Getting the Diagnosis Right: What’s in a Name?

Our trainees often struggle to provide the precise diagnosis of an autoimmune rheumatic disease (ARD), especially when a patient’s presentation does not conform to a well-defined disease entity based on clinical manifestations and/or disease-specific autoantibodies. They often debate whether to call it systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma or systemic sclerosis (SSc), myositis, or just undifferentiated connective tissue disease (UCTD). Once they have come up with a specific diagnosis, they try to follow the disease-specific clinical practice guidelines proposed by professional organizations such as the American College of Rheumatology (ACR) and/or the European Alliance of Associations for Rheumatology (EULAR). However, trainees need to realize that the optimum treatment strategy in any given patient should not only be based on these expert recommendations but also incorporate the knowledge of the nature, extent, and severity of their involved organ systems (determined by a thorough history, physical examination, and investigations), and the likely pathophysiologic basis of these specific disease manifestations. This individualized problem-based approach ultimately matters more to the patient’s treatment and outcome, as it helps determine the best treatment plan that can favorably alter the natural history of their disease.

The original descriptions and definitions of these ARDs reported many years ago were often not precise nor complete. Over the years, with advancements in medical science and technology and a better understanding of disease pathophysiology and pathogenesis, these conditions often had to be redefined.

It is important to recognize that the names of these ARDs are somewhat arbitrary, primarily based on a constellation of symptoms and signs and a particular set of disease-specific autoantibodies. Several of these autoantibodies may play a pathogenetic role in the disease process; for example, anti-dsDNA antibodies in renal, cutaneous, and neuropsychiatric SLE,¹ and anticyclic citrullinated peptide (anti-CCP) antibodies in rheumatoid arthritis (RA).² Some of these autoantibodies are thought to be specific for a definite ARD: (1) rheumatoid factor and anti-CCP antibodies in RA; (2) anti-Sm and anti-dsDNA antibodies in SLE; and (3) anticentromere, antitopoisomerase I (anti–Scl-70), and anti-RNA polymerase III antibodies in SSc. Yet, some other autoantibodies are present in several different ARDs. For example, (1) the anti–U1-RNP antibody can be associated with MCTD, SLE, SSc, and myositis; and (2) anti-Ro antibodies can be seen in Sjögren syndrome, subacute cutaneous lupus, neonatal lupus, and the antisynthetase syndrome. Conversely, various apparently disparate and mutually exclusive autoantibodies have been associated with a similar clinical phenotype: (1) antibodies to several aminoacyl transfer RNA synthetases are related to the shared phenotype of the antisynthetase syndrome; and (2) various mutually exclusive autoantibodies are related to SSc. Moreover, though some disease manifestations are unique to each condition, others can be seen in several of these diseases, such as rash, Raynaud phenomenon, inflammatory arthritis, interstitial lung disease (ILD), and sicca syndrome. Each of these manifestations can develop in several different ARDs such as RA, SLE, SSc, or polymyositis/dermatomyositis (PM/DM). Sometimes, patients can be diagnosed with UCTD due to a lack of sufficient items to fulfill the classification criteria for a defined ARD.³ With time, some of these patients may eventually accrue enough features to meet the classification criteria for a well-defined ARD such as SLE, SSc, or myositis. Moreover, the phenotype of many patients who initially fulfill the classification criteria for MCTD,⁴ with high-titer anti–U1-RNP antibodies and overlapping features of SSc, SLE, and PM, may polarize over time to exclusively manifest features characteristic of one of its component diseases.

It is essential to recognize that clinical and laboratory features may differ among patients within a defined ARD. Hence, there are classification criteria proposed by professional organizations such as the ACR and/or EULAR that include a collection of symptoms, signs, autoantibodies, and results of other diagnostic tests. These classification criteria define a homogeneous group of patients with a specific diagnosis for enrollment in research studies, comparing outcomes between different cohorts and giving a better idea about the long-term prognosis. Over the years, these classification criteria have been refined and updated multiple times by experts within the field, under the auspices of various professional organizations, to improve their operating characteristics (sensitivity, specificity, and predictive values). On the other hand, ideal diagnostic criteria should be broad and must accurately reflect different disease features to identify as many patients with the condition as possible.⁵ Unfortunately, in many patients with an ARD, no such diagnostic criteria are currently available to define their specific disease.

Ultimately, managing these ARDs does not depend on their names. Instead, it relies on the identification of the various organ systems affected in any given patient, their extent and severity, and the pathophysiology of involvement of those specific organ systems: (1) relative contribution from joint inflammation vs joint damage vs central sensitization in a patient with RA; (2) nonspecific interstitial pneumonia vs usual interstitial pneumonia pattern of lung injury causing ILD in a patient with SSc, MCTD, SLE, or RA; (3) World Health Organization group I vs group III pulmonary hypertension in a patient with SSc or MCTD; (4) proliferative lupus nephritis vs thrombotic microangiopathy as the cause of renal disease in a patient with SLE; or (5) muscle biopsy showing features of PM, DM, inclusion body myositis, or immune-mediated necrotizing myopathy in a patient with an idiopathic inflammatory myopathy. In addition, it is essential to recognize whether the prevalent pathology in any affected organ system results from activity (inflammation) that is potentially reversible with immunomodulatory therapy, as opposed to damage that is cumulative and often tends to be irreversible. Once the pathophysiology of any organ system involvement in a particular patient is recognized, it needs to be addressed with either (1) appropriate disease-modifying therapy or (2) symptomatic treatment if the specific pathophysiology of the given condition is not understood or if no proven disease-modifying therapy is available.

When choosing a specific treatment regimen, it is also essential to consider the patient’s comorbidities, even if nonrheumatologic, to understand the advantages and contraindications of a proposed therapy.

Patient preferences are equally important, with thorough knowledge of the risks, benefits, alternatives, and expectations. The clinical manifestations resulting from the nature and severity of the involved organ systems may not necessarily correlate with how a disease affects a particular patient. Hence, patient-reported expectations and outcomes are increasingly becoming recognized as an essential part of how a specific disease affects an individual. It is for this reason that a patient’s perspective of their disease is crucial during the process of shared decision making.

As a result, what is essential in following the disease course, assessing prognosis, and recommending disease-modifying therapy is not so much based on the diagnosis of a specific ARD as it is the extent and nature of various organ systems involved in any given patient and the evidence-based data on available disease-modifying and/or symptomatic therapy for these manifestations.

Thus, at the outset, trainees should not get too preoccupied with giving a specific name to the ARD that they are managing or the presence or absence of an autoantibody. Instead, they should learn to think and approach a particular manifestation of a disease or a syndrome based on its pathophysiology and pathogenesis. Since opinions about optimum investigations and management recommendations for any given patient tend to vary widely, even among experts, I prefer to apply a hands-off policy. I allow my trainees to manage their patients their way, as long as they can justify the thought process behind their decisions, which should be supported, where available, by convincing evidence from the literature. Trainees need to provide and discuss the general evidence-based management recommendations to help them confidently and effectively treat a pathophysiologic state rather than a specific ARD.

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