Association of Mycophenolate and Azathioprine Use with Cognitive Function in SLE

Chrisanna Dobrowolski¹, Jiandong Su², John McGinley¹, Melissa Fazzari¹, Kathleen Bingham³, Nicole Anderson², Dorcas Beaton⁴, Lesley Ruttan³, Joan Wither², Maria Tartaglia², Mahta Kakvan², Dennisse Bonilla², May Choi⁵, Marvin Fritzler⁶, Patricia Katz⁷, Robin Green², Chaim Putterman¹ and Zahi Touma⁸, ¹Albert Einstein College of Medicine, Bronx, NY, ²University Health Network, Toronto, ON, Canada, ³University of Toronto, University Health Network, Toronto, ON, Canada, ⁴Institute for Work & Health, Toronto, ON, Canada, ⁵Brigham and Women's Hospital | University of Calgary, Calgary, AB, Canada, ⁶University of Calgary, Calgary, AB, Canada, ⁷University of California San Francisco, San Francisco, CA, ⁸University of Toronto, Mississauga, ON, Canada

Meeting: ACR Convergence 2021

Keywords: azathioprine, Cognitive dysfunction, neuropsychiatric systemic lupus erythematosus (NPSLE), Neuropsychological Assessment, Systemic lupus erythematosus (SLE)

Session Information

Date: Sunday, November 7, 2021

Title: SLE – Diagnosis, Manifestations, & Outcomes Poster II: Manifestations (0855–0896)

Session Type: Poster Session B

Session Time: 8:30AM-10:30AM

Background/Purpose: Cognitive dysfunction (CD) is a common manifestation of systemic lupus erythematosus (SLE) which can have detrimental consequences for those affected. To date, no treatments have been approved for SLE-associated CD (SLE-CD). This study aims to assess the association of azathioprine (AZA) and mycophenolate (MMF) use with SLE-CD, given that these medications have demonstrated neuroprotective qualities in prior studies.

Methods: Consecutive adult SLE patients presenting to a single center were screened. The American College of Rheumatology (ACR) neuropsychological battery (NB) for SLE, evaluating 6 cognitive domains, was administered to consenting participants at 0, 6 and 12 months. Age and gender matched normative data were used to obtain z-scores. CD was determined by a z-score of £-1.5 in ³2 cognitive domains. Non-CD was defined as no z-score £-1.5. MMF and AZA use were recorded as cumulative dose (grams per kilogram [g/kg]), duration of treatment (number of years) and current use for ³6 months from visit day. Clinical and demographic characteristics were verified at each visit. Baseline characteristics by cognitive status and medication use were documented. Mixed-effects logistic regression models were constructed to estimate the odds of CD and non-CD with respect to AZA and MMF use over the three follow-up periods.

Results: Three hundred participants representing 676 patient visits completed the study; 157 (52%) met criteria for CD at baseline. Mean age was 41.1 years (SD 12.1) and 267 participants (89.0%) were female. Table 1 outlines baseline characteristics by CD and non-CD status. There were no significant differences in mean age, glucocorticoid dose, disease duration, SLE Disease Activity Index-2000 (SLEDAI-2K) scores, or SLICC-ACR Damage Index (SDI) scores. In contrast, there were significantly more participants with CD who identified as Black or Chinese, and significantly fewer participants identifying as White. There were also fewer married participants with CD. Table 2 documents baseline characteristics by AZA and MMF use with respect to CD status. Participants taking AZA or MMF had significantly higher SLEDAI-2K scores and higher prevalence of nephritis; participants taking MMF had higher rates of hypertension, higher daily doses of glucocorticoid medications and lower rates of smoking.

Table 3 shows results of the mixed effects models for AZA and MMF use versus CD. For each g/kg of cumulative AZA, there was on average a 24% reduced odds of CD: OR 0.76, 95% CI 0.61, 0.96, p=0.02. For each year of AZA treatment there was on average a 32% reduced odds of CD: OR 0.68 (0.50, 0.94), p=0.02. AZA use as binary variable (yes versus no) demonstrated a consistent trend toward reduced odds of CD with AZA use without reaching statistical significance: OR 0.29 (0.08, 1.12), p=0.07. Cumulative AZA dose was not significantly associated with non-CD status: 1.08 (0.91, 1.27), p=0.38 (not shown). MMF use was not associated with CD or non-CD.

Conclusion: Despite higher disease activity scores in participants taking AZA compared to those not taking AZA, cumulative AZA dose and increasing AZA treatment duration were associated with significantly lower odds of SLE-CD. MMF use was not associated with SLE-CD.

1) CD: cognitive dysfunction. Defined as a z-score of ≤_1.5 on ≥2 cognitive domains, based on neuropsychological testing.
2) Completion of post-secondary schooling including a College (≥2 years) or University (≥4 years) degree.
3) Positive lupus anticoagulant testing, and/or anti-beta2glycoprotein1 IgG or IgM, and/or anti-cardiolipin IgG or IgM above laboratory specific upper limit of normal, at baseline and again after ≥12 weeks.
4) Psychosis, seizures, stroke, neuropathy and/or transverse myelitis.
5) Known risk factors for cognitive dysfunction not captured elsewhere.
6) SLICC ACR: Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index.
7) SLEDAI_2K: Systemic Lupus Erythematosus Disease Activity Index 2000.
8) SLEDAI_2KG: Systemic Lupus Erythematosus Disease Activity Index 2000 Glucocorticoid Index.
9) Beck Depression Inventory score of 0–13 is considered minimal, 14–19 mild, 20–28 moderate and 29–63 severe.
10) Beck Anxiety Inventory score of 0-7 is considered minimal, 8_15 mild, 16_25 moderate and 26-63 severe.

AZA: azathioprine; MMF: mycophenolate; CD: cognitive dysfunction; NPSLE: neurologic and psychiatric manifestations of systemic lupus.
1) SLICC-ACR DI: Systemic Lupus International Collaborating Clinics American College of Rheumatology Damage Index.
2) SLEDAI_2K: Systemic Lupus Erythematosus Disease Activity Index 2000.
3) SLEDAI_2KG: Systemic Lupus Erythematosus Disease Activity Index 2K Glucocorticoid.
4) Positive lupus anticoagulant testing, and/or anti-beta2glycoprotein1 IgG or IgM, and/or anti-cardiolipin IgG or IgM above laboratory specific upper limit of normal, at baseline and again after ≥12 weeks
5) Psychosis, seizures, stroke, neuropathy and/or transverse myelitis.
6) Known risk factors for cognitive dysfunction not captured elsewhere.

1Cognitive dysfunction was defined as a z-score of ≤_1.5 on ≥2 cognitive domains based on comprehensive neuropsychological testing.
OR: odds ratio; CI: confidence interval.

Covariates included in the models: Systemic Lupus Erythematosus Disease Activity Index_2000 Glucocorticoid (SLEDAI_2KG) score (incorporates glucocorticoid dose with the SLE Disease Activity Index 2000 [SLEDAI_2K]), Systemic Lupus International Collaborating Clinics (SLICC) – American College of Rheumatology (ACR) Damage Index score (SDI), additional CD risk factors not captured elsewhere (hypertension, obesity, active smoker), persistent antiphospholipid antibody positivity (positive lupus anticoagulant testing, and/or anti-beta2glycoprotein1 IgG or IgM, and/or anti-cardiolipin IgG or IgM above laboratory specific upper limit of normal, at baseline and again after ≥12 weeks, recorded as binary variable), history of lupus nephritis, active use of an additional immunomodulator (antimalarials, belimumab, calcineurin inhibitor, cyclophosphamide, methotrexate, rituximab), prior use of an immunomodulator (AZA, calcineurin inhibitor, cyclophosphamide, methotrexate, MMF), Beck Depression Inventory (BDI) scores, Beck Anxiety Inventory (BAI) scores, age in years, sex (male versus female), ethnicity (Black, Caucasian, Chinese or other), education level (completion of a College or University degree recorded as binary variable), employment status (employed or full time student versus other) and marital status (married or common-law partner versus other).

Disclosures: C. Dobrowolski, None; J. Su, None; J. McGinley, None; M. Fazzari, None; K. Bingham, None; N. Anderson, None; D. Beaton, None; L. Ruttan, None; J. Wither, None; M. Tartaglia, None; M. Kakvan, None; D. Bonilla, None; M. Choi, MitogenDx, 1, 2; M. Fritzler, Inova Diagnostics Inc., 2, 6, Werfen International, 2, Alexion Canada, 6, Mitogen Diagnostics Corp., 3, 8, 9, 10; P. Katz, None; R. Green, None; C. Putterman, equllium, 2, 5, Progentec, 2, Kidneycure, 2; Z. Touma, AbbVie Inc, 2, UCB Biopharma SRL, 2, Sarkana Pharma Inc., 1, 4, Janssen Inc., 2, GlaxoSmithKline Inc., 6.

To cite this abstract in AMA style:

Dobrowolski C, Su J, McGinley J, Fazzari M, Bingham K, Anderson N, Beaton D, Ruttan L, Wither J, Tartaglia M, Kakvan M, Bonilla D, Choi M, Fritzler M, Katz P, Green R, Putterman C, Touma Z. Association of Mycophenolate and Azathioprine Use with Cognitive Function in SLE [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/association-of-mycophenolate-and-azathioprine-use-with-cognitive-function-in-sle/. Accessed .

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