Discussion
To the best of our knowledge, we present the largest case–control study of lupus DAH reported to date. There were similarities and differences between our findings and those in the work of others. For example, similar to previous studies, we found that dyspnoea was a more common presentation than haemoptysis.1 ,4–6 ,8–13 While active nephritis was often associated with DAH in our study (36% of patients), the percentage was somewhat lower than what has been described by others.1 ,5–8 ,10 ,11 ,14 ,15 In comparison to the other large case series from Asia and South America,4–7 we describe a US lupus population that is predominantly of European descent. This difference in ethnicity may have contributed to the lower percentage of nephritis.45–47 It should also be pointed out that kidney biopsies were typically only obtained if the clinician felt it would change clinical management. Given the degree of serological activity that was present in these patients (75% had decreased complement levels from baseline), it is reasonable to assume that several additional patients had early or subclinical nephritis that may have been effectively treated by the potent immunosuppression employed for DAH.48 ,49
Also notable is that all 22 patients survived their first DAH episode; further, although 6 patients had recurrence, none resulted in death. In contrast, prior studies have shown acute mortality as high as 62%.1 ,5–9 ,11 ,13 ,17 Ours is a predominantly outpatient cohort, with the majority of patients recruited and enrolled during a visit to outpatient clinic. These patients were carefully followed and monitored, and it is possible that this attention resulted in earlier diagnosis as well as more aggressive treatment. It is also notable that the majority of our patients (14/22, 64%) were diagnosed after 2007; it is therefore conceivable that newer therapeutic agents such as mycophenolate mofetil and rituximab contributed to better outcomes and more durable induction of remission. Finally, it should again be pointed out that this is the first time a lupus population predominantly of European descent has been considered in a large DAH case series; as such, it is possible that this is a population predisposed to better outcomes.1 ,15
There are no randomised clinical trials to inform our management of patients with lupus DAH. Retrospective studies have shown a survival disadvantage with cyclophosphamide, although it has been speculated that this is the result of cyclophosphamide's preferential use in the most ill patients.1 ,4 Such studies have also been unable to show a clear survival benefit of either intravenous immunoglobulin or plasmapheresis in lupus DAH, although these treatments are commonly employed in severe cases (including at our centre).1 ,5 ,12 Rituximab is another emerging treatment, although again without either retrospective or prospective data to support its use.4 In the absence of clear guidance from the literature, the approach to treatment remains individualised.
Of interest, history of both leucopenia and thrombocytopenia were strongly associated with DAH, with history of thrombocytopenia, in particular, being the strongest individual predictor of DAH in our study. In fact, after multivariate modelling, all risk was explained by just two factors: history of thrombocytopenia and history of low complement C3. We initially considered the possibility that DAH might be explained by the bleeding diathesis of thrombocytopenia itself, but this seems unlikely as only five patients presented with platelet counts below 100 000/µL and only two with platelets <50 000/µL (figure 3). For the remainder, the thrombocytopenia (<100 000/µL) was part of their medical history, but not active at the time of DAH. It should also be pointed out that thrombocytopenia, similar to nephritis and neuropsychiatric disease, is a well-known predictor of worse prognosis in lupus.50–53 Platelets are known mediators of inflammation, for example by engaging neutrophils,54 ,55 and may be depleted systemically as they concentrate at sites of local inflammation. It has also been suggested that there are immunological difference between the antiplatelet immune response in lupus, as compared to idiopathic immune thrombocytopenia,56 although it is unclear what implications this may have for other aspects and manifestations of SLE.
Figure 3Platelet count at the time of first episode of diffuse alveolar haemorrhage (DAH). While only five patients had a platelet count <100 000/µL at the time of the DAH episode, 19 of 22 had such a count as part of their lupus history.
Although thrombocytopenia ultimately dominated the multivariate model, we did note that a number of APS features, including lupus anticoagulant, arterial thrombosis, valve disease and the syndrome itself, were associated with DAH by univariate analysis. Since APS can also drive thrombocytopenia,57 these relationships are complicated and will need to be clarified in larger cohorts that ideally also include patients with primary APS. It is noteworthy that in our series, two of the patients with DAH ultimately died of thrombotic strokes, while a third had a progressive neurological decline related to refractory seizures that may have been driven by APS. While the relationship between lupus DAH and APS has not been thoroughly explored in the literature, there are many reports and series describing DAH as a complication of primary APS.35–38 Again, given the likely complex pathophysiology, these relationships will need to be tracked in larger studies.
Our study has several limitations. The rarity and acuity of DAH limit our ability to obtain prospective data, although this would obviously be the preferred methodology. As highlighted above, this is also a cohort that was primarily established in our outpatient clinics. It is therefore possible that we missed patients, especially those with poor and acute outcomes, who received their outpatient care elsewhere and were transferred to our centre for inpatient management. These data should therefore be interpreted in that light. Finally, because the acute outcomes were so good, we were not able to comment on the response to different types of treatments, which had been a goal when we devised the study.
In summary, using a case–control methodology, we showed a significant association between history of thrombocytopenia and lupus DAH. In fact, an amazing 19 of 22 patients (86%) had a history of platelets <100 000/µL at some point during their lupus course, and we would suggest that DAH should be featured prominently in the differential diagnosis when such patients present with pulmonary complaints. This is especially true as haemoptysis is only present in about one-in-four presentations, and therefore the index of suspicion must be high to establish the diagnosis of DAH. Further, although thrombocytopenia dominated the multivariate model, our univariate analysis suggests that secondary APS (similar to primary APS) may be a risk factor for DAH. While we await with interest larger multicentre considerations of this rare, but dangerous, lupus complication, we were encouraged to find that a carefully monitored cohort can fair well with DAH, especially acutely.
