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Academic Medical Centre, University of Amsterdam, Amsterdam, The NetherlandsCambridge University, Cambridge, United KingdomUniversity of Ghent, Ghent, BelgiumGlaxoSmithKline Research & Development, Stevenage, United Kingdom
Rheumatoid arthritis is an autoimmune syndrome presenting with chronic inflammation of the joints. Patients with the same diagnosis can present with different phenotypes. In some patients severe joint inflammation and early joint destruction are observed, whereas a milder phenotype can be seen in others. Conversely, patients with the same signs and symptoms may exhibit different immunological and molecular abnormalities. Since the introduction of early treatment in clinical practice, the treat to target principle, and new medicines such as biologic disease-modifying antirheumatic drugs, clinical remission can be achieved early in the disease course, albeit not in all patients. The clinical response and efficacy of biologic disease-modifying antirheumatic drugs vary among different individuals. Therefore, there is a need to develop a more personalized approach toward treatment to achieve rapid remission in every patient to prevent disability and restore and maintain quality of life, without unnecessary adverse effects, in a cost-effective manner. The latest data from explorative studies of predictive markers of response are discussed here, together with a preliminary treatment algorithm based on currently available knowledge.
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Learning Objectives: On completion of this article, you should be able to (1) recognize that rheumatoid arthritis is a heterogeneous disease and the implications for the response to treatment; (2) distinguish between primary and secondary nonresponders to anti–tumor necrosis factor therapy and integrate this knowledge in treatment decisions for patients with rheumatoid arthritis who are inadequate responders to tumor necrosis factor inhibition; and (3) assess baseline characteristics of patients with rheumatoid arthritis that may be predictive of the response to biologic treatment and formulate the implications for a stratified medicine approach.
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In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
Dr Wijbrandts served as an expert consultant to MSD. Dr Tak is an employee and shareholder of GlaxoSmithKline.
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Rheumatoid arthritis (RA) is a chronic systemic immune–mediated inflammatory disease affecting synovial tissue in multiple joints. The diagnosis is made by a combination of clinical signs and symptoms of arthritis together with autoantibody profiling and measurement of the acute phase response. The 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria have been developed for the identification of patients with RA earlier in the disease course, hereby facilitating early initiation of treatment and clinical trials in early RA.
It is important to note that patients with the same diagnosis can present with different signs and symptoms. Patients with rapid radiographic progression characterized by loss of cartilage and bone erosions will experience loss of function in early disease. Extra-articular manifestations such as pleuritis, pericarditis, and formation of rheumatoid nodules can be found in some patients. These extra-articular manifestations have become rare since the introduction of biologic disease-modifying antirheumatic drugs (bDMARDs). There are different immunological and molecular mechanisms involved in different subsets of RA. For instance, patients can be either positive or negative for autoantibodies such as anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF). The presence of ACPA is associated with more rapid joint destruction
Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset.
Heterogeneity has also been shown by studies of the major target of the disease, the synovium. Patients with RA with the same clinical symptoms may have different patterns of synovial cell infiltration,
Interindividual and intra-articular variation of proinflammatory cytokines in patients with rheumatoid arthritis: potential implications for treatment.
Fibroblast-like synoviocytes derived from patients with rheumatoid arthritis show the imprint of synovial tissue heterogeneity: evidence of a link between an increased myofibroblast-like phenotype and high-inflammation synovitis.
The notion that RA is a heterogeneous syndrome rather than a disease entity is also supported by the variability in clinical response to treatment. Biologic disease-modifying antirheumatic drugs that are used in daily clinical practice have diverse modes of action that either inhibit the effects of tumor necrosis factor (TNF; infliximab, adalimumab, etanercept, golimumab, and certolizumab), block the anti-interleukin 6 (IL-6) receptor (tocilizumab), deplete B cells (rituximab), or interfere with T-cell costimulatory signaling (abatacept). In addition to bDMARDs, there are targeted synthetic DMARDs. The first approved targeted synthetic DMARD is the Janus kinase inhibitor tofacitinib. A variable response to targeted treatment has been shown for TNF blocker,
ATTRACT Study Group Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial.
Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed.
Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.
Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis.
REFLEX Trial Group Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.
OPTION Investigators Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial.
On the group level, comparable clinical responses have been observed among different mechanisms of action, but patients who respond to a specific bDMARD are not necessarily the same as those who respond to another.
It will be important to become better at predicting which patients are more likely to respond to a specific mechanism to improve the risk-benefit ratio and cost-effectiveness in individual patients as well as the overall treatment success on the population level (Figure 1).
Clinical improvement after TNF inhibition is observed in approximately 60% to 70% of patients who previously failed conventional synthetic DMARD (csDMARD) treatment such as methotrexate (MTX). This means that 30% to 40% of patients do not respond. At present, no factors have been identified that fully explain or predict response to anti-TNF therapy, but pretreatment differences at baseline between patient groups have been identified.
Potential Synovial and Peripheral Blood Biomarkers Predictive of Clinical Response to Anti-TNF Treatment
A small study (n=8) has suggested that pretreatment increased synovial synthesis of TNF might be related to clinical efficacy.
A study of 143 patients with active RA found increased synovial tissue TNF expression in patients who subsequently exhibited clinical improvement (change in disease activity score in 28 joints [ΔDAS28] ≥1.2 at week 16) after initiation of infliximab treatment compared with those who did not (ΔDAS28 <1.2 at week 16).
The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor alpha expression in the synovium.
In addition, an increased number of synovial macrophages, including CD163+ resident macrophages and myeloid-related protein 8+ (MRP8) and MRP14+ infiltrating macrophages, as well as an increased number of synovial T cells were found in responders compared with nonresponders. Both macrophages and T cells are the main TNF-producing cells in RA synovium. Although differences were observed between groups, no distinct threshold in synovial TNF expression levels could be found differentiating responders from nonresponders to anti-TNF therapy, which is consistent with the clinical experience that the response to anti-TNF therapy is not a dichotomous phenomenon.
Clinical responses to tumor necrosis factor alpha antagonists do not show a bimodal distribution: data from the Stockholm tumor necrosis factor alpha followup registry.
This implies that response is determined by complex multifactorial biologic mechanisms. Multivariate logistic regression analysis of synovial markers revealed that the baseline synovial TNF expression in the synovial sublining explained approximately 10% of the variance in response to therapy. After adjusting for disease activity measured by DAS28 at baseline, this increased to 17%.
The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor alpha expression in the synovium.
Hence, these studies confirm that biomarkers predictive of response to anti-TNF therapy might be identified. Although the predictive value of synovial TNF expression is statistically significant, the effect is overall limited, making it invaluable for personalized health care. In line with these findings, another study found that response to anti-TNF therapy is related to higher TNF bioactivity in peripheral blood.
A subsequent study revealed a highly significant relationship between the presence of synovial lymphocyte aggregates at baseline in the synovium and clinical response to infliximab treatment at 16 weeks (P=.008).
When the presence of synovial lymphocyte aggregates at baseline was added to a combined prediction model with synovial TNF expression, DAS28 at baseline, and presence of ACPA, the explained variance in response increased from 19% to 29%. The positive predictive value (PPV) was 85%, and the negative predictive value (NPV) was 53%.
Other synovial tissue studies using gene array analysis have shown that patients with a pronounced inflammatory gene expression profile at baseline are more likely to exhibit a favorable response to anti-TNF therapy
The notion that synovial tissue analysis may help to predict clinical response on the group level in the context of stratified medicine is supported by a study describing 4 synovial subtypes using gene array analysis in 2 small cohorts of patients with RA of 49 and 20 patients, respectively.
The distinct gene expression signatures were classified as lymphoid, myeloid, low inflammation, and fibroid subtype. Based on our findings, it was hypothesized that patients with the myeloid phenotype, showing overrepresentation of myeloid and TNF-associated gene expression, would exhibit the best response to anti-TNF therapy. This was subsequently tested in an independent cohort of patients with RA.
Expression of the myeloid gene set at baseline was markedly higher in patients with a subsequent good EULAR response than in nonresponders. Based on the synovial subgroup phenotypes, an exploration was performed of possible representative serum biomarkers relating to predominant biological processes. The chosen biomarkers were soluble intercellular adhesion molecule (sICAM) and C-X-C motif chemokine 13 (CXCL13). Serum levels were determined at baseline in 198 serum samples of 326 patients with RA that received either tocilizumab or adalimumab monotherapy
Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial.
Lancet.2013; 381 ([published corrections appear in Lancet. 2013;381(9877):1540. Dosage error in article text and Lancet. 2013;382(9908):1878]): 1541-1550
and related to ACR clinical response at week 24. After looking at independent serum levels, a combination of 2 biomarkers was made by creating 4 groups with high/low, low/high, high/high, or low/low results. The patient subgroup that exhibited the combination sICAMhigh/CXCL13low had the highest clinical response to adalimumab treatment. Conversely, patients who exhibited the combination sICAMlow/CXCL13high had the highest response to tocilizumab.
In accordance with the findings discussed above, no dichotomous phenomenon was found in this study, as the remaining patients in the high/high and low/low subgroups exhibited intermediate ACR50 response rates.
Future work is needed to validate these findings in independent patient groups.
Another study that used transcription profiling of peripheral blood monocytes from patients with RA identified CD11c as a potential biomarker distinguishing at baseline between responders and nonresponders to adalimumab. CD11c is a transmembrane protein on various hematopoietic cells such as monocytes, macrophages, and neutrophils but less frequent on B cells.
CD11c levels were significantly correlated with ACR response, but they were not predictive of response to anti-TNF therapy in patients who concomitantly used MTX, hereby limiting its use as a predictive biomarker because anti-TNF therapy is usually combined with MTX.
A recent study describes the predictive role of serum MRP8/14 complex (calprotectin) levels in the peripheral blood of patients with RA. Myeloid-related protein 8 (S100A8) and MRP14 (S100A9) are endogenous Toll-like receptor 4 ligands that are expressed in granulocytes and monocytes
Serum levels of soluble receptor for advanced glycation end products and of S100 proteins are associated with inflammatory, autoantibody, and classical risk markers of joint and vascular damage in rheumatoid arthritis.
To explore the potentially predictive role as a biomarker of response in RA, serum MRP8/14 levels were measured in a prospective cohort of 170 patients treated with adalimumab (n=86), infliximab (n=60), or rituximab (n=24) (see the Table for an overview of studies of potential predictors).
Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial.
Lancet.2014; 383 ([published correction appears in Lancet. 2014;383(9914):308]): 321-332
The value of rheumatoid factor and anti-citrullinated protein antibodies as predictors of response to infliximab in rheumatoid arthritis: an exploratory study.
GISEA Group Good clinical response, remission, and predictors of remission in rheumatoid arthritis patients treated with tumor necrosis factor-alpha blockers: the GISEA study.
BRAGGSS Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis.
Ann Rheum Dis.2009; 68 ([publsihed correction appears in Ann Rheum Dis. 2011;70(8):1519]): 69-74
Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries.
In rheumatoid arthritis patients treated with tocilizumab, the rate of clinical disease activity index (CDAI) remission at 24 weeks is superior in those with higher titers of IgM-rheumatoid factor at baseline.
Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the ‘Orencia and Rheumatoid Arthritis’ registry.
Brief report: association of rheumatoid factor and anti-citrullinated protein antibody positivity with better effectiveness of abatacept: results from the Pan-European registry analysis.
Anti-cyclic citrullinated protein antibodies as a predictor of response to anti-tumor necrosis factor-alpha therapy in patients with rheumatoid arthritis.
B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: a six-month, national, multicenter, open-label study.
Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial.
Impact of patient and disease characteristics on therapeutic success during adalimumab treatment of patients with rheumatoid arthritis: data from a German noninterventional observational study.
British Society for Rheumatology Biologics Register Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register.
Impact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis: results from the Danish nationwide DANBIO registry.
Gruppo Italiano di Studio sulle Early Arthritis (GISEA) Obesity and reduction of the response rate to anti-tumor necrosis factor α in rheumatoid arthritis: an approach to a personalized medicine.
One hundred twenty-three patients were classified as (good and moderate) responders, and 47 were nonresponders to treatment according to the EULAR response criteria. The levels of MRP8/14 were measured at baseline and weeks 4 and 16 after the initiation of treatment. Responders exhibited significantly higher MRP8/14 protein complex levels at baseline compared with nonresponders in each prospective cohort (P=.010, P=.001, and P<.001, respectively) (Figure 2).
In patients treated with adalimumab, the PPV for response of a high baseline serum MRP8/14 level (cutoff at a median level of 995 ng/mL) was 86%, and the NPV for nonresponse of a low baseline serum MRP8/14 level was 35%, with a sensitivity of 57% and a specificity of 71%. In patients treated with infliximab, the PPV of a high level of serum MRP8/14 (cutoff at a median level of 2027 ng/mL) was 93%, with an NPV of 43%, a sensitivity of 62%, and a specificity of 86%. In patients treated with rituximab, the PPV of high levels (cutoff at a median level of 1665 ng/mL) for predicting response was 92%, with an NPV of predicting nonresponse also being high at 83%, yielding a sensitivity of 85% and a specificity of 91%.
These data indicate that serum MRP8/14 levels were consistently higher in responders to targeted treatment, independent of the specific mechanism of action. In responders to adalimumab and infliximab, at week 4 after the initiation of treatment, serum levels were decreased but they remained stable in nonresponders. Logistic regression analysis revealed that having high MRP8/14 serum levels at baseline increased the odds of being a responder by 3.3 up to 55.
Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial.
Lancet.2014; 383 ([published correction appears in Lancet. 2014;383(9914):308]): 321-332
The value of rheumatoid factor and anti-citrullinated protein antibodies as predictors of response to infliximab in rheumatoid arthritis: an exploratory study.
GISEA Group Good clinical response, remission, and predictors of remission in rheumatoid arthritis patients treated with tumor necrosis factor-alpha blockers: the GISEA study.
BRAGGSS Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis.
Ann Rheum Dis.2009; 68 ([publsihed correction appears in Ann Rheum Dis. 2011;70(8):1519]): 69-74
Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries.
In rheumatoid arthritis patients treated with tocilizumab, the rate of clinical disease activity index (CDAI) remission at 24 weeks is superior in those with higher titers of IgM-rheumatoid factor at baseline.
Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the ‘Orencia and Rheumatoid Arthritis’ registry.
Brief report: association of rheumatoid factor and anti-citrullinated protein antibody positivity with better effectiveness of abatacept: results from the Pan-European registry analysis.
The value of rheumatoid factor and anti-citrullinated protein antibodies as predictors of response to infliximab in rheumatoid arthritis: an exploratory study.
BRAGGSS Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis.
Ann Rheum Dis.2009; 68 ([publsihed correction appears in Ann Rheum Dis. 2011;70(8):1519]): 69-74
The value of rheumatoid factor and anti-citrullinated protein antibodies as predictors of response to infliximab in rheumatoid arthritis: an exploratory study.
BRAGGSS Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis.
Ann Rheum Dis.2009; 68 ([publsihed correction appears in Ann Rheum Dis. 2011;70(8):1519]): 69-74
Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries.
B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: a six-month, national, multicenter, open-label study.
Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial.
Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the ‘Orencia and Rheumatoid Arthritis’ registry.
Brief report: association of rheumatoid factor and anti-citrullinated protein antibody positivity with better effectiveness of abatacept: results from the Pan-European registry analysis.
Impact of patient and disease characteristics on therapeutic success during adalimumab treatment of patients with rheumatoid arthritis: data from a German noninterventional observational study.
British Society for Rheumatology Biologics Register Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register.
British Society for Rheumatology Biologics Register Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register.
Impact of patient and disease characteristics on therapeutic success during adalimumab treatment of patients with rheumatoid arthritis: data from a German noninterventional observational study.
British Society for Rheumatology Biologics Register Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register.
Impact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis: results from the Danish nationwide DANBIO registry.
Gruppo Italiano di Studio sulle Early Arthritis (GISEA) Obesity and reduction of the response rate to anti-tumor necrosis factor α in rheumatoid arthritis: an approach to a personalized medicine.
Gruppo Italiano di Studio sulle Early Arthritis (GISEA) Obesity and reduction of the response rate to anti-tumor necrosis factor α in rheumatoid arthritis: an approach to a personalized medicine.
Figure 2MRP8/14 serum levels predict response to biological treatments in patients with rheumatoid arthritis. The figures show MRP8/14 serum levels in responders versus non-responders to adalimumab (A), infliximab (B) and rituximab (C), respectively. From Ann Rheum Dis. 2015;74(3):499-505, with permission.
A treatment algorithm based on the measurement of MRP8/14 levels together with clinical predictors suggested that this may have predictive potential, although validation is needed in independent cohorts.
A personalized approach to biological therapy using prediction of clinical response based on MRP8/14 serum complex levels in rheumatoid arthritis patients.
Another interesting potential biomarker is C-reactive protein (CRP) levels measured in peripheral blood. The change in the first 3 months of treatment is associated with long-term response. Data from 662 patients treated with infliximab in the open label observational REMARK study indicated that CRP levels decline rapidly within 2 weeks of treatment in all patients, but a rebound in CRP levels was observed at weeks 6 and 14 in nonresponders.
It was however not possible to predict response reliably on the basis of the change in CRP levels during the first 2 weeks. Another study found that the clinical response during the first 3 months of treatment predicts remission (disease activity score in 28 joints including C-reactive protein level [DAS28-CRP] <2.6) and low disease activity (DAS28-CRP <3.2) at 6 months after the initiation of treatment.
Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial.
Lancet.2014; 383 ([published correction appears in Lancet. 2014;383(9914):308]): 321-332
This was investigated in 866 patients with early RA who participated in the Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab (OPTIMA) trial. They were treated with adalimumab with or without MTX. Disease activity score in 28 joints including C-reactive protein level, physician’s global assessment of arthritis, and Health Assessment Questionnaire (HAQ) at week 12 were selected as predictors to calculate the prediction score per individual for clinical response at week 26. The NPV for DAS28-CRP less than 2.6 was 94.61%, and the PPV was 85.19%.
Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial.
Lancet.2014; 383 ([published correction appears in Lancet. 2014;383(9914):308]): 321-332
Several studies have investigated the relationship between the presence of RF and ACPA at baseline on the one hand and the response to anti-TNF treatment on the other, with conflicting results.
The value of rheumatoid factor and anti-citrullinated protein antibodies as predictors of response to infliximab in rheumatoid arthritis: an exploratory study.
GISEA Group Good clinical response, remission, and predictors of remission in rheumatoid arthritis patients treated with tumor necrosis factor-alpha blockers: the GISEA study.
BRAGGSS Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis.
Ann Rheum Dis.2009; 68 ([publsihed correction appears in Ann Rheum Dis. 2011;70(8):1519]): 69-74
Anti-cyclic citrullinated protein antibodies as a predictor of response to anti-tumor necrosis factor-alpha therapy in patients with rheumatoid arthritis.
Taken together, the effect of ACPA and RF status on clinical response to anti-TNF therapy is uncertain with contradictory results in different studies.
Baseline Patient Characteristics as Predictors of Clinical Response to Anti-TNF Treatment
The previous sections described clinical (measures of disease activity) and molecular biomarkers at baseline as well as changes in these variables during the first few months as predictors of subsequent clinical response. There have also been studies of baseline patient characteristics in relationship to clinical response, including sex, age, body mass index (BMI; calculated as the weight in kilograms divided by the height in meters square), smoking, and vagus nerve tone. One study of 2625 patients treated with adalimumab found that improvement in DAS28 at 12 months was significantly greater in male patients than in female patients. The concomitant use of MTX was also a positive predictor of therapeutic response.
Impact of patient and disease characteristics on therapeutic success during adalimumab treatment of patients with rheumatoid arthritis: data from a German noninterventional observational study.
In the same study, previous bDMARD use was a negative predictor of response. Consistent with these findings, another open label trial in 6610 patients treated with adalimumab confirmed male sex and younger age as predictors of minimal disease activity and DAS28 remission (DAS28 <2.6) at week 12. Similarly, concomitant csDMARD use and anti-TNF therapy naivety were predictive of favorable response on the group level.
A positive effect of male sex on clinical response, but no effect of age, was also found in a British registry study of 2879 patients treated with etanercept and infliximab.
British Society for Rheumatology Biologics Register Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register.
Another study of patients treated with infliximab, adalimumab, or etanercept found that in the total study population only 15.2% of patients with BMI greater than 30 kg/m2 achieved remission after 1 year vs 32% of patients with BMI less than 30 kg/m2.
Gruppo Italiano di Studio sulle Early Arthritis (GISEA) Obesity and reduction of the response rate to anti-tumor necrosis factor α in rheumatoid arthritis: an approach to a personalized medicine.
Gruppo Italiano di Studio sulle Early Arthritis (GISEA) Obesity and reduction of the response rate to anti-tumor necrosis factor α in rheumatoid arthritis: an approach to a personalized medicine.
British Society for Rheumatology Biologics Register Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register.
A comparable negative effect of current smoking status on clinical efficacy of anti-TNF therapy was found in a study of 1576 patients with ankylosing spondylitis,
Impact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis: results from the Danish nationwide DANBIO registry.
in which multivariate analyses revealed that current smokers had a lower odds of achieving BASDAI 50%/20-mm response (treatment response by [50% or 20 mm reduction in Bath AS Disease Activity Index]) at 6 months than did never smokers, independent of TNF inhibitor type.
Impact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis: results from the Danish nationwide DANBIO registry.
The effect of the autonomic nervous system on drug response is a research field worth further exploration. A small study of 25 patients with RA and 8 with psoriatic arthritis found that increased parasympathetic tonus determined through measurement of resting heart rate and heart rate variability predicted subsequent ACR response after treatment. Poor response was associated with low parasympathetic measures.
A study evaluating changes in synovial cell populations 4 and 16 weeks after the initiation of rituximab treatment in 24 patients with RA found no baseline synovial characteristics predicting response at week 24.
Sixteen weeks after rituximab treatment, the number of synovial B cells, T cells, and macrophages were decreased. The change in synovial B cells after treatment was not significantly different between response groups. However, with linear regression analysis, the decrease in plasma cells at weeks 4 and 16 was shown to be predictive of the decrease in DAS28 at week 24 and correlated with a reduction in serum ACPA levels. The extent of decrease in plasma cells differed between responders and nonresponders.
Other studies have supported the concept that the clinical effect of rituximab treatment in RA is in part explained by changes in plasma cells (derived from CD20+ B cells) and leads to a subsequent reduction of autoantibody levels.
In a study of patients with RA who failed at least 1 TNF blocker, RF positivity and normal levels of CD19+ B cells together with increased CD19+CD27−IgD− (memory) peripheral blood B cells predicted a better response to rituximab treatment, in particular when all parameters were present.
FIRST/ReFIRST Study Teams Combination of B cell biomarkers as independent predictors of response in patients with rheumatoid arthritis treated with rituximab.
Several studies have shown that patients with RA who are RF and/or ACPA positive are more likely to respond to rituximab treatment than are seronegative patients.
Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries.
B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: a six-month, national, multicenter, open-label study.
Another potential biomarker of response is the presence of a type I interferon (IFN) signature at baseline. Specifically, high IFN response gene expression levels were found in peripheral blood mononuclear cells of nonresponders compared with low baseline expression levels in good responders.
The concomitant use of prednisolone may interfere with IFN gene expression, thereby influencing the predictive value of the type I IFN response as a predictor of the response to rituximab treatment. The predictive value of the type I IFN score was better in patients who did not use prednisolone at baseline, with an area under the receiver operating characteristic curve of 0.975, a sensitivity of 88%, and a specificity of 100%.
Type 1 IFNs may stimulate the production of a proliferation-induced ligand (APRIL) and B-lymphocyte stimulator (BLyS) and directly enhance B cell survival.
As described above, baseline serum MRP8/14 levels were found to be higher in responders than in nonresponders to rituximab treatment. At week 16 after the initiation of treatment, serum levels decreased by 59% in responders, but not in nonresponders.
Data are still limited and need confirmation in a larger independent cohort.
With regard to baseline patient characteristics, 1 study explored the relationship between BMI and response to rituximab treatment and found no predictive effect.
There are limited data on predictors of the response to tocilizumab. A small study of 40 patients with RA described a significant difference in type I IFN response gene expression (IFI6, MX2, and OASL; for expansion of gene symbols, see www.genenames.org) in peripheral blood between nonresponders and responders. Receiver operating characteristic analysis of models incorporating these genes revealed that the maximum area under the curve was 0.947 in predicting a moderate or good response to tocilizumab in the small validation cohort (n=15).
Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis: biomarkers identified by analysis of gene expression in peripheral blood mononuclear cells using genome-wide DNA microarray.
Baseline levels of soluble interleukin-6 receptor predict clinical remission in patients with rheumatoid arthritis treated with tocilizumab: implications for molecular targeted therapy.
Levels of interleukin-1 beta can predict response to tocilizumab therapy in rheumatoid arthritis: the PETITE (predictors of effectiveness of tocilizumab therapy) study.
All these studies need to be confirmed in independent cohorts.
In a relatively large study of 530 patients with RA, low HAQ score, high DAS28, and absence of concomitant prednisolone use at baseline were predictive of a good and moderate EULAR response to tocilizumab. In multivariate analyses, predictors of discontinuation of treatment were low baseline levels of CRP, high HAQ score, and previous exposure to different biologic agents.
In a multicenter observational study of 126 patients with RA who failed previous bDMARD therapy, the predictors of achieving DAS28-erythrocyte sedimentation rate (ESR) remission at 3 months were baseline ESR greater than 30 mm/h, CRP level greater than 10 mg/L, and the presence of extra-articular disease manifestations. In contrast, a lower likelihood of achieving DAS28 remission was associated with higher baseline hemoglobin concentrations, higher baseline DAS28-ESR, and the number of previous DMARDs and biological therapies used.
Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA).
In contrast, a relatively small study of 58 patients suggested an association between high IgM-RF titers and clinical disease activity index remission at week 24.
In rheumatoid arthritis patients treated with tocilizumab, the rate of clinical disease activity index (CDAI) remission at 24 weeks is superior in those with higher titers of IgM-rheumatoid factor at baseline.
There are only a few studies exploring biomarkers predictive of response to abatacept. A study of 71 patients using multivariate logistic regression suggested that a lower proportion of terminally differentiated effect or memory cells among total CD8+ T lymphocytes at baseline are predictive of treatment discontinuation (28 patients discontinued treatment because of lack of efficacy and 7 because of adverse events).
Receiver operating characteristic analysis revealed a statistically significant performance of this biomarker for prediction of therapy discontinuation (area under the curve, 0.760±0.07; P=.002). Another study evaluated peripheral blood CD28− T-cell subsets at baseline in 32 patients. Patients with low baseline numbers of CD8+CD28− T cells had a more than 4-fold higher probability of achieving remission within 6 months compared with patients with higher levels of this subset of T cells.
Although these studies are of interest, the findings need to be confirmed in independent patient populations.
A study of 318 patients revealed that patients with the highest IgG-ACPA levels (measured using the anti–cyclic citrullinated peptide test) at baseline found significantly greater clinical improvement in DAS28-CRP after abatacept treatment (but not after adalimumab treatment) than did patients with lower ACPA levels, although ACPA-negative patients could still respond to abatacept.
Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial.
Consistent with these findings, a cohort study of 733 patients found that after correction for disease activity, the proportion of anti–cyclic citrullinated peptide-positive patients was higher in responders than in nonresponders, which was not found for RF-positive status at baseline.
Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the ‘Orencia and Rheumatoid Arthritis’ registry.
Brief report: association of rheumatoid factor and anti-citrullinated protein antibody positivity with better effectiveness of abatacept: results from the Pan-European registry analysis.
The predictive value of ACPA status has, however, not been confirmed in all studies. A recent article describing pooled data from 9 international registries (2942 patients) reported no relationship between ACPA status at baseline and EULAR response rates after 1 year.
Brief report: association of rheumatoid factor and anti-citrullinated protein antibody positivity with better effectiveness of abatacept: results from the Pan-European registry analysis.
Taken together, it is unlikely that autoantibody status can be used as a predictor of response to abatacept treatment.
Predictors of Response to Tofacitinib Treatment
A small randomized controlled trial of tofacitinib treatment in 29 patients with RA with inadequate response to MTX found a statistically significant correlation between changes in synovial phosphorylation of signal transducer and activator of transcription 3 and clinical response after 4 months of treatment.
A recent study of 1239 participants found that patients with the IFNGrs2069705C allele had a significantly better response to TNF blocking therapy than did those carrying the wild-type allele.
Genetic variants within immune-modulating genes influence the risk of developing rheumatoid arthritis and anti-TNF drug response: a two-stage case-control study.
As another example, various transforming growth factor β1 single nucleotide polymorphisms SNPs were associated with a good response to rituximab treatment.
Two studies have suggested a potential role for BAFF gene 871C>T promoter polymorphism and the 158 V/F polymorphism of FcGR3A in prediction of response to rituximab treatment.
Data from genomic studies have, however, been inconclusive: different studies have reported different associations, and it has often been difficult to reproduce identified gene loci in independent cohorts.
Lack of validation of genetic variants associated with anti-tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis.
This could in part be explained by variability in study populations based on, for instance, ethnicity and concomitant or previous drug use as well as by differences in methodology. Furthermore, the effect of genotype on clinical response to targeted treatment in complex disorders may be limited.
Role of Antidrug Antibodies
It is important to distinguish between primary nonresponse and secondary nonresponse, as the underlying mechanisms may be completely different. Primary nonresponse can be defined as a lack of clinical improvement within the first 12 to 16 weeks of treatment.
Secondary nonresponse can be defined as a decrease or loss of response after initial improvement after the initiation of treatment, which can be explained by the formation of antidrug antibodies
or counterregulatory mechanisms driving inflammation. Antidrug antibodies were detected in 43% of patients with RA within the first year of infliximab treatment (86% of patients used concomitant MTX). Patients with antidrug antibodies were less often classified as responders.
Antidrug antibodies are not only formed against chimeric antibodies such as infliximab. In patients treated with the humanized monoclonal TNF blocker adalimumab, 17% of patients formed antidrug antibodies within 28 weeks of the initiation of treatment, of whom 79% used concomitant MTX.
After follow-up of 3 years, the presence of antidrug antibodies was associated with lower drug levels and a lower likelihood of remission or low disease activity.
Although antidrug antibody formation may explain secondary nonresponse unrelated to the mechanism of disease in an individual patient, primary nonresponse to TNF inhibition may be explained by relatively less TNF-dependent disease. Clinical response to a second TNF blocker is diminished on the group level as compared with response to a first TNF blocker, which can be explained by the subgroup of patients with less TNF-dependent disease that failed the first TNF inhibitor and subsequently also the second one.
Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a tumour necrosis factor inhibitor: a systematic review and economic evaluation.
Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study.
However, clinical response to a second TNF blocker is not decreased in patients who exhibited secondary nonresponse due to antidrug antibody formation.
Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study.
Patients who failed adalimumab or infliximab treatment associated with detectable antidrug antibodies had a similar response after switching to etanercept as compared with patients who were TNF blocker naïve. However, patients who failed adalimumab or infliximab without detectable antidrug antibodies had a diminished response to a second TNF blocker.
Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study.
These data are consistent with other studies, indicating that the clinical response to a second or third TNF blocker is generally diminished in nonresponders to a first TNF blocker.
Taken together, primary nonresponse to anti-TNF therapy may be due to a mechanism other than TNF bioactivity driving the underlying inflammatory process, reducing the likelihood of response to a second TNF blocker. Secondary nonresponse may in part be explained by antidrug antibody formation.
Thus, measurement of antidrug antibodies may help to predict which patient may benefit from switching to a second TNF blocker vs a different mechanism of action as part of a personalized medicine strategy.
Personalized Treatment Algorithm for the Use of Biologic Agents
In patients with RA who have failed 1 or a combination of csDMARDs together with low-dose glucocorticoids, biologic treatment may be indicated. According to the EULAR recommendations from 2013, first choice biologic agents in patients who have failed csDMARDs are TNF blockers, abatacept, and tocilizumab.
TNF blockers are often prescribed as first bDMARDs because these drugs have been on the market for a long time. Later studies have shown early and sustained remission with abatacept and tocilizumab as well when used as first bDMARDs.
Sustained disease remission and inhibition of radiographic progression in methotrexate-naive patients with rheumatoid arthritis and poor prognostic factors treated with abatacept: 2-year outcomes.
If there is lack of clinical response to a TNF blocker, one could choose a second TNF blocker (in the case of secondary nonresponse), abatacept, tocilizumab, rituximab, or tofacitinib (in the United States). The decision as to which biologic agent to select may be influenced by patient factors such as the risk of chronic infections (such as tuberculosis) and the possibility to use concomitant MTX. For instance, tocilizumab is the only bDMARD that was shown to be equally effective when used as monotherapy compared with combination therapy with MTX.
At present, no biomarkers are known that can predict response to any biologic DMARD in an individual patient with a high level of certainty. However, clinical response may be enriched on the group level in the context of stratified medicine. When switching to a second bDMARD after failing a first TNF blocker, it is relevant to distinguish between primary and secondary nonresponders, as discussed above (Figure 3). Primary nonresponders are less likely to respond to a second TNF blocker, as they have less TNF-dependent disease. If after an initial response to TNF blocking therapy the disease flares again because of antidrug antibody formation, one could try a second TNF inhibitor or a different mechanism of action. As discussed above, autoantibody-positive patients are more likely to respond to rituximab treatment than are autoantibody-negative patients. Thus, it would make more sense to treat an autoantibody-negative patient with tocilizumab or abatacept than with rituximab if a patient has failed treatment with a TNF inhibitor and a decision has been made to treat with a different mechanism of action (Figure 3). It can be anticipated that combinations of clinical and new molecular biomarkers will be used in the future to improve the prediction of response to treatment and move from stratified medicine on the group level to precision medicine in individual patients. Clearly, it would be best to identify biomarkers that can be used at baseline before the patient has received treatment. However, a second best and still valuable approach would be to predict the likelihood of remission after prolonged treatment on the basis of the initial response during the first few weeks of treatment. This would allow more rapid cycling of treatments until the patient gets the therapy with the best chance of success of achieving disease remission and protection against progressive joint destruction.
Figure 3Preliminary treatment algorithm, adapted from Rheumatology (Oxford). 2012;51(4):600-609, with permission.
∗Abatacept and tocilizumab can also be selected as first biologic disease-modifying antirheumatic drug. Rituximab initial non-responders switch to different mechanism of action. ∗∗ JAK inhibitor recommended for use after failure of biologic disease-modifying antirheumatic drugs.
Several studies have been performed to identify predictors of response to biologic therapy, but the clinical relevance is still limited to personalized therapy in daily practice (see the Table for overview). Various potential biomarkers still need confirmation in independent studies. Large randomized controlled switch studies are underway that may help to further improve recommendations for personalized treatment. There are, however, already biomarkers that help distinguish between responders and nonresponders on the group level. This has formed the basis for a preliminary treatment algorithm that may assist treatment decisions for patients who failed a first TNF blocker (Figure 3). This algorithm needs to evolve over time, when new data become available.
A personalized approach to biological therapy using prediction of clinical response based on MRP8/14 serum complex levels in rheumatoid arthritis patients.
The development of better personalized treatment algorithms will be important to further improve the risk-benefit ratio as well as cost-effectiveness of biologic treatments.
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Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries.
In rheumatoid arthritis patients treated with tocilizumab, the rate of clinical disease activity index (CDAI) remission at 24 weeks is superior in those with higher titers of IgM-rheumatoid factor at baseline.
Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the ‘Orencia and Rheumatoid Arthritis’ registry.
Brief report: association of rheumatoid factor and anti-citrullinated protein antibody positivity with better effectiveness of abatacept: results from the Pan-European registry analysis.
Anti-cyclic citrullinated protein antibodies as a predictor of response to anti-tumor necrosis factor-alpha therapy in patients with rheumatoid arthritis.
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Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis: biomarkers identified by analysis of gene expression in peripheral blood mononuclear cells using genome-wide DNA microarray.
Baseline levels of soluble interleukin-6 receptor predict clinical remission in patients with rheumatoid arthritis treated with tocilizumab: implications for molecular targeted therapy.
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Genetic variants within immune-modulating genes influence the risk of developing rheumatoid arthritis and anti-TNF drug response: a two-stage case-control study.
Lack of validation of genetic variants associated with anti-tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis.
Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a tumour necrosis factor inhibitor: a systematic review and economic evaluation.
Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study.
Sustained disease remission and inhibition of radiographic progression in methotrexate-naive patients with rheumatoid arthritis and poor prognostic factors treated with abatacept: 2-year outcomes.
Potential Competing Interests: Dr Wijbrandts served as an expert consultant to MSD. Dr Tak is an employee and shareholder of GlaxoSmithKline.
Individual reprints of this article and a bound reprint of the entire Symposium on Precision Medicine will be available for purchase from our website www.mayoclinicproceedings.org.
The Symposium on Precision Medicine will continue in an upcoming issue.
= no effect on response; 
= positive effect on response; 
= negative effect on response; ACPA = anti-citrullinated protein antibody; ADA = adalimumab; BMI = body mass index; CCP = cyclic citrullinated peptide; CRP = C-reactive protein; DMARD = disease-modifying antirheumatic drug; ETN = etanercept; IFN = interferon; IFX = infliximab; MRP8/14 = myeloid-related proteins 8 and 14; PB = peripheral blood; RF = rheumatoid factor; t = baseline; TNF = tumor necrosis factor.
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