In the differential diagnostic process for rheumatic inflammatory and/or connective tissue diseases (CTDs), history taking and physical examination are of main importance, more than additional investigations, as many diagnoses are clinical diagnoses with specific clinical/patterns and gold standards are often lacking. In rheumatic diseases and, especially, CTD, many organ systems apart from the joints may be involved. These include the skin and underlying tissues, muscles, salivary glands, nerves, kidneys and blood vessels. Biopsy specimens of these tissues may be helpful in establishing a diagnosis, in assessing the extent and severity of organ involvement and sometimes in monitoring therapy. In this chapter, practical information is described regarding which clinical practice might indicate a need for biopsy, and on how to prepare the patient, how to perform the biopsy and handle the biopsy specimen. In addition, the limitations and complications one should be cautious of are described. For full details of the clinical spectrum of the diseases and the histopathology, the reader is kindly referred to relevant textbooks.
Introduction
The diagnostic process for conditions in which an inflammatory rheumatologic and/or connective tissue disease (CTD) is suspected consists primarily of history taking and physical examination. These two activities give the most important information leading to a differential diagnosis; rheumatologic inflammatory diseases and/or CTD usually are characterised by typical clinical patterns in joint involvement and/or extra-articular manifestations . Additional investigations can be helpful to confirm a tentative diagnosis, rule out other diagnoses or lead to other manifestations in (but also without) relation to the presumptive disease. Before requesting additional investigation(s) one should realise that these investigations should meet with the following conditions: it should give additive information to that available from history taking and physical examination, it should be discriminative and the outcome should have therapeutic consequences. Participation in studies on clinical or translational scientific issues may also require additional investigations to complete classification and/or inclusion criteria. Organ systems other than the joint are frequently involved (extra-articular manifestations). A biopsy specimen may help to establish a diagnosis or to specify the organ involvement, to identify the extent of involvement and thus guide therapeutic measures. Some of these biopsy procedures are minimal invasive and can be done by rheumatologists themselves after adequate training. The fore-mentioned conditions for performing additional investigation are applicable to biopsy taking and subsequent histological examination. Before performing such an invasive procedure, one should bear in mind the value of the contribution to the outcome in the diagnostic and therapeutic process, taking into account the burden and complication risk of the invasive procedure for the patient. Other important factors influencing this value are the clinical information and specific question given to the pathologist and the way the tissue is handled between biopsy and microscopic examination: for specific questions specific handling or conservation might be essential.
Biopsy of the temporal artery
Indications
- •
Confirmation of the presumptive diagnosis of temporal arteritis or giant cell arteritis
- •
Fever of unknown origin (age >55 years)
Background
Temporal arteritis or giant cell arteritis (GCA) is a systemic vasculitis mainly affecting large- and medium-sized arteries. The branches of the external carotid artery, particularly the superficial temporal artery and the posterior ciliary arteries supplying the optic nerve, are affected. Clinical overlap between GCA and polymyalgia rheumatica (PMR) suggests that they are manifestations of one disease spectrum . Diagnostic criteria and provisional classification criteria for PMR and classification criteria for GCA have been described . GCA is characterised by new, localised (temporal) headache with pain on palpation or diminished pulsation of the temporal artery, accompanied with high erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) in people >50 years . Inflammation of the temporal artery may lead to ‘hair pain’, visual disturbances and jaw claudication. Involvement of branches of the thoracic aorta and the aorta itself may result in ischaemic complaints. Because non-specific symptoms are common, a diagnosis of GCA should be considered in elderly patients with constitutional symptoms including weight loss, fever and fatigue .
Colour duplex ultrasonography (CDU) and high-resolution magnetic resonance imaging (MRI) may be useful methods in the diagnostic work-up of GCA. On CDU a halo around temporal arteries (especially bilateral), either any halo or a halo 1 mm or greater in thickness and/or stenosis/occlusion, has a high specificity for (biopsy-proven) GCA, but it did not improve the diagnostic accuracy of a careful physical examination . Results on CDU are highly dependent on operator experience and therefore not widely applicable. CDU can also be used in evaluation of extracranial arteries, especially the subclavian, axillary and brachial arteries, in patients with signs of claudication, constitutional symptoms or symptoms of PMR, even without cranial symptoms .
High-resolution, contrast-enhanced MRI of temporal arteries, evaluating wall and lumen thickness and contrast enhancement, has also high specificity for (biopsy-proven) GCA. The examination protocol can easily be amended to include the assessment of extracranial involvement patterns within the same investigation . Glucocorticoid treatment influences MRI results and investigations should be performed before or shortly after starting glucocorticoid treatment .
18 F-Fluorodeoxyglucose positron emission tomography (FDG-PET) cannot be used to evaluate the temporal arteries, due to the vessel calibre and the close relation to the brain, but extracranial involvement can be detected by FDG-PET with high sensitivity and specificity and high negative predictive value .
Some authors suggest that in a patient with a typical clinical presentation and typical ultrasound imaging, GCA can be diagnosed without biopsy . Others suggest that larger prospective trials are warranted to further investigate the potential of noninvasive imaging to eventually replace temporal artery biopsy in the diagnosis of GCA .
Histopathological examination of the temporal artery is still regarded as the gold standard and remains the diagnostic test of choice . Several studies evaluating temporal artery biopsies show positive biopsy results in 20–31%. Positive biopsy results are reported to be correlated with higher age and inflammation, higher score on American College of Rheumatology (ACR) criteria and specimen length .
The differential diagnosis of GCA includes other forms of vasculitis, atherosclerosis, other causes of headache and causes of anterior optic neuropathy (AION), as published in case reports .
Key features of histopathological findings in GCA:
- •
Transmural arteritis with mononuclear cell infiltrates
- •
Granulomatous infiltrates with activated T-cells and macrophages in the medial layer
- •
Giant cells on the border of the intimal layer and the medial layer
- •
A fragmented membrana elastica interna
- •
Hyperplasia of the intimal layer
Technical procedures
The clinically most affected side should be chosen for biopsy. Biopsy should be performed as early as possible and preferably before therapy is started, but persistence of inflammatory infiltrates in the biopsies of steroid-treated patients was demonstrated .
For general measures regarding biopsy procedures we refer to Box 1 .
Biopsy procedure
- #
Generally outpatient setting.
- #
Anticoagulants, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are to be stopped several days before the procedure, depending on the half-life of the medication.
- #
If preoperative antibiotics are administered, the dosage needs to be adequate for the control of skin flora, especially Staphylococcus aureus ; they are to be started <2 h pre-operatively and continued for 48–72 h.
- #
Shave off hair in the involved area if necessary.
- #
Disinfection.
- #
Infiltration of local anaesthetic around the site of biopsy.
Biopsy specimen
- #
Formalin 10% is most widely used for routine microscopy of material embedded in paraffin.
- #
For specific techniques, including immunofluorescence, more specific transport media and fixatives are available.
- #
In the case of suspected infection a fresh, unfixed biopsy specimen is to be sent for culturing for various organisms including mycobacteria, deep fungi or by examining it for protozoa and filarial worms.
Biopsy procedure ( Fig. 1 ):
- •
Locate the temporal artery; in case the artery is not palpable, (portable) blood flow Doppler can be used to locate the artery. CDU can be used to scan the entire temporal artery vascular bed, evaluate for oedema or inflammatory stenosis, direct appropriate biopsies and locate the region where a biopsy would have highest yield .
- •
Make an incision of circa 3 cm, following the natural crease lines of the skin.
- •
Identify the artery. Incise the fascia overlying the artery.
- •
Dissect and underbind the artery proximally and distally. The biopsy specimen should have a length of preferably 2–3 cm, but a length of >1 cm might be sufficient (even up to 5 cm is recommended) .
- •
Excise the artery.
- •
Close the wound with several stitches.
Handling of the biopsy specimen:
- •
Embed the specimen in formalin 10%. The tissue is embedded in plastic and transverse cuts are made every 1–2 mm to ensure that ‘skip’ lesions are found.
- •
Apart from haematoxin–eosin staining an elastica stain (van Gieson) is mandatory.
Limitations
Negative biopsy findings do not rule out GCA: lesions may be missed, especially in small biopsies, due to the patchy involvement, and arteries other than the temporal artery might be primarily involved. Biopsy-negative GCA has been suggested to have a less severe clinical picture .
Complications
For general complications we refer to Box 2 . Complications are rarely seen . Hypoesthesia of the skin may persist for a prolonged period of time. Facial nerve injury has been described as a rare complication .
Practice points
- •
Positive histological findings are still regarded as the gold standard for GCA and may confirm a presumptive diagnosis of GCA.
- •
A negative biopsy does not necessarily rule out GCA, possibly due to skip lesions and/or the length of the biopsy specimen or due to main involvement of extracranial arteries.
- •
In those cases where biopsy is not possible, imaging modalities (USD, MRI and FDG-PET) may contribute to the diagnostic process; USD and MRI have high specificity for (biopsy-proven) GCA.
- •
Biopsy results are less influenced by glucocorticoid treatment than MRI results.
Research agenda
- •
Further investigation of the potential of noninvasive imaging to eventually replace temporal artery biopsy in the diagnosis of GCA, possibly in selected patients.
- #
Post-biopsy bleeding, especially when aspirin, NSAIDs or anticoagulants are used.
- #
Allergic reactions to the disinfectant or local anaesthetic.
- #
All invasive examinations can become a ‘point of entry’ for infections. The presence of cardiac valvular disease raises this risk for infection, especially sub-acute bacterial endocarditis; prophylactic treatment with antibiotics might be indicated.
- #
Suboptimal wound healing (or skin necrosis) in elderly and in people who use glucocorticoids.
- #
Visible scarring or keloid formation in patients, who tend to make keloid; the risk is increased in the biopsy of the upper trunk.
- #
Skin biopsy of the lower leg of an elderly patient may result in poor healing and be prone to infection.
Biopsy of the temporal artery
Indications
- •
Confirmation of the presumptive diagnosis of temporal arteritis or giant cell arteritis
- •
Fever of unknown origin (age >55 years)
Background
Temporal arteritis or giant cell arteritis (GCA) is a systemic vasculitis mainly affecting large- and medium-sized arteries. The branches of the external carotid artery, particularly the superficial temporal artery and the posterior ciliary arteries supplying the optic nerve, are affected. Clinical overlap between GCA and polymyalgia rheumatica (PMR) suggests that they are manifestations of one disease spectrum . Diagnostic criteria and provisional classification criteria for PMR and classification criteria for GCA have been described . GCA is characterised by new, localised (temporal) headache with pain on palpation or diminished pulsation of the temporal artery, accompanied with high erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) in people >50 years . Inflammation of the temporal artery may lead to ‘hair pain’, visual disturbances and jaw claudication. Involvement of branches of the thoracic aorta and the aorta itself may result in ischaemic complaints. Because non-specific symptoms are common, a diagnosis of GCA should be considered in elderly patients with constitutional symptoms including weight loss, fever and fatigue .
Colour duplex ultrasonography (CDU) and high-resolution magnetic resonance imaging (MRI) may be useful methods in the diagnostic work-up of GCA. On CDU a halo around temporal arteries (especially bilateral), either any halo or a halo 1 mm or greater in thickness and/or stenosis/occlusion, has a high specificity for (biopsy-proven) GCA, but it did not improve the diagnostic accuracy of a careful physical examination . Results on CDU are highly dependent on operator experience and therefore not widely applicable. CDU can also be used in evaluation of extracranial arteries, especially the subclavian, axillary and brachial arteries, in patients with signs of claudication, constitutional symptoms or symptoms of PMR, even without cranial symptoms .
High-resolution, contrast-enhanced MRI of temporal arteries, evaluating wall and lumen thickness and contrast enhancement, has also high specificity for (biopsy-proven) GCA. The examination protocol can easily be amended to include the assessment of extracranial involvement patterns within the same investigation . Glucocorticoid treatment influences MRI results and investigations should be performed before or shortly after starting glucocorticoid treatment .
18 F-Fluorodeoxyglucose positron emission tomography (FDG-PET) cannot be used to evaluate the temporal arteries, due to the vessel calibre and the close relation to the brain, but extracranial involvement can be detected by FDG-PET with high sensitivity and specificity and high negative predictive value .
Some authors suggest that in a patient with a typical clinical presentation and typical ultrasound imaging, GCA can be diagnosed without biopsy . Others suggest that larger prospective trials are warranted to further investigate the potential of noninvasive imaging to eventually replace temporal artery biopsy in the diagnosis of GCA .
Histopathological examination of the temporal artery is still regarded as the gold standard and remains the diagnostic test of choice . Several studies evaluating temporal artery biopsies show positive biopsy results in 20–31%. Positive biopsy results are reported to be correlated with higher age and inflammation, higher score on American College of Rheumatology (ACR) criteria and specimen length .
The differential diagnosis of GCA includes other forms of vasculitis, atherosclerosis, other causes of headache and causes of anterior optic neuropathy (AION), as published in case reports .
Key features of histopathological findings in GCA:
- •
Transmural arteritis with mononuclear cell infiltrates
- •
Granulomatous infiltrates with activated T-cells and macrophages in the medial layer
- •
Giant cells on the border of the intimal layer and the medial layer
- •
A fragmented membrana elastica interna
- •
Hyperplasia of the intimal layer
Technical procedures
The clinically most affected side should be chosen for biopsy. Biopsy should be performed as early as possible and preferably before therapy is started, but persistence of inflammatory infiltrates in the biopsies of steroid-treated patients was demonstrated .
For general measures regarding biopsy procedures we refer to Box 1 .
Biopsy procedure
- #
Generally outpatient setting.
- #
Anticoagulants, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are to be stopped several days before the procedure, depending on the half-life of the medication.
- #
If preoperative antibiotics are administered, the dosage needs to be adequate for the control of skin flora, especially Staphylococcus aureus ; they are to be started <2 h pre-operatively and continued for 48–72 h.
- #
Shave off hair in the involved area if necessary.
- #
Disinfection.
- #
Infiltration of local anaesthetic around the site of biopsy.
Biopsy specimen
- #
Formalin 10% is most widely used for routine microscopy of material embedded in paraffin.
- #
For specific techniques, including immunofluorescence, more specific transport media and fixatives are available.
- #
In the case of suspected infection a fresh, unfixed biopsy specimen is to be sent for culturing for various organisms including mycobacteria, deep fungi or by examining it for protozoa and filarial worms.
Biopsy procedure ( Fig. 1 ):
- •
Locate the temporal artery; in case the artery is not palpable, (portable) blood flow Doppler can be used to locate the artery. CDU can be used to scan the entire temporal artery vascular bed, evaluate for oedema or inflammatory stenosis, direct appropriate biopsies and locate the region where a biopsy would have highest yield .
- •
Make an incision of circa 3 cm, following the natural crease lines of the skin.
- •
Identify the artery. Incise the fascia overlying the artery.
- •
Dissect and underbind the artery proximally and distally. The biopsy specimen should have a length of preferably 2–3 cm, but a length of >1 cm might be sufficient (even up to 5 cm is recommended) .
- •
Excise the artery.
- •
Close the wound with several stitches.
Handling of the biopsy specimen:
- •
Embed the specimen in formalin 10%. The tissue is embedded in plastic and transverse cuts are made every 1–2 mm to ensure that ‘skip’ lesions are found.
- •
Apart from haematoxin–eosin staining an elastica stain (van Gieson) is mandatory.
Limitations
Negative biopsy findings do not rule out GCA: lesions may be missed, especially in small biopsies, due to the patchy involvement, and arteries other than the temporal artery might be primarily involved. Biopsy-negative GCA has been suggested to have a less severe clinical picture .
Complications
For general complications we refer to Box 2 . Complications are rarely seen . Hypoesthesia of the skin may persist for a prolonged period of time. Facial nerve injury has been described as a rare complication .
Practice points
- •
Positive histological findings are still regarded as the gold standard for GCA and may confirm a presumptive diagnosis of GCA.
- •
A negative biopsy does not necessarily rule out GCA, possibly due to skip lesions and/or the length of the biopsy specimen or due to main involvement of extracranial arteries.
- •
In those cases where biopsy is not possible, imaging modalities (USD, MRI and FDG-PET) may contribute to the diagnostic process; USD and MRI have high specificity for (biopsy-proven) GCA.
- •
Biopsy results are less influenced by glucocorticoid treatment than MRI results.
Research agenda
- •
Further investigation of the potential of noninvasive imaging to eventually replace temporal artery biopsy in the diagnosis of GCA, possibly in selected patients.
- #
Post-biopsy bleeding, especially when aspirin, NSAIDs or anticoagulants are used.
- #
Allergic reactions to the disinfectant or local anaesthetic.
- #
All invasive examinations can become a ‘point of entry’ for infections. The presence of cardiac valvular disease raises this risk for infection, especially sub-acute bacterial endocarditis; prophylactic treatment with antibiotics might be indicated.
- #
Suboptimal wound healing (or skin necrosis) in elderly and in people who use glucocorticoids.
- #
Visible scarring or keloid formation in patients, who tend to make keloid; the risk is increased in the biopsy of the upper trunk.
- #
Skin biopsy of the lower leg of an elderly patient may result in poor healing and be prone to infection.
Muscle biopsy
Indications
- •
Confirmation of the presumptive diagnosis of idiopathic inflammatory myopathies
- •
Unsuccessful response to immunosuppressive therapy in inflammatory myopathy
- •
Unexplained muscle weakness/myopathy
Background
The idiopathic inflammatory myopathies (IIMs), polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM), are characterised by proximal muscle weakness (usually painless) with raised serum muscle enzyme levels with or without other features of CTD such as Raynaud’s phenomenon, arthritis, dermatologic abnormalities and interstitial lung disease; in the case of IBM distal muscle weakness and sensory loss might occur. Reported incidences for IIM range from 1.2 to 8.4/million. PM/DM has a bimodal age with peaks <15 years and between 45 and 54 years and is seen more common in females. IBM is reported to be the most common IIM in people >50 years of age . The IIMs are to be discriminated based on characteristic clinical, immune-pathological and morphological features, regardless of whether the myopathy is expressed isolated or in connection with CTDs or malignancy. Several criteria sets for the diagnosis of PM and DM, including recent sets using modern techniques, having been developed, the Bohan and Peter criteria are most frequently used . New classification criteria were proposed to distinguish IIM in IBM, PM, DM, non-specific myositis and immune-mediated necrotising myopathy (IMNM), all accept IBM occurring as isolated conditions or associated with CTD or malignancy .
Although the diagnosis may be based on clinical examination, raised serum muscle enzyme levels, specific electromyography findings and sometimes the presence of autoantibodies, muscle biopsy offers the most definitive diagnostic information in the majority of cases . In clear cases of DM, biopsy might not be needed. In PM muscle biopsy is still regarded as the gold standard for the diagnosis, although it was suggested to be an over-diagnosed entity .
Computed tomography (CT) or especially MRI with fat suppression (magnetic resonance imaging-short TI inversion recovery; MRI-STIR) may be useful in determining the optimal biopsy site . MRI may be used to examine anatomical changes in diseased muscle noninvasively and to assess disease activity, but it cannot replace muscle biopsy for diagnostic evaluation. Muscle biopsy guided by positive MRI finding contains significantly more inflammatory cells than the biopsy taken from MRI non-affected sites. However, even in parts of muscles that look unaffected on MRI, the inflammatory cells can be found . MRI has been reported to be useful for distinguishing PM from IBM, despite some overlap in MRI findings between the two entities . When biopsy reveals negative results, in addition to very strong clinical evidence for IBM, a second biopsy might be indicated, preferentially imaging guided, as this diagnosis has therapeutic and prognostic consequences.
Symmetric proximal muscle weakness has many potential aetiologies, including certain muscular dystrophies, metabolic myopathies, drug- or toxin-induced myotoxicity, neuropathies and infectious myositis. Careful clinical evaluation may guide the choice of diagnostic tests, including muscle biopsy, to establish the correct diagnosis .
In persisting or worsening muscle weakness during glucocorticoid treatment, a (repeated) muscle biopsy might be considered to differentiate between persisting or relapsing PM/DM or IBM or glucocorticoid myopathy . This biopsy is preferably performed after MRI as it might guide the biopsy site, or in the case of complete fatty replacement of the muscle, biopsy might not be necessary .
Key features of histopathological findings:
- •
DM: Predominantly perivascular and/or interfascicular inflammation; endothelial hyperplasia of intramuscular blood vessels; necrosis and phagocytosis of muscle fibres; perifascicular atrophy due to ischaemia results
- •
PM: Endomysial mononuclear cell infiltrates, predominantly consisting of cytotoxic T-cells, expressing major histocompatibility class I (MHC class I) antigens; also found in histologically healthy appearing muscle fibres. Less pronounced are necrosis and regeneration of muscle fibres, while macrophages and B cells are sparse
- •
IBM: Endomysial mononuclear cell infiltrates with invasion of normal-looking muscle fibres and so-called rimmed vacuoles (seen in at least 0.3% of the muscle fibres)
- •
IMNM: Predominantly necrotic fibres with sparse inflammatory cells in the perivascular compartment (further details in a review of Stenzel et al. )
Technical procedures
A clinically involved muscle offers the best chance of obtaining histological confirmation of the clinical diagnosis. For general measures regarding biopsy procedures we refer to Box 1 .
Two different procedures will be discussed.
Open biopsy permits direct inspection of the muscle, enabling the collection of tissue which is more likely to contain blood vessels and no fat .
Biopsy procedure ( Fig. 2 ):
- •
Avoid muscle when infiltrating anaesthetics as pain fibres are located in the perimysial area and fascia, but not the muscle itself.
- •
Sedation, using a short-acting benzodiazepine or narcotic, may further reduce the patient’s discomfort.
- •
Make a longitudinal incision of 5 cm through subcutaneous tissue, fat and fascia.
- •
Isolate a muscle bundle and clasp it at one side only.
- •
Extricate a sample measuring approximately 1 × 1 × 1 cm.
- •
A second sample may be taken.
- •
Close fascia, subcutis and skin in layers and apply a dressing.
Percutaneous sampling of muscle is performed using specially designed instruments. Different instruments/techniques have been described . The procedure is described in general terms.
Biopsy procedure:
- •
Incise the overlying skin, subcutis and fascia with a scalpel to enable penetration of the deeper tissues by the biopsy instrument.
- •
Direct the biopsy needle tip perpendicular to the long axis of the muscle fibres to facilitate cross-sectional orientation of the specimens.
- •
Take several biopsies in the same procedure.
- •
Press the wound and apply sticking plaster and dressing.
Handling of the biopsy specimen for both procedures:
- •
Deliver the specimen at the pathology department as soon as possible.
- •
Keep the muscle tissue moist during transport by covering the specimen with a saline-moistened gauze. The specimen should not be submersed in fluid.
- •
Freeze the biopsy specimen in deeply cooled isopentane submersed in liquid nitrogen for later processing in cryostat sections, ultra-thin sections and ultra-structural studies.
- •
Frozen muscle may be safely shipped overnight on dry ice.
- •
Frozen muscle can be stored at −80 °C.
The small size of the samples obtained in percutaneous biopsy requires special care in processing. From a pathological point of view it is preferred to perform muscle biopsies in centres with expertise in myopathology and enzyme histochemistry as correct handling and storing of the biopsy specimen are essential for obtaining optimal information.
The frozen muscle biopsy specimen provides excellent muscle fibre morphology using light microscopy. Muscle biopsy specimens embedded in paraffin are useful for surveys for the morphology of inflammatory cells.
In cases of inflammatory myopathy, histochemistry, immune-histology and, sporadically, electron microscopy may help to establish a diagnosis. For details see relevant textbooks cited in Dalakas (2003) .
Additional adenosinetriphosphatase (ATPase) staining may be useful to define myosin loss or elucidate either type-1 or type-2 fibre atrophy, while different enzyme stains are used to elucidate mitochondrial pathology. Enzyme deficiencies and storage diseases may become evident by staining with periodic-acid-Schiff (PAS: glycogen and carbohydrate), Alcian blue (mucopolysaccharide), Sudan black, Oil Red (lipids) or Congo red (amyloid).
Most researchers prefer an open muscle biopsy over a needle biopsy, because the former offers a larger sample that can be properly orientated and is better suited for immune-cytochemical and ultra-structural studies. In some centres, however, percutaneous needle biopsy is used with as good results as open biopsies have; percutaneous biopsy might offer the advantage that samples can be taken from a wide area by orientating the biopsy instrument in several different directions .
Limitations
- •
Due to patchy expression a negative biopsy may not exclude the diagnosis of inflammatory myopathy.
- •
MRI guidance may require more logistical efforts.
Complications
No serious complications of either open or needle biopsy are reported. For general complications we refer to Box 2 . A dermal nerve branch may be damaged. After biopsy, patients are advised to rest for a few hours, especially after an open biopsy. After open biopsy of the leg, the patient is advised not to overuse for some days, for example, by using crutches.
Practice points
- •
Positive histological findings are still regarded as the gold standard for IIM.
- •
In cases of muscle weakness and dermatological features specific for DM, biopsy might not be needed.
- •
In case of a negative biopsy, re-biopsy (with MRI guidance) might be required.
- •
Correct handling and storing of the biopsy specimen is essential for obtaining optimal information.
- •
Specific diagnoses may require specific techniques and/or staining.
- •
Ultrasound-guided closed muscle biopsy by an experienced rheumatologist has been described .
Research agenda
- •
Validation of the (in 2004) proposed classification criteria for IIM and testing them for reliability for eventually scientific and clinical applicability.
- •
Further investigation of the potential of noninvasive imaging to eventually replace muscle biopsy in the diagnosis of IIM, possibly in selected patients.
Biopsies of the kidney
Indications
- •
Classification of lupus nephritis
- •
Unexplained persistent proteinuria and/or microscopic haematuria (with dysmorphic erythrocytes) and/or cellular casts in any patient with a (presumptive) rheumatic disease
- •
Rapidly progressive glomerulonephritis (RPGN) and acute or chronic renal failure (with suspected renal cause) in any patient with a (presumptive) rheumatic disease
Background
In rheumatology, the main indication for biopsy of the kidney will be renal disease in association with an already defined CTD. In 50–60% of the patients with systemic lupus erythematosus (SLE) renal involvement will occur. In SLE, urine findings, that is, erythrocyturia, proteinuria or cellular casts, do not correspond with the various sub-types of glomerulonephritis, necessitating renal histology for establishing the sub-type of nephritis and consequently the prognosis and optimal treatment. In the course of the disease, repeated renal biopsy may be required.
Abnormal renal findings in any patient with a rheumatic disease including rheumatoid arthritis (RA), ankylosing spondylitis and reactive arthritis may indicate kidney biopsy, as different renal complications, including medication-induced problems or renal amyloidosis may be present. A clinical presentation of RPGN, necessitating urgent treatment, may require non-delayed renal biopsy. RPGN may occur within the context of an already established rheumatic disease such as SLE, antineutrophil cytoplasmatic antibody (ANCA)-related vasculitis and relapsing polychondritis. However, RPGN may also be a part of the initial phase of a generalised auto-immune or other disease, for example, bacterial endocarditis and Goodpasture’s syndrome, requiring specific treatment. For further information on classification of vasculitis we refer to the revised Chapel Hill consensus definitions .
The interpretation of renal histology requires an experienced pathologist for evaluating the vascular, the tubulo-interstitial and the glomerular domains. Within the vascular domain, vasculitis of the arteries and arterioles has to be distinguished from vasculo-occlusive disease and changes due to hypertension or diabetes mellitus as well as arteriolar changes due to medication. In generalised rheumatic disease, different types of vascular renal disease may be present. Tubulo-interstitial disease may vary from acute inflammation to chronic fibrosis and may either be part of the disease spectrum or be induced by medication. Glomerular disease may be associated with a broad variety of well-classified multi-system auto-immune diseases. The glomerular changes may be divided into different categories. Electron microscopy is needed to detect minimal change lesions, which are sometimes seen in non-steroidal anti-inflammatory drug (NSAID)-induced nephropathy.
In systemic rheumatic disease, glomerular sclerosis may be the eventual result of prior glomerular disease. Membranous changes, consisting of thickening of the glomerular basement membrane (GBM), may be due to changes on the epithelial side of the GBM in the form of granular deposits of immunoglobulins (‘spikes’), as in idiopathic membranous glomerulopathy. Thickening of the GBM may also be due to changes from the endothelial side in the form of interposition of mesangial cell pseudopodia (‘double contour’) as in mesangiocapillary glomerulonephritis. Proliferative changes in the form of hypercellularity (‘crescent formation’) reflect destructive forms of glomerulonephritis, including RPGN. Mesangial glomerulonephritis has been associated with relapsing polychondritis. Focal proliferative glomerulonephritis may be associated with RA and, if mesangial IgA deposits are present, with reactive arthritis and ankylosing spondylitis. Diffuse proliferative glomerulonephritis with mesangial immunoglobulin A (IgA) deposits is seen in Henoch–Schönlein purpura. Membranous and mesangial glomerulonephritis may occur in mixed CTD. All of these types may be seen in lupus nephritis; the classification of lupus nephritis was revised in 2003 .
Key features of histopathological findings:
- •
Lupus nephritis: see Box 3
Box 3Related posts:
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