Systemic Inflammatory and Autoimmune Diseases (SAID) Associated with MDS: A French Multicenter Retrospective Study
Authors: Mekinian Arsene , Grignano Eric , Braun Thorsten , Olivier Decaux , Eric Liozon , Nathalie Costedoat , jean Emmanuel Kahn , Hamidou Mohamed , Puechal Xavier , Park Sophie , Toussirot Eric , Falgarone Geraldine , Launay David , Nathalie Morel , Trouiller Sebastien , Alexis Mathian , Bruno Gombert , Schoindre Yoland , Lioger Bertrand , de Wazieres Benoit , Amoura Zahir , anne Laure Buchdaul , georgin Lavialle Sophie , Jeremie Dion , Madaule Serge , Raffray Loic , Cathebras Pascale , Piette Jean Charles , Ziza Jean Marc , Rose Christian , Montestruc Francois , Lortholary Olivier , Omouri Mohamed , Denis Guilllaume , Rossignol Julien , Ades Lionel , Gardin Claude , Fenaux Pierre , Fain Olivier 
Published: October 2019

Abstract
Background/Purpose: MDS are frequently associated with SAID, but few large series of this association have been reported. In this nationwide retrospective study, we analyzed disease characteristics, treatment and outcome of patients experiencing both SAID and MDS.
Methods: A questionnaire was sent toFrench internal medicine centers to report patients diagnosed between 1993 and 2013 with both SAID and MDS, concomitantly or successively. SAID were classified according to international criteria (Chapel Hill for vasculitis, ACR 1990 for SLE, ACR 1987 for rheumatoid arthritis). MDS diagnosed > 12 months after onset of immunosuppressive treatment for SAID and infectious or drug-related inflammatory systemic diseases associated with MDS were excluded. Baseline characteristics and outcome were compared between patients with MDS associated to SAID and a cohort of 665 MDS without SAID diagnosed at Avicenne’s University hospital between 2003 and 2013.
Results:
123 patients with both MDS and SAID (mean age 70 years; 41 females and 82 males) were included. MDS subtypes were RCUD (9%), RCMD (26%), RAEB-1 (15%), RAEB- 2 (8%), RARS (1%), 5q syndrome (5%) MDS-U (9%), CMML-1 (16%) and CMML 2 (4%). Karyotype (available in 85 patients) was fav in 75%, int in 10% and unfav in 15%. In those patients, IPSS was low (23%), int-1 (49%), int-2 (19%) and high (7%). SAID was systemic vasculitis in 39 cases (32%), connective tissue disease in 31 cases (25%), inflammatory arthritis in 28 cases (23%), a neutrophilic disorder in 12 cases (10%) and remained unclassified in 13 cases (11%). Complete diagnostic SAID criteria were fulfilled in only 66% of cases, remained incomplete in 21% and SAID was unclassified in the remaining patients. Diagnosis of SAID and MDS was concomitant in 38 (31%) cases, diagnosis of SAID preceded MDS in 46 (37%) cases and was made after MDS in 39 (32%) cases. The only significant correlation between type of SAID and MDS WHO classification was between CMML and systemic vasculitis (p=0.0024). 4 / 6 patients with Behcet’s disease had trisomy 8, compared to only 4 /79 patients with other SAID (p=0.003).
The effect of MDS treatment on SAID could be assessed in 20 patients where this treatment was concomitant with or started after SAID diagnosis, including 11 patients treated with azacytidine , 5 by hydroxyurea , 3 by cyclosporine and 1 by LD araC . SAID response (complete/partial) was achieved in 15 patients (75%) after 3 months and 12 (56%) after 6 months, including in 9/11 (80%) and 6/11 (55%), respectively for azacitidine.
By comparison with 665 MDS patients without SAID, MDS patients with SAID were younger (p=0.02), more frequently males (p=0.03), had less RARS and RAEB 2 (p<0.01), more often a poor karyotype (15% versus 11%, p=0.04) and tended to have less frequently low IPSS (23% versus 34%) (Table 1). Progression to AML and overall survival did not significantly differ between the 2 groups.
Conclusion:
The spectrum of SAID associated to MDS is variable, and a substantial proportion remains difficult to classify. MDS associated to SAID occur at a younger age, more frequently in females and tend to have poorer baseline prognostic factors than MDS without SAID, but outcome does not significantly differ between the 2 groups. In a limited number of evaluable patients, MDS treatment and in particular azacitidine improved SAID in 80% of the cases, a finding that should be tested prospectively.
Table 1. Baseline characteristics of patients with MDS associated to SAID and MDS without SAID. MDS with SAIDN=123 MDS without SAIDN=665 Age (years) 70±13 73±11* Female/Male 41/82 (50%) 291/374 (78%)* Karyotype Favorable 62 (75%) 386 (69%) Karyotype Intermediate 8 (10%) 111 (20%)* Karyotype Poor 13 (15%) 64 (11%)* Bone Marrow blasts (%) 6.5±9 4±5* IPSS 0.9±0.9 0.8±0.9 IPSS low 18 (23%) 190 (34%)* Intermediate-1 39 (49%) 181 (33%)* Intermediate-2 15 (19%) 107 (19%) Poor 7 (9%) 76 (14%) RCUD 11 (9%) 73 (11%) RARS 1 (1%) 57 (9%)* RAEB-1 18 (15%) 130 (20%) RAEB- 2 10 (8%) 116 (17%)* CMML 1 /2 19(16%) / 5 (4%) 96 (14%) / 7 (1%) 5q syndrome 6 (5%) 25 (4%) RCMD 31 (26%) 136 (20%) MDS-U 11 (9%) 22 (3%) Progression to Acute Leukemia 26 (22%) 83 (21%) Survival (median, months) 72 75
* P<0.05

Disclosures
Fenaux: Celgene Janssen Novartis: Research Funding.