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Rheumatology Advance Access originally published online on March 27, 2006
Rheumatology 2006 45(10):1261-1265; doi:10.1093/rheumatology/kel101
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Thrombocytopaenia in lupus as a marker of adverse outcome—seeking Ariadne's thread

P. D. Ziakas, U. G. Dafni1, S. Giannouli, A. G. Tzioufas and M. Voulgarelis

Department of Pathophysiology, University of Athens Medical School and 1Department of Nursing, Division of Public Health, University of Athens, Greece.

Correspondence to: Michalis Voulgarelis, MD, University of Athens Medical School, Department of Pathophysiology, 75 M. Asias Street, 11527, Athens, Greece. E-mail: mvoulgar{at}med.uoa.gr


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Objective. To assess the role of thrombocytopaenia as an independent predictor of outcome in patients with systemic lupus erythematosus (SLE).

Methods. This was a single-centre, retrospective, matched case-control study (1:2). Fifty consecutive Greek SLE patients were selected at random who had developed thrombocytopaenia during the disease course (cases) were compared with 100 SLE patients with no history of thrombocytopaenia, and matched for age, sex and disease duration (controls). Overall damage was assessed at the end of follow-up, using Systemic Lupus International Collaborating Clinics index. Total number of irreversible organ-damage events for both groups were recorded. Rates for specific outcomes and incidence-rate ratios (IRRs) for damage were estimated. Multivariate analysis estimating influential clinical and immunological factors for outcome, including thrombocytopaenia, was performed.

Results. After 583 person-years of follow-up for cases and 1155 for controls, we found that thrombocytopaenic individuals have a higher risk for damage (IRR 1.96, 1.52–2.53) compared with their matched controls and this effect persists throughout the course of their disease. They also have a predilection to certain types of damage involving heart and kidneys. Among other significant factors associated with damage in multivariate analysis (disease activity, serositis, anti-cardiolipin antibodies, central nervous system involvement), thrombocytopaenia appears as the most influential.

Conclusion. Thrombocytopaenia is a quantitive and qualitative marker of impending damage in SLE patients.

KEY WORDS: Systemic lupus erythematosus, Thrombocytopaenia, Outcome, Damage, SLICC.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Systemic lupus erythematosus (SLE), the prototype of systemic autoimmunity, affects quality of life and often results in irreversible organ damage and early death. The role of thrombocytopaenia as an independent factor related to disease aggressiveness and outcome has been a matter of controversy, leading to conflicting reports [1–8]. In accordance with the most recent observations published, it has been shown that although thrombocytopaenia per se is a benign complication, it is associated with highly active disease and a worse outcome [9]. By further analysing the quantitive and qualitative aspects of outcome, we intend to enlighten the validity of thrombocytopaenia as a surrogate marker for adverse outcome and to estimate its possible association with a distinct clinical profile of damage.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Conclusion
 References
 
The Department of Pathophysiology is a tertiary referral centre for autoimmune diseases. All available medical records of SLE patients, diagnosed according to American College of Rheumatology (ACR) criteria [10], were reviewed in detail retrospectively and individual data were recorded. All patients had a routine clinical and laboratory follow up at 2 to 6 months intervals, unless a complication dictated hospitalization or more frequent evaluation. In all instances, medical records were updated in detail. Fifty-five SLE patients having developed thrombocytopaenia defined by platelet counts <100 000/mm3 during their disease course were identified. Three were excluded from the analysis as thrombocytopaenia was attributed to documented infection (two patients) and methotrexate toxicity (one patient). Two additional patients were also excluded, as they were lost in follow-up and their records were incomplete. The remaining fifty patients that were finally included in the study displayed no evidence of other causes of thrombocytopaenia. More specifically, infections, thrombotic microangiopathies, haemophagocytic syndrome and drug-related bone marrow toxicities were excluded after clinical evaluation, laboratory profile and bone marrow findings. Therefore, these patients represent a homogenous population in regard to pathophysiology, as thrombocytopaenia may be attributed to immunologically mediated platelet destruction in the context of SLE itself, and a separate subgroup analysis would not provide further information. A total of 100 patients with no history of thrombocytopaenia were selected and matched for sex, age and disease duration. The cumulative frequency of cases and controls recruited in the study was similar during follow-up time. Epidemiological profile, classification criteria and autoantibody profile were assessed at diagnosis. Antinuclear antibodies were determined by indirect immunofluorescence; anti-dsDNA by a standard ELISA; anti-extractable nuclear antigens antibodies by counterimmunoelectrophoresis; and serum C3 by nephelometry. Anti-cardiolipin antibodies were measured using a standard ELISA assay. European Consensus Lupus Activity Measurement (ECLAM score) was used as a measure of disease activity due to its reproducibility and validity in retrospective evaluation [11–13]. Thrombocytopaenia, if present, was not scored for a more accurate comparison. Systemic Lupus International Collaborating Clinics (SLICC) index [14, 15] was scored at the end of follow-up. Total number of irreversible organ-damage events, as defined and included in SLICC, were recorded in both groups. Individual damage profile was also assessed. The deceased cumulative damage was scored just before their death. Rates were generated and compared using the Mantel–Haenszel approximation. Multivariate negative binomial regression was used to estimate the impact of baseline clinical and autoimmune profile, as well as the role of thrombocytopaenia to outcome. Significance was set to 0.05. STATA v8 was used for statistical analysis. We also confirm that this study was approved and authorized by the Scientific Board of Athens University Medical School, Clinical–Pathological Division (President Prof. D. Kelekis) and conforms to standards defined by our university authorities.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Conclusion
 References
 
Overall damage
Epidemiological characteristics, anti-cardiolipin antibody profile, disease activity at onset, SLICC comparison, total number of events and incidence-rate ratios (IRRs) between the two groups are summarized in Table 1. Overall, 34/150 (23%) of patients had positive anti-cardiolipin antibodies. The two groups did not differ in the prevalence of anti-cardiolipin antibodies (14/50 vs 20/100, P = 0.27) or antiphospholipid syndrome (APS) defined by Sapporo criteria (8/50 vs 9/100, P = 0.20). The presence and isotype of these antibodies was unrelated to the severity of bleeding complications or the degree of thrombocytopaenia.


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  		TABLE 1. Baseline characteristics and damage at the end of follow-up. Occurrence of thrombocytopaenia carries higher risk for damage and the effect persists after stratification for disease duration

 
Thrombocytopaenic individuals have a worse outcome at the end of follow up compared with their matched controls using the SLICC index (P<0.001). Thrombocytopaenic group has an increased risk for damage (IRR 1.96, C.I. 1.52–2.53) compared with controls, and this risk persists after stratification for disease duration.

System-specific damage
IRRs for all features of renal damage are high for thrombocytopaenic patients, including proteinuria (IRR 3.56, P = 0.01), reduction of >50% in glomerular filtration rate (IRR 4.62, P = 0.01) and end-stage renal disease (IRR 3.30, P = 0.08). Rates of damage involving the central nervous system (CNS) do not differ significantly between the two groups, with the exception of psychosis (IRR 3.30, P = 0.08). A higher risk for valvular disease (IRR 2.97, P = 0.07) and cardiomyopathy (P = 0.01) is related to thrombocytopaenic group and persists after adjustment for anti-cardiolipin antibodies (Table 2).


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  		TABLE 2. Irreversible organ damage at the end of follow up. Thrombocytopaenia is associated with a higher risk for renal damage, valvulopathy, cardiomyopathy thrombosis, optic atrophy and psychosis

 
Therapy-related other damage and deaths
Therapy-related complications show no significant differences between the two groups. With the exception of retinal damage/atrophy (IRR 7.92, P = 0.02) and thrombosis (IRR 7.92, P = 0.02), other kinds of damage affecting quality of life such as a vascular necrosis and cataract show insignificant differences. Thrombocytopaenic patients also exhibit a higher rate for thrombotic complications, which remains significant after adjustment for anti-cardiolipin antibodies.

Eight patients died (median 11.5 years, range 3–26 after SLE diagnosis), four in each group. Pulmonary hypertension, pulmonary emboli, pulmonary infection and CNS involvement (stroke, status epilepticus) were the causes of death. The two groups did not differ in death rates (crude estimate and after adjustment for antiphospholipid antibodies). Results are summarized in Table 2.

Multivariate analysis
In multivariate analysis including baseline clinical profile, thrombocytopaenia and autoantibodies, CNS involvement (IRR 1.66), serositis (IRR 2.48), anti-cardiolipin antibodies (IRR 1.90), arthritis (IRR 1.55) and oral ulcers (IRR 1.66) are associated with a poor outcome. Malar rash (IRR 0.66) and anti-Ro positivity (IRR 0.50) carry a favourable prognosis (Table 3).


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  		TABLE 3. Multivariate analysis. CNS involvement, serositis at baseline and anti-cardiolipin antibodies predict a poor outcome. The presence of anti-Ro is protective. After adjusting for other factors, thrombocytopaenia is the most influential predictor of damage

 
If ECLAM is used as a surrogate marker of disease activity at diagnosis, it is also associated with a poor outcome (IRR 1.31) (Table 4). Anti-Ro antibodies retain their protective effect (IRR 0.58), and anti-cardiolipin antibodies (IRR 1.61) have an adverse impact on outcome.


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  		TABLE 4. Multivariate analysis. Disease activity at diagnosis (ECLAM) and thrombocytopaenia are significant predictors of damage. Anti-Ro remains protective. Note again that thrombocytopaenia is the most influential predictor of damage

 
When documented APS was included in the multivariate models in place of anti-cardiolipin antibodies, it also appeared as an independent predictor of damage (IRR >2), while estimations for other confounders remained practically unaffected (data not shown). Thrombocytopaenia in both models remains the most important factor associated with damage (IRRa 3.14 and IRRb 2.47, respectively) after adjusting for all other factors (Tables 3 and 4, respectively).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Conclusion
 References
 
SLICC index has been developed and validated as a useful instrument to measure organ damage in lupus patients, providing quantitive estimation of cumulative morbidity [14, 15]. Moreover, it appears to be a highly predictive tool for new damage accrual and mortality [16–18]. A number of efforts have been undertaken lately to associate certain epidemiological, clinical characteristics and therapeutic intervention to irreversible organ damage and early demise. Among them, increased age and disease duration, ECLAM score at diagnosis, CNS and renal disease and high dose corticosteroids seem the most influential. Damage is also an independent predictor of further damage [19–23], whereas anti-Ro positivity seems to characterize a more benign course [24].

Implications
Our analysis emphasizes the role of thrombocytopaenia in lupus in a different perspective. It identifies a subgroup of patients with an expected worse prognosis. Other baseline characteristics such as disease activity at diagnosis, CNS disease, serositis, anti-cardiolipin and anti-Ro antibodies also have a prognostic impact in accordance with recent published data, but do not reduce the negative influence of thrombocytopaenia.

Furthermore, thrombocytopaenia is linked to a certain pattern of damage, including renal damage, valvulopathy, cardiomyopathy, ocular damage and venous thrombosis. A marginal association with psychosis has also been detected. The major question arising is if thrombocytopaenia is just an early epiphenomenon of an aggressive clinical course, or if there is an underlying, common pathophysiology, connecting heterogeneous events.

Valvulopathy is the most frequent type of cardiac involvement in SLE. The presence of antibodies against phospholipids is associated with a higher prevalence of valvular abnormalities in these patients [25]. However, in our study, valvular disease occurred more frequently in thrombocytopaenic subjects, and the risk persisted after adjusting for anti-cardiolipin antibodies. Therefore, antiphospholipid antibodies are not the only risk factors for cardiac valvular disease in patients with SLE [26, 27]. Immunoglobulin and complement deposition in the valvular structure are implicated in the pathogenesis, leading to Libman–Sacks vegetations, valve thickening and valve regurgitation.

Both renal and valvular damage occur in the context of immune-mediated injury, related to a more active disease. Ocular involvement, cardiomyopathy and psychosis are also features reflecting disease activity, though a common pathophysiological disturbance cannot be excluded—disorders in microcirculation secondary to autoimmune process. Ocular manifestations of lupus are a reflection of systemic disease. The pathophysiology in the neuro-ophthalmological manifestations of SLE is thought to be due to vaso-occlusive disease of the small vessels of the nerve and brain [28–30]. Although the precise mechanism of psychosis remains speculative, a similar pattern of disturbance is reasonable. Overall, it is likely that psychiatric complaints in patients with SLE are attributable to numerous factors including acquired brain dysfunction, organ system dysfunction, iatrogenic effects of corticosteroid treatment and psychosocial stressors [31]. Whereas true vasculitis is rare, small infarcts and oedema with concurrent decreased glucose uptake and impaired blood–brain barrier have been detected using magnetic resonance imaging (MRI) and positron emission tomography (PET) [32]. Finally, cardiomyopathy represents a state of reduced myocardial perfusion, where—apart from atheroscelotic lesions—obliterative, small vessel vasculopathy has a significant contribution [33, 34]. In summary, it is plausible to hypothesize that a more active disease and a similar pathophysiology are implicated in the distinct pattern of damage characterizing thrombocytopaenic group, although direct evidence is lacking.

Limitations of the study
Our study has the limitations superimposed by its retrospective characteristics. However, all patients were followed up by the same team of physicians, medical records were frequently reviewed in detail and population is homogenous in respect to ethnicity. These results, though, may not apply to other ethnic groups. Thrombocytopaenia in SLE occurs in various forms—as an acute event coinciding with disease flares, as chronic thrombocytopaenia with relapsing–remitting course or as related to APS. However, as thrombocytopaenia is considered an immune-mediated process, it is reasonable to include all these clinical subtypes in the study. A major advantage of this analysis is that it incorporates the time of follow up in outcome, and matching reduces the confounding effect of age, sex and disease duration on outcome, permitting a more clear-cut estimation of the effects of clinically important factors.


   Conclusion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
References
 
Thrombocytopaenia marks a subgroup of SLE patients, bearing a higher risk of end-organ damage throughout their disease course. This increased risk refers also to qualitative parameters, as these patients exhibit a predilection to a distinct pattern of damage. Until Ariadne's thread marks the exit of the labyrinth of uncertainty, close monitoring and perhaps a more aggressive management may be warranted for this group of patients.

The authors have declared no conflicts of interest.

Formula


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 

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Submitted 20 December 2005; revised version accepted 21 February 2006.
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