Inflammatory Back Pain and Psoriasis: Expecting Spondyloarthritis, Discovering Lymphoma.

Inflammatory back pain is a characteristic of spondyloarthritis. It is not, however, an exclusive symptom of inflammatory rheumatic diseases as it can also be associated with non-inflammatory entities. Infrequently, the etiology can be found in neoplastic conditions such as malignant lymphoma. Even in the presence of comorbidities indicatory of underlying rheumatic disease, like psoriasis vulgaris, the clinician should not be led astray. It is essential to pay attention to contradictory findings, as treatment crucially differs depending on diagnosis. Herein, we report on a psoriasis patient who presented with characteristic inflammatory back pain and deceptive imaging results. While the patient was initially thought to suffer from an inflammatory rheumatic disease with axial involvement, it was the accompanying atypical circumstances, particularly her age, that instantly challenged the diagnosis of axial psoriatic arthritis. She was eventually diagnosed with stage IV follicular lymphoma that manifested with rare and exclusively extranodal lesions and spondyloarthritis-like morphology. This case effectively demonstrates the importance of a thorough diagnostic workup and how certain clinical factors, such as the patient's age, should be considered when confronted with inflammatory back pain.

Application of blinatumomab, a bispecific anti-CD3/CD19 T-cell engager, in treating severe systemic sclerosis: A case study.

Systemic sclerosis, a severe inflammatory autoimmune disease, shares a common thread with cancer through the underlying mechanism of inflammation. This inflammatory milieu not only drives the immune dysregulation characteristic of autoimmune diseases but also plays a pivotal role in the pathogenesis of cancer. Among the cellular components involved, B cells have emerged as key players in hematologic tumor and autoimmune disease, contributing to immune dysregulation and persistent tissue fibrosis in systemic sclerosis, as well as tumor progression and immune evasion in cancer. Consequently, novel therapeutic strategies targeting B cells hold promise in both conditions. Recent exploration of CD19 CAR T cells in severe systemic sclerosis patients has shown great potential, but also introduced possible risks and drawbacks associated with viral vectors, prolonged CAR T cell persistence, lengthy production timelines, high costs, and the necessity of conditioning patients with organotoxic and fertility-damaging chemotherapy. Given these challenges, alternative CD19-depleting approaches are of high interest for managing severe systemic autoimmune diseases. Here, we present the pioneering use of blinatumomab, a bispecific anti-CD3/anti-CD19 T cell engager in a patient with progressive, severe systemic sclerosis, offering a promising alternative for such challenging cases.

Colitis induced by IL-17A-inhibitors.

BACKGROUND: Interleukin (IL)-17A is essential for intestinal mucosal integrity, contributing to the prevention of detrimental immunity such as infectious colitis and inflammatory bowel disease (IBD). Indeed, neutralization of IL-17A has been abandoned as a therapeutic principle in IBD because of increased disease activity. However, it is controversial whether IL-17A inhibitors increase the risk of developing colitis in patients who do not have underlying IBD. Here, we present two cases of different forms of colitis that occurred during treatment with two IL-17A inhibitors, secukinumab and ixekizumab. CASE PRESENTATIONS: We report the case of a 35-year-old female with SAPHO (synovitis-acne-pustulosis-hyperostosis-osteitis) syndrome who was admitted due to severe colitis with bloody diarrhea, fever, abdominal pain and weight loss after receiving secukinumab for 3 months as well as the case of a 41-year-old male with psoriatic arthritis who presented himself to the outpatient clinic with bloody stools, abdominal pain and nausea 5 months after changing his therapy from secukinumab to ixekizumab. In both patients, treatment with IL-17A-inhibitors was stopped and tumor necrosis factor inhibitors were started. Both patients recovered, are clinically stable and show no more signs of active colitis. CONCLUSION: The role of IL-17A inhibitors in the pathogenesis of infectious colitis and new-onset IBD is not fully understood and requires further research. Patients receiving IL-17A-inhibitor therapy should be carefully screened and notified of the possible side effects.

Spontaneous abortion as differential diagnosis of intermittent glomerular proteinuria in inactive systemic lupus erythematosus.

In women of childbearing age, severe proteinuria in systemic lupus erythematosus raises concern for renal involvement and pregnancy complications. While persisting renal loss of protein is known to culminate in extensive interventions, intermittent proteinuria in inactive disease requires an adjusted approach. Contextual awareness of this urinary finding is thus essential.

A rare side effect of methotrexate therapy: drug-induced osteopathy with multiple fractures of the lower limb.

Methotrexate is associated with bone lesions that are rare and, although presenting with a typical localisation to the lower extremities and appearing with a characteristic radiologic morphology, largely unknown and often misdiagnosed as osteoporotic insufficiency fractures. The correct and early diagnosis, however, is key for treatment and prevention of further osteopathology. Here, we present a patient with rheumatoid arthritis who developed multiple painful insufficiency fractures in the left foot (processus anterior calcanei, tuber calcanei) and in the right lower leg and foot (anterior and dorsal calcaneus and at the cuboid and distal tibia) during therapy with methotrexate, which were all misdiagnosed as osteoporotic. The fractures occurred between 8 months and 35 months after starting methotrexate. Discontinuation of methotrexate resulted in rapid pain relief and no further fractures have occurred. This case powerfully demonstrates the importance of raising awareness of methotrexate osteopathy in order to take appropriate therapeutic measures, including and perniciously discontinuing methotrexate.

Reactive arthritis after SARS-CoV-2 infection.

SARS-CoV-2 has been recognised as a potential trigger of inflammatory arthritis in individuals with inflammatory rheumatic diseases as well as in previously unaffected individuals. However, new-onset arthritis after COVID-19 is a heterogeneous phenomenon that complicates differential diagnosis. For example, acute arthritis with features of viral arthritis has been reported after COVID-19, as has crystal-induced arthritis. Arthritides mimicking reactive arthritis (ReA) have also been described, but these patients often do not fulfil the typical features of ReA: several reports describe cases of patients older than 45 years at the onset of arthritis, and the characteristic genetic feature of ReA, HLA-B27, is rarely found. Because viral infections are much less likely to cause ReA than bacterial infections, and respiratory infections are rarely the cause of ReA, it is currently unknown whether SARS-CoV-2 can cause true ReA. Here, we report the case of a 30-year-old patient who presented with acute pain, swelling and redness in the left metatarsophalangeal (MTP) joint and ankle 7 days after resolution of a SARS-CoV-2 infection. Diagnostics revealed arthritis of the MTP2, synovitis of the upper ankle with significant joint effusion and peritendinitis of the flexor tendons. Based on the clinical manifestations and diagnostic test results, ReA appeared to be the most likely cause. A screening for typical ReA-associated infections was negative. The patient was treated with NSAIDs and intra-articular and systemic glucocorticoids. At a follow-up visit after discontinuation of glucocorticoids, the patient was symptom-free. Overall, we observed a ReA with typical clinical, genetic and patient characteristics after SARS-CoV-2 infection, and we conclude that a direct association with COVID-19 is highly plausible.

Dysregulated immunity in PID patients with low GARP expression on Tregs due to mutations in LRRC32.

Immune dysregulation diseases are characterized by heterogeneous clinical manifestations and may have severe disease courses. The identification of the genetic causes of these diseases therefore has critical clinical implications. We performed whole-exome sequencing of patients with immune dysregulation disorders and identified two patients with previously undescribed mutations in LRRC32, which encodes glycoprotein A repetitions predominant (GARP). These patients were characterized by markedly reduced numbers and frequencies of regulatory T cells (Tregs). Tregs with mutated LRRC32 exhibited strongly diminished cell-surface GARP expression and reduced suppressor function. In a model of conditional Garp deficiency in mice, we confirmed increased susceptibility to inflammatory diseases once GARP expression on Tregs was decreased. Garp deficiency led to an unstable Treg phenotype due to diminished Foxp3 protein acetylation and stability. Our study reinforces the understanding of the immunological mechanisms of immune dysregulation and expands the knowledge on the immunological function of GARP as an important regulator of Treg stability.

Vaccination of patients with inflammatory rheumatic diseases against SARS-CoV-2: considerations before widespread availability of the vaccines.

Vaccination against SARS-CoV-2 has become available and will hopefully end the current pandemic. Understandably, patients with inflammatory rheumatic diseases (iRMDs) and their physicians are feverishly preoccupied with questions about vaccination and the vaccines against SARS-CoV-2. However, as it will take months before all patients with iRMDs will have access to the vaccines, measures that are taken now in order to increase potential safety and efficacy of the vaccines may impose a risk for the patients with regard to reactivation of their underlying iRMD. The ad hoc commission 'Covid-19' and the board of directors of the German Society for Rheumatology have addressed this topic and have developed considerations, which are intended to answer urgent questions, to take away concerns and fears and to make initial recommendations for patients with iRMDs.

Altered T cell plasticity favours Th17 cells in early arthritis.

OBJECTIVES: The predominance of differentiated Th17 cells has been implied as a key driver of autoimmune arthritis, including early RA. Because accumulating evidence suggests that Th cell differentiation is a plastic process, we investigated plasticity and underlying molecular mechanisms to address the shift towards the Th17 phenotype in early RA. METHODS: A cohort of 61 patients with early, active, untreated RA and 45 age- and sex-matched healthy controls were studied. Viable in vitro- and in vivo-generated Th1, Th2 and Th17 cells were FACS-sorted and transdifferentiated under Th1-, Th2- or Th17-inducing conditions. The cytokine Th profile of the transdifferentiated cells was assessed by flow cytometry. Th cell-associated cytokine and transcription factor gene loci were analysed by chromatin immunoprecipitation assay and their expression by quantitative real-time PCR. RESULTS: In vitro-generated Th cells showed substantial plasticity, which was similar between RA and healthy controls, whereas in vivo-derived Th1 and Th2 cells from RA patients demonstrated an enhanced plasticity towards IL-17-expressing phenotypes compared with healthy controls. Further, in vivo-generated Th17 cells from RA patients showed a resistance to transdifferentiate into Th1 or Th2 cells. The serum/glucocorticoid-regulated kinase 1-forkhead box protein O1-IL-23 receptor (SGK1-FOXO1-IL-23R) axis together with increased RORC expression was associated with the predominant Th17 phenotype in early RA. CONCLUSIONS: Our data indicate that in vivo-originated Th subsets are prone to Th17 cell transdifferentiation in early RA, while Th17 cells are resistant to changes in their phenotype. Together, the data imply that an altered plasticity contributes to the Th17 shift in early RA.

Increased plasticity of non-classic Th1 cells toward the Th17 phenotype.

Objectives: To analyze occurrence and plasticity of two recently described distinct subtypes of Th1 cells named classic (CD161-/CCR6-) and non-classic (CD161+/CCR6+) Th1 cells in early rheumatoid arthritis (RA) patients and healthy controls (HCs).Methods: Frequencies of in vivo-generated Th1 cell populations were assessed after cytokine secretion assay for IFNγ/IL-17 and surface staining for CD161/CCR6. Viable Th1 cells (IFNγ+IL-17-) were sorted into classic Th1 (CD161-CCR6-) and non-classic Th1 (CD161+CCR6+) cells, trans-differentiated under different Th cell-inducing conditions, and assessed for plastic changes by analyzing the Th cell-associated cytokine and transcription factor profiles.Results: Ex vivo frequencies of classic (CD161-CCR6-) and non-classic (CD161+CCR6+) Th1 cells as well as related Th1 cell subpopulations CD161+CCR6- and CD161-/CCR6+ did not differ significantly between RA and HCs. However, trans-differentiation of ex vivo non-classic (CD161+CCR6+) and CD161-/CCR6+ Th1 cells resulted in a substantial shift toward Th17 and Th1/Th17 phenotypes, particularly under Th17-inducing conditions. In contrast, classic (CD161-/CCR6-) and CD161+CCR6- Th1 cells showed higher plasticity towards IL-4-producing cells, most of them shifting to a Th1/Th2 phenotype.Conclusion: Whereas non-classic (CD161+/CCR6+) and CD161-CCR6+ Th1 cells demonstrated an increased plasticity towards IL-17- phenotypes, classic Th1 and CD161+CCR6- Th1 cells showed more plasticity towards IL-4-producing phenotypes.

Genetic markers associated with clinical and radiographic response in adalimumab plus methotrexate- or methotrexate-treated rheumatoid arthritis patients in OPTIMA.

OBJECTIVES: Biologics, including tumour necrosis factor inhibitors such as adalimumab (ADA), have significantly improved outcomes in rheumatoid arthritis (RA). Because the clinical course of RA and response to therapy may be influenced by the genetic background of the patient, the objective of this retrospective parallel-assigned case-control analysis was to evaluate the associations between candidate genetic markers for RA with clinical and radiographic responses to ADA + methotrexate (MTX) or MTX monotherapy in the Optimal Protocol for Treatment Initiation with MTX and ADA (OPTIMA) study. METHODS: Three candidate genetic markers were tested: HLA-DRB1 shared epitope (SE), interleukin 4 receptor (IL4R) single nucleotide polymorphism (SNP) rs1805010, and Fc gamma receptor IIb (FcgRIIb) SNP rs1050501. Genetic associations with week 26 clinical and radiographic responses during treatment with ADA + MTX or MTX monotherapy were assessed using summary statistics, chi-square or Fisher's exact test, correlation, regression models, and corrected for multiple-comparisons. RESULTS: Low disease activity (p=0.008) and improvement in American College of Rheumatology 20%, 50% and 70% response criteria (p=0.02, 0.01, and 0.02, respectively) were associated with HLA-DRB1 SE copy numbers in the ADA + MTX treatment arm, and the FcgRIIb SNP was a predictor of remission. The IL4R SNP correlated with radiographic progression in patients receiving MTX monotherapy, supporting previous findings. CONCLUSIONS: This pharmacogenetic analysis identified genetic components that contribute to clinical responses to anti-rheumatic therapy.

Inhibiting ex-vivo Th17 responses in Ankylosing Spondylitis by targeting Janus kinases.

Treatment options for Ankylosing Spondylitis (AS) are still limited. The T helper cell 17 (Th17) pathway has emerged as a major driver of disease pathogenesis and a good treatment target. Janus kinases (JAK) are key transducers of cytokine signals in Th17 cells and therefore promising targets for the treatment of AS. Here we investigate the therapeutic potential of four different JAK inhibitors on cells derived from AS patients and healthy controls, cultured in-vitro under Th17-promoting conditions. Levels of IL-17A, IL-17F, IL-22, GM-CSF and IFNγ were assessed by ELISA and inhibitory effects were investigated with Phosphoflow. JAK1/2/3 and TYK2 were silenced in CD4+ T cells with siRNA and effects analyzed by ELISA (IL-17A, IL-17F and IL-22), Western Blot, qPCR and Phosphoflow. In-vitro inhibition of CD4+ T lymphocyte production of multiple Th17 cytokines (IL-17A, IL-17F and IL-22) was achieved with JAK inhibitors of differing specificity, as well as by silencing of JAK1-3 and Tyk2, without impacting on cell viability or proliferation. Our preclinical data suggest JAK inhibitors as promising candidates for therapeutic trials in AS, since they can inhibit multiple Th17 cytokines simultaneously. Improved targeting of TYK2 or other JAK isoforms may confer tailored effects on Th17 responses in AS.

Characteristics and treatment of new-onset arthritis after checkpoint inhibitor therapy.

Immune checkpoint inhibitors (ICIs) may cause immune-related adverse events (IRAEs). Characterisation and data on treatment of musculoskeletal IRAEs are scarce. In this cohort study, patients receiving ICI therapy who experienced arthralgia were evaluated for the presence of synovitis. Data on demographics, ICI regime, time of onset, imaging and response to therapy of synovitis were prospectively collected. Arthritis was demonstrated in 14 of 16 patients of whom 7 showed monarthritis, 5 had oligoarthritis and 2 had polyarthritis. Patients with ICI-induced arthritis were predominantly male (57%) and seronegative (69%). Regarding the detection of synovitis in staging imaging, moderate sensitivity for contrast-enhanced CT with PET-CT as reference was observed. Disease burden at baseline was high and was significantly reduced after anti-inflammatory treatment. Nine patients were treated with systemic and eight patients with intra-articular glucocorticoids. Six patients who flared on glucocorticoid treatment on tapering were given methotrexate resulting in long-term remission. Patients with synovitis were more likely to have good tumour response. Patients with ICI-induced arthritis were predominantly male and seronegative showing different patterns of arthritis with high disease burden. Good efficacy and safety was observed for methotrexate, particularly for ICI-induced polyarthritis.

Biosimilars in rheumatology: A review of the evidence and their place in the treatment algorithm.

Determining biosimilarity involves a comprehensive exercise with a focus on determining the comparability of the molecular characteristics and preclinical profile of the biosimilar and reference product, such that there is less need for extensive clinical testing to assure comparability of clinical outcomes. Three anti-TNF biosimilar agents are approved for patients with rheumatic diseases in the European Union. The infliximab (Remicade®) biosimilars CT-P13 (Remsima® and Inflectra®) and SB2 (Flixabi®) and the etanercept (Enbrel®) biosimilar SB4 (Benepali®) have shown close comparability to their reference medicinal products, having undergone extensive evaluations. Guidelines on the treatment of rheumatic diseases have acknowledged that biosimilars and biologic DMARDs (bDMARDs) are interchangeable in clinical practice, except when patients experience lack of efficacy or tolerability with the reference agent. Given that cost is a barrier to effective bDMARD use, the introduction of less costly biosimilars is likely to widen access and dissipate treatment inequalities. Physicians faced with prescribing decisions should be reassured by the robust and exhaustive process that is involved in assuring comparability of biosimilars with their reference agents. De novo usage of a biosimilar and switching to a biosimilar following lack of efficacy or tolerability with a different reference biologic agent are likely to be strategies most easily adopted, although switching during successful treatment should also be considered given the potential cost implications. The introduction of biosimilar bDMARDs has the potential to improve patient access to effective biologic therapy, to better accommodate restraints within healthcare budgets and to improve overall patient outcomes.

Pulmonary CCR2+CD4+ T cells are immune regulatory and attenuate lung fibrosis development.

BACKGROUND: Animal models have suggested that CCR2-dependent signalling contributes to the pathogenesis of pulmonary fibrosis, but global blockade of CCL2 failed to improve the clinical course of patients with lung fibrosis. However, as levels of CCR2+CD4+ T cells in paediatric lung fibrosis had previously been found to be increased, correlating with clinical symptoms, we hypothesised that distinct CCR2+ cell populations might either increase or decrease disease pathogenesis depending on their subtype. OBJECTIVE: To investigate the role of CCR2+CD4+ T cells in experimental lung fibrosis and in patients with idiopathic pulmonary fibrosis and other fibrosis. METHODS: Pulmonary CCR2+CD4+ T cells were analysed using flow cytometry and mRNA profiling, followed by in silico pathway analysis, in vitro assays and adoptive transfer experiments. RESULTS: Frequencies of CCR2+CD4+ T cells were increased in experimental fibrosis-specifically the CD62L-CD44+ effector memory T cell phenotype, displaying a distinct chemokine receptor profile. mRNA profiling of isolated CCR2+CD4+ T cells from fibrotic lungs suggested immune regulatory functions, a finding that was confirmed in vitro using suppressor assays. Importantly, adoptive transfer of CCR2+CD4+ T cells attenuated fibrosis development. The results were partly corroborated in patients with lung fibrosis, by showing higher percentages of Foxp3+ CD25+ cells within bronchoalveolar lavage fluid CCR2+CD4+ T cells as compared with CCR2-CD4+ T cells. CONCLUSION: Pulmonary CCR2+CD4+ T cells are immunosuppressive, and could attenuate lung inflammation and fibrosis. Therapeutic strategies completely abrogating CCR2-dependent signalling will therefore also eliminate cell populations with protective roles in fibrotic lung disease. This emphasises the need for a detailed understanding of the functions of immune cell subsets in fibrotic lung disease.