Towards the Lowest Efficacious Dose: Results From a Multicenter Noninferiority Randomized Open-Label Controlled Trial Assessing Tocilizumab or Abatacept Injection Spacing in Rheumatoid Arthritis in Remission.

OBJECTIVE: We assess the clinical and structural impact at two years of progressively spacing tocilizumab (TCZ) or abatacept (ABA) injections versus maintenance at full dose in patients with rheumatoid arthritis in sustained remission. METHODS: This multicenter open-label noninferiority (NI) randomized clinical trial included patients with established rheumatoid arthritis in sustained remission receiving ABA or TCZ at a stable dose. Patients were randomized to treatment maintenance (M) at full dose (M-arm) or progressive injection spacing (S) driven by the Disease Activity Score in 28 joints every 3 months up to biologics discontinuation (S-arm). The primary end point was the evolution of disease activity according to the Disease Activity Score in 44 joints during the 2-year follow-up analyzed per protocol with a linear mixed-effects model, evaluated by an NI test based on the one-sided 95% confidence interval (95% CI) of the slope difference (NI margin 0.25). Other end points were flare incidence and structural damage progression. RESULTS: Overall, 202 of the 233 patients included were considered for per protocol analysis (90 in S-arm and 112 in M-arm). At the end of follow-up, 16.2% of the patients in the S-arm could discontinue their biologic disease-modifying antirheumatic drug, 46.9% tapered the dose and 36.9% returned to a full dose. NI was not demonstrated for the primary outcome, with a slope difference of 0.10 (95% CI 0.10-0.31) between the two arms. NI was not demonstrated for flare incidence (difference 42.6%, 95% CI 30.0-55.1) or rate of structural damage progression at two years (difference 13.9%, 95% CI -6.7 to 34.4). CONCLUSION: The Towards the Lowest Efficacious Dose trial failed to demonstrate NI for the proposed ABA or TCZ tapering strategy.

Update on contribution of hip labral tears to hip pain: A narrative review.

Hip labral tears are found in 22-55% of individuals with hip pain, but labral tears without cysts are usually not responsible for hip pain, which originates mostly from other structures than the torn labrum, like osteochondral, but also tendinous injuries (rectus femoris, gluteus minimus, iliopsoas) or capsulo-ligamentous tears (iliofemoral ligaments, ligament teres). Those lesions are mainly the consequences of underlying unrecognized functional acetabular dysplasia, and/or femoroacetabular impingements. Although the early repair of labral tears in young sportsmen induces a marked and lasting relief, and might delay the onset of osteoarthritis, the microinstability fostered by labral damages seems less important than underlying dysplasias/impingements. This narrative review details recent findings on: (i) the various mechanisms of pain associated with labral tears; (ii) few evidence for hip microinstability induced by isolated labral tears; (iii) how to best detect labral tears, both clinically (including through IROP test) and on imaging (MRI, MRA, computed tomography arthrography, ultrasound). Some authors suggested to use pull-out tests during surgery, but pulling of hips do not seem to increase much diagnostic performances of ultrasounds. Ultrasound-guided intra-articular and peri-articular injections may tell how often hip pain is exclusively induced by peri-capsular injuries secondary to the acetabular dysplasia/femoro-acetabular impingements already responsible for labral tears. Further works could tell whether labral repair, tendinous debridement, plication of capsule, and/or focal denervation, may induce lasting reliefs of pain induced by the chronic contraction of surrounding muscles (rectus femoris, gluteus minimus, psoas), whose deep aponeuroses mix with the superficial fibres of the thick hip capsule.

Prolonged response on olaparib maintenance in metastatic pancreatic acinar cell carcinoma associated with a germline BRCA 2 mutation, revealed by severe panniculitis.

This 38-year-old man has a familial BRCA2 mutation. He presented with skin erythema, polyarthritis, dactylitis, and febrile erythema nodosum; a biopsy of a liver metastase revealed acinar cell carcinoma of the pancreas. After FOLFIRINOX, olaparib was initiated, and 24 months after, the patient was PS 0 and asymptomatic.

Contribution of HLA DRB1, PTPN22, and CTLA4, to RA dysbiosis.

This narrative review gathers current evidence for a contribution of rheumatoid arthritis (RA) HLA-DRB1, PTPN22 and CTLA4 polymorphisms to the gut dysbiosis observed in RA, especially at its onset (transient excess of Prevotella). The gut microbiome contains elements which are 30% heritable, including genera like Bacteroides and Veillonella, and to a lesser extent Prevotella. The first months/year seems a critical period for the selection of a core of microbiota, that should be considered as a second self by the immune system, and tolerized by regulatory T and B cells. Imperfect tolerization may increase the risk of RA following further repeated silent translocations of various gut microorganisms, including Prevotella copri, from gut to joints (fostered by a concurrent loss in gut mucosa of protective bacteria like Faecalibacterium prausnitzii). Genetics studies confirmed that Prevotella copri was partly heritable, and strong associations were observed between the overall microbial composition of stools and the HLA-DRB1 RA risk allele, either in a US cohort (P=0.00001), or the Twins UK cohort (P=0.033). This finding also stands for persons still free from RA, and was replicated in the Swiss SCREEN-RA cohort. Gene variants of PTPN22 also modify intestinal microbiota composition, compromise granulocyte-mediated antibacterial defence in gut, and reduce the suppressive effect of gut regulatory B cells. CTLA4 variants may similarly contribute to RA dysbiosis, since immunotherapy by CTLA-4 blockade depends on microbiota, and CTLA4 activates T follicular regulatory cells to reduce immune responses to segmented filamentous bacteria. Suggestions for future works are made.

Venous congestion as a central mechanism of radiculopathies.

Compression of roots/nerves can disrupt some of their functions, but does not necessarily cause pain. This is illustrated by the frequency of nearly asymptomatic spinal stenosis or disc herniations. In fact, pain of radiculopathies (and nerve entrapments) may mostly be the consequence of intraneural oedema induced by microscopical venous stasis around roots/spinal ganglia (or nerves) not or poorly shown by imaging. This narrative review first lists arguments for a role of congestion of vasa-nervorum in the pathophysiology of radiculopathies, including those induced by disc herniation and spinal stenosis, but also other sources of overpressures in spinal venous plexuses (pregnancy, vena cava atresia and thrombosis, portal hypertension, epidural varices, arterio-venous fistula, vertebral hemangioma or hemangioblastoma). It also details sources of venous congestion around nerves outside the spine, from pelvis (May-Thurner syndrome, Nut-cracker syndrome) to buttocks (superior and inferior gluteal veins), and even thighs and legs. A better recognition of a preeminent role of venous congestion in radiculopathies, plexopathies, and nerve entrapments, should have major consequences: (i) discard the dogma that compression is mandatory to induce root/nerve suffering, since root/nerve adherences in two locations can impair blood flow in vasa-nervorum through root/nerve stretching; (ii) implementation of sensitive techniques to visualise impingement of blood flow around or within roots and nerves; (iii) better prevention of roots/nerves adherence, or arachnoiditis induced by extravascular fibrin deposition secondary to venous stasis.; (iv) optimizing treatments dampening clot formation and/or extravascular fibrin leakage in the intradural/peridural spaces, or around roots/nerves, like guided injection of tissue plasminogen activator.

Overexpression of IgG2 in patients resembling IgG4-related disease with normal IgG4.

IgG4-Related Disease (IgG4-RD) results from tissue infiltration by IgG4-expressing plasma cells and lymphocytes, leading to fibrosis and organomegaly. Clinical presentation is remarkably variable according to organ involvement, and high IgG4 serum concentration, initially considered a diagnostic hallmark of IgG4-RD, tends to be forgone as an indispensable criterion for its diagnosis; it can indeed be absent in some patients, highlighting the diversity of presentation of this dysimmune condition. Nevertheless, elevation of IgG4 serum concentration in suggestive settings remains an argument in favour of IgG4-RD, and while other IgG subclasses can be elevated, this biological feature lacks any diagnostic value. We retrospectively studied 9 patients (5 females, 4 males, 31-81 years old) for whom a diagnosis of IgG4-RD had been considered, based on clinical, imaging or histological criteria, but appeared to display abnormally high serum IgG2 while IgG4 levels were normal. Increased serum IgG1 in one case and increased IgG3 in another one were also noticed. Immunohistochemical analyses of intracellular immunoglobulins could be performed on tissue lymph node biopsies from 2 patients, which demonstrated strong infiltration with IgG2-expressing plasma cells. Thus, overexpression of IgG2 subclass may highlight cases of dysimmune disorders resembling IgG4-RD, although the disease trigger might be different, notably infectious. We suggest measuring all serum IgG subclass levels in patients with features consistent with IgG4-RD.

Fibromyalgia and Associated Disorders: From Pain to Chronic Suffering, From Subjective Hypersensitivity to Hypersensitivity Syndrome.

The concept of fibromyalgia has progressed to achieve a certain consensus regarding the definition of the condition. We summarize what is known in 2020, be it in terms of diagnosis, with the criteria that have changed over the years, or at the level of the psychological profile, via the notions of "catastrophizing" and "coping" and post-traumatic syndrome. The importance of fatigue and sleep disorders is underlined, with the chronological sequence of post-traumatic syndrome, chronic fatigue, and then amplification of the pain and the onset of multiple associated symptoms. The etiopathogenic debate has been enriched thanks to neuro-imaging data to discover the start of the central neurological signature. The many associated symptoms are reanalyzed in the context of so-called sister conditions which form sometimes more or less separate entities, such as chronic fatigue syndrome or restless legs syndrome for example. What these conditions have in common is hypersensitivity, not just to pain, but also to all exteroceptive stimuli, from deep sensitivity in the neuro-vegetative system, the sense organs and certain functions of the central nervous system, to the psychological aspects and sleep control. In summary, it is possible to define fibromyalgia as a cognitive disorder of cortical integration of chronic pain, with amplification of painful and sensory nociception, decrease in the threshold for the perception of pain, and persistence of a stimulus that maintains the process in chronicity. Fibromyalgia is part of a group of chronic hypersensitivity syndromes of central origin, with a very wide range of means of expression.

Contribution of mycobiota to the pathogenesis of spondyloarthritis.

This review lists current evidences for a contribution of gut mycobiota to the pathogenesis of SpA and related conditions. Gut mycobiota has a small size as compared to bacterial microbiota, but an even greater inter- and intra-individual variability. Although most fungi (brought by food or air) are only transitory present, a core mycobiota of gut resident fungi exists, and interplays with bacteria in a complex manner. A dysbiosis of this gut mycobiota has been observed in Crohn's disease and sclerosing cholangitis, with decreased proportion of Saccharomyces cerevisiae and outgrowth of more pathogenic gut fungi. Fungal-induced lower number of commensal gut bacteria can promote translocation of some bacterial/fungal antigens through mucosae, and live fungi can also cross the epithelial border in Crohn's disease. This dysbiosis also lower the ability of bacteria to metabolize tryptophan into regulatory metabolites, consequently enhancing tryptophan metabolism within human cells, which might contribute to fatigue. Translocation of mycobiotal antigens like curdlan (beta-glucan), which plays a major role in the pathogenesis of SpA in the SGK mice, has been observed in humans. This translocation of fungal antigens in human SpA might account for the anti-Saccharomyces antibodies found in this setting. Contribution of fungal antigens to psoriasis and hidradenitis suppurativa would fit with the preferential homing of fungi in the skin area most involved in those conditions. Fungal antigens also possess autoimmune uveitis-promoting function. As genes associated with SpA (CARD9 and IL23R) strongly regulate the innate immune response against fungi, further studies on fungi contribution to SpA are needed.

Rheumatological features of Whipple disease.

Whipple disease (WD) is a rare infectious systemic disease. Rheumatologists are at the frontline of WD diagnosis due to the early rheumatological manifestations. An early diagnosis is crucial, as usual anti-rheumatic drugs, especially TNF inhibitors, may worsen the disease course. We conducted a retrospective multicentre national study from January 2010 to April 2020 to better characterize the rheumatological features of WD. Classic WD (CWD) was defined by positive periodic acid-Schiff (PAS) staining of a small-bowel biopsy sample, and non-CWD (NCWD) was defined by negative PAS staining of a small-bowel biopsy sample but at least one positive Tropheryma whipplei (TW) polymerase chain reaction (PCR) for a digestive or extradigestive specimen. Sixty-eight patients were enrolled, including 11 CWD patients. Twenty patients (30%) received TNF inhibitors during the WD course, with inefficacy or symptom worsening. More digestive symptoms and systemic biological features were observed in CWD patients than in NCWD patients, but both patient groups had similar outcomes, especially concerning the response to antibiotics and relapse rate. Stool and saliva TW PCR sensitivity were both 100% for CWD and 75% for NCWD and 89% and 60% for small-bowel biopsy sample PCR, respectively. WD encountered in rheumatology units has many presentations, which might result from different pathophysiologies that are dependent on host immunity. Given the heterogeneous presentations and the presence of chronic carriage, multiple TW PCR tests on samples from specific rheumatological sites when possible should be performed, but samples from nonspecific digestive and extradigestive sites also have great value.

Cut-off value to identify a flare using the Flare Assessment in Rheumatoid Arthritis (FLARE-RA) questionnaire: analysis of the TOSCA study.

OBJECTIVE: The Flare Assessment in RA (FLARE-RA) self-administered questionnaire aims to identify patients who had flare in the interval between two consultations. This study aimed to establish a threshold for FLARE-RA score to identify RA flare. METHODS: The Tocilizumab SubCutAneous study evaluated the efficacy and safety of s.c. tocilizumab (TCZ) to patients with active RA. Disease activity was assessed with the DAS28ESR at baseline and at week 2 (W2), W4, W12 and W24. The FLARE-RA questionnaire was administered at W12 and W24. Patient satisfaction, assessed at baseline and W24 with the Patient Acceptable Symptom State (PASS), was used as a surrogate marker of no flare. A correlation was sought between the FLARE-RA score at W12 and W24 and the area under the receiver operating characteristic (ROC) curve (AUC) for monthly DAS28ESR. The optimal FLARE-RA cut-off below which patient satisfaction reached the PASS was explored with an ROC curve. RESULTS: A total of 139 patients were included (mean age 57.3 ± 13.8 years, 74.1% women, mean RA duration 10.8 ± 9.2 years, mean DAS28ESR 5.8 ± 1.1). The correlation between the FLARE-RA score and DAS28ESR AUC was moderate at all times: ρ = 0.41 at W12 (P < 0.0001) and 0.51 at W24 (P < 0.0001). The optimal cut-off for the FLARE-RA score to identify absence of flare (i.e. an acceptable situation based on the PASS) was 2.3 with an AUC of 0.81. CONCLUSION: FLARE-RA and DAS28ESR assessment differ; we propose a FLARE-RA cut-off of 2.3, below which the situation (i.e. without flare) is acceptable for patients.

Epidemiology of cutaneous involvement in Sjögren syndrome: Data from three French pSS populations (TEARS, ASSESS, diapSS).

OBJECTIVE: To determine the prevalence and significance of dermatological disorders in primary Sjögren syndrome (pSS). METHODS: We used 2 pSS French cohorts (ASSESS, in which prevalence of skin disorders in 395 patients was evaluated; and diapSS, in which 76 on 139 pSS patients had an examination by a dermatologist) and baseline data of the TEARS randomized trial (110 patients with recent or active pSS treated with rituximab or placebo and evaluated for skin dryness using a visual analogue scale (VAS) out of 100). RESULTS: Skin manifestations included in the EULAR Sjögren syndrome disease activity index (ESSDAI) were rare in the ASSESS cohort (n=16/395, 4.1%, mainly purpuras; only 3 had high activity), but they were associated with activity in the other ESSDAI domains (peripheral neurological (P<0.001), muscular (P<0.01), haematological (P<0.05), biological (P<0.05), history of arthritis (P<0.01), splenomegaly (P<0.05) and higher gamma globulin levels (P<0.01)). In the diapSS cohort, compared to pSS patients not receiving a dermatological consultation, the pSS patients who had a dermatological consultation had significantly more dermatological involvement outside the ESSDAI score [38.2% (29/76) versus 15.9% (10/63); P<0.01]. The TEARS study showed a high prevalence of cutaneous dryness (VAS>50; 48.2%) and found that patients with dry skin had higher VAS pain (P<0.01) and drought (P<0.01) scores. CONCLUSION: ESSDAI skin activity is rare and associated with hypergammaglobulinemia and ESSDAI activity. Systematic dermatological examination is informative for non-specific lesions. The most common skin disorder is skin dryness, which is associated with a higher pain and overall subjective dryness.

Inadequacies of the Lasègue test, and how the Slump and Bowstring tests are useful for the diagnosis of sciatica.

Diagnosis of sciatica mainly relies on pain reproduction by stretching of the lumbar roots since neurological examination and medical history are usually not sufficient to guarantee diagnosis. The Lasègue test is the most popular method, which starts with the straight leg-raising test (SLR). However it is not perfect, and is not always well performed or interpreted. Passive ankle dorsiflexion at the end of the SLR (Bragard test) is more sensitive, but can also remain normal in some cases of sciatica. Other stretching tests can help to recognise lumbar root damage in patients with poorly defined pain in a lower extremity: firstly, the Christodoulides test, i.e. reproduction of L5 sciatic pain by a femoral stretch test; secondly, the Slump test, performed on a patient in a sitting position, by slowly extending their painful leg then passively bending their neck (or the opposite); and thirdly, the Bowstring test, which requires, at the end of the Lasègue test, once the knee has been slightly flexed, pressing on the course of the peroneal and/or tibial nerves in the popliteal fossea to try and reproduce the exact pain felt by the patient. The combination of all these tests takes less than 2minutes, and could improve both the sensitivity and specificity of the physical examination for the diagnosis of sciatica. This article is a review of the limitations of the Lasègue/SLR tests and of the efficacy of these other tests for stretching the lumbar roots.

Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial.

OBJECTIVES: No immunomodulatory drug has been approved for primary Sjögren's syndrome, a systemic autoimmune disease affecting 0.1% of the population. To demonstrate the efficacy of targeting interleukin 6 receptor in patients with Sjögren's syndrome-related systemic complications. METHODS: Multicentre double-blind randomised placebo-controlled trial between 24 July 2013 and 16 July 2018, with a follow-up of 44 weeks, involving 17 referral centres. Inclusion criteria were primary Sjögren's syndrome according to American European Consensus Group criteria and score ≥5 for the EULAR Sjögren's Syndrome Disease activity Index (ESSDAI, score of systemic complications). Patients were randomised to receive either 6 monthly infusions of tocilizumab or placebo. The primary endpoint was response to treatment at week 24. Response to treatment was defined by the combination of (1) a decrease of at least 3 points in the ESSDAI, (2) no occurrence of moderate or severe activity in any new domain of the ESSDAI and (3) lack of worsening in physician's global assessment on a Visual Numeric Scale ≥1/10, all as compared with enrolment. RESULTS: 110 patients were randomised, 55 patients to tocilizumab (mean (SD) age: 50.9 (12.4) years; women: 98.2%) and 55 patients to placebo (54.8 (10.7) years; 90.9%). At 24 weeks, the proportion of patients meeting the primary endpoint was 52.7% (29/55) in the tocilizumab group and 63.6% (35/55) in the placebo group, for a difference of -11.4% (95% credible interval -30.6 to 9.0) (Pr[Toc >Pla]=0.14). CONCLUSION: Among patients with primary Sjögren's syndrome, the use of tocilizumab did not improve systemic involvement and symptoms over 24 weeks of treatment compared with placebo. TRIAL REGISTRATION NUMBER: NCT01782235.

Another Look at the Contribution of Oral Microbiota to the Pathogenesis of Rheumatoid Arthritis: A Narrative Review.

Although autoimmunity contributes to rheumatoid arthritis (RA), several lines of evidence challenge the dogma that it is mainly an autoimmune disorder. As RA-associated human leukocyte antigens shape microbiomes and increase the risk of dysbiosis in mucosae, RA might rather be induced by epigenetic changes in long-lived synovial presenting cells, stressed by excessive translocations into joints of bacteria from the poorly cultivable gut, lung, or oral microbiota (in the same way as more pathogenic bacteria can lead to "reactive arthritis"). This narrative review (i) lists evidence supporting this scenario, including the identification of DNA from oral and gut microbiota in the RA synovium (but in also healthy synovia), and the possibility of translocation through blood, from mucosae to joints, of microbiota, either directly from the oral cavity or from the gut, following an increase of gut permeability worsened by migration within the gut of oral bacteria such as Porphyromonas gingivalis; (ii) suggests other methodologies for future works other than cross-sectional studies of periodontal microbiota in cohorts of patients with RA versus controls, namely, longitudinal studies of oral, gut, blood, and synovial microbiota combined with transcriptomic analyses of immune cells in individual patients at risk of RA, and in overt RA, before, during, and following flares of RA.