Biomarkers Signal the Next Horizon in Rheumatology

Issue: July 2016

I predict a generation from now rheumatology will look back and recognize the extreme discord we are experiencing in the management of patients with rheumatic diseases. On the one hand, we have a remarkable pipeline of rationally designed biologic therapeutics capable of profoundly altering the course of diseases that were untreatable a generation before us. On the other hand, we still flounder in the search for reliable biomarkers capable of pre-disease diagnosis, prediction of response to therapies, reliable identification of complication risks from therapies and monitoring of the systemic nature of multisystem diseases.

I often think of the famous portrait of Dr. William Glysson by Winthrop Chandler. In the painting, Gylsson carefully monitors the pulse of a female patient — her hand and wrist are exposed, but the rest of her body is hidden by a curtain. Think about a rheumatology practitioner performing a Clinical Disease Activity Index, asking a patient with rheumatoid arthritis (RA) how she feels and then pinching her around her body (okay, over 28 joints). Just as with Dr. Glysson’s patient, the true story of what is going on with our patients remains largely “hidden” even to this day. While the validated composite measures we now use have served us well, these have many well-known shortcomings. This serves to remind us we surely can and must do better in the future.

Need for Biomarkers

Biomarkers are not just laboratory tests, but features or characteristics (patient-reported outcomes, laboratory tests, genes and imaging among others) that correlate with the essential features of a disease and are utilized in diagnosis, prognosis, therapeutic monitoring and more. Clearly among the pressing needs in rheumatology now is the ability to identify patients with autoimmune diseases in their “preclinical phase,” when there may be no signs or symptoms, especially for conditions such as RA or systemic lupus erythematosus (SLE). There is also a need to have biomarkers of clinically significant effective size to help guide therapy in terms of drug initiation and discontinuation/reduction. For so many rheumatic diseases, we need biomarkers to help parse signs and symptoms derived from active immune-mediated disease vs. symptoms that emanate from tissue damage. If you think renal disease in SLE and vasculitis, then you need no further reminder.

So, where are we now and where do we go? For RA, all rheumatology providers use an array of biomarkers every day, including laboratory tests such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). However, they are thwarted when the patient with no joint swelling and normal acute phase reactants is in agonizing pain. Of course, we recognize this fairly well and immediately discount such symptoms when patients have intercurrent mood disorders and central pain sensitization. In other words, we “get it” when the biomarkers are in opposition to our patients’ complaints and our common sense.

But do we really “get it” 100% of the time? I have been surprised when a patient with seronegative RA, normal acute phase reactants and depression and/or fibromyalgia is found to have serious joint disease that requires treatment and even surgery. Toward the goal of building a better mousetrap has been the development of several candidate biomarkers including imaging tests, such as ultrasound and MRI, and laboratory tests, such as 14-3-3 proteins and multi-biomarker disease activity (MBDA) scores. These tests have worked well in some settings, such as diagnosis, prognosis and drug de-escalation, but have not behaved in a uniform fashion in all settings, thus raising the question of how such tests should be used going forward.

I believe no single biomarker, including the “gold standard” composite indices, which I use every day, or the CRP, ESR or MBDA tests I order, can alone give me a clarion view of all my patients with RA every day and on every occasion. I tell my residents and fellows we are confronted by a mosaic and we have no highly efficient binary marker for now. Hopefully, this means we are still needed for some time to come and technology is not ready to replace us yet.

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To glimpse the future, consider these facts about biomarkers:

Clinicians have been thwarted for years when trying to find a clinically meaningful correlation between anti-neutrophil cytoplasmic antibodies (ANCA) and disease activity in vasculitis that is supported by clinical trial results. A recent study using epitope excision/mass spectroscopy has identified that our previously ANCA-negative patients for myeloperoxidase are actually not. New insights into the autoantibodies in health and disease are now moving us ahead.
New technologies, such as large-scale sequencing of antibody repertoires and mass cytometry analysis of blood and tissues combined with advanced data analysis, provide the potential to uncover biomarkers for true precision medicine.

Keep an Open Mind

I am reminded of my personal experience in the world of HIV medicine several decades ago when this new test “HIV viral load” was introduced. I bristled at the technology and was buoyed by the criticism of many key opinion leaders at the time who said and believed they did not need another test to tell them how their patient was doing for they had the reliable CD4 count and global assessments. Times have changed. We now no longer do “tombstone trials” in HIV because we monitor viral loads as primary endpoints. Recent calls have even suggested routine monitoring of CD4 cells counts in practice is unnecessary.

In 1849, the famous French critic Jean-Baptiste Alphonse Karr said “plus ça change, plus c’est la meme chose” – “the more things change, the more they remain the same.” To me, this means one needs to keep an open mind and look for better biomarkers or a picture of you pinching patients may just hang in a museum one day.

I look forward to receiving your comments at calabrl@ccf.org or on Twitter@LCalabreseDO.

For more information:

Leonard H. Calabrese, DO, is the Chief Medical Editor, Healio Rheumatology, and Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic.

Disclosure: Calabrese reports he is a consultant for Genentech, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, Sanofi, Jansen and AbbVie; and is on the speakers bureau for Genentech, AbbVie and Bristol-Myers Squibb and Crescendo Bioscience.