A deep look into the storm: Israeli multi-center experience of coronavirus disease 2019 (COVID-19) in patients with autoimmune inflammatory rheumatic diseases before and after vaccinations.

Objective: We aimed to characterize the course of COVID-19 in autoimmune inflammatory rheumatic disease (AIIRD) patients in Israel, taking into consideration several remarkable aspects, including the outcomes of the different outbreaks, the effect of vaccination campaigns, and AIIRD activity post-recovery. Methods: We established a national registry of AIIRD patients diagnosed with COVID-19, including demographic data, AIIRD diagnosis, duration and systemic involvement, comorbidities, date of COVID-19 diagnosis, clinical course, and dates of vaccinations. COVID-19 was diagnosed by a positive SARS-CoV-2 polymerase chain reaction. Results: Israel experienced 4 outbreaks of COVID-19 until 30.11.2021. The first three outbreaks (1.3.2020 - 30.4.2021) comprised 298 AIIRD patients. 64.9% had a mild disease and 24.2% had a severe course; 161 (53.3%) patients were hospitalized, 27 (8.9%) died. The 4th outbreak (delta variant), starting 6 months after the beginning of the vaccination campaign comprised 110 patients. Despite similar demographic and clinical characteristics, a smaller proportion of AIIRD patients had negative outcomes as compared to the first 3 outbreaks, with regards to severity (16 patients,14.5%), hospitalization (29 patients, 26.4%) and death (7 patients, 6.4%). COVID-19 did not seem to influence the AIIRD activity 1-3 months post-recovery. Conclusions: COVID-19 is more severe and has an increased mortality in active AIIRD patients with systemic involvement, older age and comorbidities. Vaccination with 3 doses of the mRNA vaccine against SARS-CoV-2 protected from severe COVID-19, hospitalization and death during the 4th outbreak. The pattern of spread of COVID-19 in AIIRD patients was similar to the general population.

Switching from intravenous tocilizumab to subcutaneous administration during COVID-19 pandemic: impact on treatment efficacy and patient satisfaction.

OBJECTIVES: We aimed to assess the efficacy and patient satisfaction of subcutaneous tocilizumab (SC TCZ) in patients previously treated with intravenous tocilizumab (IV TCZ) during the COVID-19 pandemic. METHODS: We conducted a single-centre retrospective study at the Rheumatology Day Care at the Rheumatology Institute, Rambam Health Care Campus, Israel. Clinical and laboratory data of IV TCZ treated patients who switched to SC TCZ were retracted and analysed. Data were collected from the last two visits before switching to SC treatment and two visits afterwards. A telephone call conversation was conducted for all patients who continued SC treatment and did not come to follow-up visits. RESULTS: Forty patients (age 53.03 (± 15.7)) treated with IV TCZ were switched to SC TCZ in April-May 2020. Three patients were excluded from the study. Most of the patients were treated with TCZ for 6.35 (±2.89) years and had low disease activity. 26/37 (70%) patients discontinued SC TCZ therapy and switched back to IV TCZ. The majority of discontinuations were due to flare up of the underlying disease reflected by increased number of tender and/or swollen joints, prolongation of morning stiffness or increased pain VAS score. Two patients were hospitalised for IV glucocorticoids and 1 patient underwent knee arthrocentesis. 11/37 (30%) patients continued SC TCZ treatment. 3/11 (27%) expressed less satisfaction with SC TCZ therapy. CONCLUSIONS: More than half of the patients who switched from IV TCZ to SC TCZ showed signs of flare of their underlying disease or were less satisfied with SC treatment.

Hypocomplementemia during tocilizumab treatment: Long-term follow-up results.

ABSTRACT: Hypocomplementemia has been reported in patients with rheumatoid arthritis treated with tocilizumab (TCZ), but its long-term consequences are unknown. We assessed the long-term outcome of patients treated with TCZ who developed hypocomplementemia regarding serious bacterial infections or autoimmune diseases (AID).The charts of patients treated with TCZ at two rheumatology centers were reviewed retrospectively. Data regarding patients' age, gender, disease duration, autoantibodies status, previous or concomitant treatments, blood counts, liver enzymes, C3 and C4 levels at baseline and during TCZ treatment, episodes of infections, allergic reactions, and AID were analyzed. Univariate analysis was used to compare patients with low C3, C4 levels versus patients with normal C3, C4 levels. Variables that were statistically significant associated or tended to be associated with low C3 or C4 were included in multiple variable logistic regression.Of 132 patients treated with TCZ, 108 had serial measurements of serum complement concentration. Thirty-three (30%) patients developed low C4 levels and 23 (21%) had also low C3. Mean TCZ treatment period was 4.9 years (range, 1-14 years). All patients had normal complement levels at baseline. Leukopenia occurred in 18 (16.7%) patients, 14 of whom (77%) had low complement. Persistent leukopenia was observed in 8% and 5.3% of patients with normal C3 and C4 levels, respectively, as opposed to 47% and 42% of patients with low C3 or low C4, respectively. Low C3, C4 levels correlated with prolonged TCZ treatment retention time and effectiveness. There were no serious bacterial infections or new onset AID.Hypocomplementemia during TCZ treatment was accompanied by leukopenia that correlated with treatment duration. Hypocomplementemia was not associated with serious bacterial infections or new onset AID. Decreased complement levels were associated with treatment longevity. The role of monitoring complement level in predicting treatment response or assessing disease activity deserves further investigation.

Disease activity and humoral response in patients with inflammatory rheumatic diseases after two doses of the Pfizer mRNA vaccine against SARS-CoV-2.

BACKGROUND: The registration trials of messenger RNA (mRNA) vaccines against SARS-CoV-2 did not address patients with inflammatory rheumatic diseases (IRD). OBJECTIVE: To assess the humoral response after two doses of mRNA vaccine against SARS-CoV-2, in patients with IRD treated with immunomodulating drugs and the impact on IRD activity. METHODS: Consecutive patients treated at the rheumatology institute, who received their first SARS-CoV-2 (Pfizer) vaccine, were recruited to the study, at their routine visit. They were reassessed 4-6 weeks after receiving the second dose of vaccine, and blood samples were obtained for serology. IRD activity assessment and the vaccine side effects were documented during both visits. IgG antibodies (Abs) against SARS-CoV-2 were detected using the SARS-CoV-2 IgG II Quant (Abbott) assay. RESULTS: Two hundred and sixty-four patients with stable disease, (mean(SD) age 57.6 (13.18) years, disease duration 11.06 (7.42) years), were recruited. The immunomodulatory therapy was not modified before or after the vaccination. After the second vaccination, 227 patients (86%) mounted IgG Ab against SARS-CoV-2 (mean (SD) 5830.8 (8937) AU/mL) and 37 patients (14%) did not, 22/37 were treated with B cell-depleting agents. The reported side effects of the vaccine were minor. The rheumatic disease remained stable in all patients. CONCLUSIONS: The vast majority of patients with IRD developed a significant humoral response following the administration of the second dose of the Pfizer mRNA vaccine against SARS-CoV-2 virus. Only minor side effects were reported and no apparent impact on IRD activity was noted.

Longitudinally Extensive Transverse Myelitis in a Lupus-Neuromyelitis Optica Overlap.

Transverse myelitis is an inflammatory lesion of the spinal cord, occurring in different autoimmune, infectious, and traumatic diseases but is the hallmark of neuromyelitis optica (NMO), a rare neurologic autoimmune disease. Patients with systemic lupus erythematosus (SLE) may develop transverse myelitis as a neuropsychiatric complication of active disease; however, at times, NMO co-exists as an additional primary autoimmune condition in a SLE patient. Correct diagnosis of a SLE-NMO overlap is important not only for the different disease course and prognosis compared with SLE-related LETM, but especially for the emerging and highly specific NMO treatment options, not established for SLE-related LETM-such as anti-aquaporin 4 antibodies, anti-VEGF antibodies, complement modulation, or IVIg.

The Effects of Adalimumab in Behçet Disease Patients on Clinical Manifestations and on Pro-Inflammatory Cytokines Milieu: Long-Term Follow-Up.

BACKGROUND: Behçet's disease is a multi-systemic chronic relapsing inflammatory disease, classified among the vasculitides. The heterogeneity of clinical manifestations challenges the disease management. OBJECTIVES: To assess efficacy and safety of adalimumab in patients with active persistent Behçet's arthritis who did not respond to disease-modifying anti-rheumatic drugs and to assess the impact of treatment on the cytokine milieu. METHODS: Our cohort comprised 10 patients with active arthritis who received adalimumab in a 24-week investigator-initiated prospective open-label study. Patients who relapsed within 12 weeks following adalimumab discontinuation could enter a 3-year extension study. The patients underwent a comprehensive assessment including questionnaires and measurement of inflammatory cytokines, adalimumab serum levels, and anti-drug antibodies. RESULTS: A significant improvement was observed in arthritis, disease activity visual analogue scales, Behçet's disease current activity form, and interleukin-6 (IL-6) levels, but not in health assessment questionnaire and functional assessment of chronic illness therapy fatigue scale questionnaire. Resolution of oral and urogenital ulcers was achieved in all patients. Significant reduction of pain was reported by 40% of patients. The disease relapsed in 9 of 10 patients, within 2-6 weeks following adalimumab discontinuation. Of the 7 patients who continued the study, arthritis was resolved in 5. Two patients with high neutralizing antidrug antibodies titer relapsed. CONCLUSIONS: Adalimumab treatment achieved a significant improvement in arthritis, mucocutaneous manifestations, and IL-6 levels in all study patients but only 40% reported significant pain reduction. The arthritis relapsed in 90% of patients following adalimumab discontinuation and long-term treatment was required.

Digital ulcer debridement in systemic sclerosis: a systematic literature review.

Optimal wound care is an essential component in the management of systemic sclerosis (SSc) digital ulcers (DUs). DU debridement has been suggested to reduce ulcer-related pain and improve tissue healing. However, only a minority of rheumatologists perform DU debridement, and there is no standard of care/protocol. Our objectives were to (i) evaluate the current evidence for the use of debridement in DU management and (ii) assess whether there are any specific protocols. A systematic literature review was performed searching the PubMed database (between 01/01/1950-01/03/2019) in accordance with PRISMA guidelines. Two independent reviewers screened and extracted the abstracts/full manuscripts. Articles in English, which focussed on SSc-DU debridement/curettage, were included. Exclusion criteria included studies of juvenile/paediatric patients and basic/non-clinical research. Our search identified 1497 studies of which 4 studies were included in our final analysis. Three studies used scalpel debridement, and one study used this in combination with autolytic debridement. No studies specifically reported the effect on DU healing from debridement. Autolytic debridement with hyaluronate-based products was associated with significant ulcer pain and inflammation. Local anaesthetic significantly reduces pain both during and after debridement. Combined local and oral analgesia is often required for more severe or infected DUs. DU (scalpel and autolytic) debridement is being used by some clinicians in rheumatology; however, there are no standardised protocols. To improve wound care for SSc-DUs, future research should focus on developing a standardised protocol for SSc-DU debridement, with a view to facilitate randomised controlled trials to demonstrate safety and treatment efficacy.Key Points• Optimal wound care is an essential component in the management of systemic sclerosis-digital ulcers.• 'Sharp' debridement uses a scalpel, whereas 'autolytic' debridement uses dressings to optimize endogenous tissue lysis.• There is significant variation in the use of digital ulcer debridement in systemic sclerosis.• A standardized protocol and randomized controlled trials are needed to demonstrate debridement the safety and efficacy of digital ulcer debridement in systemic sclerosis.

[ADHD IN THE AGING POPULATION: A NEW DIFFERENTIAL DIAGNOSIS?]

INTRODUCTION: During midlife and aging, subjective reports regarding cognitive decline increase in frequency. Age-associated cognitive impairment, mild cognitive impairment and dementia, increase in prevalence and are frequently diagnosed. Background medical conditions and risk factors are often regarded as contributing to the cognitive decline. The contribution of prior undiagnosed ADHD (Attention Deficit Hyperactive Disorder) is seldom considered. The aim of the current study was to examine whether childhood or adult ADHD should be considered relevant in the differential diagnosis of cognitive complaints during midlife and aging. METHODS: Thirty-six subjects, aged 50-70 years, diagnosed with probable ADHD (pADHD) and 29 controls participated in the present study. The pADHD group included 12 individuals self-referred due to self-complaints regarding cognitive decline or memory impairment, previously undiagnosed with ADHD (ADHD-A) but with lifelong symptomatology of ADHD and fulfilling ADHD criteria and 24 individuals, parents of diagnosed ADHD children and reporting ADHD symptoms (ADHD-B) , without complaints regarding recent cognitive decline. The neuropsychological evaluation included the Conners' Adult ADHD Rating Scale-SL, Beck Depression Inventory, and the following cognitive tests: logical memory subscale (LM- WMS), California Verbal study was conducted at the Cognitive Neurology Clinic - Rambam Health Care Campus and was granted the approval of the local IRB committee. RESULTS: ADHD-A were impaired on attention parameters while memory and executive functions were intact. ADHD-B did not present measurable attention or other neuropsychological deficits as compared to the control group. Neither group fulfilled criteria for MCI or dementia. CONCLUSIONS: ADHD should be considered as a new/additional entity in the differential diagnosis of subjective cognitive complaints among middle-aged and older persons. The recognition of the specific cognitive and behavioral profiles of ADHD should contribute to the ability to reach optimal differentiation from pre-dementia conditions in order to tailor appropriate therapies. The pathophysiology and future trajectory of the emerging ADHD symptomatology in older patients fulfilling lifelong ADHD symptomatology remains to be clarified. When examining older adults, ADHD should be considered as a differential diagnosis.

Idiopathic pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension: can we be certain?

Idiopathic pulmonary arterial hypertension (IPAH) is an isolated small-vessel disease comprising vasoconstriction, remodeling and thrombosis of small pulmonary arteries. However, there is evidence that IPAH does not respect anatomic boundaries and might extend into large vessels such as large central thrombi. On the other hand, chronic thromboembolic pulmonary hypertension (CTEPH) represents a distinct category of pulmonary hypertension as it is thought to be due to an occlusion of the major pulmonary arteries following a thromboembolic event. However, it is currently evident that in most patients there is a concomitant small-vessel disease. The involvement of both small and large vessels in both IPAH and CTEPH, together with a high incidence of silent thromboembolic events, might create difficulties in identifying the true cause of pulmonary hypertension. An accurate diagnosis of the cause determines the management and prognosis. Patients with CTEPH can potentially be offered curative surgery in the form of pulmonary endarterectomy; however, oxygen, vasodilators, anticoagulation, and lung transplantation are more feasible options for IPAH.

Role of multisection CT angiography in the evaluation of vertebrobasilar vasospasm in patients with subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Optimal means for assessing cerebral vasospasm, mainly at the vertebrobasilar system, have not been established. The purpose of this study was to evaluate the role of multisection CT angiography (MCTA) in the detection and quantification of vertebrobasilar vasospasm (VBS) indicated on transcranial Doppler (TCD) imaging in patients with subarachnoid hemorrhage (SAH). METHODS: Forty-three MCTA studies of the vertebrobasilar arteries were performed with a multisection spiral CT scanner in 36 patients with SAH. Parameters used were 1-mm collimation, 0.625Q pitch, 120 kV, and 250 mAs. Contrast material was injected (80-100 mL, 3 mL/s) after a 15-20-second delay. Postprocessing of the vertebrobasilar system was performed by using maximum intensity projection and volume-rendering reconstruction. Vessel diameter was measured at different intracranial locations along the vertebral and basilar arteries perpendicular to their long axis by using curved reformatted multiplanar reformation. TCD imaging of the posterior circulation was performed within 24 hours. RESULTS: MCTA demonstrated narrowed arteries compatible with VBS in 13 patients, consistent with TCD findings. Despite TCD recordings of high flow velocity in three other patients, MCTA did not reveal vasospasm but did show wide arteries feeding arteriovenous malformations in two and normal-sized arteries in one. VBS in two patients was identified on MCTA but overlooked during TCD imaging. Twenty patients had normal findings on both TCD and MCTA studies. CONCLUSION: Cerebral MCTA is recommended as a reliable, rapid, and minimally invasive diagnostic method, one complementary to TCD imaging for assessing VBS in patients with SAH.

Basilar vasospasm diagnosis: investigation of a modified "Lindegaard Index" based on imaging studies and blood velocity measurements of the basilar artery.

BACKGROUND AND PURPOSE: Numerous studies have shown that cerebral vasospasm is one of the leading causes of death and neurological disability after subarachnoid hemorrhage. Most of these studies, however, have focused on anterior circulation vessels. Since the introduction of the transcranial Doppler (TCD), increasing attention has been given to basilar artery (BA) vasospasm, especially in traumatic subarachnoid hemorrhage. As shown for the anterior circulation, however, the significance of elevated flow velocities (FVs) in the posterior vessels may be ambiguous, so vasospasm may not be reliably differentiated from hyperemia. The purpose of the present study was to evaluate the potential additional value of an intracranial/extracranial FV ratio in the posterior circulation to cope with this shortcoming of the TCD in the diagnosis of BA vasospasm. METHODS: FV in the extracranial vertebral artery (VA) was measured in 20 healthy volunteers. Normative values of an intracranial/extracranial VA FV ratio (IVA/EVA) and a BA/extracranial VA FV ratio (BA/EVA) were calculated. Thirty-four patients with subarachnoid hemorrhage were then evaluated with TCD and CT angiography (CTA). The value of the IVA/EVA and BA/EVA ratios in the diagnosis and assessment of vertebrobasilar vasospasm was investigated. RESULTS: The extracranial VA could be insonated in all subjects at depths ranging from 45 to 55 mm. The average FV for the extracranial VA was 26 cm/s. The ratios between intracranial and extracranial VA FVs were 1.6 on both sides, whereas the ratio between the BA FVs and the mean extracranial VA FVs was slightly higher at 1.7. Fourteen patients (41.2%) had CTA evidence of BA vasospasm. Vasospasm was severe in 7 patients, moderate in 1, and mild in the remaining. An FV threshold of 80 cm/s was indicative of BA vasospasm in 92.8% with 3 false-positive results that could be related to vertebrobasilar hyperemia. Comparative analysis between CTA and TCD findings showed that BA/EVA was >2 in all patients with BA vasospasm (100% sensitivity) and < 2 in all but 1 patient without BA vasospasm (95% specificity). Furthermore, the BA/EVA ratio showed a close correlation with BA diameter (r=-0.8139, P<0.0001) and was >3 in all patients with severe vasospasm. CONCLUSIONS: The results of the present study showed that the BA/EVA ratio may contribute to an improved discrimination between BA vasospasm and vertebrobasilar hyperemia and enhance the accuracy and reliability of TCD in the diagnosis of BA vasospasm. Our data further suggest that the BA/EVA ratio may provide an approximation of vasospasm severity and help in identifying patients who are likely to suffer from hemodynamically significant vasospasm.