Miscellaneous Conditions
Sarcoidosis
Sarcoidosis is a multisystem disease characterized by non-caseating granulomata.
Presentation
Common presentations include:
asymptomatic bihilar lymphadenopathy
erythema nodosum, arthritis, and hilar lymphadenopathy (Löfgren’s syndrome)
uveo-parotid fever (von Heerfordt’s syndrome)
primary cerebral involvement
multisystem presentation, which can affect all organs in the body.
Other clinical features include erythema nodosum, arthralgias, skin involvement (lupus pernio), and symptoms and signs of hypercalcaemia.
Cause and immunopathogenesis
Formation of non-caseating granulomata is typical, but is not by itself diagnostic.
Differential diagnosis of non-caseating granulomata is extensive and includes:
infections (Toxoplasma, Bartonella)
lymphoma
carcinoma
berylliosis, due to beryllium exposure
vasculitis and connective tissue diseases
Crohn’s disease
chronic granulomatous disease.
Granuloma comprises a central area of macrophages, epithelioid cells, and Langerhans giant cells surrounded by lymphocytes (mainly CD4+ cells and plasma cells), monocytes, and fibroblasts.
Macrophages are activated and release enzymes and 1,25-dihydroxycholecalciferol—hence the tendency to hypercalcaemia.
IL-12 is released; IL-18 associated with granuloma formation.
Peripheral blood lymphopenia (T and B cells), cutaneous anergy, and poor in vitro tests of lymphocyte proliferation.
T cells have an ‘activated’ phenotype, and T-cell receptor studies show skewing of the Vβ chain usage which might be compatible with a response to a single, as yet unidentified, pathogen.
Disease manifestations are of a Th1 phenotype.
Serum immunoglobulins are elevated, and as a result low-level autoantibodies may be present. IgM anti-T-cell antibodies may be detected.
Bronchoalveolar lavage specimens show a lymphocytosis (predominantly CD4+ T cells with high levels of activation and adhesion markers) and monocytes/macrophages (also activated with elevated MHC class II).
Soluble activation markers, such as sIL-2R, are raised.
Investigations (see Box 14.1)
No specific diagnostic tests are available for sarcoidosis.
Raised ACE levels in about 60% of patients (released by epithelioid cells in the granulomata).
Hypercalcaemia (and hypercalciuria).
Serum immunoglobulins show a polyclonal elevation of all classes, but predominantly IgG.
Low-titre rheumatoid factors and anti-nuclear antibodies may be present.
Peripheral blood lymphocyte analysis will show a generalized lymphopenia, with a proportional reduction in all cell types.
DTH testing will show anergy. There is no clinical need to assess lymphocyte proliferation in vitro, although it will be reduced.
Biopsy with appropriate immunohistochemical staining is helpful.
The Kveim test, in which an extract of sarcoid spleen is injected under the skin and biopsied 4-6 weeks later, has been used previously: a granuloma forms at the site of injection. This test, which uses human material, is no longer considered appropriate.
BAL studies are helpful where there is interstitial lung disease, although the changes are not specific.
A gallium-67 scan is helpful in identifying granulomata.
CSF oligoclonal bands may be present (again not specific) in cerebral sarcoidosis.
Lung function testing and appropriate radiological studies are essential.
Treatment
Asymptomatic disease picked up by chance on chest radiography; requires no specific treatment.
Treat erythema nodosum with NSAIDs intially.
Symptomatic disease requires low- to moderate-dose steroids.
Occasionally patients require other immunosuppressive drugs as steroid-sparing agents (cyclophosphamide, methotrexate, and azathioprine). Ciclosporin and hydroxychloroquine may be helpful through their effects on T-lymphocyte activation. Infliximab has also been used.
Patients with uveitis may require aggressive treatment to preserve vision.
Progressive lung disease may be an indication for lung transplantation, but disease recurs in 30-80% of cases.
Prognosis
Asymptomatic disease usually resolves spontaneously over several years.
Symptomatic disease is frequently chronic.
Amyloidosis
This group of conditions which cause multisystem disease is often overlooked clinically. The diseases are characterized by the deposition of polymerized proteins in an insoluble β-pleated sheet form, either generally or in a single organ, depending on the type of polymerizing protein (Table 14.1). Once deposits are established, they are virtually impossible to eliminate. Multiple proteins have been associated with amyloid formation. Hereditary forms occur.
Table 14.1 Types of amyloid* | ||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||
AL amyloid
Presentation
Typical clinical features include:
hepatosplenomegaly
cardiac failure due to infiltration
malabsorption
nephrotic syndrome
peripheral neuropathy (especially carpal tunnel syndrome)
macroglossia may be present
deposits may occur in the skin
bleeding tendency due to selective absorption of clotting factors.
It is a disease predominantly of older people.
Cause and immunopathogenesis
In this type of amyloid the deposited protein is derived from immunoglobulin light chains (λ:κ = 2:1—the opposite of that found in myeloma).
Often associated with evidence of lymphoproliferative disease.
20% of AL amyloid patients only have myeloma; the rest have other paraproteinaemias.
Rarely, AL amyloid has been associated with heavy-chain deposition.
Investigations (see Box 14.2)
Serum and urine should be checked for the presence of monoclonal immunoglobulins and free light chains: sensitive techniques may be required to demonstrate the paraproteins, which are present in up to 80% of cases.
Paraprotein levels are often low.
Serum-free light-chain analysis is very valuable.
Some paraproteins may not be detected as the light chain is highly abnormal or polymerized in circulation, such that it does not react with the usual antisera, or the band overlaps on electrophoresis with other protein bands.
Biopsy of an affected organ and Congo red staining, which gives applegreen birefringence, is helpful. More specific immunostaining with antilight-chain antisera may give reactions, although the distorted protein structure may prevent reactivity.
Bone marrow examination is essential.
Box 14.2 Testing for AL amyloid
| ||||||||||||||
Treatment
No curative treatment, but steroids, melphalan, and colchicine may slow down the rate of progression; symptomatic organ-specific treatment will be required.
HSCT may be necessary.
Iododoxorubicin binds to AL amyloid and promotes resorption.
Bortezomib (Velcade®), a proteasome inhibitor, may be helpful.
AA amyloid
Presentation
Presents predominantly with hepatosplenomegaly, nephrotic syndrome, and malabsorption.
Cardiac and nerve involvement is rare.
Cause and immunopathogenesis
Caused by the polymerization of serum amyloid A protein (SAA), an acute-phase protein, whose levels rise in response to IL-1 and IL-6.
It is a complication of chronic infection or inflammation (TB, bronchiectasis, rheumatoid arthritis, ankylosing spondylitis, etc.).
It is a complication of periodic fever syndromes:
Investigations
Treatment
Treatment is aimed at the underlying disease to eliminate the drive to high levels of SAA.
Colchicine is a valuable prophylatic agent in some periodic fever syndromes.
Other acquired amyloidoses
Dialysis amyloid
Caused by the polymerization of β2-microglobulin (Aβ2MG).
Related to failure of certain older (cuprophane) haemodialysis membranes to clear β2MG. Current membranes do not have this problem to the same extent.
Widespread deposition of β2MG occurs, but these deposits may resolve slowly with a successful transplant or on switching to dialysis with more permeable membranes.
Serum β2MG levels will rise to very high levels (>20mg/L).
Prion disease
Alzheimer’s disease
β-amyloid protein has also been identified in certain cases of Alzheimer’s disease and is associated with the typical neurofibrillary tangles.
Protein is derived from a larger precursor amyloid β-precursor protein (AβPP). In Alzheimer’s it appears that the processing is defective, leading to an abnormal β-amyloid.
Diabetes
Amyloid deposits are found in patients with type II maturity-onset diabetes.
Amyloidogenic protein is thought to be islet amyloid polypeptide (IAPP), which is normally co-secreted with insulin.
This type of amyloid may occur in association with insulinomas.
Senile cardiac amyloid
Senile cardiac amyloid is very common in the elderly and is due to deposition of polymerized atrial natriuretic factor.
Medullary thyroid carcinoma
Medullary thyroid carcinoma may be associated with a form of amyloid derived from pro-calcitonin and calcitonin.
Inherited amyloidosis
There are a number of rare inherited amyloid deposition diseases related to rare mutations in proteins. These include:
transthyretin
apolipoprotein A-I
gelsolin
fibrinogen
cystatin C
lysozyme.
Clinical features are variable but renal and neurological involvement, both central and peripheral, are common.
Diagnosis is by identification of the mutated genes.
Familial Mediterranean fever (FMF)
Presentation
Inherited disease, most common in Jews, Arabs, Italians, Turks, and Armenians, especially those living around the Mediterranean basin.
Clinical features include attacks of abdominal pain with high fever, mimicking acute peritonitis but settling over 24-48 hours. Pleuritic chest pain, arthritis (which may be destructive and mimic RhA), and erythematous skin rashes also occur. Pericarditis may occur rarely.
Attacks usually begin before the age of 20 (90% of cases).
Typical attacks last 24-72 hours and can be triggered by physical exertion, stress, and menstruation.
Periodicity is variable and unpredictable.
AA amyloid may be a long-term complication of repeated attacks, especially in Jews.
Cause and immunopathogenesis
Inherited as an autosomal recessive.
Associated with mutations in the MEFV gene (16p13.3), encoding pyrin (also known as marenostrin), a protein that regulates caspase 1 and IL-1 secretion.
Investigations
There is a peripheral blood leucocytosis, mild anaemia, and the ESR and CRP rise during attacks. Fibrinogen levels are high (>g/L).
Serum immunoglobulins are non-specifically polyclonally elevated.
Involved serosal surfaces have an inflammatory infiltrate, mainly neutrophils. Joint fluid also shows a high neutrophil count during an acute attack.
Autoantibodies are not found.
Biopsies need to be considered if AA amyloid is suspected.
Genetic diagnosis is confirmatory.
Treatment
Colchicine in a daily dose of 1-1.5mg will reduce the frequency and severity of attacks markedly and reduce the risk of developing amyloidosis.
Colchicine taken inadvertently by pregnant women may increase the risk of Down’s syndrome.
5-10% of cases are resistant to colchicine.
Anakinra is beneficial.
TNF-receptor-associated periodic syndrome (TRAPS, familial Hibernian fever)
Presentation
Recurrent attacks of pleurisy, peritonitis, pericarditis, erythematous rash, arthritis, and myalgia, beginning in childhood.
Conjunctivitis, rarely uveitis.
15% develop amyloidosis.
Attacks usually prolonged >7 days.
Cause and immunopathogenesis
Dominant mutations in the TFRSF1A gene (12p13), encoding the TNF receptor.
Mutations occur in external domains and prevent the normal shedding of the receptor.
Diagnosis
Demonstration of TNF-R mutations.
Treatment
Corticosteroids are better than colchicine.
Anti-TNF agents (etanercept)—preferred treatment.
Anakinra.
Hyper-IgD syndrome
Clinical features
Rare autosomal recessive syndrome comprises bouts of fever, lymphadenitis, and occasionally oligoarthritis. Diffuse rash. Peritonitis and pleurisy are common.
Oral and vaginal ulcers may occur.
Attacks last 3-7 days.
Severe immunization reactions are a particular feature.
Cause and immunopathogenesis
Mutations in the MVK gene (12q24) encoding mevalonate kinase.
Predominantly occurs in Dutch and northern Europeans.
24% of cases do not have mutations in the coding part of the gene.
Investigations
Humoral immune responses may be poor, with reduced IgM, raised IgG3, and very high IgD levels. IgA may also be elevated.
IgD can be measured with commercial RID assays.
Treatment
NSAIDs for fever.
Anakinra and anti-IL-1 treatments—preferred option.
Anti-TNFs may be tried.
Statins may have a role (mevalonate kinase is part of the HMG-CoA reductase pathway).
Muckle-Wells and related syndromes
Three hereditary febrile syndromes have been described in association with dominant mutations in the gene C1AS1, coding for cryopyrin.
Muckle-Wells syndrome.
Episodic symptoms lasting up to 48 hours. Urticaria (not associated with cold), arthralgia, myalgia, headache, conjunctivitis, episcleritis. May lead to amyloidosis (25%).
Neonatal-onset multisystem inflammatory disease (NOMID), also known as CINCA (chronic infantile neurological cutaneous and articular syndrome).
Chronic disease, diffuse urticaria, epiphyseal overgrowth, conjunctivitis, uveitis (blindness), sensorineural deafness. Amyloidosis may occur as late feature.
Familial cold autoinflammatory syndrome (FCAS).
Fever, rigors, headache, arthralgia, conjunctivitis, and urticaria in response to cold exposure.
Familial cold urticaria is a milder variant of FCAS which also maps to the C1AS1 gene.
Treatment
NSAIDS are usually used.
Anakinra (IL-1RA) and canakinumab (anti-IL1b) are very effective.
Rilonacept (dimeric fusion protein with binding regions of the IL-1 receptor and the IL-1R accessory protein, fused to IgG1 Fc) appears to be highly effective.
The experimental caspase-1 inhibitor VX-765 has been shown to reduce IL-1 and is undergoing trials.
Periodic fever with aphthous ulcers, pharyngitis, and cervical adenopathy (PFAPA)
A rare syndrome characterized by periodic fever, aphthous ulceration, pharyngitis, and adenitis.
Starts early in childhood but improves as child grows up.
Cause uncertain—no gene identified yet.
Treat with corticosteroids, colchicines, or IL-1 inhibition.
Adenotonsillectomy has resolved some cases.
Schnitzler’s syndrome
A rare syndrome characterized by urticaria, skin papules, intermittent fever, bone pain, arthritis/arthralgia, and monoclonal IgM monoclonal gammopathy.
Severe anaemia of chronic disease is common.
IL-6 levels are elevated.
Evolves into lymphoma or Waldenström’s macroglobulinaemia in 15%.
Treatment may involve corticosteroids, colchicine, thalidomide, or anakinra. Preferred treatment is anakinra.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
