Connective Tissue Disease
Rheumatoid arthritis: aetiology, clinical features, and immunopathology
Aetiology
RhA is a multisystem disease in which arthritis is a major component.
An infectious trigger has been sought for many years, without success.
The best candidate pathogens are:
Mycobacterium tuberculosis
Proteus mirabilis.
The genetic background includes:
DR4 (DRβ1*0401), DR1 (DRβ1*0101) in Caucasians
DR10 (DRβ1*1001) in Spanish and Italian patients
DR9 (DRβ1*0901) in Chileans DR3 (DRβ1*0301) in Arabs
PTPN22.
Clinical features
Early clinical signs:
morning stiffness;
fatigue.
There may be low-grade fever.
Joint pain and swelling follow and the arthritis is often deforming. Hand joints are typically affected. Radiographic changes are typical.
Non-articular features include:
Sjögren’s syndrome
lymphadenopathy
scleritis
cutaneous vasculitis and ulceration
nodules of both skin and lung
pleurisy, alveolitis
pericarditis, endocarditis (with valvular involvement)
splenomegaly (with ulceration and neutropenia = Felty’s syndrome (see Table 12.1))
myositis, mononeuritis multiplex, and cord compression from spinal involvement.
Amyloid is a long-term complication from chronic inflammation (p.338).
Immunopathology
Most of the pathology is located in the joint:
activation of T cells, macrophages, and endothelial cells
increased synovial vascularity
both CD4+ and CD8+ T cells are found in the joint tissues
‘memory’ T cells (CD45RO+, CD29+) predominate
restriction of Tcr Vβ usage suggestive of a superantigenic effect.
Large quantities of cytokines can be detected in the joint fluids.
Endothelial cell activation/production of chemokines is responsible for influx of inflammatory cells:
interleukin-8 (IL-8)
RANTES
MCP-1
Gro-α
ENA-78 (epithelial neutrophil activating peptide).
Autoantibodies are produced, including:
rheumatoid factors
anti-nuclear antibodies including anti-neutrophil nuclear antibodies
anti-keratin
anti-cyclic citrullinated peptide (anti-CCP)
anti-calpastatin
anti-Sa (unknown antigen)
anti-filaggrin.
Pathogenic role of these autoantibodies is uncertain.
IgG molecules in RhA have been shown to have markedly reduced glycosylation, although the significance of this is uncertain.
Complement activation takes place, releasing anaphylotoxins, C3a, C5a.
Table 12.1 Features of Felty’s syndrome | ||||||||||||||||||||||
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Rheumatoid arthritis: immunological tests, treatment, and childhood RhA
Immunological tests (see Box 12.1)
Rheumatoid factors (RhF) are found in 67-85% of patients, depending on the type of assay used.
Most detected rheumatoid factors are IgM class.
Highest titres of RhF are found in patients with extra-articular disease.
There is no correlation of disease activity with antibody titres.
Anti-CCP antibodies are valuable, as a more specific marker, in identification of early disease.
Antibodies to filaggrin and keratin have also been said to be more specific for RhA. Assays are not widely available.
Cryoglobulins may be found, usually type II or type III (i.e. with RhF activity), often in association with Felty’s syndrome.
Hypergammaglobulinaemia due to chronic inflammation is usually present and is invariably polyclonal, although small monoclonal bands may be present.
Urine may contain an excess of free polyclonal and sometimes monoclonal light chains.
Complement C3/C4 are usually elevated, as are acute-phase proteins, although patients with Felty’s syndrome may have reduced levels.
ANAs may be found on both rat liver and HEp-2 cells. ANAs are most commonly found in Felty’s syndrome. These include antibodies against:
nuclear antigen RA-33, a ribonucleoprotein of the splicesome
Antibodies are also detected against granulocyte nuclei (GS-ANA), which may be difficult to distinguish from P-ANCA when testing is done by fluorescence; these are also associated most strongly with Felty’s syndrome.
Associated Sjögren’s syndrome will be accompanied by the presence of antibodies to Ro and/or La.
CRP is the most sensitive marker of activity because of its wide dynamic range, and is the most useful marker to monitor response to treatment.
Other markers of disease activity that have been studied include cytidine deaminase, calprotectin, and serum hyaluronate. None of these are used routinely yet.
Monitoring of cytokines is not used routinely.
Anaemia of chronic disease is often present and there may be lymphopenia (both CD4+ and CD8+ cells).
Treatment
Proper supportive care (physiotherapy, occupational therapy) is essential.
Drug therapy includes NSAIDs, usually with gastric protection, and analgesics as first line.
Low-dose corticosteroids are now back in favour to slow the progression of erosive disease (prednisolone 5-7.5mg/day).
Disease-modifying anti-rheumatic drugs (DMARDs) (see Chapter 16) include:
sulfasalazine
gold salts (interferes with TNF production)
penicillamine
methotrexate (low dose weekly)
hydroxychloroquine (interferes with TNF production)
azathioprine
leflunomide
ciclosporin and tacrolimus have been used to reduce the activation of CD4+ T cells.
Immunotherapies with biological agents include:
anti-CD4 monoclonal antibodies (mAbs)
anti-CD52 mAbs
anti-TNF agents (adalimumab, infliximab, etanercept, certolizumab, golimumab) are highly effective
IL-1 receptor antagonist (anakinra) seems less effective and has not been endorsed by NICE
rituximab (anti-CD20.
humanized anti-IL-6 receptor (tocilizumab)
Other agents undergoing trials include:
oral anti-TNF drugs
humanized anti-IL-6 receptor (tocilizumab)
CTLA4-Ig (abatacept)
anti-CD2
anti-IL-15
anti-IL-12
anti-B-lymphocyte stimulator protein (BLys) (belimumab);
Problems with all mAb-based therapies have included:
high levels of reactions to xenogeneic proteins, even if attempts have been made to humanize the antibodies
severe and persistent T-cell lymphopenia in some trials, raising concerns over risks of opportunist infections.
Surgical replacement of damaged joints may restore function and relieve pain.
Childhood rheumatoid arthritis
Childhood-onset seropositive RhA is rare and usually presents with general malaise and polyarthritis of the small joints of the hands and feet.
Because of the frequent appearance of RhF following infection, European guidance suggests that three positive tests over a 3-month period are required to confirm the diagnosis although, bearing in mind the half-life of the antibodies, this is probably too short an interval.
This disease is associated with DR4.
Diagnosis and management are as for the adult disease.
An RhF-negative polyarthritis is also seen in children and may be severe. It is associated with DR5 and DR8.
Juvenile chronic arthritis (JCA) and Still’s disease
Clinically JCA is divided into two types: pauci-articular and systemic forms. The latter is usually referred to as Still’s disease.
Aetiology and immunopathology
As with many connective tissue diseases (CTDs), the aetiology is not well understood.
The immunogenetics of pauci-articular disease is complex: DR8 and DR5 show the strongest correlation with pauci-articular disease. Other genes include DPB1 and A2.
Rubella virus has been implicated as a possible trigger.
Systemic disease is also associated most strongly with DR5 and DR8, but also with DR4.
Clinical features
Clinical diagnosis of pauci-articular disease is one of exclusion.
Usual age of onset is 1-3 years, with a 4:1 female predominance.
Systemic features are an exclusion, and the usual features are those of painful or painless swelling of one or two joints.
Uveitis may develop and regular screening is required when ANAs are detected.
Still’s disease typically has a high spiking fever, accompanied by malaise and rigors.
A pale, salmon-pink rash that comes and goes is usual, in parallel with the spikes of fever.
Hepatosplenomegaly and generalized lymphadenopathy are usually present.
There is polyarthralgia and polyarthritis.
Pericarditis and pleurisy are also common.
A rare macrophage-activation syndrome has been described, with encephalopathy, hepatitis, disseminated intravascular coagulation (DIC), and haemophagocytosis.
Amyloid may be a long-term complication.
Immunological tests (see Box 12.2)
Rheumatoid factor is rare (<5%) in pauci-articular disease and, when present, suggests that the course will be that of juvenile RhA with polyarticular disease.
ANAs are frequently present, and it is important to ensure that the normal range for significance is appropriately adjusted for the paediatric population:
in small children, titres of 1/10 and 1/20 are highly significant, whereas such titres would not be considered important in adults.
High incidence of uveitis in female patients with arthritis and positive ANA, especially if also anti-Ro+.
Antibodies to histones H1 and H3 are also associated with uveitis.
Antibodies to retinal S-antigen may also be found (in 30%).
Other antibodies detected include anti-histone antibodies (often in those without uveitis).
Detection of anti-dsDNA antibodies should lead to consideration of childhood lupus.
Frequent evidence of complement consumption with raised C3d, even when C3 levels are within the normal range.
Acute-phase proteins are minimally elevated.
High ESR should prompt a search for other causes, including leukaemia and infection.
It is important to realize that the development of diagnostically helpful antibodies often follows rather than precedes the development of clinical disease. Therefore repeating antibody measurements every 3 months is advised if there is strong clinical suspicion of disease.
In Still’s disease, there are no specific tests. ESR and CRP are very high, with anaemia, leucocytosis, and thrombocytosis.
There is a polyclonal hypergammaglobulinaemia, although the incidence of IgA deficiency is increased.
Complement activation may be present.
IL-6 and TNFα levels may be elevated.
Treatment
NSAIDs form the mainstay of therapy for pauci-articular disease, notwithstanding the risks of Reye’s syndrome.
DMARDs may be required for more severe cases.
Uveitis may be treated with etanercept, methotrexate, or mycophenolate mofetil.
Biological agents and experimental therapies as for RhA are also used.
In Still’s disease, NSAIDs are used initially, with steroids reserved for failure of response. Methotrexate is the most effective steroid-sparing agent; gold and sulfasalazine are contraindicated.
Bone marrow and stem-cell transplantation are now being used successfully for severe cases.
Adult Still’s disease
Clinical features are very similar to those of childhood Still’s disease, but occur in young adults.
There is the typical fever (for more than a week) and rash (evanescent salmon-pink), often accompanied by sore throat.
Hepatosplenomegaly and lymphadenopathy are common.
Polyserositis occurs frequently.
Polyarthralgia or polyarthritis lasting >2 weeks.
Exclusion of lymphoma may be difficult.
May be complicated by haemophagocytosis (macrophage activation syndrome).
There are no diagnostic tests other than non-specific inflammatory markers.
Neutrophilia is common.
Ferritin levels may be exceptionally high and disproportionately elevated when compared with other acute-phase markers.
Ferritin levels are controlled by IL-18, and a polymorphism in the IL-18 gene which may explain the high ferritin has been identified in adult Still’s patients.
Hyperferritinaemia may be seen if haemaphagocytosis is present and may also be found in other haemophagocytic syndromes.
NSAIDs, corticosteroids, and DMARDS are all required.
NSAIDS have a risk of inducing hepatitis and possibly of triggering haemophagocytosis.
Regular monitoring of LFTs is required.
Good response to anti-IL-1 therapies; methotrexate is also valuable.
Role of anti-TNF therapies is unclear: some may benefit.
Ciclosporin may be beneficial if there is macrophage activation syndrome.
Disease may run a chronic progressive course, a relapsing-remitting course, or resolve completely.
Ankylosing spondylitis (AS) and related spondyloarthropathies
These are a group of seronegative (RhF negative) disorders, strongly associated with HLA-B27. The group includes ankylosing spondylitis, reactive arthritis, enteropathic arthritis, psoriatic arthritis, and undifferentiated spondyloarthritis.
Clinical features
Typical clinical features of AS include spinal pain and restriction in movement, especially in the lumbar and thoracic regions, accompanied by demonstrable sacroiliitis on radiographs.
More common in men than in women.
May be associated with inflammatory bowel disease.
Complications include:
anterior uveitis
cardiac lesions involving the proximal aorta and aortic valve
pericarditis and conduction block
upper-lobe lung fibrosis.
Immunopathology
TNFα appears to play a key role: levels are high in affected joints, which are infiltrated with CD4+ and CD8+ T cells.
IL-6 levels are also elevated.
HLA B27 is critical for the development of disease: B27 transgenic mice develop spontaneous spondylitis.
Bacterial infections (especially bowel bacteria) are strongly associated.
Autoantibodies have been identified to aggrecan (a proteoglycan in cartilage) and heat shock proteins—these are not diagnostically valuable.
Diagnosis
By definition, this is an RhF-seronegative arthritis and there are no defining antibodies.
Acute-phase proteins may be normal or elevated.
IgA is often elevated.
Alkaline phosphatase and creatinine kinase (CK) may also be elevated.
More than 90% of all cases will be HLA-B27 positive but, as this is a common antigen in the Caucasian population (8%), the diagnostic value of testing for HLA-B27 is limited.
5-10% of B27-positive persons will develop AS, while 20% go on to develop a reactive arthropathy after infection with agents such as Salmonella or Chlamydia.
DR4 is associated with peripheral joint involvement.
Treatment
Previously the mainstay of treatment has been NSAIDs (with exercise and physiotherapy), sulphasalazine, and methotrexate.
AS responds dramatically well to anti-TNF drugs (etanercept, infliximab, adalimumab, golimumab), although the associated uveitis responds less well and may need other immunosupressive agents.
Tocilizumab (anti-IL-6R) and rituximab (anti-CD20) are also useful.
Other beneficial therapies include bisphosphonates and thalidomide.
Complications
Amyloid may develop and there is a recognized association with IgA nephropathy.
SAPHO syndrome
A syndrome of synovitis, acne, palmoplantar pustulosis, hyperostosis, and osteitis (with granulomata).
Acne is severe.
Hidradenitis suppurativa is also seen.
Hyperostosis of especially the sternoclavicular joint and spine.
Peripheral arthritis is seen in 92% of cases.
ESR is high.
There is a weak association with HLA-B27.
May respond to anti-TNF treatment and antibiotics (as used for acne on the basis that Propionobacterium acnes has been isolated from bone biopsies).
Bisphosphonates have also been used successfully.
Psoriatic arthritis
Clinical features
Usually develops in patients with clinical psoriasis although, if skin lesions are not present, diagnosis may be difficult.
Arthritis is frequently asymmetrical and spinal involvement is common, in contrast with RhA, which it most resembles.
Immunopathology
Disease is associated with HLA-B7 and B27.
DR4 is linked with a peripheral arthritis.
A gene has also been identified on chromosome 17.
Retroviral-like particles have been described in psoriasis.
There is a direct association of guttate psoriasis with streptococcal infections.
Major pathological process is overgrowth of keratinocytes, driven primarily by activated CD4+ T cells and the resultant release of cytokines and growth factors.
Psoriasis is associated with HLA Cw6 (also DR7, DQ3, and B57); B27 is associated with spondylitis.
Diagnosis
There are no specific immunological tests for psoriatic arthropathy.
Up to 10% of patients will be RhF positive (low titre) and may also have low-titre ANA and autoantibodies against skin antigens.
There is polyclonal hypergammaglobulinaemia.
Acute-phase proteins are elevated.
Anaemia is common and may be due to both chronic disease and folate deficiency from increased cell proliferation.
Increased cell turnover may cause hyperuricaemia and gout.
Treatment
The realization of the central role of T lymphocytes in psoriasis has led to a change in the approach to treatment towards immunomodulation.
Anti-TNF agents are extremely effective.
Care must be taken as some NSAIDs and antimalarials may exacerbate psoriasis.
Gold, penicillamine, hydroxychloroquine, methotrexate, sulfasaline, azathioprine, ciclosporin, PUVA, and retinoids have all been shown to be useful.
Reactive arthritis (including Reiter’s syndrome)
Clinical features
This group of diseases presents with a pauci-articular large-joint arthritis, accompanied by back pain (sacroiliitis) and non-articular symptoms:
balanitis, urethritis, and cervicitis keratoderma blennorrhagicum
pericarditis (with a long PR interval and non-specific T-wave changes)
conjunctivitis.
Immunopathology
Symptoms can be triggered by a variety of urogenital and intestinal infections, including Shigella, Salmonella, Campylobacter, Yersinia, Klebsiella, Proteus, Escherichia coli, Chlamydia, Mycoplasma, and Ureaplasma.
Also associated with inflammatory bowel disease and HIV infection.
55% of cases will be HLA-B27+, but most of these will be patients with spinal involvement.
Treatment
Standard treatment is with NSAIDs, together with treatment of the underlying infection or bowel disease.
Variable response to anti-TNF agents.
Bowel disease and arthritis
Other bowel diseases that are associated with arthritis include the following.
Coeliac disease (check IgA endomysial antibodies/tissue transglutaminase antibodies), which responds promptly to a gluten-free diet.
Intestinal bypass surgery/bacterial overgrowth (cryoglobulins may be present, and there may be cutaneous vasculitic lesions).
Whipple’s disease due to infection with Tropheryma whippelii (malabsorption with migratory arthritis; no specific tests apart from PCR-based detection of organism but hypogammaglobulinaemia may occur—see Chapter 7).
Systemic lupus erythematosus (SLE) and variants
SLE has taken over from syphilis as the great mimic. Clinical criteria have been defined by the American Rheumatism Association (ARA): 4 out of 11 criteria are sufficient to confirm the diagnosis (within a window of observation, not necessarily concurrently). However, many patients clearly have the disease even though they do not fit the criteria. SLE is strongly associated with other autoimmune diseases through a shared immunogenetic background.
Aetiology and immunopathology
There is a strong multigenic background to SLE. The main contributing factors are as follows.
Homozygous complement deficiency (especially C1qrs, C2, C4 deficiency).
TREX1 deficiency (X-linked gene): endothelial function gene.
HLA-A1, B8, DR3, other HLA genes associated with specific features and/or autoantibodies (DQw1, DQw2 with anti-Ro; DR2, anti-Sm. DQw6, 7, 8 with anti-phospholipid antibodies).
Multiple immune genes (STAT4, ITF5, IRAK1, PTPN22, OX40L among others).
Racial background (especially West Indian).
Female sex (M:F = 1:10-20).
Men with Klinefelter’s syndrome are at increased risk of SLE.
Mothers of boys with X-linked chronic granulomatous disease are at increased risk of lupus.
The precise cause of lupus is unknown, although a mouse model is known to be deficient in mechanisms for controlling lymphocyte apoptosis (fas).
Drugs may also trigger lupus, although the association for some of these is weak.
The likelihood of a drug causing problems is associated with acetylator status (slow acetylator status increases the risk).
SLE is the prototype immune complex disease, with evidence for incorrectly sized immune complexes being formed that are cleared inefficiently, in part due to an acquired reduction in the CR1 receptor on erythrocytes.
Many antibodies thought to be non-pathogenic are now known to be able to penetrate viable cells and interfere with an intracellular target enzyme. These include:
anti-dsDNA
anti-RNP
anti-ribosomal P antibodies.
This process is trypsin-sensitive.
Surface DNA-binding proteins and proteins with a similar structure to DNA will also bind anti-DNA antibodies and this may lead to alterations in cell function.
There is evidence of complement consumption, the level of which corresponds to disease activity.
FcgRIIA polymorphisms that reduce immune complex binding are associated with lupus nephritis.
Environmental factors contribute (e.g. UV-induced Ro antigen expression on keratinocytes, smoking, EBV exposure, silica exposure).
Clinical features (see Table 12.2)
There is no typical presentation and the disease may present to any organ specialist (see Table 12.2).
Any age group may be affected, but it is most common in younger women.
Fatigue, malaise, and weight loss are often marked in the prodrome.
Lymphadenopathy and splenomegaly are common.
Presentations with skin disease alone are of a more limited disease (which may progress), discoid lupus, and subacute cutaneous lupus.
C2-deficient lupus tends to give a very florid disease with marked cutaneous vasculitic symptoms and is invariably anti-Ro positive.
Arthritis with recurrent polyserositis is a common presentation.
A high index of suspicion for the disease is required.
Disease may be triggered by stress and by UV light (in patients who are photosensitive). The latter not only causes worsening of skin disease but also sets off systemic manifestations.
Infection may also trigger flares, but the role of immunization is more controversial.
As the disease often affects young women, pregnancy is a frequent problem.
The effect of SLE on pregnancy is unpredictable.
Conception is unlikely with severe active disease.
Disease may flare or remit during pregnancy.
Disease frequently flares post-partum (owing to sudden hormonal changes).
As autoantibodies are invariably IgG, they cross the placenta. Anti-Ro and possibly anti-La have been associated with the following.
Congenital complete heart block due to damage to the fetal conducting system.
Neonatal lupus that disappears as maternal antibody is removed from the circulation.
Complete heart block occurs in the children of 1 in 20 women positive for the antibodies, but if there has been a previously affected baby the risk rises to 1 in 4.
Table 12.2 Clinical features of SLE and associated antibodies | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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SLE: immunological testing
Detection of autoantibodies and complement abnormalities form the mainstay of diagnosis.
Full diagnostic screen must include:
anti-cardiolipin ± anti-β2GP-I, lupus anticoagulant
organ-specific autoantibodies (thyroid, gastric parietal cells, DCT, others as clinically indicated)
C3/C4
C2, particularly if atypical skin disease
serum immunoglobulins and electrophoresis
cryoglobulins if Raynaud’s is present.
Autoantibody testing
Antibodies to histones if drug-induced lupus is suspected.
Other antibodies may be sought, depending on clinical features (see Table 12.2).
Pattern of ANAs detected (on HEp2 cells) may give a clue as to other antibodies present (e.g. coarse speckled = anti-RNP), and should always be reported. Homogeneous ANAs are usually associated with antibodies to dsDNA and histones.
Multiple specificities may be present in a single patient.
A proportion of SLE patients have always been noted to be ANA negative: these patients are usually anti-Ro positive.
Rodent liver, widely used as a substrate for detecting ANA, has low levels of Ro antigen which may be leached out during the test procedure.
HEp-2 cells have much higher levels of Ro antigen, so the proportion of ANA-negative lupus falls when this substrate is used for screening.
Anti-Ku antibodies may be seen (but are also seen in other CTDs).
Certain subsets of dsDNA antibodies (not routinely measurable) appear to be specifically associated with glomerulonephritis.
Additional antibodies detected on ENA screening give further useful information.
Anti-Sm is a rare antibody that is highly specific for SLE and is found mostly in West Indians.
Anti-RNP may be found in SLE, but always with dsDNA (if anti-RNP is the only specificity, then MCTD is more likely; see ‘Mixed connective tissue disease (MCTD)’, p.283).
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