OBJECTIVES:To investigate the prevalence, clinical features, histological spectrum and outcomes of intra-renal involvement in patients with primary APS (PAPS), with particular attention to both aPL nephropathy (aPL-N) and non-aPL-N renal lesions. METHODS:This multicentric retrospective case-control study included 258 PAPS patients followed between 1984 and 2023 at two Italian referral centres. Patients with a biopsy-proven intra-renal involvement (n = 17) were compared with those without renal manifestations. Histologic classification followed the updated aPL-N criteria. Clinical, laboratory, therapeutic features, and 12-month renal responses were assessed. RESULTS:Seventeen of 258 (7%) patients underwent renal biopsy. Two out of 17 (12%) presented with acute kidney injury, 5/17 (29%) with nephrotic syndrome and 5/17 (29%) had isolated urinary abnormalities; the remaining 5 patients presented with different combination of signs/symptoms. Six (2.3%) were diagnosed with aPL-N, while 11 (4.2%) exhibited alternative glomerular lesions (e.g. membranous nephropathy, focal segmental glomerulosclerosis). Compared with controls, patients with intra-renal involvement had higher frequencies of CAPS (18% vs 0.4%, P = 0.001), thrombocytopenia (35% vs 10%, P = 0.006), epilepsy (24% vs 5%, P = 0.018) and LA positivity (100% vs 62%, P = 0.002). At 12 months, partial renal response was observed in most cases, with a worse prognosis in those with aPL-N despite anti-thrombotic treatment. All non-aPL-N patients had aPL-related events, including thrombotic, obstetric and non-thrombotic manifestations, with non-aPL-N renal disease preceding these events in 45%. CONCLUSION:Intra-renal involvement in PAPS is rare but heterogeneous, encompassing both vascular and glomerular pathologies. These findings support the need for heightened renal surveillance in PAPS, even in the absence of classic thrombotic manifestations, and highlight the importance of histologic assessment to guide tailored therapy. From a nephrologist's perspective, routine screening for aPL in glomerular disease assessment may be relevant, particularly by providing prognostic value for subsequent aPL-related events.

Abstract Background The clinical significance of IgM antiphospholipid antibodies (aPL) in antiphospholipid syndrome (APS) remains uncertain, while lupus anticoagulant is a well-established marker for thrombotic risk. Methods The objective of the study is to evaluate the impact of IgM aPL on the clinical phenotype of primary APS (PAPS). In this retrospective multicenter study, patients meeting updated Sapporo classification criteria were categorized into three aPL profiles: isolated lupus anticoagulant (isolated-LA), isolated IgM anticardiolipin and/or IgM anti-β2-glycoprotein I antibodies (isolated-IgM-aPL), and LA and IgM antibodies (LA + IgM-aPL). Clinical features were compared between isolated-LA vs. isolated-IgM-aPL and isolated-LA vs. LA + IgM-aPL groups. Results Among 202 patients, 17 (8.4%) had isolated-IgM-aPL, 145 (71.7%) isolated-LA, and 40 (19.8%) LA + IgM-aPL. Compared to isolated-LA, the isolated-IgM-aPL group had lower female prevalence (41.2% vs. 65.5%; p = 0.049), fewer venous thromboses (41.2% vs. 66%; p = 0.049), but more obstetric morbidity (58.8% vs. 26.2%; p = 0.005). There was a higher proportion of patients with livedo racemosa (47.1% vs. 20.7%; p = 0.015) and with white matter lesions (WML) (29.4% vs. 9.7%; p = 0.020) in the isolated-IgM-aPL group. In the multivariate analysis, WML remained independently associated (OR 3.7; p = 0.020). In the second comparison (isolated-LA vs. LA + IgM-aPL), a higher prevalence of livedoid vasculopathy (15.0% vs. 4.8%; p = 0.026) and WML (22.5% vs. 9.7%; p = 0.037) were observed in the LA + IgM-aPL group. Nonetheless, no independent associations were seen in the multivariate analysis. Conclusion IgM aPL may be associated with a distinct APS phenotype characterized by microvascular involvement, including livedo and WML. These findings support the need for further research into the clinical implications of IgM isotype positivity in APS.

Translating the 2024 KDIGO (Kidney Disease: Improving Global Outcomes) lupus nephritis (LN) guideline update into routine care remains challenging. While clinical trial data support early multi-agent combination therapy for nephritis to optimize kidney protection, real-world implementation is constrained by disease heterogeneity, disparities in access to advanced therapeutics, and limited incorporation of cost-effectiveness considerations. In this perspective article, we propose a pragmatic framework to adapt KDIGO recommendations to diverse healthcare settings. First, we propose a stratification model integrating clinical response kinetics, serological markers, and histological chronicity. Second, we apply implementation science frameworks to identify diagnostic and therapeutic gaps. Finally, we outline a value-based approach to evaluate the use of biologics and small molecules in terms of short- and long-term clinical outcomes and economic sustainability. Together, these strategies provide a roadmap to improve the real-world applicability of modern LN management.

OBJECTIVES:To characterize prevalence, patterns, and clinical correlates of cardiac involvement in a cohort of patients with Behçet's syndrome (BS) undergoing clinically driven cardiological assessment. METHODS:This retrospective study included adult patients with BS, followed at a tertiary referral centre (Florence, Italy), who underwent clinically driven cardiological evaluation. Clinical, demographic and therapeutic characteristics were compared in patients with and without evidence of cardiac involvement. Timing, type of cardiac involvement, disease activity, cardiovascular risk factors and treatments were analysed. RESULTS:Among 312 patients with BS, 90 underwent cardiological assessment and 49 had confirmed cardiac involvement. Arrhythmias were the most frequent manifestation (n = 15), followed by pericarditis (n = 12) and ischaemic heart disease (n = 8). Cardiac involvement occurred a median of 6.1 (2.5-8.7) years after BS diagnosis, although in a proportion of patients it preceded or coincided with diagnosis. Most patients had active systemic disease at the time of the cardiac involvement (93.9%) and were receiving immunosuppressant treatment (84%). Over 80% had at least one traditional cardiovascular risk factor, yet <40% were receiving cardiovascular primary prevention therapy before the first event. Male patients more frequently experienced ischaemic manifestations, while arrhythmias were more common in females. No cardiac-related deaths were observed. CONCLUSION:Cardiac involvement in BS is more common than traditionally reported when actively investigated. Cardiac involvement frequently occurs during active disease and in patients with a high burden of cardiovascular risk factors but suboptimal preventive therapy. These findings support the need for integrated cardio-rheumatologic management in BS.

OBJECTIVE:The 2023 American College of Rheumatology (ACR)/EULAR antiphospholipid syndrome (APS) classification criteria aim to identify patients with a high likelihood of APS for research. Phases I/II of our four-phase methodologic approach resulted in 27 candidate criteria organized in clinical and laboratory domains. Here, we summarize phase III efforts to reduce and refine criteria using patient scenarios. METHODS:Using standardized definitions for candidate criteria, the Steering Committee collected antiphospholipid antibody (aPL)-positive cases referred for "suspected APS." Treating physicians assessed APS case likelihood using a Likert scale. Poisson regression calculated risk ratios (RRs) and 95% confidence intervals (CIs) to quantify the direction and size of the association of candidate criteria with "highly likely" versus "equivocal or unlikely" APS, which guided Steering Committee candidate criteria refinement and organization. RESULTS:We collected 314 suspected APS cases (137 [44%] highly likely and 177 [56%] equivocal/unlikely APS). Provoking venous thromboembolism (VTE) or arterial thrombosis (AT) risk factors reduced the size of the association with highly likely APS (RR 4.31 [95% CI 2.11-8.78] to RR 1.56 [95% CI 0.89-2.75] for VTE and RR 3.48 [95% CI 1.91-6.32] to RR 1.64 [95% CI 0.77-3.51] for AT). Persistent lupus anticoagulant, anticardiolipin IgG antibody ≥40 U, and anti-β2-glycoprotein-I IgG antibody ≥40 U were positively associated with highly likely APS (all P < 0.05). Eventually, items within eight additive and independent clinical and laboratory domains were refined. CONCLUSION:Referred suspected APS cases provided insight into associations of individual candidate criteria with APS likelihood. RR analyses helped refine items and organize the draft classification system into eight additive and independent clinical and laboratory domains.

INTRODUCTION:Hematuria is a hallmark clinical manifestation of IgA nephropathy (IgAN) and largely reflects underlying glomerular inflammation. Despite this, current guidelines prioritize proteinuria and estimated glomerular filtration rate for risk assessment, and the association between urinary findings and underlying histologic lesions remains incompletely characterized. METHODS:Here, we conducted a multicenter retrospective cohort study of patients with biopsy-proven IgAN (July 2015-July 2025) with concurrent urinalysis. Associations between hemoglobinuria (dipstick), hematuria (microscopy), proteinuria and individual Oxford Classification MEST-C components, and composite inflammatory lesions (M1, E1, and/or C1/C2; and E1 and/or C1/C2) were evaluated using unadjusted cohort-specific logistic regression models. Pooled odds ratios (ORs) were estimated using random-effects meta-analysis. RESULTS:Among 441 patients, hemoglobinuria was associated with M1 lesions (pooled OR 1.77, 95% CI 1.25-2.51), E1 lesions (1.75, 1.44-2.11), and crescentic lesions (1.57, 1.20-2.07). Hematuria was also associated with M1 lesions (1.24, 1.14-1.35), E1 lesions (1.22, 1.13-1.31), and C1/C2 lesions (1.18, 1.09-1.28). For the composite outcome (M1, E1, and/or C1/C2), pooled ORs were 2.28 (1.76-2.97) for hemoglobinuria, 1.36 (1.22-1.51) for hematuria, and 1.20 (1.04-1.38) for proteinuria. Hemoglobinuria and hematuria were not associated with chronic lesions, whereas proteinuria was consistently associated with T1/T2 lesions (1.35, 1.20-1.52). CONCLUSIONS:Dipstick hemoglobinuria is associated with histologic markers of active disease in IgAN and may provide clinically relevant information to complement current assessment of disease activity in IgAN.

BackgroundAnti-β2glycoprotein I (β2GPI) antibodies are the hallmark of the antiphospholipid syndrome (APS). β2GPI consists of five domains, DI-DV. While DI is the primary target, the clinical relevance of antibodies against other domains remains uncertain. We analyzed two large anti-β2GPI IgG positive cohorts, to investigate whether different domain binding affects anti-β2GPI IgG assay testing and APS diagnosis.MethodsThe presence of anti-DI and anti-DIV/DV antibodies (by chemiluminescence (CLIA) and in-house ELISA, respectively) was searched in an APS ACTION (n.191) and Italian validation (n.105) cohorts. In the latter, we detected anti-β2GPI IgG reactivity by four assays (in-house and commercial ELISA, CLIA, and fluorescence enzyme immunoassay), and used a modified anti-β2GPI IgG in-house ELISA with recombinant single-domain-lacking β2GPI variants to evaluate domain-dependent reactivity.ResultsWe confirmed anti-DI, anti-DIV/DV β2GPI IgG direct reactivity in classified and non-classifiable APS in the two cohorts, and found anti-DI/anti-DIV/DV double negative (38/191, 29/105) and anti-DIV/DV single-positive (6/191, 9/105) samples. Anti-β2GPI IgG discordant samples by the four methods had the highest presence of anti-DIV/DV single-positives and anti-DI/anti-DIV/DV double-negatives, compared to four-method concordant samples: 16% vs 2% and 45% vs 11% (p <0.0001), respectively. The single-domain molecule-based assay showed that the APS serum samples depended mainly on DI, DV, and DII, slightly on DIV, and not at all on DIII.ConclusionsSerum IgG from both classified and non-classifiable APS may react with other β2GPI domains than DI and DIV-V. Anti-β2GPI domain selectivity can explain discordant results among diagnostic assays.

Background:Complement inhibitors such as eculizumab and ravulizumab are increasingly used to treat rare complement-mediated diseases. While effective, these therapies impair host defenses against encapsulated bacteria, leading to a heightened risk of invasive infections. Although vaccination is standard, the role and implementation of antibiotic prophylaxis remain inconsistent across clinical settings. Methods:A survey was conducted among European Reference Network for Rare Kidney Diseases (ERN ERKNet) centers to assess current practices regarding antibiotic prophylaxis in patients receiving complement-inhibition therapy. The survey addressed four clinical scenarios-pediatric vs. adult, transplant recipient vs. non-transplant-and explored three domains: indications for prophylaxis, choice of antibiotic, and duration. Results:Twenty-seven centers from 16 European countries participated. Systematic prophylaxis was widely endorsed, particularly for pediatric patients and transplant recipients. Penicillin-class antibiotics were preferred as first-line agents across all groups. In pediatric settings, phenoxymethylpenicillin and amoxicillin were most commonly used, whereas adult regimens included penicillin or fluoroquinolones for those with allergies. Most respondents recommended continuing prophylaxis throughout the duration of complement-inhibition therapy, regardless of vaccination status. The survey revealed areas of heterogeneity in practice, especially regarding allergy management and the duration of post-vaccination coverage. Conclusions:This ERKNet survey identifies prevailing practices and variation in antibiotic prophylaxis for patients receiving complement-inhibition therapy. Based on these findings, we propose consensus guidance to support harmonized, risk-adapted prophylaxis strategies across pediatric and adult populations. These guidance statements aim to address an important unmet need in infection prevention among complement-inhibited patients.

Systemic lupus erythematosus (SLE) guidelines predominantly focus on common major organ involvement. An international taskforce from three SLE expert groups (European Reference Network on Connective Tissue and Musculoskeletal Diseases, Systemic Lupus International Collaborating Clinics, and the European Lupus Society) previously developed consensus therapeutic strategies for 24 rare SLE manifestations. Here, 77 participants contributed to the development of consensus therapeutic strategies for 22 additional rare SLE manifestations, including diffuse pulmonary haemorrhage, rare cutaneous manifestations (bullous lupus, chilblain lupus, lupus tumidus, erythema multiforme, and toxic epidermal necrolysis-like lupus erythematosus), renal manifestations (interstitial nephritis and lupus podocytopathy), rare neurological manifestations (chorea, small fibre neuropathy, catatonia, and intracranial hypertension), rare gastrointestinal manifestations (protein-losing enteropathy, lupus hepatitis, intestinal pseudo-obstruction, and peritonitis), musculoskeletal manifestations (myositis and Jaccoud's arthropathy), and other rare manifestations such as uveitis, angioedema due to anti-C1 esterase inhibitor antibodies, interstitial cystitis, and lupus mastitis. These expert-based therapeutic strategies provide a framework for guiding therapeutic decisions where evidence-based recommendations might be insufficient.

In rare and complex connective tissue diseases, patient partnership is essential to address diagnostic delays, fragmented care, unmet needs, and the research agenda. European Reference Network (ERN) ReCONNET, the network dedicated to rare and complex connective tissue diseases, has implemented a structured and transferable model of patient partnership. Patients contribute to every phase of research and care development: from identifying unmet needs to co-authoring scientific publications. Patient input also shapes educational initiatives and strategic planning. By institutionalising partnership through governance structures and shared decision-making processes, ERN ReCONNET shows that involving patients as equal stakeholders enhances the relevance, quality, and effect of activities. This Personal View was co-written with the direct partnership of authors with lived experience of rare and complex connective tissue diseases and reports a model that can be adapted to other rare diseases and rheumatological settings, promoting a culture of patient-centred innovation in health-care systems.

BACKGROUND:Bortezomib-based regimens have long represented the standard option for systemic AL amyloidosis, whereas daratumumab has recently emerged as a promising alternative. We compared two consecutive single-center cohorts of frail, non-transplant-eligible patients treated with either bortezomib-based therapy or daratumumab monotherapy, assessing clinical and renal outcomes. METHODS:Thirty-one patients with renal AL amyloidosis were included: 17 received bortezomib-based regimens (historical cohort) and 14 received daratumumab monotherapy (prospective cohort). All had biopsy-confirmed renal amyloid deposition and were transplan-ineligible. Hematologic and organ responses followed International Society of Amyloidosis criteria. RESULTS:Baseline characteristics were similar between cohorts. Hematologic response rates were 57.1% with bortezomib versus 92.8% with daratumumab (p = 0.03), with complete responses in 28.6% and 57.1%, respectively. Renal response occurred in 35% of bortezomib-treated patients versus 71.4% with daratumumab (p = 0.04). Proteinuria declined by 76% in bortezomib responders and 72% in daratumumab responders, with stable creatinine in both groups. Among patients achieving dual hematologic and renal responses, 12-month survival was 100% in the daratumumab cohort versus 71% in the historical group. At last follow-up, renal survival was 67% versus 86%, and overall survival 47% versus 79% (p = 0.08). Major infections occurred in 18% and 14%, respectively. Repeat biopsies showed stabilization or regression of amyloid in 62% of daratumumab-treated versus 20% of historical cases. CONCLUSIONS:In frail, ASCT-ineligible patients with biopsy-proven renal AL amyloidosis, daratumumab monotherapy yielded higher hematologic and renal response rates compared with bortezomib-based regimens. These findings support early anti-CD38 therapy as a potential strategy to improve renal preservation and survival, warranting confirmation in multicenter trials.

Objectives Patients with rheumatic and musculoskeletal diseases (RMDs) have increased cardiovascular (CV) risk. European Alliance of Associations for Rheumatology (EULAR) issued CV risk management recommendations in 2015/2016 and 2022, but healthcare providers’ (HCPs’) awareness and their implementation in clinical practice are unknown. This study aims to assess HCP awareness of the EULAR CV recommendations and barriers to their implementation. Methods A cross-sectional survey was distributed via social media to all HCPs involved in treating patients with RMDs. Data on demographics, awareness of the 2015/2016 and 2022 recommendations, and perceived implementation barriers were collected. The survey was endorsed by the EULAR Study Group on Cardiovascular Involvement in Inflammatory Arthritis. Results Of 226 complete responses, 54% were hospital rheumatologists and 36% had 5 to 15 years of experience. Overall, 67% knew both recommendation sets. Knowledge scores were higher among those aware of both recommendations compared with those who knew neither. Most respondents (83%) recognised that platelet inhibitors are not recommended for primary prevention; only 8% identified the role of low systemic lupus erythematosus disease activity. Nearly all (96%) endorsed corticosteroid minimisation. Half viewed rheumatologists as primarily responsible for CV risk management; 16% knew the 1.5 multiplication factor for rheumatoid arthritis risk scoring. None correctly noted that antihypertensives and statins can be used as in the general population. Barriers included time constraints (62%), insufficient knowledge (37%), and lack of local protocols (14%). Conclusions Despite moderate awareness of EULAR CV recommendations, substantial knowledge gaps and practical barriers persist, indicating the need for focused education and improved clinical pathways to enhance CV risk management in RMD care.

Background:Chronic kidney disease (CKD) and renal cell carcinoma share a bidirectional relationship, with radical nephrectomy posing a significant risk for postoperative renal decline. This study identifies radical nephrectomy as a critical opportunity to evaluate the non-neoplastic renal parenchyma. Methods:We conducted a prospective observational study on 30 adult patients diagnosed with renal or urothelial cancer who underwent radical nephrectomy. Samples of non-neoplastic renal parenchyma were collected during surgery and analyzed using optical microscopy and immunofluorescence. Renal function was assessed pre- and postoperatively using the CKD-EPI formula. Results:The cohort comprised 30 patients (63.3% male) with a median age of 65.5 years (min 29-max 83). Following radical nephrectomy, 50% of patients with preserved preoperative renal function experienced a decline to estimated glomerular filtration rate < 60 ml/min/1.73 m². Histopathological evaluation of the non-neoplastic parenchyma revealed chronic tubulointerstitial damage in 41% (n = 12) and arteriosclerotic vascular damage in 38% (n = 11) of cases. Notably, occult nephropathies were identified in 24% (n = 7) of the cohort, comprising diabetic glomerulosclerosis (n = 2), membranous nephropathy (n = 2), fibrillary glomerulonephritis (n = 1), IgA nephropathy (n = 1), and minimal change disease (n = 1). Two cases (IgA nephropathy and minimal change disease) demonstrated spontaneous remission postsurgery, consistent with a paraneoplastic etiology. Conclusions:The non-neoplastic renal parenchyma in renal cell carcinoma patients frequently exhibits occult pathological changes, predominantly tubulointerstitial damage likely driven by the tumor microenvironment. The study highlights a higher-than-expected prevalence of undiagnosed nephropathies (24%), including paraneoplastic cases. Routine histological evaluation during radical nephrectomy is essential for optimizing patient management, avoiding unnecessary subsequent biopsies, and guiding therapeutic decisions in the oncological setting.

Cardiologists consider degenerative or infectious causes when evaluating valvular heart disease. However, the role of autoimmune disorders, though less frequent, remains clinically significant. This report describes a young male patient presenting with persistent coronary disease and a suspected valvular cusp perforation initially attributed to infective endocarditis, which ultimately proved to be a manifestation of IgG4-related disease. IgG4-related disease is a rare condition, more prevalent in Asian populations, that typically affects the pancreas, salivary glands, lacrimal glands, and the retroperitoneum. Cardiac involvement, although uncommon, can present in various ways, including pericarditis, pulmonary arterial hypertension, valve dysfunction, cardiac pseudotumor, and coronary disease. Diagnosing and managing IgG4-related cardiac involvement requires heightened clinical suspicion, serological and histopathological assessment, and prompt interdisciplinary collaboration. Notably, involving rheumatologists in the management of these rare yet impactful autoimmune cardiac diseases is essential.

[This corrects the article DOI: 10.3389/fimmu.2026.1809192.].

Background Bortezomib-based regimens have long represented the standard option for Systemic light-chain (AL) amyloidosis amyloidosis, whereas daratumumab has recently emerged as a promising alternative. We compared two consecutive single-center cohorts of frail, non-transplant-eligible patients treated with either bortezomib-based therapy or daratumumab monotherapy, assessing clinical and renal outcomes.Methods Thirty-one patients with renal AL amyloidosis were included: 17 received bortezomib-based regimens (historical cohort) and 14 received daratumumab monotherapy (prospective cohort). All had biopsy-confirmed renal amyloid deposition and were transplant-ineligible. Hematologic and organ responses followed International Society of Amyloidosis criteria.Results Baseline characteristics were similar between cohorts. Hematologic response rates were 57.1% with bortezomib versus 92.8% with daratumumab (P = .03), with complete responses in 28.6% and 57.1%, respectively. Renal response occurred in 35% of bortezomib-treated patients versus 71.4% with daratumumab (P = .04). Proteinuria declined by 76% in bortezomib responders and 72% in daratumumab responders, with stable creatinine in both groups. Among patients achieving dual hematologic and renal responses, 12-month survival was 100% in the daratumumab cohort versus 71% in the historical group. At last follow-up, renal survival was 67% versus 86%, and overall survival 47% versus 79% (P = .08). Major infections occurred in 18% and 14%, respectively. Repeat biopsies showed stabilization or regression of amyloid in 62% of daratumumab-treated versus 20% of historical cases.Conclusions In frail, Autologous Stem Cell Transplant (ASCT)-ineligible patients with biopsy-proven renal AL amyloidosis, daratumumab monotherapy yielded higher hematologic and renal response rates compared with bortezomib-based regimens. These findings support early anti-CD38 therapy as a potential strategy to improve renal preservation and survival, warranting confirmation in multicenter trials.

Autoimmune diseases remain a major cause of chronic morbidity despite substantial advances in targeted immunomodulatory therapies. In many autoantibody-mediated conditions, disease refractoriness and relapse are driven by long-lived plasma cells, which are largely resistant to conventional immunosuppression and upstream B cell–directed strategies. CD38, a surface molecule highly expressed on plasmablasts and plasma cells and functionally involved in immunometabolic regulation, has emerged as a promising therapeutic target to overcome this limitation. Clinical interest in anti-CD38 therapy has been catalyzed by experience in plasma cell dyscrasias, where anti-CD38 monoclonal antibodies induce rapid and profound depletion of antibody-secreting cells. Over recent years, accumulating reports and early-phase studies have explored the repurposing of CD38-directed therapies in severe, treatment-refractory autoimmune diseases. The most compelling evidence has emerged in lupus nephritis and immune thrombocytopenia, with additional proof-of-concept data in autoimmune cytopenias and plasma cell–driven renal disorders such as immunoglobulin light chain (AL) amyloidosis. These experiences suggest that targeting CD38 can lead to meaningful clinical and immunological improvement, often accompanied by rapid reductions in pathogenic autoantibody production. However, the current evidence base remains heterogeneous and largely derived from small cohorts, case series, and early-phase trials, and important questions remain regarding durability of response, optimal treatment strategies, and long-term safety, particularly with respect to hypogammaglobulinemia and infection risk. We summarize the biological rationale for CD38 targeting in autoimmunity and plasma cell–driven immune-mediated diseases, critically appraise the emerging clinical evidence across disease settings, and discuss key challenges and future directions for integrating plasma cell–directed therapies into immunological disease management.