IL-33 and Rheumatoid Arthritis – an update

Three years ago I’ve published a blog post on IL-33 here (link: see below); as inhibition of IL-33 could be a potential therapeutic and/or diagnostic approach. Let’s look for the studies on IL-33, which have emerged during the past three years.

There has been a study by S. Tang and colleagues in 2013: “Increased : L-33 in synovial fluid and paired serum is associated with disease activity and autoantibodies in rheumatoid arthritis.” In results the authors found: “SF IL-33 was significantly higher in RA than in OA, which was correlated with disease activity score 28, erythrocyte sedimentation rate, rheumatoid factor (RF)-IgM, RF-IgG, glucose phosphate isomerase (GPI), and immunoglobulin. …” So they concluded that IL-33 played an important role in the local pathogenesis of rheumatoid arthritis.

J. Shen and colleagues presented a study at the 2014 ACR/ARHP Annual Meeting [Abstract No. 374]: “IL-33 and Soluble ST2 Levels As Novel Predictors for Remission and Progression of Carotid Plaque in Early Rheumatoid Arthritis: A Prospective Study.” The authors want to identify predictors for treatment response, which may help to develop a form of personalized medicine. In conclusion they tell us: “Lower baseline sST2 levels independently predict disease remission and baseline detectable IL-33 independently predicts carotid plaque progression in ERA patients. This study suggests that inflammation induced by the IL-33/ST2 axis may play a significant role in the development of cardiovascular disease in RA.” This may seem far from a personalized medicine, but it’s a step towards this goal.

J. Sellam and colleagues published a study at the 2014 ACR/ARHP Annual Meeting [Abstract No. 2928]: “Serum IL-33 Level Is Increased in Rheumatoid Arthritis and Predicts Response to Rituximab in Combination with High Serum IgG Level and Autoantibody Positivity: An Open-Label, Prospective, Multicentre Biological Trial. “ Conclusion: “Serum IL-33 level, intrinsically increased in RA, represents a simple marker predicting accurately clinical response to RTX, independently of and synergistically with auto-antibodies and serum IgG level.” Does this help us right now? No. We don’t have a commercially IL-33 test, which is reimbursed to use it. But I find the result “Using ROC curve analyze, 249 pg/mL was the optimal serum IL-33 level cut-off to discriminate responders from non-responders.” intriguing. It would tell us more, when not to use rituximab, than, when to use it.

F. Rivellese and colleagues published a stuy: “Ability of Interleukin-33- and Immune Complex-Triggered Activation of Human Mast Cells to Down-Regulate Monocyte-Mediated Immune Responses.” Conclusion: “When human mast cells are activated by IL-33, an immunomodulatory phenotype develops, with human mast cells gaining the ability to suppress monocyte activation via the release of IL-10 and histamine. These findings, together with the presence of synovial mast cell-monocyte interactions and the inverse association between the expression of mast cell genes at the synovial level and disease activity, suggest that these newly described mast cell-mediated inhibitory pathways might have a functional relevance in the pathogenesis of RA.” This is a more basic study and therefore it isn’t clear to what it might mean to gain more control on disease activity. IL-33 is upregulated in RA patients to suppress monocyte activation.

These studies show that we still have a lot to learn about the role of IL-33 in rheumatoid arthritis. I’m sure that there will be a useful tool, if commercially test of IL-33 will be available. But I also hope for a breakthrough to use IL-33 (or IL-10) as a target to treat rheumatoid arthritis and/or other inflammatory rheumatic diseases.

Links:
IL-33 at the EULAR 2013 - http://rheumatologe.blogspot.de/2013/07/il-33-at-eular-2013.html 
S. Tang: Increased : L-33 in synovial fluid - http://www.ncbi.nlm.nih.gov/pubmed/24106520 
J. Shen and colleagues: IL-33 and Soluble ST2 Levels As Novel Predictors for Remission and Progression of Carotid Plaque in Early Rheumatoid Arthritis: A Prospective Study. Abstract 374 at the 2014 ACR/ARHP Annual Meeting. http://acrabstracts.org/abstract/il-33-and-soluble-st2-levels-as-novel-predictors-for-remission-and-progression-of-carotid-plaque-in-early-rheumatoid-arthritis-a-prospective-study/ 
J. Sellam and colleagues: Serum IL-33 Level Is Increased in Rheumatoid Arthritis and Predicts Response to Rituximab in Combination with High Serum IgG Level and Autoantibody Positivity: An Open-Label, Prospective, Multicentre Biological Trial. Abstract 2928 at the 2014 ACR/ARHP Annual Meeting.  http://acrabstracts.org/abstract/serum-il-33-level-is-increased-in-rheumatoid-arthritis-and-predicts-response-to-rituximab-in-combination-with-high-serum-igg-level-and-autoantibody-positivity-an-open-label-prospective-multicentre/
F. Rivellese and colleagues: Ability of Interleukin-33- and Immune Complex-Triggered Activation of Human Mast Cells to Down-Regulate Monocyte-Mediated Immune Responses. Arthritis Rheumatol. 2015 Sep;67(9):2343-53. doi: 10.1002/art.39192. http://www.ncbi.nlm.nih.gov/pubmed/25989191

IL-33 / ST2 in Rheumatoid Arthritis at the EULAR 2014 Meeting in Paris

A year ago I had written about the potential role of IL-33, a member of the IL-1 family, in rheumatoid arthritis and experimental inflammatory arthritis. Last year it had been shown, that serum IL33 levels are increased especially in anti-CCP positive RA patients. W.D. Xu and colleagues concluded, that “the role of the IL-33/ST2 axis in B-cell immunopathology in RA needs to be further addressed.”

This year J.-J. Kim and colleagues presented the following study [AB0066]: “Clinical usefulness of serum soluble ST2 in rheumatoid arthritis with anti-TNF-α therapy”. Conclusions: “The serum sST2 level was increased in RA patients, and correlated with other inflammatory markers of disease activity. Monitoring of serum sST2 levels may be a possible marker of effectiveness to anti-TNF-α therapy for RA patients, when this is supported by an extended study with more patients.”

So we see further use of IL-33/ST2 as a marker, but we don’t know more about “the role of the IL-33/ST2 axis in B-cell immunopathology in RA”. There were two more studies, one on Sjogren’s syndrome and one on Adult Onset Still’s Disease.

Link:

EULAR 2013 - http://rheumatologe.blogspot.de/2013/07/il-33-at-eular-2013.html

Studies at EULAR 2014:

[THU0054] INTERLEUKIN-33/ST2 AXIS IN PRIMARY SJOGREN’S SYNDROME: EXPRESSION IN SERUM AND SALIVARY GLAND, AND CLINICAL ASSOCIATION

S.M. Jung 1, J.Y. Kang1, H.K. Min 1, J.H. Koh 1, Y.S. Suh1, J.H. Lee 1, J. Lee 1, J.Y. Lee 1, J.-M. Kim2, J.H. Ju 1, K.-S. Park 1, S.-H. Park 1, H.-Y. Kim3

[THU0531] SERUM SOLUBLE ST2 LEVEL IN PATIENTS WITH ADULT-ONSET STILL’S DISEASE: A POTENTIAL BIOMARKER OF DISEASE ACTIVITY

J.H. Park 1, J.-J. Kim 2, D.-H. Yoo 2

[AB0066] CLINICAL USEFULNESS OF SERUM SOLUBLE ST2 IN RHEUMATOID ARTHRITIS WITH ANTI-TNF-α THERAPY

J.-J. Kim, J.-I. Choi, Y.-B. Joo, D.-H. Yoo

IL-33 at the EULAR 2013

IL-33 is an interesting cytokine. XU W.D. and colleagues published a paper recently, which looked at the potential role of IL-33, a member of the IL-1 family, in rheumatoid arthritis and experimental inflammatory arthritis. The authors think that inhibition of IL-33 could be a potential therapeutic approach. Link: http://www.ncbi.nlm.nih.gov/pubmed/23800433

There were several papers at the EULAR 2013 Meeting in Madrid, I’ll only refer to the study concerning rheumatoid arthritis. The other studies are on tendinopathy, systemic sclerosis, and lupus. Conclusions: “Serum IL33 level is increased in RA pts with anti-CCP and/or RF. Moreover, we confirm our transcriptomic analysis and demonstrate for the first time that serum IL-33 level represents a novel simple useful biomarker predicting clinical response to RTX, independently of auto-antibodies status, which usually displays a strong impact on rituximab response. The role of the IL-33/ST2 axis in B-cell immunopathology in RA needs to be further addressed.” Roche already tried to establish the rheumatoid factor as a marker for response to rituximab. IL-33 seems to be a better candidate.

I’ll look for more studies in the future, as IL-33 might get more attention both for diagnostic/prognostic and therapeutic reasons.