Disease-modifying therapies in systemic lupus erythematosus for extrarenal manifestations.

Our 2022 published working definition of disease modification in systemic lupus erythematosus (SLE) was 'minimising disease activity with the fewest treatment-associated toxicities and slowing or preventing organ damage progression'. The objective of this review was to classify current SLE treatments according to the proposed non-renal disease modification criteria excluding toxicities. Based on a review of select clinical trial (n=32) and observational study (n=54) publications for 14 SLE medications across different therapeutic classes, and the authors' clinical experience, we evaluated disease modification potential as per the proposed framework at three time points. Specific criteria used to determine disease modification potential included a drug's capacity to reduce: (1) non-renal disease activity, (2) severe flares, (3) use of steroids/immunosuppressants and (4) organ damage accrual. Criteria 1-3 were assessed at 1 year and 2-5 years and, when positive, were considered evidence for disease modification potential; criterion 4 was used to confirm disease modification at >5 years. Each treatment received one of four mutually exclusive designations at each time point: (a) criterion met, (b) indications of criterion met despite insufficient evidence in the literature, (c) inconclusive and (d) no available supportive data. This review excludes an assessment of potential toxicities. Eight of the 14 SLE treatments met ≥1 disease modification criteria up to year 5. Hydroxychloroquine improved overall survival at >5 years, suggesting long-term disease modification, but no data on specific organ systems were reported. Belimumab was the only treatment to meet all criteria. Belimumab and hydroxychloroquine met disease modification definitions across three time points. Evidence for other SLE therapies was incomplete, particularly at >5 years. Future studies are warranted for other treatments to meet the disease modification criteria. We discuss challenges to classification and possible updates to our published criteria.

Lupus Nephritis Outcomes after Stopping Immunosuppression.

Background/Objectives: Immunosuppression (IS) is a standard therapy for lupus nephritis (LN). Data on the outcomes of patients with LN after the discontinuation of immunosuppression remain uncertain. This study aimed to evaluate the outcomes and results of patients with lupus nephritis (LN) who ceased immunosuppressive (IS) therapy. Methods: Records were obtained on the clinical and laboratory features of LN patients who were treated at our Lupus Unit. They included median values and ranges for various numerical variables such as patient age, disease duration, and treatment duration. Categorical variables such as gender, LN class, IS treatment type, and patient outcomes, which were categorized as either "stable" or "flare experienced", were presented as percentages and frequencies. A flare in LN was characterized by a two-fold increase in serum creatinine levels and a rise in proteinuria following the cessation of IS medication. Results: Outcomes were assessed for 45 patients with LN who ceased IS therapy after achieving remission. The patients' median age was 55 years (29-78). The median duration of treatment was 4 years (0.5-14). The LN histology distribution was class V = 24.4%, class IV = 17.8 %, class III = 17.8%, class III + IV = 15.6%, class III + V = 6.7%, class IV + V = 2.2%, and class II + IV and II = 2.2%. At the discontinuation of IS treatment, creatinine levels were elevated in 9/45 (20%) patients. Furthermore, 28.9% of patients relapsed after IS treatment discontinuation. Patients with anti-Smith antibodies (anti-Sm) were observed to have a higher occurrence of relapses, with six patients experiencing flare compared to four patients who remained stable (p = 0.03). Five (38.5%) of the patients with flares had high creatinine levels after IS discontinuation. Conclusions: Most of our patients maintained clinical remission and stable levels of LN parameters after IS treatment discontinuation. Those with a high serum creatinine level, ongoing proteinuria, depleted complement levels, and the presence of anti-Sm antibodies were more likely to experience flares after the discontinuation of IS therapy.

Anticoagulant and non-anticoagulant therapy in thrombotic antiphospholipid syndrome: old drugs and new treatment targets.

In this review, we discuss the current evidence on classic and newer oral anticoagulant therapy, older drugs such as HCQ and statins, and new potential treatment targets in APS. Vitamin K antagonists (VKAs) remain the cornerstone treatment for thrombotic events in APS. In patients fulfilling criteria for definite APS presenting with a first venous thrombosis, treatment with VKAs with a target international normalized ratio (INR) 2.0-3.0 is recommended. In patients with arterial thrombosis, treatment with VKA with target INR 2.0-3.0 or 3.0-4.0 is recommended by recent guidelines, considering the individual's bleeding and thrombosis recurrence risk. A combination of VKAs and low-dose aspirin (75-100 mg/daily) may also be considered. According to available evidence direct oral anticoagulants should be avoided in patients with arterial thrombosis and/or those with triple aPL positivity. Adjunctive treatment with HCQ and/or statins can be considered, especially in anticoagulation treatment-refractory APS. Potential targeted treatments in APS include B-cell targeting, complement inhibition, mammalian target of rapamycin inhibition, IFN targeting, adenosine receptors agonists, CD38 targeting or chimeric antigen receptor T-cell therapy. The safety and efficacy of these treatment targets needs to be examined in well-designed randomized controlled trials.

Patient Care Pathways for Pregnancy in Rare and Complex Rheumatic Diseases: Results From an International Survey.

OBJECTIVE: To map existing organizational care pathways in clinical centers of expertise that care for pregnant women affected by rare and complex connective tissue diseases (rcCTDs). METHODS: An international working group composed of experts in the field of pregnancy in rcCTDs co-designed a survey focused on organizational aspects related to the patient's pathway before, during, and after pregnancy. The survey was distributed to subject experts through referral sampling. RESULTS: Answers were collected from 69 centers in 21 countries. Patients with systemic lupus erythematosus and/or antiphospholipid syndrome were followed by more than 90% of centers, whereas those with disorders such as IgG4-related diseases were rarely covered. In the majority of centers, a multidisciplinary team was involved, including an obstetrician/gynecologist in 91.3% of cases and other healthcare professionals less frequently. Respondents indicated that 96% of the centers provided routine pre-pregnancy care, whereas the number of patient visits during pregnancy varied across centers. A formalized care pathway was described in 49.2% of centers, and 20.3% of centers had a predefined protocol for the monitoring of pregnant patients. Access to therapies during pregnancy also was heterogeneous among different centers. CONCLUSION: In international referral centers, a high level of care is provided to patients with rcCTDs before, during, and after pregnancy. No significant discrepancies were found between European and non-European countries. However, this work highlights a potential benefit to streamlining the care approaches across countries to optimize pregnancy and perinatal outcomes among patients with rcCTDs.

Outcomes of children born to mothers with systemic lupus erythematosus exposed to hydroxychloroquine or azathioprine.

OBJECTIVES: HCQ and AZA are used to control disease activity and reduce risk of flare during pregnancy in patients with SLE. The aim of this study was to determine the outcomes of children born to mothers with SLE exposed to HCQ or AZA during pregnancy and breast-feeding. METHODS: Women attending UK specialist lupus clinics with children ≤17 years old, born after SLE diagnosis, were recruited to this retrospective study. Data were collected using questionnaires and from clinical record review. Factors associated with the outcomes of low birth weight and childhood infection were determined using multivariable mixed-effects logistic regression models. RESULTS: We analysed 284 live births of 199 mothers from 10 UK centres. The first pregnancies of 73.9% of mothers (147/199) were captured in the study; (60.4%) (150/248) and 31.1% (87/280) children were exposed to HCQ and AZA, respectively. There were no significant differences in the frequency of congenital malformations or intrauterine growth restriction between children exposed or not to HCQ or AZA. AZA use was increased in women with a history of hypertension or renal disease. Although AZA was associated with low birth weight in univariate models, there was no significant association in multivariable models. In adjusted models, exposure to AZA was associated with increased reports of childhood infection requiring hospital management [odds ratio 2.283 (1.003, 5.198), P = 0.049]. CONCLUSIONS: There were no significant negative outcomes in children exposed to HCQ in pregnancy. AZA use was associated with increased reporting of childhood infection, which warrants further study.

Literature review of lupus nephritis From the Arabian Gulf region.

INTRODUCTION: The severity of lupus nephritis (LN) varies between different ethnicities. However, there are limited data regarding disease severity for LN in patients from the Arabian Gulf region; moreover, there are no treatment guidelines developed specifically for this population. The objective of this review was to characterise the incidence of LN, current treatment practices, the severity of LN, and the pathophysiology and biomarkers associated with LN in the Arabian Gulf region. METHODS: A literature search using EMBASE was conducted in October, 2021 to identify publications reporting on the incidence, treatment practices, severity, pathophysiology or biomarkers associated with LN, from countries in the Arabian Gulf region (including Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates). Additional relevant publications were provided by collaborators. A manual review of the publications was conducted to determine their relevance and data on the outcomes of interest were extracted. RESULTS: Of 3705 publications, 54 publications were identified as relevant. LN is one of the most commonly diagnosed renal diseases within the Arabian Gulf and approximately 10%-36% of all renal biopsies are for LN. Treatment patterns within the region appear to vary and generally follow treatment guidelines recommended by the Asia Pacific League of Associations for Rheumatology (APLAR), the European Alliance of Associations for Rheumatology (EULAR) and Kidney Disease Improving Global Outcomes (KDIGO). The majority of patients receive cyclophosphamide for induction therapy, whilst others receive mycophenolate mofetil. Most studies showed that the most frequently diagnosed class of LN within the Arabian Gulf region was Class IV (up to 63% of patients with LN). Sustained or increased levels of serum creatinine and proteinuria; and depressed levels of complement C3/C4 were commonly seen among patients with LN from the Arabian Gulf region. CONCLUSIONS: This review identified that LN may manifest more severely among patients from the Arabian Gulf region than in other populations, such as Caucasian populations. A greater understanding of LN and the treatment practices within the region, as well as the development of more specific treatment guidelines for this population may help improve outcomes for patients with LN in the Arabian Gulf region.

The BILAG-2004 index is associated with development of new damage in SLE.

OBJECTIVE: To determine whether BILAG-2004 index is associated with the development of damage in a cohort of SLE patients. Mortality and development of damage were examined. METHODS: This was a multicentre longitudinal study. Patients were recruited within 12 months of achieving fourth ACR classification criterion for SLE. Data were collected on disease activity, damage, SLE-specific drug exposure, cardiovascular risk factors, antiphospholipid syndrome status and death at every visit. This study ran from 1 January 2005 to 31 December 2017. Descriptive statistics were used to analyse mortality and development of new damage. Poisson regression was used to examine potential explanatory variables for development of new damage. RESULTS: A total of 273 SLE patients were recruited with total follow-up of 1767 patient-years (median 73.4 months). There were 6348 assessments with disease activity scores available for analysis. During follow-up, 13 deaths and 114 new damage items (in 83 patients) occurred. The incidence rate for development of damage was higher in the first 3 years before stabilizing at a lower rate. Overall rate for damage accrual was 61.1 per 1000 person-years (95% CI: 50.6, 73.8). Analysis showed that active disease scores according to BILAG-2004 index (systems scores of A or B, counts of systems with A and BILAG-2004 numerical score) were associated with development of new damage. Low disease activity (LDA) states [BILAG-2004 LDA and BILAG Systems Tally (BST) persistent LDA] were inversely associated with development of damage. CONCLUSIONS: BILAG-2004 index is associated with new damage. BILAG-2004 LDA and BST persistent LDA can be considered as treatment targets.

Immunology of pregnancy and reproductive health in autoimmune rheumatic diseases. Update from the 11th International Conference on Reproduction, Pregnancy and Rheumatic Diseases.

Autoimmune rheumatic diseases (ARD) can affect women and men during fertile age, therefore reproductive health is a priority issue in rheumatology. Many topics need to be considered during preconception counselling: fertility, the impact of disease-related factors on pregnancy outcomes, the influence of pregnancy on disease activity, the compatibility of medications with pregnancy and breastfeeding. Risk stratification and individualized treatment approach elaborated by a multidisciplinary team minimize the risk of adverse pregnancy outcomes (APO). Research has been focused on identifying biomarkers that can be predictive of APO. Specifically, preeclampsia and hypertensive disorders of pregnancy tend to develop more frequently in women with ARD. Placental insufficiency can lead to intrauterine growth restriction and small-for-gestational age newborns. Such APO have been shown to be associated with maternal disease activity in different ARD. Therefore, a key message to be addressed to the woman wishing for a pregnancy and to her family is that treatment with compatible drugs is the best way to ensure maternal and fetal wellbeing. An increasing number of medications have entered the management of ARD, but data about their use in pregnancy and lactation are scarce. More information is needed for most biologic drugs and their biosimilars, and for the so-called small molecules, while there is sufficient evidence to recommend the use of TNF inhibitors if needed for keeping maternal disease under control. Other issues related to the reproductive journey have emerged as "unmet needs", such as sexual dysfunction, contraception, medically assisted reproduction techniques, long-term outcome of children, and they will be addressed in this review paper. Collaborative research has been instrumental to reach current knowledge and the future will bring novel insights thanks to pregnancy registries and prospective studies that have been established in several Countries and to their joint efforts in merging data.

Belimumab use during pregnancy: a summary of birth defects and pregnancy loss from belimumab clinical trials, a pregnancy registry and postmarketing reports.

OBJECTIVE: Describe available data on birth defects and pregnancy loss in women with systemic lupus erythematosus (SLE) exposed to belimumab. METHODS: Data collected from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports up to 8 March 2020 were described. Belimumab exposure timing, concomitant medications and potential confounding factors were summarised descriptively. RESULTS: Among 319 pregnancies with known outcomes (excluding elective terminations), 223 ended in live births from which birth defects were identified in 4/72 (5.6%) in belimumab-exposed pregnancies and 0/9 placebo-exposed pregnancies across 18 clinical trials, 10/46 (21.7%) belimumab-exposed pregnancies in the BPR prospective cohort (enrolled prior to pregnancy outcome) and 0/4 belimumab-exposed pregnancies in the BPR retrospective cohort (enrolled after pregnancy outcome), and 1/92 (1.1%) in belimumab-exposed pregnancies from postmarketing/spontaneous reports. There was no consistent pattern of birth defects across datasets. Out of pregnancies with known outcomes (excluding elective terminations), pregnancy loss occurred in 31.8% (35/110) of belimumab-exposed women and 43.8% (7/16) of placebo-exposed women in clinical trials; 4.2% (2/48) of women in the BPR prospective cohort and 50% (4/8) in the BPR retrospective cohort; and 31.4% (43/137) of belimumab-exposed women from postmarketing/spontaneous reports. All belimumab-exposed women in clinical trials and the BPR received concomitant medications and had confounding factors and/or missing data. CONCLUSIONS: Observations reported here add to limited data published on pregnancy outcomes following belimumab exposure. Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use.

Retinal toxicity in a multinational inception cohort of patients with systemic lupus on hydroxychloroquine.

OBJECTIVE: To evaluate hydroxychloroquine (HCQ)-related retinal toxicity in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort. METHODS: Data were collected at annual study visits between 1999 and 2019. We followed patients with incident SLE from first visit on HCQ (time zero) up to time of retinal toxicity (outcome), death, loss-to-follow-up or end of study. Potential retinal toxicity was identified from SLICC Damage Index scores; cases were confirmed with chart review. Using cumulative HCQ duration as the time axis, we constructed univariate Cox regression models to assess if covariates (ie, HCQ daily dose/kg, sex, race/ethnicity, age at SLE onset, education, body mass index, renal damage, chloroquine use) were associated with HCQ-related retinal toxicity. RESULTS: We studied 1460 patients (89% female, 52% white). Retinal toxicity was confirmed in 11 patients (incidence 1.0 per 1000 person-years, 0.8% overall). Average cumulative time on HCQ in those with retinal toxicity was 7.4 (SD 3.2) years; the first case was detected 4 years after HCQ initiation. Risk of retinal toxicity was numerically higher in older patients at SLE diagnosis (univariate HR 1.05, 95% CI 1.01 to 1.09). CONCLUSIONS: This is the first assessment of HCQ and retinal disease in incident SLE. We did not see any cases of retinopathy within the first 4 years of HCQ. Cumulative HCQ may be associated with increased risk. Ophthalmology monitoring (and formal assessment of cases of potential toxicity, by a retinal specialist) remains important, especially in patients on HCQ for 10+ years, those needing higher doses and those of older age at SLE diagnosis.

The BILAG2004-Pregnancy Index is a valid disease activity outcome measure for pregnant SLE patients.

Objectives: This study was to determine whether the BILAG2004-Pregnancy Index (BILAG2004-P) has construct/criterion validity and is sensitive to change. Methods: This was an observational multicentre study that recruited pregnant SLE patients. Data were collected on disease activity [using the BILAG2004-P and Physician Global Assessment (PGA)], investigations and therapy at each assessment. The overall BILAG2004-P score as determined by the highest score achieved by any system was used in the analysis. Cross-sectional analysis was used for construct and criterion validity. The comparison was with C3, C4 and anti-dsDNA for construct validity, while it was with change in therapy and PGA in criterion validity. Sensitivity to change was assessed by determining the relationship between the change in BILAG2004-P and the change in therapy between two consecutive visits. Results: A total of 97 patients with 112 pregnancies were recruited. There were 610 assessments available for construct/criterion validity analysis (98.2% of pregnancies had more than one assessment) and 497 observations for sensitivity to change analysis. Increasing BILAG2004-P scores were associated with low C3. The active BILAG2004-P score (grade A or B) was associated with an increase in therapy and the PGA of active disease. There was an increasing likelihood of higher overall scores with an increase in therapy and the PGA of active disease. In the sensitivity to change analysis, an increase in the BILAG2004-P score was associated with an increase in therapy and inversely associated with a decrease in therapy. A decrease in the BILAG2004-P score was associated with a decrease in therapy and inversely associated with an increase in therapy. Conclusion: The BILAG2004-P has criterion validity and is sensitive to change.

Prediction of Hospitalizations in Systemic Lupus Erythematosus Using the Systemic Lupus International Collaborating Clinics Frailty Index.

OBJECTIVE: The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) predicts mortality and damage accrual in systemic lupus erythematosus (SLE), but its association with hospitalizations has not been described. Our objective was to estimate the association of baseline SLICC-FI values with future hospitalizations in the SLICC inception cohort. METHODS: Baseline SLICC-FI scores were calculated. The number and duration of inpatient hospitalizations during follow-up were recorded. Negative binomial regression was used to estimate the association between baseline SLICC-FI values and the rate of hospitalizations per patient-year of follow-up. Linear regression was used to estimate the association of baseline SLICC-FI scores with the proportion of follow-up time spent in the hospital. Multivariable models were adjusted for relevant baseline characteristics. RESULTS: The 1,549 patients with SLE eligible for this analysis were mostly female (88.7%), with a mean ± SD age of 35.7 ± 13.3 years and a median disease duration of 1.2 years (interquartile range 0.9-1.5) at baseline. Mean ± SD baseline SLICC-FI was 0.17 ± 0.08. During mean ± SD follow-up of 7.2 ± 3.7 years, 614 patients (39.6%) experienced 1,570 hospitalizations. Higher baseline SLICC-FI values (per 0.05 increment) were associated with more frequent hospitalizations during follow-up, with an incidence rate ratio of 1.21 (95% confidence interval [95% CI] 1.13-1.30) after adjustment for baseline age, sex, glucocorticoid use, immunosuppressive use, ethnicity/location, SLE Disease Activity Index 2000 score, SLICC/American College of Rheumatology Damage Index score, and disease duration. Among patients with ≥1 hospitalization, higher baseline SLICC-FI values predicted a greater proportion of follow-up time spent hospitalized (relative rate 1.09 [95% CI 1.02-1.16]). CONCLUSION: The SLICC-FI predicts future hospitalizations among incident SLE patients, further supporting the SLICC-FI as a valid health measure in SLE.

Comparison of Responsiveness of British Isles Lupus Assessment Group 2004 Index, Systemic Lupus Erythematosus Disease Activity Index 2000, and British Isles Lupus Assessment Group 2004 Systems Tally.

OBJECTIVE: To compare the responsiveness of the British Isles Lupus Assessment Group 2004 index (BILAG-2004) and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) disease activity indices and to determine whether there was any added value in combining BILAG-2004, BILAG-2004 system tally (BST), or simplified BST (sBST) with SLEDAI-2K. METHODS: This was a multicenter longitudinal study of SLE patients. Data were collected on BILAG-2004, SLEDAI-2K, and therapy on consecutive assessments in routine practice. The external responsiveness of the indices was assessed by determining the relationship between change in disease activity and change in therapy between 2 consecutive visits. Comparison of indices and their derivatives was performed by assessing the main effects of the indices using logistic regression. Receiver operating characteristic curves analysis was used to describe the performance of these indices individually and in various combinations, and comparisons of area under the curve were performed. RESULTS: There were 1,414 observations from 347 patients. Both BILAG-2004 and SLEDAI-2K maintained an independent relationship with change in therapy when compared. There was some improvement in responsiveness when continuous SLEDAI-2K variables (change in score and score of previous visit) were combined with BILAG-2004 system scores. Dichotomization of BILAG-2004 or SLEDAI-2K resulted in poorer performance. BST and sBST had similar responsiveness as the combination of SLEDAI-2K variables and BILAG-2004 system scores. There was little benefit in combining SLEDAI-2K with BST or sBST. CONCLUSION: The BILAG-2004 index had comparable responsiveness to SLEDAI-2K. There was some benefit in combining both indices. Dichotomization of BILAG-2004 and SLEDAI-2K leads to suboptimal performance. BST and sBST performed well on their own; sBST is recommended for its simplicity and clinical meaningfulness.

Flares after hydroxychloroquine reduction or discontinuation: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort.

OBJECTIVES: To evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance. METHODS: We analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999-2019). We evaluated person-time contributed while on the initial HCQ dose ('maintenance'), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare. RESULTS: We studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts. CONCLUSIONS: SLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful.