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The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases 

The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases
Chapter:
The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases
Author(s):

Gavin Clunie

, Nick Wilkinson

, Elena Nikiphorou

, and Deepak R. Jadon

DOI:
10.1093/med/9780198728252.003.0004
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date: 27 July 2021

Skin disorders and rheumatic disease

The importance of examining the skin

  • The skin is the most accessible organ to examine.

  • Pattern recognition of skin symptoms and lesions is valuable in aiding diagnosis (e.g. acute or chronic sarcoid) and prognosis of rheumatic diseases (e.g. nodules and vasculitis in RA).

  • MSK abnormalities may be mirrored by skin abnormalities (e.g. joint hypermobility and skin laxity with bruising, scarring, and striae).

  • Some antirheumatic drugs produce specific and potentially serious cutaneous reactions that require prompt management.

  • Some rare autoinflammatory conditions associated with MSK symptoms can manifest primarily with skin pathology (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 18).

Regional abnormalities

The scalp

Scalp symptoms and lesions may be subtle.

  • Scalp tenderness is a sign of GCA.

  • C2 root/occipital neuropathy (e.g. in C1–C3 facet joint OA or crowned dens syndrome/CPPD disease) or shingles may be associated with dysaesthesia over the scalp and occipital neuralgia.

  • Alopecia may be localized (areata) or diffuse (e.g. in SLE or iron deficiency). Scarring alopecia is typical of discoid lupus.

  • Scalp psoriasis may be patchy and discrete, and often affects the hairline.

Face and ears

Face and ears are in sun-exposed areas. Consider ultraviolet (UV) skin sensitivity.

  • A variety of patterns of SLE-associated, UV-sensitive rashes may occur. The rash is often diffuse. Shaded areas (e.g. nasolabial folds) may not be affected (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 13).

  • As in SLE, rosacea can present with an erythematous facial rash. Distinction is sometimes difficult without biopsy.

  • Periorbital oedema occurs in dermatomyositis, angio-oedema (which may be a presenting feature of SLE), and in nephrotic syndrome.

  • Heliotrope rash refers to violaceous oedema/erythema of the eyelids in dermatomyositis (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 14).

  • The cutaneous infiltration of chronic sarcoid (lupus pernio) (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 18) across the nose and cheeks may be overt (papular) but also may be quite subtle (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Plate 21).

  • Saddle nose deformity/nasal cartilage destruction has a number of causes: PR3-positive ANCA-associated vasculitis (AAV; see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 15), relapsing polychondritis (The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 18), hereditary connective tissue disease (e.g. Stickler’s syndrome; see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 19), and lethal midline granuloma. Nasal septal perforation can occur from cocaine use.

  • Oral aphthous ulcers are common. Oral ulceration may follow disease activity (e.g. in SLE). Ulcers in reactive arthritis are typically painless. Oral aphthous ulcers are frequently idiopathic, and not associated with systemic disease.

  • Large punched-out and numerous tongue and buccal ulcers that scar are a hallmark of Behçet’s disease (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 18). They may remain for several weeks.

  • Strawberry erythema of the tongue and lips should not be missed in children. It may denote self-limiting streptococcal infections but may also herald the desquamating palmar (and sole) rash of Kawasaki disease (KD; see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 15).

  • Lacy white streaks on the buccal mucosa suggest lichen planus.

  • The pinna is a common site for gouty tophi and discoid lupus. Relapsing polychondritis typically causes softening and distortion of cartilage (but is lobe-sparing).

  • Lipid skin deposits around the eye occur in hyperlipidaemia and multicentric reticulohistiocytosis.

Hands and nails

Hands and nails should be examined closely.

  • A photosensitive eruption spares the finger webs and palms.

  • Erythema on the back of the fingers may help distinguish dermatomyositis from SLE.

  • In patients with Raynaud’s disease (RD), finger ulceration, finger pulp atrophy (with smooth tapering of the finger tips), induration, and tethering of the skin indicate scleroderma (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 13).

  • Unlike normal skin, the skin of scleroderma does not form fine wrinkles when pinched.

  • Onycholysis, nail-pitting, salmon patches, and subungual hyperkeratosis are typical of psoriasis (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 8).

  • Subungual splinter haemorrhages may be associated with trauma, infective endocarditis, vasculitis, or thromboangiitis obliterans.

  • Nailfold capillaries can be examined with an ophthalmoscope at 40 dioptres after applying a drop of oil (or surgical lubricant) to the cuticle. Enlarged (dilated) capillary loops and capillary ‘dropout’ suggests an underlying autoimmune connective tissue disease (AICTD), particularly systemic sclerosis (SScl).

  • Nailfold vasculopathy is non-specific, and can occur with vasculitis, dermatomyositis and infective endocarditis.

Types of eruption

Macular rashes

Macular rashes are flat (non-palpable) areas of altered skin colour. Papules are lumps <1 cm in diameter.

  • Maculopapular rashes are typical of viral infections.

  • A short-lived, pinkish, maculopapular eruption occurs on the trunk and limbs in systemic-onset JIA (soJIA; see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 9) and adult-onset Still’s disease (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 18). It is often prominent in the late afternoon, and coincides with temperature spikes. If scratched, the rash may blanch (Koebner phenomenon).

  • Erythema that enlarges to form erythematous patches with pale centres suggests rheumatic fever (‘erythema marginatum’).

  • A ‘bulls-eye’ erythematous lesion around a tick bite may be the erythema migrans of Lyme disease.

  • Maculopapular eruptions can occur from NSAIDs, gold, sulfasalazine, azathioprine hypersensitivity, and leflunomide (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 23).

Pustules and blisters

Blisters may be vesicles (<0.5 cm) or bullae (>0.5 cm).

  • The most common pustular rash is due to folliculitis.

  • Pustules confined to the hands and feet suggest reactive arthritis or SAPHO, although local forms of psoriasis may be indistinguishable. Psoriasis can also occur as ‘raindrop’ erythematous lesions, also known as guttate lesions.

  • Generalized pustular rashes can occur in vasculitis, the neutrophilic dermatoses, intestinal bypass syndromes, Behçet’s disease, and gonococcal bacteraemia.

  • Bullous eruptions may be due to SLE and drug reactions, pemphigus, and pemphigoid.

Plaques

Plaques are slightly raised, circumscribed areas—often disc shaped.

  • Plaques are the hallmark of psoriasis. Skin may be scaly and flake off easily. Lesions are often red.

  • Psoriatic plaques can occur anywhere on the skin, but typical sites are over the extensor surfaces of the joints, in the intergluteal cleft, at sites of skin friction (e.g. under waistbands of trousers or underwear) and the umbilicus.

  • Scaling may be a feature of discoid lupus; scaling tends to occur at the periphery of the lesion.

Vascular lesions

Bleeding into the skin that does not blanch is called purpura. It may sometimes be palpable. Telangiectases are dilated small vascular lesions that blanch on pressure.

  • Non-palpable purpura may be due to thrombocytopenia, platelet dysfunction, trauma (± capillary/skin fragility, e.g. chronic steroid use), haemophilia, anticoagulation, and hereditary connective tissue diseases (e.g. EDS; see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 19).

  • Palpable purpura suggests vasculitis, including drug-induced disease (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 15).

  • Widespread telangiectasia occurs in limited cutaneous scleroderma (lcSScl; see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 13), hereditary haemorrhagic telangiectasia, and dermatomyositis.

  • Livedoid rashes can be subtle, occur mainly over the legs, can occur in smokers but are also associated with SLE and antiphospholipid syndrome (APS).

  • Lumpy erythema on the lower legs especially, which can be tender, may be panniculitis (e.g. erythema nodosum), and related to systemic disease (e.g. sarcoid, Crohn’s)

Ulcers and ulcerating rashes

Ulcers are defined as a loss or defect of dermis and epidermis produced by sloughing of necrotic tissue.

  • Cutaneous ulceration may have more than one cause in autoimmune diseases. For example, vasculitis, venous stasis in an immobile patient, and ulceration over nodules or pressure points may all contribute to the same set of lesions. Trauma may be an important cause of cutaneous ulcers in a patient who is already predisposed towards forming these lesions.

  • An indurated, expanding, plum-coloured plaque or acneiform pustule that then ulcerates suggests pyoderma gangrenosum. The ulcer has irregular, bluish margins.

  • Neurotropic ulcers are classic sequelae of diabetes, but they can also occur in association with mononeuritis multiplex (from vasculitis) and other rheumatic diseases.

  • Vasculitic ulcers in the context of livedo reticularis and antibodies to phospholipids (e.g. cardiolipin) may denote APS (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 11).

Textural abnormalities

Abnormalities of the texture of the skin may be difficult to discern. Atrophy and thinning, laxity, thickening, and induration may all be associated with disease.

  • Generalized skin atrophy and thinning is an age-related process, but this can be accelerated by chronic steroid use; hereditary diseases of connective tissue should also be considered.

  • Skin laxity can best be demonstrated over elbow and knee extensor surfaces. Generalized laxity of connective tissue may result in varicose veins and internal organ prolapse.

  • True acral and digital puffiness in a patient with Raynaud’s disease is suggestive of SScl. Skin thickening has a variety of causes (see later in this topic and The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 13).

  • Scleroderma and scleroderma-like skin may be localized, limited, or diffuse—this distinction is important (Table 4.1).

Table 4.1 Pattern recognition in patients with skin thickening

Classification

Skin features

Morphea may be localized (guttate) or generalized

Early small skin areas affected (itchy). Progression to hidebound skin, typically on trunk (areola spared) and legs. Lesions become waxy and hypo/hyper-pigmented guttate (small <10 mm) papules usually on neck and anterior chest

Linear scleroderma

Linear band-like pattern often in dermatomal distribution. Atrophy of muscles is common. Fixed joint deformities and growth abnormalities can occur

‘Coup de sabre’

Linear scleroderma on the face/scalp can be depressed; ivory in appearance. Hemi-atrophy can occur

SScl (early)

Early morning ‘puffiness’ in hands and feet, facial ‘tightness’. Non-pitting oedema of intact dermal and epidermal appendages. High degree of suspicion needed

SScl (classic)

Firm, taut, hidebound skin proximal to MCP joints. Skin may be coarse, pigmented, and dry. Epidermal thinning, loss of hair, and sweating can occur. Telangiectasia and skin calcinosis become obvious. Skin creases disappear. Such change proximal to elbows or knees in the limbs or below the clavicles (in those with face and neck involvement) classifies disease as diffuse as opposed to limited systemic sclerosis

SScl (late)

2–15 years after onset of classical phase, skin softens, but pigmentation changes remain. Skin becomes atrophic and can ulcerate

Eosinophilic fasciitis

Phases: early—pitting oedema; progressive—peau d’orange; late—induration (‘woody feel’) with venous guttering when limb elevated. Arms and legs most commonly affected, but fingers mainly spared. Synovitis and low-grade myositis may occur. Eosinophilia is usually striking, but not always present

Lipodermato-sclerosis

Hyperpigmentation and induration of lower legs associated with venous stasis (‘champagne-bottle legs’)

Diabetes

Waxy thickening of extremities. Insidious progression. Joints of the hands become stiff, the tendons can thicken. Skin changes proximal to wrist and on the face very unlikely, but stiffening of elbow and shoulder joints not uncommon

Dependent lymphoedema

Feet/ankles/lower legs. Often pitting. Chronic presence may give hyperkeratosis. Main causes: R- or L-sided heart failure, renal failure, nephrotic syndrome, and low-protein states

Diagnostic issues in patients with skin thickening

  • Raynaud’s disease (RD) invariably precedes the onset of SScl, but is not a characteristic of morphea or linear scleroderma.

  • In patients with RD, abnormal nailfold capillaries on capillaroscopy may indicate SScl (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Plate 9).

  • The specificities of autoantibodies are often predictive of SScl subtype. In patients with RD, ANA has predictive value for identifying patients who may progress to SScl; anticentromere antibody can predict progression to limited cutaneous SScl; anti-topoisomerase I (SCL-70) and anti-RNA polymerase antibodies are linked with progression to diffuse cutaneous SScl (dcSScl).

  • Patients with dcSScl have a preponderance of visceral organ involvement in the first 5 years of disease; screening investigations are usually useful, and should include cardiovascular screening tests (refer to The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 13).

  • Eosinophilic fasciitis (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 18) may occur as a paraneoplastic syndrome, and is associated with haematological malignancies.

  • Linear scleroderma in children can produce lifelong deformities because limbs fail to develop correct length and bulk.

Skin vasculitis in adults

Background

There are a variety of ways in which systemic vasculitis may present, including fever of unknown origin, organ infarction, gastrointestinal (GI) bleeding, and high acute phase in a generally unwell patient. A vasculitic skin rash is one of the most common presenting features of systemic vasculitis, and is an important diagnostic clue (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 15).

When to consider a diagnosis of vasculitis

  • Primary systemic vasculitis is rare.

  • Cutaneous vasculitis, however, is not rare; it can follow viral or bacterial illness, can be triggered by drugs, and is associated with malignancy. Biopsy generally demonstrates degranulation of neutrophils (‘leucocytoclasis’) and evidence of vessel destruction.

  • The list of causes is long (Table 4.2); however, in about 50% of cases no cause may be found.

  • Cutaneous vasculitis may also occur in association with another autoimmune disease not normally characterized by vasculitis, such as SLE, RA, and Sjögren’s syndrome.

Table 4.2 Precipitants and associations of leucocytoclastic small vessel vasculitis

Drugs

Sulphonamides, for example (there are many). Some drugs may cause a lymphocytic vasculitis without leucocytoclasis

Infections

Hepatitis B, hepatitis C, HIV

β‎-haemolytic Streptococcus

Foreign protein

E.g. serum sickness

Autoimmune disease

Rheumatoid arthritis

Sjögren’s syndrome (anti-Ro positive)

SLE (though livedoid vasculitis may occur in association with secondary APS, and this may be lymphocytic without leucocytoclasis)

Inflammatory diseases

Sarcoid

Crohn’s disease, ulcerative colitis, chronic active hepatitis

Malignancy

Myelo- and lymphoproliferative disorders

Solid tumours

Cryoglobulinaemia

Important considerations

The following important points of clinical assessment should be followed in patients with possible vasculitic rashes.

  • Determine whether the patient has been taking a new drug. Many antibiotics, including penicillins, sulfonamides, and cephalosporins, cause cutaneous vasculitis. Biologics may too, notably anti-TNFα‎.

  • Evaluate the patient for evidence of chronic infection: hepatitis B, hepatitis C, and HIV are worth considering. Endocarditis should also be considered (e.g. the elderly, or patients who use IV drugs).

  • Look for evidence of a primary autoimmune disorder that may be associated with cutaneous vasculitis. IBD, for example, can occasionally cause a leucocytoclastic vasculitis in addition to oral ulcerations and pyoderma gangrenosum. Because SLE is common, check ANA and serum complement C3/C4.

  • Look for evidence of cryoglobulinaemic vasculitis. Serum cryoglobulins tests are often mishandled, leading to false-negative results, primarily because the sample needs to be kept warm (usually by simply holding in the closed palm of the hand) and should be taken straight to the laboratory.

  • RF is detected in 80% of patients with mixed essential cryoglobulinaemia, and may be a better screening test than the latter.

  • Age-appropriate screening for malignancy should be done. Serum and urine electrophoresis with immunofixation may be of value.

  • Urinalysis may demonstrate ‘active sediment’; evidence of haematuria, proteinuria, or red blood cell casts may be the first clue that a patient has a systemic vasculitis.

Systemic vasculitis

  • Untreated primary systemic vasculitis is generally characterized by general inflammation; many patients will complain of B-type symptoms, including fevers, weight loss, and night sweats. Patients with cutaneous vasculitis alone, on the other hand, often feel quite well.

  • The extracutaneous signs and symptoms may provide clues to the correct diagnosis:

    • Henoch–Schönlein purpura (HSP): colicky abdominal pain.

    • Eosinophilic granulomatosis with polyangiitis: adult-onset asthma, eosinophilia.

    • PR3-positive AAV: chronic sinusitis, pneumonitis.

    • Microscopic polyangiitis: haemoptysis, red blood cell casts.

  • Mononeuritis multiplex, which presents as a ‘wrist drop’ or ‘foot drop’, is suggestive of systemic vasculitis in a non-diabetic patient.

Investigations

Skin biopsy

  • Discuss the case with a histopathologist.

  • Punch biopsy is simple, and may be sufficient to yield a diagnosis. Elliptical biopsy provides more tissue, and may increase yield.

  • Use a needle to lift the skin sample. Avoid forceps-induced damage.

  • Biopsy should extend to the subcutaneous fat, which generally includes the arterioles and venules affected by primary systemic vasculitis. Idiopathic leucocytoclastic vasculitis affects the capillaries but generally spares the arterioles and venules.

  • Biopsy should be sent for routine histology and for direct immunofluorescence, which may yield important clues regarding the underlying cause:

    • IgA: HSP.

    • IgM, C3: cryoglobulinaemic vasculitis.

    • IgG, IgM, IgA, C3: SLE.

    • Low immunoreactant staining: AAV.

  • Samples for immunofluorescence should be snap frozen in liquid N2 or dry ice or transported immediately to the laboratory. Immunofluorescence cannot be done on samples treated with formalin.

  • See Table 4.3 for a list of laboratory investigations to be carried out in patients with suspected vasculitis.

Table 4.3 Laboratory tests in patients with suspected vasculitis

Haematology

FBC, ESR, lupus anticoagulant

Biochemistry

Electrolytes, urea, creatinine, LFTs, ACE, CRP, serum and urine protein electrophoresis

Microbiology

Urine microscopy for red cell casts, blood culture, Hep B and C serology, consider HIV, streptococcal antibodies. Also, save 10 mL of clotted blood for viral serology and repeat in 2–3 weeks for paired titre analysis

Immunology

Immunoglobulins (include IgG subsets if IgG4 disease being considered), cryoglobulins, ANA, ENAs, RF, anti-cardiolipin antibodies, ANCA, Complement (C3, C4, CH50/CH100, anti-C1q antibodies if considering urticarial vasculitis))

Cardiac conditions

Subclinical cardiac involvement is found in many rheumatic MSK diseases, and it is not uncommon for a cardiac abnormality to be discovered incidentally. As our ability to treat the underlying rheumatic diseases improves, our ability to identify and to treat the cardiac complications of these diseases becomes increasingly important.

Pericardium

  • Pericardial effusion has been reported in association with a large number of rheumatic diseases, including SScl, Sjögren’s syndrome, polymyositis, mixed connective tissue disease (MCTD), RA, SpAs, and systemic vasculitides.

  • In the majority of cases, effusions are discovered incidentally, are often small, clinically asymptomatic, and require no specific therapy.

  • Pericardial effusions can also occur in the setting of non-rheumatic illness. When a patient with a known rheumatic disease presents with a symptomatic effusion, it is important to consider other possible explanations, such as infection (e.g. TB, viral), malignancy, and other unrelated conditions (uraemia, hypothyroidism).

  • Pericardial effusions are common in SLE and are due to immune complex deposition into the pericardium. Effusions can be serous, serosanguinous, or haemorrhagic. Analysis of the pericardial fluid generally demonstrates evidence of complement, immune complexes, and leucocytes, consistent with an active inflammatory state.

  • Although pericardial effusions are common with SLE, they are generally trivial. Cardiac tamponade is found in <1% of patients with SLE. Since the effusion tends to reflect the overall disease, generally treatment of the underlying disease is adequate to resolve the effusion. Rarely, therapeutic pericardiocentesis may be required.

  • Pericardial effusions are found in up to 30% of patients with RA, although only a small number of these patients will present with pericarditis or evidence of tamponade.

  • Pericardial effusions are more common in RF-positive patients with a history of rheumatoid nodules. Chronic pericardial effusions can become infected, and in rare cases lead to constrictive pericarditis.

  • For both groups of patients, the presence of a symptomatic pericardial effusion is associated with increased mortality. In one study of patients with SLE who presented with cardiac tamponade, the 5-year survival was only 46%.

Myocardium

  • Myocarditis is an uncommon feature of rheumatic diseases. Myocarditis can be found among patients with active SLE and RA, although it generally does not lead to clinically significant dysfunction.

  • Cardiomyopathy among patients with RA and SLE is more likely to be due to premature coronary artery disease, followed by the development of ischaemic heart disease.

  • Although uncommon, the possibility of hydroxychloroquine-induced cardiomyopathy should be considered in patients who develop congestive heart failure in the absence of coronary artery disease. The diagnosis can be confirmed with myocardial biopsy, and the condition responds to drug cessation.

  • Eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg–Strauss vasculitis) can lead to an acute eosinophilic myocarditis that can be life-threatening if not treated promptly.

  • One-third of patients with AAV may have cardiac dysfunction as a consequence of the underlying vasculitis. The majority of these patients will have wall motion abnormalities on echocardiography, but valvulitis and ventricular aneurysm have also been reported. The majority of these lesions will be asymptomatic, but the 5-year survival rate for patients with cardiac lesions attributable to AAV is 57%.

Valvular disease

  • Aortic regurgitation is an important potential consequence of aortitis, which can occur with any of the large-vessel vasculitides (including Takayasu arteritis, GCA, and Behçet’s disease). The aortitis leads to aneurysms, which create valvular incompetence.

  • Aortic regurgitation can also occur as a consequence of AS. Unlike the vasculitides, in AS there is inflammation at the aortic root leading to dense scarring of the aortic valves. Although the mechanism is unique to this disease, it should be monitored and treated like any form of aortic insufficiency.

  • Mitral regurgitation and mitral valve prolapse are common manifestations of SLE.

  • Mitral valve prolapse may also be a feature of Ehlers–Danlos syndrome.

  • A more serious valvulitis can occur in association with SLE or APS. In the process of healing, the valves become scarred and calcified, a process that can eventually lead to clinically significant valvular disease.

  • Libman–Sacks endocarditis is a classic manifestation of SLE. In this disease, vegetations form from immune complexes, mononuclear cells, and fibrin, which attach to the valves. Although not infectious, these vegetations can embolize.

  • Haemodynamically insignificant valve lesions have also been reported in association with RA, MCTD, SScl, and Sjögren’s syndrome.

Coronary artery disease

  • Surprisingly, the primary vasculitides rarely lead to coronary artery inflammation, although coronary artery vasculitis has been reported in association with PAN and AAVs.

  • APS is associated with a substantial increased risk of myocardial infarction, even in the absence of true coronary artery disease.

  • Both RA and SLE are strongly associated with coronary artery disease. This may be the result of systemic inflammation or a response to chronic immunosuppression. Regardless, patients with these diagnoses should undergo early cardiac evaluation to address modifiable risk factors for coronary artery disease.

  • Accelerated atherosclerosis may be an important consequence of glucocorticoid exposure. Even chronic low-dose prednisone may place some patients at increased risk of cardiovascular disease.

Conduction abnormalities

  • Clinically insignificant dysrhythmias and conduction defects are common among patients with inflammatory myopathies (dermatomyositis, polymyositis) and scleroderma.

  • Clinically significant abnormalities (including heart block) can be seen in patients with SpAs as a result of the same scaring process that leads to the valvular abnormalities noted earlier.

Pulmonary conditions

Pleura

  • An exudative pleural effusion is found in up to 50% of patients with SLE. These effusions can be unilateral or bilateral, and frequently are found in association with a pericardial effusion.

  • Pleural disease is a common manifestation of RA, which is associated with pleural effusions and pleural thickening. Effusions are generally asymptomatic, and are found in the setting of active disease.

  • Asymptomatic pleural effusions can also be found in 10–30% of patients with AAV.

  • Pleural effusions are classified as transudates, typically arising as a consequence of left ventricular, renal and hepatic failure, and SLE; or exudates, usually due to infection, malignancy or pulmonary embolism.

  • By the ‘Light’ criteria (with a 75–80% sensitivity) a transudate is:

    • clear.

    • specific gravity <1.012.

    • fluid protein <2 g/dL.

    • fluid:serum protein ratio <0.5.

    • fluid:serum LDH ratio <2/3.

    • cholesterol <45 g/dL.

  • In the same criteria, an exudate is defined as:

    • cloudy.

    • specific gravity >1.020.

    • fluid protein >2.9 g/dL.

    • fluid:serum protein ratio >0.5.

    • fluid:serum LDH ratio >2/3.

    • cholesterol >45 g/dL.

  • If an exudate is identified fluid should be examined for:

    • amylase: in oesophageal rupture, pancreatitis.

    • glucose: decreased in infection, malignancy and RA.

    • pH: low in empyema.

    • Gram stain.

    • polymerase chain reaction (PCR) for tuberculosis.

Pulmonary nodules/masses

  • Both PR3-positive AAV and sarcoidosis are often diagnosed incidentally, after the discovery of lung masses. Sarcoidosis is associated with hilar lymphadenopathy, while PR3-positive AAV generally presents with multiple peripheral pulmonary nodules that can be mistaken for lung cancer.

  • In a patient with a known rheumatic disease who presents with a lung mass, it is always important to consider the possibility of malignancy. Lung cancer risk is increased among patients with RA and SScl, and many rheumatic diseases are associated with an increased risk of lymphoma.

  • PR3-positive AAV (and less commonly, AS and RA) can lead to cavitating apical lesions that can be mistaken for TB.

Interstitial lung disease (ILD)

  • ILD and pulmonary fibrosis (with a predilection for the lung bases and periphery) is a common feature of both dcSScl and the inflammatory myopathies.

  • Pulmonary fibrosis is found in 20–65% of patients with SScl. Radiographically, the lesions take on the appearance of ground glass ILD infiltrates that gradually lead to honeycombing and fibrosis.

  • ILD may be the initial manifestation of an inflammatory myopathy, and pulmonary symptoms may precede clinical evidence of muscle involvement.

  • RA is also associated with ILD.

  • Apical fibrosis can be found in 1% of patients with AS. Apical fibrosis is also an uncommon feature of rheumatoid lung.

  • Pulmonary fibrosis can also occur as the long-term sequelae of pulmonary capillaritis, which may occur in patients with AAV.

  • ILD in primary Sjögren’s syndrome can be subtle and evolve insidiously. The usual pattern is non-specific (NSIP).

  • Bronchiolitis obliterans organizing pneumonia (BOOP) has been associated with autoimmune rheumatic and connective tissue diseases but the association is not frequent.

Vasculature

  • Haemoptysis can be the result of pulmonary capillaritis, which can be found in association with the so-called pulmonary renal syndromes: SLE, AAV (predominantly microscopic polyangiitis), and anti-glomerular basement membrane syndrome. Acute or severe pulmonary vasculitis may require prompt plasmapheresis.

  • Cryoglobulinaemic vasculitis can also cause pulmonary capillaritis, although this is not one of its more common manifestations.

  • Pulmonary artery hypertension (PAH) is most commonly associated with lcSScl. Isolated PAH can also be seen with dcSScl, although it generally appears as a consequence of pulmonary fibrosis.

  • SScl causes PAH by narrowing of the small arteries and arterioles that gradually leads to obliteration of the pulmonary vascular bed.

  • RA, SLE, inflammatory myopathy, MCTD, and Sjögren’s syndrome can also be associated with PAH, but it is considered an uncommon feature of these diseases.

Airways

  • RA can lead to laryngeal obstruction when it affects the cricoarytenoid joints. It usually presents with hoarseness or odynophagia.

  • Subglottic stenosis is a common feature of PR3-positive AAV, which can lead to significant stridor.

  • Uncontrolled relapsing polychondritis can cause tracheomalacia, which is a significant cause of morbidity for this disease.

  • Any part of the airway can become symptomatic in primary Sjögren’s syndrome: xerotrachea, xerostomia, sinus symptoms.

Renal conditions

Evaluation of renal failure: overview

  • The kidneys are an essential component in the evaluation and management of the rheumatic MSK diseases.

  • In terms of time course, renal failure may be secondary to acute kidney injury (AKI) or chronic kidney disease (CKD). AKI can occur in patients with stable CKD.

  • AKI (grade 1) is defined when one of the following criteria is met:

    • Serum creatinine rises by ≥26 µmol/L within 48 hours.

    • Serum creatinine rises ≥1.5× from the reference value, which is known or presumed to have occurred within 1 week.

    • Urine output is <0.5 mL/kg/hour for >6 consecutive hours.

  • The above-listed indices are the minimum required for definition (grade 2 and 3 AKI have definitions: http://www.renal.org/guidelines/modules/acute-kidney-injury).

  • Urgent urinalysis and renal ultrasound should be obtained in all AKI patients.

  • Glomerular filtration rate value (mL/min/1.73m2) classifies renal function as WHO stage: normal (grade 1; >90), mild (grade 2; 60–89), moderate (grade 3; 30–59), severe (grade 4; 15–29), severe failure (grade 5; <15).

  • The presence of red blood cells and protein, or red blood cell casts (i.e. ‘an active sediment’) implies glomerulonephritis, which can occur with vasculitis and SLE.

Pre-renal azotaemia

  • Hypovolaemia is an important cause of pre-renal AKI. Dehydration and anaemia can both lead to pre-renal azotaemia (e.g. the elderly RA patient).

  • Renal hypoperfusion can also be caused by diminished blood flow to the kidneys. Diseases involving the renal artery (such as renal artery stenosis or thrombosis or PAN affecting the renal artery) may cause pre-renal azotaemia. This may be acute leading to AKI or slowly evolving causing CKD.

  • Conditions associated with low cardiac output (including shock, congestive heart failure, myocarditis, tamponade, and pulmonary arterial hypertension) may all predispose the patient to pre-renal AKI.

  • Hyperviscosity, which is seen with type I (monoclonal) cryoglobulinaemia, is a very rare cause of pre-renal azotaemia.

  • All of these conditions may be exacerbated by drugs that decrease renal perfusion, including NSAIDs and ACE inhibitors.

  • With pre-renal azotaemia, the fractional excretion of sodium [FENa = (UNa × PCr)/(PNa × UCr)] is <1.0; this test is not reliable in patients treated with diuretics.

Post-renal azotaemia

  • Nephrolithiasis is not a common cause of post-renal azotaemia, but should be considered in a patient with gout: 5–10% of renal calculi in the United States are caused by uric acid; this is particularly common among patients with gout who have been treated with uricosuric agents (e.g. probenecid).

  • Sarcoidosis can cause hypercalcaemia and hypercalciuria, which in turn can lead to nephrolithiasis and nephrocalcinosis, both of which can rarely cause post-renal azotaemia.

  • Methotrexate and trimethoprim/sulfamethoxazole can cause crystalluria and renal obstruction.

  • Ultrasound is a useful modality to evaluate both for the presence of obstruction leading to hydronephrosis and renal calculi.

Intrinsic renal failure: ‘active sediment’

  • Intrinsic renal disease from a rheumatological conditions can present acutely (AKI) or insidiously as evolving CKD.

  • The nephritic syndromes are an important cause of moderate/severe AKI among patients with rheumatic diseases, particularly vasculitis and SLE.

  • The presence of haematuria, proteinuria, and red blood cell casts strongly suggests the presence of glomerulonephritis.

  • A renal biopsy is crucial to determining the underlying diagnosis and the severity/chronicity of the disease.

  • Nephritic syndromes can be divided into ‘focal proliferative’ and ‘diffuse proliferative’ based on histology.

  • Causes of focal proliferative glomerulonephritis include SLE, HSP, and other forms of small vessel vasculitis.

  • Diffuse proliferative glomerulonephritis is caused by cryoglobulinaemia, SLE, anti-glomerular basement membrane disease (Goodpasture’s syndrome), and small-vessel vasculitis (including AAV and renal-limited vasculitis).

  • Direct immunofluorescence can also provide valuable information regarding the correct diagnosis: SLE biopsy demonstrates multiple immunoreactants (‘full house’ staining pattern); IgA deposition implies HSP; cryoglobulinaemic vasculitis leads to IgG and C3 deposition; sparse or absent immunoreactants on biopsy is sometimes called ‘pauci-immune’, and implies an AAV.

Intrinsic renal failure: ‘bland sediment’

  • A bland sediment refers to a urine sample that is acellular; transparent hyaline casts may be seen.

  • A bland sediment is also seen in pre-renal and post-renal azotaemia.

  • Acute tubular necrosis (ATN) reflects acute, intrinsic renal failure associated with a urine sediment that has muddy brown casts and tubular epithelial cells.

  • Nephrotoxic tubular injury from drugs is a common cause of ATN in patients with rheumatic disease.

  • Prolonged pre-renal azotaemia can lead to permanent kidney damage; therefore, diseases of the renal artery (including polyarteritis nodosa and renal artery thrombosis from APS) should be considered.

  • Interstitial nephritis is most commonly seen as a drug reaction (e.g. gold, penicillamine).

  • Interstitial nephritis can also be seen as a manifestation of several rheumatic diseases, including Sjögren’s, SLE, sarcoidosis, and EGPA.

  • NSAIDs cause renal vasoconstriction and interstitial nephritis, both of which can eventually lead to a chronic analgesic nephropathy.

  • Unlike the other forms of AAV, the mechanism of renal failure among patients with the EGPA is an interstitial nephritis; glomerulonephritis is relatively rare with this diagnosis.

  • The most common causes of secondary renal amyloidosis are AS, RA and FMF. Glomerular deposits of amyloid lead to proteinuria (which can be nephrotic range) and progressive renal failure.

SScl renal crisis

  • SScl renal crisis is a rheumatologic emergency characterized by AKI and malignant hypertension (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 25, p. [link]).

  • Patients with dcSScl are at greatest risk.

  • SScl renal crisis generally occurs within the first 4 years after diagnosis, but it can occur at any time. Patients who are treated with high-dose glucocorticoids and are anti-RNP positive are at highest risk.

  • Urinalysis generally demonstrates a bland sediment. Kidney biopsy demonstrates evidence of a thrombotic microangiopathy that histologically cannot be distinguished from malignant hypertensive nephrosclerosis, haemolytic–uraemic syndrome, SLE, or APS.

  • The cornerstone of therapy is escalating doses of ACE inhibitors, followed by angiotensin II receptor blockers (ARBs) and calcium channel blockers if adequate blood pressure control is not achieved.

Renal tubular acidosis

  • Renal tubular acidosis (RTA) is a non-anion gap metabolic acidosis caused by a failure of the renal tubules to maintain acid–base status.

  • Type I RTA, caused by an inability to excrete acid, is found with Sjögren’s syndrome and SLE.

  • Type IV RTA is most commonly caused by hyporeninaemic hypoaldosteronism, can occur as a result of treatment with NSAIDs, ACE-inhibitors, and ARBs. This is commonly associated with hyperkalaemia.

Endocrine conditions

Well-characterized MSK conditions occur in many endocrine disorders. Some are specific for certain disorders; others are non-specific, but occur with greater frequency among patients with endocrine disease. MSK features occur either as a result of metabolic disturbances or are influenced by a common link in autoimmune pathophysiology.

Diabetes

  • Dupuytren’s contracture, trigger finger, carpal tunnel syndrome, diffuse idiopathic skeletal hyperostosis (DISH), and adhesive capsulitis all occur with greater frequency among patients with diabetes.

  • Some form of tissue or joint hypomobility/stiffness is common among patients with diabetes (Table 4.4); in some cases, this can appear similar to scleroderma. These scleroderma-like skin changes are more prevalent among patients with type I diabetes.

  • Hand weakness may be due to diabetic neuropathy and may be mistaken for carpal tunnel syndrome. Neurophysiology tests help discriminate between these two diagnoses.

  • Calcification of soft tissues around the shoulder occurs in approximately 20% of diabetics, and is associated with variable symptoms and disability.

  • Diabetic amyotrophy is uncommon. It presents acutely with pain, weakness, and wasting of the proximal lower limb muscles. It may be unilateral. Differential diagnosis includes myositis (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 14) and PMR. It is associated with uncontrolled hyperglycaemia. The aetiology is unknown, but it is probably a neuromyopathy.

  • Though rare (1:500 diabetics), neuropathic arthritis can occur in advanced disease. Most patients are aged 40–60 years and have poor glycaemic control. Tarsal and metatarsal joints are most frequently affected (60%). The usual presentation is of swelling of the foot with no or little pain. Trauma may have occurred. Early radiographic changes can resemble OA.

  • Asymptomatic osteolysis can occur at the distal metatarsals and proximal phalanges with relative joint sparing: aetiology unknown.

  • Osteomyelitis is not uncommon and needs to be discriminated from cellulitis and neuropathic arthritis (Charcot’s joint). A triple-phase bone scan should be helpful. Osteomyelitis is usually disclosed by prominent blood flow in the dynamic (first) phase and increased uptake of tracer by soft tissue and bone in later stages. Cellulitis is associated with minimal uptake of tracer in bone in the delayed (third) phase. Neuropathic joints display minimal first-phase abnormalities but prominent tracer uptake in the third phase.

  • Diabetic muscle infarction can present as a painful muscle mass and is a result of arterial narrowing. Often mistaken for thrombophlebitis, myositis or vasculitis, this is a late complication of diabetes. Biopsy may be needed to confirm this diagnosis.

  • Diabetes may be associated with a ‘metabolic syndrome’ (diabetes + hypertension, hyperuricaemia, obesity).

Table 4.4 Patterns of joint and tissue hypomobility/stiffness in diabetes by reported series. Tissue changes are thought to occur from changes in hydration properties/kinetics of glycosaminoglycans (consequence of an excess local production of sugar alcohols)

Patient series

Major abnormalities

Associations

Diabetics overall

In about 30–40% mainly in long-standing disease: slow decrease in hand mobility; waxy skin thickening (‘scleroderma-like’)

Occasional lung fibrosis. Microvascular diabetic complications

Adults

55–76% prevalence of joint hypomobility in type 1/type 2 diabetes, respectively

Not associated with diabetic complications

Mature-onset diabetes (mean 61 years)

Stiffening of connective tissue (assessed in hands)

Diabetic nephropathy

Children with type 1 diabetes

31% have limited joint mobility

None with glycaemic control, retinopathy, or proteinuria

Juvenile and young adult onset (age 1–24 years) diabetes

34% had skin thickening. Changes rarely proximal to MCPs and never proximal to wrists. Joint contractures in >50%, often third or fourth fingers

No flexor tendon rubs (as seen in scleroderma)

Hypothyroidism

  • Over 25% of patients with hypothyroidism have an arthropathy—cross-sectional data. The likeliest explanation is coincidental arthritis disease: generalized OA, CPPD-related (see next bullet point) or an autoimmune arthritis (e.g. RA). Whether a specific arthritis occurs directly as a result of thyroid abnormality, is debatable.

  • Radiographically-defined chondrocalcinosis is only marginally increased compared with controls (17% vs 10%). About 1/10 patients with acute CPPD are hypothyroid.

  • Thyroid disease may also be autoimmune and the serum ANA positive, again often mistaken for assuming the presence of a primary rheumatic condition.

  • Carpal tunnel syndrome is common (7%). Up to 10% of patients with carpal tunnel syndrome may have hypothyroidism.

  • Hyperuricaemia is common, but gout attacks are rare. However, screening for hypothyroidism in patients with gout is recommended. Treated hypothyroidism then requires review of the need for uric acid-lowering therapy.

  • Myopathy is relatively common. About 1 in 20 cases of acquired myopathy are due to hypothyroidism. The presentation can mimic polymyositis with elevation of muscle enzymes, but muscle biopsy typically shows no inflammatory cell infiltrate. Improvement with thyroxine replacement is sometimes complicated by muscle cramps, but these should resolve in a few weeks.

  • The combination of weakness, muscular stiffness, and an increase in muscle mass in an adult with myxoedema is termed Hoffman’s syndrome. Muscle mass increase is sometimes striking and can take many months to resolve on treatment.

  • Lymphocytic thyroiditis (Hashimoto’s) is an autoimmune condition characterized by hypothyroidism and autoantibodies to thyroglobulin and thyroid microsomes. These antibodies are found in 40% of patients with primary Sjögren’s syndrome, but only about 10% are or have been overtly hypothyroid.

Thyrotoxicosis

  • Hyperthyroidism can cause a proximal myopathy (70%), shoulder periarthritis (7%), acropachy (thickening of extremities), and osteoporosis.

  • Graves’ disease is frequently associated with fatigue and muscular weakness. It is associated with autoimmune rheumatic and connective tissue diseases.

Thyroid acropachy

This is rare (<2% of patients with thyrotoxicosis) and most often occurs in treated patients who are hypo/euthyroid.

  • There is clubbing, and painful soft tissue swelling of hands and feet.

  • Periosteal new bone occurs on the radial aspect of the second and third metacarpals.

  • Acropachy occurs most frequently in patients who have the ophthalmopathy or dermopathy associated with autoimmune thyroid disease.

Hyperparathyroidism

See The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 16.

The following points refer to both primary and secondary disease:

  • MSK symptoms are the initial manifestation in up to 16% of patients with primary hyperparathyroidism.

  • Hyperparathyroidism, chondrocalcinosis, and CPPD frequently coexist. Acute CPPD can be triggered by parathyroidectomy.

  • Chronic CPPD arthropathy can mimic RA. Unlike RA, synovial proliferation is absent. Radiographically, erosions have a predilection for the carpus, mid-feet and second/third MCPJs. Pericapsular calcification is often present.

  • An erosive polyarthritis favouring the large joints can occur with renal osteodystrophy in patients with chronic renal failure on dialysis. It may relate to a number of different, or combination of, crystal induced inflammatory-based mechanisms (hydroxyapatite, basic calcium phosphate, pyrophosphate, urate).

  • Hyperparathyroidism is associated with a specific shoulder arthropathy characterized by intra/periarticular erosions of the humeral head. This may be sub-clinical.

  • Subjective muscle weakness and fatigability are common complaints. Typically, muscle enzymes are normal and biopsy shows type II fibre atrophy; the features of an inflammatory myopathy are generally absent.

  • The hallmark of radiographic changes is bone resorption: sub-periosteal (typically on the radial side of second and third phalanges), intracortical, subchondral, trabecular, sub-ligamentous, and localized (Brown’s tumours) resorption patterns are seen. Bone sclerosis, periostitis, and chondrocalcinosis also occur.

  • Fragility fracture is common and often precedes a diagnosis of primary hyperparathyroidism. Although significant and fast accretion of bone occurs after surgery, bone mass often remains low long term.

Acromegaly

  • Over-stimulation of bone and connective tissue cells from excessive growth hormone can result in several features: bursal and cartilage hyperplasia, synovial and bony proliferation, an OA-like picture, backache, and hypermobility.

  • Joint complaints usually manifest about 10 years after the onset of clinical acromegaly. Knees are frequently affected.

  • Joint symptoms are not typical of an inflammatory arthritis. Morning stiffness is not prominent and joint swelling is present in <50%.

  • Carpal tunnel syndrome affects >50% and is frequently bilateral.

  • Back and neck pain and radicular symptoms from nerve root compression or spinal stenosis are not uncommon and are related to axial bony proliferation.

  • A painless proximal myopathy occurs infrequently.

  • Radiographs characteristically show widened joint spaces (e.g. >2.5 mm in adult MCPJs) and a thickened heel pad (>23 mm in men and >21.5 mm in women).

  • Diagnosis relies on demonstration of a failure of growth hormone to be suppressed by a glucose tolerance test, but a lateral skull radiograph is a good screening test as 90% have enlargement of the pituitary fossa.

Gut and hepatobiliary conditions

MSK features frequently occur in patients with gut or hepatobiliary disease (Table 4.5).

  • Data on the frequency of rheumatological features are largely based on studies of hospital patients with clinically overt gut or biliary disease—leading to an underestimate of the frequency of association.

  • Well-established associations include:

    • toxic effects of medications (e.g. NSAIDs; see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 3).

    • irritable bowel syndrome and fibromyalgia.

    • functional GI motility disorders (e.g. SScl, EDS).

    • sacroiliitis, arthritis, and enthesitis in patients with SpA and IBD.

    • degenerative arthritis in haemochromatosis and Wilson’s disease.

  • The frequency of enthesitis in patients with IBD may be underestimated. Enthesitis may be detected at the medial/lateral humeral epicondyles, Achilles’ tendon insertion, calcaneal plantar fascia origin and insertion, greater trochanters, and the patellar tendon origin and its insertion at the tibial tubercle.

  • Radiology studies in patients with IBD suggest that sacroiliitis is under-recognized by clinicians.

Table 4.5 Associations between gastrointestinal (GI) and rheumatic disorders

GI disorder>

Rheumatic disorder

Association

Enteric infection

Reactive arthritis: self-limiting in most

Arthritis in 2% who get Shigella, Salmonella, Yersinia, Campylobacter, Clostridium difficile overall but in 20% of infected who are HLA-B27+

Crohn’s disease

Arthritis 20%. AS 10%. Sacroiliitis in 26%

60% of spondyloarthritis patients have histological evidence of bowel inflammation. See also below in table

Ulcerative colitis

Arthritis 20%. AS 7%. Sacroiliitis 15%

See also above in table. Severity of gut and joint inflammation varies in its association but SI joint/pine inflammation does not

Whipple’s disease

Migratory arthritis in >60%

Tropheryma whipplei identified in small bowel. Diarrhoea occurs in >75% ultimately

Intestinal bypass surgery (blind loop syndrome)

Polyarticular symptoms 50% in scleroderma

Intestinal bacterial overgrowth in small bowel? Associated with joint symptoms

Coeliac disease

Arthritis is rare

?Increased intestinal permeability

Viral enteritis

Rare (<0.5%)

Most common: Coxsackie or echo

Hepatitis A

Arthralgia 15%. Vasculitis rare

Causal association

Hepatitis B

Arthralgia 10–25%. PAN

Aetiological

Hepatitis C

Sialadenitis in >50%. Vasculitis (cryoglobulinaemic)

?Aetiological in Sjögren’s syndrome. Hepatitis C identified in 27–96% of patients with cryoglobulinaemia

Primary biliary cirrhosis

Polyarthritis 19%. Scleroderma 18%. Sjögren’s 50%

Autoimmune ‘overlap’. Features may be subclinical

Chronic active hepatitis

Polyarthralgia or arthritis in 25–50%

Autoimmunity

Haemochromatosis

OA 50%

Iron storage disease

Wilson’s disease

OA in 50% adults. Chondrocalcinosis

Copper storage disease

Severity of rheumatologic manifestations

  • Optimal surveillance strategies for the MSK manifestations of gut or biliary disease are not known in many instances.

  • Faecal calprotectin is a sensitive measure for IBD screening in patients with SpA, but modest elevations can occur in a number of scenarios.

  • Life-threatening vasculitis may occur from chronic viral infection. Hepatitis B is associated with polyarteritis nodosa, and hepatitis C may lead to cryoglobulinaemic vasculitis.

  • In most patients who develop joint inflammation or enthesitis after bacterial dysentery, the condition is self-limiting. Chronicity and severity may be linked to HLA-B27. Progressive spondylitis is rare.

Gut and hepatobiliary conditions in patients with rheumatic diseases

(Tables 4.6 and 4.7; also see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 15, ‘Vasculitis’)

  • The most common problem among patients with RA is dyspepsia associated with gastroduodenal erosions or ulcers due to NSAIDs. Peptic lesions may be clinically silent and may present with dropping haemoglobin levels or an acute bleed.

  • RA may be the most common cause of AA amyloidosis. Biopsies of the upper GI tract will demonstrate amyloid deposits in 13% of patients. There are numerous GI manifestations of amyloidosis, including GI haemorrhage, malabsorption, obstruction, and hepatosplenomegaly.

  • In SLE, serious gut and hepatobiliary manifestations are relatively uncommon (5%), but nausea, anorexia, vomiting, and diarrhoea are quite frequent.

  • SScl has numerous GI manifestations including refractory gastro-oesophageal reflux disease, gastric antral vascular ectasia (‘watermelon stomach’), oesophageal dysmotility, bacterial over-growth, and faecal incontinence.

  • The reflux associated with SScl often requires treatment with high-dose proton pump inhibitors.

  • ‘Watermelon stomach’ can lead to significant acute and chronic haemorrhage.

  • In SScl, bloating and abdominal distension caused by bacterial overgrowth may respond to cyclic courses of antibiotics.

  • Mesenteric vasculitis is classically caused by polyarteritis nodosa, but can be seen with a variety of rheumatic illnesses, including Takayasu arteritis, AAV, and (rarely) with SLE. Although mesenteric angina is the symptom most strongly associated with mesenteric vasculitis, the earliest sign of intestinal ischaemia is diarrhoea.

  • HSP is an IgA-mediated small vessel vasculitis that presents with colicky abdominal pain and purpura (adults and children). Although generally mild and self-limited in children, it can occasionally cause intussusception and bowel necrosis.

Table 4.6 Gut and hepatobiliary manifestations of rheumatological diseases I: general

Disease

Abnormalities

Presentation with

Rheumatoid arthritis (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 5)

TMJ arthritis. Oesophageal dysmotility

Impaired mastication Dysphagia, reflux

GI vasculitis (0.1%)

Ulcers, pain, infarction

Portal hypertension

Splenomegaly (Felty’s)

Liver involvement (Felty’s)

Enzyme abnormalities

Hepatosplenomegaly

Palpable viscera

Systemic lupus (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 10)

Oesophageal dysmotility

Dysphagia, reflux

GI vasculitis

Ulcers, pain, perforation

Protein-losing enteropathy

Hypoalbuminaemia

Peritonitis

Ascites (10%), serositis

Hepatosplenomegaly (30%)

Palpable viscera

Scleroderma (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 13)

Oesophageal dysmotility

Heartburn/dysphagia

Delayed gastric emptying

Aggravated reflux

Intestinal dysmotility and fibrosis (80%)

Malabsorption, pseudo-obstruction (<1%)

Pseudo- and wide-mouth diverticula

Haemorrhage, stasis, bacterial overgrowth

Polymyositis and dermatomyositis (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 14)

Muscle weakness

Aspiration, dysphagia

Disordered motility

Dysphagia, constipation

Vasculitis (rare)

Ulcers, perforation

MCTD

Hypomobility

Dysphagia, reflux, pseudo-obstruction

Sjögren’s syndrome (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 12)

Membrane desiccation

Xerostomia, dysphagia

Oesophageal webs (10%)

Dysphagia (>60%)

Gastric infiltrates/atrophy

Masses, dyspepsia

Pancreatitis

Pain, amylasaemia

Hepatic dysfunction

Hepatomegaly (~25%)

Hepatic cirrhosis

Primary biliary cirrhosis

Spondyloarthritis (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 8)

Ileocolonic inflammation

May be asymptomatic

Adult-onset Still’s disease

Hepatitis, peritonitis, hepatosplenomegaly

Pain or abnormal enzymes (~75%)

  • Systemic JIA

  • (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 9)

Serositis

Abdominal pain

Hepatomegaly

Abnormal enzymes

Marfan syndrome, joint hypermobility syndrome, Ehlers–Danlos syndrome(see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 19)

Defective collagen

  • Hypomotility, malabsorption, visceral rupture/laxity

  • Functional GI disorders

Table 4.7 Gut and hepatobiliary manifestations of rheumatic diseases II: vasculitis. See also The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 15

Disease

Frequency of GI vasculitis and features

Polyarteritis nodosa

80% (mesenteric). Buccal ulcers, cholecystitis (15%), bowel infarction, perforation, appendicitis, pancreatitis, strictures, chronic wasting syndrome

Henoch–Schönlein purpura

44–68%. Abdominal pain, melena, haematemesis, ulcers, intussusception, cholecystitis, infarction, perforation, appendicitis

EGPA

~40%. Haemorrhage, ulceration, infarction, perforation

Behçet’s disease

Buccal and intestinal ulcers, haemorrhage, perforation, pyloric stenosis, rectal ulcers

Systemic lupus erythematosus

2%. Buccal ulcers, ileocolitis, gastritis, ulceration, perforation, intussusception, volvulus (1%), pneumatosis

Kawasaki disease

Abdominal pain, intestinal obstruction, non-infective diarrhoea

AAV

<5%. Cholecystitis, appendicitis, ileocolitis, infarction

Juvenile dermatomyositis

Well recognized. Perforation, pneumatosis

MCTD

Rare. Ulceration, perforation, pancreatitis

RA and JIA

0.1%. Buccal ulcers, abdominal pain, peptic ulcers, acalculus-cholecystitis, gut infarction, and perforation

Polymyositis and dermatomyositis

Very rare. Mucosal ulcers, perforation, and pneumatosis

Cryoglobulinaemia

Rare. Ischaemia and infarction

Gut and hepatobiliary side effects from drugs used in treating rheumatic and bone diseases

(See also The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 23.)

The main rheumatology drugs causing side effects are:

  • NSAIDs—which are a common cause of GI distress. COX-2 inhibitors were developed to decrease the risk of peptic ulcer disease; most have been withdrawn from the market due to concerns regarding increased risk of cardiovascular events and those remaining may be no more effective than taking a conventional NSAID with a proton pump inhibitor.

  • Glucocorticoids may cause gastritis, peptic ulcer disease, and GI haemorrhage. Although the absolute increase in events is small, the combination of steroids and NSAIDs results in a synergistic increase in the risk of GI sequelae.

  • Methotrexate (MTX) may cause stomatitis, which may respond to supplemental folate. Nausea, emesis, and dysgeusia may respond to dose reduction. MTX can cause a transaminitis; it is therefore recommended that patients minimize alcohol intake.

  • Sulfasalazine gut and hepatobiliary side effects are common and may occur in up to 20% of patients. The most frequent are mild: indigestion, nausea, vomiting, anorexia, and abdominal pain. Gut ulceration, bloody diarrhoea and serious liver problems are rare; in 65% of patients, side effects occur in the first 3 months of treatment.

  • Azathioprine (AZA) can cause nausea (15%), vomiting (10%), and abdominal pain (8%). Diarrhoea is rare (5%). Liver enzyme abnormalities are often mild and may remit on lowering the dose. The GI side effects can occur in patients with normal levels of thiopurine methyltransferase.

  • Penicillamine causes altered taste (25% within the first 3–6 months), nausea or vomiting (18%), and stomatitis/mouth ulcers (5%). Hepatotoxicity and haemorrhagic colitis are rare.

  • Chloroquine and hydroxychloroquine, can cause non-specific GI intolerance (10%). The onset is often insidious.

  • Ciclosporin causes gingival hyperplasia, nausea, diarrhoea, and elevation in hepatic enzymes.

  • Effects of cyclophosphamide on the gut are frequent: nausea, vomiting, diarrhoea, and stomatitis. Serious hepatotoxicity is rare.

  • Leflunomide can cause nausea (8–13%), diarrhoea (up to 25%), and abnormal liver enzymes. In studies, most rises in transaminases have been mild (<2-fold) and are reversible on drug withdrawal.

  • Oral bisphosphonates (such as alendronic acid and risedronate) and strontium ranelate can cause nausea, dyspepsia, and diarrhoea. Oesophageal ulceration has occasionally been noted with alendronate, although it is thought this occurs only in people who do not follow the instructions for taking them. Myalgias and arthralgias can also occur with bisphosphonates.

  • Calcitonin either given as subcutaneous injection or as nasal spray can give abdominal pains and diarrhoea.

Malignancy

Rheumatic MSK features may be clues to the existence of cancer. Symptoms may arise directly from neoplastic tissue invasion or indirectly as a paraneoplastic phenomenon.

Primary and secondary neoplastic diseases of bone and joints

  • Synovial tumours are rare. Sarcoma (synovioma) is more common in men than women and unusual in those >60 years. It usually occurs in the legs (70%) and can occur around tendon sheaths and bursa. At diagnosis, pulmonary metastases are common.

  • Para-articular involvement by bone tumours may give a monoarticular effusion. Invasion of synovium may occur and malignant cells can be detected in joint fluid. Breast, bronchogenic carcinoma, GI tumours, and melanoma can all metastasize to joints.

  • Lymphomas and leukaemias may simulate various conditions especially in children and cause synovitis in a single or in multiple joints.

  • Arthritis complicating the presentation of myeloma or an acute leukaemia is most likely to be polyarticular and asymmetric.

  • In adults, arthritis complicating leukaemia is rare (5% of cases).

  • Leukaemia is the most common cause of neoplastic skeletal symptoms in childhood and adolescence (15% of leukaemia cases).

  • Neuroblastomas are the most frequent cause of a solid tumour metastasizing to the skeleton in children.

Clues that may lead to a suspicion of malignancy directly causing MSK symptoms

  • Constitutional symptoms without evidence for vasculitis.

  • The coexistence of bone pain from metastases (see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Plate 16). Also, consider metabolic bone diseases, sarcoid, SAPHO syndrome, and the SpA conditions.

  • Haemorrhagic joint fluid (also consider trauma, PVNS, chondrocalcinosis/pseudogout).

  • Radiographs that show adjacent bone destruction, perhaps with loss of cortex (also consider infection).

  • Radiographic calcification in soft tissue mass (consider synovioma).

Paraneoplastic idiopathic inflammatory myopathy (IIM)

  • IIMs may be due to carcinomatous neuromyopathy.

  • Polymyositis, dermatomyositis, Eaton–Lambert myasthenic syndrome (ELMS), and hypophosphataemic (oncogenic) osteomalacia are all found in association with malignancy (Table 4.8).

  • Carcinomatous neuromyopathy is characterized by symmetric muscle weakness and wasting and can pre-date the malignancy.

Table 4.8 Myopathy and links with malignancy

Condition

Typical pattern of weakness

Common cancer associations

Other features

Carcinomatous neuromyopathy

Pelvic girdle—symmetric

Lung: 15% men, 12% women. Ovary: 16%. Stomach: 7% men, 13% women

Wasting, EMG abnormality, and increase in muscle enzymes are not invariable

Dermatomyositis (+?PM)

Proximal limb. Truncal

Reflects underlying cancer frequency in local population

Response to steroids is usual

Myasthenia gravis (MG)

Frequently ocular and bulbar muscles involved

Thymus. Any

Muscle strength fluctuates (fatiguability). Responds to anti-cholinesterases

Eaton–Lambert myasthenic syndrome (ELMS)

Pelvic girdle muscles. Altered gait. Ocular muscles not affected

Small cell lung. Can occur up to 2–3 years after ELMS

Autonomic disturbances. EMG + poor response to anticholinesterase distinguish from MG

Oncogenic osteomalacia

Generalized. Develops insidiously

Small, discrete mesenchymal tumours in bone, soft tissues, and sinuses. Neurofibromatosis

Bone pain and osteomalacia. High FGF23, hypophosphataemia and low 1,25(OH)2-vit-D

Non-myopathy paraneoplastic syndromes

  • The non-myopathic paraneoplastic syndromes are rare.

  • Hypertrophic pulmonary osteoarthropathy consists of clubbing, periostitis of diaphysis of long bones, and an arthropathy (varies from arthralgias to diffuse polyarthritis). Suspicion of HPOA should be investigated with bone scintigraphy, which typically shows increased radionuclide uptake in affected bones. Radiographs often show periosteal elevation.

  • HPOA complicates 20% of primary lung tumours, but it is associated with other malignancies.

  • Polyarthritis may be the presenting feature of cancer. Most cases occur >60 years old. The arthritis associated with malignancy tends to be asymmetric, and does not cause erosions.

  • Eosinophilic fasciitis, severe bilateral palmar fasciitis (often mistaken for scleroderma), and fasciitis associated with panniculitis have been associated with malignancy.

  • Cases of ‘shoulder–hand’ syndrome (a form of osteodystrophy; see The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 22) have been reported in association with malignancy.

Rheumatological diseases associated with an increased incidence of malignancy

A number of rheumatic MSK diseases are associated with an increased incidence of malignancy compared with healthy populations.

  • Non-Hodgkin’s lymphoma is most strongly associated with RA. Myeloma and paraproteinaemia are also found in RA patients.

  • The relative risk of colon cancer among RA patients is 0.77; this may be due to the use of chronic NSAIDs in this patient population, which may be protective.

  • Non-Hodgkin’s lymphoma develops in a subset of patients with Sjögren’s syndrome (4%). Its onset may be indicated by rapid enlargement of salivary glands, the appearance of a paraprotein, or decrease in circulating immunoglobulins or RF titre.

  • SScl has been associated with an increased risk of both lung cancer and non-Hodgkin’s lymphoma.

  • Dermatomyositis is probably associated with malignancy in adults, though as convincing evidence for an association of polymyositis with malignancy is lacking. Gonadal tumours are relatively common among such patients.

  • Eosinophilic fasciitis may be associated with malignancy.

Rheumatological drugs and malignancy

(See also The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 23.)

  • Chronic azathioprine use is associated with an increased risk of skin cancer so patients taking azathioprine long term should be counselled regarding sun protection and monitoring for skin cancer.

  • Use of cyclophosphamide is associated with an increased risk of lymphoma and bladder cancer.

  • Anti-TNFα‎ drug therapy is theoretically associated with a risk of malignancy. However, patient disease registries have not identified an excess incidence in patients treated long-term with the therapy.

  • If malignancy develops while a patient is taking anti-TNFα‎ then usually its correct to stop the therapy.

  • There is incomplete data on whether starting anti-TNFα‎ increases the risk of relapse of malignancy in patients previously treated successfully for their cancer.

  • Though very high dose per weight teriparatide is associated with sarcoma development in rats, there is no evidence, at doses used in humans, that there is an increased risk.

  • The following have not been associated with an increased risk of malignancy (as of 2016): sulfasalazine, leflunomide, rituximab, abatacept, apremilast, ustekinumab, secukinumab, belimumab, and denosumab.

Neurological conditions

Entrapment neuropathies and radicular lesions are discussed in The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 3. Also, radiculopathy is included in The spectrum of disorders associated with adult rheumatic and musculoskeletal diseases Chapter 21.

Inflammatory peripheral neuropathy

  • Inflammatory neuropathies can occur as part of any AICTD, though are probably most likely to occur in association with SLE and Sjögren’s syndrome.

  • Vasculitis (and probably APS) can cause small vessel vascular lesions which compromise peripheral nerve function and cause sensory, and if severe, motor features of nerve damage.

  • Nerve conduction studies may form part of the investigations at the outset of characterizing systemic vasculitis and severe AICTDs.

  • Mononeuritis occurring as part of RA is possible but nowadays is very unlikely unless severe RA disease is left untreated.

Entrapment neuropathies

  • Entrapment neuropathies are common in rheumatological practice. Symptoms arising from these lesions include paraesthesiae, a feeling of swelling, numbness and a burning quality to pain in the distribution of the trapped nerve.

  • Median nerve irritation/entrapment may be secondary to carpal OA or inflammation secondary to inflammatory arthritis.

  • Ulnar nerve irritation (fourth and fifth finger territory symptoms) is most commonly associated with medial elbow lesions.

Spinal cord lesions

  • Spinal cord lesions usually arise due to intrinsic spinal canal or extrinsic compression or inflammation.

  • Tumours and ischaemic spinal cord lesions often present acutely with upper motor neuron features distal to the affected level and issues of bladder and bowel sphincter control.

  • Some tumours and syrinxes (thoracic, neck) can cause subacute evolution of pyramidal features in the legs (often not pain but stiffness and motor function problems).

  • Extrinsic cord compression can occur secondary to tumours, osteoporotic vertebral and a combination of (usually degenerative) lesions. In the latter, spinal cord compression is rarely acute and because it evolves very slowly is often overlooked in the elderly.

  • Transverse myelitis causes acute focal back pain and distal spinal cord symptoms and features including acute lower limb motor symptoms. It is a feature of SLE and APS.

Cerebrovascular lesions

  • Acute cerebellar or stroke-like symptoms can be a presenting feature of ischaemic lesions secondary to APS. If occurring in the non-elderly <60 years then screening for APS and SLE is mandatory.

  • Cerebral lupus can be present with profound symptoms of confusion and brain function decompensation or may be subtler presenting with mild cognitive or frontal cortex dysfunction.

  • Conventional stroke disease is a complication of many inflammatory rheumatic diseases, probably most associated with APS and ongoing poorly controlled inflammatory disease and in the context of other risk factors (e.g. smoking, metabolic syndrome in PsA, glucocorticoid-associated hyperlipidaemia).

Headache

  • Among the causes of headache in rheumatological practice, neurological causes are probably rare.

  • The hemicranial headache (with scalp sensitivity) of GCA and drug-induced headache are the most likely causes of headache encountered in rheumatology patients.

  • Other causes of headache occasionally encountered are the global headache from cranial sinus thrombosis in Behçet’s disease, and meningeal lesions (e.g. in neurosarcoid).

Neuromyopathy

  • Neuromyopathies may present to rheumatologists with focal pain or generalized pain and weakness.

  • Focal neuromyopathies can occur after nerve trauma or infection. Marked acute wasting with pain, often with raised CK and a myositis-type signal on MRI, can be seen.

  • Fluctuating neuromyopathic effects can occur in myasthenia gravis. There may be a variation of effects over a day with muscle fatigue influencing the timing, characteristics, and severity of weakness. Symptoms can be focal—as in orbital muscle myasthenia, which can present initially with diplopia—or general involving larger muscle groups.

Ophthalmic conditions

Blepharitis, conjunctivitis, uveitis, and ischaemic lesions can all occur with rheumatic MSK diseases.

Dry eye (xerophthalmia)

  • Xerophthalmia often presents with sore or gritty eyes and sensitivity in certain atmospheric environments (e.g. air-conditioning). Oddly patients can get epiphorae if tear film is not drained because of inferior orbital duct blockage through to the sinuses.

  • Blepharitis is often a consequence of dry eye—lids can get ‘sticky’.

  • Xerophthalmia is most severe in primary Sjögren’s syndrome but can occur in SOX syndrome and all autoimmune joint and connective tissue diseases (secondary Sjögren’s syndrome).

Uveitis

  • Anterior uveitis can be acute or chronic. Symptoms include ocular pain and photophobia. The eye becomes visibly erythematous.

  • The most common associations of anterior uveitis include SpAs, sarcoid, Behçet’s disease, and JIA.

  • All children and adolescents diagnosed with any form of JIA, regardless of ANA status, should have an eye examination to rule out uveitis.

Ischaemic ophthalmic lesions

  • Retinal examination is the most direct and accessible way to visualize blood vessels in vivo.

  • Ophthalmic examination is valuable in the assessment of systemic vasculitis.

  • The input of an experienced medical ophthalmologist is essential in departments that offer a service to manage vasculitis patients.

  • The ischaemic lesions of GCA can present variably but most typically with amaurosis symptoms (visual field curtaining).

Scleral and corneal disease

  • Lesions of the sclera and cornea are rare in rheumatology patients except in severe (usually high-titre seropositive) RA patients.

  • Scleral or corneal disease in an RA patient should prompt consideration of the presence of systemic RA vasculitis.

Other

  • Proptosis is a recognized feature of AAV and is usually due to granulomatous inflammation in the retro-orbital space.

  • Conjunctivitis can accompany many diseases but is an acute lesion in some cases of (SpA-associated) reactive arthritis.

  • Ophthalmoplegia is a recognized presenting feature of mononeuritis associated with systemic vasculitis. Cerebrovascular disease (thus APS and GCA also) should be considered as possible in relevant patients also.