Rheumatoid arthritis (RA) is a chronic, destructive, inflammatory polyarthritis often accompanied by systemic features. In patients with RA, the disease process results in impairment in carrying out activities of daily living due to inflammation and damage to joints. Eventually, accumulated damage may lead to the need for joint replacement. Furthermore, there is a growing recognition that patients with RA are at increased risk of cardiovascular disease.
Drug therapies for RA include symptomatic therapies and disease modifying antirheumatic drugs (DMARDs). Symptomatic therapies include nonsteroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine, and sulfasalazine. Low dose corticosteroids are often used to control disease activity, but their use is limited by well-known adverse effects. The mechanisms of action of DMARDs are varied and include antimetabolites (such as methotrexate and leflunomide), tumor necrosis factor (TNF) blockers (such as infliximab, etanercept, and adalimumab and, more recently, golimumab and certolizumab), IL-1 blockade (with anakinra), T cell co-stimulation blockade (with abatacept), and B cell depletion (with rituximab). The American College of Rheumatology (ACR) published treatment guidelines in 2008 (38
), recommending that the choice of RA treatment should be based on the presence or absence of features of poor prognosis, the level of disease activity, and the duration of disease. The ACR guidelines recommend nonbiologic DMARDs for patients with low or moderate disease activity. Biologic DMARDs are recommended for patients with persistent high disease activity lasting for 3–6 months or longer, for patients with high disease activity for a shorter time when they have features of poor prognosis, or for patients with high disease activity who are unresponsive to nonbiologic DMARDs. The cost of treatment and the level of insurance coverage are recognized to impact the choice of RA treatment regimens as well.
What Are Biomarkers and How Can They Contribute to Addressing Unresolved Questions in RA Therapy?
Biomarkers are objectively measured biological characteristics that reflect predisposition to disease, disease status, or response to pharmacologic intervention. They have the potential to contribute in several important ways to the treatment of patients with RA. Given the wide array of therapeutic options, biomarkers could be developed to help select the optimal treatment for individual patients. This could represent an important advance over the empiric method for choosing therapies used today. Biomarkers could help distinguish those patients most likely to respond to a particular therapy from those unlikely to respond. For example, a biomarker could be valuable if it could identify patients particularly likely to respond to a TNF blocker or to a B cell depleting agent. There is also precedent for developing biomarkers to identify patients at particularly high risk for developing severe adverse events in response to a particular product to allow clinicians to avoid use of that product or to proceed with extra caution.
Currently, there are a variety of biomarkers in widespread use in routine care of patients with RA and in clinical trials. Useful biomarkers generally reflect some important feature of the pathophysiology of disease. For RA, although the cause of the disease is unknown, there is a growing knowledge of the underlying predisposing factors and the mechanisms that lead to the clinical manifestations. Predisposition to RA is believed to derive from a combination of genetic predisposition and environmental factors. A variety of immunologic and inflammatory mechanisms is known to perpetuate the disease process and to damage tissues. Currently used biomarkers and ones being explored fall into the general categories of genetic biomarkers, imaging biomarkers, and biomarkers related to the immune system and inflammation.
Polymorphisms at several genetic loci have been shown to be associated with RA. Classical genetic studies showed an important association between RA and certain structurally related alleles of the DRB complex of the major histocompatibility complex (MHC) termed the “Shared Epitope.” More recently, genome-wide association studies have confirmed association with the MHC and have identified several new loci based on SNPs. The new genetic loci implicated in predisposition to RA include (39
) the following:
- PTPN22 encoding the protein lymphoid tyrosine phosphatase that has been shown to inhibit T cell activation,
- TRAF1/C5, a susceptibility locus close to the gene encoding complement component C5 and the gene encoding the signaling molecule TNF receptor-associated factor 1
- CD40, encoding a member of the TNF receptor superfamily
- TNFAIP3, encoding TNF, alpha-induced protein 3
- STAT4, encoding signal transducer and activator of transcription 4
- IRF5, encoding interferon regulatory factor 5
- CTLA4, encoding cytotoxic T-lymphocyte antigen 4
Interestingly, a number of these susceptibility loci are not associated with RA only but have also been implicated in other autoimmune diseases. Clearly, the preponderance of genetic loci related to signal transduction reflects something important about the cause of RA and other autoimmune diseases. However, it is important to be aware that the newly identified genetic loci, individually and in the aggregate, only explain a small portion of the heritability of RA, so there remains a great deal more to be learned about genetic susceptibility to RA (39
Genetic biomarkers do not vary over time for an individual; therefore, they would not be useful for assessing the level of disease activity or response to therapy. Rather, their usefulness would likely be as markers of an individual's predisposition to developing disease or as prognostic indicators. They may also permit subsetting of patient populations into patients who respond differentially to different therapies.
Joint imaging is useful for diagnosing RA, in understanding disease status/progression and in predicting prognosis. Plain films (x-rays) of hands and feet are examined to assess whether the disease process has led to erosions of the joint surface and narrowing of the joint space. Clinical trials utilize imaging as a biomarker to assess damage to joints. Erosions and joint space narrowing are assessed by blinded readers and combined in a single score (the total Sharp score) that is used to assess joint damage at baseline and over the course of the trial. Agents active at slowing or halting radiographic progression reduce the increase in Sharp score that occurs during the course of the trial compared to untreated controls. Another imaging modality that may prove useful as a biomarker in clinical trials is magnetic resonance imaging (MRI). MRI is a highly sensitive technique that reveals erosions and inflammation. Efforts are underway to standardize MRI using the RAMRIS scoring system. MRI has shown promise not only in assessing the status of a joint at one point in time but also in determining response to treatments. For example, MRI has been able to demonstrate reduction in inflammation in response to TNF blockade in a very short timeframe (40
). Ultrasound is another imaging modality that may prove utility as a biomarker of RA disease activity and progression.
Since RA is an autoimmune disease characterized by inflammation, markers of immunity and inflammation offer another potential source of useful biomarkers. Biomarkers of immunity include immune cells (circulating levels of B and T cells and specific subsets), autoantibodies, and cytokines. A variety of immune cells is involved in RA progression and initiation, including T cells, B cells, and macrophages. The autoantibodies implicated in RA include rheumatoid factor (RF), which is an antibody to immunoglobulin and anticitrullinated protein antibodies (ACPA). A variety of cytokines is involved in RA pathogenesis, including TNF-alpha, IL-1, IL-6, and others. RF and ACPA are important for diagnosing RA and as predictors of poor prognosis; however, they may not be useful for assessing disease activity or response to therapy since there is no established correlation between the levels of these autoantibodies with disease activity. An emerging area for assessing the state of the immune system in RA and other autoimmune diseases is measurement of gene expression in peripheral blood by microarray analysis. Markers of inflammation include acute phase reactants such as erythrocyte sedimentation rate as well as C-reactive protein, which are well-established biomarkers both in clinical practice and in clinical trials. Other soluble biomarkers that reflect inflammation and tissue damage in joint and bone include collagen degradation products, matrix metalloproteinases, receptor activator of nuclear factor kappa B ligand, and osteoprotegerin. Another marker of inflammation is the measurement of circulating levels of soluble receptors, such as soluble TNF receptor.
Use of Biomarkers in RA Drug Development
Qualification of RA biomarkers Biomarkers can be used in a variety of different ways in clinical trials. They can be used as an early measure of clinical activity or as a guide in drug development to make go/no go decisions. They can be used to determine optimal dosing of a new drug. They can be used to select patients most likely to respond to therapy or to select patients at risk of toxicity. Finally, in select situations, they can be used as surrogate markers to assess efficacy. Whether a particular use of a biomarker in a clinical trial is appropriate depends on whether its level of qualification is adequate for that specific purpose (termed “fitness for use”). For example, use in early decision-making in drug development, such as go–no go decisions, may require only a relatively low level of qualification. Selecting patients for phase 3 clinical trials requires a higher level of evidentiary data. Use of biomarkers as surrogate markers of efficacy in phase 3 trials necessitates the highest level of validation.
RA Biomarkers in Clinical Trials: Some Considerations
For biomarkers to be used in clinical trials, biomarkers should have been standardized and qualified in multicenter experience and shown to reliably correlate with disease status. If a biomarker is intended to be used in prescribing the drug when it is approved, the developer should consult the appropriate FDA center (CDRH or CBER) during development.
Surrogate markers are a subset of biomarkers that have been shown to predict clinical benefit; for example, blood pressure for antihypertensives as a surrogate for strokes and myocardial infarction or viral titers in HIV disease as a surrogate for progression to AIDS or development of opportunistic infections. Therapeutic effects on validated surrogate endpoints can substitute in many situations for clinical endpoints in clinical trials of efficacy. Surrogate endpoints are particularly valuable when (1) they are clearly qualified as outcome measures, such as blood pressure or hypertension trials and viral load for HIV, and when (2) relevant clinical outcomes are not measurable in the timeframe of clinical trials, for example, complete remission/partial remission versus survival for oncology trials and long-term functional outcomes in RA. In the case of serious or life-threatening disease, if a surrogate marker is not fully validated but is considered reasonably likely to predict clinical benefit, then it may be used to assess efficacy under the provisions of accelerated approval. In this case, there is a requirement for studies to validate the surrogate marker postapproval. In the case of RA drug development, the usefulness of biomarkers as surrogate markers of efficacy is not clear since clinical outcome measures are sensitive to drug effects in the time frame of a clinical trial.
Biomarkers may be particularly useful in clinical trials as part of an enrichment design. For example, rather than enrolling all comers, a clinical trial may select patients based on those most likely to response or those most likely to tolerate the drug and can target therapy to those most likely to benefit. Enrichment clinical trial designs could include randomizing patients with a gene signature on microarray that has been demonstrated to be predictive of drug responsiveness or randomizing patients based on a predictive biomarker such as anti-citrullinated protein antibodies (ACPA) status. However, there are some caveats to such enrichment designs. Efficacy observed in enrichment designs may not be generalizable to the whole patient population. If efficacy is only shown in a subset of patients, that might need to be reflected in the drug label. Generally, there should be good evidence that the criteria used for selection represent a clinically meaningful way to categorize patients. Furthermore, if it is likely that patients not belonging to a selected subpopulation will also take the drug, it is important to study the efficacy and safety of the drug in these patients as well. One approach to address issues of generalizability would be to conduct one trial in the enriched population and one in the general population. If qualitatively similar results are seen in the enriched and unenriched populations, this would suggest that the efficacy is not restricted to the selected population.
Biomarkers have the potential to facilitate drug development in RA and other rheumatic diseases. Biomarkers may be useful at various stages of drug development; for example, dose selection, assessment of clinical benefits, and selection of the target population. There are a variety of promising biomarkers that may prove to have utility in RA clinical trials. However, prior to their implementation in clinical trials, biomarkers should undergo an appropriate process to demonstrate that they have been appropriately qualified with regard to their role in clinical trials (“fitness for use”).