Association of HLA shared epitope with joint damage progression in rheumatoid arthritis

AbstractBaricitinib is an oral selective inhibitor of Janus kinase (JAK)1 and JAK2 that has proved effective and well tolerated in the treatment of rheumatoid arthritis (RA) in an extensive programme of clinical studies of patients with moderate-to-severe disease. In a phase 2b dose-ranging study of baricitinib in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in RA patients, magnetic resonance imaging showed that baricitinib 2 mg or 4 mg once daily provided dose-dependent suppression of synovitis, osteitis, erosion and cartilage loss at weeks 12 and 24 versus placebo. These findings correlated with clinical outcomes and were confirmed in three phase 3 studies (RA-BEGIN, RA-BEAM and RA-BUILD) using X-rays to assess structural joint damage. In patients naïve to DMARDs (RA-BEGIN study), baricitinib 4 mg once daily as monotherapy or combined with methotrexate produced smaller mean changes in structural joint damage than methotrexate monotherapy at week 24. Differences versus methotrexate were statistically significant for combined therapy. In patients responding inadequately to methotrexate (RA-BEAM study), baricitinib 4 mg plus background methotrexate significantly inhibited structural joint damage at week 24 versus placebo, and the results were comparable to those observed with adalimumab plus background methotrexate. In patients responding inadequately to conventional synthetic DMARDs (csDMARDs; RA-BUILD study), baricitinib 4 mg again significantly inhibited radiographic progression compared with placebo at week 24. Benefits were also observed with baricitinib 2 mg once daily, but the effects of baricitinib 4 mg were more robust. The positive effects of baricitinib 4 mg on radiographic progression continued over 1 and 2 years in the long-term extension study RA-BEYOND, with similar effects to adalimumab and significantly greater effects than placebo. Findings from the phase 3 studies of patients with RA were supported by preclinical studies, which showed that baricitinib has an osteoprotective effect, increasing mineralisation in bone-forming cells. In conclusion, baricitinib 4 mg once daily inhibits radiographic joint damage progression in patients with moderate-to-severe RA who are naïve to DMARDs or respond inadequately to csDMARDs, including methotrexate, and the beneficial effects are similar to those observed with adalimumab.

Download Full-text

Four-month metacarpal bone mineral density loss predicts radiological joint damage progression after 1 year in patients with early rheumatoid arthritis: exploratory analyses from the IMPROVED study

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2013-203749 ◽

2013 ◽

Vol 74 (2) ◽

pp. 341-346 ◽

Cited By ~ 15

Author(s):

K V C Wevers-de Boer ◽

L Heimans ◽

K Visser ◽

J Kälvesten ◽

R J Goekoop ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Bone Mineral Density ◽

Bone Mineral ◽

Early Rheumatoid Arthritis ◽

Joint Damage ◽

Metacarpal Bone ◽

Mineral Density ◽

Bone Mineral Density Loss ◽

Damage Progression

Download Full-text

Characterization of Cumulative Joint Damage Patterns in Patients with Rheumatoid Arthritis: A Clinical, Serological, and Gene Polymorphism Perspective

The Journal of Rheumatology ◽

10.3899/jrheum.131177 ◽

2015 ◽

Vol 42 (3) ◽

pp. 405-412

Author(s):

Renata Trigueirinho Alarcon ◽

Artur da Rocha Corrêa Fernandes ◽

Ieda Maria Laurindo ◽

Manoel Barros Bértolo ◽

Geraldo Castelar Pinheiro ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Gene Polymorphism ◽

Triple Negative ◽

Shared Epitope ◽

Joint Damage ◽

Morphometric Features ◽

Anticitrullinated Protein Antibodies ◽

Se Status

Objective.To characterize cumulative joint damage (CJD) patterns in rheumatoid arthritis (RA) and determine their associations with demographic/clinical features and HLA-DRB1 gene polymorphism.Methods.Hand and foot radiographs were obtained from 404 patients with RA. CJD patterns were determined by 3 derivations from Sharp/van der Heijde scores, obtained by the mathematical division of scores for hands/feet (Sharp-h/f score), fingers/wrists (Sharp-f/w score), and erosion/space narrowing (Sharp-e/sn score), respectively. DNA and serum were obtained for determination of HLA-DRB1 polymorphism, rheumatoid factor (RF), and anticitrullinated protein antibodies (ACPA).Results.Patients with wrist-dominant CJD pattern were more likely to have severe RA than those with finger-dominant pattern (68.4% vs 46.0%; p = 0.036) as were those with foot-dominant vs hand-dominant CJD pattern (76.5% vs 56.4%; p = 0.044). HLA-DRB1 shared epitope (SE) alleles were associated with erosion-dominant CJD pattern (p = 0.021). Patients with erosion-dominant CJD pattern had higher levels of RF and ACPA than those with space-narrowing–dominant CJD pattern (median RF 71.35 U/ml vs 22.05 U/ml, respectively; p = 0.003; median ACPA 187.9 U/ml vs 143.2 U/ml, respectively; p < 0.001). The majority of triple-positive patients (SE+, RF+, ACPA+) had erosion-dominant CJD pattern (62.3%) while the majority of triple-negative patients (SE–, FR–, ACPA–) had space narrowing–dominant CJD pattern (75%; p = 0.017). ACPA was associated with HLA-DRB1 SE alleles (p < 0.05). Patients with foot-dominant CJD pattern were taller than those with hand-dominant CJD pattern (p = 0.002); those with erosion-dominant CJD pattern had higher weight and body mass index than those with space narrowing–dominant CJD pattern (p = 0.014, p = 0.001).Conclusion.CJD patterns were associated with disease severity, HLA-DRB1 SE status, presence and titer of ACPA and RF, and morphometric features.

Download Full-text

Should We Redefine Treatment Targets in Rheumatoid Arthritis? Low Disease Activity Is Sufficiently Strict for Patients Who Are Anticitrullinated Protein Antibody-negative

The Journal of Rheumatology ◽

10.3899/jrheum.121438 ◽

2013 ◽

Vol 40 (8) ◽

pp. 1268-1274 ◽

Cited By ~ 13

Author(s):

Yvonne M.R. de Punder ◽

Jos Hendrikx ◽

Alfons A. den Broeder ◽

Elia Valls Pascual ◽

Piet L. van Riel ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Joint Damage ◽

Activity Level ◽

Lower Probability ◽

Treatment Target ◽

Low Disease Activity ◽

Treatment Targets ◽

Damage Progression ◽

Ratingen Score

Objective.Clinical remission currently is the treatment target for all patients with rheumatoid arthritis (RA). At the same level of inflammation, the prognosis regarding joint damage is believed to be different for anticitrullinated protein antibody (ACPA)-negative and ACPA-positive patients. Our objective was to show the difference in prognosis at similar disease activity levels, and to illustrate how this could be translated to differentiation of treatment targets.Methods.Data were used from the Nijmegen Early RA Cohort. The relation between the time-averaged disease activity level (by Disease Activity Score; DAS) and joint damage progression over 3 years was analyzed, separately for ACPA-negative and ACPA-positive patients. Joint damage was assessed as change in Ratingen score, and dichotomized as occurrence of erosions in joints that were unaffected at baseline. Linear and logistic multivariable regression models were used.Results.The regression coefficient of DAS on change in Ratingen score was 3.9 (p < 0.001) for ACPA-negative and 4.7 (p < 0.001) for ACPA-positive patients, showing less joint damage progression at the same disease activity level in ACPA-negative patients. This difference became greater with increasing disease activity. The probability for erosions in joints unaffected at baseline was 0.35 in ACPA-negative patients when time-averaged DAS was < 2.4 versus 0.80 in ACPA-positive patients.Conclusion.At the same level of inflammation, ACPA-negative patients have less joint damage and lower probability for damage in newly affected joints than ACPA-positive patients. Low disease activity might be a sufficiently strict treatment target for ACPA-negative patients to prevent progression of joint damage.

Download Full-text

Attainment and characteristics of clinical remission according to the new ACR-EULAR criteria in abatacept-treated patients with early rheumatoid arthritis: new analyses from the Abatacept study to Gauge Remission and joint damage progression in methotrexate (MTX)-naive patients with Early Erosive rheumatoid arthritis (AGREE)

Arthritis Research & Therapy ◽

10.1186/s13075-015-0671-9 ◽

2015 ◽

Vol 17 (1) ◽

Cited By ~ 22

Author(s):

Josef S. Smolen ◽

Jürgen Wollenhaupt ◽

Juan J. Gomez-Reino ◽

Walter Grassi ◽

Corine Gaillez ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Early Rheumatoid Arthritis ◽

Clinical Remission ◽

Joint Damage ◽

Damage Progression

Download Full-text

FRI0278 The First Early Rheumatoid Arthritis, Certolizumab Pegol, Multicenter, Double-Blind, Randomized, Parallel-Group Study: C-Opera, in Patients Fulfilling the 2010 Acr/Eular Classification Criteria, Demonstrates Inhibition of Joint Damage Progression

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2014-eular.1448 ◽

2014 ◽

Vol 73 (Suppl 2) ◽

pp. 484.1-484 ◽

Cited By ~ 3

Author(s):

T. Atsumi ◽

K. Yamamoto ◽

T. Takeuchi ◽

H. Yamanaka ◽

N. Ishiguro ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Early Rheumatoid Arthritis ◽

Certolizumab Pegol ◽

Joint Damage ◽

Classification Criteria ◽

Double Blind ◽

Parallel Group Study ◽

Damage Progression ◽

Parallel Group

Download Full-text

Continued inhibition of structural damage over 2 years in patients with rheumatoid arthritis treated with rituximab in combination with methotrexate

Annals of the Rheumatic Diseases ◽

10.1136/ard.2009.119222 ◽

2010 ◽

Vol 69 (6) ◽

pp. 1158-1161 ◽

Cited By ~ 52

Author(s):

Stanley B Cohen ◽

Edward Keystone ◽

Mark C Genovese ◽

Paul Emery ◽

Charles Peterfy ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Structural Damage ◽

Joint Space Narrowing ◽

Joint Damage ◽

Joint Space ◽

Tnf Inhibitors ◽

Inadequate Response ◽

Intention To Treat ◽

Damage Progression ◽

Sustained Effects

BackgroundRituximab inhibited structural damage at 1 year in patients with rheumatoid arthritis (RA) who had had a previous inadequate response to tumour necrosis factor (TNF) inhibitors.ObjectiveTo assess structural damage progression through 2 years.MethodsIntention-to-treat patients with one post-baseline radiograph (rituximab n=281; placebo n=187) received background methotrexate (MTX) and were randomised to rituximab (2×1000 mg infusions, 2 weeks apart) or placebo; patients were eligible for rituximab re-treatment every 6 months. By week 104, 82% of the placebo population had received ≥1 dose of rituximab. Radiographic end points included the change in total Sharp score (TSS), erosion and joint space narrowing scores at week 104.ResultsAt week 104, significantly lower changes in TSS (1.14 vs 2.81; p<0.0001), erosion score (0.72 vs 1.80; p<0.0001) and joint space narrowing scores (0.42 vs 1.00; p<0.0009) were observed with rituximab plus MTX vs placebo plus MTX. Within the rituximab group, 87% who had no progression of joint damage at 1 year remained non-progressive at 2 years.ConclusionsRituximab plus MTX demonstrated significant and sustained effects on joint damage progression in patients with RA and a previously inadequate response to TNF inhibitors.

Download Full-text