Clinical aspects of autoimmune rheumatic diseases

Series

www.thelancet.com Vol 382 August 31, 2013 797

Autoimmune Rheumatic Diseases 1

Clinical aspects of autoimmune rheumatic diseasesFiona Goldblatt, Sean G O’Neill

Multisystem autoimmune rheumatic diseases are heterogeneous rare disorders associated with substantial morbidity and mortality. Eff orts to create international consensus within the past decade have resulted in the publication of new classifi cation or nomenclature criteria for several autoimmune rheumatic diseases, specifi cally for systemic lupus erythematosus, Sjögren’s syndrome, and the systemic vasculitides. Substantial progress has been made in the formulation of new criteria in systemic sclerosis and idiopathic infl ammatory myositis. Although the autoimmune rheumatic diseases share many common features and clinical presentations, diff erentiation between the diseases is crucial because of important distinctions in clinical course, appropriate drugs, and prognoses. We review some of the dilemmas in the diagnosis of these autoimmune rheumatic diseases, and focus on the importance of new classifi cation criteria, clinical assessment, and interpretation of autoimmune serology. In this era of improvement of mortality rates for patients with autoimmune rheumatic diseases, we pay particular attention to the eff ect of leading complications, specifi cally cardiovascular manifestations and cancer, and we update epidemiology and prognosis.

IntroductionAutoimmune diseases form a range of disorders from organ-specifi c (eg, Hashimoto’s thyroiditis) to systemic disorders with multi-organ involvement. Disorders that mainly, but not exclusively, aff ect joints and muscles are grouped together as the autoimmune rheumatic diseases, and include rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren’s syndrome, systemic sclerosis (scleroderma), idiopathic infl ammatory myositis, and the systemic vasculitides. These multi-system autoimmune rheumatic diseases are hetero-geneous disorders associated with substantial morbidity and mortality. Although these diseases can present classically, which makes diagnosis simple, they also share many common features, including consti tutional disturbance, arthralgia and arthritis, myalgia, sicca symp-toms, and pulmonary, renal, and neurological involve-ment, which can make diff erentiation between the diseases diffi cult.

Up to 50% of patients with an apparent autoimmune rheumatic disease cannot be readily diagnosed with a specifi c disorder in the fi rst 12 months of follow-up.1 The term undiff erentiated connective tissue disease is often used to describe this group of patients. Some patients with this presentation will progress to a defi ned autoimmune rheumatic disease during 5 years of follow-up, a smaller proportion resolve completely, and most remain symptomatic but undefi ned.2–4 Patients who remain symptomatic generally have a good prog-nosis, although the persistent symptoms and un-certainty about the diagnosis can lead to substantial patient frustration and morbidity. Less common is when convincing features of two autoimmune rheu-matic diseases are present, and terms such as rhupus (rheumatoid arthritis and systemic lupus erythema-tosus) or overlap syn drome (eg, scleroderma-lupus overlap) are often used. Management is largely guided by the dominant clinical phenotype. A more specifi c

diagnosis can be reached by review with an experienced clinician, eff ective use and judicious interpretation of immunopathological tests, together with careful follow-up, thereby helping to inform treat ment decisions and prognosis.

Rheumatology is entering an exciting time; several revised classifi cation criteria of autoimmune rheumatic diseases are available to help with diagnostic challenges and expanding treatment opportunities. This Review sum marises recent advances in understanding the clinical features of systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, idiopathic infl am ma tory myositis, and the systemic vasculitides, in particular concentrating on developments in classifi cation criteria, epidemiology, and prognosis, many as a result of international collaboration, and the long-term follow-up of dedicated cohorts of patients over several decades. Further articles in this Series will assess patho genesis and treatment of the autoimmune rheumatic diseases.

Use of autoantibodies in diagnosisAttempts to refi ne classifi cation criteria for various auto immune rheumatic diseases show the dilemma faced by clinicians in establishing early diagnosis and

Lancet 2013; 382: 797–808

See Editorial page 744

This is the fi rst in a Series of three papers about autoimmune rheumatic diseases

Department of Rheumatology, The Repatriation General Hospital, Adelaide, SA, Australia (F Goldblatt PhD); Flinders Medical Centre, Adelaide, SA, Australia (F Goldblatt); University of New South Wales South Western Sydney Clinical School, NSW, Australia (S G O’Neill PhD); and Department of Rheumatology, Liverpool Hospital, Liverpool, NSW, Australia (S G O’Neill)

Correspondence to:Dr Sean G O’Neill, Department of Rheumatology, Liverpool Hospital, Locked Bag 7103, Liverpool BC NSW 1871, [email protected]

Search Strategy and selection criteria

We searched the Cochrane Library and Medline from Jan 1, 1990, to Dec 31, 2012, with the search terms “systemic lupus erythematosus”, “SLE”, “Sjögren’s syndrome”, “systemic sclerosis”, “scleroderma”, “infl ammatory myositis”, “dermatomyositis”, “polymyositis”, “inclusion body myositis”, “systemic vasculitis”, “giant cell arteritis”, “temporal arteritis”, “Takayasu’s arteritis”, “polyarteritis nodoa”, “Wegener’s granulomatosis”, “granulomatosis with polyangiitis”, “Churg Strauss syndrome”, “microscopic polyangiitis” in combination with the term “clinical”. We mainly selected publications from the past 5 years, but did not exclude commonly referenced and highly regarded older publications. Reference lists of articles identifi ed by this search strategy were also reviewed and we selected those we judged relevant. Our reference list was modifi ed on the basis of comments from peer reviewers.

http://crossmark.dyndns.org/dialog/?doi=10.1016/S0140-6736(13)61499-3&domain=pdf

Series

798 www.thelancet.com Vol 382 August 31, 2013

prognosis. Although diagnosis can be straightforward when characteristic features of specifi c diseases are present, patients ultimately diagnosed with an auto-immune rheumatic disease are often a diagnostic challenge. Many of the early symptoms are prodromal features of constitutional disturbance that are clinically indistin guishable (including fevers, weight loss, poly-arthralgia, polymyalgia, headache, malaise, and fatigue) and variable organ-specifi c manifestations, such as sicca symptoms or Raynaud’s phenomenon, which might not be disease specifi c (tables 1 and 2). Patients are often initially extensively assessed for infectious causes and cancer before diagnosis of an autoimmune rheumatic disease is considered.

In the setting of undiff erentiated disease, clinicians need to carefully interpret the results of autoantibody tests and consider the clinical context, sensitivity, specifi city, and implications of the test undertaken. A growing number of autoantibodies have specifi city for particular clinical pheno types, and can off er prognostic information and diagnostic certainty (table 3). Further more, in patients ultimately diagnosed with systemic lupus erythematosus, Sjögren’s syndrome, and systemic sclerosis, several anti-bodies precede symptoms by many years.5–7 Patients with

systemic lupus erythematosus might have detectable antinuclear antibodies many years before symptom onset, and fi ndings from studies in military recruits have shown a gradual increase of more specifi c antibody accumulation in the months before diagnosis.5 Asymptomatic mothers of children with complete heart block often have anti-Ro/SSA, and many eventually develop clinical features of Sjögren’s syn drome or systemic lupus erythematosus.7 Patients with Raynaud’s phenomenon and nailfold capilla-roscopy abnormalities who also have anti centromere, anti-topoisomerase I, or anti-RNA poly merase III anti bodies are 60 times more likely to develop systemic sclerosis than are those with Raynaud’s alone, with around 80% of such patients developing systemic sclerosis within 15 years.8

Autoantibodies are increasingly recognised in patients with myositis, and the presence of mutually exclusive myositis-specifi c antibodies helps to confi rm diagnosis of an idiopathic infl ammatory myositis and to classify phenotype, guide treatment, and predict prognosis. Many of these antibodies can now be routinely requested as part of the myositis immunoblot (anti-Jo-1, Mi-2, Ku, PM-Scl100, PM-Scl75, SRP, PL-7, PL-12, EJ, OJ). Of the antisynthetase myositis-specifi c antibodies that are directed against aminoacyl-transfer RNA synthetases,

Systemic lupus erythematosus Sjögren’s syndrome Systemic sclerosis Idiopathic infl ammatory myositis

Constitutional signs and symptoms (eg, fever, fatigue, and weight loss)

Common Fatigue (severe) Less prominent primary symptoms Common, mainly fatigue, usually without fever

Arthritis or arthralgia Common, typically nonerosive Common, nonerosive Arthralgia common, synovitis rare Polyarticular, and mild, erosive, and deforming with anti-Jo-1

Muscle symptoms Myalgia, myositis (1–4%) Myalgia Myalgia, disuse atrophy, myositis (rare)

Substantial weakness, occasional pain

Mucocutaneous manifestations Malar, discoid rashes, photosensitivity, mouth ulcers

Dryness, oral infections, hypergammaglobulinaemia purpura

Skin fi brosis, sclerodactyly, calcinosis, telangiectasia†

Rashes with dermatomyositis (eg, Gottron’s papules, heliotropic rash eyes, V signs, and shawl signs)

Raynaud’s syndrome Yes (about 20% of patients) Yes Frequent, severe Yes

Sicca syndrome 10–20% of patients Prominent mouth and eyes Occasional <10% of patients

Cardiovascular disease Pericarditis, early cardiovascular disease, and Libman-Sacks endocarditis

Uncommon Right heart failure and secondary pulmonary hypertension

Arrhythmias, valvular heart disease, and ischaemia

Pulmonary symptoms Serositis, pulmonary embolism, interstitial lung disease, pulmonary hypertension, shrinking lung

Chronic cough and lymphoproliferative disorders

Interstitial lung diseas and pulmonary hypertension (10–50% of patients)

Dry cough, shortness of breath, respiratory muscle weakness, interstitial lung disease, pulmonary hypertension, and bronchiolitis obliterans organising pneumonia

Gastrointestinal symptoms Mesenteric vasculitis Dysphagia and primary biliary cirrhosis

Oesophageal dysfunction, gastro-oesophageal refl ux disease, diarrhoea, and faecal incontinence

Dysphagia most common, gastro-oesophageal refl ux disease

Renal symptoms Yes (30–50% of patients), glomerulonephritis

Interstitial lymphocytic nephritis, distal tubular acidosis, and interstitial cystitis

Renal crisis (diff use systemic sclerosis), more common mild dysfunction

Very rare

Neurological symptoms Headache, mood, cognitive disorders (20–30% of patients), other more severe and rare

CNS, peripheral nervous system, autonomic nervous system; Adie’s pupil, orthostatic intolerance

Very infrequent, includes cranial neuropathies

CNS very uncommon

Haematological symptoms Common, decreased white cell count, platelets, and haemoglobin

Decreased white cell count, anaemia (<10% of patients)

Anaemia secondary to gastrointestinal blood loss

Very rare

*Clinical features of systemic vasculitides in table 2. †Dependent on whether disease subtype is limited or diff use.

Table 1: Representative clinical features of the autoimmune rheumatic diseases*

Series


anti-Jo-1 is most frequently present, in 20–25% of patients with polymyositis or dermatomyositis. This cohort can develop the classical antisynthetase syn-drome of fever (80%), lung fi brosis (70%), mechanic’s hands, polyarthropathy (nonerosive aff ecting fi ngers, wrists, elbows, and knees), and Raynaud’s (60%) in association with myositis. No commercially available assay exists for the newly described TRIM33 antibody (also known as TIF1γ antibody), reportedly present in up to 15% of patients with idiopathic infl ammatory myositis.9 Amyo pathic dermatomyositis is a subtype of dermatomyositis in which patients present with 6 months or longer of classic, biopsy proven rashes in the absence of clinical or laboratory evidence of myositis. About half of these patients are positive for the CADM-140 antibody (also known as anti-MDA-5), which can help clarify diagnosis.

Recent advances in disease defi nitions and classifi cationClinicians need to recognise the important distinctions between nomenclature systems, classifi cation criteria, and diagnostic criteria. Diagnostic criteria are intended for clinical use to confi rm the presence of a disease. Nomenclature systems, such as those discussed in

reference to systemic vasculitis, specify the name to be used once a specifi c diagnosis is made. Classifi cation criteria are fi ndings that allow the classifi cation of a patient into a particular category for further study and are crucial to ensure standardisation of patients entered into clinical studies so that outcomes and responses can be consistently and confi dently compared. To fulfi l the classifi cation criteria implies the presence of a disease, but the converse is not necessarily true; in clinical practice a patient might be diagnosed with a particular disease although they do not fulfi l the published classifi cation criteria. The past 5 years have seen renewed eff orts to devise and validate classifi cation criteria for many autoimmune rheumatic diseases.10 These eff orts have been characterised by international collaborations that have linked together present understanding of clinical and laboratory features of specifi c diseases, with the goal of creating practical, accurate classifi cation criteria, validated in a range of populations.

The American College of Rheumatology (ACR) 1982 revised classifi cation criteria for systemic lupus erythema tosus, and the 1997 update (to remove the presence of the lupus erythematosus cell and include antiphospholipid antibodies) have been used worldwide for 30 years.11,12 The criteria have high specifi city for the

Giant cell arteritis Polyarteritis nodosa Granulomatosiswith polyangiitis

Eosinophilic granulomatosis with polyangiitis

Microscopic polyangiitis

Predominant blood vessel type Large Muscular arteries (medium or small arteries)

Arterioles-venules, sometimes arteries, veins



Granulomatous infl ammation Yes No Yes Yes No

ANCA positivity No No 80–90% (cytoplasmic ANCA/ antiproteinase 3)

50% (perinuclear ANCA/myeloperoxidase)

75% (perinuclear ANCA/myeloperoxidase)

Upper respiratory tract symptoms No No Sinusitis, epistaxis, nasal septal perforation, saddle nose deformity, nasal crusting, and subglottic stenosis

Nasal polyps and allergic rhinitis Usually absent or mild

Lung No Asthma Nodules, infi ltrates or cavitary lesions, and haemoptysis

Asthma, infi ltrates, and haemoptysis

Alveolar haemorrhage

Glomerulonephritis No No Yes Yes Yes

Renal hypertension No Yes No No No

Gastrointestinal No Yes No Yes (eosinophilic gastroenteritis); pain, diarrhoea, and bleeding

Yes

Cardiac Uncommon, coronary artery involvement, ischaemic heart disease, congestive cardiac failure

Yes (myocarditis) Yes (valvular infarction) Yes (eosinophilic myocardial infi ltration, cardiomyopathy in 50% of patients)

Uncommon (congestive cardiac failure)

Skin No Nodules, livido reticularis painful serpiginous rash

Yes Yes (tender nodules) Yes

Mononeuritis multiplex Yes Common Occasional Common Common

Ocular Yes(vasculitic optic neuritis)

Yes (scleritis) Yes (including retro-orbital granulomata)

Uncommon (scleritis and uveitis) Yes (typically mild)

Distinguishing features Blindness, headaches, scalp tenderness, jaw claudicationOften associated with polymyalgia rheumatica

ANCA-negative, testicular involvement, painful rash

Destructive upper airways disease, granulomatous infl ammation

Asthma, allergy, eosinophilia, granulomatous infi ltrates with abundant eosinophils

No granulomatous infl ammation

ANCA=antineutrophil cytoplasmic antibody.

Table 2: Comparison of clinicopathological features of systemic vasculitides

Series


diagnosis of systemic lupus erythematosus, but are often wrongly used by clinicians as diagnostic criteria. This practice can lead to underdiagnosis of early disease or the overuse of vague terms such as lupus-like or undif-ferentiated autoimmune rheumatic disease. The criteria have been criticised because they only include a few defi nitions of various features of systemic lupus erythema tosus (eg, neuropsychiatric systemic lupus erythematosus), rely heavily on the presence of cutaneous manifestations and arthritis, and do not require any immunological criteria for classifi cation.

In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) group proposed an updated classifi cation system including 11 clinical and six immunological criteria.13 These criteria address several of the previously listed issues by the inclusion of broader defi nitions for the clinical abnormalities, especially for cutaneous and neuropsychiatric lupus, and by the inclusion of low complement concentrations as immunological criteria. Furthermore, both clinical and immunological criteria need to be fulfi lled (panel 1). Classifi cation of systemic lupus erythematosus needs to meet four criteria, including

Antibody prevalence Main clinical mainfestations and associations

Systemic lupus erythematosus

Double-stranded DNA 70–80 Kidney disease, skin disease

Nucleosomes 60–90 Kidney disease, skin disease

Smith Small nuclear ribonucleoproteins (spliceosomes, U1-RNP, 70kD, A, C)

10–3015–25

Kidney diseaseRaynaud’s syndrome, puff y fi ngers, myositis, and hypergammaglobulinaemia

N-methyl-D-aspartate receptor 33–50 CNS lupus

Phospholipids(cardiolipin, β2 GP1, prothrombin)

20–30 Thrombosis, pregnancy loss, thickened heart valve disease, and livido reticularis

α-Actinin 20 Kidney disease

Ribosomes P0, P1, and P2 4–12 Hepatic, central nervous manifestations (psychosis)

C1q 40–50 Kidney disease, associated with disease activity

Systemic lupus erythematosus and Sjögren’s syndrome

Ro/SSA 30–40 Kidney disease in systemic lupus erythematosus in the absence of anti-La/SSB, skin disease in systemic lupus erythematosus and photosensitivity; congenital heart block and neonatal lupus erythematosus, sicca symptoms; subacute cutaneous lupus, hypergammaglobulinaemia, leucopenia; interstitial nephritis and increased risk of non-Hodgkin lymphoma in patients with Sjögren’s syndrome

La/SSB 15–20 Congenital heart block and neonatal lupus erythematosus, sicca symptoms; photosensitivity, subacute cutaneous lupus erythematosus, hypergammaglobulinaemia, leucopenia; increased risk of increased non-Hodgkin lymphoma in patients with Sjögren’s syndrome

α-Fodrine 46–100 in Sjögren’s syndrome and30 in systemic lupus erythematosus

Sicca symptoms

Idiopathic infl ammatory myositis

Jo-1, Pl-7, Pl-12, OJ, EJ 20–30 Anti-synthetase syndrome

Signal recognition particle 2–8 Necrotising myopathy

Mi-2 8–12 in idiopathic infl ammatory myositis,15–20 dermatomyositis

Dermatomyositis and idiopathic infl ammatory myositis

TRIM33 10–30 of dermatomyositis Dermatomyositis, malignancy

U1-RNP/U2-RNP 8–15 Mixed connective tissue more commonly than systemic lupus erythematosus, systemic sclerosis, and undiff erentiated connective tissue disorder

PM/Scl 12–16 Dermatomyositis and systemic sclerosis overlap, systemic sclerosis, and dermatomyositis

Ku 1–7 Myositis overlap, systemic lupus erythematosus, idiopathic infl ammatory myositis, and systemic sclerosis

CADM-140/anti-MDA-5 antibody(clinically amyopathic dermatomyositis /anti-melanoma-diff erentiation-associated gene 5)

Infrequent Amyopathic dermatomyositis (53%) with interstitial lung disease

Systemic sclerosis

Centromere 15–40 Limited systemic sclerosis, pulmonary hypertension

Scl-70/topoisomerase 10–40 Diff use cutaneous systemic sclerosis, pulmonary fi brosis

RNA polymerase III 5–25 Diff use cutaneous systemic sclerosis, renal crisis, pulmonary hypertension

Autoantibodies without disease specifi city

Rheumatoid factor 30–40, 90–95, and 10–20 Systemic lupus erythematosus, Sjögren’s syndrome and myositis

Antibodies against proteasome subunits 40–60, 50–60, and 40 Idiopathic infl ammatory myositis, systemic lupus erythematosus, and Sjögren’s syndrome

Table 3: Autoantibody prevalence in autoimmune rheumatic diseases

Series


the presence of at least one clinical and one immunological criterion, or the presence of biopsy proven lupus nephritis with a positive antinuclear antibody or anti-DNA antibody. In a validation sample, this approach resulted in a higher sensitivity for diagnosis of systemic lupus erythematosus than with the ACR criteria (97% vs 83%), but a lower specifi city (84% vs 96%). Although the ACR classifi cation criteria continue to perform well compared with the gold standard of physician diagnosis, the SLICC classifi cation criteria provide an updated alternative for physicians undertaking clinical research in patients with systemic lupus erythematosus. The criteria have not yet been widely accepted, but they address many of the criticisms of the ACR criteria, and were developed with a collaborative, international approach that might help with their approval. If widely accepted, these criteria could lead to the inclusion in clinical and epidemiological studies of patients with more diverse disease manifestations than in previous studies—eg, more patients with neuro psychiatric manifestations or those with lupus nephritis in the absence of skin and joint disease. An apparent reduction in the relative frequency of skin and joint disease might be seen too. The broader defi nitions used will hopefully allow earlier classifi cation of systemic lupus erythematosus, helping the study of early intervention.

The absence of a gold standard objective test and the nonspecifi c nature of many of the symptoms of Sjögren’s syndrome have caused dispute over a classifi cation criteria; 11 systems have been judged as suboptimum and not endorsed by the ACR or European League Against Rheumatism (EULAR).14 Ocular-oral symptoms are not reliable in the diagnosis or classifi cation of primary Sjögren’s syndrome, and conversely, many patients (up to 30%) with anti-SSA/Ro or SSB/La autoantibodies or both, increased antinuclear antibody and rheumatoid factor, positive labial salivary gland biopsy, or positive Schirmer’s test might not report dry eyes, dry mouth, or either symptom.14 In the past decade, the American–European Consensus Group criteria15 were widely used because they were believed to have better specifi city than many earlier criteria because of the need to show evidence of autoimmunity. However, the criteria were criticised for inclusion of subjective symptoms and opportunities to use alternative diagnostic tests of unequal diagnostic equivalence. New classifi -cation criteria were necessary to better support aetio-logical and genetic research and treatment trials, especially in this era of possible biological treatments for Sjögren’s syndrome. In view of the potentially serious adverse eff ects of biological agents, any new criteria used for enrolment into clinical trials should be clear, be easy to apply, and have high specifi city. Most clinicians believe that diagnosis should only apply to patients with clear evidence of autoimmunity or target organ infi ltration.

The recently published and provisionally approved ACR classifi cation criteria14 for Sjögren’s syndrome are based entirely on objective measures. To defi ne a case of

Sjögren’s syndrome, at least two of the following criteria are needed: positive serum anti-SSA or anti-SSB or both, or positive rheumatoid factor and antinuclear antibody titre of 1/320 or more; keratoconjunctivitis sicca with ocular staining score of 3 or more (ocular staining score replaces the Rose Bengal score in the assessment of conjunctival and corneal damage due to kerato-conjunctivitis sicca16); or presence of focal lymphocytic sialadenitis with a focus score of 1 focus/4 mm² or more in labial salivary gland biopsy samples, in the absence of exclusion criteria (eg, history of head and neck radiation, hepatitis C infection, sarcoidosis, immunoglobulin-G4-related disease). Results from validation studies show high sensitivity and specifi city for the criteria, with values dependent on the agreed gold standard. When compared with the American–European Consensus Group criteria, sensitivity of the ACR criteria was 94·7% and specifi city was 93·3%.14 The criteria are better than the existing alternatives and the international approach to their development will hopefully lead to widespread accept-ance. The exclusion of symptoms from the criteria, though a strength in terms of accuracy and reproducibility, might not appeal to patients and clinicians. Classifi cation needs the involvement of at least two diff erent specialties, which might also limit the widespread use of the criteria.

The characteristic skin fi brosis seen in systemic sclerosis has many diff erential diagnoses including

Panel 1: Systemic Lupus International Collaborating Clinics criteria for classifi cation of systemic lupus erythematosus

Clinical criteria• Acute cutaneous lupus• Chronic cutaneous lupus• Oral ulcers• Non-scarring alopecia• Synovitis in two or more joints (includes tenderness and

30 min of early morning stiff ness)• Serositis• Renal: urine protein-to-creatinine ratio or 24 h collection

representing 500 mg protein/24 h• Neurological• Haemolytic anaemia• Leucopenia• Thrombocytopenia

Immunological criteria• Antinuclear antibodies• Anti-double-stranded DNA• Anti-Smith• Antiphospholipid antibody• Low complement• Direct Coombs test in the absence of haemolytic anaemia

Classifi cation needs four criteria sequentially, including one clinical and one immunological, or biopsy-proven lupus nephritis with a positive antinuclear antibody or anti-double-stranded DNA antibody. Items are only generally scored if present without other known causes.

Series


thyroid disease, diabetes, amyloidosis, nephrogenic systemic fi brosis, eosinophilic fasciitis, and exposure to various drugs and environmental toxins. Additionally, localised cutaneous forms of scleroderma exist, including the various morpheas. Thus, early disease can pose diag-nostic challenges. After systemic sclerosis is diagnosed, disease is further defi ned as limited or diff use cutaneous systemic sclerosis mainly by the extent of skin involve-ment. Specifi c patterns of Raynaud’s phenomenon, organ involvement, and antibody profi les are suggestive of each group.17,18 The classifi cation is often one of best fi t and patients can have features of both subgroups.

Limited cutaneous systemic sclerosis typically presents after many years of Raynaud’s phenomenon. The skin involvement is usually restricted to the extremities and face.18 Although this is generally regarded as the milder pattern of systemic sclerosis, some patients develop pulmonary hypertension in the absence of interstitial lung disease. Anticentromere antibodies are seen in more than 50% of patients, and antiScl-70 in less than 10%.19,20 Diff use cutaneous systemic sclerosis is charac-terised by more aggressive and widespread skin changes, including involvement of the proximal limbs and trunk.18 Skin changes often begin less than 1 year after the onset of Raynaud’s phenomenon. Renal disease, interstitial lung disease, gastrointestinal disease, and myocardial disease are more common and severe than in limited cutaneous systemic sclerosis. AntiScl-70 antibodies are present in roughly 30% of patients and are associated with pulmonary fi brosis.21

The 2001 LeRoy and Medsger criteria22 further acknow-ledge limited systemic sclerosis as patients with Raynaud’s and positive systemic sclerosis-associated

autoantibodies, and abnormal nailfold capillaroscopy, or both, in the absence of skin thickening. The fi nding of nailfold capillaroscopy abnormalities and the presence of an autoantibody associated with systemic sclerosis have subsequently been shown to be strong predictors of progression to systemic sclerosis in patients with Raynaud’s phenomenon, with 80% being diagnosed with systemic sclerosis within 15 years.8

Despite the distinctions between the types of systemic sclerosis, the ACR criteria used for classifi cation with systemic sclerosis were designed for specifi city and consequently do not identify many individuals with limited cutaneous systemic sclerosis, nor those with limited systemic sclerosis. An international eff ort is in progress to update the classifi cation of patients with systemic sclerosis with a working group supported by ACR and EULAR.23,24 The new criteria will hopefully enable earlier classifi cation and thus therapeutic inter-vention before fi brosis, vasculopathy, and end-organ dysfunction are advanced. Substantial progress has been made and further results are eagerly awaited.

The 1975 Bohan and Peter criteria25,26 for idiopathic infl ammatory myositis have long been regarded as gold standard for diagnosis and inclusion into clinical trials (panel 2). These disorders have distinct clinical presen-tations, pathological fi ndings, response to treatment, and prognosis, depending on the individual’s immunogenetic profi le and presumably various potential environmental and infectious triggers.27,28 The Bohan and Peter criteria broadly classify the most common forms into subsets on the basis of clinical and histopathological diagnostic features available at the time of publication as primary idiopathic polymyositis, primary idiopathic dermato-myositis, polymyositis or dermatomyositis with cancer, juvenile dermatomyositis (or polymyositis) associated with vasculitis, and polymyositis or dermatomyositis with associated collagen vascular diseases. Inclusion body myositis and other infl ammatory myopathies were not recognised when these criteria were developed and hence were not included. Increasingly advanced understanding of immuno pathogenesis and immunohistochemistry, use of muscle MRI, and recognition of specifi c auto-antibody associations have markedly broadened our knowledge of these diseases since the 1980s. Myositis-associated auto antibodies (anti-SSA, SSB, U1RNP, U3RNP, PM-Scl, and Ku) or myositis-specifi c autoanti-bodies are present in serum samples of roughly 70–90% of patients with myositis, with myositis-specifi c auto-antibodies recorded only in idiopathic infl ammatory myositis29 (table 3). Increasing evidence suggests that the myositis-specifi c autoantibodies defi ne widely diff erent subgroups within idiopathic infl ammatory myositis, allowing better descrip tion of clinical symptoms and prognosis and assisting in development of more adequate treatments. The International Myositis Assessment and Clinical Studies (IMACS) group and other collaborating groups, with the support of the ACR and EULAR, have

Panel 2: Bohan and Peter criteria for the diagnosis of polymyositis and dermatomyositis• Proximal muscle weakness, usually symmetrical• Raised concentrations of serum muscle enzymes (creatine kinase and aldolase)• Electromyographic abnormalities:

• Common: myopathic potential low amplitude, short duration, and polyphasic action potentials

• Characteristic triad: myopathic potentials; fi brillations, positive sharp waves, increased insertional activity; complex repetitive discharges

• Muscle biopsy fi ndings typical of polymyositis or dermatomyositis: necrosis, phagocytosis, regeneration, and infl ammation

• Dermatological features of dermatomyositis, Gottron’s sign or papules, or heliotropic rash

• Defi nite dermatomyositis needs four criteria (including rash) and defi nite polymyositis needs four criteria (without rash); probable disease comprises three criteria (including rash) for dermatomyositis and three criteria (without rash) for polymyositis; possible disease needs two criteria (including rash) for dermatomyositis and two criteria (without rash) for polymyositis

• Exclusion criteria include motor neuron disease, myasthenia gravis, infectious causes, granulomatous diseases (eg, sarcoidosis), endocrine (eg, hypothyroidism), and toxic causes (eg, alcohol and drugs) of myopathies

Series


initiated large-scale consensus eff orts in a continuing multi disciplinary project to develop up-to-date clas-sifi cation criteria to help distinguish subsets of patients in a clinically meaningful way.

Classifi cation of vasculitides (a broad range of rare disorders characterised by an infl ammatory necrosis of the blood vessel walls) has been problematic because of competing systems, the complex nature of the diseases, and rapid evolution in understanding the pathogenesis of the disorders since various criteria were defi ned. Until recently, a combination of the 1990 ACR30 and Chapel Hill Consensus Conference (CHCC) nomenclature31 were most widely used. A defi nition for microscopic polyangiitis was included in the 1994 CHCC criteria, which allowed a clear diff erentiation from polyarteritis nodosa for the fi rst time. Consequently, many patients diagnosed with polyarteritis nodosa with the ACR criteria were reclassifi ed as having microscopic polyangiitis, and this should be considered in the interpretation and comparison of previous data. Despite many attempts to reclassify defi nitions, substantial limitations have persisted—eg, the incompatibility of ACR and CHCC 1994 criteria for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and polyarteritis nodosa.

To further improve classifi cation and make it more relevant to clinical and pathological assessment of the vasculitidies, expert committees were formed to update diagnostic and classifi cation criteria for uniformity and treatment based on the clinical, serological, and histopathological features of vasculitis. Revised nomen-clature was proposed in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.32 This system defi nes the name that should be used for a specifi cally defi ned disease process and is not a classifi cation or diagnostic criteria. Nevertheless, the criteria are a useful method for physicians to classify patients with clinical vasculitis. Primary systemic vasculitides continue to be described mainly according to the aff ected vessel size, and by the presence or absence of ANCA. When justifi able, the criteria also sought to remove eponymous names.

The large vessel subgroup consists of giant cell arteritis and Takaysu arteritis. The subgroup of medium sized arteries include polyarteritis nodosa and Kawaski disease. The small vessel subgroup is characterised by two features. The fi rst is the presence of ANCA, and is known as ANCA-associated vasculitis, the major clinico patho-logical variants being granulomatosis with polyangiitis (previously Wegener’s granulomatosis), eosinophilic granulomatosis with polyangiitis (Churg-Strauss syn-drome), and microscopic polyangiitis. The second is immune complex vasculitis, which includes immuno-globulin A vasculitis (Henoch-Schönlein), characterised by immunoglobulin A-dominant immune deposits, and cryoglobulinaemic vasculitis (eg, essential, associated with hepatitis C). The additional classifi cation of ANCA-associated vasculitis is a consequence of advances in

knowledge about ANCA; with the clear specifi cation that polyarteritis nodosa is not associated with ANCA, this subgroup can be more easily diagnosed from the otherwise clinically and pathologically indistinguishable ANCA-associated vasculitis.

EpidemiologyChanges in classifi cation criteria pose several chal-lenges to understanding the epidemiology of the auto-immune rheumatic diseases. The changes make historic comparisons diffi cult, and the use of diff erent criteria in diff erent parts of the world further restricts assessment of the global burden of these diseases. The rarity of individual autoimmune rheumatic diseases also contributes to the diffi culties in the creation of accurate data on incidence and prevalence. Although improved understanding of these disorders and the widespread use of autoantibody testing have led to earlier detection of cases, huge variation in access to health care worldwide and in methods of antibody testing remain. Together with the fi nding that antibodies might be present years before development of the clinical phenotype, assessment of geographical or environmental contributors to disease is very diffi cult. Despite these restrictions, progress has been made through long-term follow-up of large cohorts and international collaboration.

Sjögren’s syndrome is one of the most common autoimmune diseases worldwide with an estimated preva lence of between 300 and 600 per 100 000, and a 9:1 female ratio.33 However, the true prevalence might be much higher in view of the nonspecifi c nature, and hence under-reporting of many of the symptoms. Other issues are the absence of large epidemiological studies and the diffi culties associated with interpretation of existing studies because of diff erent inclusion criteria and disease defi nitions. In isolation, the disease is referred to as primary Sjögren’s syndrome or as secondary Sjögren’s syndrome if in conjunction with another autoimmune rheumatic disease (roughly 30% of patients with auto-immune rheumatic disease have secondary symptoms of Sjögren’s syndrome), most commonly rheumatoid arthritis or systemic lupus erythematosus.

In most studies, incidence rates of systemic lupus erythema tosus are between one and ten per 100 000 per year.34 Prevalence estimates vary between 20 and 200 per 100 000.34,35 The data vary widely between studies, partly dependent on the population studied—eg, sex, ethnicity, geographical location, and age. The incidence of systemic lupus erythematosus seems to be increasing, partly because of changes in classifi cation criteria and the increased recognition of milder cases.36,37 The method of case ascertainment also contributes to diff erences between studies, with higher prevalence seen in studies that use self-reported diagnoses.38,39

Systemic lupus erythematosus is more common in non-Caucasian populations. Findings from various studies show a three to four times increase in prevalence

Series


and a markedly higher burden in non-Caucasians world-wide.34 This clinical fi nding has been confi rmed in several large registry studies.40 International collaboration has contributed large sample sizes that have provided a foundation for several genetic studies in the present genomic era. A recent genome-wide association study identifi ed around 30 genetic risk loci for systemic lupus erythematosus, some of which are present in many ethnic groups.41 These fi ndings have shed light on the pathogenesis of the disease and have contributed to the growth of interest in the dendritic cell and interferon α pathway. This topic is further considered in the next Review in this Series by Marie Wahren-Helenius and Thomas Döner.42 Genetic risk factors might help to explain some of the phenotypic heterogeneity recorded in systemic lupus erythematosus.43

Estimates of incidence and prevalence of systemic sclerosis vary widely dependent on geographical location, population studied, defi nitions of disease, and method of case ascertainment. Worldwide, reported incidence rates range from 0·06 to 12 per 100 000 per year, with a prevalence of between 0·7 and 50 per 100 000.44 Despite diff erences in methods, the disease seems to be more common in Australia (23 per 100 000) and North America (27 per 100 000) than in Japan (four per 100 000) and Europe (eight to 15 per 100 000). Additionally, increasing prevalence along a north–south gradient has been recorded within Europe.44,45 The disease is more com-mon and more severe in African–Americans than in Caucasians of similar socioeconomic status.46 Recent genetic studies have identifi ed several risk loci for systemic sclerosis, many of which are implicated in other autoimmune rheumatic diseases, suggesting shared and disease-specifi c pathogenesis.47,48 Despite the high preva-lence of positive antinuclear antibodies in relatives of patients with systemic sclerosis, the concordance rate in monozygotic twins is only around 5%, suggesting a large role for environmental triggers or chance in the develop-ment of clinical disease.49 Many environmental triggers have been suggested, and might help account for geo-graphical clustering of the disease, with two prominent examples being silica exposure and organic solvent exposure in a minority of cases.50,51

Idiopathic infl ammatory myopathies have an estimated incidence of 0·1–1 per 100 000 per year. The sex ratio varies between disorders; for polymyositis and dermato-myositis, women are twice as likely as men and boys to be aff ected, with a bimodal distribution of age of onset; both childhood and adult forms are recognised. Con-versely, inclusion body myositis aff ects mainly men older than 50 years; both childhood and adult forms are recognised. However, polymyositis as a standalone clinical entity is increasingly recognised as uncommon and might have been previously misdiagnosed. Many patients diagnosed with polymyositis with the Bohan and Peter criteria are likely to have inclusion body myositis or upon reinterpretation, the muscle biopsies should be

more appropriately reclassifi ed as immune-mediated necrotising myopathy.52

The rarity of the vasculitides, along with changing nomenclature, makes estimates of incidence and preva-lence inherently unreliable.53 However, estimates have been made for ANCA-associated vasculitis, which in mainly European studies has an incidence of between one and two cases per 100 000 people per year. Giant cell arteritis has a wide geographical and possible seasonal variation in incidence. In North America and Europe the incidence is between 20 and 30 cases per 100 000 people per year with evidence of an increasing burden of disease with increasing northerly latitude.54 The prevalence of giant cell arteritis in the USA is estimated at 278 cases per 100 000 people older than 50 years.55 Polyarteritis nodosa has become rare with increased recognition of ANCA-associated vasculitis.

Selected clinical outcomesIn the past 30–40 years, mortality rates for patients with autoimmune rheumatic diseases have mainly fallen and causes of morbidity have changed. Reasons for these improvements are multifactorial, but are most probably attributable to earlier diagnosis and diagnosis of milder disease, availability of immunosuppressives and bio-logical treatments, and improvements in supportive regimens. Consequently, alternative causes for morbidity and death have become more predominant in many of the autoimmune rheumatic diseases and include cardio-vascular complications, cancer, infection, and adverse eff ects of long-term use of corticosteroids.

Cardiovascular diseaseAtherosclerotic cardiovascular disease is an infl ammatory disease.56 Premature death from cardiovascular disease was reported in patients with systemic lupus erythema-tosus in the 1970s,57 and the risk of death from cardio-vascular disease and thrombotic events has not improved in recent years.58,59 Traditional cardiovascular risk factors do not explain the increased burden of cardiovascular disease in systemic lupus erythematosus,60,61 and infl am-mation, treatment side-eff ects, and factors specifi c to systemic lupus erythematosus probably contribute.62 Although the relative risk of acute myocardial infarction in women aged 35–44 years with systemic lupus erythema-tosus has been estimated to be up to 52 times that of age-matched women without the disease, the rarity of acute myocardial infarction in young women means that the absolute rate of cardiovascular disease events is low. Thus, surrogate markers and large cohorts are needed to study cardiovascular disease in patients with systemic lupus erythematosus, an issue that is even more challenging in rarer autoimmune rheumatic diseases.

Despite the clear occurrence of microvascular disease, whether accelerated atherosclerosis arises in patients with systemic sclerosis remains controversial.63–65 Myo-cardial fi brosis can happen, typically in a patchy

Series


distribution that contrasts with the segmental defects recorded in coronary vascular disease. By contrast with valvular and pericardial lesions in patients with systemic lupus erythematosus and idiopathic infl ammatory myo-sitis, left ventricular diastolic dysfunction seems to be common, suggesting a role for fi brosis and over-production of collagen in the heart in systemic sclerosis. Right ventricular dysfunction is common in patients with systemic sclerosis, systemic lupus erythematosus, and idiopathic infl ammatory myositis, and can arise in the absence of pulmonary hypertension.66

One approach to assess the link between rare autoimmune rheumatic diseases and cardiovascular disease is seen in a recent study67 of 336 479 patients admitted to hospital with 32 diff erent immune-mediated diseases in Sweden between 1964 and 2008. The investigators reported a standardised incidence ratio of 2·9 for patients admitted to hospital with coronary heart disease during the 12 months after discharge from hospital with an immune-mediated disease. Very high risks were recorded in patients with systemic lupus erythematosus, systemic sclerosis, idiopathic infl ammatory myositis, and polyarteritis nodosa. A study68 with a similar approach has also documented an increased risk of pulmonary embolism after admission with an immune-mediated disease, suggesting that at least part of the risk of cardiovascular disease might relate to increased risk of thrombosis. Findings from several studies have confi rmed the presence of subclinical atherosclerosis or endothelial dysfunction in patients with autoimmune rheumatic diseases.69 How much of the increased risk of cardio-vascular disease is due to increased atherosclerotic plaque burden or rather an increased chance of plaque rupture or thrombosis remains unresolved.

CancerThe risk of cancer is increased in patients with various autoimmune rheumatic diseases, most clearly docu-mented with non-Hodgkin lymphoma.70–72 The association suggests that disordered immune function contributes to the patho genesis of various cancers, but has also raised concerns about the contribution of immunosuppressive drugs. Conversely, most clearly in the case of idiopathic infl am matory myositis, the association suggests that cancer contributes to the development of autoimmunity.

One of the earliest reported extraglandular associations of Sjögren’s syndrome was lymphoma,73 with reports of roughly 5% of patients developing non-Hodgkin lymphoma,74 with a relative risk of 6, compared with a relative risk of 2·7 in patients with systemic lupus erythematosus.70 In patients with systemic lupus erythematosus and non-Hodgkin lymphoma, eff orts to defi ne the relative contribution of disease activity or drug exposure to the risk of non-Hodgkin lymphoma have suggested possible higher risk in patients given cyclo-phosphamide and high steroid exposure.71 Patients with

systemic lupus erythematosus have a slightly increased risk of other cancers, including lung cancer and other haematological cancers.75 Patients with sys temic sclerosis also have an increased incidence of cancer. Lung cancer, oesophageal and oropharyngeal carcinomas, and haemato logical cancers are all increased.76,77 The increased risk of lung cancer is not confi ned to areas of fi brosis alone,78 and is especially increased in smokers with systemic sclerosis.

Patients with idiopathic infl ammatory myositis are at increased risk of cancer—especially patients with dermato-myositis (about 15%)—although fi ndings from epidemio-logical studies have shown that patients with polymyositis and inclusion body myositis are at increased risk too. The amyopathic dermatomyositis subgroup is being more commonly recognised, and data from reports suggest a similar proportion of this subgroup to those with classic dermatomyositis will develop cancer, high lighting the need for comparable surveillance. A large proportion of these cancers are detected within 1 year before or after diagnosis of infl ammatory myopathy and the extent of the search that should be done for occult neoplasm depends on the clinical circumstances. Because of the belief that the increased risk persists beyond 5 years,79 continuing surveillance is strongly recom mended. Comprehensive less invasive monitoring is generally adequate, although if a PET or CT scan is available, this screening is a good alternative to broad screening especially in the high-risk subgroup. The most commonly associated cancers are those commensurate with age and sex, including ovarian, breast, lung, pan creatic, and colorectal cancers, and non-Hodgkin lymphoma.80 Presence of anti-TRIM33 (TIF1γ) seems to be most strongly associated with the risk of developing cancer (sensitivity 78%, specifi city 89% for cancer in patients with idiopathic infl ammatory myositis81) followed by anti-Mi-2, and anti-RNP autoantibodies. Although patients with Jo-1 and PM-Scl seem to be substantially less predisposed to developing cancer, the physician should remain vigilant to this possibility.

Disease damage and mortalityIn patients with systemic lupus erythematosus, survival in western nations has improved from around 50% at 5 years in the 1950s, to between 80 and 90% at 10 years in many cohorts since the 1980s.59,82,83 This improvement is partly attributable to diagnosis of milder disease and improve ments in treatment of renal disease and infection. Predictors of mortality vary across cohorts; renal disease, damage accrual, hypertension, and cortico-steroid use are associated in several reports.58,83,84 Hydroxychloroquine use is associated with improved survival and less damage accrual.85,86

Compared with apparently more serious diseases, the symptoms of Sjögren’s syndrome can seem minor. However, the chronicity of the disease, complexity of symptoms, and frequent disabling fatigue are asso-ciated with a high burden of illness,87–89 with some

Series


patients reporting a negative eff ect on quality of life equal to that associated with rheumatoid arthritis or systemic lupus erythematosus.90 Few studies have been done on the natural course of primary Sjögren’s disease. Apart from the oral region in which up to 62% of patients have substantial damage, end-organ damage is uncommon compared with systemic lupus erythema-tosus. Com pared with the general population, mortality rates are not signifi cantly diff erent, except in those who develop lymphoma.91

10 year survival in patients with systemic sclerosis varies widely between studies; recent estimates were 65% for diff use systemic sclerosis and 92% for limited cutaneous systemic sclerosis in a Canadian cohort.92 Although renal crisis remains an important contributor to mortality, its contribution has decreased, with cardiac disease, pul-monary fi brosis, and pulmonary arterial hypertension accounting for most deaths related to systemic sclerosis.93,94 Extensive pulmonary fi brosis (>20%) on high-resolution CT, combined with a forced vital capacity of less than 70% in borderline cases, is associated with a poor prognosis.95,96 The prognosis for patients with pulmonary arterial hyper-tension related to systemic sclerosis remains extremely poor, especially when coexistent pulmonary fi brosis is present. In this setting, the 3 year survival is 21% even with treatment for pulmonary arterial hypertension.97

Idiopathic infl ammatory myositis is a potentially treat-able disease although data from reports suggest that up to a third of patients with this disease are left with mild to severe disability. Small cohort studies reported 5 year survival rates of 96%98 and a 10 year survival rates of 84%.99 Increasingly, the myositis-specifi c autoanti bodies are helping to predict the clinical course of patients with infl ammatory myositis, treatment response, and longer term prognosis. Nearly 60% of patients with myositis who are anti-Jo-1 positive develop interstitial lung disease; serial pulmonary function testing and echo cardiographic monitoring should be prioritised in this subgroup. The therapeutic response in patients with antisynthetase syndrome is much lower than in patients with other myositis-specifi c autoantibodies.98,99 By con trast, patients with nonsynthetase myositis-specifi c auto antibodies with anti-Mi-2 and anti-TRIM33 anti bodies rarely progress to clinically signifi cant interstitial lung disease or respiratory symptoms. Patients with dermato myositis with anti-Mi-2 antibodies typically have a slightly milder myopathic phenotype and have a good treatment response, those with necrotising myopathy with anti-signal recognition particle anti bodies typically have markedly raised concen trations of creatine kinase, more cardiac involvement, and are more likely to be treatment resistant with a poorer prognosis in com parison with patients with all varieties of dermato myositis. With the increasing recognition of pro nounced disease heterogeneity in idiopathic infl am matory myositis, the use of autoantibodies to better defi ne clinical course, treatment response, and prog nosis are expected.

ConclusionsClassifi cation criteria for autoimmune rheumatic diseases have been the source of considerable debate as rheumatologists strive to ensure appropriate identifi -cation of disease and thereby apply targeted treatments to improve patient outcomes. In the past 10 years, large-scale international cooperation has resulted in the continuing development of comprehensive classifi cation and nomenclature criteria for the autoimmune rheu-matic diseases. These new approaches mirror our present understanding of these diseases, and it is hoped that these criteria will gain global acceptance to allow more accurate diagnosis, clearer comparisons of global disease burden and outcomes, and standardised patient enrolment into clinical trials. Furthermore, the evolving identifi cation and use of additional autoantibody tests for the autoimmune rheumatic diseases should contribute to earlier recognition of the diseases and help clinicians to face the diagnostic challenge of these uncommon disorders. Together with advances in epidemiological studies, therapeutic trials and treatment availabilities, and management of associated complications, continued improvements in mortality rates and gains in patient quality of life are expected.Confl icts of interest We declare that we have no confl icts of interest.

Acknowledgments We thank Marie Wahren-Helenius and Thomas Dörner for their contribution to table 3.

References 1 Alarcón GS, Williams GV, Singer JZ, et al. Early undiff erentiated

connective tissue disease. I. Early clinical manifestation in a large cohort of patients with undiff erentiated connective tissue diseases compared with cohorts of well established connective tissue disease. J Rheumatol 1991; 18: 1332–39.

2 Willi ams HJ, Alarcon GS, Joks R, et al. Early undiff erentiated connective tissue disease (CTD). VI. An inception cohort after 10 years: disease remissions and changes in diagnoses in well established and undiff erentiated CTD. J Rheumatol 1999; 26: 816–25.

3 Bodol ay E, Csiki Z, Szekanecz Z, et al. Five-year follow-up of 665 Hungarian patients with undiff erentiated connective tissue disease (UCTD). Clin Exp Rheumatol 2003; 21: 313–20.

4 Mosca M, Tani C, Talarico R, Bombardieri S. Undiff erentiated connective tissue diseases (UCTD): simplifi ed systemic autoimmune diseases. Autoimmun Rev 2011; 10: 256–58.

5 Arbuc kle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003; 349: 1526–33.

6 Eriks son C, Kokkonen H, Johansson M, Hallmans G, Wadell G, Rantapää-Dahlqvist S. Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden. Arthritis Res Ther 2011; 13: R30.

7 Julkunen H, Eronen M. L ong-term outcome of mothers of children with isolated heart block in Finland. Arthritis Rheum 2001; 44: 647–52.

8 Koenig M, Joyal F, Frit zler MJ, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum 2008; 58: 3902–12.

9 Hoshino K, Muro Y, Sugi ura K, Tomita Y, Nakashima R, Mimori T. Anti-MDA5 and anti-TIF1-gamma antibodies have clinical signifi cance for patients with dermatomyositis. Rheumatology (Oxford) 2010; 49: 1726–33.

Series


10 Singh JA, Solomon DH, Dougados M, et al, and the Classifi cation and Response Criteria Subcommittee of the Committee on Quality Measures, American College of Rheumatology. Development of classifi cation and response criteria for rheumatic diseases. Arthritis Rheum 2006; 55: 348–52.

11 Tan EM, Cohen AS, Frie s JF, et al. The 1982 revised criteria for the classifi cation of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–77.

12 Hochberg MC. Updating the American College of Rheumatology revised criteria for the classifi cation of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.

13 Petri M, Orbai AM, Ala rcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classifi cation criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64: 2677–86.

14 Shiboski SC, Shiboski CH, Cri swell L, et al, and the Sjögren’s International Collaborative Clinical Alliance (SICCA) Research Groups. American College of Rheumatology classifi cation criteria for Sjögren’s syndrome: a data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 2012; 64: 475–87.

15 Vitali C, Bombardieri S, Jonsson R, et al, and the European Study Group on Classifi cation Criteria for Sjögren’s Syndrome. Classifi cation criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002; 61: 554–58.

16 Whitcher JP, Shiboski CH, Shiboski SC, et al, and the Sjögren’s International Collaborative Clinical Alliance Research Groups. A simplifi ed quantitative method for assessing keratoconjunctivitis sicca from the Sjögren’s Syndrome International Registry. Am J Ophthalmol 2010; 149: 405–15.

17 LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classifi cation, subsets and pathogenesis. J Rheumatol 1988; 15: 202–05.

18 Silman AJ. Scleroderma. Baillieres Clin Rheumatol 1995; 9: 471–82.19 Diot E, Giraudeau B, Diot P, et al. Is anti-topoisomerase I a serum

marker of pulmonary involvement in systemic sclerosis? Chest 1999; 116: 715–20.

20 Tan EM, Rodnan GP, Garcia I, Moroi Y, Fritzler MJ, Peebles C. Diversity of antinuclear antibodies in progressive systemic sclerosis. Anti-centromere antibody and its relationship to CREST syndrome. Arthritis Rheum 1980; 23: 617–25.

21 Nihtyanova SI, Denton CP. Autoantibodies as predictive tools in systemic sclerosis. Nat Rev Rheumato l 2010; 6: 112–16.

22 LeRoy EC, Medsger TA Jr. Criteria for the classifi cation of early systemic sclerosis. J Rheumatol 2001; 28: 1573–76.

23 Fransen J , Johnson SR, van den Hoogen F, et al. Items for developing revised cl assifi cation criteria in systemic sclerosis: results of a consensus exercise. Arthritis Care Res (Hoboken) 2012; 64: 351–57.

24 Johnson SR, Fransen J, Khanna D, et al. Validation of potential classifi cation criteria for systemic sclerosis. Arthritis Care Res (Hoboken) 2012; 64: 358–67.

25 Bohan A, Peter JB. Polymyositis and dermatomyositis (fi rst of two parts). N Engl J Med 1975; 292 : 344–47.

26 Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med 1975; 292: 403–07.

27 Shamim EA, Rider LG, Pandey JP, et al. Diff erences in idiopathic infl ammatory myopathy phenotypes and genotypes between Mesoamerican Mestizos and North American Caucasians: ethnogeographic infl uences in the genetics and clinical expression of myositis. Arthritis Rheum 2002; 46: 1885–93.

28 O’Hanlon TP, Carrick DM, Targoff IN , et al. Immunogenetic risk and protective factors for the idiopathic infl ammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1, and -DQA1 allelic profi les distingu ish European American patients with diff erent myositis autoantibodies. Medicine (Baltimore) 2006; 85: 111–27.

29 Vincze M, Danko K. Idiopathic infl ammatory myopathies. Best Pract Res Clin Rheumatol 2012; 26: 25–45.

30 H under GG, Arend WP, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classifi cation of vasculitis. Introduction. Arthritis Rheum 1990; 33: 1065–67.

31 Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international cons ensus conference. Arthritis Rheum 1994; 37: 187–92.

32 Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised international chapel hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013; 65: 1–11.

33 Helmick CG, Felson DT, Lawrence RC, et al, and the National Arthritis Data Workgroup. Estim ates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthriti s Rheum 2008; 58: 15–25.

34 Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus 2006; 15: 308–18.

35 J ohnson AE, Gordon C, Palmer RG, Bacon PA. The prevalence and incidence of systemic lupus erythematosus in Birmingham, England. Relationship to ethnicity and country of birth. Arthritis Rheum 1995; 38: 551–58.

36 Uramoto KM, Michet CJ Jr, Thumboo J, Sunku J, O’Fallon WM, Gabriel SE. Trends in the incidence and mortality of systemic lupus erythematosus, 1950-1992. Arthritis Rheum 1999; 42: 46–50.

37 Voss A, Green A, Junker P. Systemic lupus erythematosus in Denmark: clinical and epidemiological characterization of a county-based cohort. Scand J Rheumat ol 1998; 27: 98–105.

38 Ward MM. Prevalence of physician-diagnosed systemic lupus erythematosus in the United States: results from the third national health and nutrition examination survey. J Womens Health (Larchmt) 2004; 13: 713–18.

39 Hochberg MC, Perlmutter DL, Medsger TA, et al. Prevalence of self-reported physician-diagnosed systemic lupus erythematosus i n the USA. Lupus 1995; 4: 454–56.

40 Villa-Blanco I, Calvo-Alén J. Utilizing registries in systemic lupus erythematosus clinical research. Expert Rev Clin Immunol 2012; 8: 353–60.

41 Guerra SG, Vyse TJ, Cunninghame Graham DS. The genetics of lupus: a functional perspective. Arthritis Res Ther 2012; 14: 211.

42 Wahren-Herlenius M, Dörner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 2013; 382: 819–31.

43 Alonso-Perez E, Suarez-Gestal M, Calaza M, et al, and th e European Consortium of SLE DNA Collections. Further evidence of subphenotype association with systemic lupus erythematosus susceptibility loci: a European cases only study. PLoS One 2012; 7: e45356.

44 Chiffl ot H , Fautrel B, Sordet C, Chatelus E, Sibilia J. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum 2008; 37: 223– 35.

45 Walker UA, Tyndall A, Czirják L, et al, and the EUSTAR co-authors. Geographical variation of disease manifestations in systemic sclerosis: a report f rom the EULAR Scleroderma Trials and Research (EUSTAR) group database. Ann Rheum Dis 2009; 68: 856–62.

46 Steen V, Domsic RT, Luc as M, Fertig N, Medsger TA Jr. A clinical and serologic comparison of African American and Caucasian patients with systemic sclerosis. Arthritis Rheum 2012; 64: 2986–94.

47 Broen JC, Coenen MJ, Radstake TR. Genetics of systemic sclerosis: an update. Curr Rheum atol Rep 2012; 14: 11–21.

48 Martín JE, Bossini-Castillo L, Martín J. Unraveling the genetic component of systemic sclerosis. Hum Genet 2012; 131: 1023–37.

49 Feghali-Bostwick C, Medsger TA Jr, Wright TM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum 2003; 48: 1956–63.

50 McCormic ZD, Khuder SS, Aryal BK, Ames AL, Khuder SA. Occ upational silica exposure as a risk factor for scleroderma: a meta-analysis. Int Arch Occup Environ Health 2010; 83: 763–69.

51 Aryal BK, Khuder SA, Schaub EA. Meta-analysis of systemic sclerosis and exposure to solvents. Am J Ind Med 2001; 40: 271–74.

52 van der Meulen MF, Bronner IM, Hoogendijk JE, et al. Pol ymyositis: an overdiagnosed entity. Neurology 2003; 61: 316–21.

53 Ntatsaki E, Watts RA, Scott DG. Epidemiology of ANCA-associated vasculitis. Rheum Dis Clin North Am 2010; 36: 447–61.

54 Richards BL, March L, Gabriel SE. Epidemiology of large-vessel vasculidities. Best Pract Res Clin Rheumatol 2010; 24: 871–83.

55 Lawrence RC, Felson DT, Helmick CG, et al, and the National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008; 58: 26–35.

Series


56 Hansson GK , Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011; 12: 204–12.

57 Urowitz MB, Bookman AA, Koehler BE, Gordo n DA, Smythe HA, Ogryzlo MA. The bimodal mortality pattern of systemic lupus erythematosus. Am J Med 1976; 60: 221–25.

58 B ernatsky S, Boivin JF, Joseph L, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum 2006; 54: 2550–57.

59 Cervera R, Khamashta MA, Font J, et al, and the European Working Party on Systemic Lupus Erythematosus. Morbidity and mortality i n systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1000 patients. Medicine (Baltimore) 2003; 82: 299–308.

60 Esdaile JM, Abrahamowicz M, Grodzicky T, et al. T raditional Framingham risk factors fail to fully account for accelerated atherosclerosis in syste mic lupus erythematosus [see comment]. Arthritis Rheum 2001; 44: 2331–37.

61 O’Neill SG, Pego-Reigosa JM, Hingorani AD, Bessant R, Isenberg DA, Rahman A. Use of a strategy based on calculated risk scores in managing cardiovascular risk factors in a large British cohort of patients wi th systemic lupus erythematosus. Rheumatology (Oxford) 2009; 48: 573–75.

62 Bruce IN. ‘Not only...but also’: factors that contribute to accelerated atherosclerosis and premature coronary heart disease in systemic lupus erythematosus. Rheumatology (Oxford) 2005; 44: 1492–502.

63 Au K, Singh MK, Bodukam V, et al. Atherosclerosis in systemic sclerosis: a systematic review and meta-analysis. Arthritis Rheum 2011; 63: 2078–90.

64 Nussinovitch U, Shoenfeld Y. Atherosclerosis and macrovascular involvement in systemic sclerosis: my th or reality. Autoimmun Rev 2011; 10: 259–66.

65 Ngian GS, Sahhar J, Wicks IP, Van Doornum S. Cardiovascular disease in systemic sclerosis--an emerging association? Arthritis Res Ther 2011; 13: 237.

66 Plazak W, Kopec G, Tomkiewicz-Pajak L, et al. Heart structure and function in pa tients with generalized autoimmune diseases: echocardiography with tissue Doppler study. Acta Cardiol 2011; 66: 159–65.

67 Zöller B, Li X, Sundquist J, Sundquist K. Risk of subsequent coronary heart dise ase in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden. PLoS One 2012; 7: e33442.

68 Zöller B, Li X, Sund quist J, Sundquist K. Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow-up study from Sweden. Lancet 2012; 379: 24 4–49.

69 Shoenfeld Y, Gerli R, Doria A, et al. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation 2005; 112: 3337–47.

70 Ekström S medby K, Vajdic CM, Falster M, et al. Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. Blood 2008; 111: 4029–38.

71 Bernatsky S, Ramsey- Goldman R, Rajan R, et al. Non-Hodgkin’s lymphoma in systemic lupus erythematosus. Ann Rheum Dis 2005; 64: 1507–09.

72 Dias C, Isenberg DA. Susceptibility of patients with rheumatic diseases to B-cell non-Hodgkin lym phoma. Nat Rev Rheumatol 2011; 7: 360–68.

73 Theander E, Henriksson G, Ljungberg O, Mandl T, Manthorpe R, Jacobsson LT. Lymphoma and other malignancies in primary Sjögren’s syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis 2006; 65: 796–803.

74 Tzioufas AG, Voulgarelis M. Update on Sjö gren’s syndrome autoimmune epithelitis: from classifi cation to increased neoplasias. Best Pract Res Clin Rheumatol 2007; 21: 989–1010.

75 Bernatsky S, Boivin JF, Joseph L, et al. An international cohort stu dy of cancer in systemic lupus erythematosus. Arthritis Rheum 2005; 52: 1481–90.

76 Bussone G, Mouthon L. Interstitial lung disease in syst emic sclerosis. Autoimmun Rev 2011; 10: 248–55.

77 Derk CT, Rasheed M, Artlett CM, Jimenez SA. A cohort study of cancer incidence in systemic sclerosis. J Rheumatol 2006; 33: 1113–16.

78 Pontifex EK, Hill CL, Roberts-Thomson P. Risk factors for lung cancer in patients with scleroderma: a nested case-control study. Ann Rheum Dis 2007; 66: 551–53.

79 Stockton D, Doherty VR, Brewster DH. Risk of cancer in patients with dermatomyositis or polymyositis, and follow-up implications: a Scottish popula tion-based cohort study. Br J Cancer 2001; 85: 41–45.

80 Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specifi c cancer types in dermatomyositis and polymyositis: a population-based study. Lancet 2001; 357: 96–100.

81 Trallero-Araguás E, Rodrigo-Pendás JA, Selva-O’Cal laghan A, et al. Usefulness of anti-p155 autoantibody for diagnosing cancer-associated dermatomyositis: a systematic review and meta-analysis. Arthritis Rheum 2012; 64: 523–32.

82 Merrell M, Shulman LE. Determination of prognosis in chronic disease, illustra ted by systemic lupus erythematosus. J Chronic Dis 1955; 1: 12–32.

83 O’Neill S, Cervera R. Systemic lupus erythematosus. Best Pract Res Clin Rheumatol 2010; 24: 841–55.

84 Urowitz MB, Gladman DD, Tom BD, Ibañez D, Farewell VT. Changing patterns in mortality and disease outcomes for patients with sy stemic lupus erythematosus. J Rheumatol 2008; 35: 2152–58.

85 Petri M, Purvey S, Fang H, Magder LS. Predictors of organ damage in systemic lupus erythematosus: the Hopkins Lupus Cohort. Arthritis Rheum 20 12; 64: 4021–28.

86 Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical effi cacy and side eff ects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010; 69: 20–28.

87 Malladi AS, Sack KE, Shiboski SC, et al. Primary Sjögren’s syndrome as a systemic disease: a study of participants enrolled in an international Sjögren’s syndrome registry. Arthritis Care Res (Hoboken) 2012 ; 64: 911–18.

88 Newton JL, Frith J, Powell D, et al, and the UK primary Sjögren’s syndrome registry. Autonomic symptoms are common and are associat ed with overall symptom burden and disease activity in primary Sjögren’s syndrome. Ann Rheum Dis 2012; 71: 1973–79.

89 Bjerrum K, Prause JU. Primary Sjögren’s syndrome: a subjective description of the disease. Clin Exp Rheumatol 1990; 8: 283–88.

90 Sutcliff e N, Stoll T, Pyke S, Isenberg DA. Functional disability and end organ damage in patients with systemic lupus erythematosus (SLE), SLE and Sjögren’s syndrome (SS), and primary SS. J Rheumatol 1998; 25: 63–68.

91 Ioannidis JP, Vassiliou VA, Moutsopoulos HM. Long-term risk of mortality and lymphoproliferative disease and predictive classifi cation of primary Sjögren’s syndrome. Arthritis Rheum 2002; 46: 741–47.

92 Al-Dha her FF, Pope JE, Ouimet JM. Determinants of morbidity and mortality of systemic sclerosis in Canada. Semin Arthritis Rheum 2010; 39: 269–77.

93 Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis 2007; 66: 940–44.

94 Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 2010; 69: 1809–15.

95 Goh NS , Desai SR, Veeraraghavan S, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Res pir Crit Care Med 2008; 177: 1248–54.

96 Moore OA, Goh N, Corte T, et al. Extent of disease on high-resolution computed tomography lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease. Rheumatology (Oxford) 2013; 52: 155–60.

97 Le Pavec J, Girgis RE, Lechtzin N, et al. Systemic sclerosis-related pulmonary hypertension as sociated with interstitial lung disease: impact of pulmonary arterial hypertension therapies. Arthritis Rheum 2011; 63: 2456–64.

98 Sultan SM, Ioannou Y, Moss K, Isenberg DA. Outcome in patients with idiopathic infl ammatory myositis: m orbidity and mortality. Rheumatology (Oxford) 2002; 41: 22–26.

99 Marie I, Hachulla E, Hatron PY, et al. Polymyositis and dermatomyositis: short term and longterm outcome, and predictive factors of prognosis. J Rheumatol 2001; 28: 2230–37.

Documents

Clinical aspects of autoimmune rheumatic diseases