The HyperPed-COVID international registry: Impact of age of onset, disease presentation and geographical distribution on the final outcome of MIS-C.

OBJECTIVES: The aim of the study was to establish an international multicenter registry to collect data on patients with Multisystem Inflammatory Syndrome in Children (MIS-C), in order to highlight a relationship between clinical presentation, age of onset and geographical distribution on the clinical outcome. STUDY DESIGN: Multicenter retrospective study involving different international societies for rare immunological disorders.1009 patients diagnosed with MIS-C between March and September 2022, from 48 centers and 22 countries were collected. Five age groups (<1, 1-4, 5-11, 12-16, >16 years) and four geographic macro-areas, Western Europe, Central-Eastern Europe, Latin America, Asian-African resource-limited countries (LRC), were identified. RESULTS: Time to referral was significantly higher in LRC. Intensive anti-inflammatory treatment, including biologics, respiratory support and mechanic ventilation were more frequently used in older children and in European countries. The mortality rate was higher in very young children (<1 year), in older patients (>16 years of age) and in LRC. Multivariate analysis identified the residence in LRC, presence of severe cardiac involvement, renal hypertension, lymphopenia and non-use of heparin prophylaxis, as the factors most strongly associated with unfavorable outcomes. CONCLUSIONS: The stratification of patients by age and geographic macro-area provided insights into the clinical presentation, treatment and outcome of MIS-C. The mortality and sequelae rates exhibited a correlation with the age and geographical areas. Patients admitted and treated in LRC displayed more severe outcomes, possibly due to delays in hospital admission and limited access to biologic drugs and to intensive care facilities.

Development and initial validation of parent and child versions of the Juvenile Arthritis Disease Activity Score.

OBJECTIVE: To develop parent- and child-centered versions of the Juvenile Arthritis Disease Activity Score (JADAS) and to provide preliminary evidence of their validity. METHODS: Validation analyses were conducted on two large multinational datasets of patients with juvenile idiopathic arthritis (JIA) and included assessment of construct validity, internal consistency and structure, discriminative validity, responsiveness to change, and predictive validity. RESULTS: The parJADAS and patJADAS include four parent/patient-reported outcomes, each measured on a 0-10 scale: assessment of overall disease activity; rating of pain intensity; assessment of activity of joint disease; duration of morning stiffness. Both scores are calculated as the simple linear sum of the scores of their 4 components, which yields for both of them a global score of 0-40. The parJADAS and patJADAS demonstrated good construct validity, yielding high correlations with other JIA composite disease activity measures and moderate correlations with physician global rating and joint counts. Internal consistency was satisfactory, with Cronbach' s alpha > 0.80, and exploratory factor analysis showed that both indices are monodimensional. Both instruments discriminated well between different disease states, with discriminative ability being not affected by the presence of damage, proved able to predict important disease outcomes, and showed fair responsiveness to clinically important change, with standardized response mean of 0.71. CONCLUSION: Both parJADAS and patJADAS were found to possess good measurement properties and to serve as surrogate of physicians' evaluations. Regular home completion of the two instruments through digital technologies offers a suitable and pragmatic approach to deliver remote symptom monitoring and telehealth.

Dimethyl Fumarate Delays Multiple Sclerosis in Radiologically Isolated Syndrome.

OBJECTIVE: The radiologically isolated syndrome (RIS) represents the earliest detectable pre-clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum. METHODS: We conducted a multi-center, randomized, double-blinded, placebo-controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with central nervous system (CNS) demyelination were included. Within 12 MS centers in the United States, participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240 mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow-up period of 96 weeks. An intention-to-treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at ClinicalTrials.gov, NCT02739542 (ARISE). RESULTS: Participants from 12 centers were recruited from March 9, 2016, to October 31, 2019, with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96-week study period was highly reduced in the unadjusted Cox proportional-hazards regression model (hazard ratio [HR] = 0.18, 95% confidence interval [CI] = 0.05-0.63, p = 0.007). More moderate adverse reactions were present in the DMF (34 [32%]) than placebo groups (19 [21%]) but severe events were similar (DMF, 3 [5%]; placebo, 4 [9%]). INTERPRETATION: This is the first randomized clinical trial demonstrating the benefit of a disease-modifying therapy in preventing a first acute clinical event in people with RIS. ANN NEUROL 2023;93:604-614.

Therapeutic lag: Is treatment effect delayed in progressive MS?

BACKGROUND: Randomized clinical trials (RCTs) in progressive multiple sclerosis (MS) often revealed non-significant treatment effects on disability progression. OBJECTIVES: To investigate whether the failure to detect a significant benefit from treatment may be motivated by a delay in treatment effect, possibly related to baseline characteristics. METHODS: We re-analyzed data from two RCTs testing interferon-beta and glatiramer-acetate versus placebo in progressive MS with no significant effect on EDSS progression. We first designed a time-dependent Cox model with no treatment effect up to time = t0, and constant hazard ratio (HR) after time = t0. We selected the best-fitting t0 from 0 (standard Cox model) to 2.5 years. Furthermore, we modeled the delay as a function of baseline EDSS and fitted the resulting Cox model to the merged dataset. RESULTS: The time-dependent Cox model revealed a significant benefit of treatment delayed by t0 = 2.5 years for the SPECTRIMS study (HR = 0.65 (0.43-0.98), p = 0.041), and delayed by t0 = 2 years for the PROMISE study (HR = 0.65, (0.42-0.99), p = 0.044). In the merged dataset, the HR for the EDSS-dependent delayed effect was 0.68 (0.56, 0.82), p < 0.001. CONCLUSION: The assumption of a delayed treatment effect improved the fit to the data of the two examined RCTs, uncovering a significant, although shifted, benefit of treatment.

Race and ethnicity in multiple sclerosis phase 3 clinical trials: A systematic review.

BACKGROUND: Distinctive differences in multiple sclerosis (MS) have been observed by race and ethnicity. We aim to (1) assess how often race and ethnicity were reported in clinical trials registered on ClinicalTrials.gov, (2) evaluate whether the population was diverse enough, and (3) compare with publications. METHODS: We included phase 3 clinical trials registered with results on ClinicalTrials.gov between 2007 and 2023. When race and/or ethnicity were reported, we searched for the corresponding publications. RESULTS: Out of the 99 included studies, 56% reported race and/or ethnicity, of which only 26% of those primarily completed before 2017. Studies reporting race or ethnicity contributed to a total of 33,891 participants, mainly enrolled in Eastern Europe. Most were White (93%), and the median percentage of White participants was 93% (interquartile range (IQR) = 86%-98%), compared to 3% for Black (IQR = 1%-12%) and 0.2% for Asian (IQR = 0%-1%). Four trials omitted race and ethnicity in publications and even when information was reported, some discrepancies in terminology were identified and categories with fewer participants were often collapsed. CONCLUSION: More efforts should be done to improve transparency, accuracy, and representativeness, in publications and at a design phase, by addressing social determinants of health that historically limit the enrollment of underrepresented population.

Creating an automated tool for a consistent and repeatable evaluation of disability progression in clinical studies for multiple sclerosis.

BACKGROUND: The lack of standardized disability progression evaluation in multiple sclerosis (MS) hinders reproducibility of clinical study results, due to heterogeneous and poorly reported criteria. OBJECTIVE: To demonstrate the impact of using different parameters when evaluating MS progression, and to introduce an automated tool for reproducible outcome computation. METHODS: Re-analyzing BRAVO clinical trial data (NCT00605215), we examined the fluctuations in computed treatment effect on confirmed disability progression (CDP) and progression independent of relapse activity (PIRA) when varying different parameters. These analyses were conducted using the msprog package for R, which we developed as a tool for CDP assessment from longitudinal data, given a set of criteria that can be specified by the user. RESULTS: The BRAVO study reported a hazard ratio (HR) of 0.69 (95% confidence interval (CI): 0.46-1.02) for CDP. Using the different parameter configurations, the resulting treatment effect on CDP varied considerably, with HRs ranging from 0.59 (95% CI: 0.41-0.86) to 0.72 (95% CI: 0.48-1.07). The treatment effect on PIRA varied from an HR = 0.62 (95% CI: 0.41-0.93) to an HR = 0.65 (95% CI: 0.40-1.04). CONCLUSIONS: The adoption of an open-access tool validated by the research community, with clear parameter specification and standardized output, could greatly reduce heterogeneity in CDP estimation and promote repeatability of study results.

Determining minimal clinically important differences in the Hammersmith Functional Motor Scale Expanded for untreated spinal muscular atrophy patients: An international study.

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is a rare and progressive neuromuscular disorder with varying severity levels. The aim of the study was to calculate minimal clinically important difference (MCID), minimal detectable change (MDC), and values for the Hammersmith Functional Motor Scale Expanded (HFMSE) in an untreated international SMA cohort. METHODS: The study employed two distinct methods. MDC was calculated using distribution-based approaches to consider standard error of measurement and effect size change in a population of 321 patients (176 SMA II and 145 SMA III), allowing for stratification based on age and function. MCID was assessed using anchor-based methods (receiver operating characteristic [ROC] curve analysis and standard error) on 76 patients (52 SMA II and 24 SMA III) for whom the 12-month HFMSE could be anchored to a caregiver-reported clinical perception questionnaire. RESULTS: With both approaches, SMA type II and type III patients had different profiles. The MCID, using ROC analysis, identified optimal cutoff points of -2 for type II and -4 for type III patients, whereas using the standard error we found the optimal cutoff points to be 1.5 for improvement and -3.2 for deterioration. Furthermore, distribution-based methods uncovered varying values across age and functional status subgroups within each SMA type. CONCLUSIONS: These results emphasize that the interpretation of a single MCID or MDC value obtained in large cohorts with different functional status needs to be made with caution, especially when these may be used to assess possible responses to new therapies.

Profiling migraine patients according to clinical and psychophysical characteristics: clinical validity of distinct migraine clusters.

AIMS: Investigate if different clinical and psychophysical bedside tools can differentiate between district migraine phenotypes in ictal/perictal (cohort 1) and interictal (cohort 2) phases. METHOD: This observational study included two independent samples in which patients were subgrouped into distinct clusters using standardized bedside assessment tools (headache frequency, disability, cervical active range of motion, pressure pain threshold in different areas): (A) cohort 1-ictal/perictal migraine patients were subgrouped, based on previous studies, into two clusters, i.e., Cluster-1.1 No Psychophysical Impairments (NPI) and Cluster-1.2 Increased Pain Sensitivity and Cervical Musculoskeletal Dysfunction (IPS-CMD); (B) cohort 2-interictal migraine patients were subgrouped into three clusters, i.e., Cluster-2.1 NPI, Cluster-2.2 IPS, and Cluster-2.3 IPS-CMD. Clinical characteristics (multiple questionnaires), somatosensory function (comprehensive quantitative sensory testing (QST)), and cervical musculoskeletal impairments (cervical musculoskeletal assessment) were assessed and compared across headache clusters and a group of 56 healthy controls matched for sex and age. RESULTS: Cohort 1: A total of 156 subjects were included. Cluster-1.2 (IPS-CMD) had higher headache intensity (p = 0.048), worse headache-related (p = 0.003) and neck-related disability (p = 0.005), worse quality of life (p = 0.003), and higher symptoms related to sensitization (p = 0.001) and psychological burden (p = 0.005) vs. Cluster-1.1(NPI). Furthermore, Cluster-1.2 (IPS-CMD) had (1) reduced cervical active and passive range of motion (p < 0.023), reduced functionality of deep cervical flexors (p < 0.001), and reduced values in all QST(p < 0.001) vs. controls, and (2) reduced active mobility in flexion, left/right lateral flexion (p < 0.045), and reduced values in QST (p < 0.001) vs. Cluster-1.1 (NPI). Cohort 2: A total of 154 subjects were included. Cluster-2.3 (IPS-CMD) had (1) longer disease duration (p = 0.006), higher headache frequency (p = 0.006), disability (p < 0.001), and psychological burden (p = 0.027) vs. Cluster-2.2 (IPS) and (2) higher headache-related disability (p = 0.010), neck-related disability (p = 0.009), and higher symptoms of sensitization (p = 0.018) vs. Cluster-2.1 (NPI). Cluster-2.3(IPS-CMD) had reduced cervical active and passive range of motion (p < 0.034), and reduced functionality of deep cervical flexors (p < 0.001), vs. controls, Custer-2.1 (NPI), and Cluster-2.2 (IPS). Cluster-2.2 (IPS) and 2.3 (IPS-CMD) had reduced QST values vs. controls (p < 0.001) and Cluster-2.1 (p < 0.039). CONCLUSION: A battery of patient-related outcome measures (PROMs) and quantitative bedside tools can separate migraine clusters with different clinical characteristics, somatosensory functions, and cervical musculoskeletal impairments. This confirms the existence of distinct migraine phenotypes and emphasizes the importance of migraine phases of which the characteristics are assessed. This may have implications for responders and non-responders to anti-migraine medications.

Development and Initial Validation of the ONCOREUM Score to Differentiate Childhood Cancer with Arthropathy from Juvenile Idiopathic Arthritis.

OBJECTIVE: To develop and validate a weighted score, the ONCOREUM score, that aids physicians in differentiation of cancer with arthropathy from juvenile idiopathic arthritis (JIA). STUDY DESIGN: Data were extracted from the ONCOREUM Study, a multicenter, cross-sectional investigation aimed at comparing children with cancer and arthropathy to children with JIA. Three statistical approaches were applied to develop the ONCOREUM score and assess the role of each variable in the diagnosis of cancer with arthropathy, including 2 approaches based on multivariable stepwise selection (models 1 and 2) and 1 approach on a Bayesian model averaging method (model 3). The ß coefficients estimated in the models were used to assign score points. Considering that not missing a child with cancer is a mandatory clinical objective, discriminating performance was assessed by fixing sensitivity at 100%. Score performance was evaluated in both developmental and validation samples (representing 80% and 20% of the study population, respectively). RESULTS: Patients with cancer and arthropathy (49 with solid tumors and 46 with hematologic malignancies without peripheral blasts) and 677 patients with JIA were included. The highest area under the receiver operating characteristic (ROC) curve (AUC) in the validation data set was yielded by model 1, which was selected to constitute the ONCOREUM score. The score ranged from -18 to 21.8, and the optimal cutoff obtained through ROC analysis was -6. The sensitivity, specificity, and AUC of the cutoff in the validation sample were 100%, 70%, and 0.85, respectively. CONCLUSIONS: The ONCOREUM score is a powerful and easily applicable tool that may facilitate early differentiation of malignancies with articular complaints from JIA.

Pediatric Recurrent Pericarditis: Appropriateness of the Standard of Care and Response to IL-1 Blockade.

OBJECTIVE: To analyze, in a cohort of pediatric patients with recurrent pericarditis undergoing anti-interleukin (IL)-1 treatment: the agent and dosing used as first-line treatment, the long-term efficacy of IL-1 blockers, the percentage of patients achieving a drug-free remission, and the presence of variables associated with drug-free remission. STUDY DESIGN: Data were collected from patients' charts. The annualized relapse rate (ARR) was used for evaluation of treatment efficacy, and bivariate logistic regression analysis was used for variables associated with drug-free remission. RESULTS: Fifty-eight patients, treated between 2008 and 2018, were included in the study (mean follow-up. 2.6 years). Of the 56 patients treated with first-line drugs, 14 not responsive patients were underdosed. Fifty-seven patients were treated with anakinra: the ARR before and during daily treatment was 3.05 and 0.28, respectively (P < .0001); an increase to 0.83 was observed after the reduction/withdrawal of treatment (P < .0001). The switch from anakinra to canakinumab (5 patients) was associated to an increase of the ARR (0.49 vs 1.46), but without statistical significance (P = .215). At last follow-up, only 9 of the 58 patients had withdrawn all treatments. With the limits of a retrospective study and the heterogeneity between the patients enrolled in the study, a shorter duration of treatment with anakinra was the only variable associated with drug-free remission. CONCLUSIONS: This study shows that most pediatric patients with recurrent pericarditis needing IL-1 blockade received an inadequate treatment with first-line agents. The effectiveness of anakinra is supported by this study, but few patients achieved drug-free remission. The different rate of response to anakinra and canakinumab may suggest a possible role of IL-1α in the pathogenesis of recurrent pericarditis.

Paediatric rheumatologists do not score the physician's global assessment of juvenile idiopathic arthritis disease activity in the same way.

OBJECTIVES: To assess the heterogeneity in factors affecting physician's global assessment of disease activity (PhGA) and in PhGA scoring of multiple JIA patient's case scenarios. METHODS: An electronic web-based questionnaire of factors potentially considered in PhGA was sent worldwide to members of PRINTO and the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN). The respondents were asked to rate from 0 to 100 the relevance of 17 factors possibly affecting PhGA scoring and to derive a PhGA score of 17 detailed JIA patient cases. The median and interquartile range was used to measure the heterogeneity in the scoring. To demonstrate the consistency among the PhGA scores of the patient cases provided by multiple physicians, we assessed the inter-rater reliability using intra-class correlation. RESULTS: The questionnaire was completed by 491 respondents. A large individual variation was observed in the impact of different factors on PhGA when assessing JIA. For non-systemic JIA the presence of fever had the largest variation and swollen joint count had the smallest. For sJIA, the largest variation was seen in the presence of erosions and the smallest in the presence of fever. The intra-class correlation of the group for PhGA scoring of patient cases was 0.53 (95% CI 0.38, 0.72). CONCLUSIONS: In a sample of worldwide respondents, the scoring of the PhGA is divergent. Consensus on PhGA scoring guidelines is required to obtain a consistent assessment of patients.

Validation of the PEDiatric Behçet's Disease classification criteria: an evidence-based approach.

OBJECTIVES: to validate the PEDiatric Behçet's Disease classification criteria (PEDBD) with an evidence-based approach. METHODS: 210 pediatric patients (70 Behçet's disease (BD), 40 Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis, 35 familial Mediterranean fever, 26 hyper-IgD syndrome, 22 TNF-Receptor associated Periodic fever Syndrome, 17 undefined recurrent fevers) were randomly selected from the Eurofever Registry. A set of 11 experienced clinicians/researchers blinded to the original diagnosis evaluated the patients. Using the table consensus as gold standard (agreement ≥ 80%), the PEDBD, ISG and ICBD criteria were applied to BD patients and to confounding diseases with other autoinflammatory conditions in order to define their sensitivity, specificity and accuracy. RESULTS: At the end of the third round, a consensus was reached in 139/210 patients (66.2%). The patients with a consensus ≥80% were classified as confirmed-BD (n = 24), and those with an agreement of 60-79% as probable-BD (n = 10). When comparing these patients with the confounding diseases group, an older age at disease onset, the presence of oral and genital ulcers, skin papulo-pustular lesions, a positive pathergy test and posterior uveitis were BD distinctive elements. The ISG, ICBD and PEDBD criteria were applied to confirmed-BD and to the confounding disease group, showing a sensitivity of 0.50, 0.79 and 0.58, a specificity of 1.00, 0.97, 0.99, and an accuracy of 0.91, 0.94 and 0.92, respectively. CONCLUSIONS: the PEDBD criteria were very specific, while the ICBD resulted to be more sensitive. The complexity of childhood BD suggests larger prospective international cohorts to further evaluate the performance of the criteria.

Improving the efficiency of clinical trials in multiple sclerosis.

BACKGROUND: Phase 3 clinical trials for disease-modifying therapies in relapsing-remitting multiple sclerosis (RRMS) have utilized a limited number of conventional designs with a high degree of success. However, these designs limit the types of questions that can be addressed, and the time and cost required. Moreover, trials involving people with progressive multiple sclerosis (MS) have been less successful. OBJECTIVE: The objective of this paper is to discuss complex innovative trial designs, intermediate and composite outcomes and to improve the efficiency of trial design in MS and broaden questions that can be addressed, particularly as applied to progressive MS. METHODS: We held an international workshop with experts in clinical trial design. RESULTS: Recommendations include increasing the use of complex innovative designs, developing biomarkers to enrich progressive MS trial populations, prioritize intermediate outcomes for further development that target therapeutic mechanisms of action other than peripherally mediated inflammation, investigate acceptability to people with MS of data linkage for studying long-term outcomes of clinical trials, use Bayesian designs to potentially reduce sample sizes required for pediatric trials, and provide sustained funding for platform trials and registries that can support pragmatic trials. CONCLUSION: Novel trial designs and further development of intermediate outcomes may improve clinical trial efficiency in MS and address novel therapeutic questions.

Recurrent motor branch neuropathy in carpal tunnel syndrome: An ultrasound study.

INTRODUCTION/AIMS: The reason for the variable rate of progression of patients with carpal tunnel syndrome (CTS) to thenar muscles impairment is not fully understood. The aim of this study was to evaluate the occurrence of ultrasound signs of recurrent motor branch (RMB) neuropathy in patients with CTS and to correlate imaging findings with clinical and electrophysiological data. METHODS: Two cohorts were recruited, one consisting of CTS patients with electrodiagnostic evidence of prolonged median distal motor latency from wrist to thenar eminence and another consisting of sex- and age-matched healthy controls. Ultrasound reliability of RMB measurement was assessed by the calculation of the interclass correlation coefficient (ICC). Patients were evaluated with electrodiagnostic tests and asked to complete the Boston Carpal Tunnel Questionnaire. The difference between the RMB diameter in patients and controls was analyzed using a t test. Correlations between RMB diameter and other parameters were assessed using linear mixed models. RESULTS: 46 hands from 32 patients with CTS and 50 hands from 50 controls were evaluated. The intra- and interobserver agreements in RMB measurement were very good (ICC = 0.84; 95% confidence interval [CI], 0.75 to 0.90) and good (ICC = 0.79; 95% CI, 0.69 to 0.87). The RMB diameter was significantly larger in patients than in controls (P < .0001). No significant correlation was found between the RMB diameter and other variables, except for BMI and median nerve cross-sectional area. DISCUSSION: Ultrasound is reliable in identifying the RMB and characterizing its abnormalities. In this patient cohort, ultrasound allowed for detection of definite signs of RMB compression neuropathy.

Type I spinal muscular atrophy patients treated with nusinersen: 4-year follow-up of motor, respiratory and bulbar function.

BACKGROUND: We report the 4-year follow-up in type I patients treated with nusinersen and the changes in motor, respiratory and bulbar function in relation to subtype, age and SMN2 copy number. METHODS: The study included SMA 1 patients with at least one assessment after 12, 24 and 48 months from the first dose of nusinersen. The assessments used were Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination (HINE-II). RESULTS: Forty-eight patients, with ages ranging from 7 days to 12 years (mean 3.3 years, SD 3.6 years) were included in the study. The CHOP INTEND and HINE-II scores significantly increased between baseline and 48 months (p < 0.001). When age at starting treatment subgroups (<210 days, <2 years, 2-4 years, 5-11 years, ≥12 years) were considered, the CHOP INTEND increased significantly in patients younger than 4 years at treatment, while the HINE-2 increased significantly in patients younger than 2 years at treatment. In a mixed-model analysis, age, nutritional and respiratory status were predictive of changes on both scales while SMN2 copy number and decimal classification were not. CONCLUSIONS: Our results confirm the safety profile previously reported and support the durability of the efficacy of nusinersen at 4 years with an overall stability or mild improvement and no evidence of deterioration over a long period of time.

Profiling migraine patients according to clinical and psychophysical characteristics: a cluster analysis approach.

AIM: This study aims to profile migraine patients according clinical and psychophysical characteristics. METHOD: In this observational study, two cohorts of migraine patients(episodic/chronic) were included. Cohort-1: ictal/perictal phase; Cohort-2: interictal phase.The following variables were assessed: headache frequency; disability; cervical active range of motion(AROM) in flexion, extension, right/left lateral flexion, right/left rotation; pressure-pain threshold(PPT) over: temporalis, two cervical areas(C1/C4 vertebral segments), and two distal pain-free areas(hand/leg). Cluster analysis was performed using the K-means algorithm. Differences across clusters were investigated. RESULTS: Cohort-1: 100 patients were included, and two clusters were identified. Cluster-1.1 (19%), Cluster-1.2 (81%). Cluster 1.1 had a higher percentage of men (P = .037) and higher disability (P = .003) compared to Clusters 1.2. Cluster 1.2 had reduced AROM in flexion, extension, and left/right lateral flexion (P < .037), and lower PPT value in all areas (P < .001) compared to Cluster 1.1. Cohort-2: 98 patients were included and three clusters were identified. Cluster-2.1(18%), Cluster-2.2(45%), and Cluster-2.3(37%). Cluster-2.1 had a higher percentage of men compared to clusters-2.2 and 2.3 (P = .009). Cluster-2.3 had higher headache frequency, and disability compared to Cluster-2.2 (P < .006), and higher disability compared to Cluster-2.1 (P = .010). Cluster-2.3 had reduced AROM in all directions compared to Clusters-2.1 and 2.2 (P < .029). Clusters-2.2 and 2.3 have lower PPT values in all areas compared to Cluster-1.1 (P < .001). CONCLUSION: In the Ictal/perictal phase, two clusters were identified according to clinical and psychophysical characteristics, with one group showing no psychophysical impairment and one with increased pain-sensitivity and cervical musculoskeletal-dysfunctions.In the interictal phase, three clusters could be identified, with one group showing no psychophysical impairment, one increased pain-sensitivity, and one increased pain sensitivity and cervical musculoskeletal-dysfunctions.

Trigeminocervical pain sensitivity during the migraine cycle depends on headache frequency.

OBJECTIVE: This experimental study aimed to assess pain sensitivity in low-frequency episodic migraine (LFEM), high-frequency episodic migraine (HFEM), and chronic migraine (CM) patients across the different phases of the migraine cycle. METHOD: In this observational, experimental study, clinical characteristics (diary and time from the last/next headache attack), and quantitative sensory testing (QST) (wind-up pain ratio (WUR) and pressure pain threshold (PPT) from the trigeminal area and PPT from the cervical spine) was performed. LFEM, HFEM, and CM were assessed in each of the 4 migraine phases (HFEM and LFEM: interictal, preictal, ictal, and postictal; CM: interictal and ictal) and compared vs. each other's (matched for the phase) and controls. RESULTS: A total of 56 controls, 105 LFEM, 74 HFEM, and 32 CM were included. No differences in QST parameters were observed between LFEM, HFEM, and CM in any of the phases. During the interictal phase and when comparing with controls the following were found: 1) LFEM had lower trigeminal PPT (p = 0.001) and 2) lower cervical PPT (p = 0.001). No differences were observed between HFEM or CM and healthy controls. During the ictal phase and when comparing with controls the following were found: HFEM and CM had 1) lower trigeminal PPTs (HFEM p = 0.001; CM = p < 0.001), 2) lower cervical PPT s (HFEM p = 0.007; CM p < 0.001), and 3) higher trigeminal WUR (HFEM p = 0.001, CM p = 0.006). No differences were observed between LFEM and healthy controls. During the preictal phase and when comparing with controls the following were found: 1) LFEM had lower cervical PPT (p = 0.007), 2) HFEM had lower trigeminal (p = 0.013) and 3) HFEM had lower cervical (p = .006) PPTs. During the postictal phase and when comparing with controls the following were found: 1) LFEM had lower cervical PPT (p = 0.003), 2) HFEM had lower trigeminal PPT (p = 0.005), and 3) and HFEM had lower cervical (p = 0.007) PPTs. CONCLUSION: This study suggested that HFEM patients have a sensory profile matching CM better than LFEM. When assessing pain sensitivity in migraine populations, the phase with respects to headache attacks is of utmost importance and can explain the inconsistency in pain sensitivity data reported in the literature.

The challenge of early diagnosis of autoimmune lymphoproliferative syndrome in children with suspected autoinflammatory/autoimmune disorders.

OBJECTIVES: To test the usefulness of an extended panel of lymphocyte subsets in combination with Oliveira's diagnostic criteria for the identification of autoimmune lymphoproliferative syndrome (ALPS) in children referred to a paediatric rheumatology centre. METHODS: Patients referred from 2015 to 2018 to our rheumatology unit for an autoimmune or autoinflammatory condition were retrospectively analysed. Oliveira's required criteria [chronic lymphoproliferation and elevated double-negative T (DNT)] were applied as first screening. Flow cytometry study included double-negative CD4-CD8-TCRαß+ T lymphocytes (DNT), CD25+CD3+, HLA-DR+CD3+ T cells, B220+ T cells and CD27+ B cells. Data were analysed with a univariate logistic regression analysis, followed by a multivariate analysis. Sensitivity and specificity of the Oliveira's required criteria were calculated. RESULTS: A total of 264 patients were included in the study and classified as: (i) autoimmune diseases (n = 26); (ii) juvenile idiopathic arthritis (JIA) (35); (iii) monogenic systemic autoinflammatory disease (27); (iv) periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (100); (v) systemic undefined recurrent fever (45); (vi) undetermined-systemic autoinflammatory disease (14); or (vii) ALPS (17). Oliveira's required criteria displayed a sensitivity of 100% and specificity of 79%. When compared with other diseases the TCRαß+B220+ lymphocytes were significantly increased in ALPS patients. The multivariate analysis revealed five clinical/laboratory parameters positively associated to ALPS: splenomegaly, female gender, arthralgia, elevated DNT and TCRαß+B220+ lymphocytes. CONCLUSIONS: Oliveira's required criteria are useful for the early suspicion of ALPS. TCRαß+B220+ lymphocytes should be added in the diagnostic work-up of patients referred to the paediatric rheumatology unit for a suspected autoimmune or autoinflammatory condition, providing a relevant support in the early diagnosis of ALPS.

Exposure to natalizumab throughout pregnancy: effectiveness and safety in an Italian cohort of women with multiple sclerosis.

OBJECTIVE: Assessing the risk of clinical and radiological reactivation during pregnancy and post partum in women with multiple sclerosis (MS) treated with natalizumab (NTZ) throughout pregnancy (LONG_EXP) compared with women interrupting treatment before (NO_EXP) and within >-30 days and ≤90 days from conception (SHORT_EXP), and describing newborns' outcomes. METHODS: Maternal clinical and radiological outcomes and obstetric and fetal outcomes were retrospectively collected and compared among groups (NO_EXP, SHORT_EXP, LONG_EXP). Predictors of clinical and radiological reactivation were investigated through univariable and multivariable analysis. RESULTS: 170 eligible pregnancies from 163 women referring to 29 Italian MS centres were included. Annualised relapse rate (ARR) was significantly lower in LONG_EXP (n=66, 0.02 (0.001-0.09)) compared with NO_EXP (n=31, 0.43 (0.21-0.75), p=0.002) and SHORT_EXP (n=73, 0.46 (0.30-0.66), p=0.0004) during pregnancy, and in LONG_EXP (0.12 (0.05-0.24)) compared with SHORT_EXP (0.30 (0.17-0.50), p=0.008) during post partum. Gadolinium-enhancing (Gd+) lesions were less frequent in LONG_EXP (n=6/50, 2.00%) compared with NO_EXP (n=9/21, 42.86%) and SHORT_EXP after delivery (n=17/49, 34.69%, p=0.010).Delaying NTZ resumption after delivery significantly increased the risk of relapses (OR=1.29 (95% CI 1.07 to 1.57), p=0.009) and Gd+ lesions (OR=1.49 (95% CI 1.17 to 1.89, p=0.001). Newborns' weight, length, head circumference and gestational age did not differ among groups after adjusting for confounders. Anaemia was tracked in 4/69 LONG_EXP newborns. Congenital anomaly rate was within the expected range for the untreated MS population. CONCLUSIONS: Our findings indicate that in women with MS treated with NTZ before conception, continuation of NTZ throughout pregnancy and its early resumption after delivery mitigate the risk of clinical and radiological reactivation. This approach has no major impact on newborns' outcomes.

Cervical musculoskeletal impairments in the 4 phases of the migraine cycle in episodic migraine patients.

OBJECTIVE: To assess cervical musculoskeletal impairments during the 4 phases of a migraine cycle in episodic migraine patients, controlling for the presence of concomitant neck pain. METHODS: Differences in cervical musculoskeletal impairments were assessed during the 4 migraine phases in episodic migraine patients and compared with healthy controls controlling for concomitant neck pain. Cervical musculoskeletal impairments were assessed as follow: cervical active range of motion; flexion rotation test; craniocervical flexion test and calculation of activation pressure score; the total number of myofascial trigger points in head/neck muscles; the number of positivevertebral segments (headache's reproduction) during passive accessory intervertebral movement; pressure pain thresholds over C1, C2, C4, C6 vertebral segments bilaterally, trigeminal area, hand, and leg. Signs of pain sensitization were assessed by evaluating mechanical pain threshold over trigeminal area and hand, pressure pain thresholds, and the wind-up ratio. The Bonferroni-corrected p-value (05/4 = 0.013) was adopted to assess the difference between groups, while a p-value of 0.05 was considered significant for the correlation analysis. RESULTS: A total of 159 patients and 52 controls were included. Flexion rotation test and craniocervical flexion test were reduced in all 4 phases of the migraine cycle versus healthy controls (p < 0.001). The number of myofascial trigger points and positive vertebral segments was increased in all 4 phases of the migraine cycle versus healthy controls (p < 0.001). Flexion, extension, and total cervical active range of motion and cervical pressure pain thresholds were reduced in episodic migraine in the ictal phase versus controls (p < 0.007) with no other significant differences. Outside the ictal phase, the total cervical active range of motion was positively correlated with trigeminal and leg pressure pain threshold (p < 0.026), the number of active myofascial trigger points and positive positive vertebral segments were positively correlated with higher headache frequency (p=0.045), longer headache duration (p < 0.008), and with headache-related disability (p = 0.031). Cervical pressure pain thresholds were positively correlated with trigeminal, hand, and leg pressure pain threshold (p < 0.001), and trigeminal and leg mechanical pain thresholds (p < 0.005), and negatively correlated with the wind-up ratio (p < 0.004). CONCLUSION: In all phases of the migraine cycle, independent of the presence of concomitant neck pain, episodic migraine patients showed reduced flexion rotation test and craniocervical flexion test and an increased number of myofascial trigger points and passive accessory vertebral segments. These impairments are correlated with enhanced headache duration, headache-related disability, and signs of widespread pain sensitization. Reduction in active cervical movement and increased mechanical hyperalgesia of the cervical was consistent in ictal episodic migraine patients and the subgroups of episodic migraine patients with more pronounced widespread sensitization.