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.

Mechanisms underlying DMARD inefficacy in difficult-to-treat rheumatoid arthritis: a narrative review with systematic literature search.

Management of RA patients has significantly improved over the past decades. However, a substantial proportion of patients is difficult-to-treat (D2T), remaining symptomatic after failing biological and/or targeted synthetic DMARDs. Multiple factors can contribute to D2T RA, including treatment non-adherence, comorbidities and co-existing mimicking diseases (e.g. fibromyalgia). Additionally, currently available biological and/or targeted synthetic DMARDs may be truly ineffective ('true' refractory RA) and/or lead to unacceptable side effects. In this narrative review based on a systematic literature search, an overview of underlying (immune) mechanisms is presented. Potential scenarios are discussed including the influence of different levels of gene expression and clinical characteristics. Although the exact underlying mechanisms remain largely unknown, the heterogeneity between individual patients supports the assumption that D2T RA is a syndrome involving different pathogenic mechanisms.

EULAR definition of difficult-to-treat rheumatoid arthritis.

BACKGROUND: Despite treatment according to the current management recommendations, a significant proportion of patients with rheumatoid arthritis (RA) remain symptomatic. These patients can be considered to have 'difficult-to-treat RA'. However, uniform terminology and an appropriate definition are lacking. OBJECTIVE: The Task Force in charge of the "Development of EULAR recommendations for the comprehensive management of difficult-to-treat rheumatoid arthritis" aims to create recommendations for this underserved patient group. Herein, we present the definition of difficult-to-treat RA, as the first step. METHODS: The Steering Committee drafted a definition with suggested terminology based on an international survey among rheumatologists. This was discussed and amended by the Task Force, including rheumatologists, nurses, health professionals and patients, at a face-to-face meeting until sufficient agreement was reached (assessed through voting). RESULTS: The following three criteria were agreed by all Task Force members as mandatory elements of the definition of difficult-to-treat RA: (1) Treatment according to European League Against Rheumatism (EULAR) recommendation and failure of ≥2 biological disease-modifying antirheumatic drugs (DMARDs)/targeted synthetic DMARDs (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated); (2) presence of at least one of the following: at least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life; and (3) the management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient. CONCLUSIONS: The proposed EULAR definition for difficult-to-treat RA can be used in clinical practice, clinical trials and can form a basis for future research.

Healthcare utilization and economic burden of difficult-to-treat rheumatoid arthritis: a cost-of-illness study.

OBJECTIVES: To determine the impact of difficult-to-treat rheumatoid arthritis (D2T RA) on (costs related to) healthcare utilization, other resource use and work productivity. METHODS: Data regarding healthcare utilization, other resource use and work productivity of 52 D2T (according to the EULAR definition) and 100 non-D2T RA patients were collected via a questionnaire and an electronic patient record review during a study visit. Annual costs were calculated and compared between groups. Multivariable linear regression analysis was performed to assess whether having D2T RA was associated with higher costs. RESULTS: Mean (95% CI) annual total costs were €37 605 (€27 689 - €50 378) for D2T and €19 217 (€15 647 - €22 945) for non-D2T RA patients (P<0.001). D2T RA patients visited their rheumatologist more frequently, were more often admitted to day-care facilities, underwent more laboratory tests and used more drugs (specifically targeted synthetic DMARDs), compared with non-D2T RA patients (P<0.01). In D2T RA patients, the main contributors to total costs were informal help of family and friends (28%), drugs (26%) and loss of work productivity (16%). After adjustment for physical functioning (HAQ), having D2T RA was no longer statistically significantly associated with higher total costs. HAQ was the only independent determinant of higher costs in multivariable analysis. CONCLUSIONS: The economic burden of D2T RA is significantly higher than that of non-D2T RA, indicated by higher healthcare utilization and higher annual total costs. Functional disability is a key determinant of higher costs in RA.

Difficult-to-treat rheumatoid arthritis: contributing factors and burden of disease.

OBJECTIVES: Treatment of difficult-to-treat (D2T) RA patients is generally based on trial-and-error and can be challenging due to a myriad of contributing factors. We aimed to identify risk factors at RA onset, contributing factors and the burden of disease. METHODS: Consecutive RA patients were enrolled and categorized as D2T, according to the EULAR definition, or not (controls). Factors potentially contributing to D2T RA and burden of disease were assessed. Risk factors at RA onset and factors independently associated with D2T RA were identified by logistic regression. D2T RA subgroups were explored by cluster analysis. RESULTS: Fifty-two RA patients were classified as D2T and 100 as non-D2T. Lower socioeconomic status at RA onset was found as an independent risk factor for developing D2T RA [odds ratio (OR) 1.97 (95%CI 1.08-3.61)]. Several contributing factors were independently associated with D2T RA, occurring more frequently in D2T than in non-D2T patients: limited drug options because of adverse events (94% vs 57%) or comorbidities (69% vs 37%), mismatch in patient's and rheumatologist's wish to intensify treatment (37% vs 6%), concomitant fibromyalgia (38% vs 9%) and poorer coping (worse levels). Burden of disease was significantly higher in D2T RA patients. Three subgroups of D2T RA patients were identified: (i) 'non-adherent dissatisfied patients'; (ii) patients with 'pain syndromes and obesity'; (iii) patients closest to the concept of 'true refractory RA'. CONCLUSIONS: This comprehensive study on D2T RA shows multiple contributing factors, a high burden of disease and the heterogeneity of D2T RA. These findings suggest that these factors should be identified in daily practice in order to tailor therapeutic strategies further to the individual patient.

Non-adherence in difficult-to-treat rheumatoid arthritis from the perspectives of patients and rheumatologists: a concept mapping study.

OBJECTIVES: Treatment non-adherence is more frequent among difficult-to-treat (D2T) than among non-D2T RA patients. Perceptions of non-adherence may differ. We aimed to thematically structure and prioritize barriers to (i.e. causes and reasons for non-adherence) and facilitators of optimal adherence from the patients' and rheumatologists' perspectives. METHODS: Patients' perceptions were identified in semi-structured in-depth interviews. Experts selected representative statements regarding 40 barriers and 40 facilitators. Twenty D2T and 20 non-D2T RA patients sorted these statements during two card-sorting tasks: first, by order of content similarity and, second, content applicability. Additionally, 20 rheumatologists sorted the statements by order of content applicability to the general RA population. The similarity sorting was used as input for hierarchical cluster analysis. The applicability sorting was analysed using descriptive statistics, prioritized and the results compared between D2T RA patients, non-D2T RA patients and rheumatologists. RESULTS: Nine clusters of barriers were identified, related to the healthcare system, treatment safety/efficacy, treatment regimen and patient behaviour. D2T RA patients prioritized adverse events and doubts about effectiveness as the most important barriers. Doubts about effectiveness were more important to D2T than to non-D2T RA patients (P = 0.02). Seven clusters of facilitators were identified, related to the healthcare system and directly to the patient. All RA patients and rheumatologists prioritized a good relationship with the healthcare professional and treatment information as the most helpful facilitators. CONCLUSIONS: D2T RA patients, non-D2T RA patients and rheumatologists prioritized perceptions of non-adherence largely similarly. The structured overviews of barriers and facilitators provided in this study may guide improvement of adherence.

Characteristics of difficult-to-treat rheumatoid arthritis: results of an international survey.

OBJECTIVES: Patients with difficult-to-treat rheumatoid arthritis (RA) remain symptomatic despite treatment according to current European League Against Rheumatism (EULAR) management recommendations. These focus on early phases of the disease and pharmacological management. We aimed to identify characteristics of difficult-to-treat RA and issues to be addressed in its workup and management that are not covered by current management recommendations. METHODS: An international survey was conducted among rheumatologists with multiple-choice questions on disease characteristics of difficult-to-treat RA. Using open questions, additional items to be addressed and items missing in current management recommendations were identified. RESULTS: 410 respondents completed the survey: 50% selected disease activity score assessing 28 joints >3.2 OR presence of signs suggestive of active disease as characteristics of difficult-to-treat RA; 42% selected fatigue; 48% selected failure to ≥2 conventional synthetic disease-modifying antirheumatic drugs (DMARDs) AND ≥2 biological/targeted synthetic DMARDs; 89% selected inability to taper glucocorticoids below 5 mg or 10 mg prednisone equivalent daily. Interfering comorbidities, extra-articular manifestations and polypharmacy were identified as important issues missing in current management recommendations. CONCLUSIONS: There is wide variation in concepts of difficult-to-treat RA. Several important issues regarding these patients are not addressed by current EULAR recommendations.

Rediscovering the therapeutic use of glucocorticoids in rheumatoid arthritis.

PURPOSE OF REVIEW: This review will focus on new information obtained on how to apply glucocorticoids in the treatment of rheumatoid arthritis, aiming at an optimal risk-benefit ratio. Moreover, advances in the development of new preparations such as liposomal glucocorticoids will be discussed. RECENT FINDINGS: In early rheumatoid arthritis, treatment regimens with a disease-modifying drug and initially medium-dose glucocorticoids (>7.5 but ≤30 mg prednisone equivalent) are noninferior compared with regimens with disease-modifying drugs and initially high-dose glucocorticoids (>30 mg prednisone equivalent) and have repeatedly been proven to be more effective than methotrexate monotherapy. Use of glucocorticoids following such a scheme during a period of 6 months to 2 years was not associated with increased mortality, nor with substantial bone loss if bone protective measures had been taken. New drug delivery systems, and in particular long-circulating liposomes, aiming at enhancing the biodistribution and the target site accumulation of glucocorticoids and thereby improving the balance between their efficacy and toxicity, are promising; more results on the effects in rheumatoid arthritis patients are expected to be reported during the years to come. SUMMARY: Combination therapy including methotrexate and glucocorticoids should be the initial treatment in patients with early rheumatoid arthritis. Treatment regimens including medium-dose glucocorticoids are noninferior compared with regimens with initially high-dose glucocorticoids. Studies on new glucocorticoid preparations and new drug delivery systems improving the balance between efficacy and toxicity of glucocorticoid therapy are ongoing.

Glucocorticoids in systemic sclerosis: weighing the benefits and risks - a systematic review.

OBJECTIVES: To identify indications for which different dosages of glucocorticoids (GCs) have been prescribed in systemic sclerosis (SSc), and to assess the efficacy and safety of GCs in SSc. METHODS: A literature search focusing on experimental studies, observational studies, and case reports describing GC use in SSc was conducted using PubMed, EMBASE and Cochrane databases. Information about the study population, GC therapy and its effects was recorded. Available data have been summarised, and efficacy and safety of GCs have been assessed for different indications and dosages. RESULTS: Forty-four studies and 93 case reports were included in this review. GCs were applied in the treatment of interstitial lung disease (ILD), diffuse cutaneous disease, myopathy, painful hands and cardiac involvement, or accompanying anti-thymocyte globulin to prevent serum sickness in the context of stem cell transplantation. GCs were used in different dosages, predominantly in combination with other immunosuppressive treatments. Monotherapy with GCs led to inconsistent results. Most adverse events recorded were infections. Twenty-three cases of scleroderma renal crisis (SRC) have been reported, mainly in patients with early diffuse disease (n=10) or with anti-thymocyte treatment (n=10). These patients were treated with low to medium dose GCs (n=10), high-dose GCs (n=11) and pulse therapy (n=2). CONCLUSIONS: Evidence of a beneficial role of GCs in SSc is limited. GCs have been part of the therapeutic strategy in the management of ILD, diffuse cutaneous disease or myositis. Awareness for the risk of SRC should persist, especially in patients with diffuse disease who are also treated with possibly nephrotoxic drugs.

Intra-articular glucocorticoid injections decrease the number of steroid hormone receptor positive cells in synovial tissue of patients with persistent knee arthritis.

OBJECTIVES: To explore changes in the number of steroid hormone receptor positive cells in synovial tissue (ST) after intra-articular glucocorticoid injection, to correlate these changes with changes in clinical variables, and to evaluate whether the number of steroid hormone receptor positive cells predicted the clinical response to glucocorticoid injection. METHODS: Fourteen patients with persistent knee arthritis despite at least two previous injections in an outpatient setting received an intra-articular injection with glucocorticoids, followed by 3 days of admission with bed rest. Clinical efficacy was assessed at 6 and 12 weeks. ST biopsies were performed 2 weeks before and 12 weeks after the injection. The presence of different cell types (T cells, macrophages, fibroblast-like synoviocytes) and numbers of glucocorticoid, androgen and oestrogen α and ß receptor positive cells were evaluated by histochemistry. RESULTS: Patients showed, despite previous failures, good clinical response to glucocorticoid injection, with significant improvement in erythrocyte sedimentation rate, visual analogue scale (VAS) for pain, and joint disability score. The number of steroid hormone receptor positive cells decreased markedly (p<0.05 for all four receptors). The decrease in oestrogen receptor α positive cells correlated significantly with the improvement in VAS for pain and joint disability score. The number of glucocorticoid, androgen and oestrogen α and ß receptor positive cells before injection did not predict the effect of treatment. CONCLUSIONS: Intra-articular glucocorticoid injections followed by bed rest for persistent arthritis are clinically effective and significantly decrease the number of steroid hormone receptor positive cells in ST. The relevance of the latter needs further study.

[Low dosed prednisolone in older patients with rheumatoid arthritis]. / Laag gedoseerde glucocorticoïden bij reumatoïde artritis.

Glucocorticoids are used in the treatment of rheumatoid arthritis since many decades. Glucocorticoids are proven effective in decreasing inflammatory activity of this disease and in retarding the progression of erosive joint damage. However, they also have multiple possible adverse effects, which are depending on dose and duration of treatment. Due to increasing treatment options (i.e. biologic and targeted synthetic disease modifying antirheumatic drugs) the use of glucocorticoids is subject of debate. The GLORIA study recently showed that addition of 5 mg prednisolone during 2 years is an effective treatment strategy in elderly patients with rheumatoid arthritis, without a substantial risk of adverse events. So, low dose prednisolone remains an attractive treatment option due to its effacacy, ease of use, safety and low cost.

Prediction Aided Tapering In rheumatoid arthritis patients treated with biOlogicals (PATIO): protocol for a randomized controlled trial.

BACKGROUND: Biological disease-modifying anti-rheumatic drugs (bDMARDs) are effective in the treatment of rheumatoid arthritis (RA) but are expensive and increase the risk of infection. Therefore, in patients with a stable low level of disease activity or remission, tapering bDMARDs should be considered. Although tapering does not seem to affect long-term disease control, (short-lived) flares are frequent during the tapering process. We have previously developed and externally validated a dynamic flare prediction model for use as a decision aid during stepwise tapering of bDMARDs to reduce the risk of a flare during this process. METHODS: In this investigator-initiated, multicenter, open-label, randomized (1:1) controlled trial, we will assess the effect of incorporating flare risk predictions into a bDMARD tapering strategy. One hundred sixty RA patients treated with a bDMARD with stable low disease activity will be recruited. In the control group, the bDMARD will be tapered according to "disease activity guided dose optimization" (DGDO). In the intervention group, the bDMARD will be tapered according to a strategy that combines DGDO with the dynamic flare prediction model, where the next bDMARD tapering step is not taken in case of a high risk of flare. Patients will be randomized 1:1 to the control or intervention group. The primary outcome is the number of flares per patient (DAS28-CRP increase > 1.2, or DAS28-CRP increase > 0.6 with a current DAS28-CRP ≥ 2.9) during the 18-month follow-up period. Secondary outcomes include the number of patients with a major flare (flare duration ≥ 12 weeks), bDMARD dose reduction, adverse events, disease activity (DAS28-CRP) and patient-reported outcomes such as quality of life and functional disability. Health Care Utilization and Work Productivity will also be assessed. DISCUSSION: This will be the first clinical trial to evaluate the benefit of applying a dynamic flare prediction model as a decision aid during bDMARD tapering. Reducing the risk of flaring during tapering may enhance the safety and (cost)effectiveness of bDMARD treatment. Furthermore, this study pioneers the field of implementing predictive algorithms in clinical practice. TRIAL REGISTRATION: Dutch Trial Register number NL9798, registered 18 October 2021, https://www.trialregister.nl/trial/9798 . The study has received ethical review board approval (number NL74537.041.20).

Using real-world data to dynamically predict flares during tapering of biological DMARDs in rheumatoid arthritis: development, validation, and potential impact of prediction-aided decisions.

BACKGROUND: Biological disease-modifying antirheumatic drugs (bDMARDs) are effective in the treatment of rheumatoid arthritis. However, as bDMARDs may also lead to adverse events and are expensive, tapering them is of great clinical interest. Tapering according to disease activity-guided dose optimization (DGDO) does not seem to affect long term remission rates, but flares are frequent during this process. Our objective was to develop a model for the prediction of flares during bDMARD tapering using data from routine care and to evaluate its potential clinical impact. METHODS: We used a joint latent class model to repeatedly predict the probability of a flare occurring within the next 3 months. The model was developed using longitudinal data on disease activity (DAS28) and other routine care data from two clinics. Predictive accuracy was assessed in cross-validation and external validation was performed with data from the DRESS (Dose REduction Strategy of Subcutaneous tumor necrosis factor inhibitors) trial. Additionally, we simulated the reduction in number of flares and bDMARD dose when implementing the model as a decision aid during bDMARD tapering in the DRESS trial. RESULTS: Data from 279 bDMARD courses were used for model development. The final model included two latent DAS28-trajectories, bDMARD type and dose, disease duration, and seropositivity. The area under the curve of the final model was 0.76 (0.69-0.83) in cross-validation and 0.68 (0.62-0.73) in external validation. In simulation of prediction-aided decisions, the mean number of flares over 18 months decreased from 1.21 (0.99-1.43) to 0.75 (0.54-0.96). The reduction in he bDMARD dose was mostly maintained, increasing from 54 to 64% of full dose. CONCLUSIONS: We developed a dynamic flare prediction model, exclusively based on data typically available in routine care. Our results show that using this model to aid decisions during bDMARD tapering may significantly reduce the number of flares while maintaining most of the bDMARD dose reduction. TRIAL REGISTRATION: The clinical impact of the prediction model is currently under investigation in the PATIO randomized controlled trial (Dutch Trial Register number NL9798).

Changes in macrophage inhibitory factor correlate with changes in bone mineral density in glucocorticoid-treated patients with rheumatoid arthritis.

OBJECTIVES: To investigate whether changes in bone density and turnover are associated with changes in inflammatory mediators in RA patients treated with glucocorticoids (GCs) upon vitamin D treatment in comparison with alendronate treatment. METHODS: RA patients (n = 40) on long-term oral GC treatment received either alfacalcidol or alendronate. At baseline and after 18 months, we measured cytokines capable of antagonizing GCs [macrophage migration inhibitory factor (MIF), IL-13 and IL-7], cytokines causing T-cell differentiation (IL-6, IL-7, IL-12, IL-10 and IL-23) and cytokines produced by effector T cells (IFN-γ, IL-4, IL-17, IL-22). Associations of cytokine profiles with bone markers and BMD changes of the lumbar spine were explored using multiple regression analyses that corrected for study medication and risk factors of osteoporosis (gender, age, cumulative/change in GC dose). RESULTS: Alendronate, unlike alfacalcidol, increased BMD changes in the lumbar spine. Most cytokines were below detection limits. MIF and IL-23 were detectable in almost all samples; neither alfacalcidol nor alendronate significantly influenced serum concentrations of these cytokines. Interestingly, changes in MIF correlated positively with changes in BMD of the lumber spine (Pearson's correlation = 0.31), and in multivariate analysis adjusting for treatment, age and change in GC dose (P = 0.022). CONCLUSION: During GC treatment, changes in the GC-antagonist MIF were positively correlated with changes in BMD, which could mean MIF has bone-protecting capacities in patients suffering from GC-induced bone destruction. Further studies need to validate the importance of these findings.

Palmar Fasciitis and Polyarthritis Syndrome: A Rare Paraneoplastic Syndrome in a Patient With Prostate Carcinoma.

A 73-year-old patient was seen in our hospital for treatment of metastatic adenocarcinoma of the prostate (pT1aN0M1a R0, BRCA-2 gene mutation). Prostatectomy and regional radiotherapy were performed and goserelin, a luteinizing hormone-releasing hormone (LHRH) analog, had been started because of disease progression. Castration-resistant progressive disease developed, and enzalutamide was added. A decrease of the prostate-specific antigen (PSA) level was achieved. Before the start of enzalutamide, the patient developed bilateral pain and stiffness of both hands combined with thickening of the hands. The symptoms progressed rapidly to bilateral flexion and extension contractures. The patient became unable to tie his shoelaces and had to use adjusted cutlery to eat. Consultation of the rheumatologist, X-rays, ultrasound and palmar skin biopsy of the hands were performed. The clinical picture resembles descriptions of "palmar fasciitis and polyarthritis syndrome" (PFPAS), a rare paraneoplastic syndrome. Positive effects of immunosuppressive medication have been reported in some cases. In our patient, treatment with oral prednisone (30 mg daily) showed no effect, therefore treatment was switched to methylprednisone pulses and methotrexate. PFPAS is an uncommon paraneoplastic syndrome characterized by rapid onset of bilateral arthritis of the hands, fasciitis of the palms, progressive stiffness and contractures. The scarcity of knowledge about PFPAS makes it difficult to recognize it at an early stage. As a paraneoplastic syndrome, it has been linked to various malignancies. Thus far, PFPAS has been described in only two other cases of prostate cancer.

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.

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.

Glucocorticoid-targeted therapies for the treatment of rheumatoid arthritis.

INTRODUCTION: The beneficial effects of glucocorticoids are highly regarded in the treatment of inflammatory diseases. In rheumatoid arthritis, these drugs are widely used because they effectively reduce signs and symptoms of the disease, and exert disease-modifying effects. However, both patients and physicians frequently associate glucocorticoids with a variety of adverse effects which hamper adherence. Due to this ambivalent nature of these drugs, several new glucocorticoids or glucocorticoid receptor ligands are being developed, aiming at improving their benefit-risk balance. Areas covered: Focussing on rheumatoid arthritis, we discuss current approaches to achieve this goal, including an optimized application of conventional glucocorticoids and the development of novel formulations aiming at minimizing adverse effects while keeping or even enhancing the anti-inflammatory efficacy. Expert opinion: Glucocorticoids - be it conventional or modified/delayed-release formulations - have so far been convincing in clinical practice, and their widespread use will therefore continue. They are not likely to be replaced by novel drugs in the near future although some investigational preparations are promising, and results obtained from currently ongoing clinical trials in humans are eagerly awaited. As a result of these developmental activities, a further improvement of the benefits-risk balance of glucocorticoids or glucocorticoid receptor ligands is expected.