Inaugural dropped head syndrome and camptocormia in inflammatory myopathies: a retrospective study.

OBJECTIVES: Inaugural axial muscle involvement, defined as dropped head syndrome (DHS) and/or camptocormia (CC), is poorly described in inflammatory myopathies (IM). This study aimed to further characterize IM patients with inaugural DHS/CC, their outcome and care management. METHODS: This retrospective study included IM patients diagnosed between 2000 and 2021. The main inclusion criterion was IM revealed by axial muscle deficit (DHS/CC). RESULTS: Twenty-seven patients were included; median (IQR) age at first symptoms was 66.0 years (55.5-75.0); 21 were female (77.8%). There were nine IBM, 33.3%, nine overlap myositis (OM, 33.3%), five DM, 18.5%, two immune checkpoint inhibitor-related myositis (7.4%), one focal myositis (3.7%) and one myositis with anti-Hu antibodies (3.7%). Age at first symptoms was ≤70 years in 16 patients (59.3%), including all DM patients and 8/9 OM patients (88.9%). In this group, partial remission of the disease was obtained in 9/16 (56.3%) and complete remission in 1/16 patients (6.3%); regression of DHS/CC was achieved in 3/16 patients (18.8%). Conversely, in the group of 11 patients aged >70 years at first symptoms, there were eight IBM (72.7%). Partial remission was obtained in 5/11 patients (45.5%), the disease was stable in 6/11 patients (54.5%); no complete remission was obtained nor regression of DHS/CC. CONCLUSION: The analysis of IM patients with inaugural DHS/CC delineates two groups of patients according to the age at first symptoms in terms of clinical and outcome specificities, and proposes an adapted diagnostic and care management approach to prevent long-term complications.

Evolution of monoclonal gammopathy of undetermined significance in patients treated with JAK inhibitors for rheumatic diseases: data from the MAJIK-SFR registry.

OBJECTIVE: Monoclonal gammopathy of undetermined significance (MGUS) is common, but there are scarce data regarding the effect of DMARDs on this premalignant condition. We aimed to evaluate the impact of JAK inhibitors (JAKis) on MGUS when initiated for an active rheumatic disease. METHODS: Patients with monoclonal abnormality prior to JAKi initiation for an active rheumatic disease were identified through the MAJIK-SFR Registry, a French multicentre prospective study. Clinical and biological data were collected using a standardized case report form. RESULTS: Twenty patients were identified with a mean age of 65 years and a diagnosis of RA (n = 15), PsA (n = 3), and axial SpA (n = 2). The JAKi prescribed was baricitinib (n = 9), tofacitinib (n = 6) or upadacitinib (n = 5), with a mean duration of 15.5 months. Seventeen patients had individualized serum monoclonal protein (IgG kappa n = 9; IgG lambda n = 4; IgM kappa n = 3; IgA lambda n = 1) ranging from 0.16 to 2.3 g/dl, and three patients did not have an initial measurable spike but they had a positive serum immunofixation. With a follow-up of 4-28 months, the serum monoclonal protein level decreased in 8 of 17 patients (47%), remained stable in 8 patients (47%) and increased in 1 patient (6%). The maximal decrease observed was an initial IgG kappa of 2.3 g/dl, decreasing to 0.2 g/dl at month 14. CONCLUSION: This study provides reassuring and promising data on MGUS evolution in patients treated with JAKis for rheumatic diseases, which may guide the choice of treatment in patients with both conditions.

Diagnosis and treatment of Tropheryma whipplei infection in patients with inflammatory rheumatic disease: Data from the French Tw-IRD registry.

OBJECTIVES: Tropheryma whipplei infection can manifest as inflammatory joint symptoms, which can lead to misdiagnosis of inflammatory rheumatic disease and the use of disease-modifying antirheumatic drugs. We investigated the impact of diagnosis and treatment of Tropheryma whipplei infection in patients with inflammatory rheumatic disease. METHODS: We initiated a registry including patients with disease-modifying antirheumatic drugs-treated inflammatory rheumatic disease who were subsequently diagnosed with Tropheryma whipplei infection. We collected clinical, biological, treatment data of the inflammatory rheumatic disease, of Tropheryma whipplei infection, and impact of antibiotics on the evolution of inflammatory rheumatic disease. RESULTS: Among 73 inflammatory rheumatic disease patients, disease-modifying antirheumatic drugs initiation triggered extra-articular manifestations in 27% and resulted in stabilisation (51%), worsening (34%), or improvement (15%) of inflammatory rheumatic disease. At the diagnosis of Tropheryma whipplei infection, all patients had rheumatological symptoms (mean age 58 years, median inflammatory rheumatic disease duration 79 months), 84% had extra-rheumatological manifestations, 93% had elevated C-reactive protein, and 86% had hypoalbuminemia. Treatment of Tropheryma whipplei infection consisted mainly of doxycycline plus hydroxychloroquine, leading to remission of Tropheryma whipplei infection in 79% of cases. Antibiotic treatment of Tropheryma whipplei infection was associated with remission of inflammatory rheumatic disease in 93% of cases and enabled disease-modifying antirheumatic drugs and glucocorticoid discontinuation in most cases. CONCLUSIONS: Tropheryma whipplei infection should be considered in inflammatory rheumatic disease patients with extra-articular manifestations, elevated C-reactive protein, and/or hypoalbuminemia before disease-modifying antirheumatic drugs initiation or in inflammatory rheumatic disease patients with an inadequate response to one or more disease-modifying antirheumatic drugs. Positive results of screening and diagnostic tests for Tropheryma whipplei infection involve antibiotic treatment, which is associated with complete recovery of Tropheryma whipplei infection and rapid remission of inflammatory rheumatic disease, allowing disease-modifying antirheumatic drugs and glucocorticoid discontinuation.

Risk of infections in psoriatic arthritis or axial spondyloarthritis patients treated with targeted therapies: A meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the risk of global infections in patients with psoriatic arthritis (PsA) and axial spondyloarthritis encompassing ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA) treated with targeted therapies. METHODS: Medline and Cochrane databases were systematically searched up to March 2021 for randomized controlled trials (RCTs) performed in patients with PsA or axial spondyloarthritis treated with biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). Global infections (any infections reported, including bacterial, viral and fungal infections, except serious infections) were the primary outcome. Secondary outcomes included serious infections defined as life-threatening infections or any infection requiring intravenous antibiotics or hospitalization. The relative risk of infections was determined by meta-analysis of RCTs. RESULTS: A total of 60 RCTs were included (20,418 patients), encompassing 17 b/tsDMARDs, compared with placebo, conventional synthetic drugs (csDMARDs) or non-steroidal anti-inflammatory drugs (NSAIDs). An increased risk of any infection for patients exposed to these drugs was found (RR 1.15, 95% CI [1.06-1.25]), mainly with high doses and longer duration of treatment. Most infections were respiratory tract or ear, nose, and throat (ENT) infections. Subgroup analyses showed a statistically significant increased risk of infections for axial spondyloarthritis patients (RR 1.32, 95% CI [1.14-1.52]), but not for PsA patients (RR 1.05, 95% CI [0.97-1.14]). Infection risk was highest with TNF inhibitors (RR 1.23, 95% CI [1.11-1.37]) and IL-17 inhibitors (RR 1.30, 95% CI [1.07-1.59]). No increased risk of serious infections was shown. CONCLUSION: In contrast to serious infections, the risk of global infections is moderately increased with b/tsDMARDs in spondyloarthritis, and is associated in particular with use of TNF and IL-17 inhibitors.

Incidence of infections in patients with psoriatic arthritis and axial spondyloarthritis treated with biological or targeted disease-modifying agents: a systematic review and meta-analysis of randomised controlled trials, open-label studies and observational studies.

OBJECTIVE: To estimate the incidence of infections among patients with psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA), two distinct phenotypes included in the large group of spondyloarthritis (SpA), treated with tumour necrosis-factor-inhibitors, interleukin-17-inhibitors, Janus kinase-inhibitors, IL-23 or IL-12/23-inhibitors (IL-12/23i), phosphodiesterase 4-inhibitors or cytotoxic T-lymphocyte associated protein 4-Ig. METHODS: A meta-analysis of randomised controlled trials (RCTs), open-label extension and observational studies was conducted. Serious infections were defined as infections that were life-threatening, required intravenous antibiotics and/or hospitalisation. Non-serious infections did not meet these severity criteria. The incidence rates (IR) were reported for each diagnosis by treatment class and study type using random-effect model to create a 95% CI. RESULTS: Among 23 333 PsA patients and 11 457 axSpA patients, there were 1.09 serious infections per 100 patient-years (PY) (95% CI 0.85 to 1.35) with similar IR in PsA (0.96 per 100 PY 95% CI 0.69 to 1.28) and axSpA (1.09 per 100 PY 95% CI 0.76 to 1.46). The IR was lower in RCTs (0.77 per 100 PY 95% CI 0.41 to 1.20) compared with observational studies (1.68 per 100 PY 95% CI 1.03 to 2.47). In PsA patients, the lowest IR value was observed with IL-12/23i (0.29 per 100 PY 95% CI 0.00 to 1.03). There were 53.0 non-serious infections per 100 PY (95% CI 43.47 to 63.55) in 7257 PsA patients and 5638 axSpA patients. The IR was higher in RCTs (69.95 per 100 PY 95% CI 61.59 to 78.84) compared with observational studies (15.37 per 100 PY 95% CI 5.11 to 30.97). CONCLUSION: Serious infections were rare events in RCTs and real-life studies. Non-serious infections were common adverse events, mainly in RCTs. PROSPERO REGISTRATION NUMBER: CRD42020196711.

Serological response to SARS-CoV-2 vaccination in patients with inflammatory rheumatic disease treated with disease modifying anti-rheumatic drugs: A cohort study and a meta-analysis.

INTRODUCTION: Vaccination is considered as a cornerstone of the management of COVID-19 pandemic. However, while vaccines provide a robust protection in immunocompetent individuals, the immunogenicity in patients with inflammatory rheumatic diseases (IRD) is not well established. METHODS: A monocentric observational study evaluated the immunogenicity of a two-dose regimen vaccine in adult patients with IRD (n=123) treated with targeted or biological therapies. Serum IgG antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins were measured after the second vaccination. In addition, a search for observational studies performed in IRD under biologic or targeted therapies up to September 31, 2021 (PROSPERO registration number: CRD42021259410) was undertaken in publication databases, preprint servers, and grey literature sources. Studies that reported sample size, study date, location, and seroprevalence estimate were included. A meta-analysis was conducted to identify demographic differences in the prevalence of SARS-CoV-2 antibodies. RESULTS: Of 123 patients (median age 66 IQR 57-75), 69.9% have seroconverted after vaccination. Seroconverted patients were older than non-seroconverted ones in our cohort. Rituximab was associated with a significantly low antibody response. Besides, we identified 20 seroprevalence studies in addition to our cohort including 4423 participants in 11 countries. Meta-analysis confirmed a negative impact of rituximab on seroconversion rate and suggested a less substantial effect of abatacept, leflunomide and methotrexate. CONCLUSION: Rituximab impairs serological response to SARS-CoV-2 vaccines in patients with IRD. This work suggests also a negative impact of abatacept, methotrexate or leflunomide especially when associated to biological therapy.

Predictive factors of effective tibial nerve release in tarsal tunnel syndrome.

BACKGROUND: Factors that may affect surgical decompression results in tarsal tunnel syndrome are not known. METHODS: A retrospective single-center study included patients who had undergone surgical tibial nerve release. The effectiveness of decompression was evaluated according to whether the patient would or would not be willing to undergo another surgical procedure in similar preoperative circumstances. RESULTS: The patients stated for 43 feet (51%) that they would agree to a further procedure in similar circumstances. Six feet with space-occupying lesions on imaging had improved results, but neurolysis failed in 9 feet with bone-nerve contact. Neurolysis was significantly less effective when marked hindfoot valgus (p = 0.034), varus (p = 0.014), or fasciitis (p = 0.019) were present. CONCLUSIONS: If imaging reveals a compressive space-occupying lesion, surgery has a good prognosis. In feet with static hindfoot disorders or plantar fasciitis, conservative treatment must be optimized. Bone-nerve contact should systematically be sought.

Comparison of paediatric and adult classification criteria in juvenile idiopathic arthritis during the transition from paediatric to adult care.

OBJECTIVES: To determine the characteristics of juvenile idiopathic arthritis (JIA) patients seen during the transition period in order to compare paediatric classification criteria with those for adults. METHODS: Patients with JIA according to the ILAR classification and who had a consultation at transition between 2010 and 2017 were included in a retrospective bi-centre (Lyon, Lausanne) study. JIA classification criteria were compared to ACR/EULAR 2010 criteria for rheumatoid arthritis (RA), Yamaguchi criteria for adult-onset Still's disease (AOSD), ASAS criteria for spondyloarthritis and CASPAR criteria for psoriatic arthritis. RESULTS: One hundred and thirty patients were included: 13.9% with systemic JIA, 22.3% with polyarticular JIA, 22.3% with oligoarticular JIA, 34.6% with enthesitis-related arthritis (ERA) and 6.9% with psoriatic arthritis; 13.1% had suffered from uveitis; 14.5% of patients had erosions or carpitis, mainly those with psoriatic arthritis, polyarticular or systemic JIA; 37.5% of patients with ERA displayed radiological sacroiliitis. When comparing paediatric JIA criteria with adult classifications, we found that: 66.6% of patients with systemic JIA fulfilled the criteria for AOSD, 87.5% of rheumatoid factor-positive polyarticular JIA and 9.5% of rheumatoid factor-negative polyarticular JIA met the criteria for RA, and 34.5% of oligoarticular JIA fulfilled the criteria for spondyloarthritis. Finally, 77.7% of patients with ERA met the criteria for spondyloarthritis, and 100% of patients with psoriatic arthritis JIA met the criteria for psoriatic arthritis. CONCLUSION: Oligoarticular JIA and rheumatoid factor-negative polyarticular JIA seem to be paediatric entities, whereas the other types of JIA tended to meet the respective adult classification criteria.

Increased high molecular weight adiponectin and lean mass during tocilizumab treatment in patients with rheumatoid arthritis: a 12-month multicentre study.

BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular (CV) disease. Adiponectin is involved in the metabolism of glucose and lipids with favourable effects on CV disease, especially its high molecular weight (HMW) isoform. Body composition changes are described in RA with various phenotypes including obesity. The effects of tocilizumab on serum adiponectin and body composition, especially fat mass, in patients with RA are not well determined. METHODS: Patients with active RA despite previous csDMARDs and/or bDMARDs and who were tocilizumab naïve were enrolled in a multicentre open-label study. They were evaluated at baseline, 1, 3, 6 and 12 months. Clinical assessment included body mass index (BMI) and anthropometric measurements. Lipid and metabolic parameters, serum adiponectin (total and HMW), leptin, resistin and ghrelin were measured at each time point. Body composition (lean mass, fat mass, % fat, fat in the android and gynoid regions) was evaluated at baseline, 6 and 12 months. RESULTS: One hundred seven patients were included. Both total and HMW adiponectin significantly increased from baseline to month 3, peaking respectively at month 3 (p = 0.0105) and month 1 (p < 0.0001), then declining progressively until month 6 to 12 and returning to baseline values. Significant elevation in HMW adiponectin persisted at month 6 (p = 0.001). BMI and waist circumference significantly increased at month 6 and 12, as well as lean mass at month 6 (p = 0.0097). Fat mass, percentage fat and android fat did not change over the study period. Lipid parameters (total cholesterol and LDL cholesterol) increased while glycaemia, insulin and HOMA-IR remained stable. Serum leptin, resistin and ghrelin did not change during follow-up. CONCLUSIONS: Tocilizumab treatment in RA patients was associated with a significant increase in total and HMW adiponectin, especially at the onset of the treatment. Tocilizumab also induced a significant gain in lean mass, while fat mass did not change. These variations in adiponectin levels during tocilizumab treatment could have positive effects on the CV risk of RA patients. In addition, tocilizumab may have an anabolic impact on lean mass/skeletal muscle. TRIAL REGISTRATION: The ADIPRAT study was a phase IV open-label multicentre study retrospectively registered on ClinicalTrials.gov under the number NCT02843789 (date of registration: July 26, 2016).

Infliximab induces clinical resolution of sacroiliitis that coincides with increased circulating FOXP3+ T cells in a patient with IPEX syndrome.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency due to mutations of FOXP3, a master transcription factor of regulatory T cells (Treg). IPEX syndrome leads to fatal course in most cases during early childhood or severe multi-organ immune-mediated disorders in patients who survive. Currently hematopoietic stem cell transplantation represents the only known effective cure for IPEX syndrome. However, older patients with a mild disease not severe enough to justify transplantation, raise concerns regarding the appropriate therapeutic management, which is therefore based on supportive and replacement therapies combined with pharmacological immunosuppression. Herein, we report the case of a 22-year-old man with an incomplete IPEX syndrome without endocrine disorders having suffered from severe enteropathy since his birth treated with a combination of various immunosuppressant agents. He developed severe exacerbation of inflammatory low back pain in relation to sacroiliitis. Eventually, infliximab was initiated to control his back pain with rapid resolution as well as digestive improvement and also reduced biological inflammatory markers. In parallel, flow cytometry analysis revealed an increase in the frequency of circulating FOXP3+ CD4+ Treg cells. Altogether these data highlight that anti-TNF may represent a promising therapeutic option in patients with IPEX syndrome.

Rheumatoid Arthritis in the View of Osteoimmunology.

Rheumatoid arthritis is characterized by synovial inflammation and irreversible bone erosions, both highlighting the immense reciprocal relationship between the immune and bone systems, designed osteoimmunology two decades ago. Osteoclast-mediated resorption at the interface between synovium and bone is responsible for the articular bone erosions. The main triggers of this local bone resorption are autoantibodies directed against citrullinated proteins, as well as pro-inflammatory cytokines and the receptor activator of nuclear factor-κB ligand, that regulate both the formation and activity of the osteoclast, as well as immune cell functions. In addition, local bone loss is due to the suppression of osteoblast-mediated bone formation and repair by inflammatory cytokines. Similarly, inflammation affects systemic bone remodeling in rheumatoid arthritis with the net increase in bone resorption, leading to systemic osteoporosis. This review summarizes the substantial progress that has been made in understanding the pathophysiology of systemic and local bone loss in rheumatoid arthritis.

Methotrexate Restores CD73 Expression on Th1.17 in Rheumatoid Arthritis and Psoriatic Arthritis Patients and May Contribute to Its Anti-Inflammatory Effect through Ado Production.

OBJECTIVES: Th1.17 are highly polyfunctional, potentially harmful CD4+ effector T cells (Teff) through IFN-γ and IL-17A coproduction. Th1.17 take part in the pathophysiology of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in which their hyper activation results in part from defects in negative regulation mechanisms. We recently demonstrated that the ecto-nucleotidase CD73 delineates a Th1.17-enriched Teff population and acts as an endogenous regulatory mechanism. Because Methotrexate (MTX), used as first line treatment of RA and PsA, increases extracellular concentrations of AMP and immunosuppressive adenosine, we investigated the modulation of CD73 by MTX treatment on Teff in RA/PsA patients. METHODS: In a prospective cohort of 26 RA and 15 PsA patients before or under MTX treatment, we evaluated CD73 expression on blood Teff subsets, their cytokine production and AMPase functions. RESULTS: We showed a decreased CD73 expression on Th1.17 and Th1 in untreated patients compared to healthy donors that was partly restored under MTX. This decrease in untreated patients leads to a halved Ado production by Th1.17 cells. CD73+ Teff remained functional under MTX treatment, but their CD73 re-expression may contribute to control their activation. CONCLUSION: Our study unveils uncovered mode of action of MTX on Teff subsets modulation and in the adenosine-dependent termination of inflammation in RA and PsA.

Osteoclast-Derived Autotaxin, a Distinguishing Factor for Inflammatory Bone Loss.

OBJECTIVE: The severity of rheumatoid arthritis (RA) correlates directly with bone erosions arising from osteoclast (OC) hyperactivity. Despite the fact that inflammation may be controlled in patients with RA, those in a state of sustained clinical remission or low disease activity may continue to accrue erosions, which supports the need for treatments that would be suitable for long-lasting inhibition of OC activity without altering the physiologic function of OCs in bone remodeling. Autotaxin (ATX) contributes to inflammation, but its role in bone erosion is unknown. METHODS: ATX was targeted by inhibitory treatment with pharmacologic drugs and also by conditional inactivation of the ATX gene Ennp2 in murine OCs (ΔATXC tsk ). Arthritic and erosive diseases were studied in human tumor necrosis factor-transgenic (hTNF+/- ) mice and mice with K/BxN serum transfer-induced arthritis. Systemic bone loss was also analyzed in mice with lipopolysaccharide (LPS)-induced inflammation and estrogen deprivation. Joint inflammation and bone erosion were assessed by histology and micro-computed tomography. The role of ATX in RA was also examined in OC differentiation and activity assays. RESULTS: OCs present at sites of inflammation overexpressed ATX. Pharmacologic inhibition of ATX in hTNF+/- mice, as compared to vehicle-treated controls, significantly mitigated focal bone erosion (36% decrease; P < 0.05) and systemic bone loss (43% decrease; P < 0.05), without affecting synovial inflammation. OC-derived ATX was revealed to be instrumental in OC bone resorptive activity and was up-regulated by the inflammation elicited in the presence of TNF or LPS. Specific loss of ATX in OCs from mice subjected to ovariectomy significantly protected against the systemic bone loss and erosion that had been induced with LPS and K/BxN serum treatments (30% reversal of systemic bone loss [P < 0.01]; 55% reversal of erosion [P < 0.001]), without conferring bone-protective properties. CONCLUSION: Our results identify ATX as a novel OC factor that specifically controls inflammation-induced bone erosions and systemic bone loss. Therefore, ATX inhibition offers a novel therapeutic approach for potentially preventing bone erosion in patients with RA.

Osteoimmunology of Bone Loss in Inflammatory Rheumatic Diseases.

Over the past two decades, the field of osteoimmunology has emerged in response to a range of evidence demonstrating the reciprocal relationship between the immune system and bone. In particular, localized bone loss, in the form of joint erosions and periarticular osteopenia, as well as systemic osteoporosis, caused by inflammatory rheumatic diseases including rheumatoid arthritis, the prototype of inflammatory arthritis has highlighted the importance of this interplay. Osteoclast-mediated resorption at the interface between synovium and bone is responsible for the joint erosion seen in patients suffering from inflammatory arthritis. Clinical studies have helped to validate the impact of several pathways on osteoclast formation and activity. Essentially, the expression of pro-inflammatory cytokines as well as Receptor Activator of Nuclear factor κB Ligand (RANKL) is, both directly and indirectly, increased by T cells, stimulating osteoclastogenesis and resorption through a crucial regulator of immunity, the Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1). Furthermore, in rheumatoid arthritis, autoantibodies, which are accurate predictors both of the disease and associated structural damage, have been shown to stimulate the differentiation of osteoclasts, resulting in localized bone resorption. It is now also evident that osteoblast-mediated bone formation is impaired by inflammation both in joints and the skeleton in rheumatoid arthritis. This review summarizes the substantial progress that has been made in understanding the pathophysiology of bone loss in inflammatory rheumatic disease and highlights therapeutic targets potentially important for the cure or at least an alleviation of this destructive process.

A bicentre retrospective study of features and outcomes of patients with reactive arthritis.

OBJECTIVE: Reactive arthritis (ReA) is a sterile arthritis following an extra-articular infection, usually of the gastrointestinal or genitourinary tract. The aim of this study was to assess the incidence and the clinical and therapeutic characteristics of ReA and to compare them with those of a historical cohort. We hypothesised that improved hygiene together with prevention and treatment of sexually transmitted infections may have decreased the incidence of ReA. METHODS: All patients with ReA diagnosed in the University Hospital Centres of Lyon Sud and Besançon from January 2002 to December 2012 were included in the study retrospectively and were compared with ReA patients diagnosed from January 1986 to December 1996 in the same two hospitals. Medical records were reviewed, clinical features, treatments and outcomes were analysed and diagnoses were compared with international diagnostic criteria. RESULTS: Twenty-seven patients were included between 2002 and 2012 compared with 31 between 1986 and 1996. The overall incidence of ReA in patients hospitalised in the rheumatology department did not change, although the current evolution is more severe with development of chronic disease in the form of more frequent spondyloarthritis. While the incidence of Chlamydiae trachomatis has decreased, new microbes are now found to be involved. CONCLUSIONS: ReA still exists and its incidence has been stable over the last 30 years. However, ReA currently more often progress to spondyloarthritis. Our study also highlights the need for diagnostic criteria that accurately detect ReA.

Genetic analysis of adults heterozygous for ALPL mutations.

Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an ALPL mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous ALPL mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an ALPL mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C > G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for ALPL mutations may have unspecific symptoms not attributable to their heterozygosity.