Systemic features

Features of systemic illness such as weight loss, fever and malaise occur commonly in MARDs, but MARDs are an uncommon cause overall. Presentation with non-intentional weight loss is rarely due to a MARD. Only 2–3% of people presenting with unintentional weight loss have a MARD, whereas 25% have a malignancy and one-third have a gastrointestinal cause . Cancer causes the most rapid weight loss up to 6.5% per month in elderly patients . Fever is a common feature of systemic illness, and when occurring without the presence of an obvious infection, it poses a diagnostic challenge. The pattern of fever may be helpful, a quotidian fever being typical for adult-onset Still’s disease (classically accompanied by an evanescent salmon pink rash). Fever of unknown origin (FUO) may be defined as a febrile illness of >3 weeks duration, a temperature of >38.3 °C on several occasions, without a diagnosis after standardized history-taking, physical examination and cultures in a non-immunocompromised patients. In this setting, a cause for FUO may not be found in up to 50% of cases despite the use of a structured approach for investigation, but 22% have a non-infectious inflammatory condition .

Cardiovascular system

Cardiovascular involvement is common in patients with MARD, for example, SLE may result in pericarditis or pericardial effusion; pulmonary hypertension is a feature of SLE or systemic sclerosis. Intermittent claudication and absent or diminished pulses with or without a bruit may be a feature of a large vessel vasculitis (Takayasu arteritis and giant cell arteritis) and also of atherosclerosis. Valvular heart disease may be a result of inflammation, for example, aortitis occurring in association with ankylosing spondylitis, bacterial endocarditis or Libman–Sachs endocarditis occurring in SLE.

It is increasingly recognized that inflammation is a major risk factor for the development of cardiovascular disease resulting in changes to lipoprotein metabolism, immune activation and subsequent proliferation of smooth muscle cells, narrowing of arteries and atheroma formation . Therefore, for part of the assessment of a patient with a MARD assessment of traditional cardiovascular risk factors is required as treatment of such co-morbidities may improve outcomes.

Respiratory system

The major respiratory symptoms – cough, wheezing, dyspnoea, hoarseness and haemoptysis – are relatively non-specific, but they can help differentiate between infection malignancy and inflammation. Cough is most commonly due to an upper respiratory tract infection with asthma being the second most common cause. In the developing world, tuberculosis (TB) is the most common cause of lower respiratory tract infections. Interstitial lung disease is a much less common cause. Haemoptysis is most commonly due to infection especially in countries where TB is common, whereas it is rarely caused by systemic vasculitis . Late-onset asthma is a typical feature of EGPA but EGPA is a rare cause of asthma; however, it needs to be considered when late-onset asthma is difficult to control and especially in association with other systemic features. Shortness of breath may reflect the insidious development of interstitial lung disease, cardiac disease or pleural effusion. More acute onset of shortness of breath may reflect pneumonia, asthma or pulmonary oedema.

Gastrointestinal system

Diarrhoea is commonly due to infection, inflammation, malignancy or malabsorption. It is a relatively uncommon feature of MARDs apart from systemic sclerosis where impaired bowel motility, bacterial overgrowth and malabsorption occur not infrequently. Malena may occur due to vasculitis of the gut.

Renal system

Renal impairment may be quite advanced with up to 80% of excretory function lost before becoming symptomatic. Symptoms of renal failure include fatigue, oliguria or anuria. Nephrotic syndrome presents with peripheral oedema, which worsens during the day. Ascites and pleural effusions may be present in severe cases, and the patient may notice frothiness of the urine. Acute nephritis is a clinical syndrome characterized by the onset of haematuria, proteinuria, hypertension and oliguria; the urine develops a smoky appearance due to the presence of red blood cells. Causes include both primary glomerular diseases such as crescentic glomerulonephritis, focal segmental glomerulosclerosis or immunoglobulin A (IgA) nephropathy, and systemic conditions such as IgA vasculitis (Henoch–Schönlein), polyarteritis nodosa and ANCA-associated vasculitis and SLE.

Acute kidney injury (AKI) describes renal impairment ranging from mild alteration with no actual damage to the kidney to complete organ failure. Severity can be assessed using serum creatinine and urine output. The most common cause of AKI is sepsis accounting for nearly 50% of cases with other common causes being major surgery, cardiogenic shock, hypovolaemia, drug related, hepatorenal syndrome or renal tract obstruction . Systemic inflammatory disease is therefore an uncommon cause of AKI, but when present it is a key determinant of long-term outcome and mortality.

Nervous system

Headache is a common symptom in adults, but features such as photophobia neck stiffness and cognitive impairment indicate possible meningitis or encephalitis. New-onset headache in an older patient may be indicative of giant cell arteritis. In younger patients presenting with stroke, the possibility of a systemic cause should be considered including SLE, antiphospholipid syndrome, cardiac emboli, Behçet’s syndrome (venous sinus thrombosis), vasculitis either primary cerebral or small/medium/large vessel, sarcoid and infection. Sensori-motor neuropathy may occur not only in isolation but also as part of a MARD; the pattern of involvement may be important – mononeuritis multiplex and axonal length-dependent neuropathy. Transverse myelitis may be a feature of SLE or Devic’s (neuromyelitis optica) syndrome.

Ophthalmic system

The eye is involved in many systemic diseases, and therefore a detailed ocular history and examination including fundoscopy is a key component of the assessment of the patients with a possible autoimmune disease .

A red eye is one of the most common symptoms, and the pattern of redness may help make a diagnosis of the underlying systemic condition. Conjunctivitis with redness of the conjunctiva, with a discomfort rather than pain or photophobia and a sticky discharge, may be due to a bacterial or viral infection, and corneal staining may occur in sicca syndrome. Episcleritis results in redness of the eyeball, which only involves a segment of the eyeball, causing discomfort and not pain. It is common, not serious and is no threat to the sight; it is associated rarely with a systemic inflammatory disease. Scleritis is much less common causing intense pain, and it is a threat to sight. Approximately 50% of cases will be associated with an identifiable systemic inflammatory disease, most commonly rheuamtod arthritis (RA), GPA, SLE and relapsing polychondritis. Iritis causes redness around the cornea, with pain and photophobia, and the most common cause is ankylosing spondylitis. Anterior uveitis causes pain and photophobia, corneal precipitates may be visible and the pupils are small. Anterior uveitis is associated with sarcoidosis, and it may be bilateral, recurrent severe and potentially sight threatening. Anterior and posterior uveitis (panuveitis) is a key defining feature of Behçet’s syndrome, and they can lead to sight loss. The differential diagnosis of iritis and arthritis includes sarcoidosis, Behçet’s syndrome, psoriasis and gonococcal infection, and when with intestinal involvement, it includes inflammatory bowel disease or Whipple’s disease.

Corneal inflammation presents with pain, photophobia and watering, and it may be caused by GPA, Cogan’s syndrome and other types of vasculitis.

A dry eye is the defining feature of Sjögren’s syndrome particularly when it occurs in combination with dryness of the mouth (sicca syndrome). The eyes feel gritty, and they are red and sticky. Other systemic causes include rheuamtod arthritis (RA), systemic sclerosis, mixed connective tissue disease and sarcoidosis.

It is important to establish a history of visual loss. Major unilateral visual impairment results in an asymmetric pupillary response, and the cause is either within the retina or within the optic nerve. An ischaemic optic neuropathy may be associated with giant cell arteritis, and it is the most common cause of visual loss in that condition (40%) . Visual loss may be permanent and bilateral. Vision may be lost overnight or during the daytime, and patients may have experienced transient episodes of visual loss, which may be partial affecting either the top or bottom half of the visual field. Retinal vascular occlusion is a common cause of blindness; retinal artery occlusion is usually of embolic origin from either the carotid arteries or the cardiac arteries due to thrombosis in the left atrium or ventricle myxoma or endocarditis. However, it may occur in SLE, large vessel vasculitis or polyarteritis nodosa.

Ear, nose and throat

Nasal crusting and/or epistaxis may be a feature of systemic vasculitis, sarcoid, lymphoma, infection, TB and cocaine use. The presence of these features in a patient with other systemic features may be the first clue to the true underlying diagnosis especially vasculitis. Nasal polyposis is a feature of EGPA. Nasal bridge collapse may indicate GPA or relapsing polychondritis; in the latter condition, it is associated with inflammation of the cartilage of the ear.

Musculoskeletal

The pattern of arthritis is important; septic arthritis typically presents as a monoarthritis, but it can be multifocal particularly in the immunocompromised. Monoarthritis may also be due to other forms of inflammatory arthritis such as crystal arthritis, reactive arthritis or a limited form of polyarthritis. Monoarthritis should be urgently investigated by joint aspiration with the aspirated fluid sent for culture and polarizing light microscopy looking for crystals of both monosodium urate (gout) and calcium pyrophosphate (calcium pyrophosphate deposition disease). Oligoarticular onset large joint arthritis is typically a feature of the spondyloarthropathies, but it may also be a feature of infection (gonococcal infection, meningococcus, Lyme, human immunodeficiency virus (HIV) or sepsis), sarcoidosis, paraneoplastic or Behçet’s syndrome.

Predominately, muscle pain especially shoulder and hip girdle may be suggestive of polymyalgia rheumatic (PMR), and systemic upset is not uncommon in PMR. If associated with weakness, it is suggestive of polymyositis.

Dermatological

Skin rashes are often a component of systemic disease, and the possible causes are numerous including infection, sarcoid, Behçet’s syndrome and vasculitis. The type of rash and its distribution may be important. A photosensitive rash occurs in limbs typically exposed to the sun and the shawl area. Erythema nodosum presenting with raised red lumps typically over the shins may be indicative of infection, sarcoid, drug exposure or inflammatory bowel disease. The combination of ankle pain and swelling and erythema nodosum is suggestive of acute sarcoidosis. Palpable purpura is the classical rash of cutaneous vasculitis, and it should prompt a comprehensive search for the evidence of other organ involvements. Infection particularly meningococcaemia can present with a very rapid onset of rash, and it can be quickly fatal unless recognized quickly and antibiotics administered.

A drug reaction must be considered in all cases as the skin reaction may range from a mild brief erythema to a full-blown toxic epidermal necrolysis or Dressler’s syndrome. The occurrence of systemic features helps raise the possibility of a systemic cause of the rash.

Drug history

A history of all recent drug exposures should be obtained from all patients. A number of drugs are well recognized as triggers for the development of SLE, or vasculitis, and many more have been associated in isolated case reports. The most common drugs to be implicated in the development of autoimmune syndromes are propylthiouracil carbimazole, allopurinol, hydralazine, minocycline d -penicillamine and phenytoin. Cocaine can cause nasal destruction mimicking GPA or relapsing polychondritis. Recently, a syndrome of vasculitis and autoantibody formation combined with neutropaenia has been described with the use of cocaine adulterated with levamisole . If the use of recreational drugs is suspected, then urine toxicology should be performed.

Travel history

In certain situations, a detailed travel history including country and geographical environment (rural, forested, urban, desert or aquatic) is required particularly with the increase in intercontinental travel with the increased risk of importation of a variety of pathogens. In Europe, malaria and dengue, and arboviruses such as chikungunya, West Nile fever and Japanese encephalitis are being increasingly seen as a result of their emergence and re-emergence particularly in South East Asia . The latter may present with malaise, headache, fever and rash. A history of vaccination and the use of malaria prophylaxis (if relevant travel) should be obtained.

Occupational history

Many people are exposed to infectious agents during the course of their work. For example, hepatitis B and C, TB and multi resistant staphylococcus aureus (MRSA) may occur in health workers; brucellosis, borreliosis, strongyloides and toxoplasmosis in farmers and vets; and leptospirosis in those exposed to dirty water.

Sexual history

The combination of uveitis, oligoarthritis and either diarrhoea or genital discharge is suggestive of a reactive arthritis, and a detailed sexual history should be obtained including the occurrence of unprotected sexual intercourse. HIV seroconversion illness may present with a multisystem illness. Gonococcal infection may present with the combination of rash and inflammatory arthritis.

Vaccination history

Patients with MARD often require immunosuppression with glucocorticoids and other immunosuppressive drugs. These will increase infection risk, and therefore the assessment of vaccination status is essential particularly influenza, pneumococcal, zoster and in endemic or high-risk individuals with hepatitis B virus (HBV) . Similarly, the assessment of bacillus Calmette–Guerin (BCG) status and the risk of previous TB should be performed.