Page of

Miscellaneous diseases 

Miscellaneous diseases
Chapter:
Miscellaneous diseases
Source:
Rheumatology (Oxford Desk Reference)
DOI:
10.1093/med/9780199229994.003.0018

  • Acromegaly [link]

  • Diabetes mellitus [link]

  • Adult onset Still's disease [link]

  • Amyloidosis [link]

  • Autoinflammatory syndromes [link]

  • Hyperimmunoglobulinaemia D with periodic fever syndrome [link]

  • TNF-receptor-associated periodic syndrome [link]

  • Cryopyrin-associated periodic syndrome [link]

  • Haemochromatosis [link]

  • Haemoglobinopathies [link]

  • Haemophilia [link]

  • Sarcoidosis [link]

  • Panniculitis [link]

  • Alkaptonuria [link]

  • Gaucher's disease [link]

  • Eosinophilia-myalgia syndrome and toxic oil syndrome [link]

  • Metabolic myopathies [link]

  • Synovial osteochondromatosis [link]

  • Pigmented villonodular synovitis [link]

  • Bone tumours [link]

Acromegaly

Acromegaly is caused by over secretion of growth hormone usually by a pituitary tumour.

Definition

Acromegaly is caused by over secretion of growth hormone usually by a pituitary tumour, resulting in soft tissue over-growth in adults and gigantism in children.

Aetiology

  • Acromegaly is usually caused by a benign pituitary tumour (acidophilic tumour), resulting in over-production of growth hormone (GH).

  • Growth hormone stimulates the growth of all tissue, with an increase in protein synthesis. Epiphyseal chondrocytes proliferate and in adults there is reactivation of chondral proliferation. Excess GH accelerates the aging process and increases the occurrence and severity of OA.

Clinical features

Acromegaly progresses slowly with enlargement of the head, face, hands, and feet.

Key features on history

Musculoskeletal

  • Back pain occurs in 50%, predominately in the lumbar spine.

  • 70–90% of patients develop arthralgia.

Neuropathy

Parasthesiae and pain in the hand suggestive of carpal tunnel syndrome is common, due to compression and hypertrophy of the median nerve. Carpal tunnel syndrome occurs in 50% of patients.

Myopathy

Proximal muscle weakness occurs in 50%.

Key features on examination

Soft tissue over-growth

  • Characteristic facies – prominent supraorbital ridge, large nose, prognathism, thickened lips and tongue.

  • Coarse thickened skin. Increased thickness of the heal pad.

Musculoskeletal

  • ‘Spade-like’ hands due to soft tissue over-growth.

  • Thoracic kyphosis and rib enlargement leading to barrel chest.

  • Signs of OA: crepitus, loss range of movement, and deformity of large joints, knees, hips, and shoulders. The first MCP is typically involved.

  • Palpable bursae may be thickened.

Neuropathy

  • Signs of carpal tunnel syndrome: median motor and sensory impairment, positive Phalen's and Tinel's sign.

  • Ulnar and popliteal nerves may be enlarged and palpable.

  • Spinal cord compression and cauda equina syndrome are rare.

Muscle disease

Proximal weakness out of proportion to the increased muscle mass. Decreased exercise tolerance.

General investigations

Radiological investigations

  • Cartilage hypertrophy. Widening of the joint space occurs combined with soft tissue and synovial hypertrophy. Most frequently seen in the knees, MCP, and interphalangeal (IP) joints.

  • Cartilaginous and osseous degeneration. Thickened cartilage is prone to premature degeneration. The earliest sign is the vacuum sign in the knee joints. Small osteophytes and increased joint space are very suggestive of acromegaly.

  • In the terminal phalanges a typical feature is the enlargement of the tuft and base of the distal phalange.

Figure 18.1 Standing plain radiograph of knee, showing early osteoarthritic changes and an increase in joint space.

Figure 18.1
Standing plain radiograph of knee, showing early osteoarthritic changes and an increase in joint space.

Differential diagnosis

The combination of clinical and radiological features should make the diagnosis straightforward. In acromegaly, non-weight bearing joints, such as elbows and shoulders are involved unlike primary OA. Hyperostosis may resemble DISH.

Treatment

  • Treatment is of the primary pituitary tumour. Soft tissue over-growth manifestations are often improved by reduction in GH levels.

  • Degenerative hyperostotic manifestations do not improve after reduction of GH levels.

References

Liote F, Orcel P. Osteoarticular disorders of endocrine origin. Baillieres Best Pract Res Clin Rheumatol 2000; 14: 251–76.

Forgacs S. Acromegaly. In: Hochberg M, Silman A, Smolen J, Weinblatt M, Weisman M (eds) Rheumatology, 3rd edn. Ottawa: Mosby 2003

Diabetes mellitus

Diabetes mellitus is characterized by chronic hyperglycaemia this leads to metabolic dysfunction and protein disorders. A variety of musculoskeletal disorders occur in long duration diabetics.

Diabetic osteoarthropathy

This is a late complication of diabetes mellitus, occurring in up to 1.4% of diabetics predominately in the over 50 years of age group.

It affects predominately the foot joints, with the MTPJs most commonly involved.

Clinical features

Key features on history

The pain is much less severe than expected because neuropathy is always also present.

  • Musculoskeletal: swelling of the foot joints that is relatively painless.

  • Neurological: parasthesiae and numbness.

  • Cutaneous: ulcer formation.

Key features on examination

  • Musculoskeletal: increased joint mobility due laxity of the joint capsule.

  • Soft tissue swelling: metatarsal joint destruction with foot shortening, collapse of the medial arch led to development of the ‘rocker bottom foot’.

  • Neurological: sensory neuropathy, loss of vibration sense and decreased reflexes.

  • Cutaneous: neuropathic plantar ulcers occur in association with bone destruction.

Radiological investigation

Plain radiology is the best means of making the diagnosis.

Three stages can be identified on plain radiographs

  • Porosis, cortical defects, and subluxation.

  • Osteolysis, fragmentation, fractures, periosteal reaction.

  • Cortical defect filing, deforming arthritis, ankylosis.

MRI is useful for distinguishing diabetic osteoarthropathy from osteomyelitis.

Differential diagnosis

Diabetic osteoarthropathy must be distinguished from infection, osteoarthritis, other neuropathic arthropathies, tumours, and inflammatory arthritis.

Pathogenesis

  • Neuropathy is the major cause of osteoarthropathy and the osteolysis is due to neurogenic factors and not inflammation.

  • Infection and microangiopathy play a less significant role.

Prognosis

Osteolysis may stop spontaneously with healing.

Treatment

  • Conservative management is key with good care of ulcers; a combined approach with a diabetic foot care team is essential. Surgery should be avoided if possible.

  • Good control of diabetes is essential both to treat established disease, and also to prevent developvment of late complications of diabetes such as neuropathy and osteoarthropathy.

Diabetic cheiroarthropathy

Most commonly occurs in long-standing type I diabetics.

Clinical features

Key features on history

  • Parasthesiae and pain are the earliest features, which progresses very slowly.

  • Loss of hand function.

Key features on examination

  • Thick, tight waxy skin.

  • Joint restriction and sclerosis of tendon sheaths.

  • Typical prayer sign with the patient unable to press the hands together.

Pathogenesis

Diabetic microangiopathy is thought to be the main factor.

Treatment

There is no specific treatment apart from good diabetic control, analgesia and symptomatic management.

Diabetic femoral amyotrophy

  • Diabetic femoral amyotrophy is characterized by severe unilateral anterior thigh pain followed by wasting and weakness of quadriceps muscles and loss knee reflex. It is bilateral in 50% of patients.

  • Recovery begins at 3 months and is usually complete by 18 months.

Muscle infarction

  • Muscle infarction is a rare cause of severe pain in diabetics. There is acute severe pain and swelling of muscle, typically the thigh.

  • Muscle biopsy shows necrosis and oedema.

  • Resolution occurs over a few weeks, but recurrence is common.

References

Liote F, Orcel P. Osteoarticular disorders of endocrine origin. Baillieres Best Pract Res Clin Rheumatol 2000; 14: 251–76.

Adult onset Still's disease

Definition

Adult onset Still's disease (AOSD) is a rare condition characterized by recurrent episodes of inflammation.

Diagnostic criteria

There are several sets of diagnostic criteria of which the Yamaguchi are the most sensitive (93.5%).

Yamaguchi criteria for Adult onset Still's disease

Major criteria

  • Arthritis.

  • Swelling or limitation of motion, warmth, pain, stiffness.

  • Duration of 6 weeks.

  • Exclusion other reasons for arthropathy.

  • Fever (>39.0°C) persisting, intermittent.

  • Typical rash: persistent eruption is NOT characteristic of the disease.

  • Elevated WBC > 10 000.

Minor criteria

  • Sore throat.

  • Lymphadenopathy or splenomegaly.

  • Abnormal LFTs – not attributable to drug toxicity or allergy.

  • Negative ANA or RF.

Exclusion criteria

Infection, malignancy, vasculitis.

To establish a diagnosis of AOSD, patients require five criteria including two major criteria. From Yamaguchi et al. (1992).

Epidemiology

  • The incidence is 1–2/million/year.

  • Sex distribution is equal.

  • The peak age of onset is 16–35 years.

Aetiology

  • The aetiology is unknown, but the clinical presentation with fever, rash, sore throat, and lymphadenopathy suggests an infectious cause. A viral aetiology has most often been suggested, but no agent has yet been identified.

  • There is no clear association with HLA or other genetic markers. No clear environmental factors have been found.

  • Pro-inflammatory cytokines, such as IL-1, Il-6, IL-18, interferon gamma, TNF, and macrophage colony stimulating factor are raised, and thought to have role in the pathogenesis.

Clinical features

AOSD affects many organs. The full spectrum of clinical features may not be present at onset and only may develop over a few weeks.

Key features on history

Systemic

  • Fever is almost universal with virtually all patients exhibiting a fever > 39°C, spiking usually during the evening or night.

  • Sore throat occurs in up to 92% of cases.

  • Weight loss of > 10% occurs in 75%.

  • Lymphadenopathy occurs in 65%. Hepatosplenomegaly occurs in 50%.

Musculoskeletal

  • Joint pain is a common feature and is greatest during febrile episodes.. It becomes worse during the course of illness and may be very mild at presentation.

  • Myalgia (75%) can be severe and also increases during febrile episodes.

  • Abdominal pain is usually mild and infrequently severe enough to warrant laparotomy.

  • Pleurisy and pericarditis occur in 30–40% of patients.

Key features on examination

Musculoskeletal

  • Initially the synovitis is migratory and additive, but becomes more persistent. This can involve both large and small joints (both PIPJ and DIPJ of the hands), with the knee being most commonly involved (84%).

  • The axial skeleton is infrequently involved.

Skin

  • The rash is characteristically salmon pink, macular, or maculopapular.

  • It is evanescent and occurs during febrile attacks lasting for several hours.

  • Lymphadenopathy (65%) most commonly occurs in the cervical region, the nodes are mobile and tender.

General investigations

The diagnosis is often delayed due to the non-specific nature of the illness.

  • FBC anaemia of chronic disease, leucocytosis (WBC>15 × 109/l in 80%), thrombocytosis.

  • Acute phase response (ESR and CRP) is raised in all patients.

  • Liver function abnormal in 75%.

  • Ferritin: hyperferritinaemia with extreme elevation is common. It is unrelated to iron metabolism and is due to cytokine-induced increased synthesis by the reticulo-endothelial system.

Serological investigations

  • ANCA, ANA, RF, anticardiolipin antibodies. These are usually negative.

  • Complement levels are normal.

  • Cryoglobulins.

Synovial fluid

Synovial fluid is inflammatory with raised white cell count.

Biopsy

Lymph node and skin biopsy are not needed for the diagnosis, but is often performed to exclude malignancy or vasculitis.

Differential diagnosis

  • The differential diagnosis is broad and the diagnosis is essentially that of exclusion. Granulomatous disorders, vasculitis, infection, malignancy, and connective tissue disease all need to be ruled out.

  • Schnitzler syndrome is rare, but shares many features with AOSD, including high fever, lymphadenopathy, hepatosplenomegaly, raised acute phase response, and leucocytosis. However, there is urticaria and a monoclonal IgM gammopathy and less marked elevation in ferritin.

Prognosis

  • The course is monophasic in 61.5% of cases and relapsing in 38.5%. The median duration of treatment is 10 years.

  • Chronic articular involvement occurs in one-third.

  • Presence of polyarthritis especially shoulder or hip joint early in the disease course is predictive of a chronic course.

  • Death is uncommon, but is due to infection, hepatic failure, and disseminated intravascular coagulation.

Pathology

  • Lymph node histology shows infiltrates of plasma cells, and polymorphonuclear leucocytes and reactive hyperplasia.

  • Skin biopsy shows a mild perivascular inflammation of the superficial dermis with few lymphocytes or neutrophils.

  • Liver biopsy mononuclear sinusoidal and portal tract infiltrates with mild Kupffer cell hyperplasia. Focal hepatitis is less common.

Patient advice

  • Diagnosis of exclusion.

  • Requires long-term therapy, but in general the prognosis is good.

Treatment

  • There are no randomized controlled trials in AOSD.

  • Often, in the first instance, around 20–25% of patients respond well. Aspirin is often still used in relatively high doses.

  • Oral corticosteroids usually give quick symptom relief. 0.5–1.0 mg/kg may be required initially. Pulse intravenous corticosteroids are not usually needed. Depending on response the dose may be tapered quite quickly

  • Chronic polyarthritis is managed with low dose oral corticosteroids. Immunosuppressive agents, such as methotrexate, may have a place in reducing steroid exposure and preventing long-term joint damage. Other immunosuppressive drugs that have been utilized include azathioprine, leflunomide, ciclosporin, and cyclophosphamide.

  • Other agents used experimentally include intravenous gamma globulin, inhibitors of TNF-alpha, IL-1, and Il-6.

Follow-up

Every 3–6 months as patients condition dictates. AOSD is a relapsing condition and lifelong follow-up is required.

Resources

Guidelines

There are no guidelines specifically for AOSD, but reference should be made to local guidance on steroid induced osteoporosis, use and monitoring of immunosuppressive therapy and vaccination.

Patient organizations

International Still's Disease Foundation. www.stillsdisease.org

ICD-10 coding

M06.1 Adult-oset Still's disease.

References

Efthimiou P, Kontzias A, Ward CM, Ogden N. Adult-onset Still's disease: can recent advances in our understanding of its pathogenesis lead to targeted therapy. Nat Clin Pract Rheumatol 2007; 3: 328–35.

Esdaile JM. Adult Still's disease. In: Hochberg M, Silman A, Smolen J, Weinblatt M, Weisman M (eds) Rheumatology, 3rd edn. Ottawa: Mosby, 2003: 793–80.

Kadar J, Petrovicz E. Adult-onset Still's disease. Best Prac Res Clin Rheumatol 2004; 18: 663–74.

Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult-Still's disease. J Rheumatol 1992; 19: 424–30.

Amyloidosis

Definition

The amyloidoses are a group of disorders characterized by deposition of extracellular amyloid fibrils.

Epidemiology

AA type

The most common type of systemic amyloidosis worldwide is AA type. The most common associations in Western countries are chronic inflammatory conditions, whilst in regions where infection is common it is associated with tuberculosis and leprosy (Table 18.1). The reported frequency of AA amyloidosis in inflammatory disease varies widely across the world is probably dependent on the means of diagnosis.

Table 18.1 Associations of AA amyloidosis

Inflammatory arthritis (60%)

Rheumatoid arthritis (most common worldwide (33%))

Juvenile idiopathic arthritis (17%)

Others including ankylosing spondylitis (10%)

Chronic Infection (15%)

Bronchiectasis (5%)

Injection drug abuse (4%)

Complication paraplegia (ulcers etc) (2%)

Osteomyelitis (1%)

Tuberculosis (1%)

Periodic fever syndromes (9%)

Familial Mediterranean fever (5%)

TNF-receptor-associated periodic fever syndrome (2%)

Inflammatory Bowel Disease (5%)

Malignancy (1%)

Percentages from a series of 374 patients (Lachmann et al., 2007).

AL type

In the USA, AL type is most common, the incidence in Olmsted County was estimated to be 1/100 000 between 1950 and 1989. In Holland, the prevalence is 1/75 000. 20% of people with multiple myeloma develop AL amyloidosis.

Aß2-microglobulin

Aß2-microglobulin amyloidosis occurs in chronic haemodialysis.

Aetiology

  • Amyloid deposition reflects a conformational change in the structure of the precursor protein and is the final common endpoint of several different processes.

  • There are at least 23 amyloid precursors. A common feature is a β-pleated sheet either in the native protein or after conformational change, which is deposited, and disrupts the organization and function of tissues and organs.

  • In the AA type the fibrils are derived from the acute phase protein serum amyloid A (SAA) through a process of cleavage, misfolding and aggregation into a highly ordered abnormal β-sheet conformation. SAA is an apolipoprotein constituent of high-density lipoprotein, which is synthesized by hepatocytes stimulated by pro-inflammatory cytokines. Prolonged over synthesis of SAA is a requirement for development of AA amyloidosis, but why only a small proportion of patients with chronic inflammation develop amyloidosis is unknown.

  • In the AL type, the precursor is Ig light chain (κ or λ), λ light chains are more amyloidogenic. Structural changes in the light chain may be responsible for amyloidogenesis, either deletions resulting in small chains or glycosylation.

  • In Aß2-microglobulin amyloidosis, the precursor protein is ß2-microglobulin. Improved haemodialysis techniques have reduced the frequency of this complication.

Clinical features

Key features on history

General

Symptoms suggestive of amyloidosis include proteinuria especially developing in the context of chronic inflammatory disease or infection. In a recent series of AA amyloid the mean duration of symptomatic inflammatory disease before development of amyloidosis was 17 years (Lachmann et al, 2007). The clinical features of AA amyloid are the same irrespective of the underlying inflammatory disease.

Musculoskeletal

  • In AL type amyloidosis joint involvement is infrequent. Joint stiffness occurs more than pain. Involves both large and small joints either in a symmetrical or asymmetrical manner.

  • Aß2-microglobulin amyloidosis occurs in the setting of chronic dialysis. Always involves the joints and skeleton. There is infiltration of the carpal ligament leading to symptoms of carpal tunnel syndrome, which in this setting should prompt investigation for amyloidosis. Neck pain is due to a destructive spondyloarthropathy.

  • Musculoskeletal involvement is not a feature of familial transthyretin amyloidoses, but neuropathic joints can develop due to the severe neuropathy.

Renal disease

Renal disease is the typical presentation of AA (97% at presentation) and AL amyloidosis. Development of proteinuria in a patient with longstanding active inflammatory disease should prompt investigation for AA amyloidosis.

Neuropathy

A sensorimotor proximal or distal polyneuropathy is the presenting feature in 10–20% of AL amyloidosis. Occurs in the familial TTR amyloidoses

Cardiac

Cardiac involvement occurs in 20% of AL patients, but is much rarer (<10%) in AA amyloidosis, and results in a cardiomyopathy and arrhythmias.

Key features on examination

Musculoskeletal

  • In AL amyloidosis there is stiffness of joints with little swelling. Infiltration of the skin may produce palpable pads e.g. over the shoulders.

  • 2-microglobulin. Stiff painful peripheral joints with a destructive arthropathy, most common sites are wrist, shoulders, hips, knees, and spine.

Neuropathy

  • Proximal and distal sensorimotor neuropathy. Autonomic neuropathy may occur with postural hypotension, and incontinence. Neuropathy is not seen in AA amyloidosis.

  • Signs of carpal tunnel syndrome especially in Aß2-microglobulin amyloidosis.

General investigations

There are no specific serological or urine markers of amyloidosis. CRP, SSA, and other acute phase reactants are not specific markers, as they are raised in chronic inflammation and most patients with chronic inflammation do not develop amyloidosis.

  • Assessment of renal function with quantification of proteinuria (nephrotic range > 3 g/24 h). Hypoproteinaemia supports a diagnosis of nephrotic syndrome.

  • Serum and urine immunofixation, serum-free light chains. The presence of monoclonal Ig or free light chains suggests AL amyloidosis.

  • Bone marrow aspiration may be required to demonstrate monoclonal plasma cell proliferation and production of free light chains.

  • Investigations for hereditary forms of amyloidosis – mutations in genes encoding for transthyretin, fibrinogen A -chain, apolipoprotein A-I, apolipoprotein A-II, and lysozyme.

Biopsy

Rectal biopsy or subcutaneous fat aspiration are the techniques of choice for obtaining tissue for diagnosis.

Imaging

X-ray

Plain radiographic features of amyloidosis include osteoporosis, lytic lesions, pathological fractures, osteonecrosis, subchondral cysts and erosions.

Ultrasound

US may show thickening of soft tissues around joints and especially in the wrist.

MRI

  • MRI may show thickened synovium and soft tissue infiltration.

  • MRI is the method of choice for investigating possible amyloid deposits, especially in Aß2-microglobulin amyloidosis.

Nuclear medicine

Serum amyloid P (SaP) scanning uses iodinated SaP that binds to amyloid fibrils. It is useful in demonstrating the extent of amyloid deposition and can be used to measure response to treatment.

Synovial fluid

The synovial fluid is characteristically non-inflammatory and may contain amyloid fibrils.

Differential diagnosis

This is from other causes of nephrotic syndrome or neuropathy. Drugs particularly gold and penicillin may cause proteinuria.

Pathology

Samples for assessment of possible amyloidosis should be stained using Congo red and examined under polarizing light microscopy. Amyloid fibrils will have apple green birefringence.

Treatment

  • AA amyloidosis: the treatment is to control the underlying inflammatory condition or chronic infection. With treatment regression of amyloid deposits can be observed using serial SaP scanning.

  • AL amyloidosis: the aim is to reduce production of amyloid forming monoclonal light chain by treatment of the underlying plasma cell dyscrasia.

Prognosis

  • The median survival in AA amyloidosis is 133 months.

  • Factors associated with a poor prognosis are age at presentation and end-stage renal failure.

Resources

Patient organizations

Amyloidosis support network. www.amyloidosis.org.

ICD-10 coding

E.85Amyloidosis

References

Buxbaum J. Amyloidosis. In: Hochberg MC, Silman A, Smolen JS, Weinblatt M, Weisman MH (eds) Rheumatology. Ottawa: Mosby, 2004: 2015–25.

Comenzo RL. Current and emerging views and treatments of systemic immunoglobulin light-chain (Al) amyloidosis. Contrib Nephrol 2007; 153: 195–210.

Kiss E, Keusch G, Zanetti M, et al. Dialysis-related amyloidosis revisited. Am J Res 2005; 185: 1460–7.

Lachmann HJ, Goodman HJ, Gibertson JA, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med 2007; 356: 2361–71.

See also

Rheumatoid arthritis

Autoinflammatory syndromes.

Autoinflammatory syndromes

The autoinflammatory syndromes are a group of inherited conditions characterized by inflammation, arthralgias, and a propensity for development of secondary AA amyloidosis.

The conditions include: familial Mediterranean fever (FMF), hyperimmunoglobulin D with periodic fever syndrome (HIDS), tumour-necrosis factor (TNF)-receptor- associated periodic syndrome (TRAPS), cryopyrin associated periodic syndrome (CAPS). They are distinguished from systemic onset JIA in the child because children are usually well between attacks. The conditions are all very rare and are best investigated at specialized centres.

Familial Mediterranean fever

Classification criteria

The Tel Hashomer criteria are widely used to clinically define FMF.

Tel Hashomer criteria for FMF

Major criteria

  • Recurrent febrile episodes accompanied by peritonitis, synovitis or pleuritis

  • Amyloidosis of the AA-type without predisposing disease

  • Favourable response to colchicine treatment

Minor criteria

  • Recurrent febrile episodes

  • Erysipelas like erythema

  • FMF in a first degree relative

Definitive diagnosis: 2 major or 1 major and 2 minor. Probable diagnosis: 1 major and 1 minor.

The specificity in a Jewish population is > 95%.

Epidemiology

  • Autosomal recessive condition

  • Most frequent in individuals of non-Ashkenazi Jewish, Armenian, Arab, or Turkish ethnic origin.

  • Relatively common amongst non-Ashkenazi (Eastern European) Jews and Italians.

  • Carrier frequencies of 1:3 and 1:5 have been reported in some populations.

Aetiology

Molecular genetics

The FMF gene, MEFV, is located on the short arm of chromosome 16p13.3 and is a 10-exon gene encoding pyrin a 781 amino acid protein.

There are 4 common missense mutations – substitution of isoleucine for methionine at codon 680 (M680I); valine for methionine at 694 (M694V); of isoleucine for methionine at codon 694 (M694I); alanine for valine at 726 (V726A), but over 100 variants have been described.

The MEFV gene produces a pyrin and is expressed in myeloid cells. Pyrin is believed to regulate inflammation by via apoptosis. Mutated variants of pyrin are unable to regulate inflammation especially pathways involving IL-1B and NFkB.

Clinical features

Key features on history

  • The acute attacks of FMF are characterized by fever, serositis, rash, and arthralgia. The duration of attacks is 24–72 h, but joint pain can last for 1 week.

  • Attacks are not truly periodic, but can occur at widely varying intervals and, thus, are episodic.

  • There is often no obvious precipitant, but emotion, exercise, and menstruation have all been associated.

  • Between attacks patients are asymptomatic.

Systemic

The height of the fever varies between patients, but is higher in children.

Cutaneous

Tender red plaques on the legs.

Serosal

  • Abdominal pain is the second most common feature and occurs in >90%.

  • Pleurisy is common and often occurs with abdominal pain. Sharp, stabbing chest pain, worse on inspiration, coughing. Pain may be referred to the shoulder from the diaphragm.

  • Pericardial chest pain is uncommon.

Musculoskeletal

  • Arthralgias with or without joint swelling present initially in childhood. Most frequently, monarticular, typically involving the knee or ankle. Polyarticular or oligoarticular presentations are less common.

  • Prolonged episodes of myalgia can develop in association with fever (protracted febrile myalgia); and are thought to be due to vasculitis.

Key features on examination

Cutaneous

The most characteristic lesion is a tender erythematous plaque on the dorsum of the foot, ankle, or calf.

Musculoskeletal

  • Inflammatory synovitis most commonly affecting the lower limb joints, in a monarticular pattern. The effusion may be quite large.

  • Destructive arthritis rarely occurs.

Serosal

  • Diffuse abdominal tenderness, which may be sufficiently severe to mimic an acute abdomen.

  • Signs of a pleural effusion may be present.

  • Pericarditis is uncommon.

General investigations

Investigation is directed at establishing the diagnosis.

  • FBC anaemia (only if severe GI or renal haemorrhage), leucocytosis.

  • Acute phase response. The ESR, CRP, serum amyloid A (SAA), fibrinogen, and haptoglobin are all raised.

Serological investigations

  • ANA, ANCA, RF should all be negative. A positive ANA or ANCA suggests the presence of a connective tissue disease or other vasculitis.

  • Complement levels are normal.

Genetic screening

Patients with typical clinical features should be screened for the common mutations (see above)

Differential diagnosis

The diagnosis is based on clinical manifestations. Patients with typical clinical features may not have demonstrable mutations. Since the advent of genetic screening patients with milder features are being discovered who do not fulfil recognized criteria.

Prognosis

  • Overall prognosis is determined by the risk of development of AA amyloidosis.

  • The risk of amyloidosis varies between mutations with the risk apparently highest for patients with the M694V mutation. A family history of amyloidosis also increases the risk suggesting that other genes are important including the SAA1 a/a genotype.

Patient advice

  • Recessively inherited condition. Recurrent attacks of abdominal pain, fever, and joint pain.

  • Amyloidosis is the most serious complication.

Treatment

  • Colchicine (1–2 mg/day) is the basis of treatment. The dose is limited by gastrointestinal side effects – diarrhoea, cramping, and bloating.

  • Colchicine prevents acute inflammatory attacks and also the long-term development of amyloidosis.

  • Glucocorticoids appear to be ineffective.

  • Anecdotal reports describe successful use of TNF-alpha blockade and Anakinra in colchicine resistant cases.

Follow-up

Long-term follow-up is required with regular urinalysis is necessary to detect development of amyloidosis.

Resources

Internet resources

OMIM 249100 www.ncbi.nlm.nih.gov/entrez/

ICD-10 code

E85.0 Non-neuropathic heredofamilial amyloidosis. Familial Mediterranean fever

References

Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997; 40: 1879–85.

Ozel AM, Demitürk L, Yazgan Y, Avsar K, Günay A, Gürbüz AK et al. Familial Mediterranean fever: a review of the disease and clinical and laboratory findings in 105 patients. Dig Liver Dis 2000; 32: 504–9.

Yao Q, Furst D. Autoinflammatory diseases: an update of clinical and genetic aspects. Rheumatology 2008; 47: 946–51

Hyperimmunoglobulinaemia D with periodic fever syndrome

HIDS is characterized by recurrent attacks similar to FMF, but with the presence of raised levels of IgD in serum.

Epidemiology

A rare condition, most pedigrees are clustered in northern Europe.

Aetiology

Molecular genetics

HIDS is a recessively inherited condition defined by mutations in the mevalonate kinase gene (MVK) located at 12q24, which catalyses the conversion of mevalonic acid to 5-phosphomevalonic acid, a key stage in the biosynthesis of cholesterol and isoprenoid. The most common mutation is a substitution of isoleucine for valine at codon 377 (V377I). The exact mechanism is uncertain, defective apoptosis of lymphocytes may be important, and the role of raised IgD is unknown. IgD can increase TNF-α and IL-1 levels.

Clinical features

Key features on history

  • The median age of onset is <6 months.

  • Vaccinations may trigger attacks, as well as infections, emotion, trauma, and surgery.

  • The usual length of attacks of high fever is 3–7 days. The interval between attacks is variable, but typically 4–6 weeks.

Serosal

The majority of patients have attacks of abdominal pain, which may be severe enough to require laparotomy.

Diarrhoea is seen more frequently than in FMF.

Musculoskeletal

  • 70% of patients experience arthralgias, with knees and ankles most commonly involved.

  • Attacks may be polyarticular in contrast to FMF.

Key features on examination

Lymphadenopathy

Widespread, tender lymphadenopathy is more common in HIDS than the other autoinflammatory syndromes. Swelling varies with attacks.

Musculoskeletal

Large joint arthritis varying with severity of the febrile episode and with abdominal pain.

Mucocutaneous

  • Crops of erythematous red macules 0.5–2.0 cm in diameter are the most common feature.

  • Painful aphthous orogenital ulcers are sometimes found.

  • Hepatosplenomegaly is seen.

General investigations

  • FBC leucocytosis with left shift.

  • Acute phase response. The ESR, CRP, serum amyloid A (SAA), fibrinogen and haptoglobin are all raised.

  • Serum IgD elevation > 14.1mg/dl on two occasions at least 1 month apart.

  • Urine mevalonic acid levels are raised during attacks

  • Genetic screening

  • Mutational analysis initially looking for the most common mutations V377I or I268T mutations. If this is negative a more comprehensive genome screen can be conducted.

Differential diagnosis

This is from the other autoinflammatory conditions. Some patients have MVK mutation, but normal IgD levels and are termed variant HIDS.

Prognosis

Unlike the other autoinflammatory syndromes amyloidosis has not been reported in HIDS. The frequency and severity of attacks tend to diminish with age.

Treatment

There is no proven treatment. NSAIDs may control fever and joint pain. Corticosteroids may help some patients. Colchicine is ineffective.

Resources

Internet resources

OMIM 260920

www.ncbi.nlm.nih.gov/entrvez/

References

Drenth JP, Haagsma CJ, van der Meer JM. HypergammaglobulinaemiaD and periodic fever syndrome. Medicine (Baltimore) 1994; 73: 133–44.

Yao Q, Furst D. Autoinflammatory diseases: an update of clinical and genetic aspects. Rheumatology 2008; 47: 946–51.

TNF-receptor-associated periodic syndrome

TRAPs comprise a group of dominantly inherited fever syndromes, which were previously known under a variety of terms including, e.g. familial Hibernian fever. The discovery of the genetic basis led to the syndromes being linked, being due to mutations in the 55 Kd receptor for TNF-α.

Epidemiology

The original pedigrees were described in Hibernian families, but a broad ethnic distribution has since been described.

The condition is inherited as an autosomal dominant.

Aetiology

Molecular genetics

TNF-α has two receptors a 55kDa molecule (p55) and a 75kDa molecule (p75). The p55 receptor is encoded by TNFRSF1A on chromosome 12p13.2, whilst the p75 receptor is encoded by TNFRSF1B on chromosome 1p36.3-p36.2. The p55 receptor is expressed on a wide variety of cell types, whilst the p75 is restricted to leucocytes and endothelial cells. TRAPs is caused by mutations in TNFRSF1A.

The most frequent mutation is R92Q. Levels of TNFRSF1A protein is low in plasma and the aberrant form of TNFR1 is present on cell surface. Neutralization of TNF-α is impeded and TNF-α driven inflammation is uncontrolled. However, the precise pathogenesis of the clinical features is not completely understood.

Clinical features

  • The median age of onset is 3 years.

  • The duration of attacks is longer than for the other syndromes lasting longer than 1 week.

Serosal

  • Abdominal pain and serositis may be severe.

  • Pleurisy with chest pain occurs.

  • Scrotal pain due to inflammation of the tunica vaginalis occurs but uncommonly.

Musculoskeletal

  • Arthralgia is more frequent than arthritis occurring in two-thirds of patients. Usually non-erosive, and monarticular or oligoarticular.

  • Myalgia occurs frequently, unlike FMF. There is a region of muscle pain, which is warm and tender. There is an overlying area of erythema which blanches with pressure. Biopsy shows a panniculitis, fasciitis and perivascular inflammation, but no myositis.

Ocular

8% of patients experience conjunctivitis, periorbital oedema, and or periorbital pain. Iritis and uveitis are less common.

General investigations

  • FBC leucocytosis with left shift. Anaemia of chronic disease.

  • Acute phase response. The ESR, CRP, serum amyloid A (SAA), fibrinogen and haptoglobin are all raised.

  • Polyclonal increase in gamma globulins.

  • Mevalonic aciduria.

Serological investigations

  • ANA, ANCA, RF should all be negative. A positive ANA or ANCA suggests the presence of a connective tissue disease or other vasculitis.

  • Complement levels are normal.

Genetic screening

Mutational analysis initially looking for the most common mutations.

Differential diagnosis

This is from the other autoinflammatory conditions. The diagnosis is made by establishing a mutation in TNFRSF1A in a patient with an unexplained fever syndrome.

Prognosis

14% of patients develop AA amyloidosis.

Treatment

  • Colchicine is ineffective in preventing the febrile attacks and also it does not prevent amyloidosis.

  • Glucocorticoids can be used to treat acute attacks.

  • Etanercept has been used with mixed results, but is considered useful as a steroid sparing agent.

Resources

Internet resources

OMIM142680 www.ncbi.nlm.nih.gov/omim

References

Dodé C, André M, Bienvenu T, Hausfater, Pêcheux C, Bienvenu J, et al. The enlarging clinical, genetic, and population spectrum of tumour necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 2002; 46: 2181–8.

Yao Q, Furst D. Autoinflammatory diseases: an update of clinical and genetic aspects. Rheumatology 2008; 47: 946–51.

Cryopyrin-associated periodic syndrome

The cryopyrin associated periodic syndrome (CAPS) is a group conditions previously considered to be separate entities, but recently shown to be due to mutations in the CIAS1 gene. The group includes Muckle Well syndrome (MWS), familial cold inflammatory condition (FCAS), and neonatal onset multi-system inflammatory disease (NOMID)/chronic infantile neurological cutaneous and articular syndrome (CINCA).

MWS is characterized by attacks of fever, malaise, arthralgias, and urticaria.

Epidemiology

  • A rare condition, the initial cases were all described in Europe.

  • The inheritance is autosomal dominant.

Aetiology

Molecular genetics

CAPS is caused by mutations in the CIAS1 gene located on chromosome 1q44. The encoded protein is cryopyrin and >40 mutations are known. The CIAS1 gene product cryopyrin (also known as PYPAF1 or NALP3) is part of the inflammasome and is essential for activation of caspase 1 and processing of IL-1 and IL-18. Thus, the effects of mutations may be mediated by their effects on IL-1, IL-18, and NFkB.

Clinical features

Key features on history and examination

  • The age of onset is variable from infancy to adolescence.

  • Attacks last 12–48 h.

  • FCAS is the mildest syndrome. CINCA/NOMID is the most severe.

Musculoskeletal

Arthralgias are more common and affect predominately large joints. The pattern is typically oligoarticular.

Cutaneous

The rash is erythematosus geographical plaque, reminiscent of urticaria, but they do not itch. They ‘ache’.

Sensorineural hearing loss

  • 70% of cases with MWS develop progressive sensori neural hearing loss.

  • Deafness also occurs in CINCA/NOMID.

General investigations

  • FBC leucocytosis with left shift.

  • Acute phase response. The ESR, CRP, serum amyloid A (SAA), fibrinogen, and haptoglobin are all raised.

Genetic screening

Mutational analysis initially looking for the most common mutations.

Differential diagnosis

This is from the other autoinflammatory conditions.

Prognosis

25% of patients develop AA amyloidosis.

Treatment

  • There is no proven treatment. NSAIDs may control fever and joint pain. Corticosteroids may help some patients.

  • Therapy targeting the IL-1B pathway with IL-!ra (anakinra) have been effective in a small number of patients.

Table 18.2 Major discriminating features of the auotinflammatory condition

FMF

TRAPS

HIDS

CAPS

Age of onset

<20 years

<20 years

Median 6 months

<6 months

Fever duration

1–3 days

> 7 days

3–7 days

1–2 days

Serositis

±±

±±

±

±

Musculoskeletal

Monarthritis

Monarthritis, myalgia

Polyarthritis

Deforming arthritis

Cutaneous

Erysipeloid

Erysipeloid

Macules, papules, urticaria

Urticaria

Adenopathy

Rare

Rare

Yes

Rare

Deafness

No

No

No

Yes

Amyoidosis

±±±

±±

±

±

Inheritance

Recessive

Dominant

Recessive

Dominant

Gene mutation

MEFV

TNFRSF1A

MVK

CIAS1

Gene product

Pyrin/marenostrin

TNFR1A

Mevalonate kinase

Cryopyrin

Therapy

Colchicine

±±

Glucocorticoids

±

TNF-α blockers

±

±

±

IL-1 antagonists

±

±

±±

Adapted from Yao & Furst (2008).

Resources

Internet resources

OMIM 191100

www.ncbi.nlm.nih.gov/omim

References

Aksentijevich I, Putnam C, Remmer EF, Mueller JL, Le J, Kolodner RD, et al. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum 2007; 56: 1273–85.

Yao Q, Furst D. Autoinflammatory diseases: an update of clinical and genetic aspects. Rheumatology 2008; 47: 946–51.

Haemochromatosis

Haemochromatosis is an inherited condition of iron storage, which results in a characteristic arthropathy, first described in 1964.

Epidemiology

  • Haemochromatosis is most common in Northern European populations – the highest prevalence being Ireland, UK, Brittany and Scandinavia.

  • The annual incidence is 2–4/100 000 with a prevalence of 20–80/100 000.

  • In the USA 1 in 227 white Caucasians are homozygous for the HFE C282Y mutation. In Ireland the rate is 1 in 83.

  • Males and females are affected equally. Males present typically between ages 25–70 and females after the menopause.

  • There is an association with HLA-A3-B14 (relative risk 23).

Aetiology

  • Iron is poorly excreted in man and in haemochromatosis there is increased absorption from the diet leading to iron overload.

  • Hepcidin controls extracellular iron concentration by binding to and inducing the degradation of the cellular iron exporter ferroportin. Iron absorption is related to hepcidin, which has a key position in the pathological changes in haemochromatosis. Deficiency of hepcidin is seen in many iron overload states with increased iron absorption. The precise mechanism by which the HFE C282Y protein, ferroportin and hepcidin interact is unclear.

Genetics

Haemochromatosis is an autosomal recessive condition, due to mutation in the HFE gene located on the short arm of chromosome 6p21.3. The most common mutation is C282Y reflecting mutation of cys to tyr at locus 282. A number of other mutations have been described, e.g. H63D (his to asp at locus 63). In Northern Europe 90% patients are homozygous for C282Y and 5% heterozygous C282Y/H63D. The compound heterozygotes are less severely affected. However, 25% of C282Y homozygotes do not develop iron overload.

Clinical features

Key features on history

  • Onset of iron overload is uncommon before 30 years of age.

  • Presentation is with gradual stiffness, pain on use and enlargement of the MCP joints. There is evolution into a polyarticular arthropathy.

  • There may be episodes of acute pseudogout, which may involve the knee, wrist, intervertebral disk and symphysis pubis.

  • Fatigue is a common feature.

  • Non-specific abdominal pain and discomfort may be the presentation of liver disease.

Key features on examination

Arthropathy

Patients develop a characteristic pattern of OA, with involvement of the 2nd and 3rd MCP joints. The tenderness is mild and the joint is not warm. There is an absence of soft tissue swelling.

Cardiac

Cardiac involvement is uncommon, but an arrhythmia may be an early feature.

Liver

Cirrhosis is a late feature.

Endocrine

Diabetes is late manifestation and occurs when cirrhosis is established. Hypogonadism is also a late feature.

Cutaneous

Skin pigmentation is not diagnostic and is a slate grey colour, rather than brown. It is caused by melanin and not iron.

General investigations

  • Investigation is directed at establishing the diagnosis and assessing the extent and severity of organ involvement.

  • Initial screening for the diagnosis is measurement of serum iron, transferrin, and ferritin. A transferrin saturation of >62% makes haemochromatosis very likely. Serum ferritin alone may be misleading as it is elevated in inflammatory states.

  • A liver biopsy is only needed for prognostic purposes in patients with severe iron overload (ferritin >1000 µg/l) and abnormal liver function.

  • The acute phase response is normal and the rheumatoid factor negative.

Genetic screening

HFE genotyping should be performed when screening iron studies are abnormal. Homozygosity for the C282Y mutation or for the compound heterozygous C282Y/H63D confirms the diagnosis.

Imaging

  • There are typical changes of OA with joint space narrowing, subchondral sclerosis, and cysts. Prominent hook-like osteophytes are present especially at the MCP joints.

  • The pattern of joint involvement is not typical for OA, with involvement of the MCP, midcarpal, radiocarpal, elbows and glenohumeral joints. The 2nd and 3rd MCPs are typically involved.

  • 30% of patients have radiological evidence of chondrocalcinosis.

Differential diagnosis

  • This is from other types of osteoarthritis and inflammatory arthritis.

  • Secondary iron overload is excluded by an absence of a history of blood transfusions, parenteral iron administration and anaemia (b-thalassaemia, sideroblastic anaemia).

  • Porphyria cutanea tarda may present with raised transferrin saturation and ferritin concentration with abnormalities of liver function. The skin is more fragile with blisters and the pigmentation is deeper. The diagnosis is made on the demonstration of the presence of uroporphyrins.

  • Alcoholic liver disease may be associated with increased ferritin and transferrin saturation.

Prognosis

  • The rate of progression of the arthropathy is extremely variable, but regular venesection does not improve the arthropathy. The damage to synovial membrane and cartilage is irreversible.

  • The overall prognosis is excellent if venesection is started early in the disease. Patients with cirrhosis have 200-fold risk of hepatocellular carcinoma.

Pathology

Synovial biopsies characteristically show haemosiderin deposition in type B synovial lining cells.

Synovial fluid

Synovial fluid is mildly inflammatory and calcium pyrophosphate crystals may be present.

Patient advice

  • Family members should be screened as early initiation of regular phlebotomy can prevent development of systemic disease.

  • Alcohol and excess vitamin C should be avoided as this can increase iron absorption.

Figure 18.2 Haemochromatosis, showing osteoarthritis MCPs joints.

Figure 18.2
Haemochromatosis, showing osteoarthritis MCPs joints.

Treatment

  • Therapy is directed to removing excess iron by venesection. Initially this is weekly until transferrin saturation is normal with a ferritin 20–50 g/l. Maintenance phlebotomy is thereafter required to maintain normal transferrin saturation.

  • Venesection does not appear to have a significant impact on progression of the arthropathy. Treatment is otherwise symptomatic with analgesics, NSAIDs, and exercises.

  • Liver function improves with venesection, as does the cardiomyopathy.

Resources

Patient organization

The haemochromatosis society UK.

www.haemochromatosis.org.uk

Other

OMIM:

www.ncbi.nlm.nih.gov/entrez/

OMIM 235200

ICD-10

E83.1 Disorders of iron metabolism

References

Adams PC, Barton JC. Haemochromatosis. Lancet 2007; 370: 1855–60.

Bacon BR, Olynk JK, Brunt EM et al. HFE genotype in patients with haemochromatosis and other liver disease. Ann Intern Med 1999; 130: 953–62.

Puechal X. Genetic haemochromatosis: why is discovery of the HLA-H gene of such interest to rheumatologists. Rev Rhumatisme 1997; 64: 527–9. [in English.]

Schumacher HR. Haemochromatosis and arthritis. Arthritis Rheum 1994; 7: 41–50.

See also

Osteoarthritis

Calcium pyrophosphate deposition disease

Haemoglobinopathies

Haemoglobinopathies result from inherited defects in the structure and function of haemoglobin. Sickle cell disease is the most common haemoglobinopathy causing an arthropathy.

Epidemiology

  • Sickle cell disease occurs in people from Africa, Southern Italy, Northern Greece, Southern Turkey, Saudi Arabia, and Central and Southern India.

  • Painful crisis are more common men than women. In men they occur most frequently between ages 15 and 25 years, in women the frequency is constant between ages 15 and 40 years.

Aetiology

Sickle cell haemoglobin (HbS) occurs when there is a single nucleotide substitution in the β-globin gene, at position B6, valine is substituted for glutamic acid. The β-globin gene is located at 11p15.5. In hypoxic conditions HbS forms liquid crystals that deform the erythrocytes into rigid sickle shaped cells. This leads to vaso-occlusion. This also occurs in the other sickle syndromes.

Genetics

Sickle cell disease is an autosomal recessive condition, due to inheritance of the HbS gene from both parents (i.e. homozygous). The heterozygous state sickle cell trait is not associated with rheumatic disease. Other sickle cell syndromes occur when HbS is combined with other abnormal Hb genes, e.g. sickle cell HbC disease (HbS from one parent and HbC from the other), or HbS with β-thalassaemia (S-β+-thalassaemia.)

Clinical features

Key features on history

Painful crisis

  • A history of sickle cell disease is usually available but should be sort in a patient presenting with painful veno-occlusive disease, dactylitis, or osteonecrosis from an appropriate ethnic background.

  • Painful crisis is the typical feature of sickle cell disease. One or more joints may become inflamed. The may spread either in an additive manner or be migratory.

  • Pain occurs most frequently in the juxta-articular regions of long bones, but also occurs the back, ribs, and rarely the abdomen. Acute back pain may be the only feature.

  • Duration of the crisis is from a few minutes to several weeks, but persistence beyond 2 weeks is unusual in uncomplicated crisis.

There are four distinct phases to the crisis:

  • Prodromal: the patient is restless and vaguely unwell.

  • Initial: jaundice and increasing pain.

  • Established: pain reaches it maximum.

  • Resolution: pain gradually decreases and resolves over 2 weeks.

Precipitating factors include:

  • Cold

  • Pregnancy

  • Emotional stress

  • High altitude travelling

Dactylitis

  • In children aged 6 months to 2 years vaso-occlusive crisis occur in bones of hand and feet leading to dactylitis.

  • Symptoms improve over 1 week but may recur.

Osteonecrosis

  • Occurs in up to 20% of patients at the femoral head. Initially may be indistinguishable from an acute crisis, but the pain does not settle after 2 weeks. Pain gets worse on walking and at night.

  • Osteonecrosis can occur at other joints particularly the shoulder, where there is pain and loss of range of movement.

Osteomyelitis

  • Usually follows an episode of painful crisis and should be considered if the crisis lasts more than 2 weeks.

  • Multiple sites may be involved, which can be symmetrical.

Septic arthritis

  • Uncommon in sickle cell disease, occurs in the presence of acute osteomyelitis, but more often as a result of haematogenous spread.

  • Acute increase in pain in patients with known osteonecrosis of the hip should be assessed for septic arthritis.

Key features on examination

Painful crisis

  • There may be marked localized joint swelling.

  • Patients develop jaundice.

Dactylitis

  • Acute painful non-pitting swelling of hands and feet.

  • Shortening of digits due to necrosis of the epiphysis is a consequence of previous dactylitis.

Osteonecrosis

  • Osteonecrosis is a late feature.

  • Pain and marked loss of range of movement, especially at the hip and shoulder.

Osteomyelitis and septic arthritis

  • Soft tissue swelling and persistent pyrexia.

General investigations

  • Initial screening for the diagnosis is a sickle cell test, which should be performed in unexplained bone pain or osteonecrosis. If positive it should be followed with haemoglobin electrophoresis.

  • In each painful crisis haemoglobin and reticulocyte count should be determined to exclude an aplastic crisis.

  • A raised ESR and leucocytosis suggest infection. In uncomplicated SS, the ESR is normal, but rises during the resolving phase of the crisis and to a much higher level in infection. The CRP is a more sensitive measure of the inflammatory response.

  • Hyperuricaemia is common (40%), but acute gout is rare.

  • Blood cultures and joint aspiration should be performed when sepsis is suspected. Sickle cell patients are particularly prone to infections with Haemophilus influenzae, Streptococcus pneumoniae and Salmonella.

Imaging

Plain radiographs

  • Plain radiographs are not useful in the early stages of osteomyelitis.

  • Osteonecrosis can be assessed using the Steinberg classification system, but early in the process the X-ray is normal and MRI is more useful.

MRI

  • MRI shows abnormalities due to osteonecrosis much earlier than X-ray and should be used. The overall sensitivity is reported to be 91%.

  • Gadolinium-enhanced MRI demonstrates osteomyelitis with irregular marrow enhancement. Acute infarcts appear as thin linear enhancement.

Ultrasound

A finding of >4 mm of subperiosteal fluid is suggestive of osteomyelitis.

Differential diagnosis

  • Infection of bone or joint should always be considered. Rarely a chronic destructive synovitis occurs, which needs to be differentiated from rheumatoid disease.

  • Rheumatic fever is common in the same regions as sickle cell disease and the migratory arthritis of rheumatic fever must be differentiated.

  • The ANA is often positive, but SLE occurs no more frequently in these patient.

Pathology

  • The occlusion of small blood vessels in the bone marrow leads to many of the complication of sickle disease, such as painful crisis, dactylitis, and osteonecrosis. Polymerization of HbS in a deoxygenated state leads to increased rigidity of red cells and vaso occlusion. This leads to hypoxia and tissue damage.

  • Salmonella infection especially osteomyelitis is common in sickle cell disease. The reason is unclear, but may relate to reticuloendothelial failure, iron overload, and defects in the alternate complement pathway.

Synovial fluid

Synovial fluid is non-inflammatory, straw coloured and sterile in uncomplicated arthritis.

Patient advice

  • Family members should be screened for the presence of abnormal haemoglobins.

  • Advice about avoidance of sickle crisis.

Treatment

  • Appropriate analgesia including is necessary. In severe crisis opiates may be needed.

  • Rehydration is essential and may be intravenous.

  • Intravenous antibiotics should be started if infection is suspected.

  • Osteonecrosis of the femoral head should be treated with rest and avoidance of weight bearing. Decompression should be considered in early osteonecrosis.

Figure 18.3 Avascular necrosis of the hip in a patient with sickle cell disease.

Figure 18.3
Avascular necrosis of the hip in a patient with sickle cell disease.

Resources

Patient organizations

Sickle Cell Association of America. Available at: www. sicklecelldisease.org

Others

OMIM: www.ncbi.nlm.nih.gov/entrez/

OMIM 603903 (sickle cell disease)

ICD-10 coding

D57Sickle cell disease

References

Cordner S,De Ceular K. Musculoskeletal manifestations of haemoglobinopathies. Curr Opin Rheumatol 2003;

See also

Osteoarthritis

Calcium pyrophosphate deposition disease

Osteonecrosis

Osteomyelitis

Septic arthritis

Haemophilia

Definition

Deficiency of factor VIII (Haemophilia A) or factor IX (Haemophilia B or Christmas disease) is due to X-linked inherited defects in the blood coagulation cascade resulting in recurrent musculoskeletal haemorrhage.

Epidemiology

  • Factor VIII deficiency has an incidence of 1:5000 male births and Factor IX deficiency an incidence of 1:30 000 male births.

  • There are no ethnic or geographical variations, and no HLA associations.

Aetiology

  • Haemophilia is inherited as a sex-linked recessive trait. Thus, males only are affected and females are carriers.

  • The factor VIII gene is located on the long arm of the X chromosome at Xq28. It is 168kb long and has 26 exons. Factor VIII is a plasma glycoprotein which circulates in a non-covalent association with von Willebrand factor. A variety of mutations have been described, the most common of which is a translocation in intron 22 which causes 40–50% of cases.

  • The factor IX gene is located on the long arm of the X chromosome at Xq27. It is 34kb long and has eight exons. Missense and nonsense mutations account for 80% of mutations. There is no common mutation.

  • Deficiencies of other clotting factors are very rare, as is the acquired form of factor VIII deficiency.

  • The severity of the bleeding disorder depends on the levels of plasma coagulation factors that, in turn, reflect the precise mutation.

  • Iron deposition appears to be important in the development of synovitis. Ferritin-induced production of superoxide anions and OH radicals causes damage to both cartilage and synovium, which leads to fibrosis of the joint.

Clinical features

Key features on history

General

Try to establish the nature and severity of the bleeding disorder. Does the patient receive factor VIII injections and which haemophilia centre does the patient attend.

Acute haemarthrosis

The diagnosis of haemophilia is usually well established before the first musculoskeletal bleeding episode.

  • Age of onset depends on the severity of the bleeding disorder.

  • Weight-bearing joints on the dominant side are most commonly affected and the child's ability to walk is affected. Knee, elbow, and ankle are the most commonly affected joints.

  • Intra-articular bleeding can occur spontaneously in severe disease and after minor trauma in moderate disease.

  • Intra-articular haemorrhage presents with initial joint stiffness followed by acute pain, warmth, and swelling. Rising intra-articular pressure eventual stops the bleeding.

  • Milder bleeding episodes are less dramatic, and may be restricted to the subsynovium or be unrecognized by the patient.

  • Muscle haemorrhage is acutely painful and may be crippling.

Subacute arthropathy

Follows recurrent haemorrhage into one or more joints, there is pain without evidence of acute haemorrhage.

Key features on examination

Acute haemarthrosis

  • The joint is swollen, hot, and very tender.

  • Bruising appears as the swelling subsides.

Subacute arthropathy

  • Examination reveals a ‘boggy synovitis’, with synovial thickening and chronic effusion.

  • Peri-articular muscles are weak and the joint ligaments lax.

Chronic arthropathy

  • The affected joint is disorganized. There is bony thickening, deformity, loss of range of movement, and crepitus.

  • Joint contractures are present due to fibrosis or ankylosis.

  • Soft tissue swelling and effusions are uncommon at this stage.

Haemophiliac pseudotumour

Destructive lesion occurring in bones associated with fracture, local infection and ulceration. Due to recurrent haemorrhage into the subperiosteal region, which then becomes encapsulated and subsequently enlarges.

General investigations

  • Coagulation screen including bleeding time, platelet count, prothrombin time, partial thromboplastin time, factor VIII and factor XI levels will confirm the diagnosis.

  • The acute phase response is normal. RF and ANA are negative.

  • The joint should be aspirated and the synovial fluid cultured, if there is doubt about the diagnosis.

Imaging

X-rays

Plain radiographic appearances depend on the stage of disease.

Early disease

  • Periarticular soft tissue swelling.

  • Periarticular demineralization.

  • Increased radiodensity of synovium.

Intermediate

  • Growth arrest lines (Harris lines).

  • Widening or premature fusion of the epiphysis.

  • Widening of the femoral or humeral intercondylar notches.

  • Squaring of the inferior border of the patella.

  • Proximal radial head enlargement.

  • Increased talotibial slant and flattening of talus.

Late

  • Irregularity of cartilage with narrowing.

  • Central and marginal erosions.

  • Subarticular sclerosis, bone cysts, osteophyte formation.

  • Joint disorganization.

  • Bony ankylosis.

Ultrasound

  • Useful to demonstrate degree of synovial hypertrophy.

  • Assess soft lesions, such as muscle haematoma.

MRI

  • Demonstrates blood in the joint cavity and subsynovium.

  • Detect changes in hyaline cartilage before changes become apparent using plain radiography.

  • Assess degree synovial hypertrophy.

Synovial fluid

The synovial fluid is characteristically bloody, the first sample being heavily blood stained.

Differential diagnosis

  • Acute arthropathy is usually readily recognized in previously diagnosed patients. The main differential diagnosis of the single hot joint is infection, which should be excluded by synovial fluid culture.

  • Rarely musculoskeletal haemorrhage is the presenting event. The differential of haemarthrosis then includes trauma (intra-articular fracture), bleeding disorder (platelet deficiency, anti-coagulant therapy, acquired factor VIII deficiency), blood dyscrasia, villonodular synovitis, joint neoplasms

  • Von Willebrand disease (deficiency or dysfunction of the adhesive glycoprotein von Willebrand factor), although more common does not present with acute haemarthrosis.

Pathology

Haemophiliac synovitis is characterized by synovial hypertrophy, monocyte infiltration, deposition of haemosiderin in the synovium, and subsynovium, and new vessel formation.

Patient advice

  • Genetic counselling. X-linked recessive condition, which runs true in families. 80% of mothers of an isolated patient are expected to be haemophilia carriers.

  • Rare condition resulting in bleeding disorder and arthropathy.

  • Avoidance of trauma both accidental and surgical.

  • Avoidance aspirin and other drugs affecting platelet function.

  • Avoidance of intramuscular injection.

Treatment

Management is best performed in specialist haemophilia centre with an appropriate multi disciplinary team.

Acute arthropathy

  • Immediate factor replacement is required and may already been started by the patient at home.

  • Prompt treatment of haemarthrosis is essential, aspiration is only needed when the diagnosis is unclear, the joint very distended or where infection needs to be excluded.

  • The joint should be iced, elevated, rested, and appropriate analgesics used. Graduated physiotherapy, local ultrasound, isometric exercises are required to mobilize the patient.

Subacute arthropathy

  • The development of the characteristic boggy synovitis indicates potential destructive disease.

  • Acute rapid treatment of bleeding is required. The use of early prophylactic therapy with factor replacement before joint damage occurs successfully prevents development of subacute arthropathy.

  • Physiotherapy to maintain muscle strength and prevent contracture development is necessary.

  • Intra-articular or oral corticosteroids only produce a short-term benefit.

Chronic arthropathy

May not be completely preventable even with modern treatment and prophylactic regimen. Joint arthroplasty (elbow, knee) should be considered, but is technically difficult. Ankle arthroplasty is less successful and consideration is still given to arthrodesis.

Resources

Patient organizations

Haemophila Society (UK): www.haemophilia.org.uk

Others

OMIM: www.ncbi.nlm.nih.gov/entrez/

OMIM: haemophilia A 306700

OMIM: haemophilia B 306900

ICD-10 coding

D66Hereditary factor VIII deficiency

D67Hereditary factor IX deficiency

References

Bolton-Maggs PHB, Pasi KJ. Haemophilias A and B. Lancet 2003; 361: 1801–9.

Resnick D. Bleeding disorders. In: Resnick D. Diagnosis of Bone and Joint Disorders, 4th edn. Saunders, 2002; 2346–73.

Sarcoidosis

Sarcoidosis is a multisystem granulomatous disease of unknown cause.

Definition

Sarcoidosis is a multisystem disease of unknown aetiology characterized by the formation of non-caseating granulomata in affected organs.

Epidemiology

  • In the USA the incidence is 10.9/100 000 in Caucasians and 35.5/100 000 in Afro-Americans. The incidence in Scandinavia is 15–20/100 000.

  • Females are affected more frequently.

  • Onset is typically aged <40 years.

  • There is seasonal clustering of acute sarcoidosis in the spring.

Aetiology

  • The aetiology is unknown. However, three factors seem to be important. Exposure to a triggering antigen, acquired cellular immunity to the antigen, and development of effector cells that promote a non-specific inflammatory response.

  • Inflammatory alveolitis precedes granuloma formation and is composed of CD4+ T-cells and mononuclear phagocytes. Accumulation and activation antigen-specific Th1 lymphocytes is critical to granuloma formation. The mechanisms of granuloma resolution are not well understood.

  • Acute sarcoidosis in is associated with HLA B8, DR3. HLA-DR3. No consistent non-HLA associations have been established.

Clinical features

Acute sarcoidosis occurs typically as Löfgren's syndrome: a triad of constitutional illness, polyarthritis and erythema nodosum

Key features on history

Systemic

Fever and malaise are common.

Musculoskeletal

Typically begins in the ankles and may spread to knees, wrists, elbows, PIPs, and MCPs. Occurs in 70%. Monarthritis is uncommon. The axial skeleton and sacroiliac joints are spared.

Cutaneous

Erythema nodosum occurs in up to two-thirds of patients with acute sarcoidosis.

Key features on examination

Musculoskeletal

The ankle joints are typically warm, red, and very tender.

Cutaneous

Raised warm tender nodules (erythema nodosum) are typically present over the calves, but may occur on the forearms.

Chronic sarcoidosis

This is uncommon and most cases occur in Afro-Carribean patients.

Key features on history

Musculoskeletal

  • Chronic oligo- or polyarticular arthropathy occurs late in the disease, and is associated with interstitial lung disease and other organ involvement.

  • Dactylitis: diffuse swelling of a digit that may be tender.

Key features on examination

Musculoskeletal

  • Oligo or poly articular involvement knees, ankles, wrists, and small joints of the hands and feet. Joint destruction is rare.

  • Dactylitis with soft tissue swelling over digits, and tenderness and stiffness of neighbouring joints is common.

Muscle disease

  • Asymptomatic skeletal muscle involvement is common and a random muscle biopsy may confirm the diagnosis.

  • Acute sarcoid myopathy is rare and indistinguishable from acute polymyositis, with development of acute proximal myopathy, raised CK, and myopathic changes on EMG.

  • Chronic sarcoid myopathy presents with bilateral symmetrical proximal muscle wasting and weakness. The CK is usually normal.

Osseous sarcoidosis

Bone lesions occur in up to 5% of patients, usually in those with chronic cutaneous or internal organ involvement.

Pulmonary

Pulmonary fibrosis is present in 25%.

Cutaneous

  • Skin involvement is common (25–35%). Macules, papules, and plaques may arise as single or isolated lesions.

  • Lupus pernio: violaceous lesions on nose, cheeks, lips and ears.

General investigations

Investigation is directed at establishing the diagnosis, and assessing the extent and severity of organ involvement.

  • FBC: anaemia of chronic disease.

  • Acute phase response (ESR and CRP).

  • Liver function: ALP may be raised in one-third of patients.

  • Bone biochemistry: activated in macrophages in the granulomata increase hydroxylation of 25-hydroxyvitamin D to 3 to 1,25 hydroxyvitamin D3 and this leads to hypercalcaemia in 10% and hypercalcuria in 40%. Plasma 1,25 hydroxyvitamin D3 levels are raised.

  • ACE: angiotensin-converting enzyme (ACE) is produced by epithelioid cells of the granulomata and activated alveolar macrophages. Elevated ACE levels are seen in 40–90% of cases. Elevated ACE levels are seen in other granulomatous diseases and in some non-granulomatous diseases such as Gaucher's disease, thyrotoxicosis, liver cirrhosis and diabetes mellitus.

Radiological investigations

  • Chest X-ray: this is abnormal in 95% of cases. In acute disease this may show bilateral hilar lymphadenopathy. There may evidence of interstitial lung disease, which will need assessment with high resolution CT.

  • Osseous sarcoidosis cysts, lytic lesions with periosteal reaction, reticular lace-like changes, sclerosis, and destructive changes.

Nuclear medicine

  • Gallium-67 citrate scintigraphy reveals increased uptake by sarcoid granulomata typically in the parotid and lachrymal glands (Panda sign). Uptake is non-specific and occurs in lymphoma, TB, and fungal infection.

  • 18F-FDG-PET may be useful in assessing extent organ involvement and identifying potential biopsy sites.

Bronchoscopy and bronchiolar alveolar lavage

  • The lavaged fluid typically shows a 30–50% lymphocytosis with a CD4/CD8 T-cell ratio >3.5.

  • Pulmonary function testing. This shows restrictive pattern with reduction in vital capacity, residual volume, and total lung capacity. 65% of patients have airflow limitation at presentation.

Biopsy of an affected organ should be obtained where possible to confirm diagnosis and, in particular, to exclude infection or malignant disease.

Kveim test: the reagent is no longer available.

Differential diagnosis

  • This is from other types of acute inflammatory arthritis, including reactive arthritis, rheumatoid disease, and occasionally gout.

  • Chronic sarcoid arthritis may resemble RA, but is generally milder. Monarticular disease must be differentiated from infection.

  • Upper airways disease needs to be distinguished from Wegener's granulomatosis, keratoconjunctivitis, and parotid involvement from Sjögren's syndrome. The uveitis needs to be distinguished from spondyloarthropathy and Behçet's syndrome

  • Erythema nodosum has many causes. Other granulomatous diseases, such as Mycobacterial infection, fungal infection, berylliosis, and local reactions to tumours or lymphoma. Appropriate serological investigations, biopsies and cultures may be required in regions where Mycobacterial/fungal diseases are common.

Disease assessment

  • Severity of involvement of target organs should be carefully assessed

  • Slit lamp examination is required to assess asymptomatic eye involvement.

Prognosis

  • Acute sarcoidosis (including Löfgren's syndrome) has an excellent prognosis with a 90% remission rate. The arthritis lasts from 2 weeks to 4 months. In a Spanish series 8% had active disease at 2 years and 6% relapsed (Mana et al., 1999).

  • Overall, 60% of cases remit spontaneously with 10-20% responding to corticosteroids. In 10–30% there is a chronic course, of these 50% have progressive pulmonary disease.

Pathology

The sarcoid granuloma is well circumscribed; round or oval, non-caseating, and made up of compact radially arranged epithelioid cells. The giant cells are Langerhans type. The centre of the granuloma is composed of CD4+ Th1 T cells and macrophage derived cells.

Patient advice

  • Acute disease: self-limiting process most likely to be a reaction to infection and typically no treatment is required.

  • Chronic disease: life-long condition requiring treatment with corticosteroids.

Treatment

  • Acute sarcoid arthritis: most patients respond well to NSAIDs. Occasional patients with severe arthropathy require a short course of corticosteroids (prednisolone 15–40 mg/day).

  • Chronic sarcoid arthritis: many patients simply require NSAIDs. Those with major organ involvement need corticosteroids.

  • Cutaneous sarcoidosis may respond to hydroxychloroquin. Low dose once weekly oral methotrexate may permit reduction in prednisolone dosage.

  • The role of other immunosuppressive agents and TNF-alpha blockade is unknown, although positive isolated case reports support their use.

Resources

Patient organizations

American lung association: www.lungusa.org

Foundation for sarcoidosis research: www.stopsarcoidosis.org

ICD-10 coding

D86Sarcoidosis

References

ManaJ, Gomez-Vaquero C, Montero A et al. Löfgren's syndrome revisited: a study of 186 patients. Am J Med 1999; 107: 240-5.

Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357:2153-65.

Panniculitis

Panniculitis is inflammation of adipose tissue most typically within subcutaneous fat. Erythema nodosum (EN) is the most common variety.

Classification

Panniculitis can be divided into four categories based on the histopathological appearance.

Table 18.4 Causes of erythema nodosum

Systemic

Sarcoidosis

Pregnancy

Inflammatory bowel disease

Connective tissue diseases

Malignancy

Sweet's syndrome

Behçet's disease

Infections

Streptococcal pharyngitis

Mycobacterial

Coccidioidomycosis

Blastomycosis

Histoplasmosis

Psittacosis

Yersinosis

Salmonellosis

Cat scratch fever

Leprosy

Drugs

Antibiotics – penicillin, sulphonamides

Oral contraceptive pill

Epidemiology

  • The panniculitides can occur at any age, but most typically in young adults.

  • They occur more commonly in women.

  • EN has an annual incidence of 2–3/100 000; other types of panniculitis are much rarer.

  • EN is associated with HLA-B8.

Erythema nodosum

Key features on history

EN is usually acute and self-limited, and heals without scar formation.

  • Acute development of one or more tender red nodules on the anterior shins.

  • Prodromal fever, malaise, arthralgias.

Key features on examination

  • Tender red palpable nodules over the anterior shins.

  • Older lesions appear bruised, ulceration is rare.

Aetiopathogenesis of EN

  • Up to 50% of cases of EN have an underlying cause, with sarcoidosis and infection being the most common.

  • Löfgren's syndrome is a triad of EN, acute arthropathy, and bilateral hilar lymphadenopathy.

Table 18.3 Classification of the panniculitides

Septal panniculitis

Erythema nodosum

Vilanova's disease

Lobular panniculitis

Weber-Christian disease

Rothmann–Makai syndrome

Subcutaneous fat necrosis of the newborn

Post-steroid

Calcifying

Enzymatic

Pancreatic

Alpha1-antitrypsin deficiency

Physical or factitious

Histiocytic cytophagic syndromes

Lipodystrophy syndromes

Connective tissue associated

Lipodermalosclerosis

Mixed panniculitis

Lupus profundus

Behçet's erythema nodosum

Panniculitis/vasculitis

Leucocytoclastic vasculitis

Polyarteritis nodosa

Erythema induratum

From Callen (2004)

Weber–Christian disease

Key features on history

Fever

  • Recurrent tender nodules that can occur anywhere.

  • Arthralgias, myalgias.

  • Abdominal pain due to mesenteric panniculitis.

Key features on examination

Recurrent multiple subcutaneous nodules, these result in fat destruction and scar formation.

Investigation

Biopsy reveals lobular panniculitis with fat degeneration, foamy histiocytes, and giant cell formation.

Pancreatic panniculitis

Patients with a wide variety of pancreatic conditions may develop a lobular panniculitis.

Key features on examination

  • Subcutaneous fat necrosis.

  • There may be an accompanying polyarthritis with osseous intramedullary fat necrosis.

Lupus profundus

Key features on history

  • Panniculitis is a rare complication of SLE occurring in 1–3% of patients with SLE.

  • Activity of panniculitis appears not to mirror activity of SLE.

Key features on examination

  • The lesions are tender red-blue subcutaneous nodules, which may ulcerate.

  • Typically they occur on face, upper arms thighs, and buttocks.

Alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin is associated with panniculitis. Histologically, the appearances are a lobular, septal, or a mixed panniculitis.

Post-steroid panniculitis

Panniculitis may follow steroid therapy especially in children. It may recur with reuse of corticosteroids. The pathogenesis is not known.

Histiocytic cytophagic panniculitis

This is a chronic histiocytic disease of subcutaneous fat, accompanied with panniculitis, fever, serositis, and lymph adenopathy. The haemophagocytic syndrome may occur. Prednisolone and immunosuppression may be useful.

Lipoatrophic panniculitis

Rothmann–Makai syndrome (lipogranulomatosis subcutanea) is a form of subcutaneous lipoatrophy that occurs after an inflammatory disease in children. There are multiple erythematous lesions on the extremities which heal with subcutaneous atrophy. Fever may be present. Treatment is uncertain.

Investigation

Histologically, there is evidence of both septal and lobular panniculitis.

General investigations

  • Infection screen, especially looking for evidence of upper respiratory tract infection, throat swab, and ASO titre.

  • Chest radiograph looking for infection (especially Mycobacterial) or bilateral hilar lymphadenopathy suggestive of acute sarcoidosis.

  • Appropriate serological investigations, biopsy, and cultures may be required in areas where Mycobacterial and fungal infections are common.

  • Investigation for inflammatory bowel disease is unnecessary in asymptomatic patients, as this usually symptomatic when accompanied by panniculitis.

  • Autoantibody serology if there is evidence of a connective tissue disorder

  • Amylase and lipase should be measured in patients possibly with pancreatic disease.

  • Biopsy if the diagnosis is in doubt. A deep wedge biopsy including subcutaneous fat is necessary

Figure 18.4 MRI Sagittal T1-weighted showing multiple low signal areas indicating osteonecrosis and marrow oedema. In a patients with metastatic pancreatic fat necrosis.

Figure 18.4
MRI Sagittal T1-weighted showing multiple low signal areas indicating osteonecrosis and marrow oedema. In a patients with metastatic pancreatic fat necrosis.

Differential diagnosis

The differential diagnosis of EN includes other forms of panniculitis, insect bites (history and evidence of a puncture wound), thrombophlebitis, and cellulitis.

Treatment

  • EN is usually self-limiting, NSAIDs may be needed for arthralgias/myalgias.

  • Chronic relapsing forms of panniculitis may respond to corticosteroids or other immunosuppressive drugs.

References

Callen JP. Panniculitis. In: Isenberg DA, Maddison PJ, Woo P, Glass D, Breedveld FC (eds) Oxford Textbook of Rheumatology, 3rd edn. Oxford: 2004: 1031–35.

See also

Sarcoidosis

SLE

Alkaptonuria

Definition

A rare autosomal recessive condition resulting from lack of homogentisic acid oxidase, and the accumulation of homogentisic acid causing ochronosis and ochronotic arthropathy. Ochronosis is the characteristic black pigmentation seen in alkpatonuric patients.

Alkaptonuria was the first human condition in which the pattern of Mendelian inheritance was recognized by Garrod in 1902. Garrod in 1908 hypothesized that a specific enzyme was lacking.

Epidemiology

  • The highest frequency occurs in Slovakia (1/19 000).

  • The overall frequency is 1/250 000 – 1/million live births.

Aetiology

  • Alkaptonuria is due to lack of the enzyme homogentisic acid oxidase (HGO). The gene for this enzyme is located on 3q21–23. A variety of different mutations have been described including nonsense, missense and frame shift mutations. There does not appear to be any correlation between the HGO mutation and severity of disease. Homogentisic acid oxidase catalyses the oxidative cleavage of the ring of homogentisic acid into maleylacetoacetic acid. Homogentisic acid then accumulates slowly in the tissues, resulting in the characterstic black pigmentation. The renal clearance of homogentisic acid is high suggesting active renal tubular excretion.

  • Inheritance as an autosomal recessive condition.

  • The exact mechanism by which pigment deposition results in arthropathy is not known.

Clinical features

Key features on history

  • In infancy, the first feature may be the mother noticing a dark discolouration of the nappies.

  • In adults there is often a history of dark urine (in half of patients this is the presenting feature) or urine that darkens on standing.

Musculoskeletal

  • Joint pain often starts before the age of 30 years. Initially, this is spinal and then a peripheral arthritis develops.

  • Episodic joint inflammation occurs later.

Cutaneous

  • Pigmentation of the sclera and ear is rarely seen before 20–30 years of age.

  • Adult alkpatonuric patients may have dark urine or urine that darkens on standing.

Key features on examination

Musculoskeletal

  • Marked spinal stiffness at all levels with kyphosis.

  • Large joint osteoarthritis is common, particularly knee, hip, and shoulder.

  • Small joint involvement is unusual.

  • They may be a joint effusion.

Cutaneous

  • Ochronotic pigmentation in the eye is visible at the insertion of the rectus muscles, and may spread to the conjunctiva and sclerae.

  • Pigmentation of the auricular cartilage appears as a slate-blue or grey colour in the concha, antihelix, and tragus.

General investigations

  • The acute phase response is normal. RF and ANA are negative. HLA-B27 is generally negative.

  • A sample of urine should be left to stand. It will darken if it contains excessive amounts of homogentisic acid.

  • Homogentisic acid levels in plasma and urine may be determined by high-performance liquid chromatography.

Imaging

X-rays

On plain radiography of the lumbar spine the characteristic findings are:

  • Wafer like calcification of intervertebral discs.

  • Narrowing of disc spaces.

  • Ossification of the of the ligaments.

In peripheral joints the appearances of osteoarthritis develop about 10 years after the spinal changes. Multiple intra-articular radio-opaque loose bodies may be seen in the knees.

Synovial fluid

Effusions occur in around 50% of patients. The synovial fluid is characteristically non-inflammatory, containing mainly mononuclear cells (100–700 cells/mm3). Pyrophosphate and apatite crystals have been found in alkaptonuric patients.

Figure 18.5 Lumbar disc calcification in a patient with longstanding ochronosis.

Figure 18.5
Lumbar disc calcification in a patient with longstanding ochronosis.

Differential diagnosis

  • The main differential diagnosis is from osteoarthritis, ankylosing spondylitis, and calcium pyrophosphate deposition disease.

  • Ankylosing spondylitis can be distinguished from ochronosis by the presence of syndesmophytes, erosion, and fusion of the sacroiliac joints.

  • Osteophytosis on X-ray is not present in ochronosis, but is a typical feature of osteoarthritis. Ochronosis affects shoulders and sacroiliac joint, which are less frequently involved in osteoarthritis.

Pathology

Biopsies show ochronotic pigment in the cartilage. This is located within collagen bundles causing loss of striation, swelling, and fracture.

Patient advice

  • Genetic counselling about mode of inheritance. Screening of first degree relatives.

  • Rare inherited condition resulting in arthropathy.

Treatment

  • There is no treatment for the underlying enzymatic defect. Vitamin C has been used, but is not effective. Nitisinone has been used on an experimental basis and reduces urinary HGA levels. The long-term effect on joint function is unknown.

  • Analgesics, NSAIDs, physiotherapy as required.

  • Joint replacement may be required in severe cases.

  • Lumbar spinal stenosis may require surgical decompression.

Resources

Patient organizations

The Alkaptonuria society. www.alkaptonuria.info

Others

OMIM: www.ncbi.nlm.nih.gov/entrez/

OMIM 203500

ICD-10 coding

E70.2Disorders of tyrosine metabolism

References

Phornphutkul C, Introne W, Perry M, et al. Natural history of alkaptonuria. N Engl J Med 2002; 347: 2111–21.

Suwannarat P, O’Brien K, Perry MB, et al. Use of nitisinone in alkaptonuria. Metabolism 2005; 7: 719–28.

See also

Osteoarthritis

Spondyloarthropathy

Gaucher's disease

Definition

Gaucher's disease results from accumulation of glucosylceramide in organs in the storage Gaucher cells.

Three types of Gaucher's disease are recognized.

Types of Gaucher's disease

Type 1 (non-neuronopathic)

  • Organomegaly.

  • Hypersplenism leading to haematological abnormalities.

  • Bone lesions due to medullary infiltration by Gaucher cells.

  • No CNS involvement.

Type 2 (acute neuronopathic)

  • Early CNS involvement.

  • Fatal by age 2 years.

Type 3 (subacute neuronopathic)

  • Organ involvement.

  • Medullary lesions.

  • CNS involvement, but less severe than in type 2.

Epidemiology

Gaucher's disease is an autosomal recessive condition

Type 1 is the most common and occurs most frequently in Ashkenazi Jew (prevalence 15–40/100 000), but occurs in all ethnic groups (1/100 000). Can occur at any age, but the median age is 30 years.

Type 2 and 3 are much rarer and predominately occur in non-Jewish patients. Type 2 presents age <6months and type 3 age <20 years.

Aetiology

Biochemistry

Gaucher's disease arises from a defect in the gene for glucocerebrosidase, which results in decreased activity. Glucocerebrosidase is 65 kDa membrane associated monomeric protein, which hydrolyses β-glucosidic ester bonds. Decreased activity of the enzyme results in accumulation of glucosylceramide linked by a β-glucosidic bond. Glucosylceramide is the end product of glycosphingolipid catabolism and is normally degraded into ceremide and glucose by glucocerebrosidase.

Molecular genetics

The gene for β-glucocerebrosidase is located at 1q21. The most common mutations are N370S. and L444P. A wide phenotypic difference is seen with some mutations leading to a mild phenotype (e.g. R496H), whilst some lead to loss of catalytic activity and enzyme stability (e.g. L444P).

Clinical features

Type 1

Key features on history

There is a broad spectrum of severity, with onset at any age. Mental development is normal.

Musculoskeletal

  • Episodic arthralgias. Most frequently involving the spine, hips, legs, and shoulders.

  • Fractures may occur to bone fragility.

  • Acute pain, tenderness possibly with fever may occur in osteonecrosis.

Key features on examination

Haematological

Hepatosplenomegaly.

Musculoskeletal

  • Pain and limitation of movement occur in osteonecrosis.

  • Growth retardation.

Type 2

Key features on history

  • Early onset of oculomotor abnormalities.

Key features on examination

Haematological

  • Hepatosplenomegaly

Neurological

  • Bilateral fixed strabismus and oculomotor apraxia are early signs.

  • Hypertonia neck muscles and opisthotonus.

Type 3

Intermediate between types 1 and 3. The neurological features are similar to type 2.

General investigations

  • Investigation is directed at establishing the diagnosis.

  • FBC anaemia, leucopaenia, thrombocytopaenia due to hypersplenism.

  • Cholestatic enzymes may be increased but liver failure is uncommon.

  • Serum ACE, tartrate resistant acid phosphatase is raised.

  • Leucocyte glucocerebrosidase is elevated.

Genetic screening

Patients with typical clinical features should be screened for the common mutations.

Imaging

  • Plain radiographs show typical appearances.

  • Failure of skeletal remodelling leads to development of the ‘Erlenmeyer flask’ deformity with expansion of the contours of long bones, there is cortical thinning and loss of the normal concavity. Vertebral bodies show depression of the superior and inferior endplates ‘H-vertebra’.

  • Bone marrow infiltration results in osteolytic lesions.

  • Osteonecrosis results in joint damage with appearances identical to idiopathic osteonecrosis.

  • MR is the most sensitive method of assessing for assessing bone marrow infiltration by Gaucher cells and can be used to assess response to treatment.

Bone marrow biopsy

The diagnosis is made on the demonstration of Gaucher cells in bone marrow biopsy. The cells are large mono- or multinucleated cells with a typical ‘wrinkled tissue paper’ appearance of the cytoplasm.

Differential diagnosis

The diagnosis is based on clinical manifestations and the radiological appearances. The plain radiographic appearances are not specific for Gaucher's disease. The diagnosis should be considered in a patient with hepatosplenomegaly, osteopaenia, focal osteosclerosis, osteonecrosis, and Erlenmeyer flask deformities.

Prognosis

  • The prognosis is variable dependent on the precise mutation as there is a very broad clinical heterogeneity.

  • The more severe forms have a worse prognosis with progressive hypersplenism, bone pain, skeletal deformity, and fracture. However, enzyme replacement therapy reverses hypersplenism and bone pain, and reduces fractures.

  • Type 2 is fatal before age 2 years.

Patient advice

  • Gaucher's disease is a recessively inherited condition.

  • The prognosis is dependent on the exact gene mutation and is quite good with enzyme replacement therapy.

Treatment

Enzyme replacement with macrophage targeted glucocerebrosidase reverses haematological and hepatosplenomegaly within a few weeks, but the osseous complications take longer to reverse. The optimum treatment regimens for milder type 1 disease is still uncertain.

Resources

Patient organizations

www.gaucher.org.uk

Others

OMIM www.ncbi.nlm.nih.gov/entrez/

Gaucher's disease type 1 OMIM 230800

Gaucher's disease type 2 OMIM 230900

Gaucher's disease type 3 OMIM 231000

ICD-10 code

E55.2Other sphingolipidosis

References

Vom Dahl S, Poll L, Di Rococco M, Ciana G, Denes C, Mariani G, Mass M. Evidence-based recommendations for monitoring bone disease and the response to enzyme replacement therapy in Gaucher patients. Curr Med Res Opin 2006; 22: 1045–64.

Eosinophilia-myalgia syndrome and toxic oil syndrome

Definition

Eosinophilia-myalgia syndrome (EMS), toxic oil syndrome and eosinophilic fasciitis are united by the clinical features of eosinophilia and fasciitis. They should however be considered separate illnesses as toxins have been implicated in the development of EMS and Toxic Oil Syndrome but not eosinophilic fasciitis. The latter condition will be dealt with separately.

First defined in 1989 EMS was an epidemic associated with the ingestion of L-tryptophan preparations from a single Japanese manufacturer (Showa Denko). L-tryptophan, an essential amino acid, has been available over the counter since the 1970s and has been used to treat insomnia, depression and premenstrual symptoms.

Diagnostic criteria

The US Centres for Disease Control and Prevention (CDC) defined the syndrome according to 3 criteria:

  • Eosinophil count greater than 1000/mm3.

  • Incapacitating myalgia.

  • Exclusion of other infectious or neoplastic illness that could account for the other two findings.

Epidemiology

EMS was initially described in 3 patients in New Mexico in October 1989. In excess of 1500 cases were subsequently reported within the US over the following two years.

The syndrome occurred most commonly in Caucasian females over 35 years of age. The daily dose ranged from 10–15 000 mg (median 1500 mg) with the development of symptoms occurring at a median of 127 days after first ingestion of the formulation. It is worth noting, however, that up to 14% of cases of EMS were not related to L-tryptophan. Nevertheless, since the epidemic only a few incident cases have been described.

Toxic oil syndrome was another epidemic occurring in Spain in 1981 which followed the ingestion of adulterated rapeseed cooking oil. The oil had been denatured with 2 percent aniline for industrial use, refined, then sold illegally as pure olive oil.

Aetiology and pathophysiology

Due to the epidemic nature of EMS and its association with a single source of L-tryptophan, a contaminant was highly likely to be the culprit. This was subsequently found to be ethylidene bis[tryptophan] (EBT). Experiments revealed that mice administered L-tryptophan from the batch in question developed myofascial thickening. Further analysis found a second contaminant (phenylamino)alanine to be associated with the condition. This was found to be chemically similar to an aniline derivative implicated in toxic oil syndrome.

Abnormal tryptophan metabolism in patients with both syndromes has been found however this may simply be a consequence of an inflammatory response. Up-regulation of pro-inflammatory cytokines is a feature. In addition, excessive amounts of tryptophan inhibit histamine degradation which leads to eosinophilia and myalgia. The exact pathogenesis of the conditions however remains unknown.

Clinical features

EMS most commonly presented with a flu-like illness with marked myalgia and arthralgia as well as profound weakness and fatigue. By definition all patients suffered from myalgia and eosinophilia.

Toxic oil syndrome usually manifest as an atypical pneumonia with non-productive cough, pleuritic chest pain, headache, fever and pulmonary infiltrates on CXR.

Clinical features common to both conditions were protean and included:

Symptoms and signs

  • Myalgia.

  • Arthralgia.

  • Rash.

  • Peripheral oedema.

  • Cough.

  • Dyspnoea.

  • Fever.

  • Alopecia.

  • Neuropathy (sensory or sensorimotor involvement in a glove and stocking distribution).

  • Hepatomegaly.

Investigations

  • Leucocytosis.

  • Eosinophilia (>500 mm3).

  • Elevated ESR.

  • Elevated aldolase.

  • Abnormal CXR.

  • Abnormal LFTs.

Scleroderma-like skin change was unique to eosinophilia-myalgia syndrome.

General investigations

Relevant investigations to exclude differential diagnoses should be performed (see individual chapters).

Salient investigation for the syndromes include:

  • Eosinophilia (mandatory for EMS, although may be missed if present in early disease only).

  • Leukocytosis.

  • Raised IgE levels (toxic oil syndrome only).

  • ANAs especially in EMS.

  • Normal CK levels in almost all patients.

  • Elevated aldolase.

  • Abnormal LFTs common (transaminitis).

Imaging

  • CXR: normal to acute infiltrates, pleural effusion.

  • Other helpful imaging modalities include: MR brain, PFTs, EMG/NCS.

Histology

Histological analysis of affected tissue reveals:

  • Capillary endothelial cell hyperplasia with swelling and necrosis.

  • Inflammatory cell infiltrate in connective tissue, nerve, and muscle.

  • Fibrosis particularly in the fascia.

Differential diagnosis

  • Churg–Strauss syndrome.

  • Eosinophilic pneumonia.

  • Hypereosinophilic syndrome.

  • Systemic sclerosis.

  • Polymyalgia rheumatica.

  • Trichinosis.

  • Hypothyroidism.

  • Occult malignancy.

Treatment

Avoidance of the offending toxins was critical. Symptomatic relief of the myriad clinical features was required as no drug was found to alter the natural history of the conditions. NSAIDs and corticosteroids were frequently used, especially in early disease. Chronic symptoms have been found to be extremely resistant to treatment.

Physiotherapy and occupational therapy was necessary for musculoskeletal manifestations and functional impairment.

Prognosis

When L-tryptophan was recalled from the market in November 1989, the incidence of EMS plummeted. The mortality rate for the first year was 2.7% for EMS and 1.5–3.6 % for toxic oil syndrome. Death resulted from progressive polyneuropathy and myopathy in the majority of patients with EMS. Both conditions were associated with long-term morbidity most commonly patients complaining of myalgia, muscle cramps, and neuropathy. Only 10% of patients surveyed 4 years after disease onset were symptom free.

Resources

Assessment tools

Not applicable

Guidelines

Not applicable

Patient organizations

The National Eosinophilia-Myalgia Syndrome Network: http://www.nemsn.org/

ICD-10 codes

M35.8Other specified systemic involvement of CTD

References

Kilbourne EM, Philen RM, Kamb ML, Falk H. Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia syndrome. J Rheumatol Suppl. 1996; 46: 81–91.

Posada de la Paz M, Philen RM, Borda AI. Toxic oil syndrome: the perspective after 20 years. Epidemiol Rev 2001; 23: 231–47.

Sullivan EA, Staehling N, Philen RN. Eosinophiliamyalgia syndrome among the non-L-tryptophan users and pre-epidemic cases. J Rheumatol 1996; 23: I784–7.

Tabuenca JM. Toxic-allergic syndrome caused by ingestion of rapeseed oil denatured with aniline. Lancet 1981; 2: 567–8

Varga J, Kähäri VM. Eosinophilia-myalgia syndrome, eosinophilic fasciitis, and related fibrosing disorders. Curr Opin Rheumatol 1997; 9: 562–70.

Metabolic myopathies

Definition

The metabolic myopathies are a diverse group of disorders characterized by abnormalities of skeletal muscle energy production. They arise as a consequence of inherited defects in glycogen, lipid, purine, or mitochondrial metabolism. The term ‘secondary metabolic myopathy’ has been used to describe muscle damage from miscellaneous insults, such as drugs, toxins, and endocrinopathy.

Metabolic myopathies are traditionally managed within a neurology setting; however, it is imperative that rheumatologists are aware of these diseases as they often mimic other conditions, particularly inflammatory myositis. Furthermore, they can be life threatening and are potentially treatable.

Epidemiology

The metabolic myopathies are rare diseases and epidemiological data are limited. McArdle's disease is one of the more common with a prevalence of approximately one per 100 000. Symptoms may develop at any age, but usually appear in childhood or early adult life.

General clinical features

Metabolic myopathies classically present with episodes of reversible muscle dysfunction induced by exercise.

  • Symptoms include muscle cramps, pain, weakness, stiffness, and myoglobinuria.

  • Less commonly, they manifest as persistent, progressive muscle weakness.

  • In rare cases, there may be a mixture of dynamic and permanent muscle symptoms.

  • Children typically present with severe multisystem manifestations, whereas adult-onset disease primarily affects muscles.

Aetiology and pathophysiology

The specific genetic and biochemical abnormalities responsible for many of the metabolic myopathies have been identified. The majority are enzyme defects that lead to a block in muscle adenosine triphosphate (ATP) production. A basic understanding of muscle energy metabolism is fundamental to understanding the pathogenesis of these conditions.

Overview of muscle energy metabolism

Glycogen, glucose and free fatty acids (FFAs) are the main substrates for muscle ATP production.

  • Glycogen is metabolized in the cytoplasm to pyruvate, which then diffuses into mitochondria.

  • Short and medium chain fatty acids cross freely into the mitochondria.

  • Long-chain fatty acids require binding to carnitine for transport across the mitochondrial membrane. This process is mediated by the carnitine palmitoyltransferases I and II.

  • Within the mitochondria, oxidative decarboxylation of pyruvate and B-oxidation of FFAs results in acetyl- co-enzyme A formation, ultimately driving ATP production.

  • Additional sources of ATP include anaerobic glycolysis (pyruvate is converted to lactate) and the purine nucleotide cycle.

The potential for dysfunction

Episodic muscle dysfunction may be the end result of defects anywhere along the pathway. However, the pattern of symptoms may allow prediction of the likely site of the abnormality.

  • FFAs are the principal muscle energy substrate at rest and during prolonged low intensity exertion, e.g. walking. Lipid oxidation defects therefore tend to produce symptoms several hours into moderate exercise or on fasting.

  • Utilization of glycogen is necessary for more strenuous exertion, such as running, or on intense, isometric exercise, e.g. lifting weights. Disorders of glycogen metabolism typically cause symptoms within a few minutes of commencing vigorous exercise.

  • In mitochondrial myopathies, muscle pain and fatigue may be precipitated by normal daily activities.

The mechanisms by which these defects may lead to rhabdomyolysis are not well understood. In addition, the pathological processes underlying progressive muscle weakness are unclear. These patients tend to have more extensive glycogen or lipid deposition within muscle, which could potentially interfere with contraction; however, this is not universally seen.

Disorders of glycogen metabolism

These conditions are commonly termed the ‘glycogen storage disorders’ or ‘glycogenoses’. They result from a variety of enzyme defects leading to derangements in glycogen synthesis, glycogenolysis, or glycolysis.

  • Inheritance is autosomal recessive, with the exception of type VIII (hepatic form) and type IX, which are X-linked recessive traits.

  • The clinical manifestations of these conditions are extremely diverse, ranging from severe multisystem disease in infancy to isolated progressive muscle weakness in the elderly.

  • Amongst the more common of these, myophosphorylase (McArdle's disease) or phosphofructokinase (PFK) deficiencies typically cause episodic muscle symptoms, whereas acid maltase or debranching enzyme deficiencies are more likely to present with a progressive myopathy.

Myophosphorylase deficiency (McArdle's disease)

  • Symptoms often develop in childhood but may not become clinically significant until adolescence

  • Muscle fatigue, weakness and aching pain characteristically emerge during the first few minutes of strenuous exertion

  • Brief rest or intake of carbohydrate when symptoms appear may subsequently improve exercise tolerance, termed the ‘second wind’ phenomenon.

  • Acute, painful muscle contractures are seen. These differ from ordinary cramps in that they solely occur on exercise, may last for hours, pain is exacerbated by stretching the muscle and electrical activity is absent on EMG.

  • Symptoms may culminate in muscle necrosis, myoglobinuria (cola coloured urine) and rarely renal failure.

  • Muscle function usually returns to normal between episodes, although mild permanent weakness may develop in long-standing disease.

Phosphofructokinase deficiency (Tarui's disease)

  • Clinical presentation may be indistinguishable from McArdle's disease.

  • Symptoms are exacerbated, rather than improved by carbohydrate intake.

  • May be a mild haemolytic anaemia (phosphofructokinase is also found in red blood cells).

  • Rarely manifests as progressive myopathy in older adults.

Table 18.5 Glycogenoses

Type

Enzyme defect

Clinical features

II

Acid maltase (α-glucosidase)

Adult form: proximal myopathy with respiratory involvement

III

Debrancher

Hepatomegaly, hypoglycaemia,

progressive myopathy

IV

Brancher

Hepatosplenomegaly, cirrhosis, cardiomyopathy, myopathy

V

Myo- phosphorylase

Exercise intolerance, myoglobinuria

VII

Muscle PFK

Exercise intolerance, myoglobinuria, haemolytic anaemia

VIII

Phosphorylase b kinase

Various types affecting liver, heart Muscle form: exercise intolerance, myoglobinuria

IX

PGA kinase

Seizures, mental impairment

Exercise intolerance, myoglobinuria

X

Muscle PGA mutase

Exercise intolerance, myoglobinuria

XI

Muscle LDH

Exercise intolerance, myoglobinuria

XII

Aldolase A

Haemolytic anaemia, exercise intolerance, myopathy

XIII

ββ-Enolase

Exercise intolerance

*

AMP-activated protein kinase

Cardiomyopathy, Proximal myopathy

PFK, phosphofructokinase; PGA phosphoglycerate; LDH, lactate dehydrogenase; *not yet classified

Acid maltase deficiency (Pompe's disease)

  • Deficiency of lysosomal acid α-glucosidase.

  • Classic infantile form is rapidly fatal.

  • Late onset variant manifests at any age from early childhood onwards; onset as late as 68 has been reported. Prognosis improves with older age onset.

  • Slowly progressive proximal muscle weakness is almost universal and is the presenting symptom in 80%.

  • Propensity for respiratory muscle involvement. About 70% patients die from respiratory failure.

  • May be increased risk of cerebral aneurysm.

Debranching enzyme deficiency

  • May cause progressive myopathy in the 2nd to 3rd decade.

  • Weakness and wasting is often predominantly distal.

  • Respiratory muscles are occasionally involved.

  • A mild sensory axonal polyneuropathy is frequently seen.

Disorders of lipid metabolism

These include:

  • Carnitine deficiency syndromes: muscle or systemic.

  • Fatty acid transport defects: carnitine palmitoyltransferase II deficiency is the most common.

  • Defects of β oxidation enzyme.

Clinical features

Reversible muscle symptoms are classically precipitated by prolonged moderate exertion, e.g. walking, but may also be induced by fasting, cold exposure, infection, or general anaesthesia. Muscle pain is a frequent symptom but cramps are less common than in the glycogenoses and acute, painful contractures, and ‘second wind’ phenomena are not seen.

  • Episodes of hypoketotic hypoglycaemia and coma may result from depletion of glycogen stores on fasting in conjunction with failure of hepatic conversion of fatty acids to ketoacids.

  • Lipid deposition may lead to progressive myopathy, cardiomyopathy and fatty infiltration of the liver.

  • Abnormal tissue and serum carnitine levels.

Carnitine deficiency syndromes

  • Primary muscle carnitine deficiency causes a lipid storage myopathy. It usually presents in early life with progressive, proximal muscle weakness.

  • Systemic carnitine deficiency often presents in infancy. Features include recurrent episodes of hypoketotic hypoglycaemia, encephalopathy, and cardiomyopathy.

  • Muscle carnitine deficiency may also be seen in mitochondrial disorders or may be acquired, notably secondary to haemodialysis or drugs, e.g. valproate.

Fatty acid transport defects [carnitine palmitoyltransferase (CPT) II deficiency]

  • Commonest cause of recurrent rhabdomyolysis and myoglobinuria. The associated risk of acute tubular necrosis is higher than in the glycogenoses.

  • Clinical manifestations are usually evident by the age of 20, but may appear as late as the fifth decade.

  • The Ser113Leu mutation is found in 65% of patients.

  • Episodic muscle pain and stiffness on sustained low intensity exercise or fasting is characteristic.

  • Attacks of rhabdomyolysis may be life threatening due to respiratory failure, renal failure, or cardiac arrhythmias.

  • Muscle function is usually normal between attacks.

Defects of oxidation enzymes

These affect a variety of mitochondrial enzymes, including the short, medium, long, and very long-chain acyl-CoA dehydrogenases (VLCAD), and produce a wide spectrum of clinical phenotypes. VLCAD deficiency presents similarly to CPT II deficiency and may be clinically indistinguishable.

Disorders of purine metabolism

Adenosine monophosphate (myoadenylate) deaminase (AMPD) deficiency

About 1.2–3.7% of the general population are homozygous for AMPD mutations and deficiency of AMPD has been reported in up to 3% of muscle biopsies. However, the clinical significance of this is debatable. It has been suggested that AMPD deficiency may result in exercise intolerance and myalgia in a subset of affected individuals. Conversely, the prevalence of AMPD deficiency does not appear to be increased in patients with muscle symptoms compared with the general population.

Mitochondrial myopathies

These are a diverse group of multisystem diseases resulting from abnormalities of the respiratory chain. Inheritance is either maternal or Mendelian according to whether genetic defects affect mitochondrial or nuclear DNA.

  • Muscle involvement is common but the predominant symptoms are usually extra-muscular, e.g. blindness, deafness, encephalopathy, ophthalmoplegia, and seizures.

  • There are numerous recognized syndromes, such as MERRF (myoclonic epilepsy with ragged red fibres), MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes), and PEO (progressive external ophthalmoplegia).

  • A subset of patients may present with progressive muscle weakness in the absence of overt systemic manifestations, and a detailed family history and thorough evaluation for potential associated features is therefore required.

Investigation of metabolic myopathies

Investigation beyond basic blood and urine tests is generally undertaken in a specialist setting.

Laboratory

General

  • FBC: haemolytic anaemia can occur in some glycogenoses.

  • LFTs, renal profile, bone profile, LDH, urate.

  • Rhabdomyolysis may lead to elevated creatinine, potassium, urate, phosphate, and reduced calcium.

  • Serum myoglobin may be detectable in acute rhabdomyolysis, but is cleared rapidly (within 1–6 h).

Creatine kinase (CK)

  • CK should be tested at rest and during acute attacks of muscle symptoms.

  • Glycogenoses tend to cause a persistently raised CK. Elevation is usually mild to moderate, although CK may be very high in acid maltase deficiency.

  • In lipid oxidation defects, CK is usually normal between episodes of rhabdomyolysis.

Urine myoglobin

  • Dark urine, positive for blood on dipstick, but with no red cells/casts on microscopy may indicate myoglobinuria.

  • Semi-quantitative assay for haem pigments have approximately 80% sensitivity for myoglobin.

  • Crucially, lack of detectable urine myoglobin does not exclude rhabdomyolysis.

Imaging

MR and CT scanning have been utilized in glycogen storage disorders to characterize muscle pathology and are useful to guide muscle biopsy. Nuclear MR spectroscopy provides an assessment of muscle metabolism, and may be useful in detecting glycolytic and mitochondrial defects.

Histology

Muscle biopsy

Diagnosis often rests on specific biochemical testing of muscle tissue for enzyme activity. However, given the large number of potential defects, this should be targeted according to initial clinical evaluation. Microscopy may reveal lipid or glycogen storage vacuoles but equally may be normal. Ragged red fibres suggest mitochondrial myopathy, but are not pathognomonic.

Other

Forearm ischaemic lactate test

  • Involves exercising the forearm with an inflated blood pressure cuff in situ to create anaerobic conditions, and serial blood tests for lactate, pyruvate, CK, and ammonia.

  • This test carries a risk of rhabdomyolysis and a non-ischaemic version has been advocated.

  • Glycogenoses cause absence or blunting of the normal rise in lactate (with the exception of acid maltase, brancher and phosphorylase b kinase deficiencies).

  • Results are normal in disorders of lipid metabolism.

  • Lactate and pyruvate may be elevated in mitochondrial myopathies.

Electromyography (EMG)

  • May show myopathic features in glycogenoses, especially in patients with progressive weakness. Marked insertional irritability may be evident in acid maltase deficiency.

  • Often normal in mitochondrial disorders and between symptomatic episodes in CPT II deficiency.

Further tests

These should be directed by the clinical presentation.

  • Carnitine levels may be abnormal in disorders of lipid metabolism. Serum and urine analysis for fatty acid metabolites is often informative.

  • Enzyme testing in white blood cells or skin fibroblasts may be useful in acid maltase deficiency.

  • Identification of the responsible genetic defect is now possible in many of the metabolic myopathies.

Differential diagnosis of myopathy

Muscle pain, fatigue, and cramps are ubiquitous complaints, and it may be difficult to determine whether an underlying pathological process is likely. However, severe, aching pain on exertion, prolonged cramps, and myoglobinuria are suggestive of metabolic muscle disease. A thorough family history and evaluation for extramuscular features are mandatory. The numerous alternative causes for muscle cramps should also be considered, including:

  • Electrolyte abnormalities: low calcium, magnesium.

  • Peripheral vascular disease.

  • Hypothyroidism, hyperparathyroidism.

  • Drugs/toxins, e.g. diuretics, statins, alcohol.

  • Motor neurone disease: leg cramps are common.

  • Peripheral neuropathy and radiculopathy.

In patients presenting with progressive muscle weakness, the differential is wide and includes the idiopathic inflammatory myopathies, muscular dystrophies, endocrinopathies, and drugs.

Treatment

General management strategies include:

  • Avoidance of activities that precipitate symptoms.

  • Dietary modification: A high protein diet and pyridoxine supplements have been advocated for McArdle's disease; however, a recent Cochrane Review concluded there was insufficient evidence to recommend any specific intervention. A low fat, high carbohydrate diet with supplementary intake before exercise appears useful in CPT II deficiency.

  • Carnitine, riboflavin, and medium chain triglycerides have been trialled in disorders of lipid metabolism with some success.

  • Low dose creatine supplements have been shown to be beneficial in McArdle's disease, although higher doses appeared to be detrimental.

  • Moderate intensity exercise programme have been shown to improve symptoms in mitochondrial disorders and glycogenoses and are likely to be helpful in other metabolic myopathies.

Novel therapeutic strategies include enzyme replacement and gene therapies. Intravenous recombinant acid α-glucosidase has been shown to have beneficial effects in acid maltase deficiency. Progress towards gene therapy has been made using animal models, although it remains to be seen whether this is transferable to humans.

Resources

ICD-10 codes

E74.0 Glycogen storage disease

E75.6 Lipid storage disorder unspecified

G71.3 Mitichondrial myopathy

References

Bonnefont JP, Djouadi F, Prip-Buus C, Gobin S, Munnich A, Bastin J. Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Aspects Med 2004; 25: 495–520.

Darras BT, Friedman NR. Metabolic myopathies: a clinical approach; part I. Pediatr Neurol 2000; 22(2): 87–97.

Dimauro S, Lamperti C. Muscle glycogenoses. Muscle Nerve 2001; 24: 984–99.

DiMauro S. Muscle glycogenoses: an overview. Acta Myol 2007; XXVI: 35–41.

Haller RG. Treatment of McArdle disease. Arch Neurol 2002; 57: 923–4.

Hanisch F, Joshi P, Zierz S. AMP deaminase deficiency in skeletal muscle is unlikely to be of clinical relevance J Neurol 2008;255: 318–22.

Kishnani PS, Corzo D, Nicolino M, et al. Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology. 2007; 68: 99–109.

Niranjanan N, Holton J, Hanna M. Is it really myositis? A consideration of the differential diagnosis. Curr Opin Rheumatol 2004; 16: 684–91

Pierelli PL, Amabile G, Valente G, et al. Muscular cramps: proposals for a new classification. Acta Neurol Scand 2003; 107: 176–86.

Quinlivan R, Beynon RJ, Martinuzzi A. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V). Cochrane Database Syst Rev. 2008; 2:CD003458.

Vorgerd M, Zange J, Kley R, et al. Effect of high-dose creatine therapy on symptoms of exercise intolerance in McArdle disease: double-blind, placebo-controlled crossover study. Arch Neurol 2002; 59: 97–101.

Winkel LP, Van den Hout JM, Kamphoven JH, et al. Enzyme replacement therapy in late-onset Pompe's disease: a three-year follow-up. Ann Neurol. 2004; 55: 495–502.

Wortmann RL. Metabolic and mitochondrial myopathies. Curr Opin Rheumatol 1999; 11(6): 462–7.

See also

Polymyositis ([link])

Dermatomyositis ([link])

Synovial osteochondromatosis

Definition

Synovial osteochondromatosis is a rare condition of synovium causing multiple loose bodies with in a joint cavity.

Epidemiology

  • Occurs equally in males and females.

  • Onset is typically aged 30–50 years.

Aetiology

Results from metaplasia of synovial tissue into cartilage, which can subsequently calcify or ossify. The trigger for the condition is unknown.

Clinical features

Key features on history

  • Usually occurs in a single joint and rarely polyarticular.

  • Most commonly affects the knee (>50% cases) hip, shoulder, elbows, TMJ and hands.

  • Presentation is with pain and swelling of the joint.

  • Joint locking.

Key features on examination

  • A firm mass may be palpable.

  • There is often restriction of movement, with pain and swelling.

Figure 18.6 Shoulder arthrography showing multiple intra-articular loose bodies typical of synovial osteochondromatosis.

Figure 18.6
Shoulder arthrography showing multiple intra-articular loose bodies typical of synovial osteochondromatosis.

General investigations

Imaging

X-ray

  • There is the characteristic appearance of popcorn in the joint if the loose bodies are calcified.

  • Secondary OA may develop.

MRI

MRI can demonstrate the chondromata before calcification.

Differential diagnosis

Similar calcified loose bodies can be seen following joint trauma, osteochondritis dessicans, tumoural calcinosis, and severe OA.

Prognosis

Progression is generally slow with eventual development of secondary OA. The condition may be self-limiting with cessation of production of new chondromata. Synovial chondromata do not become malignant.

Pathology

The synovium is hyperplastic with numerous villi. There are cartilaginous nodules within the synovium and also within the joint space.

Synovial fluid

Non-specific inflammatory changes may be seen

Patient advice

  • Rare condition, for which symptomatic treatment is usually adequate.

  • Surgical removal of loose bodies may be necessary

Treatment

  • NSAIDs for pain relief and reduction inflammation.

  • Arthroscopy or open arthrotomy for removal of loose bodies and synovectomy. These may need to be repeated as the condition may recur.

References

Crotty JM, Monu JU, Pope TL. Synovial osteochondromatosis. Radiol Clin N Am 1996; 34: 327–42.

Pigmented villonodular synovitis

Definition

Pigmented villonodular synovitis (PVNS) is a group of benign proliferative conditions of the synovium and mesenchyme.

Epidemiology

  • Occurs equally in males and females.

  • The incidence is around 2/million/year.

Aetiology

The aetiology is clonal in nature and PVNS is now considered to be a benign neoplasm of synovium.

Clinical features

Key features on history

There are three modes of presentation

  • Isolated tenosynovitis: this typically presents in the hand with a painless mass on a finger adherent to a tendon.

  • Diffuse form: the diffuse form of PVNS usually affects the knee. Presentation is a gradual onset of pain, swelling, and stiffness, affecting a single joint. Less commonly the hip, ankle, hand, shoulder, or spine are involved.

  • Localized form: this is the least common. Presentation is with joint swelling and locking due to a free floating pedunculated intra-articular mass.

Key features on examination

  • Isolated tenosynovitis: a painless mass adherent to a tendon.

  • Diffuse form: warm swollen joint with restricted range of movement.

  • Localized form: swollen joint, which may lock..

Investigation

Imaging

X-rays

Plain radiographs do not show the lesion, but in joints with a tight capsule there may be scalloped lesions with sclerotic margins, due to local erosion or pressure from the mass.

CT

CT scanning shows high attenuation because of the presence of haemosiderin pigment.

MRI

MRI is the investigation of choice. The lesion appears dark on all sequences because of the ferromagnetic nature of haemosiderin causing shortening of the T1 and T2 relaxation time. The extent of the lesion can be delineated and used to plan surgery.

Joint aspiration

Aspirated synovial fluid is haemorrhagic or brown in colour, due to recurrent haemorrhage.

Differential diagnosis

The isolated form needs to be distinguished from other lesions such as ganglions and foreign body granulomata.

PVNS as a cause of haemarthrosis needs to be distinguished from other causes of bloody knee effusions, such as trauma, clotting disorders, neuropathic joints, sickle cell anaemia, and hypermobility. Recurrent haemorrhagic effusions should raise the possibility of PVNS.

Localized form needs to differentiated from other causes of joint locking, such as menisceal tears.

Prognosis

Progression is generally very slow; however, the diffuse form can cause significant disability.

Pathology

Exuberant proliferation of synovial lining cells. They are invasive and form finger-like extensions or villi, which fill the joint space with lobulated masses that invade into the subsynovial connective tissue leading to bone erosions and destruction. Histologically, there are multinucleated giant cells and haemosiderin laden macrophages, giving rise to the characteristic colour of the lesion.

Patient advice

  • Benign lesion.

  • Surgery is curative in the isolated and localized forms.

  • Diffuse form requires extensive removal synovium and possible joint replacement, and may be disabling.

Treatment

  • Isolated tenosynovitis: surgical treatment is aimed at removing the mass from the tendon sheath and is curative.

  • Diffuse form: there are no randomized controlled trials in PVNS. Surgery is usually synovectomy, but it is usually difficult to achieve a curative resection. No medical treatment is successful. Radiation synovectomy has been used in combination with extensive surgical debridement. In the hip and knee total synovectomy followed by total arthroplasty has been successful with a low recurrence rate.

  • Localized form: surgical excision of the free floating mass is curative.

Resources

ICD-10 coding

M12.2 villonodular synovitis (pigmented)

References

Tyler WK, Vidal AF, Williams RJ, Healey JH. Pigmented villonodular synovitis. J Am Acad Orthop Surg 2006; 14: 376–85..

Bone tumours

Definition

Primary tumours of bone are generally rare and comprise a spectrum from benign lesions to aggressively malignant lesions.

Epidemiology

Generally rare conditions that can occur at any age group. Certain lesions, however, have very clearly defined age-specific occurrence.

Classification

The World Health Organization has developed a classification system for bone tumours based on histopathological criteria.

Classification of bone tumours

Bone-forming tumours

  • Benign: osteoma, osteoid osteoma.

  • Intermediate: malignant osteoblastoma.

  • Malignant: osteosarcoma.

Cartilage-forming tumours

  • Benign: chondroma, osteochondroma, chondroblastoma, chondroidmyxoid fibroma.

  • Malignant: chondrosarcoma.

Giant cell tumour (osteoclastoma)

Marrow tumours (round cell tumours)

  • Ewing sarcoma, neuroectodermal tumour, lymphoma, myeloma

Adapted from Dixon (2004).

Osteoma

Slowly growing benign lesion of well-differentiated mature bone tissue.

Key features on history

  • Usually present in between ages 20 and 40 years.

  • Often asymptomatic.

  • Presents with a slow growing hard mass.

Key features on examination

Hard, firm swelling or mass.

General investigations

Imaging

  • X-ray: dense radio-opaque well defined <3 cm in diameter.

Differential diagnosis

Multiple osteomata are part of Gardner's syndrome – colonic polyposis, osteomata, and soft tissue tumours.

Pathology

Thick trabeculae of mature bone.

Treatment

Excision for symptoms or cosmetic reasons.

Osteoid osteoma

Benign osteoblastic lesion, with a clearly demarcated outline.

Key features on history

  • Present between age 5 and 30 and is more common in men.

  • Pain is constant, worse at night, poorly localized, and not relieved by rest. Pain may be worsened by alcohol and relieved by aspirin.

  • Most commonly located in the femur or tibia, but also occurs in short bones and the spinal column.

Key features on examination

Muscle atrophy, localized swelling, and tenderness.

General investigations

Imaging

  • X-ray: small round area of osteolysis (nidus), surrounded by a halo of hyperostosis.

  • CT scan: shows the nidus clearly and enables surgery to be planned.

  • Bone scintigraphy: shows an area of increased uptake of radioisotope.

Differential diagnosis

This is from other bone tumours. When occurring close to a joint, may be mistaken for a monarthropathy.

Pathology

Cellular, highly vascular with immature bone and osteoid.

Treatment

  • Surgical removal of the nidus.

  • Incomplete resection may lead to recurrence.

Osteosarcoma

Malignant tumour of bone. Characterized by formation of bone or osteoid by tumour cells.

Key features on history

Pain arising from the tumour is often not very severe, and is increased by activity. In the later stages lump may be palpable. Pathological fracture may occur. The course is usually quite rapid.

Key features on examination

Localized tenderness with a palpable mass. Overlying skin may be warm due to marked vascularity of the tumour.

General investigations

Imaging

X-ray

The characteristic radiological features are:

  • Periosteal reaction with formation of long spicules of bone radiating perpendicular to the bone giving a ‘sunburst’ appearance. This can also be seen in benign lesion such as haemangioma and other malignant lesions such as Ewing's sarcoma.

  • Codman's triangle reflects elevation of the periosteum from the underlying cortex and can also occur in osteomyelitis or Ewing's sarcoma.

CT

  • CT is useful to assess the local extent of bone.

  • CT of the thorax should be performed at presentation because pulmonary metastasis is common.

MRI

MRI is the optimum method to assess extent of the lesion in bone.

Differential diagnosis

Osteosarcoma needs to be distinguished from other malignant bone tumours.

Pathology

There is a wide spectrum of pathological appearances, but the production of osteoid or bone is essential for the diagnosis.

Treatment

Pre- and post-operative chemotherapy and surgery.

Prognosis

The combination of chemotherapy and surgery has improved survival rates to 60–70% at 5 years.

Chondroma

Benign tumour characterized by formation of mature cartilage. Solitary lesions arising in the medulla (enchondroma)

Key features on history

  • Often asymptomatic.

  • When superficial may become palpable as lump.

  • Pain occurs if there is a pathological fracture or malignant transformation.

Key features on examination

Palpable mass. Due to swelling of the bone.

General Investigations

Imaging

X-ray

  • Small or moderate-sized osteolytic round or ovoid areas with well-defined margins, which expand and thin the cortex.

  • Usually located in the metaphysis.

Differential diagnosis

  • Radiologically from epidermal cysts in the terminal phalanges.

  • Multiple enchondromata often unilateral occur in Ollier's disease. Maffucci syndrome is multiple enchondromata occurring in association with haemangiomata.

Pathology

The lesion is composed of mature cartilage.

Treatment

Surgical resection or curettage of small lesions.

Prognosis

Generally good, but there is a risk of malignant transformation, especially in multiple enchondromatosis.

Osteochondroma

Cartilage capped bony projection on the outside surface of bone.

Key features on history

  • Osteochondromata are the most common bone tumour, comprising 40% of benign tumours and 20% of all bone tumours.

  • Most common sites are metaphysis of long bones.

  • Multiple osteochondromata are associated with disturbance of growth with shortness and deformity.

  • Diagnosis is usually aged <20 years.

  • Usually diagnosed as an incidental finding or presents as a painless mass.

  • Pain is due fracture.

Key features on examination

Painless bony deformity.

General Investigations

Imaging

X-ray

Plain X-rays show a bony projection with a cartilage capped surface.

Treatment

Surgical resection only for symptomatic lesions.

Prognosis

The risk of malignant transformation to a chondrosarcoma is < 1%. The risk is much higher in cases of multiple osteochondromatosis.

Chondrosarcoma

Malignant tumour characterized by formation of cartilage.

Key features on history

  • Pain is usually the first symptom, with a firm swelling.

  • Variable duration of symptoms from weeks to years.

Key features on examination

Firm swelling.

General investigations

Imaging

X-rays

Intra-osseous osteolytic tumour. May show thickening and expansion of cortex. Extension into soft tissue suggests a high-grade malignancy.

MRI/CT

Best method of delineating extra-osseous extent.

Pathology

Cartilage forming tumour, with pleomorphic cells.

Treatment

Surgical resection is required. They are relatively radio- resistant and chemotherapeutic regimens are poorly developed.

Prognosis

  • The 5-year survival is 50–50%.

  • The most common site of metastasis is the lung.

References

Dixon. Bone Tumours. In: Hochberg M, Silman A, Smolen J, Weinblatt M, Weisman M (eds) Rheumatology, 3rd edn. Ottawa: Mosby 2004; 2185–99.

Schajowicz F. Tumours and tumour like lesions of bone, 2nd edn. Berlin: Springer Verlag, 1994.

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