Heat Shock Proteins Can Be Surrogate Autoantigens for Induction of Antigen Specific Therapeutic Tolerance in Rheumatoid Arthritis

Technologies that enable induction of therapeutic tolerance may revolutionize the treatment of autoimmune diseases by their supposed potential to induce drug-free and lasting disease remission. In combination with diagnostic tests that screen for individuals at risk, these approaches may offer chances to halt disease before serious damage in the tissues can occur. In fact, for healthy individuals at risk, this could lead to a preventive form of vaccination. For therapeutic tolerance to re-instate natural self-tolerance it seems essential to induce tolerance for the critical autoantigens involved in disease. However, for most autoimmune diseases such antigens are poorly defined. This is the case for both disease inciting autoantigens and antigens that become involved through epitope spreading. A possible source of surrogate auto-antigens expressed in tissues during inflammation are heat shock proteins (HSP) or stress proteins. In this mini-review we discuss unique characteristics of HSP which provide them with the capacity to inhibit inflammatory processes. Various studies have shown that epitopes of HSP60 and HSP70 molecules can function as vaccines to downregulate a variety of autoimmune inflammatory diseases. Currently, several research groups are developing cell therapies with the intention to reach therapeutic tolerance. In this review, in which we are proposing to ex vivo load tolerant dendritic cells with a Treg inducing HSP70 derived peptide called B29, we are discussing the chances to develop this as an autologous tolDC therapeutic tolerance therapy for rheumatoid arthritis

EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis

Objective To develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficult-to-treat rheumatoid arthritis (D2T RA). Methods An EULAR Task Force was established comprising 34 individuals: 26 rheumatologists, patient partners and rheumatology experienced health professionals. Two systematic literature reviews addressed clinical questions around diagnostic challenges, and pharmacological and non-pharmacological therapeutic strategies in D2T RA. PtCs were formulated based on the identified evidence and expert opinion. Strength of recommendations (SoR, scale A–D: A typically consistent level 1 studies and D level 5 evidence or inconsistent studies) and level of agreement (LoA, scale 0–10: 0 completely disagree and 10 completely agree) of the PtCs were determined by the Task Force members. Results Two overarching principles and 11 PtCs were defined concerning diagnostic confirmation of RA, evaluation of inflammatory disease activity, pharmacological and non-pharmacological interventions, treatment adherence, functional disability, pain, fatigue, goal setting and self-efficacy and the impact of comorbidities. The SoR varied from level C to level D. The mean LoA with the overarching principles and PtCs was generally high (8.4–9.6). Conclusions These PtCs for D2T RA can serve as a clinical roadmap to support healthcare professionals and patients to deliver holistic management and more personalised pharmacological and non-pharmacological therapeutic strategies. High-quality evidence was scarce. A research agenda was created to guide future research

Heat Shock Proteins Can Be Surrogate Autoantigens for Induction of Antigen Specific Therapeutic Tolerance in Rheumatoid Arthritis

Technologies that enable induction of therapeutic tolerance may revolutionize the treatment of autoimmune diseases by their supposed potential to induce drug-free and lasting disease remission. In combination with diagnostic tests that screen for individuals at risk, these approaches may offer chances to halt disease before serious damage in the tissues can occur. In fact, for healthy individuals at risk, this could lead to a preventive form of vaccination. For therapeutic tolerance to re-instate natural self-tolerance it seems essential to induce tolerance for the critical autoantigens involved in disease. However, for most autoimmune diseases such antigens are poorly defined. This is the case for both disease inciting autoantigens and antigens that become involved through epitope spreading. A possible source of surrogate auto-antigens expressed in tissues during inflammation are heat shock proteins (HSP) or stress proteins. In this mini-review we discuss unique characteristics of HSP which provide them with the capacity to inhibit inflammatory processes. Various studies have shown that epitopes of HSP60 and HSP70 molecules can function as vaccines to downregulate a variety of autoimmune inflammatory diseases. Currently, several research groups are developing cell therapies with the intention to reach therapeutic tolerance. In this review, in which we are proposing to ex vivo load tolerant dendritic cells with a Treg inducing HSP70 derived peptide called B29, we are discussing the chances to develop this as an autologous tolDC therapeutic tolerance therapy for rheumatoid arthritis

Heat Shock Proteins Can Be Surrogate Autoantigens for Induction of Antigen Specific Therapeutic Tolerance in Rheumatoid Arthritis

Technologies that enable induction of therapeutic tolerance may revolutionize the treatment of autoimmune diseases by their supposed potential to induce drug-free and lasting disease remission. In combination with diagnostic tests that screen for individuals at risk, these approaches may offer chances to halt disease before serious damage in the tissues can occur. In fact, for healthy individuals at risk, this could lead to a preventive form of vaccination. For therapeutic tolerance to re-instate natural self-tolerance it seems essential to induce tolerance for the critical autoantigens involved in disease. However, for most autoimmune diseases such antigens are poorly defined. This is the case for both disease inciting autoantigens and antigens that become involved through epitope spreading. A possible source of surrogate auto-antigens expressed in tissues during inflammation are heat shock proteins (HSP) or stress proteins. In this mini-review we discuss unique characteristics of HSP which provide them with the capacity to inhibit inflammatory processes. Various studies have shown that epitopes of HSP60 and HSP70 molecules can function as vaccines to downregulate a variety of autoimmune inflammatory diseases. Currently, several research groups are developing cell therapies with the intention to reach therapeutic tolerance. In this review, in which we are proposing to ex vivo load tolerant dendritic cells with a Treg inducing HSP70 derived peptide called B29, we are discussing the chances to develop this as an autologous tolDC therapeutic tolerance therapy for rheumatoid arthritis

Heat shock proteins can be surrogate autoantigens for induction of antigen specific therpeutic tolerance in rheumatoid arthritis

Technologies that enable induction of therapeutic tolerance may revolutionize the treatment of autoimmune diseases by their supposed potential to induce drug-free and lasting disease remission. In combination with diagnostic tests that screen for individuals at risk, these approaches may offer chances to halt disease before serious damage in the tissues can occur. In fact, for healthy individuals at risk, this could lead to a preventive form of vaccination. For therapeutic tolerance to re-instate natural self-tolerance it seems essential to induce tolerance for the critical autoantigens involved in disease. However, for most autoimmune diseases such antigens are poorly defined. This is the case for both disease inciting autoantigens and antigens that become involved through epitope spreading. A possible source of surrogate auto-antigens expressed in tissues during inflammation are heat shock proteins (HSP) or stress proteins. In this mini-review we discuss unique characteristics of HSP which provide them with the capacity to inhibit inflammatory processes. Various studies have shown that epitopes of HSP60 and HSP70 molecules can function as vaccines to downregulate a variety of autoimmune inflammatory diseases. Currently, several research groups are developing cell therapies with the intention to reach therapeutic tolerance. In this review, in which we are proposing to ex vivo load tolerant dendritic cells with a Treg inducing HSP70 derived peptide called B29, we are discussing the chances to develop this as an autologous tolDC therapeutic tolerance therapy for rheumatoid arthritis

Is prediction of clinical response to methotrexate in individual rheumatoid arthritis patients possible? A systematic literature review

Objectives: To identify, by a systematic literature review, predictors of clinical response to methotrexate treatment in rheumatoid arthritis patients, which would facilitate personalised treatment. Methods: PubMed and Embase databases were searched for original articles. Additionally, congress abstracts of European League Against Rheumatism and American College of Rheumatology annual meetings of the past 2 years were screened. Articles describing predictors of clinical response to methotrexate after 3 to 6 months were included, since this reflects the time span used to determine treatment effectiveness and decide on treatment changes in treat-to-target recommendations. Results: Thirty articles were included, containing 100 different predictors and 11 predictive models. Nineteen predictors and 2 predictive models were studied in multiple cohorts. Female gender was found to be a predictor of non-response in two studies (odds ratios 0.55 and 0.54), but these findings could not be replicated in two other studies. In two studies, smoking predicted non-response (adjusted odds ratios 0.35 and 0.60), although this was inconsistent over all response criteria assessed. Rheumatoid factor positivity predicted non-response in two studies (adjusted hazard ratio 0.61, adjusted odds ratio 0.4), but this was not found in three other studies. Heterogeneity in studies prohibited further comparison of predictive values between studies. Additionally, a validated epigenetic model was found (area under the curve 0.90 and 0.91). Conclusions: No predictors were identified reliably predicting clinical response to methotrexate after 3 to 6 months in the individual patient: clinical predictors were weak. However, a promising epigenetic model was found that needs further validation

Is prediction of clinical response to methotrexate in individual rheumatoid arthritis patients possible? A systematic literature review

Objectives: To identify, by a systematic literature review, predictors of clinical response to methotrexate treatment in rheumatoid arthritis patients, which would facilitate personalised treatment. Methods: PubMed and Embase databases were searched for original articles. Additionally, congress abstracts of European League Against Rheumatism and American College of Rheumatology annual meetings of the past 2 years were screened. Articles describing predictors of clinical response to methotrexate after 3 to 6 months were included, since this reflects the time span used to determine treatment effectiveness and decide on treatment changes in treat-to-target recommendations. Results: Thirty articles were included, containing 100 different predictors and 11 predictive models. Nineteen predictors and 2 predictive models were studied in multiple cohorts. Female gender was found to be a predictor of non-response in two studies (odds ratios 0.55 and 0.54), but these findings could not be replicated in two other studies. In two studies, smoking predicted non-response (adjusted odds ratios 0.35 and 0.60), although this was inconsistent over all response criteria assessed. Rheumatoid factor positivity predicted non-response in two studies (adjusted hazard ratio 0.61, adjusted odds ratio 0.4), but this was not found in three other studies. Heterogeneity in studies prohibited further comparison of predictive values between studies. Additionally, a validated epigenetic model was found (area under the curve 0.90 and 0.91). Conclusions: No predictors were identified reliably predicting clinical response to methotrexate after 3 to 6 months in the individual patient: clinical predictors were weak. However, a promising epigenetic model was found that needs further validation