LUPUS: A GP Guide to Diagnosis
There is no doubt that lupus runs in families suggesting a genetic contribution to the disease. Family members of a patient with lupus have an estimated 3-10% chance of developing the disease themselves although, frequently, it is not lupus that develops but another connective tissue disease such as Sjögren's syndrome or MCTD. Amongst identical twins the risk of lupus rises to between 30-40%. There are some early studies which find a much higher association, however, many of these were probably subject to ascertainment bias. The fact that the penetrance is not 100% suggests strongly that factors other than genetics are important in the development of the disease. Such factors could be either environmental or random. Random genetic events include recombination of T cell receptor and immunoglobulin which may contribute to the pathogenesis of the disease. This theory would be concordant with the observation that most twin studies have shown that the time of onset of disease can vary enormously between identical twins even though they effectively have identical genetic makeup and are exposed to the same environmental agents. The genes which are now known to be important in predisposing towards lupus are the DR genes, the complement genes, the X chromosome and race.
The DR genes are a set of polymorphic sequences located on chromosome 6. They are critically important in presenting antigen to responding T cells and there is now increasing evidence that different DR genes have particular preferences for different antigens. A number of epidemiological studies have examined associations between DR and lupus and all are agreed that DR2 and DR3 are increased compared to the general population. The reason for this association is not clear. Work from the late '70s has suggested that patients who are DR3 positive, in particular, have defective clearance of immune complexes, although more recent work suggesting a specific binding of individual peptides of autoantigens may be more important.
Complement is critical in the pathogenesis of lupus. Patients with homozygous complement deficiencies have a very high frequency of lupus. For example, lupus or lupus-like syndromes occur in 80% of patients with total C1q deficiency, approximately 60% of those with C2 deficiency and about 30% of patients with C4 deficiency. Complement is also important for protection against intracellular infections, though why it should be protective in lupus is still a mystery. It is possible that complement is important in the clearance of immune complexes which themselves are thought to be involved in the pathogenesis of disease. The complement gene, C4, has two different loci, C4a and C4b. Absence of one of the loci, C4a, is quite common in the healthy population and is considerably commoner in patients with lupus, however, those who lack this gene on one chromosome almost always have it on the other. In addition, any patients with C4a deficiency are likely to have both copies of C4b, so true C4 deficiency is extremely rare. The C4a null gene, however, is more common in lupus compared to the normal population though this may be because the C4 loci also lie on chromosome 6 and C4a null is in linkage disequilibrium with DR3.
Lupus is approximately 9 times more common in women than men, suggesting that either it is a factor directly connected with the presence of two X chromosomes or, more likely, an indirect effect associated with sex hormones. Lupus is uncommon before the menarche and in most cases also relatively mild when it occurs post-menopausally. Both in vitro and work in animal models suggest that oestrogens in particular have a pro-inflammatory effect and are liable to make lupus worse, whereas the opposite is observed with androgens and to a lesser extent progesterones. Apart from conferring risk, the implication of this is that hormone replacement therapy (HRT) and oral contraceptives should be used with extreme caution with patients with lupus, though some recent studies have suggested that HRT may be safe in patients with late onset disease. It is also possible that progesterone-only pills have a weak therapeutic effect providing they are tolerated.
For reasons which are unclear, lupus is approximately 4 times more common in Afro-Caribbeans than in Western Caucasians. Precise figures are not available but it is likely that the same holds for Oriental races, particularly those derived from equatorial islands such as the Philippines, Seychelles and the West Indies. In contrast to this, the frequency of lupus in rural Africa is reported to be low with a higher frequency in urban African populations. The reason for this is unknown though it is possible that the mixture of the 'correct' racial background (Asian or African) with an environmental agent associated with western urban civilisation may add up to cause lupus. Alternatively, it is possible that interbreeding between different races, which has occurred particularly on tropical island populations, may result in a mixture of different risk factor genes being aggregated into the same population.
Although much remains unknown about genetic factors predisposing to lupus, there is no doubt that it is a polygenic rather than monogenic disease. As a rare disease its relative risk is increased when there is an affected member of the family. However, it is still not considered worthwhile to screen all family members for evidence of lupus, particularly as some studies have shown that unaffected family members can be antinuclear antibody positive, in which case screening tests are difficult to interpret. Nevertheless, the familial tendency is such that any manifestations which could be interpreted as being due to lupus should be taken seriously and it should be considered as a possible diagnosis if another family member is affected. It is always worthwhile seeking a family history of other autoimmune diseases which may or may not be related to lupus. Sjögren's syndrome is strongly associated with lupus and organ specific autoimmune diseases, such as thyroid disease and diabetes, are more common in families with lupus, probably because they are also associated with the DR3 gene.
In conclusion, family history of lupus or other autoimmune diseases, including organ-specific disease, should point the clinician towards lupus in the patient with the realisation that it is not, as such, genetic but a disease in which risk factors are inherited.
Prof. Patrick Venables
Kennedy Institute of Rheumatology
1, Aspenlea Road
Hammersmith
London, W6 8LH