12 Connective tissue disease

Rheumatoid arthritis: immunological tests, treatment, and childhood RhA

Juvenile chronic arthritis (JCA) and Still’s disease

Adult Still’s disease

Ankylosing spondylitis (AS) and related spondyloarthropathies

SAPHO syndrome

Psoriatic arthritis

Reactive arthritis (including Reiter’s syndrome)

Systemic lupus erythematosus (SLE) and variants

SLE: immunological testing

SLE: treatment and paediatric SLE

Drug-related lupus (DRL)

Sjögren’s syndrome

IgG₄-related chronic sclerosing dacryoadenitis

Undifferentiated connective tissue disease

Mixed connective tissue disease (MCTD)

Polymyositis (PM), inclusion body myositis (IBM), and dermatomyositis (DM)

PM/DM: diagnosis and treatment

Overlap syndromes

Systemic sclerosis (SSc): CREST and limited variants

SSc: diagnosis and treatment

Scleroderma mimics

Eosinophilic fasciitis (Shulman’s syndrome)

Anti-phospholipid syndrome (APS)

APS: diagnosis and treatment

Raynaud’s phenomenon

Livedo reticularis

Rheumatic fever

Fibromyalgia

Websites

An infectious trigger has been sought for many years, without success.

The best candidate pathogens are:

The genetic background includes:

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:

Amyloid is a long-term complication from chronic inflammation (p.338).

Large quantities of cytokines can be detected in the joint fluids.

Endothelial cell activation/production of chemokines is responsible for influx of inflammatory cells:

Autoantibodies are produced, including:

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.

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:

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.

True P-ANCA may be found in RhA vasculitis.

Associated Sjögren’s syndrome will be accompanied by the presence of antibodies to Ro and/or La.

In active disease, both CRP and ESR will be elevated.

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).

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:

Immunotherapies with biological agents include:

Other agents undergoing trials include:

Problems with all mAb-based therapies have included:

Surgical replacement of damaged joints may restore function and relieve pain.

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.

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.

Still’s disease typically has a high spiking fever, accompanied by malaise and rigors.

ANAs are frequently present, and it is important to ensure that the normal range for significance is appropriately adjusted for the paediatric population:

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.

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.

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.

RhF and ANA will be negative.

Ferritin levels may be exceptionally high and disproportionately elevated when compared with other acute-phase markers.

NSAIDs, corticosteroids, and DMARDS are all 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.

More common in men than in women.

May be associated with inflammatory bowel disease.

Complications include:

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.

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.

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.

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.

Arthritis is frequently asymmetrical and spinal involvement is common, in contrast with RhA, which it most resembles.

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.

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.

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.

keratoderma blennorrhagicum

pericarditis (with a long PR interval and non-specific T-wave changes)

conjunctivitis.

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.

RhF and ANA will be absent. Atypical P-ANCA may be seen where there is inflammatory bowel disease.

Variable response to anti-TNF agents.

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).

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.

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:

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).

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.

As autoantibodies are invariably IgG, they cross the placenta. Anti-Ro and possibly anti-La have been associated with the following.

Full diagnostic screen must include:

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.

Antibodies to dsDNA should be checked regardless of the ANA result if SLE is suspected.

Additional antibodies detected on ENA screening give further useful information.

Anti-C1q antibodies appear to be associated with lupus nephritis, as well as with urticarial vasculitis.

ANCA may also be found in SLE, although it is difficult to identify these accurately in the presence of high-titre ANA. Solid-phase assays with specific antigens (PR3 and MPO) help here.

Antibodies to lipoprotein lipase have been associated with the pathogenesis of lupus nephritis (in association with antibodies to dsDNA and ribosomal P antigen).

Rheumatoid factors are usually present but contribute little to the diagnostic process.

For investigation of anti-phospholipid antibodies, see ‘Anti-phospholipid syndrome (APS)’, p.294.

Severe difficulties in diagnosis may occur as ANAs may frequently be found in chronic infection, including bacterial endocarditis and particularly infection with enteric organisms, and in association with drugs—phenothiazines, ACE inhibitors, minocycline (see ‘Drug-induced lupus (DRL)’, p.278).

C4 reductions are common and do not reliably relate to disease activity, as C4 null alleles are common.

When disease is quiescent, the following rule of thumb applies.

C3 levels are reduced in active disease although, because of an acute-phase response with increased synthesis, the level may not drop below the lower end of the normal range.

A measure of C3 breakdown is required (C3d), but suitable assays for routine diagnostic laboratories are now limited.

Measuring haemolytic complement as a monitor of disease activity is too crude and is not recommended.

Measurement of haemolytic complement is essential when SLE is thought to be due to a complete deficiency, and this testing should always be followed up with measurement of individual components.

Genetic testing for deficiency may be required.

Assays of immune complexes are difficult (impossible?) to standardize and add little to the management.

Rare patients with acquired angioedema may have antibodies to C1q or C1 inhibitor.

Renal biopsy may be helpful in view of the wide range of histopathological abnormalities that may be identified.

Electrophoresis of serum may show a reduction in the β-region due to low C3 and a reduced albumin, and a raised α2-band will be seen if there is a nephrotic syndrome.

IgA deficiency is common in SLE, and rare patients may be pan-hypogammaglobulinaemic (distinct from hypogammaglobulinaemia secondary to aggressive immunotherapy).

Cryoglobulins, if present, will be type II or type III.

High CRPs in patients with SLE suggest intercurrent infection (which may be hard to distinguish from a flare).

Regular monitoring of creatinine and electrolytes, LFTs, TFTs, and urine (casts, red cells, protein) are all essential.

Imaging is essential to confirm organ-specific problems, and MRI is particularly valuable.

Complement studies and acute-phase markers give an indicator of current activity, although this must always be interpreted in the light of clinical symptoms.

There is no value in monitoring ANA titres.

Frequency of monitoring depends on disease activity and the type of drugs being used (i.e. more frequent when cytotoxics are being used).

It is worth rechecking full serology every so often (every 6–12 months) as antibodies may come and go, and the clinical disease pattern may evolve or change in parallel.

As the half-life of antibodies is about 3 weeks, measurements of autoantibodies are rarely of value more frequently than monthly (unless a patient is being plasmapheresed).

Rashes can be treated with topical steroids.

Sunblocks are essential in sunny climes.

Fatigue, arthralgia, and skin disease respond well to antimalarials: hydroxychloroquine is the safest. Mepacrine is an alternative (beware skin discoloration).

Systemic disease usually responds to low-dose steroids (20–30mg/day). Azathioprine (2–4mg/kg daily—check TPMT level first) can be used as a steroid-sparing agent.

Mycophenolate mofetil (MMF) is an alternative to azathioprine (and is valuable where there is renal disease).

Methotrexate (weekly oral or SC) is now being used for arthritis.

More serious organ involvement (e.g. glomerulonephritis, haemolytic anaemia) requires aggressive therapy with pulsed IV steroid with IV (5–10mg/kg/pulse) or oral (2–4mg/kg daily) cyclophosphamide.

Neurological involvement is difficult to treat and there is no consensus. High-dose steroids can be tried but may be more likely to trigger a steroid psychosis. The role of cytotoxics is uncertain.

Plasmapheresis may be an adjunct in severe disease while waiting for a clinical effect from cytotoxics, but should not be used alone because of potential rebound worsening of the disease.

In pregnancy, if possible avoid drugs other than prednisolone (metabolized by placenta).

IVIg should be used only with care as it may make the immune complex component of the disease worse (contraindicated if there is a high-titre RhF, renal impairment (high dose)).

Aim should always be for the lowest dose of treatment compatible with maintaining remission.

Immune ablation with stem cell transplantation has been used for severe disease in adults and children.

Rituximab (anti-CD20), in combination with corticosteroids and cyclophosphamide has been used in refractory disease

Other anti-B cell agents are undergoing trials

Anti-T cell treatments undergoing trials:

Oral contraceptives are not contraindicated, but low-oestrogen or progesterone-only pills should be used.

Splenectomy may be required for thrombocytopenia where this is antibody mediated and resistant to immunosuppressive therapy. Great care needs to be taken with these patients in view of the increased infective risk.

Patients on any form of immunosuppressive therapy need to have their humoral and cellular immune status monitored (see Box 12.3), and preventive measures, such as low-dose co-trimoxazole and antifungals, may be required.

Anti-phospholipid syndrome requires anticoagulation (see p.296).

Difficulties arise because the marker antibodies are frequently not present until the child has been ill for some time, making diagnosis difficult. There is also often overlap of symptoms with childhood CTDs.

Before puberty, the male to female ratio is increased compared with that in adults (1:5).

The use of diagnostic tests should be applied just as in adult disease. However, where there is a high suspicion of disease, but no antibodies, tests should be repeated at regular intervals (every 2–3 months) as antibodies may appear later.

Chemical features of drugs associated with DRL include the presence of:

Patient factors include:

Specificity of anti-nuclear antibody is usually but not exclusively anti-histone (>95%):

The presence of ANCA has also been associated with hydralazine-induced lupus (with glomerulonephritis)

It is important to take a clear drug history when patients are identified with ANCA in order to exclude the possibility of drug-induced lupus.

Symptoms tend to be mild.

Patients with persistent symptoms should be treated in the normal way.

There is an immunogenetic background, shared with other autoimmune diseases, including B8 and DR3. There is a strong association, independent of ethnic background, with DQA1*0501.

B-cell activating factor (BAFF) is elevated, especially in patients with hypergammaglobulinaemia. Possibly produced by glandular epithelial cell in response to type I interferons.

CD40⁺ B cells more resistant to apoptosis.

Proto-oncogenes are also expressed, and the disease is frequently accompanied by monoclonal expansion of B cells within the glands, accompanied by IgMκ paraprotein production and the development of type II cryoglobulins.

Disease may terminate in frank lymphoma, usually extra-nodal low-grade B-cell lymphomas.

Antibodies to A-fodrin may be associated with the disease.

There may be subclinical pancreatitis.

Fatigue and malaise are marked and early features.

Arthralgia, arthritis, and fibromyalgic pain are common.

Interstitial lung disease may be found on CT scanning.

A Fanconi syndrome may occur.

Both CNS and peripheral nerve involvement have been reported.

Features of other autoimmune diseases will be present.

Raynaud’s may be present if there are cryoglobulins.

Salivary glands may be enlarged. Lymphadenopathy should always be taken seriously if it does not settle once local infection has been dealt with (risk of lymphoma). Consider CT of salivary glands ± biopsy.

Biopsy of minor salivary glands may be diagnostically useful.

Secondary Sjögren’s appears to be more limited (sicca symptoms).

Clinical diagnosis may be made by Schirmer’s test (normal >15mm wetting in 5min; <5mm is abnormal); Rose Bengal staining of the cornea may demonstrate corneal damage.

Typically associated with anti-Ro antibodies (both Ro52 and Ro60) and anti-La antibodies.

If ANA is negative and primary Sjögren’s syndrome is suspected, salivary gland antibodies may be helpful.

HEp-2 screening may also pick up other specificities known to be associated, such as antibodies to the Golgi body and the nuclear mitotic apparatus.

RhF will be found in 90% of patients developing arthritis, 70% will be positive for anti-Ro, and 40% for anti-La. ANA will usually show a fine speckled appearance. DsDNA will be negative.

Thyroid antibodies are common (30%) and mitochondrial antibodies will be found in those going on to develop PBC.

Complements will usually be normal or elevated (this is not a complement-consuming disorder). Low levels should raise questions about the primary underlying diagnosis.

There is invariably a marked restricted-clonality hypergammaglobulinaemia, often with IgMκ paraproteins on immunofixation.

Increase in IgG is restricted to IgG1, with reductions seen in IgG2, IgG3, and IgG4, hence the electrophoretic appearances. Therefore measurement of IgG subclasses is a helpful adjunctive test, as no other conditions except myeloma give this pattern.

Cryoglobulins should always be sought, particularly if there is any cutaneous involvement.

β₂-microglobulin should be monitored as a marker of lymphoproliferation.

ESR and CRP are high, with an anaemia of chronic disease.

Raised alkaline phosphatase of liver origin may indicate PBC.

Thyroid function must be checked at baseline and regularly thereafter.

Long-term monitoring of patients should be undertaken at the clinical level. Regular checks for paraproteins and evidence of lymphoproliferation are essential.

Clinical checks should include thyroid and liver, in view of the strong association with Sjögren’s syndrome.

There is no value in monitoring the autoantibodies, unless there is a clinical change.

Hydroxychloroquine is valuable for the arthralgia and fatigue.

Topical ocular ciclosporin has been approved by the FDA.

The role of steroids and cytotoxics is less clear, and it has been suggested that these may increase the rate of progression to lymphoma. However, they are necessary if there is extraglandular involvement and/or vasculitis.

Methotrexate (weekly orally or subcutaneously) may be used.

Anti-TNF drugs do not appear to be helpful.

Other biological agents (rituximab, epratuzumab) are undergoing trials.

Long-term follow-up needs to be instituted for early identification of malignancy.

Refer all suspicious persistent swellings for CT/MRI and biopsy.

Inflammatory sclerosing masses with plasma cell infiltrates in submandibular and lacrimal glands.

IgG4 significantly raised without changes in other IgG subclasses (unique abnormality that is diagnostic).

Responds to corticosteroids.

Typical features include:

Such patients need to be treated symptomatically while being followed clinically and serologically (testing as for lupus, see ‘SLE: immunological testing’, p.272).

Capillaroscopy may identify abnormalities.

Some patients with chronic fatigue may have positive ANA and/or low C4. These need to be followed to exclude the possibility of a prodromal CTD.

Interval measurement of ENA antibodies is helpful (every 6–12 months).

Some will resolve spontaneously and others will progress to a more clearly defined disease.

Early intervention with DMARDs may alter the natural history.

Serositis, leucopenia, thrombocytopenia, sclerodactyly, pulmonary fibrosis (with reduced gas transfer, 70%), pulmonary hypertension (major cause of death), and aseptic meningitis may also occur.

Trigeminal neuropathy may occur in 10%.

Fatigue and malaise are common in the prodrome.

Up to 50% of patients develop nephritis.

Cryoglobulins may be detected.

C3/C4 may be reduced.

Autoantibodies show a coarse speckled ANA, absent or low level of anti-dsDNA antibodies, and strongly positive anti-U1 RNP (90–100% of true MCTD patients).

Presence of high levels of anti-dsDNA suggests SLE not MCTD.

RhF is positive in 40–60%.

Anti-phospholipid antibodies may be associated with pulmonary hypertension.

ESR/CRP are elevated and there is an anaemia of chronic disease.

Thrombocytopenia may be due to anti-platelet antibodies or the presence of anti-phospholipid antibodies.

CK may be elevated from muscle involvement but also in aseptic meningitis and trigeminal neuropathy.

Steroids plus cytotoxic agents (azathioprine, cyclophosphamide) are used for severe organ involvement. Methotrexate is used where there is evidence of erosive joint disease.

Anticoagulation is used for the anti-phospholipid antibodies (see p.294).

Raynaud’s phenomenon (see p.296).

Other organ-based symptoms are managed appropriately.

PM and IVBM are associated with HLA DR3 (DRB1*0301 and DQB1*0201) and DRw52 (75% of cases.

Juvenile DM is associated with DQA1*0501.

Older patients tend to be more affected, but the diseases can occur at any age.

In adult patients there is a strong association with underlying malignancy:

Seasonal variations have been noted in onset.

Muscle infiltrate with both CD4⁺ and CD8⁺ T cells.

B cells seem to play little role, and the pathogenicity of the autoantibodies known to occur is uncertain.

Complement is involved in the muscle fibre destruction.

A very wide range of autoantibodies have been identified, although many are not routinely available through diagnostic laboratories. The PM/DM-associated antibodies comprise one of the most complex sets of any autoimmune disease (see Table 12.3).

Most important antibody is anti-Jo-1. This antibody, together with the rarer antibodies (Table 12.3), identifies the anti-synthetase syndrome.

Other antibodies, recognizing other nuclear antigens, have been identified.

Polymyositis may occur as part of overlap syndromes, such as:

Amyopathic DM may be associated with antibodies to CDM-140.

Gottren’s papules are often seen on the knuckles, and the typical heliotrope rash around the eyes and a generalized erythematous rash (may be photosensitive) mark out DM.

Signs of inflammatory arthritis and scleroderma; ‘mechanic’s hands’ (thickened, cracked skin) identify the anti-synthetase syndrome.

Dyspnoea from lung involvement (interstitial lung disease). If there is accompanying pain, pulmonary embolus may be suspected.

Although the heart is rarely involved, presentations with atypical chest pain used to be diagnostically difficult due to raised CK. This is less of a problem since the introduction of cardiac-specific troponins as diagnostic test for myocardial damage.

Diaphragmatic involvement typically leads to dyspnoea when lying flat.

Gastrointestinal disease may occur (slowed transit, reflux).

Renal disease is rare, but high serum myoglobin levels may trigger renal impairment if there is very active myositis.

MRI is excellent at identifying affected muscles non-invasively. Biopsy may not be necessary in a typical presentation associated with typical autoantibodies.

Lung function tests, including gas transfer, mouth pressures, and CT of lungs, are essential.

Anti-Jo-1 recognizes primarily a cytoplasmic antigen. This will not be recognized on rodent liver. If PM/DM are suspected, screening on HEp-2 cells is most revealing as many of the cytoplasmic and nuclear antigens associated with myositis can be identified from the patterns of staining. Antibodies to Jo-1 should be specifically requested.

Mi-2 antibodies are preferentially associated with DM rather than PM.

Nucleolar ANA may also be seen, although these may also be found in patients with scleroderma.

Antibodies to Ku, SRP, Mi-2, PM–Scl, and other synthetases may be available from certain specialist centres.

Failure to control disease with acceptable levels of steroids is an indication for second-line therapy:

Both steroids and cyclophosphamide can be given as intravenous pulse therapy, particularly if there is progressive lung disease.

Intolerance of, contraindications to, or failure of first- and second-line agents should lead to consideration of the use of high-dose IVIg.

Patients with malignancy-associated PM/DM respond poorly to immunosuppressive therapy, as do those with the anti-synthetase syndrome and IBM.

Rituximab has been used in resistant disease.

Hydroxychloroquine may help in resistant skin disease.

Infliximab and etanercept have both been used in small series.

‘Rhupus’: a form of lupus with more aggressive destructive arthritis more typical of rheumatoid arthritis, but with other typical lupus features.

Polymyositis–scleroderma overlap: features of polymyositis and scleroderma, although the myositis may be mild.

SLE–myositis overlap: features of SLE with prominent myositis.

Childhood onset is rare.

A wide range of MHC antigens have been associated with scleroderma variants, including DR1, DR3, DRw52, DR5, although there is significant racial variation.

Choctaw Indians in Oklahoma have a very high incidence of SSc associated with abnormalities in the fibrillin-1 gene FBN1.

Chromosomal abnormalities (ring chromosomes, chromatid breaks, etc.) are common in SSc—significance is uncertain.

Parvovirus B19 has been associated with SSc development.

Strong association of scleroderma-like conditions with environmental factors:

Precise immunological involvement is unclear, but targets include endothelial cells and fibroblasts, with cytokine production leading to increased collagen synthesis.

Obvious vascular changes, such as vasomotor instability (Raynaud’s), but also direct damage to blood vessels, such as can be seen in nailfold capillaries.

Unlike other connective tissue diseases, there is very little in the way of a systemic inflammatory response and CRP/ESR may be low or normal.

A variety of autoantibodies have been identified (see Box 12.7), although the significance of some of them has not been fully elucidated (see Part 2).

Increased TGF-β and platelet-derived growth factor (PDGF) may play a role in the fibrosis.

Scleroderma-like disease is seen in chronic GvHD. In SSc, microchimerism due to persistence of fetal cells in the mother or

maternal cells in the child is common and may be the triggering event (i.e. SSc is a naturally occurring chronic GvHD).

Raynaud’s phenomenon is severe.

CREST syndrome has a more generalized involvement, and may give rise to late pulmonary hypertension, but less often to renal involvement.

Systemic sclerosis, on the other hand, leads to major renal and lung involvement. Involvement of the kidney may lead to rapid onset of severe hypertension and renal failure due to obliteration of the glomeruli (scleroderma kidney).

Lung disease includes interstitial fibrosis, an increased risk of carcinoma, bronchiectasis, and pulmonary hypertension.

Gastrointestinal involvement leads to severe oesophageal reflux, malabsorption due to poor small bowel motility, and bacterial overgrowth. Secondary problems may arise from a deficiency of key vitamins and minerals. Poor colonic motility may lead to pseudo-obstruction.

There is an association with thyroid disease, primary biliary cirrhosis, and rare neurological involvement (neuropathy).

The vascular disturbance may lead to ischaemia of the ends of digits which, if not treated rapidly, will lead to dry gangrene and progressive reabsorption of the terminal phalanges.

Systemic forms are often accompanied by a prodrome of malaise and fatigue.

Rarely, there may be renal and lung involvement without cutaneous involvement.

Assays for individual nucleolar antigens are not routinely available, apart from RNA Pol III.

In the CREST syndrome there may also be antibodies to the M2 antigen (25%). 30% will be positive for rheumatoid factor.

ESR/CRP will be low.

All patients should be screened for thyroid disease.

All patients with Raynaud’s should also be checked for cryoglobulins.

Thermography is useful to confirm abnormal responses to cold challenge.

Nailfold capillaroscopy is valuable for diagnosis and objective monitoring of progression.

Baseline lung function, including gas transfer, CXR ± CT scanning should be carried out for all systemic forms.

Echocardiography should be carried out to monitor for the development of pulmonary hypertension.

Renal function needs to be assessed at presentation and then monitored regularly.

No immunological tests are valuable for monitoring.

NSAIDs and steroids should be avoided if possible as they may worsen or trigger the development of renal crises.