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.

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.

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.

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.

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.

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.

Tumor Necrosis Factor Alpha Overexpression Induces Mainly Osteoclastogenesis at the Vertebral Site.

Syndesmophyte occurrence and axial bone loss were investigated in the heterozygous Tg187 tumor necrosis factor (TNF) transgenic mouse model (Tg-huTNF) of arthritis. Female and male Tg-huTNF mice were compared to wild-type mice (WT) at 2, 4, 6, 8, and 10 weeks. Syndesmophytes, intervertebral disc space, osteoclasts, osteoid surface, and vertebra microarchitecture were assessed by histomorphometry and microcomputed tomography. No spontaneous syndesmophyte formation was detected in Tg-huTNF compared to WT mice. However, increased porosity was observed mainly in peridiscal lumbar vertebra. Accordingly, bone microarchitecture parameters were altered in Tg-huTNF mice, with decrease in bone volume fraction, and trabecular number and thickness after 6 weeks compared to WT (p < 0.05). Osteoclast count and surface were increased (p < 0.01). Moreover, the non-mineralized (osteoid) surface was also increased in Tg-huTNF after 6 weeks (p < 0.01). Despite increased osteoclast and osteoid surfaces, an imbalance between both was observed in favour of osteoid surface at the early phase and then to osteoclast surface. These results demonstrated an axial bone loss in the Tg-huTNF model, additional to the common limb arthritis, related to overexpression of TNF. However, the absence of syndesmophyte and the increase of osteoid surface suggested that chronic inflammation might block bone mineralisation. Finally, the relative increased osteoid surface was not enough to compensate the high osteoclast activity.

Fibromyalgia in Spondyloarthritis: Effect on Disease Activity Assessment in Clinical Practice.

OBJECTIVE: Spondyloarthritis (SpA) is the second most frequent inflammatory rheumatic disease, characterized by spinal involvement, peripheral arthritis, or enthesitis with marked pain, stiffness, and fatigue. Fibromyalgia (FM) may be associated with SpA, and shares some common symptoms. We aimed to determine how FM influences assessment of SpA disease activity, which is mainly dependent on patient-based outcome measures such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) or the Ankylosing Spondylitis Disease Activity Score (ASDAS). METHODS: This single-center cross-sectional study included consecutive patients with SpA according to the Assessment of SpondyloArthritis International Society criteria. FM was diagnosed according to the 1990 American College of Rheumatology criteria. Patient characteristics, BASDAI, ASDAS/C-reactive protein (CRP), Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index, and the Medical Outcomes Study Short Form-36 questionnaire were recorded and compared. RESULTS: The study included 103 patients with SpA; 81 with axial and 22 with peripheral forms. Eighteen patients presented with concomitant FM, of whom 12 had axial SpA and 6 peripheral SpA. Demographic characteristics did not differ except for sex, with a female predominance in the FM group that was more marked in peripheral forms. BASDAI was higher in patients with FM [median (IQR): 4.2 (4.2) vs 2.2 (3.1); p = 0.0068], whereas ASDAS-CRP was not significantly different [median (IQR): 2.7 (2) vs 2 (1.3); p = 0.1264]. Nevertheless, median ASDAS-CRP corresponded to high disease activity in patients with SpA or FM compared with moderate activity in non-FM patients. CONCLUSION: FM is a frequent comorbidity in patients with SpA, especially in peripheral forms. In patients with SpA-FM, disease activity may be overestimated when measured by BASDAI and to a lesser extent by ASDAS-CRP, and this overestimation could lead to inappropriate treatment escalation.

The collection of NFATc1-dependent transcripts in the osteoclast includes numerous genes non-essential to physiologic bone resorption.

Osteoclasts are specialized secretory cells of the myeloid lineage important for normal skeletal homeostasis as well as pathologic conditions of bone including osteoporosis, inflammatory arthritis and cancer metastasis. Differentiation of these multinucleated giant cells from precursors is controlled by the cytokine RANKL, which through its receptor RANK initiates a signaling cascade culminating in the activation of transcriptional regulators which induce the expression of the bone degradation machinery. The transcription factor nuclear factor of activated T-cells c1 (NFATc1) is the master regulator of this process and in its absence osteoclast differentiation is aborted both in vitro and in vivo. Differential mRNA expression analysis by microarray is used to identify genes of potential physiologic relevance across nearly all biologic systems. We compared the gene expression profile of murine wild-type and NFATc1-deficient osteoclast precursors stimulated with RANKL and identified that the majority of the known genes important for osteoclastic bone resorption require NFATc1 for induction. Here, five novel RANKL-induced, NFATc1-dependent transcripts in the osteoclast are described: Nhedc2, Rhoc, Serpind1, Adcy3 and Rab38. Despite reasonable hypotheses for the importance of these molecules in the bone resorption pathway and their dramatic induction during differentiation, the analysis of mice with mutations in these genes failed to reveal a function in osteoclast biology. Compared to littermate controls, none of these mutants demonstrated a skeletal phenotype in vivo or alterations in osteoclast differentiation or function in vitro. These data highlight the need for rigorous validation studies to complement expression profiling results before functional importance can be assigned to highly regulated genes in any biologic process.

Rheumatoid arthritis and fibromyalgia: a frequent unrelated association complicating disease management.

OBJECTIVE: To assess the value of the 28-joint Disease Activity Score (DAS28) in evaluating disease activity in rheumatoid arthritis (RA) associated with fibromyalgia (FM). In this situation, because of the weight of the subjective measures included in the DAS28 equation, the patient's status may be overestimated, leading to inappropriate treatment. We analyze the relationship between RA and FM and discuss whether the association is random or a marker of poor prognosis. METHODS: A questionnaire, developed when biologic therapies were introduced, was administered and the results analyzed in a consecutive, female outpatient population including 105 patients with RA, 49 with RA and FM (RAF), and 28 with FM. Psychosocial characteristics, disease presentation, and radiographic joint destruction evaluation were compared in the 3 populations. RESULTS: The presentation of RA was the same in patients with RA and RAF, but the 2 populations differed by socioprofessional characteristics, significantly higher disease activity in patients with RAF, and significantly more severe joint destruction in patients with RA. The RAF group was similar to the FM control population in socioprofessional and some physical characteristics. Regression analysis using the DAS28 measures differed significantly in the weight allowed to 28-joint counts for pain and swelling, but the constant factor was higher in patients with RAF. CONCLUSION: DAS28 overestimated objective RA severity in patients who also had FM. The association between RA and FM does not appear to be a marker of worse prognosis, but rather a fortuitous association between the 2 diseases and one that may afford these patients some protection against joint destruction.

Safety, efficacy and predictive factors of efficacy of a single intra-articular injection of non-animal-stabilized-hyaluronic-acid in the hip joint: results of a standardized follow-up of patients treated for hip osteoarthritis in daily practice.

AIM: To evaluate, in daily clinical practice, the efficacy and tolerability of a single intra-articular injection of non-animal-stabilized hyaluronic acid (NASHA) in patients treated for symptomatic hip OA (HOA). METHODS: Standardized follow-up (FU). PATIENTS: forty patients suffering from HOA treated by a single intra-articular injection of NASHA in the painful hip under fluoroscopy. EVALUATION: patient global assessment (PGA) and walking pain (WP) on a 100 mm visual analogue scale, WOMAC index, Lequesne index at each visit. STATISTICS: last observation carried forward. Treatment efficacy was assessed using OMERACT-OARSI response criteria, minimal clinically important improvement (MCII), patient acceptable symptom state (PASS) obtained from PGA, WOMAC and WP. Predictive factors of efficacy were also studied. RESULTS: Efficacy evaluation: 34 patients were assessable (mean FU 159 days). All clinical variables (WP, PGA, WOMAC, Lequesne index) decreased significantly between baseline and last evaluation. Twenty-two patients (71%) were classified OMERACT-OARSI responders, 25 subjects (75.8%) were classified PASS+, and 19 (61.3%) fulfilled criteria for MCII. Out of clinical and radiological variables only Lequesne index (p = 0.04) and WOMAC (p = 0.04) at baseline were found to be predictive of treatment efficacy. Safety evaluation: the treatment was well tolerated. There were no severe adverse events related to the treatment or to the procedure. However 15 of the 28 assessable patients experienced transient increase of pain in the target hip during the first week after injection. CONCLUSION: Viscosupplementation of the hip with NASHA is easily feasible in daily clinical practice, safe and well tolerated despite a frequent increase of pain the days following injection. Prospective controlled trials are needed to confirm these data and to evaluate both safety and efficacy of a second course of treatment.

Langerhans cell histiocytosis reveals a new IL-17A-dependent pathway of dendritic cell fusion.

IL-17A is a T cell-specific cytokine that is involved in chronic inflammations, such as Mycobacterium infection, Crohn's disease, rheumatoid arthritis and multiple sclerosis. Mouse models have explained the molecular basis of IL-17A production and have shown that IL-17A has a positive effect not only on granuloma formation and neurodegeneration through unknown mechanisms, but also on bone resorption through Receptor activator of NF-kappaB ligand (RANKL) induction in osteoblasts. Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology, lacking an animal model, that cumulates symptoms that are found separately in various IL-17A-related diseases, such as aggressive chronic granuloma formation, bone resorption and soft tissue lesions with occasional neurodegeneration. We examined IL-17A in the context of LCH and found that there were high serum levels of IL-17A during active LCH and unexpected IL-17A synthesis by dendritic cells (DCs), the major cell type in LCH lesions. We also found an IL-17A-dependent pathway for DC fusion, which was highly potentiated by IFN-gamma and led to giant cells expressing three major tissue-destructive enzymes: tartrate resistant acidic phosphatase and matrix metalloproteinases 9 and 12. IFN-gamma expression has been previously documented in LCH and observed in IL-17A-related diseases. Notably, serum IL-17A-dependent fusion activity correlates with LCH activity. Thus, IL-17A and IL-17A-stimulated DCs represent targets that may have clinical value in the treatment of LCH and other IL-17A-related inflammatory disorders.

Infliximab therapy in rheumatoid arthritis and ankylosing spondylitis-induced specific antinuclear and antiphospholipid autoantibodies without autoimmune clinical manifestations: a two-year prospective study.

Treatment of rheumatoid arthritis (RA) with infliximab (Remicade) has been associated with the induction of antinuclear autoantibodies (ANA) and anti-double-stranded DNA (anti-dsDNA) autoantibodies. In the present study we investigated the humoral immune response induced by infliximab against organ-specific or non-organ-specific antigens not only in RA patients but also in patients with ankylosing spondylitis (AS) during a two-year followup. The association between the presence of autoantibodies and clinical manifestations was then examined. The occurrence of the various autoantibodies was analyzed in 24 RA and 15 AS patients all treated with infliximab and in 30 RA patients receiving methotrexate but not infliximab, using the appropriate methods of detection. Infliximab led to a significant induction of ANA and anti-dsDNA autoantibodies in 86.7% and 57% of RA patients and in 85% and 31% of AS patients, respectively. The incidence of antiphospholipid (aPL) autoantibodies was significantly higher in both RA patients (21%) and AS patients (27%) than in the control group. Most anti-dsDNA and aPL autoantibodies were of IgM isotype and were not associated with infusion side effects, lupus-like manifestations or infectious disease. No other autoantibodies were shown to be induced by the treatment. Our results confirmed the occurrence of ANA and anti-dsDNA autoantibodies and demonstrated that the induction of ANA, anti-dsDNA and aPL autoantibodies is related to infliximab treatment in both RA and AS, with no significant relationship to clinical manifestations.