Navigating the landscape of SLE treatment: An expert viewpoint on the rationality and limitations of early biologic intervention.

The approval of biologics, namely belimumab and anifrolumab, is being a game-changer in the approach to systemic lupus erythematosus (SLE). Currently we are indeed facing a revolution in the treatment paradigm of SLE, encompassing early combination of biologics with standard treatment in severe manifestations. In this regard, a lively discussion is taking place regarding the better positioning of biologics in the treatment of not necessarily severe, yet refractory and/or disfiguring manifestations which expose patients to worsened quality of life, reduced workability and enhanced risk of organ damage especially related to the misuse of glucocorticoids in the long run. Growing evidence supports the early use of targeted treatments in those patients, including the use of biologics before traditional immunosuppression, to achieve control of disease activity while minimizing treatment-related damage, privileging the timely use of therapeutics selectively impacting on key disease mechanisms in spite of a widespread immunosuppression. Patient profiling on a clinical and endotypical basis is helping in identifying better candidates to targeted drugs. More inflammatory organ involvement including persistent arthritis and infiltrating skin lesions seem likely to respond to anifrolumab, while B-mediated manifestations, a lively serology and a relapsing-remitting SLE course hint at a suitable role for belimumab. This seems at least partially connected to the inner effect of either drug, dampening inflammation through down-regulation of interferon signalling in the case of anifrolumab, while plastically modulating the B cell pool composition and function when coming to belimumab. Nevertheless, the mechanisms of both drugs are immunologically entangled at some extent, thereby requiring careful management especially in patients with longer disease history burdened with mixed manifestations. In this viewpoint we go over pros and cons of anticipatory biologic use in SLE, exploring features linked with better efficacy of either drug and the pathogenic and practical rationale for their positioning before traditional immunosuppression in moderate refractory SLE to be optimally managed in the 21st Century.

Effectiveness and safety of low dose Rituximab as remission-maintenance treatment for patients with refractory idiopathic inflammatory myopathies: results of a retrospective study from a monocentric cohort.

OBJECTIVE: Our aim was to assess efficacy and safety of Rituximab (RTX) in patients with refractory Idiopathic inflammatory myopathies (IIM) from a monocentric cohort. Thereafter, we evaluated the efficacy of a low-dose RTX regimen as a remission-maintenance therapy. METHODS: We retrospectively evaluated a cohort of patients affected with IIM treated with RTX. All patients were refractory to glucocorticoids (GC) and at least one immunosuppressant. Two infusions of 1 g two weeks apart were considered as standard cycle of RTX, a single dose of 1 g every six months was deemed as a low-dose RTX regimen. Complete and partial response were defined according to physician's judgment, laboratory and radiological features. RESULTS: Thirty-six patients affected with IIM were enrolled. Eighteen patients (50%) required the use of RTX for muscular involvement, 6 (16.7%) for interstitial lung disease (ILD), 12 (33.3%) for both myositis and ILD. We observed complete response to RTX in 25 patients (69.4%), partial response in 7 (19.4%) and no response in 4 (11.1%), with an overall response of 88.8% (partial and complete response). From the subgroup of twenty-five patients that achieved a complete response, six were treated with a low dose maintenance therapy maintaining a complete response to RTX. Twenty-six patients who achieved a complete or partial response were able to decrease the mean daily GC dose. Infections were the major adverse events detected in our study. CONCLUSIONS: RTX shows favorable outcomes in refractory patients with IIM. A low-dose regimen of RTX appears to be effective in maintaining remission after induction with standard dose. Key Points • The precise pathogenic mechanism of idiopathic inflammatory myopathies (IIM) remains elusive; however, a growing body of data support the autoimmune hypothesis. In this context, rituximab, a B cell-depleting agent, has emerged as a second-line therapeutic option in IIM. • Several studies have assessed It its effectiveness in refractory IIM patients. • Limited information exists on the use of Rituximab as maintenance therapy in patients who have achieved remission following induction therapy with Rituximab.

Anifrolumab in Refractory Systemic Lupus Erythematosus: A Real-World, Multicenter Study.

OBJECTIVE: To report real-world experience on the use of anifrolumab (ANI) in refractory systemic lupus erythematosus (SLE). METHODS: The present study is a multicenter, retrospective study involving 9 Italian SLE referral centers participating in a compassionate use program for the use of ANI in adult patients with active SLE in whom all the available treatment choices failed, were not tolerated, or were contraindicated. At baseline and 1, 3, 6, 9, and 12 months of treatment, overall and organ-specific disease activity, flares, daily glucocorticoid (GC) dose, and adverse events were recorded. RESULTS: A total of 26 patients were enrolled. At 4 weeks after starting ANI, a significant decrease in the Systemic Lupus Erythematosus Disease Activity Index 2000 (P = 0.01), Systemic Lupus Erythematosus-Disease Activity Score (P = 0.01), and physician global assessment (P = 0.001) was recorded, and the same trend was maintained over time. A significant reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index-activity (P < 0.001) and in tender (P = 0.03) and swollen (P = 0.02) joint counts was also recorded. At 3 months of follow-up, 33% of patients already achieved a remission state, whereas 46% were in Lupus Low Disease Activity State (LLDAS); at 6 months, 50% were in remission and 80% were in LLDAS. A significant reduction in the mean GC daily dose was observed, starting from week 4 (P = 0.04). A total of 4 disease flares according to the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index were recorded (3 mild-moderate and 1 severe). Overall, 4/20 patients with at least 24 weeks of follow-up (20%) were considered nonresponders. CONCLUSION: This study provides real-world experience on the use of ANI in patients with refractory SLE, confirming its rapid effectiveness and an overall acceptable safety profile.

Tailoring the treatment of inflammatory rheumatic diseases by a better stratification and characterization of the clinical patient heterogeneity. Findings from a systematic literature review and experts' consensus.

Inflammatory rheumatic diseases are different pathologic conditions associated with a deregulated immune response, codified along a spectrum of disorders, with autoinflammatory and autoimmune diseases as two-end phenotypes of this continuum. Despite pathogenic differences, inflammatory rheumatic diseases are commonly managed with a limited number of immunosuppressive drugs, sometimes with partial evidence or transferring physicians' knowledge in different patients. In addition, several randomized clinical trials, enrolling these patients, did not meet the primary pre-established outcomes and these findings could be linked to the underlying molecular diversities along the spectrum of inflammatory rheumatic disorders. In fact, the resulting patient heterogeneity may be driven by differences in underlying molecular pathology also resulting in variable responses to immunosuppressive drugs. Thus, the identification of different clinical subsets may possibly overcome the major obstacles that limit the development more effective therapeutic strategies for these patients with inflammatory rheumatic diseases. This clinical heterogeneity could require a diverse therapeutic management to improve patient outcomes and increase the frequency of clinical remission. Therefore, the importance of better patient stratification and characterization is increasingly pointed out according to the precision medicine principles, also suggesting a new approach for disease treatment. In fact, based on a better proposed patient profiling, clinicians could more appropriately balance the therapeutic management. On these bases, we synthetized and discussed the available literature about the patient profiling in regard to therapy in the context of inflammatory rheumatic diseases, mainly focusing on randomized clinical trials. We provided an overview of the importance of a better stratification and characterization of the clinical heterogeneity of patients with inflammatory rheumatic diseases identifying this point as crucial in improving the management of these patients.

Retention Rate of Ixekizumab in Psoriatic Arthritis: A Real-World Study.

We aimed to examine the drug retention rate (DRR) of the interleukin-17 inhibitor ixekizumab in a real-world monocentric cohort of psoriatic arthritis (PsA) patients and to assess the predictors of drug discontinuation. Consecutive PsA patients who underwent treatment with ixekizumab from October 2019 to February 2023 were enrolled in this observational, retrospective, monocentric study. Clinical records were assessed at baseline and throughout the follow-up period. We collected sociodemographic data, smoking habits, body mass index, the presence of Human Leukocyte Antigen B27, comorbidities, disease involvement and duration, previous therapy, discontinuation of ixekizumab, reasons for discontinuation, and adverse events (AEs). DRR was evaluated as time to drug discontinuation and assessed through Kaplan-Meier curves. Baseline factors predicting drug discontinuation were investigated through logistic regression models. Eighty PsA patients were included in this study. Ixekizumab was administered at a dose of 160 mg by subcutaneous injection at baseline, followed by 80 mg every four weeks thereafter. Ixekizumab had a 38-month-cumulative DRR of 43.8%, accounting for both inefficacy and AEs. When considering only inefficacy, the DRR was 62.6%. Comorbidities (p = 0.665), obesity (p = 0.665), smoking (p = 0.884), disease duration ≤ 2 years (p = 0.071), axial (p = 0.131) and skin involvement (p = 0.460), and previous therapies, including conventional synthetic (p = 0.504) and biological (p = 0.474) Disease-Modifying Antirheumatic Drugs (bDMARDs), as well as the number of previous bDMARDs or targeted synthetic Disease-Modifying Antirheumatic Drugs (tsDMARDs), did not significantly affect the DRR (p = 0.349). Multivariate analysis found no independent predictors of drug discontinuation. The most frequent AEs leading to discontinuation were skin reactions; no severe infections were observed. In our real-world study, comorbidities, disease duration, and previous therapies did not affect the DRR of ixekizumab. Ixekizumab had a favorable safety profile, with no severe AEs observed.

Monoclonal antibodies targeting interleukins for systemic lupus erythematosus: updates in early clinical drug development.

INTRODUCTION: The advent of biological therapies has already revolutionized treatment strategies and disease course of several rheumatologic conditions, and monoclonal antibodies (mAbs) targeting cytokines and interleukins represent a considerable portion of this family of drugs. In systemic lupus erythematosus (SLE) dysregulation of different cytokine and interleukin-related pathways have been linked to disease development and perpetration, offering palatable therapeutic targets addressable via such mAbs. AREAS COVERED: In this review, we provide an overview of the different biological therapies under development targeting cytokines and interleukins, with a focus on mAbs, while providing the rationale behind their choice as therapeutic targets and analyzing the scientific evidence linking them to SLE pathogenesis. EXPERT OPINION: An unprecedented number of clinical trials on biological drugs targeting different immunological pathways are ongoing in SLE. Their success might allow us to tackle present challenges of SLE management, including the overuse of glucocorticoids in daily clinical practice, as well as SLE heterogenicity in treatment response among different individuals, hopefully paving the way toward precision medicine.

Modern Management of Pregnancy in Systemic Lupus Erythematosus: From Prenatal Counseling to Postpartum Support.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that predominantly affects women of childbearing age. Pregnancy in SLE patients poses unique challenges due to the potential impact on maternal and fetal outcomes. We provide an overview of the management of SLE during pregnancy, including preconception risk stratification and counseling, treatment, and disease activity monitoring. These assessments are critical to minimize maternal and fetal adverse events in pregnant patients with SLE. Disease flares, preeclampsia, antiphospholipid syndrome complications, and maternal mortality are the major risks for a woman with SLE during gestation. Timely treatment of SLE relapse, differentiation of preeclampsia from lupus nephritis, and tailored management for antiphospholipid syndrome are essential for a successful pregnancy. Fetal outcomes include neonatal lupus (NL), preterm birth, cesarean delivery, fetal growth restriction (FGR), and small-for-gestational-age (SGA) infants. We focused on NL, linked to maternal anti-Ro/SS-A and anti-La/SS-B antibodies, which can lead to various manifestations, particularly cardiac abnormalities, in newborns. While there is a common consensus regarding the preventive effect of hydroxychloroquine, the role of echocardiographic monitoring and fluorinated steroid treatment is still debated. Finally, close postpartum monitoring and counseling for subsequent pregnancies are crucial aspects of care.

The Retention Rate and Safety of JAK Inhibitors in Rheumatoid Arthritis: Real Word Data from a Monocentric Cohort.

Background/Objectives: To date, the literature concerning real-world data on the retention rate and safety of Janus kinase inhibitors (JAKis) is limited. To retrospectively evaluate the overall drug retention rate (DRR) of different JAKis in a monocentric cohort of patients with rheumatoid arthritis (RA). Methods: Patients diagnosed with RA and treated with JAKis who were evaluated at our outpatient clinic from March 2017 to December 2023 were included in the study. Demographic, clinical characteristics, and comorbidities were recorded. The DRR was evaluated as the time to drug discontinuation, and baseline predictors of drug discontinuation were investigated through Cox regression after adjusting for baseline confounders. Results: The global DRR for JAKis was 51.3%. The DRR was 37.5% for tofacitinib, 46.6% for baricitinib, 69.4% for upadacitinib, and 53.5% for filgotinib. Considering all JAKis, the only significant predictor of drug discontinuation was the use of JAKis as a first-line treatment (HR 95% CI [0.25 (0.13-0.46)]. When considering each JAKi individually, a longer disease duration predicted TOF discontinuation (HR95% CI [1.05 (1.01-1.09)], while seropositivity protected against TOF being withdrawn (HR95% CI [0.41 (0.17-0.97)]. No independent predictors emerged for other JAKis. Conclusions: the use of JAKis as a first-line treatment as well as disease duration and serology may impact the DRR of JAKis, which may inform tailored treatment strategies in clinical practice.

Circulating extracellular vesicles and small non-coding RNAs cargo in idiopathic inflammatory myopathies reveal differences across myositis subsets.

OBJECTIVE: To investigate the epigenetic footprint of idiopathic inflammatory myopathies (IIM) through characterization of circulating extracellular vesicles (EVs) and the expression of EV-derived small non-coding RNAs (sncRNAs). METHODS: In this cross-sectional study, EVs were isolated by size-exclusion chromatography from plasma of patients with IIM and age- and sex-matched healthy donors (HD). EV-derived sncRNAs were sequenced and quantified using Next-Generation Sequencing (NGS). Following quality control and normalization, filtered count reads were used for differential microRNA (miRNA) and piwi-interacting RNA (piRNA) expression analyses. Putative gene targets enriched for pathways implicated in IIM were analyzed. Patients' clinical and laboratory characteristics at the time of sampling were recorded. RESULTS: Forty-seven IIM patients and 45 HD were enrolled. MiR-486-5p (p < 0.01), miR-122-5p, miR-192-5p, and miR-32-5p were significantly upregulated (p < 0.05 for all), while miR-142-3p (p < 0.001), miR-141-3p (p < 0.01), let-7a-5p (p < 0.05) and miR-3613-5p (p < 0.05) downregulated in EVs from IIM patients versus HD. MiR-486-5p was associated with raised muscle enzymes levels. Several target genes of up/downregulated miRNAs in IIM participate in inflammation, necroptosis, interferon and immune signaling. Six piRNAs were significantly dysregulated in IIM EVs versus HD (p < 0.05). Within IIM, miR-335-5p was selectively upregulated and miR-27a-5p downregulated in dermatomyositis (n = 21, p < 0.01). Finally, plasma EV levels were significantly increased in cancer-associated myositis (CAM, n = 12) versus non-CAM IIM (n = 35, p = 0.02) and HD (p < 0.01). EVs cargo in CAM was significantly enriched of let-7f-5p and depleted of miR-143-3p. CONCLUSION: Through an unbiased screening of EV-derived sncRNAs, we characterize miRNAs and piRNAs in the EVs cargo as potential biomarkers and modifiers of diverse IIM phenotypes.

Effect of Sustained Clinical Remission on the Risk of Lupus Flares and Impaired Kidney Function in Patients With Lupus Nephritis.

Introduction: This retrospective study on patients with biopsy-proven lupus nephritis (LN) aimed to assess the probability of sustained clinical remission (sCR) and to investigate sCR effects on disease flares and impaired kidney function (IKF). Methods: sCR was defined as clinical-Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) = 0 and estimated glomerular filtration rate (eGFR) >60 ml/min per 1.73 m2 lasting ≥1 year; IKF: eGFR <60 ml/min per 1.73 m2 for >3 months. We analyzed the probability of achieving and maintaining sCR, and the yearly risk of flare. Cox models were used to identify predictors of sCR and IKF with variables analyzed as time-dependent covariates when appropriate. Results: Of 303 patients followed-up with for 14.8 (interquartile range: 9.8-22) years, 257 (84.8%) achieved sCR. The probability of achieving sCR progressively increased over time reaching 90% at 15 years. Baseline age (hazard ratio [HR]: 1.017; 95% confidence interval [CI]: 0.005-1.029; P = 0.004), hydroxychloroquine intake (HR: 1.385; 95% CI: 1.051-1.825; P = 0.021), and absence of arterial hypertension (HR: 0.699; 95% CI: 0.532-0.921; P = 0.011) were independent predictors of sCR. Among patients who achieved sCR, 142 (55.3%) developed a lupus flare after a median time of 3.6 (2.3-5.9) years. In the remaining 115 patients, sCR persisted for 9.5 (5.8-14.5) years. The probability of sCR to persist at 15 years was 38%. SLE flare risk decreased to 10%, 5%, and 2% in patients with sCR lasting <5, 5 to 10, and >10 years, respectively. At the last observation, 57 patients (18.81%) had IKF. sCR achievement (HR: 0.18, P < 0.001) and its duration (HR: 0.83, P < 0.001) were protective against IKF. Conclusion: sCR is an achievable target in LN management and protects against IKF. The longer the sCR, the higher the chance of its persistence and the lower the risk of SLE flares.

Corrigendum to "Effect of Sustained Clinical Remission on the Risk of Lupus Flares and Impaired Kidney Function in Patients With Lupus Nephritis" [Kidney International Reports Volume 9, Issue 4, April 2024, Pages 1047-1056].

[This corrects the article DOI: 10.1016/j.ekir.2024.01.016.].

The SLE-DAS provides an accurate and feasible flare tool in the clinical setting: a validation study.

OBJECTIVE: To assess the criterion validity of the SLE disease activity score (SLE-DAS) flare tool and compare its performance in identifying flares against other instruments. METHODS: Patients with SLE fulfilling SLE-DAS low disease activity at baseline were included from two academic lupus clinics. During follow-up, flares were identified by the senior attending clinician, applying the expert-consensus-based definition as gold-standard. The first clinical flare from flaring patients, and the first visit after baseline in patients without flares were analysed. In each no flare/flare visits, we assessed flares by SLE-DAS (score increase ≥1.72), classic-SELENA Flare Index (c-SELENA FI), revised-SELENA FI (r-SELENA FI), and SLEDAI-2K (score increase ≥4). We estimated the sensitivity, specificity, and Cohen's Kappa agreement of each flare tool against the gold-standard. RESULTS: A total of 442 patients were included and followed-up for 22.9 (14.2) months. Incidence of flares was 8.19/100 patient-years, with 69 patients experiencing flares. The SLE-DAS identified 96.6% of the expert-defined flares implying a treatment change and classified 28.0% of those as moderate/severe. Sensitivity and specificity for the gold-standard flare definition were: SLE-DAS 97.1% and 97.3%, c-SELENA FI 88.4% and 98.1%, r-SELENA FI 88.4% and 96.8%, SLEDAI-2K 56.5% and 99.2%, respectively. Kappa coefficients of these instruments were 0.902 (95% CI: 0.847, 0.957), 0.870 (95% CI: 0.805, 0.935), 0.832 (95% CI: 0.761, 0.903), and 0.663 (95% CI: 0.557, 0.769), respectively. The number of flare misclassifications was lowest with the SLE-DAS, and highest with the SLEDAI-2K. CONCLUSION: The SLE-DAS accurately identifies and categorizes flares as mild or moderate/severe. It is feasible and, thus, may help the physicians' treatment decisions in the clinical practice setting.

Is per-protocol kidney biopsy required in lupus nephritis?

Baseline kidney biopsy is recommended in lupus nephritis (LN). Biopsy allows to classify different forms of LN and differentiate other forms of renal involvement, such as tubulo-interstitial nephritis or thrombotic microangiopathy. The indications for repeat biopsy are more controversial. Some authors feel that good clinical monitoring is sufficient to assess prognosis and make therapeutic decisions. Based on the recently demonstrated discordance between clinical and histological response, some physicians recommend per-protocol biopsies either at 6 months in stable patients to verify the response to induction therapy, or after one-to-two years to assess treatment efficacy and tune the duration of maintenance therapy. Others recommend repeating kidney biopsy in case of incomplete response or to discriminate between active and chronic lesions. By definition, a per-protocol kidney biopsy differs from a repeat biopsy in that the former is foreseen at fixed timepoints, regardless of the clinical response. Although any decision should always consider the patient's overall clinical condition, there are no doubts that repeat kidney biopsy represents a useful tool in difficult cases to evaluate treatment response, modulate treatment intensity, and predict long-term renal outcome both in quiescent lupus and during flares. How to harmonize per-protocol biopsies in the LN course remains challenging.

Should ACR/EULAR criteria be revised changing the RF and ACPA scores?

Current classification criteria for rheumatoid arthritis (RA) encompass clinical and immunological items and are capable of correctly identifying the majority of symptomatic RA patients. The presence of positive rheumatoid factor (RF) and/or and anti-cyclic citrullinated protein/peptide antibodies (ACPA) gaining increasing importance according to their serological titer eases the recognition of RA, yet the debate is open on whether this scoring system ought to be optimized by hierarchizing ACPA or the combination of ACPA and RF over single positivity, prioritizing specificity over sensitivity. The risk of misdiagnosis and misclassification are often entangled, yet they are not the same. In fact, while ideal diagnosis requires 100% sensitivity and specificity, classification criteria are conceived to gather a homogeneous patient population, favoring specificity over sensitivity. Nevertheless, as they are frequently summoned to support the diagnostic process in clinical practice, issues arise on how comprehensive those should be and on how frequently they should be updated in light of novel acquisitions regarding measurable RA-related abnormalities. In this viewpoint two different views on the topic are confronted, discussing the performance of available criteria and the potentiality and pitfalls of their refinement according to novel data on ACPA and RF contribution and emergence of newly discovered specificities.

Assessment of disease activity and damage in SLE: Are we there yet?

Systemic Lupus Erythematosus is a systemic autoimmune disease characterized by a great heterogenicity in course and clinical manifestations. Although prognosis improved in the last decades of the 20th century, mortality remains higher than in the general population and uncontrolled disease activity and therapy-related adverse effects have been identified as major contributors to damage accrual and poor outcomes. Assessment of disease activity and damage in SLE represents a great challenge even to the expert rheumatologist. Global disease activity indices are tools developed to assess activity across multiple organ systems. Several disease activity indices have been developed over the years, each with its own strengths and weaknesses, and knowing them is essential for understanding research studies, such as clinical trials, in which they are used. Organ-specific activity indices have been developed concurrently to represent organ involvement such as glomerulonephritis, cutaneous and musculoskeletal lupus manifestations. Regarding damage, the SLICC/ACR damage index has proven to be an effective tool for damage accrual assessment, yet not devoid of drawbacks. This review provides an overview of the most frequently utilized indices developed for the assessment of activity and damage in SLE highlighting their pros and cons when applied to the research and clinical setting.

New onset sarcoidosis following biologic treatment in patients with seronegative inflammatory arthritis: A case series and systematic literature review.

OBJECTIVE: To report cases of new onset sarcoidosis upon biologic (bDMARDs) treatment administration in patients with seronegative inflammatory arthritis in a real-life cohort, alongside a systematic literature review (SLR) on this topic. METHODS: We performed a retrospective analysis on clinical records of patients with seronegative arthritis followed up in a monocentric cohort who underwent bDMARDs treatment due to the underlying rheumatic disease and described any newly diagnosed sarcoidosis in this cohort. Only ascertained cases with available radiological and/or histological documentation were considered. A SLR on new-onset sarcoidosis in seronegative arthritis receiving bDMARDs was performed across MEDLINE (through PubMed), Scopus and Ovid (Cochrane, Embase) electronic databases using appropriate strings. RESULTS: In our cohort, 4 new-onset cases of sarcoidosis were reported among patients with seronegative inflammatory arthritis receiving biologics. Three out of 4 patients were receiving anti-tumor necrosis factor alpha (TNFα) while 1 patient was on secukinumab (anti-IL17A) prior to sarcoidosis onset. The SLR disclosed 46 new-onset sarcoidosis cases upon biological treatment for seronegative arthritis, of whom 43 occurred during treatment with anti-TNFα, while 3 during anti-IL-17A therapy. In our cohort as well as in the majority of cases reported in the SLR, sarcoidosis presented with lymph nodal and lung involvement and displayed a benign course with spontaneous resolution in about 1 fourth of the cases. CONCLUSION: The use of biologics may relate to the onset of sarcoidosis; hence, clinicians must remain aware of the potential occurrence or reactivation of sarcoidosis when starting biologic treatment in patients with inflammatory arthritis, performing adequate patient assessment and surveillance. Since TNFα inhibitors may represent a therapeutic option for sarcoidosis, further evaluation on larger cohorts is needed to investigate any causal link with the development of sarcoidosis.

Characterization of Serum Cytokine Profiles of Patients with Active Lupus Nephritis.

Cytokines contribute to the pathogenesis of lupus nephritis (LN), yet their value as prognostic biomarkers is still debated. We aimed to describe the serum cytokines' profiles and prospectively assess correlations with disease features and renal response in a multicentric cohort of consecutive adult patients with biopsy-proven active LN. Cytokine associations with clinical and serological data were performed at LN diagnosis (T0), and at 3 (T3) and 6 months (T6) of follow up. Renal response according to EULAR definition was assessed at T3, T6 and T12. BAFF and interleukin (IL)-37 were measured by ELISA; IL-2, IL-10, IL-17A and IL-18 by a bead-based multiplex cytokine assay (Luminex). Thirty-nine patients with active LN (age 40.5 ± 15.6 years; F 71.8%; 84.6% proliferative LN) were enrolled, of whom twenty-nine displayed complete longitudinal records. At T0, we observed higher levels of IL-37 and IL-17 in proliferative vs. non-proliferative LN (IL-37: 0.0510 (0.0110-0.2300) vs. 0.0000 (0.0000-0.0397) ng/mL, p = 0.0441; IL-17: 2.0920 (0.5125-17.9400) vs. 0.0000 (0.0000-0.6025) pg/mL, p = 0.0026, respectively), and positive correlations between IL-10 and 24 h proteinuria (r = 0.416, p = 0.0249) and anti-dsDNA levels (r = 0.639, p = 0.0003). BAFF was higher in patients with low complement (p < 0.0001). We observed a sustained correlation between BAFF and IL-10 throughout T6 (r = 0.654, p = 0.0210). Higher baseline IL-37 and BAFF levels were associated with renal response at T3 and T6, respectively, while baseline IL-18 levels were higher in patients achieving response at T12. Our study highlights the complexity of the cytokine network and its potential value as a marker of active LN and renal response.

Detection of Myositis Autoantibodies by Multi-Analytic Immunoassays in a Large Multicenter Cohort of Patients with Definite Idiopathic Inflammatory Myopathies.

BACKGROUND: The usefulness of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) for the assessment of idiopathic inflammatory myopathies (IIMs) is acknowledged, but laboratory standardization remains a challenge. We detected MSAs/MAAs by multi-analytic line immunoassay (LIA) and particle-based multi-analyte technology (PMAT) in a multicenter cohort of patients with IIMs. METHODS: We tested the sera from 411 patients affected with definite IIM, including 142 polymyositis (PM), 147 dermatomyositis (DM), 19 cancer-associated myositis, and 103 overlap myositis syndrome (OM), and from 269 controls. MSAs/MAAs were determined by 16Ags LIA in all sera, and anti-HMGCR by ELISA in 157/411 IIM sera and 91/269 control sera. The analytical specificity of LIA/HMGCR ELISA was compared with that of PMAT in 89 MSA+ IIM sera. RESULTS: MSAs/MAAs were positive in 307/411 (75%) IIM patients and 65/269 (24%) controls by LIA (Odds Ratio 9.26, 95% CI 6.43-13.13, p < 0.0001). The sensitivity/specificity of individual MSAs/MAAs were: 20%/100% (Jo-1), 3%/99.3% (PL-7), 4%/98.8% (PL-12), 1%/100% (EJ), 0.7%/100% (OJ), 9%/98% (SRP), 5.6%/99.6% (TIF1γ), 4.6%/99.6% (MDA5), 8%/96% (Mi-2), 1.5%/98% (NXP2), 1.7%/100% (SAE1), 4%/92% (Ku), 8.5%/99% (PM/Scl-100), 8%/96% (PM/Scl-75), and 25.5%/79% (Ro52). Anti-HMGCR was found in 8/157 (5%) IIM patients and 0/176 (0%) controls by ELISA (p = 0.007). Concordance between LIA/HMGCR ELISA and PMAT was found in 78/89 (88%) samples. Individual MSAs detected by LIA were associated with IIM subsets: Jo-1 with PM and OM, PL-12 with OM, Mi-2, TIF1γ, and MDA5 with DM, SRP with PM, and PM/Scl-75/100 with OM (p < 0.001 for all). CONCLUSIONS: Since MSAs are mostly mutually exclusive, multi-specific antibody profiling seems effective for a targeted clinical-serologic approach to the diagnosis of IIMs.

Interstitial lung disease with and without progressive fibrosing phenotype in patients with idiopathic inflammatory myopathies: data from a large multicentric cohort.

OBJECTIVES: Patients with connective tissue diseases can develop interstitial lung disease (ILD), leading to a progressive fibrosing ILD (PF-ILD) phenotype in some cases. We aimed to investigate the occurrence of PF-ILD in idiopathic inflammatory myopathies (IIMs), and factors potentially predicting this phenotype. Secondary aims were to assess the radiological pattern and factors associated with IIMs-ILD. METHODS: Patients with IIMs from our multicentric prospective cohort were retrospectively evaluated. Data were recorded at IIMs and ILD diagnosis, and during follow-up. Patients with ILD were classified according to the predominant high-resolution CT (HRCT) pattern: non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP) and organising pneumonia (OP). PF-ILD was defined according to the 2022 American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS) and Latin American Thoracic Society (ALAT) guidelines. Univariate and multivariate analyses were performed to identify factors associated to ILD and to PF-ILD. RESULTS: Of 253 patients with IIMs, 125 (49%) had ILD: 99 (78%) at IIMs diagnosis and 26 (22%) during follow-up (21/26 within 5 years). Multivariate analysis identified anti-Jo-1, anti-MDA5, anti-Ro52, high score on manual muscle test, mechanic's hands and Raynaud's phenomenon as independently associated with ILD. The predominant HRCT pattern was NSIP (50% of patients), followed by UIP (28%) and OP (22%). At 1-year follow-up, PF-ILD occurred in 18% of IIMs-ILD. PF-ILD was predicted by anti-MDA5, heliotropic rash, xerostomia and xerophthalmia at univariate but not at multivariate analysis. CONCLUSION: Patients with IIM should be carefully screened for ILD at IIMs diagnosis and yearly during follow-up. All patients with IIMs-ILD should be carefully monitored to capture ILD progression since a consistent proportion of them are expected to develop PF-ILD.