Comparative effectiveness of antitumour necrosis factor agents, biologics with an alternative mode of action and tofacitinib in an observational cohort of patients with rheumatoid arthritis in Switzerland.

BACKGROUND: Multiple biologic and targeted synthetic disease-modifying rheumatic drugs (b/tsDMARDs) are approved for the management of rheumatoid arthritis (RA), including TNF inhibitors (TNFi), bDMARDs with other modes of action (bDMARD-OMA) and Janus kinase inhibitors (JAKi). Combination of b/tsDMARDs with conventional synthetic DMARDs (csDMARDs) is recommended, yet monotherapy is common in practice. OBJECTIVE: To compare drug maintenance and clinical effectiveness of three alternative treatment options for RA management. METHODS: This observational cohort study was nested within the Swiss RA Registry. TNFi, bDMARD-OMA (abatacept or anti-IL6 agents) or the JAKi tofacitinib (Tofa) initiated in adult RA patients were included. The primary outcome was overall drug retention. We further analysed secondary effectiveness outcomes and whether concomitant csDMARDs modified effectiveness, adjusting for potential confounding factors. RESULTS: 4023 treatment courses of 2600 patients were included, 1862 on TNFi, 1355 on bDMARD-OMA and 806 on Tofa. TNFi was more frequently used as a first b/tsDMARDs, at a younger age and with shorter disease duration. Overall drug maintenance was significantly lower with TNFi compared with Tofa [HR 1.29 (95% CI 1.14 to 1.47)], but similar between bDMARD-OMA and Tofa [HR 1.09 (95% CI 0.96 to 1.24)]. TNFi maintenance was decreased when prescribed without concomitant csDMARDs [HR: 1.27 (95% CI 1.08 to 1.49)], while no difference was observed for bDMARD-OMA or Tofa maintenance with respect to concomitant csDMARDs. CONCLUSION: Tofa drug maintenance was comparable with bDMARDs-OMA and somewhat higher than TNFi. Concomitant csDMARDs appear to be required for optimal effectiveness of TNFi, but not for bDMARD-OMA or Tofa.

[S3 guidelines on treatment of polymyalgia rheumatica : Evidence-based guidelines of the German Society of Rheumatology (DGRh), the Austrian Society of Rheumatology and Rehabilitation (ÖGR) and the Swiss Society of Rheumatology (SGT) and participating medical scientific specialist societies and other organizations]. / S3-Leitlinie zur Behandlung der Polymyalgia rheumatica : Evidenzbasierte Leitlinie der Deutschen Gesellschaft für Rheumatologie (DGRh), der Österreichischen Gesellschaft für Rheumatologie und Rehabilitation (ÖGR) und der Schweizerischen Gesellschaft für Rheumatologie (SGR) und der beteiligten medizinisch-wissenschaftlichen Fachgesellschaften und weiterer Organisationen.

Polymyalgia rheumatica (PMR) occurs almost exclusively in persons aged 50 years or older and it is the second most common inflammatory rheumatic disease in older people after rheumatoid arthritis. Since there are no specific tests for PMR, the exclusion of clinically similar differential diagnoses is essential to ascertain the diagnosis. These recommendations for the management of PMR assume an already established diagnosis of PMR. It is recommended to initiate treatment with glucocorticoids immediately after diagnosis and to provide appropriate patient information and education about the impact of the disease and its treatment. Methotrexate should be considered in patients at high risk for relapse and/or glucocorticoid-related adverse events. These guidelines have been elaborated because there is significant heterogeneity in the management of PMR in clinical practice in Germany (but also Europe and worldwide), despite the large number of patients with this disease. These guidelines are primarily based on the 2015 EULAR-ACR recommendations for the management of PMR, which were updated by the guideline committee and adapted to the German speaking countries.

Calcium pyrophosphate deposition disease: a frequent finding in patients with long-standing erosive gout.

OBJECTIVE: To characterize patients with both monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in their synovial fluid (SF). METHOD: Forty-nine gout patients with acute arthritis were included. Those patients with MSU crystals only in their SF were compared to those patients with both MSU and CPP crystals in their SF. RESULTS: A total of 36 out of 49 patients (73.5%) had only MSU crystals, whereas 13 out of 49 (26.5%) had both MSU and CPP crystals in their SF. Co-deposition of CPP crystals was associated with long-standing gout disease (p = 0.022), kidney dysfunction (p = 0.024), and erosive arthritis (p = 0.049), but not with age. CONCLUSION: Long-standing gout may be a risk factor for CPP deposition disease, and the frequency of CPP co-deposition may be higher than expected.

Biological agents in monotherapy for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease, which results in joint destruction and permanent disability. The advent of disease-modifying antirheumatic drugs (DMARDs) has made a profound impact on the outcome and prognosis of RA. Methotrexate (MTX) is a central agent in RA therapy, and is used either alone or in combination with biological DMARDs. However, a large proportion of RA patients (20%-40%) either do not respond to or are unable to tolerate MTX or the alternative agents used in place of MTX (including leflunomide, sulfasalazine, azathioprine, hydroxycholoquine and combination DMARDs). For these patients, monotherapy with biological DMARDs is a key treatment option that balances tolerability with improved clinical outcomes. This article reviews the data for four biological agents approved for use as monotherapy in Switzerland (adalimumab, certolizumab pegol, etanercept and tocilizumab) in order to formulate a consensus statement on their roles in biologic monotherapy of RA.

[The rheumatic hand - diagnostics in practice]. / Die rheumatische Hand - Diagnostik in der Praxis.

Many rheumatic diseases show changes and are visible in the hands. The pattern of distribution in the relevant joints, soft-tissue changes, skin manifestations, neurological and vascular symptoms and clinical findings provide fundamental information. Imaging and lab results provide diagnostic support. In this review, common diseases are presented in terms of their clinical expressions in the hands: osteoarthritis, rheumatoid arthritis, gout, calcium pyrophosphate dihydrate deposition disease, psoriatic arthritis, reactive arthritis, systemic sclerosis, dermatomyositis/polymyositis and systemic lupus erythematosus. Furthermore, we discuss pathological findings of the hands as a result of diabetic cheiroarthropathia, endocarditis, secondary hypertrophic osteo-arthropathy and chronic regional pain syndrom.

Which subgroup of patients with rheumatoid arthritis benefits from switching to rituximab versus alternative anti-tumour necrosis factor (TNF) agents after previous failure of an anti-TNF agent?

BACKGROUND: Patients with rheumatoid arthritis (RA) with an inadequate response to TNF antagonists (aTNFs) may switch to an alternative aTNF or start treatment from a different class of drugs, such as rituximab (RTX). It remains unclear in which clinical settings these therapeutic strategies offer most benefit. OBJECTIVE: To analyse the effectiveness of RTX versus alternative aTNFs on RA disease activity in different subgroups of patients. METHODS: A prospective cohort study of patients with RA who discontinued at least one aTNF and subsequently received either RTX or an alternative aTNF, nested within the Swiss RA registry (SCQM-RA) was carried out. The primary outcome, longitudinal improvement in 28-joint count Disease Activity Score (DAS28), was analysed using multivariate regression models for longitudinal data and adjusted for potential confounders. RESULTS: Of the 318 patients with RA included; 155 received RTX and 163 received an alternative aTNF. The relative benefit of RTX varied with the type of prior aTNF failure: when the motive for switching was ineffectiveness to previous aTNFs, the longitudinal improvement in DAS28 was significantly better with RTX than with an alternative aTNF (p = 0.03; at 6 months, -1.34 (95% CI -1.54 to -1.15) vs -0.93 (95% CI -1.28 to -0.59), respectively). When the motive for switching was other causes, the longitudinal improvement in DAS28 was similar for RTX and alternative aTNFs (p = 0.40). These results were not significantly modified by the number of previous aTNF failures, the type of aTNF switches, or the presence of co-treatment with a disease-modifying antirheumatic drug. CONCLUSION: This observational study suggests that in patients with RA who have stopped a previous aTNF treatment because of ineffectiveness changing to RTX is more effective than switching to an alternative aTNF.

Abundant expression of the interleukin (IL)23 subunit p19, but low levels of bioactive IL23 in the rheumatoid synovium: differential expression and Toll-like receptor-(TLR) dependent regulation of the IL23 subunits, p19 and p40, in rheumatoid arthritis.

OBJECTIVE: Interleukin (IL)23, composed of a p19 and a p40 subunit, is suggested to play key roles in rheumatoid arthritis (RA), dependent on the promotion and proliferation of IL17-producing T helper (Th)17 cells. However, previous studies on IL23 expression in human tissues were based on the p19 subunit only. We aimed to study the expression and regulation of IL23 subunits p19 and p40 in RA compared to patients with osteoarthritis (OA). METHODS: The expression of p19 and p40 in synovial tissues was analysed by in situ hybridisation and immunohistochemistry. IL23 in RA and OA synovial fluids and sera was determined by ELISA. Toll-like receptor (TLR)-dependent induction of p19, p40 and bioactive IL23 was determined in RA synovial fibroblasts (RASF), monocytes and monocyte-derived dendritic cells (MDDCs) by real-time PCR and reverse transcriptase (RT)-PCR, Western blot and functional assays. RESULTS: The p19 subunit was abundantly expressed in RA but not in OA synovial tissues. p19 was most prominently expressed by RASF in the synovial lining layer and at the site of invasion, but no heterodimeric IL23 was detected at these sites. Correspondingly, soluble IL23 was not detectable or found at very low levels in synovial fluids and sera of patients with RA. By in vitro experiments, we confirmed that TLR-activated RASF expressed p19 but not p40, in contrast to monocytes, which produced IL23 following TLR stimulation. CONCLUSION: The TLR-dependent induction of p19 but not p40 in RASF and the abundant expression of p19 along with the low or undetectable levels of IL23 in patients with RA provides strong evidence that p19 does not necessarily indicate the presence of IL23, as has been proposed to date.

Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (RA).

BACKGROUND: Rheumatoid arthritis (RA) has been associated with an increased risk of infections, but the underlying pathways have not yet been identified. Toll-like receptors (TLR) probably play a role in synovial inflammation and may also contribute to the understanding of the role of infections in RA. OBJECTIVES: To investigate if the synovial expression of TLR3 and TLR7 in RA correlates with that of inflammatory cytokines, and to assess whether this has functional consequences for local cytokine production and to study potential links between the TLR3/7 axis and TLR4 in RA synovium. METHODS: Immunohistochemistry was used to study the expression of TLR3, TLR7, interferon alpha (IFNalpha), tumour necrosis factor alpha (TNFalpha) and interleukins IL1beta, IL12, IL17 and IL18 in RA synovium obtained by arthroscopy from 34 patients with RA. Monocytes, monocyte-derived dendritic cells (MoDCs) and RA synovial fibroblasts were stimulated via TLR3 (poly-IC) and TLR7 (loxorubin), after which IL1beta, IL6 and TNFalpha were measured by Luminex bead array technology. Following preincubation with IFNalpha, IL1beta and IL18, TLR3 and TLR7 mRNA expression was assessed using real-time PCR. Cytokine production after preincubation with IFNalpha and subsequent TLR stimulation was measured. RESULTS: Synovial TLR3/7 expression was co-expressed with IFNalpha, IL1beta and IL18, but not with TNFalpha, IL12 and IL17. Stimulation of TLR3/TLR7 on monocytes, MoDCs or synovial fibroblasts led to secretion of type I IFN but no biologically active IL1beta or IL18 could be detected. Type I IFNalpha increased TLR3/7 mRNA expression whereas IL1beta and IL18 did not. In spite of the fact that the mRNA level of TLR4 remained unchanged, IFNalpha enhanced the response to TLR4 agonists, a phenomenon that was clearly more marked in patients with RA. CONCLUSION: Type I interferons are highly co-expressed with TLR3/TLR7 in RA synovium. They enhance TLR3/TLR7-mediated cytokine production and also TLR4-mediated responses.

The TNF superfamily member LIGHT contributes to survival and activation of synovial fibroblasts in rheumatoid arthritis.

OBJECTIVES: The TNF superfamily member LIGHT has a T-cell co-stimulatory role and has previously been associated with inflammation and autoimmunity. To investigate its role in rheumatoid arthritis (RA), a disease where activated T cells contribute in a prominent way, we have analysed the expression of LIGHT and its receptors in RA and analysed its effects on synovial fibroblasts in vitro. METHODS: The expression of LIGHT was measured in synovial tissues and fluids and the receptors of LIGHT were detected on synovial fibroblasts derived from patients with RA and osteoarthritis (OA). The effects of recombinant LIGHT on the production of proinflammatory cytokines and proteases and on the apoptosis of synovial fibroblasts was assessed. RESULTS: LIGHT mRNA was present in synovial tissues of patients with RA but not with OA. Correspondingly, soluble LIGHT protein could be detected in RA synovial fluid samples at much higher levels than in synovial fluid from patients with OA. Immunohistochemical detection of LIGHT and analysis of synovial fluid cells by flow cytometry revealed CD4 T cells as the major source of LIGHT in the rheumatoid joint. Synovial fibroblasts from RA patients were found to express the LIGHT receptors HVEM and LTbetaR. Recombinant LIGHT induced RA synovial fibroblasts to upregulate MMP-9 mRNA, CD54 and IL-6 in an NF-kappaB-dependent fashion. In vitro, exposure of cultured synovial fibroblasts to LIGHT reduced FAS-mediated apoptosis significantly, without affecting the rate of spontaneous apoptosis. CONCLUSIONS: The results provide evidence for a novel T-cell-dependent activation of synovial fibroblasts by LIGHT in joints of patients with RA, contributing to an inflammatory and destructive phenotype.

[Evidence-based therapy of Raynaud's syndrome]. / Evidenzbasierte Therapie des Raynaud-Syndroms.

Raynaud's syndrome has a prevalence of 3-5% in the general population. Despite its high frequency, the majority of available therapies have not been validated in randomized controlled trials. Effective therapies with a high level of evidence include the calcium channel blocker nifedipine. As analyzed by meta-analyses, nifedipine showed improvement of the peripheral circulation, as well as reduction of both the intensity and frequency of attacks in patients with primary and secondary Raynaud's syndrome as compared to placebo. Similar results in a metaanalysis were obtained for intravenous infusions of iloprost in patients with secondary Raynaud's phenomenon associated with systemic sclerosis. In addition, intravenous infusions of iloprost improved healing of fingertip ulcers in patients with systemic sclerosis. Therapies with significant effects in single randomized controlled trials include angiotensin II-receptor type 1 antagonists (losartan), the calcium channel blockers felodipine und amlodipine, serotonin-reuptake-inhibitors (fluoxetine) und phosphodiesterase-V-inhibitors (sildenafil, vardenafil). However, the results for these promising substances have to be confirmed in long-term trials with larger patient numbers.

The role of CD40 ligand and tumor necrosis factor alpha signaling in the transgenic K/BxN mouse model of rheumatoid arthritis.

OBJECTIVE: Spontaneous arthritis in the KRN transgenic mouse (K/BxN) model is due to the autoreactivity of the transgenic T cell receptor and subsequent induction of autoantibodies directed against glucose-6-phosphate isomerase (G6PI). This study sought to analyze the potential of anti-CD40 ligand (anti-CD40L) and anti-tumor necrosis factor alpha (anti-TNFalpha) antibodies in preventing and treating arthritis in this murine model. METHODS: Groups of K/BxN mice were injected with anti-CD40L and anti-TNFalpha antibodies during various stages of arthritis. Disease was assessed by clinical scoring, measurements of paw swelling, and histology. The results were correlated with the levels of autoantibodies in the serum, as assessed by enzyme-linked immunosorbent assay. RESULTS: Anti-CD40L antibody treatment was able to diminish significantly the arthritis development in K/BxN mice when given a week before the onset of clinically apparent disease. However, no effect on disease was seen when the antibodies were administered after clinical onset. Surprisingly, neutralizing anti-TNFalpha antibodies were unable to prevent arthritis in K/BxN mice. The success of antibody treatment in preventing disease correlated with low levels of anti-G6PI antibodies in the serum. CONCLUSION: These results suggest that anti-CD40L treatment can prevent arthritis development in a model of immunoglobulin-mediated arthritis, but anti-TNFalpha treatment cannot. The unsuccessful treatment of established disease was possibly due to the continued presence of autoreactive antibodies in the arthritic mice.

Human rheumatoid factor production is dependent on CD40 signaling and autoantigen.

High-affinity pathologic rheumatoid factor (RF) B cells occur in autoimmune diseases such as rheumatoid arthritis, but are deleted in healthy individuals. The reasons for the survival and differentiation of these autoreactive B cells in rheumatoid arthritis are not known. Previous studies in mice transgenic for a human IgM RF have shown that peripheral encounter with soluble human IgG leads to deletion of high-affinity RF B cells; however, deletion can be prevented when concomitant T cell help is provided. This study aimed to further discern the minimal factors necessary not only for the in vivo survival of RF B cells, but also for their differentiation into Ab-secreting cells. The combination of MHC class II-reactive T cells and Ag induced the production of RF in human IgM RF transgenic mice, while either stimulus alone was ineffective. Neutralizing Abs against CD40 ligand (CD40L), but not against IL-4 or IL-15, abrogated IgM-RF production. Moreover, blockade of CD40L-CD40 allowed IgG to delete the RF precursor cells. Most importantly, activating Abs to CD40 could substitute entirely for T cell help in promoting the survival of RF precursors and in stimulating RF synthesis in T cell deficient animals. The data indicate that CD40 signaling alone can prevent deletion of RF B cells by Ag and in the presence of IgG is sufficient to trigger RF synthesis. The results suggest that selective induction of apoptosis in high-affinity RF B cells may be achieved by blockade of CD40L-CD40 interaction.

Rheumatoid factor B cell tolerance via autonomous Fas/FasL-independent apoptosis.

Normal individuals do not express the high-affinity autoantibodies specific for self-IgG (rheumatoid factors, RF) that are commonly seen in rheumatoid arthritis patients. Studies of transgenic mice expressing a human IgM rheumatoid factor have shown that one mechanism by which higher affinity RF B cells are tolerized to IgG is through abortive RF B cell activation followed by deletion in the absence of T cell help. We show that RF B cell deletion occurs through an intrinsic apoptotic mechanism that is independent of the Fas/FasL pathway and does not involve active killing by T cells, as it occurs in RAG-1-deficient RF transgenic mice to the same extent as in the parental RF transgenic line.

Viral peptide specific cytotoxic T lymphocytes are of high avidity to host-MHC but only low avidity to donor-MHC after allogeneic bone marrow transplantation.

In the thymus maturing T lymphocytes are positively selected for efficient interaction with self-MHC molecules. Consequently, mature peripheral T cells recognize foreign (microbial) antigens in association with self-MHC molecules (known as MHC restricted recognition). In experimental bone marrow transplantation (BMT) lymphohaemopoietic stem cells from an MHC disparate donor transfused to an irradiated host give rise to mature T lymphocytes with host-MHC restriction specificity. While experiments with T cell receptor transgenic mice have largely confirmed this concept, many studies using genetically unmanipulated animals analysing polyclonal T cell repertoires have also shown donor-MHC restricted T cell activities after allogeneic BMT. To analyse this discrepancy we generated 18 virus specific cytotoxic T cell (CTL) clones, 16 from F1 into parent and two from fully allogeneic bone marrow chimeras, and analysed the MHC restriction specificity in proliferation and cytotoxicity assays. The cytotoxicity of all the clones was primarily host-MHC restricted. However, the CTL clones proliferated to viral antigen presented by both donor- or host-MHC. Our model allowed CTL cloning by cross-specific stimulation with antigen plus either donor-MHC or else host-MHC. Interestingly, even the 14 CTL clones which had been raised with donor-MHC systematically killed host-MHC but not donor-MHC expressing cells. Thus, after BMT, CTLs may proliferate crossreactively to donor-MHC but cytolysis is predominantly directed to host-MHC expressing cells. Since lytic CTL activity probably reflects high avidity CTL interaction necessary for viral clearance in vivo, the data suggest that the donor-MHC restricted CTL activity may not be protective and that virus may escape CTL surveillance in donor cells.

Peptides control the gain and loss of allele specificity by mutated MHC class I molecules.

To analyze the molecular basis of MHC class I allele-restricted peptide recognition, a set of eight Ld/Lq mutants was constructed and tested for peptide recognition by allele-restricted and peptide-specific CTL. The MHC molecules H-2Ld and H-2Lq differ at six amino acid positions (95, 97, 107, 116, 155, 157) located within the alpha 2 domain of the molecule. Both molecules present the lymphocytic choriomeningitis virus (LCMV) nucleoprotein-derived peptide RPQASGVYM and the murine cytomegalovirus (MCMV) pp89-derived peptide YPHFMPTNL to the respective virus-specific CD8+ CTL is a strictly allele-restricted fashion. All mutated MHC class I molecules did still bind the LCMV peptide and seven of eight mutants retained MCMV peptide binding. The exchange Arg-->Trp at position 97 of Lq in pocket C of the peptide binding groove prevented binding of the MCMV ligand and this loss was compensated by the additional exchange of Ile-->Leu in position 95 (pocket F). Within the Lq molecule, single mutations at either position 97 on the floor of the groove or position 155 of the wall sufficed for a gain of LCMV peptide recognition by Ld-restricted CTL. Altogether, six of eight mutants resulted in a gain of recognition by CTL specific for the other allele. Thus, six of the eight mutants lost MHC-restricted recognition and were accepted by both Ld- as well as Lq-restricted CTL when presenting the LCMV peptide. Only one case of simultaneous recognition of the MCMV peptide by both Ld- as well as Lq-restricted CTL was noted. In other mutations, a gain of recognition by Ld-restricted CTL was associated with a loss of recognition of Lq-restricted CTL. Analysis of extracted MCMV peptide from mutant molecules excluded quantitative differences in presented MCMV peptide as a reason for the lack of CTL recognition. Altogether, the results show that, rather than aminoacids at certain residue positions, individual peptides govern MHC allele specificity of CTL recognition.

Peptide-induced T-cell tolerance to prevent autoimmune diabetes in a transgenic mouse model.

A synthetic peptide corresponding to an immunodominant epitope of lymphocytic choriomeningitis virus glycoprotein (LCMV GP) was used to prime or to tolerize CD8+ T cells in vivo, dependent on mode of immunization. Peptide-specific tolerance was then examined in transgenic mice expressing LCMV GP in the beta islet cells of the pancreas; these mice develop CD8+ T-cell-mediated diabetes within 8-14 days after LCMV infection. Specific peptide-induced tolerance prevented autoimmune destruction of beta islet cells and diabetes in this transgenic mouse model.

Enhancement of disease by neutralizing antiviral antibodies in the absence of primed antiviral cytotoxic T cells.

The effects of neutralizing antibodies on the disease course in mice infected with the noncytopathic lymphocytic choriomeningitis virus (LCMV) were evaluated. Whereas non-neutralizing antisera exhibiting high enzyme-linked immunosorbent assay titers had no effect on T cell responses and their consequences, neutralizing antisera modulated them variably. Neutralizing antibodies were able to prevent lethal choriomeningitis after intracerebral infection with a neurotropic LCMV-isolate (ARMSTRONG) although they could not control local virus replication. The same antibodies exhibited little or no protective effect on choriomeningitis induced by LCMV-WE, a viscerotrope isolate. Surprisingly, these antibodies rendered mice much more susceptible to choriomeningitis after intracerebral infection with LCMV DOCILE, a very rapidly spreading lymphocyto-viscerotrope virus; in this situation antibodies prevented overwhelming infection which causes deletion of immunopathogenic cytotoxic T cell responses. Thus preexisting neutralizing antiviral antibodies had little influence on local virus spread in peripheral tissues but they reduced hematogenic spread and infection of antigen-presenting cells; thereby they influenced the primary cytotoxic T cell (CTL) response and indirectly modulated the extent of T cell-mediated immunopathology in peripheral organs. These results may explain why vaccines inducing neutralizing antibodies but no CTL may enhance an immunopathological disease caused by challenge infection with a noncytopathic virus.