Original research••

Clinical, biological, prognostic characteristics of patients with immune-mediated thrombotic thrombocytopenic purpura and Sjögren’s disease

•,,,,,,,,.

...

Abstract

Objectives The association between immune-mediated thrombotic thrombocytopenic purpura (iTTP) and Sjögren disease (SjD) has been poorly investigated. This study presents the first retrospective cohort of iTTP-SjD aiming to identify risk factors for iTTP occurrence in SjD patients and examine their clinical course.

Methods Patients with iTTP-SjD were identified within the French TTP Registry based on American College of Rheumatology/European League Against Rheumatism 2016 criteria. A comparative analysis was conducted with two control groups comprising primary SjD (pSjD) patients from the French ASSESS cohort and idiopathic iTTP patients from the French TTP Registry. Demographic, clinical and biological data were retrospectively collected.

Results Thirty iTTP-SjD patients were included and compared with 65 pSjD and 45 idiopathic iTTP patients. The majority of iTTP-SjD patients (n=18) were diagnosed with SjD at the time of iTTP diagnosis. In comparison with the pSjD cohort, iTTP-SjD patients were diagnosed with SjD at a younger age (p=0.039) and showed a higher prevalence of anti-SjS-related antigen A antibody positivity and xerostomia (p=0.015, p=0.035, respectively). EULAR Sjogren’s Syndrome Disease Activity Index showed similar activity levels between the two groups. iTTP-SjD patients were treated with plasma exchange (n=28), corticosteroids, rituximab (n=19) and caplacizumab (n=3). In comparison with the idiopathic iTTP cohort, mortality rates (log-rank tests, p=0.228), biological and clinical iTTP relapses (multivariate analysis, p=0.181) were comparable and short-term outcomes (survival at day 30, relapse) were favourable.

Conclusion iTTP can be a rare complication in patients with SjD. Further studies involving larger cohorts and long-term follow-up are warranted to confirm these findings and to explore the efficacy of immunomodulators and caplacizumab in iTTP-SjD patients.

Key messages

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) should be considered in all Sjögren disease (SjD) patients with thrombocytopenia.
iTTP-SjD patients have a higher prevalence of anti-SjS-related antigen A antibody positivity compared with SjD patients.
No distinctions in severity, outcomes or relapses were observed between iTTP-SjD and idiopathic iTTP patients.
Patients with iTTP should be systematically screened for autoimmune disorders including SjD.

Introduction

The increased susceptibility of patients with systemic autoimmune disease (SAID) to develop additional autoimmunity is well-documented in epidemiological studies.1–3 Thrombotic thrombocytopenic purpura (TTP), a rare and life-threatening thrombotic microangiopathy (TMA), is specifically related to a severe deficiency of ADAMTS13 (A disintegrin and metalloproteinase with thrombospondin-1 motifs, 13th member). This deficiency is mainly linked to the presence of autoantibodies directed against ADAMTS13, leading to immune-mediated TTP (iTTP).4 5 The prevalence of TTP is ~10 cases per million people, with iTTP accounting for 75% of all TTP cases.6 ADAMTS13 is the specific von-Willebrand factor (VWF)-cleaving protease and its deficiency leads to the accumulation of ultralarge multimers of VWF in the circulation with the formation of platelet-rich microthrombi in the arteriolo-capillary microcirculation responsible for microangiopathic haemolytic anaemia, profound thrombocytopenia, visceral damage and multi-organ failures.4–6 In iTTP, anti-ADAMTS13 autoantibodies enhance the clearance of ADAMTS13 or inhibit its activity. Therapeutic plasma exchange (TPE), corticosteroids, the anti-CD20 monoclonal antibody rituximab and caplacizumab (a nanobody directed against the A1 domain of VWF) are used at the acute phase of iTTP.7 A significant number of SAID have been reported in association with iTTP (5%–18% of all TTP cases), including systemic lupus erythematous (SLE) and Sjögren disease (SjD), and less commonly antiphospholipid syndrome and mixed connective tissue disorders.8–10 Additionally, iTTP is characterised by a relapsing tendency and monitoring of ADAMTS13 activity is required during the long-term follow-up, to document a biological relapse (called ‘ADAMTS13 relapse’ if ADAMTS13 activity is <20%) and to prevent clinical relapse with pre-emptive rituximab.11 Patients with iTTP are predisposed to develop another SAID during their follow-up.8

SjD is a common SAID that predominantly affects women, typically around the age of 50, with a female-to-male predominance of 9:1.12 It is defined by the association of eye and oral dryness, anti-Ro-SjS-related antigen A (SSA) antibodies and/or lymphocytic infiltration of exocrine glands, according to American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2016 criteria.13 This infiltration leads to glandular dysfunction resulting in widespread dryness (including mouth and eyes) that affects more than 80% of patients.12 SjD is also characterised by fatigue, musculoskeletal pain and various systemic complications and an increased risk of lymphoma. Other haematological complications can occur, such as peripheral autoimmune cytopenias or associations with other autoimmune haematological disease like iTTP.8 12 14 In patients with active systemic disease, immunosuppressive or immunomodulatory treatments may be used, as in other autoimmune diseases.12 15 SjD may occur alone but frequently occurs in patients with other autoimmune diseases, known as polyautoimmunity.12

The most common SAID associated with iTTP is SLE8 and SjD shares several pathophysiological features with SLE. In the literature, there are only few case reports of patients with TTP and SjD13 16–21 without any observational study examining this association. The aim of the current study was to describe the baseline biological and clinical characteristics and outcomes of a cohort of SjD-associated iTTP (iTTP-SjD) patients and to compare this cohort with patients having either primary SjD (pSjD) or iTTP.

Methods

Cases ascertainment

Between 1 January 1999 and 31 December 2019, we carried out a retrospective survey to identify cases of SjD-associated iTTP selected from the French registry for TTP. Cases included all patients with a first episode of iTTP (severe deficiency in ADAMTS13 (activity <10%) and detectable anti-ADAMTS13 IgG) associated with a diagnosis of SjD fulfilling the ACR/EULAR 2016 criteria for SjD13 during the clinical history (before, at the same time or after the diagnosis of TTP). Thus, all French rheumatology and internal medicine practitioners registered to the ‘Club Rhumatismes et Inflammation’ (CRI) were contacted by electronic newsletters to collect additional cases. The CRI is a subset of the French Society of Rheumatology including a network of more than 2000 physicians from different medical specialties and involved in the treatment of autoimmune and inflammatory diseases.

The SjD control population was selected from the ASSESS cohort established in 2006, including 395 patients fulfilling the American-European Consensus Group criteria for SjD. This cohort included only pSjD. We selected 65 controls who were matched to our cases according to the length of SjD progression (time since diagnosis) to avoid any bias in disease severity. None of the 395 patients included in the ASSESS cohort experienced any iTTP episode.

The iTTP control population was selected from the French registry of the Reference Centre for TMA. We selected 45 patients with a first episode of idiopathic iTTP characterised by a severe decreased in ADAMTS13 activity (<10%) associated with either positive anti-ADAMTS13 IgG (>15 U/mL) and/or a recovery of ADAMTS13 activity during remission. Those patients did not have any underlying clinical conditions, known SAID or biological autoimmunity. These patients were matched to the cases based on the year of TTP diagnosis in order to have a homogeneous group in terms of therapeutic management.

Data collection

Demographic data, clinical and biological features, were collected retrospectively or prospectively at the time of enrolment for all patients. For SjD, the following items were collected: date of diagnosis, sequence of disease onset in relation to TTP, SjD systemic involvement, SjD activity at the time of TTP diagnosis using the EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI)22 and clinESSDAI scores.23 In our study, we used a modified ESSDAI that excluded items that could be affected by the TTP episode (general signs, renal and haematological impairment). Biological data were collected including anti-SSA antibodies, cryoglobulinaemia, gamma-globulin levels and complement consumption. The use of immunosuppressive agents was also collected. For TTP, the following items were collected: date of diagnosis, cardiovascular history, biological factors, French score,24 French severity score,25 clinical manifestations of TTP (cerebral involvement, cardiac involvement, renal involvement, digestive involvement), treatments used during the acute episode of TTP and their adverse effects, prognostic factors (response to treatment, time to ADAMTS13 activity recovery >20%, ADAMTS13 activity and presence of anti-ADAMTS13 IgG at 3 months, clinical or biological relapse called ‘ADAMTS13 relapse’). ADAMTS13 relapse is defined by the drop in ADAMTS13 activity below 20%, without clinical signs, haemolysis or thrombocytopenia. TTP outcomes were defined according to the 2017 consensus on the standardisation of terminology in TTP and related TMA.26

Statistical analysis

We compared the characteristics of patients with SjD-TTP to those with idiopathic iTTP and pSjD. Categorical variables are reported as numbers (percentages). Quantitative variables are reported as median (IQR) unless otherwise specified. Baseline characteristics, treatments and prognostic factors were compared with t-tests for continuous variables, and χ² tests for categorical variables. Clinical and biological relapse-free survival was calculated by Kaplan-Meier method from TTP diagnosis to last follow-up. P values for different variables at diagnosis were determined by log-rank test in univariate analysis and compared with Cox proportional HRs models, adjusted based on the use of rituximab at the time of TTP diagnosis. Differences with a p value <0.05 were considered statistically significant. Analyses were performed using JMP, V.17 (SAS Institute, Cary, NC, USA).

Results

Of 36 patients screened in the French Registry for TTP with a suspicion of SjD associated with iTTP, 9 were excluded because they did not meet the ACR-EULAR 2016 criteria for SjD, 1 patient was prospectively included in this study because they were hospitalised in our department at the onset of the study, and two patients were reported by the CRI. Overall, in the present study, 28 iTTP-SjD cases were observed among 1231 iTTP patients in the French TTP Registry (2.2%) (figure 1).

Figure 1

Request permission

Flow chart of the study. ACR-EULAR, American College of Rheumatology-EULAR; CRI, Club Rhumatismes et Inflammation; iTTP, immune-mediated TTP; SjD, Sjögren’s disease; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura.

SjD outcomes in iTTP-SjD patients

Baseline characteristics of iTTP-SjD patients are summarised in table 1. The mean age at diagnosis of SjD was 46.3 (IQR 38.39–59.93). The majority of patients (n=18, 60%) were diagnosed with SjD at the time of iTTP diagnosis. Nine patients (30%) had a known SjD at iTTP diagnosis and three (10%) developed SjD after iTTP diagnosis (6 months, 1 and 4 years after diagnosis). Seven patients (23%) had another AID associated with SjD, including SLE in four patients (13%), rheumatoid arthritis (RA) in one patient (3%) and Hashimoto thyroiditis in two patients (7%). One patient (3%) presented with cryoglobulinaemic vasculitis. Regarding disease activity at diagnosis of iTTP, the median ESSDAI was 10 (IQR 8–12) with a modified ESSDAI of 2 (IQR 1–3.75) after removal of items impacted by iTTP (renal, haematological and general signs). There was no difference considering glandular, lymphadenopathy, neurological, muscular, pulmonary and cutaneous domains of the ESSDAI score. Eight (33%) patients had hypergammaglobulinaemia and nine (33%) had complement consumption. In addition, 23 (79%) patients had presented systemic manifestations from SjD to iTTP diagnosis, after exclusion of the items impacted by the iTTP, mainly represented by joint involvement (inflammatory arthralgia) in 9 (31%) patients and biological involvement in 13 (45%) patients. At the time of the latest news, 16 (55%) patients received hydroxychloroquine and 8 (28%) patients had corticosteroids as treatment for SjD (table 3). Only one patient had been treated with rituximab for SjD manifestations.

Table 1

•

Comparison of baseline characteristics between iTTP-SjD and pSjD patients

TTP outcomes in iTTP-SjD patients

Baseline characteristics of iTTP-SjD patients are summarised in table 2. In the iTTP-SjD group, sex ratio was 29F/1M with a median age of 47.5 years (IQR 37.75–61). Regarding iTTP biological parameters, median haemoglobin level was 80 g/L (IQR 64.5–91.5), and median platelet count of 12 x10^∧9/L (8.75–19.25). Patients had preserved renal function, with a median glomerular filtration rate (GFR) according to Cockcroft-Gault of 75.87 mL/min (IQR 51.11–92.04). They also showed signs of haemolysis, with a median lactate dehydrogenase level 3.92 times greater than normal (IQR 2.59–6.71). All patients had severe ADAMTS13 deficiency at diagnosis (activity <10%). 26 patients (90%) had positive anti-ADAMTS13 IgG (>15 U/mL) and all patients recovered a detectable ADAMTS13 activity in remission. Regarding severity, 25 (86%) had a French severity score between 0 and 2, and 4 (14%) had a score of 3 or 4. At diagnosis, six patients (20%) had fever. 23 patients (77%) developed neurological signs at baseline (headaches and/or confusion and/or seizure and/or coma and/or focal neurological deficiency), 4 (13%) presented cardiac signs (chest pain and signs of myocardial ischaemia on examination), 13 (43%) presented digestive symptoms (epigastralgia and/or nausea/vomiting and/or diarrhoea) and 10 (33%) had signs of renal impairment (serum creatinine >176 µmol/L and/or haematuria >10 red blood cell/mm³ and/or proteinuria >0.3 g/L).

Table 2

•

Comparison of baseline characteristics between iTTP-SjD and idiopathic iTTP patients

iTTP treatments and outcomes are summarised in table 3. All patients received TPE, 28 (97%) received corticosteroid and 19 (66%) were treated with rituximab. Three patients were treated with caplacizumab (10%). Five patients (17%) required rescue therapy (intravenous immunoglobin, vincristine, obinutuzumab, bortezomib, cyclophosphamide, ciclosporin and/or splenectomy).

Table 3

•

Comparison of treatment and outcomes between iTTP-SjD and idiopathic iTTP

Patient outcome was mostly favourable, with complete remission for 29 patients (97%) and a median time to remission of 13 days (IQR 5–24). 13 patients (43%) had an exacerbation and 2 (7%) relapsed clinically. One patient (3%) died before day 30. Most patients were hospitalised in intensive care units (80%). Time to ADAMTS13 activity improvement (activity >20%) was 73.5 days (IQR 19.5–163.75), six patients (25%) had ADAMTS13 activity below 20%, and seven (44%) had positive anti-ADAMTS13 IgG levels (>15 U/mL) 3 months after their last TPE. During follow-up, six patients (20.7%) received a pre-emptive rituximab infusion because of ADAMTS13 relapse (ADAMTS13 activity <20%). In the latest update, all patients who survived after day 30 remained alive.

Case–control study of iTTP-SjD patients compared with pSjD without iTTP

30 patients iTTP-SjD were compared with 65 pSjD patients. There was a higher proportion of women (97% vs 85%, p=0.0008) in the iTTP-SjD group. The age at SjD diagnosis was statistically lower in the iTTP-SjD group compared with the pSjD group (p=0.039).

Anti-SSA antibodies and xerostomia were more prevalent in the iTTP-SjD group compared with the pSjD group (p=0.015 and p=0.035, respectively) (table 1). Regarding disease activity, after excluding items affected by TTP, the modified ESSDAI score was similar between the two groups (p=0.20). Patients in the iTTP-SjD group had more frequently complement consumption (p=0.048). At the time of latest update, there were more patients treated with hydroxychloroquine and corticosteroids in the iTTP-SjD group compared with the pSjD group (p<0.0001 and p=0.025, respectively) (table 3). There was no significant difference for the other treatments. During the follow-up of SjD, from the time of SjD diagnosis to iTTP diagnosis for iTTP-SjD or to the assessment of SjD in the pSjD group, excluding domains affected during TTP, there was a trend towards an increased proportion of systemic manifestations of SjD in the iTTP-SjD group compared with the pSjD group, but without reaching statistical significance (p=0.20).

Case–control study of SjD-TTP patients compared with idiopathic iTTP

30 patients with iTTP-SjD were compared with a cohort of 45 patients with idiopathic iTTP. There was a higher proportion of women (p=0.0008) in the iTTP-SjD group (table 2). Patients were significantly older in the iTTP-SjD group compared with those in the idiopathic iTTP group (p=0.004) and had a higher prevalence of pre-existing hypertension (p=0.018). Both groups were generally similar, except for haemoglobin and Cockcroft GFR, which were significantly lower in the iTTP-SjD group (p=0.026 and p=0.0017, respectively). Anti-ADAMTS13 IgG were similarly present in both groups. Patients in both groups had a similar clinical presentation. The French severity score was similar between groups. iTTP-SjD patients required more salvage therapy compared with idiopathic iTTP patients (p=0.023), but achieved complete remission similarly. In addition, the time to achieve an ADAMTS13 activity over 20% was comparable between the iTTP-SjD group and the idiopathic iTTP group (p=0.61). Relapse rate was also similar in both groups (p=0.384) (table 3). Moreover, in the idiopathic iTTP group, there was a trend for more ADAMTS13 relapses, although not significant (p=0.17). However, the composite endpoint of clinical or ADAMTS13 relapse was statistically higher in the idiopathic iTTP group compared with the iTTP-SjD group (43.9% vs 20.69%, p=0.044).

Clinical and ADAMTS13-relapse free survival

The endpoint criteria were defined as ‘clinical and/or ADAMTS13 relapse following pre-emptive rituximab infusion’ composite criteria, excluding from the analysis patients without sustained follow-up, especially those who could not receive rituximab at the time of management (before 2006). We observed a significantly higher relapse rate in the idiopathic iTTP group compared with iTTP-SjD group (18/41 vs 6/29, p=0.044) (table 3).

By conducting a survival analysis (figure 2), we found that the mean follow-up was 83.5 months in the idiopathic iTTP group and 60.9 months in the iTTP-SjD group. The median survival time was 148.1 months in the idiopathic iTTP group, while it was not reached in the iTTP-SjD group. No statistically significant difference was observed between the two groups for the composite criteria (log-rank test, p=0.228) (figure 2, online supplemental table 1).

Figure 2

Request permission

Kaplan-Meier curves showing clinical and ADAMTS13-relapse free survival by the time of diagnosis in the two groups. ADAMTS13, A Disintegrin And Metalloproteinase with Thrombospondin Motifs 13; iTTP, immune-mediated TTP; SjD, Sjögren’s disease; TTP, thrombotic thrombocytopenic purpura.

When considering initial treatment with rituximab, no statistical difference was found between the two groups for the composite criteria (HR 0.525 (0.204; 1.348), p=0.181), neither susceptible confounding factors such as age at iTTP diagnosis, gender, high French severity score (3–4), positive anti-ADAMTS13 IgG (>15 U/mL) at iTTP diagnosis, positive anti-ADAMTS13 IgG (>15 IU/mL) 3 months after the last TPE, use of salvage therapy or cardiac involvement (data not shown).

Discussion

Here, we report the first iTTP-SjD cohort, including 30 patients. The two control populations selected had clinical, biological and prognostic characteristics consistent with those described in the literature,6 14 giving us good external validity for our findings.

In cases of suspected TMA or persistent thrombocytopenia in SjD patients, even in the absence of active disease, measuring ADAMTS13 activity is recommended for TTP diagnosis. If severe ADAMTS13 deficiency (activity <10%) confirms a diagnosis of TTP, anti-ADAMTS13 IgG titres should be measured to document the mechanism of this deficiency. Patients with SjD developing iTTP were predominantly female, younger and more likely to have anti-SSA antibodies compared with those with pSjD without having more active disease. Moreover, their clinical and biological presentations of TTP were similar to those of patients with idiopathic iTTP, with favourable outcomes observed in most cases.

Regarding SjD, at iTTP diagnosis, the modified ESSDAI of the iTTP-SjD group compared with the ESSDAI of the pSjD group was similar, signifying that iTTP occurred in biologically more active but not in clinically more active SjD patients. However, iTTP-SjD tended to develop more systemic manifestations during the follow-up of the disease. Therefore, close monitoring of these patients seems necessary, as they may tend to develop additional systemic manifestations.

iTTP-SjD patients were older than idiopathic iTTP patients and showed a higher proportion of arterial hypertension. Indeed, age and cardiovascular comorbidities are known to be poor prognostic factors in iTTP.25 The clinical presentation of iTTP was relatively similar between the two groups, including severity at baseline. In iTTP, complement activation may play a role, which could explain the observed complement consumption in patients with iTTP-SjD.

Three patients from the iTTP-SjD group had been treated with caplacizumab, but their exclusion from the survival analysis did not affect the results. In our study, the use of salvage therapy was more frequent in the iTTP-SjD group compared with the idiopathic iTTP group. This suggests a poorer initial response to first-line therapy and a more complex underlying autoimmune profile, without affecting refractory rates or survival. Today, it is recommended to monitor ADAMTS13 activity in order to perform a pre-emptive rituximab infusion when the activity drops below 10%–20%, in order to avoid clinical relapses.11 27 28 In this sense, our composite criteria ‘clinical and/or ADAMTS13 relapse following pre-emptive rituximab infusion’ was relevant in assessing patient prognosis. We found a statistically significant difference in the composite criteria ‘clinical and/or ADAMTS13 relapse following by pre-emptive rituximab infusion’ with a lower risk of overall relapse in the iTTP-SjD group than in the idiopathic iTTP group. This result was not confirmed in the survival analysis or in the multivariate analyses taking into account rituximab treatment at initial diagnosis or age. However, these results may have been affected by a lack of statistical power in view of our patient numbers. Indeed, one of our hypotheses was that SjD patients might respond better to rituximab because of their state of lymphocyte hyperactivation, as has been suggested in SLE. Indeed, several studies have suggested a better efficacy of rituximab in the treatment of iTTP associated with SLE, particularly with regard to relapses.29 30 In this study, 66% of iTTP-SjD patients were treated with rituximab, and most of them had favourable outcomes.

Overall, the outcomes of iTTP-SjD were comparable to those of idiopathic iTTP. It was classically described that SLE-associated iTTP had a poorer clinical course than idiopathic iTTP, particularly in terms of mortality, despite the use of more aggressive treatments.31 This was challenged by a more recent study showing a better response to treatment in SLE patients with anti-ADAMTS13 antibodies.32 These results seem consistent with those of our study. The association of belimumab, a monoclonal Ab against BAFF, and rituximab has been found promising in patients with SLE-associated iTTP.33 Interestingly, this association that avoids the effect of the increase of BAFF after rituximab has been assessed successfully in active SLE34 and active SjD35 without iTTP.

This study highlighted the association with other autoimmune disease at the diagnosis of iTTP. Patients with iTTP should be screened for SAID to detect underlying lupus, SjD, RA and eventually refer to a rheumatologist during remission.

This study has several limitations. First, the results have to be interpreted with caution due to their retrospective nature. The ESSDAI scores for the iTTP-SjD cases were calculated retrospectively, which could lead to underscoring if data for certain domains are missing. However, given the low incidence of iTTP-SjD, conducting a prospective study would have been challenging. Second, the small number of patients may have limited the statistical power, especially in determining the risk factors for developing iTTP in SjD patients, but also in highlighting a statistical difference in relapse rate during follow-up. Third, five iTTP-SjD patients also had concomitant SAID such as SLE or RA, which would likely have been excluded from the ASSESS cohort but were included in our cohort given the rarity of the disease. Fourth, there may be an ascertainment bias: if anti-Ro/SSA had not been detected in iTTP patients, a diagnosis of SjD might not have been considered. In contrast, non-iTTP patients with dryness symptoms referred to a rheumatologist would have benefited from a full diagnostic work-up, including a salivary gland biopsy to check for Sjogren’s syndrome. This may explain the lower prevalence of anti-Ro/SSA. Finally, these results should be reevaluated in light of the recent use of caplacizumab.

Conclusion

We confirm here that iTTP can be a rare complication in patients with SjD. In that way, iTTP should be considered in cases where thrombocytopenia appears. This complication may occur in any SjD patient, with the only risk factors being elevated biological activity. The severity, prognosis and rates of clinical and ADAMTS13-relapse were comparable between iTTP-SjD and idiopathic iTTP patients. Further studies involving larger cohorts and extended follow-up times are warranted to definitely confirm these findings. The impact of caplacizumab in the management of these patients should be further assessed.

Supplementary PDF

XM, PC, IB and BSJ are joint senior authors.
Collaborators: N/A.
Contributors: JL collected clinical and laboratory information, interpreted the results and wrote the manuscript; XM, PC, IB, GN and BSJ designed the study, interpreted the results and critically reviewed the manuscript; LG made the statistical analysis, interpreted the results and critically reviewed the manuscript; GN and AV interpreted the results and critically reviewed the manuscript; RB collected clinical and laboratory information and critically reviewed the manuscript; PC and BSJ are responsible for the overall content as guarantors; and the final version of the manuscript was read and approved by all authors.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: GN received speaker fees from Novartis, Amgen, Galapagos and BMS. AV is a member of the French advisory boards for Sanofi and Takeda and received speaker fees from Sanofi, Octapharma, LFB-Biomédicaments and Takeda. XM received fees from BMS, Galapagos, GSK, Novartis and Pfizer. PC is a member of advisory boards and received speaker fees from Sanofi, Alexion, Octapharma and Takeda. IB received speaker fees from Galapagos. BSJ received speaker fees from Sanofi, Takeda and LFB-Biomédicaments. JL, LG and RB declare no conflicts of interest.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Data availability statement

Data are available upon reasonable request. Original anonymised data and response to specific questions are available upon reasonable request from the corresponding authors PC (paul.coppo@aphp.fr) and BSJ (berangere.joly@aphp.fr).

Ethics statements

Patient consent for publication:

Ethics approval:

This study involves human participants. Written informed consent was obtained from all patients according to the Declaration of Helsinki, and the study was approved by the Ethics Committees of the Hospital Saint-Antoine (Paris, France). No patient refused enrolment in the study and participants gave informed consent to participate in the study before taking part.

Somers EC, Thomas SL, Smeeth L, et al. Are individuals with an autoimmune disease at higher risk of a second autoimmune disorder? Am J Epidemiol 2009; 169:749–55.
doi:10.1093/aje/kwn408•Google Scholar
Somers EC, Thomas SL, Smeeth L, et al. Autoimmune diseases co-occurring within individuals and within families: a systematic review. Epidemiology 2006; 17:202–17.
doi:10.1097/01.ede.0000193605.93416.df•Google Scholar
Conrad N, Misra S, Verbakel JY, et al. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. Lancet 2023; 401:1878–90.
doi:10.1016/S0140-6736(23)00457-9•Google Scholar
Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339:1585–94.
doi:10.1056/NEJM199811263392203•Google Scholar
Furlan M, Robles R, Solenthaler M, et al. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura. Blood 1998; 91:2839–46.
Google Scholar
Joly BS, Coppo P, Veyradier A, et al. Thrombotic thrombocytopenic purpura. Blood 2017; 129:2836–46.
doi:10.1182/blood-2016-10-709857•Google Scholar
Coppo P, Cuker A, George JN, et al. Thrombotic thrombocytopenic purpura: Toward targeted therapy and precision medicine. Res Pract Thromb Haemost 2019; 3:26–37.
doi:10.1002/rth2.12160•Google Scholar
Roriz M, Landais M, Desprez J, et al. Risk Factors for Autoimmune Diseases Development After Thrombotic Thrombocytopenic Purpura. Medicine (Balt) 2015; 94.
doi:10.1097/MD.0000000000001598•Google Scholar
Amoura Z, Costedoat-Chalumeau N, Veyradier A, et al. Thrombotic thrombocytopenic purpura with severe ADAMTS-13 deficiency in two patients with primary antiphospholipid syndrome. Arthritis Rheum 2004; 50:3260–4.
doi:10.1002/art.20551•Google Scholar
Espinosa G, Bucciarelli S, Cervera R, et al. Thrombotic microangiopathic haemolytic anaemia and antiphospholipid antibodies. Ann Rheum Dis 2004; 63:730–6.
doi:10.1136/ard.2003.007245•Google Scholar
Jestin M, Benhamou Y, Schelpe A-S, et al. Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura. Blood 2018; 132:2143–53.
doi:10.1182/blood-2018-04-840090•Google Scholar
Mariette X, Criswell LA. Primary Sjögren’s Syndrome. N Engl J Med 2018; 378:931–9.
doi:10.1056/NEJMcp1702514•Google Scholar
Shiboski CH, Shiboski SC, Seror R, et al. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren’s Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts. Arthritis Rheumatol 2017; 69:35–45.
doi:10.1002/art.39859•Google Scholar
Brito-Zerón P, Baldini C, Bootsma H, et al. Sjögren syndrome. Nat Rev Dis Primers 2016; 2:16047.
doi:10.1038/nrdp.2016.47•Google Scholar
Seror R, Nocturne G, Mariette X, et al. Current and future therapies for primary Sjögren syndrome. Nat Rev Rheumatol 2021; 17:475–86.
doi:10.1038/s41584-021-00634-x•Google Scholar
Carvalho JF, Shoenfeld Y. Sjögren’s Syndrome Associated With Thrombotic Thrombocytopenic Purpura: A Case-Based Review. Rheumatol Ther 2021; 8:621–9.
doi:10.1007/s40744-020-00265-w•Google Scholar
Miller DD, Krenzer JA, Kenkre VP, et al. Sequential Immune Thrombocytopenia (ITP) and Thrombotic Thrombocytopenic Purpura (TTP) in an Elderly Male Patient with Primary Sjogren’s Syndrome: When in Doubt, Use the PLASMIC Score. Case Rep Med 2021; 2021.
doi:10.1155/2021/6869342•Google Scholar
Hegde R, Ismail R, Vegunta A, et al. Atypical posterior reversible encephalopathy syndrome in a case of thrombotic thrombocytopenic purpura with Sjogren’s syndrome. Radiol Case Rep 2021; 16:1552–6.
doi:10.1016/j.radcr.2021.03.035•Google Scholar
Zhou L, Zhu Y, Jiang M, et al. Pregnancy-associated thrombotic thrombocytopenic purpura complicated by Sjögren’s syndrome and non-neutralising antibodies to ADAMTS13: a case report. BMC Pregnancy Childbirth 2021; 21.
doi:10.1186/s12884-021-04167-9•Google Scholar
Kasturiarachi BM, Alsbrook DL, Crook J, et al. An Immunologic Storm: A Case of Encephalitis and Thrombotic Thrombocytopenic Purpura With Underlying Likely Sjogren’s Syndrome Induced by A COVID-19 Immune Response. Neurohospitalist 2022; 12:529–35.
doi:10.1177/19418744221079447•Google Scholar
Silvério-António M, Alves Ribeiro L, Medeiros J, et al. Sjögren’s syndrome presenting as thrombotic thrombocytopenic purpura in a male patient with previous Kikuchi-Fujimoto disease. Clin Exp Rheumatol 2022; 40:2472–3.
doi:10.55563/clinexprheumatol/utteqf•Google Scholar
Seror R, Theander E, Brun JG, et al. Validation of EULAR primary Sjögren’s syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann Rheum Dis 2015; 74:859–66.
doi:10.1136/annrheumdis-2013-204615•Google Scholar
Seror R, Meiners P, Baron G, et al. Development of the ClinESSDAI: A clinical score without biological domain. A tool for biological studies. Ann Rheum Dis 2016; 75:1945–50.
doi:10.1136/annrheumdis-2015-208504•Google Scholar
Coppo P, Schwarzinger M, Buffet M, et al. Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience. PLoS One 2010; 5.
doi:10.1371/journal.pone.0010208•Google Scholar
Benhamou Y, Assié C, Boelle P-Y, et al. Development and validation of a predictive model for death in acquired severe ADAMTS13 deficiency-associated idiopathic thrombotic thrombocytopenic purpura: the French TMA Reference Center experience. Haematologica 2012; 97:1181–6.
doi:10.3324/haematol.2011.049676•Google Scholar
Scully M, Cataland S, Coppo P, et al. Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost 2017; 15:312–22.
doi:10.1111/jth.13571•Google Scholar
Hie M, Gay J, Galicier L, et al. Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura. Blood 2014; 124:204–10.
doi:10.1182/blood-2014-01-550244•Google Scholar
Haute Autorité de Santé HAS. Purpura thrombotique thrombocytopénique [en ligne]. Saint-Denis La Plaine 2022;
Available: here
Google Scholar
Li J, Jiang J-J, Wang C-Y, et al. Clinical features and prognosis of patients with thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus: a review of 25 cases. Ital J Pediatr 2019; 45.
doi:10.1186/s13052-019-0641-y•Google Scholar
Mutoh T, Ohashi K, Nagai T, et al. Upfront rituximab therapy for thrombotic thrombocytopenic purpura in systemic lupus erythematosus: a case-based review. Rheumatol Int 2023; 43:373–81.
doi:10.1007/s00296-022-05182-5•Google Scholar
Letchumanan P, Ng H-J, Lee L-H, et al. A comparison of thrombotic thrombocytopenic purpura in an inception cohort of patients with and without systemic lupus erythematosus. Rheumatology (Oxford) 2009; 48:399–403.
doi:10.1093/rheumatology/ken510•Google Scholar
Yue C, Su J, Fan X, et al. Immune-mediated thrombotic thrombocytopenic purpura in patients with and without systemic lupus erythematosus: a retrospective study. Orphanet J Rare Dis 2020; 15.
doi:10.1186/s13023-020-01510-9•Google Scholar
Liu J, Yan M, Wen R, et al. Sequential treatment of rituximab and belimumab in thrombotic thrombocytopenia purpura associated with systemic lupus erythematous: A respective case series and literature review. Int J Rheum Dis 2023; 26:960–4.
doi:10.1111/1756-185X.14556•Google Scholar
Shipa M, Embleton-Thirsk A, Parvaz M, et al. Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus : A Randomized Controlled Trial. Ann Intern Med 2021; 174:1647–57.
doi:10.7326/M21-2078•Google Scholar
Mariette X, Barone F, Baldini C, et al. A randomized, phase II study of sequential belimumab and rituximab in primary Sjögren’s syndrome. JCI Insight 2022; 7.
doi:10.1172/jci.insight.163030•Google Scholar