the primary analysis. Conclusions In early RA, progression of joint damage increases with increasing disease activity on MTX. RTX plus MTX retards damage independently of its effects on disease activity, since even in HDA destruction is halted, contrasting MTX monotherapy. This indicates that beyond cytokine blockade (TNF- and IL-6 inhibitors), also cell-directed therapy (anti-CD20 antibody) conveys profound anti-destructive effects and dissociates the link between disease activity and joint damage.

Persistence of subclinical sonographic joint activity in rheumatoid arthritis in sustained clinical remission

Background Sonographic assessment, measuring grey scale (GS) and power Doppler (PD) signals, is a sensitive tool for the evaluation of inflammatory joint activity in patients with rheumatoid arthritis (RA). We evaluated the persistence of PD and GS signals in previously clinically active RA joints that have reached a state of continuous clinical inactivity. Methods We performed sonographic imaging of 22 joints of the hands of patients with RA, selected all joints without clinical activity but showing ongoing sonographic signs of inflammation, and evaluated the time from last clinical joint activity. Results A total of 90 patients with RA with 1980 assessed joints were included in this study. When comparing the mean time from clinical swelling, we found a significantly longer period of clinical inactivity in joints showing low sonographic activity (mean±SD time from swelling of 4.1±3.2 vs 3.1±2.9 years for PD1 vs PD≥2, p=0.031 and 4.5±3.4 vs 3.3±3.2 years for GS1 vs GS≥2, p≤0.0001). Conclusions We conclude that subclinical joint activity is long-lasting in RA joints in clinical remission, but attenuates over time. The latter conclusion is based on the observed shorter time duration from last clinical activity for strong compared with weaker sonographic signals.

Disease activity states of the DAPSA, a psoriatic arthritis specific instrument, are valid against functional status and structural progression

Background Recently, disease activity states were developed for the Disease Activity index for PSoriatic Arthritis (DAPSA). Here, we assess if different DAPSA disease activity states are associated with different degrees of functional impairment and different extents of joint damage progression in patients with psoriatic arthritis (PsA). Methods We used data from two pivotal trials of tumour necrosis factor (TNF) inhibitors in PsA (IMPACT II and GO-REVEAL) and identified patients in DAPSA remission (REM, ≤4), and low, moderate or high disease activity (LDA, ≤14; MDA, ≤28; HDA, >28) at 6 months. Across these groups we compared the functional scores (Health Assessment Questionnaire Disability Index, HAQ and physical component scale of the Short Form-36, PCS), and 1-year structural progression (PsA-modified Sharp/van der Heijde Score). Results We identified 310 from GO-REVEAL and 130 from IMPACT II, with a mean (SD) baseline DAPSA of 48.8 (26.4) and 44.6 (17.9), respectively. HAQ scores increased across patients groups in the four DAPSA disease activity states, while PCS decreased (p<0.001 for both). The mean progression in the combined cohort was −0.47 for REM, −0.28 for LDA, −0.14 for MDA and 0.51 for HDA (p<0.001). This association was also significant in the individual trial cohorts, and in the subgroups of patients treated with TNF inhibitors or placebo. Higher DAPSA scores were significantly and independently associated with probability of structural progression in multiple analyses. Conclusions Disease activity states of the PsA specific DAPSA score are highly valid for future use as endpoints in clinical trials or as targets in clinical practice. Trial registration numbers IMPACT 2: NCT02152254; GO-REVEAL: NCT00265096.

Chronicity of rheumatoid arthritis affects the responsiveness of physical function, but not of disease activity measures in rheumatoid arthritis clinical trials

BACKGROUND In previous studies it has been indicated that functional measures are less responsive in patients with established or late rheumatoid arthritis (RA) as compared with early RA, potentially because chronic irreversible functional damage is present. Therefore, they may not be useful as disease activity measures. We aimed to investigate whether this is specific to functional measures, or if it similarly also relates to other typical RA disease activity measures. METHODS We performed a pooled analysis of patient level clinical trial data of patients with RA. We investigated the effects of duration of RA on the responsiveness of all RA core set measures by using logistic regression analysis. We performed a number of sensitivity analyses to support our findings. RESULTS The probability of response in functional scores decreased from ~60% in early disease to ~30% in established/late disease (p=0.0023). No other core set variable or composite index behaved in this way. The effect of chronicity solely on functional responses was confirmed in all sensitivity analyses, particularly also when joint damage was used as a surrogate of chronicity, responsiveness decreased from >60% in patients with little structural damage to <20% in patients with severe joint damage (p<0.001). CONCLUSIONS Physical function is among the most important outcomes of RA, but in contrast with other core set measures it is not a reliable measure for disease activity.

Cartilage damage and bone erosion are more prominent determinants of functional impairment in longstanding experimental arthritis than synovial inflammation

ABSTRACT Chronic inflammation of articular joints causing bone and cartilage destruction consequently leads to functional impairment or loss of mobility in affected joints from individuals affected by rheumatoid arthritis (RA). Even successful treatment with complete resolution of synovial inflammatory processes does not lead to full reversal of joint functionality, pointing to the crucial contribution of irreversibly damaged structural components, such as bone and cartilage, to restricted joint mobility. In this context, we investigated the impact of the distinct components, including synovial inflammation, bone erosion or cartilage damage, as well as the effect of blocking tumor necrosis factor (TNF) on functional impairment in human-TNF transgenic (hTNFtg) mice, a chronic inflammatory erosive animal model of RA. We determined CatWalk-assisted gait profiles as objective quantitative measurements of functional impairment. We first determined body-weight-independent gait parameters, including maximum intensity, print length, print width and print area in wild-type mice. We observed early changes in those gait parameters in hTNFtg mice at week 5 – the first clinical signs of arthritis. Moreover, we found further gait changes during chronic disease development, indicating progressive functional impairment in hTNFtg mice. By investigating the association of gait parameters with inflammation-mediated joint pathologies at different time points of the disease course, we found a relationship between gait parameters and the extent of cartilage damage and bone erosions, but not with the extent of synovitis in this chronic model. Next, we observed a significant improvement of functional impairment upon blocking TNF, even at progressed stages of disease. However, blocking TNF did not restore full functionality owing to remaining subclinical inflammation and structural microdamage. In conclusion, CatWalk gait analysis provides a useful tool for quantitative assessment of functional impairment in inflammatory destructive arthritis. Our findings indicate that cartilage damage and bone erosion, but not synovial inflammation, are the most important determinants for progressive functional impairment in this chronic erosive arthritis model. Summary: Gait-profile assessment is an objective quantitative measurement to monitor functional impairment in arthritis models. Longstanding functional impairment correlates with inflammation-driven structural damage.