Connective Tissue Disease in Primary Care

Graham Davenport, MA, MSc, FRCGP

General Practitioner and Past President of the Primary Care Rheumatology Society

Reports on the Rheumatic Diseases Series 5 : Hands On

Introduction

Connective tissue diseases (CTD) are chronic inflammatory autoimmune disorders which can affect all connective tissues, i.e. joints, skin, muscles and blood vessels, and therefore have multiple effects on many different organs throughout the body. Although the commonest one is rheumatoid arthritis (RA), it predominantly affects joints, and is usually considered separately from other CTD, and therefore will not be discussed here.

CTD individually are very rare but most general practitioners (GPs) will have a few patients affected. They are usually managed in secondary or tertiary care but in view of their protean manifestations and multisystem effects, GPs have to be involved. GPs cannot expect to be knowledgeable about all the rare CTD but they need to be aware of the many common presentations and differential diagnoses, which investigations to carry out, how to monitor the treatment prescribed in secondary care and, most importantly, how to support these patients through a lifetime of chronic illness.

How do they present?

Patients with CTD commonly present with either (a) generalised arthralgia/arthritis or (b) Raynaud's phenomenon.

 

(a) Arthritis in systemic lupus erythematosus (SLE) is often asymmetrical and usually non-erosive but there is invariably considerable arthralgia, pain and early morning stiffness with a normal or marginally raised erythrocyte sedimentation rate (ESR). A proportion develop Jaccoud's arthritis with ulnar deviation, swan-neck deformities and subluxations. Absence of erosions and reversibility of the swan-neck deformities in early disease help to distinguish it from RA.

Practical tip If there are marked symptoms of arthralgia with associated pain and stiffness but little objective evidence of clinical synovitis, think of CTD.

 

(b) Raynaud's phenomenon is common in general practice and usually due to primary Raynaud's disease, but 10% is secondary to CTD which often have a number of other features suggesting individual organ involvement.

1. SLE is associated with a number of skin changes including malar rash, discoid rash, photosensitivity, livedo reticularis and alopecia.
   
   Practical tip The classic 'butterfly' malar rash of SLE spares the nasolabial folds, which helps to distinguish it from acne rosacea and seborrhoeic dermatitis.
   
   Asymptomatic proteinuria, pleurisy and pleural effusions, and neuropsychiatric symptoms (see red flags) can also occur.
   
   
2. Systemic sclerosis (SS) is characterised by the unique skin changes of scleroderma which include tightening and thickening of the skin, dermal atrophy, telangiectases and variable pigmentation. Calcinosis in the finger tips can resemble gouty tophi. SS is also associated with severe arthralgia.
   
   Pulmonary hypertension occurs especially in the CREST syndrome (see box):
   
   

   CREST syndrome Calcinosis Raynaud's phenomenon Esophageal hypomobility Sclerodactyly Telangiectases

   
   Depression occurs in 50% of patients with scleroderma.1
   
   
3. Dermatomyositis is associated with a distinctive purplish rash mainly on the face and hands, and periorbital oedema is often present. Gottron's papules are erythematous flat skin lesions over the interphalangeal joints. Profound muscle weakness occurs in polymyositis and dermatomyositis and is bilateral and symmetrical, affecting the proximal muscles of the shoulder and pelvic girdles.
   
   Practical tip Although patients with polymyalgia rheumatica (PMR) also have painful muscles which they are reluctant to use, there is no actual weakness.
   
   
4. Sjögren's syndrome is classically associated with kerato-conjunctivitis sicca (or dry eye syndrome), xerostomia (dry mouth), parotid gland enlargement, arthritis/severe arthralgia and Raynaud's phenomenon.

 

(c) Apart from arthralgia and Raynaud's phenomenon, CTD also present with non-specific syndromes:

• Fatigue, lethargy, aches and pains Most CTD can present with these very common and vague non-specific symptoms but before GPs put a label of chronic fatigue syndrome or fibromyalgia on these 'tired all the time' patients, it is vital to investigate and exclude CTD.
• Pyrexia of unknown origin (PUO) GPs are so used to seeing mild self-limiting viral infections that it is easy to forget and overlook the fact that fever is a frequent presentation of CTD, e.g. temporal arteritis is found in about 15% of patients over 65 years with PUO.
• Anorexia and weight loss These symptoms immediately make GPs think of malignancy but they occur frequently in all CTD – even fairly 'benign' conditions like PMR.
• Depression Depression is a common accompaniment to most chronic diseases and has multiple causes including chronic pain, insomnia, disability affecting work and family life and worries and fears regarding the future.
  
  Practical tip GPs can identify these patients by two simple questions:
  • During the last month, have you been bothered by feeling down, depressed or hopeless?
  • During the last month, have you been bothered by having little interest or pleasure in doing things?

  If a patient responds 'yes' to either question, then further screening with more detailed questionnaires is advised.

What are the red flags?

1. PMR is a disease of exclusion. The symptoms of pain and stiffness around shoulder and pelvic girdles, together with vague systemic symptoms of anorexia, fever, fatigue and weight loss, can occur in many conditions – especially occult malignancy. Patients who do not respond readily to 20 mg steroids daily need a reassessment of their diagnosis and a search for an underlying neoplasm.
   
   Practical tip It is important to measure the creatine kinase level to exclude the much rarer polymyositis and dermatomyositis.
   
   
2. Temporal arteritis It is important to remember that temporal arteritis is not just a localised inflammation of the temporal arteries but can be a generalised vasculitis affecting the larger arteries such as the subclavian and even aorta. It is therefore vital to distinguish it from PMR and treat with high dose corticosteroids, i.e. at least 60 mg daily (see box).
   
   
   

   Symptoms to ask about in all PMR patients Temporal headache (but can be occipital) Scalp tenderness around temporal artery which may be thickened and pulseless Pain in the jaw on chewing (jaw claudication) Marked systemic symptoms, e.g. fatigue, night sweats, fever, weight loss. Depression is not uncommon. Blurred vision or flashing lights. All visual symptoms need an emergency referral to prevent blindness.

   
   Practical tip Never delay starting steroids even if a temporal artery biopsy is readily available.
   
   
3. Raynaud's disease can be severe and cause an acutely ischaemic finger which requires emergency admission for intravenous prostacyclins. Raynaud's phenomenon may be due to primary disease but always look for an underlying CTD. Patients often complain of cold discoloured fingers but unless they go through the colour change from white to blue and finally red, usually associated with marked pain or discomfort, then they probably have not got Raynaud's.
   
   Practical tip To aid diagnosis, ask the patient to photograph their hands the next time it occurs (see photograph).
   
   
   
   
4. Septic arthritis An acute hot joint in a CTD, such as SLE, should not be considered a flare-up of disease activity until sepsis has been excluded. It is much commoner in the immunosuppressed and needs to be excluded by aspiration. Sepsis cannot be treated by oral antibiotics in primary care but needs admission for intravenous antibiotics.
   
   
5. Cerebral lupus is a serious condition occurring in up to 1 in 6 of SLE patients and can cause prolonged headaches, seizures, strokes, acute psychotic episodes and severe depression. It is usually associated with a flare-up in disease activity elsewhere. It is important to exclude other causes such as corticosteroid psychosis, sepsis and malignant hypertension. Non-steroidal anti-inflammatory drugs (NSAIDs) can cause cerebral symptoms of headache, confusion and giddiness which may be confused with cerebral lupus.
   
   Practical tip Depression in SLE is common but only a small proportion will be due to cerebral lupus.2
   
   
6. Increased cardiovascular risk Premature coronary artery disease due to accelerated atherosclerosis results in women with SLE having an increased risk of myocardial infarction equivalent to triple vessel coronary disease.3 Regular annual screening of SLE patients for cardiovascular risk factors is recommended with a low threshold for intervention, i.e. target blood pressure (BP) in SLE is 130/80 and target low-density lipoprotein (LDL) <2.6 mmol/l, and use of prophylactic low-dose aspirin in all SLE patients.4
   
   Practical tip Statins have recently been shown to have disease-modifying activity in SLE and therefore may have dual benefit in these patients.5
   
   
7. Osteoporosis Osteoporotic fractures can occur very quickly in patients with CTD who have started long-term treatment with corticosteroids. Bone loss is greatest in the first 6 months of treatment with fractures often occurring in the first 3 months.6 Patients placed on corticosteroids should be co-prescribed bisphosphonates as well as adequate calcium and vitamin D7 (see box). It is not acceptable to delay osteoporosis prevention treatment because 1 in 6 patients taking corticosteroids (>7.5 mg daily) suffer a vertebral fracture within a year. Bone loss induced by long-term steroid therapy is rapid but the increase in fracture rate is even more rapid. For a given bone mineral density, the risk of fracture in steroid-induced osteoporosis is twice as high as in post-menopausal osteoporosis.
   
   

   Royal College of Physicians' guidelines for the management of glucocorticoid-induced osteoporosis For patients aged over 65 years, or with a previous fragility fracture, the risk of osteoporosis is high; therefore, advise general measures and start treatment. Patients aged under 65 years without previous fragility fractures and who are starting oral corticosteroids for more than 3 months should have their bone mineral density (T-score) measured uding dual x-ray absorptiometry: T-score over 0: reassure and advise general measures T-score 0 to –1.5: general measures and repeat test in 1–3 years T-score less than –1.5: treat for osteoporosis.

   
   
8. Thrombosis Thrombotic episodes can occur in SLE but especially in the antiphospholipid (Hughes) syndrome (see box):
   
   

   Consider antiphospholipid syndrome in women who have: Recurrent miscarriage and placental insufficiency Venous and arterial thromboses Embolic phenomena: transient ischaemic attacks TIA) and cerebrovascular accidents (CVA) Thrombocytopenia

   These patients require long-term anticoagulation and close monitoring during pregnancy.
   
   In patients with CTD who are seeking contraceptive advice, there is no evidence that the combined oral contraceptive pill engenders any greater risk unless the patient has a positive lupus anticoagulant or cardiolipin antibodies, in which case it should be avoided.
   
   
9. Scleroderma crisis This occurs in SS as a result of rapidly increasing hypertension associated with deteriorating renal function, progressing to acute renal failure. Frequent monitoring of blood pressure in SS patients and early intervention with angiotensin-converting enzyme (ACE) inhibitors is essential to prevent a crisis.
   
   
10. Risk of malignancy GPs need to be aware of the increased risk of malignancy in some CTD, particularly in Sjögren's syndrome, SS and dermatomyositis. GPs need to retain a high index of suspicion in patients who develop a myositis and have risk factors such as a strong family history of malignancy, especially ovarian. These patients should be screened on presentation. Alveolar cell carcinoma of the lung can occur in SS, usually associated with pulmonary fibrosis. Immunosuppressive treatment may be associated with malignancy, e.g. cyclophosphamide and carcinoma of the bladder, azathioprine and non-Hodgkin's lymphoma. Conversely, occult malignancy, especially lung and breast, can present with a polyarthropathy or a polymyalgia-like syndrome.

How do I investigate?

The advantage for GPs is that the diagnosis of CTD is usually on clinical grounds and investigations can often add very little. Tests should only be ordered if there is reasonable clinical evidence to suspect a CTD rather than performing an 'autoimmune screen' in patients who are just unwell. This is because up to 15% of healthy women of middle age or older will have a positive antinuclear factor (ANF). The relevant tests are as follows:

1. Inflammatory markers ESR and C-reactive protein (CRP) are fairly non-specific tests which indicate the presence of inflammation and are useful to monitor disease activity as well as in the diagnosis of inflammatory joint disease. However, a normal ESR and CRP can occur in SLE and other CTD such as SS. An ESR can also be elevated in non-inflammatory conditions such as osteoarthritis and in normal individuals. It tends to rise with age, and women over 80 years can often have an ESR of about 40 mm. The ESR can be markedly elevated in temporal arteritis and in Sjögren's syndrome with levels of over 100 mm occurring frequently.
   
   
2. Full blood count Many patients with SLE will have a mild neutropenia and lymphopenia which suggest the need for further investigations in the arthralgic patient. Anaemia of chronic disease is common and may improve with control of disease activity. Other anaemias can occur such as haemolytic anaemia in SLE.
   
   Practical tip It is important to remember that not all anaemia is due to the disease process, e.g. all NSAIDs can cause upper and lower gastrointestinal bleeding and may be a cause of occult blood loss resulting in an iron-deficiency anaemia.
   
   
3. Autoantibody tests Antinuclear antibody (ANA) is often positive in low titre especially in the elderly and although a positive ANA test does not necessarily imply the presence of CTD, in the presence of appropriate symptoms it needs further investigation and referral to a rheumatologist. ANA are detected in approximately 80–90% of SLE patients, and is therefore the best screening test. However, some patients are ANA positive but have antibodies which recognise different sets of nuclear proteins, termed extractable nuclear antigens (ENA) (see box). The commonest is anti-Ro which is usually clinically associated with photosensitivity. Although additional tests such as complement levels and antibodies to dsDNA are highly specific for SLE, they have poor sensitivity and are usually associated with more severe disease activity and are not useful as diagnostic aids in general practice.
   
   In patients suspected to have scleroderma, the ANA is positive in 70–80%, although other specific ENA tests that are associated with the limited and diffuse subgroups (anti-centromere and anti-Scl-70) are only detected in approximately 50% and 25% respectively.
   
   Practical tip Rheumatoid factor, like ANA, is widespread in the normal population and can be positive in all the CTD as well as RA and therefore is of little use as a diagnostic tool.
   
   

   ENA antibodies
   RNP	SLE, scleroderma and 'overlap' CTD
   Sm	SLE (associated with risk of renal disease)
   Ro, La	SLE and Sjögren's (associated with photosensitivity and neonatal heartblock)
   Centromere	Limited cutaneous SS
   Scl-70	Diffuse cutaneous SS
   Cardiolipin	SLE and antiphospholipid syndrome (arterial and venous thromboses, mid-trimester foetal loss)

   
   
4. Urinalysis The simple tests are often the best – if a patient whom you suspect as having CTD has dip-test haematuria and proteinuria, after excluding infection pick up the phone to your local nephrologist!
   
   
5. Synovial fluid aspiration This can be helpful in the differential diagnosis from other conditions such as osteoarthritis and gout as well as excluding septic arthritis.
   
   Practical tip Ultrasound may be useful to distinguish erosive arthropathy from the non-erosive arthropathy of SLE.

How do we monitor these patients?

Treatment of CTD is usually initiated in secondary care and includes NSAIDs, corticosteroids and immunosuppressives.

1. NSAIDs Recent evidence of the increased cardiovascular risk with COX-2 inhibitors has resulted in guidelines from the European Medicines Agency to avoid their use in patients with established ischaemic heart disease, cerebrovascular disease and peripheral vascular disease. All NSAIDs are now thought to increase cardiovascular risk and GPs should try and avoid using them in hypertensive patients, patients with poor renal function, and elderly patients at risk of heart failure (see box).
   
   

   For patients on NSAIDs: Use the lowest dose for the shortest time Check for over-the-counter NSAIDs self-treatment Avoid co-prescribing with low-dose aspirin and ACE-inhibitors Monitor at least annually – blood pressure, full blood count, renal and liver function Consider that better control of the disease activity with immunosuppressives may enable reduction in NSAID dosage

   
   Practical tip Although NSAIDs are often useful in SLE they can cause deteriorating renal function or neuropsychiatric symptoms.
   
   
2. Corticosteroid therapy Ensure patients are carrying a steroid card and co-prescribe bisphosphonates and calcium with vitamin D if indicated. Monitor patients for the development of infections, diabetes and heart failure in the elderly.
   
   
3. Immunosuppressive drugs Monitoring of these drugs by protocols on computer templates has enabled these drugs to be safely used in primary care. Main side-effects:
   • Gastrointestinal, e.g. stomatitis and nausea with methotrexate which can often be resolved by folic acid treatment.
   • Bone marrow suppression can occur with all immunosuppressives and therefore regular blood counts are mandatory, especially with a dose increase.
   • Hepatic toxicity Patients on methotrexate should be advised not to drink alcohol.
   • Drug interactions Many drugs can increase the toxicity of immunosuppressives and all co-prescribing needs careful monitoring.
   • Pulmonary involvement Methotrexate can cause a pneumonitis which can be fatal if untreated. All patients on methotrexate who develop a persistent cough or dyspnoea need further investigations to exclude this condition.
   
   Practical tip Avoid live vaccines but ensure these patients have pneumococcal vaccination and an annual influenza vaccination.
   
   
4. Other symptom-specific treatments
   
   • SLE Photosensitivity can be minimised by prescribing sunblock creams for exposed parts.
   • Sjögren's syndrome Dry eyes and dry mouth of the sicca syndrome can be helped by artificial tears and saliva. Good dental care is also important.
   • Raynaud's disease All patients should be advised to stop smoking and to keep their hands warm. Beta-blockers should be stopped if possible. Drug treatment includes calcium channel blockers such as nifedipine, prazosin and topical nitroglycerin.

How do we support these patients?

Most CTD are chronic lifelong diseases with exacerbations and relapses and GPs are ideally placed to support patients with these conditions. Good communications, robust management plans and teamwork between primary and secondary care, using nurse practitioners, clinical nurse specialists and other allied professionals, will enable GPs to manage these patients in the community, but rapid access to secondary care during crises and relapses is essential. GPs have a critical role in education of the patient and directing patients to other sources of information and support. Empowerment of the patient to manage their own disease is a vital part of this education and the essence of the Expert Patient Programme. Expert patient and support groups are not just about managing the practical aspects of living with a chronic disabling condition. They enable patients to acknowledge, express and explore their fears and concerns and allow them to regain control over their disease.

Conclusion

There is no need for GPs to panic when confronted by a patient with a rare CTD. Although most GPs do not have rheumatological expertise, they have widespread knowledge and experience which will enable them to manage the multisystem effects of CTD. By partnership with the patient and a holistic approach, we can enable patients to retain control over their disease and to help them achieve the optimum quality of life.

COMMENT Professor Graham Hughes The London Lupus Centre London Bridge Hospital Connective tissue diseases are no longer regarded as 'small print' , rare diseases. Lupus, for example, is diagnosed with increasing frequency throughout the world. With a prevalence of up to 1 in 800 women, it is commoner than leukaemia or multiple sclerosis. The antiphospholipid (Hughes) syndrome is now regarded as the commonest treatable cause of recurrent miscarriage, as well as a major cause of stroke, migraine and deep-vein thrombosis. A third example, Sjögren's syndrome, is now regarded as a major connective tissue disease, causing chronic symptoms of fatigue and arthralgia in the over 50s, and often misdiagnosed as fibromyalgia, myalgic encephalomyelitis and so on. The 'take home' message with this family of diseases is to think of them. Diseases such as lupus, antiphospholipid syndrome, Sjögren's and myositis all have relatively easy screening tests such as the antinuclear antibody, anticardiolipin and creatine phosphokinase. The therapeutic rewards for early diagnosis and treatment of these diseases are considerable.

Other Titles in this series

• June 2008 No 15
  pGALS – A Screening Examination of the Musculoskeletal System in School-Aged Children
• February 2008 No 14
  Management of Shoulder Disorders in Primary Care
• October 2007 No 13
  Management of Back Pain in Primary Care
• June 2007 No 12
  Diagnosing Inflammatory Disorders
• February 2007 No 11
  Osteoporosis
• October 2006 No 10
  Common Foot Disorders
• February 2006 No 8
  Management of Cardiovascular Risk in RA and SLE
• October 2005 No 7
  Hypermobility
• June 2005 No 6
  An Exercise in Knee Pain Self-Management
• February 2005 No 5
  Chronic Knee Pain in the Elderly
• October 2004 No 4
  Anterior Knee Pain
• June 2004 No 3
  Carpal Tunnel Syndrome
• February 2004 No 2
  Plantar Fasciitis and Heel Pain
• September 2003 No 1
  Polymyalgia Rheumatica

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