Osteopetrosis and related osteoclast disorders in adults: A review and knowledge gaps On behalf of the European calcified tissue society and ERN BOND.

Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.

Impact on patient outcomes of spondyloarthritis-inflammatory bowel disease multi-disciplinary meetings.

OBJECTIVES: To assess the impact on patient outcomes of the spondyloarthritis (SpA) and inflammatory bowel disease (IBD) multidisciplinary team (MDT) meetings in a large university hospital. METHODS: A single-centre retrospective observational case-note review was conducted assessing the outcome of all 226 cases discussed at the SpA-IBD MDT meetings in a large UK university hospital between 2017-2022. RESULTS: A total of 226 patients were discussed. It was deemed that 97% of MDT meetings helped to improve communication between teams, and 100% were educational. A total of 57% of discussions led to an instant change of disease management, while 40% of discussions resulted in a treatment plan that avoided the use of dual advanced therapy. This improved patient safety by reducing immunosuppression. The MDT meetings were highly cost and time efficient; 125 referrals between specialists were avoided, and in 51 cases there was a significant chance of reducing future drug costs. A timely investigation or appointment was arranged following 50% of MDT discussions, helping to clarify the diagnosis and optimise patient care. 9% of meetings enabled drugs to be prescribed to patients that are not yet licenced for the other speciality, thereby improving treatment options available in the management of complex cases. CONCLUSION: The MDT meetings have been beneficial for patients, the clinical team and the institution. This approach might be considered by other rheumatology and gastroenterology departments.

Challenges in the management of tumor-induced osteomalacia (TIO).

Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare acquired paraneoplastic disease, which is challenging to diagnose and treat. TIO is characterized by hypophosphatemia resulting from excess levels of tumor-secreted fibroblast growth factor 23 (FGF23), one of the key physiological regulators of phosphate metabolism. Elevated FGF23 results in renal phosphate wasting and compromised vitamin D activation, ultimately resulting in osteomalacia. Patients typically present with progressive and non-specific symptoms, including bone pain, multiple pathological fractures, and progressive muscle weakness. Diagnosis is often delayed or missed due to the non-specific nature of complaints and lack of disease awareness. Additionally, the disease-causing tumour is often difficult to detect and localize because they are often small, lack localizing symptoms and signs, and dwell in widely variable anatomical locations. Measuring serum/urine phosphate should be an inherent diagnostic component when assessing otherwise unexplained osteomalacia, fractures and weakness. In cases of hypophosphatemia with inappropriate (sustained) phosphaturia and inappropriately normal or frankly low 1,25-dihydroxy vitamin D, differentiation of the potential causes of renal phosphate wasting should include measurement of FGF23, and TIO should be considered. While patients experience severe disability without treatment, complete excision of the tumour is typically curative and results in a dramatic reversal of symptoms. Two additional key current unmet needs in optimizing TIO management are: (1 and 2) the considerable delay in diagnosis and consequent delay between the onset of symptoms and surgical resection; and (2) alternative management. These may be addressed by raising awareness of TIO, and taking into consideration the accessibility and variability of different healthcare infrastructures. By recognizing the challenges associated with the diagnosis and treatment of TIO and by applying a stepwise approach with clear clinical practice guidelines, patient care and outcomes will be improved in the future.

A comparison of clinical examination and ultrasound enthesitis indices in patients with psoriatic arthritis, adjusted for concomitant fibromyalgia.

OBJECTIVES: To: (a) determine the extent of ultrasound (US)-detected peripheral enthesitis in a cohort of patients with psoriatic arthritis (PsA); (b) compare this with three clinical examination (CE) enthesitis indices; and (c) determine the effect of concurrent fibromyalgia on the evaluation of enthesitis. METHODS: A prospective single-centre cross-sectional study of consecutive outpatients with established PsA undergoing clinical examination for enthesitis and US examination for inflammatory and structural lesions of enthesitis. Multivariable analyses tested for association between US scores, CE enthesitis indices and influence of concurrent fibromyalgia. RESULTS: A total of 106 patients were assessed. Of these, 91/106 (85.8%) had CE enthesitis and 105/106 (99.1%) had ⩾1 US feature of enthesitis. There was a moderate correlation between US entheseal inflammation and both the Leeds Enthesitis Index (LEI) (Spearman rank, r = 0.36) and Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC) (r = 0.44). US entheseal damage did not correlate with CE enthesitis indices. Twenty-eight (26.4%) patients were classified as having concurrent fibromyalgia, in whom multivariable regression analyses demonstrated no correlation between US scores and CE enthesitis indices. PsA patients without fibromyalgia demonstrated a statistically significant association between both LEI (r = 0.48, p < 0.0001) and SPARCC (r = 0.62, p < 0.0001) and US entheseal inflammation. CONCLUSION: There is a moderate association between US entheseal inflammation, but not damage, and CE enthesitis indices in patients with PsA. The presence of concurrent fibromyalgia is linked with higher CE enthesitis scores, without an increase in US inflammation, suggesting that CE enthesitis indices should be used/interpreted with caution in these patients. Imaging, including US, should be the preferred modality to detect enthesitis in PsA patients with concurrent fibromyalgia.

Loss and gain of bone in spondyloarthritis: what drives these opposing clinical features?

The breadth of bone lesion types seen in spondyloarthritis is unprecedented in medicine and includes increased bone turnover, bone loss and fragility, osteitis, osteolysis and erosion, osteosclerosis, osteoproliferation of soft tissues adjacent to bone and spinal skeletal structure weakness. Remarkably, these effects can be present simultaneously in the same patient. The search for a potential unifying cause of effects on the skeleton necessarily focuses on inflammation arising from the dysregulation of immune response to microorganisms, particularly dysregulation of TH17 lymphocytes, and the dysbiosis of established gut and other microbiota. The compelling notion that a common antecedent pathological mechanism affects existing bone and tissues with bone-forming potential (entheses), simultaneously with variable effect in the former but bone-forming in the latter, drives basic research forward and focuses our awareness on the effects on these bone mechanisms of the increasing portfolio of targeted immunotherapies used in the clinic.

Long-term effectiveness of tumour necrosis factor-α inhibitor treatment for psoriatic arthritis in the UK: a multicentre retrospective study.

OBJECTIVE: Real-world evidence of the long-term effectiveness of TNF-α inhibitor (TNFi) therapy in patients with PsA is limited. This study was conducted to describe patterns of TNFi therapy and treatment responses in patients with PsA treated in UK clinical practice. METHODS: A multicentre, retrospective, observational cohort study of consenting patients treated with TNFi for PsA with ≥3 years follow-up from first TNFi initiation (observation period) was carried out in 11 UK National Health Service hospitals. Data were collected concerning baseline patient characteristics, PsA-related treatment pathways and TNFi treatment responses (PsA response criteria components: swollen/tender joint counts, physician and patient global assessments). RESULTS: The mean age of patients (n = 141) was 50.3 (s.d.: 12.1) years (50% male). During a median observation period of 4.5 (range: 3.4-5.5) years, patients received a median of one (range: one to five) TNFi. Twelve-week response rates for first TNFi (where available) were as follows: 80% (n = 64/80) for swollen joint counts, 79% (n = 63/79) for tender joint counts, 79% (n = 37/47) for physician global assessments, 69% (n = 41/59) for patient global assessments and 79% (n = 37/47) for PsA response criteria. At the end of the observation period, the proportions of patients remaining on first, second, third and fourth/fifth TNFi were 56, 15, 5 and 3%, respectively; 21% of patients permanently discontinued TNFi therapy. CONCLUSION: Long-term TNFi therapy is generally well tolerated and may be effective; however, after initial TNFi failure, there appears to be progressively less benefit and more adverse effects with successive TNFi switches. Strategies are needed for effective therapy for PsA beyond the first TNFi failure.

Prevalence and predictors of tumour necrosis factor inhibitor persistence in psoriatic arthritis.

Objectives: To evaluate TNF-α inhibitor (TNFi) persistence when used as first- or second-line biologic therapy for the management of PsA, and to determine baseline clinical and laboratory parameters associated with TNFi persistence. Methods: A retrospective single-centre cohort study was performed on all patients with PsA initiated on TNFi therapy between 2003 and 2015. Demographic, clinical and laboratory characteristics were compared with TNFi persistence, using Kaplan-Meier survival and Cox proportional hazards models. Results: One hundred and eighty-eight patients with PsA were prescribed TNFi therapy as first-line biologic therapy over a period of 635 person-years [46% male, mean (s.d.) age 47.3 (11.4) years; median (interquartile range) disease duration 11 (7-16) years]. At 12 months of follow-up 79% of patients persisted with TNFi therapy, and 73% at 24 months. Of those discontinuing TNFi, 35% stopped due to primary inefficacy, 22% secondary inefficacy and 43% adverse events. Multivariable analysis identified female sex (hazard ratio (HR) 2.57; 95% CI: 1.26, 5.24; P = 0.01) and the presence of metabolic syndrome-related co-morbidities (HR = 2.65, 95% CI: 1.24, 5.69; P = 0.01) as predictors of lower persistence. Of 32 cases treated with a second TNFi, persistence at 12 months was 56%. TNFi persistence was 2-fold less likely in these 32 cases compared with first-line TNFi users (HR = 2.02, 95% CI: 1.20, 3.42; P = 0.01). Conclusion: Patients with PsA who are female and have metabolic syndrome-related co-morbidities have lower TNFi persistence. Although persistence was lower in patients who had switched to a second TNFi, a substantial proportion of these cases responded, advocating switching to a second TNFi as a valid therapeutic strategy.

Effect of anti-TNF and conventional synthetic disease-modifying anti-rheumatic drug treatment on work disability and clinical outcome in a multicentre observational cohort study of psoriatic arthritis.

Objectives: To determine the effect of medical treatment on work disability in patients with active PsA in a real-world setting. Methods: Four hundred patients with active PsA commencing or switching to anti-TNF or conventional synthetic DMARD (csDMARD) were recruited to a multicentre UK prospective observational cohort study. Work disability was measured using the work productivity and activity-specific health problem instrument and peripheral joint activity was measured with the disease activity in PsA composite measure. Results: Four hundred patients were recruited, of whom 229 (57.25%) were working (of any age). Sixty-two patients of working age (24%) were unemployed. At 6 months there was a 10% improvement in presenteeism ( P = 0.007) and a 15% improvement in work productivity ( P = 0.001) among working patients commenced on csDMARDs ( n = 164) vs a larger and more rapid 30% improvement in presenteeism ( P < 0.001) and 40% improvement in work productivity ( P < 0.001) among those commenced on anti-TNF therapy ( n = 65). Clinical response was poor among patients commenced on a csDMARD ( n = 272), with an 8.4 point improvement in disease activity in PsA ( P < 0.001) vs those commenced on anti-TNF therapy ( n = 121), who had a 36.8 point improvement ( P < 0.001). Conclusion: We report significant and clinically meaningful improvements in both work disability and clinical outcomes after commencement of anti-TNF therapy in a real-world setting. Improvements in all outcomes among those commencing csDMARDs were slower and of a smaller magnitude.

Factors influencing work disability in psoriatic arthritis: first results from a large UK multicentre study.

OBJECTIVE: The aim of this study was to determine the extent to which structural damage, clinical disease activity, demographic and social factors are associated with work disability (WD) in PsA. METHODS: Four hundred patients fulfilling CASPAR (Classification Criteria for Psoriatic Arthritis) criteria for PsA were recruited from 23 hospitals across the UK. Demographic, socio-economic, work, clinical and radiographic data were collected. WD was assessed with the Work Productivity and Activity Impairment Specific Health Problem (WPAI-SHP) questionnaire reporting WD as a percentage of absenteeism (work time missed), presenteeism (impairment at work/reduced effectiveness) and work productivity loss (overall work impairment/absenteeism plus presenteeism). Logistic and linear regressions were conducted to investigate associations with WD. RESULTS: Two hundred and thirty-six participants of any age were in work. Absenteeism, presenteeism and productivity loss rates were 14% (s.d. 29.0), 39% (s.d. 27.2) and 46% (s.d. 30.4), respectively. Ninety-two (26%) participants of working age were unemployed. Greater age, disease duration of 2-5 years and worse physical function were associated with unemployment. Patients reported that employer awareness and helpfulness exerted a strongly positive influence on remaining in employment. Higher levels of global and joint-specific disease activity and worse physical function were associated with greater levels of presenteeism and productivity loss among those who remained in work. CONCLUSION: Reduced effectiveness at work was associated with measures of disease activity, whereas unemployment, considered the endpoint of WD, was associated with employer factors, age and disease duration. A longitudinal study is under way to determine whether treatment to reduce disease activity ameliorates WD in the real-world setting.

Late-onset neutropenia in patients with rheumatoid arthritis after treatment with rituximab.

OBJECTIVE: Late-onset neutropenia (LON) is an adverse effect of rituximab (RTX) in hematological malignancies, a finding that was recently reported in rheumatoid arthritis (RA). The aim of our study was to estimate its incidence in RA. METHODS: We retrospectively reviewed complete blood (cell) count of patients with RA who received RTX between October 2007 and July 2011 to identify neutropenia (≤ 1.5 × 10(9)) up to 12 months following RTX. RESULTS: One hundred eight patients received RTX, median age 64 years (range 25-86). A total of 237 cycles were given. Five patients developed LON after a median of 151 days (71-184). Two developed pneumonia. CONCLUSION: LON occurs infrequently after RTX, but can present with infection.