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Ann Rheum Dis. 2007 September; 66(9): 1173–1177.
Published online 2007 January 9. doi:  10.1136/ard.2006.062984
PMCID: PMC1955129

Development of additional autoimmune diseases in a multiethnic cohort of patients with systemic lupus erythematosus with reference to damage and mortality

Abstract

Objectives

To determine the prevalence of other autoimmune diseases (AID) in black, Caucasian and South Asian patients with systemic lupus erythematosus (SLE) compared with the prevalence of these AID in the UK population, and to assess the impact of these additional AID on damage scores and mortality.

Methods

The prevalence and chronology of development of additional AID in SLE patients was determined by case note review. Comparisons were made with prevalence data for AID in the general UK population. The impact of additional AID on mortality and damage scores at up to 10 years was determined in the index cases (patients who developed another AID either in the same year or within 5 years of onset of SLE) compared with controls matched for sex, age, ethnicity and year of onset of SLE.

Results

There was no significant difference in the total number of AID that developed in patients from each ethnic group but differences in the frequency of some AID were noted. Mortality and damage scores were worse at 5 years in the study cases than the controls, particularly in the peripheral vascular category.

Conclusion

Patients with SLE might develop other AID that could complicate management of SLE by having an adverse impact on damage scores and mortality.

Several studies have documented an association between systemic lupus erythematosus (SLE) and other individual autoimmune diseases (AID) such as Sjogren's syndrome, autoimmune haemolytic anaemia and antiphospholipid syndrome (APS).1,2,3 However, there is a paucity of studies looking comprehensively at the wider range of other AID that complicate lupus. Furthermore, there is very little information about the prevalence of these AID in patients with SLE compared to the general UK population. Little is known about the occurrence of these AID in different ethnic groups with SLE, and the long‐term effects on damage and mortality associated with having a second AID.

In an earlier report, we described the range of other AID observed in a cohort of 215 patients with SLE, followed‐up for approximately 10 years.4

We have now doubled the size of our cohort (n = 401) with a follow‐up period ranging from 2–25 years (mean 12.1 years). In the present report, we now describe (1) the prevalence of other AID in SLE compared with the general UK population, (2) the frequency of these AID with reference to ethnic group, and (3) the outcome of those patients who developed another AID concomitantly with SLE (i.e. in the same year of diagnosis), or within 5 years of onset of SLE, based on damage scores and mortality. We present information on follow‐up at 1, 5 and 10 years post diagnosis of SLE.

Methods

Prevalence study

We determined the prevalence of other AID in patients with SLE by retrospective review of well documented clinical and laboratory records of 401 patients who had been managed at the University College London Hospital, Rheumatology Department between January 1978 and December 2004. Comparisons were then made with available prevalence data for those with AID in the UK.

To be included in this study, patients had to meet well established diagnostic criteria (including clinical findings, histological and serological data) for the diagnosis of other AID. Thus, the European Consensus Criteria were used for Sjogren's syndrome,5 the Bohan and Peter Criteria for myositis,6 the revised ACR Criteria for rheumatoid arthritis,7 the International Consensus Criteria for antiphospholipid syndrome,8 and the revised criteria of the European Society of Paediatric Gastroenterology and Nutrition for coeliac disease.9

For the remaining AID, the patients met detailed descriptions as set out in the Oxford Textbook of Medicine,10 and the Cecil Textbook of Medicine.11

We noted the time of onset of SLE (when the patients met at least four of the revised ACR classification criteria for SLE12), and the time of onset of other AID in each ethnic group (self‐reported), namely black patients (B), Caucasians (C), South Asians (A) (i.e. Indian subcontinent) and “others” (O). These groups were chosen as they represented the commonest ethnicities in our cohort and in the UK population.

Case‐control study

The SLICC/ACR Damage Index13 was used to determine the 1, 5 and 10‐year damage scores for cases (defined here as patients who developed another AID either concomitantly or within 5 years of onset of SLE). The majority of patients who developed another AID within 5 years of onset of SLE did so in years 2 and 3. For each case, we identified a control patient matched for current age, sex, ethnic origin, age of diagnosis and duration of SLE, but who had no AID other than SLE. Comparison of the Damage Index scores in cases and controls was designed to investigate the effect of having a second AID on development of damage in patients with SLE. We also noted the frequency and causes of death in the cases and controls over the 10‐year period.

Statistical methods

Continuous data were summarised as mean (standard deviation (SD)) or median (inter‐quartile range (IQR)) as appropriate. Independent groups were compared using analysis of variance (ANOVA) while paired comparisons in the case‐control study were made using the Wilcoxon Matched Pairs test. Categorical data were presented as n (%) and compared using the Chi‐squared test or McNemar test as appropriate.

Results

Of the 401 patients with SLE, 364 were female (91%) and 37 (9%) were male. The ethnic breakdown of the entire cohort was as follows: Caucasians, 258 (64%); black patients, 75 (19%); South Asians, 38 (9%); others, 30 (8%).

The mean age of onset of SLE was 28.9 (SD 8.3) years in South Asians, 32.9 (SD10.1) in black patients, 36.0 (SD 14.7) years in Caucasians and 35.20 (SD 8.8) for others. Although Caucasians appeared to have a higher age of onset of SLE than South Asians and black patients, this difference was not statistically significant (p = 0.21).

The prevalence of AID in SLE patients

There were 131 patients (33% of the cohort) who had at least one other AID, including 100 (25%) with one other AID, 26 (7%) with two and 5 (1%) with three AID in addition to SLE. The percentages closely approximate those of our previous analysis of 215 patients in the same cohort in the year 2000, when we found that 65 (30%) had at least one other AID, including 51 (24%) having one other AID, 12 (6%) having two and 2 (1%) having three different autoimmune diseases in addition to SLE.3

Table 11 shows the prevalence of other AID in our cohort of patients with SLE compared with available data on the general UK population.

Table thumbnail
Table 1 Prevalence of AID in patients with SLE compared to the UK population

Chronology of AID development in patients with SLE

There were 167 incidences of other AID in the 131 patients. There were various combinations of the sequence of development of these AID in individual patients. For example, some patients presented with an AID concomitantly with SLE and then later developed other AID. There were also patients who developed an AID before SLE then acquired another AID at the time of onset of SLE.

AID before SLE

Of the 131 patients, 52 (39.7%) presented with one (n = 44) or two (n = 8) other AID before SLE at a mean age of 29.9 (SD 13.8) years. The mean age of onset of SLE in this group was 37.7 (SD 16.4) years. Hypothyroidism most often preceded SLE in 19 patients (31.7% of the 60 incidences of other AID in this group).

AID presenting concomitantly with SLE

Of the 131 patients, 54 (41.2%) presented with one (n = 50), two (n = 3) or three (n = 1) other AID concomitantly with SLE at a mean age of 31.4(SD 10.4) years. Sjogren's syndrome most frequently presented concomitantly with SLE in 22 patients (37.3% of the 59 incidences of other AID in this group).

AID after SLE

Of the 131 patients, 43 (32.8%) presented with one (n = 38) or two (n = 5) AID after SLE at a mean age of 42.8(SD 13.1) years. The mean age of onset of SLE in this group was 35.51 (SD12.7) years. Sjogren's syndrome most frequently developed after SLE in 20 patients (41.7% of the 48 incidences of other AID in this group).

To investigate the chronology of development of additional AID, they were categorised into Sjogren's syndrome, autoimmune thyroid diseases, antiphospholipid syndrome and “other”, and the frequency of occurrence before, in the same year and after SLE was compared. To enable independent comparison, on an individual patient basis, in those patients who had >1 AID only the first was considered. Nine of these patients had two other AID that developed in the same year (as each other). One was randomly chosen, but the trends and results were almost identical if the other was chosen. There was a strong association between other AID and when it occurred relative to SLE (p<0.001).

Table 22 indicates that those patients whose additional AID was autoimmune thyroid disease were more likely to develop this before SLE, whereas in those with Sjogren's syndrome over half the patients developed this in the same year.

Table thumbnail
Table 2 Chronology of additional AID

The same trend can be seen within the Caucasian sub‐group but due to small numbers of patients in other ethnic groups it was not possible to assess whether the chronology of other AID varied by ethnicity.

Frequency of AID by ethnic origin

In the entire cohort, 86 (22%) Caucasians, 23 (6%) black patients and 17 (5%) South Asians had other AID.

Analysing the frequency of AID by ethnic group, we found that among the South Asians, 13 (76.5%) had one AID, 3 (17.6%) had two and 1 (5.9%) had three other AID. Among the black population, the figures were 16 (69.6%), 6 (26.1%) and 1 (4.3%) respectively. Among the Caucasians, 66 (76.7%) had one other AID, 17 (19.8%) had two and 3 (3.5%) had three, whereas among the “other” patients (i.e. not in any of these three ethnic groups), none had two or three other AID, but 5 patients had one AID. There was no statistical difference in the total number of AID that each ethnic group was likely to develop (p = 0.87).

In South Asians (A), autoimmune hypothyroidism was the most common other AID representing 27.3% (6 of the 22 incidences) of other AID in this ethnic group. In black patients (B), Sjogren's syndrome was the most common other AID representing 32.3% (10 of the 31 incidences) and in Caucasians(C), Sjogren's syndrome was the most common other AID representing 23.9% (26 of 109 incidences) of other AID in this ethnic group.

The second most common other AID was Sjogren's syndrome in South Asians, 22.7% (5 of 22 incidences), myositis in black patients, 19.4% (6 of 31 incidences), and antiphospholipid syndrome in Caucasians, 16.5% (18 of 109 incidences).

Antiphospholipid syndrome and myositis occurred with equal frequency in South Asians and were the third most common other AID in this group. In black patients and Caucasians, hypothyroidism was the third most common AID.

Subgroup analysis revealed that a higher proportion of South Asians developed thyroid disease compared to the black patients in our cohort (p = 0.05).

Damage and mortality in patients with other AID

Case‐control study

In all, 61 patients presented with AID concomitantly with SLE (n = 46) or within 5 years of the diagnosis (n = 15). These patients were included in the case‐control analysis.

The SLICC/ACR damage scores of these 61 patients (5 South Asians, 11 black patients, 42 Caucasians and 3 “others”) were compared with matched controls with SLE. Table 33 presents the damage scores of all 61 case‐control pairs at year 1, indicating that in 48 (79%) pairs the scores were the same. In 7 pairs the cases had a higher score that their controls and in 6 pairs, the control had a higher score than their corresponding case. Overall, there was no difference in damage scores at year 1 (p = 1.0).

Table thumbnail
Table 3 Damage scores at year 1

Within this group of 61 pairs, there were 42 and 38 pairs who developed SLE concomitantly with another AID and who were alive and with follow‐up after 5 and 10 years respectively. The median (IQR) damage scores for cases and controls at (1) year 5 were 0 (0, 1.0) and 0 (0, 0) and (2) at year 10 were 0.5(0, 1.0) and 0(0, 1.0). Table 44 presents the damage scores after 5 and 10 years follow‐up for these pairs.

Table thumbnail
Table 4 Damage scores at years 5 and 10 for pairs in which the case developed a concomitant AID

After 5 years follow‐up the cases had more damage than their controls (odds ratio (95% CI) 2.8 (0.95, 9.9)) with this difference approaching significance (p = 0.064). After 10 years, although the odds ratio was similar 2.5 (0.72, 10) there was limited statistical power to detect this (p = 0.18). For those pairs in which the case developed other AID within 5 years of SLE there was no difference in damage between them and their controls and 5 years (p = 0.69) or 10 years (p = 0.73).

Representing damage in terms of total damage score, however, could obscure effects of a second AID on organ‐specific damage. To investigate this possibility, we compared accrual of damage to each system in those cases and controls that had damage at years 1, 5 and 10 (shown in table 55).

Table thumbnail
Table 5 Categories and percentages of damage accrual in cases and controls

The table shows that some organs/systems did seem to accrue damage more rapidly in patients with another AID than in controls with no other AID. This is particularly true of the peripheral vascular system. By contrast, damage accrual was more prominent in controls than cases for the skin and kidneys.

It was not possible to test for statistical association between damage category and case/control status (table 55)) because there were so few pairs where both cases and their controls had damage.

There were four deaths (two black patients and two Caucasians) in the first 5 years among patients with other AID. All four patients were female and had developed other AID concomitantly with SLE. One patient had myositis only and died of pancreatitis and sepsis, one had myositis and ITP and died as a result of complications of ITP. The other two patients died as a result of lymphoproliferative malignancies. One had Sjogren's syndrome only, the other had Sjogren's syndrome and myositis.

In the control group, one patient died at 5 years after diagnosis of SLE as a result of a malignancy (carcinoma of the breast). Although the numbers of deaths were too small to be analysed statistically, there were four times more deaths in the cases than in the controls.

By year 10, there were two additional deaths (one case and one control). One, a female Caucasian had antiphospholipid syndrome and died of a thrombotic cerebrovascular event. The other, a black female, had SLE only and died of renal failure.

Discussion

Out study suggests that up to a third of lupus patients might develop another AID and that the prevalence of some of these AID could be higher than in the general UK population. Furthermore, the presence of a second AID can impact on the development of damage in these patients. The strength of our study, in comparison to previous work, is that we were able to collect data on multiple diseases in a relatively large cohort of patients with SLE, with follow‐up of up to 25 years. Our study was limited by the fact that some of the UK prevalence data were derived from studies that were conducted several years ago,20 hence these figures could be an underestimate. There is a need for more current studies of the prevalence of AID in the UK population. It is striking, however, that one‐third of all the patients in our cohort have at least one other AID and it seems very unlikely that AID are as common as this in the general UK population.

Despite this high proportion of patients with another AID in our cohort, the absolute number of patients with any particular AID is relatively small, given that lupus is an uncommon disease and the size of the whole cohort is only 401. Our prevalence data are therefore largely descriptive, and we cannot exclude the possibility that our cohort might differ in several epidemiological aspects from the cohorts used to define the UK prevalences. Approximately a third of patients in our cohort are referred from other tertiary centres to manage complications of their lupus, hence there could be some overrepresentation of the more complicated cases of SLE in this cohort. In addition, our patients are seen at least every 6 months in our lupus clinic, and such regular follow‐up increases the likelihood that other AID will be detected in our cohort compared to the general population. Thirteen of the 401 patients in our cohort have been lost to follow‐up (including one from this study). It is not known whether these patients might have subsequently developed other AID.

Despite these caveats, it is clear that SLE and other AID co‐exist commonly in individual patients. It is important to be aware of this, because symptoms of different AID can often be very similar, which means that diagnosis of a second AID could potentially be delayed by wrongful attribution of symptoms to the first. For example, it is easy to assume that severe fatigue in a patient with SLE is due to this disease, when in fact the real cause is undiagnosed hypothyroidism.

Because of our small sample size, we were unable to determine if there was an association between ethnic group and chronology of development of AID. Our study demonstrated a statistically significant association between the chronology of development of thyroid diseases (in particular hypothyroidism), Sjogren's syndrome and SLE. This finding however, needs to be interpreted with caution, given the relatively small number of patients with other AID. Pyne and colleagues had previously identified a higher prevalence of hypothyroidism in our cohort of lupus patients than in the general population.22 These findings are supported by other analyses of thyroid disease in lupus patients.23 Our results on chronology of development of AID could result from the behaviour of different medical specialists. For example, lupus specialists probably carry out Schirmer's test for tear production and antiphospholipid assays more commonly than other specialists. This could partially explain why Sjogren's syndrome and the antiphospholipid syndrome were usually diagnosed at or after the diagnosis of SLE whereas this was not true of thyroid disease.

An ethnic predilection for some AID has been previously recognised, e.g. myositis is more common in black patients,24 and Sjogren's syndrome in Caucasians.25 A larger sample size might have enabled us to comment further on this phenomenon beyond our finding that autoimmune thyroid diseases were more common in South Asians compared to black patients.

The three most prevalent AID in our cohort, and in the Caucasian and South Asian patients, were Sjogren's syndrome, hypothyroidism and antiphospholipid syndrome. Attia and colleagues examined the occurrence of other AID in 60 Arab and Asian patients from the Indian subcontinent with SLE under follow‐up for 12 years in Abu Dhabi and reported similar findings.26

It is unclear why some patients with SLE have an increased tendency to develop other AID. No studies have yet demonstrated whether it is more active lupus, environmental or genetic factors that increase the risk. There were 5 patients in the cohort who had a total of four AID. Clustering of AID within an individual has been described elsewhere as the polyendocrine syndromes.27 Clustering of AID within families is also well recognised, and studies of families with multiple AID have led to interesting discoveries of genetic factors that could potentially explain this phenomenon. One such discovery is the recognition of a single nucleotide polymorphism (rs2476601, encoding R620W) in the intracellular tyrosine phosphatase (PTPN22) that could confer risk of four separate autoimmune phenotypes (type 1 diabetes, rheumatoid arthritis, SLE and Hashimoto's thyroiditis) in the families that were studied.28 This finding suggests a common underlying etiologic pathway for some autoimmune disorders.

There was some evidence from this study suggesting that patients with other AID have worse damage scores at 5 years post diagnosis of lupus than patients with SLE only. Clinical correlation and a larger sample size would be needed to confirm this, to observe trends in the evolution of damage and to clarify just how much of a specific form of damage is directly attributable to the presence of another AID.

Increased damage in our patients with other AID was predominantly found in certain organs or systems. The majority of patients with damage in the peripheral vascular category had venous thromboses as a result of the APS. The increase in neuropsychiatric damage in the first year (mainly cognitive impairment or psychosis, seizures and cerebral vascular accidents) was partially explicable by the occurrence of strokes in patients with APS as well as SLE. Musculoskeletal damage in years 5 to 10 included deforming arthritis (particularly in those with rheumatoid arthritis), osteoporotic fractures that were steroid‐ induced in at least half of the patients, and muscle atrophy including steroid myopathy. Lupus patients with other AID might therefore be at increased risk of morbidity from these additional AID and the treatments that are required for this, in particular the higher doses of steroids. With the advent of new therapies such as anti‐TNF drugs, and Rituximab, and treatments for osteoporosis, we expect that damage and hence morbidity in the cohort should improve.

Mortality in SLE is higher than in the general population and currently is largely attributable to infection, atherosclerosis and malignancy.29,30 We postulate that patients with additional AID could have a higher mortality than those with SLE alone. Longer‐term studies on larger cohorts would provide additional information in this regard.

In conclusion, physicians should be aware that patients with SLE might present with a variety of other AID and this could have an impact on damage and mortality. They should therefore not necessarily attribute all of a patient's signs and symptoms to SLE only. Strategies for managing lupus patients who have additional AID should include close monitoring for the adverse effects associated with the prolonged use of higher doses of corticosteroids and other immunosuppressants that might be required to treat the combined autoimmune disorders.

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