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Guest Commentary: Defeating lupus starts with a diagnosis
October 2015
EDIT CONNECT
SHARING OPTIONS:
Autoimmune diseases are more widespread than many might appreciate: systemic lupus erythematosus (SLE) for
example, affects as many as five million people worldwide1, yet remains without any significant therapeutic options. The underlying cause of SLE
is yet to be deciphered, but it is known that B cells play a central role in its pathogenesis, which includes antibody-dependent and antibody-independent
mechanisms, such as the presentation of autoantigens, T cells and the production of proinflammatory and regulatory cytokines2. High circulating
levels of autoantibodies that are reactive with DNA/RNA molecular complexes, and the deposition of such autoantibody-immune complexes, can induce the
activation of dendritic cells, which can promote the progression of SLE and organ damage3. Symptoms can vary between patients, yet the vast
majority of those living with SLE have to cope with joint pain and swelling, leading to arthritis in many cases. More severe symptoms can affect the brain
and nervous system, kidneys, digestive tract, vascular system and internal organs.
One of the challenges at the
heart of tackling this disease is the intense difficulty associated with reaching an accurate diagnosis early in the disease. This is due to the first
symptoms of SLE often overlapping with other rheumatic diseases or resembling other disorders and infectious diseases. While R&D in the pharmaceutical
industry has continued despite this highly diverse disease presentation, approval for novel medicines for SLE has lagged behind that of other autoimmune
diseases such as rheumatoid arthritis (RA). In fact, the FDA has approved only one novel treatment for SLE in the past 50 years (Benlysta). This isn’t
due to any sort of relaxed approach to R&D, but rather a collection of hurdles in front of the developers:
The heterogeneity amongst SLE patients is a major
obstacle for pharmaceutical development and remains something that the industry needs to overcome before work on identifying effective and curative therapies
will succeed. Clearly, there is a need for new technologies and biomarkers that allow for the definition of more homogeneous subgroups of SLE patients who
are more likely to respond to a new treatment. Using the full power of biomarkers for SLE patient stratification and treatment response prediction should
therefore prove essential for efficient clinical development and regulatory approval.
The diagnostic
gap
Existing diagnostics (Dx) for SLE are somewhat limited, lacking a highly sensitive but disease-
specific test. The detection of antinuclear antibody (ANAs) staining patterns in patient blood using immunofluorescence microscopy is the most commonly
applied starting point. The problem with these tests lies in their relatively low degree of specificity. ANA tests, for example, will produce a positive
result in approximately 98 percent of SLE patients. While this may seem like a highly promising test, approximately 20 percent of healthy individuals also
receive the same positive result6,7. Therefore, despite ANAs having an excellent level of sensitivity for SLE, the conversely low degree of
specificity makes using ANAs in isolation suboptimal due to the risk of overdiagnosis, or even misdiagnosis8,9.
An alternative to ANA tests are anti-extractable nuclear antigen (ENA) antibody tests and anti-double-stranded DNA (anti-dsDNA) antibody tests,
which are also established criteria of the American College of Rheumatologists’ (ACR) SLE classification. Anti-dsDNA antibodies are found in up to 70
percent of SLE patients at some point during the course of the disease—even prior to the onset of clinical symptoms10. However, anti-dsDNA
titres tend to fluctuate in SLE patients11, and today’s commercial tests differ in their sensitivity and specificity in detecting
SLE.
The anti-cyclic citrullinated peptide (CCP) antibody, an established marker in the diagnosis and
prognostication of RA, can also be useful in SLE patients. SLE patients occasionally develop an erosive arthritis similar to that of RA. Recent research has
shown that the anti-CCP antibody can be employed as a highly specific marker of erosive arthritis in SLE12.
Throwing the diagnostic kitchen sink at SLE
To help overcome the deficits in existing
methods, an array approach is preferable. This makes it possible to combine the strengths of individual tests while mitigating some of their known
weaknesses. Together, it becomes possible to build up an accurate composite picture of the type of SLE and even disease severity in a patient. Lupus
nephritis, for example, is associated with particular levels of anti-C1q and anti-dsDNA antibodies that tend to precede flare-ups of disease activity. Anti-
U1-RNP autoantibodies are associated with Raynaud’s phenomenon and a reduced probability of nephritis. Autoantibody profiles like these make it
possible to diagnose or even predict SLE-associated organ damage.
Disease activity and severity can be similarly
determined by assessing distinct autoantibody profiles that are characteristic of different aspects of the disease (e.g. combined anti-Ro/La
antibodies are associated with secondary Sjögren’s syndrome (SjS) and photosensitivity, but a lower risk of nephritis).
A suite of autoantibody assays that extend traditional Dx, such as anti-dsDNA tests, offers clinicians the ability to define
subgroups of SLE patients. The recently developed SLE stratification array (NavigAID SLE, from Protagen) distinguishes between four main groups of SLE patients. Groups range from a highly reactive patient group who have a high disease activity
score and possess broad and homogenous positive autoantibody reactivity, through to a smaller group of patients who have comparatively low levels of
autoantibody reactivity. These distinct groups were defined via the analysis of over 1,000 SLE patient samples with different disease states and ethnicities.
This has generated a distinct collection of SLE-specific autoantibody profiles that provide the framework for future diagnostic research into not only SLE,
but autoimmune diseases in a much broader sense.
Early steps toward better Dx and better
treatment
With these diagnostic foundations in place, there is now the capacity to begin implementing
array techniques that enable accurate diagnoses of SLE patients and the prediction of an individual’s disease state and severity. The subgroups of SLE
patients generated from autoantibody profiles raise the possibility of defining different SLE immunotypes, and thus the rationale for assigning patients to
certain therapies. Such a therapeutic response prediction can be beneficial to the subsequent development of companion diagnostics (CDx). It is hoped that
pharmaceutical companies will eventually begin to align CDx development with clinical programs for SLE treatment, allowing those trials to benefit from the
highly relevant patient stratification. Implementation of CDx combats the “one-size-fits-all” approach to drugs used in the treatment of
autoimmune diseases, and form part of a market that has already been identified as having significant potential for revenue generation. In addition to
patient health and possible financial benefits, a drug-CDx co-development model during clinical trials could result in the earlier identification of possible
side effects, a shortening of overall trial lengths, improved success rates to reach the patient and numerous improvements to drug efficacy and
safety.
For now, diagnostic arrays facilitate highly useful definitions of homogenous groups of SLE patients. Such
Dx allow for accurate diagnoses, patient stratification, response prediction and potentially form the basis of autoimmune CDx.
Petra Budde is head of medical research at Protagen, with responsibility for both leading the SLE biomarker development program and commercial projects. She has 15 years of experience in proteomics biomarker research in the field of diabetes and autoimmune diseases. Peter Schulz-Knappe
joined Protagen in 2010 as chief scientific officer. He has a strong scientific background, having trained as a medical doctor before working as a cell
biologist, and brings over 25 years of protein and peptide biochemistry experience, coupled with biomarker discovery and development expertise. He has more
than 15 years of management experience in R&D.
References
1 The Lupus Foundation of America, “What is lupus?,”
2015. [Online]. Available: http://www.lupus.org/answers/entry/what-is-lupus.
2 V. S.-F. Chan, H. H.-L.
Tsang, R. C.-Y. Tam, L. Lu, and C.-S. Lau, “B-cell-targeted therapies in systemic lupus erythematosus,” Cell. Mol. Immunol., vol. 10,
no. 2, pp. 133–142, 2013.
3 I. Sanz and F. E.-H. Lee, “B cells as therapeutic targets in
SLE.,” Nat. Rev. Rheumatol., vol. 6, no. 6, pp. 326–337, 2010.
4 A. T. Borchers,
S. M. Naguwa, Y. Shoenfeld, and M. E. Gershwin, “The geoepidemiology of systemic lupus erythematosus,” Autoimmunity Reviews, vol. 9, no.
5. 2010.
5 M. C. Pike and L. Kelley, “Data quality challenges in systemic lupus erythematosus
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6 M. Mahler and M. J. Fritzler, “The clinical significance of the dense fine speckled immunofluorescence pattern on HEp-2 cells for
the diagnosis of systemic autoimmune diseases,” Clin. Dev. Immunol., vol. 2012, 2012.
7
A. Watanabe, M. Kodera, K. Sugiura, T. Usuda, E. M. Tan, Y. Takasaki, Y. Tomita, and Y. Muro, “Anti-DFS70 Antibodies in 597 Healthy Hospital
Workers,” Arthritis Rheum., vol. 50, no. 3, pp. 892–900, 2004.
8 S. Narain, H. B.
Richards, M. Satoh, M. Sarmiento, R. Davidson, J. Shuster, E. Sobel, P. Hahn, and W. H. Reeves, “Diagnostic accuracy for lupus and other systemic
autoimmune diseases in the community setting,” Arch. Intern. Med., vol. 164, no. 22, pp. 2435–41, 2004.
9 C.-C. Liu, A. H. Kao, S. Manzi, and J. M. Ahearn, “Biomarkers in systemic lupus erythematosus: challenges and prospects for
the future.,” Ther. Adv. Musculoskelet. Dis., vol. 5, no. 4, pp. 210–33, 2013.
10
M. R. Arbuckle, M. T. McClain, M. V Rubertone, R. H. Scofield, G. J. Dennis, J. A. James, and J. B. Harley, “Development of autoantibodies before
the clinical onset of systemic lupus erythematosus.,” N. Engl. J. Med., vol. 349, no. 16, pp. 1526–1533, 2003.
11 J. J. Manson and A. Rahman, “Systemic lupus erythematosus.,” Orphanet J. Rare Dis., vol.
1, p. 6, 2006.
12 A. Budhram, R. Chu, S. Rusta-Sallehy, G. Ioannidis, J. Denburg, J. Adachi, and D.
Haaland, “Anti-cyclic citrullinated peptide antibody as a marker of erosive arthritis in patients with systemic lupus erythematosus: a systematic
review and meta-analysis.,” Lupus, 2014.
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