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  • Review Article
  • Open Access

Detection of autoantibodies in a point-of-care rheumatology setting

  • 1Email author,
  • 2 and
  • 3
Autoimmunity Highlights20134:52

https://doi.org/10.1007/s13317-013-0052-9

  • Received: 28 January 2013
  • Accepted: 2 May 2013
  • Published:

Abstract

Autoimmune rheumatic diseases are common and confront society with serious medical, social, and financial burdens imposed by their debilitating nature. Many autoimmune diseases are associated with a particular set of autoantibodies, which have emerged as highly useful to define and classify disease, predict flares, or monitor efficacy of therapy. However, current practice for monitoring autoantibodies is protracted, labor-intensive, and expensive. This review provides an overview on the value of point-of-care (POC) biosensor technology in the diagnosis and management of patients with autoimmune rheumatic diseases. Real-time measurement of autoantibodies will clearly benefit the rheumatology practice in emergency and urgent care settings, where definitive diagnosis is essential for initiation of correct critical care therapy. Immediate serological information in clinic will provide considerable value for long-term patient care and an opportunity for an instant, result-deduced therapeutic action, avoiding delays and improving compliance, especially in field-based and remote areas. We describe the particular autoantibodies that are useful disease and activity markers and would, therefore, be attractive to POC applications. Already existing biosensors and platforms that show promise for autoantibody testing are summarized and comparatively evaluated. As POC assessment is gaining momentum in several areas of patient care, we propose that rheumatology is poised to benefit from this innovative and affordable technology.

Keywords

  • Point-of-care (POC) testing
  • Autoantibodies
  • Autoimmunity
  • Rheumatic diseases

Autoimmune rheumatic diseases afflict 2–3 % of the population [1] and create enormous burden on individuals and society due to poor quality of life and lower productivity [2]. This heterogeneous group of clinical conditions are typically linked by the presence of autoantibodies directed against self-constituents. Often, serum autoantibodies are the only objective serological markers for an underlying rheumatic disease and as such, are part of classification criteria developed to provide a common language for diagnosis, monitoring, therapeutic trials, and international publications. While patient history and physical examination are the cornerstone of the differential diagnosis, current practice analysis shows that most clinicians readily act only after receiving confirmatory or exclusionary laboratory test results [3, 4].

Traditionally, the consultative and diagnostic services in rheumatology are not considered clinical emergencies that would require same-day diagnostic or clinical decisions. While this may hold true for chronic and non-inflammatory conditions, it should also be recognized that most inflammatory and autoimmune conditions that constitute a major part of academic or private rheumatology practice have to be diagnosed and acted upon quickly to curb irreversible immune-mediated damage and mortality. This is especially true for patients whose management includes critical care and aggressive therapy after diagnosis. Currently, it is necessary to use the services of centralized laboratories to obtain this information, which can delay diagnosis and appropriate treatment.

It has been estimated that 10–25 % of all patients with rheumatologic disorders visiting the emergency departments require hospital admission, and up to one-third of the hospitalized patients need intensive care [5, 6]. These emergencies may present as a rapidly evolving and confusing multisystem organ failure, can mimic other conditions or initially mislead with deceptively benign clinical signs. High level of suspicion, clinical knowledge, and detection of circulating autoantibody markers contribute significantly to a timely diagnosis. Table 1 summarizes the use of specific autoantibody testing for the diagnostic process in acute clinical settings. Test selection and interpretation of results is often dependent on the observed clinical complexity, but a characteristic combination of particular clinical and timely laboratory features help to refine the pretest assessment of disease probability. Both positive and negative predictive values of a test result may be useful. For example, a patient visiting the ER with extensive palpable purpura may trigger suspicion of systemic vasculitis, which could be directly supported by a positive ANCA test. Unfortunately, laboratory tests for autoimmune disorders require significant processing time; most autoimmune serology tests performed in reference laboratories take at least several days. Turnaround times for tests ordered by practices in remote or outreach clinics are longer, as much as 7 days.
Table 1

Autoimmune serology assessment for possible rheumatic disease in emergency settings

Symptom

Positive test result

Disease

Airway problems

 Hemoptysis

Anti-dsDNA, other lupus serologies

Alveolar hemorrhage in SLE

 Airflow obstruction

Anti-CCP, RF

Cricoarytenoid arthritis in rheumatoid arthritis (RA)

 Mucopurulent rhinorrhea; subglottic stenosis; hypopharyngeal ulcerations

Anti-neutrophil cytoplasmic antibodies (ANCA, MPO or PR3)

Wegener’s granulomatosis

 Stridor, laryngotracheal strictures

Anti-type II collagen

Relapsing polychondritis

 Acute pneumonitis

Anti-dsDNA, other lupus serologies

SLE

Pulmonary–renal problems

 Pulmonary hemorrhage and acute renal failure

Anti-GBM, MPO-ANCA, PR3-ANCA

Goodpasture’s syndrome; systemic vasculitis

Neuropsychiatric problems

 Encephalopathy, psychosis, focal central nervous system disease

Anti-N-methyl-d-aspartate receptor (NMDA-R), anti-ribosomal P antibodies, antiphospholipid antibodies

Neuropsychiatric SLE, antiphospholipid syndrome

 Weakness, paralysis, bilateral sensory deficit, impaired sphincter control

Lupus serologies

Transverse myelitis in SLE

 Seizures

Anti-dsDNA, other lupus serologies

Lupus cerebritis

Thromboembolic problems

 DVT, pulmonary thromboembolism, fetal loss, retinal artery occlusion

Anti-phospholipid antibodies

Antiphospholipid syndrome

Neuromuscular problems

 Progressive symmetric muscle weakness; dysphagia; dysphonia

Anti-Jo-1, other myositis-specific autoantibodies

Dermatomyositis, polymyositis

 Unusual weakness and hypokalemia

Anti-Ro/SSA; anti-La/SSB

Sjogren’s syndrome hypokalemic paralysis

Cardiac problems

 Pleuritic or positional chest pain, dyspnea, tachycardia

Anti-dsDNA, other lupus serologies, Anti-phospholipid antibodies

SLE pleuro-pericarditis, pericardial tamponade

 Congenital heart block; neonatal carditis

Anti-Ro/SSA; anti-La/SSB

Neonatal SLE

Renal problems

 Rapidly progressive renal failure

MPO-ANCA, PR3-ANCA, anti-dsDNA and other lupus serologies, anti-phospholipid antibodies

Microscopic polyangiitis, WG, lupus nephritis, catastrophic antiphospholipid syndrome

 Accelerated hypertension

Anti-Scl-70; anti-centromeres, anti-RNA-Polymerase III

Renal crisis in systemic sclerosis

Joint problems

 Pain, stiffness, swelling with symptoms of systemic disease

Anti-CCP, RF and lupus serologies

RA, SLE

Ocular problems

 Red, painful, photophobic eye

RF, anti-CCP, lupus serologies

RA, Behcet’s, juvenile RA, SLE

Gastrointestinal problems

 Colicky abdominal pain

Lupus serologies

SLE mesenteric arteritis

Skin problems

 Petechiae, palpable purpura, hemorrhagic blisters, ulcerations and gangrene

SLE and RA serologies

SLE, rheumatoid vasculitis

 Neonatal skin rash

Anti-Ro/SSA, anti-La/SSB

Neonatal lupus

Hematological problems

 Anemia, thrombocytopenia, leukopenia

Anti-DNA and lupus serologies; anti-erythrocyte, anti-platelet antibodies

SLE, autoimmune hemolytic anemia

 Thrombocytopenia

Antiphospholipid antibodies

Antiphospholipid syndrome

The outpatient rheumatology practice of dealing with autoimmune conditions collides with a different problem: assessing active disease resulting in progressive organ damage and early mortality. Establishing reliable biomarkers that accurately predict disease activity is a major challenge faced by practicing physicians. Such tests should be clinically meaningful, affordable, and easy, and should distinguish cross-sectional differences between patients with active and inactive disease as well as longitudinal changes in disease expression or activity in individual patients [7].

Quantitative measures of autoimmune activity, in contrast to critical care analytes, are generally not considered important in the biomarker field, as changes in autoantibody concentration are believed to be slow and of minor importance to the patient outcome. This misconception is particularly apparent in the rapid humoral immune response observed in autoimmune loop conditions like SLE and antiphospholipid syndrome [8, 9]. However, serial and routine testing in a cost-effective and readily accessible way requires technology and assays that currently do not exist.

Previous research suggests that some of the autoantibodies listed in Table 1 as diagnostic aids behave like parameters that wax and wane with disease activity, thus holding promise to provide prognostic clinical information and, when at their best, to guide therapy. When target organ involvement is considered, autoantibodies may correlate with important clinical outcomes. Current candidate autoantibody disease activity markers are summarized in Table 2. The more recently described value of regular autoantibody “profiling” in patients with Wegener’s granulomatosis due to change in epitope specificity of PR3-ANCA during active disease [10] and the association of high and low anti-NMDA-R autoantibody titers with unique CNS symptoms in neuropsychiatric SLE [11] underscores the importance of autoantibody assays for optimal management.
Table 2

Associations between autoantibody changes and disease activity

Disease/condition

Autoantibody

Change

Clinical prediction

Systemic lupus erythematosus

Anti-dsDNA

Active flare [1517]

Anti-dsDNA

Active flare [18]

Anti-nucleosome

Active disease/lupus nephritis [1921]

Anti-C1q

Lupus nephritis [2224]/active disease [25]

Anti-NMDA-R

Permanent CNS impairment [26, 27]

Anti-NMDA-R

Transient CNS symptoms [26, 27]

Anti-CRP

Lupus nephritis/response to therapy [28]

Anti-interferon-α

Inactive disease [29]

Systemic vasculitis

Anti-PR3

Active disease/disease relapse [3032]

Anti-MPO

Active disease/disease relapse [33, 34]

Anti-GBM

Active disease/disease relapse [35, 36]

Scleroderma

Anti-topoisomerase I

Active scleroderma [3739]

Rheumatoid arthritis

Anti-drug (adalimumab)

Treatment failure [40]

Antiphospholipid syndrome/SLE

Anti-phospholipid

Procoagulant state, thrombosis [4143]

Necrotizing myopathy

Anti-signal recognition particle

Decreased muscle strength, increased creatine kinase activity [44]

Thrombotic thrombocytopenic purpura

Anti-ADAMTS13 antibodies

Disease relapse [45, 46]

Pregnancy in SLE

Anti-Ro(SSA)/anti-Ro52

Congenital heart block [47, 48]

Anti-La(SSB)

Neonatal lupus [49]

Autoantibody serum screening

Anti-DFS70

ANA-positive healthy individuals [50, 51]

It is beyond the scope of this paper to discuss discrepancies observed among studies that characterize autoantibodies as disease activity markers. Many believe that lack of prospective or longitudinal studies, clearly defined methodology, patient selection bias, use of inconsistent definitions for disease activity, frequency of testing, and effects of therapy contribute to conflicting results [12, 13]. It should also be noted that disease activity, disease severity, and the ensuing irreversible damage should be conceptually differentiated, and measurement tools for these parameters may be different [14]. Despite these potential problems in interpreting laboratory results, the need of clinicians to judge disease activity has made the practice of ordering autoantibodies widespread and frequent, with 92 % of US rheumatologists using serial anti-dsDNA autoantibody titers to monitor disease activity in SLE [4].

New technologies, that deliver quantitative information in a simple, fast, and low-cost fashion when combined with frequent visits and blood sampling may provide for the first time a tool to definitively establish the predictive value of autoantibody fluctuations in disease flares. Point-of-care (POC) testing, otherwise referred as near patient, bedside or extra-laboratory testing for clinically important analytes, has gathered strength in diverse medical specialties. By virtue of its near real-time data collection capability, POC testing has the potential to change the paradigm in the practice of medicine, and we anticipate that rheumatology will not be an exception.

Devising a reliable assay for measuring a specific antibody in human serum is more difficult than measuring most non-antibody analytes in biological fluids, because any one antibody specificity is usually a tiny fraction of total serum immunoglobulin. Non-specific binding of immunoglobulin may have impeded the development of a reliable antibody biosensor. However, recent and evolving advances in the field of immunosensor technologies have provided high accuracy in quantification and low detection limit in testing for some autoantibodies used in clinical practice.

Current POC immunoassay technologies come in various configurations and complexities. Table 3 provides a partial list of new biosensors and their platforms that have the potential to measure autoantibodies in “real” clinical samples. Surface plasmon resonance-based sensors are the most rapid method, but will require adaptation to inexpensive miniaturized devices. Lateral flow based methods will probably be restricted to non-quantitative readouts. Devices that required specialized antigen tags may have limited practical potential. Electrochemical amplification methods using readily available autoantigens are especially promising. Autoantibody biosensors have generally equaled or surpassed traditional central laboratory methods in performance metrics, such as sensitivity, specificity, and especially time to result. Advances in the development and application of portable, antibody-based immunosensors are presented in several recent review papers [5256].
Table 3

Devices with potential to measure autoantibodies (Ab) at point-of-care

Autoantibody

Detection technology/assay platform

Assay duration

References

Anti-dsDNA

Electrochemical reduction of redox-tagged probe/Ab inhibition in single-step cell

~45 min

[60]

Decreased resonance frequency/piezoelectric quartz crystal microbalance

<60 min

[61]

Refractive index change/surface plasmon resonance sensor chip

~5 min

[62]

Anti-CCP

Formation of visual line by colored nanoparticles/lateral flow chromatography

10 min

[66]

Refractive index change/surface plasmon resonance sensor chip

~5 min

[67]

Anti-chromatin

Peroxidase-mediated electrochemical amplification/flow-through cell

20 min

[64]

Anti-IgG (RF) Anti-MCV

Formation of visual line by colored nanoparticles/lateral flow chromatography

15 min

[65]

Anti-Ro/SSA, Anti-Ro52, Anti-La/SSB

Luminescence by luciferase-tagged probe/bead immobilized Ab in two-step cells

25 min

[63]

Anti-β2-glyco-protein I

Refractive index change/surface plasmon resonance sensor chip

~5 min

[68]

The American College of Rheumatology (ACR) has recognized the value of decentralized laboratory testing in their position statement on the issue [57] in which not only patient convenience (a single site for physician contact and serology testing), but also cost savings associated with return visits just to implement treatment options would be benefited. According to the ACR, rheumatologists, in directing their office laboratories, are the most qualified for determining the utility of specific tests, analyzing their results and applying these results to therapeutic situations. Immediate autoantibody diagnostics can also help to establish autoimmune disease units in hospitals, as recently suggested [58, 59].

Sites for POC serology testing could include outpatient rheumatology clinics, intensive care units, and emergency or urgent care facilities, as well as hospital infusion centers. Another attractive possibility is the use of POC serology testing in field-based, remote or rudimentary clinical settings, thereby bringing laboratory-based medicine to low-resource areas. In all these environments, POC devices would be of value to rheumatology physicians, who can immediately act on the information. In the outpatient clinic, a rapid test result could affect physician evaluation of the patient, thereby facilitating action and likely improving the usefulness of the office visit. POC methods should enhance patient compliance for laboratory testing and decrease the number of return visits. The efficiency and quality of health care from both the physician and the patient perspective is likely to improve as a result.

At this point it is unlikely that POC testing will replace the traditional central clinical laboratory model in all situations. Establishing rigid quality control of POC testing that satisfies regulatory requirements and oversight could be challenging. Handling and disposal of potentially biohazardous and chemical fluids may need to be addressed. Physical records, transfer of test results into a patient chart, and reimbursement issues will also play a major role in acceptance of POC technology.

POC serology testing is truly a work in progress, and its successful deployment requires a long-term commitment. The anti-CCP assay has recently been commercialized, but general acceptance of POC autoantibody testing in rheumatology has yet to happen. The optimum technology should be reliable, fast, inexpensive, quantitative, and easy to put in place and use. The latter features will make POC testing attractive to clinical rheumatology staff whose primary focus is patient care. Analyses of health care in the future predict that medicine will be more decentralized, and realization of POC testing has the promise to accelerate this paradigm shift for patient management.

Abbreviations

ADAMTS13: 

A desintegrin and metalloproteinase with a trombospondin type 1 motif, member 13

ANCA: 

Anti-neutrophil cytoplasmic antibodies

APL: 

Anti-phospholipid

CCP: 

Cyclic citrullinated peptide

CRP: 

C-reactive protein

DFS70: 

Dense fine speckles 70 kDa

DVT: 

Deep venous thrombosis

GBM: 

Glomerular basement membrane

MCV: 

Mutated citrullinated vimentin

MPO: 

Myeloperoxidase

NMDA-R: 

N-methyl-d-aspartate receptor

NPSLE: 

Neuropsychiatric systemic lupus erythematosus

POC: 

Point-of-care

PR3: 

Proteinase 3

RA: 

Rheumatoid arthritis

RF: 

Rheumatoid factor

SLE: 

Systemic lupus erythematosus

Declarations

Conflict of interest

Konstantin N. Konstantinov, Antonios Tzamaloukas, Robert L. Rubin declare that they have no conflict of interest.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2005. Informed consent was obtained from all patients for being included in the study.

Animal studies

No animal studies were carried out by the authors for this article.

Authors’ Affiliations

(1)
Division of Rheumatology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Mail Stop MSC10-5550, Albuquerque, NM 87131, USA
(2)
Renal Section, Raymond G. Murphy VA Medical Center, 1501 San Pedro SE, Albuquerque, NM 87108, USA
(3)
Department of Molecular Genetics and Microbiology, MCS08-4660, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA

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