Antimodified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying antirheumatic drugs

Figueiredo, C.; Bang, Holger; Cobra, Jayme Fogagnolo; Englbrecht, Matthias; Hueber, Axel J.; Haschka, Judith; Manger, Bernhard; Kleyer, Arnd; Reiser, Michaela; Finzel, Stephanie; Tony, Hans‐Peter; Kleinert, Stefan; Wendler, J.; Schuch, Florian; Ronneberger, Monika; Feuchtenberger, Martin; Fleck, Martin; Manger, Karin; Ochs, Wolfgang; Schmitt-Haendle, Matthias; Lorenz, Hanns‐Martin; Nuesslein, Hubert; Alten, Rieke; Henes, Joerg; Krueger, Klaus; Rech, Juergen; Schett, Georg

doi:10.1136/annrheumdis-2016-209297

Cited by 49 publications

(57 citation statements)

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“…Interfering with such triggers would allow retarding or even inhibiting the onset of the disease. Notably, currently available therapies for RA, such as cytokine (TNF and IL-6) blockers or inhibitors of the JAK-STAT pathway 43 , exclusively tackle the inflammatory phase of the disease but do not interfere with the underlying processes that initiate the onset of arthritis and therefore often need to be given life-long 44 .…”

Section: Discussionmentioning

confidence: 99%

Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis

et al. 2020

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Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.

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Section: Discussionmentioning

confidence: 99%

Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis

et al. 2020

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“…As for the second outcome, initial DFR, Figueiredo et al recently showed that patients with a broad pattern of AMPA response are at high risk of disease relapse in the first year after DMARD tapering [ 27 ]. Although the trend we found for initial DFR was significant for the number of AMPAs, our findings do not fully support Figueiredo’s observation that a broad autoantibody profile is unfavourable for DFR because we did not identify a dose-dependent effect.…”

Section: Discussionmentioning

confidence: 99%

Baseline autoantibody profile in rheumatoid arthritis is associated with early treatment response but not long-term outcomes

et al. 2018

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BackgroundThe autoantibody profile of seropositive rheumatoid arthritis (RA) is very diverse and consists of various isotypes and antibodies to multiple post-translational modifications. It is yet unknown whether this varying breadth of the autoantibody profile is associated with treatment outcomes. Therefore, we investigated whether the composition of the autoantibody profile in RA, as a marker of the underlying immunopathology, influences initial and long-term treatment outcomes.MethodsIn serum from 399 seropositive patients with RA in the IMPROVED study, drawn at baseline and at the moment of drug tapering, we measured IgG, IgM, and IgA isotypes for anti-cyclic citrullinated peptide-2 and anti‐carbamylated protein antibodies, IgM and IgA rheumatoid factor, and reactivity against four citrullinated and two acetylated peptides (anti-modified protein antibodies (AMPAs)). We investigated the effect of the breadth of the autoantibody profile on (1) change in disease activity score (DAS)44 between 0 and 4 months, (2) initial drug-free remission (DFR, drug-free DAS44 < 1.6) achieved between 1 and 2 years of follow up, and (3) long-term sustained DFR until last follow up.ResultsPatients with a broad autoantibody profile at baseline had a significantly better early treatment response: ΔDAS 0–4 months of 1–2, 3–4, and 5–6 vs 7–8 isotypes, -1.5 (p < 0.001), -1.7 (p = 0.03), and -1.8 (p = 0.04) vs -2.2. Similar results were observed for AMPA number. However, patients with a broad baseline autoantibody profile achieved less initial DFR. For long-term sustained DFR there was no longer an association with the breadth of the autoantibody response. When assessing autoantibodies at the moment of tapering, similar trends were observed.ConclusionsA broad baseline autoantibody profile is associated with a better early treatment response. The breadth of the baseline autoantibody profile, reflecting a break in tolerance against several different autoantigens and extensive isotype switching, may indicate a more active humoral autoimmunity, which could make the underlying disease processes initially more suppressible by medication. The lack of association with long-term sustained DFR suggests that the relevance of the baseline autoantibody profile diminishes over time.Trial registrationISRCTN11916566. Registered on 7 November 2006. EudraCT, 2006- 06186-16. Registered on 16 July 2007.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1520-4) contains supplementary material, which is available to authorized users.

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“…RNA isolation, cDNA synthesis, ARTISAN PCR and sequencing were performed as previously described 20 21. The same methodology using acetylated-vimentin (HC55) and lysine-vimentin (HC56)22 streptavidin-tetramers was used to isolate two AAPA-IgG sequences. The ACPA-IgG 7E4 sequence was provided by Dr Rispens, Sanquin, The Netherlands 23.…”

Section: Methodsmentioning

confidence: 99%

Antibodies and B cells recognising citrullinated proteins display a broad cross-reactivity towards other post-translational modifications

et al. 2020

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ObjectiveAutoantibodies against antigens carrying distinct post-translational modifications (PTMs), such as citrulline, homocitrulline or acetyllysine, are hallmarks of rheumatoid arthritis (RA). The relation between these anti-modified protein antibody (AMPA)-classes is poorly understood as is the ability of different PTM-antigens to activate B-cell receptors (BCRs) directed against citrullinated proteins (CP). Insights into the nature of PTMs able to activate such B cells are pivotal to understand the ‘evolution’ of the autoimmune response conceivable underlying the disease. Here, we investigated the cross-reactivity of monoclonal AMPA and the ability of different types of PTM-antigens to activate CP-reactive BCRs.MethodsBCR sequences from B cells isolated using citrullinated or acetylated antigens were used to produce monoclonal antibodies (mAb) followed by a detailed analysis of their cross-reactivity towards PTM-antigens. Ramos B-cell transfectants expressing CP-reactive IgG BCRs were generated and their activation on stimulation with PTM-antigens investigated.ResultsMost mAbs were highly cross-reactive towards multiple PTMs, while no reactivity was observed to the unmodified controls. B cells carrying CP-reactive BCRs showed activation on stimulation with various types of PTM-antigens.ConclusionsOur study illustrates that AMPA exhibit a high cross-reactivity towards at least two PTMs indicating that their recognition pattern is not confined to one type of modification. Furthermore, our data show that CP-reactive B cells are not only activated by citrullinated, but also by carbamylated and/or acetylated antigens. These data are vital for the understanding of the breach of B-cell tolerance against PTM-antigens and the possible contribution of these antigens to RA-pathogenesis.

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Antimodified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying antirheumatic drugs

Abstract: 2009-015740-42; Results.

Cited by 49 publications

References 46 publications

Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis

Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis

Baseline autoantibody profile in rheumatoid arthritis is associated with early treatment response but not long-term outcomes

Antibodies and B cells recognising citrullinated proteins display a broad cross-reactivity towards other post-translational modifications

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