Systemic lupus erythematosus (SLE)

Overview of SLE

SLE is a heterogenous multisystem autoimmune (AI) disease resulting in immune complex deposition in various organs. Diagnosis requires clinical findings combined with serology, particularly antinuclear antibodies (ANA).

Women are more commonly affected than men, at a ratio of around 10:1, and onset is usually between puberty and menopause. Certain ethnic groups are at higher risk, including people of African-Caribbean origin and from South America.

Clinical features of SLE

SLE can affect multiple organs and also often causes constitutional symptoms such as fever, fatigue and weight loss.

The revised American College of Rheumatology classification criteria, commonly used for diagnosis, can be remembered using the mnemonic SOAP BRAIN MD as follows:

Serositis	Pleuritis (pleural rub on examination, pleuritic pain or effusion on imaging) or pericarditis (pericardial rub on examination, ECG changes, evidence of pericardial effusion)
Oral ulcers	Oral or nasopharyngeal. Generally painless, most commonly involving the hard palate
Arthralgia & arthritis	Symmetrical arthralgia or arthritis is common; however, joint damage is rare. Joint subluxation due to non-erosive arthropathy can occur – Jaccoud’s arthropathy
Photosensitivity	Skin rash on exposure to sunlight
Blood abnormalities	Leukopenia, lymphopaenia or thrombocytopaenia on more than one occasion
Renal	Persistent proteinuria >0.5 g/day or 3+ on dip. Casts in urine
ANA positivity	ANA positivity at any titre, however at low titres (<1:320) there will be many false positives
Immunological	Antibodies as described below
Neurological	Seizures or psychosis in absence of other cause
Malar rash	‘Butterfly’ rash to face, sparing the nasolabial folds
Discoid rash	Erythematous, scaly, disc-like plaques

Table 1 Diagnostic features in SLE

Other respiratory manifestations can occur, including pulmonary fibrosis or hypertension, and shrinking lung syndrome. This is characterised by increased dyspnoea, diaphragmatic elevation and decreased lung volumes on CXR, and restrictive pulmonary function tests with no parenchymal lung disease. This can be treated with steroids.

Investigations in SLE

Full blood count can show decreased white blood cells, lymphocytes or platelets. ESR increases with disease activity, whereas CRP classically does not, and so a raised CRP suggests another cause for symptoms such as infection.

Antinuclear antibodies are the hallmark of serological diagnosis of SLE, although can be nonspecific. Around 10% of healthy individuals will have low-titre ANA positivity, which is of no consequence if not accompanied by relevant clinical features (Box 1). Conversely, there can be very rare cases of ANA-negative SLE, although this occurs in less than 5% of cases. Other autoantibodies may be found and are correlated with specific clinical features (Table 2).

Additionally, reduced levels of C3 and C4 are common in SLE, and often correlate with increased disease activity. Furthermore, hereditary deficiencies of the classical complement pathway (C1q, C1r, C1s, C2, C4) can cause SLE.

Autoantibody	Association	Comment
ANA		>95% positivity rate in SLE
dsDNA	Lupus nephritis	If positive, correlates with disease activity
Sm	Renal and neurological disease	Most specific, however only positive in up to 30% patients
Ro/SS-A	Sjögren’s overlap Neonatal heart block Cutaneous neonatal lupus
La/SS-B
U1 RNP	Mixed connective tissue disease
Histone	Drug-induced lupus
Antiphospholipid antibodies	Thrombosis Pregnancy loss	There is a common overlap between antiphospholipid syndrome and SLE

Table 2 Autoantibodies in SLE and their associated clinical features.

ANA testing Indirect immunofluorescence is used to test for ANA, and the tests are repeated at serial dilutions until fluorescence is no longer detected. Therefore, the higher the second number in the ratio, the ‘stronger’ the positive result, as it is present at a higher dilution factor. The starting dilution used varies in different laboratories, but around 1:80 tends to be the first dilution used – therefore, this is the ‘weakest’ positive ANA. ANA is positive at 1:80 titre in around 10% of the population. Given the 1% prevalence of ANA-positive rheumatic disease in the general population, there is a large number of false positive ANA results. Different staining patterns can also be seen, which can be associated with certain underlying autoimmune diseases and autoantibodies; however, they are not specific. Patterns include homogenous staining, associated with histone proteins, speckled staining, associated with U1 RNP and Sm antibodies, centromere staining, associated with limited cutaneous systemic sclerosis; and nucleolar staining, associated with multiple rarer autoantibodies.

Box 1 ANA testing and significance

Management of SLE

Conservative measures such as wearing sun cream, preventing sun exposure, staying hydrated and regular exercise are very important.

Pharmacological treatment may include the following:

• Glucocorticoids can help in achieving remission and treating flares. 
• Hydroxychloroquine is used as a disease-modifying agent to prevent flares, maintain remission, and is particularly useful to treat joint symptoms and malar rash. It is generally well tolerated and does not require blood monitoring. Retinal toxicity is a rare but important side effect, and patients should have ophthalmology review 5 yearly and stop taking the drug straight away if any visual symptoms develop.
• Mycophenolate mofetil (MMF) is an immunosuppressive agent which helps to prevent flares, and is particularly effective in lupus nephritis.
• Azathioprine is another immunosuppressive drug which is effective in the management of SLE. It is generally less commonly used than MMF. However, it is safe to use throughout pregnancy and, therefore, is commonly seen in this cohort. Thiopurine methyltransferase enzyme should be tested prior to initiation, as those with a low level of this are at higher risk of side effects.
• Cyclophosphamide is used in severe flares that do not respond to conventional therapy, particularly with lupus nephritis. It has side effects, including haemorrhagic cystitis and risk of developing transitional cell carcinoma of the bladder if used long-term. Mesna is given concomitantly to prevent bladder irritation. 
• Rituximab is an anti-CD20 monoclonal antibody that has recently started to be used in SLE for patients who do not respond to conventional treatments. It depletes B cells, which are key inflammatory mediators in SLE. Serum sickness, a type III hypersensitivity reaction which causes fever, maculopapular rash and arthralgia, can occur 7-10 days following administration, and first-dose infusion reactions with fevers are not uncommon. Progressive multifocal leukoencephalopathy (PML) is the most important side effect to be aware of, although this is extremely rare. This is a progressive and often fatal demyelinating disease caused by reactivation of the JC virus.
• Belimumab is a recently approved monoclonal antibody against B-cell activating factor (BAFF), a B-cell differentiation factor. This has been shown to decrease severe flares and decrease cumulative steroid exposure.

Lupus nephritis

Renal involvement is common in SLE, and onset is usually early in the disease. This can be the first presenting feature or may occasionally occur without any systemic features of SLE. Lupus nephritis is usually associated with increased mortality. Patients generally present with proteinuria, with or without deranged renal function on blood tests. Renal biopsy is the gold standard for diagnosis, and lupus nephritis can be classified histologically into 6 distinct subtypes, which are summarised below.

Class I	Minimal mesangial glomerulonephritis These patients essentially have normal renal function and urinalysis. This is rare to see as such patients would not have a renal biopsy.
Class II	Mesangial proliferative glomerulonephritis. Mesangial hypercellularity is seen on biopsy, with very few subendothelial deposits on electron microscopy. Microscopic haematuria or proteinuria will be seen, but there will very rarely be any other features. This does not generally need any specific treatment.
Class III	Focal glomerulonephritis Sclerosis of less than 50% of glomeruli seen on light microscopy. Proteinuria and haematuria are seen, and some patients will have clinical features of nephrotic syndrome, hypertension and deranged renal function.
Class IV	Diffuse glomerulonephritis This is the most common and severe type seen. On light microscopy, more than 50% of glomeruli are affected. Patients will have nephrotic syndrome, hypertension and deranged renal function on blood tests. Other markers of SLE activity will also be present, such as hypocomplementemia and elevated anti-dsDNA. This requires aggressive treatment with corticosteroids and immunosuppression.
Class V	Lupus membranous nephropathy Glomerular walls are diffusely thickened on light microscopy, with subepithelial immune deposits on immune fluorescence and electron microscopy. Patients present with nephrotic syndrome, similar to primary membranous nephritis. Some patients may have no other systemic features of SLE and no positive autoantibodies.
Class VI	Advanced sclerosing lupus nephritis This is a late stage of lupus nephritis, with sclerosis of over 90% of glomeruli. There is no active glomerulonephritis. Investigations show progressively worsening renal dysfunction with ongoing protein leak. Immunosuppression is not helpful as the immune-mediated injury has already occurred.

Table 3 Histopathological classification of lupus nephritis

Drug-induced lupus erythematosus (DILE)

Multiple drugs have been shown to cause DILE. The most common include:

Sulfasalazine	Minocycline
Hydralazine	Quinidine
Isoniazid	TNF alpha
Procainamide

Drug-induced lupus usually occurs in patients at older ages than SLE, and renal, neurological and skin features are rare. Common presenting features include arthritis, fever, serositis and myalgia. TNF alpha-induced lupus-like syndrome (TAILS), however, commonly presents with skin involvement.

ANA is commonly positive in DILE, and anti-histone antibodies are seen more frequently in drug-induced lupus than in idiopathic SLE. Other antibodies, such as anti-Sm and anti DsDNA are occasionally seen.

Treatment is to remove the causative drug.

References

• Clunie GPR, Wilkinson N, Nikiphorou E, Deepak Jadon. Oxford handbook of rheumatology. Oxford: Oxford University Press; 2018.
• Bloch DB. Measurement and clinical significance of antinuclear antibodies[Internet]. Shmerling RH, Ramirez Curtis M, editors. UptoDate. 2021 [cited 2022 Jun 10]. Available from: https://www.uptodate.com/contents/measurement-and-clinical-significance-of-antinuclear-antibodies
• Anders H-J, Saxena R, Zhao M, Parodis I, Salmon JE, Mohan C. Lupus nephritis. Nature Reviews Disease Primers [Internet]. 2020 Jan 23 [cited 2022 Jun 10];6(1):1–25. Available from: https://www.nature.com/articles/s41572-019-0141-9
• Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Annals of the rheumatic diseases [Internet]. 2019 [cited 2022 Feb 22];78(9):1151–9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31383717 
• Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R, et al. Systemic lupus erythematosus. Nature Reviews Disease Primers [Internet]. 2016 Jun 16 [cited 2022 Feb 11];2(1). Available from: https://www.nature.com/articles/nrdp201639 
• Williams VL, Cohen PR. TNF alpha antagonist-induced lupus-like syndrome: report and review of the literature with implications for treatment with alternative TNF alpha antagonists. International Journal of Dermatology. 2011 Apr 20;50(5):619–25
• Tan EM, Feltkamp TE, Smolen JS, Butcher B, Dawkins R, Fritzler MJ, et al. Range of antinuclear antibodies in “healthy” individuals. Arthritis and Rheumatism [Internet]. 1997 Sep 1 [cited 2022 Jan 28];40(9):1601–11. Available from: https://pubmed.ncbi.nlm.nih.gov/9324014

Antiphospholipid syndrome (APLS)

Overview of antiphospholipid syndrome

Antiphospholipid syndrome is a chronic autoimmune condition which increases the risk of thrombus. It can be primary or associated with another autoimmune condition such as SLE.

Diagnosis is usually made either following thrombus or pregnancy complications, in combination with positive antiphospholipid antibodies.

Clinical features of antiphospholipid syndrome

Antiphospholipid syndrome can cause arterial, venous or microvascular thrombosis. DVT is the most common vascular manifestation, although pulmonary emboli and ischaemic strokes are also common. Cardiac valve abnormalities are seen in 30-50% of patients. Skin manifestations, such as livedo reticularis, can also be associated with antiphospholipid syndrome. Diagnosis is commonly made due to obstetric complications, such as recurrent early miscarriage, fetal loss, intrauterine growth restriction, pre-eclampsia or placental insufficiency.

Investigations in antiphospholipid syndrome

Routine blood tests will usually be normal in primary APLS; however, a prolonged APTT can be seen. Additionally, thrombocytopenia can be seen in around 30% of patients, particularly around the time of a thrombotic event.

Diagnosis of APLS requires at least one of the antiphospholipid antibodies to be positive on two occasions within 5 years of the thrombotic event. These are anti-2 glycoprotein-1 antibodies, anti-cardiolipin antibodies and lupus anticoagulant. Those with more than one positive antibody have a higher risk for thrombotic events.

Patients can have false positive syphilis results, as non-treponemal tests such as VDRL use cardiolipin antigens.

Management of antiphospholipid syndrome

Decisions surrounding use of antiplatelet agents and anticoagulation are complex and depend on whether there has been a previous clot, whether there is concomitant SLE and whether the thrombotic event was provoked. 

• Hydroxychloroquine is used in patients with concomitant SLE, as it has anticoagulant and anti-inflammatory activity.
• Those who have had unprovoked thrombotic events are usually treated with warfarin (target INR 3-4). DOACs are not generally used as there is limited evidence regarding their safety and efficacy in APLS.
• In pregnancy, mothers are usually given low-dose aspirin and low-molecular-weight heparin (LMWH) – treatment dose with previous thrombosis, otherwise prophylactic dose.
• In refractory cases, rituximab (anti-CD20 B cell-depleting monoclonal antibody) can be used.

References

• Clunie GPR, Wilkinson N, Nikiphorou E, Deepak Jadon. Oxford handbook of rheumatology. Oxford: Oxford University Press; 2018.
• Tektonidou MG, Andreoli L, Limper M, Amoura Z, Cervera R, Costedoat-Chalumeau N, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Annals of the Rheumatic Diseases [Internet]. 2019 Oct 1 [cited 2022 Feb 3];78(10):1296–304. Available from: https://ard.bmj.com/content/78/10/1296
• de Larrañaga G, Trombetta L, Wingeyer SP, Remondino G. False positive reactions in confirmatory tests for syphilis in presence of antiphospholipid antibodies: misdiagnosis with prognostic and social consequences. Dermatology Online Journal [Internet]. 2006 May 30 [cited 2022 Feb 3];12(4):22. Available from: https://pubmed.ncbi.nlm.nih.gov/17083877/
• Schreiber K, Sciascia S, de Groot PG, Devreese K, Jacobsen S, Ruiz-Irastorza G, et al. Antiphospholipid syndrome. Nature Reviews Disease Primers [Internet]. 2018 Jan 11 [cited 2022 Feb 2];4(1). Available from: https://www.nature.com/articles/nrdp2017103

Sjögren’s syndrome

Overview of Sjögren’s syndrome

Sjögren’s syndrome is an autoimmune disorder where the predominant pathophysiological feature is lymphocytic infiltration of exocrine glands. Clinical manifestations can vary from sicca symptoms to systemic involvement. Sjögrens can be primary, where it is an isolated phenomenon, or secondary, where it is associated with another autoimmune condition, such as rheumatoid arthritis, SLE or primary biliary cirrhosis.

It is most common in females, with onset in middle age, and has a similar prevalence to rheumatoid arthritis of 1%.

Clinical features of Sjögren’s syndrome

Mucosal dryness is the most characteristic clinical feature – involving the eyes, oropharynx, nose and vagina. These are known as sicca symptoms. There can be extraglandular manifestations, such as arthritis, cutaneous vasculitis, peripheral neuropathy and autoimmune hepatitis. Fatigue is very common and often the most troubling symptom.

There is also an increased risk of lymphoid malignancy, the strongest association being with MALT lymphoma (a non-Hodgkin’s lymphoma).

Investigations in Sjögren’s syndrome

Over 70% have a positive ANA, and anti-Ro (SS-A) and La (SS-B) antibodies are common, with anti-Ro being the most specific. Rheumatoid factor can be positive, and patients can be misdiagnosed as having rheumatoid arthritis.

Schirmer’s test can be performed in clinic: a piece of filter paper is slipped under the eyelid and left for 5 minutes; if <5 mm of the paper is wet after 5 minutes, this suggests impaired tear secretion. Other investigations include measurement of saliva production and labial gland biopsy, which can help in diagnosis of antibody-negative patients.

Management of Sjögren’s syndrome

Treatment depends on the patient’s symptoms. Artificial tears and saliva can be useful for xerophthalmia and xerostomia, as well as close contact with opticians and dentists. Advice regarding lubricants can be given for vaginal dryness. Regular pilocarpine can also help with sicca symptoms. 

Hydroxychloroquine is the most common DMARD (disease-modifying antirheumatic drug) used and can be particularly helpful for joint symptoms; evidence of other benefits is limited. With more severe features such as vasculitis or ILD, systemic immunosuppression may be required, such as glucocorticoids or cyclophosphamide.

Patients who are Ro or La positive should be carefully monitored during pregnancy due to the risk of development of foetal heart block. These patients will have regular ultrasounds throughout pregnancy to detect this at an early stage, in order to prepare for potential pacemaker insertion after birth. Babies born to Ro- or La-positive mothers can also exhibit a photosensitive skin rash due to passive transfer of antibodies across the placenta, called cutaneous neonatal lupus erythematosus.

References

• Price EJ, Rauz S, Tappuni AR, Sutcliffe N, Hackett KL, Barone F, et al. The British Society for Rheumatology guideline for the management of adults with primary Sjögren’s Syndrome. Rheumatology. 2017 Jun 28;56(10)
• Brito-Zerón P, Baldini C, Bootsma H, Bowman SJ, Jonsson R, Mariette X, et al. Sjögren syndrome. Nature Reviews Disease Primers [Internet]. 2016 Jul 7 [cited 2022 Jan 12];2(1):1–20. Available from: 
• Upala S, Yong WC, Sanguankeo A. Association between primary Sjögren’s syndrome and pregnancy complications: a systematic review and meta-analysis. Clinical Rheumatology. 2016 Jun 8;35(8):1949–55
• Clunie GPR, Wilkinson N, Nikiphorou E, Deepak Jadon. Oxford handbook of rheumatology. Oxford: Oxford University Press; 2018
• Baer A. Diagnosis and classification of Sjögren’s syndrome [Internet]. Fox R, Romain P, editors. UpToDate. 2021 [cited 2022 Feb 19]. Available from: https://www.uptodate.com/contents/diagnosis-and-classification-of-sjogrens-syndrome 

Systemic sclerosis (SSc)

Overview of systemic sclerosis

Systemic sclerosis is an immune-mediated multisystem connective tissue disease. The main three processes involved are inflammation, vasculopathy and fibrosis. It is classified into limited cutaneous or diffuse cutaneous, depending on the pattern of skin involvement. These are associated with specific antibodies, and the specific autoantibody can predict the pattern of disease.

Clinical features of systemic sclerosis

Scleroderma

This is another name for the condition and describes the most recognised clinical feature where the skin becomes increasingly thickened and hard. Often, in the early stages, this can be very itchy and sometimes swollen. Hypo- and hyperpigmentation, known as salt-and-pepper skin, can occur. Telangiectasia is commonly seen and can be associated with other complications, such as pulmonary hypertension. Calcinosis cutis is also a common feature of systemic sclerosis, describing calcification of soft tissue. Patients often have abnormal nailfold capillaries, which can be seen on capillaroscopy.

Raynaud’s phenomenon

This is also almost universal, and is generally worse than primary Raynaud’s phenomenon. Digital ulcers can occur as a consequence of the underlying vasculopathy. 

Gastrointestinal involvement

Almost all patients will have some form of gastrointestinal involvement. Gastro-oesophageal reflux is common, and micro-aspiration as a result of this increases the risk of ILD. Gastric antral vascular ectasia is associated with certain subtypes and can cause iron deficiency anaemia and bleeding. Small intestinal bacterial overgrowth (SIBO) is also associated with SSc and can cause malabsorption, bloating and diarrhoea.

Pulmonary involvement

This is frequently seen, with ILD and pulmonary arterial hypertension being the most common manifestations. ILD presents with exertional dyspnoea, non-productive cough, fine bibasal inspiratory crackles, and a restrictive pattern on lung function testing. Pulmonary arterial hypertension also presents with exertional dyspnoea. Isolated decrease in DLCO on lung function testing can be an early clue to the development of PAH.

Renal involvement

Renal involvement is common in scleroderma, although it is often subclinical. The most important renal manifestation to be aware of is a renal crisis. This is much more common in patients with diffuse cutaneous scleroderma, particularly early on in the disease course. There has been an association with the use of corticosteroids, and therefore, these are often avoided in patients with susceptible antibodies such as Scl-70 and RNA polymerase III, early in the disease. Scleroderma renal crisis is characterised by acute renal failure with significant hypertension. Management is with ACE inhibitors unless there is evidence of CNS involvement, in which case infusions such as sodium nitroprusside are used to lower blood pressure.

Classification of systemic sclerosis

	Limited cutaneous SSc	Diffuse cutaneous SSc
Pattern of skin involvement	Only head and distal to elbow/knee	Diffuse skin involvement, including skin proximal to elbow/knee
Autoantibody	>95% ANA 70%-80% anti-centromere	>95% ANA 60% Scl-70 (topoisomerase) Also U3RNP, RNA polymerase III and other rarer antibodies
Lung	PAH > pulmonary fibrosis	Pulmonary fibrosis
Scleroderma renal crisis	Lesser risk	Greater risk

Table 4 Classification of systemic sclerosis and associated features

Raynaud’s phenomenon Raynaud’s phenomenon is classified as primary or secondary. Primary Raynaud’s generally affects young females early in life, with symmetrical involvement. There is not usually digital ulceration or nailfold vasculopathy. Secondary Raynaud’s is associated with rheumatological conditions such as systemic sclerosis, SLE and inflammatory myopathies, and haematological disorders such as cryoglobulinaemia and POEMS syndrome. Conservative measures such as gloves, hand warmers and smoking cessation are first-line. Pharmacological treatment can be used, such as nifedipine, losartan, sildenafil or fluoxetine. Combination therapies can be used if still symptomatic and blood pressure allows.

Box 2 Raynaud’s phenomenon

References

• Denton CP, Khanna D. Systemic sclerosis. The Lancet [Internet]. 2017 Oct [cited 2022 Feb 2];390(10103):1685–99. Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30933-9/fulltext 
• Nihtyanova SI, Denton CP. Autoantibodies as predictive tools in systemic sclerosis. Nature Reviews Rheumatology [Internet]. 2010 Feb 1 [cited 2022 Feb 20];6(2):112–6. Available from: https://pubmed.ncbi.nlm.nih.gov/20125179/ 
• Mouthon L, Bussone G, Berezné A, Noël L-H, Guillevin L. Scleroderma Renal Crisis. The Journal of Rheumatology [Internet]. 2014 Jun 1 [cited 2022 Feb 20];41(6):1040–8. Available from: https://www.jrheum.org/content/41/6/1040 
• Varga J. Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults [Internet]. Axford JS, Ramirez Curtis M, editors. UpToDate. 2021 [cited 2022 Feb 20]. Available from: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-systemic-sclerosis-scleroderma-in-adults 
• Trang G, Steele R, Baron M, Hudson M. Corticosteroids and the risk of scleroderma renal crisis: a systematic review. Rheumatology International. 2010 Dec 4;32(3):645–53

Inflammatory myopathies

Overview of inflammatory myopathies

This is a group of disorders characterised by muscle inflammation and breakdown. The most common forms are polymyositis (PM) and dermatomyositis (DM). These are more common in women than men.

Clinical features of inflammatory myopathies

Symmetrical proximal muscle weakness is the most common finding in both conditions, usually starting in the lower limbs. Muscle pain is less marked than in other conditions such as polymyalgia rheumatica; however, does occur in up to half of cases. 

In addition, dermatomyositis has characteristic cutaneous features. Onset is often weeks to months prior to muscle weakness. Classical cutaneous features include:

• Gottron’s papules: violaceous plaques over the metacarpophalangeal and proximal interphalangeal joints
• Heliotrope rash: a purple-coloured rash around the eyes often associated with periorbital oedema
• Shawl sign: a macular eruption across the back
• V sign: a macular eruption across the anterior chest under the neck

Depending on the antibody, other organ systems may be involved. The most important thing to be aware of is respiratory involvement. ILD is common, and in some autoantibody subtypes can be rapidly progressive. There can also be cardiovascular involvement, and this significantly increases the risk of mortality.

Investigations in inflammatory myopathies

Muscle enzymes are classically elevated. Creatine kinase is the most commonly used; however, the transaminases and LDH can be elevated. Although cardiac involvement can occur, elevated troponin T values may be due to cross-reactivity with the creatine kinase assay, and in such situations, troponin I should be used to investigate further.

Inflammatory markers such as ESR and CRP do not correlate well with disease activity. 

Multiple different autoantibodies are associated with inflammatory myopathies and tend to predict the disease course. ANA is the most common antibody. In exams, it is often stated that anti-Mi2 is most associated with dermatomyositis and anti-Jo-1 with polymyositis; however, there are many other antibodies. 

MRI of muscles can show oedema in active myositis and can also be used to identify an appropriate site for biopsy. Muscle biopsy is gold standard; however, is not always required if the patient has classical features, raised muscle enzymes and a suggestive autoantibody.

EMG can be used to identify a myopathic process and will be abnormal in 90% of patients.

 And so, when patients are diagnosed, it is common to screen for malignancy with thorough examination and sometimes further investigations. Certain antibodies are more associated with this, such as TIF1y.

Management of inflammatory myopathies

Initial treatment is generally with glucocorticoids, usually prednisolone 1-2 mg/kg. DMARDs such as methotrexate can be used as steroid-sparing agents, and there is increasing evidence for the use of biologic agents such as rituximab. IVIG has also been demonstrated to be effective.

Anti-synthetase syndrome

This is a subtype of myositis with its own classical features. Skin on the hands can be thickened and cracked, particularly at the tips of the fingers; this is known as ‘mechanic’s hands’. Raynaud’s phenomenon, arthritis and fevers are other common features. Interstitial lung disease is also commonly associated. Anti-Jo-1 antibodies are the most commonly seen; however, Anti-PL7 and PL12 may also be present and are more associated with ILD.

Inclusion-body myositis

This is a rarer form of inflammatory myositis, accounting for around 20% of cases. It is more common in middle-aged men. Compared to PM or DM as it presents with more predominant distal weakness, such as reduced grip strength, along with proximal muscle weakness. Dysphagia is also commonly seen, although dysarthria is not. An open biopsy is required for diagnosis.

Patients are not generally steroid responsive; however, these are usually given as initial treatment with subsequent DMARD therapy, such as methotrexate.

References

• Witt LJ, Curran JJ, Strek ME. The Diagnosis and Treatment of Antisynthetase Syndrome. Clinical pulmonary medicine [Internet]. 2016 Sep 1 [cited 2022 Feb 20];23(5):218–26. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006392/ 
• Clunie GPR, Wilkinson N, Nikiphorou E, Deepak Jadon. Oxford handbook of rheumatology. Oxford: Oxford University Press; 2018
• Christopher-Stine L, Vleugels RA, Amato AA. Clinical Manifestations of Dermatomyositis and Polymyositis and Adults [Internet]. Targoff IN, Shefner JN, Callen J, Ramirez Curtis M, Ofori AO, editors. UpToDate. 2022 [cited 2022 Jan 12]. Available from: https://www.uptodate.com/contents/clinical-manifestations-of-dermatomyositis-and-polymyositis-in-adult
• Turner MR, Talbot K. Mimics and chameleons in motor neurone disease. Practical Neurology [Internet]. 2013 Jun 1 [cited 2022 Jan 14];13(3):153–64. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664389/

Primary vasculitides

Overview of primary vasculitides

Primary vasculitides are a group of conditions characterised by inflammation within blood vessels. These can be primary or secondary to another condition, such as SLE or rheumatoid arthritis. They are classified by the size of vessel they generally affect; however, this is not absolute.

Large-vessel vasculitis

There are two main types of primary large-vessel vasculitis: giant cell arteritis (GCA) and Takayasu’s arteritis. Large vessel generally refers to the aorta or its main branches. We will discuss the two main primary causes here; however, there are other secondary causes, such as infection. Clinical features depend on which vessel is involved.

Giant cell arteritis

GCA is the most common form of vasculitis. It generally occurs in middle-aged (>50) Caucasians and has a 2:1 female-to-male ratio. There is an association with polymyalgia rheumatica. This is one of the few rheumatological emergencies, particularly when associated with eye involvement, as there is a very high risk of blindness.

Classical presentation is with a new headache, scalp or temporal artery tenderness, and jaw claudication. Headache can occur anywhere but is most commonly temporal. Visual loss may be present, and this is irreversible. Patients may describe amaurosis fugax as a ‘curtain coming down’ on their vision. The best predictor for future visual loss is previous episodes of visual loss.

Blood tests generally show elevated CRP and ESR. US of the temporal artery is often performed, which may show a ‘halo’ around the artery. Gold standard diagnosis is with temporal artery biopsy; however, a negative biopsy does not rule out the disease, as there is a ‘skip lesion’ pattern, and also, often, patients will have had some treatment by the time they have the biopsy. PET-CT may be performed to look for other areas of large vessel involvement. If there is any suggestion of visual involvement, urgent ophthalmological assessment should be arranged.

Anterior ischaemic optic neuropathy is the most common ocular manifestation of GCA. Posterior ischaemic optic neuropathy can occur but is less common. Central retinal vein occlusion can be seen, but this is much rarer.

Treatment is with high-dose glucocorticoids such as 60 mg oral prednisolone or, if there is visual involvement, 1000 mg IV methylprednisolone for 3 days before stepping down to oral. Steroids can then slowly be weaned over around 12 months, depending on response. Given these patients will be on high-dose steroids for a long period of time, bone protection and gastroprotection should be prescribed. In patients who have steroid-resistant or dependent disease, DMARDs such as methotrexate or biologic agents such as tocilizumab can be used.

Polymyalgia rheumatica (PMR)

Polymyalgia rheumatica as an autoinflammatory condition with an unknown pathophysiology which affects the shoulder and hip girdle. This is not a form of vasculitis; however, it shares some common features with GCA, and 10-20% of patients with PMR will go on to develop GCA. PMR occurs in a similar patient group to GCA, as described above. 

Patients typically present with symmetrical muscle pain and stiffness in the hip and shoulder girdle, which is worst in the morning. This can be so severe it can limit activities of daily living, for example, with tasks that require patients to lift their arms above their head. Systemic symptoms such as malaise, anorexia, and fatigue are common. Low-grade fever can be seen; however, if present, this should prompt thorough investigation to rule out infection. It is important to rule out concomitant GCA when assessing someone presenting with PMR symptoms.

CRP and ESR are almost always raised, and normal values should prompt investigation for an alternative diagnosis. There are no associated autoantibodies.

Treatment is with low-dose prednisolone (15-20 mg), and patients often feel significant symptomatic relief even after one dose. If there is no response to steroids, another diagnosis should be considered. Prednisolone is subsequently weaned slowly.

Takayasu’s arteritis

Takayasu’s is a granulomatous arteritis which affects the aorta and its main branches. It generally affects young women from the ages of 20-40 and is most common in Japan and Southeast Asia. 

Classical findings are manifestations of the consequences of vascular inflammation, such as bruits, claudication and asymmetrical or absent pulses.

Investigation is with cross-sectional imaging and angiography.

Initial treatment is with medium-dose glucocorticoids, such as 40-60 mg prednisolone, and then DMARDs, such as methotrexate, azathioprine, or MMF, if the features are steroid-resistant.

Medium-vessel vasculitis

Polyarteritis nodosa (PAN)

This is a rare condition; however, questions are relatively common in examinations. 

Systemic features such as fever, weight loss, arthralgia and fatigue are very common. Cutaneous manifestations, including ulcers, livedo reticularis, and purpura, occur in around 50% of patients. Other common features include non-specific abdominal pain, orchitis and mononeuritis multiplex. Up to half of all patients will have some renal involvement, usually renal ischaemia causing hypertension due to activation of the renin-angiotensin-aldosterone pathway. Renal artery aneurysms can also be present.

Antibodies are typically negative, although p-ANCA is sometimes positive. Inflammatory markers can be elevated. Treatment is generally with glucocorticoids, and then steroid-sparing agents such as cyclophosphamide can be used.

There is a correlation with hepatitis B infection, and this should be screened for at diagnosis.

Kawasaki’s disease

This generally occurs in children; however, sequelae can cause morbidity and mortality in the adult population. Classical features include fever over 40 degrees for over 5 days, widespread erythematous rash, strawberry tongue, desquamation to the hands and feet and bilateral conjunctival erythema. The most important complication to be aware of is coronary artery aneurysms, so monitoring with echocardiography is essential. Treatment is with IVIG and aspirin; urgent treatment is important to avoid the development of cardiovascular complications.

Small-vessel vasculitis

ANCA-associated vasculitides

These conditions are classically severe small-vessel vasculitides associated with anti-neutrophil proteins. However, confusingly, not all patients are ANCA-positive. They most commonly affect older adults.

These often start off with systemic features, including malaise, fevers, night sweats, weight loss, anorexia and arthralgia, which are commonly misdiagnosed before presenting with more classical symptoms.

Glucocorticoids are generally used to induce remission, followed by ongoing treatment to maintain remission, such as cyclophosphamide and rituximab.

The three key subtypes are granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA).

Granulomatosis with polyangiitis

GPA was formerly known as Wegener’s granulomatosis.

Clinical features are as follows:

• Up to 90% of patients have ENT involvement, such as nasal crusting, sinusitis, rhinorrhoea, otorrhoea or otitis media. Hearing loss is common and can be conductive or sensorineural. Nasal bone and cartilage destruction can lead to saddle-nose deformity or nasal septal perforation.
• Renal involvement affects up to 90% of patients, usually as a rapidly progressive glomerulonephritis.
• Lung involvement can occur, affecting the airways or parenchyma, and presents with haemoptysis, dyspnoea, stridor or wheeze. Imaging can show nodules, pulmonary infiltrates or hilar lymphadenopathy.
• Cutaneous vasculitis is seen in around half of patients, commonly presenting as purpuric lesions on the lower limbs.
• Mononeuritis multiplex can be seen, but less commonly than in microscopic polyangiitis. It is usually associated with a worse prognosis.

Investigation findings include:

• If the disease is flaring, blood tests will often show elevated WCC, platelets and inflammatory markers.
• ANCA is positive in around 80-90% of patients, and GPA is most commonly associated with PR3-ANCA (C-ANCA). However, up to 20% are MPO-ANCA positive, and some are ANCA negative, particularly if the disease is quiescent.
• Urinalysis and microscopy may show microscopic haematuria or red cell casts.
• Diagnosis is confirmed by biopsy of involved tissue, usually renal or skin, which shows granulomatous inflammation. Renal biopsy will show ‘pauci-immune’ glomerulonephritis, meaning there are few immune deposits in the glomeruli.

Microscopic polyangiitis (MPA)

This shares many features with GPA; however, lacks the granulomatous inflammation. It is one of the pulmonary-renal syndromes, along with anti-GBM disease, and haemoptysis and renal involvement are the most common features.

Eighty percent of patients are ANCA-positive. This is usually an MPO-ANCA antibody with a P-ANCA (perinuclear) pattern on immunofluorescence.

Eosinophilic granulomatosis with polyangiitis (EGPA)

This was formerly known as Churg-Strauss syndrome.

Although classified as an ANCA-associated vasculitis, only around 50% of patients have a detectable ANCA antibody. It is a triad of features including late-onset asthma, eosinophilia and systemic vasculitis.

Specific clinical features are as follows:

• Respiratory involvement is the most common presentation of EGPA, with asthma generally presenting 8-10 years prior to systemic vasculitis. The asthma is often difficult to control, and patients will have required multiple courses of oral steroids. Leukotriene inhibitors such as montelukast have been associated with unmasking EGPA. Imaging can reveal ‘fleeting’ pulmonary infiltrates, nodules or pleural effusion.
• Cutaneous ulcers and nodules are common.
• Cardiac involvement can occur in severe disease and is an important cause of mortality, causing around half of all deaths. This can manifest with pericarditis, arrhythmias or heart failure. 
• Mononeuritis multiplex may be seen.

Investigation findings include:

• Eosinophilia, usually >1.5 x 109/L.
• In uncontrolled disease, there is often a leucocytosis with elevated inflammatory markers.
• ANCA is positive in around half of patients, and this will usually be MPO-ANCA.

Immune complex-associated vasculitides

Anti-glomerular basement membrane (GBM) disease

This is also called Goodpasture disease.

This is another pulmonary-renal syndrome. It affects pulmonary and glomerular capillaries and is caused by deposition of anti-basement membrane antibodies.

Most patients present with rapidly progressive glomerulonephritis, occasionally with concomitant pulmonary haemorrhage. Other manifestations of respiratory involvement include dyspnoea and cough.

Blood tests show an AKI, and anti-GBM antibodies may be present. Urinalysis shows proteinuria and haematuria, with red cell and granular casts on microscopy. Chest imaging may show pulmonary infiltrates. Lung function testing may show an increased DLCO if pulmonary haemorrhage is present. Renal biopsy is required for formal diagnosis unless contraindicated. This will reveal linear deposition of IgG along glomerular capillaries.

IgA vasculitis (Henoch Schönlein purpura, HSP) 

This is classically described in children; however can occur in people at any age.

Palpable purpura is the most common presenting symptom, usually over the buttocks and legs, alongside arthritis, abdominal pain and renal involvement. Arthritis is usually oligoarticular and involves large joints of the lower limbs. GI involvement can range from mild abdominal pain with nausea and vomiting to intussusception, although this is rare in adults. Renal involvement is more common in adults and carries a higher risk of ESRF than in children.

There are no specific blood tests for HSP, although serum IgA can be raised. Biopsy is generally not required in children; however, is often necessary in adult patients. 

HSP is generally self-limiting, and management is supportive. The use of glucocorticoids is controversial.

Hypocomplimentaemic urticarial vasculitis

This is a rare condition which causes a combination of urticaria and cutaneous vasculitis, with purpura and livedo reticularis. Extra-cutaneous manifestations can occur similarly to other forms of vasculitis, with arthralgia or arthritis, pulmonary involvement, and proteinuria or haematuria. 

Blood tests will often show raised ESR, reduced complement, positive ANA and positive C1q antibodies.

Cryoglobulinaemic vasculitis

This is a rare form of vasculitis caused by the presence of cryoglobulin immune complexes in blood vessels. Most commonly, this involves the skin, kidneys and peripheral nerves. There are three types of cryoglobulins:

Type	Composition	Aetiology	Presentation
1	Monoclonal IgG or IgM	MGUS, multiple myeloma, Waldenstrom’s macroglobulinaemia, CLL	Raynaud’s, digital ischaemia, livedo reticularis Hyperviscosity syndrome: visual disturbance, headache, neurological symptoms
2	Monoclonal IgG/M and polyclonal IgG/M	HCV, SLE, Sjögren’s	Meltzer’s triad: palpable purpura, arthralgia and weakness
3	Mixed polyclonal IgG and IgM	Autoimmune disease, HCV

Table 5 Classification of cryoglobulinaemia

References

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• Lyons HS, Quick V, Sinclair AJ, Nagaraju S, Mollan SP. A new era for giant cell arteritis. Eye [Internet]. 2019 Oct 3 [cited 2022 Jan 21];34:1013–26. Available from: https://www.nature.com/articles/s41433-019-0608-7
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• Johnston SL, Lock RJ, Gompels MM. Takayasu arteritis: a review. Journal of Clinical Pathology [Internet]. 2002 Jul 1 [cited 2021 Oct 8];55(7):481–6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1769710/
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• Kitching AR, Anders H-J, Basu N, Brouwer E, Gordon J, Jayne DR, et al. ANCA-associated vasculitis. Nature Reviews Disease Primers [Internet]. 2020 Aug 27 [cited 2022 Jan 13];6(1). Available from: https://www.nature.com/articles/s41572-020-0204-y
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Sarcoidosis

Clinical features of sarcoidosis

Sarcoidosis is a multisystem inflammatory disorder characterised by non-caseating granulomas on histology. 

Acute sarcoidosis (Löfgren’s syndrome) classically presents with a triad of erythema nodosum, fever and bilateral hilar lymphadenopathy. These features are not always all present, and polyarthritis is also commonly seen. It is generally self-limiting, and lymphadenopathy tends to resolve within 1 year.

Chronic sarcoid is more variable and can affect almost any organ system. Lung disease is the most common manifestation, either as bi-hilar lymphadenopathy or, at later stages, as pulmonary fibrosis. The most classic skin involvement is lupus pernio, a violaceous plaque or nodules that affects the nose, cheeks and ears. Cardiac and neurological involvement has a poor prognosis of up to 25% mortality. Granulomas can be found anywhere, including liver, kidneys, and GI tract; however, symptoms are generally caused by release of mediators, not the granulomas themselves.

Investigations in sarcoidosis

Blood tests can reveal hypercalcaemia or elevated serum ACE. ACE is produced by granulomas, so can be used to monitor disease activity as a marker of granuloma burden. 

Chest X-ray may show bi-hilar lymphadenopathy or pulmonary fibrosis. Findings are generally graded by the Scadding stages:

Stage I	Bi-hilar lymphadenopathy
Stage II	Bi-hilar lymphadenopathy with parenchymal disease
Stage III	Parenchymal disease alone without lymphadenopathy
Stage IV	Pulmonary fibrosis

Table 6 Scadding staging system for sarcoidosis

Sarcoid can mimic many other diseases, including TB and malignancies, so tissue diagnosis is generally required. This can be obtained from the most easily accessible lesion, often using techniques such as EBUS.

Management of sarcoidosis

Acute sarcoidosis is generally self-limiting and does not require intervention.

Management of chronic sarcoidosis varies from case to case, depending on presentation and organ involvement. A global summary, which should be adequate for MRCP purposes, is that glucocorticoids are indicated where there is risk of significant or progressive organ involvement, demonstrated by the mnemonic PUNCH: 

• Progressive lung involvement
• Uveitis
• Neurological involvement
• Cardiac involvement
• Hypercalcaemia

References

• Chauhan A, Jandial A, Mishra K, Sandal R. Acute arthritis, skin rash and Lofgren’s syndrome. BMJ Case Reports. 2021 Jun;14(6):e239239
• Grunewald J, Grutters JC, Arkema EV, Saketkoo LA, Moller DR, Müller-Quernheim J. Sarcoidosis. Nature Reviews Disease Primers. 2019 Jul 4;5(1)
• Clunie GPR, Wilkinson N, Nikiphorou E, Deepak Jadon. Oxford handbook of rheumatology. Oxford: Oxford University Press; 2018
• Gerke AK. Treatment of Sarcoidosis: A Multidisciplinary Approach. Frontiers in Immunology [Internet]. 2020 Nov 19 [cited 2022 May 8];11. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732561/

Hereditary connective tissue disorders

Marfan syndrome

Marfan syndrome is caused by a mutation in the Fibrillin-1 gene (FBN1) and is inherited in an autosomal dominant pattern, although 25% of patients have de novo mutations.

Diagnosis of Marfan’s is made using the Ghent criteria, the key components of which are aortic root dilatation, ectopia lentis and FBN1 gene mutation.

Clinical features of Marfan syndrome

Patients have characteristic musculoskeletal findings. Excess growth of the long bones results in greater height than expected for their genetic background and increased arm length and arm-span-to-height ratio. Chest wall deformity is often present, with pectus carinatum more common than excavatum. Arachnodactyly (long, slim fingers) is also seen. There may be a high-arched palate.

The aortic root is often involved in up to 50% of children and 80% of adults. This manifests as aortic root dilation, aortic regurgitation and aortic dissection, which is the most common cause of morbidity and mortality. Other cardiac features are mitral valve prolapse, tricuspid regurgitation and subsequent heart failure. They can have a high risk of pneumothorax due to emphysematous changes and lung bullae in the upper lobes.

Ectopia lentis is another common feature of Marfan’s and is classically an upward dislocation of the lens. Dural ectasia (enlargement of the spinal canal) in the lumbosacral spine is common.

Homocystinuria is a condition that mimics Marfan’s; however, it has some distinguishing features, and differentiating between the two is a common exam question. Homocystinuria is caused by mutations in multiple genes, such as CBS, which encodes the cystathionine beta-synthase enzyme. Homocystinuria causes marfanoid body habitus and also causes ectopia lentis; however, the lens usually dislocates downward. Intellectual disability is commonly present, and there is a high incidence of thrombotic events, neither of which are associated with Marfan’s.

Osteogenesis imperfecta

Osteogenesis imperfecta is a heritable connective tissue disorder caused by type 1 collagen abnormalities, either decreased production or disrupted structure or processing.

Classification of osteogenesis imperfecta

Originally, four subtypes were described, and these are most commonly asked about in MRCP, although the disease is now felt to be a spectrum, and other subgroups have been added. Types I and IV encompass 90% of patients.

Type	Genetics	Sclera	Features
Type I	Autosomal dominant Quantitative defect	Blue	Least severe Fractures when start walking Hearing loss 50%
Type II	Autosomal recessive Qualitative defect	Blue	Die in utero or early infancy
Type III	Autosomal recessive Qualitative defect	Normal	Most severe survivable form Fractures at birth
Type IV	Autosomal dominant Qualitative defect	Normal	Moderate severity Bowing bones and vertebral fractures Hearing normal

Table 7 Clinical features and heritability of osteogenesis imperfecta types I to IV

Clinical features of osteogenesis imperfecta

Other suggestive features include short stature, scoliosis, easy bruising, increased skin laxity and dental abnormalities. Very mild disease can present as premature osteoporosis, particularly postpartum, or accelerated osteoporosis following menopause.

Management is supportive, including physiotherapy, targeted surgical intervention as required, and screening for osteoporosis.

Ehlers-Danlos syndrome (EDS)

This is a heterogeneous group of disorders with common features including hypermobility, soft and ‘stretchy’ skin, bruising and poor wound healing. There are fourteen types, of which thirteen have had a causative gene mutation identified. These mostly occur in genes which code for type I, III or V collagen subunits or relevant enzymes.

EDS can affect any organ or tissue structure and can present with a variety of signs or symptoms, although those mentioned above are classical. It is important to be aware of vascular EDS, which can cause arterial aneurysms or dissections due to vascular fragility.

Diagnosis is difficult, as some features of EDS are common in healthy individuals, and there is considerable overlap with other diseases. Examination of the skin in classical EDS may reveal hyper-extensibility, abnormal scarring, or velvety or ‘doughy’ texture, whereas, in vascular EDS, the skin is usually thin with visible veins. Hypermobility can be assessed using the Beighton scale. In individuals where there is high clinical suspicion, genetic testing is usually undertaken for diagnosis, except for hypermobile EDS, which has no genetic test and, therefore, requires careful clinical assessment alone.

There is no specific treatment for EDS, and management is directed at the patient’s features. In vascular EDS there should be regular screening for asymptomatic aneurysms and dissections.

References

• Beary JF. Osteogenesis imperfecta: An overview [Internet]. Firth HV, TePas E, editors. UpToDate. 2021 [cited 2022 Feb 25]. Available from: https://www.uptodate.com/contents/osteogenesis-imperfecta-an-overview
• Meester JAN, Verstraeten A, Schepers D, Alaerts M, Van Laer L, Loeys BL. Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Annals of Cardiothoracic Surgery [Internet]. 2017 Nov [cited 2022 Jun 1];6(6):582–94. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721110/
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• Clunie GPR, Wilkinson N, Nikiphorou E, Deepak Jadon. Oxford handbook of rheumatology. Oxford: Oxford University Press; 2018
• Sacharow SJ, Picker JD, Levy HL. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency [Internet]. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, et al., editors. PubMed. Seattle (WA): University of Washington, Seattle; 1993 [cited 2022 Jun 3]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1524/

Other rare autoinflammatory disorders

Behçet’s syndrome

This is a rare autoinflammatory disorder characterised by oral and genital ulcers and increased thrombotic risk. It is more common in males of Middle Eastern origin and is associated with HLA B51. The diagnosis is clinical as there is no clear diagnostic test, although a positive pathergy test is suggestive (insertion of a needle causes formation of a papule or pustule at the insertion site).

Clinical features include:

• Oral ulcers are often the first sign of disease. These are generally painful and may prevent eating.
• Genital ulcers are the most specific feature of Behçet’s, particularly if they heal with scarring, as few other conditions do this. They are most commonly found on the scrotum in men and vulva in women.
• There can be a wide range of thrombotic manifestations, from DVT to cerebral venous sinus thrombosis. Pulmonary artery aneurysms are relatively common and are rarely seen in other conditions.
• Up to 75% of patients have skin involvement, which varies from an acneiform rash to erythema nodosum.
• Uveitis is relatively common and can be the presenting feature.
• Gastrointestinal involvement mimicking IBD can be seen due to bowel ulceration.

Management depends on the specific organ involved. Oral and genital ulcers can be treated with topical steroids or oral colchicine. If this is not sufficient, DMARDs such as azathioprine and anti-TNF alpha agents such as infliximab can be used.

Relapsing polychondritis

This is a rare autoinflammatory disorder which causes immune-mediated destruction of cartilage. 

Clinical features include:

• Auricular cartilage is the most commonly affected, followed by nasal cartilage. 
• Episcleritis and anterior scleritis commonly co-exist. 
• Seronegative asymmetric polyarthritis affecting the small joints is a common presenting symptom. 
• Laryngotracheal cartilage is affected in up to 50% and can present with cough, hoarseness or stridor. Other respiratory manifestations include recurrent lower respiratory tract infections. 
• Cardiac involvement is the second most common cause of mortality after respiratory causes. Aortic regurgitation secondary to aortic root dilatation is the most common cardiac feature. 
• Other systems, such as the kidneys, GI tract, and CNS can be involved, but this is rarer.

Treatment varies widely, from NSAIDs and colchicine to biologics such as anti-TNF agents, depending on severity.

Familial Mediterranean fever (FMF)

This is an autosomal recessive disease caused by a mutation in the MEFV gene, which encodes the pyrin protein. Diagnosis is by genetic testing.

It is most common in Mediterranean populations. Onset is generally in childhood, with 90% of patients experiencing an attack before the age of 20.

Episodes of fever and serositis characterise the disease. These can occur at a varying frequency and generally last up to 72 hours. Symptoms will depend on the site of inflammation; for example, abdominal pain mimicking an acute abdomen can occur with peritonitis and chest pain can be caused by pericarditis or pleuritis. Arthritis is also a common symptom. This is generally monoarticular, affecting the large joints. 

Treatment is with oral colchicine. This helps to prevent flares and decrease the risk of the development of complications such as amyloidosis. IL-1 inhibitors such as anakinra and canakinumab are starting to be used in colchicine-refractory cases.

Adult-onset Still’s disease (AOSD)

AOSD is the term for systemic juvenile idiopathic arthritis when seen in a patient over 16 years old.

It typically presents with daily fevers, a salmon-coloured maculopapular rash and arthritis. The rash is usually non-pruritic and flares with episodes of fever. Joint involvement can initially be in an oligoarticular pattern but progresses to a more severe polyarthritis. Sore throat, lymphadenopathy and splenomegaly may also be found.

There is no definitive diagnostic test. ESR and CRP are markedly raised, and there is a neutrophilic leucocytosis. Elevated ferritin is very common and likely represents an acute phase response. Typically, antibodies are negative.

Mild-to-moderate disease is treated with NSAIDs once other causes are excluded. If patients do not respond to NSAIDs, either glucocorticoids or biologic therapy are initiated. Biologic therapy is usually with IL-1 inhibitors such as anakinra or canakinumab.

IgG4-related disease

This is a heterogeneous disease characterised by inflammation and fibrosis. Many of the subtypes were considered separate entities until it became clear that lesions shared histological findings of abundant IgG4-positive plasma cells.

Patients are usually constitutionally well; fever or elevated CRP suggest another disease process. There can be single or multi-organ involvement at diagnosis, and disease progression is variable.

There are four different phenotypes that have been recognised recently:

• Pancreatobiliary: diabetes, exocrine insufficiency, sclerosing cholangitis and autoimmune pancreatitis.
• Head and neck limited: orbital involvement, sinusitis, thyroiditis, cranial nerve palsies and hearing loss. This tends to affect younger women of Asian origin.
• Retroperitoneal: sequelae of retroperitoneal fibrosis, including hydronephrosis, aortitis, and compression of various structures.
• Mikulicz’s (systemic): enlargement of the lacrimal and salivary glands with xerostomia and xerophthalmia, with any of the other features previously described.

Treatment is generally with glucocorticoids, then biologic agents such as rituximab to maintain remission.

Amyloidosis

Amyloidosis encompasses a group of multisystemic diseases caused by abnormal protein folding and deposition in tissues, known as amyloid deposits. These accumulate faster than they can be cleared away and, therefore, build up within organs and tissues, interfering with structure and function. Multiple different proteins can be involved, and the clinical presentation can differ depending on the subtype.

Subtypes of amyloidosis

Classification is based on the precursor protein:

Subtype	Precursor	Association	Clinical features
AL amyloid	Monoclonal Ig light chains	Myeloma Waldenström’s macroglobulinaemia MGUS	Nephrotic syndrome Macroglossia Periorbital ecchymosis Right ventricular failure Can affect any organ excluding brain
AA amyloid	Amyloid A protein	Chronic inflammation/infection Rheumatoid arthritis Tuberculosis FMF	Renal involvement most common, such as nephrotic syndrome Hepatomegaly
Dialysis-related amyloidosis	Beta-2 microglobulin	Dialysis	Arthritis Carpal tunnel syndrome Cysts in bone
ATTR amyloidosis	Transthyretin fibril protein	Wild-type ATTR accumulation or genetic mutations in ATTR	Right ventricular failure AV block Carpal tunnel syndrome Spinal stenosis

Table 8 Clinical features and associations of amyloidosis subtypes

There are also other genetic forms of amyloidosis which will not be discussed here.

Diagnosis and management of amyloidosis

Histological confirmation is required to establish a diagnosis. With Congo red stain, the sample appears red under normal light and apple green under polarised light microscopy.

Management is tailored toward the clinical manifestations and treating the underlying causative disorder.

References

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