21: Is It an Autoimmune Rheumatic Disease?

Is It an Autoimmune Rheumatic Disease?

Mohammed Tikly1 and David D’Cruz2

1 Chris Hani Baragwanath Academic Hospital and University of the Witwatersrand, Johannesburg, South Africa

2 Louise Coote Lupus Unit, Guys and St Thomas’ Hospitals, London, UK

Systemic autoimmune rheumatic diseases, also commonly referred to as connective tissue diseases, are immune‐mediated inflammatory disorders associated with autoantibodies. The diagnosis of these disorders, such as systemic lupus erythematosus and scleroderma, can be challenging because many of the presenting clinical features are non‐specific and this often results in delayed diagnosis. Classification criteria for the major systemic autoimmune rheumatic diseases (see Chapters 12 and 18) have been developed primarily as a means of standardizing patient populations for clinical research rather than for diagnosis in routine clinical practice. These classification criteria are extremely limited for the early diagnosis of these disorders as they were designed to be highly specific and therefore lack diagnostic sensitivity.

In patients presenting with non‐specific symptoms and signs, such as Raynaud’s phenomenon, inflammatory arthritis, sicca symptoms and constitutional symptoms of fever, malaise and fatigue, it is often not possible to make a definitive diagnosis of a specific autoimmune rheumatic disease, especially early in the course of the illness (Box 21.1, Figure 21.1). Most patients over a period of months, or sometimes, years, fulfil classification criteria for one or more of the major systemic autoimmune rheumatic diseases. From a management perspective, it is important not only to recognize and treat potentially aggressive disease, but also to avoid overtreatment in patients where either the diagnosis is unclear or the disease has a potentially benign course.

Image described by caption.

Figure 21.1 Raynaud’s phenonenon with thumb involvement in scleroderma

Autoantibody profile in diagnosis

Antinuclear antibodies are a hallmark of systemic autoimmune rheumatic diseases and can be found in a variety of clinical settings. However, their occurrence does not necessarily indicate the presence of any specific disease – they are thus sensitive but not specific diagnostically. Serology is of particular value in situations where clinical expression of the autoimmune rheumatic disease is incomplete, where the presence of a particular antinuclear antibody profile may be diagnostic. It is therefore imperative that requests for antinuclear antibody tests and the interpretation of the results be done in the light of clinical findings.

The indirect immunofluorescence test, using the HEp2 cell substrate, is the gold standard for detecting antinuclear antibodies (Table 21.1). In systemic lupus erythematosus and scleroderma, antinuclear antibodies can be detected in 95% or more of untreated patients with active disease by this method. In patients suspected of having an autoimmune rheumatic disease, the indirect immunoflourescence test is enough as a screening test for antinuclear antibodies. It is not cost‐effective to test automatically for anti‐dsDNA or other antibody specificities. The individual antinuclear antibody fluorescent patterns are of limited diagnostic utility but may provide guidance to more specific immunological tests. A false negative antinuclear antibody test result sometimes occurs if either the antigen is outside the nucleus (for example, anti Jo‐1 and anti‐ribosomal P protein antibodies, both often categorized under the umbrella term ‘antinuclear antibodies’) or if it is present in a form not recognized by a particular autoantibody (for example, when anti‐Ro is directed exclusively to determinants on the native Ro molecule not expressed in cultured HEp2 cells). In such cases, the clinical picture dictates that specific autoantibody assays should be undertaken.

Table 21.1 Antinuclear antibodies in various diseases detected by indirect immunofluorescence

Condition Frequency of antinuclear antibodies (%)
Systemic autoimmune rheumatic diseases
Drug‐induced lupus 100
Systemic lupus erythematosus 98
Scleroderma 95
Sjögren’s syndrome 80
Pauciarticular juvenile idiopathic arthritis 70
Polymyositis or dermatomyositis 60
Rheumatoid arthritis 20
Organ‐specific autoimmune diseases
Primary autoimmune cholangitis 100
Autoimmune hepatitis 70
Myasthenia gravis 50
Autoimmune thyroid disease 45
Idiopathic pulmonary hypertension 30
Other conditions
Waldenstrom’s macroglobulinaemia 20
Subacute bacterial endocarditis 20
Infectious mononucleosis 15
Leprosy 15
HIV 10
Normal population
Children 8
Adults 15

Having detected antinuclear antibodies with the screening test, it is important to determine their specificity. This is part of the standard operating procedure of serology laboratories, but the process is greatly facilitated by the clinician giving sufficient clinical information when requesting the antinuclear antibody test. Specific antinuclear antibody tests are often helpful in stratifying patients into clinical subsets, which may be useful in the further management of specific clinical manifestations and prognostication (Table 21.2). These autoantibodies are usually present from the beginning of the clinical presentation and are detectable throughout the course of the disease. Some studies have shown that autoantibodies may be present for many years prior to clinical presentation. In some instances, such as the anti‐dsDNA test, autoantibody titres may fluctuate with disease activity. Many serology laboratories use commercial kits to detect specific autoantibodies and there is a move to using bead‐based multiplex immunoassays. Although the newer tests are less labour intensive, they vary in sensitivity and sometimes produce false‐positive results. This is especially the case with the anti‐dsDNA, anti‐Ro‐52 and anti‐Sm assays.

Table 21.2 Specificity of autoantibodies in diagnosis and disease expression

Disease Antibody Frequency (%) Clinical association
Systemic lupus erythematous Anti‐dsDNA 70 Lupus nephritis

Anti‐nucleosome 70 Early disease, lupus nephritis, drug‐induced lupus

Anti‐Sm 10–25* Vasculitis, neuropsychiatric lupus

Anti‐U1RNP 30‐50* Raynaud’s phenomenon, swollen fingers, arthritis, myositis, mixed connective tissue disease

Anti‐Ro 40 Photosensitive rash, subacute cutaneous lupus erythematosus, neonatal lupus, congenital heart block, Sjögren’s syndrome

Anti‐La 15 As for anti‐Ro

Antiribosomal P protein 15 Neuropsychiatric lupus (psychosis or depression)
Sjögren’s syndrome Anti‐Ro 60–90 Extraglandular disease, vasculitis, lymphoma

Anti‐La 35–85 As for anti‐Ro
Systemic sclerosis Anticentromere 5–30# Limited cutaneous disease, microvascular or macrovascular disease, telangiectasia, pulmonary hypertension

Antitopoisomerase 1 (anti‐Scl‐70) 25 Diffuse cutaneous disease, interstitial lung disease

Anti‐RNA polymerases 20 Rapidly progressive diffuse cutaneous disease, scleroderma renal crisis

Antifibrillarin (anti‐U3RNP) 5–20* Diffuse cutaneous disease in blacks, pulmonary hypertension

Anti‐ThRNP 4 Limited cutaneous disease

Anti‐PM‐Scl 5 Scleroderma‐polymyositis overlap

Anti‐Ku 2 Scleroderma‐polymyositis overlap
Dermatomyositis and polymyositis Anti‐Jo‐1 30 Antisynthetase syndrome: mechanic’s hands, interstitial lung disease

(antibodies to other tRNA synthetases) (3) (antisynthetase syndrome)

Anti‐SRP 4 Severe necrotizing myositis

Anti‐Mi2 10 Dermatomyositis

Cancer‐associated myositis
Clinically amyopathic dermatomyositis with interstitial lung disease
Systemic ANCA‐associated vasculitis** cANCA/antiproteinase 3 80–90 Granulomatosis with polyangiitis (Wegener’s granulomatosis)

pANCA/antimyeloperoxidase 90 Microscopic polyangiitis

Anti‐double‐stranded DNA antibody.

*Higher frequency in people of African or Indian origin.

With sensitive enzyme‐linked immunosorbent assays.

#Low frequency in people of African origin.

**Antineutrophil cytoplasmic antibodies.

Which systemic autoimmune rheumatic disease?

Although the clinical presentation in the early stages can be similar between the systemic autoimmune rheumatic diseases, the evolution of typical clinical features over weeks or months usually distinguishes the characteristic patterns associated with the different diseases. Early diagnosis is aided by recognition of distinctive serological profiles that are generally present with the earliest clinical manifestations. Diagnosis can also be facilitated by typical laboratory abnormalities and histological changes in the tissues involved. For example, microscopic polyangiitis presenting with weight loss, fever, polyarthritis and active urinary sediment can be distinguished from lupus by an autoimmune response characterized by p‐ANCA antibodies directed against myeloperoxidase and the typical histological picture of pauci‐immune focal necrotizing glomerulonephritis. Similarly, clinically amyopathic dermatomyositis that presents with photosensitive eruptions on the face, arms and hands and is associated with myalgia can be distinguished from lupus by the distribution of the skin eruption, a raised serum creatine kinase, anti‐MDA5 and other myositis antibodies and typical changes on muscle biopsy, despite the absence of frank muscle weakness.

Diagnosis is often complicated if lupus is part of an overlap syndrome and the patient fulfils classification criteria for more than one systemic autoimmune rheumatic disease. Sometimes the overlap features are evident at initial presentation; at other times, the picture evolves sequentially. Patients who fulfil criteria for both systemic lupus erythematosus and rheumatoid arthritis are sometimes referred to as having ‘rhupus’. These patients are usually diagnosed as having rheumatoid arthritis initially because of typical rheumatoid features such as erosive arthritis, subcutaneous nodules and rheumatoid factor. An overlap syndrome should be considered when these features are accompanied by cutaneous, renal, haematological or other clinical manifestations characteristic of systemic lupus erythematosus and the presence of anti‐dsDNA antibodies.

Development of Sjögren’s syndrome during the course of systemic lupus erythematosus is well established but occasionally, patients with primary Sjögren’s syndrome develop typical features of lupus, especially photosensitive eruptions typical of subacute cutaneous lupus erythematosus, after many years of disease.

A distinctive type of overlap syndrome is that of ‘mixed connective tissue disease’ (Box 21.2). Here patients have an overlap of puffy fingers of early scleroderma (Figure 21.2), systemic lupus erythematosus, polymyositis, and a characteristic serological profile that includes high levels of antibodies to U1RNP. However, there is much controversy as to whether this is a distinct systemic rheumatic disease, with critics and protagonists.

Image described by caption and surrounding text.

Figure 21.2 Swollen ‘puffy’ fingers of patient with undifferentiated autoimmune rheumatic disease

Nov 5, 2018 | Posted by in RHEUMATOLOGY | Comments Off on 21: Is It an Autoimmune Rheumatic Disease?
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