Autoimmune diseases Part 1: background and diagnosis

Autoimmune diseases

Immunity is a core function of our physiology. We depend on it to protect us from disease and infection. Regulation of immunity is a delicate balance between protection and active immune response. Too little response and we can succumb to infective agents. Too great a response and we can suffer from pathological processes, such as the cytokine storm seen in some cases of COVID-19 and in some people with sepsis. A further potential issue can occur with a dysregulated immune response which can result in autoimmune diseases.¹ These autoimmune diseases occur when antibodies made by auto-reactive B and T lymphocytes are directed against a person’s own tissue causing functional damage (Figure 1). The damage can be organ-specific or generalised and is caused either by T cells or by auto-antibodies.

T cell lymphocytes infiltrate organs and produce lymph node-like structures in the affected organ, which then destroy the organ using a heightened immune response.²

Autoantibodies directly cause pathological damage involving binding of the antibody to an antigen to form of immune complexes which then deposit and damage the affected tissues.^1,3

It is not clear what causes autoimmune diseases, but two factors are important in the development of these conditions. First, genetics: from twin studies we find that autoimmune diseases are genetically predisposed in some individuals and that indeed there are genes which are markers for some autoimmune diseases.^1,4

Secondly, environmental triggers: a multiplicity of these has been suggested. The most widely researched are infectious agents, particularly streptococci. These have been implicated in the development of rheumatic heart disease. Other suggested environmental factors include cigarette smoking, which is a risk factor for rheumatoid disease, and low vitamin D levels and risk of developing multiple sclerosis.⁵

PREVALENCE AND COSTS OF AUTOIMMUNE DISEASE

Autoimmune diseases appear to be increasingly prevalent. The reasons for this are not clear. In the UK it is estimated that 3-5% of the population, or 4 million people, are suffering from at least one autoimmune disease, but it is thought that many people also have more than one autoimmune condition.^6,7 The incidence of autoimmune conditions is increasing by between 3% – 9% every year. This includes:

• 7.0% increase per year of rheumatic diseases, such as rheumatoid arthritis (RA)
• 6.3% increase of endocrinological conditions, such as type 1 diabetes
• 3.7% increase of neurological diseases, such as multiple sclerosis
• 4-9% increase per year, the greatest increase, in coeliac disease.

There are over 100 distinct autoimmune diseases. Women make up 80% of those who suffer from these conditions. Most people who develop autoimmune conditions do so as adults 20-40 years of age, although some conditions such type 1 diabetes usually develop in children.⁸

Autoimmune diseases cost approximately £13bn per year in the UK, including the following direct and indirect costs:⁷

• £2.6bn for multiple sclerosis
• £8.7bn for RA
• £1.9bn for type 1 diabetes

The indirect costs relate to loss of time at work, sick leave, and attendant benefit costs.

Early suspicion of a diagnosis of autoimmune disease combined with early treatment reduces the rates of complication.⁵ For all general practice nurses recognition of the symptoms and signs of possible autoimmune disease is therefore crucial.

COMMON AUTOIMMUNE DISEASES

The most common autoimmune diseases include RA, Hashimoto’s thyroiditis, coeliac disease, Graves’ disease, type 1 diabetes, vitiligo, pernicious anaemia, alopecia areata, multiple sclerosis, seronegative arthritides, and systemic lupus erythematosus (SLE).⁸

This module will focus on RA, sero-negative arthritides, autoimmune diseases of the thyroid, and SLE.

HISTORY

You should take a thorough history and conduct a general examination in all people who you suspect may have an autoimmune disease.⁹

Although these diseases may have a common inflammatory origin and microscopic appearance, they have a diverse, multisystem effect on the signs and symptoms in those affected. However, some features of note may be generally recognised as regularly occurring for most people who have an autoimmune condition.

Ask about the onset of their symptoms and the range of symptoms involved. Ask specifically about:

• Joint issues – stiffness and/or joint swelling and any diurnal variation (Inflammatory pain is typically worse in the morning and with rest or inactivity)
• Skin symptoms
• General wellbeing – changes in energy levels or exercise tolerance, weight loss
• Pyrexia
• Taste changes or mouth ulceration
• Upper or lower gastrointestinal symptoms
• Pain symptoms and any focal symptoms relating to specific areas of functional loss or pain.

Ask about any family history of autoimmune disorders or connective tissue disorders and any previous history of illness. Ask about medication taken to improve symptoms, including over the counter remedies and complimentary therapies.

Suspected RA and other arthritides

The presentation of autoimmune arthritis is variable. Most people have an insidious onset, but others can have a rapid, or relapsing and remitting course (such as a palindromic presentation).

RA typically causes symmetrical synovitis of the small joints of the hands and feet, although any synovial joint may be affected. You need to ask specifically about pain, swelling, heat and stiffness in affected joints. There may also be swelling around the joint and you will need to look for the presence of rheumatoid nodules.

Autoimmune arthritides can also cause extra-articular features that you will need to enquire about, such as vasculitis, or involvement of other body systems (for example, eye, lungs, and heart). Ask about the presence of any systemic features of malaise, fatigue, fever, sweats, and weight loss.

The family history is important. Ask if there is any family history of RA or arthritides (ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease (IBD) associated with arthritis or undifferentiated seronegative arthritis).

Ankylosing spondylitis is associated with spinal pain, stiffness, and limitation of movement.

Psoriatic arthropathy is associated with psoriatic skin and nail lesions and often involves the distal phalangeal joints. IBD presents with abdominal pain, rectal bleeding, change in bowel habit and weight loss.

Suspected autoimmune diseases of the thyroid

Ask about the typical symptoms of hyper- or hypothyroidism and their severity and duration. Table 1 outlines the range of symptoms associated with over and underactive thyroid disease.

TABLE 1. SYMPTOMS ASSOCIATED WITH THYROID DISEASE

In both over and underactive thyroid disease there is also the possibility of compression symptoms – dysphagia, neck fullness, choking, dyspnoea. These can be caused by swelling associated with goitre.

Ask about current or recent pregnancy. Has the patient any current or recent non-thyroidal illness or other possible causes of a transiently suppressed thyroid-stimulating hormone (TSH) level? You will also need to ask about any drug treatment that may affect thyroid function tests (TFTs), including levothyroxine medication, and any previous head or neck surgery or recent exposure to radioactive iodine contrast media.

Other risk factors associated with hyper and hypothyroidism that you will need to enquire about include:

• Smoking history
• Personal history of autoimmune disorders, such as type 1 diabetes mellitus, vitiligo, Addison’s disease, or coeliac disease.
• Family history of thyroid disease; personal or family history of hypothalamic-pituitary disease.
• Any possible features of pituitary disease, such as a history of brain or metastatic cancer; headache or visual field defects.

Suspected SLE

There are a number of features of SLE you will need to ask about specifically.¹⁰

Ask about fever. More than 50% of people with SLE will report fever as part of their active disease presentation. Weight loss, mouth ulcers and oesophageal symptoms, including dysphagia, are further clues. Patients may also report lymph node swelling – usually in the neck or axilla – and morning joint stiffness. Facial rashes, particularly when exposed to the sun are further features of SLE.

A rare presentation of SLE is with generalised seizures. Patients may also report palpitations and breathlessness and may have mood or personality changes.

EXAMINATION

There are features of a general examination that may be common to many autoimmune disorders. These can include:

• Pallor due to anaemia
• Joint swelling: synovitis, which feels ‘boggy’ to the touch, limitation of the range of movement of joints or joint deformity
• Skin changes: including Raynaud’s phenomenon which typically presents with episodes of clearly demarcated pallor of the digit(s), followed by at least one other colour change (cyanosis and/or erythema); Malar flush or facial butterfly rash, more associated with SLE
• Lymphadenopathy
• Raised temperature
• Cranial nerve pathologies: including visual field defects, nystagmus, or facial palsy
• Alopecia
• Raised blood pressure
• Pulse irregularities: bradycardia, tachycardias, or arrhythmias
• Mouth or nasal ulcers.

Specific additional features to consider in thyroid autoimmune diseases are tremor, agitation, palmar erythema, muscle wasting, an enlarged thyroid or nodules in the thyroid and the appearance of the eyes. Look specifically for eye irritation, photophobia, or excessive watering of the eyes. The eye and/or eyelids may appear red or swollen and there are some typical changes to the appearance of the eyes or eyelids that may be particularly significant:

• Eyelid retraction
• Lid lag (delay in moving the eyelid as the eye moves downward)
• Proptosis (eyeball protrusion – an inability to fully close the eyes as the upper and lower lids do not fully appose)

Patients may report persistent double vision in any direction of gaze. They may also have an unexplained deterioration in visual acuity, a change in the intensity or quality of colour vision in one or both eyes, orbital aching and/or restricted eye movements. There may be a history of globe subluxation, where one or both eyes suddenly feel that they have 'popped out'. Typically this lasts more than a few seconds, is painful, and the lids cannot be closed.

COMPLICATIONS AND PROGNOSIS

For all autoimmune diseases, the complications are likely to be more severe and the prognosis worse where there are significant delays in diagnosis or commencing treatment, where the disease is more generalised and where a person has other multi-morbidities.⁵

RA and other arthritides

The complications of rheumatoid arthritis and seronegative arthritides include:⁹

• Anaemia
• Interstitial lung disease
• Amyloidosis
• Neuropathy, including carpal tunnel syndrome
• Secondary osteoarthritis
• Vasculitis
• Osteoporosis.

Autoimmune thyroid diseases

The complications include:⁹

• Visual impairment due to orbitopathy in Graves’ disease related hyperthyroidism
• Thyrotoxic crisis
• Compression of oesophagus and/or trachea
• Atrial fibrillation
• Coronary heart disease
• Osteoporosis
• Mood disorders
• Increased risk of miscarriage and preterm delivery
• Dyslipidaemia.

Systemic lupus erythematosus

The complications include:¹⁰

• Pancytopenia – anaemia, leucopenia and thrombocytopaenia
• Pericarditis
• Miscarriage
• Depression
• Chronic kidney disease and nephropathy
• Hypertension and pulmonary hypertension.

DIAGNOSTIC TESTS

The list of alternative conditions which may present similarly to autoimmune disease is long.

Conditions that may cause synovitis and may be confused with RA and other autoimmune arthritides and shown in Box 1.⁹ Some of those that may present similarly to thyroid disorders are listed in Box 2,⁹ and those which can present similarly to SLE are listed in Box 3.⁹

BOX 1. CONDITIONS WITH SIMILAR PRESENTATIONS TO RA AND OTHER AUTOIMMUNE ARTHRITIDES⁹

• Fibromyalgia – suspect if there are numerous myofascial trigger points and somatic symptoms are present.

• Osteoarthritis

• Polyarticular gout – suspect if the person has risk factors for gout, or visible tophi.

• Polymyalgia rheumatica – suspect if the main symptoms are shoulder pain and stiffness.

• Reactive arthritis – suspect if the person has recently had a viral or bacterial infection.

• Sarcoidosis – a chest X-ray may be helpful if this is suspected.

• Septic arthritis – suspect if a single joint is hot and swollen.

BOX 2. CONDITIONS WITH SIMILAR PRESENTATIONS TO AUTOIMMUNE THYROID DISORDERS ⁹

• Non-thyroidal illness or 'sick euthyroid syndrome'

• Endocrine/autoimmune conditions such as type 1 diabetes mellitus, Addison's disease, coeliac disease, atrophic gastritis with pernicious anaemia, or hypopituitarism

• End-organ damage such as chronic kidney disease, chronic liver disease, and heart failure

• Metabolic abnormalities such as hypercalcaemia

• Vitamin and mineral deficiencies such as vitamin B1 deficiency, folate deficiency, iron deficiency, and vitamin D deficiency

• Stress, poor sleep, alcohol misuse, anxiety, and depression

• Dementia — in older people symptoms of dementia may be difficult to distinguish from hypothyroidism

• Post-viral syndromes and chronic fatigue syndrome

• Polymyalgia rheumatica and fibromyalgia

• Obesity and obstructive sleep apnoea

• Menopause — be aware that in menopausal women symptoms of thyroid dysfunction may be mistaken for menopause

• Carbon monoxide poisoning

BOX 3. CONDITIONS WITH SIMILAR PRESENTATIONS TO SLE¹⁰

• Other autoimmune diseases, including rheumatoid arthritis, systemic sclerosis

• Lyme disease

• HIV

• Leukaemia or other haematological malignancies

• Fibromyalgia

• Glomerulonephritis

In order to differentiate from this list and to make a diagnosis you should consider the following baseline investigations before undertaking further, disease-specific investigation:11

• Full blood count
• Urea and electrolytes
• Erythrocyte sedimentation rate and C-reactive protein
• Liver function tests
• Urinalysis
• ECG.

Rheumatoid arthritis and arthritides⁹

Blood can be taken for rheumatoid factor. If this is negative, consider measuring anti-cyclic citrullinated peptide (anti-CCP) antibodies as these are found in about 80% of people with RA.

X-ray of the hands and feet may also help with diagnosis and determination of disease severity.

Autoimmune thyroid disease⁹

Blood should be taken for thyroid function tests – Thyroid Stimulating Hormone (TSH) and free T3 and T4. Consider checking additional blood tests, such as:

• TSH-receptor antibodies (TRAbs) if a diagnosis of Graves' disease is suspected or the person is pregnant
• Thyroid peroxidase antibodies (TPOAbs) if a woman is postpartum and a diagnosis of postpartum thyroiditis is suspected.

Glycated haemoglobin (HbA1c) should be taken to assess for associated type 1 diabetes and coeliac serology taken to assess for coeliac disease if a diagnosis of autoimmune thyroid disease is suspected. Serum lipids should also be taken to assess for associated dyslipidaemia.

Arrange an ultrasound of the neck to image palpable thyroid enlargement or focal nodularity in adults with normal thyroid function if malignancy is suspected.

Systemic Lupus Erythematosus¹⁰

Specific blood tests can be helpful:

• Antinuclear Antibody (ANA) – if this is positive an anti-double stranded DNA test can help confirm a diagnosis
• Activated Prothrombin Time which may be prolonged in people with antiphospholipid antibodies
• Anti-Smith antigen – This is a test usually performed in secondary care. Approximately 30% of people with SLE produce antibodies to these proteins, which are highly specific for SLE and can be confirmatory of the diagnosis.

SUMMARY

All primary care health professionals need to be alert to the possibility of people presenting with symptoms and signs of autoimmune diseases. However, dealing with people with suspected or confirmed autoimmune disease is a challenge for everyone in primary care. The early presentations can be complex and multi-system, and involve an assessment of interplaying symptoms and signs. The importance of an early diagnosis and assessment of possible flares and complications is however critical as any delay to treatment can, sadly, worsen outcomes.

An early index of suspicion when a person presents with generalised symptomatology which includes, skin, joint and or decreased energy levels should prompt a thought that autoimmune disease could be part of the differential diagnosis.

In Part 2, we will discuss the treatment of autoimmune diseases, including disease modifying antirheumatic drugs and other immunotherapies, how biologics work, monitoring and the risks of treatment.

REFERENCES

1. Johns Hopkins University Department of Pathology. Auto-Immunity Basics. https://pathology.jhu.edu/autoimmune/damage

2. Rosenblum M D, Remedios K A, Abbas A K. Mechanisms of human autoimmunity. JCI 2015;125(6): 2228–2233. https://doi.org/10.1172/JCI78088

3. Nagy G, Huszthy PC, Fossum E, et al. Selected aspects in the pathogenesis of autoimmune diseases. Mediators Inflamm 2015;2015:351732. doi: 10.1155/2015/351732 https://doi.org/10.1155/2015/351732

4. Angum F, Khan T, Kaler J, et al. The prevalence of autoimmune disorders in women: a narrative review. Cureus 2020;12(5):e8094. https://doi.org/10.7759/cureus.8094

5. Wang L, Wang F"�S, Gershwin ME, et al. Human autoimmune diseases: a comprehensive update. (Review).J Intern Med 2015;278:369– 395. https://doi.org/10.1111/joim.12395

6. Cooper GS, Bynum ML, Somers EC. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J Autoimmun 2009; 33(3-4):197–207 https://doi.org/10.1016/j.jaut.2009.09.008

7. British Society for Immunology Report for parliamentarians into autoimmune conditions 2018. https://www.immunology.org/sites/default/files/connect-immune-research-are-you-autoimmune-report.pdf

8. Autoimmune registry. Estimates of prevalence for autoimmune disease 2021. https://www.autoimmuneregistry.org/autoimmune-statistics

9. NICE. Clinical Knowledge Summaries. Hypothyroidism; 2021. https://cks.nice.org.uk/topics/hypothyroidism/

10. BMJ Best Practice. Systemic lupus erythematosus. https://bestpractice.bmj.com/topics/en-gb/103

11. Castro C, Gourley M. Diagnostic testing and interpretation of tests for autoimmunity. JACI 2010; 125(2 Suppl 2): S238–S247 https://doi.org/10.1016/j.jaci.2009.09.041