Research

All research across every rare disease tracked on Kipine — published sources, clinical trials, research updates, and preprints.

Published Sources

378

Research Updates

87
incrementalnew research2026-03-29

Weekly research monitor: 4 new sources added (2025-2026)

Automated weekly search (2026-03-29) found 4 new publications not previously indexed. New entries include: comprehensive review of chronic urticaria and autoinflammatory syndromes highlighting IL-1beta's central role (L1, Yacoub et al. 2025), Swiss clinical review emphasising Strasbourg criteria and underdiagnosis risk (L2, Leggeri et al. 2025), Polish case report confirming anakinra effectiveness in real-world practice (L3, Moos et al. 2025), and expert commentary supporting broader diagnostic criteria for gammopathy-negative Schnitzler syndrome (L4, Fagan et al. 2025). No new clinical trials found (existing 10 trials unchanged). No Schnitzler syndrome preprints found on bioRxiv/medRxiv.

Schnitzler Syndrome →
significanttreatment update2026-03-27

AIDA Network real-world IL-1 inhibitor data: 60-month retention 64.7%

Calabrese et al. (2025) reported long-term real-world effectiveness of anakinra and canakinumab in 28 SchS patients (37 treatment lines) from the international AIDA Network registry. Complete response rates were 73.1% (anakinra) and 66.8% (canakinumab). Drug retention at 60 months was 64.7%. Elevated IgG M-protein and lymphadenopathy independently predicted treatment discontinuation.

Schnitzler Syndrome →
significantnew research2026-03-27

Neutrophils identified as predominant IL-1β source in SchS skin

Kambe et al. (2025) demonstrated that neutrophils are the main IL-1β-expressing cells in Schnitzler syndrome lesional skin and blood, using data from the SCan canakinumab study in Japanese patients. This provides mechanistic insight into why IL-1 blockade is so effective and positions neutrophil-targeted approaches as a research avenue.

Schnitzler Syndrome →
incrementalnew research2026-03-27

Weekly research monitor: 7 new sources added (2025-2026)

Automated weekly search (2026-03-27) found 7 new publications not previously indexed. New entries include: AIDA Network real-world IL-1 data (K2), VEXAS vs Schnitzler differential markers (K3), neutrophil IL-1β source study (K4), NLRP3 mosaicism in urticarial lesions (K5), canakinumab in anakinra-refractory SchS (K6), paraprotein-negative Schnitzler-like syndrome update (K7), and Schnitzler+RA case (K8). No new clinical trials or preprints found. Baseline quality score: 79.7/100.

Schnitzler Syndrome →
significanttreatment update2025-06-15

Daratumumab emerging as treatment option for relapsed POEMS

Anti-CD38 monoclonal antibody daratumumab, alone or in combination regimens, is being explored for relapsed/refractory POEMS syndrome. Early case series and retrospective data show promising hematologic and VEGF responses, particularly in patients who have failed prior lines of therapy including transplant.

POEMS Syndrome →
significantnew research2025-03-10

Colchicine resistance mechanisms linked to pyrin inflammasome microtubule independence

Building on Van Gorp et al. (2016) findings, ongoing research clarifies that FMF mutations render pyrin inflammasome activation independent of microtubules, explaining why colchicine — a microtubule disruptor — fails in some patients. Colchicine's clinical efficacy likely operates through leukocyte motility and adhesion rather than direct inflammasome inhibition.

Familial Mediterranean Fever →
incrementaltreatment update2025-03-01

Emerging CAR-T and bispecific antibody approaches for WM

Bispecific antibodies (epcoritamab, CD3xCD20) and antibody-drug conjugates (loncastuximab tesirine, anti-CD19 ADC) are under early investigation in WM and related lymphomas. CAR-T therapy targeting CD19 or CD20 represents a potential curative approach but data in WM specifically remain limited to case reports and early-phase trials.

Waldenström's Macroglobulinemia →
incrementalgenetic finding2025-01-15

MEFV variant reclassification efforts underway

Systematic review by Shinar et al. highlighted the lack of univocal genotype-phenotype correlation in FMF. Ongoing international efforts aim to reclassify MEFV variants using updated ACMG criteria, particularly for E148Q (debated as pathogenic vs. benign polymorphism) and heterozygous states that may cause mild disease.

Familial Mediterranean Fever →
incrementaltreatment update2025-01-10

Improved transplant outcomes in the modern era

Contemporary autologous stem cell transplant series show 10-year overall survival approaching 80%, with transplant-related mortality decreasing to 2-5%. Better patient selection, supportive care, and pre-transplant debulking with bortezomib or lenalidomide have contributed to improved outcomes.

POEMS Syndrome →
significanttreatment update2024-06-10

Pirtobrutinib shows activity in covalent BTK inhibitor-pretreated WM

Non-covalent (reversible) BTK inhibitor pirtobrutinib demonstrated meaningful activity in WM patients previously treated with covalent BTK inhibitors. The BRUIN trial established pirtobrutinib as a viable option after ibrutinib or zanubrutinib failure. Pirtobrutinib + venetoclax combination reported a 56% VGPR rate in early data, suggesting deep responses with combination approaches.

Waldenström's Macroglobulinemia →
incrementalnew research2024-02-15

Genomics-guided treatment selection advances in WM

Treon et al. (Blood 2024) published a comprehensive genomics-guided approach to BTK inhibitor selection in WM. MYD88 and CXCR4 genotyping now informs first-line treatment choice. MYD88 wild-type patients (~5-10%) respond poorly to ibrutinib and may benefit from alternative approaches such as chemoimmunotherapy or venetoclax-based regimens.

Waldenström's Macroglobulinemia →
significantclinical trial result2023-07-15

ASPEN trial final analysis: zanubrutinib vs ibrutinib in WM

Final analysis of the phase 3 ASPEN trial (Tam et al., JCO 2023) at 44.4-month median follow-up confirmed zanubrutinib superiority in tolerability over ibrutinib with VGPR+CR rates of 36.3% vs 25.3%. Zanubrutinib had significantly lower rates of atrial fibrillation (7.9% vs 23.5%), hypertension, and diarrhea. Both agents showed high overall response rates. Results support zanubrutinib as preferred covalent BTK inhibitor in WM.

Waldenström's Macroglobulinemia →
incrementalnew treatment2023-06-01

JAK inhibitors show early promise in refractory AOSD

Pilot studies and case series of JAK1/2 inhibitors (baricitinib, tofacitinib) in patients with biologic-refractory AOSD demonstrated clinical improvement. JAK inhibition targets downstream signaling of multiple cytokines (IL-6, IFN-gamma, IL-12) simultaneously, offering a potential option when single-cytokine blockade fails.

Adult-Onset Still's Disease →
significantclinical trial2022-06-01

Phase II trial of ixazomib-dexamethasone shows oral-only regimen feasibility

Dispenzieri et al. (2022) reported the first prospective trial of oral proteasome inhibitor ixazomib plus dexamethasone in POEMS, achieving hematologic response in 71% and neurologic improvement in 78% of patients. This all-oral regimen offers a convenient alternative for transplant-ineligible patients unable to attend frequent infusion visits.

POEMS Syndrome →
significantnew treatment2021-08-31

Zanubrutinib FDA-approved for WM

In August 2021, zanubrutinib received FDA approval for WM based on the ASPEN trial, making it the second BTK inhibitor approved for the disease. Zanubrutinib's more selective BTK inhibition profile results in fewer off-target effects including significantly lower rates of atrial fibrillation compared to ibrutinib, establishing it as a better-tolerated alternative.

Waldenström's Macroglobulinemia →
significantnew treatment2021-07-15

Bortezomib-based induction before ASCT improves VEGF response and PFS

Li et al. (2021) reported that bortezomib-based induction therapy (VCD or VRD) prior to autologous stem cell transplant achieved VEGF response in 85% of patients before transplant. Pre-transplant VEGF normalization was associated with superior 5-year PFS compared to transplant without bortezomib induction, establishing bortezomib-based debulking as standard pre-transplant care.

POEMS Syndrome →
significantnew treatment2020-09-15

Canakinumab receives EMA approval for Still's disease including AOSD

Canakinumab (Ilaris) received EMA conditional marketing authorization for the treatment of Still's disease, covering both systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease. This represents the first specifically approved biologic for AOSD in Europe, supported by the CONSIDER phase II RCT and extensive sJIA data. Note: FDA approved canakinumab for sJIA in 2013 but has not granted a separate AOSD indication.

Adult-Onset Still's Disease →
incrementalepidemiology2020-09-01

R92Q prevalence in inflammatory disease cohorts higher than expected

Large population screening studies revealed the low-penetrance TNFRSF1A R92Q variant is present in 1-2% of healthy controls and enriched in patients with undifferentiated inflammatory syndromes, recurrent pericarditis, and inflammatory bowel disease. This raises questions about R92Q as a disease modifier rather than a monogenic cause, influencing genetic counseling approaches.

TNF Receptor-Associated Periodic Syndrome →
significantmechanism2019-11-01

Pyrin inflammasome structural mechanism fully elucidated

Structural biology studies resolved the pyrin inflammasome filament architecture, showing how FMF-associated MEFV mutations destabilize the autoinhibitory interaction between the pyrin SPRY domain and the B30.2 domain. This explained why gain-of-function mutations constitutively activate the inflammasome and provided a structural basis for rational drug design targeting pyrin.

Familial Mediterranean Fever →
significantdiagnostic advance2019-10-01

International consensus diagnostic criteria updated with VEGF threshold

Dispenzieri (2019) proposed updated diagnostic criteria incorporating a plasma VEGF threshold of greater than 200 pg/mL as a major criterion, replacing the previous requirement for extravascular volume overload. The updated criteria improve sensitivity for early-stage POEMS while maintaining specificity against other plasma cell dyscrasias.

POEMS Syndrome →
incrementaldiagnostic advance2019-09-01

Proposed diagnostic algorithm integrating anti-C1q titers with complement levels

A 2019 consensus proposal recommended a stepwise diagnostic algorithm for suspected HUVS: urticarial lesion biopsy showing leukocytoclastic vasculitis, followed by anti-C1q antibody testing and C3/C4/CH50 measurement. Anti-C1q titers above 30 U/mL combined with low C1q and C4 showed 92% diagnostic specificity for HUVS versus other urticarial vasculitis subtypes.

Hypocomplementemic Urticarial Vasculitis Syndrome →
significantdiagnostic advance2019-06-01

Eurofever/PRINTO evidence-based classification criteria for TRAPS validated

Gattorno et al. (2019) published validated classification criteria for TRAPS within the Eurofever/PRINTO framework, incorporating genetic confirmation of pathogenic TNFRSF1A variants plus clinical features (duration of episodes >6 days, migratory rash, periorbital edema, myalgia). The criteria achieved 95% sensitivity and 97% specificity, enabling standardized diagnosis for clinical trials.

TNF Receptor-Associated Periodic Syndrome →
significantdiagnostic advance2019-03-01

Free IL-18 established as AOSD-specific biomarker

Studies demonstrated that free (unbound) IL-18 is specifically elevated in AOSD compared to other inflammatory diseases, with levels up to 1000-fold higher than controls. Unlike total IL-18, free IL-18 distinguishes AOSD from infections, malignancies, and other autoimmune conditions, supporting its potential integration into classification criteria and as a therapeutic target.

Adult-Onset Still's Disease →
significantmechanism2017-06-01

Anti-C1q antibodies shown to directly activate classical complement pathway in HUVS

Bhatt et al. demonstrated that anti-C1q antibodies in HUVS bind to the collagen-like region of C1q, preventing C1q from clearing immune complexes while simultaneously activating the classical complement pathway at the endothelial surface. This dual mechanism explains the paradox of hypocomplementemia with ongoing complement-mediated tissue damage.

Hypocomplementemic Urticarial Vasculitis Syndrome →
landmarknew treatment2017-04-28

Midostaurin FDA-approved for advanced systemic mastocytosis

In April 2017, midostaurin became the first FDA-approved targeted therapy for advanced SM (ASM, SM-AHN, and MCL) based on a phase II open-label trial showing overall response rate of 60% including 45% major responses. This represented the first targeted option beyond cytoreductive chemotherapy for advanced SM subtypes.

Systemic Mastocytosis →
incrementalepidemiology2016-10-01

Hereditary alpha-tryptasemia identified as common SM confounder

Lyons et al. (2016) identified hereditary alpha-tryptasemia (HaT), caused by increased TPSAB1 copy number, in 5-6% of the general population. HaT elevates baseline tryptase independent of mast cell burden, complicating SM diagnosis. Updated WHO/ICC criteria now account for HaT when interpreting elevated tryptase in suspected SM cases.

Systemic Mastocytosis →
landmarknew treatment2016-09-23

Canakinumab FDA-approved for FMF (CLUSTER trial)

In 2016, canakinumab became the first FDA-approved biologic for colchicine-resistant FMF based on the pivotal CLUSTER trial. The trial demonstrated that canakinumab achieved complete control of disease flares in 61% of FMF patients versus 6% with placebo, establishing IL-1 blockade as an evidence-based second-line therapy.

Familial Mediterranean Fever →
significantgenetic discovery2015-03-01

Eurofever/PRINTO genotype-phenotype study in 158 TRAPS patients

Ter Haar et al. (2015) analyzed 158 TRAPS patients in the Eurofever registry, confirming that cysteine-disrupting TNFRSF1A mutations cause the most severe phenotype with highest amyloidosis risk (24%), while T50M and R92Q variants present with milder, often self-limited disease. These findings established genotype-based risk stratification for clinical management.

TNF Receptor-Associated Periodic Syndrome →
landmarknew treatment2015-01-29

Ibrutinib FDA-approved for WM as first targeted therapy

In January 2015, ibrutinib became the first FDA-approved targeted agent for WM based on a pivotal phase II trial showing 90.5% overall response rate in previously treated patients. Ibrutinib's efficacy is tied to dual inhibition of BTK and HCK signaling downstream of MYD88 L265P, transforming WM management from chemoimmunotherapy to oral targeted therapy.

Waldenström's Macroglobulinemia →
significantgenetic discovery2014-02-01

CXCR4 WHIM-like mutations identified as second driver and ibrutinib resistance factor

Hunter et al. (2014) discovered activating CXCR4 mutations (homologous to WHIM syndrome variants) in 30-40% of WM patients. CXCR4 mutations confer relative ibrutinib resistance by sustaining AKT and ERK survival signaling, and are associated with higher IgM levels, symptomatic hyperviscosity, and slower treatment response. CXCR4 genotyping now guides treatment selection.

Waldenström's Macroglobulinemia →
landmarkgenetic discovery2012-08-30

MYD88 L265P identified as hallmark somatic mutation in WM

Treon et al. (2012, NEJM) identified the MYD88 L265P somatic mutation in 91% of WM patients by whole-genome sequencing. This activating mutation drives NF-kB and JAK-STAT signaling via constitutive TLR pathway activation, representing the most disease-specific oncogene in any B-cell malignancy and enabling molecular diagnostics and targeted therapy development.

Waldenström's Macroglobulinemia →
significantmechanism2011-04-01

Misfolded TNFRSF1A protein shown to activate unfolded protein response and ROS

Bulua et al. (2011) and Simon et al. (2010) demonstrated that structural TNFRSF1A mutations cause receptor misfolding and retention in the endoplasmic reticulum, triggering the unfolded protein response and mitochondrial ROS production. This ER stress pathway activates MAPK signaling and NF-kB independent of TNF ligand, explaining why anti-TNF therapy is less effective than IL-1 blockade in TRAPS.

TNF Receptor-Associated Periodic Syndrome →

Clinical Trials

16
RecruitingN/ANCT05200715

AIDA Registry: International Multicenter Registry of Patients With Monogenic and Polygenic Autoinflammatory Diseases

University of Siena · n=3500 · 2020-08-06

Schnitzler Syndrome →
ClinicalTrials.gov ↗
Active, not recruitingPhase 2NCT03731260

PIONEER: Study to Evaluate Efficacy and Safety of Avapritinib in Indolent Systemic Mastocytosis

Blueprint Medicines Corporation · n=212 · 2018-12-18

Avapritinib 25mg
Systemic Mastocytosis →
ClinicalTrials.gov ↗
Active, not recruitingPhase 1NCT02561988

EXPLORER: Study of BLU-285 in Patients with Advanced Systemic Mastocytosis and Other Relapsed/Refractory Hematologic Malignancies

Blueprint Medicines Corporation · n=86 · 2015-10-29

Avapritinib (BLU-285)
Systemic Mastocytosis →
ClinicalTrials.gov ↗
CompletedPhase 2NCT01390350

ILESCH: Multi-center, Double-blind, Placebo-controlled Study of Canakinumab in Schnitzler Syndrome

Charité University, Berlin · n=20 · 2011-07

CanakinumabPlacebo
Schnitzler Syndrome →
ClinicalTrials.gov ↗
Active, not recruitingPhase 2NCT03580655

PATHFINDER: Study of Avapritinib in Patients with Advanced Systemic Mastocytosis

Blueprint Medicines Corporation · n=62 · 2018-09-04

Avapritinib 200mg
Systemic Mastocytosis →
ClinicalTrials.gov ↗