LUPUS: A GP Guide to Diagnosis
It would be wrong to suggest that the management of lupus is easy. The disease has numerous manifestations and each person has their own pattern of disease which can change over time, sometimes very rapidly. In general, patients who present with severe lupus, e.g. of the kidneys or CNS, tend to have persistent serious disease. Patients who have mild disease may continue to have mild disease but, as time goes by, many will develop more serious manifestations, so constant vigilance is required.
Treatment of specific disease manifestations is dealt with in the relevant chapters so an overview of the drug management is given here. Treatment depends upon clinical assessment of the extent of organ involvement and also of its severity (Table 1).
Tests are dealt with in 'Testing for Lupus'. However, clinical assessment of disease activity is as important as the results of laboratory tests. Tiredness, fever or mood disturbance can indicate a flare of disease, as well as more obvious manifestations such as rash or arthritis. Where there is significant internal organ involvement then appropriate tests can be used to assess disease activity e.g. serum creatinine, urinary protein or lung function tests. Otherwise, it is often possible to identity a test which reflects disease activity in an individual patient. This may be the DNA binding level, the serum C4 or C3 concentration, the white cell count, haemoglobin or even the ESR. Such clinical and laboratory assessment helps one to decide whether it is necessary to use more aggressive treatment or, alternatively, whether the dose of medication can be reduced.
It is reasonable to divide lupus into mild, intermediate or severe disease, although even in mild disease symptoms such as malaise or arthralgia can be very disabling. The main therapeutic agents are shown in Table 2, although other drugs may be used in specific circumstances and are discussed in the relevant chapters. The management of clotting problems associated with antiphospholipid (cardiolipin) antibodies is fully discussed in 'Hughes Syndrome' and of lupus in pregnancy in 'Pregnancy & HRT'.
Common manifestations are arthralgia, rashes, photosensitivity and fatigue. Often symptoms can be reasonably controlled by NSAIDs and measures to reduce sun exposure, including use of high number sunscreens. Hydroxychloroquine is often useful in this type of disease and when combined with NSAIDs can usually keep patients fairly comfortable. However, fatigue may be disabling despite control of other symptoms and may justify the use of low dose steroid e.g. prednisolone 5-7.5mg daily. Higher doses of steroid should generally be avoided in this type of disease since the risk of toxicity is likely to outweigh benefits.
This category includes those with pleurisy, pericarditis, severe rashes and haematological manifestations such as thrombocytopenia and leucopenia. In such cases steroids are usually required. The aim is to use a dose sufficient to control the disease and then reduce it to as low a maintenance dose as possible. It is difficult to generalise regarding dose. Pleurisy can usually be controlled by about 20mg prednisolone daily whereas haematological features may require doses of 1mg/kg for disease suppression.
Hydroxychloroquine may be adequate in conjunction with steroids but often immunosuppression is required. Azathioprine has been used most widely but recently methotrexate and cyclosporine have proved useful in some cases. All of these drugs take some time to take effect, e.g. 1-3 months, and during this period steroids will be required in a dose sufficient to control the disease. Once the patient is stabilised on the immunosuppressive drug every effort should be made to reduce the dose of steroid to the lowest at which disease control can be maintained.
Renal, CNS and severe skin or haematological disease fall into this category. Steroids will inevitably be required plus an immunosuppressive drug. Prednisolone 1mg/kg or pulsed intravenous methylprednisolone may be needed to bring the disease under control. Hydroxychloroquine is rarely adequate in this type of disease. Azathioprine or methotrexate may be useful for their immunosuppressive and steroid-sparing effects but many patients will require more vigorous treatment with cyclophosphamide. This can be given either as intermittent intravenous bolus infusions or in a daily oral regimen. The dose and frequency used will depend upon the severity of disease, e.g. acute cerebral vasculitis may require weekly intravenous cyclophosphamide plus pulsed intravenous steroid whereas subacute disease such as deteriorating renal function may respond to monthly intravenous cyclophosphamide and oral steroids.
Additional treatments sometimes used in severe lupus include intravenous immunoglobulin and plasma exchange. The former is widely used for thrombocytopenia but can be helpful for other manifestations. Plasma exchange is used less frequently now than in the past but many still believe that it can be helpful in acute, severe disease, particularly cerebral lupus.
The correct use of steroids is the key to the management of lupus. The disease may be under-treated but a more common mistake is to continue high dose steroids for too long. Mild disease may respond to 5-10mg prednisolone daily. For more severe disease 20-40mg may be required and for severe disease 1mg/kg or more, or the use of pulsed intravenous methylprednisolone. Every effort should be made to taper the dose to the lowest possible dose sufficient to maintain disease control. In patients who have had severe disease there is often a flare-up when the daily prednisolone dose is reduced to between 7.5 and 15mg daily and this should be borne in mind when monitoring the patient.
Increased susceptibility to infection is a major concern, especially in those who are also on immunosuppressive drugs. Steroids may aggravate hypertension which probably contributes to the increased cardiovascular mortality in lupus. Steroid-induced osteoporosis is also a big worry. A daily dose of 7.5mg prednisolone will reduce bone density and osteoporosis is common in patients with lupus on long-term steroids. Ideally, patients on steroids should have their bone density measured every one to two years but the lack of DEXA machines in many districts means that this is not always possible. Cyclical etidronate (didronel PMO) now has a product licence for the prevention of steroid osteoporosis and there is a strong case for all post-menopausal women on steroids to go onto this drug. Other patients on long-term steroids should also be considered for this treatment. Osteonecrosis (avascular necrosis) is also fairly common and seems to be associated particularly with the use of high-dose oral steroids or pulsed intravenous methylprednisolone.
Hydroxychloroquine is generally preferred to chloroquine because the risk of ocular toxicity is believed to be greater with the latter. Ocular toxicity is related both to the daily and cumulative dose and the daily dose should not exceed 6.5mg/kg lean body weight. So long as this dose is not exceeded the risk of eye problems is very small. The manufacturers recommend a baseline ophthalmological check and regular 6-monthly review but, recently, the Royal College of Ophthalmologists has recommended that patients should have baseline and annual vision acuity checks performed by the prescribing doctor and be referred to an ophthalmologist only if a visual problem is identified at baseline or reduced acuity or blurred vision develop on treatment. The addition of mepacrine 50-100mg daily may be useful in those not responding to hydroxychloroquine alone.
This is generally used in a dose of 1-2.5mg/kg. Nausea is not uncommon while leucopenia and thrombocytopenia occur in some 4% of cases. This can be a problem if patients already have such features of their disease. In general, a full blood count is required every 2 weeks for the first 2 months of treatment and monthly thereafter, but more frequent monitoring will be required if there is pre-existing leucopenia or thrombocytopenia.
This is used in a once weekly regimen typically starting at a dose of 7.5mg per week, building up to 20mg weekly if required. Many rheumatologists also give folic acid 5-10mg once weekly (not on the same day as the methotrexate) to reduce the risk of side effects. Nausea and mouth ulcers are not uncommon and leucopenia, thrombocytopenia and abnormal liver function tests occur occasionally. Blood counts and liver function tests are monitored as for azathioprine.
This is used in a dose of 2.5-5mg/kg daily. Hypertension and an increase in serum creatinine are common and this makes it difficult to use in lupus where such features are often already present. Careful monitoring of blood pressure and creatinine are essential.
This is being used increasingly in patients with lupus and internal organ involvement. It has been shown to improve the outcome of renal disease to a greater extent than steroids alone. Most rheumatologists regard it as essential for the treatment of severe CNS, renal or pulmonary disease and other serious manifestations. It can be given in a daily oral dose of 0.5-2mg/kg or as intravenous infusions. The dose and frequency of intravenous infusions vary according to disease severity, but doses of 7.5-15mg/kg every 1 to 4 weeks are used commonly.
The main hazards are increased risk of infection, ovarian failure, bladder toxicity and increased risk of subsequent malignancy. The risk of haemorrhagic cystitis can be reduced somewhat by giving MESNA concurrently. Ovarian failure is closely related to the dose given and also the age of the patient - over 25 the risk increases significantly. In young women who want children subsequently, ovarian harvest and storage of eggs should be considered.
This is a recognised treatment for thrombocytopenic purpura and can be helpful for other manifestations of lupus. The mode of action is unclear but saturation of Fc receptors and alteration of the idiotypic network are possible mechanisms. It is usually given in a dose of about 0.5g/kg as an intravenous infusion on three consecutive days and repeated at intervals depending on response.
In certain circumstances other drugs may be needed to control specific disease manifestations or when more commonly-used drugs prove ineffective. These include mepacrine, quinacrine, danazol, dapsone, acitretin, thalidomide and clofazimine and are discussed elsewhere in this guide.
The management of lupus requires careful disease monitoring and interpretation of laboratory results and judicious use of the available drugs. It involves a constant struggle to strike the correct balance between under-treatment and over-treatment of the disease. Patients are often well informed about their disease and should be viewed as partners in disease management. Close collaboration between GP and specialist is essential for optimal disease management.
Table 1 - Questions to ask in the management of Lupus What are the disease manifestations? |
Table 2 - Drugs used for Lupus NSAIDs |
Dr. Robin Butler
Consultant Rheumatologist
Leopold Muller Arthritis Research Centre
Robert Jones & Agnes Hunt Orthopaedic Hospital
Oswestry
Shropshire, SY10 7AG