Reduced humoral immune response after BNT162b2 coronavirus disease 2019 messenger RNA vaccination in cancer patients under antineoplastic treatment.

BACKGROUND: Cancer patients are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment remain unclear. PATIENTS AND METHODS: In this interventional prospective multicohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Vaccine safety and efficacy (until 3 months post-booster) were assessed. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) antibody levels were followed over time (until 28 days after the booster) and in vitro SARS-CoV-2 50% neutralization titers (NT50) toward the wild-type Wuhan strain were analyzed 28 days after the booster. RESULTS: Local and systemic adverse events (AEs) were mostly mild to moderate (only 1%-3% of patients experienced severe AEs). Local, but not systemic, AEs occurred more frequently after the booster dose. Twenty-eight days after the booster vaccination of 197 cancer patients, RBD-binding antibody titers and NT50 were lower in the chemotherapy group {234.05 IU/ml [95% confidence interval (CI) 122.10-448.66] and 24.54 (95% CI 14.50-41.52), respectively} compared with healthy individuals [1844.93 IU/ml (95% CI 1383.57-2460.14) and 122.63 (95% CI 76.85-195.67), respectively], irrespective of timing of vaccination during chemotherapy cycles. Extremely low antibody responses were seen in hematology patients receiving rituximab; only two patients had RBD-binding antibody titers necessary for 50% protection against symptomatic SARS-CoV-2 infection (<200 IU/ml) and only one had NT50 above the limit of detection. During the study period, five cancer patients tested positive for SARS-CoV-2 infection, including a case of severe COVID-19 in a patient receiving rituximab, resulting in a 2-week hospital admission. CONCLUSION: The BNT162b2 vaccine is well-tolerated in cancer patients under active treatment. However, the antibody response of immunized cancer patients was delayed and diminished, mainly in patients receiving chemotherapy or rituximab, resulting in breakthrough infections.

Erdheim-Chester disease detected with 99mTc MDP bone SPECT/CT.

Erdheim-Chester disease (ECD) is a rare non-Langerhans' cell histiocytosis. Mild but permanent juxta-articular bone pain in mainly knees and ankles is the most frequent associated symptom. Despite the pathognomonic radiographic findings, most cases are still diagnosed by the pathologist.The lesions consist of lipid-storing CD 68 +/CD 1a--non-Langerhans' cell histiocytes, most frequently localized in bone but also involving multiple organ systems in the body. We present a case report in which the diagnosis of ECD was established with 99mTc MDP bone SPECT/CT.

Camurati-Engelmann disease: review of the clinical, radiological, and molecular data of 24 families and implications for diagnosis and treatment.

Camurati-Engelmann disease (CED) is a rare autosomal dominant type of bone dysplasia. This review is based on the unpublished and detailed clinical, radiological, and molecular findings in 14 CED families, comprising 41 patients, combined with data from 10 other previously reported CED families. For all 100 cases, molecular evidence for CED was available, as a mutation was detected in TGFB1, the gene encoding transforming growth factor (TGF) beta1. Pain in the extremities was the most common clinical symptom, present in 68% of the patients. A waddling gait (48%), easy fatigability (44%), and muscle weakness (39%) were other important features. Radiological symptoms were not fully penetrant, with 94% of the patients showing the typical long bone involvement. A large percentage of the patients also showed involvement of the skull (54%) and pelvis (63%). The review provides an overview of possible treatments, diagnostic guidelines, and considerations for prenatal testing. The detailed description of such a large set of CED patients will be of value in establishing the correct diagnosis, genetic counselling, and treatment.

Healthcare consumption and direct costs of rheumatoid arthritis in Belgium.

The aim of this study was to compare the socioeconomic consequences of early and late rheumatoid arthritis in Belgium and to assess the patient out-of-pocket contributions. This multicentre longitudinal study in Belgium evaluated patients with rheumatoid arthritis. Early disease was defined as diagnosis since less than 1 year. At baseline sociodemographic and disease characteristics were assessed and during the following year patients recorded all healthcare- and non-healthcare-related direct costs and out-of-pocket contributions. The study included 48 patients with early and 85 patients with late rheumatoid arthritis. Mean disease duration was 0.5 vs 12.5 years in patients with early and late rheumatoid arthritis, respectively. The disease activity score (DAS28) was comparable between both groups (4.1 vs 4.5, p = 0.14), but physical function (Health Assessment Questionnaire, HAQ) was more impaired in patients with long-standing disease (1.0 vs 1.7, p < 0.001). Work disability had increased from 2% in patients with early to 18% in patients with late disease. The annual societal direct costs per patient were 3055 Euros (median: 1518 Euros) opposed to 9946 Euros (median: 4017 Euros) for early and late rheumatoid arthritis, respectively. The higher direct cost for patients with long-standing disease was seen for all categories, but especially for physiotherapy and need for devices and adaptations. Patients with early as well as late disease contribute out of pocket about one-third to the direct healthcare costs. Within each group, HAQ was a strong determinant of costs. In Belgium, patients with long-standing rheumatoid arthritis are nine times more likely to be work disabled than patients with less than 1 year disease duration and have a threefold increase in costs. Differences in healthcare consumption between patients could be mainly explained by differences in physical function (HAQ).

Evaluation of the role of the SQSTM1 gene in sporadic Belgian patients with Paget's disease.

A positional cloning effort in French Canadian families with Paget's disease of bone (PDB) resulted in the identification of a mutation in the sequestosome1 (SQSTM1) gene in a subset of both familial and sporadic PDB cases. This was confirmed in samples of mainly United Kingdom (UK) origin. In this study, we performed both mutation analysis and association studies in order to evaluate the role of this gene in a collection of isolated Belgian PDB patients. A mutation in the SQSTM1 gene was found in only 6 of 111 patients (5.4%). In all cases it involves the P392L mutation, previously shown to be common in both familial and sporadic cases. To perform association studies, we selected 8 single nucleotide polymorphisms (SNPs) and looked for linkage disequilibrium (LD) between these. Haplotype analysis indicated that typing of 3 Tag SNPs (IVS1 + 633A/C, IVS5 - 23A/G, and 976A/G) enables us to identify the most common haplotypes. Association studies for the 3 selected SNPs, based on 105 PDB cases without a SQSTM1 mutation and 159 control individuals, did not support a possible influence of natural variants in the SQSTM1 gene either on the pathogenesis of PDB or on the disease severity. In conclusion, our study confirms that the P392L mutation is a recurrent mutation causing PDB in different populations. We were not able to show an association between SQSTM1 polymorphisms and PDB in our population but this clearly needs to be extended to other populations. The presented identification of haplotype Tag SNPs will be of major help for such studies.

Reproducibility and reliability of measurements using a linear isokinetic dynamometer, Aristokin.

BACKGROUND: This study was performed to investigate the intra-observer reproducibility and reliability of measurements using a linear isokinetic dynamometer (Aristokin). METHODS: Sixteen female volunteers (age 18 to 23 years) participated in 4 test sessions, each consisting of 6 warming-up movements followed by 6 repetitions of 4 different movements. During each session, the subjects consecutively performed lifting movements by flexing elbows and shoulders (at 65 cm per sec), total lifting movements with arms and legs (at 65 cm per sec), and extension movements of the legs in sitting position (at 40 and 60 cm per sec). The first 3 test sessions were performed at a weekly interval, the 4th was executed 4 weeks after the 3rd session. Force, power and explosivity (force developed per sec) were recorded. RESULTS: The intra-observer reproducibility was investigated of the 6 repetitions of the movements during each test session. The highest reproducibility for mean peak power and force was found in the combination of the 3rd, 4th, 5th and 6th measurement (intraclass correlation coefficient 0.85 to 0.99). Using this combination, the intra-observer reliability was investigated, defined as the consistency of results obtained during the 4 test sessions, performed at a weekly or longer interval. Comparison between these sessions showed that the results for mean force in the arm movement differed significantly (p=0.01) although a high between sessions correlation was found (0.96). Results for mean force and power for the 3 other movements were reliable, and no significant learning effect was observed. Lower reliability and reproducibility were observed for other parameters including explosivity and power and force at the first 0.25 sec of the test movement. CONCLUSIONS: Even after standard warming-up movements, the first 2 out of 6 measurement repetitions during a test session are not reproducible and should not be used in calculations of the results. For the combination of the 3rd to 6th repetitions, a high reliability was found for the measurement of mean force and power of the total lifting movement and of the sitting leg extension movements repeated in 4 sessions over a period of 6 weeks.

Evaluation of the role of RANK and OPG genes in Paget's disease of bone.

Paget's disease of bone (PDB) is one of the most common bone disorders in the western world. PDB is characterized by focal areas of increased osteoclastic bone resorption and bone formation, which leads to the formation of poorly structured bone. These abnormalities of bone turnover and structure predispose affected individuals to various complications including bone pain, deformity, pathological fracture, and an increased risk of osteosarcoma. One of the main mechanisms of osteoclast formation and activation involves the receptor activator of nuclear factor -kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway, where binding of RANKL to RANK results in the differentiation of osteoclast precursors. OPG, on the other hand, acts as an inhibitor of osteoclastogenesis by serving as a decoy receptor for RANKL. Recently, mutations in the RANK gene have been shown to cause familial expansile osteolysis, a rare bone disorder showing great similarity to PDB. We performed mutation analysis in the RANK and OPG genes in 28 PDB patients to investigate whether mutations in these genes could be responsible for PDB. Our data suggest that RANK is not directly involved in PDB in our set of patients, as no mutations in the RANK coding region could be identified and allele frequencies of RANK polymorphisms did not differ in PDB patients as compared with the random population. Also, in the OPG gene, we could not detect PDB-causing mutations. However, of the several polymorphisms identified, one (400 + 4 C/T in intron 2), showed a statistically significant increased frequency for the C allele in PDB patients, suggesting that individuals harboring this allele may be more susceptible for developing PDB.

Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease.

Camurati-Engelmann disease (CED; MIM 131300), or progressive diaphyseal dysplasia, is a rare, sclerosing bone dysplasia inherited in an autosomal dominant manner. Recently, the gene causing CED has been assigned to the chromosomal region 19q13 (refs 1-3). Because this region contains the gene encoding transforming growth factor-beta 1 (TGFB1), an important mediator of bone remodelling, we evaluated TGFB1 as a candidate gene for causing CED.

Adding compression to mobilization in a rehabilitation program after knee surgery. A preliminary clinical observational study.

The cyclical loading of cartilage, which occurs during normal use of an articulation, stimulates biosynthetic activity of the chondrocytes. Therefore functional stimulation may contribute to joint repair. In this study the researchers added mobilization with compression to a standardized rehabilitation program in patients recovering from intra-articular reconstructive surgery of the anterior cruciate ligament. Thirty patients were treated with a standardized physical therapy program following surgery. For half of the patients, mobilization under compression was added to this rehabilitation program. The knee flexion range of motion (FROM) was measured using a goniometer. Patients who received mobilizations with compression reached a pre-set goal of 130 degrees FROM after a mean of six treatment sessions, compared to 11 sessions in the control group. This rapid progression was characterized by a significantly greater increase of FROM during the first two treatment sessions. The explanation for this observed effect may lie in fast response processes which could include rheological changes in synovial fluid, enhanced exchange between synovial fluid and cartilage matrix or increased synovial turnover rather than complex metabolic phenomena. The faster recovery of the pre-set goal (130 degrees of FROM) in the group receiving mobilizations with compression, would appear to justify future clinical trials investigating the potential benefits of adding these techniques to current rehabilitation programs.

Localisation of the gene causing diaphyseal dysplasia Camurati-Engelmann to chromosome 19q13.

Camurati-Engelmann disease, progressive diaphyseal dysplasia, or diaphyseal dysplasia Camurati-Engelmann is a rare, autosomal dominantly inherited bone disease, characterised by progressive cortical expansion and sclerosis mainly affecting the diaphyses of the long bones associated with cranial hyperostosis. The main clinical features are severe pain in the legs, muscular weakness, and a waddling gait. The underlying cause of this condition remains unknown. In order to localise the disease causing gene, we performed a linkage study in a large Jewish-Iraqi family with 18 affected subjects in four generations. A genome wide search with highly polymorphic markers showed linkage with several markers at chromosome 19q13. A maximum lod score of 4.9 (theta=0) was obtained with markers D19S425 (58.7 cM, 19q13.1) and D19S900 (67.1 cM, 19q13. 2). The disease causing gene is located in a candidate region of approximately 32 cM, flanked by markers D19S868 (55.9 cM, 19q13.1) and D19S571 (87.7 cM, 19q13.4).

Soluble HLA-DR antigen levels in serum correlate with rheumatoid arthritis disease activity and the presence of disease-associated epitopes.

We investigated correlations between soluble HLA-DR (sHLA-DR) molecules and several clinical, biological and genetic parameters associated with rheumatoid arthritis (RA) disease activity. Serum sHLA-DR concentrations were determined in 146 samples from 89 RA patients by an ELISA format, using an antibody combination of mouse and rat monoclonal anti-human HLA-DR antibodies. The mean sHLA-DR serum level in RA patients was significantly increased with 277+/-19 ng/ml compared to 142+/-13 ng/ml of 80 healthy controls (P<0.001). In ascending order of significance, correlations were found between serum sHLA-DR and EULAR swelling and pain scores, Waaler-Rose, RA factor, ESR and CRP (P=0.025 to P<0.001). High sHLA-DR levels were defined above 374 ng/ml that was the 95% confidence interval of the controls. Thirty-seven blood samples (25%) in 31 RA patients were above this level. The EULAR pain and swelling scores, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and RA factor were higher (P=0.044 to P<0.001) at the moment of high sHLA-DR concentrations, compared to the lower concentrations. Higher disease activity was further found in groups of RA patients respectively heterozygous or homozygous for the disease-associated epitope (Q)R/KRAA within the HLA-DRB1 chain, compared to the group without this epitope (P<0.017 for part of the results). Likewise, sHLA-DR was respectively 169+/-17 (no disease associated epitope), 324+/-34 (heterozygous) and 442+/-69 ng/ml (homozygous for the disease-associated epitope on HLA-DRB1 alleles) (P<0.017). In conclusion, this study shows significant correlations between serum sHLA-DR levels and RA disease activity parameters, as well as increased sHLA-DR in patients with disease-associated epitope on HLA-DRB1 alleles.

Pain threshold in patients with rheumatoid arthritis and effect of manual oscillations.

Using a pressure algometer pain threshold (PT) measurements were carried out in the paraspinal area as well as at the knee and ankle joints in 30 adults with active rheumatoid arthritis (RA) and in 30 healthy adults. The group of RA patients was then randomly divided in two. In 15 RA patients a manual oscillation technique was applied at T12 and L4 for 12 minutes. The 15 other patients were resting. Immediately after the experimental procedure the PT was measured again at the same points in all patients. The RA patients showed a significantly (p < 0.05) lower PT than the healthy adults at all investigated points, which suggests that in RA certain changes arise in the peripheral and central nociceptive processing system, as mentioned in the literature. In the second measurement session for the RA patients the PT was significantly higher (p<0.05) after manual oscillations than after rest, at the paraspinal area of T6, L1 and L3. Further research into the long-term effect of repeated manual oscillation sessions is warranted.

Calcitonin reserve in different stages of atrophic autoimmune thyroiditis.

The objective of this study was to determine the calcitonin (CT) hormone reserve in different severity of atrophic autoimmune thyroiditis (AAT). Forty-eight female patients with AAT were divided into four groups based on basal and peak thyrotropin (TSH) values (after oral thyrotropin-releasing hormone [TRH], free triiodothyronine (FT3) and free thyroxine (FT4) ranging from normal in group 1 to overt hypothyroidism in group 4. All had thyroid antibodies. The control group comprised euthyroid females of comparable age, without thyroid antibodies. Basal CT and CT response to calcium infusion (area under the curve) were investigated as parameters of CT reserve. Basal CT was lower in groups 2 to 4 of patients with AAT (compared to controls), but the difference was not significant. Stimulated CT levels were lower (p < 0.05) in all groups of patients compared to controls, with markedly reduced CT-secretory reserve in group 4. Thyroid antibody concentrations and, basal and postinfusion calcium levels were not significantly different among the various groups. In conclusion CT deficiency (especially stimulated values) occurs in AAT and is more severe in hypothyroid patients than in earlier stages of AAT.

Progressive diaphyseal dysplasia (Camurati-Engelmann's disease). Improvement of clinical signs and of bone scintigraphy during pregnancy.

The case of a woman suffering from progressive diaphyseal dysplasia is presented. Characteristic symptoms of crippling pain in both legs, severe aching in both forearms, and episodic temporofrontal and occipital headache were only partially regulated by corticosteroid treatment. However, pregnancy resulted in a progressive disappearance of these symptoms, allowing withdrawal of steroid treatment. Tc-99m MDP scintigraphy performed immediately after delivery showed a decrease of the intense uptake in the forearms, tibiae, and skull, which had been documented prior to pregnancy. However, widespread pain recurred within 6 weeks after delivery, accompanied by a recurrence of multiple severely hyperactive foci on bone scintigraphy. Alterations of immune modulated processes and changes in bone mineral homeostasis and in endogenous cortisol metabolism during pregnancy can be considered as possible explanations for the temporary improvement in clinical and scintigraphic signs of progressive diaphyseal dysplasia in this patient.

False positive ELISA serologic test for Lyme borreliosis in patients with connective tissue diseases.

Three patients are reported with false positive enzyme-linked immunosorbent assay (ELISA) for IgG antibodies against Borrelia burgdorferi, respectively associated with undifferentiated connective tissue disease or systemic lupus erythematosus. These cases further document that Lyme serology should be interpreted with caution and within the clinical context.

Femoral periosteal thickening in pustulotic arthroosteitis, including 3-year followup by magnetic resonance imaging.

We describe 2 female patients with femoral periosteal thickening, in association with signs of pustulotic arthroosteitis in the sternocostoclavicular region and spine. In one patient, inflammatory changes were seen in muscular tissue surrounding this area of periosteal thickening, with fibrosis in the corresponding marrow. Over a period of up to 4 years after bone biopsy, cortical hyperostosis was observed spreading over a longer segment of her femoral diaphysis, while its thickness decreased over the longterm. Bone biopsy probably contributed to the striking periosteal thickening surrounded by inflammatory lesions in the surrounding muscles of this patients.