Review Open Access
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Rheumatol. Mar 12, 2016; 6(1): 1-8
Published online Mar 12, 2016. doi: 10.5499/wjr.v6.i1.1
Return to clinical in contrast to serologically-based diagnoses
Bruce M Rothschild
Bruce M Rothschild, Department of Medicine, Ohio Medical University, Rootstown, OH 44272, United States
Author contributions: Rothschild BM solely contributed to this paper.
Conflict-of-interest statement: The authors declare no conflicts of interest regarding this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Bruce M Rothschild, MD, FACR, Professor of Medicine, Department of Medicine, Ohio Medical University, 5500 Market Street, Rootstown, OH 44272, United States.
Telephone: +1-785-6151523 Fax: +1-724-4272707
Received: June 8, 2015
Peer-review started: June 10, 2015
First decision: September 18, 2015
Revised: September 23, 2015
Accepted: November 13, 2015
Article in press: November 17, 2015
Published online: March 12, 2016


The future of rheumatology is predicated upon a return to basics. The advent and facile availability of laboratory testing led to reduction of emphasis on clinical skills. Recognition that immunologic abnormalities are not limited to individuals who clearly have related pathology provides new motivation for reorientation of training programs to assure that graduates have appropriate information gathering, diagnostic and procedural skills. Inadequate accessibility to rheumatologic care requires innovative approaches and especially training and educating those individuals who provide primary care. While the rheumatologist can elicit the patient’s history remotely, telerheumatology will be feasible only when the individual interacting physically with the patient has confidence in their examination skills and when those skills have been validated. Named syndromes or diseases will be modified to avoid impugning the individual or compromising their future access to health, disability and life insurance. Interventions will be pursued in a more cost-effective, evidence-based manner. The future of rheumatology is dependent upon the rheumatologist’s ability to amortize the inadequate reimbursement for direct patient interaction, depending on skills of interpretation of standard X-rays, ultrasound performance and results.

Key Words: Laboratory test, Immunology, Procedure, Telerheumatology, Nomenclature, Radiology, Ultrasound

Core tip: Rheumatology started as a clinical practice, dependent on skills of eliciting pertinent history, performing complete physical examination and recognition and interpretation of radiologic findings. Laboratory testing has distracted from those origins and it is time to return to those basic skills.


Rheumatology is undergoing a number of transitions, with the future representing a return to basics. Training programs will reemphasize development and validation of clinical skills. Serologic diagnostic approaches are being reevaluated with emphasis on clinical diagnosis.

Limitations of serology-based diagnosis

Significance of serologic test results has been a source of controversy ever since. Sharp et al[1] recognized anti-RNP antibodies and identified them as the arbiter for diagnosis of mixed connective tissue disease (MCTD). The MCTD that he associated with anti-RNP antibodies presented as a well-defined syndrome, consisting of a mixture of symptoms attributable to various connective tissue/collagen vascular diseases. That combination did not represent co-occurrence of more than one connective tissue disease, and was insufficient in character and associated phenomena to define a single (up until then) recognized entity.

Sharp et al[1] had clearly identified a previously unrecognized syndrome. As the characteristics of the phenomenon he recognized were promulgated, rheumatologists started recognizing it in the absence of anti-RNP antibodies. Thus, some perceived presence of anti-RNP antibodies as unnecessary to the diagnosis of MCTD. More widespread testing revealed that those antibodies had less specificity than originally thought[2-4]. Clinical diagnosis of Sharp’s disorder has become the more common approach.

Dr. Sharp’s was but one of many attempts at standardization in rheumatology. It must be remembered that such efforts were intended to create more uniform/homeogeneous groups for scientific studies, not for clinical diagnosis[5,6]. His is not unlike DRGs, developed for a similar research purpose but subsequently “hijacked” for a national clinical coding system by non-clinicians. These attempts to establish uniform groups make the assumption that disease/symptom classifications have validity and are not simply conventions, philosophical categorizations made to help guide therapeutic approaches.

Practice of rheumatology started with establishing our own laboratories for performance of sophisticated tests, declining to accept as valid any test results performed at other facilities. At some point, such tests were delegated to various outside laboratories, with loss of oversight by the ordering physician. Whether this was a manifestation of inadequate familiarity with the techniques involved or unappreciated “interference” by insurance companies designating where tests could or could not be performed, interpretation of those tests became more complicated.

Original performance of antinuclear antibody assessment on rat or mouse liver or kidney slices had well-established normal ranges, known frequency of false positives and interpretable patterns[7]. When replaced by microscopic examination of tissue culture Hep-2 cells, similar validation of pattern implications was less stringent[8]. It can no longer be specifically attributed to the originally-associated disorders. Even presence of a positive ANA can be misleading, as it is present in 5% of the general population. Given the prevalence of lupus, 95% of individuals with a positive ANA don’t actually have lupus. And 5%-30% of individuals with lupus do not have a positive ANA[9].

Similarly, serology-based practitioners have used presence or absence of rheumatoid factor as defining whether an individual is suffering from rheumatoid arthritis. The titer-based nature of the test reflects the need for sufficient sensitivity to indicate greater than normal amount of rheumatoid factor in the blood (noting that antibodies reacting with components of other antibodies are routinely present in normal individuals). This reduces specificity - for abnormal amounts in the blood, not actually for diagnosis of rheumatoid arthritis. Rheumatoid factor is elevated in other connective tissue disorders, other forms of inflammatory arthritis, malignancy, chronic infections (e.g., endocarditis, rheumatic fever, tuberculosis, syphilis, viral disease, parasitic disease), rheumatic fever, pulmonary fibrosis, sarcoidosis and chronic renal disease). The tradeoff between sensitivity and specificity results in a titer cutoff that has a 5% false positive result. While that cutoff may be 1:40, it is not unusual to have 1:160 titers in normal healthy individuals. The former impression that presence of rheumatoid factor has specificity for diagnosis of a specific variety of inflammatory arthritis probably derives from lumping of all inflammatory arthritis as rheumatoid, as described below.

Perhaps the most eggarious of the serologic approaches is to diagnoses ankylosing spondylitis simply because the HLA-B27 histocompatibility antigen is present. HLA-B27 is present in 90% of individuals with ankylosing spondylitis and 50% of individuals with other forms of spondyloarthropathy, but is also common in healthy individuals. A recent Turkish study found HLA-B27 present in 18% of the general population, while the prevalence in Caucasians is 13% and in African Americans, 4%[10]. Given that ankylosing spondylitis is only present in 0.2% of the population, 98% of HLA-B27 positive individuals will not have the disease. Thus, the reversion from serologic to clinical diagnostic approaches will eliminate the patient’s psychic trauma resulting from receiving such a misdiagnosis and facilitate the clinician who must subsequently disabuse that patient of the perceived life-style and morbidity implications of a disease they don’t have.

Reinvestment in clinical skills

In the transition from clinical diagnoses to those based on testing by outside laboratories, a standard rheumatology procedure became similarly outsourced, actual examination of joint fluid. Examination by the rheumatologist originally provided an approximation of white and red blood cell content, allowing verification of outside laboratory actual counts[11]. Loss of cells in clots or other handling misadventures were recognized and the reliability of results provided by outside laboratories, independently assessed. This was a “side benefit” of rheumatologist-performed polarizing examination for crystals. It was also difficult to find a reference laboratory with acceptable reliability[12-15]. Concern with this issue apparently fell by the wayside, perhaps related to changes in training program priorities. Clinically oriented individuals recognize the importance of their performance of this evaluation, but serologically-oriented individuals have delegated this to outside laboratories. The future of rheumatology involves restoration of its practice by rheumatologists and re-establishing their expertise in its performance[13].

Perhaps one of the major factors stimulating renewed attention to clinical evaluation is the availability of so many effective biologic agents (e.g., acting on tumor necrosis factor, interleukins 1 and 6, T cells)[16-18]. These target the inflammatory process, but have no direct effect on mechanical sources of pain and morbidity. It has become much more critical for the rheumatologist to be able to distinguish inflammatory components of a patient’s complaints and limitations from those of mechanical origin[11,19]. Pain and limited ambulation (and sometimes swelling) resulting from ligamentous laxity producing knee instability may be misinterpreted as a component of the patient’s inflammatory arthritis, if the responsible knee instability is not recognized. Similarly, distinguishing wrist pain related to tendonitis [often of mechanical origin (e.g., DeQuervain’s tenosynovitis)] is critical in its resolution, and in avoiding more aggressive anti-inflammatory and biologic therapies - for a problem that will not yield to such intervention[11,19], but will subject the patient to potential toxicity.

One of the most important lessons is for the clinician to have the patient point to the site of pain[11]. The complaint of hip pain is a classic example. This term is commonly used to identify pain in the buttock, back or lateral aspect of the pelvis, rarely for the groin - which is actually the anatomical location of the hip. While pain in the buttock or back may lead to investigation for fibromyalgia or sacroiliitis, it is pain in the lateral aspect of the pelvis which affords the rheumatologist the rare opportunity to safely provide immediate relief. That area is home to a series of bursae[20]. Previously referred to simply as trochanteric bursitis, it has now been realized that there are actually four bursae that are typically involved as a group - and that treatment of only one usually is ineffective. All four bursae (gluteus medius, gluteus minimus, subgluteus medius and subgluteus minimus) need to be injected with a water insoluble corticosteroid. Water soluble steroids simply diffuse to the whole body, while non-soluble ones remain localized to the affected area. They expose the patient to less systemic complications. The lidocaine in the injection provides immediate relief and verifies the accuracy of the diagnosis, while the corticosteroid provides lasting benefit. Of course, for this disorder and for others (e.g., epicondylitis, DeQuervain’s tenosynovitis), it is important to examine clinical history for activities of daily life and occupational derivations - issues which need resolution, if recurrence is to be avoided.

Clinical skills of physical examination are also being reemphasized, especially the importance of assuring the examination is complete and inclusive[11]. Uniformity is critical, to reduce interobserver variability[21,22]. This includes assuring ability to perform arthrocentesis of all joints. The “no touch” joint aspiration technique was recognized and promoted a third of a century ago. It is predicated upon understanding joint anatomy, a subject typically not addressed in medical school. Renewed access to the anatomy laboratory provides the opportunity to dissect and identify surface markers that allow facile joint access joint[11]. Much of this has been relegated to utilization of ultrasound for needle placement, allowing clinical skills to deteriorate, rather than utilizing ultrasound images to refine those clinical skills.

Role of procedures

Rheumatology has been a field badly in need of a procedure. Reimbursement for time spent with patients has been woefully inadequate, while procedures are typically well compensated. Closed muscle biopsies, fat and synovial membrane biopsies have been pursued, but are not major revenue generators. Rheumatologists will have difficulty maintaining the level of our services if we cannot amortize the inadequately reimbursed clinical examinations.

An early consideration was developing endoscopy (gastroscopy) skills, as it was thought that rheumatologists should be able to evaluate the ulcers caused by the medications we prescribe. Assessing significance of gastrointestinal complaints is complicated as most symptomatic individuals actually do not have endoscopic evidence of damage, while many non-steroidal anti-inflammatory drug-related ulcers are not symptomatic. A mechanism existed in the 1980’s to establish just such training. It was, however, abandoned because hospital credentialing at that time was usually limited to those who had completed a gastroenterology training program, with general surgeons grudgingly allowed to perform the procedure. Rheumatologists were not getting credentialed, despite appropriate training.

Infusions have been touted as revenue-generators, leading to a potential conflict of interest between patient and practice revenue. Performance and examination of X-rays would seem the most appropriate procedure for rheumatologists to add to the armamentarium. Thus, training in radiologic techniques will be emphasized as well as developing skills necessary for skeletal radiologic evaluations[11]. Because some rheumatologists practice in an environment where the organization/hospital has an agreement with a radiology group for sole performance of X-ray examinations, there has been a perception that stream of revenue is totally lost. However, training in skeletal radiology provides the opportunity to bill for reexamination of X-ray images, whenever there are findings that general radiologists have not recognized. The generalist has a search image and pattern of review that is different than that of the skeletal radiologist (e.g., rheumatologist trained in skeletal radiology), so each has significant contributions to patient care and it is appropriate for both to bill.

Attempting to find a fully billable procedure has led rheumatologists to consider diagnostic ultrasound. While an excellent and informative technique[23-25], it is quite time-expensive, although shortcuts with limited examinations have been pursued[26]. It has been used for needle localization for arthrocentesis for those without confidence in their clinical skills to localize the joint[27-29], but does have a value in recognizing calcium pyrophosphate deposition disease and gout, as well as distinguishing synovial effusions from synovial proliferation and recognizing erosions[27,28,30,31]. There has been significant controversy as to whether it is more sensitive than the clinical examination for recognition of effusions, most of which seems to relate to examination skills. It may be one of the best radiologic techniques for recognizing and identification of shoulder pathology[32], a 20 min examination which unfortunately is not sufficiently recompensed for that time allocation.

Diagnostic appellations

We’ve also learned to examine what’s in a name: An identification helpful to patients or a diagnosis that can be used to discriminate (e.g., by insurers). Names often have unintended deleterious effects, stigmatizing people, industries or communities and can misdirect therapy[33,34]. This is exemplified by changes in utilization of the diagnostic appellation, rheumatoid arthritis. The criteria originally proposed by Ropes et al[5] were modified by a committee of what was then the American Rheumatism Association modification of criteria for rheumatoid arthritis in 1987[35].

Diagnosis of rheumatoid arthritis has been predicated on committee-derived criteria which subsequently expanded its purview and deleted past exceptions[36-39]. The resulting patient cohort may be more inclusive, but specificity is problematic. This has commonly resulted[40-42] in lumping as rheumatoid arthritis additional patients with predominantly non-axial disease[43-45]. Expansion of these criteria was accompanied by the requirement that there be no “alternative diagnosis that better explains the synovitis”. The latter assumes adequate diagnostic skills to recognize other disorders. Spondyloarthropathy and calcium pyrophosphate deposition disease are the major disorders that share clinical presentations with that of rheumatoid arthritis[46-48], It is critical to recognize the symmetrical pattern, marginal localization of and axial joint sparing characteristics of rheumatoid arthritis[49-51], if these alternative diagnoses are to be recognized.

Examination of the archeologic record reveals two distinct patterns, thus challenging the specificity incurred when utilizing the 1987 criteria for diagnosis of rheumatoid arthritis. Predominant metacarpal phalangeal joint involvement, distribution of erosions to the bare areas of peripheral joints and periarticular osteopenia characterizes the arthritis present in seven populations, with joint ankyloses conspicuously absent[38,39,49,52].

Erosions in skeletons from other archeologic sites involved fewer joints and were typically localized to the areas originally covered by cartilage (subchondral)[53-57]. Joints were often fused[46,48,50,54,56,58-62]. Radiologic examination revealed periarticular osteopenia in less than half, in contrast to its universal presence in the first group[46,48,50,54,56,58-62]. Why are the patterns and distribution of joint involvement so different in these populations? “Osseotropism” and “rheumotrophism” have been suggested to help characterize the phenomena[57]. It seems useful to examine how individuals with this second pattern of arthritis compare with those more universally recognized as having spondyloarthropathy, those with axial joint disease[46,48,54,57,62,63]. Vertebral centra bridging in the form of syndesmophytes and sacroiliac joint and zygapophyseal erosions or fusion through their articular surfaces are definitive for the diagnosis of spondyloarthropathy[46,48,54,57,62,63]. It is the latter form of fusion through the articular surface of sacroiliac joints that provides insights to the subchondral propensity of erosion localization in peripheral joints. Fusion requires that the integrity of the subchondral cartilage be compromised, such that trabeculae can bridge what was originally a synovial lined space. This propensity is not found in individuals with rheumatoid arthritis.

The biomechanics of the two diseases are also quite different[53,64]. As might be expected, a disorder that disrupts articular surfaces should produce joints which glide less easily than one in which the joint surface is smooth. One method to quantify such variation is use of an accelerometer, which characterizes as vibration intensity/power the joints resistance to transitional movement[64,65]. High vibration/power was noted in individuals with subchondral erosions, independent of presence or absence of peripheral joint fusion or axial joint disease, in contrast to low vibration/power in individuals with marginal erosions lacking peripheral joint fusion or axial joint disease, the group classically recognized as having rheumatoid arthritis[64,65]. There was no overlap of vibration/power “signatures” between the groups.

Critical examination of the zoologic record also provides clarity. Previous diagnosis of rheumatoid arthritis in pigs and dogs[66-69] was apparently related to lack of familiarity with alternative (to rheumatoid arthritis) diagnoses, as the classic subchondral erosions and peripheral joint fusion of spondyoarthropathy were present[51,54,62,70,71]. Systematic assessment revealed frequent evidence of the above-noted patterns associated with spondyloarthropathy, but none of those associated with rheumatoid arthritis, among more than 30000 mammals examined in zoological collections around the world[46,50,72]. The animals have a disorder clearly distinguishable from classic rheumatoid arthritis.

Peripheral joint fusion clearly represents a pathophysiology distinct from that of natural course of rheumatoid arthritis[38]. The term “natural” is used, as corticosteroid therapy has many complications, including altering disease course to allow joint fusion. The biomechanics and epidemiology (both archeologic and zoological) of erosive arthritis clearly separate rheumatoid arthritis and spondyloarthropathy. Those studies further note that isolated wrist and ankle affliction is indicative of spondyloarthropathy and not rheumatoid arthritis. The lumper-splitter controversy, wherein lumpers considered most inflammatory arthritis as part of the rheumatoid arthritis syndrome, is being superceded by the splitters[6,73,74].

Therapeutic intervention

While methotrexate and tumor necrosis factor inhibitors might be considered the “boutique” treatments for inflammatory arthritis[75], because of less insurance company obstruction to their use and expansion of available biologic agents, therapeutic intervention also is returning to the basics and perhaps more cost-effective agents. Use of one of the older agents, hydroxychlorquine (plaquenil), is undergoing resurgence, with renewed recognition of its efficacy[76]. Sulfasalazine is another example. It originally was developed specifically for treatment of rheumatoid arthritis because of the perspective that it was infectious in origin[77,78]. At the time of its conception, antibiotics were predominantly sulfa-based. Combining that antibiotic with the anti-inflammatory effect of salicylate was therefore logical but proved to be ineffective - in the short term. It was subsequently recognized that sulfasalazine had delayed benefit, requiring months for its efficacy to manifest. Renewed consideration of sulfasazine therapy resulted from recognition of inflammatory arthritis of the spondyloarthropathy variety in gorillas[79]. How do you treat a 600 pound individual with an attitude? Eye contact is considered a threat gesture and they don’t cooperate in the same manner as chimpanzees for the vascular access necessary to assure medication safety. Anesthetizing gorillas at frequent intervals is not an option, because of anesthesia-related mortality. A medication was required which did not require the close laboratory monitoring so necessary with methotrexate and the ophthalmologic evaluations required with hydroxychloroquine use[80,81]. Sulfasalazine seems the safest of the disease modifying (DMARD), has documented efficacy in gorillas, and is actually now standard veterinary treatment for the disease (except perhaps in dogs, where some develop dry eyes from the drug)[79]. Recognition of its efficacy across the vertebrate spectrum[79], led to reexamination of its use in humans and recognition that it offers a safe alternative (without the cancer risk) to methotrexate.


Telemedicine or remote provision of services has been suggested as a new approach, especially in underserved areas[82]. Working with physicians and physician extenders, this has proven a useful approach in Alaska[83]. If needed for cardiology (for which extensive education and experience are provided in medical school and residencies), how much more so that might seem for rheumatology. However, that very difference in training and experience is fundamental to the difficulty of providing rheumatology services in such a manner[84]. It would require establishment and validation of physical examination (not limited to the joints) and history taking skills, assurance that those skills are maintained

Those history taking skills require attention to nuances and vocabulary variation in different geographic and ethnic populations. There are major discrepancies between patient-completed questionnaires and their verbal response to essentially the same questions (e.g., attention to hesitancy in responses, suggesting they are thinking about the question. If so, it is useful to have patient verbalize what they are considering and often dismissing - precluding access to important diagnostic information. “Absenting substantial revision of medical school and post-graduate education and training, telerheumatology does not seem feasible”[84], not ready for prime time.


The future of rheumatology is predicated upon patient advocacy as always, but now more proactive with those who make the laws/regulations that insurance companies are obligated to follow[81]. This derives from insurance companies with oxymoronic names stonewalling evidence-based appeals and even FDA-approved usages in favor of medicines unapproved for a given indication. The future direction is illustrated by the change in the American College of Physicians’ journal name from Arthritis and Rheumatism to Arthritis and Rheumatology. Rheumatism was an old term for aches and pains. Rheumatology deals with much more than arthritis and now recognizes derivation of those aches and pains. It has changed from simply recording symptoms to identifying their causes. That is the future of rheumatology, pursuing a more scientific, evidence-based approach, examining and testing preconceived notions to provide appropriate care with an approach that maximizes efficacy and safety.


P- Reviewer: Mezalek ZT, Mohammed RHA, Tanaka H, Tommasini A S- Editor: Qiu S L- Editor: A E- Editor: Jiao XK

1.  Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972;52:148-159.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Alarcón-Segovia D, Cardiel MH. Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J Rheumatol. 1989;16:328-334.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  LeRoy EC, Maricq HR, Kahaleh MB. Undifferentiated connective tissue syndromes. Arthritis Rheum. 1980;23:341-343.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 140]  [Cited by in F6Publishing: 51]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
4.  Reichlin M. Mixed Connective tissue disease. Modern Topics in Rheumatology. London: Heinemann 1976; 162-166.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA. Diagnostic criteria for rheumatoid arthritis: 1958 revision by a committee of the American Rheumatism Association. Ann Rheum Dis. 1959;18:49-51.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 634]  [Cited by in F6Publishing: 140]  [Article Influence: 30.2]  [Reference Citation Analysis (0)]
6.  Silman AJ. Rheumatology in the future: An epidemiological view. Ann Rheumatic Dis. 1991;50:505-506.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
7.  Kumar Y, Bhatia A, Minz RW. Antinuclear antibodies and their detection methods in diagnosis of connective tissue diseases: A journey revisited”. Diag Pathol. 2009;4:1-10.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 20]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
8.  Ulvestad E. Performance characteristics and clinical utility of a hybrid ELISA for detection of ANA”. APMIS:. Acta Pathol Microbiol Immunol Scand. 2001;109:217-22.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 2]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
9.  Rothschild BM, Jones JV, Chesney C, Pifer DD, Thompson LD, James KK, Badger H. Relationship of clinical findings in systemic lupus erythematosus to seroreactivity. Arthritis Rheum. 1983;26:45-51.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 3]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
10.  Bayram B, Sayin E, Bozari S, Sahin FM. HLA-B27 allele frequency in a Turkish study population with primary osteoarthritis. J Primatol. 2014;3:1-3.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
11.  Rothschild BM Rheumatology: A Primary Care Approach. New York: Yorke Medical Press 1982; .  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Pascual E, Sivera F, Andrés M. Synovial fluid analysis for crystals. Curr Opin Rheumatol. 2011;23:161-169.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 5]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
13.  Punzi L, Ramonda R, Oliviero F. Why are rheumatologists still reluctant to perform joint-fluid analysis? Joint Bone Spine. 2015;82:139-140.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
14.  Schumacher HR, Chen LX, Mandell BF. The time has come to incorporate more teaching and formalized assessment of skills in synovial fluid analysis into rheumatology training programs. Arthritis Care Res. 2012;64:1271-1273.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 2]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
15.  Swan A, Amer H, Dieppe P. The value of synovial fluid assays in the diagnosis of joint disease: a literature survey. Ann Rheum Dis. 2002;61:493-498.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 190]  [Cited by in F6Publishing: 59]  [Article Influence: 10.0]  [Reference Citation Analysis (0)]
16.  Russell AS. Relative efficacies: antimalarials to abatacept - the choice is ours. J Rheumatol Suppl. 2009;82:17-24.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
17.  Van der Velde G, Pham B, Machado M, Ieraci L, Witteman W, Bombardier C, Krahn M. Cost-effectiveness of biologic response modifiers compared to disease-modifying antirheumatic drugs for rheumatoid arthritis: A systematic review. Arthritis Care Res. 2011;63:65-78.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 30]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
18.  Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S, Iwata N, Umebayashi H, Murata T, Miyoshi M. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: A randomized double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008;371:998-1006.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 569]  [Cited by in F6Publishing: 131]  [Article Influence: 43.8]  [Reference Citation Analysis (0)]
19.  Rothschild B. Mechanical solution for a mechanical problem: Tennis elbow. World J Orthop. 2013;4:103-106.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 7]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
20.  Rothschild B. Trochanteric area pain, the result of a quartet of bursal inflammation. World J Orthop. 2013;4:100-102.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 4]  [Cited by in F6Publishing: 1]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
21.  Goldenberg DL Fibromyalgia. New York: Berkley Publishing Co 2002; .  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Vega Morales D. Squeeze test in inflammatory arthritis need for standardization? Rheum. 2015;5:8.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Sedie AD, Riente L, Filippucci E, Iagnocco A, Meenagh G, Epis O, Grassi W, Valesini G, Montecucco C, Bombardieri S. Ultrasound imaging for the rheumatologist. Clin Exp Rheumatol. 2008;26:391-394.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Klauser AS, Peetrons P. Developments in musculoskeletal ultrasound and clinical applications. Skeletal Radiol. 2010;39:1061-1071.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 18]  [Article Influence: 10.4]  [Reference Citation Analysis (0)]
25.  Rothschild B, Sebes J. Diagnostic ultrasound for assessment of joint and extremity pathology. Compr Ther. 1989;15:37-46.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Ohrndorf S, Fischer IU, Kellner H, Strunk J, Hartung W, Reiche B, Burmester GR, Walther M, Schmidt WA, Backhaus M. Reliability of the novel 7-joint ultrasound score: Results from an inter- and intraobserver study performed by rheumatologists. Arthritis Care Res. 2012;64:1238-1243.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Keen HI, Wakefield RJ, Grainger AJ, Hensor EM, Emery P, Conaghan PG. Can ultrasonography improve on radiographic assessment in osteoarthritis of the hands? A comparison between radiographic and ultrasonographic detected pathology. Ann Rheum Dis. 2008;67:1116-1120.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 31]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
28.  Magni-Manzoni S, Epis O, Ravelli A, Klersy C, Veisconti C, Lanni S, Muratore V, Sciré CA, Rossi S, Montecucco C. Comparison of clinical versus ultrasound-determined synovitis in juvenile idiopathic arthritis. Arthritis Rheum. 2009;61:1497-1504.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 119]  [Cited by in F6Publishing: 47]  [Article Influence: 10.8]  [Reference Citation Analysis (0)]
29.  Matsos M, Harish S, Zia P, Ho Y, Chow A, Ioannidis G, Khalidi N. Ultrasound of the hands and feet for rheumatological disorders: influence on clinical diagnostic confidence and patient management. Skeletal Radiol. 2009;38:1049-1054.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 8]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
30.  Rothschild BM, Bruno MA. Imaging in Calcium Pyrophosphate Deposition Disease, 2015-01-03.  Available from: http//  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Girish G, Melville DM, Kaeley GS, Brandon CJ, Goyal JR, Jacobson JA, Jamadar DA. Imaging appearances in gout. Arthritis. 2013;2013:673401.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 10]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
32.  Bruyn GA, Pineda C, Hernandez-Diaz C, Ventura-Rios L, Moya C, Garrido J, Groen H, Pena A, Espinosa R, Möller I. Validity of ultrasonography and measures of adult shoulder function and reliability of ultrasonography in detecting shoulder synovitis in patients with rheumatoid arthritis using magnetic resonance imaging as a gold standard. Arthritis Care Res (Hoboken). 2010;62:1079-1086.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 13]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
33.  Costenbader KH, Schur PH. We need better classification and terminology for “people at high risk of or in the process of developing lupus”. Arthritis Care Res (Hoboken). 2015;67:593-596.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 14]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
34.  Fukuda K, Wang R, Vallat B. Naming diseases: first do no harm. Science. 2015;348:643.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 12]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
35.  Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315-324.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13000]  [Cited by in F6Publishing: 8116]  [Article Influence: 393.9]  [Reference Citation Analysis (0)]
36.  Can G, Solmaz D, Binicier O, Akar S, Birlik M, Soysal O, Akkoc N, Manisali M, Onen F. High frequency of inflammatory back pain and other features of spondyloarthritis in patients with rheumatoid arthritis. Rheumatol Int. 2013;33:1289-1293.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 2]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
37.  Rothschild BM. Rheumatoid arthritis at a time of passage. J Rheumatol. 2001;28:245-250.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Rothschild BM. What qualifies as rheumatoid arthritis? J Rheumatol. 2013;3:3-5.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 3]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
39.  Rothschild BM, Woods RJ, Ortel W. Rheumatoid arthritis “in the buff”: erosive arthritis in defleshed bones. Am J Phys Anthropol. 1990;82:441-449.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 16]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
40.  François RJ, Eulderink F, Bywaters EG. Commented glossary for rheumatic spinal diseases, based on pathology. Ann Rheum Dis. 1995;54:615-625.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 13]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
41.  Hacking P, Allen T, Rogers J. Rheumatoid arthritis in a medieval skeleton. Int J Osteoarchaeol. 1994;4:251-255.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 2]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
42.  Rogers J, Waldron T, Dieppe P, Watt I. Arthropathies in palaeopathology: The basis of classification according to most probable cause. J Archaeol Sci. 1987;14:179-193.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 125]  [Cited by in F6Publishing: 10]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
43.  Rogers J, Waldron T.  A Field Guide to Joint Disease in Archaeology. New York: John Wiley and Sons 1995; .  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Rothschild BM. Field guide to joint disease in archeology. Amer J Phys Anthropol. 1996;101:299-301.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Rothschild BM. Rheumatoid arthritis in a Medieval skeleton: An illogical diagnosis for a case of spondyloarthropathy. Intl J Osteoarchaeol. 1994;5:218-219.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Rothschild BM, Woods RJ. Spondyloarthropathy: erosive arthritis in representative defleshed bones. Am J Phys Anthropol. 1991;85:125-134.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 68]  [Cited by in F6Publishing: 17]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
47.  Rothschild BM, Woods RJ, Rothschild C. Calcium pyrophosphate deposition disease: description in defleshed skeletons. Clin Exp Rheumatol. 1992;10:557-564.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Rothschild BM, Woods RJ, Rothschild C. Erosive arthritis of the spondyloarthropath variety: Diagnostic criteria based on virgin populations. Paleopathol Bull. 1991;72:6-7.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Rothschild BM, Woods RJ, Rothschild C, Sebes JI. Geographic distribution of rheumatoid arthritis in ancient North America: Implications for pathogenesis. Semin Arthritis Rheum. 1992;22:181-187.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 22]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
50.  Rothschild BM, Martin LD. Skeletal Impact of Disease. Albuquerque, New Mexico Museum of Natural History Press, 2006. .  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Silman AJ. Problems complicating the genetic epidemiology of rheumatoid arthritis. J Rheumatol. 1997;24:194-196.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Alves C, Colin EM, van Oort WJ, Sluimer JP, Hazes JM, Luime JJ. Periarticular osteoporosis: a useful feature in the diagnosis of early rheumatoid arthritis? Reliability and validity in a cross-sectional diagnostic study using dual-energy X-ray absorptiometry. Rheumatology (Oxford). 2011;50:2257-2263.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 2]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
53.  Rothschild BM. Two faces of “rheumatoid arthritis”: type a versus type B disease. J Clin Rheumatol. 1997;3:334-338.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 3]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
54.  Rothschild BM. Paleopathology, its character and contribution to understanding and distinguishing among rheumatologic diseases: perspectives on rheumatoid arthritis and spondyloarthropathy. Clin Exp Rheumatol. 1995;13:657-662.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Rothschild BM. Toward a mental image of rheumatoid arthritis. Curr Rheum. 1984;5:6-8.  [PubMed]  [DOI]  [Cited in This Article: ]
56.  Rothschild BM. Clinical practice implications of rheumatoid arthritis in antiquity. Prog Rheum. 1990;4:85-90.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Rothschild BM. Osseotypes and spondyloarthropathy exposed. Curr Rheum Rev. 2005;1:57-63.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 1]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
58.  Dutour O, Panuel M, Rothschild BM. Spondyloarthropathies in early Holocene Saharan population. J Comp Human Biol. 1994;45:S44.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Rothschild BM, Rothschild C. Reliability of Ossuary Sites for Analysis of Paleopathologic Epidemiology. J Paleopathol. 1994;6:35-40.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Rothschild BM, Rothschild C. Inflammatory arthritis in the first century Negev. Prog Rheum. 1993;5:112-115.  [PubMed]  [DOI]  [Cited in This Article: ]
61.  Rothschild BM, Woods RJ. Symmetrical erosive disease in Archaic Indians: the origin of rheumatoid arthritis in the New World? Semin Arthritis Rheum. 1990;19:278-284.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 3]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
62.  Rothschild BM, Woods RJ. Implications of osseous changes for diagnosis of spondyloarthropathy. J Orthop Rheuml. 1992;5:155-162.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Rothschild BM, Robinson S. Pathologic acromioclavicular and sternoclavicular manifestations in rheumatoid arthritis, sponyloarthropathy and calcium pyophosphate deposition disease. APLAR J Rheuml. 2007;10:204-208.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Article Influence: 0.1]  [Reference Citation Analysis (0)]
64.  Reddy NP, Rothschild BM, Verrall E, Joshi A. Noninvasive measurement of acceleration at the knee joint in patients with rheumatoid arthritis and spondyloarthropathy of the knee. Ann Biomed Eng. 2001;29:1106-1111.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 4]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
65.  Shah EN, Reddy NP, Rothschild BM. Fractal analysis of acceleration signals from patients with CPPD, rheumatoid arthritis, and spondyloarthroparthy of the finger joint. Comput Methods Programs Biomed. 2005;77:233-239.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Anderson ST, Schiller CA. Rheumatoid-like arthritis in a lion tailed macaque. J Rheumatol. 1991;18:1247-1250.  [PubMed]  [DOI]  [Cited in This Article: ]
67.  Halliwell RE, Lavelle RB, Butt KM. Canine rheumatoid arthritis--a review and a case report. J Small Anim Pract. 1972;13:239-248.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 2]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
68.  Pedersen NC, Castles JJ, Weisner K. Noninfectious canine arthritis: rheumatoid arthritis. J Am Vet Med Assoc. 1976;169:295-303.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Sikes D. A rheumatoidlike arthritis in swine. Lab Invest. 1959;8:1406-1415.  [PubMed]  [DOI]  [Cited in This Article: ]
70.  Nunn CL, Rothschild B, Gittleman JL. Why are some species more commonly afflicted by arthritis than others? A comparative study of spondyloarthropathy in primates and carnivores. J Evol Biol. 2007;20:460-470.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 3]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
71.  Rothschild BM, Rothschild C, Woods RJ. Inflammatory arthritis in canids: spondyloarthropathy. J Zoo Wildl Med. 2001;32:58-64.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 1]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
72.  Rothschild BM, Rothschild C. Trans-mammalian pandemic of inflammatory arthritis (Spondyloarthropathy variety): Persistence since the Pleistocene. Paleontol Soc Pub. 1996;8:330.  [PubMed]  [DOI]  [Cited in This Article: ]
73.  Moll JM, Haslock I, Macrae IF, Wright V. Associations between ankylosing spondylitis, psoriatic arthritis, Reiter’s disease, the intestinal arthropathies, and Behcet’s syndrome. Medicine (Baltimore). 1974;53:343-364.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 341]  [Cited by in F6Publishing: 138]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
74.  Zeidler H, Calin A, Amor B. A historical perspective of the spondyloarthritis. Curr Opin Rheumatol. 2011;23:327-333.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 1]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
75.  Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, Martín Mola E, Pavelka K, Sany J, Settas L. For the TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2003;363:675-681.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1195]  [Cited by in F6Publishing: 248]  [Article Influence: 70.3]  [Reference Citation Analysis (0)]
76.  Cusnir I, Dobing S, Jones N, Russell A. Antimalarial drugs alone may still have a role in rheumatoid arthritis. J Clin Rheumatol. 2015;21:193-195.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
77.  Pinals RS. History of enteric coated sulfasalazine in rheumatoid arthritis. J Rheumatol Suppl. 1988;16:1-4.  [PubMed]  [DOI]  [Cited in This Article: ]
78.  Schur PH. Disease-modifying antirheumatic drugs (DMARDs). Beyond the Basics. [updated 2013 Mar 3; accessed 2015 Jun 6].  Available from: http//  [PubMed]  [DOI]  [Cited in This Article: ]
79.  Neiffer DL, Rothschild BM, Marks SK, Urvater JA, Watkins DI. Management of reactive arthritis in a juvenile gorilla (Gorilla gorilla gorilla) with long-term sulfasalazine therapy. J Zoo Wildl Med. 2000;31:539-551.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
80.  Rothschild B, Yakubov LE. Prospective 6-month, double-blind trial of hydroxychloroquine treatment of CPDD. Compr Ther. 1997;23:327-331.  [PubMed]  [DOI]  [Cited in This Article: ]
81.  Rothschild B; St. Clair EW. Rheumatologists make a difference through advocacy: The ACR is advancing issues that matter to practices and patients. Rheumatologist. 2015;5:11-12.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Roberts LJ, Lamont EG, Lim I, Sabesan S, Barrett C. Telerheumatology: an idea whose time has come. Intern Med J. 2012;42:1072-1078.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 15]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
83.  Reisman J. A battle to breathe. Discover Magazine. 2015;8:20-21.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Rothschild B. Telerheumatology: not ready for prime time. Intern Med J. 2013;43:468-469.  [PubMed]  [DOI]  [Cited in This Article: ]